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Sample records for reuptake inhibitor atomoxetine

  1. Atomoxetine, a norepinephrine reuptake inhibitor, reduces seizure-induced respiratory arrest.

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    Zhang, Honghai; Zhao, Haiting; Feng, Hua-Jun

    2017-08-01

    Sudden unexpected death in epilepsy (SUDEP) is a devastating epilepsy complication, and no effective preventive strategies are currently available for this fatal disorder. Clinical and animal studies of SUDEP demonstrate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death after generalized seizures in many cases. Enhancing brain levels of serotonin reduces S-IRA in animal models relevant to SUDEP, including the DBA/1 mouse. Given that serotonin in the brain plays an important role in modulating respiration and arousal, these findings suggest that deficits in respiration and/or arousal may contribute to S-IRA. It is well known that norepinephrine is an important neurotransmitter that modulates respiration and arousal in the brain as well. Therefore, we hypothesized that enhancing noradrenergic neurotransmission suppresses S-IRA. To test this hypothesis, we examined the effect of atomoxetine, a norepinephrine reuptake inhibitor (NRI), on S-IRA evoked by either acoustic stimulation or pentylenetetrazole in DBA/1 mice. We report the original observation that atomoxetine specifically suppresses S-IRA without altering the susceptibility to seizures evoked by acoustic stimulation, and atomoxetine also reduces S-IRA evoked by pentylenetetrazole in DBA/1 mice. Our data suggest that the noradrenergic signaling is importantly involved in S-IRA, and that atomoxetine, a medication widely used to treat attention deficit hyperactivity disorder (ADHD), is potentially useful to prevent SUDEP. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

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    Kobayashi, Toru; Washiyama, Kazuo; Ikeda, Kazutaka

    2010-01-01

    Atomoxetine and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attention-deficit/hyperactivity disorder and depression, respectively. Furthermore, recent studies have suggested that NRIs may be useful for the treatment of several other psychiatric disorders. However, the molecular mechanisms underlying the various effects of NRIs have not yet been sufficiently clarified. G-protein-activated inwardly rectifying K+ (GIRK or Kir3) channels have an important function in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to be a potential treatment for several neuropsychiatric disorders and cardiac arrhythmias. In this study, we investigated the effects of atomoxetine and reboxetine on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, extracellular application of atomoxetine or reboxetine reversibly reduced GIRK currents. The inhibitory effects were concentration-dependent, but voltage-independent, and time-independent during each voltage pulse. However, Kir1.1 and Kir2.1 channels were insensitive to atomoxetine and reboxetine. Atomoxetine and reboxetine also inhibited GIRK currents induced by activation of cloned A1 adenosine receptors or by intracellularly applied GTPγS, a nonhydrolyzable GTP analogue. Furthermore, the GIRK currents induced by ethanol were concentration-dependently inhibited by extracellularly applied atomoxetine but not by intracellularly applied atomoxetine. The present results suggest that atomoxetine and reboxetine inhibit brain- and cardiac-type GIRK channels, revealing a novel characteristic of clinically used NRIs. GIRK channel inhibition may contribute to some of the therapeutic effects of NRIs and adverse side effects related to nervous system and heart function. PMID:20393461

  3. Atomoxetine, a selective norepinephrine reuptake inhibitor, improves short-term histological outcomes after hypoxic-ischemic brain injury in the neonatal male rat.

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    Toshimitsu, Masatake; Kamei, Yoshimasa; Ichinose, Mari; Seyama, Takahiro; Imada, Shinya; Iriyama, Takayuki; Fujii, Tomoyuki

    2018-03-30

    Despite the recent progress of perinatal medicine, perinatal hypoxic-ischemic (HI) insult remains an important cause of brain injury in neonates, and is pathologically characterized by neuronal loss and the presence of microglia. Neurotransmitters, such as norepinephrine (NE) and glutamate, are involved in the pathogenesis of hypoxic-ischemic encephalopathy via the interaction between neurons and microglia. Although it is well known that the monoamine neurotransmitter NE acts as an anti-inflammatory agent in the brain under pathological conditions, its effects on perinatal HI insult remains elusive. Atomoxetine, a selective NE reuptake inhibitor, has been used clinically for the treatment of attention-deficit hyperactivity disorder in children. Here, we investigated whether the enhancement of endogenous NE by administration of atomoxetine could protect neonates against HI insult by using the neonatal male rat model. We also examined the involvement of microglia in this process. Unilateral HI brain injury was induced by the combination of left carotid artery dissection followed by ligation and hypoxia (8% O 2 , 2 h) in postnatal day 7 (P7) male rat pups. The pups were randomized into three groups: the atomoxetine treatment immediately after HI insult, the atomoxetine treatment at 3 h after HI insult, or the vehicle treatment group. The pups were euthanized on P8 and P14, and the brain regions including the cortex, striatum, hippocampus, and thalamus were evaluated by immunohistochemistry. HI insult resulted in severe brain damage in the ipsilateral hemisphere at P14. Atomoxetine treatment immediately after HI insult significantly increased NE levels in the ipsilateral hemisphere at 1 h after HI insult and reduced the neuronal damage via the increased phosphorylation of cAMP response element-binding protein (pCREB) in all brain regions examined. In addition, the number of microglia was maintained under atomoxetine treatment compared with that of the vehicle

  4. Monoamine depletion by reuptake inhibitors

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    Hinz M

    2011-10-01

    Full Text Available Marty Hinz1, Alvin Stein2, Thomas Uncini31Clinical Research, NeuroResearch Clinics Inc, Cape Coral, FL; 2Stein Orthopedic Associates, Plantation, FL; 3DBS Labs Inc, Duluth, MN, USABackground: Disagreement exists regarding the etiology of cessation of the observed clinical results with administration of reuptake inhibitors. Traditionally, when drug effects wane, it is known as tachyphylaxis. With reuptake inhibitors, the placebo effect is significantly greater than the drug effect in the treatment of depression and attention deficit hyperactivity disorder, leading some to assert that waning of drug effects is placebo relapse, not tachyphylaxis.Methods: Two groups were retrospectively evaluated. Group 1 was composed of subjects with depression and Group 2 was composed of bariatric subjects treated with reuptake inhibitors for appetite suppression.Results: In Group 1, 200 subjects with depression were treated with citalopram 20 mg per day. A total of 46.5% (n = 93 achieved relief of symptoms (Hamilton-D rating score ≤ 7, of whom 37 (39.8% of whom experienced recurrence of depression symptoms, at which point an amino acid precursor formula was started. Within 1–5 days, 97.3% (n = 36 experienced relief of depression symptoms. In Group 2, 220 subjects were treated with phentermine 30 mg in the morning and citalopram 20 mg at 4 pm. In this group, 90.0% (n = 198 achieved adequate appetite suppression. The appetite suppression ceased in all 198 subjects within 4–48 days. Administration of an amino acid precursor formula restored appetite suppression in 98.5% (n = 195 of subjects within 1–5 days.Conclusion: Reuptake inhibitors do not increase the total number of monoamine molecules in the central nervous system. Their mechanism of action facilitates redistribution of monoamines from one place to another. In the process, conditions are induced that facilitate depletion of monoamines. The "reuptake inhibitor monoamine depletion theory" of this paper

  5. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

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    Serotonin and norepinephrine reuptake inhibitors (SNRIs) Antidepressant SNRIs help relieve depression symptoms, such as irritability and sadness, ... effects they may cause. By Mayo Clinic Staff Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a class ...

  6. Cardiovascular Side Effects of Atomoxetine and Its Interactions with Inhibitors of the Cytochrome P450 System

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    Pashtoon Murtaza Kasi

    2011-01-01

    Full Text Available Attention deficit hyperactivity disorder (ADHD is one of the most common neurobehavioral disorders of childhood and adolescence. Classically, stimulants have been used in the treatment of this condition. Atomoxetine (Strattera; Eli Lilly and Company is a selective norepinephrine reuptake inhibitor (SNRI, one of the first medications in the nonstimulant class of medications that has been approved by the FDA for the treatment of ADHD. Atomoxetine is a phenoxypropylamine derivative and is structurally related to the antidepressant fluoxetine. The common side effects reported with the use of atomoxetine include mainly GI disturbances. Cardiovascular side effects are less commonly reported. The increase in the noradrenergic tone may explain some of the side effects noted with the use of this medication. Here, we present a case of a patient who presented with syncope, orthostatic hypotension, and tachycardia and discuss the various clinical implications based on the pharmacokinetics and pharmacodynamics of the drug.

  7. Atomoxetine

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    ... develop serious symptoms very suddenly, so it is important to pay attention to his or her behavior every day. Ask ... treatment program to increase the ability to pay attention and decrease ... selective norepinephrine reuptake inhibitors. It works by increasing the ...

  8. Analytical Strategies for the Determination of Norepinephrine Reuptake Inhibitors in Pharmaceutical Formulations and Biological Fluids.

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    Saka, Cafer

    2016-01-01

    Norepinephrine reuptake inhibitors (NRIs) are a class of antidepressant drugs that act as reuptake inhibitors for the neurotransmitters norepinephrine and epinephrine. The present review provides an account of analytical methods published in recent years for the determination of NRI drugs. NRIs are atomoxetine, reboxetine, viloxazine and maprotiline. NRIs with less activity at other sites are mazindol, bupropion, tapentadol, and teniloxazine. This review focuses on the analytical methods including chromatographic, spectrophotometric, electroanalytical, and electrophoresis techniques for NRI analysis from pharmaceutical formulations and biological samples. Among all of the published methods, liquid chromatography with UV-vis or MS-MS detection is the most popular technique. The most the common sample preparation techniques in the analytical methods for NRIs include liquid-liquid extraction and solid-phase extraction. Besides the analytical methods for single components, some of the simultaneous determinations are also included in this review.

  9. Atomoxetine Induced Hypothermia: A Case Report

    OpenAIRE

    Abali, Osman; Yilmaz, Onat

    2011-01-01

    Adverse drug reactions are common in drugs used during childhood and adolescence. Atomoxetine, a selective reuptake inhibitor, was introduced as a safe non-stimulant alternative treatment for attention deficit hyperactivity disorder. Described common side effects of atomoxetine include: headache, abdominal pain, decreased appetite, fatigue, nausea, vomiting and dizziness. In our case, we present an adolescent male who developed hypothermia under atomoxetine treatment. To our knowledge, this i...

  10. Selective serotonin reuptake inhibitors and risk for gastrointestinal bleeding

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    Batić-Mujanović Olivera

    2014-01-01

    Full Text Available The most of the known effects of selective serotonin reuptake inhibitors, beneficial or harmful, are associated with the inhibitory action of the serotonin reuptake transporter. This mechanism is present not only in neurons, but also in other cells such as platelets. Serotoninergic mechanism seems to have an important role in hemostasis, which has long been underestimated. Abnormal activation may lead to a prothrombotic state in patients treated with selective serotonin reuptake inhibitors. On one hand there may be an increased risk of bleeding, and on the other hand reduction in thrombotic risk may be possible. Serotonin is critical to maintain a platelet haemostatic function, such as platelet aggregation. Evidences from the studies support the hypothesis that antidepressants with a relevant blockade of action of serotonin reuptake mechanism may increase the risk of bleeding, which can occur anywhere in the body. Epidemiological evidences are, however, the most robust for upper gastrointestinal bleeding. It is estimated that this bleeding can occur in 1 in 100 to 1 in 1.000 patient-years of exposure to the high-affinity selective serotonin reuptake inhibitors, with very old patients at the highest risk. The increased risk may be of particular relevance when selective serotonin reuptake inhibitors are taken simultaneously with nonsteroidal anti-inflammatory drugs, low dose of aspirin or warfarin.

  11. Triple Reuptake Inhibitors: A Premise and Promise

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    Marks, David M.; Pae, Chi-Un; Patkar, Ashwin A.

    2008-01-01

    On the horizon there is a new class of psychoactive medications which work by inhibiting the neuronal reuptake of serotonin, norepinephrine, and dopamine. There are multiple potential indications for these drugs. Research suggests that they may have a role in treating depressive disorders, and it is plausible they may have potential efficacy in obesity, addiction, and pain syndromes. The current review describes some of the molecules in development presently and explores the research relevant...

  12. Serotonin and noradrenaline reuptake inhibitors improve micturition control in mice.

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    Marco Redaelli

    Full Text Available Poor micturition control may cause profound distress, because proper voiding is mandatory for an active social life. Micturition results from the subtle interplay of central and peripheral components. It involves the coordination of autonomic and neuromuscular activity at the brainstem level, under the executive control of the prefrontal cortex. We tested the hypothesis that administration of molecules acting as reuptake inhibitors of serotonin, noradrenaline or both may exert a strong effect on the control of urine release, in a mouse model of overactive bladder. Mice were injected with cyclophosphamide (40 mg/kg, to increase micturition acts. Mice were then given one of four molecules: the serotonin reuptake inhibitor imipramine, its metabolite desipramine that acts on noradrenaline reuptake, the serotonin and noradrenaline reuptake inhibitor duloxetine or its active metabolite 4-hydroxy-duloxetine. Cyclophosphamide increased urine release without inducing overt toxicity or inflammation, except for increase in urothelium thickness. All the antidepressants were able to decrease the cyclophosphamide effects, as apparent from longer latency to the first micturition act, decreased number of urine spots and volume of released urine. These results suggest that serotonin and noradrenaline reuptake inhibitors exert a strong and effective modulatory effect on the control of urine release and prompt to additional studies on their central effects on brain areas involved in the social and behavioral control of micturition.

  13. Triple Reuptake Inhibitors: A Premise and Promise

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    Marks, David M.; Patkar, Ashwin A.

    2008-01-01

    On the horizon there is a new class of psychoactive medications which work by inhibiting the neuronal reuptake of serotonin, norepinephrine, and dopamine. There are multiple potential indications for these drugs. Research suggests that they may have a role in treating depressive disorders, and it is plausible they may have potential efficacy in obesity, addiction, and pain syndromes. The current review describes some of the molecules in development presently and explores the research relevant to possible clinical uses for this class of medications. PMID:20046357

  14. Selective serotonin reuptake inhibitors for fibromyalgia syndrome

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    Walitt, Brian; Urrútia, Gerard; Nishishinya, María Betina; Cantrell, Sarah E; Häuser, Winfried

    2016-01-01

    Background Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms. Objectives The objective was to assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs) in the treatment of fibromyalgia. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5), MEDLINE (1966 to June 2014), EMBASE (1946 to June 2014), and the reference lists of reviewed articles. Selection criteria We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline. Data collection and analysis Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. Main results The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks) and 383 participants, who were pooled together. All studies had one or more sources of potential major bias. There was a small (10%) difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6%)) and placebo (39/171 (22.8%)) risk difference (RD) 0.10, 95% confidence interval (CI) 0.01 to 0.20; number needed to treat for an additional

  15. Selective serotonin reuptake inhibitors for fibromyalgia syndrome

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    Brian Walitt

    Full Text Available ABSTRACT BACKGROUND: Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms. OBJECTIVES: To assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs in the treatment of fibromyalgia. METHODS: Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5, MEDLINE (1966 to June 2014, EMBASE (1946 to June 2014, and the reference lists of reviewed articles. Selection criteria: We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline. Data collection and analysis: Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. MAIN RESULTS: The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks and 383 participants, who were pooled together. All studies had one or more sources of potential major bias. There was a small (10% difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6% and placebo (39/171 (22.8% risk difference (RD 0.10, 95% confidence interval (CI 0.01 to 0.20; number needed to treat for an

  16. Relative contributions of norepinephrine and serotonin transporters to antinociceptive synergy between monoamine reuptake inhibitors and morphine in the rat formalin model.

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    Fei Shen

    Full Text Available Multimodal analgesia is designed to optimize pain relief by coadministering drugs with distinct mechanisms of action or by combining multiple pharmacologies within a single molecule. In clinical settings, combinations of monoamine reuptake inhibitors and opioid receptor agonists have been explored and one currently available analgesic, tapentadol, functions as both a µ-opioid receptor agonist and a norepinephrine transporter inhibitor. However, it is unclear whether the combination of selective norepinephrine reuptake inhibition and µ-receptor agonism achieves an optimal antinociceptive synergy. In this study, we assessed the pharmacodynamic interactions between morphine and monoamine reuptake inhibitors that possess different affinities and selectivities for norepinephrine and serotonin transporters. Using the rat formalin model, in conjunction with measurements of ex vivo transporter occupancy, we show that neither the norepinephrine-selective inhibitor, esreboxetine, nor the serotonin-selective reuptake inhibitor, fluoxetine, produce antinociceptive synergy with morphine. Atomoxetine, a monoamine reuptake inhibitor that achieves higher levels of norepinephrine than serotonin transporter occupancy, exhibited robust antinociceptive synergy with morphine. Similarly, a fixed-dose combination of esreboxetine and fluoxetine which achieves comparable levels of transporter occupancy potentiated the antinociceptive response to morphine. By contrast, duloxetine, a monoamine reuptake inhibitor that achieves higher serotonin than norepinephrine transporter occupancy, failed to potentiate the antinociceptive response to morphine. However, when duloxetine was coadministered with the 5-HT3 receptor antagonist, ondansetron, potentiation of the antinociceptive response to morphine was revealed. These results support the notion that inhibition of both serotonin and norepinephrine transporters is required for monoamine reuptake inhibitor and opioid

  17. Use of selective serotonin reuptake inhibitors reduces fertility in men

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    Nørr, L; Bennedsen, Birgit; Fedder, Jens

    2016-01-01

    Clinical review of the present data on the effects of selective serotonin reuptake inhibitors (SSRIs) on male fertility was the objective of the study. PubMed and Scopus were searched for publications in English or Danish and reviewed. Human trials, animal studies and in vitro studies were included...

  18. Selective serotonin reuptake inhibitor (SSRI antidepressants, prolactin and breast cancer

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    Janet eAshbury

    2012-12-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are a widely prescribed class of anti-depressants. Laboratory and epidemiologic evidence suggests that a prolactin-mediated mechanism secondary to increased serotonin levels at neuronal synapses could lead to a potentially carcinogenic effect of SSRIs. In this population-based case-control study, we evaluated the association between SSRI use and breast cancer risk as a function of their relative degree of inhibition of serotonin reuptake as a proxy for their impact on prolactin levels. Cases were 2,129 women with primary invasive breast cancer diagnosed from 2003-2007, and controls were 21,297 women randomly selected from the population registry. Detailed information for each SSRI prescription dispensed was compiled using the Saskatchewan prescription database. Logistic regression was used to evaluate the impact of use of high and lower inhibitors of serotonin reuptake and duration of use, as well as to assess the effect of individual high inhibitors on the risk of breast cancer. Exclusive users of high or lower inhibitors of serotonin reuptake were not at increased risk for breast cancer compared with nonusers of SSRIs (OR = 1.01, CI = 0.88-1.17 and OR = 0.91, CI = 0.67-1.25 respectively, regardless of their duration of use or menopausal status. While we cannot rule out the possibility of a clinically important risk increase (OR = 1.83, CI = 0.99-3.40 for long-term users of sertraline (≥24 prescriptions, given the small number of exposed cases (n=12, the borderline statistical significance and the wide confidence interval, these results need to be interpreted cautiously. In this large population-based case-control study, we found no conclusive evidence of breast cancer risk associated with the use of SSRIs even after assessing the degree of serotonin reuptake inhibition and duration of use. Our results do not support the serotonin-mediated pathway for the prolactin-breast cancer hypothesis.

  19. The treatment of kleptomania with serotonin reuptake inhibitors.

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    Lepkifker, E; Dannon, P N; Ziv, R; Iancu, I; Horesh, N; Kotler, M

    1999-01-01

    Kleptomania is characterized by an irresistible impulse to steal objects not needed for personal use or for their monetary value. Several recent case reports have shown that Serotonin Specific Reuptake Inhibitors (SSRIs) could be effective in the treatment of kleptomania just as it is in other obsessive-compulsive spectrum disorders. We report five cases of kleptomania patients who were successfully treated with fluoxetine or paroxetine in combination with a psychotherapeutic intervention. In one case, the discontinuation of the medication repeatedly led to the resurgence of the kleptomanic behavior. Our case series illustrates the effectiveness of SSRIs in kleptomania. It thus supports the assumption that this syndrome involves a dysfunctional serotoninergic mechanism.

  20. Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.

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    Dreyfus, Nicolas; Myers, Jason K; Badescu, Valentina O; de Frutos, Oscar; de la Puente, Maria Luz; Ding, Chunjin; Filla, Sandra A; Fynboe, Karsten; Gernert, Douglas L; Heinz, Beverly A; Hemrick-Luecke, Susan K; Johnson, Kirk W; Johnson, Michael P; López, Pilar; Love, Patrick L; Martin, Laura J; Masquelin, Thierry; McCoy, Michael J; Mendiola, Javier; Morrow, Denise; Muhlhauser, Mark; Pascual, Gustavo; Perun, Thomas J; Pfeifer, Lance A; Phebus, Lee A; Richards, Simon J; Rincón, Juan Antonio; Seest, Eric P; Shah, Jikesh; Shaojuan, Jia; Simmons, Rosa Maria A; Stephenson, Gregory A; Tromiczak, Eric G; Thompson, Linda K; Walter, Magnus W; Weber, Wayne W; Zarrinmayeh, Hamideh; Thomas, Craig E; Joshi, Elizabeth; Iyengar, Smriti; Johansson, Anette M

    2013-06-13

    The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.

  1. Pharmacodynamics of norepinephrine reuptake inhibition: Modeling the peripheral and central effects of atomoxetine, duloxetine, and edivoxetine on the biomarker 3,4-dihydroxyphenylglycol in humans.

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    Kielbasa, William; Lobo, Evelyn

    2015-12-01

    Norepinephrine, a neurotransmitter in the autonomic sympathetic nervous system, is deaminated by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). Inhibition of the NE transporter (NET) using DHPG as a biomarker was evaluated using atomoxetine, duloxetine, and edivoxetine as probe NET inhibitors. Pharmacokinetic and pharmacodynamic data were obtained from healthy subjects (n = 160) from 5 clinical trials. An indirect response model was used to describe the relationship between drug plasma concentration and DHPG concentration in plasma and cerebrospinal fluid (CSF). The baseline plasma DHPG concentration (1130-1240 ng/mL) and Imax (33%-37%) were similar for the 3 drugs. The unbound plasma drug IC50 (IC50U ) based on plasma DHPG was 0.973 nM for duloxetine, 0.136 nM for atomoxetine, and 0.041 nM for edivoxetine. The baseline CSF DHPG concentration (1850-2260 ng/mL) was similar for the 3 drugs, but unlike plasma DHPG, the Imax for DHPG was 38% for duloxetine, 53% for atomoxetine, and75% for edivoxetine. The IC50U based on CSF DHPG was 2.72 nM for atomoxetine, 1.22 nM for duloxetine, and 0.794 nM for edivoxetine. These modeling results provide insights into the pharmacology of NET inhibitors and the use of DHPG as a biomarker. © 2015, The American College of Clinical Pharmacology.

  2. Prenatal exposure to selective serotonin reuptake inhibitors and childhood overweight at 7 years of age

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    Grzeskowiak, Luke E; Gilbert, Andrew L; Sørensen, Thorkild

    2013-01-01

    To investigate a possible association between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and childhood overweight at 7 years of age.......To investigate a possible association between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and childhood overweight at 7 years of age....

  3. Effects of Methylphenidate and Atomoxetine on Cortical Inhibition in ADHD

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    J Gordon Millichap

    2006-09-01

    Full Text Available The effects of methylphenidate (MPH, a psychostimulant, and atomoxetine (ATX, a selective norepinephrine reuptake inhibitor, on short interval-cortical inhibition (SICI were measured in motor cortex with transcranial magnetic stimulation, in a study at Cincinnati Children’s Medical Center, OH, and other centers.

  4. Treatment of selective mutism: focus on selective serotonin reuptake inhibitors.

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    Kaakeh, Yaman; Stumpf, Janice L

    2008-02-01

    Abstract Selective mutism is a pediatric psychiatric disorder that occurs when a child consistently fails to speak in specific situations in which speaking is expected, such as at school and social gatherings, but speaks appropriately in other settings. Selective mutism often is diagnosed when a child starts school and does not talk to teachers or peers, but talks to family members at home; the condition is frequently accompanied by anxiety and shyness. Although the underlying etiology of the condition remains unclear, psychotherapy is the preferred initial treatment, with the support of parents and teachers. If the child does not respond to psychotherapy, addition of pharmacologic treatment should be considered, depending on the severity of symptoms and presence of other illnesses. Although data are limited to case reports and trials with small patient populations and short follow-up periods, some patients with selective mutism respond to therapy with selective serotonin reuptake inhibitors (SSRIs). Fluoxetine is the most studied SSRI as treatment for the condition, although further investigation is required to determine the optimal dosage and duration of therapy.

  5. Selective serotonin reuptake inhibitors and intraoperative blood pressure.

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    van Haelst, Ingrid M M; van Klei, Wilton A; Doodeman, Hieronymus J; Kalkman, Cor J; Egberts, Toine C G

    2012-02-01

    The influence of selective serotonin reuptake inhibitors (SSRIs) on blood pressure is poorly understood. We hypothesized that if SSRIs have an influence on blood pressure, this might become manifest in changes in intraoperative blood pressure. We aimed to study the association between perioperative use of SSRIs and changes in intraoperative blood pressure by measuring the occurrence of intraoperative hyper- and hypotension. We conducted a retrospective observational follow-up study among patients who underwent elective primary total hip arthroplasty. The index group included users of SSRIs. The reference group included a random sample (ratio 1:3) of nonusers of an antidepressant agent. The outcome was the occurrence of intraoperative hypo- and hypertensive episodes (number, mean and total duration, and area under the curve (AUC)). The outcome was adjusted for confounding factors using regression techniques. The index group included 20 users of an SSRI. The reference group included 60 nonusers. Users of SSRIs showed fewer intraoperative hypotensive episodes, a shorter mean and total duration, and a smaller AUC when compared to the reference group. After adjustment for confounders, SSRI use was associated with a significantly shorter total duration of hypotension: mean difference of -29.4 min (95% confidence interval (CI) -50.4 to -8.3). Two users of an SSRI and two patients in the reference group had a hypertensive episode. Continuation of treatment with SSRIs before surgery was associated with a briefer duration of intraoperative hypotension.

  6. Understanding the pharmacogenetics of selective serotonin reuptake inhibitors.

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    Fabbri, Chiara; Minarini, Alessandro; Niitsu, Tomihisa; Serretti, Alessandro

    2014-08-01

    The genetic background of antidepressant response represents a unique opportunity to identify biological markers of treatment outcome. Encouraging results alternating with inconsistent findings made antidepressant pharmacogenetics a stimulating but often discouraging field that requires careful discussion about cumulative evidence and methodological issues. The present review discusses both known and less replicated genes that have been implicated in selective serotonin reuptake inhibitors (SSRIs) efficacy and side effects. Candidate genes studies and genome-wide association studies (GWAS) were collected through MEDLINE database search (articles published till January 2014). Further, GWAS signals localized in promising genetic regions according to candidate gene studies are reported in order to assess the general comparability of results obtained through these two types of pharmacogenetic studies. Finally, a pathway enrichment approach is applied to the top genes (those harboring SNPs with p pharmacogenetics, the present review discusses the proposal of moving from the analysis of individual polymorphisms to genes and molecular pathways, and from the separation across different methodological approaches to their combination. Efforts in this direction are justified by the recent evidence of a favorable cost-utility of gene-guided antidepressant treatment.

  7. A concise total synthesis of (R)-fluoxetine, a potent and selective serotonin reuptake inhibitor

    International Nuclear Information System (INIS)

    Fatima, Angelo de; Lapis, Alexandre Augusto M.; Pilli, Ronaldo A.

    2005-01-01

    (R)-Fluoxetine, potent and selective serotonin reuptake inhibitor, has been synthesized in six steps, 50% overall yield and 99% ee from benzaldehyde via catalytic asymmetric allylation with Maruoka's catalyst. (author)

  8. A concise total synthesis of (R)-fluoxetine, a potent and selective serotonin reuptake inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Fatima, Angelo de; Lapis, Alexandre Augusto M.; Pilli, Ronaldo A. [Universidade Estadual de Campinas, SP (Brazil). Inst. de Quimica]. E-mail: pilli@iqm.unicamp.br

    2005-05-15

    (R)-Fluoxetine, potent and selective serotonin reuptake inhibitor, has been synthesized in six steps, 50% overall yield and 99% ee from benzaldehyde via catalytic asymmetric allylation with Maruoka's catalyst. (author)

  9. The market dynamics of selective serotonin re-uptake inhibitors: a ...

    African Journals Online (AJOL)

    The market dynamics of selective serotonin re-uptake inhibitors: a private sector study in South Africa. Frasia Oosthuizen, Pariksha Jolene Kondiah, Hawa Bibi Moosa, Siddiqa Naroth, Nabeel Ismail Patel, Divashnee Reddy, Amanda Soobramoney ...

  10. In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder

    DEFF Research Database (Denmark)

    Gidaya, Nicole B; Lee, Brian K; Burstyn, Igor

    2014-01-01

    We investigated whether there is an association between increased risk for autism spectrum disorders (ASD) and selective serotonin reuptake inhibitors (SSRIs) used during pregnancy. This study used Denmark's health and population registers to obtain information regarding prescription drugs, ASD...

  11. Paediatric outcomes following intrauterine exposure to serotonin reuptake inhibitors: a systematic review

    DEFF Research Database (Denmark)

    Fenger-Grøn, Jesper; Thomsen, Morten; Andersen, Kristian Skytte

    2011-01-01

    The use of serotonine reuptake inhibitors (SRIs) is increasing among Danish pregnant women. This systematic review addresses the potential adverse effects on the foetus and child of maternal SRI medication. The literature indicates a slightly increased risk of cardiovascular malformations...

  12. Selective serotonin reuptake inhibitor suppression of HIV infectivity and replication.

    Science.gov (United States)

    Benton, Tami; Lynch, Kevin; Dubé, Benoit; Gettes, David R; Tustin, Nancy B; Ping Lai, Jian; Metzger, David S; Blume, Joshua; Douglas, Steven D; Evans, Dwight L

    2010-11-01

    To test the hypothesis that the selective serotonin reuptake inhibitor (SSRI) citalopram would down-regulate human immunodeficiency virus (HIV) infectivity and that the greatest effects would be seen in people with depression. Depression is a risk factor for morbidity and mortality in HIV/acquired immune deficiency syndrome. Serotonin (5-HT) neurotransmission has been implicated in the pathobiology of depression, and pharmacologic therapies for depression target this system. The 5-HT transporter and 5-HT receptors are widely distributed throughout the central nervous and immune systems. Depression has been associated with suppression of natural killer cells and CD8(+) lymphocytes, key regulators of HIV infection. Ex vivo models for acute and chronic HIV infection were used to study the effects of citalopram on HIV viral infection and replication in 48 depressed and nondepressed women. For both the acute and chronic infection models, HIV reverse transcriptase activity was measured in the citalopram treatment condition and the control condition. The SSRI significantly down-regulated the reverse transcriptase response in both the acute and chronic infection models. Specifically, citalopram significantly decreased the acute HIV infectivity of macrophages. Citalopram also significantly decreased HIV viral replication in the latently infected T-cell line and in the latently infected macrophage cell line. There was no difference in down-regulation by depression status. These studies suggest that an SSRI enhances natural killer/CD8 noncytolytic HIV suppression in HIV/acquired immune deficiency syndrome and decreases HIV viral infectivity of macrophages, ex vivo, suggesting the need for in vivo studies to determine a potential role for agents targeting serotonin in the host defense against HIV.

  13. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia.

    Science.gov (United States)

    Welsch, Patrick; Üçeyler, Nurcan; Klose, Petra; Walitt, Brian; Häuser, Winfried

    2018-02-28

    Fibromyalgia is a clinically defined chronic condition of unknown etiology characterized by chronic widespread pain that often co-exists with sleep disturbances, cognitive dysfunction and fatigue. People with fibromyalgia often report high disability levels and poor quality of life. Drug therapy, for example, with serotonin and noradrenaline reuptake inhibitors (SNRIs), focuses on reducing key symptoms and improving quality of life. This review updates and extends the 2013 version of this systematic review. To assess the efficacy, tolerability and safety of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo or other active drug(s) in the treatment of fibromyalgia in adults. For this update we searched CENTRAL, MEDLINE, Embase, the US National Institutes of Health and the World Health Organization (WHO) International Clinical Trials Registry Platform for published and ongoing trials and examined the reference lists of reviewed articles, to 8 August 2017. We selected randomized, controlled trials of any formulation of SNRIs against placebo or any other active treatment of fibromyalgia in adults. Three review authors independently extracted data, examined study quality, and assessed risk of bias. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 50% or greater and of 30% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardized mean differences (SMD) for fatigue, sleep problems, health-related quality of life, mean pain intensity, depression, anxiety, disability, sexual function, cognitive disturbances and tenderness. For tolerability we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawals due to adverse events and for nausea, insomnia and somnolence as specific adverse events. For safety we calculated NNTH for serious adverse events. We undertook meta

  14. Triple Reuptake Inhibitors: The Next Generation of Antidepressants

    OpenAIRE

    Marks, David M; Pae, Chi-Un; Patkar, Ashwin A

    2008-01-01

    Depression has been associated with impaired neurotransmission of serotonergic, norepinephrinergic, and dopaminergic pathways, although most pharmacologic treatment strategies for depression enhance only serotonin and norepinephrine neurotransmission. Current drug development efforts are aimed at a new class of antidepressants which inhibit the reuptake of all three neurotransmitters in the hope of creating medications with broader efficacy and/or quicker onset of action. The current review e...

  15. Mixture and single-substance toxicity of selective serotonin reuptake inhibitors toward algae and crustaceans

    DEFF Research Database (Denmark)

    Christensen, Anne Munch; Faaborg-Andersen, S.; Ingerslev, Flemming

    2007-01-01

    Selective serotonin reuptake inhibitors (SSRIs) are used as antidepressant medications. primarily in the treatment of clinical depression. They are among the pharmaceuticals most often Prescribed in the industrialized countries. Selective serotonin reuptake inhibitors are compounds with an identi......Selective serotonin reuptake inhibitors (SSRIs) are used as antidepressant medications. primarily in the treatment of clinical depression. They are among the pharmaceuticals most often Prescribed in the industrialized countries. Selective serotonin reuptake inhibitors are compounds...... with an identical mechanism of action in mammals (inhibit reuptake of serotonin), and they have been found in different aqeous as well as biological samples collected in the environment. In the present study, we tested the toxicities of five SSRIs (citalopram, fluoxetine, fluoxamine, paroxetine, and sertraline.......027 to 1.6 mg/L, and in daphnids, test EC50s ranged from 0.92 to 20 mg/L, with sertraline being one of the most toxic compounds. The test design and statistical analysis of results from mixture tests were based on isobole analysis. It was demonstrated that the mixture toxicity of the SSRIs in the two...

  16. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study

    Science.gov (United States)

    de Abajo, Francisco José; Rodríguez, Luis Alberto García; Montero, Dolores

    1999-01-01

    Objective To examine the association between selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding. Design Population based case-control study. Setting General practices included in the UK general practice research database. Subjects 1651 incident cases of upper gastrointestinal bleeding and 248 cases of ulcer perforation among patients aged 40 to 79 years between April 1993 and September 1997, and 10 000 controls matched for age, sex, and year that the case was identified. Interventions Review of computer profiles for all potential cases, and an internal validation study to confirm the accuracy of the diagnosis on the basis of the computerised information. Main outcome measures Current use of selective serotonin reuptake inhibitors or other antidepressants within 30 days before the index date. Results Current exposure to selective serotonin reuptake inhibitors was identified in 3.1% (52 of 1651) of patients with upper gastrointestinal bleeding but only 1.0% (95 of 10 000) of controls, giving an adjusted rate ratio of 3.0 (95% confidence interval 2.1 to 4.4). This effect measure was not modified by sex, age, dose, or treatment duration. A crude incidence of 1 case per 8000 prescriptions was estimated. A small association was found with non-selective serotonin reuptake inhibitors (relative risk 1.4, 1.1 to 1.9) but not with antidepressants lacking this inhibitory effect. None of the groups of antidepressants was associated with ulcer perforation. The concurrent use of selective serotonin reuptake inhibitors with non-steroidal anti-inflammatory drugs increased the risk of upper gastrointestinal bleeding beyond the sum of their independent effects (15.6, 6.6 to 36.6). A smaller interaction was also found between selective serotonin reuptake inhibitors and low dose aspirin (7.2, 3.1 to 17.1). Conclusions Selective serotonin reuptake inhibitors increase the risk of upper gastrointestinal bleeding. The absolute effect is, however

  17. Commentary: Considerations on the Pharmacological Treatment of Compulsions and Stereotypies with Serotonin Reuptake Inhibitors in Pervasive Developmental Disorders.

    Science.gov (United States)

    Gordon, C. T.

    2000-01-01

    This commentary discusses study results that indicate the nonselective serotonin reuptake inhibitor (SRI) clomipramine is more efficacious than the relatively selective norepinephrine reuptake inhibitor desipramine and placebo in treating repetitive or ritualized behaviors in children with autism. The need for concurrent genetic and biochemical…

  18. Dependence and withdrawal reactions to benzodiazepines and selective serotonin reuptake inhibitors. How did the health authorities react?

    DEFF Research Database (Denmark)

    Nielsen, Margrethe; Hansen, Ebba Holme; Gøtzsche, Peter C

    2013-01-01

    Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time.......Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time....

  19. CYP450 genotype and aggressive behavior on selective serotonin reuptake inhibitors

    NARCIS (Netherlands)

    Ekhart, Corine; Matic, Maja; Kant, Agnes; Schaik, Ron van; van Puijenbroek, Eugène

    2017-01-01

    AIM: Genetic variants for selective serotonin reuptake inhibitor (SSRI) metabolizing enzymes have been hypothesized to be a risk factor for aggression as adverse drug effect of SSRIs. Our aim was to assess the possible involvement of these polymorphisms on aggression when using SSRIs. MATERIALS &

  20. Mechanism-based PK/PD modeling of selective serotonin reuptake inhibitors

    NARCIS (Netherlands)

    Geldof, Marian

    2007-01-01

    The main objective of the investigations was to explore the PK/PD correlations of fluvoxamine, as a prototype for the Selective Serotonin Reuptake Inhibitors (SSRIs). In the various investigations, a spectrum of different biomarkers was used, each reflecting a specific process on the causal path

  1. Helicobacter pylori and risk of upper gastrointestinal bleeding among users of selective serotonin reuptake inhibitors

    DEFF Research Database (Denmark)

    Dall, Michael; Schaffalitzky de Muckadell, Ove B; Møller Hansen, Jane

    2011-01-01

    A number of studies have reported a possible association between use of selective serotonin reuptake inhibitors (SSRIs) and serious upper gastrointestinal bleeding (UGB). We conducted this case-control study to assess if Helicobacter pylori (H. pylori) potentiates the risk of serious UGB in SSRI ...

  2. Are Selective Serotonin Reuptake Inhibitors Safe for Drivers? What is the Evidence?

    NARCIS (Netherlands)

    Ravera, Silvia; Ramaekers, Johannes G.; de Jong-van den Berg, Lolkje T. W.; de Gier, Johan J.; de Jong-van den Berg, [No Value

    Background: Selective serotonin reuptake inhibitors (SSRIs) are widely used medications to treat several psychiatric diseases and, above all, depression. They seem to be as effective as older antidepressants but have a different adverse effect profile. Despite their favorable safety profile, little

  3. The effect of selective serotonin reuptake inhibitors in healthy subjects. A systematic review

    DEFF Research Database (Denmark)

    Knorr, Ulla; Kessing, Lars Vedel; Knorr, Ulla

    2010-01-01

    BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) show antidepressant properties in many patients with a diagnosis of depression. An understanding of the underlying mechanisms of the effect of SSRIs in healthy patients may lead to an understanding of the yet unclear pathophysiology of d...

  4. Increased Bleeding Risk With Concurrent Use of Selective Serotonin Reuptake inhibitors and Coumarins

    NARCIS (Netherlands)

    Schalekamp, Tom; Klungel, Olaf H; Souverein, Patrick C; de Boer, Anthonius

    2008-01-01

    BACKGROUND: Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. Because use of selective serotonin reuptake inhibitors (SSRIs) is also associated with an increased risk of bleeding, we assessed the odds ratio (OR) of abnormal bleeding associated with

  5. The age-dependent effects of selective serotonin reuptake inhibitors in humans and rodents: A review.

    NARCIS (Netherlands)

    Olivier, J.D.A.; Blom, T.; Arentsen, T.; Homberg, J.R.

    2011-01-01

    The selective serotonin reuptake inhibitor (SSRI) Prozac(R) (fluoxetine) is widely prescribed for the treatment of depression and anxiety-related disorders. While extensive research has established that fluoxetine is safe for adults, safety is not guaranteed for (unborn) children and adolescents.

  6. Anhedonia Predicts Poorer Recovery among Youth with Selective Serotonin Reuptake Inhibitor Treatment-Resistant Depression

    Science.gov (United States)

    McMakin, Dana L.; Olino, Thomas M.; Porta, Giovanna; Dietz, Laura J.; Emslie, Graham; Clarke, Gregory; Wagner, Karen Dineen; Asarnow, Joan R.; Ryan, Neal D.; Birmaher, Boris; Shamseddeen, Wael; Mayes, Taryn; Kennard, Betsy; Spirito, Anthony; Keller, Martin; Lynch, Frances L.; Dickerson, John F.; Brent, David A.

    2012-01-01

    Objective: To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment. Method: The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication…

  7. Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies

    DEFF Research Database (Denmark)

    Wemakor, Anthony; Casson, Karen; Garne, Ester

    2015-01-01

    Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association be...

  8. Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction in Adolescents: A Review.

    Science.gov (United States)

    Scharko, Alexander M.

    2004-01-01

    Objective: To review the existing literature on selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction in adolescents. Method: A literature review of SSRI-induced adverse effects in adolescents focusing on sexual dysfunction was done. Nonsexual SSRI-induced adverse effects were compared in adult and pediatric populations.…

  9. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review

    NARCIS (Netherlands)

    Ruhé, Henricus G.; Huyser, Jochanan; Swinkels, Jan A.; Schene, Aart H.

    2006-01-01

    OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are frequently used as a first antidepressant for major depressive disorder but have response rates of 50% to 60% in daily practice. For patients with insufficient response to SSRIs, switching is often applied. This article aims to

  10. The market dynamics of selective serotonin re-uptake inhibitors: a ...

    African Journals Online (AJOL)

    re-uptake inhibitors: a private sector study in South Africa. Afri Health ... the public and private sectors to reduce medicine costs, and increase ... Fig 1: Comparison between the market volume of generics vs. originators for the period June 2009 ...

  11. In Utero Exposure to Selective Serotonin Reuptake Inhibitors and Risk for Autism Spectrum Disorder

    Science.gov (United States)

    Gidaya, Nicole B.; Lee, Brian K.; Burstyn, Igor; Yudell, Michael; Mortensen, Erik L.; Newschaffer, Craig J.

    2014-01-01

    We investigated whether there is an association between increased risk for autism spectrum disorders (ASD) and selective serotonin reuptake inhibitors (SSRIs) used during pregnancy. This study used Denmark's health and population registers to obtain information regarding prescription drugs, ASD diagnosis, and health and socioeconomic status. There…

  12. Increased Frequency of Encopresis in a Child Diagnosed With Attention Deficit/Hyperactivity Disorder and Encopresis After Atomoxetine Use: A Case Report.

    Science.gov (United States)

    Yektaş, Çiğdem; Cansiz, Mehmet Akif; Tufan, Ali Evren

    2016-01-01

    Attention deficit hyperactivity disorder (ADHD) is among the most frequently reported coexisting psychiatric conditions in children with encopresis. Some case reports state that atomoxetine-a selective presynaptic norepinephrine reuptake inhibitor-approved for treatment of ADHD is also effective in the treatment of coexisting encopresis. Contrasting those reports, here we present a case diagnosed with ADHD and secondary encopresis without constipation whose encopretic symptoms increased after atomoxetine treatment and discuss possible mechanisms.

  13. Serotonin reuptake inhibitors and bone health: A review of clinical studies and plausible mechanisms

    Directory of Open Access Journals (Sweden)

    Ravisha Wadhwa

    2017-06-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are currently the treatment of choice in depression and constitute major portion of prescription in depressive patients. The role of serotonin receptors in bone is emerging, raising certain questions regarding the effect of blockade of serotonin reuptake in the bone metabolism. Clinical studies have reported an association of SSRI antidepressants which with increase in fracture and decrease in bone mineral density. This review focus on recent evidence that evaluate the association of SSRIs with the risk of fracture and bone mineral density and also the probable mechanisms that might be involved in such effects.

  14. Atomoxetine Does Not Alter Cocaine Use in Cocaine Dependent Individuals: A Double Blind Randomized Trial

    Science.gov (United States)

    Middleton, Lisa S.; Wong, Conrad J.; Nuzzo, Paul A.; Campbell, Charles L.; Rush, Craig R.; Lofwall, Michelle R.

    2016-01-01

    Background Cocaine abuse continues to be a significant public health problem associated with morbidity and mortality. To date, no pharmacotherapeutic approach has proven effective for treating cocaine use disorders. Preclinical and clinical evidence suggests that noradrenergic activity may play a role in mediating some effects of cocaine and may be a rational target for treatment. Methods This double blind, placebo-controlled randomized, parallel group, 12-week outpatient clinical trial enrolled cocaine dependent individuals seeking treatment to examine the potential efficacy of the selective norepinephrine reuptake inhibitor, atomoxetine (80 mg/day; p.o.; n=25), compared to placebo (n=25). Subjects were initially stratified on cocaine use (atomoxetine and placebo groups (X2=0.2, p=.66; OR=0.89 [95% CI 0.41 – 1.74). Atomoxetine was generally well tolerated in this population. Conclusions These data provide no support for the utility of atomoxetine in the treatment of cocaine dependence. PMID:23200303

  15. Are Selective Serotonin Reuptake Inhibitors Safe for Drivers? What is the Evidence?

    OpenAIRE

    Ravera, Silvia; Ramaekers, Johannes G.; de Jong-van den Berg, Lolkje T. W.; de Gier, Johan J.; de Jong-van den Berg, [No Value

    2012-01-01

    Background: Selective serotonin reuptake inhibitors (SSRIs) are widely used medications to treat several psychiatric diseases and, above all, depression. They seem to be as effective as older antidepressants but have a different adverse effect profile. Despite their favorable safety profile, little is known about their influence on traffic safety. Objective: To conduct a literature review to summarize the current evidence on the role of SSRIs in traffic safety, particularly concerning undesir...

  16. The effect of antenatal depression and selective serotonin reuptake inhibitor treatment on nerve growth factor signaling in human placenta

    NARCIS (Netherlands)

    Kaihola, Helena; Olivier, Jocelien; Poromaa, Inger Sundström; Åkerud, Helena

    2015-01-01

    Depressive symptoms during pregnancy are common and may have impact on the developing child. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant treatment, but unfortunately, these treatments can also negatively affect the behavioral development and health of a

  17. Effects of tryptophan depletion on selective serotonin reuptake inhibitor-remitted patients with obsessive compulsive disorder.

    Science.gov (United States)

    Hood, Sean D; Broyd, Annabel; Robinson, Hayley; Lee, Jessica; Hudaib, Abdul-Rahman; Hince, Dana A

    2017-12-01

    Serotonergic antidepressants are first-line medication therapies for obsessive-compulsive disorder, however it is not known if synaptic serotonin availability is important for selective serotonin reuptake inhibitor efficacy. The present study tested the hypothesis that temporary reduction in central serotonin transmission, through acute tryptophan depletion, would result in an increase in anxiety in selective serotonin reuptake inhibitor-remitted obsessive-compulsive disorder patients. Eight patients (four males) with obsessive-compulsive disorder who showed sustained clinical improvement with selective serotonin reuptake inhibitor treatment underwent acute tryptophan depletion in a randomized, double-blind, placebo-controlled, within-subjects design, over two days one week apart. Five hours after consumption of the depleting/sham drink the participants performed a personalized obsessive-compulsive disorder symptom exposure task. Psychological responses were measured using the Spielberger State Anxiety Inventory, Yale-Brown Obsessive Compulsive Scale and Visual Analogue Scales. Free plasma tryptophan to large neutral amino acid ratio decreased by 93% on the depletion day and decreased by 1% on the sham day, as anticipated. Psychological rating scores as measured by Visual Analogue Scale showed a significant decrease in perceived control and increase in interfering thoughts at the time of provocation on the depletion day but not on the sham day. A measure of convergent validity, namely Visual Analogue Scale Similar to past, was significantly higher at the time of provocation on both the depletion and sham days. Both the depletion and time of provocation scores for Visual Analogue Scale Anxiety, Spielberger State Anxiety Inventory, Yale-Brown Obsessive Compulsive Scale and blood pressure were not significant. Acute tryptophan depletion caused a significant decrease in perceived control and increase in interfering thoughts at the time of provocation. Acute tryptophan

  18. Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat

    Science.gov (United States)

    Jackson, Helen C; Needham, Andrew M; Hutchins, Lisa J; Mazurkiewicz, Sarah E; Heal, David J

    1997-01-01

    The effects of the potent 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI), sibutramine, on the cumulative food intake of freely-feeding male Sprague-Dawley rats during an 8 h dark period were investigated and compared to those of the selective 5-HT reuptake inhibitor (selective serotonin reuptake inhibitor, SSRI), fluoxetine; the selective noradrenaline reuptake inhibitor, nisoxetine; the 5-HT and noradrenaline reuptake inhibitors, venlafaxine and duloxetine; and the 5-HT releaser and 5-HT reuptake inhibitor, (+)-fenfluramine. Sibutramine (3 and 10 mg kg−1, p.o.) and (+)-fenfluramine (1 and 3 mg kg−1, p.o.) produced a significant, dose-dependent decrease in food intake over the 8 h dark period. These responses became apparent within the first 2 h following drug administration. Fluoxetine (3, 10 and 30 mg kg−1, p.o.), and nisoxetine (3, 10 and 30 mg kg−1, p.o.) had no significant effect on food intake during the 8 h dark period. However, a combination of fluoxetine and nisoxetine (30 mg kg−1, p.o., of each) significantly decreased food intake 2 and 8 h after drug administration. Venlafaxine (100 and 300 mg kg−1, p.o.) and duloxetine (30 mg kg−1, p.o.) also significantly decreased food intake in the 2 and 8 h following drug administration. The results of this study demonstrate that inhibition of 5-HT and noradrenaline reuptake by sibutramine, venlafaxine, duloxetine, or by a combination of fluoxetine and nisoxetine, markedly reduces food intake in freely-feeding rats and suggest that this may be a novel approach for the treatment of obesity. PMID:9283714

  19. Inhibitors of serotonin reuptake and specific imipramine binding in human blood plasma

    International Nuclear Information System (INIS)

    Brusov, O.S.; Fomenko, A.M.; Katasonov, A.B.; Lidemann, R.R.

    1985-01-01

    This paper describes a method of extraction of endogenous inhibitors of specific IMI binding and of 5-HT reuptake, from human blood plasma and the heterogeneity of these compounds is demonstrated. Specific binding was determined as the difference between binding of 3 H-IMI in the absence and in the presence of 50 microM IMI. Under these conditions, specific binding amounted to 70-80% of total binding of 3 H-IMI. It is shown that extract obtained from human blood contains a material which inhibits dose-dependently both 5-HT reuptake and specific binding of 3 H-IMI. Gel-chromatography of extracts of human blood plasma on Biogel P-2 is also shown

  20. Comparative efficacy and safety of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors in older adults: a network meta-analysis.

    Science.gov (United States)

    Thorlund, Kristian; Druyts, Eric; Wu, Ping; Balijepalli, Chakrapani; Keohane, Denis; Mills, Edward

    2015-05-01

    To establish the comparative efficacy and safety of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors in older adults using the network meta-analysis approach. Systematic review and network meta-analysis. Individuals aged 60 and older. Data on partial response (defined as at least 50% reduction in depression score from baseline) and safety (dizziness, vertigo, syncope, falls, loss of consciousness) were extracted. A Bayesian network meta-analysis was performed on the efficacy and safety outcomes, and relative risks (RRs) with 95% credible intervals (CrIs) were produced. Fifteen randomized controlled trials were eligible for inclusion in the analysis. Citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, fluoxetine, and sertraline were represented. Reporting on partial response and dizziness was sufficient to conduct a network meta-analysis. Reporting on other outcomes was sparse. For partial response, sertraline (RR=1.28), paroxetine (RR=1.48), and duloxetine (RR=1.62) were significantly better than placebo. The remaining interventions yielded RRs lower than 1.20. For dizziness, duloxetine (RR=3.18) and venlafaxine (RR=2.94) were statistically significantly worse than placebo. Compared with placebo, sertraline had the lowest RR for dizziness (1.14) and fluoxetine the second lowest (1.31). Citalopram, escitalopram, and paroxetine all had RRs between 1.4 and 1.7. There was clear evidence of the effectiveness of sertraline, paroxetine, and duloxetine. There also appears to be a hierarchy of safety associated with the different antidepressants, although there appears to be a dearth of reporting of safety outcomes. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.

  1. Use of selective-serotonin reuptake inhibitors and platelet aggregation inhibitors among individuals with co-occurring atherosclerotic cardiovascular disease and depression or anxiety

    Directory of Open Access Journals (Sweden)

    J Douglas Thornton

    2016-12-01

    Full Text Available Objective: Medications commonly used to treat heart disease, anxiety, and depression can interact resulting in an increased risk of bleeding, warranting a cautious approach in medical decision making. This retrospective, descriptive study examined the prevalence and the factors associated with the use of both selective-serotonin reuptake inhibitor and platelet aggregation inhibitor among individuals with co-occurring atherosclerotic cardiovascular disease and anxiety or depression. Methods: Respondents aged 22 years and older, alive throughout the study period, and diagnosed with co-occurring atherosclerotic cardiovascular disease and anxiety or depression (n = 1507 in years 2007 through 2013 of the Medical Expenditures Panel Survey were included. The use of treatment was grouped as follows: selective-serotonin reuptake inhibitor and platelet aggregation inhibitor, selective-serotonin reuptake inhibitor or platelet aggregation inhibitor, and neither selective-serotonin reuptake inhibitor nor platelet aggregation inhibitor. Results: Overall, 16.5% used both selective-serotonin reuptake inhibitor and platelet aggregation inhibitor, 61.2% used selective-serotonin reuptake inhibitor or platelet aggregation inhibitor, and 22.3% used neither selective-serotonin reuptake inhibitor nor platelet aggregation inhibitor. Respondents aged over 65 years (adjusted odds ratio = 1.93 (95% confidence interval = 1.08–3.45 and having a diagnosis of diabetes (adjusted odds ratio = 1.63 (95% confidence interval = 1.15–2.31 and hypertension (adjusted odds ratio = 1.84 (95% confidence interval = 1.04–3.27 were more likely to be prescribed the combination. Conclusion: The drug interaction was prevalent in patients who are already at higher risk of health disparities and worse outcomes thus requiring vigilant evaluation.

  2. The Safety of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Research

    NARCIS (Netherlands)

    Reed, V.A.; Buitelaar, J.K.; Anand, E.; Day, K.A.; Treuer, T.; Upadhyaya, H.P.; Coghill, D.R.; Kryzhanovskaya, L.A.; Savill, N.C.

    2016-01-01

    Atomoxetine is a noradrenergic reuptake inhibitor prescribed for attention-deficit/hyperactivity disorder (ADHD) that first gained approval in the USA in 2002 and has been authorized in 97 countries worldwide. The aim of this paper is to comprehensively review publications that addressed one or more

  3. Improving Response Inhibition in Parkinson’s Disease with Atomoxetine

    Science.gov (United States)

    Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R.; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L.; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.; Rowe, James B.

    2015-01-01

    Background Dopaminergic drugs remain the mainstay of Parkinson’s disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. Methods This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Results Patients with Parkinson’s disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. Conclusions This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson’s disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson’s disease. PMID:24655598

  4. Improving response inhibition in Parkinson's disease with atomoxetine.

    Science.gov (United States)

    Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L; Regenthal, Ralf; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

    2015-04-15

    Dopaminergic drugs remain the mainstay of Parkinson's disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Patients with Parkinson's disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson's disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson's disease. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

  5. Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors.

    Science.gov (United States)

    Liu, Shuang; Zha, Congxiang; Nacro, Kassoum; Hu, Min; Cui, Wenge; Yang, Yuh-Lin; Bhatt, Ulhas; Sambandam, Aruna; Isherwood, Matthew; Yet, Larry; Herr, Michael T; Ebeltoft, Sarah; Hassler, Carla; Fleming, Linda; Pechulis, Anthony D; Payen-Fornicola, Anne; Holman, Nicholas; Milanowski, Dennis; Cotterill, Ian; Mozhaev, Vadim; Khmelnitsky, Yuri; Guzzo, Peter R; Sargent, Bruce J; Molino, Bruce F; Olson, Richard; King, Dalton; Lelas, Snjezana; Li, Yu-Wen; Johnson, Kim; Molski, Thaddeus; Orie, Anitra; Ng, Alicia; Haskell, Roy; Clarke, Wendy; Bertekap, Robert; O'Connell, Jonathan; Lodge, Nicholas; Sinz, Michael; Adams, Stephen; Zaczek, Robert; Macor, John E

    2014-07-10

    A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.

  6. A Concise Total Synthesis of (R)-Fluoxetine, a Potent and Selective Serotonin Reuptake Inhibitor

    OpenAIRE

    de Fátima, Ângelo; Lapis, Alexandre Augusto M.; Pilli, Ronaldo A.

    2005-01-01

    (R)-Fluoxetine, potent and selective serotonin reuptake inhibitor, has been synthesized in six steps, 50% overall yield and 99% ee from benzaldehyde via catalytic asymmetric allylation with Maruoka's catalyst. (R)-Fluoxetina, um inibidor potente e seletivo da recaptação da serotonina, foi sintetizada em seis etapas, 50% de rendimento total e 99% de excesso enantiomérico a partir do benzaldeído via alilação catalítica assimétrica empregando-se o sistema catalítico desenvolvido por Maruoka e...

  7. Maternal use of selective serotonin reuptake inhibitors and risk of miscarriage

    DEFF Research Database (Denmark)

    Johansen, Rie Laurine Rosenthal; Mortensen, Laust Hvas; Andersen, Anne-Marie Nybo

    2015-01-01

    -exposed pregnancies were characterised by an unhealthier maternal lifestyle and mental health profile than unexposed pregnancies, whereas no convincing differences were observed between pregnancies exposed to SSRIs during versus before pregnancy. Substantial disagreement was found between prescriptions and self......BACKGROUND: The use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy has been associated with miscarriage, but the association may be biased by maternal mental illness, lifestyle and exposure misclassification. METHODS: A register study on all pregnancies in Denmark between 1996......-reported use of SSRIs, but it did not affect the estimated hazard ratios. CONCLUSION: Confounding by indication and lifestyle in pregnancy may explain the association between SSRI use and miscarriage....

  8. Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition.

    Science.gov (United States)

    Yu, Guo; Li, Guo-Fu; Markowitz, John S

    2016-05-01

    Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children (≥6 years of age), adolescents, and adults. Its metabolism and disposition are fairly complex, and primarily governed by cytochrome P450 (CYP) 2D6 (CYP2D6), whose protein expression varies substantially from person to person, and by race and ethnicity because of genetic polymorphism. These differences can be substantial, resulting in 8-10-fold differences in atomoxetine exposure between CYP2D6 poor metabolizers and extensive metabolizers. In this review, we have attempted to revisit and analyze all published clinical pharmacokinetic data on atomoxetine inclusive of public access documents from the new drug application submitted to the United States Food and Drug Administration (FDA). The present review focuses on atomoxetine metabolism, disposition, and genetic polymorphisms of CYP2D6 as they specifically relate to atomoxetine, and provides an in-depth discussion of the fundamental pharmacokinetics of the drug including its absorption, distribution, metabolism, and excretion in pediatric and adult populations. Further, a summary of relationships between genetic variants of CYP2D6 and to some degree, CYP2C19, are provided with respect to atomoxetine plasma concentrations, central nervous system (CNS) pharmacokinetics, and associated clinical implications for pharmacotherapy. Lastly, dosage adjustments based on pharmacokinetic principles are discussed.

  9. Maternal use of selective serotonin reuptake inhibitors during pregnancy is associated with Hirschsprung's disease in newborns - a nationwide cohort study

    DEFF Research Database (Denmark)

    Nielsen, Sebastian Werngreen; Møller Ljungdalh, Pernille; Nielsen, Jan

    2017-01-01

    of the association between maternal use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and development of Hirschsprung's Disease in the newborn child. The study examined a nationwide, unselected cohort of children born in Denmark from 1 January 1996 until 12 March 2016 (n = 1,256,317). We...... of Hirschsprung's disease was 16/19.807 (0.08%) compared to 584/1.236.510 (0.05%) in the unexposed cohort. In women who redeemed a minimum of one prescription of selective serotonin reuptake inhibitors, the adjusted odds ratio for development of Hirschsprung's disease was 1.76 (95%CI: 1.07-2.92). In women who...

  10. Serotonin noradrenaline reuptake inhibitors: New hope for the treatment of chronic pain.

    Science.gov (United States)

    Delgado, Pedro L

    2006-01-01

    Depression and painful symptoms occur frequently together. Over 75% of depressed patients report painful symptoms such as headache, stomach pain, neck and back pain as well as non-specific generalized pain. In addition, World Health Organization data have shown that primary care patients with chronic pain have a four fold greater risk of becoming depressed than pain-free patients. Increasingly, pain is considered as an integral symptom of depression and there evidence to suggest that pain and depression may arise from a common neurobiological dysfunction. Serotonergic cell bodies, in the raphe nucleus, and noradrenergic cell bodies in the locus coeruleus send projections to various parts of the brain, where they are involved in the control of mood, movement, cognitive functioning and emotions. In addition both serotonergic and noradrenergic neurons project to the spinal cord. These descending pathways serve to inhibit input from the intestines, skeletal muscles and other sensory inputs. Usually, these inhibitory effects are modest, but in times of stress, in the interest of the survival of the individual, they can completely inhibit the input from painful stimuli. A dysfunction of the serotonergic and noradrenergic neurons can thus affect both the ascending and descending pathways resulting in the psychological symptoms of depression and somatic pain symptoms such as chronic pain, fibromyalgia, non-cardiac chest pain, or irritable bowel syndrome. In view of this, it is not surprising that tricyclic antidepressants have been a standard treatment of chronic pain for many years. In contrast and in spite of their improved tolerance, selective serotonin reuptake inhibitors do not appear to be particularly effective in the treatment of pain. Recently, a number of open and controlled trials with selective serotonin and noradrenaline reuptake inhibitors such as venlafaxine, milnacipran and duloxetine, suggest that these compounds may be more effective in relieving pain

  11. Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations

    DEFF Research Database (Denmark)

    Solem, Espen Victor Jimenez; Andersen, Jon Thor Trærup; Petersen, Morten

    2012-01-01

    Objectives:To analyse the relation between selective serotonin reuptake inhibitor (SSRI) use and major congenital malformations, with focus on malformations of the heart. DESIGN: Register-based retrospective nationwide cohort study, using the Danish Medical Birth Registry. SETTING: Denmark...... exposure during pregnancy. RESULTS: The authors identified 848¿786 pregnancies; 4183 were exposed to an SSRI throughout the first trimester and 806 pregnancies paused exposure during pregnancy. Risks of congenital malformations of the heart were similar for pregnancies exposed to an SSRI throughout...... the first trimester, adjusted OR 2.01 (95% CI 1.60 to 2.53), and for pregnancies with paused SSRI treatment during pregnancy, adjusted OR 1.85 (95% CI 1.07 to 3.20), p value for difference: 0.94. The authors found similar increased risks of specific congenital malformations of the heart for the individual...

  12. Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of congenital anomalies

    DEFF Research Database (Denmark)

    Wemakor, A.; Casson, K.; Garne, E.

    2015-01-01

    Objective / Background The Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants are widely prescribed in pregnancy, but there is evidence that they may cause congenital anomalies, particularly congenital heart defects (CHD). Objective: To determine the specificity of association between...... first trimester pregnancy exposure to individual SSRI and specific congenital anomalies (CAs). Methods Population-based case-malformed control study covering 3.3 million births from 12 EUROCAT registries 1995-2009. CAs included non-syndromic live births, fetal deaths and terminations of pregnancy......% confidence intervals (CI) were calculated adjusted for registry. Results SSRI use in first trimester pregnancy was associated with CHD overall (OR 1.38, 95 % CI 1.05-1.82, n=109); and with severe CHDs (OR 1.56, 95 % CI 1.03-2.38, n=29). Specific associations between SSRI and Tetralogy of Fallot (OR 3.36, 95...

  13. Possible role of selective serotonin reuptake inhibitor sertraline on oxidative stress responses.

    Science.gov (United States)

    Battal, D; Yalin, S; Eker, E D; Aktas, A; Sahin, N O; Cebo, M; Berköz, M

    2014-01-01

    The naphthylamine derivative sertraline is a potent and selective inhibitor of serotonin reuptake into presynaptic terminals and the most widely used that has been shown to have both antidepressant and antianxiety effects. In the present study the possible role of sertraline (acute and chronically doses) was evaluated on lipid peroxidation levels and antioxidant enzyme activities in plasma and brain tissues of (10, 40, 80 mg/kg) sertraline treated Wistar albino rats (n=48). Lipid peroxidation levels (MDA) of plasma and brain tissue increased in all acute and chronic sertraline treated rats (p Catalase (CAT) levels of plasma and brain tissue and paraoxonase (PON) levels of plasma decreased (p < 0.05) as compared with vehicle group. Based on the data, it can be concluded that high dose sertraline administration enhances oxidative stress. Therefore, dose adjustment in depression patients seems significant as it may help prevention of further prognosis of the diseases.

  14. Exposure to Selective Serotonin Reuptake Inhibitors in Early Pregnancy and the Risk of Miscarriage

    DEFF Research Database (Denmark)

    Andersen, Jon Thor Trærup; Andersen, Nadia Lyhne; Horwitz, Henrik

    2014-01-01

    OBJECTIVE: To investigate whether exposure to selective serotonin reuptake inhibitors (SSRIs) in early pregnancy is associated with miscarriage. METHODS: This was a nationwide cohort study identifying all registered pregnancies in Denmark from 1997 to 2010. All births were identified using...... the Medical Birth Registry, and all records of induced abortion or miscarriage were gathered from the National Hospital Register. Data on SSRI use were gathered from the National Prescription Register. Cox proportional hazard regression models were used to calculate the hazard of miscarriage in women exposed...... to an SSRI in early pregnancy and the hazard of miscarriage in women discontinuing treatment before pregnancy. RESULTS: We identified 1,279,840 pregnancies (911,569 births, 142,093 miscarriages, 226,178 induced abortions). Of the 22,884 exposed to an SSRI during the first 35 days of pregnancy, 12.6% (2...

  15. Great boast, small roast on effects of selective serotonin reuptake inhibitors

    DEFF Research Database (Denmark)

    Katakam, Kiran Kumar; Sethi, Naqash Javaid; Jakobsen, Janus Christian

    2018-01-01

    Our systematic review in BMC Psychiatry concluded that selective serotonin reuptake inhibitors (SSRIs) compared with placebo significantly increase the risk of serious adverse events (SAEs) in patients with major depression and the potential beneficial effects of SSRIs seem to be outweighed...... by the harms. Hieronymus et al. accused us of methodological inaccuracies and blatant errors. In their post-hoc analysis of our data, they reported that SSRIs only increase the risk of SAEs in elderly and seems safe for non-elderly patients. They also found our review misleading because our efficacy analyses...... were based on the 17-item Hamilton Depression Rating Scale; we included suboptimal SSRI doses; and we missed some 'pivotal trials'. We do not agree with Hieronymus et al. regarding several of the 'errors' they claim that we have made. However, we acknowledge that they have identified minor errors...

  16. QT interval prolongation in users of selective serotonin reuptake inhibitors in an elderly surgical population

    DEFF Research Database (Denmark)

    van Haelst, Ingrid M M; van Klei, Wilton A; Doodeman, Hieronymus J

    2014-01-01

    OBJECTIVE: To investigate the association between the use of a selective serotonin reuptake inhibitor (SSRI) and the occurrence of QT interval prolongation in an elderly surgical population. METHOD: A cross-sectional study was conducted among patients (> 60 years) scheduled for outpatient...... preanesthesia evaluation in the period 2007 until 2012. The index group included elderly users of an SSRI. The reference group of nonusers of antidepressants was matched to the index group on sex and year of scheduled surgery (ratio, 1:1). The primary outcome was the occurrence of QT interval prolongation shown...... on electrocardiogram. The QT interval was corrected for heart rate (QTc interval). The secondary outcome was the duration of the QTc interval. The outcomes were adjusted for confounding by using regression techniques. RESULTS: The index and reference groups included 397 users of an SSRI and 397 nonusers, respectively...

  17. An Association Between Selective Serotonin Reuptake Inhibitor Use and Serious Upper Gastrointestinal Bleeding

    DEFF Research Database (Denmark)

    Dall, Michael; Schaffalitzky de Muckadell, Ove B; Lassen, Annmarie Touborg

    2009-01-01

    BACKGROUND & AIMS: In vitro studies have shown that selective serotonin reuptake inhibitors (SSRIs) inhibit platelet aggregation. It is controversial whether use of SSRIs is a cause of clinically important bleeding; results from observational studies have been equivocal. METHODS: A population......-based case-control study was conducted in the county of Funen, Denmark. The 3652 cases all had a first discharge diagnosis of serious upper gastrointestinal bleeding (UGB) from 1995 to 2006. All cases were manually validated. Controls (n = 36,502), matched for age and sex, were selected by risk-set sampling....... Data on drug exposure and medical history were retrieved from a prescription database and the county's patient register. Confounders were controlled for by conditional logistic regression and the case-crossover design. RESULTS: The adjusted odds ratio (OR) of UGB among current, recent, and past users...

  18. Death and dependence: current controversies over the selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Nutt, David J

    2003-12-01

    Recent years have seen a considerable media interest in the adverse effects of the selective serotonin reuptake inhibitors (SSRIs). This has led to claims that these antidepressants may lead to suicide and homicide and that they cause dependence or even addiction. Such claims have caused great concerns to many patients and have confused doctors in both primary care and psychiatric practice. In this article I review the basis of these claims and show that many seem to emerge from the misinterpretation of evidence and the use of imprecise definitions. Although the SSRIs are not free of problems they compare very favourably with other antidepressants and other classes of psychotropic drugs. There is no evidence they are addictive in the formal sense of leading to a drug dependence syndrome. Some suggestions on the way these issues can be more precisely defined and studied in future are given.

  19. Interferon and ribavarin associated depression in hcv patients and role of selective serotonin reuptake inhibitors

    International Nuclear Information System (INIS)

    Bashir, K.; Hussain, C.A.; Amer, K.

    2013-01-01

    Objective: To determine the frequency and severity of depression associated with antiviral therapy of Hepatitis C Virus (HCV) infection and effect of selective serotonin reuptake Inhibitors (SSRIs) to treat these depressive symptoms. Type of Study: Observational Analytical study. Place of Study and Duration: The study was conducted at Psychiatry, Medicine and Pathology department of Combined Military Hospital Sialkot Pakistan from February 2009 to July 2010. Subjects and Methods: All the patients in this study were suffering from HCV infection and were managed with Interferon (3 m.i.u. s/c thrice weekly) and Cap Ribavirin (400 mg bid) for six months. Patients were assessed by Hospital Anxiety and Depression Scale (HADS) - Urdu Version and Beck's Depressive Inventory (BDI) Scores after twelve weeks of antiviral therapy. Depressed patients were managed with selective serotonin reuptake inhibitors (SSRIs) for six weeks and again evaluated on HADS and BDI Scores. Response to SSRIs was defined as complete response, partial response and no response. Results: A total of 105 patients were studied out of which 75 were male and 30 were female with mean age 29.4 years. Out of these 54 (51.43%) patients developed depression and this tendency to develop depression was not related with the age and sex of the patients. The mean HADS and BDI scores before and after treatments with SSRIs were compared for significance and it was quite significant. There was not a single patient who did not show response to SSRIs. Conclusion: Depression is frequently associated with antiviral therapy of HCV RNA viraemia with interferon and SSRIs have proved an effective and safe remedy in these patients. (author)

  20. Diminished Neural Processing of Aversive and Rewarding Stimuli During Selective Serotonin Reuptake Inhibitor Treatment

    Science.gov (United States)

    McCabe, Ciara; Mishor, Zevic; Cowen, Philip J.; Harmer, Catherine J.

    2010-01-01

    Background Selective serotonin reuptake inhibitors (SSRIs) are popular medications for anxiety and depression, but their effectiveness, particularly in patients with prominent symptoms of loss of motivation and pleasure, has been questioned. There are few studies of the effect of SSRIs on neural reward mechanisms in humans. Methods We studied 45 healthy participants who were randomly allocated to receive the SSRI citalopram, the noradrenaline reuptake inhibitor reboxetine, or placebo for 7 days in a double-blind, parallel group design. We used functional magnetic resonance imaging to measure the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (sight of moldy strawberries and/or an unpleasant strawberry taste) on the final day of drug treatment. Results Citalopram reduced activation to the chocolate stimuli in the ventral striatum and the ventral medial/orbitofrontal cortex. In contrast, reboxetine did not suppress ventral striatal activity and in fact increased neural responses within medial orbitofrontal cortex to reward. Citalopram also decreased neural responses to the aversive stimuli conditions in key “punishment” areas such as the lateral orbitofrontal cortex. Reboxetine produced a similar, although weaker effect. Conclusions Our findings are the first to show that treatment with SSRIs can diminish the neural processing of both rewarding and aversive stimuli. The ability of SSRIs to decrease neural responses to reward might underlie the questioned efficacy of SSRIs in depressive conditions characterized by decreased motivation and anhedonia and could also account for the experience of emotional blunting described by some patients during SSRI treatment. PMID:20034615

  1. Early Neurological Outcome of Young Infants Exposed to Selective Serotonin Reuptake Inhibitors during Pregnancy : Results from the Observational SMOK Study

    NARCIS (Netherlands)

    de Vries, N.K.S.; van der Veere, C.N.; Reijneveld, S.A.; Bos, A.F.

    2013-01-01

    Background: Use of selective serotonin reuptake inhibitors (SSRI) during pregnancy is common while the effect on the infant's neurological outcome is unknown. Our objective was to determine the effects of prenatal SSRI-exposure on the infants' neurological functioning, adjusted for maternal mental

  2. Treatment of Selective Serotonin Reuptake Inhibitor-Resistant Depression in Adolescents: Predictors and Moderators of Treatment Response

    Science.gov (United States)

    Asarnow, Joan Rosenbaum; Emslie, Graham; Clarke, Greg; Wagner, Karen Dineen; Spirito, Anthony; Vitiello, Benedetto; Iyengar, Satish; Shamseddeen, Wael; Ritz, Louise; Birmaher, Boris; Ryan, Neal; Kennard, Betsy; Mayes, Taryn; DeBar, Lynn; McCracken, James; Strober, Michael; Suddath, Robert; Leonard, Henrietta; Porta, Giovanna; Keller, Martin; Brent, David

    2009-01-01

    Adolescents who did not improve with Selective Serotonin Reuptake Inhibitor (SSRI) were provided an alternative SSRI plus cognitive-behavioral therapy (CBT). The superiority of the CBT/combined treatment as compared to medication alone is more evident in youths who had more comorbid disorders, no abuse history, and lower hopelessness.

  3. Risk of Suicidal Events With Atomoxetine Compared to Stimulant Treatment: A Cohort Study.

    Science.gov (United States)

    Linden, Stephan; Bussing, Regina; Kubilis, Paul; Gerhard, Tobias; Segal, Richard; Shuster, Jonathan J; Winterstein, Almut G

    2016-05-01

    Antidepressant effects on increased suicidality in children have raised public concern in recent years. Approved in 2002 for attention-deficit/hyperactivity disorder treatment, the selective noradrenalin-reuptake-inhibitor atomoxetine was initially investigated for the treatment of depression. In post-hoc analyses of clinical trial data, atomoxetine has been associated with an increased risk of suicidal ideation in children and adolescents. We analyzed whether the observed increased risk of suicidal ideation in clinical trials translates into an increased risk of suicidal events in pediatric patients treated with atomoxetine compared with stimulants in 26 Medicaid programs. Employing a retrospective cohort design, we used propensity score-adjusted Cox proportional hazard models to evaluate the risk of suicide and suicide attempt in pediatric patients initiating treatment with atomoxetine compared with stimulants from 2002 to 2006. The first-line treatment cohort included 279 315 patients. During the first year of follow-up, the adjusted hazard ratio for current atomoxetine use compared with current stimulant use was 0.95 (95% CI 0.47-1.92, P = .88). The second-line treatment cohort included 220 215 patients. During the first year of follow-up, the adjusted hazard ratio for current atomoxetine use compared with current stimulant use was 0.71 (95% CI 0.30-1.67, P = .43). First- and second-line treatment of youths age 5 to 18 with atomoxetine compared with stimulants was not significantly associated with an increased risk of suicidal events. The low incidence of suicide and suicide attempt resulted in wide confidence intervals and did not allow stratified analysis of high-risk groups or assessment of suicidal risk associated with long-term use of atomoxetine. Copyright © 2016 by the American Academy of Pediatrics.

  4. Placebo-controlled trial of atomoxetine for weight reduction in people with schizophrenia treated with clozapine or olanzapine.

    Science.gov (United States)

    Ball, M Patricia; Warren, Kimberly R; Feldman, Stephanie; McMahon, Robert P; Kelly, Deanna L; Buchanan, Robert W

    2011-04-01

    In recent years, several pharmacological and psychosocial interventions have examined ways to prevent or treat weight gain in people receiving second-generation antipsychotics. While there has been some success, in general, results have not been compelling. Atomoxetine is a selective norepinepherine reuptake inhibitor found to be associated with appetite suppression. Therefore, we examined whether atomoxetine may be of benefit for those who have gained weight on either clozapine or olanzapine. The study was a double-blind, placebo-controlled trial. All participants received the same psychosocial platform: a structured support and exercise group. People with schizophrenia or schizoaffective disorder, on olanzapine or clozapine, who had gained at least 7% of their pre-clozapine or pre-olanzapine weight were eligible for a 24-week, randomized, parallel group, double-blind comparison of adjunctive atomoxetine or placebo. Thirty-seven participants (20 atomoxetine, 17 placebo) were randomized and 26 participants (14 atomoxetine, 12 placebo; 70.2%) completed the study. There were no significant group differences in baseline BMI (atomoxetine: 34.5±4.9; placebo: 35.7±7.0) or weight (atomoxetine: 102.2±15.7 kg; placebo: 104.3±17.5 kg). Both treatment groups showed modest, not significant, trends in weight loss, averaging about 2 kg. Gender or baseline antipsychotic treatment did not modify treatment effects on weight. Secondary outcomes included neuropsychological assessments, symptom assessments (BPRS, SANS) and safety assessments. Of these, only the group difference in Gordon distractibility test scores was statistically significant and favored treatment with atomoxetine. Atomoxetine is not effective for weight loss in this population, but both olanzapine and clozapine participants can lose weight with structured group support and exercise.

  5. Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity

    International Nuclear Information System (INIS)

    Tiradentes, R.V.; Pires, J.G.P.; Silva, N.F.; Ramage, A.G.; Santuzzi, C.H.; Futuro, H.A. Neto

    2014-01-01

    Serotonergic mechanisms have an important function in the central control of circulation. Here, the acute effects of three selective serotonin (5-HT) reuptake inhibitors (SSRIs) on autonomic and cardiorespiratory variables were measured in rats. Although SSRIs require 2-3 weeks to achieve their full antidepressant effects, it has been shown that they cause an immediate inhibition of 5-HT reuptake. Seventy male Wistar rats were anesthetized with urethane and instrumented to record blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and respiratory frequency. At lower doses, the acute cardiovascular effects of fluoxetine, paroxetine and sertraline administered intravenously were insignificant and variable. At middle and higher doses, a general pattern was observed, with significant reductions in sympathetic nerve activity. At 10 min, fluoxetine (3 and 10 mg/kg) reduced RSNA by -33±4.7 and -31±5.4%, respectively, without changes in blood pressure; 3 and 10 mg/kg paroxetine reduced RSNA by -35±5.4 and -31±5.5%, respectively, with an increase in blood pressure +26.3±2.5; 3 mg/kg sertraline reduced RSNA by -59.4±8.6%, without changes in blood pressure. Sympathoinhibition began 5 min after injection and lasted approximately 30 min. For fluoxetine and sertraline, but not paroxetine, there was a reduction in heart rate that was nearly parallel to the sympathoinhibition. The effect of these drugs on the other variables was insignificant. In conclusion, acute peripheral administration of SSRIs caused early autonomic cardiovascular effects, particularly sympathoinhibition, as measured by RSNA. Although a peripheral action cannot be ruled out, such effects are presumably mostly central

  6. Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity

    Energy Technology Data Exchange (ETDEWEB)

    Tiradentes, R.V. [Departamento de Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Centro Universitário do Espírito Santo, Colatina, ES (Brazil); Pires, J.G.P. [Centro Universitário do Espírito Santo, Colatina, ES (Brazil); Escola de Medicina da Empresa Brasileira de Ensino, Vitória, ES (Brazil); Silva, N.F. [Departamento de Morfologia, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Ramage, A.G. [Department of Neuroscience, Physiology and Pharmacology, University College London, London (United Kingdom); Santuzzi, C.H. [Departamento de Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Centro Universitário do Espírito Santo, Colatina, ES (Brazil); Futuro, H.A. Neto [Escola de Medicina da Empresa Brasileira de Ensino, Vitória, ES (Brazil); Departamento de Morfologia, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Escola Superior de Ciências da Saúde, Santa Casa de Misericórdia de Vitória, Vitória, ES (Brazil)

    2014-05-30

    Serotonergic mechanisms have an important function in the central control of circulation. Here, the acute effects of three selective serotonin (5-HT) reuptake inhibitors (SSRIs) on autonomic and cardiorespiratory variables were measured in rats. Although SSRIs require 2-3 weeks to achieve their full antidepressant effects, it has been shown that they cause an immediate inhibition of 5-HT reuptake. Seventy male Wistar rats were anesthetized with urethane and instrumented to record blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and respiratory frequency. At lower doses, the acute cardiovascular effects of fluoxetine, paroxetine and sertraline administered intravenously were insignificant and variable. At middle and higher doses, a general pattern was observed, with significant reductions in sympathetic nerve activity. At 10 min, fluoxetine (3 and 10 mg/kg) reduced RSNA by -33±4.7 and -31±5.4%, respectively, without changes in blood pressure; 3 and 10 mg/kg paroxetine reduced RSNA by -35±5.4 and -31±5.5%, respectively, with an increase in blood pressure +26.3±2.5; 3 mg/kg sertraline reduced RSNA by -59.4±8.6%, without changes in blood pressure. Sympathoinhibition began 5 min after injection and lasted approximately 30 min. For fluoxetine and sertraline, but not paroxetine, there was a reduction in heart rate that was nearly parallel to the sympathoinhibition. The effect of these drugs on the other variables was insignificant. In conclusion, acute peripheral administration of SSRIs caused early autonomic cardiovascular effects, particularly sympathoinhibition, as measured by RSNA. Although a peripheral action cannot be ruled out, such effects are presumably mostly central.

  7. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults.

    Science.gov (United States)

    Banzi, Rita; Cusi, Cristina; Randazzo, Concetta; Sterzi, Roberto; Tedesco, Dario; Moja, Lorenzo

    2015-05-01

    This is an updated version of the Cochrane review published in 2005 on selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headache. The original review has been split in two parts and this review now only regards tension-type headache prevention. Another updated review covers migraine. Tension-type headache is the second most common disorder worldwide and has high social and economic relevance. As serotonin and other neurotransmitters may have a role in pain mechanisms, SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been evaluated for the prevention of tension-type headache. To determine the efficacy and tolerability of SSRIs and SNRIs compared to placebo and other active interventions in the prevention of episodic and chronic tension-type headache in adults. For the original review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2003, Issue 4), MEDLINE (1966 to January 2004), EMBASE (1994 to May 2003), and Headache Quarterly (1990 to 2003). For this update, we revised the original search strategy to reflect the broader type of intervention (SSRIs and SNRIs). We searched CENTRAL (2014, Issue 10) on the Cochrane Library, MEDLINE (1946 to November 2014), EMBASE (1980 to November 2014), and PsycINFO (1987 to November 2014). We also checked the reference lists of retrieved articles and searched trial registries for ongoing trials. We included randomised controlled trials comparing SSRIs or SNRIs with any type of control intervention in participants 18 years and older, of either sex, with tension-type headache. Two authors independently extracted data (headache frequency, index, intensity, and duration; use of symptomatic/analgesic medication; quality of life; and withdrawals) and assessed the risk of bias of trials. The primary outcome is tension-type headache frequency, measured by the number of headache attacks or the number of days with headache per evaluation period. The original

  8. Atomoxetine treatment for nicotine withdrawal: a pilot double-blind, placebo-controlled, fixed-dose study in adult smokers

    Directory of Open Access Journals (Sweden)

    Silverstone Peter H

    2012-03-01

    Full Text Available Abstract Background Many effective treatments for nicotine addiction inhibit noradrenaline reuptake. Three recent studies have suggested that another noradrenaline reuptake inhibitor, atomoxetine, may reduce smoking behaviors. Methods The present double-blind, placebo-controlled, fixed-dose study was carried out over 21 days during which administration of 40 mg atomoxetine was compared to placebo in 17 individuals. Of these, nine were randomized to atomoxetine and eight to placebo. Baseline and weekly measurements were made using the Cigarette Dependence Scale (CDS, Cigarette Withdrawal Scale (CWS, Questionnaire of Smoking Urges (QSU, reported number of cigarettes smoked, and salivary cotinine levels. Results The study results showed that all those on placebo completed the study. In marked contrast, of the nine individuals who started on atomoxetine, five dropped out due to side effects. In a completer analysis there were statistically significant differences at 14 and 21 days in several measures between the atomoxetine and placebo groups, including CDS, CWS, QSU, number of cigarettes smoked (decreasing to less than two per day in the treatment group who completed the study, and a trend towards lower mean salivary cotinine levels. However, these differences were not seen in a last observation carried forward (LOCF analysis. Conclusions In summary, this is the first study to examine the use of atomoxetine in non-psychiatric adult smokers for a period of more than 7 days, and the findings suggest that atomoxetine might be a useful treatment for nicotine addiction. However, the dose used in the current study was too high to be tolerated by many adults, and a dose-finding study is required to determine the most appropriate dose for future studies of this potential treatment for smoking cessation.

  9. Reduction of intraspecific aggression in adult rats by neonatal treatment with a selective serotonin reuptake inhibitor

    Directory of Open Access Journals (Sweden)

    Manhães de Castro R.

    2001-01-01

    Full Text Available Most studies suggest that serotonin exerts an inhibitory control on the aggression process. According to experimental evidence, this amine also influences growth and development of the nervous tissue including serotoninergic neurons. Thus, the possibility exists that increased serotonin availability in young animals facilitates a long-lasting effect on aggressive responses. The present study aimed to investigate the aggressive behavior of adult rats (90-120 days treated from the 1st to the 19th postnatal day with citalopram (CIT, a selective serotonin reuptake inhibitor (20 mg/kg, sc, every 3 days. Aggressive behavior was induced by placing a pair of rats (matched by weight in a box (20 x 20 x 20 cm, and submitting them to a 20-min session of electric footshocks (five 1.6-mA - 2-s current pulses, separated by a 4-min intershock interval. When compared to the control group (rats treated for the same period with equivalent volumes of saline solution, the CIT group presented a 41.4% reduction in the duration of aggressive response. The results indicate that the repeated administration of CIT early in life reduces the aggressive behavior in adulthood and suggest that the increased brain serotoninergic activity could play a role in this effect.

  10. Does selective serotonin reuptake inhibitor (SSRI) fluoxetine affects mussel Mytilus galloprovincialis?

    International Nuclear Information System (INIS)

    Gonzalez-Rey, Maria; Bebianno, Maria João

    2013-01-01

    Fluoxetine (FLX) the active pharmaceutical ingredient (API) in Prozac ® is a widely prescribed psychoactive drug which ubiquitous occurrence in the aquatic environment is associated to a poor removal rate in waste-water treatment plant (WWTP) systems. This API acts as a selective serotonin reuptake inhibitor (SSRI) frequently reported to cause disrupting effects in non-target species. The objective of this study includes a multibiomarker response evaluation on mussel Mytilus galloprovincialis during two weeks exposure to 75 ng L −1 FLX assessing antioxidant enzymes activities – superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST); lipid peroxidation (LPO), acetylcholinesterase (AChE) neurotoxic response and endocrine disruption through alkali-labile phosphates (ALP) indirect measurement of vitellogenin-like proteins. Results show transient tissue-specific enzymatic responses and damage affecting mostly mussel gills. However, the clear ALP levels inhibition throughout time in both sex-differentiated gonads gives evidence to FLX reinforced action as an endocrine disruptor rather than an oxidative or neurotoxic inducer. - Highlights: ► Short-time exposure of Mytilus galloprovincialis to antidepressant fluoxetine. ► Tissue-specific transient antioxidant enzymes activities alteration. ► Lipid peroxidation (LPO) induction in exposed-tissues. ► Acetylcholinesterase (AChE) activity upregulation in exposed gills. ► ALP levels downregulation in exposed sex-differentiated mussels. - Exposure to 75 ng L −1 antidepressant fluoxetine (FLX) induces tissue-specific multibiomarker responses alteration in mussel Mytilus galloprovincialis.

  11. Selective Serotonin Reuptake Inhibitors in Human Pregnancy: To Treat or Not to Treat?

    Directory of Open Access Journals (Sweden)

    Orna Diav-Citrin

    2012-01-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are increasingly prescribed during pregnancy. The purpose of the present paper is to summarize and evaluate the current evidence for the risk/benefit analysis of SSRI use in human pregnancy. The literature has been inconsistent. Although most studies have not shown an increase in the overall risk of major malformations, several studies have suggested that SSRIs may be associated with a small increased risk for cardiovascular malformations. Others have noted associations between SSRIs and specific types of rare major malformations. In some studies, there appears to be a small increased risk for miscarriages, which may be associated with the underlying maternal condition. Neonatal effects have been described in up to 30% of neonates exposed to SSRIs late in pregnancy. Persistent pulmonary hypertension of the newborn has also been described with an absolute risk of <1%. The risk associated with treatment discontinuation, for example, higher frequency of relapse and increased risk of preterm delivery, should also be considered. The overall benefit of treatment seems to outweigh the potential risks.

  12. Reviewing the serotonin reuptake inhibitors (SSRIs) footprint in the aquatic biota: Uptake, bioaccumulation and ecotoxicology

    International Nuclear Information System (INIS)

    a Comba, 3000-548 Coimbra (Portugal))" data-affiliation=" (REQUIMTE, Group of Bromatology, Pharmacognosy and Analytical Sciences, Faculty of Pharmacy, University of Coimbra, Polo III, Azinhaga de Sta Comba, 3000-548 Coimbra (Portugal))" >Silva, Liliana J.G.; a Comba, 3000-548 Coimbra (Portugal))" data-affiliation=" (REQUIMTE, Group of Bromatology, Pharmacognosy and Analytical Sciences, Faculty of Pharmacy, University of Coimbra, Polo III, Azinhaga de Sta Comba, 3000-548 Coimbra (Portugal))" >Pereira, André a Comba, 3000-548 Coimbra (Portugal))" data-affiliation=" (REQUIMTE, Group of Bromatology, Pharmacognosy and Analytical Sciences, Faculty of Pharmacy, University of Coimbra, Polo III, Azinhaga de Sta Comba, 3000-548 Coimbra (Portugal))" >M.P.T.; Meisel, Leonor M.; a Comba, 3000-548 Coimbra (Portugal))" data-affiliation=" (REQUIMTE, Group of Bromatology, Pharmacognosy and Analytical Sciences, Faculty of Pharmacy, University of Coimbra, Polo III, Azinhaga de Sta Comba, 3000-548 Coimbra (Portugal))" >Lino, Celeste M.; a Comba, 3000-548 Coimbra (Portugal))" data-affiliation=" (REQUIMTE, Group of Bromatology, Pharmacognosy and Analytical Sciences, Faculty of Pharmacy, University of Coimbra, Polo III, Azinhaga de Sta Comba, 3000-548 Coimbra (Portugal))" >Pena, Angelina

    2015-01-01

    Selective serotonin re-uptake inhibitors (SSRIs) antidepressants are amongst the most prescribed pharmaceutical active substances throughout the world. Their presence, already described in different environmental compartments such as wastewaters, surface, ground and drinking waters, and sediments, and their remarkable effects on non-target organisms justify the growing concern about these emerging environmental pollutants. A comprehensive review of the literature data with focus on their footprint in the aquatic biota, namely their uptake, bioaccumulation and both acute and chronic ecotoxicology is presented. Long-term multigenerational exposure studies, at environmental relevant concentrations and in mixtures of related compounds, such as oestrogenic endocrine disruptors, continue to be sparse and are imperative to better know their environmental impact. - Highlights: • Current knowledge of uptake and bioaccumulation of SSRIs. • Ecotoxicology and effects of SSRIs in the aquatic biota. • Identification of existing knowledge gaps. - A comprehensive review focussing SSRIs antidepressants footprint in the aquatic biota, namely their uptake, bioaccumulation, and both acute and chronic ecotoxicology is presented

  13. The selective serotonin reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and spatial reversal learning

    Science.gov (United States)

    Brown, Holden D.; Amodeo, Dionisio A.; Sweeney, John A.; Ragozzino, Michael E.

    2011-01-01

    Previous findings indicate treatment with a selective serotonin reuptake inhibitor (SSRI) facilitates behavioral flexibility when conditions require inhibition of a learned response pattern. The present experiment investigated whether acute treatment with the SSRI, escitalopram, affects behavioral flexibility when conditions require inhibition of a naturally-biased response pattern (elevated conflict test) and/or reversal of a learned response pattern (spatial reversal learning). An additional experiment was carried out to determine whether escitalopram, at doses that affected behavioral flexibility, also reduced anxiety as tested in the elevated plus-maze. In each experiment, Long-Evans rats received an intraperitoneal injection of either saline or escitalopram (0.03, 0.3 or 1.0 mg/kg) 30 minutes prior to behavioral testing. Escitalopram, at all doses tested, enhanced acquisition in the elevated conflict test, but did not affect performance in the elevated plus-maze. Escitalopram (0.3 and 1.0 mg/kg) did not alter acquisition of the spatial discrimination, but facilitated reversal learning. In the elevated conflict and spatial reversal learning test, escitalopram enhanced the ability to maintain the relevant strategy after being initially selected. The present findings suggest that enhancing serotonin transmission with a SSRI facilitates inhibitory processes when conditions require a shift away from either a naturally-biased response pattern or a learned choice pattern. PMID:22219222

  14. Social inequalities in suicide: the role of selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Clouston, Sean A P; Rubin, Marcie S; Colen, Cynthia G; Link, Bruce G

    2014-10-01

    We aimed to examine the relationship between socioeconomic status (SES) and suicide associated with the introduction and diffusion of selective serotonin reuptake inhibitors (SSRIs). Negative binomial regression was used to estimate county-level suicide rates among persons aged 25 years or older using death certificate data collated by the National Center for Health Statistics from 1968 to 2009; SES was measured using the decennial US Census. The National Health and Nutrition Examination Survey and the Medical Expenditure Panel Survey were used to measure SSRI use. Once SSRIs became available in 1988, a 1% increase in SSRI usage was associated with a 0.5% lower suicide rate. Prior to the introduction of SSRIs, SES was not related to suicide. However, with each 1% increase in SSRI use, a 1-standard deviation (SD) higher SES was associated with a 0.6% lower suicide rate. In 2009, persons living in counties with SES 1 SD above the national average were 13.6% less likely to commit suicide than those living in counties with SES 1 SD below the national average--a difference of 1.9/100,000 adults aged ≥25 years. Higher SSRI use was associated with lower suicide rates among US residents aged ≥25 years; however, SES inequalities modified the association between SSRI use and suicide. © The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Can a Selective Serotonin Reuptake Inhibitor Act as a Glutamatergic Modulator?

    Directory of Open Access Journals (Sweden)

    Marcos Emilio Frizzo, PhD

    2017-01-01

    Full Text Available Sertraline (Zoloft and fluoxetine (Prozac are selective serotonin reuptake inhibitors whose antidepressant mechanism of action is classically attributed to an elevation of the extracellular levels of serotonin in the synaptic cleft. However, the biological effects of these drugs seem to be more complex than their traditionally described mechanism of action. Among their actions is the inhibition of different types of Na+ and K+ channels, as well as of glutamate uptake activity. The clearance of extracellular glutamate is essential to maintain the central nervous system within physiological conditions, and this excitatory neurotransmitter is removed from the synaptic cleft by astrocyte transporters. This transport depends upon a hyperpolarized membrane potential in astrocytes that is mainly maintained by Kir4.1 K+ channels. The impairment of the Kir4.1 channel activity reduces driving force for the glutamate transporter, resulting in an accumulation of extracellular glutamate. It has been shown that sertraline and fluoxetine inhibit Kir4.1 K+ channels. Recently, we demonstrated that sertraline reduces glutamate uptake in human platelets, which contain a high-affinity Na+-dependent glutamate uptake system, with kinetic and pharmacological properties similar to astrocytes in the central nervous system. Considering these similarities between human platelets and astrocytes, one might ask if sertraline could potentially reduce glutamate clearance in the synaptic cleft and consequently modulate glutamatergic transmission. This possibility merits investigation, since it may provide additional information regarding the mechanism of action and perhaps the side effects of these antidepressants.

  16. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy.

    LENUS (Irish Health Repository)

    O'Brien, Sinead M

    2012-02-03

    OBJECTIVE: Approximately 30% of patients with depression fail to respond to a selective serotonin reuptake inhibitor (SSRI). Few studies have attempted to define these patients from a biological perspective. Studies suggest that overall patients with depression show increased production of proinflammatory cytokines. We examined pro- and anti-inflammatory cytokine levels in patients who were SSRI resistant. METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in DSM-1V major depressives who were SSRI resistant, in formerly SSRI resistant patients currently euthymic and in healthy controls. RESULTS: Patients with SSRI-resistant depression had significantly higher production of the pro-inflammatory cytokines IL-6 (p=0.01) and TNF-alpha (p=0.004) compared to normal controls. Euthymic patients who were formerly SSRI resistant had proinflammatory cytokine levels which were similar to the healthy subject group. Anti-inflammatory cytokine levels did not differ across the 3 groups. CONCLUSION: Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery.

  17. The effects of maternal depression and maternal selective serotonin reuptake inhibitor exposure on the offspring

    Directory of Open Access Journals (Sweden)

    Jocelien DA Olivier

    2013-05-01

    Full Text Available It has been estimated that 20% of pregnant women suffer from depression and it is well documented that maternal depression can have long-lasting effects on the child. Currently, common treatment for maternal depression has been the selective serotonin reuptake inhibitor medications (SSRIs which are used by 2-3% of pregnant women in the Nordic countries and by up to 10% of pregnant women in the United States. Antidepressants cross the placenta and are transferred to the fetus, thus, the question arises as to whether children of women taking antidepressants are at risk for altered neurodevelopmental outcomes and, if so, whether the risks are due to SSRI medication exposure or to the underlying maternal depression. This review considers the effects of maternal depression and SSRI exposure on offspring development in both clinical and preclinical populations. As it is impossible in humans to study the effects of SSRIs without taking into account the possible underlying effects of maternal depression (healthy pregnant women do not take SSRIs, animal models are of great value. For example, rodents can be used to determine the effects of maternal depression and/or perinatal SSRI exposure on offspring outcomes. Unraveling the joint (or separate effects of maternal depression and SSRI exposure will provide more insights into the risks or benefits of SSRI exposure during gestation and will help women make informed decisions about using SSRIs during pregnancy.

  18. An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish.

    Science.gov (United States)

    McDonald, M Danielle

    2017-07-01

    Pharmaceuticals and personal care products (PPCPs) are found in measureable quantities within the aquatic environment. Selective serotonin reuptake inhibitor (SSRI) antidepressants are one class of pharmaceutical compound that has received a lot of attention. Consistent with most PPCPs, the pharmacokinetics and physiological impacts of SSRI treatment have been well-studied in small mammals and humans and this, combined with the evolutionary conservation of the serotonergic system across vertebrates, allows for the read-across of known SSRI effects in mammals to potential SSRI impacts on aquatic organisms. Using an Adverse Outcome Pathway (AOP) framework, this review examines the similarities and differences between the mammalian and teleost fish SSRI target, the serotonin transporter (SERT; SLC6A4), and the downstream impacts of elevated extracellular serotonin (5-HT; 5-hydroxytryptamine), the consequence of SERT inhibition, on organ systems and physiological processes within teleost fish. This review also intends to reveal potentially understudied endpoints for SSRI toxicity based on what is known to be controlled by 5-HT in fish. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Upper gastrointestinal bleeding in a patient with depression receiving selective serotonin reuptake inhibitor therapy.

    Science.gov (United States)

    Kumar, Deepak; Saaraswat, Tanuj; Sengupta, S N; Mehrotra, Saurabh

    2009-02-01

    Serotonin plays an important role in the normal clotting phenomenon and is released by platelets. Platelets are dependent on a serotonin transporter for the uptake of serotonin, as they cannot synthesize it themselves. Selective serotonin reuptake inhibitors (SSRIs) block the uptake of serotonin into platelets and can cause problems with clotting leading to bleeding. This case report highlights the occurrence of upper gastrointestinal bleeding in the index case on initiating SSRI therapy for depression and the prompt resolution of the same on its discontinuation on two separate occasions. SSRIs may cause upper gastrointestinal (GI) bleeding. Physicians should be aware of the same and should try to rule out previous episodes of upper GI bleed or the presence of other risk factors which might predispose to it before prescribing SSRIs; they should also warn the patients about this potential side effect. Also, the presence of thalassemia trait in the index patient deserves special attention and needs to be explored to see if it might in any way contribute in potentiating this side effect of SSRIs.

  20. Impact of prestroke selective serotonin reuptake inhibitor treatment on stroke severity and mortality.

    Science.gov (United States)

    Mortensen, Janne Kaergaard; Larsson, Heidi; Johnsen, Søren Paaske; Andersen, Grethe

    2014-07-01

    Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased risk of bleeding but also a possible neuroprotective effect in stroke. We aimed to examine the implications of prestroke SSRI use in hemorrhagic and ischemic stroke. We conducted a registry-based propensity score-matched follow-up study among first-ever patients with hemorrhage and ischemic stroke in Denmark (2003-2012). Multiple conditional logistic regression was used to compute adjusted odds ratios of severe stroke and death within 30 days. Among 1252 hemorrhagic strokes (626 prestroke SSRI users and 626 propensity score-matched nonusers), prestroke SSRI use was associated with an increased risk of the strokes being severe (adjusted propensity score-matched odds ratios, 1.41; confidence interval, 1.08-1.84) and an increased risk of death within 30 days (adjusted propensity score-matched odds ratios, 1.60; confidence interval, 1.17-2.18). Among 8956 patients with ischemic stroke (4478 prestroke SSRI users and 4478 propensity score-matched nonusers), prestroke SSRI use was not associated with the risk of severe stroke or death within 30 days. Prestroke SSRI use is associated with increased stroke severity and mortality in patients with hemorrhagic stroke. Although prestroke depression in itself may increase stroke severity and mortality, this was not found in SSRI users with ischemic stroke. © 2014 American Heart Association, Inc.

  1. Effect of proton pump inhibitors on the serum concentrations of the selective serotonin reuptake inhibitors citalopram, escitalopram, and sertraline.

    Science.gov (United States)

    Gjestad, Caroline; Westin, Andreas A; Skogvoll, Eirik; Spigset, Olav

    2015-02-01

    The selective serotonin reuptake inhibitors (SSRIs) citalopram, escitalopram, and sertraline are all metabolized by the cytochrome P-450 isoenzyme CYP2C19, which is inhibited by the proton pump inhibitors (PPIs) omeprazole, esomeprazole, lansoprazole, and pantoprazole. The aim of the present study was to evaluate the effect of these PPIs on the serum concentrations of citalopram, escitalopram, and sertraline. Serum concentrations from patients treated with citalopram, escitalopram, or sertraline were obtained from a routine therapeutic drug monitoring database, and samples from subjects concomitantly using PPIs were identified. Dose-adjusted SSRI serum concentrations were calculated to compare data from those treated and those not treated with PPIs. Citalopram concentrations were significantly higher in patients treated with omeprazole (+35.3%; P Escitalopram concentrations were significantly higher in patients treated with omeprazole (+93.9%; P escitalopram is affected to a greater extent than are citalopram and sertraline. When omeprazole or esomeprazole are used in combination with escitalopram, a 50% dose reduction of the latter should be considered.

  2. Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson's Disease.

    Science.gov (United States)

    Borchert, Robin J; Rittman, Timothy; Passamonti, Luca; Ye, Zheng; Sami, Saber; Jones, Simon P; Nombela, Cristina; Vázquez Rodríguez, Patricia; Vatansever, Deniz; Rae, Charlotte L; Hughes, Laura E; Robbins, Trevor W; Rowe, James B

    2016-07-01

    Cognitive impairment is common in Parkinson's disease (PD), but often not improved by dopaminergic treatment. New treatment strategies targeting other neurotransmitter deficits are therefore of growing interest. Imaging the brain at rest ('task-free') provides the opportunity to examine the impact of a candidate drug on many of the brain networks that underpin cognition, while minimizing task-related performance confounds. We test this approach using atomoxetine, a selective noradrenaline reuptake inhibitor that modulates the prefrontal cortical activity and can facilitate some executive functions and response inhibition. Thirty-three patients with idiopathic PD underwent task-free fMRI. Patients were scanned twice in a double-blind, placebo-controlled crossover design, following either placebo or 40-mg oral atomoxetine. Seventy-six controls were scanned once without medication to provide normative data. Seed-based correlation analyses were used to measure changes in functional connectivity, with the right inferior frontal gyrus (IFG) a critical region for executive function. Patients on placebo had reduced connectivity relative to controls from right IFG to dorsal anterior cingulate cortex and to left IFG and dorsolateral prefrontal cortex. Atomoxetine increased connectivity from the right IFG to the dorsal anterior cingulate. In addition, the atomoxetine-induced change in connectivity from right IFG to dorsolateral prefrontal cortex was proportional to the change in verbal fluency, a simple index of executive function. The results support the hypothesis that atomoxetine may restore prefrontal networks related to executive functions. We suggest that task-free imaging can support translational pharmacological studies of new drug therapies and provide evidence for engagement of the relevant neurocognitive systems.

  3. Beta-adrenoreceptor blockade abolishes atomoxetine-induced risk taking.

    Science.gov (United States)

    Yang, Fan Nils; Pan, Jing Samantha; Li, Xinwang

    2016-01-01

    Clinical studies have shown that patients with exaggerated risk-taking tendencies have high baseline levels of norepinephrine. In this work, we systemically manipulated norepinephrine levels in rats and studied their behavioral changes in a probabilistic discounting task, which is a paradigm for gauging risk taking. This study aims to explore the effects of the selective norepinephrine reuptake inhibitor (atomoxetine at doses of 0.6, 1.0 and 1.8 mg/kg), and receptor selective antagonists (propranolol at a single dose of 1.0/kg, and prazosin at a single dose of 0.1 mg/kg), on risk taking using a probabilistic discounting task. In this task, there were two levers available to rats: pressing the 'small/certain' lever guaranteed a single food pellet, and pressing the 'large/risky' lever yielded either four pellets or none. The probability of receiving four food pellets decreased across the four experimental blocks from 100% to 12.5%. Atomoxetine increased the tendency to choose the large/risky lever. It significantly reduced the lose-shift effect (i.e. pressing a different lever after losing a trial), but did not affect the win-stay effect (i.e. pressing the same lever after winning a trial). Furthermore, co-administration of beta-adrenoreceptor antagonist, propranolol, eliminated the effects of atomoxetine on risk taking and the lose-shift effect; but co-administration of alpha1-adrenoreceptor antagonist, prazosin, did not. Atomoxetine boosted NE levels and increased risk taking. This was because atomoxetine decreased rats' sensitivity to losses. These effects were likely mediated by beta-adrenoreceptor. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. There is an association between selective serotonin reuptake inhibitor use and uncomplicated peptic ulcers: a population-based case-control study

    DEFF Research Database (Denmark)

    Dall, M; Schaffalitzky de Muckadell, O B; Lassen, Annmarie Touborg

    2010-01-01

    Persons who use serotonin reuptake inhibitors (SSRIs) seem to be at increased risk of having serious upper gastrointestinal bleeding. In vitro studies have shown that SSRIs inhibit platelet aggregation. It remains unknown if SSRIs have a direct ulcerogenic effect....

  5. Bioimpedance in monitoring of effects of selective serotonin reuptake inhibitor treatment

    Directory of Open Access Journals (Sweden)

    Kuznecova LV

    2011-06-01

    Full Text Available Vasiliy Grigorievich Alexeev, Ludmila Vasilievna KuznecovaDepartment of Physiology, SP Botkin Moscow City Clinical Hospital, Moscow, RussiaBackground: Bioimpedance has been shown to be a safe technique when used in a number of biomedical applications. In this study, we used the Electro Interstitial Scan (EIS to perform bioimpedance measurements to follow up the efficacy of selective serotonin reuptake inhibitor (SSRI treatment in subjects diagnosed to have major depressive disorder.Methods: We recruited 59 subjects (38 women, 21 men aged 17–76 (mean 47 years diagnosed with major depressive disorder by psychiatric assessment at the Botkin Hospital according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV. Baseline Clinical Global Impression scores and EIS (electrical conductivity and dispersion α parameter measurements were done before starting SSRI therapy. Treatment follow-up was undertaken using EIS bioimpedance measurements and by treatment response based on the Hamilton Depression Scale and Clinical Global Impression, every 15 days for 60 days. At day 45, we classified the patients into two groups, ie, Group 1, including treatment responders, and Group 2, including nonresponders. At day 60, patients were classified into two further groups, ie, Group 3, comprising treatment responders, and Group 4, comprising nonresponders.Results: Comparing Group 1 and Group 2, electrical conductivity measurement of the pathway between the two forehead electrodes had a specificity of 72% and a sensitivity of 85.3% (P < 0.0001, with a cutoff >4.32. Comparing Group 3 and Group 4, electrical conductivity measurements in the same pathway had a specificity of 47.6% and a sensitivity of 76.3% (P < 0.16, with a cutoff >5.92. Comparing Group 1 and Group 2, the electrical dispersion α parameter of the pathway between the two disposable forehead electrodes had a specificity of 80% and a sensitivity of 85.2% (P < 0.0001 with a

  6. Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: Changes in drug disposition.

    Directory of Open Access Journals (Sweden)

    Andreas Austgulen Westin

    Full Text Available Pregnancy may cause changes in drug disposition. The clinical consequences may be profound and even counterintuitive; in some cases pregnant women may need more than twice their usual drug dose in order to maintain therapeutic drug levels. For antidepressants, evidence on drug disposition in pregnancy is scarce. The aim of this study was to determine the effects of pregnancy on serum levels of selective serotonin reuptake inhibitors (SSRIs and venlafaxine in a large and naturalistic patient material, in order to provide tentative dose recommendations for pregnant women.Using patient data from two routine therapeutic drug monitoring (TDM services in Norway with linkage to the national birth registry, dose-adjusted serum drug concentrations of SSRIs and venlafaxine during pregnancy were compared to the women's own baseline (non-pregnant values, using a linear mixed model.Overall, the TDM databases contained 196,726 serum concentration measurements from 54,393 women. After data linkage and drug selection (SSRIs or venlafaxine only, we identified 367 analyses obtained from a total of 290 pregnancies in 281 women, and 420 baseline observations from the same women. Serum concentrations in the third trimester were significantly lower than baseline for paroxetine (-51%; 95% confidence interval [CI], -66%, -30%; p<0.001, fluvoxamine (-56%; CI, -75%, -23%; p = 0.004 and citalopram (-24%; CI, -38%, -7%; p = 0,007, and higher than baseline for sertraline (+68%; CI, +37%, +106%; p<0.001. For escitalopram, fluoxetine and venlafaxine concentrations did not change significantly.For paroxetine and fluvoxamine the pronounced decline in maternal drug serum concentrations in pregnancy may necessitate a dose increase of about 100% during the third trimester in order to maintain stable concentrations. For fluoxetine, venlafaxine, citalopram, escitalopram and sertraline, the present study indicates that dose adjustments are generally not necessary during pregnancy.

  7. Selective serotonin reuptake inhibitors and gastrointestinal bleeding: a case-control study.

    Directory of Open Access Journals (Sweden)

    Alfonso Carvajal

    Full Text Available BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs have been associated with upper gastrointestinal (GI bleeding. Given their worldwide use, even small risks account for a large number of cases. This study has been conducted with carefully collected information to further investigate the relationship between SSRIs and upper GI bleeding. METHODS: We conducted a case-control study in hospitals in Spain and in Italy. Cases were patients aged ≥18 years with a primary diagnosis of acute upper GI bleeding diagnosed by endoscopy; three controls were matched by sex, age, date of admission (within 3 months and hospital among patients who were admitted for elective surgery for non-painful disorders. Exposures to SSRIs, other antidepressants and other drugs were defined as any use of these drugs in the 7 days before the day on which upper gastrointestinal bleeding started (index day. RESULTS: 581 cases of upper GI bleeding and 1358 controls were considered eligible for the study; no differences in age or sex distribution were observed between cases and controls after matching. Overall, 4.0% of the cases and 3.3% of controls used an SSRI antidepressant in the week before the index day. No significant risk of upper GI bleeding was encountered for SSRI antidepressants (adjusted odds ratio, 1.06, 95% CI, 0.57-1.96 or for whichever other grouping of antidepressants. CONCLUSIONS: The results of this case-control study showed no significant increase in upper GI bleeding with SSRIs and provide good evidence that the magnitude of any increase in risk is not greater than 2.

  8. [Selective serotonin reuptake inhibitors in the therapy of various types of endogenous depressions].

    Science.gov (United States)

    Panteleeva, G P; Abramova, L I; Korenev, A N

    2000-01-01

    In order to specify differential indications for the use of selective serotonin reuptake inhibitors (SSRI) their therapeutic effect was investigated in apathic-adynamic, melancholic and anxious depressions. Group of 151 patients received monotherapy with one of SSRI-drugs: citalopram--22 patients (mean daily dosage--27.4 mg), paroxetine--47 patients (23 mg), sertraline--19 patients (107 mg), fluvoxamine--28 patients (162 mg), fluoxetine--35 patients (20 mg). The state of the patients was estimated 5 times during 42 days of therapy by clinical estimations and according to Hamilton Depression Scale (HAM-D). Therapeutic effects of the drugs were determined according to the degree of reduction of the total HAM-D scores and they were considered as "significant" (a reduction of the scores by 50% and more), "moderate" (by 21-49%), and "insignificant" (by 1-20%). Positive antidepressive effect, including "significant" was obtained in the case of the use of all the drugs studied. Differential evaluation of the three components of antidepressive activity (thymoleptic, sedative-anxiolytic, and stimulative) according to the degrees and data of expression of drugs' therapeutic effect has allowed to determine indications for the therapy of endogenous depressions by each of SSRI: to recommend cytalopram for the treatment of various types of depressive states mainly, for anxious and apatho-adynamic types; paroxetin--for treatment of melancholic depressions as well as for anxious and apatho-dynamic ones; sertralin++--for depression with anxiety and fobic disorders; fluvoxamine--for melancholic and anxious depression; fluoxetine--for apatho-adynamic depressions.

  9. Neurodevelopment of children prenatally exposed to selective reuptake inhibitor antidepressants: Toronto sibling study.

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    Nulman, Irena; Koren, Gideon; Rovet, Joanne; Barrera, Maru; Streiner, David L; Feldman, Brian M

    2015-07-01

    The reproductive safety of selective reuptake inhibitor (SRI) antidepressants needs to be established to provide optimal control of maternal depression while protecting the fetus. To define a child's neurodevelopment following prenatal exposure to SRIs and to account for genetic and environmental confounders in a sibling design using the Toronto Motherisk prospective database. Intelligence and behavior of siblings prenatally exposed and unexposed to SRIs were assessed by using the Wechsler Preschool and Primary Scale of Intelligence-Third Edition, Child Behavior Checklist, and Conners Parent Rating Scale-Revised and subsequently compared. Mothers, diagnosed with depression using DSM-IV, were assessed for intelligence quotient (IQ) and for severity of depressive symptoms with the Center for Epidemiologic Studies Depression scale. Prenatal drug doses and durations of exposure, child's age, child's sex, birth order, severity of maternal depression symptoms, and Full Scale IQ, the primary outcome measure, of both the mother and the child were considered in the analyses. Forty-five sibling pairs (ages 3 years to 6 years 11 months, prenatally exposed and unexposed to SRIs) did not differ in their mean ± SD Full Scale IQs (103 ± 13 vs 106 ± 12; P = .30; 95% CI, -7.06 to 2.21) or rates of problematic behaviors. Significant predictor of children's intelligence was maternal IQ (P = .043, β = 0.306). Severity of maternal depression was a significant predictor of Child Behavior Checklist Internalizing (P = .019, β = 0.366), Externalizing (P = .003, β = 0.457), and Total scores (P = .001, β = 0.494). Drug doses and durations of exposure during pregnancy did not predict any outcomes of interest in the exposed siblings. SRI antidepressants were not found to be neurotoxic. Maternal depression may risk the child's future psychopathology. The sibling design in behavioral teratology aids in separating the effects of maternal depression from those of SRIs, providing stronger

  10. Atomoxetine restores the response inhibition network in Parkinson’s disease

    Science.gov (United States)

    Rae, Charlotte L.; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E.; Jones, P. Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

    2016-01-01

    Abstract Parkinson’s disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson’s disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson’s disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson’s disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson’s disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced

  11. Combinatorial support vector machines approach for virtual screening of selective multi-target serotonin reuptake inhibitors from large compound libraries.

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    Shi, Z; Ma, X H; Qin, C; Jia, J; Jiang, Y Y; Tan, C Y; Chen, Y Z

    2012-02-01

    Selective multi-target serotonin reuptake inhibitors enhance antidepressant efficacy. Their discovery can be facilitated by multiple methods, including in silico ones. In this study, we developed and tested an in silico method, combinatorial support vector machines (COMBI-SVMs), for virtual screening (VS) multi-target serotonin reuptake inhibitors of seven target pairs (serotonin transporter paired with noradrenaline transporter, H(3) receptor, 5-HT(1A) receptor, 5-HT(1B) receptor, 5-HT(2C) receptor, melanocortin 4 receptor and neurokinin 1 receptor respectively) from large compound libraries. COMBI-SVMs trained with 917-1951 individual target inhibitors correctly identified 22-83.3% (majority >31.1%) of the 6-216 dual inhibitors collected from literature as independent testing sets. COMBI-SVMs showed moderate to good target selectivity in misclassifying as dual inhibitors 2.2-29.8% (majority virtual hits correlate with the reported effects of their predicted targets. COMBI-SVM is potentially useful for searching selective multi-target agents without explicit knowledge of these agents. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Is atomoxetine effective in some comorbid mental disorders in ADHD?

    Directory of Open Access Journals (Sweden)

    Cesneková D.

    2016-09-01

    Full Text Available Attention-Deficit/Hyperactivity Disorder (ADHD is connected with high level of psychiatric comorbidity in paediatric population. Depressive disorder is common comorbid disorder co-existing with ADHD. Atomoxetine is worldwide approved for treatment of ADHD in paediatric population; in addition atomoxetine is effective and safe in treatment of some comorbid disorders in ADHD. Pharmacotherapy of depression is limited and residual symptoms are common. Fluoxetine is currently considered to be the gold standard of treatment of depression, but effectiveness of acute phase of treatment is not sufficient. Atomoxetine as a selective noradrenaline reuptake inhibitor or olanzapine as a multi receptors antagonist drug in combination with fluoxetine could be perspective augmented treatment strategy of depression just for their antidepressant effect. The aim of our following study is to evaluate and compare effectiveness and safety of monotherapy and combined/augmented therapy in acute phase of depression treatment in adolescence, as well as introduce complex modern research methodology of effectiveness and safety of treatment.

  13. Therapeutic administration of atomoxetine combined with rTMS and occupational therapy for upper limb hemiparesis after stroke: a case series study of three patients.

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    Kinoshita, Shoji; Kakuda, Wataru; Yamada, Naoki; Momosaki, Ryo; Okuma, Ryo; Watanabe, Shu; Abo, Masahiro

    2016-03-01

    Atomoxetine, a selective noradrenaline reuptake inhibitor, has been reported to enhance brain plasticity, but has not yet been used in stroke patients. We reported the feasibility and clinical benefits on motor functional recovery of the combination of repetitive transcranial magnetic stimulation (rTMS) and intensive occupational therapy (OT) in stroke patients. This pilot study was designed to evaluate the additive effects of oral atomoxetine to rTMS/OT in post-stroke hemiparetic patients. The study included three post-stroke patients with upper limb hemiparesis. Treatment with 40 mg/day atomoxetine commenced 2 weeks before admission. After confirming tolerance, the dose was increased to 120 mg/day. Low-frequency rTMS/OT was provided daily for 15 days during continued atomoxetine therapy. Motor function of the affected upper limb was evaluated with the Fugl-Meyer Assessment and Wolf Motor Function test. All patients completed the protocol and showed motor improvement up to 4 weeks after the treatment. No atomoxetine-related side effects were noted. Our protocol of triple therapy of atomoxetine, low-frequency rTMS, and OT is safe and feasible intervention for upper limb hemiparesis after stroke.

  14. Effects of atomoxetine on attention and impulsivity in the five-choice serial reaction time task in rats with lesions of dorsal noradrenergic ascending bundle.

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    Liu, Yia-Ping; Huang, Teng-Shun; Tung, Che-Se; Lin, Chen-Cheng

    2015-01-02

    Atomoxetine, a noradrenaline reuptake inhibitor (NRI), which is a non-stimulating medicine that is used for the treatment of patients with attention deficit hyperactivity disorder (ADHD), has been found to be effective in reducing behavioral impulsivity in rodents, but its efficacy in a dorsal noradrenergic ascending bundle (DNAB)-lesioned condition has not been examined. The present study aimed to investigate the effects of DNAB lesions on attention and impulsive control in the five-choice serial reaction time task (5-CSRTT) in rats treated with atomoxetine. The drug-induced changes in noradrenaline efflux in the medial prefrontal cortex were also measured. 5-CSRTT-trained rats were included in one of the following groups: N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)/Atomoxetine, Sham/Atomoxetine, DSP-4/Saline, or Sham/Saline. Acute atomoxetine (0.3 mg/kg) was administered 14 days after the DSP-4 regime. The behavioral testing included manipulations of the inter-trial interval (ITI), stimulation duration and food satiety. In vivo microdialysis of the noradrenaline efflux in the medial prefrontal cortex and the expression of the noradrenaline transporter (NAT) in the DNAB areas were examined. Atomoxetine reduced impulsivity and perseveration in the long-ITI condition with no effects on any other variables. This phenomenon was not influenced by DSP-4 pre-treatment. The DNAB-lesioned rats had lower noradrenaline efflux in the medial prefrontal cortex. DSP-4 caused no change in NAT expression in the DNAB areas. These findings suggested that noradrenaline reuptake may not be exclusively responsible for the atomoxetine effects in adjusting impulsivity. The role of DNAB should also be considered, particularly in conditions requiring greater behavioral inhibition. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Serotonin reuptake inhibitors and mortality in epilepsy: A linked primary-care cohort study.

    Science.gov (United States)

    Josephson, Colin B; Gonzalez-Izquierdo, Arturo; Denaxas, Spiros; Fitzpatrick, Natalie K; Sajobi, Tolulope T; Engbers, Jordan D T; Patten, Scott; Jette, Nathalie; Wiebe, Samuel

    2017-11-01

    Preliminary evidence suggests that serotonin reuptake inhibitor (SRI) use may increase postictal respiratory drive and prevent death. We sought to determine whether SRIs are associated with improved all-cause and possible seizure-specific mortality in patients with epilepsy. Patients with epilepsy and a random 10:1 sample without epilepsy were extracted from The ClinicAl research using LInked Bespoke studies and Electronic health Records (CALIBER) resource. The hazard ratio (HR) of all-cause and possible seizure-specific mortality, treating SRI use as a time-varying covariate, was determined using the date of a second SRI prescription as exposure and in discrete 6-month periods over the entire duration of follow-up. We used Cox regression and competing risk models with Firth correction to calculate the HR. We controlled for age, sex, depression, comorbidity, (Charlson comorbidity index) and socioeconomic status (Index of Multiple Deprivation). We identified 2,718,952 eligible patients in CALIBER, of whom 16,379 (0.60%) had epilepsy. Median age and follow-up were 44 (interquartile range [IQR] 29-61]) and 6.4 years (IQR 2.4-10.4 years), respectively, and 53% were female. A total of 2,178 patients (13%) had at least two SRI prescriptions. Hazard of all-cause mortality was significantly elevated following a second prescription for an SRI (HR 1.64 95% confidence interval [95% CI] 1.44-1.86; p < 0.001). The HR was similar in 163,778 age, sex, and general practitioner (GP) practice-matched controls without epilepsy. Exposure to an SRI was not associated with seizure-related death (HR 1.08, 95% CI 0.59-1.97; 0.796). There is no evidence in this large population-based cohort that SRIs protect against all-cause mortality or seizure-specific mortality. Rather, SRI use was associated with increased mortality, irrespective of epilepsy, which is probably due to various factors associated with the use of antidepressants. Larger studies with systematically collected clinical

  16. Are selective serotonin reuptake inhibitors safe for drivers? What is the evidence?

    Science.gov (United States)

    Ravera, Silvia; Ramaekers, Johannes G; de Jong-van den Berg, Lolkje T W; de Gier, Johan J

    2012-05-01

    Selective serotonin reuptake inhibitors (SSRIs) are widely used medications to treat several psychiatric diseases and, above all, depression. They seem to be as effective as older antidepressants but have a different adverse effect profile. Despite their favorable safety profile, little is known about their influence on traffic safety. To conduct a literature review to summarize the current evidence on the role of SSRIs in traffic safety, particularly concerning undesirable effects that could potentially impair fitness to drive, experimental and pharmacoepidemiologic studies on driving impairment, 2 existing categorization systems for driving-impairing medications, and the European legislative procedures for assessing fitness to drive before issuing a driver's license and driving under the influence of medicines. The article search was performed in the following electronic databases: MEDLINE, PsycINFO, ScienceDirect, and SafetyLit. The English-language scientific literature was searched using key words such as SSRIs and psychomotor performance, car crash or traffic accident, and adverse effects. For inclusion in this review, papers had to be full-text articles, refer to possible driving-related adverse effects, and be experimental or pharmacoepidemiologic studies on SSRIs and traffic accident risks. No restrictions concerning publication year were applied. Ten articles were selected as background information on driving-related adverse effects, and 15 articles were selected regarding experimental and pharmacoepidemiologic work. Regarding SSRI adverse effects, the most reported undesirable effects referring to driving impairment were anxiety, agitation, sleep disturbances, headache, increased risk of suicidal behavior, and deliberate self-harm. Regarding the remaining issues addressed in this article, inconsistencies were found between the outcomes of the selected experimental and epidemiologic studies and between the 2 existing categorization systems under

  17. Effects of selective serotonin reuptake inhibitor treatment on plasma oxytocin and cortisol in major depressive disorder.

    Science.gov (United States)

    Keating, Charlotte; Dawood, Tye; Barton, David A; Lambert, Gavin W; Tilbrook, Alan J

    2013-04-29

    Oxytocin is known for its capacity to facilitate social bonding, reduce anxiety and for its actions on the stress hypothalamopituitary adrenal (HPA) axis. Since oxytocin can physiologically suppress activity of the HPA axis, clinical applications of this neuropeptide have been proposed in conditions where the function of the HPA axis is dysregulated. One such condition is major depressive disorder (MDD). Dysregulation of the HPA system is the most prominent endocrine change seen with MDD, and normalizing the HPA axis is one of the major targets of recent treatments. The potential clinical application of oxytocin in MDD requires improved understanding of its relationship to the symptoms and underlying pathophysiology of MDD. Previous research has investigated potential correlations between oxytocin and symptoms of MDD, including a link between oxytocin and treatment related symptom reduction. The outcomes of studies investigating whether antidepressive treatment (pharmacological and non-pharmacological) influences oxytocin concentrations in MDD, have produced conflicting outcomes. These outcomes suggest the need for an investigation of the influence of a single treatment class on oxytocin concentrations, to determine whether there is a relationship between oxytocin, the HPA axis (e.g., oxytocin and cortisol) and MDD. Our objective was to measure oxytocin and cortisol in patients with MDD before and following treatment with selective serotonin reuptake inhibitors, SSRI. We sampled blood from arterial plasma. Patients with MDD were studied at the same time twice; pre- and post- 12 weeks treatment, in an unblinded sequential design (clinicaltrials.govNCT00168493). Results did not reveal differences in oxytocin or cortisol concentrations before relative to following SSRI treatment, and there were no significant relationships between oxytocin and cortisol, or these two physiological variables and psychological symptom scores, before or after treatment. These outcomes

  18. Reduced short interval cortical inhibition correlates with atomoxetine response in children with attention-deficit hyperactivity disorder (ADHD).

    Science.gov (United States)

    Chen, Tina H; Wu, Steve W; Welge, Jeffrey A; Dixon, Stephan G; Shahana, Nasrin; Huddleston, David A; Sarvis, Adam R; Sallee, Floyd R; Gilbert, Donald L

    2014-12-01

    Clinical trials in children with attention-deficit hyperactivity disorder (ADHD) show variability in behavioral responses to the selective norepinephrine reuptake inhibitor atomoxetine. The objective of this study was to determine whether transcranial magnetic stimulation-evoked short interval cortical inhibition might be a biomarker predicting, or correlating with, clinical atomoxetine response. At baseline and after 4 weeks of atomoxetine treatment in 7- to 12-year-old children with ADHD, transcranial magnetic stimulation short interval cortical inhibition was measured, blinded to clinical improvement. Primary analysis was by multivariate analysis of covariance. Baseline short interval cortical inhibition did not predict clinical responses. However, paradoxically, after 4 weeks of atomoxetine, mean short interval cortical inhibition was reduced 31.9% in responders and increased 6.1% in nonresponders (analysis of covariance t 41 = 2.88; P = .0063). Percentage reductions in short interval cortical inhibition correlated with reductions in the ADHD Rating Scale (r = 0.50; P = .0005). In children ages 7 to 12 years with ADHD treated with atomoxetine, improvements in clinical symptoms are correlated with reductions in motor cortex short interval cortical inhibition. © The Author(s) 2014.

  19. High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor.

    Science.gov (United States)

    Coetzee, Dirk D; López, Víctor; Smith, Carine

    2016-01-11

    Extracts from and alkaloids contained in plants in the genus Sceletium have been reported to inhibit ligand binding to serotonin transporter. From this, the conclusion was made that Sceletium products act as selective serotonin-reuptake inhibitors. However, other mechanisms which may similarly result in the anxiolytic or anti-depressant effect ascribed to Sceletium, such as monoamine release, have not been investigated. The current study investigated simultaneously and at two consecutive time points, the effect of high-mesembrine Sceletium extract on both monoamine release and serotonin reuptake into both human astrocytes and mouse hippocampal neurons, as well as potential inhibitory effects on relevant enzyme activities. Human astrocytes and mouse hippocampal cells were treated with citalopram or Sceletium extract for 15 and 30min, after which protein expression levels of serotonin transporter (SERT) and vesicular monoamine transporter-2 (VAMT-2) was assessed using fluorescent immunocytochemistry and digital image analysis. Efficacy of inhibition of acetylcholinesterase (AChE) and monoamine oxidate-A (MAO-A) activity were assessed using the Ellman and Olsen methods (and appropriate controls) respectively. We report the first investigation of mechanism of action of Sceletium extract in the context of serotonin transport, release and reuptake in a cellular model. Cell viability was not affected by Sceletium treatment. High-mesembrine Sceletium extract down-regulated SERT expression similarly to citalopram. In addition, VMAT-2 was upregulated significantly in response to Sceletium treatment. The extract showed only relatively mild inhibition of AChE and MAO-A. We conclude that the serotonin reuptake inhibition activity ascribed to the Sceletium plant, is a secondary function to the monoamine-releasing activity of high-mesembrine Sceletium extract (Trimesemine(TM)). Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Dependence and withdrawal reactions to benzodiazepines and sellective serotonin reuptake inhibitors: How did the health authorities react?

    DEFF Research Database (Denmark)

    Nielsen, Margrethe

    2013-01-01

    AIM: Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time. METHODS: Documentary study. We searched the web-sites of the European Medicines Agency and the drug agencies in USA...... it is difficult for many patients to stop treatment. In the perspective of a precautionary principle, drug agencies have failed to acknowledge that SSRIs can cause dependence and have minimised the problem with regard to its frequency and severity. In the perspective of a risk management principle, the drug...

  1. Atomoxetine effects on attentional bias to drug-related cues in cocaine dependent individuals.

    Science.gov (United States)

    Passamonti, Luca; Luijten, M; Ziauddeen, H; Coyle-Gilchrist, I T S; Rittman, T; Brain, S A E; Regenthal, R; Franken, I H A; Sahakian, B J; Bullmore, E T; Robbins, T W; Ersche, K D

    2017-08-01

    Biased attention towards drug-related cues and reduced inhibitory control over the regulation of drug-intake characterize drug addiction. The noradrenaline system has been critically implicated in both attentional and response inhibitory processes and is directly affected by drugs such as cocaine. We examined the potentially beneficial effects of the noradrenaline reuptake inhibitor atomoxetine in improving cognitive control during two tasks that used cocaine- and non-cocaine-related stimuli. A double-blind, placebo-controlled, and cross-over psycho-pharmacological design was employed. A single oral dose of atomoxetine (40 mg) was administered to 28 cocaine-dependent individuals (CDIs) and 28 healthy controls. All participants performed a pictorial attentional bias task involving both cocaine- and non-cocaine-related pictures as well as a verbal go/no-go task composed of cocaine- and food-related words. As expected, CDIs showed attentional bias to cocaine-related cues whilst controls did not. More importantly, however, atomoxetine, relative to placebo, significantly attenuated attentional bias in CDIs (F 26  = 6.73, P = 0.01). During the go/no-go task, there was a treatment × trial × group interaction, although this finding only showed a trend towards statistical significance (F 26  = 3.38, P = 0.07). Our findings suggest that atomoxetine reduces attentional bias to drug-related cues in CDIs. This may result from atomoxetine's modulation of the balance between tonic/phasic activity in the locus coeruleus and the possibly parallel enhancement of noradrenergic neurotransmission within the prefrontal cortex. Studying how cognitive enhancers such as atomoxetine influence key neurocognitive indices in cocaine addiction may help to develop reliable biomarkers for patient stratification in future clinical trials.

  2. An Open-Label Pilot Study of Combined Augmentation With Creatine Monohydrate and 5-Hydroxytryptophan for Selective Serotonin Reuptake Inhibitor- or Serotonin-Norepinephrine Reuptake Inhibitor-Resistant Depression in Adult Women.

    Science.gov (United States)

    Kious, Brent M; Sabic, Hana; Sung, Young-Hoon; Kondo, Douglas G; Renshaw, Perry

    2017-10-01

    Many women with major depressive disorder (MDD) respond inadequately to standard treatments. Augmentation of conventional antidepressants with creatine monohydrate and 5-hydroxytryptophan (5-HTP) could correct deficits in serotonin production and brain bioenergetics associated with depression in women, yielding synergistic benefit. We describe an open-label study of 5-HTP and creatine augmentation in women with MDD who had failed selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) monotherapy. Fifteen women who were adequately adherent to an SSRI or SNRI and currently experiencing MDD, with a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or higher, were treated with 5 g of creatine monohydrate daily and 100 mg of 5-HTP twice daily for 8 weeks, with 4 weeks of posttreatment follow-up. The primary outcome was change in mean HAM-D scores. Mean HAM-D scores declined from 18.9 (SD, 2.5) at pretreatment visits to 7.5 (SD, 4.4) (P creatine and 5-HTP may represent an effective augmentation strategy for women with SSRI- or SNRI-resistant depression. Given the limitations of this small, open-label trial, future study in randomized, placebo-controlled trials is warranted.

  3. Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence

    Science.gov (United States)

    Kenny, Jonathan D.; Taylor, Norman E.; Brown, Emery N.; Solt, Ken

    2015-01-01

    Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg IV), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg IV) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1–4 Hz) to θ (4–8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes

  4. Dextroamphetamine (but Not Atomoxetine Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence.

    Directory of Open Access Journals (Sweden)

    Jonathan D Kenny

    Full Text Available Methylphenidate induces reanimation (active emergence from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each. When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6. After a single dose of propofol (8 mg/kg i.v., the mean emergence times for rats that received normal saline (vehicle and dextroamphetamine (1 mg/kg i.v. were 641 sec and 404 sec, respectively (n = 8 each. The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8, this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1-4 Hz to θ (4-8 Hz during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation

  5. Neurophysiologic predictors of response to atomoxetine in young adults with attention deficit hyperactivity disorder: a pilot project.

    Science.gov (United States)

    Leuchter, Andrew F; McGough, James J; Korb, Alexander S; Hunter, Aimee M; Glaser, Paul E A; Deldar, Ahmed; Durell, Todd M; Cook, Ian A

    2014-07-01

    Atomoxetine is a non-stimulant medication with sustained benefit throughout the day, and is a useful pharmacologic treatment option for young adults with Attention-Deficit/Hyperactivity Disorder (ADHD). It is difficult to determine, however, those patients for whom atomoxetine will be both effective and advantageous. Patients may need to take the medication for several weeks before therapeutic benefit is apparent, so a biomarker that could predict atomoxetine effectiveness early in the course of treatment could be clinically useful. There has been increased interest in the study of thalamocortical oscillatory activity using quantitative electroencephalography (qEEG) as a biomarker in ADHD. In this study, we investigated qEEG absolute power, relative power, and cordance, which have been shown to predict response to reuptake inhibitor antidepressants in Major Depressive Disorder (MDD), as potential predictors of response to atomoxetine. Forty-four young adults with ADHD (ages 18-30) enrolled in a multi-site, double-blind placebo-controlled study of the effectiveness of atomoxetine and underwent serial qEEG recordings at pretreatment baseline and one week after the start of medication. qEEG measures were calculated from a subset of the sample (N = 29) that provided useable qEEG recordings. Left temporoparietal cordance in the theta frequency band after one week of treatment was associated with ADHD symptom improvement and quality of life measured at 12 weeks in atomoxetine-treated subjects, but not in those treated with placebo. Neither absolute nor relative power measures selectively predicted improvement in medication-treated subjects. Measuring theta cordance after one week of treatment could be useful in predicting atomoxetine treatment response in adult ADHD. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence.

    Science.gov (United States)

    Kenny, Jonathan D; Taylor, Norman E; Brown, Emery N; Solt, Ken

    2015-01-01

    Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg i.v.), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg i.v.) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1-4 Hz) to θ (4-8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes

  7. Atomoxetine restores the response inhibition network in Parkinson's disease.

    Science.gov (United States)

    Rae, Charlotte L; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E; Jones, P Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

    2016-08-01

    Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction

  8. Atomoxetine Prevents Dexamethasone-Induced Skeletal Muscle Atrophy in Mice

    Science.gov (United States)

    Jesinkey, Sean R.; Korrapati, Midhun C.; Rasbach, Kyle A.; Beeson, Craig C.

    2014-01-01

    Skeletal muscle atrophy remains a clinical problem in numerous pathologic conditions. β2-Adrenergic receptor agonists, such as formoterol, can induce mitochondrial biogenesis (MB) to prevent such atrophy. Additionally, atomoxetine, an FDA-approved norepinephrine reuptake inhibitor, was positive in a cellular assay for MB. We used a mouse model of dexamethasone-induced skeletal muscle atrophy to investigate the potential role of atomoxetine and formoterol to prevent muscle mass loss. Mice were administered dexamethasone once daily in the presence or absence of formoterol (0.3 mg/kg), atomoxetine (0.1 mg/kg), or sterile saline. Animals were euthanized at 8, 16, and 24 hours or 8 days later. Gastrocnemius muscle weights, changes in mRNA and protein expression of peroxisome proliferator–activated receptor-γ coactivator-1 α (PGC-1α) isoforms, ATP synthase β, cytochrome c oxidase subunit I, NADH dehydrogenase (ubiquinone) 1 β subcomplex, 8, ND1, insulin-like growth factor 1 (IGF-1), myostatin, muscle Ring-finger protein-1 (muscle atrophy), phosphorylated forkhead box protein O 3a (p-FoxO3a), Akt, mammalian target of rapamycin (mTOR), and ribosomal protein S6 (rp-S6; muscle hypertrophy) in naive and muscle-atrophied mice were measured. Atomoxetine increased p-mTOR 24 hours after treatment in naïve mice, but did not change any other biomarkers. Formoterol robustly activated the PGC-1α-4-IGF1–Akt-mTOR-rp-S6 pathway and increased p-FoxO3a as early as 8 hours and repressed myostatin at 16 hours. In contrast to what was observed with acute treatment, chronic treatment (7 days) with atomoxetine increased p-Akt and p-FoxO3a, and sustained PGC-1α expression and skeletal muscle mass in dexamethasone-treated mice, in a manner comparable to formoterol. In conclusion, chronic treatment with a low dose of atomoxetine prevented dexamethasone-induced skeletal muscle wasting and supports a potential role in preventing muscle atrophy. PMID:25292181

  9. Atomoxetine treatment may decrease striatal dopaminergic transporter availability after 8 weeks: pilot SPECT report of three cases

    Directory of Open Access Journals (Sweden)

    Akay AP

    2015-11-01

    Full Text Available Aynur Pekcanlar Akay,1 Gamze Capa Kaya,2,3 Burak Baykara,1 Yusuf Demir,2,3 Handan Özek,1 Sevay Alsen,1 Mine Sencan Eren,2,3 Neslihan Inal Emiroglu,1 Turkan Ertay,2,3 Yesim Ozturk,4 Suha Miral,1 Hatice Durak,2,3 Evren Tufan4 1Department of Child and Adolescent Psychiatry, 2Department of Nuclear Medicine, 3Department of Pediatrics, Dokuz Eylul University Medical Faculty, Izmir, 4Department of Child and Adolescent Psychiatry, Abant İzzet Baysal University, Bolu, Turkey Abstract: Attention deficit/hyperactivity disorder is one of the most common neurodevelopmental disorders. The pathophysiology is thought to involve noradrenaline and dopamine. The role of dopamine transporter (DAT was evaluated in imaging studies using mostly dopamine reuptake inhibitors. Atomoxetine is a selective noradrenaline reuptake inhibitor. Here we report the results of a pilot study conducted to evaluate changes in striatal DAT after 8 weeks of atomoxetine treatment. Our results suggest that 8 weeks of atomoxetine treatment may change striatal DAT bioavailability as measured via SPECT but that change was not correlated with genotype or clinical improvement. Keywords: neuroimaging, dopamine, noradrenaline, SLC6A3 protein, human, pragmatic clinical trial, pilot study

  10. Use of selective serotonin reuptake inhibitors and risk of re-operation due to post-surgical bleeding in breast cancer patients: a Danish population-based cohort study

    DEFF Research Database (Denmark)

    Gärtner, Rune; Cronin-Fenton, Deirdre; Hundborg, Heidi Holmager

    2010-01-01

    Selective serotonin reuptake inhibitors (SSRI) decrease platelet-function, which suggests that SSRI use may increase the risk of post-surgical bleeding. Few studies have investigated this potential association.......Selective serotonin reuptake inhibitors (SSRI) decrease platelet-function, which suggests that SSRI use may increase the risk of post-surgical bleeding. Few studies have investigated this potential association....

  11. A chiral synthesis of dapoxetine hydrochloride, a serotonin re-uptake inhibitor, and its 14C isotopomer

    International Nuclear Information System (INIS)

    Wheeler, W.J.; O'Bannon, D.D.

    1992-01-01

    The 14 C-isotopmer of dapoxetine-[ 14 C] HCl (S (+) -N,N-dimethyl-α[2-(1-naphthalenyloxy)ethyl-2- 14 C]benzenemeth a-n amine hydrochloride, 1a), a potent serotonin re-uptake inhibitor has been prepared by a chiral synthesis, starting with tert. -butyloxyphenylglycine (3). Borane reduction, followed by activation of the resulting alcohol 4 as its mesylate 5b, provided the chiral starting material. The radiolabel was introduced by reaction of 5b with sodium cyanide-[ 14 C]. The desired product (1) was then elaborated from nitrile 6a,b via a five step synthesis in an overall 19.5% radiochemical yield. (Author)

  12. Increased risk of severe congenital heart defects in offspring exposed to selective serotonin-reuptake inhibitors in early pregnancy

    DEFF Research Database (Denmark)

    Knudsen, Tanja Majbrit; Hansen, Anne Vinkel; Garne, Ester

    2014-01-01

    BACKGROUND: Previous studies suggest a possible association between maternal use of selective serotonin-reuptake inhibitors (SSRIs) during early pregnancy and congenital heart defects (CHD). The purpose of this study was to verify this association by using validated data from the Danish EUROCAT...... terminated due to congenital anomalies. The study population consisted of all registered pregnancies (n = 72,280) in Funen, Denmark in the period 1995-2008. SSRI-use was assessed using The Danish National Prescription Registry, information on marital status, maternal educational level, income, and country...... of origin from Statistics Denmark was used as indicators of socioeconomic situation, and the CHD were studied in subgroups defined by EUROCAT. Logistic Regression was used to investigate the association between redeemed prescriptions for SSRIs and CHD. RESULTS: The risk of severe CHD in the offspring...

  13. Effects of selective serotonin reuptake inhibitors on thought-action fusion, metacognitions, and thought suppression in obsessive-compulsive disorder.

    Science.gov (United States)

    Besiroglu, Lutfullah; Çetinkaya, Nuralay; Selvi, Yavuz; Atli, Abdullah

    2011-01-01

    We aimed to assess whether cognitive processes change over time in patients with obsessive-compulsive disorder (OCD) receiving selective serotonin reuptake inhibitors without cognitive behavioral therapy and to investigate the factors associated with probable cognitive changes. During the 16 weeks of the study, 55 patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for OCD received open-label treatment with sertraline (100-200 mg/d) or fluoxetine (40-80 mg/d) and were assessed using the Yale-Brown Obsessive-Compulsive Scale, Beck Depression Inventory (BDI), Thought-Action Fusion Scale (TAFS), Metacognitions Questionnaire (MCQ-30), and White Bear Suppression Inventory (WBSI). The Yale-Brown Obsessive-Compulsive Scale (P < .001), BDI (P < .001), TAFS morality (P < .005), MCQ-30 (P < .01), and WBSI (P < .005) scores at follow-up were significantly lower than baseline scores. When we excluded OCD patients with depressive disorder (n = 12), statistical significance in paired comparisons for MCQ and WBSI disappeared. Similarly, when OCD patients with religious obsessions (n = 16) were excluded, paired comparisons for MCQ and TAF morality were not statistically significant. Changes in BDI, TAFS morality, MCQ-30, and WBSI (P < .005) were significantly correlated with changes in severity of obsessions, but not that of compulsions. After controlling for the change in depression severity, significant correlations between changes in obsessive and cognitive scales did not continue to have statistical significance. The BDI changes (P < .05) significantly explained the changes in symptom severity in a linear regression model. Our findings suggest that selective serotonin reuptake inhibitors can change appraisals of obsessive intrusions via their effects on negative emotions. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. Non-tricyclic and Non-selective Serotonin Reuptake Inhibitor Antidepressants and Recurrent Falls in Frail Older Women.

    Science.gov (United States)

    Naples, Jennifer G; Kotlarczyk, Mary P; Perera, Subashan; Greenspan, Susan L; Hanlon, Joseph T

    2016-12-01

    To determine the risk of recurrent falls associated with antidepressants other than tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRIs) among frail older women. This is a secondary analysis of the Zoledronic acid in frail Elders to STrengthen bone, or ZEST, trial data treated as a longitudinal cohort in 181 frail, osteoporotic women aged ≥65 years in long-term care. The primary exposure was individual non-TCA/non-SSRI antidepressants (i.e., serotonin norepinephrine reuptake inhibitors, mirtazapine, trazodone, and bupropion) at baseline and 6 months. The main outcome was recurrent (at least two) falls within 6 months after antidepressant exposure. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were derived using a generalized estimating equations model. At least 15% of women experienced recurrent falls between 0-6 and 6-12 months. At baseline and 6 months, 18.2% and 6.9% had a non-TCA/non-SSRI antidepressant, respectively. Adjusting for demographics, health status, and other drugs that increase risk of falls, non-TCA/non-SSRI antidepressant exposure significantly increased the risk of recurrent falls (AOR: 2.14; 95% CI: 1.01-4.54). Fall risk further increased after removing bupropion from the non-TCA/non-SSRI antidepressant group in sensitivity analyses (AOR: 2.73; 95% CI: 1.24-6.01). Other antidepressant classes may not be safer than TCAs/SSRIs with respect to recurrent falls in frail older women. Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  15. A randomized controlled trial of a novel mixed monoamine reuptake inhibitor in adults with ADHD

    Directory of Open Access Journals (Sweden)

    Wesnes Keith

    2008-06-01

    Full Text Available Abstract Background NS2359 is a potent reuptake blocker of noradrenalin, dopamine, and serotonin. The aim of the study was to investigate the efficacy, safety and cognitive function of NS2359 in adults with a DSM IV diagnosis of ADHD. Methods The study was a multi-centre, double-blind, randomized placebo-controlled, parallel group design in outpatient adults (18–55 years testing 0.5 mg NS2359 vs. placebo for 8 weeks. Multiple assessments including computerized neuropsychological evaluation were performed. Results There was no significant difference between NS2359 (n = 63 versus placebo (n = 63 on the primary outcome measure reduction in investigator rated ADHD-RS total score (7.8 versus 6.4; p Conclusion No overall effect of NS2359 was found on overall symptoms of ADHD. There was also a modest signal of improvement in the inattentive adults with ADHD and cognition warranting further exploration using differing doses.

  16. Investigation of the mechanisms underlying the hypophagic effects of the 5-HT and noradrenaline reuptake inhibitor, sibutramine, in the rat

    Science.gov (United States)

    Jackson, Helen C; Bearham, M Clair; Hutchins, Lisa J; Mazurkiewicz, Sarah E; Needham, Andrew M; Heal, David J

    1997-01-01

    Sibutramine is a novel 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin- noradrenaline reuptake inhibitor, SNRI) which is currently being developed as a treatment for obesity. Sibutramine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine the pharmacological mechanisms underlying sibutramine-induced hypophagia. Individually-housed male Sprague-Dawley rats were maintained on reversed phase lighting with free access to food and water. Drugs were administered at 09 h 00 min and food intake was monitored over the following 8 h dark period. Sibutramine (10 mg kg−1, p.o.) produced a significant decrease in food intake during the 8 h following drug administration. This hypophagic response was fully antagonized by the α1-adrenoceptor antagonist, prazosin (0.3 and 1 mg kg−1, i.p.), and partially antagonized by the β1-adrenoceptor antagonist, metoprolol (3 and 10 mg kg−1, i.p.) and the 5-HT receptor antagonists, metergoline (non-selective; 0.3 mg kg−1, i.p.); ritanserin (5-HT2A/2C; 0.1 and 0.5 mg kg−1, i.p.) and SB200646 (5-HT2B/2C; 20 and 40 mg kg−1, p.o.). By contrast, the α2-adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg−1, i.p.) and the β2-adrenoceptor antagonist, ICI 118,551 (3 and 10 mg kg−1, i.p.) did not reduce the decrease in food intake induced by sibutramine. These results demonstrate that β1-adrenoceptors, 5-HT2A/2C-receptors and particularly α1-adrenoceptors, are involved in the effects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypophagia is related to its ability to inhibit the reuptake of both noradrenaline and 5-HT, with the subsequent activation of a variety of noradrenaline and 5-HT receptor systems. PMID:9283694

  17. The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study

    NARCIS (Netherlands)

    Kuiken, Sjoerd D.; Tytgat, Guido N. J.; Boeckxstaens, Guy E. E.

    2003-01-01

    BACKGROUND & AIMS: Although widely prescribed, the evidence for the use of antidepressants for the treatment of irritable bowel syndrome (IBS) is limited. In this study, we hypothesized that fluoxetine (Prozac), a selective serotonin reuptake inhibitor, has visceral analgesic properties, leading to

  18. Simultaneous initiation (coinitiation) of pharmacotherapy with triiodothyronine and a selective serotonin reuptake inhibitor for major depressive disorder: a quantitative synthesis of double-blind studies

    NARCIS (Netherlands)

    Papakostas, George I.; Cooper-Kazaz, Rena; Appelhof, Bente C.; Posternak, Michael A.; Johnson, Daniel P.; Klibanski, Anne; Lerer, Bernard; Fava, Maurizio

    2009-01-01

    To examine the efficacy and overall tolerability of the simultaneous initiation of treatment (coinitiation) with triiodothyronine (T3) and a selective serotonin reuptake inhibitor (SSRI) for major depressive disorder (MDD). Sources of date were Medline/Pubmed, EMBASE, the Cochrane database, and

  19. Rate of improvement during and across three treatments for panic disorder with or without agoraphobia : Cognitive behavioral therapy, selective serotonin reuptake inhibitor or both combined

    NARCIS (Netherlands)

    Van Apeldoorn, Franske J.; Van Hout, Wiljo J. P. J.; Timmerman, Marieke E.; Mersch, Peter Paul A.; den Boer, Johan A.

    2013-01-01

    Background: Existing literature on panic disorder (PD) yields no data regarding the differential rates of improvement during Cognitive Behavioral Therapy (CBT), Selective Serotonin Reuptake Inhibitor (SSRI) or both combined (CBT+SSRI). Method: Patients were randomized to CBT, SSRI or CBT+SSRI which

  20. Use of dihydro-isobenzofuran in combination with serotonin reuptake inhibitors for CNS disease e.g. depression, anxiety, bipolar disorder, obsessive compulsory disorder

    DEFF Research Database (Denmark)

    2013-01-01

    NOVELTY - For treatment of a CNS disease in a patient, dihydro-isobenzofuran compound (I) in combination with serotonin reuptake inhibitor, is used. USE - For treatment of CNS disease (claimed) including depression, anxiety, bipolar disorder, obsessive compulsory disorder, post traumatic stress d...

  1. Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects

    Directory of Open Access Journals (Sweden)

    Shin D

    2017-03-01

    Full Text Available Dongseong Shin,1 SeungHwan Lee,2 Sojeong Yi,2 Seo Hyun Yoon,2 Joo-Youn Cho,2 Mi Young Bahng,3 In-Jin Jang,2 Kyung-Sang Yu2 1Clinical Trials Center, Gachon University Gil Medical Center, Incheon, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 3Department of Product Development, Dong-A ST, Seoul, Korea Objective: DA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5 in the plasma and urine after administration of a single oral dose in healthy male subjects.Methods: A dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP enzymes on the pharmacokinetics of DA-8031 was evaluated.Results: After a single dose, plasma DA-8031 reached the maximum concentration at a median of 2–3 h and was eliminated with terminal elimination half-life of 17.9–28.7 h. The mean renal clearance was 3.7–5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20–80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalized Cmax and AUC0–t of DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported.Conclusion: In conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20

  2. Methylphenidate and Atomoxetine Inhibit Social Play Behavior through Prefrontal and Subcortical Limbic Mechanisms in Rats

    Science.gov (United States)

    Achterberg, E.J. Marijke; van Kerkhof, Linda W.M.; Damsteegt, Ruth; Trezza, Viviana

    2015-01-01

    Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD. PMID:25568111

  3. Two-week administration of the combined serotonin-noradrenaline reuptake inhibitor duloxetine augments functioning of mesolimbic incentive processing circuits.

    Science.gov (United States)

    Ossewaarde, Lindsey; Verkes, Robbert J; Hermans, Erno J; Kooijman, Sabine C; Urner, Maren; Tendolkar, Indira; van Wingen, Guido A; Fernández, Guillén

    2011-09-15

    Anhedonia and lack of motivation are core symptoms of major depressive disorder (MDD). Neuroimaging studies in MDD patients have shown reductions in reward-related activity in terminal regions of the mesolimbic dopamine (DA) system, such as the ventral striatum. Monoamines have been implicated in both mesolimbic incentive processing and the mechanism of action of antidepressant drugs. However, not much is known about antidepressant effects on mesolimbic incentive processing in humans, which might be related to the effects on anhedonia. To investigate the short-term effects of antidepressants on reward-related activity in the ventral striatum, we investigated the effect of the combined serotonin-norepinephrine reuptake inhibitor duloxetine. Healthy volunteers underwent functional magnetic resonance imaging in a randomized, double-blind, placebo-controlled, crossover study. After taking duloxetine (60 mg once a day) or placebo for 14 days, participants completed a monetary incentive delay task that activates the ventral striatum during reward anticipation. Our results (n = 19) show enhanced ventral striatal responses after duloxetine administration compared with placebo. Moreover, this increase in ventral striatal activity was positively correlated with duloxetine plasma levels. This is the first study to demonstrate that antidepressants augment neural activity in mesolimbic DA incentive processing circuits in healthy volunteers. These effects are likely caused by the increase in monoamine neurotransmission in the ventral striatum. Our findings suggest that antidepressants may alleviate anhedonia by stimulating incentive processing. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  4. Selective serotonin reuptake inhibitors (SSRIs) for post-partum depression (PPD): a systematic review of randomized clinical trials.

    Science.gov (United States)

    De Crescenzo, Franco; Perelli, Federica; Armando, Marco; Vicari, Stefano

    2014-01-01

    The treatment of postpartum depression with selective serotonin reuptake inhibitors (SSRIs) has been claimed to be both efficacious and well tolerated, but no recent systematic reviews have been conducted. A qualitative systematic review of randomized clinical trials on women with postpartum depression comparing SSRIs to placebo and/or other treatments was performed. A comprehensive literature search of online databases, the bibliographies of published articles and grey literature were conducted. Data on efficacy, acceptability and tolerability were extracted and the quality of the trials was assessed. Six randomised clinical trials, comprising 595 patients, met quality criteria for inclusion in the analysis. Cognitive-behavioural intervention, psychosocial community-based intervention, psychodynamic therapy, cognitive behavioural therapy, a second-generation tricyclic antidepressant and placebo were used as comparisons. All studies demonstrated higher response and remission rates among those treated with SSRIs and greater mean changes on depression scales, although findings were not always statistically significant. Dropout rates were high in three of the trials but similar among treatment and comparison groups. In general, SSRIs were well tolerated and trial quality was good. There are few trials, patients included in the trials were not representative of all patients with postpartum depression, dropout rates in three trials were high, and long-term efficacy and tolerability were assessed in only two trials. SSRIs appear to be efficacious and well tolerated in the treatment of postpartum depression, but the available evidence fails to demonstrate a clear superiority over other treatments. © 2013 Elsevier B.V. All rights reserved.

  5. Comparison of paroxetine and dapoxetine, a novel selective serotonin reuptake inhibitor in the treatment of premature ejaculation

    Directory of Open Access Journals (Sweden)

    Abdulmuttalip Simsek

    2014-10-01

    Full Text Available Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor and the first drug approved for the on-demand treatment of premature ejaculation (PE. Our objective in this study was to characterize the efficacy of on-demand dapoxetine (30 and 60 mg and daily paroxetine (20 mg usage in treating PE. We conducted a 1 month study involving a total of 150 patients. Patients were divided into three groups of 50. Group 1 were treated with on-demand dapoxetine (30 mg, Group 2 with on-demand dapoxetine (60 mg and Group 3 with daily paroxetine (20 mg. Our outcome measurement was increased from baseline intravaginal ejaculatory latency time (IELT after treatment. The IELT increased from baseline to posttreatment by 117%, 117% and 170% in the paroxetine group (P 0.05, while the 60 mg dapoxetine group had a larger posttreatment IELT increase compared with the 30 mg dapoxetine (P < 0.05 and paroxetine (P < 0.01 groups. Dapoxetine (60 mg 1-3 h before planned intercourse is a very effective treatment modality for PE. However, an on-demand dose of 30 mg dapoxetine is no more effective than the currently prescribed paroxetine treatment.

  6. Dependence and withdrawal reactions to benzodiazepines and selective serotonin reuptake inhibitors. How did the health authorities react?

    Science.gov (United States)

    Nielsen, Margrethe; Hansen, Ebba Holme; Gøtzsche, Peter C

    2013-01-01

    Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time. Documentary study. We searched the web-sites of the European Medicines Agency and the drug agencies in USA, UK, and Denmark for documents mentioning benzodiazepines or SSRIs. We supplemented with other relevant literature that could contribute to our study. The searches were performed in 2009 in PubMed, Google, BMJ and JAMA. It took many years before the drug regulators acknowledged benzodiazepine dependence and SSRI withdrawal reactions and before the prescribers and the public were informed. Drug regulators relied mainly on the definitions of dependence and withdrawal reactions from the diagnostic psychiatric manuals, which contributed to the idea that SSRIs do not cause dependence, although it is difficult for many patients to stop treatment. In the perspective of a precautionary principle, drug agencies have failed to acknowledge that SSRIs can cause dependence and have minimised the problem with regard to its frequency and severity. In the perspective of a risk management principle, the drug agencies have reacted in concordance with the slowly growing knowledge of adverse drug reactions and have sharpened the information to the prescribers and the public over time. However, solely relying on spontaneous reporting of adverse effects leads to underestimation and delayed information about the problems. Given the experience with the benzodiazepines, we believe the regulatory bodies should have required studies from the manufacturers that could have elucidated the dependence potential of the SSRIs before marketing authorization was granted.

  7. An analysis of psychotropic drug sales. Increasing sales of selective serotonin reuptake inhibitors are closely related to number of products.

    Science.gov (United States)

    Nielsen, Margrethe; Gøtzsche, Peter

    2011-01-01

    Prescribing of selective serotonin reuptake inhibitors (SSRIs) has increased dramatically. To compare the sales of benzodiazepines and SSRIs within the primary care sector in Denmark and relate changes in usage to number of indications and products on the market. We used data from various sources to establish the sales curves of psychotropic drugs in the period 1970 to 2007, based on the Anatomic Therapeutic Classification system and Defined Daily Doses. Fluctuations in sales of psychotropic drugs that cannot be explained by disease prevalence were caused by changes in sales of the benzodiazepines and SSRIs. We found a decline in the sales of benzodiazepines after a peak in 1986, likely due to the recognition that they cause dependence. From a low level in 1992, we found that the sales of SSRIs increased almost linearly by a factor of 18, up to 44 DDD per 1000 inhabitants, which was closely related to the number of products on the market that increased by a factor of 16. Sales of antidepressant drugs are mainly determined by market availability of products indicating that marketing pressures are playing an important role. Thus the current level of use of SSRIs may not be evidence-based, which is supported by studies showing that the effect of SSRIs has been overestimated.

  8. Single photon emission computed tomography before and after treatment of anxiety using a selective serotonin reuptake inhibitor

    International Nuclear Information System (INIS)

    Warwick, J.M.; Heerden, B.B. van; Stein, D.J.; Niehaus, D.J.H.; Seedat, S.; Linden, G. van der; Harvey, B.A.

    2002-01-01

    Background: The selective serotonin reuptake inhibitors (SSRIs) are currently recommended as first line medications for a number of different anxiety disorders, including obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and social anxiety disorder (social phobia) (SAD). This raises the question of what effects these agents have on the functional neuroanatomy of anxiety disorders. Methods: Single photon emission computed tomography (SPECT) brain scanning was undertaken in patients with OCD, PTSD, and SAD before and after treatment with citalopram, the most selective of the SSRIs. Statistical parametric mapping (SPM) was used to compare scans (pre- vs post-medication, and responders vs nonresponders) in the combined group of subjects. Results: Citalopram pharmacotherapy resulted in significant deactivation within anterior and superior cingulate and left hippocampus. Deactivation within the anterior cingulate, left paracingular cortex, and right inferior frontal cortex was more marked in treatment responders. Baseline activation did not, however, predict response to pharmacotherapy. Conclusion: Although each of the anxiety disorders may be mediated by different neurocircuits, there are some overlaps in the functional neuroanatomy of their response to SSRI treatment. The current data is consistent with previous work demonstrating the importance of limbic circuits in this spectrum of disorders. These play a crucial role in cognitive-affective processing, and are innervated by serotonergic neurons

  9. Action of selective serotonin reuptake inhibitor on aggressive behavior in adult rat submitted to the neonatal malnutrition

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    Medeiros Jairza Maria Barreto

    2001-01-01

    Full Text Available The effect of the malnutrition during suckling on the aggressiveness was investigated in adult rats treated or not with citalopram, a selective serotonin reuptake inhibitor (SSRI. The animals were divided into two groups according to the diet used: nourished group-- the rats received the control diet with 23% protein during the life; and malnourished group-- the rats had its mothers submitted to diet with 7.8% protein during suckling. At 120 days of age, each group was sub-divided according to the treatment: acute -- consisting a single i.p. injection of saline solution or 20-mg/Kg citalopram; chronic -- consisting the single injections (1 per day during 14 days of saline or 20 mg/Kg citalopram. The acute or chronic treatment with SSRI reduces aggressive response in nourished rats, but not in malnourished ones. Thus, the malnutrition during the critical period of brain development seems to induce durable alterations in the function of the serotoninergic neurotransmission

  10. Rapid Onset of the Effects of Combined Selective Serotonin Reuptake Inhibitors and Electroacupuncture on Primary Depression: A Meta-Analysis.

    Science.gov (United States)

    Zhang, Yue; Qu, Shan-shan; Zhang, Ji-ping; Sun, Ya-ling; Liu, Wei-lu; Xie, Ling; Huang, Yong; Chen, Jun-qi

    2016-01-01

    To evaluate the efficacy and safety of combined selective serotonin reuptake inhibitors (SSRIs) and electroacupuncture therapies for the early treatment of primary depression. Randomized controlled trials (RCTs) were analyzed to compare therapy combining SSRIs and electroacupuncture to SSRI therapy alone. The RCTs were identified by searching, among others, PubMed, the Cochrane Library, the Chinese National Knowledge Infrastructure, the Chongqing VIP database for Chinese Technical Periodicals, WANFANG DATA, and the Chinese Biological Medical Literature Database. Scores from Self-Rated Depression Scale (SDS), the Hamilton Depression Scale (HAMD), the Side Effect Rating Scale (SERS), and the Treatment Emergent Symptom Scale (TESS) were analyzed and coded by two independent investigators and used to evaluate the safety and efficacy of treatment. Statistical analyses were performed using RevMan 5.2 software. Six RCTs were analyzed. The meta-analysis revealed that the combined therapy of SSRIs and electroacupuncture were associated with superior scores on the HAMD, SDS, and SERS measures compared with SSRIs alone after 1-4 weeks of treatment: HAMD scores, mean difference (MD)(1 week), 2.32 (95% confidence interval [CI](1 week), 1.47-3.16, p(1 week)electroacupuncture therapies is more efficient than treatments with SSRIs alone and leads to a better and earlier control of depressive symptoms.

  11. Morphological changes of intestinal mucosa in patients with different clinical variants of irritable bowel syndrome using tetracyclic antidepressants and selective serotonin reuptake inhibitor

    OpenAIRE

    Nagieva S.; Svintsitskyy A.; Kuryk O.; Korendovych I.

    2015-01-01

    Objective. To assess histological changes of colonic mucosa in patients with clinically different types of irritable bowel syndrome (IBS) before and after the treatment with tetracyclic antidepressant and selective serotonin reuptake inhibitor. Methods. Adult patients (over 18 years) with confirmed diagnosis of IBS were examined. Biopsy specimens were taken from colon during colonoscopy for the next histological examination. One expert gastrointestinal pathologist assessed all tissue samples....

  12. Serum Prolactin Levels in Patients with Major Depressive Disorder Receiving Selective Serotonin-Reuptake Inhibitor Monotherapy for 3 Months: A Prospective Study

    OpenAIRE

    Park, Young-Min

    2017-01-01

    Objective It is unclear whether selective serotonin-reuptake inhibitors (SSRIs) can significantly increase the prolactin level. The purpose of this study was to identify the relationship between the prolactin level and the administration of SSRIs such as escitalopram and sertraline. An additional purpose was to determine whether the elevation of prolactin differs between escitalopram and sertraline treatment. Methods Serum prolactin levels were measured at baseline and after 3 months in 23 pa...

  13. The SSRI [Selective serotonin reuptake inhibitor] effect of harmaline in Syrien Rue [Peganum harmala

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    Basar ALTINTERiM

    2012-09-01

    Full Text Available Harmal [Peganum harmala] or Syrian Rue is a plant from which harmine was first isolated, as well as a source of alkaloids, i.e., harmaline and tetrahydroharmine. The alkaloids in harmal, has a wide spectrum of pharmacological actions in various scales. The beta-carboline alkaloids [harmine, harmal, harmaline and harmalol] are found in the harmal seeds and a minor amounts in the aerial parts of plant. Peganum harmala, is a central nervous system stimulant and a reversible inhibitor of MAO-A. Generally speaking, herbs should be combined cautiously with antidepressants and patients should be monitored carefully after starting combination therapy. There are few studies on whether herbs and antidepressant drugs work together well or might cause adverse effects. What is important is the use of drugs with which the plant, that is to determined how much and how often. [J Contemp Med 2012; 2(3.000: 201-203

  14. Global gene expression in larval zebrafish (Danio rerio) exposed to selective serotonin reuptake inhibitors (fluoxetine and sertraline) reveals unique expression profiles and potential biomarkers of exposure

    International Nuclear Information System (INIS)

    Park, June-Woo; Heah, Tze Ping; Gouffon, Julia S.; Henry, Theodore B.; Sayler, Gary S.

    2012-01-01

    Larval zebrafish (Danio rerio) were exposed (96 h) to selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline and changes in transcriptomes analyzed by Affymetrix GeneChip ® Zebrafish Array were evaluated to enhance understanding of biochemical pathways and differences between these SSRIs. The number of genes differentially expressed after fluoxetine exposure was 288 at 25 μg/L and 131 at 250 μg/L; and after sertraline exposure was 33 at 25 μg/L and 52 at 250 μg/L. Same five genes were differentially regulated in both SSRIs indicating shared molecular pathways. Among these, the gene coding for FK506 binding protein 5, annotated to stress response regulation, was highly down-regulated in all treatments (results confirmed by qRT-PCR). Gene ontology analysis indicated at the gene expression level that regulation of stress response and cholinesterase activities were influenced by these SSRIs, and suggested that changes in transcription of these genes could be used as biomarkers of SSRI exposure. - Highlights: ► Exposure of zebrafish to selective serotonin reuptake inhibitors (SSRIs). ► Fluoxetine and sertraline generate different global gene expression profiles. ► Genes linked to stress response and acetylcholine esterase affected by both SSRIs. - Global gene expression profiles in zebrafish exposed to selective serotonin reuptake inhibitors.

  15. Short-term use of serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding.

    Science.gov (United States)

    Wang, Yen-Po; Chen, Yung-Tai; Tsai, Chia-Fen; Li, Szu-Yuan; Luo, Jiing-Chyuan; Wang, Shuu-Jiun; Tang, Chao-Hsiun; Liu, Chia-Jen; Lin, Han-Chieh; Lee, Fa-Yauh; Chang, Full-Young; Lu, Ching-Liang

    2014-01-01

    The association between selective serotonin receptor inhibitors (SSRIs) and risk of upper gastrointestinal bleeding remains controversial. Previous studies have generally evaluated the issue for approximately 3 months, even though the SSRI-mediated inhibition of platelet serotonin concentrations occurs within 7-14 days. The authors explored the risk of upper gastrointestinal bleeding after short-term SSRI exposure by a case-crossover design. The records of psychiatric inpatients with upper gastrointestinal bleeding were retrieved from the Taiwan National Health Insurance Database (1998-2009). Rates of antidepressant use were compared for case and control periods with time windows of 7, 14, and 28 days. The adjusted self-matched odds ratios from a conditional logistic regression model were used to determine the association between SSRI use and upper gastrointestinal bleeding. A total of 5,377 patients with upper gastrointestinal bleeding were enrolled. The adjusted odds ratio for the risk of upper gastrointestinal bleeding after SSRI exposure was 1.67 (95% CI=1.23-2.26) for the 7-day window, 1.84 (95% CI=1.42-2.40) for the 14-day window, and 1.67 (95% CI=1.34-2.08) for the 28-day window. SSRIs with high and intermediate, but not low, affinity for serotonin transporter were associated with upper gastrointestinal bleeding. An elevated risk of upper gastrointestinal bleeding after SSRI exposure was seen in male but not female patients. Short-term SSRI use (7-28 days) is significantly associated with upper gastrointestinal bleeding. Gender differences may exist in the relationship between SSRI use and upper gastrointestinal bleeding. Physicians should carefully monitor signs of upper gastrointestinal bleeding even after short-term exposure to SSRIs, as is done with nonsteroidal anti-inflammatory drugs and aspirin.

  16. Chronic atomoxetine treatment during adolescence does not influence decision-making on a rodent gambling task, but does modulate amphetamine's effect on impulsive action in adulthood.

    Science.gov (United States)

    Silveira, Mason M; Murch, W Spencer; Clark, Luke; Winstanley, Catharine A

    2016-06-01

    In addition to the symptoms of inattention, hyperactivity, and impulsivity, individuals with attention deficit hyperactivity disorder exhibit impaired performance on tests of real-world cost/benefit decision-making. Atomoxetine, a nonstimulant drug approved for the treatment of attention deficit hyperactivity disorder, is a selective norepinephrine reuptake inhibitor administered chronically during adolescence, a time during which the frontal brain regions necessary for executive function undergo extensive maturation. This treatment protocol can affect behavior well into adulthood, but whether it produces long-term changes in complex decision-making has not been investigated. Twenty-four Long-Evans rats were administered saline or 1.0 mg/kg atomoxetine daily from postnatal day 40 to 54. Two weeks after treatment, the adult rats were trained and assessed on the rodent gambling task, in which the animals chose from four options varying in reward, punishment, and uncertainty. Impulsive action was also measured by recording the number of premature responses made. Regardless of the treatment administered during adolescence, rats learned to favor the advantageous options characterized by small, low-penalty rewards in lieu of the larger, higher-penalty reward options. Rodent gambling task performance was then assessed following acute treatment with atomoxetine (0.1-1.0 mg/kg) and amphetamine (0.3-1.5 mg/kg). Across groups, the highest dose of atomoxetine impaired decision-making and decreased premature responding at all doses tested. Amphetamine also impaired choice performance, but selectively increased impulsive action in rats that had previously received atomoxetine treatment during adolescence. These findings contribute to our understanding of the long-term effects associated with chronic adolescent atomoxetine exposure and suggest that this treatment does not alter decision-making under conditions of risk and uncertainty in adulthood.

  17. Atomoxetine Induced Seperation Anxiety: A Case Report

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    Gonca Gul Celik

    2013-06-01

    Full Text Available Atomoxetine, a selective norepinephrine (NE inhibitor, is introduced as a safe non-stimulant alternative treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD, especially co-morbid ADHD and anxiety disorder and/or Tourette syndrome. Generally known side effects were including weight loss, decrease appetite, nausea and somnolence, exacerbation of tics. In this paper, we want to present an adolescent case with ADHD-inattention type who developed separation anxiety during Atomoxetine treatment. It will be discussed in light of current knowledge about possible neurotransmitter systems associated with side effects of Atomoxetine. Consequently, atomoxetine treatment may trigger anxiety or obsessional thoughts although without any premorbid psychopathology. However, it is unclear whether effects of genetic, gender or adolescence period are associated with this. [Cukurova Med J 2013; 38(3.000: 503-505

  18. Selective serotonin reuptake inhibitors and the risk of hepatocellular carcinoma in hepatitis B virus-infected patients

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    Chang CM

    2017-11-01

    Full Text Available Chia-Ming Chang,1–3 Ming-Shun Hsieh,1–4 Tsung-Chieh Yang,3,5 Vivian Chia-Rong Hsieh,6 Jen-Huai Chiang,7 Hsien-Hao Huang,1,3 Chorng-Kuang How,1,3 Sung-Yuan Hu,8 David Hung-Tsang Yen1,3 1Department of Emergency Medicine, Taipei Veterans General Hospital, 2Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, 3College of Medicine, National Yang-Ming University, Taipei, 4Department of Emergency Medicine, 5Division of Gastroenterology, Department of Internal Medicine, Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan, 6Department of Health Services Administration, 7Management Office for Health Data, China Medical University, 8Department of Emergency Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China Background: This study aimed to investigate the association between the use of selective serotonin reuptake inhibitors (SSRIs and the risk of hepatocellular carcinoma (HCC in patients with chronic hepatitis B virus (HBV infection.Methods: We conducted a population-based cohort study by using claims data from the Taiwan National Health Insurance Research Database (NHIRD. The study cohort comprised 1380 newly diagnosed HBV-infected patients with SSRI use who were frequency matched by age, sex, liver cirrhosis, and index year with HBV-infected patients without SSRI use in the comparison cohort. Each patient case was followed from 2000 to 2012 to identify incident HCC cases. Cox proportional hazards regression was performed to evaluate the association between SSRI use and HCC risk. The further sensitivity analysis used case-control study design. A total of 9070 HCC subjects retrieved from NHIRD, and equal non-HCC subjects were analyzed after matching for age and sex.Results: We identified 9 and 24 HCC cases in the study and comparison cohorts during the follow-up period of 7056 and 6845 person-years, respectively. The incidence rate of HCC was 1.28 and 3

  19. Successful Treatment with Atomoxetine of an Adolescent Boy with Attention Deficit/Hyperactivity Disorder, Extreme Obesity, and Reduced Melanocortin 4 Receptor Function

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    Wilfried Pott

    2013-03-01

    Full Text Available Objective: Recent case reports suggest a link between reduced melanocortinergic tone and both obesity and attention deficit / hyperactivity disorder (ADHD. We present the case of a 13-year-old, male, obese MC4R mutation carrier with ADHD. Case Report: The boy carries a heterozygous mutation in the melanocortin 4 receptor gene (MC4R; Met281Val, that leads to a reduced receptor function. Dominant mutations of this type represent major gene effects for obesity. He participated in a lifestyle intervention program for obesity and received treatment with the selective norepinephrine re-uptake inhibitor atomoxetine for 31 months. The boy markedly reduced his BMI from 47.2 to 29.6 kg/m². Conclusion: Atomoxetine proved to efficiently reduce weight in a severely obese MC4R mutation carrier with ADHD. We briefly discuss possible mechanisms for our observation, including evidence for the functional connectivity between melanocortinergic, dopaminergic, and norepinephrinergic brain circuitries.

  20. Aggravation by paroxetine, a selective serotonin reuptake inhibitor, of antral lesions generated by nonsteroidal anti-inflammatory drugs in rats.

    Science.gov (United States)

    Takeuchi, Koji; Tanaka, Akiko; Nukui, Kazuo; Kojo, Azusa; Gyenge, Melinda; Amagase, Kikuko

    2011-09-01

    Recent clinical studies have suggested a risk of adverse gastric reactions from the concomitant use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with nonsteroidal anti-inflammatory drugs (NSAIDs). We examined the adverse effects of SSRIs on antral lesions produced by indomethacin in rats. Rats fasted for 24 h were refed for 1 h, then administered indomethacin (30 mg/kg s.c.) 1 h after the refeeding and killed 6 h later. Paroxetine (1-10 mg/kg) was given orally 30 min before indomethacin. Indomethacin caused antral lesions in refed rats. Paroxetine dose-dependently aggravated these lesions, despite provoking no damage by itself. Similar results were obtained when other NSAIDs such as diclofenac, flurbiprofen, and loxoprofen were coadministered with paroxetine or when indomethacin was coadministered with other antidepressants such as fluvoxamine and milnacipran, but not imipramine or maprotiline. Exogenous 5-HT also worsened the indomethacin-induced antral damage, whereas the aggravating effect of paroxetine was attenuated by ondansetron, a selective 5-HT(3) antagonist, but not antagonists for other 5-HT receptor subtypes. Indomethacin plus paroxetine had no effect on gastric secretion but significantly decreased mucosal superoxide dismutase (SOD) activity as well as GSH content. The antral damage induced by indomethacin plus paroxetine was significantly prevented by antisecretory (acid or pepsin) agents and mucosal protective agents as well as SOD and allopurinol. These results suggest that SSRIs aggravate NSAID-induced antral lesions, probably via the activation of 5HT(3) receptors, and the mechanism of aggravation may involve the corrosive action of acid/pepsin as well as an impaired antioxidative system.

  1. Pharmacokinetics and pharmacodynamics of edivoxetine (LY2216684), a norepinephrine reuptake inhibitor, in pediatric patients with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Kielbasa, William; Quinlan, Tonya; Jin, Ling; Xu, Wen; Lachno, D Richard; Dean, Robert A; Allen, Albert J

    2012-08-01

    Edivoxetine (LY2216684) is a selective and potent norepinephrine reuptake inhibitor (NERI). The pharmacokinetics (PK) and pharmacodynamics (PD) of edivoxetine were assessed in children and adolescent patients with attention-deficit/hyperactivity disorder (ADHD) following single and once-daily oral doses of edivoxetine. During a phase 1 open-label safety, tolerability, and PK study, pediatric patients were administered edivoxetine at target doses of 0.05, 0.1, 0.2 and 0.3 mg/kg, and blood samples were collected to determine plasma concentrations of edivoxetine for PK assessments and plasma 3,4-dihydroxyphenylglycol (DHPG) concentrations for PD assessments. Edivoxetine plasma concentrations were measured using liquid chromatography with tandem mass spectrometric detection, and DHPG was measured using liquid chromatography with electrochemical detection. Edivoxetine PK was comparable between children and adolescents. The time to maximum concentration (t(max)) of edivoxetine was ∼2 hours, which was followed by a mono-exponential decline in plasma concentrations with a terminal elimination half-life (t(1/2)) of ∼6 hours. Dose-dependent increases in area under the edivoxetine plasma concentration versus time curve from zero to infinity (AUC(0-∞)) and maximum plasma concentration (C(max)) were observed, and there was no discernable difference in the apparent clearance (CL/F) or the apparent volume of distribution at steady state (V(ss)/F) across the dose range. In adolescents, edivoxetine caused a maximum decrease in plasma DHPG concentrations from baseline of ∼28%, most notably within 8 hours of edivoxetine administration. This initial study in pediatric patients with ADHD provides new information on the PK profile of edivoxetine, and exposures that decrease plasma DHPG consistent with the mechanism of action of a NERI. The PK and PD data inform edivoxetine pharmacology and can be used to develop comprehensive population PK and/or PK-PD models to guide dosing

  2. The effect of antenatal depression and selective serotonin reuptake inhibitor treatment on nerve growth factor signaling in human placenta.

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    Helena Kaihola

    Full Text Available Depressive symptoms during pregnancy are common and may have impact on the developing child. Selective serotonin reuptake inhibitors (SSRIs are the most prescribed antidepressant treatment, but unfortunately, these treatments can also negatively affect the behavioral development and health of a child during pregnancy. In addition, serotonin (5-HT exerts neurotrophic actions with thus far not fully known effects in the offspring. The neurotrophic growth factor (NGF is involved in neuronal cell survival and differentiation, and altered placenta levels have been found to increase the risk for pregnancy complications, similar to those found in women treated with SSRIs. We therefore investigated whether the NGF signaling pathway was altered in the placenta from women treated with SSRIs (n = 12 and compared them with placenta from depressed (n = 12 and healthy mothers (n = 12. Results from immunohistochemical stainings revealed that placental NGF protein levels of SSRI-treated women were increased in both trophoblasts and endothelial cells compared with depressed and control women. In addition, downstream of the NGF receptor TrkA, increased levels of the signaling proteins ROCK2 and phosphorylated Raf-1 were found in stromal cells and a tendency towards increased levels of ROCK2 in trophoblasts and endothelial cells in SSRI-treated women when compared to healthy controls. SSRI-treated women also displayed increased levels of phosphorylated ROCK2 in all placental cell types studied in comparison with depressed and control women. Interestingly, in placental endothelial cells from depressed women, NGF levels were significantly lower compared to control women, but ROCK2 levels were increased compared with control and SSRI-treated women. Taken together, these results show that the NGF signaling and downstream pathways in the placenta are affected by SSRI treatment and/or antenatal depression. This might lead to an altered placental function, although the

  3. Preschool outcomes following prenatal serotonin reuptake inhibitor exposure: differences in language and behavior, but not cognitive function.

    Science.gov (United States)

    Johnson, Katrina C; Smith, Alicia K; Stowe, Zachary N; Newport, D Jeffrey; Brennan, Patricia A

    2016-02-01

    To test the hypothesis that prenatal exposure to serotonin reuptake inhibitors (SRIs) is associated with language and behavioral outcomes in preschool-aged children, while accounting for confounds such as concomitant exposures and maternal mental illness. An observational, prospective, longitudinal study of mental illness in pregnancy was conducted at a university-based women's mental health clinic (April 2010-November 2012). A sample of 178 mother-child dyads participated in a laboratory visit at preschool age (2.5-5.5 years). The majority of women (87%) received psychotropic medication during pregnancy. Psychiatric status (based on DSM-IV), other medication use, and substance use were serially assessed and tested as confounds. Primary outcome measures included standardized measures of expressive language and cognitive function and mother and alternate caregiver ratings of child behavior problems, including the Pervasive Developmental Disorders (PDD) subscale of the Child Behavior Checklist. Linear regression analyses revealed that, after controlling for relevant covariates, expressive language scores from the Test of Early Language Development, 3rd edition, were negatively associated with prenatal SRI exposure (β = -0.15, t = -2.41), while the PDD behavioral problems subscales completed by alternate caregivers and mothers were positively associated with prenatal SRI exposure (β = 0.17, t = 2.01; β = 0.16, t = 2.00, respectively). Cognitive function, measured using the Differential Ability Scales, 2nd edition, was not associated with any medication exposures. The current data suggest a small but significant association between prenatal SRI exposure and preschool outcomes, including expressive language and behavior problems. These data corroborate data from recent, population-based studies, although overall, published findings are mixed. Replication and identification of moderating risk factors are needed to understand potential clinical implications.

  4. Selective serotonin reuptake inhibitors potentiate the rapid antidepressant-like effects of serotonin4 receptor agonists in the rat.

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    Guillaume Lucas

    2010-02-01

    Full Text Available We have recently reported that serotonin(4 (5-HT(4 receptor agonists have a promising potential as fast-acting antidepressants. Here, we assess the extent to which this property may be optimized by the concomitant use of conventional antidepressants.We found that, in acute conditions, the 5-HT(4 agonist prucalopride was able to counteract the inhibitory effect of the selective serotonin reuptake inhibitors (SSRI fluvoxamine and citalopram on 5-HT neuron impulse flow, in Dorsal Raphé Nucleus (DRN cells selected for their high (>1.8 Hz basal discharge. The co-administration of both prucalopride and RS 67333 with citalopram for 3 days elicited an enhancement of DRN 5-HT neuron average firing rate, very similar to what was observed with either 5-HT(4 agonist alone. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5-HT(1A receptors, that was two to three times stronger when the 5-HT(4 agonist was combined with citalopram. Similarly, co-administration of citalopram synergistically potentiated the enhancing effect of RS 67333 on CREB protein phosphorylation within the hippocampus. Finally, in the Forced Swimming Test, the combination of RS 67333 with various SSRIs (fluvoxamine, citalopram and fluoxetine was more effective to reduce time of immobility than the separate administration of each compound.These findings strongly suggest that the adjunction of an SSRI to a 5-HT(4 agonist may help to optimize the fast-acting antidepressant efficacy of the latter.

  5. Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Dobry, Yuriy; Rice, Timothy; Sher, Leo

    2013-01-01

    At present, there are scarce clinical and basic lab data concerning the risk of acute serotonin toxicity from selective serotonin reuptake inhibitors (SSRIs) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) co-administration. The health care community can strongly benefit from efforts to address the high risks associated with serotonin syndrome from this specific drug combination. The aim of this work is to review the risk of serotonin syndrome in adolescents and young adults prescribed with SSRIs and are concurrently using ecstasy. An electronic search of the major behavioral science bibliographic databases (Pubmed, PsycINFO, Medline) was conducted to retrieve peer-reviewed articles, which detail the clinical characteristics, biological mechanisms and social implications of SSRIs, MDMA, and their potential synergism in causing serotonin syndrome in the pediatric and young adult population. Search terms included "serotonin syndrome", "ecstasy", "MDMA", "pediatric", and "SSRI". Additional references were incorporated from the bibliographies of these retrieved articles. MDMA, in combination with the widely-prescribed SSRI antidepressant class, can lead to rapid, synergistic rise of serotonin (5-HT) concentration in the central nervous system, leading to the acute medical emergency known as serotonin syndrome. This review addresses such complication through an exploration of the theoretical mechanisms and clinical manifestations of this life-threatening pharmacological interaction. The increasing incidences of recreational ecstasy use and SSRI pharmacotherapy among multiple psychiatric disorders in the adolescent population have made this an overlooked yet increasingly relevant danger, which poses a threat to public health. This can be curbed through further research, as well as greater health care provision and attention from a regulatory body owing.

  6. Comparison of the neurobiological effects of attribution retraining group therapy with those of selective serotonin reuptake inhibitors

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    C. Wang

    2013-03-01

    Full Text Available The aim of this study was to compare the effectiveness of attribution retraining group therapy (ARGT with selective serotonin reuptake inhibitors (SSRIs in the treatment of major depressive disorder (MDD, generalized anxiety disorder (GAD, and obsessive-compulsive disorder (OCD. Subjects were sequentially recruited and randomized into two groups, one receiving ARGT (n = 63 and the other SSRIs (n = 66 for 8 weeks. Fifty-four ARGT outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 16 and 55 SSRI outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 17 completed the study. All subjects were assessed using the Hamilton Depression Scale and Hamilton Anxiety Scale before and after treatment. The 10-item Yale-Brown Obsessive Compulsive Scale was employed only for OCD subjects. Plasma levels of serotonin, norepinephrine, cortisol, and adrenocorticotropic hormone were also measured at baseline and 8 weeks after completion of treatment. Symptom scores were significantly reduced (P < 0.001 in both the ARGT and SSRI groups at the end of treatment. However, MDD, GAD and OCD patients in the ARGT group had significantly lower plasma cortisol concentrations compared to baseline (P < 0.05, whereas MDD and OCD patients receiving SSRIs showed significantly increased plasma levels of serotonin (P < 0.05. These findings suggest that ARGT may modulate plasma cortisol levels and affect the hypothalamus-pituitary-adrenal axis as opposed to SSRIs, which may up-regulate plasma serotonin levels via a different pathway to produce an overall improvement in the clinical condition of the patients.

  7. Comparison of the neurobiological effects of attribution retraining group therapy with those of selective serotonin reuptake inhibitors

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    C. Wang

    Full Text Available The aim of this study was to compare the effectiveness of attribution retraining group therapy (ARGT with selective serotonin reuptake inhibitors (SSRIs in the treatment of major depressive disorder (MDD, generalized anxiety disorder (GAD, and obsessive-compulsive disorder (OCD. Subjects were sequentially recruited and randomized into two groups, one receiving ARGT (n = 63 and the other SSRIs (n = 66 for 8 weeks. Fifty-four ARGT outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 16 and 55 SSRI outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 17 completed the study. All subjects were assessed using the Hamilton Depression Scale and Hamilton Anxiety Scale before and after treatment. The 10-item Yale-Brown Obsessive Compulsive Scale was employed only for OCD subjects. Plasma levels of serotonin, norepinephrine, cortisol, and adrenocorticotropic hormone were also measured at baseline and 8 weeks after completion of treatment. Symptom scores were significantly reduced (P < 0.001 in both the ARGT and SSRI groups at the end of treatment. However, MDD, GAD and OCD patients in the ARGT group had significantly lower plasma cortisol concentrations compared to baseline (P < 0.05, whereas MDD and OCD patients receiving SSRIs showed significantly increased plasma levels of serotonin (P < 0.05. These findings suggest that ARGT may modulate plasma cortisol levels and affect the hypothalamus-pituitary-adrenal axis as opposed to SSRIs, which may up-regulate plasma serotonin levels via a different pathway to produce an overall improvement in the clinical condition of the patients.

  8. Cellular correlates of enhanced anxiety caused by acute treatment with the selective serotonin reuptake inhibitor fluoxetine in rats

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    Shilpa eRavinder

    2011-12-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are used extensively in the treatment of depression and anxiety disorders. The therapeutic benefits of SSRIs typically require several weeks of continuous treatment. Intriguingly, according to clinical reports, symptoms of anxiety may actually increase during the early stages of treatment although more prolonged treatment alleviates affective symptoms. Consistent with earlier studies that have used animal models to capture this paradoxical effect of SSRIs, we find that rats exhibit enhanced anxiety-like behavior on the elevated plus-maze one hour after a single injection of the SSRI fluoxetine. Next we investigated the potential neural substrates underlying the acute anxiogenic effects by analyzing the morphological and physiological impact of acute fluoxetine treatment on principal neurons of the basolateral amygdala (BLA, a brain area that plays a pivotal role in fear and anxiety. Although earlier studies have shown that behavioral or genetic perturbations that are anxiogenic for rodents also increase dendritic spine-density in the BLA, we find that a single injection of fluoxetine does not cause spinogenesis on proximal apical dendritic segments on BLA principal neurons an hour later. However, at the same time point when a single dose of fluoxetine caused enhanced anxiety, it also enhanced action potential firing in BLA neurons in ex vivo slices. Consistent with this finding, in vitro bath application of fluoxetine caused higher spiking frequency and this increase in excitability was correlated with an increase in the input resistance of these neurons. Our results suggest that enhanced excitability of amygdala neurons may contribute to the increase in anxiety-like behavior observed following acute fluoxetine treatment.

  9. An association between initiation of selective serotonin reuptake inhibitors and suicide - a nationwide register-based case-crossover study.

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    Charlotte Björkenstam

    Full Text Available BACKGROUND: Treatment with selective serotonin reuptake inhibitors (SSRI is one of the most common treatments for depression. It is however not clear whether or not there is an increased short-term suicide risk during initiation with SSRI. METHODS: A register-based nationwide case-crossover study including 5,866 suicides, 1,698 women and 4,168 men, from the Death Register 2007-2010 in Sweden. SSRI initiation was defined as a dispensed prescription of SSRI within 28 days prior to the date of suicide with no previous dispensed prescription of SSRI within 4 months prior that prescription. The control period took place one year earlier. Odds ratio (OR was estimated using conditional logistic regression. RESULT: During the 28 day period prior to suicide 48 women and 138 men were exposed to SSRI initiation (while not being exposed in the control period and 22 women and 43 men were exposed in the control period (while not being exposed in the case period. The OR for suicide after initiation with SSRI was 2.7 (95% CI: 1.6-44 for women, and 4.3 (95% CI: 3.0-6.1 for men. The highest OR was found 8-11 days after initiation with SSRI 9.7 (95% CI: 3.0-31.7 for women and men combined. CONCLUSION: The main limitation in this study is confounding by indication, but the descriptive question is however not confounded by indication. Together with plausible biological mechanisms and previous clinical and epidemiological observations our findings, linking initiation of SSRI to increased short-term suicide risk, deserve further attention specifically in the clinical setting.

  10. Risk of preeclampsia after gestational exposure to selective serotonin reuptake inhibitors and other antidepressants: A study from The Norwegian Mother and Child Cohort Study.

    Science.gov (United States)

    Lupattelli, Angela; Wood, Mollie; Lapane, Kate; Spigset, Olav; Nordeng, Hedvig

    2017-10-01

    To describe the risk of early- and late-onset preeclampsia across pregnancies exposed to antidepressants and to evaluate the impact of timing and length of gestational exposure to antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), on preeclampsia. The Norwegian Mother and Child Cohort, a prospective population-based study, and the Medical Birth Registry of Norway provided information on antidepressant exposure, depression, and anxiety symptoms in pregnancy, preeclampsia diagnoses, and important covariates. Within a pregnancy cohort of depressed women, we compared the risk of late-onset preeclampsia between SSRI-exposed and nonmedicated pregnancies using marginal structural models (weighted) and modified Poisson regression models. Of the 5887 pregnancies included, 11.1% were exposed at any time before week 34 to SSRIs, 1.3% to serotonin-norepinephrine reuptake inhibitors, 0.4% to tricyclic antidepressants, and 0.5% to other antidepressants. The risks of early- and late-onset preeclampsia by exposure status in pregnancy were 0.3% and 3.6% (nonmedicated), 0.4% and 3.7% (SSRIs), 1.5% and 4.1% (serotonin-norepinephrine reuptake inhibitors), and 7.1% and 10.0% (tricyclic antidepressants). Compared with nonmedicated pregnancies, SSRI-exposed in mid and late gestation had adjusted relative risks for late-onset mild preeclampsia of 0.76 (95% confidence interval, 0.38-1.53) and 1.56 (0.71-3.44) (weighted models), respectively. There was no association between SSRI exposure in pregnancy and severe late-onset preeclampsia. We have provided evidence that SSRI use in early and midpregnancy does not substantially increase the risk of late-onset preeclampsia. © 2017 The Authors. Pharmacoepidemiology & Drug Safety published by John Wiley & Sons Ltd.

  11. Antidepressant drugs specifically inhibiting noradrenaline reuptake enhance recognition memory in rats.

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    Feltmann, Kristin; Konradsson-Geuken, Åsa; De Bundel, Dimitri; Lindskog, Maria; Schilström, Björn

    2015-12-01

    Patients suffering from major depression often experience memory deficits even after the remission of mood symptoms, and many antidepressant drugs do not affect, or impair, memory in animals and humans. However, some antidepressant drugs, after a single dose, enhance cognition in humans (Harmer et al., 2009). To compare different classes of antidepressant drugs for their potential as memory enhancers, we used a version of the novel object recognition task in which rats spontaneously forget objects 24 hr after their presentation. Antidepressant drugs were injected systemically 30 min before or directly after the training phase (Session 1 [S1]). Post-S1 injections were used to test for specific memory-consolidation effects. The noradrenaline reuptake inhibitors reboxetine and atomoxetine, as well as the serotonin noradrenaline reuptake inhibitor duloxetine, injected prior to S1 significantly enhanced recognition memory. In contrast, the serotonin reuptake inhibitors citalopram and paroxetine and the cyclic antidepressant drugs desipramine and mianserin did not enhance recognition memory. Post-S1 injection of either reboxetine or citalopram significantly enhanced recognition memory, indicating an effect on memory consolidation. The fact that citalopram had an effect only when injected after S1 suggests that it may counteract its own consolidation-enhancing effect by interfering with memory acquisition. However, pretreatment with citalopram did not attenuate reboxetine's memory-enhancing effect. The D1/5-receptor antagonist SCH23390 blunted reboxetine's memory-enhancing effect, indicating a role of dopaminergic transmission in reboxetine-induced recognition memory enhancement. Our results suggest that antidepressant drugs specifically inhibiting noradrenaline reuptake enhance cognition and may be beneficial in the treatment of cognitive symptoms of depression. (c) 2015 APA, all rights reserved).

  12. A naturalistic long-term comparison study of selective serotonin reuptake inhibitors in the treatment of panic disorder.

    Science.gov (United States)

    Dannon, Pinhas N; Iancu, Iulian; Lowengrub, Katherine; Gonopolsky, Yehudit; Musin, Ernest; Grunhaus, Leon; Kotler, Moshe

    2007-01-01

    Selective serotonin reuptake inhibitors (SSRIs) are currently considered as the first drug of choice in the treatment of panic disorder (PD). The aim of this long-term, naturalistic comparison study was to compare 4 SSRIs with respect to tolerability and treatment outcome of PD. Outcome measures included relapse rates and adverse effects. Two hundred patients with PD were enrolled in our study. All subjects met DSM-IV criteria for PD or PD with agoraphobia (PDA). All patients were assigned to receive SSRI monotherapy for 12 months with either citalopram (n = 50), fluoxetine (n = 50), fluvoxamine (n = 50), or paroxetine (n = 50) in a randomized, nonblinded fashion. Both the treating psychiatrist and the patients were not blind to the assigned treatment, but the clinician raters were blind to the study medication. The study design allowed for assignment of a particular SSRI as indicated according to the clinical judgment of the study psychiatrists. The Panic Self-Questionnaire, which is a self-report scale, was administered at baseline and then once per month during the duration of the 12-month study. The visual analog scale and the Clinical Global Impression Scale were administered at baseline and then once per month during the period of the study. Reports of sexual dysfunction were assessed using a nonstructured clinical interview at monthly visits. The body weight of study subjects was measured at baseline, and then at the 12th month visit end point. Of 200 patients who entered the study, 127 patients (63.5%) completed the full 12-month protocol. Retention rates were highest for paroxetine (76% [38/50]), intermediate for citalopram (68% [34/50]) and fluvoxamine (60% [30/50]), and lowest for fluoxetine (50% [25/50]). Patients who completed the 12-month protocol responded favorably to the study treatment. The paroxetine and the citalopram groups had significantly lower rates of panic symptoms as measured at visits on weeks 4 and 8. At visits on months 3, 6, 9, and

  13. Functioning in patients with major depression treated with duloxetine or a selective serotonin reuptake inhibitor in East Asia

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    Novick D

    2016-02-01

    Full Text Available Diego Novick,1 William Montgomery,2 Josep Maria Haro,3 Maria Victoria Moneta,3 Gang Zhu,4 Li Yue,5 Jihyung Hong,6 Héctor Dueñas,7 Roberto Brugnoli8 1Eli Lilly and Company, Windlesham, Surrey, UK; 2Eli Lilly Australia Pty Ltd, West Ryde, NSW, Australia; 3Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, CIBERSAM, Universitat de Barcelona, Barcelona, Spain; 4Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, 5Lilly Suzhou Pharmaceutical Company, Ltd, Shanghai, People’s Republic of China; 6Department of Healthcare Management, Gachon University, Seongnam, South Korea; 7Eli Lilly de Mexico, Mexico City, Mexico; 8School of Medicine, Sapienza University of Rome, Rome, ItalyPurpose: To assess and compare the levels of functioning in patients with major depressive disorder treated with either duloxetine with a daily dose of ≤60 mg or a selective serotonin reuptake inhibitor (SSRI as monotherapy for up to 6 months in a naturalistic setting in East Asia. In addition, this study examined the impact of painful physical symptoms (PPS on the effects of these treatments.Patients and methods: Data for this post hoc analysis were taken from a 6-month prospective observational study involving 1,549 patients with major depressive disorder without sexual dysfunction. The present analysis focused on a subgroup of patients from East Asia (n=587. Functioning was measured using the Sheehan Disability Scale (SDS. Depression severity was assessed using the 16-item Quick Inventory of Depressive Symptomatology-Self Report. PPS were rated using the modified Somatic Symptom Inventory. A mixed model with repeated measures was fitted to compare the levels of functioning between duloxetine-treated (n=227 and SSRI-treated (n=225 patients, adjusting for baseline patient characteristics.Results: The mean SDS total score was similar between the two treatment cohorts (15.46 [standard deviation =6.11] in the duloxetine

  14. The role of genetic factors in predicting results of obesity treatment with sibutramine – serotonin-norepinephrine reuptake inhibitor

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    Marina Galieva

    2016-12-01

    Full Text Available Aim. To study the influence of SERT and GNB3 gene polymorphisms on the results of the treatment of obesity by serotonin-norepinephrine reuptake inhibitors. Methods. Patients who didn’t achieve significant weight loss in 3 month period during PrimaVera Study were selected for the genetic evaluation and compared with the group of “effective treatment”. The study included 66 patients (57 females and 9 males, mean age 39.29 ± 12.64 years, who received Reduxin (sibutramine + MCC at the dose of 10 mg. Term follow-up was 3 months. Clinical examination and determination of biochemical parameters was performed at baseline and at the end of the observation period. In order to assess the type of eating behavior and identify hidden depressions a validated questionnaire was used (questionnaire "The types of eating disorders» (DEBQ, Beck Depression Scale. Also conducted a genetic study to assess SERT and GBN3 gene polymorphisms. Results. In the second group presence of S-allele SERT-gene was significantly associated with higher rates of external type of eating behavior. A statistically significant correlation between the genotype or allele of either body weight, rates of blood pressure, heart rate and cholesterol have not been found. In the first group there was a statistically significant association of S-allele carrier with less weight loss -2.8 kg (compared to l-allele and higher rates at baseline glucose 5.38 ± 0.63 mmol / l (compared to L-allele of -3.28 kg and 5.04 ± 0.91 mmol / l. In the study of GBN3 polymorphism in the second group among CC genotype carriers there were higher levels of systolic blood pressure (SBP before treatment (129.27 ± 9.16 mmHg, SBP and diastolic blood pressure after 3 months of treatment (127.36 ± 8.16 and 78.36 ± 4.3 mmHg compared with CT genotype (117.27 ± 12.5; 115.45 ± 10.6; 72.91 ± 6.0 mm Hg, respectively (p <0.05. Also among the carriers of C-allele there were more severe manifestations of

  15. Age-related changes in prefrontal norepinephrine transporter density: The basis for improved cognitive flexibility after low doses of atomoxetine in adolescent rats

    Science.gov (United States)

    Bradshaw, Sarah E.; Agster, Kara L.; Waterhouse, Barry D.; McGaughy, Jill A.

    2016-01-01

    Adolescence is a period of major behavioral and brain reorganization. As diagnoses and treatment of disorders like attention deficit hyperactivity disorder (ADHD) often occur during adolescence, it is important to understand how the prefrontal cortices change and how these changes may influence the response to drugs during development. The current study uses an adolescent rat model to study the effect of standard ADHD treatments, atomoxetine and methylphenidate on attentional set shifting and reversal learning. While both of these drugs act as norepinephrine reuptake inhibitors, higher doses of atomoxetine and all doses of methylphenidate also block dopamine transporters (DAT). Low doses of atomoxetine, were effective at remediating cognitive rigidity found in adolescents. In contrast, methylphenidate improved performance in rats unable to form an attentional set due to distractibility but was without effect in normal subjects. We also assessed the effects of GBR 12909, a selective DAT inhibitor, but found no effect of any dose on behavior. A second study in adolescent rats investigated changes in norepinephrine transporter (NET) and dopamine beta hydroxylase (DBH) density in five functionally distinct subregions of the prefrontal cortex: infralimbic, prelimbic, anterior cingulate, medial and lateral orbitofrontal cortices. These regions are implicated in impulsivity and distractibility. We found that NET, but not DBH, changed across adolescence in a regionally selective manner. The prelimbic cortex, which is critical to cognitive rigidity, and the lateral orbitofrontal cortex, critical to reversal learning and some forms of response inhibition, showed higher levels of NET at early than mid- to late adolescence. PMID:26774596

  16. Targeting impulsivity in Parkinson’s disease using atomoxetine

    Science.gov (United States)

    Housden, Charlotte R.; Regenthal, Ralf; Barker, Roger A.; Müller, Ulrich; Rowe, James; Sahakian, Barbara J.; Robbins, Trevor W.

    2014-01-01

    Noradrenergic dysfunction may play a significant role in cognition in Parkinson’s disease due to the early degeneration of the locus coeruleus. Converging evidence from patient and animal studies points to the role of noradrenaline in dopaminergically insensitive aspects of the parkinsonian dysexecutive syndrome, yet the direct effects of noradrenergic enhancement have not to date been addressed. Our aim was to directly investigate these, focusing on impulsivity during response inhibition and decision making. To this end, we administered 40 mg atomoxetine, a selective noradrenaline re-uptake inhibitor to 25 patients with Parkinson’s disease (12 female /13 male; 64.4 ± 6.9 years old) in a double blind, randomized, placebo controlled design. Patients completed an extensive battery of neuropsychological tests addressing response inhibition, decision-making, attention, planning and verbal short term memory. Atomoxetine improved stopping accuracy on the Stop Signal Task [F(1,19) = 4.51, P = 0.047] and reduced reflection impulsivity [F(1,9) = 7.86, P = 0.02] and risk taking [F(1,9) = 9.2, P = 0.01] in the context of gambling. The drug also conferred effects on performance as a function of its measured blood plasma concentration: it reduced reflection impulsivity during information sampling [adjusted R2 = 0.23, F(1,16) = 5.83, P = 0.03] and improved problem solving on the One Touch Stockings of Cambridge [adjusted R2 = 0.29, F(1,17) = 8.34, P = 0.01]. It also enhanced target sensitivity during sustained attention [F(1,9) = 5.33, P = 0.046]. The results of this exploratory study represent the basis of specific predictions in future investigations on the effects of atomoxetine in Parkinson’s disease and support the hypothesis that targeting noradrenergic dysfunction may represent a new parallel avenue of therapy in some of the cognitive and behavioural deficits seen in the disorder. PMID:24893708

  17. Time courses of improvement and symptom remission in children treated with atomoxetine for attention-deficit/hyperactivity disorder: analysis of Canadian open-label studies

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    Turgay Atilla

    2011-05-01

    Full Text Available Abstract Background The relatively short durations of the initial pivotal randomized placebo-controlled trials involving atomoxetine HCl for the treatment of attention-deficit/hyperactivity disorder (ADHD provided limited insight into the time courses of ADHD core symptom responses to this nonstimulant, selective norepinephrine reuptake inhibitor. The aim of this analysis was to evaluate time courses of treatment responses or remission, as assessed by attainment of prespecified scores on the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-PI and the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S scales, during up to 1 year of atomoxetine treatment in children with ADHD. Methods Using pooled data from three Canadian open-label studies involving 338 children ages 6-11 years with ADHD who were treated with atomoxetine for 3, 6 and 12 months, and survival analysis methods for interval-censored data, we estimated the time to: 1 improvement and robust improvement defined by ≥25% and ≥40% reductions from baseline ADHDRS-IV-PI total scores, respectively; and 2 remission using two definitions: a final score of ADHDRS-IV-PI ≤18 or a final score of CGI-ADHD-S ≤2. Results The median time to improvement was 3.7 weeks (~1 month, but remission of symptoms did not occur until a median of 14.3 weeks (~3.5 months using the most stringent CGI-ADHD-S threshold. Probabilities of robust improvement were 47% at or before 4 weeks of treatment; 76% at 12 weeks; 85% at 26 weeks; and 96% at 52 weeks. Probabilities of remission at these corresponding time points were 30%, 59%, 77%, and 85% (using the ADHDRS-IV scale and 8%, 47%, 67%, and 75% (using the CGI-ADHD-S scale. The change from atomoxetine treatment month 5 to month 12 of -1.01 (1.03 was not statistically significant (p = .33. Conclusions Reductions in core ADHD symptoms during atomoxetine treatment are gradual. Although approximately one-half of study

  18. Steroidogenic disruptive effects of the serotonin-noradrenaline reuptake inhibitors duloxetine, venlafaxine and tramadol in the H295R cell assay and in a recombinant CYP17 assay

    DEFF Research Database (Denmark)

    Islin, Julie; Munkboel, Cecilie Hurup; Styrishave, Bjarne

    2018-01-01

    The aim of this study was to determine the steroidogenic endocrine disrupting effect of the three most widely used serotonin-noradrenaline reuptake inhibitors duloxetine, venlafaxine and tramadol, using two in vitro models, the H295R assay and a recombinant CYP17 enzyme assay. Steroid hormones were...... quantified using LC-MS/MS. Duloxetine showed endocrine disrupting effects at 5-20μM with CYP17 being the main target. Venlafaxine also affected the steroidogenesis, mainly by affecting the CYP17 lyase reaction, although at much higher concentrations i.e. 100μM. Tramadol only exerted minor effects...... on the steroidogenesis with the lowest observed effect at 314μM. Based on the H295R results, the inhibition of CYP17 by duloxetine and venlafaxine was investigated in a recombinant CYP17 assay with the use of the 4 major CYP17 substrates pregnenolone, progesterone, 17α-hydroxypregnenolone and 17α...

  19. The effect of selective serotonin reuptake inhibitors in healthy first-degree relatives of patients with major depressive disorder - an experimental medicine blinded controlled trial

    DEFF Research Database (Denmark)

    Knorr, Ulla Benedichte

    2012-01-01

    .37). In univariate analyses, no statistically significant correlations were found between change in the primary and secondary outcomes, respectively, and the covariates age, sex, Hamilton depression score 17-items, and plasma escitalopram levels. In conclusion, the present trial does not support an effect......The mechanisms of action for selective serotonin re-uptake in-hibitors (SSRI) in depressed patients remain widely unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. Further, the serotonergic neurotransmitter system seems closely...... linked to personality and cognition. It is not known if SSRIs have a direct effect on the HPA system, personality or cognition that is independent of their effect on depression. Thus, healthy individuals with a genetic liability for depression represent a group of particular interest when investigating...

  20. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis

    DEFF Research Database (Denmark)

    Jakobsen, Janus Christian; Katakam, Kiran Kumar; Schou, Anne

    2017-01-01

    -term effects. Conclusions: SSRIs might have statistically significant effects on depressive symptoms, but all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial......Background: The evidence on selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder is unclear. Methods: Our objective was to conduct a systematic review assessing the effects of SSRIs versus placebo, 'active' placebo, or no intervention in adult participants with major...... depressive disorder. We searched for eligible randomised clinical trials in The Cochrane Library's CENTRAL, PubMed, EMBASE, PsycLIT, PsycINFO, Science Citation Index Expanded, clinical trial registers of Europe and USA, websites of pharmaceutical companies, the U.S. Food and Drug Administration (FDA...

  1. The six most widely used selective serotonin reuptake inhibitors decrease androgens and increase estrogens in the H295R cell line

    DEFF Research Database (Denmark)

    Hansen, Cecilie Hurup; Larsen, Lizette Weber; Sørensen, Amalie Møller

    2017-01-01

    Selective serotonin reuptake inhibitors (SSRIs) used as first line of treatment in major depressive disorder (MDD) are known to exert negative effects on the endocrine system and fertility. The aim of the present study was to investigate the possible endocrine disrupting effect of six SSRIs...... in the pathway. Furthermore, all SSRIs relatively increased the estrogen/androgen ratio, indicating stimulating effects on the aromatase. Our study demonstrates the potential of SSRIs to interfere with steroid production in the H295R cells around Cmax levels and indicates that these drugs should be investigated...... validated LC-MS/MS method. All 6 SSRIs were found to exert endocrine disrupting effects on steroid hormone synthesis at concentrations just around Cmax. Although the mechanisms of disruption were all different, they all resulted in decreased testosterone levels, some due to effects on CYP17, some earlier...

  2. Increasing the risk of spontaneous abortion and major malformations in newborns following use of serotonin reuptake inhibitors during pregnancy: A systematic review and updated meta-analysis

    Directory of Open Access Journals (Sweden)

    Nikfar Shekoufeh

    2012-11-01

    Full Text Available Abstract Selective serotonin reuptake inhibitors (SSRIs are the most frequently used antidepressants during pregnancy. There are conflicting results about their influence on pregnancy outcomes. The goal of this study was to update our previous meta-analysis about pregnancy outcomes following exposure to SSRIs. For this purpose, all relevant databases were searched from 1990 to March 2012 for studies investigating the pregnancy outcomes following exposure to any therapeutic dosage of any SSRI (fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine during pregnancy. Types of outcome investigated were spontaneous abortion, major malformations, cardiovascular malformations, and minor malformations. A total of 25 studies met our criteria and were included in the meta-analysis. The odds ratio (OD values are 1.87 (95% CI: 1.5 to 2.33, P

  3. Rapid screening of selective serotonin re-uptake inhibitors in urine samples using solid-phase microextraction gas chromatography-mass spectrometry.

    Science.gov (United States)

    Salgado-Petinal, Carmen; Lamas, J Pablo; Garcia-Jares, Carmen; Llompart, Maria; Cela, Rafael

    2005-07-01

    In this paper a solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) method is proposed for a rapid analysis of some frequently prescribed selective serotonin re-uptake inhibitors (SSRI)-venlafaxine, fluvoxamine, mirtazapine, fluoxetine, citalopram, and sertraline-in urine samples. The SPME-based method enables simultaneous determination of the target SSRI after simple in-situ derivatization of some of the target compounds. Calibration curves in water and in urine were validated and statistically compared. This revealed the absence of matrix effect and, in consequence, the possibility of quantifying SSRI in urine samples by external water calibration. Intra-day and inter-day precision was satisfactory for all the target compounds (relative standard deviation, RSD, detection limits achieved were detected and tentatively identified.

  4. Anhedonia in depressed patients on treatment with selective serotonin reuptake inhibitor anti-depressant--A two-centered study in Malaysia.

    Science.gov (United States)

    Yee, Anne; Chin, Soo Cheng; Hashim, Aili Hanim bt; Harbajan Singh, Manveen Kaur A P; Loh, Huai Seng; Sulaiman, Ahmad Hatim; Ng, Chong Guan

    2015-01-01

    Anhedonia is the reduced ability to experience pleasure. It is a core symptom of depression and is particularly difficult to treat. This study aims to compare the level of anhedonia between depressed patients on anti-depressants and healthy subjects. A total of 111 depressed patients on selective serotonin reuptake inhibitor (SSRI) and 82 healthy subjects were recruited from the outpatient psychiatric services at two major general hospitals in a cross-sectional study. Subjects were assessed using the Mini International Neuropsychiatric Interview 5.0.0 or MINI, Beck's Depression Index (BDI), and Snaith-Hamilton Pleasure Scale (SHAPS). Relevant personal and sociodemographic information were also collected. There was a significant association between educational level and SHAPS-M scores (P depressed subjects treated with anti-depressant compared with the healthy subjects, after adjusting the confounding factors, BDI score, and educational level. Anhedonia often persists in depressed patients despite on SSRI anti-depressant treatment.

  5. The novel triple monoamine reuptake inhibitor tesofensine induces sustained weight loss and improves glycemic control in the diet-induced obese rat: comparison to sibutramine and rimonabant

    DEFF Research Database (Denmark)

    Hansen, Henrik H; Hansen, Gitte; Tang-Christensen, Mads

    2010-01-01

    Tesofensine, a novel triple monoamine reuptake inhibitor, produces a significant weight loss in humans. The present study aimed at characterizing the weight-reducing effects of tesofensine in a rat model of diet-induced obesity. Sibutramine and rimonabant were used as reference comparators....... Compared to baseline, long-term treatment with tesofensine (28 days, 1.0 or 2.5mg/kg, p.o.) resulted in a significant, dose-dependent and sustained weight loss of 5.7 and 9.9%, respectively. Sibutramine (7.5mg/kg, p.o.) treatment caused a sustained weight loss of 7.6%, whereas the employed dose...... of rimonabant (10mg/kg, p.o.) only produced a transient weight reduction. While all compounds exhibited a significant inhibitory effect on food intake which gradually wore off, the hypophagic effect of tesofensine was longer lasting than sibutramine and rimonabant. In contrast to tesofensine, the body weight...

  6. Blockade of the high-affinity noradrenaline transporter (NET) by the selective 5-HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice

    Science.gov (United States)

    Nguyen, Hai T; Guiard, Bruno P; Bacq, Alexandre; David, Denis J; David, Indira; Quesseveur, Gaël; Gautron, Sophie; Sanchez, Connie; Gardier, Alain M

    2013-01-01

    BACKGROUND AND PURPOSE Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT]ext). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA]ext). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined. EXPERIMENTAL APPROACH This study examined the effects of escitalopram, on both [5-HT]ext and [NA]ext in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT−/−) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA]ext, either by a direct mechanism involving the inhibition of the low- or high-affinity noradrenaline transporters, or by an indirect mechanism promoted by [5-HT]ext elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT]ext and/or [NA]ext affected the antidepressant-like activity of escitalopram. KEY RESULTS In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT]ext and [NA]ext. As expected, escitalopram failed to increase cortical [5-HT]ext in SERT−/− mice, whereas its neurochemical effects on [NA]ext persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5-HT uptake mediated by low-affinity monoamine transporters. CONCLUSIONS AND IMPLICATIONS These experiments suggest that escitalopram enhances, although moderately, cortical [NA]extin vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET). PMID:22233336

  7. Pharmacological Characterization of H05, a Novel Serotonin and Noradrenaline Reuptake Inhibitor with Moderate 5-HT2A Antagonist Activity for the Treatment of Depression.

    Science.gov (United States)

    Xu, Xiangqing; Wei, Yaqin; Guo, Qiang; Zhao, Song; Liu, Zhiqiang; Xiao, Ting; Liu, Yani; Qiu, Yinli; Hou, Yuanyuan; Zhang, Guisen; Wang, KeWei

    2018-06-01

    Multitarget antidepressants selectively inhibiting monoaminergic transporters and 5-hydroxytryptamine (5-HT) 2A receptor have demonstrated higher efficacy and fewer side effects than selective serotonin reuptake inhibitors. In the present study, we synthesized a series of novel 3-(benzo[d][1,3]dioxol-4-yloxy)-3-arylpropyl amine derivatives, among which compound H05 was identified as a lead, exhibiting potent inhibitory effects on both serotonin ( K i = 4.81 nM) and norepinephrine (NE) ( K i = 6.72 nM) transporters and moderate 5-HT 2A antagonist activity (IC 50 = 60.37 nM). H05 was able to dose-dependently reduce the immobility duration in mouse forced swimming test and tail suspension test, with the minimal effective doses lower than those of duloxetine, and showed no stimulatory effect on locomotor activity. The administration of H05 (5, 10, and 20 mg/kg, by mouth) significantly shortened the immobility time of adrenocorticotropin-treated rats that serve as a model of treatment-resistant depression, whereas imipramine (30 mg/kg, by mouth) and duloxetine (30 mg/kg, by mouth) showed no obvious effects. Chronic treatment with H05 reversed the depressive-like behaviors in a rat model of chronic unpredictable mild stress and a mouse model of corticosterone-induced depression. Microdialysis analysis revealed that the administration of H05 at either 10 or 20 mg/kg increased the release of 5-HT and NE from the frontal cortex. The pharmacokinetic (PK) and brain penetration analyses suggest that H05 has favorable PK properties with good blood-brain penetration ability. Therefore, it can be concluded that H05, a novel serotonin and NE reuptake inhibitor with 5-HT 2A antagonist activity, possesses efficacious activity in the preclinical models of depression and treatment-resistant depression, and it may warrant further evaluation for clinical development. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  8. The Safety of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Research.

    Science.gov (United States)

    Reed, Victoria A; Buitelaar, Jan K; Anand, Ernie; Day, Kathleen Ann; Treuer, Tamás; Upadhyaya, Himanshu P; Coghill, David R; Kryzhanovskaya, Ludmila A; Savill, Nicola C

    2016-07-01

    Atomoxetine is a noradrenergic reuptake inhibitor prescribed for attention-deficit/hyperactivity disorder (ADHD) that first gained approval in the USA in 2002 and has been authorized in 97 countries worldwide. The aim of this paper is to comprehensively review publications that addressed one or more of seven major safety topics relevant to atomoxetine treatment of children and adolescents (aged ≥6 years) diagnosed with ADHD. While the review focuses on children and adolescents, publications in which data from patients aged >18 years and from 6 to 18 years were analyzed in the same dataset were included. Using a predefined search strategy, including agreement of two reviewers when selecting papers, reduced the potential for bias. Using this process, we identified 70 eligible papers (clinical trials, epidemiological studies, and case reports) across the seven topics. We also referred to the European Summary of Product Characteristics (SPC) and US label. We found 15 papers about suicidality, three about aggression/hostility, seven about psychosis/mania, six about seizures, seven about hepatic effects, 29 about cardiovascular effects, and 28 about growth and development. The main findings (i.e., those from the largest and most well-conducted studies/analyses) are as follows. A large register-based study of pediatric and adult patients (6818 received atomoxetine) calculated a hazard ratio of 0.96 for suicide-related events during treatment with atomoxetine, and a meta-analysis of 23 placebo-controlled studies (N = 3883), published in 2014, found no completed suicides and no statistically significant association between atomoxetine and suicidality. The frequency of aggression/hostility was not statistically significantly higher with atomoxetine, e.g., experienced by 1.6 % (N = 21/1308) of atomoxetine-treated patients versus 1.1 % (N = 9/806) of placebo-treated patients in one meta-analysis. Symptoms of psychosis and mania were mainly observed in patients

  9. Striatal Activation Predicts Differential Therapeutic Responses to Methylphenidate and Atomoxetine.

    Science.gov (United States)

    Schulz, Kurt P; Bédard, Anne-Claude V; Fan, Jin; Hildebrandt, Thomas B; Stein, Mark A; Ivanov, Iliyan; Halperin, Jeffrey M; Newcorn, Jeffrey H

    2017-07-01

    Methylphenidate has prominent effects in the dopamine-rich striatum that are absent for the selective norepinephrine transporter inhibitor atomoxetine. This study tested whether baseline striatal activation would predict differential response to the two medications in youth with attention-deficit/hyperactivity disorder (ADHD). A total of 36 youth with ADHD performed a Go/No-Go test during functional magnetic resonance imaging at baseline and were treated with methylphenidate and atomoxetine using a randomized cross-over design. Whole-brain task-related activation was regressed on clinical response. Task-related activation in right caudate nucleus was predicted by an interaction of clinical responses to methylphenidate and atomoxetine (F 1,30  = 17.00; p atomoxetine. The rate of robust response was higher for methylphenidate than for atomoxetine in youth with high (94.4% vs. 38.8%; p = .003; number needed to treat = 2, 95% CI = 1.31-3.73) but not low (33.3% vs. 50.0%; p = .375) caudate activation. Furthermore, response to atomoxetine predicted motor cortex activation (F 1,30  = 14.99; p atomoxetine in youth with ADHD, purportedly reflecting the dopaminergic effects of methylphenidate but not atomoxetine in the striatum, whereas motor cortex activation may predict response to atomoxetine. These data do not yet translate directly to the clinical setting, but the approach is potentially important for informing future research and illustrates that it may be possible to predict differential treatment response using a biomarker-driven approach. Stimulant Versus Nonstimulant Medication for Attention Deficit Hyperactivity Disorder in Children; https://clinicaltrials.gov/; NCT00183391. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

  10. The monoamine reuptake inhibitor BTS 74 398 fails to evoke established dyskinesia but does not synergise with levodopa in MPTP-treated primates.

    Science.gov (United States)

    Hansard, Matthew J; Smith, Lance A; Jackson, Michael J; Cheetham, Sharon C; Jenner, Peter

    2004-01-01

    Long-term treatment of Parkinson's disease (PD) with levodopa (L-dopa) induces dyskinesia that, once established, is provoked by each dose of L-dopa or a dopamine (DA) agonist. In contrast, monoamine reuptake inhibitors may reverse motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates without provoking established involuntary movements. We now examine whether the potent monoamine reuptake blocker BTS 74 398 induces established dyskinesia in MPTP-treated common marmosets primed previously with L-dopa and whether co-administration of BTS 74 398 with L-dopa potentiates motor behaviour and dyskinesia induced by acute L-dopa treatment. Administration of BTS 74 398 (2.5, 5.0, or 10.0 mg/kg, p.o.) in MPTP-treated common marmosets increased locomotor activity and reduced motor disability in a dose-related manner but did not provoke involuntary movements. BTS 74 398 (2.5, 5.0, or 10.0 mg/kg p.o.) co-administered with a threshold dose of L-dopa (2.5 mg/kg p.o.) did not evoke a motor response or induce dyskinesia. Similarly, concomitant administration of BTS 74 398 (5.0 mg/kg p.o.) with a submaximal L-dopa dose (12.5 mg/kg p.o.) did not potentiate the motor response produced by L-dopa alone and there was no alteration in the dyskinesia provoked by L-dopa challenge. BTS 74 398 reverses motor abnormalities in MPTP-treated marmosets without evoking established dyskinesia but no additive improvement occurs when administered in combination with L-dopa. The lack of synergy with L-dopa may suggest different sites of drug action. Copyright 2003 Movement Disorder Society

  11. Treatment with selective serotonin reuptake inhibitors and mirtapazine results in differential brain activation by visual erotic stimuli in patients with major depressive disorder.

    Science.gov (United States)

    Kim, Won; Jin, Bo-Ra; Yang, Wan-Seok; Lee, Kyuong-Uk; Juh, Ra-Hyung; Ahn, Kook-Jin; Chung, Yong-An; Chae, Jeong-Ho

    2009-06-01

    The objective of this study was to identify patterns of brain activation elicited by erotic visual stimuli in patients treated with either Selective Serotonin Reuptake Inhibitors (SSRIs) or mirtazipine. Nine middle-aged men with major depressive disorder treated with an SSRI and ten middle-aged men with major depressive disorder treated with mirtazapine completed the trial. Ten subjects with no psychiatric illness were included as a control group. We conducted functional brain magnetic resonance imaging (fMRI) while a film alternatively played erotic and non-erotic contents for 14 minutes and 9 seconds. The control group showed activation in the occipitotemporal area, anterior cingulate gyrus, insula, orbitofrontal cortex, and caudate nucleus. For subjects treated with SSRIs, the intensity of activity in these regions was much lower compared to the control group. Intensity of activation in the group treated with mirtazapine was less than the control group but grea-ter than those treated with SSRIs. Using subtraction analysis, the SSRI group showed significantly lower activation than the mirtazapine group in the anterior cingulate gyrus and the caudate nucleus. Our study suggests that the different rates of sexual side effects between the patients in the SSRI-treated group and the mirtazapine-treated group may be due to different effects on brain activation.

  12. Association of the Polygenic Scores for Personality Traits and Response to Selective Serotonin Reuptake Inhibitors in Patients with Major Depressive Disorder

    Science.gov (United States)

    Amare, Azmeraw T.; Schubert, Klaus Oliver; Tekola-Ayele, Fasil; Hsu, Yi-Hsiang; Sangkuhl, Katrin; Jenkins, Gregory; Whaley, Ryan M.; Barman, Poulami; Batzler, Anthony; Altman, Russ B.; Arolt, Volker; Brockmöller, Jürgen; Chen, Chia-Hui; Domschke, Katharina; Hall-Flavin, Daniel K.; Hong, Chen-Jee; Illi, Ari; Ji, Yuan; Kampman, Olli; Kinoshita, Toshihiko; Leinonen, Esa; Liou, Ying-Jay; Mushiroda, Taisei; Nonen, Shinpei; Skime, Michelle K.; Wang, Liewei; Kato, Masaki; Liu, Yu-Li; Praphanphoj, Verayuth; Stingl, Julia C.; Bobo, William V.; Tsai, Shih-Jen; Kubo, Michiaki; Klein, Teri E.; Weinshilboum, Richard M.; Biernacka, Joanna M.; Baune, Bernhard T.

    2018-01-01

    Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS, n = 529) and the International SSRI Pharmacogenomics Consortium (ISPC, n = 865). The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at p trait GWAS meta-analyses, we identified eight loci associated with (a) SSRIs response and conscientiousness near YEATS4 gene and (b) SSRI remission and neuroticism eight loci near PRAG1, MSRA, XKR6, ELAVL2, PLXNC1, PLEKHM1, and BRUNOL4 genes. An assessment of a polygenic load for personality traits may assist in conjunction with clinical data to predict whether MDD patients might respond favorably to SSRIs. PMID:29559929

  13. Randomized controlled trials of serotonin-norepinephrine reuptake inhibitor in treating major depressive disorder in children and adolescents: a meta-analysis of efficacy and acceptability

    Directory of Open Access Journals (Sweden)

    Y. Xu

    2016-01-01

    Full Text Available New generation antidepressant therapies, including serotonin-norepinephrine reuptake inhibitor (SNRIs, were introduced in the late 1980s; however, few comprehensive studies have compared the benefits and risks of various contemporary treatments for major depressive disorder (MDD in young patients. A comprehensive literature search of PubMed, Cochrane, Embase, Web of Science, and PsycINFO databases was conducted from 1970 to January 2015. Only clinical trials that randomly assigned one SNRI or placebo to patients aged 7 to 18 years who met the diagnostic criteria for major depressive disorder were included. Treatment success, dropout rate, and suicidal ideation/attempt outcomes were measured. Primary efficacy was determined by pooling the risk ratios (RRs of treatment response and remission. Acceptability was determined by pooling the RRs of dropouts for all reasons and for adverse effects as well as suicide-risk outcomes. Five trials with a total of 973 patients were included. SNRIs were not significantly more effective than placebo for treatment response but were for remission. The comparison of patients taking SNRIs that dropped out for all reasons and those taking placebo did not reach statistical significance. Significantly more patients taking SNRIs dropped out for adverse effects than those taking placebo. No significant difference was found in suicide-related risk outcomes. SNRI therapy does not display a superior efficacy and is not better tolerated compared to placebo in these young patients. However, duloxetine has a potential beneficial effect for depression in young populations, showing a need for further research.

  14. Pharmacokinetics of paroxetine, a selective serotonin reuptake inhibitor, in Grey parrots (Psittacus erithacus erithacus): influence of pharmaceutical formulation and length of dosing.

    Science.gov (United States)

    van Zeeland, Y R A; Schoemaker, N J; Haritova, A; Smit, J W; van Maarseveen, E M; Lumeij, J T; Fink-Gremmels, J

    2013-02-01

    Paroxetine, a selective serotonin reuptake inhibitor, may be beneficial in the treatment of behavioural disorders in pet birds. The lack of pharmacokinetic data and clinical trials currently limits the use of this drug in clinical avian practice. This paper evaluates the pharmacokinetic properties and potential side effects of single and repeated dosing of paroxetine in Grey parrots (Psittacus erithacus erithacus). Paroxetine pharmacokinetics were studied after single i.v. and single oral dosing, and after repeated oral administration during 1 month. Plasma paroxetine concentrations were determined by liquid chromatography-tandem mass spectrometry. No undesirable side effects were observed during the study. Pharmacokinetic analysis revealed a quick distribution and rapid elimination after i.v. administration. Oral administration of paroxetine HCl dissolved in water resulted in a relatively slow absorption (T(max)=5.9±2.6 h) and a low bioavailability (31±15%). Repeated administration resulted in higher rate of absorption, most likely due to a saturation of the cytochrome P450-mediated first-pass metabolism. This study shows that oral administration of paroxetine HCl (4 mg/kg twice daily) in parrots results in plasma concentrations within the therapeutic range recommended for the treatment of depressions in humans. Further studies are needed to demonstrate the clinical efficacy of this dosage regimen in parrots with behavioural disorders. © 2012 Blackwell Publishing Ltd.

  15. Five Patients With Burning Mouth Syndrome in Whom an Antidepressant (Serotonin-Noradrenaline Reuptake Inhibitor) Was Not Effective, but Pregabalin Markedly Relieved Pain.

    Science.gov (United States)

    Ito, Mikiko; Tokura, Tatsuya; Yoshida, Keizo; Nagashima, Wataru; Kimura, Hiroyuki; Umemura, Eri; Tachibana, Masako; Miyauchi, Tomoya; Kobayashi, Yuka; Arao, Munetaka; Ozaki, Norio; Kurita, Kenichi

    2015-01-01

    Burning mouth syndrome (BMS) causes idiopathic pain or a burning sensation in clinically normal oral mucosa. Burning mouth syndrome is a chronic disease with an unknown etiology. Burning mouth syndrome is also idiopathic, and a consensus regarding diagnosis/treatment has not been reached yet. Recent studies have supported the suggestion that BMS is a neuropathic pain disorder in which both the peripheral and central nervous systems are involved. Tricyclic antidepressants (nortriptyline and amitriptyline), serotonin-noradrenaline reuptake inhibitors (SNRIs) (duloxetine and milnacipran), and antiepileptic drugs, potential-dependent calcium channel α2δ subunit ligands (gabapentine and pregabalin), are currently recommended as the first-choice drugs for neuropathic pain. In this study, we report 5 patients with BMS in whom there was no response to SNRI (milnacipran or duloxetine), or administration was discontinued because of adverse reactions, but in whom pregabalin therapy markedly reduced or led to the disappearance of pain in a short period. Pregabalin, whose mechanism of action differs from that of SNRIs, may become a treatment option for BMS patients who are not responsive to or are resistant to SNRIs.

  16. A neurobiological perspective on attachment problems in sexual offenders and the role of selective serotonin re-uptake inhibitors in the treatment of such problems.

    Science.gov (United States)

    Beech, Anthony R; Mitchell, Ian J

    2005-02-01

    This paper describes what is currently known about attachment from the development, social-cognitive and biological literatures and outlines the impact on organisms given adverse development experiences that can have an effect upon attachment formation in childhood across these three literatures. We then describe the effects that 'insecure' attachment styles arising in childhood can affect brain chemistry and brain function and subsequently adult social/romantic relationships. In the paper, we note that a number of sexual offenders report adverse childhood experiences and that they possess attachment styles that, taken together, make it likely that they will either seek out intimate attachments in ways where they will have sex with children, perhaps confusing sex with intimacy or in aggressive ways as particularly happens with men who sexually assault adult women. The last section of the paper describes chemical treatment for sexual offenders, focusing on the use of selective serotonin re-uptake inhibitors (SSRIs). We note evidence for the role of SSRIs in promoting more social/affiliative behaviors and speculate on the effects that SSRIs have in the treatment of sexual offenders by targeting areas of the social brain. Here, we would argue that it would be useful to carry out treatment where there is a combination of SSRI treatment (to promote more prosocial feelings and behaviors) in conjunction with therapy that typically addresses thoughts and behaviors, i.e., cognitive-behavioral therapy/schema-focused therapy.

  17. In vitro anti-Candida activity of selective serotonin reuptake inhibitors against fluconazole-resistant strains and their activity against biofilm-forming isolates.

    Science.gov (United States)

    Costa Silva, Rose Anny; da Silva, Cecília Rocha; de Andrade Neto, João Batista; da Silva, Anderson Ramos; Campos, Rosana Sousa; Sampaio, Letícia Serpa; do Nascimento, Francisca Bruna Stefany Aires; da Silva Gaspar, Brenda; da Cruz Fonseca, Said Gonçalves; Josino, Maria Aparecida Alexandre; Grangeiro, Thalles Barbosa; Gaspar, Danielle Macedo; de Lucena, David Freitas; de Moraes, Manoel Odorico; Cavalcanti, Bruno Coêlho; Nobre Júnior, Hélio Vitoriano

    2017-06-01

    Recent research has shown broad antifungal activity of the classic antidepressants selective serotonin reuptake inhibitors (SSRIs). This fact, combined with the increased cross-resistance frequency of the genre Candida regarding the main treatment today, fluconazole, requires the development of novel therapeutic strategies. In that context, this study aimed to assess the antifungal potential of fluoxetine, sertraline, and paroxetine against fluconazole-resistant Candida spp. planktonic cells, as well as to assess the mechanism of action and the viability of biofilms treated with fluoxetine. After 24 h, the fluconazole-resistant Candida spp. strains showed minimum inhibitory concentration (MIC) in the ranges of 20-160 μg/mL for fluoxetine, 10-20 μg/mL for sertraline, and 10-100.8 μg/mL for paroxetine by the broth microdilution method (M27-A3). According to our data by flow cytometry, each of the SSRIs cause fungal death after damaging the plasma and mitochondrial membrane, which activates apoptotic signaling pathways and leads to dose-dependant cell viability loss. Regarding biofilm-forming isolates, the fluoxetine reduce mature biofilm of all the species tested. Therefore, it is concluded that SSRIs are capable of inhibit the growth in vitro of Candida spp., both in planktonic form, as biofilm, inducing cellular death by apoptosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Maternal Use of Selective Serotonin Reuptake Inhibitors and Lengthening of the Umbilical Cord: Indirect Evidence of Increased Foetal Activity-A Retrospective Cohort Study.

    Directory of Open Access Journals (Sweden)

    Julia Kivistö

    Full Text Available Antenatal depression affects up to 19% of pregnant women. Some of these women are also in need of antidepressant treatment. Nevertheless, the impact of maternal antidepressant treatment and prenatal depression on the course of pregnancy, foetal development and delivery outcomes is not fully understood.We analysed data from 24 818 women who gave birth at Kuopio University Hospital between 2002-2012. Logistic regression analysis was used to estimate associations between the use of selective serotonin reuptake inhibitors (SSRIs during pregnancy and the progression of pregnancy, development of the foetus and delivery outcomes.Altogether, 369 (1.5% women used SSRIs. A regression model adjusted for age, overweight, nulliparity, prior termination, miscarriages, smoking, maternal alcohol consumption, chronic illness and polyhydramnion showed that pregnant women exposed to SSRI medication had significantly lower Apgar scores at 1 minute (p < 0.0001 and 5 minutes (p < 0.0001 and more admissions to the neonatal intensive care unit (p < 0.0001 than unexposed pregnant women. In addition, exposed newborns had longer umbilical cords (p < 0.0001 than non-exposed newborns.In addition to the previously known associates with maternal SSRI exposure, such as lowered Apgar scores, SSRI exposure appeared to be associated with increased umbilical cord length. The observation related to increased umbilical cord length may be explained by an SSRI-induced increase in the movements of the developing foetus.

  19. Synthesis of [11C]dapoxetine·HCl, a serotonin re-uptake inhibitor: biodistribution in rat and preliminary PET imaging in the monkey

    International Nuclear Information System (INIS)

    Livni, E.; Satterlee, W.; Robey, R.L.

    1994-01-01

    [ 11 C]Dapoxetine · HCl, S-(+)-N,N-dimethyl-a-[2-(naphthalenyloxy)ethyl] benzenemethanamine hydrochloride, a potent serotonin re-uptake inhibitor was prepared from its mono-methyl precursor, S-(+)-N-methyl-a-[2-(naphthalenyloxy)ethyl]benzene methanamine hydrochloride. Biodistribution was determined in rats at 5, 30 and 60 min after injection and preliminary PET studies were performed in a Rhesus monkey. 11 CH 3 I was bubbled into a solution of S-(+)-N-methyl-α-[2-(naphthalenyloxy)ethyl]benzene methanamine hydrochloride (3.0 mg in DMSO) and the mixture was heated at 110 o C for 8 min. [ 11 C]Dapoxetine · HCl was purified by HPLC on a C 18 cartridge eluted with MeOH: phosphate buffer, pH 7.2 (75:25) with a 10% yield (end of synthesis). The time required for the synthesis was 40 min, from the end of bombardment. Radiochemical purity of the final product was > 99% and specific activity was routinely > 400 mCi/μmol [EOS]. (author)

  20. 5-HT2C receptors in the BNST are necessary for the enhancement of fear learning by selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Pelrine, Eliza; Pasik, Sara Diana; Bayat, Leyla; Goldschmiedt, Debora; Bauer, Elizabeth P

    2016-12-01

    Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat anxiety and depression, yet they paradoxically increase anxiety during initial treatment. Acute administration of these drugs prior to learning can also enhance Pavlovian cued fear conditioning. This potentiation has been previously reported to depend upon the bed nucleus of the stria terminalis (BNST). Here, using temporary inactivation, we confirmed that the BNST is not necessary for the acquisition of cued or contextual fear memory. Systemic administration of the SSRI citalopram prior to fear conditioning led to an upregulation of the immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the oval nucleus of the BNST, and a majority of these neurons expressed the 5-HT2C receptor. Finally, local infusions of a 5-HT2C receptor antagonist directly into the oval nucleus of the BNST prevented the fear memory-enhancing effects of citalopram. These findings highlight the ability of the BNST circuitry to be recruited into gating fear and anxiety-like behaviors. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

    Science.gov (United States)

    Ye, Zheng; Rae, Charlotte L.; Nombela, Cristina; Ham, Timothy; Rittman, Timothy; Jones, Peter Simon; Rodríguez, Patricia Vázquez; Coyle‐Gilchrist, Ian; Regenthal, Ralf; Altena, Ellemarije; Housden, Charlotte R.; Maxwell, Helen; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

    2016-01-01

    Abstract Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinson's disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double‐blind randomized three‐way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinson's disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion‐weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinson's disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave‐one‐out cross‐validation (LOOCV) to predict patients’ responses in terms of improved stopping efficiency. We identified two optimal models: (1) a “clinical” model that predicted the response of an individual patient with 77–79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion‐weighted imaging scan; and (2) a “mechanistic” model that explained the behavioral response with 85% accuracy for each drug, using drug‐induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinson's disease, the individual patient's response to each drug can be predicted using a pattern of clinical and neuroimaging features. Hum Brain Mapp 37:1026–1037

  2. The effects of prolonged administration of norepinephrine reuptake inhibitors on long-term potentiation in dentate gyrus, and on tests of spatial and object recognition memory in rats.

    Science.gov (United States)

    Walling, Susan G; Milway, J Stephen; Ingram, Matthew; Lau, Catherine; Morrison, Gillian; Martin, Gerard M

    2016-02-01

    Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200 Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30-32 days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25-30 days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60 days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this

  3. The effects of compound stimulus extinction and inhibition of noradrenaline reuptake on the renewal of alcohol seeking

    Science.gov (United States)

    Furlong, T M; Pan, M J; Corbit, L H

    2015-01-01

    Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli can reduce their impact on relapse; however, the expression of extinction can be disrupted when testing occurs outside the context where extinction learning took place, an effect termed renewal. Behavioral and pharmacological methods have recently been shown to augment extinction learning; yet, it is not known whether the improved expression of extinction following these treatments remains context-dependent. Here we examined whether two methods, compound–stimulus extinction and treatment with the noradrenaline reuptake inhibitor atomoxetine, would reduce the vulnerability of extinction to a change in context. Following alcohol self-administration, responding was extinguished in a distinct context. After initial extinction, further extinction was given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg kg−1; Experiment 2). A stimulus extinguished as part of a compound elicited less responding than a stimulus receiving equal extinction alone regardless of whether animals were tested in the training or extinction context; however, reliable renewal was not observed in this paradigm. Importantly, atomoxetine enhanced extinction relative to controls even in the presence of a reliable renewal effect. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Importantly, both methods improve extinction even when the context is changed between extinction training and test, and thus could be utilized to enhance the outcome of extinction-based treatments for alcohol-use disorders. PMID:26327688

  4. The glycine reuptake inhibitor org 25935 interacts with basal and ethanol-induced dopamine release in rat nucleus accumbens.

    Science.gov (United States)

    Lidö, Helga Höifödt; Stomberg, Rosita; Fagerberg, Anne; Ericson, Mia; Söderpalm, Bo

    2009-07-01

    The mesolimbic dopamine (DA) projection from the ventral tegmental area to nucleus accumbens (nAc), a central part of the reward system, is activated by ethanol (EtOH) and other drugs of abuse. We have previously demonstrated that the glycine receptor in the nAc and its amino acid agonists may be implicated in the DA activation and reinforcing properties of EtOH. We have also reported that the glycine transporter 1 inhibitor, Org 25935, produces a robust and dose-dependent decrease in EtOH consumption in Wistar rats. The present study explores the interaction between EtOH and Org 25935 with respect to DA levels in the rat nAc. The effects of Org 25935 (6 mg/kg, i.p.) and/or EtOH (2.5 g/kg, i.p.) on accumbal DA levels were examined by means of in vivo microdialysis (coupled to HPLC-ED) in freely moving male Wistar rats. The effect of Org 25935 on accumbal glycine output was also investigated. Systemic Org 25935 increased DA output in a subpopulation of rats (52% in Experiment 1 and 38% in Experiment 2). In Experiment 2, EtOH produced a significant increase in DA levels in vehicles (35%) and in Org 25935 nonresponders (19%), whereas EtOH did not further increase the DA level in rats responding to Org 25935 (2%). The same dose of Org 25935 increased glycine levels by 87% in nAc. This study demonstrates that Org 25935, probably via increased glycine levels, (i) counteracts EtOH-induced increases of accumbal DA levels and (ii) increases basal DA levels in a subpopulation of rats. The results are in line with previous findings and it is suggested that the effects observed involve interference with accumbal GlyRs and are related to the alcohol consumption modulating effect of Org 25935.

  5. Normal Bone Microstructure and Density But Worse Physical Function in Older Women Treated with Selective Serotonin Reuptake Inhibitors, a Cross-Sectional Population-Based Study.

    Science.gov (United States)

    Larsson, Berit; Mellström, Dan; Johansson, Lisa; Nilsson, Anna G; Lorentzon, Mattias; Sundh, Daniel

    2018-05-05

    Depression in the elderly is today often treated with selective serotonin reuptake inhibitors (SSRIs) because of their favorable adverse effect profile. However, treatment with SSRIs is associated with increased risk of fractures. Whether this increased risk depends on reduced bone strength or increased fall risk due to reduced physical function is not certain. The aim was therefore to investigate if treatment with SSRIs is associated with impaired bone microstructure, bone density, or physical function in older women. From an ongoing population-based study, 1057 women (77.7 ± 1.5 years) were included. Validated questionnaires were used to assess information regarding medical history, medications, smoking, mental and physical health, and physical activity. Physical function was measured using clinically used tests: timed up and go, walking speed, grip strength, chair stand test, and one leg standing. Bone mineral density (BMD) was measured at the hip and spine with dual-energy X-ray absorptiometry (Hologic Discovery A). Bone geometry and microstructure were measured at the ultradistal and distal (14%) site of radius and tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT). Treatment with SSRIs was associated with higher BMD at the femoral neck, total hip, and lumbar spine, whereas no associations were found for any HR-pQCT-derived measurements. The use of SSRIs was associated with lower grip strength, walking speed, and fewer chair stand rises. These associations were valid also after adjustments for known risk factors for falls. Treatment with SSRIs was, independently of covariates, associated with worse physical function without any signs of inferior bone geometry and microstructure.

  6. Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats

    Energy Technology Data Exchange (ETDEWEB)

    De Long, Nicole E.; Barry, Eric J. [Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON L8S 4K1 (Canada); Pinelli, Christopher; Wood, Geoffrey A. [Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1 (Canada); Hardy, Daniel B. [Department of Obstetrics and Gynecology, Physiology and Pharmacology, University of Western, London, ON N6A 3K6 (Canada); Morrison, Katherine M. [Department of Pediatrics, McMaster University, Hamilton, ON L8S 4K1 (Canada); Taylor, Valerie H. [Department of Psychiatry, University of Toronto, Toronto, ON M5S 1A1 (Canada); Gerstein, Hertzel C. [Department of Medicine, McMaster University, Hamilton, ON L8S 4K1 (Canada); Holloway, Alison C., E-mail: hollow@mcmaster.ca [Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON L8S 4K1 (Canada)

    2015-05-15

    Hypothesis: 10–15% of women take antidepressant medications during pregnancy. A recent clinical study reported that the use of selective serotonin reuptake inhibitor antidepressants during pregnancy is linked with an increased risk of postnatal obesity. While obesity is often associated with fatty liver, dyslipidemia and inflammation, to date, the effects of perinatal exposure to SSRIs on these outcomes are unknown. Methods: Female nulliparous Wistar rats were given vehicle (N = 15) or fluoxetine hydrochloride (FLX 10 mg/kg/d; N = 15) orally for 2 weeks prior to mating until weaning. We assessed glucometabolic changes and hepatic pathophysiology in the offspring. Results: Fluoxetine exposed offspring demonstrated altered glucose homeostasis without any alterations to beta cell mass. FLX-exposed offspring had a significant increase in the number of offspring with mild to moderate NASH and dyslipidemia. There was also increased inflammation of the liver in FLX-exposed offspring; males had significant elevations in TNFα, IL6 and monocyte chemoattractant protein 1 (MCP1), while female offspring had higher expression of TNFα, and increased macrophage infiltration (MCP1). Limitations: This is an animal study. Further research examining the metabolic outcomes of children exposed to antidepressants in utero are required, given the increase in childhood obesity and psychiatric medication use during pregnancy. Conclusion: These data demonstrate that fetal and neonatal exposure to FLX results in evidence of increased adiposity, fatty liver and abnormal glycemic control. Since these are all hallmarks of the metabolic syndrome, this raises concerns regarding the long term metabolic sequelae of fetal exposure to SSRIs in human populations. - Highlights: • Antenatal exposure to fluoxetine results in postnatal adiposity in the offspring. • Offspring exposed to fluoxetine have abnormal glycemic control in adulthood. • Maternal exposure to fluoxetine causes fatty liver in

  7. 5-HT1A and 5-HT7 receptor crosstalk in the regulation of emotional memory: implications for effects of selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Eriksson, Therese M; Holst, Sarah; Stan, Tiberiu L; Hager, Torben; Sjögren, Benita; Ogren, Sven Öve; Svenningsson, Per; Stiedl, Oliver

    2012-11-01

    This study utilized pharmacological manipulations to analyze the role of direct and indirect activation of 5-HT(7) receptors (5-HT(7)Rs) in passive avoidance learning by assessing emotional memory in male C57BL/6J mice. Additionally, 5-HT(7)R binding affinity and 5-HT(7)R-mediated protein phosphorylation of downstream signaling targets were determined. Elevation of 5-HT by the selective serotonin reuptake inhibitor (SSRI) fluoxetine had no effect by itself, but facilitated emotional memory performance when combined with the 5-HT(1A)R antagonist NAD-299. This facilitation was blocked by the selective 5-HT(7)R antagonist SB269970, revealing excitatory effects of the SSRI via 5-HT(7)Rs. The enhanced memory retention by NAD-299 was blocked by SB269970, indicating that reduced activation of 5-HT(1A)Rs results in enhanced 5-HT stimulation of 5-HT(7)Rs. The putative 5-HT(7)R agonists LP-44 when administered systemically and AS19 when administered both systemically and into the dorsal hippocampus failed to facilitate memory. This finding is consistent with the low efficacy of LP-44 and AS19 to stimulate protein phosphorylation of 5-HT(7)R-activated signaling cascades. In contrast, increasing doses of the dual 5-HT(1A)R/5-HT(7)R agonist 8-OH-DPAT impaired memory, while co-administration with NAD-299 facilitated of emotional memory in a dose-dependent manner. This facilitation was blocked by SB269970 indicating 5-HT(7)R activation by 8-OH-DPAT. Dorsohippocampal infusion of 8-OH-DPAT impaired passive avoidance retention through hippocampal 5-HT(1A)R activation, while 5-HT(7)Rs appear to facilitate memory processes in a broader cortico-limbic network and not the hippocampus alone. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. Effect of Time-Dependent Selective Serotonin Reuptake Inhibitor Antidepressants During Pregnancy on Behavioral, Emotional, and Social Development in Preschool-Aged Children.

    Science.gov (United States)

    Lupattelli, Angela; Wood, Mollie; Ystrom, Eivind; Skurtveit, Svetlana; Handal, Marte; Nordeng, Hedvig

    2018-03-01

    To evaluate the effect of prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) on children's behavioral, emotional, and social development by age 5 years, and over time since age 1.5 years. The prospective Norwegian Mother and Child Cohort Study was linked to the Medical Birth Registry of Norway. We included women who reported depressive/anxiety disorders before and/or during pregnancy. Children born to women who used SSRIs in early (weeks 0-16), mid- (weeks 17-28), or late (> week 29) pregnancy were compared to those who were unexposed. Children's internalizing and externalizing behaviors (Child Behavior Checklist) and temperament traits (Emotionality, Activity and Shyness Temperament Questionnaire) were measured at 1.5, 3, and 5 years. Mean scores were calculated and standardized. General linear marginal structural models were fitted to account for time-varying exposure and confounders, and censoring; 3-level growth-curve models were used. A total of 8,359 mother-child dyads were included, and 4,128 children had complete outcome data at age 5 years. Children exposed to SSRIs in late pregnancy had an increased risk of anxious/depressed behaviors by age 5 years compared with unexposed children (adjusted β = 0.50, 95% CI = 0.04, 0.96). Such risk was not evident for earlier timings of exposure. There was no evidence for a substantial prenatal SSRI effect on externalizing, social, and emotional problems. These findings suggest no substantial increased risk for externalizing, emotional, or social problems in preschool-aged children following prenatal SSRI exposure. Although the role of chance and potential unmeasured confounding cannot be ruled out, late-pregnancy SSRI exposure was associated with greater anxious/depressed behaviors in the offspring. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

  9. Prenatal serotonin reuptake inhibitor (SRI antidepressant exposure and serotonin transporter promoter genotype (SLC6A4 influence executive functions at 6 years of age

    Directory of Open Access Journals (Sweden)

    Whitney eWeikum

    2013-10-01

    Full Text Available Prenatal exposure to serotonin reuptake inhibitor (SRI antidepressants and maternal depression may affect prefrontal cognitive skills (executive functions; EFs including self-control, working memory and cognitive flexibility. We examined long-term effects of prenatal SRI exposure on EFs to determine whether effects are moderated by maternal mood and/or genetic variations in SLC6A4 (a gene that codes for the serotonin transporter [5-HTT] central to the regulation of synaptic serotonin levels and behavior. Children who were exposed to SRIs prenatally (SRI-exposed N=26 and non-exposed (N=38 were studied at age 6 years (M=6.3 SD=0.5 using the Hearts & Flowers task (H&F to assess EFs. Maternal mood was measured during pregnancy (3rd trimester and when the child was age 6 years (Hamilton Depression Scale. Parent reports of child behavior were also obtained (MacArthur Health & Behavior Questionnaire. Parents of prenatally SRI-exposed children reported fewer child externalizing and inattentive (ADHD behaviors. Generalized estimate equation modeling showed a significant 3-way interaction between prenatal SRI exposure, SLC6A4 variant, and maternal mood at the 6-year time-point on H&F accuracy. For prenatally SRI-exposed children, regardless of maternal mood, the H&F accuracy of children with reduced 5HTT expression (a short [S] allele remained stable. Even with increasing maternal depressive symptoms (though all below clinical threshold, EFs of children with at least one short allele were comparable to children with the same genotype whose mothers reported few if any depressive symptoms – in this sense they showed resilience. Children with two long (L alleles were more sensitive to context. When their mothers had few depressive symptoms, LL children showed extremely good EF performance – better than any other group. When their mothers reported more depressive symptoms, LL children’s EF performance was worse than that of any other group.

  10. Increasing the Risk of Spontaneous Abortion and Major Malformations in Newborns Following Use of Serotonin Reuptake Inhibitors during Pregnancy: a Systematic Review and Updated Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Mohammad Abdollahi

    2012-11-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are the most frequently used antidepressants during pregnancy. There are conflicting results about their influence on pregnancy outcomes.The goal of this study was to update our previous meta-analysis about pregnancy outcomes following exposure to SSRIs. For this purpose, all relevant databases were searched from 1990 to March 2012 for studies investigating the pregnancy outcomes following exposure to any therapeutic dosage of any SSRI (fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine during pregnancy. Types of outcome investigated were spontaneousabortion, major malformations, cardiovascular malformations, and minor malformations. A total of 25 studies met our criteria and were included in the meta-analysis. The odds ratio (OD values are 1.87 (95% CI: 1.5 to 2.33, P< 0.0001 for spontaneous abortion, 1.272 (95%CI: 1.098 to 1.474, P = 0.0014 for major malformations, 1.192 (95% CI: 0.39 to 3.644, P=0.7578 for cardiovascular malformations, and 1.36 (95% CI: 0.61 to 3.04, P= 0.4498 for minor malformations. The results demonstrated that SSRIs increase the risk of spontaneousabortion and major malformations during pregnancy while they don’t increase the risk of cardiovascular malformations and minor malformations. Our previous meta-analysis only showed an increase in the risk of spontaneous abortion following the use of SSRIs duringpregnancy. This might be due to increase in the number of studies included or addition of two new SSRIs (citalopram and escitalopram. The message to researchers is to try considering SSRIs individually during pregnancy to reduce heterogeneity, although all are aware ofinevitable limitations to study on pregnant mothers.

  11. Association of the Polygenic Scores for Personality Traits and Response to Selective Serotonin Reuptake Inhibitors in Patients with Major Depressive Disorder

    Directory of Open Access Journals (Sweden)

    Azmeraw T. Amare

    2018-03-01

    Full Text Available Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD. Moreover, personality traits are thought to be associated with response to antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs. In addition, we performed meta-analyses of genome-wide association studies (GWASs on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS, n = 529 and the International SSRI Pharmacogenomics Consortium (ISPC, n = 865. The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at p < 0.05 across PT thresholds in both cohorts. A significant association was also found between the PGS for conscientiousness and SSRIs treatment response in the PGRN-AMPS sample. In the cross-trait GWAS meta-analyses, we identified eight loci associated with (a SSRIs response and conscientiousness near YEATS4 gene and (b SSRI remission and neuroticism eight loci near PRAG1, MSRA, XKR6, ELAVL2, PLXNC1, PLEKHM1, and BRUNOL4 genes. An assessment of a polygenic load for personality traits may assist in conjunction with clinical data to predict whether MDD patients might respond favorably to SSRIs.

  12. Common selective serotonin reuptake inhibitor side effects in older adults associated with genetic polymorphisms in the serotonin transporter and receptors: data from a randomized controlled trial.

    Science.gov (United States)

    Garfield, Lauren D; Dixon, David; Nowotny, Petra; Lotrich, Francis E; Pollock, Bruce G; Kristjansson, Sean D; Doré, Peter M; Lenze, Eric J

    2014-10-01

    Antidepressant side effects are a significant public health issue, associated with poor adherence, premature treatment discontinuation, and, rarely, significant harm. Older adults assume the largest and most serious burden of medication side effects. We investigated the association between antidepressant side effects and genetic variation in the serotonin system in anxious, older adults participating in a randomized, placebo-controlled trial of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Adults (N = 177) aged ≥ 60 years were randomized to active treatment or placebo for 12 weeks. Side effects were assessed using the Udvalg fur Kliniske Undersøgelser side-effect rating scale. Genetic polymorphisms were putative functional variants in the promoters of the serotonin transporter and 1A and 2A receptors (5-HTTLPR [L/S + rs25531], HTR1A rs6295, HTR2A rs6311, respectively). Four significant drug-placebo side-effect differences were found: increased duration of sleep, dry mouth, diarrhea, and diminished sexual desire. Analyses using putative high- versus low-transcription genotype groupings revealed six pharmacogenetic effects: greater dry mouth and decreased sexual desire for the low- and high-expressing serotonin transporter genotypes, respectively, and greater diarrhea with the 1A receptor low-transcription genotype. Diminished sexual desire was experienced significantly more by high-expressing genotypes in the serotonin transporter, 1A, or 2A receptors. There was not a significant relationship between drug concentration and side effects nor a mean difference in drug concentration between low- and high-expressing genotypes. Genetic variation in the serotonin system may predict who develops common SSRI side effects and why. More work is needed to further characterize this genetic modulation and to translate research findings into strategies useful for more personalized patient care. Published by Elsevier Inc.

  13. Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac

    Science.gov (United States)

    Zhou, L; Ma, S L; Yeung, P K K; Wong, Y H; Tsim, K W K; So, K F; Lam, L C W; Chung, S K

    2016-01-01

    Intracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1−/−) or Epac2 (Epac2−/−) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2−/− mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer's disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2−/− mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2−/− mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis. PMID:27598965

  14. Repeated administration of the monoamine reuptake inhibitor BTS 74 398 induces ipsilateral circling in the 6-hydroxydopamine lesioned rat without sensitizing motor behaviours.

    Science.gov (United States)

    Lane, E L; Cheetham, S C; Jenner, P

    2005-01-01

    BTS 74 398 (1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone monocitrate) is a monoamine reuptake inhibitor that reverses motor deficits in MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmosets without provoking established dyskinesia. However, it is not known whether BTS 74 398 primes the basal ganglia for dyskinesia induction. In this study, the ability of BTS 74 398 to sensitize 6-hydroxydopamine (6-OHDA)-lesioned rats for the production of abnormal motor behaviours and the induction of striatal DeltaFosB were determined in comparison with l-3,4-dihydroxyphenylalanine methyl ester (L-dopa). Acute administration of BTS 74 398 induced a dose-dependent ipsilateral circling response in unilaterally 6-OHDA-lesioned rats whereas L-dopa produced dose-dependent contraversive rotation. The ipsilateral circling response to BTS 74 398 did not alter during 21 days of administration. In contrast, L-dopa treatment for 21 days caused a marked increase in rotational response. Repeated administration of both L-dopa and BTS 74 398 increased general motor activity and stereotypic behaviour. In L-dopa-treated rats, orolingual, locomotive, forelimb and axial abnormal movements developed whereas BTS 74 398 produced only locomotion with a side bias but no other abnormal movements. Sensitization of circling responses and the development of abnormal movements in 6-OHDA-lesioned rats have been associated with the potential of dopaminergic drugs to induce dyskinesia. Furthermore, striatal DeltaFosB immunoreactivity, shown to correlate with dyskinesia induction, was increased by L-dopa but was unaffected by repeated BTS 74 398 administration. The lack of such changes following repeated BTS 74 398 treatment suggests that it may be an effective antiparkinsonian therapy that is unlikely to produce involuntary movements.

  15. Dissociation of the role of the prelimbic cortex in interval timing and resource allocation: beneficial effect of norepinephrine and dopamine reuptake inhibitor nomifensine on anxiety-inducing distraction

    Directory of Open Access Journals (Sweden)

    Alexander R Matthews

    2012-12-01

    Full Text Available Emotional distracters impair cognitive function. Emotional processing is dysregulated in affective disorders such as depression, phobias, schizophrenia, and PTSD. Among the processes impaired by emotional distracters, and whose dysregulation is documented in affective disorders, is the ability to time in the seconds-to-minutes range, i.e. interval timing. Presentation of task-irrelevant distracters during a timing task results in a delay in responding suggesting a failure to maintain subjective time in working memory, possibly due to attentional and working memory resources being diverted away from timing, as proposed by the Relative Time-Sharing model. We investigated the role of the prelimbic cortex in the detrimental effect of anxiety-inducing task-irrelevant distracters on the cognitive ability to keep track of time, using local infusions of norepinephrine and dopamine reuptake inhibitor nomifensine in a modified peak-interval procedure with neutral and anxiety-inducing distracters. Given that some antidepressants have beneficial effects on attention and working memory, e.g., decreasing emotional response to negative events, we hypothesized that nomifensine would improve maintenance of information in working memory in trials with distracters, resulting in a decrease of the disruptive effect of emotional events on the timekeeping abilities. Our results revealed a dissociation of the effects of nomifensine infusion in prelimbic cortex between interval timing and resource allocation, and between neutral and anxiety-inducing distraction. Nomifensine was effective only during trials with distracters, but not during trials without distracters. Nomifensine reduced the detrimental effect of the distracters only when the distracters were anxiety-inducing, but not when they were neutral. Results are discussed in relation to the brain circuits involved in Relative Time-Sharing of resources, and the pharmacological management of affective disorders.

  16. Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats

    International Nuclear Information System (INIS)

    De Long, Nicole E.; Barry, Eric J.; Pinelli, Christopher; Wood, Geoffrey A.; Hardy, Daniel B.; Morrison, Katherine M.; Taylor, Valerie H.; Gerstein, Hertzel C.; Holloway, Alison C.

    2015-01-01

    Hypothesis: 10–15% of women take antidepressant medications during pregnancy. A recent clinical study reported that the use of selective serotonin reuptake inhibitor antidepressants during pregnancy is linked with an increased risk of postnatal obesity. While obesity is often associated with fatty liver, dyslipidemia and inflammation, to date, the effects of perinatal exposure to SSRIs on these outcomes are unknown. Methods: Female nulliparous Wistar rats were given vehicle (N = 15) or fluoxetine hydrochloride (FLX 10 mg/kg/d; N = 15) orally for 2 weeks prior to mating until weaning. We assessed glucometabolic changes and hepatic pathophysiology in the offspring. Results: Fluoxetine exposed offspring demonstrated altered glucose homeostasis without any alterations to beta cell mass. FLX-exposed offspring had a significant increase in the number of offspring with mild to moderate NASH and dyslipidemia. There was also increased inflammation of the liver in FLX-exposed offspring; males had significant elevations in TNFα, IL6 and monocyte chemoattractant protein 1 (MCP1), while female offspring had higher expression of TNFα, and increased macrophage infiltration (MCP1). Limitations: This is an animal study. Further research examining the metabolic outcomes of children exposed to antidepressants in utero are required, given the increase in childhood obesity and psychiatric medication use during pregnancy. Conclusion: These data demonstrate that fetal and neonatal exposure to FLX results in evidence of increased adiposity, fatty liver and abnormal glycemic control. Since these are all hallmarks of the metabolic syndrome, this raises concerns regarding the long term metabolic sequelae of fetal exposure to SSRIs in human populations. - Highlights: • Antenatal exposure to fluoxetine results in postnatal adiposity in the offspring. • Offspring exposed to fluoxetine have abnormal glycemic control in adulthood. • Maternal exposure to fluoxetine causes fatty liver in

  17. Atomoxetine treatment in adults with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Walker, Daniel J; Mason, Oren; Clemow, David B; Day, Kathleen A

    2015-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is a CNS disorder that has its onset in childhood, but often persists into adulthood. There is growing recognition that adult ADHD can result in multiple negative consequences for individuals. ADHD is also often associated with a number of comorbid psychiatric disorders. Atomoxetine (ATX), a nonstimulant, selective noradrenergic reuptake inhibitor, was approved in the United States in 2002 for the treatment of ADHD in children and adolescents, as well as adults. We review here the safety and efficacy of ATX in adults with ADHD, including data in special populations, functional outcomes, as well as provider and patient real-world perceptions. We searched the databases Embase, MEDLINE and PsycINFO using the terms 'ADHD' and 'adult' and 'ATX' capturing publications from January 1, 1998, to March 27, 2014. Only publications in English were considered. ATX demonstrated significantly greater improvement than placebo (PBO) on the Conners Adult ADHD Rating Scale-Investigator rated:Screening Version (CAARS-Inv:SV) in all trials (N = 6; total score difference ranged from -3.5 to -5.5). For long-term trials using the CAARS-Inv:SV, ATX demonstrated significantly greater improvement than PBO in three of four trials (total score differences ranged from -0.1 to -6.0). In short-term studies, ATX showed significantly greater improvement than PBO on the Adult ADHD Quality-of-Life scale total score in three of three studies, but results were mixed on the Sheehan Disability Scale. Three studies of ATX have reported statistically significant improvement (compared with PBO) on the Behavior Rating Inventory of Executive Function-Adult Version Self Report scale. The most common adverse events (occurring in ≥ 10% of patients taking ATX) were nausea, dry mouth, decreased appetite, insomnia and fatigue. ATX is an important treatment option for the right patient. ATX can provide long-term, consistent symptom relief and functional improvement

  18. Selective Serotonin Reuptake Inhibitors (SSRIs)

    Science.gov (United States)

    ... and a rapid heart rate. Seek immediate medical attention if you have any of these signs or symptoms. Antidepressants and pregnancy. Talk to your doctor about the risks and benefits of using specific antidepressants. Some antidepressants may harm ...

  19. Atomoxetine in abstinent cocaine users: Cognitive, subjective and cardiovascular effects.

    Science.gov (United States)

    DeVito, Elise E; Herman, Aryeh I; Konkus, Noah S; Zhang, Huiping; Sofuoglu, Mehmet

    2017-08-01

    No pharmacotherapies are approved for the treatment of cocaine use disorders (CUD). Behavioral treatments for CUD are efficacious for some individuals, but recovery rates from CUD remain low. Cognitive impairments in CUD have been linked with poorer clinical outcomes. Cognitive enhancing pharmacotherapies have been proposed as promising treatments for CUD. Atomoxetine, a norepinephrine transporter inhibitor, shows potential as a treatment for CUD based on its efficacy as a cognitive enhancer in other clinical populations and impact on addictive processes in preclinical and human laboratory studies. In this randomized, double-blind, crossover study, abstinent individuals with CUD (N=39) received placebo, 40 and 80mg atomoxetine, over three sessions. Measures of attention, response inhibition and working memory; subjective medication effects and mood; and cardiovascular effects were collected. Analyses assessed acute, dose-dependent effects of atomoxetine. In addition, preliminary analyses investigating the modulation of atomoxetine dose effects by sex were performed. Atomoxetine increased heart rate and blood pressure, was rated as having positive and negative subjective drug effects, and had only modest effects on mood and cognitive enhancement. Copyright © 2017. Published by Elsevier Inc.

  20. Comparative efficacy of selective serotonin reuptake inhibitors (SSRI) in treating major depressive disorder: a protocol for network meta-analysis of randomised controlled trials.

    Science.gov (United States)

    Jia, Yongliang; Zhu, Hongmei; Leung, Siu-Wai

    2016-06-07

    There have been inconsistent findings from randomised controlled trials (RCTs) and systematic reviews on the efficacies of selective serotonin reuptake inhibitors (SSRIs) as the first-line treatment of major depressive disorder (MDD). Besides inconsistencies among randomised controlled trials (RCTs), their risks of bias and evidence grading have seldom been evaluated in meta-analysis. This study aims to compare the efficacy of SSRIs by conducting a Bayesian network meta-analysis, which will be the most comprehensive evaluation of evidence to resolve the inconsistency among previous studies. SSRIs including citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and vilazodone have been selected. Systematic database searching and screening will be conducted for the RCTs on drug treatment of patients with MDD according to pre-specified search strategies and selection criteria. PubMed, the Cochrane Library, EMBASE, ScienceDirect, the US Food and Drug Administration Website, ClinicalTrial.gov and WHO Clinical Trials will be searched. Outcome data including Hamilton Depression Rating Scale (HDRS), Montgomery-Åsberg Depression Rating Scale (MADRS) and Clinical Global Impression (CGI) from eligible RCTs will be extracted. The outcomes will be analysed as ORs and mean differences under a random-effects model. A Bayesian network meta-analysis will be conducted with WinBUGS software, to compare the efficacies of SSRIs. Subgroup and sensitivity analysis will be performed to explain the study heterogeneity and evaluate the robustness of the results. Meta-regression analysis will be conducted to determine the possible factors affecting the efficacy outcomes. The Cochrane risk of bias assessment tool will be used to assess the RCT quality, and the Grading of Recommendation, Assessment, Development and Evaluation will be used to assess the strength of evidence from the meta-analysis. No ethical approval is required because this study includes neither

  1. The effects of the adjunctive bupropion on male sexual dysfunction induced by a selective serotonin reuptake inhibitor: a double-blind placebo-controlled and randomized study.

    Science.gov (United States)

    Safarinejad, Mohammad Reza

    2010-09-01

    To determine the safety and efficacy of adjunctive bupropion sustained-release (SR) on male sexual dysfunction (SD) induced by a selective serotonin reuptake inhibitor (SSRI), as SD is a common side-effect of SSRIs and the most effective treatments have yet to be determined. The randomized sample consisted of 234 euthymic men who were receiving some type of SSRI. The men were randomly assigned to bupropion SR (150 mg twice daily, 117) or placebo (twice daily, 117) for 12 weeks. Efficacy was evaluated using the Clinical Global Impression-Sexual Function (CGI-SF; the primary outcome measure), the International Index of Erectile Function (IIEF), Arizona Sexual Experience Scale (ASEX), and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) (secondary outcome measures). Participants were followed biweekly during study period. After 12 weeks of treatment, the mean (sd) scores for CGI-SF were significantly lower, i.e. better, in patients on bupropion SR, at 2.4 (1.2), than in the placebo group, at 3.9 (1.1) (P= 0.01). Men who received bupropion had a significant increase in the total IIEF score (54.4% vs 1.2%; P= 0.003), and in the five different domains of the IIEF. Total ASEX scores were significantly lower, i.e. better, among men who received bupropion than placebo, at 15.5 (4.3) vs 21.5 (4.7) (P= 0.002). The EDITS scores were 67.4 (10.2) for the bupropion and 36.3 (11.7) for the placebo group (P= 0.001). The ASEX score and CGI-SF score were correlated (P= 0.003). In linear regression analyses the CGI-SF score was not affected significantly by the duration of SD, type of SSRI used and age. Bupropion is an effective treatment for male SD induced by SSRIs. These results provide empirical support for conducting a further study of bupropion.

  2. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis.

    Science.gov (United States)

    Anglin, Rebecca; Yuan, Yuhong; Moayyedi, Paul; Tse, Frances; Armstrong, David; Leontiadis, Grigorios I

    2014-06-01

    There is emerging concern that selective serotonin reuptake inhibitors (SSRIs) may be associated with an increased risk of upper gastrointestinal (GI) bleeding, and that this risk may be further increased by concurrent use of nonsteroidal anti-inflammatory (NSAID) medications. Previous reviews of a relatively small number of studies have reported a substantial risk of upper GI bleeding with SSRIs; however, more recent studies have produced variable results. The objective of this study was to obtain a more precise estimate of the risk of upper GI bleeding with SSRIs, with or without concurrent NSAID use. MEDLINE, EMBASE, PsycINFO, the Cochrane central register of controlled trials (through April 2013), and US and European conference proceedings were searched. Controlled trials, cohort, case-control, and cross-sectional studies that reported the incidence of upper GI bleeding in adults on SSRIs with or without concurrent NSAID use, compared with placebo or no treatment were included. Data were extracted independently by two authors. Dichotomous data were pooled to obtain odds ratio (OR) of the risk of upper GI bleeding with SSRIs +/- NSAID, with a 95% confidence interval (CI). The main outcome and measure of the study was the risk of upper GI bleeding with SSRIs compared with placebo or no treatment. Fifteen case-control studies (including 393,268 participants) and four cohort studies were included in the analysis. There was an increased risk of upper GI bleeding with SSRI medications in the case-control studies (OR=1.66, 95% CI=1.44,1.92) and cohort studies (OR=1.68, 95% CI=1.13,2.50). The number needed to harm for upper GI bleeding with SSRI treatment in a low-risk population was 3,177, and in a high-risk population it was 881. The risk of upper GI bleeding was further increased with the use of both SSRI and NSAID medications (OR=4.25, 95% CI=2.82,6.42). SSRI medications are associated with a modest increase in the risk of upper GI bleeding, which is lower than has

  3. A non-selective (amitriptyline), but not a selective (citalopram), serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache.

    OpenAIRE

    Bendtsen, L; Jensen, R; Olesen, J

    1996-01-01

    OBJECTIVES: Although the tricyclic antidepressant amitriptyline is extensively used in the prophylactic treatment of chronic tension-type headache, only few studies have investigated the efficacy of this treatment and the results are contradictory. In addition, the new selective serotonin reuptake inhibiting antidepressants, which are widely used in depression and of potential value in pain management, have never been investigated in a placebo controlled study of tension-type headache. The ai...

  4. Novel selective and potent 5-HT reuptake inhibitors with 5-HT1D antagonist activity: chemistry and pharmacological evaluation of a series of thienopyran derivatives.

    Science.gov (United States)

    Torrado, Alicia; Lamas, Carlos; Agejas, Javier; Jiménez, Alma; Diaz, Nuria; Gilmore, Jeremy; Boot, John; Findlay, Jeremy; Hayhurst, Lorna; Wallace, Louise; Broadmore, Richard; Tomlinson, Rosemarie

    2004-10-15

    A series of compounds combining the naphthylpiperazine and thienopyran scaffolds has been prepared and evaluated for 5-HT reuptake inhibition with 5-HT1D antagonist activity. The design of these compounds has been based on the 'overlapping type' strategy where two pharmacophores are linked in a single molecule. The resultant dual pharmacological profile has the potential to deliver a more efficient treatment for depression.

  5. A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial.

    Science.gov (United States)

    Goodyer, I M; Dubicka, B; Wilkinson, P; Kelvin, R; Roberts, C; Byford, S; Breen, S; Ford, C; Barrett, B; Leech, A; Rothwell, J; White, L; Harrington, R

    2008-05-01

    To determine if, in the short term, depressed adolescents attending routine NHS Child and Adolescent Mental Health Services (CAMHS), and receiving ongoing active clinical care, treatment with selective serotonin reuptake inhibitors (SSRIs) plus cognitive behaviour therapy (CBT) compared with SSRI alone, results in better healthcare outcomes. A pragmatic randomised controlled trial (RCT) was conducted on depressed adolescents attending CAMHS who had not responded to a psychosocial brief initial intervention (BII) prior to randomisation. Six English CAMHS participated in the study. A total of 208 patients aged between 11 and 17 years were recruited and randomised. All participants received active routine clinical care in a CAMHS outpatient setting and an SSRI and half were offered CBT. The duration of the trial was a 12-week treatment phase, followed by a 16-week maintenance phase. Follow-up assessments were at 6, 12 and 28 weeks. The primary outcome measure was the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA). Secondary outcome measures were self-report depressive symptoms, interviewer-rated depressive signs and symptoms, interviewer-rated psychosocial impairment and clinical global impression of response to treatment. Information on resource use was collected in interview at baseline and at the 12- and 28-week follow-up assessments using the Child and Adolescent Service Use Schedule (CA-SUS). Of the 208 patients randomised, 200 (96%) completed the trial to the primary end-point at 12 weeks. By the 28-week follow-up, 174 (84%) participants were re-evaluated. Overall, 193 (93%) participants had been assessed at one or more time points. Clinical characteristics indicated that the trial was conducted on a severely depressed group. There was significant recovery at all time points in both arms. The findings demonstrated no difference in treatment effectiveness for SSRI + CBT over SSRI only for the primary or secondary outcome measures at

  6. Farmacogenética de inibidores seletivos de recaptação de serotonina: uma revisão Pharmacogenetics of selective serotonine reuptake inhibitors: a review

    Directory of Open Access Journals (Sweden)

    Diana Klanovicz Silva

    2008-01-01

    Full Text Available A variabilidade da resposta aos medicamentos se deve em grande parte a fatores genéticos, e essa variabilidade afeta os efeitos terapêuticos e as reações adversas, de forma que a mesma dose de um medicamento pode ser benéfica para um paciente mas ineficaz para outro. Os fármacos conhecidos como inibidores seletivos de recaptação de serotonina (ISRSs pertencem a uma classe de medicamentos utilizados para o tratamento de uma série de patologias relacionadas com a serotonina, especialmente a depressão. O objetivo deste trabalho é reunir os dados presentes na literatura sobre a associação de genes candidatos com a resposta a ISRSs, fornecendo assim um panorama sobre o estado atual de conhecimento sobre o assunto. A resposta ao tratamento com ISRSs depende da variabilidade de genes codificantes de proteínas envolvidas com o papel da serotonina no cérebro. Com os avanços conquistados a partir do Projeto Genoma Humano, foi possível detectar essas variações, e várias delas mostraram ter importância farmacogenética. Portanto, alguns dos genes relacionados à farmacogenética dos ISRSs já são conhecidos, o que torna clara a necessidade de maiores investigações prospectivas para determinar a real utilidade desse conhecimento na prática clínica, com relação à possibilidade da determinação da dose adequada do fármaco correto para cada paciente, prática que vem sendo denominada de "medicina personalizada".A large proportion of the variability in drug response is due to genetic factors, and this variability affects therapeutic effects and adverse reactions, so that the same dosage of a drug can be beneficial to some patients, but ineffective to others. The drugs known as selective serotonin reuptake inhibitors (SSRI belong to a pharmacological class used in the management of a number of diseases related to serotonin, especially depression. The aim of this paper is to collect data from the literature about the association of

  7. Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Venerito, M; Schneider, C; Costanzo, R; Breja, R; Röhl, F-W; Malfertheiner, P

    2018-06-01

    Nonsteroidal anti-inflammatory drugs, low-dose aspirin, non-aspirin antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors and corticosteroids increase the risk of gastroduodenal bleeding. To determine in a retrospective cohort study the contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients taking these drugs. Among patients with peptic ulcer disease diagnosed by endoscopy from 01/2004 to 12/2014 (N = 1719, 60% males, age 65.8 ± 14.5), 56.9% had peptic ulcer bleeding (cases) and 43.1% uncomplicated peptic ulcer disease (controls). Demographics, intake of nonsteroidal anti-inflammatory drugs, aspirin, non-aspirin antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors, proton pump inhibitors and corticosteroids were documented. H. pylori status was determined by histology, rapid urease test or serology. Adjusted odds ratios (OR) were estimated by logistic regression analysis. Helicobacter pylori infection increased the risk of peptic ulcer bleeding in nonsteroidal anti-inflammatory drug and aspirin users (OR = 2.91, 95% CI = 1.71-4.98 and OR = 2.23, 95% CI = 1.52-3.28, respectively), but not in patients on anticoagulants, selective serotonin reuptake inhibitor or corticosteroid therapy. H. pylori-positive status substantially increased the risk of peptic ulcer bleeding in patients on non-aspirin antiplatelet agents (OR = 4.37, 95% CI = 1.28-14.99), concomitant aspirin/nonsteroidal anti-inflammatory drug intake (OR = 5.85, 95% CI = 1.68-20.36) and combined antiplatelet therapy (OR = 8.43, 95% CI = 1.09-65.17). After further adjustment for proton pump inhibitor intake, H. pylori infection was still a risk factor for peptic ulcer bleeding in nonsteroidal anti-inflammatory drug and aspirin users. Helicobacter pylori infection increases the risk of peptic ulcer bleeding in peptic ulcer disease patients on nonsteroidal anti-inflammatory drugs, aspirin and non

  8. Expression of brain derived neurotrophic factor, activity-regulated cytoskeleton protein mRNA, and enhancement of adult hippocampal neurogenesis in rats after sub-chronic and chronic treatment with the triple monoamine re-uptake inhibitor tesofensine

    DEFF Research Database (Denmark)

    Larsen, Marianne Hald; Rosenbrock, Holger; Sams-Dodd, Frank

    2007-01-01

    The changes of gene expression resulting from long-term exposure to monoamine antidepressant drugs in experimental animals are key to understanding the mechanisms of action of this class of drugs in man. Many of these genes and their products are either relevant biomarkers or directly involved...... in structural changes that are perhaps necessary for the antidepressant effect. Tesofensine is a novel triple monoamine reuptake inhibitor that acts to increase noradrenaline, serotonin, and dopamine neurotransmission. This study was undertaken to examine the effect of sub-chronic (5 days) and chronic (14 days......) administration of Tesofensine on the expression of brain derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton protein (Arc) in the rat hippocampus. Furthermore, hippocampi from the same animals were used to investigate the effect on cell proliferation by means of Ki-67- and Neuro...

  9. Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): a pooled analysis of 10 studies.

    Science.gov (United States)

    Papakostas, George I; Stahl, Stephen M; Krishen, Alok; Seifert, Cheryl A; Tucker, Vivian L; Goodale, Elizabeth P; Fava, Maurizio

    2008-08-01

    The goal of this work was to compare the efficacy of the norepinephrine and dopamine reuptake inhibitor bupropion with the selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder with high levels of anxiety (anxious depression). Ten double-blind, randomized studies from 1991 through 2006 were combined (N = 2122). Anxious depression was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) anxiety-somatization factor score >or= 7. Among patients with anxious depression (N = 1275), response rates were greater following SSRI than bupropion treatment according to the HAM-D-17 (65.4% vs. 59.4%, p = .03) and the Hamilton Rating Scale for Anxiety (61.5% vs. 54.5%, p = .03). There was also a greater reduction in HAM-D-17 mean +/- SD scores (-14.1 +/- 7.6 vs. -13.2 +/- 7.9, p = .03) and a trend toward statistical significance for a greater reduction in HAM-A mean +/- SD scores (-10.5 +/- 7.4 vs. -9.6 +/- 7.6, p = .05) in favor of SSRI treatment among patients with anxious depression. There was no statistically significant difference in efficacy between bupropion and the SSRIs among patients with moderate/low levels of anxiety. There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression (6% difference in response rates). Using the number-needed-to-treat (NNT) statistic as 1 indicator of clinical significance, nearly 17 patients would need to be treated with an SSRI than with bupropion in order to obtain 1 additional responder. This difference falls well above the limit of NNT = 10, which was suggested by the United Kingdom's National Institute of Clinical Excellence. Nevertheless, the present work is of theoretical interest because it provides preliminary evidence suggesting a central role for serotonin in the regulation of symptoms of negative affect such as anxiety.

  10. The effect of sibutramine, a serotonin-norepinephrine reuptake inhibitor, on platelets and fibrin networks of male Sprague-Dawley rats: a descriptive study.

    Science.gov (United States)

    van der Schoor, Ciska; Oberholzer, Hester Magdalena; Bester, Megan Jean; van Rooy, Mia-Jeanne

    2014-12-01

    Sibutramine is used in the treatment of obesity due to its ability to influence feelings of hunger and satiety by inhibiting the re-uptake of serotonin and noradrenalin in the central nervous system (CNS). Sibutramine use has been associated with numerous adverse events in particular cardiovascular complications possibly due to the formation of thrombi. This ultrastructural descriptive study investigated the effect of sibutramine on blood coagulation, specifically the effect on morphology of platelets and fibrin networks using scanning electron microscopy. Male Sprague-Dawley rats treated with either a recommended therapeutic dose [low dosage 1.32 mg/kg] or a toxicological higher dose [high dosage 13.2 mg/kg] of sibutramine for 28 days were used and compared to control animals. Blood samples were collected and plasma smears were prepared for platelet evaluation. Following the addition of thrombin to the plasma samples, the morphology of the fibrin clots was evaluated. Platelet evaluation by scanning electron microscopy revealed morphology typical of a prothrombotic state with a characteristic excessive platelet activation in both low-dose (LD) and high-dose (HD) rats. The fibrin clots of sibutramine-treated rats, LD and HD revealed fused thick fibers with thin fibers forming a net-like structure over the thick fibers which differ considerably from the organized structure of the control animals. It can be concluded that sibutramine alters the ultrastructure of platelets and fibrin networks creating a prothrombotic state.

  11. 5-HT has contrasting effects in the frontal cortex, but not the hypothalamus, on changes in noradrenaline efflux induced by the monoamine releasing-agent, d-amphetamine, and the reuptake inhibitor, BTS 54 354.

    Science.gov (United States)

    Géranton, Sandrine M; Heal, David J; Stanford, S Clare

    2004-03-01

    There is extensive evidence for functional interactions between central noradrenergic and serotonergic neurones. Here, dual-probe microdialysis was used in freely-moving rats to compare the effects of 5-HT on noradrenergic transmission in the rat frontal cortex and hypothalamus. We studied the effects of the 5-HT synthesis inhibitor, para-chlorophenylalanine (pCPA; which depleted 5-HT stores in both the frontal cortex and the hypothalamus), on spontaneous efflux of noradrenaline and on the noradrenergic responses to d-amphetamine, and the monoamine reuptake inhibitor, BTS 54 354. pCPA pretreatment alone did not affect spontaneous noradrenaline efflux in either brain region, whether or not alpha2-autoreceptors were inactivated by administration of the alpha2-antagonist, atipamezole (1 mg/kg i.p). However, in the frontal cortex, pCPA pretreatment augmented the amplitude of, and prolonged, the noradrenergic response to local infusion of d-amphetamine (10 microM). In contrast, pCPA abolished the increase in cortical noradrenaline efflux induced by local infusion of BTS 54 354 (50 microM). In the hypothalamus, pCPA did not affect the amplitude of the response to either of these agents but did prolong the effects of d-amphetamine on noradrenaline efflux. These findings suggest that serotonergic transmission has complex effects on the noradrenergic response to drugs that increase noradrenergic transmission in the frontal cortex, but has less influence in the hypothalamus.

  12. Atomoxetine-Induced Electrocardiogram Changes

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-12-01

    Full Text Available An 11-year-old boy with attention deficit hyperactivity disorder (ADHD who developed palpitations and unusual cardiac repolarization changes on the electrocardiogram (ECG during standard dose treatment with atomoxetine is reported from Parkview Clinic and Birmingham Children's Hospital, Birmingham, UK.

  13. Calcium Signaling Pathway Is Associated with the Long-Term Clinical Response to Selective Serotonin Reuptake Inhibitors (SSRI and SSRI with Antipsychotics in Patients with Obsessive-Compulsive Disorder.

    Directory of Open Access Journals (Sweden)

    Hidehiro Umehara

    Full Text Available Selective serotonin reuptake inhibitors (SSRI are established first-line pharmacological treatments for obsessive-compulsive disorder (OCD, while antipsychotics are used as an augmentation strategy for SSRI in OCD patients who have either no response or a partial response to SSRI treatment. The goal of the present study was to identify genetic variants and pathways that are associated with the long-term clinical response of OCD patients to SSRI or SSRI with antipsychotics.We first performed a genome-wide association study of 96 OCD patients to examine genetic variants contributing to the response to SSRI or SSRI with antipsychotics. Subsequently, we conducted pathway-based analyses by using Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS to examine the combined effects of genetic variants on the clinical response in OCD.While we failed to detect specific genetic variants associated with clinical responses to SSRI or to SSRI with an atypical antipsychotic at genome-wide levels of significance, we identified 8 enriched pathways for the SSRI treatment response and 5 enriched pathways for the treatment response to SSRI with an antipsychotic medication. Notably, the calcium signaling pathway was identified in both treatment responses.Our results provide novel insight into the molecular mechanisms underlying the variability in clinical response to SSRI and SSRI with antipsychotics in OCD patients.

  14. Effect of mirtazapine versus selective serotonin reuptake inhibitors on benzodiazepine use in patients with major depressive disorder: a pragmatic, multicenter, open-label, randomized, active-controlled, 24-week trial.

    Science.gov (United States)

    Hashimoto, Tasuku; Shiina, Akihiro; Hasegawa, Tadashi; Kimura, Hiroshi; Oda, Yasunori; Niitsu, Tomihisa; Ishikawa, Masatomo; Tachibana, Masumi; Muneoka, Katsumasa; Matsuki, Satoshi; Nakazato, Michiko; Iyo, Masaomi

    2016-01-01

    This study aimed to evaluate whether selecting mirtazapine as the first choice for current depressive episode instead of selective serotonin reuptake inhibitors (SSRIs) reduces benzodiazepine use in patients with major depressive disorder (MDD). We concurrently examined the relationship between clinical responses and serum mature brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF. We conducted an open-label randomized trial in routine psychiatric practice settings. Seventy-seven MDD outpatients were randomly assigned to the mirtazapine or predetermined SSRIs groups, and investigators arbitrarily selected sertraline or paroxetine. The primary outcome was the proportion of benzodiazepine users at weeks 6, 12, and 24 between the groups. We defined patients showing a ≥50 % reduction in Hamilton depression rating scale (HDRS) scores from baseline as responders. Blood samples were collected at baseline, weeks 6, 12, and 24. Sixty-five patients prescribed benzodiazepines from prescription day 1 were analyzed for the primary outcome. The percentage of benzodiazepine users was significantly lower in the mirtazapine than in the SSRIs group at weeks 6, 12, and 24 (21.4 vs. 81.8 %; 11.1 vs. 85.7 %, both P  depressive episodes may reduce benzodiazepine use in patients with MDD. Trial registration UMIN000004144. Registered 2nd September 2010. The date of enrolment of the first participant to the trial was 24th August 2010. This study was retrospectively registered 9 days after the first participant was enrolled.

  15. Atomoxetine's Effect on Societal Costs in Sweden

    Science.gov (United States)

    Myren, Karl-Johan; Thernlund, Gunilla; Nylen, Asa; Schacht, Alexander; Svanborg, Par

    2010-01-01

    Objective: To compare societal costs between patients treated with atomoxetine and placebo in Sweden. Method: Ninety-nine pediatric ADHD patients were randomized to a 10-week double-blind treatment with atomoxetine (n = 49) or placebo (n = 50). All parents received four sessions of psycho-education. Parents filled out a resource utilization…

  16. Efficacy of atomoxetine in adult attention-Deficit/Hyperactivity Disorder: a drug-placebo response curve analysis

    Directory of Open Access Journals (Sweden)

    Reimherr Fred

    2005-10-01

    Full Text Available Abstract Background The objective of this study was to evaluate the efficacy of atomoxetine, a new and highly selective inhibitor of the norepinephrine transporter, in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD among adults by using drug-placebo response curve methods. Methods We analyzed data from two double-blind, placebo-controlled, parallel design studies of adult patients (Study I, N = 280; Study II, N = 256 with DSM-IV-defined ADHD who were recruited by referral and advertising. Subjects were randomized to 10 weeks of treatment with atomoxetine or placebo, and were assessed with the Conners Adult ADHD Rating Scales and the Clinical Global Impression of ADHD Severity scale before and after treatment. Results Those treated with atomoxetine were more likely to show a reduction in ADHD symptoms than those receiving placebo. Across all measures, the likelihood that an atomoxetine-treated subject improved to a greater extent than a placebo-treated subject was approximately 0.60. Furthermore, atomoxetine prevented worsening of most symptom classes. Conclusion From these findings, we conclude that atomoxetine is an effective treatment for ADHD among adults when evaluated using several criteria.

  17. Distinct Neural-Functional Effects of Treatments With Selective Serotonin Reuptake Inhibitors, Electroconvulsive Therapy, and Transcranial Magnetic Stimulation and Their Relations to Regional Brain Function in Major Depression: A Meta-analysis.

    Science.gov (United States)

    Chau, David T; Fogelman, Phoebe; Nordanskog, Pia; Drevets, Wayne C; Hamilton, J Paul

    2017-05-01

    Functional neuroimaging studies have examined the neural substrates of treatments for major depressive disorder (MDD). Low sample size and methodological heterogeneity, however, undermine the generalizability of findings from individual studies. We conducted a meta-analysis to identify reliable neural changes resulting from different modes of treatment for MDD and compared them with each other and with reliable neural functional abnormalities observed in depressed versus control samples. We conducted a meta-analysis of studies reporting changes in brain activity (e.g., as indexed by positron emission tomography) following treatments with selective serotonin reuptake inhibitors (SSRIs), electroconvulsive therapy (ECT), or transcranial magnetic stimulation. Additionally, we examined the statistical reliability of overlap among thresholded meta-analytic SSRI, ECT, and transcranial magnetic stimulation maps as well as a map of abnormal neural function in MDD. Our meta-analysis revealed that 1) SSRIs decrease activity in the anterior insula, 2) ECT decreases activity in central nodes of the default mode network, 3) transcranial magnetic stimulation does not result in reliable neural changes, and 4) regional effects of these modes of treatment do not significantly overlap with each other or with regions showing reliable functional abnormality in MDD. SSRIs and ECT produce neurally distinct effects relative to each other and to the functional abnormalities implicated in depression. These treatments therefore may exert antidepressant effects by diminishing neural functions not implicated in depression but that nonetheless impact mood. We discuss how the distinct neural changes resulting from SSRIs and ECT can account for both treatment effects and side effects from these therapies as well as how to individualize these treatments. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  18. Use of selective serotonin reuptake inhibitors and risk of re-operation due to post-surgical bleeding in breast cancer patients: a Danish population-based cohort study

    Directory of Open Access Journals (Sweden)

    Lash Timothy L

    2010-01-01

    Full Text Available Abstract Background Selective serotonin reuptake inhibitors (SSRI decrease platelet-function, which suggests that SSRI use may increase the risk of post-surgical bleeding. Few studies have investigated this potential association. Methods We conducted a population-based study of the risk of re-operation due to post-surgical bleeding within two weeks of primary surgery among Danish women with primary breast cancer. Patients were categorised according to their use of SSRI: never users, current users (SSRI prescription within 30 days of initial breast cancer surgery, and former users (SSRI prescription more than 30 days before initial breast cancer surgery. We calculated the risk of re-operation due to post-surgical bleeding within 14 days of initial surgery, and the relative risk (RR of re-operation comparing SSRI users with never users of SSRI adjusting for potential confounders. Results 389 of 14,464 women (2.7% were re-operated. 1592 (11% had a history of SSRI use. Risk of re-operation was 2.6% among never users, 7.0% among current SSRI users, and 2.7% among former users. Current users thus had an increased risk of re-operation due to post-operative bleeding (adjusted relative risk = 2.3; 95% confidence interval (CI = 1.4, 3.9 compared with never users. There was no increased risk of re-operation associated with former use of SSRI (RR = 0.93, 95% CI = 0.66, 1.3. Conclusions Current use of SSRI is associated with an increased risk of re-operation due to bleeding after surgery for breast cancer.

  19. Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

    NARCIS (Netherlands)

    Fossa, Anthony A.; Wisialowski, Todd A.; Cremers, Thomas; van der Hart, Marieke; Tseng, Elaine; Deng, Shibing; Rollema, Hans; Wang, Ellen Q.

    2012-01-01

    Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood

  20. Atomoxetine in abstinent cocaine users: Sex differences

    Directory of Open Access Journals (Sweden)

    Elise E. DeVito

    2017-10-01

    Full Text Available Data presented are from a sex-differences secondary analysis of a human laboratory investigation of single doses of atomoxetine (40 mg and 80 mg versus placebo in abstinent individuals with cocaine use disorders (CUD. Subjective drug effects, cognitive performance and cardiovascular measures were assessed. The primary atomoxetine dose analyses (which do not consider sex as a factor are reported in full elsewhere (DeVito et al., 2017 [1].

  1. Selective serotonin reuptake inhibitor sertraline inhibits voltage ...

    Indian Academy of Sciences (India)

    2016-10-04

    Oct 4, 2016 ... der, social anxiety disorder, and obsessive-compulsive dis- order. Because of .... to describe the interaction kinetics between the drugs and channels (Park et al. ..... of the human cardiac hKv1.5 channel. Circ. Res. 77 575–583.

  2. Sweat testing for the detection of atomoxetine from paediatric patients with attention deficit/ hyperactivity disorder: application to clinical practice.

    Science.gov (United States)

    Marchei, Emilia; Papaseit, Esther; Garcia-Algar, Oscar; Bilbao, Amaia; Farré, Magí; Pacifici, Roberta; Pichini, Simona

    2013-03-01

    Atomoxetine (ATX) is a selective norepinephrine reuptake inhibitor approved since 2002 for the treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents, and adults as an alternative treatment to methylphenidate. Within the framework of a project evaluating the use of alternative biological matrices for therapeutic monitoring of psychoactive drugs in paediatric and non-paediatric individuals, the excretion of ATX and its principal metabolites has been recently studied in oral fluid and hair. The aim of this study was to describe the excretion profile of ATX and its metabolites 4-hydroxyatomoxetine (4-OH-ATX) and N-desmethylatomoxetine (N-des-ATX) in sweat following the administration of different dosage regimens (60, 40, 35, and 18 mg/day) of ATX to six paediatric patients. Sweat patches were applied to the back of each participant and removed at timed intervals. ATX and its metabolites were measured in patches using a previously validated liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Independently from the administered dose, ATX appeared in the sweat patches 1 h post administration and reached its maximum concentration generally at 24 h. Peak ATX concentrations ranged between 2.31 and 40.4 ng/patch and did not correlate with the administered drug dose, or with body surface area. Total ATX excreted in sweat ranged between 0.008 and 0.121 mg, corresponding to 0.02 and 0.3% of the administered drug. Neither 4-OH-ATX, nor N-des-ATX was detected in either of the collected sweat patches. Measuring ATX in sweat patches can provide information on cumulative drug use from patch application until removal. Copyright © 2012 John Wiley & Sons, Ltd.

  3. Increased prefrontal hemodynamic change after atomoxetine administration in pediatric attention-deficit/hyperactivity disorder as measured by near-infrared spectroscopy.

    Science.gov (United States)

    Ota, Toyosaku; Iida, Junzo; Nakanishi, Yoko; Sawada, Satomi; Matsuura, Hiroki; Yamamuro, Kazuhiko; Ueda, Shotaro; Uratani, Mitsuhiro; Kishimoto, Naoko; Negoro, Hideki; Kishimoto, Toshifumi

    2015-03-01

    Atomoxetine, approved in Japan for the treatment of pediatric attention-deficit/hyperactivity disorder (ADHD) in April 2009, is a nonstimulant that is thought to act presynaptically via the inhibition of norepinephrine reuptake. Near-infrared spectroscopy is a non-invasive optical tool that can be used to study oxygenation and hemodynamic changes in the cerebral cortex. The present study examined the effects of a clinical dose of atomoxetine on changes in prefrontal hemodynamic activity in children with ADHD, as measured by near-infrared spectroscopy using the Stroop Color-Word Task. Ten children with ADHD participated in the present study. We used 24-channel near-infrared spectroscopy to measure the relative concentrations of oxyhemoglobin in the frontal lobes of participants in the drug-naïve condition and those who had received atomoxetine for 8 weeks. Measurements were conducted every 0.1 s during the Stroop Color-Word Task. We used the ADHD Rating Scale-IV-Japanese version (Home Version) to evaluate ADHD symptoms. We found a significant decrease in ADHD Rating Scale-IV-Japanese version scores, from 30.7 to 22.6 (P=0.003). During the Stroop Color-Word Task, we found significantly higher levels of oxyhemoglobin changes in the prefrontal cortex of participants in the atomoxetine condition compared with those in the drug-naïve condition. This increase in oxyhemoglobin changes might indicate an intensified prefrontal hemodynamic response induced by atomoxetine. Near-infrared spectroscopy is a sensitive tool for measuring the pharmacological effects of atomoxetine in children with ADHD. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.

  4. Subchronic administration of atomoxetine causes an enduring reduction in context-induced relapse to cocaine seeking without affecting impulsive decision making.

    Science.gov (United States)

    Broos, Nienke; Loonstra, Rhianne; van Mourik, Yvar; Schetters, Dustin; Schoffelmeer, Anton N M; Pattij, Tommy; De Vries, Taco J

    2015-07-01

    Previous work has established a robust relationship between impulsivity and addiction, and revealed that impulsive decision making predisposes the vulnerability to cocaine-seeking behavior in rats. An important next step is to assess whether elevated relapse vulnerability can be treated via the reduction of impulsive decision making. Therefore, this study explored whether subchronic atomoxetine treatment can reduce relapse vulnerability by reducing impulsive decision making. Rats were trained in the delayed reward task and were subjected to 3 weeks of cocaine self-administration. Following drug self-administration, animals were divided to different experimental groups and received the noradrenaline transporter inhibitor and attention-deficit/hyperactivity disorder drug atomoxetine or vehicle subchronically for 20 days. On days 1 and 10 after treatment cessation, a context-induced reinstatement test was performed. Throughout the entire experiment, changes in impulsive decision making were continuously monitored. Subchronic treatment with atomoxetine reduced context-induced reinstatement both 1 and 10 days after treatment cessation, only in animals receiving no extinction training. Interestingly, neither subchronic nor acute atomoxetine treatments affected impulsive decision making. Our data indicate that the enduring reduction in relapse sensitivity by atomoxetine occurred independent of a reduction in impulsive decision making. Nonetheless, repeated atomoxetine administration seems a promising pharmacotherapeutical strategy to prevent relapse to cocaine seeking in abstinent drug-dependent subjects. © 2014 Society for the Study of Addiction.

  5. Atomoxetine Open-Label Trial in ADHD

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2002-07-01

    Full Text Available Atomoxetine (originally named tomoxetine, a new therapy for attention deficit hyperactivity disorder (ADHD marketed by Eli Lilly, was compared to methylphenidate in a prospective, randomized, open-label study for 10 weeks duration, at the University of Nebraska Medical Center, Massachusetts General Hospital, Mount Sinai Medical Center, Carolinas Medical Center, and Lilly Research Laboratories.

  6. Prescribing Patterns of Methylphenidate and Atomoxetine for ...

    African Journals Online (AJOL)

    Purpose: To determine the prescribing pattern of methylphenidate and atomoxetine to patients with. Attention-Deficit/Hyperactivity Disorder (ADHD) in South Africa. Methods: A retrospective, cross-sectional pharmacoepidemiological study was conducted based on the data from a medical aid administrator in South Africa for ...

  7. Prescribing Patterns of Methylphenidate and Atomoxetine for ...

    African Journals Online (AJOL)

    Purpose: To determine the prescribing pattern of methylphenidate and atomoxetine to patients with Attention-Deficit/Hyperactivity Disorder (ADHD) in South Africa. Methods: A retrospective, cross-sectional pharmacoepidemiological study was conducted based on the data from a medical aid administrator in South Africa for ...

  8. A pharmacokinetic/pharmacodynamic investigation: assessment of edivoxetine and atomoxetine on systemic and central 3,4-dihydroxyphenylglycol, a biochemical marker for norepinephrine transporter inhibition.

    Science.gov (United States)

    Kielbasa, William; Pan, Alan; Pereira, Alvaro

    2015-03-01

    Inhibition of norepinephrine (NE) reuptake into noradrenergic nerves is a common therapeutic target in the central nervous system (CNS). In noradrenergic nerves, NE is oxidized by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). In this study, 40 healthy male subjects received the NE transporter (NET) inhibitor edivoxetine (EDX) or atomoxetine (ATX), or placebo. The pharmacokinetic and pharmacodynamic profile of these drugs in plasma and cerebrospinal fluid (CSF) was assessed. In Part A, subjects received EDX once daily (QD) for 14 or 15 days at targeted doses of 6mg or 9mg. In Part B, subjects received 80mg ATX QD for 14 or 15 days. Each subject received a lumbar puncture before receiving drug and after 14 or 15 days of dosing. Plasma and urine were collected at baseline and after 14 days of dosing. Edivoxetine plasma and CSF concentrations increased dose dependently. The time to maximum plasma concentration of EDX was 2h, and the half-life was 9h. At the highest EDX dose of 9mg, DHPG concentrations were reduced from baseline by 51% at 8h postdose in CSF, and steady-state plasma and urine DHPG concentrations decreased by 38% and 26%, respectively. For 80mg ATX, the decrease of plasma, CSF, or urine DHPG was similar to EDX. Herein we provide clinical evidence that EDX and ATX decrease DHPG concentrations in the periphery and CNS, presumably via NET inhibition. EDX and ATX concentrations measured in the CSF confirmed the availability of those drugs in the CNS. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  9. Do Children and Adolescents with ADHD Respond Differently to Atomoxetine?

    Science.gov (United States)

    Wilens, Timothy E.; Kratochvil, Christopher; Newcorn, Jeffrey H.; Gao, Haitao

    2006-01-01

    Objective: Controversy exists over changes in tolerability and response to medications across the life span. Here the authors report data contrasting the efficacy and tolerability of atomoxetine between children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Method: Data were analyzed for children ages 6-11 (510 atomoxetine,…

  10. Adolescent Atomoxetine Treatment in a Rodent Model of ADHD: Effects on Cocaine Self-Administration and Dopamine Transporters in Frontostriatal Regions

    Science.gov (United States)

    Somkuwar, Sucharita S; Jordan, Chloe J; Kantak, Kathleen M; Dwoskin, Linda P

    2013-01-01

    Cocaine abuse and attention deficit/hyperactivity disorder (ADHD) are often comorbid. Preclinical research indicates that medial prefrontal (mPFC) and orbitofrontal (OFC) cortices are important neural substrates for both disorders. Using the spontaneously hypertensive rat (SHR) model of ADHD, we reported that adolescent treatment with the stimulant methylphenidate, a dopamine (DAT) and norepinephrine (NET) transporter inhibitor, enhanced cocaine self-administration during adulthood, and was associated with increased DAT function in mPFC. This study investigates the effects of atomoxetine ((R)-N-methyl-γ-(2-methylphenoxy)-benzenepropanamine hydrochloride) treatment, a selective NET inhibitor, during adolescence on cocaine self-administration and on DAT function and cell-surface expression in mPFC and OFC during adulthood. SHR acquired cocaine self-administration faster than Wistar–Kyoto and Wistar. Across cocaine doses, SHR earned more cocaine infusions and had higher progressive-ratio breakpoints than Wistar–Kyoto and Wistar, demonstrating that the SHR phenotype models comorbid ADHD and cocaine abuse. Prior atomoxetine treatment did not augment cocaine self-administration in SHR, but acquisition was enhanced in Wistar–Kyoto. No strain differences were found for DAT kinetic parameters or cellular localization in the vehicle controls. Atomoxetine did not alter DAT kinetic parameters or localization in SHR mPFC. Rather, atomoxetine decreased Vmax and DAT cell surface expression in SHR OFC, indicating that inhibition of NET by atomoxetine treatment during adolescence indirectly reduced DAT function and trafficking to the cell surface in OFC, specifically in the ADHD model. Thus, atomoxetine, unlike methylphenidate, does not enhance vulnerability to cocaine abuse in SHR and may represent an important alternative for teens with ADHD when drug addiction is a concern. PMID:23822950

  11. Inhibitors

    Science.gov (United States)

    ... JM, and the Hemophilia Inhibitor Research Study Investigators. Validation of Nijmegen-Bethesda assay modifications to allow inhibitor ... webinars on blood disorders Language: English (US) Español (Spanish) File Formats Help: How do I view different ...

  12. Serotonin synthesis, release and reuptake in terminals: a mathematical model

    Directory of Open Access Journals (Sweden)

    Best Janet

    2010-08-01

    Full Text Available Abstract Background Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system. Methods We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data. Results We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to

  13. Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain – an in vivo study

    Directory of Open Access Journals (Sweden)

    Udvardi PT

    2013-12-01

    Full Text Available Patrick T Udvardi,1,2 Karl J Föhr,3 Carolin Henes,1,2 Stefan Liebau,2 Jens Dreyhaupt,4 Tobias M Boeckers,2 Andrea G Ludolph11Department of Child and Adolescent Psychiatry and Psychotherapy, 2Institute of Anatomy and Cell Biology, 3Department of Anaesthesiology, 4Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, GermanyAbstract: Attention-deficit/hyperactivity disorder (ADHD is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR antagonist. The compound's effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip] or saline (0.9%, ip for 21 consecutive days on postnatal days (PND 21–41. In humans, atomoxetine's earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR, mesencephalon (MES, and hippocampus (HC was analyzed either directly after treatment (PND 42 or 2 months after termination of treatment (PND 101 to assess the compound's long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine's effects

  14. Síndrome de Gilles de la Tourette associada ao transtorno de déficit de atenção com hiperatividade: resposta clínica satisfatória a inibidor seletivo da recaptura de serotonina e metilfenidato Tourette syndrome associated with attention-deficit hyperactivity disorder: satisfactory clinical response to selective serotonin reuptake inhibitor and methylphenidate

    Directory of Open Access Journals (Sweden)

    Roberta Benitez Freitas Passos

    2010-01-01

    Full Text Available A Síndrome de Gilles de la Tourette (SGT, caracterizada pela presença de tiques motores e vocais, apresenta elevada associação com transtorno obsessivo-compulsivo (TOC e transtorno de déficit de atenção com hiperatividade (TDAH. Essas condições frequentemente causam mais prejuízo aos pacientes do que os tiques, propriamente. Relata-se o caso clínico de um paciente com SGT e comorbidade com TDAH e TOC. O tratamento com inibidor seletivo de recaptura de serotonina (ISRS e metilfenidato promoveu melhora significativa dos sintomas de TDAH, sintomas compulsivos e tiques.Tourette Syndrome (TS, characterized by motor and vocal tics, is often associated with obsessive compulsive disorder (OCD and attention-deficit hyperactivity disorder (ADHD. These associated conditions frequently cause more impairment in patients than tics themselves. We report the case of TS with comorbid ADHD and OCD. Treatment with selective serotonin reuptake inhibitor and methylphenidate, led to significantly improvement of ADHD symptoms, compulsive symptoms and tics.

  15. High-Dose Atomoxetine Treatment of ADHD in Youths with Limited Response to Standard Doses

    Science.gov (United States)

    Kratochvil, Christopher J.; Michelson, David; Newcorn, Jeffrey H.; Weiss, Margaret D.; Busner, Joan; Moore, Rodney J.; Ruff, Dustin D.; Ramsey, Janet; Dickson, Ruth; Turgay, Atilla; Saylor, Keith E.; Luber, Stephen; Vaughan, Brigette; Allen, Albert J.

    2007-01-01

    Objective: To assess the utility and tolerability of higher than standard atomoxetine doses to treat attention-deficit/hyperactivity disorder (ADHD). Method: Two randomized, double-blind trials of atomoxetine nonresponders ages 6 to 16 years were conducted comparing continued treatment with same-dose atomoxetine to treatment using greater than…

  16. Effects of atomoxetine on heart rhythm in children and adolescents.

    Science.gov (United States)

    Tanidir, Ibrahim Cansaran; Tanidir, Canan; Ozturk, Erkut; Bahali, Kayhan; Gunes, Hatice; Ergul, Yakup; Uneri, Ozden Sukran; Akdeniz, Celal; Tuzcu, Volkan

    2015-12-01

    The aim of this study was to examine the effects of atomoxetine on heart rhythm using 12-lead electrocardiography (ECG) and 24 h Holter monitoring. Children and adolescents who were diagnosed with attention deficit-hyperactivity disorder according to DSM-IV-TR were referred to a pediatric cardiology clinic for cardiologic examination before and after 4 or 5 weeks of atomoxetine treatment. Cardiac examination, complete blood count, biochemistry, thyroid function tests, 12-lead ECG and 24 h Holter monitoring were performed routinely in all patients. Each subject underwent 24 h Holter ECG monitoring before atomoxetine was started and after 4 or 5 weeks of effective dose atomoxetine treatment. Forty-one patients were included in this prospective study. No statistically significant change was found in QT, QTc or QT interval dispersion or blood pressure before and after 4 or 5 weeks of atomoxetine treatment. There was a statistically significant increase in heart rate (both during the day and at night) and QRS duration, and a statistically significant decrease in P wave dispersion. Three patients had rhythm disturbances. All of these three patients were asymptomatic and none of these arrhythmias reached clinical significance. Atomoxetine did not cause significant changes in ECG or Holter variables. In two patients, who had undiagnosed subclinical extrasystoles, extra beats were increased after 4th week of treatment, but still remained clinically insignificant. Before and after atomoxetine treatment, listening to the heart sounds for a longer time, may help clinicians to notice an extra beat. If an extra beat is identified then 24 Holter monitoring is recommended. © 2015 Japan Pediatric Society.

  17. Safety of Atomoxetine in Combination with Intravenous Cocaine in Cocaine- Experienced Participants

    Science.gov (United States)

    Cantilena, Louis; Kahn, Roberta; Duncan, Connie C.; Li, Shou-Hua; Anderson, Ann; Elkashef, Ahmed

    2012-01-01

    Objectives Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine, and also whether cognitive function was affected by atomoxetine during short-term administration. Methods In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 mg and 40 mg) was infused intravenously in sequential daily sessions. Results Pre-infusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Pre-infusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80 mg and 100 mg atomoxetine doses. All ECG parameters were unchanged. VAS scores for “bad effect” in the atomoxetine group were significantly higher at baseline, then declined, and for “likely to use” declined with atomoxetine treatment. On the ARCI the atomoxetine group scored significantly lower on amphetamine, euphoria and energy subscales (pAtomoxetine did not affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. Conclusions Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine. PMID:22987022

  18. Selective serotonin reuptake inhibitorprescribing before, during and after pregnancy

    DEFF Research Database (Denmark)

    Charlton, Ra; Jordan, S; Pierini, A

    2015-01-01

    OBJECTIVE: To explore the prescribing patterns of selective serotonin reuptake inhibitors (SSRIs) before, during and after pregnancy in six European population-based databases. DESIGN: Descriptive drug utilisation study. SETTING: Six electronic healthcare databases in Denmark, the Netherlands......, Italy (Emilia Romagna/Tuscany), Wales and the rest of the UK. POPULATION: All women with a pregnancy ending in a live or stillbirth starting and ending between 2004 and 2010. METHODS: A common protocol was implemented across databases to identify SSRI prescriptions issued (UK) or dispensed (non......-UK) in the year before, during or in the year following pregnancy. MAIN OUTCOME MEASURES: The percentage of deliveries in which the woman received an SSRI prescription in the year before, during or in the year following pregnancy. We also compared the choice of SSRIs and changes in prescribing over the study...

  19. The association study between the interaction of serotonin and norepinephrine transporter gene polymorphisms and the effects of selective serotonin reuptake inhibitors%5-羟色胺和去甲肾上腺素转运体基因多态性的交互作用与重性抑郁障碍临床疗效的关联研究

    Institute of Scientific and Technical Information of China (English)

    孟亚琴; 孙宁; 王彦芳; 段慧君; 李素萍; 彭菊意; 杜巧荣; 张克让

    2013-01-01

    Objective To explore the relevance of the interaction of serotonin and norepinephrine transporter gene polymorphisms and the effects of selective serotonin reuptake inhibitors.Methods The subjects comprised 246 patients according to the diagnostic and statistical manual of mental disorders in the fourth edition (DSM-Ⅳ) criterion for major depressive disorder(MDD).The clinical efficacy were assessed by using 17 Hamilton depression quantity (HAMD) scale after selective serotonin reuptake inhibitors(SSRIs) citalopram (20 to 60 mg/d) or paroxetine (20 to 60 mg/d) were used randomly for 1,2,4,6 weeks.Polymerase chain reaction(PCR),sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE)and DNA sequencing analysis were used to detect the genotype of 5-HTT gene single nucleotide polymorphisms (SNP) of VNTR and LPR and SNPs at rs2242446 and rs5569 of NET.SPSS13.0 software were used for statistical analysis.Results (1) An association between 5-HTT LPR and the efficacy of SSRIs was found after 6 weeks in these samples (P =0.023).The clinical efficiency of LL genotype was higher than SS + LS genotype(OR =2.225,OR 95% CI=1.118,4.427).(2) The interaction of 5-HTT LPR and NET rs5569 and the SSRIs antidepressant effects was statistical significance (P =0.01).Conclusion Preliminary study found that the interaction of 5-HTT LPR and NET rs5569 may be related to SSRIs antidepressant effects in China' s patients with MDD.%目的 探讨5-羟色胺和去甲肾上腺素转运体基因多态性的交互作用与选择性5-羟色胺再摄取抑制剂临床疗效的关联研究.方法 收集符合美国精神障碍诊断与统计手册第四版(DSM-Ⅳ)重性抑郁障碍(MDD)诊断标准的患者246例,给予选择性5-羟色胺再摄取抑制剂(SSRIs)西酞普兰(20~ 60mg/d)或帕罗西汀(20 ~ 60 mg/d),在治疗后1,2,4,6周运用17项汉密尔顿抑郁量表(HAMD)评定临床疗效;应用聚合酶链反应技术(PCR)、聚丙烯酰胺凝胶电

  20. Safety of atomoxetine in combination with intravenous cocaine in cocaine-experienced participants.

    Science.gov (United States)

    Cantilena, Louis; Kahn, Roberta; Duncan, Connie C; Li, Shou-Hua; Anderson, Ann; Elkashef, Ahmed

    2012-12-01

    Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine and also whether cognitive function was affected by atomoxetine during short-term administration. In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 and 40 mg) was infused intravenously in sequential daily sessions. Preinfusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Preinfusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80- and 100-mg atomoxetine doses. All electrocardiogram parameters were unchanged. Visual Analog Scale (VAS) scores for "bad effect" in the atomoxetine group were significantly higher at baseline, then declined, and for "likely to use" declined with atomoxetine treatment. On the Addiction Research Center Inventory, the atomoxetine group scored significantly lower on amphetamine, euphoria, and energy subscales (P affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine.

  1. Atomoxetine pharmacogenetics: associations with pharmacokinetics, treatment response and tolerability.

    Science.gov (United States)

    Brown, Jacob T; Bishop, Jeffrey R

    2015-01-01

    Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder and is predominantly metabolized by the CYP2D6 enzyme. Differences in pharmacokinetic parameters as well as clinical treatment outcomes across CYP2D6 genotype groups have resulted in dosing recommendations within the product label, but clinical studies supporting the use of genotype guided dosing are currently lacking. Furthermore, pharmacokinetic and clinical studies have primarily focused on extensive as compared with poor metabolizers, with little information known about other metabolizer categories as well as genes involved in the pharmacodynamics of atomoxetine. This review describes the pharmacogenetic associations with atomoxetine pharmacokinetics, treatment response and tolerability with considerations for the clinical utility of this information.

  2. Urinary Retention Associated with Atomoxetine Use: A Case Report

    Directory of Open Access Journals (Sweden)

    Nilfer Sahin

    2016-02-01

    Full Text Available Atomoxetine is a well-studied non-stimulant treatment agent, and is also the first-choice non-stimulant drug for the conventional treatment of Attention Deficit Hyperactivity Disorder owing to its effectiveness and tolerability. Urinary retention is a type of urological emergency that is associated with the inability to urinate despite the bladder being full and a strong urge to urinate. It is known that urinary retention can also develop due to the use of anticholinergic drugs. In this manuscript, we present a 12-year-old male case who developed acute urinary retention in the period following atomoxetine treatment.

  3. [Atomoxetine for treatment of children and adolescents with ADHD].

    Science.gov (United States)

    Resen, Katarina; Pagsberg, Anne Katrine; Jörgens, Gesche

    2014-03-03

    Atomoxetine reduces ADHD symptoms in children and adolescents significantly and is indicated for ADHD with co-morbid anxiety, depression and tics or with an increased risk of abuse. Number needed to treat is 3.4-5. Common adverse effects are stomach pain, decreased appetite and somnolence. Serious adverse effects include increased vascular tone, decreased growth rate and increased suicidal behaviour. In most cases adverse effects are mild to moderate and transient. Since atomoxetine was launched in 2006, 117 cases of toxic exposures have been reported in Denmark.

  4. Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area

    NARCIS (Netherlands)

    Dremencov, Eliyahu; El Mansari, Mostafa; Blier, Pierre

    Background: Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are efficacious in depression because of their ability to increase 5-HT neurotransmission. However, owing to a purported inhibitory effect of 5- HT on dopamine (DA) neuronal activity in the ventral tegmental area (VTA), this increase

  5. Selective Serotonin Reuptake Inhibitors for Treatment of Selective Mutism

    Directory of Open Access Journals (Sweden)

    Mazlum Çöpür

    2012-03-01

    Full Text Available Some authors suggest that selective mutism should be considered as a variant of social phobia or a disorder in the obsessive-compulsive spectrum. Recent studies indicate that pharmacological treatments may be effective in the treatment of selective mutism. In this article, four cases who were treated with citalopram and escitalopram are presented. The results indicate that the drugs were well tolerated, and the level of social and verbal interactions improved significantly. These findings have shown that citalopram and escitalopram can be considered in medication of selective mutism; nevertheless, it is essential that research be done with more cases than previous ones, in order to prove their accuracy

  6. Atomoxetine Treatment of ADHD in Children with Comorbid Tourette Syndrome

    Science.gov (United States)

    Spencer, Thomas J.; Sallee, F. Randy; Gilbert, Donald L.; Dunn, David W.; McCracken, James T.; Coffey, Barbara J.; Budman, Cathy L.; Ricardi, Randall K.; Leonard, Henrietta L.; Allen, Albert J.; Milton, Denai R.; Feldman, Peter D.; Kelsey, Douglas K.; Geller, Daniel A.; Linder, Steven L.; Lewis, Donald W.; Winner, Paul K.; Kurlan, Roger M.; Mintz, Mark

    2008-01-01

    Objective: This study examines changes in severity of tics and ADHD during atomoxetine treatment in ADHD patients with Tourette syndrome (TS). Method: Subjects (7-17 years old) with ADHD ("Diagnostic and Statistical Manual of Mental Disorders, DSM-IV") and TS were randomly assigned to double-blind treatment with placebo (n = 56) or atomoxetine…

  7. Norepinephrine transporter blocker atomoxetine increases salivary alpha amylase

    NARCIS (Netherlands)

    Warren, C.M.; van den Brink, R.L.; Nieuwenhuis, S.; Bosch, J.A.

    It has been suggested that central norepinephrine (NE) activity may be inferred from increases in salivary alpha-amylase (SAA), but data in favor of this proposition are limited. We administered 40mg of atomoxetine, a selective NE transporter blocker that increases central NE levels, to 24 healthy

  8. Atomoxetine/Methylphenidate Effects on Social Play Behavior

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2015-02-01

    Full Text Available Researchers at Utrecht University, The Netherlands, and University “Roma Tre,” Rome, Italy, studied the neural substrates of the previously identified social play-suppressant effects of methylphenidate (MPH and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD.

  9. Amphetamine Positive Urine Toxicology Screen Secondary to Atomoxetine

    Directory of Open Access Journals (Sweden)

    Joshua L. Fenderson

    2013-01-01

    Full Text Available The aim of this paper is to report the first case of atomoxetine leading to false-positive urine drug screen. An otherwise healthy 27-year-old female with a history of attention deficit hyperactivity disorder (ADHD treated with atomoxetine had an acute onset tonic-clonic seizure. On arrival to the hospital, a urine toxicological drug screen with immunochemical cloned enzyme donor immunoassay (CEDIA was performed. Results were positive for amphetamines; however, the presence of these substances could not be confirmed with urine gas chromatography-mass spectrometry (GC-MS. She denied any illicit drug use, herbal medications, or supplements, and her other prescription medications have not been previously known to cause a false-positive result for amphetamines. While stimulant treatments for ADHD could certainly result in a positive result on urine screen for amphetamines, there have been no reports of false-positive results for amphetamines secondary to patients using atomoxetine. We implicate atomoxetine, and/or its metabolites, as a compound or compounds which may interfere with urine drug immunoassays leading to false-positive results for amphetamines CEDIA assays.

  10. Atomoxetine Treatment for ADHD: Younger Adults Compared with Older Adults

    Science.gov (United States)

    Durell, Todd; Adler, Lenard; Wilens, Timothy; Paczkowski, Martin; Schuh, Kory

    2010-01-01

    Objective: Atomoxetine is a nonstimulant medication for treating child, adolescent, and adult ADHD. This meta-analysis compared the effects in younger and older adults. Method: A post hoc analysis was conducted using data from two double-blind, placebo-controlled clinical trials. Data from patients aged 18-25 years were compared with data from…

  11. Atomoxetine for the Treatment of ADHD in Incarcerated Adolescents.

    Science.gov (United States)

    Jillani, Sarah; Patel, Prina; Trestman, Robert; Kamath, Jayesh

    2016-06-01

    Effective interventions for adolescents with attention deficit/hyperactivity disorder (ADHD) in the correctional setting may improve care during incarceration, decrease risk of substance relapse, and reduce recidivism after release from the correctional setting of these individuals. The present report delineates the epidemiology of adolescent ADHD in the correctional setting and its association with substance use disorders and comorbid psychiatric illnesses. Evidence suggests that adolescents with ADHD have a higher risk of arrest and incarceration during adulthood. The present report examines evidence related to efficacy of atomoxetine, a nonstimulant medication for the treatment of adolescent ADHD, and presents data from a case series evaluating the effectiveness of atomoxetine for the treatment of adolescent ADHD in the Connecticut correctional setting. The results from the case series suggest that atomoxetine is effective for the treatment of adolescent ADHD in the context of significant past substance use. In summary, adolescents with ADHD have an elevated risk of incarceration and developing substance use disorders. The present review and pilot case series suggest that atomoxetine is an effective treatment for adolescents with ADHD in the correctional setting. © 2016 American Academy of Psychiatry and the Law.

  12. Efficacy of Atomoxetine in Children with Severe Autistic Disorders and Symptoms of ADHD: An Open-Label Study

    Science.gov (United States)

    Charnsil, Chawanun

    2011-01-01

    Objective: This study aims to examine the efficacy of atomoxetine in treating symptoms of attention deficit hyperactivity disorder (ADHD) in children with severe autistic disorder. Method: Children with severe autistic disorder who had symptoms of ADHD were given atomoxetine for 10 weeks. The efficacy of atomoxetine was evaluated by using the…

  13. Extended Efficacy of Once-Daily Atomoxetine in ADHD

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2004-07-01

    Full Text Available The efficacy of atomoxetine administered once daily (final dose 1.3 +/- 0.3 mg/kg; mean 44.5 mg per day; range 10-80 mg per day in the morning was assessed throughout the day, including evening and early morning, in a total of 197 children, 6 to 12 years of age (71% male, diagnosed with attention-deficit/hyperactivity disorder (ADHD (69% had combined subtype ADHD, and 35% had comorbid oppositional defiant disorder.

  14. MONITORING OF ATOMOXETINE EFFICIENCY IN CORRECTION OF THE SCHOOL DYSADAPTATION

    Directory of Open Access Journals (Sweden)

    O.A. Sobokar'

    2008-01-01

    Full Text Available In the given article, the authors highlight the results of the research into the school dysadaptation of the children, who have undergone intracranial vascular injuries in neonatal period. Researchers also studied the efficiency of atomoxetine for the correction of this pathology. The authors demonstrated both its high efficiency and good tolerance and safety in the event of the attention deficiency and hyperactivity disorder.Key words: school dysadaptation, attention_deficit and hyper activity disorder, treatment, children.

  15. Atomoxetine and Methylphenidate Treatment in Children with ADHD: The Efficacy, Tolerability and Effects on Executive Functions

    Science.gov (United States)

    Yildiz, Ozlem; Sismanlar, Sahika G.; Memik, Nursu Cakin; Karakaya, Isik; Agaoglu, Belma

    2011-01-01

    The aim of this study was to compare the safety, efficacy, tolerability, and the effects of atomoxetine and OROS-MPH on executive functions in children with ADHD. This study was an open-label study that only included two medication groups. Children were randomized to open-label atomoxetine or OROS-MPH for 12 weeks. Primary efficacy measures were…

  16. Atomoxetine versus Stimulants in the Community Treatment of Children with ADHD: An Electronic Diary Study

    Science.gov (United States)

    Whalen, Carol K.; Henker, Barbara; Ishikawa, Sharon S.; Emmerson, Natasha A.; Swindle, Ralph; Johnston, Joseph A.

    2010-01-01

    Objective: To compare the morning and afternoon/evening functioning of children with ADHD treated in the community with either atomoxetine or long-acting stimulants and reported to be doing well. Method: 109 8- to 12-year-olds and their mothers participated in one of three groups: stimulants (STIM, N = 26), atomoxetine (ATMX, N = 25), or…

  17. Research on atomoxetine in Dutch ASD/ADHD children : The RADAR study

    NARCIS (Netherlands)

    Harfterkamp, Maria

    2016-01-01

    Symptoms of attention deficit/hyperactivity disorder (ADHD) are frequently present in children with an autism spectrum disorder (ASD). In her study Myriam Harfterkamp showed that atomoxetine appears to be a promising treatment of ADHD in children and adolescents with ASD. Atomoxetine was superior to

  18. Neuroprotective effects of atomoxetine against traumatic spinal cord injury in rats

    Directory of Open Access Journals (Sweden)

    Qing-Xian Hou

    2016-03-01

    Results: There was no significant difference in the caspase-3 activity between the control and the sham groups or between the MP and the atomoxetine groups (P=0.811. The administration of atomoxetine significantly reduced tissue tumour necrosis factor alpha (TNF-α, and nitric oxide (NO levels compared to the trauma group (P

  19. Open-Label Trial of Atomoxetine Hydrochloride in Adults with ADHD

    Science.gov (United States)

    Johnson, Mats; Cederlund, Mats; Rastam, Maria; Areskoug, Bjorn; Gillberg, Christopher

    2010-01-01

    Background: While atomoxetine is an established treatment for attention-deficit/hyperactivity disorder in children, few studies have examined its efficacy for adults. Methods: Open-label trial of atomoxetine in 20 individuals with ADHD, aged 19-47 years, for 10 weeks, and a total of one year for responders. Results: Ten patients met primary…

  20. Core ADHD Symptom Improvement with Atomoxetine versus Methylphenidate: A Direct Comparison Meta-Analysis

    Science.gov (United States)

    Hazell, Philip L.; Kohn, Michael R.; Dickson, Ruth; Walton, Richard J.; Granger, Renee E.; van Wyk, Gregory W.

    2011-01-01

    Objective: Previous studies comparing atomoxetine and methylphenidate to treat ADHD symptoms have been equivocal. This noninferiority meta-analysis compared core ADHD symptom response between atomoxetine and methylphenidate in children and adolescents. Method: Selection criteria included randomized, controlled design; duration 6 weeks; and…

  1. Safety and Tolerability of Atomoxetine over 3 to 4 Years in Children with ADHD

    Science.gov (United States)

    Donnelly, Craig; Bangs, Mark; Trzepacz, Paula; Jin, Ling; Zhang, Shuyu; Witte, Michael M.; Ball, Susan G.; Spencer, Thomas J.

    2009-01-01

    Data from 13 double-blind, placebo-controlled trials and three open-label extension studies were pooled to examine the safety of atomoxetine for treating attention deficit hyperactivity disorder in children and adolescents for less than or equal to three or four years. Results show that atomoxetine is safe and well tolerated in the subjects.

  2. Pilot of a randomised controlled trial of the selective serotonin reuptake inhibitor sertraline versus cognitive behavioural therapy for anxiety symptoms in people with generalised anxiety disorder who have failed to respond to low-intensity psychological treatments as defined by the National Institute for Health and Care Excellence guidelines.

    Science.gov (United States)

    Buszewicz, Marta; Cape, John; Serfaty, Marc; Shafran, Roz; Kabir, Thomas; Tyrer, Peter; Clarke, Caroline S; Nazareth, Irwin

    2017-08-01

    Generalised anxiety disorder (GAD) is common, causing unpleasant symptoms and impaired functioning. The National Institute for Health and Care Excellence (NICE) guidelines have established good evidence for low-intensity psychological interventions, but a significant number of patients will not respond and require more intensive step 3 interventions, recommended as either high-intensity cognitive behavioural therapy (CBT) or a pharmacological treatment such as sertraline. However, there are no head-to-head comparisons evaluating which is more clinically effective and cost-effective, and current guidelines suggest that treatment choice at step 3 is based mainly on patient preference. To assess clinical effectiveness and cost-effectiveness at 12 months of treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline compared with CBT for patients with persistent GAD not improved with NICE-defined low-intensity psychological interventions. Participant randomised trial comparing treatment with sertraline with high-intensity CBT for patients with GAD who had not responded to low-intensity psychological interventions. Community-based recruitment from local Improving Access to Psychological Therapies (IAPT) services. Four pilot services located in urban, suburban and semirural settings. People considered likely to have GAD and not responding to low-intensity psychological interventions identified at review by IAPT psychological well-being practitioners (PWPs). Those scoring ≥ 10 on the Generalised Anxiety Disorder-7 (GAD-7) anxiety measure were asked to consider involvement in the trial. Aged ≥ 18 years, a score of ≥ 10 on the GAD-7, a primary diagnosis of GAD diagnosed on the Mini International Neuropsychiatric Interview questionnaire and failure to respond to NICE-defined low-intensity interventions. Inability to participate because of insufficient English or cognitive impairment, current major depression, comorbid anxiety disorder(s) causing

  3. A pilot study of the effects of atomoxetine on driving performance in adults with ADHD.

    Science.gov (United States)

    Barkley, Russell A; Anderson, Deborah L; Kruesi, Markus

    2007-02-01

    There is a high risk of vehicular crashes, traffic citations, and poorer driving performance in adults with ADHD. This pilot study examines the value of a new nonstimulant (atomoxetine) for improving the driving performance of adults with ADHD. Atomoxetine (1.2 mg/kg daily for 3 weeks) and a placebo are studied on 18 adults with ADHD (M age = 37 years) using ratings of ADHD symptoms, impairment, and safe driving behavior; a virtual reality driving simulator; and ratings of simulator performance. Atomoxetine improves self-ratings of ADHD symptoms, impairments, safe driving behavior, and simulator driving performance. No effects of atomoxetine are evident on others' ratings of driving behavior or on the simulator. Practice effects on the simulator may have obscured those drug effects. The authors find a mixed pattern of results such that atomoxetine warrants further study for its effects on driving in this high-risk population.

  4. Monoamine reuptake site occupancy of sibutramine: Relationship to antidepressant-like and thermogenic effects in rats.

    Science.gov (United States)

    Li, Yu-Wen; Langdon, Shaun; Pieschl, Rick; Strong, Todd; Wright, Robert N; Rohrbach, Kenneth; Lelas, Snjezana; Lodge, Nicholas J

    2014-08-15

    Sibutramine was formerly marketed as an anti-obesity agent. The current study investigated the relationships between monoamine reuptake site occupancy for sibutramine and both its antidepressant-like efficacy and thermogenic effects. Sibutramine's effects on locomotor activity (LMA) and food intake were also evaluated. Sibutramine occupied monoamine reuptake binding sites with the rank order of potency of NET>SERT>DAT; at 10mg/kg, po, occupancy was 95% NET, 81% SERT and 73% DAT. Sibutramine produced antidepressant-like behavior in the forced swim test; at the lowest effective dose (3mg/kg, po) occupancy was 61%, 90% and 23% at SERT, NET and DAT sites, respectively. Sibutramine also increased body core temperature in a dose- and time-dependent manner; at the lowest effective dose (30mg/kg) SERT, NET and DAT occupancies were respectively 78%, 86% and 59%. A significant decrease in food consumption was observed at 3 and 10mg/kg, po. LMA was increased at ≥10mg/kg, sc. The relationship between efficacy in the FST and occupancy was also determined for citalopram, fluoxetine and reboxetine. Similarly, the relationship between thermogenesis and target occupancy for several single or double/triple reuptake inhibitors was measured and showed that >40-50% DAT binding was required for thermogenesis. Thermogenesis was blocked by the D1 antagonist SCH39166 (3mg/kg, sc). Our findings indicate that the antidepressant-like effect of sibutramine may result from additive or synergistic actions on the three reuptake binding targets. At higher doses, sibutramine produces thermogenesis; DAT inhibition and activation of dopamine D1 receptors are required for this effect. Published by Elsevier B.V.

  5. Real-World Dosing Patterns of Atomoxetine in Adults with Attention-Deficit/Hyperactivity Disorder.

    Science.gov (United States)

    Kabul, Samaneh; Alatorre, Carlos; Montejano, Leslie B; Farr, Amanda M; Clemow, David B

    2015-12-01

    The aim was to investigate the dosing patterns of atomoxetine monotherapy in adult patients with attention-deficit/hyperactivity disorder (ADHD) in a retrospective analysis. Adult (≥ 18 years) patients with ADHD newly initiated on atomoxetine with ≥ 1 outpatient pharmacy claim for atomoxetine between January 2006 and December 2011 were selected from the Truven Health MarketScan(®) Commercial database. After a 30-day titration period, dosing patterns of atomoxetine monotherapy were analyzed in the 12 months following initiation. In addition, patient demographic and clinical characteristics were compared to identify characteristics associated with suboptimal versus recommended dosing. Of the 12,412 adult patients with ADHD newly initiated on atomoxetine, 4548 (36.6%) were suboptimally dosed, whereas 3323 (26.7%) were treated at recommended dose. Overall, study patients were treated at a mean (standard deviation [SD]) dose of 68.5 (44.9) mg/day. The suboptimal dosing cohort included significantly more females (54% vs. 44%, P atomoxetine therapy in a real-world setting are often dosed suboptimally. Increasing the awareness on optimal dosing strategy among clinicians and patients is warranted to maximize the therapeutic benefits of atomoxetine among adult patients with ADHD. © 2015 Eli Lilly and Company. CNS Neuroscience and Therapeutics published by John Wiley & Sons Ltd.

  6. Atomoxetine for the treatment of attention-deficit/hyperactivity disorder in children and adolescents: a review

    Directory of Open Access Journals (Sweden)

    Paul Hammerness

    2009-03-01

    Full Text Available Paul Hammerness, Katherine McCarthy, Elizabeth Mancuso, Cassandra Gendron, Daniel GellerClinical and Research Program in Pediatric Psychopharmacology, Massachusetts General Hospital and Harvard Medical School, Cambridge, MA, USAObjective: This review examines and summarizes the pharmacodynamic and pharmacokinetic properties, short- and longer-term efficacy, the moderating effect of comorbid disorders, as well as short- and long-term safety and tolerability of atomoxetine for the treatment of pediatric attention-deficit/hyperactivity disorder (ADHD.Methods: A systematic literature search was performed to review the extant literature on articles pertaining to the pharmacological treatment with atomoxetine in pediatric and/or adolescent ADHD.Results: There is an extensive literature on atomoxetine; over 4000 children have participated in clinical trials of atomoxetine, demonstrating its short- and longer-term efficacy. In addition, studies have examined the moderating effect of comorbid disorders on atomoxetine response, as well as atomoxetine’s therapeutic potential for other psychiatric conditions. Short- and longer-term safety and tolerability continue to be reported.Conclusions: Atomoxetine is indicated for both acute and maintenance/extended treatment of pediatric ADHD. Clinicians and families must be familiar with atomoxetine’s evidence base, including its profile of clinical response and its possible effectiveness in the presence of comorbidity.Keywords: ADHD, atomoxetine, pediatric

  7. The efficacy of atomoxetine in treating adult attention deficit hyperactivity disorder (ADHD): A meta-analysis of controlled trials.

    Science.gov (United States)

    Ravishankar, Vinutha; Chowdappa, Suresh Vedaveni; Benegal, Vivek; Muralidharan, Kesavan

    2016-12-01

    Atomoxetine, a non-stimulant, is FDA approved drug used in the management of adult ADHD. Since the presentation of adult ADHD is different from the childhood onset condition, there is an urgent need to study the efficacy of atomoxetine on the different symptom domains of adult ADHD. To study the efficacy of atomoxetine in treating adult ADHD compared to placebo, we performed a Medline search for English language publications of Randomized Controlled Trials (RCTs) comparing atomoxetine to placebo for adult ADHD using the keywords "adult ADHD", "atomoxetine" and "placebo". A total of 41 RCTs were returned of which we included 13 relevant RCTs reporting data on 1824 patients with adult ADHD in the analysis. Standardized mean difference between atomoxetine and placebo for the mean baseline-to-endpoint change in total ADHD scores, impulsivity/hyperactivity and inattention scores was calculated, with a 95% confidence limit. Atomoxetine had superior efficacy than placebo on overall adult ADHD scores [-0.45; 95% CI -0.54, -0.35; overall effect pAtomoxetine was superior to placebo on the domains of both inattention [-0.42; 95% CI -0.49, -0.35; overall effect pAtomoxetine was significantly more efficacious (pAtomoxetine is efficacious in treating adult ADHD compared to placebo, though the efficacy is significantly superior for inattention than hyperactivity/impulsivity. Copyright © 2016. Published by Elsevier B.V.

  8. Time-to-onset and -resolution of adverse events before/after atomoxetine discontinuation in adult patients with ADHD.

    Science.gov (United States)

    Upadhyaya, Himanshu; Tanaka, Yoko; Lipsius, Sarah; Kryzhanovskaya, Ludmila A; Lane, Jeannine R; Escobar, Rodrigo; Trzepacz, Paula T; Allen, Albert J

    2015-01-01

    Adults with attention-deficit/hyperactivity disorder treated with atomoxetine were examined for time-to-onset and -resolution of common treatment-emergent adverse events (TEAEs) and male sexual dysfunction, and for changes in blood pressure (BP) and heart rate (HR) upon atomoxetine discontinuation. 12-week open-label atomoxetine (40-100 mg/day) was followed by 12-week double-blind maintenance treatment (atomoxetine 80 or 100 mg/day). Responders were then randomized to atomoxetine (n = 266) or placebo (n = 258) for 25-week randomized withdrawal. Examined were (1) median time-to-onset and -resolution of TEAEs during atomoxetine treatment, and (2) within group, visitwise mean changes for sitting HR, systolic BP, and diastolic BP for the postrandomization placebo group. Common adverse events (AEs) appeared early, within week 1 of atomoxetine treatment. Some AEs resolve relatively rapidly, whereas others have a more lingering course of resolution (including male sexual side effects); median resolution times were 3 - 53 days. BP and HR increases during atomoxetine treatment returned to baseline upon atomoxetine discontinuation. Atomoxetine is associated with common AEs, with 3- to 53-day median resolution times. ClincialTrials.gov - NCT00700427.

  9. [Clinical effect of atomoxetine hydrochloride in 66 children with narcolepsy].

    Science.gov (United States)

    Zhang, Shen; Ding, Changhong; Wu, Husheng; Fang, Fang; Wang, Xiaohui; Ren, Xiaotun

    2015-10-01

    To observe the efficacy and safety of atomoxetine hydrochloride in children with narcolepsy. Totally 66 patients with narcolepsy who were conformed international classification of sleep disturbances (ICSD-2) diagnostic criteria treated with atomoxetine hydrochloride seen from November 2010 to December 2014 were enrolled into this study, 42 of them were male and 24 female, mean age of onset was 7.5 years (3.75-13.00 years), mean duration before diagnosis was 1.75 years (0.25-5.00 years). Complete blood count, liver and kidney function, multiple sleep latency test (MSLT), polysomnography (PGS), neuroimaging and electroencephalography (EEG) were performed for each patient. For some of the children HLA-DR2 gene and serum markers of infection were tested. The 66 cases were followed up from 2 to 49 months (average 18 months) to observe the clinical efficacy and adverse reactions. In 62 cases excessive daytime sleepiness was improved, in 11 cases (16.7%) it was controlled (16.7%), in 29 cases (43.9%) the treatment was obviously effective and in 22 (33.3%) it was effective; cataplexy occurred in 54 cases, in 18 (33.3%) it was controlled, in 19 (35.2%) the treatment was obviously effective and in 10 (18.5%) effective; night sleep disorders existed in 55 cases, in 47 cases it was improved, in 14 (25.5%) it was controlled, in 20 (36.4%) the treatment was obviously effective and in 13 (23.6%) effective; hypnagogic or hypnopompic hallucination was present in 13 cases, in only 4 these symptoms were controlled. Sleep paralysis existed in 4 cases, it was controlled in only 1 case. In 18 cases attention and learning efficiency improved.Anorexia occurred in 18 cases, mood disorder in 5 cases, depression in 2 cases, nocturia, muscle tremors, involuntary tongue movement each occurred in 1 case. P-R interval prolongation and atrial premature contraction were found in 1 case. Atomoxetine hydrochloride showed good effects in patients with narcolepsy on excessive daytime sleepiness

  10. High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors

    NARCIS (Netherlands)

    Verhaegh, B P M; de Vries, F; Masclee, A A M; Keshavarzian, A; de Boer, A; Souverein, P C; Pierik, M J; Jonkers, D M A E

    2016-01-01

    BACKGROUND: Microscopic colitis (MC) is a chronic bowel disorder characterised by watery diarrhoea. Nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), selective serotonin reuptake inhibitors (SSRIs) and statins have been associated with MC. However, underlying mechanisms

  11. Combined methylphenidate and atomoxetine pharmacotherapy in attention deficit hyperactivity disorder.

    Science.gov (United States)

    Ozbaran, Burcu; Kose, Sezen; Yuzuguldu, Onur; Atar, Burcu; Aydin, Cahide

    2015-01-01

    Pharmacological treatment of attention deficit hyperactivity disorder (ADHD) includes stimulant and non-stimulant medications. Our purpose in this study is to investigate efficacy, safety and tolerability of combined methylphenidate and atomoxetine pharmacotherapy. We included 12 patients of the 824 patients with ADHD using methylphenidate and atomoxetine combined therapy between the years 2010 and 2014. Kiddie-SADS, Turgay DSM-IV Based Child and Adolescent Behavior Disorders Screening and Rating Scale, Child Behavior Checklist, Clinic Global Impression Scale Severity and Impression (CGIS-S-I) scales were used. Patients were between the ages of 7 and 17 years. Before combined pharmacotherapy the CGIS-S score mean was 5.08. Mean CGIS-S score after the combined pharmacotherapy was 3.08 (P = 0.03; -2,980). The most common side effects were irritability (n = 5, 41.6%), appetite reduction (n = 3, 25%), palpitations (n = 2, 16.7%), headache (n = 1, 8.3%). Nine of these 12 patients showed significant improvement in their symptoms, combined therapy enhanced the effectiveness of monotherapy.

  12. [Atomoxetine and piracetam in the treatment of attention deficit hyperactivity disorder in children].

    Science.gov (United States)

    Zavadenko, N N; Suvorinova, N Iu

    2008-01-01

    Therapeutic effect of atomoxetine and piracetam has been assessed in the open controlled study included 42 patients with attention deficit hyperactivity disorder (ADHD), aged from 6 to 13 years. Group 1 (16 patients) received atomoxetine (strattera) in daily dosage 0,8-1,2 mg/kg as a monotherapy for 6 weeks. Patients of group 2 (14 children) received piracetam as a monotherapy in daily dosage 50-70 mg/kg for 6 weeks. No pharmacological therapy was conducted in group 3 (a control one) which included 12 patients with ADHD. The high effectiveness of both atomoxetine and piracetam has been shown. However, comparing to piracetam, the therapeutic effect of atomoxetine was reached earlier (two weeks after the beginning of therapy) and was more pronounced for all components of syndromes.

  13. Efficacy and Safety of Atomoxetine in the Treatment of Children and Adolescents with Attention Deficit Hyperactivity Disorder

    OpenAIRE

    Kohn, Michael R.; Tsang, Tracey W.; Clarke, Simon D.

    2012-01-01

    Several non-stimulant medications have been used in the treatment of attention deficit hyperactivity disorder (ADHD). Atomoxetine, was introduced in 2002. The safety and efficacy of atomoxetine in the treatment of ADHD for children, adolescents, and adults has been evaluated in over 4000 patients in randomized controlled studies and double blinded studies as well as in recent large longitudinal studies. This paper provides an updated summary of the literature on atomoxetine, particularly in r...

  14. Efficacy and Safety of Atomoxetine in the Treatment of Children and Adolescents with Attention Deficit Hyperactivity Disorder

    Directory of Open Access Journals (Sweden)

    Michael R. Kohn

    2012-01-01

    Full Text Available Several non-stimulant medications have been used in the treatment of attention deficit hyperactivity disorder (ADHD. Atomoxetine, was introduced in 2002. The safety and efficacy of atomoxetine in the treatment of ADHD for children, adolescents, and adults has been evaluated in over 4000 patients in randomized controlled studies and double blinded studies as well as in recent large longitudinal studies. This paper provides an updated summary of the literature on atomoxetine, particularly in relation to findings on the short- and long-term safety of atomoxetine in children and adolescents arising from recent large longitudinal cohort studies. Information is presented about the efficacy, safety, and tolerability of this medication.

  15. Efficacy and Safety of Atomoxetine in the Treatment of Children and Adolescents with Attention Deficit Hyperactivity Disorder

    Science.gov (United States)

    Kohn, Michael R.; Tsang, Tracey W.; Clarke, Simon D.

    2012-01-01

    Several non-stimulant medications have been used in the treatment of attention deficit hyperactivity disorder (ADHD). Atomoxetine, was introduced in 2002. The safety and efficacy of atomoxetine in the treatment of ADHD for children, adolescents, and adults has been evaluated in over 4000 patients in randomized controlled studies and double blinded studies as well as in recent large longitudinal studies. This paper provides an updated summary of the literature on atomoxetine, particularly in relation to findings on the short- and long-term safety of atomoxetine in children and adolescents arising from recent large longitudinal cohort studies. Information is presented about the efficacy, safety, and tolerability of this medication. PMID:23641171

  16. Effect of atomoxetine on hyperactivity in an animal model of attention-deficit/hyperactivity disorder (ADHD).

    Science.gov (United States)

    Moon, Su Jin; Kim, Chang Ju; Lee, Yeon Jung; Hong, Minha; Han, Juhee; Bahn, Geon Ho

    2014-01-01

    Hyperactivity related behaviors as well as inattention and impulsivity are regarded as the nuclear symptoms of attention-deficit/hyperactivity disorder (ADHD). To investigate the therapeutic effects of atomoxetine on the motor activity in relation to the expression of the dopamine (DA) D2 receptor based on the hypothesis that DA system hypofunction causes ADHD symptoms, which would correlate with extensive D2 receptor overproduction and a lack of DA synthesis in specific brain regions: prefrontal cortex (PFC), striatum, and hypothalamus. Young male spontaneously hypertensive rats (SHR), animal models of ADHD, were randomly divided into four groups according to the daily dosage of atomoxetine and treated for 21 consecutive days. The animals were assessed using an open-field test, and the DA D2 receptor expression was examined. The motor activity improved continuously in the group treated with atomoxetine at a dose of 1 mg/Kg/day than in the groups treated with atomoxetine at a dose of 0.25 mg/Kg/day or 0.5 mg/Kg/day. With respect to DA D2 receptor immunohistochemistry, we observed significantly increased DA D2 receptor expression in the PFC, striatum, and hypothalamus of the SHRs as compared to the WKY rats. Treatment with atomoxetine significantly decreased DA D2 expression in the PFC, striatum, and hypothalamus of the SHRs, in a dose-dependent manner. Hyperactivity in young SHRs can be improved by treatment with atomoxetine via the DA D2 pathway.

  17. Effect of atomoxetine on hyperactivity in an animal model of attention-deficit/hyperactivity disorder (ADHD.

    Directory of Open Access Journals (Sweden)

    Su Jin Moon

    Full Text Available Hyperactivity related behaviors as well as inattention and impulsivity are regarded as the nuclear symptoms of attention-deficit/hyperactivity disorder (ADHD.To investigate the therapeutic effects of atomoxetine on the motor activity in relation to the expression of the dopamine (DA D2 receptor based on the hypothesis that DA system hypofunction causes ADHD symptoms, which would correlate with extensive D2 receptor overproduction and a lack of DA synthesis in specific brain regions: prefrontal cortex (PFC, striatum, and hypothalamus.Young male spontaneously hypertensive rats (SHR, animal models of ADHD, were randomly divided into four groups according to the daily dosage of atomoxetine and treated for 21 consecutive days. The animals were assessed using an open-field test, and the DA D2 receptor expression was examined.The motor activity improved continuously in the group treated with atomoxetine at a dose of 1 mg/Kg/day than in the groups treated with atomoxetine at a dose of 0.25 mg/Kg/day or 0.5 mg/Kg/day. With respect to DA D2 receptor immunohistochemistry, we observed significantly increased DA D2 receptor expression in the PFC, striatum, and hypothalamus of the SHRs as compared to the WKY rats. Treatment with atomoxetine significantly decreased DA D2 expression in the PFC, striatum, and hypothalamus of the SHRs, in a dose-dependent manner.Hyperactivity in young SHRs can be improved by treatment with atomoxetine via the DA D2 pathway.

  18. Effects of selective serotonin reuptake inhibition on neural activity related to risky decisions and monetary rewards in healthy males

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Fisher, Patrick M; Haahr, Mette E

    2014-01-01

    the involvement of the normally functioning 5HT-system in decision-making under risk and processing of monetary rewards. The data suggest that prolonged SSRI treatment might reduce emotional engagement by reducing the impact of risk during decision-making or the impact of reward during outcome evaluation.......Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are commonly prescribed antidepressant drugs targeting the dysfunctional serotonin (5-HT) system, yet little is known about the functional effects of prolonged serotonin reuptake inhibition in healthy individuals. Here we used...... functional MRI (fMRI) to investigate how a three-week fluoxetine intervention influences neural activity related to risk taking and reward processing. Employing a double-blinded parallel-group design, 29 healthy young males were randomly assigned to receive 3 weeks of a daily dose of 40 mg fluoxetine...

  19. Combined Norepinephrine / Serotonergic Reuptake Inhibition: Effects on Maternal Behavior, Aggression and Oxytocin in the Rat

    Directory of Open Access Journals (Sweden)

    Elizabeth Thomas Cox

    2011-06-01

    Full Text Available BACKGROUND: Few systematic studies exist on the effects of chronic reuptake of monoamine neurotransmitter systems during pregnancy on the regulation of maternal behavior, although many drugs act primarily through one or more of these systems. Previous studies examining fluoxetine and amfonelic acid treatment during gestation on subsequent maternal behavior in rodents indicated significant alterations in postpartum maternal care, aggression and oxytocin levels. In this study, we extended our studies to include chronic gestational treatment with desipramine or amitriptyline to examine differential effects of reuptake inhibition of norepinephrine and combined noradrenergic and serotonergic systems on maternal behavior, aggression, and oxytocin system changes. METHODS: Pregnant Sprague-Dawley rats were treated throughout gestation with saline or one of three doses of either desipramine, which has a high affinity for the norepinephrine monoamine transporter, or amitriptyline, an agent with high affinity for both the norepinephrine and serotonin monoamine transporters. Maternal behavior and postpartum aggression were assessed on postpartum days one and six respectively. Oxytocin levels were measured in relevant brain regions on postpartum day seven. Predictions were that amitriptyline would decrease maternal behavior and increase aggression relative to desipramine, particularly at higher doses. Amygdaloidal oxytocin was expected to decrease with increased aggression. RESULTS: Amitriptyline and desiprimine differentially reduced maternal behavior, and at higher doses reduced aggressive behavior. Hippocampal oxytocin levels were lower after treatment with either drug but were not correlated with specific behavioral effects. These results, in combination with previous findings following gestational treatment with other selective neurotransmitter reuptake inhibitors, highlight the diverse effects of multiple monoamine systems thought to be involved in

  20. Evaluation of the Potential Pharmacokinetic Interaction between Atomoxetine and Fluvoxamine in Healthy Volunteers.

    Science.gov (United States)

    Todor, Ioana; Popa, Adina; Neag, Maria; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Vlase, Laurian; Gheldiu, Ana-Maria; Briciu, Corina

    2017-01-01

    Attention deficit hyperactivity disorder (ADHD) is frequently associated with other psychiatric pathologies. Therefore, the present study investigated a possible pharmacokinetic interaction between atomoxetine (ATX), a treatment option for ADHD, and an antidepressant, namely, fluvoxamine (FVX). Designed as an open-label, non-randomized clinical trial, the study included 2 periods. In period 1 (reference), each subject received ATX 25 mg (single-dose), whereas in period 2 (test), all subjects were given a combination of ATX 25 mg + FVX 100 mg, following a 6-day pretreatment regimen with the enzymatic inhibitor. Non-compartmental methods were employed to determine the pharmacokinetic parameters of ATX and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide. The results revealed significant differences between the study periods for Cmax, AUC0-t and AUC0-∞ values corresponding to ATX and its metabolite. Small, but statistically significant increases in AUC values were reported for both parent drug (1,583.05 ± 1,040.29 vs. 2,111.55 ± 1,411.59 ng*h/ml) and 4-hydroxyatomoxetine-O-glucuronide (5,754.71 ± 1,235.5 vs. 6,293.17 ± 1,219.34 ng*h/ml) after combined treatment of ATX and the enzymatic inhibitor. FVX had a modest effect on the pharmacokinetics of ATX and 4-hydroxyatomoxetine-O-glucuronide. The presence or absence of any clinical consequences associated with this pharmacokinetic drug-drug interaction needs to be established in future studies. © 2016 S. Karger AG, Basel.

  1. Adverse drug reaction labelling for atomoxetine, methylphenidate and modafinil

    DEFF Research Database (Denmark)

    Aagaard, Lise; Hansen, Ebba Holme

    2013-01-01

    Medical product information contains information about efficacy and safety for marketed pharmaceuticals. Three studies have compared safety labelling for different therapeutic categories in different countries and detected large variations in a number of reported adverse drug reactions (ADRs......). The rapid increase in use of medications for treatment of ADHD symptoms has created concern due to lack of information about effects from long-term use. The aim of this study was to compare ADR information in product information (PI)/summary of product characteristics (SPC) for oral formulations...... of atomoxetine, methylphenidate and modafinil marketed by the same pharmaceutical companies in Australia, Denmark and the United States. Discrepancies in listed ADRs were defined as types of ADRs (system organ class) not listed in all countries. For ADRs where discrepancies were detected, we extracted...

  2. Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain – an in vivo study

    Science.gov (United States)

    Udvardi, Patrick T; Föhr, Karl J; Henes, Carolin; Liebau, Stefan; Dreyhaupt, Jens; Boeckers, Tobias M; Ludolph, Andrea G

    2013-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET) inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist. The compound’s effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B) are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip]) or saline (0.9%, ip) for 21 consecutive days on postnatal days (PND) 21–41. In humans, atomoxetine’s earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR), mesencephalon (MES), and hippocampus (HC) was analyzed either directly after treatment (PND 42) or 2 months after termination of treatment (PND 101) to assess the compound’s long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine’s effects beyond NET inhibition. Taken together, these data reveal that atomoxetine seems to decrease glutamatergic transmission in a brain region-specific manner. Long-term data show that the compound’s impact is not due to an acute pharmacological effect but lasts or even amplifies after a drug-free period of 2 months, leading to altered development of

  3. Atomoxetine Treatment in Children and Adolescents with Attention-Deficit/hyperactivity Disorder and Comorbid Oppositional Defiant Disorder

    Science.gov (United States)

    Newcorn, Jeffrey H.; Spencer, Thomas J.; Biederman, Joseph; Milton, Denai R.; Michelson, David

    2005-01-01

    Objective: To examine (1) moderating effects of oppositional defiant disorder (ODD) on attention-deficit/hyperactivity disorder (ADHD) treatment response and (2) responses of ODD symptoms to atomoxetine. Method: Children and adolescents (ages 8-18) with ADHD were treated for approximately 8 weeks with placebo or atomoxetine (fixed dosing: 0.5,…

  4. Efficacy and safety of atomoxetine hydrochloride in Korean adults with attention-deficit hyperactivity disorder.

    Science.gov (United States)

    Lee, Soyoung Irene; Song, Dong-Ho; Shin, Dong Won; Kim, Ji Hoon; Lee, Young Sik; Hwang, Jun-Won; Park, Tae Won; Yook, Ki-Hwan; Lee, Jong Il; Bahn, Geon Ho; Hirata, Yuko; Goto, Taro; Takita, Yasushi; Takahashi, Michihiro; Lee, Sanghoon; Treuer, Tamás

    2014-12-01

    This article aims to assess the efficacy and safety of atomoxetine in Korean adults with attention-deficit hyperactivity disorder (ADHD). This post hoc double-blind, placebo-controlled study of atomoxetine (40-120 mg/day) over 10 weeks in adults with ADHD at 45 Japanese, Korean, and Taiwanese study sites focused on patient data from Korea (atomoxetine, n = 37; placebo, n = 37). Primary efficacy outcome was change in baseline-to-endpoint Conners' Adult ADHD Rating Scale-Investigator-rated: Screening Version (CAARS-Inv:SV) Total ADHD Symptoms score. Secondary efficacy outcomes included changes in Adult ADHD Quality of Life (AAQoL) total, Behavior Rating Inventory of Executive Function-Adult Version Self-Report (BRIEF-A:Self-Report), and Clinical Global Impression-ADHD-Severity (CGI-ADHD-S) scale scores. Atomoxetine-treated patients demonstrated a mean 18.9-point reduction in CAARS-Inv:SV total ADHD Symptoms score, compared with the 7.45-point reduction in placebo-treated patients (P ≤ 0.01). Significantly greater improvement was found for atomoxetine versus placebo in CGI-ADHD-S (P ≤ 0.01), BRIEF-A:Self-Report global executive composite (P ≤ 0.05), and metacognition index (P ≤ 0.01) executive function scores. Nausea, decreased appetite, and dry mouth were reported with significantly greater frequency by atomoxetine-treated patients, and only one placebo-treated patient discontinued because of adverse event. A 2.1-kg reduction in weight and a 7.5-beat/minute increase in pulse rate were observed in atomoxetine-treated patients. These data support a significant benefit of 80- to 120-mg once daily atomoxetine versus placebo for treatment of ADHD in adult Korean patients. A high placebo response rate was observed in this adult Korean sample; a higher discontinuation rate was also observed in atomoxetine-treated patients. These observations warrant further investigation. © 2014 Wiley Publishing Asia Pty Ltd.

  5. The influence of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite.

    Science.gov (United States)

    Todor, Ioana; Popa, Adina; Neag, Maria; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Vlase, Laurian; Gheldiu, Ana-Maria; Chira, Ruxandra; Briciu, Corina

    2015-01-01

    To evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O-glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers. 22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20-40 mg paroxetine, for 6 days. Atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period. Paroxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26±94.93 to 372.53±128.28 ng/mL, while AUC0-t and AUC0-∞ also increased from 1151.19±686.52 to 6452.37±3388.76 ng*h/mL, and from 1229.15±751.04 to 7111.74±4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-∞ decreased from 688.76±270.27 to 131.01±100.43 ng*h/mL, and from 4810.93±845.06 to 2606.04±923.88 and from 4928.55±853.25 to 3029.82 ±941.84 respectively. Multiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide.

  6. Atomoxetine reduces hyperactive/impulsive behaviours in neurokinin-1 receptor ‘knockout’ mice

    Science.gov (United States)

    Pillidge, Katharine; Porter, Ashley J.; Vasili, Temis; Heal, David J.; Stanford, S. Clare

    2014-01-01

    Background Mice with functional ablation of the neurokinin-1 receptor gene (NK1R−/−) display behavioural abnormalities which resemble the hyperactivity, inattention and impulsivity seen in Attention Deficit Hyperactivity Disorder (ADHD). Here, we investigated whether the established ADHD treatment, atomoxetine, alleviates these abnormalities when tested in the light/dark exploration box (LDEB) and 5-Choice Serial Reaction-Time Task (5-CSRTT). Methods Separate cohorts of mice were tested in the 5-CSRTT and LDEB after treatment with no injection, vehicle or atomoxetine (5-CSRTT: 0.3, 3 or 10 mg/kg; LDEB: 1, 3 or 10 mg/kg). Results Atomoxetine reduced the hyperactivity displayed by NK1R−/− mice in the LDEB at a dose (3 mg/kg) which did not affect the locomotor activity of wildtypes. Atomoxetine (10 mg/kg) also reduced impulsivity in NK1R−/− mice, but not wildtypes, in the 5-CSRTT. No dose of drug affected attention in either genotype. Conclusions This evidence that atomoxetine reduces hyperactive/impulsive behaviours in NK1R−/− mice consolidates the validity of using NK1R−/− mice in research of the aetiology and treatment of ADHD. PMID:25450119

  7. Off-label use of atomoxetine in adults: is it safe?

    Directory of Open Access Journals (Sweden)

    Peter Silverstone

    2012-07-01

    Full Text Available Atomoxetine has been approved for the treatment of attention deficit/hyperactivity disorder in both adults and children. However, it is also being examined for several off-label uses in adults including mood disorders, eating disorders, cognitive dysfunction, and the treatment of addictions. Prior to such use it is important to examine the reported adverse events to see if this represents an appropriate level of risk. This is particularly important in the light of recent warnings from several regulatory bodies about an increase in blood pressure in a significant percentage of patients taking atomoxetine. To understand the risks a literature review was performed, and which identified the following potential problems. The first is that this drug should not be given in patients with known cardiovascular problems, and that all adult patients who receive atomoxetine should be monitored for changes in blood pressure throughout treatment. Secondly, there are several clinical situations in which atomoxetine should be closely monitored, or avoided, including patients who have a history or risk of narrow angle glaucoma, epileptic seizures, Tourette’s syndrome, a history of urinary outflow obstruction, or who are pregnant or lactating. In conclusion, the current literature suggests that atomoxetine can be safely used off-label provided the above precautions are taken.

  8. The effect of atomoxetine on random and directed exploration in humans.

    Science.gov (United States)

    Warren, Christopher M; Wilson, Robert C; van der Wee, Nic J; Giltay, Eric J; van Noorden, Martijn S; Cohen, Jonathan D; Nieuwenhuis, Sander

    2017-01-01

    The adaptive regulation of the trade-off between pursuing a known reward (exploitation) and sampling lesser-known options in search of something better (exploration) is critical for optimal performance. Theory and recent empirical work suggest that humans use at least two strategies for solving this dilemma: a directed strategy in which choices are explicitly biased toward information seeking, and a random strategy in which decision noise leads to exploration by chance. Here we examined the hypothesis that random exploration is governed by the neuromodulatory locus coeruleus-norepinephrine system. We administered atomoxetine, a norepinephrine transporter blocker that increases extracellular levels of norepinephrine throughout the cortex, to 22 healthy human participants in a double-blind crossover design. We examined the effect of treatment on performance in a gambling task designed to produce distinct measures of directed exploration and random exploration. In line with our hypothesis we found an effect of atomoxetine on random, but not directed exploration. However, contrary to expectation, atomoxetine reduced rather than increased random exploration. We offer three potential explanations of our findings, involving the non-linear relationship between tonic NE and cognitive performance, the interaction of atomoxetine with other neuromodulators, and the possibility that atomoxetine affected phasic norepinephrine activity more so than tonic norepinephrine activity.

  9. Atomoxetine reduces hyperactive/impulsive behaviours in neurokinin-1 receptor 'knockout' mice.

    Science.gov (United States)

    Pillidge, Katharine; Porter, Ashley J; Vasili, Temis; Heal, David J; Stanford, S Clare

    2014-12-01

    Mice with functional ablation of the neurokinin-1 receptor gene (NK1R(-/-)) display behavioural abnormalities which resemble the hyperactivity, inattention and impulsivity seen in Attention Deficit Hyperactivity Disorder (ADHD). Here, we investigated whether the established ADHD treatment, atomoxetine, alleviates these abnormalities when tested in the light/dark exploration box (LDEB) and 5-Choice Serial Reaction-Time Task (5-CSRTT). Separate cohorts of mice were tested in the 5-CSRTT and LDEB after treatment with no injection, vehicle or atomoxetine (5-CSRTT: 0.3, 3 or 10mg/kg; LDEB: 1, 3 or 10mg/kg). Atomoxetine reduced the hyperactivity displayed by NK1R(-/-) mice in the LDEB at a dose (3mg/kg) which did not affect the locomotor activity of wildtypes. Atomoxetine (10mg/kg) also reduced impulsivity in NK1R(-/-) mice, but not wildtypes, in the 5-CSRTT. No dose of drug affected attention in either genotype. This evidence that atomoxetine reduces hyperactive/impulsive behaviours in NK1R(-/-) mice consolidates the validity of using NK1R(-/-) mice in research of the aetiology and treatment of ADHD. Copyright © 2014. Published by Elsevier Inc.

  10. Effect of atomoxetine on executive function impairments in adults with ADHD.

    Science.gov (United States)

    Brown, Thomas E; Holdnack, James; Saylor, Keith; Adler, Lenard; Spencer, Thomas; Williams, David W; Padival, Anoop K; Schuh, Kory; Trzepacz, Paula T; Kelsey, Douglas

    2011-02-01

    To assess the effect of atomoxetine on ADHD-related executive functions over a 6-month period using the Brown Attention-Deficit Disorder Scale (BADDS) for Adults, a normed, 40-item, self-report scale in a randomized, double-blind, placebo-controlled clinical trial. In a randomized, double-blind clinical trial, adults with ADHD received either atomoxetine 25 to 100 mg/day or placebo for 6 months. Patients completed the BADDS to report their current daily functioning in 5 clusters of ADHD-related impairments of executive functioning: (1) Organizing and Activating to Work; (2) Focusing for Tasks; (3) Regulating Alertness and Effort; (4) Modulating Emotions; and (5) Utilizing Working Memory. Mean scores were significantly more improved in the atomoxetine group compared to the placebo group: total score, -27.0 versus -19.0 (p executive function impairments in adults with ADHD as assessed by the BADDS.

  11. Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic failure.

    Science.gov (United States)

    Ramirez, Claudia E; Okamoto, Luis E; Arnold, Amy C; Gamboa, Alfredo; Diedrich, André; Choi, Leena; Raj, Satish R; Robertson, David; Biaggioni, Italo; Shibao, Cyndya A

    2014-12-01

    The clinical presentation of autonomic failure is orthostatic hypotension. Severely affected patients require pharmacological treatment to prevent presyncopal symptoms or frank syncope. We previously reported in a proof of concept study that pediatric doses of the norepinephrine transporter blockade, atomoxetine, increases blood pressure in autonomic failure patients with residual sympathetic activity compared with placebo. Given that the sympathetic nervous system is maximally activated in the upright position, we hypothesized that atomoxetine would be superior to midodrine, a direct vasoconstrictor, in improving upright blood pressure and orthostatic hypotension-related symptoms. To test this hypothesis, we compared the effect of acute atomoxetine versus midodrine on upright systolic blood pressure and orthostatic symptom scores in 65 patients with severe autonomic failure. There were no differences in seated systolic blood pressure (means difference=0.3 mm Hg; 95% confidence [CI], -7.3 to 7.9; P=0.94). In contrast, atomoxetine produced a greater pressor response in upright systolic blood pressure (means difference=7.5 mm Hg; 95% CI, 0.6 to 15; P=0.03) compared with midodrine. Furthermore, atomoxetine (means difference=0.4; 95% CI, 0.1 to 0.8; P=0.02), but not midodrine (means difference=0.5; 95% CI, -0.1 to 1.0; P=0.08), improved orthostatic hypotension-related symptoms as compared with placebo. The results of our study suggest that atomoxetine could be a superior therapeutic option than midodrine for the treatment of orthostatic hypotension in autonomic failure. © 2014 American Heart Association, Inc.

  12. Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers

    Science.gov (United States)

    Loghin, Corina; Haber, Harry; Beasley, Charles M; Kothare, Prajakti A; Kauffman, Lynnette; April, John; Jin, Ling; Allen, Albert J; Mitchell, Malcolm I

    2013-01-01

    Aim The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QTc in 131 healthy CYP2D6 poor metabolizer males were compared. Methods Atomoxetine doses were selected to result in plasma concentrations that approximated expected plasma concentrations at both the maximum recommended dose and at a supratherapeutic dose in CYP2D6 extensive metabolizers. Ten second electrocardiograms were obtained for time-matched baseline on days −2 and −1, three time points after dosing on day 1 for moxifloxacin and five time points on day 7 for atomoxetine and placebo. Maximum mean placebo-subtracted change from baseline model-corrected QT (QTcM) on day 7 was the primary endpoint. Results QTcM differences for atomoxetine 20 and 60 mg twice daily were 0.5 ms (upper bound of the one-sided 95% confidence interval 2.2 ms) and 4.2 ms (upper bound of the one-sided 95% confidence interval 6.0 ms), respectively. As plasma concentration of atomoxetine increased, a statistically significant increase in QTc was observed. The moxifloxacin difference from placebo met the a priori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QTcM for moxifloxacin was 4.8 ms and this difference was statistically significant. Moxifloxacin plasma concentrations were below the concentrations expected from the literature. However, the slope of the plasma concentration−QTc change observed was consistent with the literature. Conclusion Atomoxetine was not associated with a clinically significant change in QTc. However, a statistically significant increase in QTc was associated with increasing plasma concentrations. PMID:22803597

  13. Improving visual memory, attention, and school function with atomoxetine in boys with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Shang, Chi-Yung; Gau, Susan Shur-Fen

    2012-10-01

    Atomoxetine is efficacious in reducing symptoms of attention- deficit/hyperactivity disorder (ADHD), but its effect on visual memory and attention needs more investigation. This study aimed to assess the effect of atomoxetine on visual memory, attention, and school function in boys with ADHD in Taiwan. This was an open-label 12 week atomoxetine treatment trial among 30 drug-naíve boys with ADHD, aged 8-16 years. Before administration of atomoxetine, the participants were assessed using psychiatric interviews, the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), the school function of the Chinese version of the Social Adjustment Inventory for Children and Adolescents (SAICA), the Conners' Continuous Performance Test (CPT), and the tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB) involving visual memory and attention: Pattern Recognition Memory, Spatial Recognition Memory, and Reaction Time, which were reassessed at weeks 4 and 12. Our results showed there was significant improvement in pattern recognition memory and spatial recognition memory as measured by the CANTAB tasks, sustained attention and response inhibition as measured by the CPT, and reaction time as measured by the CANTAB after treatment with atomoxetine for 4 weeks or 12 weeks. In addition, atomoxetine significantly enhanced school functioning in children with ADHD. Our findings suggested that atomoxetine was associated with significant improvement in visual memory, attention, and school functioning in boys with ADHD.

  14. Atomoxetine for Orthostatic Hypotension in an Elderly Patient Over 10 Weeks: A Case Report.

    Science.gov (United States)

    Hale, Genevieve M; Brenner, Michael

    2015-09-01

    Several nonpharmacologic strategies for orthostatic hypotension exist including avoiding large carbohydrate-rich meals; limiting alcohol consumption; maintaining adequate hydration; adding salt to foods; and using compression stockings, tilt-table exercises, or abdominal binders. If these fail, however, only limited evidence-based pharmacologic treatment options are available including the use of fludrocortisone, midodrine, pyridostigmine, and droxidopa as well as pseudoephedrine, ocetreotide, and atomoxetine. This report discusses a case of atomoxetine use for 10 weeks in an elderly patient with primary orthostatic hypotension. An 84-year-old man with long-standing primary orthostatic hypotension presented to our ambulatory cardiology pharmacotherapy clinic after several unsuccessful pharmacologic therapies including fludrocortisone, midodrine, and pyridostigmine. Nonpharmacologic strategies were also implemented. Atomoxetine was initiated, and the patient showed gradual improvements in symptoms and blood pressure control over the course of 10 weeks. Our data suggest that low-dose atomoxetine is an effective and safe agent for symptom improvement and blood pressure control in elderly patients with primary orthostatic hypotension. © 2015 Pharmacotherapy Publications, Inc.

  15. How Oppositionality, Inattention, and Hyperactivity Affect Response to Atomoxetine versus Methylphenidate: A Pooled Meta-Analysis

    Science.gov (United States)

    van Wyk, Gregory W.; Hazell, Philip L.; Kohn, Michael R.; Granger, Renee E.; Walton, Richard J.

    2012-01-01

    Objective: To assess how threshold oppositional defiant disorder (ODD), inattention, and hyperactivity-impulsivity affect the response to atomoxetine versus methylphenidate. Method: Systematic review of randomized controlled trials (RCTs; greater than or equal to 6 weeks follow-up). The primary measure was core symptom response--greater than or…

  16. Atomoxetine ameliorates nocturnal enuresis with subclinical attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Ohtomo, Yoshiyuki

    2017-02-01

    Recent studies have shown that incontinence and attention-deficit/hyperactivity disorder (ADHD) coexist and there is an interaction between them. The treatment for nocturnal enuresis (NE) and ADHD, however, has not been established. At the first visit to the outpatient clinic, physical examination and history taking were carried out in 265 new patients with NE. After excluding the possibility of comorbid ADHD and related disorders, patients with monosymptomatic NE (MNE) were treated with desmopressin and/or alarm, and those with non-monosymptomatic NE (NMNE) were treated with anti-cholinergics and/or alarm. This 12 week treatment did not work in 65 patients, and they were re-assessed for comorbid ADHD. A total of 24 were diagnosed with ADHD, and they were treated with atomoxetine (1.8 mg/kg/day) in addition to ongoing therapy for NE. After 8 weeks of atomoxetine, the average wet nights per months was significantly decreased: 18.5-4.6 in the MNE group (P = 0.001), and 22.1-12.4 in the NMNE group (P = 0.0251). Overall, atomoxetine was beneficial in 19 of 24 patients. Atomoxetine may be a suitable option for refractory NE with comorbid ADHD. © 2016 Japan Pediatric Society.

  17. Effect of Atomoxetine on Executive Function Impairments in Adults with ADHD

    Science.gov (United States)

    Brown, Thomas E.; Holdnack, James; Saylor, Keith; Adler, Lenard; Spencer, Thomas; Williams, David W.; Padival, Anoop K.; Schuh, Kory; Trzepacz, Paula T.; Kelsey, Douglas

    2011-01-01

    Objective: To assess the effect of atomoxetine on ADHD-related executive functions over a 6-month period using the Brown Attention-Deficit Disorder Scale (BADDS) for Adults, a normed, 40-item, self-report scale in a randomized, double-blind, placebo-controlled clinical trial. Method: In a randomized, double-blind clinical trial, adults with ADHD…

  18. Factors affecting treatment adherence to atomoxetine in ADHD: a systematic review

    Directory of Open Access Journals (Sweden)

    Treuer T

    2016-05-01

    Full Text Available Tamás Treuer,1 Luis Méndez,2 William Montgomery,3 Shenghu Wu4 1Neuroscience Research, Eli Lilly and Company, Budapest, Hungary; 2Eli Lilly de Mexico, Mexico City, Mexico; 3Global Patient Outcomes and Real World Evidence, Eli Lilly Australia Pty Ltd, West Ryde, NSW, Australia; 4Neuroscience Research, Eli Lilly Asia, Inc, Shanghai, People’s Republic of China Abstract: The purpose of this paper was to systematically review the literature related to research about the factors affecting treatment adherence and discontinuation of atomoxetine in pediatric, adolescent, and adult patients with attention-deficit/hyperactivity disorder (ADHD. Medline was systematically searched using the following prespecified terms: “ADHD”, “Adherence”, “Compliance”, “Discontinuation”, and “Atomoxetine”. We identified 31 articles that met all inclusion and exclusion criteria. The findings from this review indicate that persistence and adherence to atomoxetine treatment were generally high. Factors found to influence adherence and nonadherence to atomoxetine treatment in ADHD in this review include age, sex, the definition of response used, length of treatment, initial dose of treatment, comorbid conditions, and reimbursement. Tolerability was cited as an important reason for treatment discontinuation. More research is needed to understand those factors that can help to identify patients at risk for poor adherence and interventions that could improve treatment adherence early in the stage of this illness to secure a better long-term prognosis. Keywords: atomoxetine, treatment discontinuation, adherence, compliance, ADHD medication, relapse

  19. Atomoxetine Treatment for Pediatric Patients with Attention-Deficit/Hyperactivity Disorder with Comorbid Anxiety Disorder

    Science.gov (United States)

    Geller, Daniel; Donnelly, Craig; Lopez, Frank; Rubin, Richard; Newcorn, Jeffrey; Sutton, Virginia; Bakken, Rosalie; Paczkowski, Martin; Kelsey, Douglas; Sumner, Calvin

    2007-01-01

    Objective: Research suggests 25% to 35% of children with attention-deficit/hyperactivity disorder (ADHD) have comorbid anxiety disorders. This double-blind study compared atomoxetine with placebo for treating pediatric ADHD with comorbid anxiety, as measured by the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored…

  20. A critical appraisal of atomoxetine in the management of ADHD

    Directory of Open Access Journals (Sweden)

    Childress AC

    2015-12-01

    Full Text Available Ann C ChildressCenter for Psychiatry and Behavioral Medicine, Inc., Las Vegas, NV, USAAbstract: Attention-deficit/hyperactivity disorder (ADHD is a common neurobehavioral disorder beginning in childhood and often continuing into adulthood. A wealth of data shows that ADHD symptoms respond well to pharmacological treatment. Stimulant medications, including amphetamine and methylphenidate, are most commonly used to treat ADHD. However, with the approval of atomoxetine (Strattera®, [ATX] by the US Food and Drug Administration in late 2002, an effective non-stimulant option became available. The US Food and Drug Administration approved ATX for the treatment of ADHD in children, adolescents, and adults. Although the effect size of ATX is generally lower than that of stimulants, the American Academy of Child and Adolescent Psychiatry Practice Parameter for the treatment of ADHD lists ATX as a first-line treatment option. ATX is widely prescribed and accounted for 6% of the prescriptions of ADHD visits in the US in 2010. Numerous trials have found that ATX improves quality of life and emotional lability in addition to core ADHD symptoms. Although some improvement may be seen in a patient as early as one week after the initiation of treatment, ATX generally takes longer to have a full effect. The median time to response using 25% improvement in ADHD symptoms in pooled trials was 3.7 weeks. Data from these trials indicate that the probability of symptom improvement may continue to increase up to 52 weeks after treatment is initiated. ATX has been shown to be safe and effective in combination with stimulants. It has also been studied systematically in subjects with ADHD and comorbid oppositional defiant disorder, anxiety, depression, and substance use disorders. The mechanism of action of ATX, its efficacy, and adverse events reported in trials is reviewed.Keywords: attention-deficit/hyperactivity disorder, Strattera, non-stimulants, pharmacotherapy

  1. Amphetamines, atomoxetine and the risk of serious cardiovascular events in adults.

    Directory of Open Access Journals (Sweden)

    Hedi Schelleman

    Full Text Available To compare the incidence rates of serious cardiovascular events in adult initiators of amphetamines or atomoxetine to rates in non-users.This was a retrospective cohort study of new amphetamines (n=38,586 or atomoxetine (n=20,995 users. Each medication user was matched to up to four non-users on age, gender, data source, and state (n=238,183. The following events were primary outcomes of interest 1 sudden death or ventricular arrhythmia, 2 stroke, 3 myocardial infarction, 4 a composite endpoint of stroke or myocardial infarction. Cox proportional hazard regression was used to calculate propensity-adjusted hazard ratios for amphetamines versus matched non-users and atomoxetine versus matched non-users, with intracluster dependence within matched sets accounted for using a robust sandwich estimator.The propensity-score adjusted hazard ratio for amphetamines use versus non-use was 1.18 (95% CI: 0.55-2.54 for sudden death/ventricular arrhythmia, 0.80 (95% CI: 0.44-1.47 for stroke, 0.75 (95% CI: 0.42-1.35 for myocardial infarction, and 0.78 (95% CI: 0.51-1.19 for stroke/myocardial infarction. The propensity-score adjusted hazard ratio for atomoxetine use versus non-use was 0.41 (95% CI: 0.10-1.75 for sudden death/ventricular arrhythmia, 1.30 (95% CI: 0.52-3.29 for stroke, 0.56 (95% CI: 0.16-2.00 for myocardial infarction, and 0.92 (95% CI: 0.44-1.92 for stroke/myocardial infarction.Initiation of amphetamines or atomoxetine was not associated with an elevated risk of serious cardiovascular events. However, some of the confidence intervals do not exclude modest elevated risks, e.g. for sudden death/ventricular arrhythmia.

  2. Atomoxetine for hoarding disorder: A pre-clinical and clinical investigation.

    Science.gov (United States)

    Grassi, Giacomo; Micheli, Laura; Di Cesare Mannelli, Lorenzo; Compagno, Elisa; Righi, Lorenzo; Ghelardini, Carla; Pallanti, Stefano

    2016-12-01

    Despite several studies suggested that inattention and impulsivity-compulsivity could represent two core dimensions of hoarding disorder (HD), only a small case series study investigated the effectiveness of attention-deficit-hyperactivity-disorder (ADHD) medications in HD. The aim of the present study was to target attentional and inhibitory control networks in HD patients through the ADHD medication atomoxetine, moving from a preclinical investigation on an animal model of compulsive-like behavior (marble burying test) to a clinical investigation on both medicated and unmedicated patients with a primary diagnosis of HD without ADHD. Our preclinical investigation showed that acute administration of atomoxetine significantly reduced the compulsive-like behaviours of mice in the marble burying test without affecting neither locomotor activity and coordination nor exploration behaviours. When compared, atomoxetine and fluoxetine showed similar effects on the marble burying test. However, fluoxetine impaired both locomotor and exploratory activity. In our clinical investigation 12 patients were enrolled and 11 patients completed an open trial with atomoxetine at flexible dose (40-80 mg) for 12 weeks. At the endpoint the mean UCLA Hoarding Severity Scale score decreased by 41.3% for the whole group (p = 0003). Six patients were classified as full responders (mean symptom reduction of 57.2%) and three patients as partial responders (mean symptom reduction of 27.3%). Inattentive and impulsivity symptoms showed a significant mean score reduction of 18.5% from baseline to the endpoint (F (1,9) = 20.9, p = 0.0013). Hoarding symptoms improvement was correlated to reduction of patients' disability and increased in their global functioning. These preclinical and clinical data suggest that atomoxetine may be effective for HD and therefore should be considered for future controlled trials. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Efficacy and Safety Extrapolation Analyses for Atomoxetine in Young Children with Attention-Deficit/Hyperactivity Disorder.

    Science.gov (United States)

    Upadhyaya, Himanshu; Kratochvil, Christopher; Ghuman, Jaswinder; Camporeale, Angelo; Lipsius, Sarah; D'Souza, Deborah; Tanaka, Yoko

    2015-12-01

    This extrapolation analysis qualitatively compared the efficacy and safety profile of atomoxetine from Lilly clinical trial data in 6-7-year-old patients with attention-deficit/hyperactivity disorder (ADHD) with that of published literature in 4-5-year-old patients with ADHD (two open-label [4-5-year-old patients] and one placebo-controlled study [5-year-old patients]). The main efficacy analyses included placebo-controlled Lilly data and the placebo-controlled external study (5-year-old patients) data. The primary efficacy variables used in these studies were the ADHD Rating Scale-IV Parent Version, Investigator Administered (ADHD-RS-IV-Parent:Inv) total score, or the Swanson, Nolan and Pelham (SNAP-IV) scale score. Safety analyses included treatment-emergent adverse events (TEAEs) and vital signs. Descriptive statistics (means, percentages) are presented. Acute atomoxetine treatment improved core ADHD symptoms in both 6-7-year-old patients (n=565) and 5-year-old patients (n=37) (treatment effect: -10.16 and -7.42). In an analysis of placebo-controlled groups, the mean duration of exposure to atomoxetine was ∼ 7 weeks for 6-7-year-old patients and 9 weeks for 5-year-old patients. Decreased appetite was the most common TEAE in atomoxetine-treated patients. The TEAEs observed at a higher rate in 5-year-old versus 6-7-year-old patients were irritability (36.8% vs. 3.6%) and other mood-related events (6.9% each vs. atomoxetine may improve ADHD symptoms, but possibly to a lesser extent than in older children, with some adverse events occurring at a higher rate in 5-year-old patients.

  4. Differences between children and adolescents in treatment response to atomoxetine and the correlation between health-related quality of life and Attention Deficit/Hyperactivity Disorder core symptoms: Meta-analysis of five atomoxetine trials

    Directory of Open Access Journals (Sweden)

    Schacht Alexander

    2010-12-01

    Full Text Available Abstract Objectives To explore the influence of age on treatment responses to atomoxetine and to assess the relationship between core symptoms of attention deficit/hyperactivity disorder (ADHD and health-related quality of life (HR-QoL outcomes. Data Sources Data from five similar clinical trials of atomoxetine in the treatment of children and adolescents with ADHD were included in this meta-analysis. Study Selection Atomoxetine studies that used the ADHD Rating Scale (ADHD-RS and the Child Health and Illness Profile Child Edition (CHIP-CE as outcome measures were selected. Interventions Treatment with atomoxetine. Main Outcome Measures Treatment group differences (atomoxetine vs placebo in terms of total score, domains, and subdomains of the CHIP-CE were compared across age groups, and correlations between ADHD-RS scores and CHIP-CE scores were calculated by age. Results Data of 794 subjects (611 children, 183 adolescents were pooled. At baseline, adolescents showed significantly (p Conclusions Atomoxetine was effective in improving some aspects of HR-QoL in both age groups. Correlations between core symptoms of ADHD and HR-QoL were low to moderate.

  5. The Influence of CYP2D6 Phenotype on the Pharmacokinetic Profile of Atomoxetine in Caucasian Healthy Subjects

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    Todor Ioana

    2017-06-01

    Full Text Available Objective: To analyze a potential phenotypic variation within the studied group based on the pharmacokinetic profile of atomoxetine and its active metabolite, and to further investigate the impact of CYP2D6 phenotype on atomoxetine pharmacokinetics. Methods: The study was conducted as an open-label, non-randomized clinical trial which included 43 Caucasian healthy volunteers. Each subject received a single oral dose of atomoxetine 25 mg. Subsequently, atomoxetine and 4-hydroxyatomoxetine-O-glucuronide (glucuronidated active metabolite plasma concentrations were determined and a noncompartmental method was used to calculate the pharmacokinetic parameters of both compounds. Further on, the CYP2D6 metabolic phenotype was assessed using the area under the curve (AUC metabolic ratio (atomoxetine/ 4-hydroxyatomoxetine-O-glucuronide and specific statistical tests (Lilliefors (Kolgomorov-Smirnov and Anderson-Darling test. The phenotypic differences in atomoxetine disposition were identified based on the pharmacokinetic profile of the parent drug and its metabolite. Results: The statistical analysis revealed that the AUC metabolic ratio data set did not follow a normal distribution. As a result, two different phenotypes were identified, respectively the poor metabolizer (PM group which included 3 individuals and the extensive metabolizer (EM group which comprised the remaining 40 subjects. Also, it was demonstrated that the metabolic phenotype significantly influenced atomoxetine pharmacokinetics, as PMs presented a 4.5-fold higher exposure to the parent drug and a 3.2-fold lower exposure to its metabolite in comparison to EMs. Conclusions: The pharmacokinetic and statistical analysis emphasized the existence of 2 metabolic phenotypes: EMs and PMs. Furthermore, it was proved that the interphenotype variability had a marked influence on atomoxetine pharmacokinetic profile.

  6. Fractal analysis of striatal dopamine re-uptake sites

    International Nuclear Information System (INIS)

    Kuikka, J.T.; Bergstroem, K.A.; Tiihonen, J.; Raesaenen, P.; Karhu, J.

    1997-01-01

    Spatial variation in regional blood flow, metabolism and receptor density within the brain and in other organs is measurable even with a low spatial resolution technique such as emission tomography. It has been previously shown that the observed variance increases with increasing number of subregions in the organ/tissue studied. This resolution-dependent variance can be described by fractal analysis. We studied striatal dopamine re-uptake sites in 39 healthy volunteers with high-resolution single-photon emission tomography using iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane ([ 123 I]β-CIT). The mean fractal dimension was 1.15±0.07. The results indicate that regional striatal dopamine re-uptake sites involve considerable spatial heterogeneity which is higher than the uniform density (dimension=1.00) but much lower than complete randomness (dimension=1.50). There was a gender difference, with females having a higher heterogeneity in both the left and the right striatum. In addition, we found striatal asymmetry (left-to-right heterogeneity ratio of 1.19±0.15; P<0.001), suggesting functional hemispheric lateralization consistent with the control of motor behaviour and integrative functions. (orig.). With 5 figs., 1 tab

  7. Fractal analysis of striatal dopamine re-uptake sites

    Energy Technology Data Exchange (ETDEWEB)

    Kuikka, J.T.; Bergstroem, K.A. [Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Finland); Tiihonen, J.; Raesaenen, P. [Department of Forensic Psychiatry, University of Kuopio and Niuvanniemi Hospital, Kuopio (Finland); Karhu, J. [Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio (Finland)

    1997-09-01

    Spatial variation in regional blood flow, metabolism and receptor density within the brain and in other organs is measurable even with a low spatial resolution technique such as emission tomography. It has been previously shown that the observed variance increases with increasing number of subregions in the organ/tissue studied. This resolution-dependent variance can be described by fractal analysis. We studied striatal dopamine re-uptake sites in 39 healthy volunteers with high-resolution single-photon emission tomography using iodine-123 labelled 2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)tropane ([{sup 123}I]{beta}-CIT). The mean fractal dimension was 1.15{+-}0.07. The results indicate that regional striatal dopamine re-uptake sites involve considerable spatial heterogeneity which is higher than the uniform density (dimension=1.00) but much lower than complete randomness (dimension=1.50). There was a gender difference, with females having a higher heterogeneity in both the left and the right striatum. In addition, we found striatal asymmetry (left-to-right heterogeneity ratio of 1.19{+-}0.15; P<0.001), suggesting functional hemispheric lateralization consistent with the control of motor behaviour and integrative functions. (orig.). With 5 figs., 1 tab.

  8. A pilot study for augmenting atomoxetine with methylphenidate: safety of concomitant therapy in children with attention-deficit/hyperactivity disorder

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    Ball Susan

    2007-09-01

    Full Text Available Abstract Background This study examined augmenting atomoxetine with extended-release methylphenidate in children whose attention-deficit/hyperactivity disorder (ADHD previously failed to respond adequately to stimulant medication. Methods Children with ADHD and prior stimulant treatment (N = 25 received atomoxetine (1.2 mg/kg/day plus placebo. After 4 weeks, patients who were responders (n = 4 were continued on atomoxetine/placebo while remaining patients were randomly assigned to either methylphenidate (ATX/MPH (1.1 mg/kg/day or placebo augmentation (ATX/PB for another 6 weeks. Patients and sites were blind to timing of active augmentation. Safety measures included vital signs, weight, and adverse events. Efficacy was assessed by ADHD rating scales. Results Categorical increases in vital signs occurred for 5 patients (3 patients in ATX/MPH, 2 patients in ATX/PBO. Sixteen percent discontinued the study due to AE, but no difference between augmentation groups. Atomoxetine treatment was efficacious on outcome measures (P ≤ .001, but methylphenidate did not enhance response. Conclusion Methylphenidate appears to be safely combined with atomoxetine, but conclusions limited by small sample. With atomoxetine treatment, 43% of patients achieved normalization on ADHD ratings.

  9. In vivo evaluation of striatal dopamine reuptake sites using 11C-nomifensine and positron emission tomography

    International Nuclear Information System (INIS)

    Aquilonius, S.-M.; Bergstroem, K.; Eckernaes, S.-Aa.; Leenders, K.L.; Hartvig, P.; Lundquist, H.; Antoni, G.; Gee, A.; Rimland, A.; Uhlin, J.; Langstroem, B.

    1987-01-01

    In vitro nomifensine demonstrates high affinity and specificity for dopamine reuptake sites in the brain. In the present study 11 C-nomifensine was administered i.v. in trace amounts (10-50 μg) to ketamine anaesthetized Rhesus monkeys (6-10 kg b.w.) and the timecourse of radioactivity within different brain regions was measured by positron emission tomography (PET). Six base-line experiments lasting for 60-80 min were performed. The procedure was repeated after pretreatment with nomifensine (2-6 mg/kg i.v.), another reuptake inhibitor, mazindol (0.3 mg/kg i.v.), desipramine (0.5 mg/kg i.v.) or spiperone (0.3 mg/kg i.v.) before the administration of a second 11 C-nomifensine dose. The highest radioactivity uptake was found in the dopamine innervated striatum and the lowest in a region containing the cerebellum, known to be almost devoid of dopaminergic neurons. The difference between striatal and cerebellar uptake of 11 C-nomifensine derived radioactivity was markedly reduced after nomifensine and mazindol but not after desipramine and spiperone. These results indicate that in vivo the striatal uptake of 11 C-nomifensine, as measured with PET, involves specific binding with the dopamine reuptake sites. In the first human applications of 11 C-nomifensine and PET in a healthy volunteer, the regional uptake of radioactivity was similar to that in base-line experiments with Rhesus monkeys. In the healthy subject the striatal/cerebellar ratio was 1.6, 50 min after the injection of 11 C-nomifensine. In a hemi-parkinsonian patient this ratio was 1.1 contralaterally and 1.3 ipsilaterally to the affected side. 11 C-nomifensine and PET seems to be an auspicious method to measure the striatal dopaminergic nerve terminals of man in vivo. (author)

  10. Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites.

    Science.gov (United States)

    Byeon, Ji-Yeong; Kim, Young-Hoon; Na, Han-Sung; Jang, Jong-Hwa; Kim, Se-Hyung; Lee, Yun-Jeong; Bae, Jung-Woo; Kim, In Su; Jang, Choon-Gon; Chung, Myeon-Woo; Lee, Seok-Yong

    2015-11-01

    To investigate the effect of the variant CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (NAT), in healthy subjects, a single oral dose of atomoxetine was administered to 62 subjects with a CYP2D6*wt/*wt (*wt = *1 or *2, n = 22), CYP2D6*wt/*10 (n = 22) or CYP2D6*10/*10 (n = 18) genotype. Plasma samples were then collected for 24 h after atomoxetine administration. The concentrations of atomoxetine and its metabolites were assayed using LC-MS/MS. For atomoxetine, the Cmax, AUC0-∞, t1/2 and CL/F showed genotype-dependent differences. The CYP2D6*10/*10 and CYP2D6*wt/*10 groups showed 1.74- and 1.15-fold higher Cmax, 3.40- and 1.33-fold higher AUC0-∞, and 69.7 and 24.6 % lower CL/F, compared to those of the CYP2D6*wt/*wt group, respectively. The Cmax and t1/2 for 4-HAT were lower and longer in the CYP2D6*10/*10 group than those in the CYP2D6*wt/*wt group, but the AUC0-∞ was not different between these groups. The Cmax, AUC0-∞ and t1/2 for NAT were profoundly greater in the CYP2D6*10/*10 group than they were in the CYP2D6*wt/*wt group. The concentration of active moieties of atomoxetine (atomoxetine + 4-HAT) in the CYP2D6*10/*10 group was 3.32-fold higher than that in the CYP2D6*wt/*wt group. The mean exposure to active moieties of atomoxetine was markedly higher in subjects with the CYP2D6*10/*10 genotype compared to that in those with the CYP2D6*wt/*wt genotype. The higher systemic exposure of the active atomoxetine moieties in CYP2D6*10/*10 individuals may increase the risk of concentration-related adverse events of atomoxetine, although this has not yet been clinically confirmed.

  11. Characterization of the binding of /sup 3/H-norzimeldine, a 5-HT uptake inhibitor, to rat brain homogenates

    Energy Technology Data Exchange (ETDEWEB)

    Hall, H. (Department of Biochemical Neuropharmacology, Research and Development Laboratories, Astra Laekemedel, Soedertaelje, Sweden)

    1984-01-01

    The binding of radiolabelled norzimeldine, a potent selective 5-HT reuptake inhibitor, to rat brain homogenates is described. /sup 3/H-Norzimeldine binds to a site with high affinity (Ksub(D) = 10.5 nM) in a saturable manner (Bsub(max) = 15.4 pmol/g wet weight in the cerebral cortex). The number of binding sites in the various regions of the brain parallels the capacity of the 5-HT reuptake mechanism. Drugs that inhibit the reuptake of 5-HT are also potent inhibitors of the /sup 3/H-norzimeldine binding, as are the tricyclic antidepressants, which are non-specific inhibitors of the noradrenaline and the 5-HT reuptake. Lesioning experiments using DSP4 (a NA neurotoxin) and p-chloroamphetamine (a 5-HT neurotoxin) suggest that the binding site is located on the presynaptic 5-HT nerve terminal, although a small component of the binding may be to noradrenergic uptake sites as well.

  12. Characterization of the binding of 3H-norzimeldine, a 5-HT uptake inhibitor, to rat brain homogenates

    International Nuclear Information System (INIS)

    Hall, H.

    1984-01-01

    The binding of radiolabelled norzimeldine, a potent selective 5-HT reuptake inhibitor, to rat brain homogenates is described. 3 H-Norzimeldine binds to a site with high affinity (Ksub(D) = 10.5 nM) in a saturable manner (Bsub(max) = 15.4 pmol/g wet weight in the cerebral cortex). The number of binding sites in the various regions of the brain parallels the capacity of the 5-HT reuptake mechanism. Drugs that inhibit the reuptake of 5-HT are also potent inhibitors of the 3 H-norzimeldine binding, as are the tricyclic antidepressants, which are non-specific inhibitors of the noradrenaline and the 5-HT reuptake. Lesioning experiments using DSP4 (a NA neurotoxin) and p-chloroamphetamine (a 5-HT neurotoxin) suggest that the binding site is located on the presynaptic 5-HT nerve terminal, although a small component of the binding may be to noradrenergic uptake sites as well.(author)

  13. Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers.

    Science.gov (United States)

    Todor, Ioana; Popa, Adina; Neag, Maria; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Vlase, Laurian; Gheldiu, Ana-Maria; Briciu, Corina

    2016-01-01

    To evaluate the impact of bupropion on the pharmacokinetic profile of atomoxetine and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide, in healthy volunteers. An open-label, non-randomized, two-period, sequential clinical trial was conducted as follows: during Period I (Reference), each volunteer received a single oral dose of 25 mg atomoxetine, whilst during Period II (Test), a combination of 25 mg atomoxetine and 300 mg bupropion was administered to all volunteers, after a pretreatment regimen with bupropion for 7 days. Next, after determining atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations, their pharmacokinetic parameters were calculated using a noncompartmental method and subsequently compared to determine any statistically significant differences between the two periods. Bupropion intake influenced all the pharmacokinetic parameters of both atomoxetine and its metabolite. For atomoxetine, Cmax increased from 226±96.1 to 386±137 ng/mL and more importantly, AUC0-∞ was significantly increasedfrom 1580±1040 to 8060±4160 ng*h/mL, while the mean t1/2 was prolonged after bupropion pretreatment. For 4-hydroxyatomoxetine-O-glucuronide, Cmax and AUC0-∞  were decreased from 707±269 to 212±145 ng/mL and from 5750±1240 to 3860±1220 ng*h/mL, respectively. These results demonstrated that the effect of bupropion on CYP2D6 activity was responsible for an increased systemic exposure to atomoxetine (5.1-fold) and also for a decreased exposure to its main metabolite (1.5-fold). Additional studies are required in order to evaluate the clinical relevance of this pharmacokinetic drug interaction.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

  14. A Randomized Double-Blind Study of Atomoxetine versus Placebo for Attention-Deficit/Hyperactivity Disorder Symptoms in Children with Autism Spectrum Disorder

    Science.gov (United States)

    Harfterkamp, Myriam; van de Loo-Neus, Gigi; Minderaa, Ruud B.; van der Gaag, Rutger-Jan; Escobar, Rodrigo; Schacht, Alexander; Pamulapati, Sireesha; Buitelaar, Jan K.; Hoekstra, Pieter J.

    2012-01-01

    Objective: The efficacy of atomoxetine as treatment of symptoms of attention-deficit/hyperactivity disorder (ADHD) in patients with autism spectrum disorder (ASD) has not been established. Method: In this study, 97 patients aged 6 to 17 years with ADHD and ASD were randomly assigned to double-blind treatment with 1.2 mg/kg/day atomoxetine or…

  15. Safety and improvement of movement function after stroke with atomoxetine: A pilot randomized trial

    Science.gov (United States)

    Ward, Andrea; Carrico, Cheryl; Powell, Elizabeth; Westgate, Philip M.; Nichols, Laurie; Fleischer, Anne; Sawaki, Lumy

    2016-01-01

    Background: Intensive, task-oriented motor training has been associated with neuroplastic reorganization and improved upper extremity movement function after stroke. However, to optimize such training for people with moderate-to-severe movement impairment, pharmacological modulation of neuroplasticity may be needed as an adjuvant intervention. Objective: Evaluate safety, as well as improvement in movement function, associated with motor training paired with a drug to upregulate neuroplasticity after stroke. Methods: In this double-blind, randomized, placebo-controlled study, 12 subjects with chronic stroke received either atomoxetine or placebo paired with motor training. Safety was assessed using vital signs. Upper extremity movement function was assessed using Fugl-Meyer Assessment, Wolf Motor Function Test, and Action Research Arm Test at baseline, post-intervention, and 1-month follow-up. Results: No significant between-groups differences were found in mean heart rate (95% CI, –12.4–22.6; p = 0.23), mean systolic blood pressure (95% CI, –1.7–29.6; p = 0.21), or mean diastolic blood pressure (95% CI, –10.4–13.3; p = 0.08). A statistically significant between-groups difference on Fugl-Meyer at post-intervention favored the atomoxetine group (95% CI, 1.6–12.7; p = 0.016). Conclusion: Atomoxetine combined with motor training appears safe and may optimize motor training outcomes after stroke. PMID:27858723

  16. Impact of psychostimulants and atomoxetine on the expression of 8-hydroxyguanine glycosylase 1 in human cells.

    Science.gov (United States)

    Schmidt, Andreas Johannes; Clement, Hans-Willi; Gebhardt, Stefan; Hemmeter, Ulrich Michael; Schulz, Eberhard; Krieg, Jürgen-Christian; Kircher, Tilo; Heiser, Philip

    2010-06-01

    Oxidative DNA damage as one sign of reactive oxygen species induced oxidative stress is an important factor in the pathogenesis of various psychiatric disorders. Altered levels of DNA base damage products as well as the expression of the main repair enzyme 8-hydroxyguanine glycosylase 1 have been described. The aim of the present study was to examine the effects of drugs (amphetamine, methylphenidate and atomoxetine) used in the treatment of attention deficit-hyperactivity disorder on the expression of this enzyme via reverse transcriptase-polymerase chain reaction in human neuroblastoma SH-SY5Y and human monocytic U-937 cells at concentrations of 50, 500 and 5,000 ng/ml. We observed decreased expression of this enzyme for all applied substances. In U-937 cells, the significance level was reached after treatment with 5,000 ng/ml amphetamine as well as after treatment with 50, 500 and 5,000 ng/ml atomoxetine. Incubation of SH-SY5Y cells with 50 and 5,000 ng/ml amphetamine and 5,000 ng/ml methylphenidate led to significant decreases of 8-hydroxyguanine glycosylase 1. As a positive correlation between the expression of 8-hydroxyguanine glycosylase 1 and the level of oxidative DNA damage products has been described, we accordingly consider these substances (amphetamine, methylphenidate and atomoxetine) to possibly play a protective role in this process.

  17. Atomoxetine in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. Systematic Review of Review Papers 2009-2011. An Update for Clinicians

    Directory of Open Access Journals (Sweden)

    Chris J. Bushe Mbbs

    2011-01-01

    Full Text Available Attention deficit/hyperactivity disorder (ADHD is a common disorder and a plethora of new data has been published from clinical trials and national epidemiological databases in the last three years. In the United Kingdom Atomoxetine is currently the only licensed non-stimulant medication. As part of a systematic review of atomoxetine data Jan 2009-June 2011 formal searches found 750 citations. From these 13 met criteria for either review or systematic review papers and contained clinical data synthesis on atomoxetine. No individual review paper alone would be sufficient for clinicians to be updated at that time on all clinical aspects of atomoxetine data. The crucial data relating to clinical parity of atomoxetine and methylphenidate in trials and meta-analysis where relevant confounding biases are removed are not often discussed. Systematic review of complex data is critical for ADHD clinicians and will need regular updating due to the large volume of new data.

  18. An Open-Label, Randomized Trial of Methylphenidate and Atomoxetine Treatment in Children with Attention-Deficit/Hyperactivity Disorder.

    Science.gov (United States)

    Shang, Chi-Yung; Pan, Yi-Lei; Lin, Hsiang-Yuan; Huang, Lin-Wan; Gau, Susan Shur-Fen

    2015-09-01

    The efficacy of both methylphenidate and atomoxetine has been established in placebo-controlled trials. The present study aimed to directly compare the efficacy of methylphenidate and atomoxetine in improving symptoms among children with attention-deficit/hyperactivity disorder (ADHD). The study sample included 160 drug-naïve children and adolescents 7-16 years of age, with DSM-IV-defined ADHD, randomly assigned to osmotic-release oral system methylphenidate (OROS-methylphenidate) (n=80) and atomoxetine (n=80) in a 24 week, open-label, head-to-head clinical trial. The primary efficacy measure was the score of the ADHD Rating Scale-IV Parents Version: Investigator Administered and Scored (ADHD-RS-IV). The secondary efficacy measures included the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) and Chinese Swanson, Nolan, and Pelham IV scale (SNAP-IV), based on the ratings of investigators, parents, teachers, and subjects. At week 24, mean changes in ADHD-RS-IV Inattention scores were 13.58 points (Cohen's d, -3.08) for OROS-methylphenidate and 12.65 points (Cohen's d, -3.05) for atomoxetine; and mean changes in ADHD-RS-IV Hyperactivity-Impulsivity scores were 10.16 points (Cohen's d, -1.75) for OROS-methylphenidate and 10.68 points (Cohen's d, -1.87) for atomoxetine. In terms of parent-, teacher-, and self-ratings on behavioral symptoms, both of the two treatment groups significantly decreased on the SNAP-IV scores at the end-point, with effect sizes ranging from 0.9 to 0.96 on the Inattention subscale and from 0.61 to 0.8 on the Hyperactivity/Impulsivity subscale for OROS-methylphenidate; and from 0.51 to 0.88 on the Inattention subscale and from 0.29 to 0.57 on the Hyperactivity/Impulsivity subscale for atomoxetine. No statistically significant differences between treatment groups were observed on the outcome measures. Vomiting, somnolence, and dizziness were reported more often for atomoxetine than for OROS-methylphenidate, whereas insomnia was reported

  19. Atomoxetine treatment and ADHD-related difficulties as assessed by adolescent patients, their parents and physicians

    Directory of Open Access Journals (Sweden)

    Lehmann Martin

    2009-08-01

    Full Text Available Abstract Background The degree of ADHD-related difficulties – reflecting overall impairment, social functioning, and quality of life – may be perceived differently by adolescent patients, parents and physicians. The primary aim of this study was to investigate ADHD-related difficulties during atomoxetine treatment, as perceived by the three different raters. Secondary objectives focused on effectiveness and tolerability of atomoxetine treatment in a population of adolescent patients with ADHD. Methods Adolescents with ADHD, aged 12–17 years, received open-label atomoxetine (0.5–1.2 mg/kg/day up to 24 weeks. ADHD-related difficulties at various times of the day were rated using the Global Impression of Perceived Difficulties (GIPD instrument. Inter-rater agreement was analyzed using Cohen's Kappa with 95% confidence intervals (95% CI. ADHD-Rating Scale (ADHD-RS and Clinical Global Impression Severity (GGI-S scores were assessed by the investigator; and spontaneous adverse events, vital signs and laboratory parameters were collected for tolerability assessments. Results 159 patients received atomoxetine. Patients' baseline mean GIPD total ratings were significantly lower than parents' and physicians' scores (12.5 [95%CI 11.6;13.5] vs. 17.2 [16.2;18.2] and 18.8 [17.8;19.8]. For all raters, GIPD scores significantly improved over time. Changes were greatest within the first two weeks. Kappa coefficients varied between 0.186 [0.112;0.259] and 0.662 [0.529;0.795], with strongest agreements between parent and physician assessments, and significant improvements of patient/physician agreements over time (based on 95% CIs. ADHD-RS and CGI-S scores significantly improved over the course of the study (based on 95% CIs. Tolerability results were consistent with earlier reports. Conclusion ADHD-related difficulties were perceived differently by the raters in this open-label trial, but consistently improved during atomoxetine treatment. The GIPD

  20. Microautoradiography of [{sup 123}I]ADAM in mice treated with fluoxetine and serotonin reuptake inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Ye, X.-X.; Chen, J.-C.; Liu, R.-S.; Wey, S.-P.; Lee, J.-S.; Chen, C.-C.; Fu, Y.-K.; Ting, Gann; Hwang, J.-J. E-mail: jjhwang@ym.edu.tw

    2004-07-01

    A radiopharmaceutical, {sup 123}I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([{sup 123}I]ADAM), has been developed recently for evaluation of how serotonin transporters (SERT) function in the brain. However, the detailed biodistribution and specific binding in certain brain areas are not well investigated. In this study, both phosphor plate imaging and microautoradiography were applied to explore the binding characteristics of [{sup 123}I]ADAM in SERT neurons. The effect of two psychotropics and one narcotic on the binding of [{sup 123}I]ADAM to SERT was also studied. Fluoxetine and desipramine, both are psychotropics and specific SERT ligands and decreased the affinity of [{sup 123}I]ADAM, while p-chloroamphetamine (PCA), a narcotic, destroyed most of serotonergic neurons, as well as reducing the concentration of serotonin and the number of SERT in the brain as shown by the biodistribution of [{sup 123}I]ADAM. Significant and selective accumulation of [{sup 123}I]ADAM in the areas from midbrain to brain stem in normal mice with maximum target-to-background ratio was found at 90 minutes postinjection. A rapid clearance of [{sup 131}I]ADAM at 120 minutes postinjection was found in the CA1, CA3 and ThN brain areas. In addition, the inhibition effect on binding ability of [{sup 123}I]ADAM to SERT by the psychotropics and the narcotic was found to have the order of: PCA > fluoxetine > desipramine.

  1. Microautoradiography of [123I]ADAM in mice treated with fluoxetine and serotonin reuptake inhibitors

    International Nuclear Information System (INIS)

    Ye, X.-X.; Chen, J.-C.; Liu, R.-S.; Wey, S.-P.; Lee, J.-S.; Chen, C.-C.; Fu, Y.-K.; Ting, Gann; Hwang, J.-J.

    2004-01-01

    A radiopharmaceutical, 123 I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([ 123 I]ADAM), has been developed recently for evaluation of how serotonin transporters (SERT) function in the brain. However, the detailed biodistribution and specific binding in certain brain areas are not well investigated. In this study, both phosphor plate imaging and microautoradiography were applied to explore the binding characteristics of [ 123 I]ADAM in SERT neurons. The effect of two psychotropics and one narcotic on the binding of [ 123 I]ADAM to SERT was also studied. Fluoxetine and desipramine, both are psychotropics and specific SERT ligands and decreased the affinity of [ 123 I]ADAM, while p-chloroamphetamine (PCA), a narcotic, destroyed most of serotonergic neurons, as well as reducing the concentration of serotonin and the number of SERT in the brain as shown by the biodistribution of [ 123 I]ADAM. Significant and selective accumulation of [ 123 I]ADAM in the areas from midbrain to brain stem in normal mice with maximum target-to-background ratio was found at 90 minutes postinjection. A rapid clearance of [ 131 I]ADAM at 120 minutes postinjection was found in the CA1, CA3 and ThN brain areas. In addition, the inhibition effect on binding ability of [ 123 I]ADAM to SERT by the psychotropics and the narcotic was found to have the order of: PCA > fluoxetine > desipramine

  2. Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies

    DEFF Research Database (Denmark)

    Jordan, Sue; Morris, Joan K.; Davies, Gareth I.

    2016-01-01

    of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta...... of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1...... importance, justifying modifications to preconception care....

  3. Biochemical and locomotor responses of Carcinus maenas exposed to the serotonin reuptake inhibitor fluoxetine.

    Science.gov (United States)

    Mesquita, Sofia Raquel; Guilhermino, Lúcia; Guimarães, Laura

    2011-10-01

    The aim of this study was to assess the effects of the widely used anti-depressant fluoxetine on behaviour (locomotion), moulting, neuromuscular transmission, energy production and anti-oxidant defences' efficiency of the epibenthic crab Carcinus maenas. Crabs were individually exposed to fluoxetine concentrations for 7d. Effects on locomotion were assessed at the end of the exposure using an open field test adapted to C. maenas in the present study. Tissue samples were later collected to evaluate fluoxetine effects on physiological functions using the activity of key enzymes and other parameters as biomarkers, namely: N-acetyl-β-glucosaminidase (NAGase) in the epidermis (moulting) and the hepatopancreas; cholinesterases (ChE) in muscle (neuromuscular cholinergic transmission); NADP(+)-dependent isocitrate dehydrogenase (IDH) and lactate dehydrogenease (LDH) in muscle (energy production); glutathione S-transferases (GST) in hepatopancreas (biotransformation and oxidative stress system); glutathione reductase (GR), and glutathione peroxidade (GPx), total glutathione levels (TG) and lipid peroxidation levels in the hepatopancreas (anti-oxidant defences and oxidative damage). Because no information on C. maenas NAGase activity was previously available, its variation during the moult cycle was also investigated. The results showed that locomotion was significantly increased at fluoxetine concentrations equal or above 120 μg L⁻¹, with animals spending more time moving, walking longer distances than controls. Levels of NAGase activity were found to vary in relation to C. maenas moult cycle, but no alterations were observed after exposure to fluoxetine. Significant increases in the activity of ChE, GST and GR enzymes, and the levels of TG were found, with a lowest observed effect concentration (LOEC) of 120 μg L⁻¹. Effects on locomotion were significantly and positively correlated to those induced on ChE activity. The results raise concern when hypothesising conditions of chronic exposure in the wild. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. Treatment of depression in acute coronary syndromes with selective serotonin reuptake inhibitors

    NARCIS (Netherlands)

    van Melle, Joost P.; de Jonge, Peter; van den Berg, Maarten P.; Pot, Harm J.; van Veldhuisen, Dirk J.

    2006-01-01

    Depression in patients with acute coronary syndromes (ACS) is common and associated with impaired cardiovascular prognosis in terms of cardiac mortality and new cardiovascular events. It remains unclear whether antidepressant treatment may reverse these effects. In this review, the literature is

  5. The market dynamics of selective serotonin re-uptake inhibitors: a ...

    African Journals Online (AJOL)

    Methodology: This was a retrospective, descriptive study that measured generic market volume as a percentage of the total ... sive system of procurement, distribution, drug informa- ... pharmaceutical and health care industries used by gov-.

  6. Serotonin Reuptake Inhibitors in Pregnancy: Can Genes Help Us in Predicting Neonatal Adverse Outcome?

    Directory of Open Access Journals (Sweden)

    Valentina Giudici

    2014-01-01

    Full Text Available Lots has been written on use of SSRI during pregnancy and possible short and long term negative outcomes on neonates. the literature so far has described a various field of peripartum illness related to SSRI exposure during foetal life, such as increased incidence of low birth weight, respiratory distress, persistent pulmonary hypertension, poor feeding, and neurobehavioural disease. We know that different degrees of outcomes are possible, and not all the newborns exposed to SSRIs during pregnancy definitely will develop a negative outcome. So far, still little is known about the possible etiologic mechanism that could not only explain the adverse neonatal effects but also the degree of clinical involvement and presentation in the early period after birth. Pharmacogenetics and moreover pharmacogenomics, the study of specific genetic variations and their effect on drug response, are not widespread. This review describes possible relationship between SSRIs pharmacogenetics and different neonatal outcomes and summarizes the current pharmacogenetic inquiries in relation to maternal-foetal environment.

  7. A Review of the US Army Experience Using Selective Serotonin Reuptake Inhibitors in Aircrew

    Science.gov (United States)

    2009-10-01

    post - partum depression , dysmenorrhea, and pre-menstrual dysphoric disorder, conditions unique to female reproductive health. A surprising number of...Martin.quattlebaum@amedd.army.mil ABSTRACT As many as 300,000 soldiers may suffer from post traumatic stress disorder (PTSD), depression , or anxiety...soldiers may suffer from post traumatic stress disorder (PTSD), depression , or anxiety and less than half of them seek care, citing adverse career

  8. Are Selective Serotonin Reuptake Inhibitors a Secondary Cause of Low Bone Density?

    Directory of Open Access Journals (Sweden)

    Kim Chau

    2012-01-01

    Full Text Available Background. Osteoporosis is a chronic disease that can significantly impact numerous aspects of health and wellness. The individual consequences of osteoporosis can be devastating, often resulting in substantial loss of independence and sometimes death. One of the few illnesses with greater disease burden than low bone mineral density (BMD is major depressive disorder (MDD. Both depression and antidepressant use have been identified as secondary causes of osteoporosis. The objective of this paper is to review and summarize the current findings on the relationship between antidepressant use and BMD. Methods. Relevant sources were identified from the Pubmed and MEDLINE databases, citing articles from the first relevant publication to September 1st, 2010. Results. 2001 articles initially met the search criteria, and 35 studies were thoroughly reviewed for evidence of an association between SSRI use and BMD, and 8 clinical studies were detailed and summarized in this paper. Conclusions. Current findings suggest a link between mental illness and osteoporosis that is of clinical relevance. Additional longitudinal studies and further research on possible mechanisms surrounding the association between SSRI use on bone metabolism need to be conducted. Treatment algorithms need to recognize this association to ensure that vulnerable populations are screened.

  9. Sibutramine, a serotonin-norepinephrine reuptake inhibitor, causes fibrosis in rats.

    Science.gov (United States)

    Oberholzer, Hester Magdalena; van der Schoor, Ciska; Bester, Megan Jean

    2015-07-01

    Sibutramine hydrochloride monohydrate is a weight loss agent indicated for the treatment of obesity. Although it has been banned from most markets, studies are still relevant as it is often a hidden ingredient in herbal and over the counter slimming products. Sibutramine induces liver fibrosis with steatosis in female Sprague-Dawley rats fed a high-energy diet without significant weight gain. In this study, using the same animal model, the effect of Sibutramine on lung morphology was investigated using histological evaluation of the terminal bronchiole and transmission electron microscopy evaluation of the respiratory tissue. From these results Sibutramine was found to induce lung fibrosis in Sprague-Dawley rats as increased collagen synthesis, mast cell accumulation and aggregates of Bronchus Associated Lymphoid Tissue (BALT) in the terminal bronchiole as well as increased collagen deposition in the respiratory tissue was seen. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Treatment patterns, health care resource utilization, and costs in Japanese adults with attention-deficit hyperactivity disorder treated with atomoxetine

    Directory of Open Access Journals (Sweden)

    Imagawa H

    2018-02-01

    Full Text Available Hideyuki Imagawa,1 Saurabh P Nagar,2 William Montgomery,3 Tomomi Nakamura,1 Masayo Sato,1 Keith L Davis2 1Medical Development Unit Japan, Eli Lilly Japan K.K., Kobe, Japan; 2RTI Health Solutions, Research Triangle Park, NC, USA; 3Global Patient Outcomes and Real World Evidence, Eli Lilly Australia, NSW, Australia Objective: To describe the characteristics and medication treatment patterns of adult patients with attention-deficit/hyperactivity disorder (ADHD prescribed atomoxetine in Japan. Materials and methods: A retrospective analysis of insurance claims data was conducted using the Japan Medical Data Center database. Adults (≥18 years with ADHD who had ≥1 atomoxetine claim from January 1, 2013 to December 31, 2014, and ≥180 to ≤900 days of follow-up were included. First atomoxetine claim defined the index date. Patient characteristics included age, gender, and comorbid conditions. Treatment patterns assessed included rates of atomoxetine discontinuation, switching, persistence, adherence (assessed via the medication possession ratio, and use of concomitant medications. Results: A total of 457 adults met all the inclusion criteria. Mean (SD age was 32.7 (10.4 years, and 61.0% of patients were male. Nearly 72.0% of the patients had at least one comorbid mental health condition in the baseline period; depression (43.8% and insomnia (40.7% were the most common mental health comorbidities. Most common physical comorbidities were chronic obstructive pulmonary disease (14.4% and diabetes (12.9%. Non-ADHD-specific psychotropics were prescribed to 59.7% of patients during the baseline period and to 65.9% during the follow-up period; 6.6% were prescribed non-ADHD-specific psychotropics concomitantly with atomoxetine. Overall, 40.0% of adults discontinued atomoxetine during the entire follow-up period and 65.9% were persistent with atomoxetine therapy at 3 months post-index date. Mean (SD atomoxetine medication possession ratio was 0.57 (0

  11. Atomoxetine for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD in children with ADHD and dyslexia

    Directory of Open Access Journals (Sweden)

    Rubin Richard

    2009-12-01

    Full Text Available Abstract Background The objective of this study was to assess the effects of atomoxetine on treating attention-deficit/hyperactivity disorder (ADHD, on reading performance, and on neurocognitive function in youth with ADHD and dyslexia (ADHD+D. Methods Patients with ADHD (n = 20 or ADHD+D (n = 36, aged 10-16 years, received open-label atomoxetine for 16 weeks. Data from the ADHD Rating Scale-IV (ADHDRS-IV, Kaufman Test of Educational Achievement (K-TEA, Working Memory Test Battery for Children (WMTB-C, and Life Participation Scale for ADHD-Child Version (LPS-C were assessed. Results Atomoxetine demonstrated significant improvement for both groups on the ADHDRS-IV, LPS-C, and K-TEA reading comprehension standard and composite scores. K-TEA spelling subtest improvement was significant for the ADHD group, whereas the ADHD+D group showed significant reading decoding improvements. Substantial K-TEA reading and spelling subtest age equivalence gains (in months were achieved for both groups. The WMTB-C central executive score change was significantly greater for the ADHD group. Conversely, the ADHD+D group showed significant phonological loop score enhancement by visit over the ADHD group. Atomoxetine was well tolerated, and commonly reported adverse events were similar to those previously reported. Conclusions Atomoxetine reduced ADHD symptoms and improved reading scores in both groups. Conversely, different patterns and magnitude of improvement in working memory component scores existed between ADHD and ADHD+D patients. Though limited by small sample size, group differences in relation to the comparable changes in improvement in ADHD symptoms could suggest that brain systems related to the therapeutic benefit of atomoxetine in reducing ADHD symptoms may be different in individuals with ADHD+D and ADHD without dyslexia. Trial Registration Clinical Trial Registry: ClinicalTrials.gov: NCT00191048

  12. Assessment of effects of atomoxetine in adult patients with ADHD: consistency among three geographic regions in a response maintenance study.

    Science.gov (United States)

    Tanaka, Yoko; Escobar, Rodrigo; Upadhyaya, Himanshu P

    2017-06-01

    A previous study (Upadhyaya et al. in Eur J Psychiatry 2013b; 27:185-205) reported that adults with attention-deficit/hyperactivity disorder (ADHD) demonstrated maintenance of response for up to 25 weeks after initially responding to atomoxetine treatment. In the present report, the consistency of treatment effect across three geographic regions (Europe, United States/Canada [US/Can], and Latin America [Latin Am]) was explored. Data were analyzed from a phase 3, multicenter, randomized, double-blind, maintenance-of-response (randomized withdrawal) trial of atomoxetine versus placebo in adults with ADHD. Patients were randomized to atomoxetine (N = 266) or placebo (N = 258) for 25 weeks. Consistency assessments included the interaction test, pairwise t tests, noninferiority, and the criteria from Basic Principles on Global Clinical Trials (Ministry of Health, Labour and Welfare of Japan 2007). Atomoxetine-treated patients maintained the improved ADHD symptoms relative to placebo-treated patients on the Conners' Adult ADHD Rating Scale Investigator-Rated: Screening Version 18-Item (CAARS-Inv:SV) total score in all three regions (atomoxetine-placebo mean difference = -4.55, -3.18, and -0.07 for Europe, US/Can, and Latin Am, respectively). For the Latin Am region, the mean change in total score (0.41) was notably smaller for the placebo group than for Europe (5.87) and US/Can (4.39). Similar results were observed for the CAARS-Inv:SV hyperactivity/impulsivity and inattention subscale scores. Overall, patients maintained the response with atomoxetine treatment compared to placebo; however, the magnitude of treatment effect differed among the regions studied, being numerically higher in the EU and US/Can than Latin Am. Trial registration http://www.clinicaltrials.gov/(NCT00700427 ).

  13. Priapism associated with the use of stimulant medications and atomoxetine for attention-deficit/hyperactivity disorder in children.

    Science.gov (United States)

    Eiland, Lea S; Bell, Edward A; Erramouspe, John

    2014-10-01

    To review the association of priapism with stimulant medications and atomoxetine commonly used in the treatment of attention-deficit/hyperactivity disorder (ADHD). A comprehensive literature search was conducted through PubMed (1966-May 15, 2014) using the search terms priapism, methylphenidate, amphetamine, atomoxetine, attention-deficit disorder with hyperactivity, and pediatrics. Google Scholar, Scopus, and the Food and Drug Administration (FDA) Web site were also searched. References from identified literature were also reviewed. All identified literature focused on ADHD treatment. Literature regarding priapism caused by methylphenidate, amphetamines, and atomoxetine were included. Stimulant medications and atomoxetine have been linked to the occurrence of priapism in children. Specifically, methylphenidate has been implicated in a recent FDA safety announcement warning as a result of 15 case reports (mean age = 12.5 years), and thus, the drug label and medication guides have been updated to reflect this concern. Prolonged erections and priapism occurred with immediate- and long-acting products, dose increases, and drug withdrawal periods. Priapism has also occurred in 4 patients taking amphetamines and one 11-year-old patient taking atomoxetine for ADHD. Priapism has been associated with stimulants, amphetamines, and atomoxetine use for ADHD in children. Providers and health care practitioners should educate male patients prescribed these ADHD medications as well as caregivers regarding the signs, symptoms, and complications with priapism. Discontinuation and evaluation of the medication is warranted if this adverse drug reaction occurs. Depending on the priapism subtype, other products may be initiated or medications not associated with priapism may be utilized. © The Author(s) 2014.

  14. Demonstration of clomipramine and venlafaxine occupation at serotonin reuptake sites in man in vivo.

    Science.gov (United States)

    Malizia, A L; Melichar, J M; Brown, D J; Gunn, R N; Reynolds, A; Jones, T; Nutt, D J

    1997-01-01

    We describe the use of 11CRTI-55 and the Multiple Objects Coincidences Counter (MOCC) to detect in-vivo binding to peripheral serotonin reuptake sites (left chest comprising platelet and lung serotonin reuptake sites) in man. Displacement and preloading experiments with clomipramine and venlafaxine in two healthy volunteers demonstrated that 11CRTI-55 binding is decreased in a dose-dependent fashion by both these drugs which bind to the serotonin transporter. In addition parallel data from the total head curve (representing 11CRTI-55 binding to central serotonin and dopamine (DA) reuptake sites) suggest that prior blockade of the serotonin transporter may be a useful strategy to maximize radioactive counts in the head when measuring the DA transporter. The MOCC is likely to be useful to determine sequential indices of relative serotonin reuptake blockade in patients on treatment.

  15. Fluoxetine Is a Potent Inhibitor of Coxsackievirus Replication

    OpenAIRE

    Zuo, Jun; Quinn, Kevin K.; Kye, Steve; Cooper, Paige; Damoiseaux, Robert; Krogstad, Paul

    2012-01-01

    No antiviral drugs currently exist for the treatment of enterovirus infections, which are often severe and potentially life threatening. Molecular screening of small molecule libraries identified fluoxetine, a selective serotonin reuptake inhibitor, as a potent inhibitor of coxsackievirus replication. Fluoxetine did not interfere with either viral entry or translation of the viral genome. Instead, fluoxetine and its metabolite norfluoxetine markedly reduced the synthesis of viral RNA and prot...

  16. Predictors of pharmacological treatment outcomes with atomoxetine or methylphenidate in patients with attention-deficit/hyperactivity disorder from China, Egypt, Lebanon, Russian Federation, Taiwan, and United Arab Emirates.

    Science.gov (United States)

    Treuer, T; Feng, Q; Desaiah, D; Altin, M; Wu, S; El-Shafei, A; Serebryakova, E; Gado, M; Faries, D

    2014-09-01

    The reduced availability of data from non-Western countries limits our ability to understand attention-deficit/hyperactivity disorder (ADHD) treatment outcomes, specifically, adherence and persistence of ADHD in children and adolescents. This analysis assessed predictors of treatment outcomes in a non-Western cohort of patients with ADHD treated with atomoxetine or methylphenidate. Data from a 12-month, prospective, observational study in outpatients aged 6-17 years treated with atomoxetine (N = 234) or methylphenidate (N = 221) were analysed post hoc to determine potential predictors of treatment outcomes. Participating countries included the Russian Federation, China, Taiwan, Egypt, United Arab Emirates and Lebanon. Factors associated with remission were analysed with stepwise multiple logistic regression and classification and regression trees (CART). Cox proportional hazards models with propensity score adjustment assessed differences in atomoxetine persistence among initial-dose cohorts. In patients treated with atomoxetine who had available dosing information (N = 134), Cox proportional hazards revealed lower (atomoxetine-treated patients were associated with age (older), country (United Arab Emirates) and gender (female) (all p atomoxetine) and prior atomoxetine use were associated with greater remission rates. These findings may help clinicians assess factors upon initiation of ADHD treatment to improve course prediction, proper dosing and treatment adherence and persistence. Observational study, therefore no registration. © 2014 John Wiley & Sons Ltd.

  17. Effects of atomoxetine with and without behavior therapy on the school and home functioning of children with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Waxmonsky, James G; Waschbusch, Daniel A; Pelham, William E; Draganac-Cardona, Lillian; Rotella, Bryan; Ryan, Lynn

    2010-11-01

    To evaluate the effects of atomoxetine alone and in combination with behavior therapy on the school functioning of children with attention-deficit/hyperactivity disorder (ADHD). Most atomoxetine studies have not assessed school functioning other than by measuring the change in ADHD symptoms. Combining behavior therapy with atomoxetine may be particularly beneficial for the academic domain as medication has not been found to produce sustained benefits in this realm. However, there is little research examining the effects of combining atomoxetine and behavior therapy. In an 8-week open-label trial, 56 children aged 6-12 years with ADHD diagnosed according to DSM-IV-TR were randomly assigned to receive atomoxetine and behavior therapy or atomoxetine alone. Behavior therapy consisted of an 8-week parenting course, a child social skills course, and a teacher-implemented daily report card of classroom behavior. The primary outcome was direct observation of the subject's classroom behavior. Secondary outcomes included change in ADHD symptoms and functioning at home and school. All data were collected between March 2007 and May 2008. Classroom observations showed that atomoxetine decreased rule violations (P parent-rated symptoms of inattention (P parents, teachers, and direct observation. The addition of behavior therapy led to further improvements at home but not at school. clinicaltrials.gov Identifier: NCT00918567. © Copyright 2010 Physicians Postgraduate Press, Inc.

  18. Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

    International Nuclear Information System (INIS)

    Fossa, Anthony A.; Wisialowski, Todd A.; Cremers, Thomas; Hart, Marieke van der; Tseng, Elaine; Deng, Shibing; Rollema, Hans; Wang, Ellen Q.

    2012-01-01

    Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure–response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. -- Highlights: ► Acute RBX produces blood pressure increases acutely that decrease with chronic RBX ► Chronic RBX increases brain NE levels, a preclinical surrogate of improved efficacy ► Short-term screening of NRI often underestimates the chronic therapeutic index ► Chronic cardiovascular

  19. Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

    Energy Technology Data Exchange (ETDEWEB)

    Fossa, Anthony A., E-mail: anthony.fossa@icardiac.com [Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States); Wisialowski, Todd A. [Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States); Cremers, Thomas; Hart, Marieke van der [Brains On-Line B.V., University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen (Netherlands); Tseng, Elaine; Deng, Shibing; Rollema, Hans; Wang, Ellen Q. [Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States)

    2012-11-01

    Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure–response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. -- Highlights: ► Acute RBX produces blood pressure increases acutely that decrease with chronic RBX ► Chronic RBX increases brain NE levels, a preclinical surrogate of improved efficacy ► Short-term screening of NRI often underestimates the chronic therapeutic index ► Chronic cardiovascular

  20. Atomoxetine treatment of attention-deficit/hyperactivity disorder in young adults with assessment of functional outcomes: a randomized, double-blind, placebo-controlled clinical trial.

    Science.gov (United States)

    Durell, Todd M; Adler, Lenard A; Williams, Dave W; Deldar, Ahmed; McGough, James J; Glaser, Paul E; Rubin, Richard L; Pigott, Teresa A; Sarkis, Elias H; Fox, Bethany K

    2013-02-01

    Attention-deficit/hyperactivity disorder (ADHD) is associated with significant impairment in multiple functional domains. This trial evaluated efficacy in ADHD symptoms and functional outcomes in young adults treated with atomoxetine. Young adults (18-30 years old) with ADHD were randomized to 12 weeks of double-blind treatment with atomoxetine (n = 220) or placebo (n = 225). The primary efficacy measure of ADHD symptom change was Conners' Adult ADHD Rating Scale (CAARS): Investigator-Rated: Screening Version Total ADHD Symptoms score with adult prompts. Secondary outcomes scales included the Adult ADHD Quality of Life-29, Clinical Global Impression-ADHD-Severity, Patient Global Impression-Improvement, CAARS Self-Report, Behavior Rating Inventory of Executive Function-Adult Version Self-Report, and assessments of depression, anxiety, sleepiness, driving behaviors, social adaptation, and substance use. Atomoxetine was superior to placebo on CAARS: Investigator-Rated: Screening Version (atomoxetine [least-squares mean ± SE, -13.6 ± 0.8] vs placebo [-9.3 ± 0.8], 95% confidence interval [-6.35 to -2.37], P < 0.001), Clinical Global Impression-ADHD-Severity (atomoxetine [-1.1 ± 0.1] vs placebo [-0.7 ± 0.1], 95% confidence interval [-0.63 to -0.24], P < 0.001), and CAARS Self-Report (atomoxetine [-11.9 ± 0.8] vs placebo [-7.8 ± 0.7], 95% confidence interval [-5.94 to -2.15], P < 0.001) but not on Patient Global Impression-Improvement. In addition, atomoxetine was superior to placebo on Adult ADHD Quality of Life-29 and Behavior Rating Inventory of Executive Function-Adult Version Self-Report. Additional assessments failed to detect significant differences (P ≥ 0.05) between atomoxetine and placebo. The adverse event profile was similar to that observed in other atomoxetine studies. Nausea, decreased appetite, insomnia, dry mouth, irritability, dizziness, and dyspepsia were reported significantly more often with atomoxetine than with placebo. Atomoxetine reduced

  1. Synthesis and evaluation of racemic [11C]NS2456 and its enantiomers as selective serotonin reuptake radiotracers for PET

    International Nuclear Information System (INIS)

    Smith, D.F.; Bender, D.; Marthi, K.; Cumming, P.; Hansen, S.B.; Peters, D.; Oestergaard Nielsen, E.; Scheel-Krueger, J.; Gjedde, A.

    2001-01-01

    Positron emission tomography (PET) radiotracers are needed for quantifying serotonin uptake sites in the living brain. Therefore, we evaluated a new selective serotonin reuptake inhibitor, NS2456, to determine whether it is suited for use in PET. Racemic NS2456 [(1RS,5SR)-8-methyl-3-[4-trifluoromethoxyphenyl]-8-azabicyclo [3.2.1]oct-2-ene] and its N-demethylated analog, racemic NS2463, selectively inhibited serotonin uptake in rat brain synaptosomes; their IC 50 values were 3000-fold lower for [ 3 H]serotonin than for either [ 3 H]dopamine or [ 3 H]noradrenaline. The enantiomers of NS2463 were also potent inhibitors of serotonin uptake in vitro, but they failed to show stereoselectivity. Racemic NS2463 as well as its enantiomers were radiolabelled by N-methylation with C-11, yielding [ 11 C]NS2456 for use in PET of the living porcine brain. The compounds crossed the blood-brain barrier rapidly and accumulated preferentially in regions rich in serotonin uptake sites (e.g., brainstem, subthalamus and thalamus). However, their binding potentials were relatively low and no stereoselectivity was found. Thus, neither racemic [ 11 C]NS2456 nor its [ 11 C]-labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites

  2. Parent Stress in a Randomized Clinical Trial of Atomoxetine and Parent Training for Children with Autism Spectrum Disorder

    Science.gov (United States)

    Lecavalier, Luc; Pan, Xueliang; Smith, Tristram; Handen, Benjamin L.; Arnold, L. Eugene; Silverman, Laura; Tumuluru, Rameshwari V.; Hollway, Jill; Aman, Michael G.

    2018-01-01

    We previously reported a 2 × 2 randomized clinical trial of atomoxetine (ATX) and parent training (PT) for attention deficit hyperactivity disorder (ADHD) symptoms and behavioral noncompliance in 128 children with autism spectrum disorder, ages 5-14 years. Children were randomized to one of four conditions: ATX alone, placebo alone, ATX + PT, or…

  3. Randomized, Controlled Trial of Atomoxetine for Attention-Deficit/Hyperactivity Disorder in Adolescents with Substance Use Disorder

    Science.gov (United States)

    Thurstone, Christian; Riggs, Paula D.; Salomonsen-Sautel, Stacy; Mikulich-Gilbertson, Susan K.

    2010-01-01

    Objective: To evaluate the effect of atomoxetine hydrochloride versus placebo on attention-deficit/hyperactivity disorder (ADHD) and substance use disorder (SUD) in adolescents receiving motivational interviewing/cognitive behavioral therapy (MI/CBT) for SUD. Method: This single-site, randomized, controlled trial was conducted between December…

  4. Differential effects of atomoxetine on executive functioning and lexical decision in attention-deficit/hyperactivity disorder and reading disorder

    NARCIS (Netherlands)

    de Jong, Christien G. W.; van de Voorde, Séverine; Roeyers, Herbert; Raymaekers, Ruth; Allen, Albert J.; Knijff, Simone; Verhelst, Helene; Temmink, Alfons H.; Smit, Leo M. E.; Rodriques-Pereira, Rob; Vandenberghe, Dirk; van Welsen, Inge; ter Schuren, Liesbeth; Al-Hakim, Mazim; Amin, Azad; Vlasveld, Laurens; Oosterlaan, Jaap; Sergeant, Joseph A.

    2009-01-01

    The effects of a promising pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), atomoxetine, were studied on executive functions in both ADHD and reading disorder (RD) because earlier research demonstrated an overlap in executive functioning deficits in both disorders. In

  5. Atomoxetine for attention-deficit/hyperactivity disorder symptoms in children with pervasive developmental disorders: a pilot study.

    NARCIS (Netherlands)

    Troost, P.W.; Steenhuis, M.P.; Tuynman-Qua, H.G.; Kalverdijk, L.J.; Buitelaar, J.K.; Minderaa, R.B.; Hoekstra, P.J.

    2006-01-01

    OBJECTIVE: This pilot study examined the effects of atomoxetine on attention-deficit/hyperactivity disorder (ADHD) symptoms and autistic features in children with pervasive developmental disorders (PDD). METHOD: Twelve children (aged 6-14 years) with PDD accompanied by ADHD symptoms entered a

  6. Effectiveness and safety of atomoxetine for ADHD in population between 6 and 19 years: a systematic review

    Directory of Open Access Journals (Sweden)

    José Calleja

    2012-09-01

    Full Text Available Introduction: Attention deficit hyperactivity disorder (ADHD is generally treated with pharmacological interventions such as psychostimulants. The most used widely used one is methylphenidate followed by atomoxetine. Purpose: To identify, synthesize and evaluate the best available evidence on the effectiveness and safety of atomoxetine in ADHD treatment in the 6-19 year-old population. Methods: A systematic review of intervention studies that evaluated effectiveness of atomoxetine compared with placebo and methylphenidate was conducted. Outcomes assessed were educational functioning, psychosocial functioning, quality of life and adverse effects. The search was done up to February 2012 in English and Spanish in the following databases: PubMed/MEDLINE, LILACS, Cochrane, DARE and National Guideline Clearinghouse. The articles were independently evaluated by two investigators. Results: Of the 108 studies found initially, 11 were included, among which five systematic reviews, one primary article and 5 clinical guidelines. Conclusions: Atomoxetine is recommended as a second option in ADHD and was found to be superior to placebo. Its use is recommended when methylphenidate fails or comorbidities are present.

  7. Atomoxetine for attention-deficit/hyperactivity disorder symptoms in children with pervasive developmental disorders : A pilot study

    NARCIS (Netherlands)

    Troost, Pieter W.; Steenhuis, Mark-Peter; Tuynman-Qua, Hanneke G.; Kalverdijk, Luuk J.; Buitelaar, Jan K.; Minderaa, Ruud B.; Hoekstra, Pieter J.

    2006-01-01

    Objective: This pilot study examined the effects of atomoxetine on attention-deficit/hyperactivity disorder (ADHD) symptoms and autistic features in children with pervasive developmental disorders (PDD). Method: Twelve children (aged 6-14 years) with PDD accompanied by ADHD symptoms entered a

  8. Methylphenidate and Atomoxetine Enhance Prefrontal Function through alpha[subscript 2]-Adrenergic and Dopamine D[subscript 1] Receptors

    Science.gov (United States)

    Gamo, Nao J.; Wang, Min; Arnsten, Amy F. T.

    2010-01-01

    Objective: This study examined the effects of the attention-deficit/hyperactivity disorder treatments, methylphenidate (MPH) and atomoxetine (ATM), on prefrontal cortex (PFC) function in monkeys and explored the receptor mechanisms underlying enhancement of PFC function at the behavioral and cellular levels. Method: Monkeys performed a working…

  9. Clinical Responses to Atomoxetine in Attention-Deficit/Hyperactivity Disorder: The Integrated Data Exploratory Analysis (IDEA) Study

    Science.gov (United States)

    Newcorn, Jeffrey H.; Sutton, Virginia K.; Weiss, Margaret D.; Sumner, Calvin R.

    2009-01-01

    Data from six randomized controlled trials in the U.S. reveal that 47 percent of patients aged six to 18 years showed a much improved clinical response to atomoxetine as a treatment for attention deficit hyperactivity disorder while 40 percent did not have a response. Augmenting or switching treatment in non-responders by week 4 is suggested.

  10. A Review of Atomoxetine Effects in Young People with Developmental Disabilities

    Science.gov (United States)

    Aman, Michael G.; Smith, Tristram; Arnold, L. Eugene; Corbett-Dick, Patricia; Rameshwari.Tumuluru; Hollway, Jill A.; Hyman, Susan L.; Mendoza-Burchamm, Marissa; Pan, Xueliang; Mruzek, Daniel W.; Lecavalier, Luc; Levato, Lynne; Silverman, Laura B.; Handen, Benjamin

    2014-01-01

    This review summarizes the pharmacokinetic characteristics, pharmacodynamic properties, common side effects, and clinical advantages and disadvantages associated with atomoxetine (ATX) treatment in typically developing children and adults with ADHD. Then the clinical research to date in developmental disabilities (DD), including autism spectrum disorders (ASD), is summarized and reviewed. Of the 11 relevant reports available, only two were placebo-controlled randomized clinical trials, and both focused on a single DD population (ASD). All trials but one indicated clinical improvement in ADHD symptoms with ATX, although it was difficult to judge the magnitude and validity of reported improvement in the absence of placebo controls. Effects of ATX on co-occurring behavioral and cognitive symptoms were much less consistent. Appetite decrease, nausea, and irritability were the most common adverse events reported among children with DD; clinicians should be aware that, as with stimulants, irritability appears to occur much more commonly in persons with DD than in typically developing individuals. Splitting the dose initially, starting below the recommended starting dose, and titrating slowly may prevent or ameliorate side effects. Patience is needed for the slow build-up of benefit. Conclusions: ATX holds promise for managing ADHD symptoms in DD, but properly controlled, randomized clinical trials of atomoxetine in intellectual disability and ASD are sorely needed. Clinicians and researchers should be vigilant for emergence of irritability with ATX treatment. Effects of ATX on cognition in DD are virtually unstudied. PMID:24732041

  11. RP-HPLC Determination of Atomoxetine Hydrochloride in Bulk and Pharmaceutical Formulations

    Directory of Open Access Journals (Sweden)

    H. R. Prajapati

    2011-01-01

    Full Text Available A reversed phase high performance liquid chromatographic (RP–HPLC method was developed and subsequently validated for the determination of atomoxetine hydrochloride in bulk and pharmaceutical formulation. The separation was done by a PerkinElmer Brownlee analytical C8 column (260 mm x 4.6 mm, 5 µm using methanol: 50 mM KH2PO2 buffer (PH adjusted to 6.8 with 0.1 M NaOH, 80:20 v/v as an eluent. UV detection was performed at 270 nm at a flow rate 1.0 mL/min. The validation of the method was performed, and specificity, reproducibility, precision accuracy and ruggedness were confirmed. The correlation coefficient was found to be 0.997 for atomoxetine hydrochloride. The recovery was in the range of 99.94 to 100.98% and limit of quantification was found to be 5.707 µg/mL. The method is simple, rapid, selective and economical too and can be used for the routine analysis of drug in pharmaceutical formulations.

  12. Pilot study of atomoxetine in patients with Parkinson's disease and dopa-unresponsive Freezing of Gait.

    Science.gov (United States)

    Revuelta, Gonzalo J; Embry, Aaron; Elm, Jordan J; Gregory, Chris; Delambo, Amy; Kautz, Steve; Hinson, Vanessa K

    2015-01-01

    Freezing of gait (FoG) is a common and debilitating condition in Parkinson's disease (PD) associated with executive dysfunction. A subtype of FoG does not respond to dopaminergic therapy and may be related to noradrenergic deficiency. This pilot study explores the effects of atomoxetine on gait in PD patients with dopa-unresponsive FoG using a novel paradigm for objective gait assessment. Ten patients with PD and dopa-unresponsive FoG were enrolled in this eight-week open label pilot study. Assessments included an exploratory gait analysis protocol that quantified spatiotemporal parameters during straight-away walking and turning, while performing a dual task. Clinical, and subjective assessments of gait, quality of life, and safety were also administered. The primary outcome was a validated subjective assessment for FoG (FOG-Q). Atomoxetine was well tolerated, however, no significant change was observed in the primary outcome. The gait analysis protocol correlated well with clinical scales, but not with subjective assessments. DBS patients were more likely to increase gait velocity (p = 0.033), and improved in other clinical assessments. Objective gait analysis protocols assessing gait while dual tasking are feasible and useful for this patient population, and may be superior correlates of FoG severity than subjective measures. These findings can inform future trials in this population.

  13. Relationships Between Functional Outcomes and Symptomatic Improvement in Atomoxetine-Treated Adult Patients with Attention-Deficit/Hyperactivity Disorder: Post Hoc Analysis of an Integrated Database

    NARCIS (Netherlands)

    Bruyckere, K. De; Bushe, C.; Bartel, C.; Berggren, L.; Kan, C.C.; Dittmann, R.W.

    2016-01-01

    BACKGROUND: Atomoxetine treatment is associated with improvements in functional outcomes in patients with attention-deficit/hyperactivity disorder (ADHD), although relationships between improvements in these outcomes and reductions in ADHD symptoms have not been comprehensively investigated in

  14. Atomoxetine administration combined with intensive speech therapy for post-stroke aphasia: evaluation by a novel SPECT method.

    Science.gov (United States)

    Yamada, Naoki; Kakuda, Wataru; Yamamoto, Kazuma; Momosaki, Ryo; Abo, Masahiro

    2016-09-01

    We clarified the safety, feasibility, and efficacy of atomoxetine administration combined with intensive speech therapy (ST) for patients with post-stroke aphasia. In addition, we investigated the effect of atomoxetine treatment on neural activity of surrounding lesioned brain areas. Four adult patients with motor-dominant aphasia and a history of left hemispheric stroke were studied. We have registered on the clinical trials database (ID: JMA-IIA00215). Daily atomoxetine administration of 40 mg was initiated two weeks before admission and raised to 80 mg 1 week before admission. During the subsequent 13-day hospitalization, administration of atomoxetine was raised to 120 mg and daily intensive ST (120 min/day, one-on-one training) was provided. Language function was assessed using the Japanese version of The Western Aphasia Battery (WAB) and the Token test two weeks prior to admission, on the day of admission, and at discharge. At two weeks prior to admission and at discharge, each patient's cortical blood flow was measured using (123)I-IMP-single photon emission computed tomography (SPECT). This protocol was successfully completed by all patients without any adverse effects. Four patients showed improved language function with the median of the Token Test increasing from 141 to 149, and the repetition score of WAB increasing from 88 to 99. In addition, cortical blood flow surrounding lesioned brain areas was found to increase following intervention in all patients. Atomoxetine administration and intensive ST were safe and feasible for post-stroke aphasia, suggesting their potential usefulness in the treatment of this patient population.

  15. Atomoxetine treatment outcomes in adolescents and young adults with attention-deficit/hyperactivity disorder: results from a post hoc, pooled analysis.

    Science.gov (United States)

    Adler, Lenard A; Wilens, Timothy; Zhang, Shuyu; Dittmann, Ralf W; D'Souza, Deborah N; Schuh, Leslie; Durell, Todd M

    2012-02-01

    Many children with attention-deficit/hyperactivity disorder (ADHD) continue to experience this disorder as adults, which may, in part, be due to the discontinuity of health care that often occurs during the transition period between late adolescence and young adulthood. Although atomoxetine is reported to be efficacious in both adolescents and young adults, no longitudinal studies have been designed to assess directly the effects of atomoxetine treatment during this transition period. As a first step, we present the results of a post hoc, pooled analysis that compared the efficacy and safety profile of atomoxetine in these 2 patient populations. The aim of the present study was to assess the efficacy and safety profile of atomoxetine treatment in adolescents and young adults with ADHD. A post hoc, pooled analysis was conducted by combining data from 6 double-blind trials (6-9 weeks in duration) that studied adolescents (12-17 years of age; atomoxetine, n = 154; placebo, n = 88; mean final dose = 1.38 mg/kg) and 3 trials (10 weeks in duration) that studied young adults (18-30 years of age; atomoxetine, n = 117; placebo, n = 125; mean final dose = 1.21 mg/kg). Efficacy measures used in these analyses were ADHD Rating Scale (ADHDRS) for adolescents, Conners' Adult ADHD Rating Scale (CAARS) for young adults, and Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) for both age groups. Treatment response was defined as ≥30% reduction from baseline in total ADHD symptom score. In adolescents (mean age, 13.4 years), atomoxetine improved ADHD significantly compared with placebo (ADHDRS total score change, -12.9 vs -7.5; P young adults (mean age, 24.7 years), atomoxetine improved ADHD significantly (CAARS total score change, -13.6 vs -7.7; P young adults (13.7% vs 4.8%, respectively; P = 0.024); in adolescents no statistically significant differences were observed in frequency of nausea between atomoxetine and placebo treatment (4.5% vs 10.2%, respectively; P = 0

  16. Atomoxetine Use in Attention-Deficit/Hyperactivity Disorder and Comorbid Tic Disorder in Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections.

    Science.gov (United States)

    Demirkaya, Sevcan Karakoç; Demirkaya, Mithat; Yusufoğlu, Canan; Akın, Elif

    2017-02-01

    Attention-deficit/hyperactivity disorder (ADHD) is a common comorbid disease in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), in which tic-like involuntary movements are frequently seen clinical conditions. In contrast to psychostimulants, atomoxetine is considered as having minimal effects on tics. Here we report two cases with ADHD and PANDAS who were treated with atomoxetine for their ADHD and comorbid tics.

  17. Blockade of α2-adrenergic receptors in prelimbic cortex: impact on cocaine self-administration in adult spontaneously hypertensive rats following adolescent atomoxetine treatment.

    Science.gov (United States)

    Baskin, Britahny M; Nic Dhonnchadha, Bríd Á; Dwoskin, Linda P; Kantak, Kathleen M

    2017-10-01

    Research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder demonstrated that chronic methylphenidate treatment during adolescence increased cocaine self-administration established during adulthood under a progressive ratio (PR) schedule. Compared to vehicle, chronic atomoxetine treatment during adolescence failed to increase cocaine self-administration under a PR schedule in adult SHR. We determined if enhanced noradrenergic transmission at α2-adrenergic receptors within prefrontal cortex contributes to this neutral effect of adolescent atomoxetine treatment in adult SHR. Following treatment from postnatal days 28-55 with atomoxetine (0.3 mg/kg) or vehicle, adult male SHR and control rats from Wistar-Kyoto (WKY) and Wistar (WIS) strains were trained to self-administer 0.3 mg/kg cocaine. Self-administration performance was evaluated under a PR schedule of cocaine delivery following infusion of the α2-adrenergic receptor antagonist idazoxan (0 and 10-56 μg/side) directly into prelimbic cortex. Adult SHR attained higher PR break points and had greater numbers of active lever responses and infusions than WKY and WIS. Idazoxan dose-dependently increased PR break points and active lever responses in SHR following adolescent atomoxetine vs. vehicle treatment. Behavioral changes were negligible after idazoxan pretreatment in SHR following adolescent vehicle or in WKY and WIS following adolescent atomoxetine or vehicle. α2-Adrenergic receptor blockade in prelimbic cortex of SHR masked the expected neutral effect of adolescent atomoxetine on adult cocaine self-administration behavior. Moreover, greater efficacy of acute idazoxan challenge in adult SHR after adolescent atomoxetine relative to vehicle is consistent with the idea that chronic atomoxetine may downregulate presynaptic α2A-adrenergic autoreceptors in SHR.

  18. Neural correlates of atomoxetine improving inhibitory control and visual processing in Drug-naïve adults with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Fan, Li-Ying; Chou, Tai-Li; Gau, Susan Shur-Fen

    2017-10-01

    Atomoxetine improves inhibitory control and visual processing in healthy volunteers and adults with attention-deficit/hyperactivity disorder (ADHD). However, little is known about the neural correlates of these two functions after chronic treatment with atomoxetine. This study aimed to use the counting Stroop task with functional magnetic resonance imaging (fMRI) and the Cambridge Neuropsychological Test Automated Battery (CANTAB) to investigate the changes related to inhibitory control and visual processing in adults with ADHD. This study is an 8-week, placebo-controlled, double-blind, randomized clinical trial of atomoxetine in 24 drug-naïve adults with ADHD. We investigated the changes of treatment with atomoxetine compared to placebo-treated counterparts using the counting Stroop fMRI and two CANTAB tests: rapid visual information processing (RVP) for inhibitory control and delayed matching to sample (DMS) for visual processing. Atomoxetine decreased activations in the right inferior frontal gyrus and anterior cingulate cortex, which were correlated with the improvement in inhibitory control assessed by the RVP. Also, atomoxetine increased activation in the left precuneus, which was correlated with the improvement in the mean latency of correct responses assessed by the DMS. Moreover, anterior cingulate activation in the pre-treatment was able to predict the improvements of clinical symptoms. Treatment with atomoxetine may improve inhibitory control to suppress interference and may enhance the visual processing to process numbers. In addition, the anterior cingulate cortex might play an important role as a biological marker for the treatment effectiveness of atomoxetine. Hum Brain Mapp 38:4850-4864, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  19. Safety of Methylphenidate and Atomoxetine in Children with Attention-Deficit/Hyperactivity Disorder (ADHD): Data from the Italian National ADHD Registry.

    Science.gov (United States)

    Cortese, Samuele; Panei, Pietro; Arcieri, Romano; Germinario, Elena A P; Capuano, Annalisa; Margari, Lucia; Chiarotti, Flavia; Curatolo, Paolo

    2015-01-01

    The aim of this study was to assess the type and frequency of adverse events (AEs) in children with attention-deficit/hyperactivity disorder (ADHD) treated with methylphenidate or atomoxetine over a 5-year period in a large naturalistic study. We draw on data from the Italian ADHD Registry, a national database for postmarketing phase IV pharmacovigilance of ADHD medications across 90 centers. AEs were defined as severe or mild as per the classification of the Italian Medicines Agency. AE frequency in the two treatment groups was compared using incidence rates per 100 person-years (IR100PY) and incidence rate ratios (IRRs). Mantel-Haenszel adjusted IRRs were calculated to control for psychiatric comorbidity. A total of 1350 and 753 participants (aged 6-18 years, mean age 10.7 ± 2.8) were treated with methylphenidate and atomoxetine, respectively, from 2007 to 2012. Ninety participants (7 %) were switched from methylphenidate to atomoxetine, and 138 (18 %) from atomoxetine to methylphenidate. Thirty-seven children treated with atomoxetine and 12 with methylphenidate had their medication withdrawn. Overall, 645 patients (26.8 %) experienced at least one mild AE (including decreased appetite and irritability, for both drugs) and 95 patients (3.9 %) experienced at least one severe AE (including severe gastrointestinal events). IR100PY were significantly higher in the atomoxetine-treated group compared with the methylphenidate-treated group for a number of mild and severe AEs and for any severe or mild AEs. After controlling for comorbidities, IRR was still significantly higher in the atomoxetine group compared with the methylphenidate group for a number of mild (decreased appetite, weight loss, abdominal pain, dyspepsia, stomach ache, irritability, mood disorder and dizziness) and severe (gastrointestinal, neuropsychiatric, and cardiovascular) AEs. In this naturalistic study, methylphenidate had a better safety profile than atomoxetine.

  20. Development of norepinephrine transporter reuptake inhibition assays using SK-N-BE(2C cells

    Directory of Open Access Journals (Sweden)

    Ann M. Decker

    2018-05-01

    Full Text Available This report describes efforts to develop and validate novel norepinephrine transporter reuptake inhibition assays using human neuroblastoma SK-N-BE(2C cells in 24-well format. Before conducting the assays, the SK-N-BE(2C cells were first evaluated for their ability to uptake [3H]norepinephrine and were shown to have a saturable uptake with a KM value of 416 nM. Using this determined KM value, reuptake inhibition assays were then conducted with a variety of ligands including antidepressants, as well as piperazine and phenyltropane derivatives. The results obtained with the SK-N-BE(2C cells indicate that this model system can detect a range of ligand potencies, which compare well with other established transporter assays. Our data suggest that SK-N-BE(2C cells have potential utility to serve as another model system to detect norepinephrine reuptake inhibition activity.

  1. Atomoxetine in patients with ADHD: A clinical and pharmacological review of the onset, trajectory, duration of response and implications for patients.

    Science.gov (United States)

    Clemow, David B; Bushe, Chris J

    2015-12-01

    This article reviews data providing new insight into the trajectory of response and maintenance of response of atomoxetine in the treatment of child and adult attention-deficit hyperactivity disorder (ADHD). This nonsystematic review includes: onset of action and duration of effect, response rate, effect size, time to optimal response and norepinephrine transporter blockade biomarker data. Atomoxetine can have an onset of action within 1-2 weeks of starting treatment, but there is an incrementally increasing response for up to 24 weeks or longer. Responder rates and effect sizes are similar to methylphenidate. Upon treatment discontinuation, relapse rates are lower than expected. In adults, 50% maintain their response for at least 6 months after stopping atomoxetine, following 6 months of treatment. Single-dose atomoxetine can provide 24-hour efficacy, despite a 5-hour plasma half-life. Hypotheses can be generated relating to neuroadaptive changes, to explain these findings. Atomoxetine has a trajectory of response that is incremental over a long period of time, with a greater than expected maintenance of response. This has implications for physician atomoxetine dosing and efficacy assessment, patient education and outcomes, and for clinical trial design and assessment of comparative efficacy with stimulant medications. © The Author(s) 2015.

  2. A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients.

    Science.gov (United States)

    Bushe, Chris; Day, Kathleen; Reed, Victoria; Karlsdotter, Kristina; Berggren, Lovisa; Pitcher, Ashley; Televantou, Foula; Haynes, Virginia

    2016-05-01

    The lack of head-to-head clinical studies powered to compare atomoxetine and osmotic release oral system (OROS) methylphenidate necessitates treatment comparison by methods that include indirect evidence such as network meta-analysis (NMA). A NMA assessing the relative treatment effects of atomoxetine and OROS methylphenidate in adults with attention-deficit/hyperactivity disorder (ADHD) was conducted. Studies were identified by systematic literature review. Analyses summarised improvements in efficacy, measured by ADHD-specific scales, using Cohen'sdto calculate the standardised mean difference (SMD), and all cause discontinuations. Results showed effect sizes (SMD, 95% credible interval (CrI)) relative to placebo that did not differ significantly between atomoxetine (0.46, 0.36-0.56) and OROS methylphenidate (0.51, 0.40-0.63) in clinical studies of up to 12 weeks' duration (SMD, 95% CrI for atomoxetine versus OROS methylphenidate: -0.05, -0.18-0.08). Patients treated with these medications responded better than those given placebo across all analyses. There was also no significant difference in discontinuation rates between atomoxetine and OROS methylphenidate (odds ratio, 95% CrI: 0.85, 0.53-1.35). Between-study heterogeneity was low overall. Results of this NMA suggest that the efficacy of atomoxetine and OROS methylphenidate in adults does not differ significantly. Clinical guidelines may require amendment to reflect these recent data. © The Author(s) 2016.

  3. Atomoxetine Improved Attention in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Dyslexia in a 16 Week, Acute, Randomized, Double-Blind Trial

    Science.gov (United States)

    Williams, David; Shaywitz, Sally; Shaywitz, Bennett; Hooper, Stephen R.; Wigal, Sharon B.; Dunn, David; McBurnett, Keith

    2013-01-01

    Abstract Objective The purpose of this study was to evaluate atomoxetine treatment effects in attention-deficit/hyperactivity disorder (ADHD-only), attention-deficit/hyperactivity disorder with comorbid dyslexia (ADHD+D), or dyslexia only on ADHD core symptoms and on sluggish cognitive tempo (SCT), working memory, life performance, and self-concept. Methods Children and adolescents (10–16 years of age) with ADHD+D (n=124), dyslexia-only (n=58), or ADHD-only (n=27) received atomoxetine (1.0–1.4 mg/kg/day) or placebo (ADHD-only subjects received atomoxetine) in a 16 week, acute, randomized, double-blind trial with a 16 week, open-label extension phase (atomoxetine treatment only). Changes from baseline were assessed to weeks 16 and 32 in ADHD Rating Scale-IV-Parent-Version:Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv); ADHD Rating Scale-IV-Teacher-Version (ADHDRS-IV-Teacher-Version); Life Participation Scale—Child- or Parent-Rated Version (LPS); Kiddie-Sluggish Cognitive Tempo (K-SCT) Interview; Multidimensional Self Concept Scale (MSCS); and Working Memory Test Battery for Children (WMTB-C). Results At week 16, atomoxetine treatment resulted in significant (pDyslexia-only, atomoxetine versus placebo significantly improved K-SCT Youth subscale scores from baseline. At Week 32, atomoxetine-treated ADHD+D subjects significantly improved from baseline on all measures except MSCS Family subscale and WMTB-C Central Executive and Visuo-spatial Sketchpad component scores. The atomoxetine-treated dyslexia-only subjects significantly improved from baseline to week 32 on ADHDRS-IV-Parent:Inv Inattentive subscale, K-SCT Parent and Teacher subscales, and WMTB-C Phonological Loop and Central Executive component scores. The atomoxetine-treated ADHD-only subjects significantly improved from baseline to Week 32 on ADHDRS-Parent:Inv Total and subscales, ADHDRS-IV-Teacher-Version Hyperactive/Impulsive subscale, LPS Self-Control and Total, all K-SCT subscales, and

  4. The efficacy of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of clinical research.

    Science.gov (United States)

    Savill, Nicola C; Buitelaar, Jan K; Anand, Ernie; Day, Kathleen Ann; Treuer, Tamás; Upadhyaya, Himanshu P; Coghill, David

    2015-02-01

    Atomoxetine was first licensed to treat attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in the US in 2002. The aim of this paper is to comprehensively review subsequent publications addressing the efficacy of atomoxetine in 6- to 18-year-olds with ADHD. We identified 125 eligible papers using a predefined search strategy. Overall, these papers demonstrate that atomoxetine is an effective treatment for the core ADHD symptoms (effect sizes 0.6-1.3, vs. placebo, at 6-18 weeks), and improves functional outcomes and quality of life, in various pediatric populations with ADHD (i.e., males/females, patients with co-morbidities, children/adolescents, and with/without prior exposure to other ADHD medications). Initial responses to atomoxetine may be apparent within 1 week of treatment, but can take longer (median 23 days in a 6-week study; n=72). Responses often build gradually over time, and may not be robust until after 3 months. A pooled analysis of six randomized placebo-controlled trials (n=618) indicated that responses at 4 weeks may predict response at 6-9 weeks, although another pooled analysis of open-label data (n=338) suggests that the probability of a robust response to atomoxetine [≥40% decrease in ADHD-Rating Scale (ADHD-RS) scores] may continue to increase beyond 6-9 weeks. Atomoxetine may demonstrate similar efficacy to methylphenidate, particularly immediate-release methylphenidate, although randomized controlled trials are generally limited by short durations (3-12 weeks). In conclusion, notwithstanding these positive findings, before initiating treatment with atomoxetine, it is important that the clinician sets appropriate expectations for the patient and their family with regard to the likelihood of a gradual response, which often builds over time.

  5. Efficacy of atomoxetine for symptoms of attention-deficit/hyperactivity disorder in children with a history of child abuse.

    Science.gov (United States)

    Sugimoto, Atsunori; Suzuki, Yutaro; Endo, Taro; Matsumoto, Keita; Sugiyama, Toshiro; Someya, Toshiyuki

    2015-04-01

    Recent studies suggest that the severity and drug response of depression and anxiety are correlated with childhood abuse. However, whether a history of child abuse can predict the severity and/or drug response of attention-deficit/hyperactivity disorder (ADHD) is unclear. Therefore, we conducted a retrospective study to assess the efficacy of atomoxetine in children with a history of child abuse. We reviewed 41 cases of children treated with atomoxetine. Specifically, we compared dissociation associating symptoms (DAS) and other symptoms (OS) measured via the ADHD Rating Scale (ADHD-RS) in abused and nonabused children at baseline and at 8 weeks after atomoxetine administration. At baseline, abused children had higher total scores (38.7±9.3 vs. 30.5±9.4, p=0.011), and greater levels of hyperactivity/impulsivity (17.3±5.8 vs. 11.3±6.0, p=0.004) on the ADHD-RS than did nonabused children, whereas the inattention scores were similar between the two groups (21.4±4.8 vs. 19.2±4.6). Additionally, the total score and the two subscores decreased at week 8 for both groups. In the nonabused group, DAS (5.5±2.3 vs. 3.9±1.7, patomoxetine treatment. However, DAS in the abused group did not change after atomoxetine treatment (5.9±2.3 vs. 5.1±1.8), whereas OS significantly decreased (32.8±7.6 vs. 25.7±7.2, p=0.002). If DAS were caused by traumatic experiences in abused children, trauma treatment tools other than pharmacotherapy might be useful to treat DAS. These tools may include eye movement desensitization and reprocessing and trauma-focused cognitive behavioral therapy.

  6. Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments*

    Science.gov (United States)

    Jordan, Chloe J.; Harvey, Roxann C.; Baskin, Britahny B.; Dwoskin, Linda P.; Kantak, Kathleen M.

    2014-01-01

    Background Attention-deficit/hyperactivity disorder (ADHD) is often comorbid with cocaine abuse. Controversy exists regarding long-term consequences of ADHD medications on cocaine abuse liability. Whereas childhood methylphenidate treatment may be preventative, methylphenidate in teens appears to further increase later cocaine abuse risk. In rodents, adolescent methylphenidate treatment further increases adult cocaine self-administration in the Spontaneously Hypertensive Rat (SHR) model of ADHD, whereas adolescent atomoxetine treatment does not. Effects of ADHD medications on cocaine cue reactivity, a critical component of addiction, are unknown. Methods To investigate this, SHR, Wistar-Kyoto (inbred control) and Wistar (outbred control) rats received therapeutically relevant doses of methylphenidate (1.5 mg/kg, oral) and atomoxetine (0.3 mg/kg, intraperitoneal), or respective vehicles from post-natal day 28–55. Cocaine seeking, reflecting cue reactivity, was measured in adulthood during self-administration maintenance and cue-induced reinstatement tests conducted under a second-order schedule. Results Compared to control strains, SHR earned more cocaine infusions, emitted more cocaine-seeking responses during maintenance and reinstatement testing, and required more sessions to reach the extinction criterion. Compared to vehicle, adolescent methylphenidate, but not atomoxetine, further increased cocaine intake during maintenance testing in SHR. Adolescent atomoxetine, but not methylphenidate, decreased cocaine seeking during reinstatement testing in SHR. Neither medication had effects on cocaine intake or cue reactivity in control strains. Conclusions The SHR successfully model ADHD and cocaine abuse comorbidity and show differential effects of adolescent ADHD medications on cocaine intake and cue reactivity during adulthood. Thus, SHR have heuristic value for assessing neurobiology underlying the ADHD phenotype and for evaluating pharmacotherapeutics for ADHD

  7. Studying the association complex formation of atomoxetine and fluvoxamine with eosin Y and its application in their fluorimetric determination

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    Derayea, Sayed M.; Omar, Mahmoud A.; Abu-hassan, Ahmed A.

    2018-03-01

    A simple, sensitive and non-extractive spectrofluorimetric method has been developed and validated for the determination of two psychoanaleptic drugs, atomoxetine and fluvoxamine, in pure forms and pharmaceutical dosage forms. The proposed method is based on the formation of binary complexes between eosin Y and the studied drugs in the presence of a Teorell-Stenhagen buffer. The quenching of the native fluorescence of eosin Y due to complex formation with the studied drugs was measured spectrofluorimetrically at 545 nm after excitation at 302 nm. At the optimum reaction conditions, the fluorescence quenching values (ΔF) and concentrations were rectilinear over the concentration ranges of 0.2-2.2 and 0.3-2.2 µg ml-1 for atomoxetine and fluvoxamine, respectively. The developed method was successfully applied for the determination of the studied drugs in their pharmaceutical formulations with average percentage recoveries of 100.13 ± 0.66 and 99.69 ± 0.44 for atomoxetine and fluvoxamine, respectively (n = 5), without interference from common excipients.

  8. Studying the association complex formation of atomoxetine and fluvoxamine with eosin Y and its application in their fluorimetric determination.

    Science.gov (United States)

    Derayea, Sayed M; Omar, Mahmoud A; Abu-Hassan, Ahmed A

    2018-03-01

    A simple, sensitive and non-extractive spectrofluorimetric method has been developed and validated for the determination of two psychoanaleptic drugs, atomoxetine and fluvoxamine, in pure forms and pharmaceutical dosage forms. The proposed method is based on the formation of binary complexes between eosin Y and the studied drugs in the presence of a Teorell-Stenhagen buffer. The quenching of the native fluorescence of eosin Y due to complex formation with the studied drugs was measured spectrofluorimetrically at 545 nm after excitation at 302 nm. At the optimum reaction conditions, the fluorescence quenching values (Δ F ) and concentrations were rectilinear over the concentration ranges of 0.2-2.2 and 0.3-2.2 µg ml -1 for atomoxetine and fluvoxamine, respectively. The developed method was successfully applied for the determination of the studied drugs in their pharmaceutical formulations with average percentage recoveries of 100.13 ± 0.66 and 99.69 ± 0.44 for atomoxetine and fluvoxamine, respectively ( n  = 5), without interference from common excipients.

  9. An open-label, dose-titration tolerability study of atomoxetine hydrochloride in Japanese adults with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Takahashi, Michihiro; Takita, Yasushi; Goto, Taro; Ichikawa, Hironobu; Saito, Kazuhiko; Matsumoto, Hideo; Tanaka, Yasuo

    2011-02-01

    The main purpose of this first atomoxetine study in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) was to investigate the tolerability of an 8-week treatment regimen. This was an open-label, dose escalation study conducted in 45 Japanese patients aged at least 18 years with DSM-IV-defined ADHD. Patients received atomoxetine orally for 8 weeks. Atomoxetine administration was started at 40 mg/day (7 days), and subsequently increased to a maximum dose of 120 mg/day. Tolerability was assessed by discontinuation rate due to adverse events. Adverse events, laboratory tests, vital signs and electrocardiograms were collected. In addition, ADHD symptoms were assessed by using the Japanese version of the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) scores. Thirty-nine patients completed the study period. Atomoxetine was well tolerated with a 6.7% (3/45) discontinuation rate due to nausea, malaise and anorexia. The most commonly reported adverse events were nausea, nasopharyngitis and headache; there were no unexpected safety concerns. No deaths or serious adverse events were reported. Mean CAARS-Inv:SV-J total ADHD symptom scores decreased in a time-dependent manner; the mean change from baseline to endpoint was -15.0 (Patomoxetine was well tolerated in these patients and suggested that atomoxetine at a maximum dose of 120 mg/day would be safe in Japanese ADHD patients. © 2011 The Authors. Psychiatry and Clinical Neurosciences © 2011 Japanese Society of Psychiatry and Neurology.

  10. A liquid chromatography/tandem mass spectrometry assay for the analysis of atomoxetine in human plasma and in vitro cellular samples

    Science.gov (United States)

    Appel, David I.; Brinda, Bryan; Markowitz, John S.; Newcorn, Jeffrey H.; Zhu, Hao-Jie

    2012-01-01

    A simple, rapid and sensitive method for quantification of atomoxetine by liquid chromatography- tandem mass spectrometry (LC-MS/MS) was developed. This assay represents the first LC-MS/MS quantification method for atomoxetine utilizing electrospray ionization. Deuterated atomoxetine (d3-atomoxetine) was adopted as the internal standard. Direct protein precipitation was utilized for sample preparation. This method was validated for both human plasma and in vitro cellular samples. The lower limit of quantification was 3 ng/ml and 10 nM for human plasma and cellular samples, respectively. The calibration curves were linear within the ranges of 3 ng/ml to 900 ng/ml and 10 nM to 10 μM for human plasma and cellular samples, respectively (r2 > 0.999). The intra- and inter-day assay accuracy and precision were evaluated using quality control samples at 3 different concentrations in both human plasma and cellular lysate. Sample run stability, assay selectivity, matrix effect, and recovery were also successfully demonstrated. The present assay is superior to previously published LC-MS and LC-MS/MS methods in terms of sensitivity or the simplicity of sample preparation. This assay is applicable to the analysis of atomoxetine in both human plasma and in vitro cellular samples. PMID:22275222

  11. Open-label, dose-titration tolerability study of atomoxetine hydrochloride in Korean, Chinese, and Taiwanese adults with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Takahashi, Michihiro; Goto, Taro; Takita, Yasushi; Chung, Sang-Keun; Wang, Yufeng; Gau, Susan Shur-Fen

    2014-03-01

    The primary objective of this study was to assess the overall safety and tolerability of atomoxetine in Korean, Chinese, and Taiwanese adults with attention-deficit/hyperactivity disorder (ADHD). A total of 44 patients aged ≥18 years who met the Conners' Adult ADHD Diagnostic Interview for DSM-IV diagnostic criteria for ADHD were enrolled from China, Korea, and Taiwan. In this open-label, dose-escalation study, patients received atomoxetine orally once daily over a period of eight weeks, starting at 40 mg/day (one week) up to a maximum dosage of 120 mg/day. Tolerability was evaluated by rate of discontinuation due to adverse events. Safety was assessed by recording all adverse events, laboratory tests, vital signs, and electrocardiograms. ADHD symptoms were evaluated by the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) for efficacy assessment. Thirty-four patients (77.3%) completed the study. Atomoxetine was well tolerated with a discontinuation rate of 2.3% (1/44) due to adverse events. The most commonly reported adverse events were nausea, dizziness, and somnolence. The mean change from baseline to endpoint in CAARS-Inv:SV total ADHD symptom score was -12.5 (P atomoxetine clinical trial in adult patients with ADHD in China, Korea, and Taiwan. Atomoxetine was well tolerated in doses of up to 120 mg/day with no unknown safety concerns. Copyright © 2012 Blackwell Publishing Asia Pty Ltd.

  12. Does Comorbid Disruptive Behavior Modify the Effects of Atomoxetine on ADHD Symptoms as Measured by a Continuous Performance Test and a Motion Tracking Device?

    Science.gov (United States)

    Wehmeier, Peter M; Kipp, Laura; Banaschewski, Tobias; Dittmann, Ralf W; Schacht, Alexander

    2015-07-01

    To compare the reduction of ADHD symptoms under atomoxetine in patients with and without comorbid oppositional defiant disorder (ODD) or conduct disorder (CD) using a computer-based continuous performance test (cb-CPT) combined with an infrared motion tracking (MT) device. Secondary analysis of a placebo-controlled study in ADHD patients (6-12 years old) treated with atomoxetine (target dose: 1.2 mg/kg per day). Cb-CPT/MT scores were analyzed using ANCOVA (last observation carried forward [LOCF]). The data (N = 125) suggested a more pronounced atomoxetine effect in the group with comorbid ODD/CD as measured by all cb-CPT/MT parameters except for "normalized variation of reaction time" (nVRT). The results showed that atomoxetine reduced ADHD severity as measured by cb-CPT and MT parameters regardless of whether comorbid ODD/CD was present. The treatment effect of atomoxetine on hyperactivity appears to be more pronounced in the subgroup of patients with comorbid ODD/CD than in the subgroup without this comorbidity. © 2012 SAGE Publications.

  13. Acute atomoxetine treatment of younger and older children with ADHD: A meta-analysis of tolerability and efficacy

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    Vaughan Brigette S

    2008-09-01

    Full Text Available Abstract Background Atomoxetine is FDA-approved as a treatment of attention-deficit/hyperactivity disorder (ADHD in patients aged 6 years to adult. Among pediatric clinical trials of atomoxetine to date, six with a randomized, double-blind, placebo-controlled design were used in this meta-analysis. The purpose of this article is to describe and compare the treatment response and tolerability of atomoxetine between younger children (6–7 years and older children (8–12 years with ADHD, as reported in these six acute treatment trials. Methods Data from six clinical trials of 6–9 weeks duration were pooled, yielding 280 subjects, ages 6–7 years, and 860 subjects, ages 8–12 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-diagnosed ADHD. Efficacy was analyzed using the ADHD Rating Scale-IV (ADHD-RS, Conners' Parent Rating Scale-revised (CPRS-R:S, and the Clinical Global Impression of ADHD Severity (CGI-ADHD-S. Results Atomoxetine was superior to placebo in both age categories for mean (SD change in ADHD-RS total, total T, and subscale scores; 3 CPRS-R:S subscales; and CGI-ADHD-S from baseline. Although there were no significant treatment differentials between the age groups for these efficacy measures, the age groups themselves, regardless of treatment, were significantly different for ADHD-RS total (younger: ATX = -14.2 [13.8], PBO = -4.6 [10.4]; older: ATX = -15.4 [13.2], PBO = -7.3 [12.0]; p = .001, total T (younger: ATX = -15.2 [14.8], PBO = -4.9 [11.2]; older: ATX = -16.4 [14.6], PBO = -7.9 [13.1]; p = .003, and subscale scores (Inattentive: younger: ATX = -7.2 [7.5], PBO = -2.4 [5.7]; older: ATX = -8.0 [7.4], PBO = -3.9 [6.7]; p = .043; Hyperactive/Impulsive: younger: ATX = -7.0 [7.2], PBO = -2.1 [5.4]; older: ATX = -7.3 [7.0], PBO = -3.4 [6.3]; p Conclusion Atomoxetine is an effective and generally well-tolerated treatment of ADHD in both younger and older children as assessed by three

  14. Meta-Analysis of Suicide-Related Behavior or Ideation in Child, Adolescent, and Adult Patients Treated with Atomoxetine

    Science.gov (United States)

    Wietecha, Linda A.; Wang, Shufang; Buchanan, Andrew S.; Kelsey, Douglas K.

    2014-01-01

    Abstract Objective: This meta-analysis examined suicide-related events in the acute phases of double-blind, placebo-controlled atomoxetine trials in pediatric and adult patients with attention-deficit/hyperactivity disorder (ADHD). Methods: A total of 3883 pediatric and 3365 adult patients were included. Potential events were identified from the adverse events database using a text-string search. Mantel–Haenszel risk ratios (MHRR) were calculated for potential suicide-related events categorized according to United States Food and Drug Administration defined codes. Results: In this data set, no completed suicides were reported in the pediatric or adult populations. One pediatric (attempted suicide) (and no adult patient events) was categorized as suicidal behavior in the atomoxetine group. The frequency of combined suicidal behavior or ideation with atomoxetine treatment was 0.37% in pediatric patients (vs. 0.07% with placebo) and 0.11% in adults (vs. 0.12% with placebo) and the risk compared with placebo was not statistically significant (MHRR=1.57; p=0.42 and MHRR=0.96; p=0.96, respectively). In pediatric patients, suicidal ideation only was reported more frequently compared with placebo (MHRR=1.63; p=0.41). Conclusions: Overall in this data set, no completed suicides and 1 pediatric patient suicidal behavior event were reported in atomoxetine-treated pediatric and adult patients. Suicidal ideation was uncommon among atomoxetine-treated pediatric and adult patients, although it was reported more frequently in atomoxetine-treated pediatric patients compared with placebo; the reporting rate difference was not statistically significant. The MHRR of suicidal ideation was consistent with a previous meta-analysis of similar design. There was no evidence of increased risk for suicidal behavior in atomoxetine-treated pediatric or adult patients. Clinical trial registration information: http://www.clinicaltrials.gov. The data reported are from an analysis of 23 pediatric

  15. Adverse pregnancy outcomes after exposure to methylphenidate or atomoxetine during pregnancy

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    Bro SP

    2015-01-01

    Full Text Available Søren Pauli Bro,1 Maiken Ina Siegismund Kjaersgaard,2 Erik Thorlund Parner,2 Merete Juul Sørensen,3 Jørn Olsen,4 Bodil Hammer Bech,4 Lars Henning Pedersen,4,5 Jakob Christensen,6,7 Mogens Vestergaard11Research Unit and Section for General Practice, Department of Public Health, 2Section for Biostatistics, Department of Public Health, Aarhus University, 3Regional Center for Child and Adolescent Psychiatry, Aarhus University Hospital, 4Section for Epidemiology, Department of Public Health, 5Department of Clinical Medicine – Obstetrics and Gynecology, Aarhus University, 6Department of Clinical Pharmacology, 7Department of Neurology, Aarhus University Hospital, Aarhus, DenmarkObjective: To determine if prenatal exposure to methylphenidate (MPH or atomoxetine (ATX increases the risk of adverse pregnancy outcomes in women with attention deficit/hyperactivity disorder (ADHD.Materials and methods: This was a population-based cohort study of all pregnancies in Denmark from 1997 to 2008. Information on use of ADHD medication, ADHD diagnosis, and pregnancy outcomes was obtained from nationwide registers.Results: We identified 989,932 pregnancies, in which 186 (0.02% women used MPH/ATX and 275 (0.03% women had been diagnosed with ADHD but who did not take MPH/ATX. Our reference pregnancies had no exposure to MPH/ATX and no ADHD diagnosis. Exposure to MPH/ATX was associated with an increased risk of spontaneous abortion (SA; ie, death of an embryo or fetus in the first 22 weeks of gestation (adjusted relative risk [aRR] 1.55, 95% confidence interval [CI] 1.03–2.36. The risk of SA was also increased in pregnancies where the mother had ADHD but did not use MPH/ATX (aRR 1.56, 95% CI 1.11–2.20. The aRR of Apgar scores <10 was increased among exposed women (aRR 2.06, 95% CI 1.11–3.82 but not among unexposed women with ADHD (aRR 0.99, 95% CI 0.48–2.05.Conclusion: MPH/ATX was associated with a higher risk of SA, but our study indicated that it may at

  16. Safety and tolerability of atomoxetine in treatment of attention deficit hyperactivity disorder in adult patients: an integrated analysis of 15 clinical trials.

    Science.gov (United States)

    Camporeale, Angelo; Porsdal, Vibeke; De Bruyckere, Katrien; Tanaka, Yoko; Upadhyaya, Himanshu; Deix, Claudia; Deberdt, Walter

    2015-01-01

    The safety profile of atomoxetine in the treatment of attention deficit hyperactivity disorder has been studied in many clinical trials. We performed an integrated safety analysis of 15 clinical trials in adults with attention deficit hyperactivity disorder. The analysis pooled patient data into three groups: acute placebo-controlled trials; long-term placebo-controlled trials; all trials. In total, 4829 adults (18-77 years, median: 36 years) were exposed to atomoxetine. Statistically significantly more atomoxetine-treated than placebo-treated patients experienced treatment-emergent adverse events (81.3% vs. 68.3% acute; 90.6% vs. 76.8% long term) and discontinued due to adverse events (8.9% vs. 4.0% acute; 17.9% vs. 6.3% long term). No statistically significant differences were observed in the proportion of patients experiencing serious adverse events. No previously unknown adverse events were identified. The most common adverse events included nausea, dry mouth, decreased appetite, insomnia and erectile dysfunction. Mean increases in heart rate (+5.2 beats per min) and blood pressure (systolic +2 mmHg, diastolic +1.9 mmHg) were modest. The proportion of patients experiencing clinically significant increases in blood pressure and heart rate at any time was statistically significantly higher with atomoxetine (systolic blood pressure 13-17%, diastolic blood pressure 37-40%, heart rate 42-43%) compared to placebo (systolic blood pressure 8-13%, diastolic blood pressure 29-34%, heart rate 21-26%). There was no increased risk of suicidal ideation or behaviour. Our findings confirm atomoxetine's known safety profile. From a safety perspective, atomoxetine is a useful treatment option for adults with attention deficit hyperactivity disorder. © The Author(s) 2014.

  17. Performance on a strategy set shifting task during adolescence in a genetic model of attention deficit/hyperactivity disorder: Methylphenidate vs. atomoxetine treatments

    Science.gov (United States)

    Harvey, Roxann C; Jordan, Chloe J; Tassin, David H; Moody, Kayla R; Dwoskin, Linda P; Kantak, Kathleen M

    2013-01-01

    Research examining medication effects on set shifting in teens with attention deficit/hyperactivity disorder (ADHD) is lacking. An animal model of ADHD may be useful for exploring this gap. The Spontaneously Hypertensive Rat (SHR) is a commonly used animal model of ADHD. SHR and two comparator strains, Wistar-Kyoto (WKY) and Wistar (WIS), were evaluated during adolescence in a strategy set shifting task under conditions of a 0-sec or 15-sec delay to reinforcer delivery. The task had three phases: initial discrimination, set shift and reversal learning. Under 0-sec delays, SHR performed as well as or better than WKY and WIS. Treatment with 0.3 mg/kg/day atomoxetine had little effect, other than to modestly increase trials to criterion during set shifting in all strains. Under 15-sec delays, SHR had longer lever press reaction times, longer latencies to criterion and more trial omissions than WKY during set shifting and reversal learning. These deficits were not reduced systematically by 1.5 mg/kg/day methylphenidate or 0.3 mg/kg/day atomoxetine. Regarding learning in SHR, methylphenidate improved initial discrimination, whereas atomoxetine improved set shifting but disrupted initial discrimination. During reversal learning, both drugs were ineffective in SHR, and atomoxetine made reaction time and trial omissions greater in WKY. Overall, WIS performance differed from SHR or WKY, depending on phase. Collectively, a genetic model of ADHD in adolescent rats revealed that neither methylphenidate nor atomoxetine mitigated all deficits in SHR during the set shifting task. Thus, methylphenidate or atomoxetine monotherapy may not mitigate all set shift task-related deficits in teens with ADHD. PMID:23376704

  18. Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Hanwella Raveen

    2011-11-01

    Full Text Available Abstract Background Psychostimulants and non stimulants are effective in the treatment of ADHD. Efficacy of both methylphenidate and atomoxetine has been established in placebo controlled trials. Direct comparison of efficacy is now possible due to availability of results from several head-to-head trials of these two medications. Methods All published, randomized, open label or double blind trials, comparing efficacy of methylphenidate with atomoxetine, in treatment of ADHD in children, diagnosed using DSM-IV™ criteria were included. The outcome studied was ADHDRS-IVParent:Inv score. The standardized mean difference (SMD was used as a measure of effect size. Results Nine randomized trials comparing methylphenidate and atomoxetine, with a total of 2762 participants were included. Meta-analysis did not find a significant difference in efficacy between methylphenidate and atomoxetine (SMD = 0.09, 95% CI -0.08-0.26 (Z = 1.06, p = 0.29. Synthesis of data from eight trials found no significant difference in response rates (RR = 0.93 95% CI 0.76-1.14, p = 0.49. Sub group analysis showed a significant standardized mean difference favouring OROS methylphenidate (SMD = 0.32, 95% CI 0.12-0.53 (Z = 3.05, p I2 = 67%. Subgroup analysis demonstrated the heterogeneity to be due to the open label trials (p = 0.001, I2 = 81%. Conclusions In general atomoxetine and methylphenidate have comparable efficacy and equal acceptability in treatment of ADHD in children and adolescents. However OROS methylphenidate is more effective than atomoxetine and may be considered as first line treatment in treatment of ADHD in children and adolescents.

  19. A modelled economic evaluation comparing atomoxetine with methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder in Spain

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    Dilla Tatiana

    2009-04-01

    Full Text Available Abstract Background Attention Deficit/Hyperactivity Disorder (ADHD is a neurobehavioural disorder, affecting 3–6% of school age children and adolescents in Spain. Methylphenidate (MPH, a mild stimulant, had long been the only approved medication available for ADHD children in Spain. Atomoxetine is a non-stimulant alternative in the treatment of ADHD with once-a-day oral dosing. This study aims to estimate the cost-effectiveness of atomoxetine compared to MPH. In addition, atomoxetine is compared to 'no medication' for patient populations who are ineligible for MPH (i.e. having stimulant-failure experience or co-morbidities precluding stimulant medication. Methods An economic model with Markov processes was developed to estimate the costs and benefits of atomoxetine versus either MPH or 'no medication'. The incremental cost per quality-adjusted life-year (QALY was calculated for atomoxetine relative to the comparators. The Markov process incorporated 14 health states, representing a range of outcomes associated with treatment options. Utility values were obtained from the utility valuation survey of 83 parents of children with ADHD. The clinical data were based on a thorough review of controlled clinical trials and other clinical literature, and validated by international experts. Costs and outcomes were estimated using Monte Carlo simulation over a 1-year duration, with costs estimated from the perspective of the National Health Service in Spain. Results For stimulant-naïve patients without contra-indications to stimulants, the incremental costs per QALY gained for atomoxetine were € 34 308 (compared to an immediate-release MPH and € 24 310 (compared to an extended-release MPH. For those patients who have stimulant-failure experience or contra-indications to stimulants, the incremental costs per QALY gained of atomoxetine compared to 'no medication' were € 23 820 and € 23 323, respectively. Conclusion The economic evaluation showed

  20. Acute neuropharmacological effects of atomoxetine on inhibitory control in ADHD children: A fNIRS study

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    Masako Nagashima

    2014-01-01

    Full Text Available The object of the current study is to explore the neural substrate for effects of atomoxetine (ATX on inhibitory control in school-aged children with attention deficit hyperactivity disorder (ADHD using functional near-infrared spectroscopy (fNIRS. We monitored the oxy-hemoglobin signal changes of sixteen ADHD children (6–14 years old performing a go/no-go task before and 1.5 h after ATX or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design. Sixteen age- and gender-matched normal controls without ATX administration were also monitored. In the control subjects, the go/no-go task recruited the right inferior and middle prefrontal gyri (IFG/MFG, and this activation was absent in pre-medicated ADHD children. The reduction of right IFG/MFG activation was acutely normalized after ATX administration but not placebo administration in ADHD children. These results are reminiscent of the neuropharmacological effects of methylphenidate to up-regulate reduced right IFG/MFG function in ADHD children during inhibitory tasks. As with methylphenidate, activation in the IFG/MFG could serve as an objective neuro-functional biomarker to indicate the effects of ATX on inhibitory control in ADHD children. This promising technique will enhance early clinical diagnosis and treatment of ADHD in children, especially in those with a hyperactivity/impulsivity phenotype.

  1. Multi-spectroscopic characterization of bovine serum albumin upon interaction with atomoxetine

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    Arunkumar T. Buddanavar

    2017-06-01

    Full Text Available The quenching interaction of atomoxetine (ATX with bovine serum albumin (BSA was studied in vitro under optimal physiological condition (pH=7.4 by multi-spectroscopic techniques. The mechanism of ATX-BSA system was a dynamic quenching process and was confirmed by the fluorescence spectra and lifetime measurements. The number of binding sites, binding constants and other binding characteristics were computed. Thermodynamic parameters ∆H° and ∆S° indicated that intermolecular hydrophobic forces predominantly stabilized the drug-protein system. The average binding distance between BSA and ATX was studied by Försters theory. UV-absorption, Fourier transform infrared spectroscopy (FT-IR, circular dichroism (CD, synchronous spectra and three-dimensional (3D fluorescence spectral results revealed the changes in micro-environment of secondary structure of protein upon the interaction with ATX. Displacement of site probes and the effects of some common metal ions on the binding of ATX with BSA interaction were also studied.

  2. Effectiveness of atomoxetine and methylphenidate for problematic online gaming in adolescents with attention deficit hyperactivity disorder.

    Science.gov (United States)

    Park, Jeong Ha; Lee, Young Sik; Sohn, Ji Hyun; Han, Doug Hyun

    2016-11-01

    There is a high prevalence of problematic online gaming in adolescents with attention deficit hyperactivity disorder (ADHD). In the current study, we compared the effectiveness of atomoxetine (ATM) and methylphenidate (MPH) on problematic online gaming in adolescents with ADHD. We recruited 86 adolescents diagnosed with ADHD together with Internet gaming disorder. These participants were divided into two treatment groups: 44 participants were treated with MPH for 12 weeks, and 42 participants were treated with ATM for 12 weeks. During the 3-month study period, the MPH group showed greater improvement in Korean ADHD rating scale scores than the ATM group. The ATM group showed greater improvement in Child Depression Inventory scores than the MPH group. However, Young Internet Addiction Scale and Behavioral Inhibition & Activation Scales score changes did not differ significantly between the MPH and ATM groups. In both groups, changes in Young Internet Addiction Scale scores were positively correlated with the changes in Behavioral Inhibition & Activation Scales scores. Both MPH and ATM reduced the severity of Internet gaming disorder symptoms, and this reduction was correlated with impulsivity reduction, which also resulted from both ADHD medications. These findings suggest impulsivity plays a critical role in the development of problematic online gaming. Copyright © 2016 John Wiley & Sons, Ltd.

  3. Tic Symptoms Induced by Atomoxetine in Treatment of ADHD: A Case Report and Literature Review.

    Science.gov (United States)

    Yang, Rongwang; Li, Rong; Gao, Weijia; Zhao, Zhengyan

    Patients with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for tic disorders. Atomoxetine (ATX) has been accepted as an alternative medication for patients with ADHD and a comorbid tic disorder. It is rarely reported that tic symptoms are induced by ATX. This present report described a boy with ADHD who developed tic symptoms during ATX initiation. We used an ABAB trial to confirm the tics were related to ATX administration. In addition, we reviewed the published literature of patients whose tic symptoms were confirmed or suspected of relating to ATX usage. This present case with an ABAB design showed on-off control of tics with or without ATX, which allowed us to make a strong conclusion that the tics were related to ATX administration. Literature review also indicated that ATX might induce tic symptoms in children with ADHD, especially in those being boys and having a history of tics. The time from starting ATX to tics symptoms appearing was approximately 19 days. The most common tic symptoms were eye blinking, vocal tics, or throat clearing, and neck movements. These tics symptoms in most cases could be resolved after discontinuing ATX without further pharmacotherapy. Pediatricians and child psychiatrists should be well aware of this potential adverse effect in children with ADHD receiving ATX.

  4. An improved automated synthesis and in vivo evaluation of PET radioligand for serotonin re-uptake sites. [11C]McN5652X

    International Nuclear Information System (INIS)

    Sasaki, Masahiro; Suhara, Tetsuya; Suzuki, Kazutoshi; Kubodera, Akiko.

    1996-01-01

    Carbon-11 labeled serotonin (5-HT) re-uptake inhibitor, [ 11 C]McN5 652X ((6S,10bR)-trans-( + )-1,2,3,5,6,10b-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline), has recently been reported to be favorable for studying human 5-HT re-uptake site by positron emission tomography (PET) because of its rapid and high specific binding characteristics as radioligands. [ 11 C]McN5652X has been synthesized by S-methylation of the corresponding des-methyl precursor A with [ 11 C]iodomethane. One serious disadvantage of this procedure, however, is the lack of stability of A. The improved method for the synthesis of A has been desired. We have found that the decomposition of A is significantly reduced by adding a protecting agent for SH groups, dithiothreitol (DTT), into the reaction medium immediately after the demethylation of McN5652X. By using this stabilized precursor A, we have developed an automated procedure giving [ 11 C]McN5652X with 98.6±0.4% radiochemical purity in high specific activity (181.3±7.4GBq/μmol). Preclinical evaluation of the produ ct was carried out by injecting the solution of [ 11 C]McN5652X obtained by this procedure into mice. [ 11 C]McN5652X showed the high accumulation into mouse thalamus, striatum and cerebral cortex, organs known to have high level of 5-HT receptor density, after intravenous injection. Human PET studies also showed the high uptakes of this radioligand into the thalamus, striatum and midbrain

  5. The effects of atomoxetine on emotional control in adults with ADHD: An integrated analysis of multicenter studies.

    Science.gov (United States)

    Asherson, P; Stes, S; Nilsson Markhed, M; Berggren, L; Svanborg, P; Kutzelnigg, A; Deberdt, W

    2015-06-01

    To investigate the effects of atomoxetine on emotional control in adults with ADHD. We performed an integrated analysis using individual patient data pooled from three Eli Lilly-sponsored studies. An integrated analysis can be viewed as a meta-analysis of individual patient-level data, rather than study-level summary data. Two populations were identified: a large sample of patients with pre-treatment baseline data (the "overall population"; n=2846); and a subset of these patients with placebo-controlled efficacy data from baseline to 10 or 12 weeks after initiating treatment (the "placebo-controlled population"; n=829). At baseline, in the overall population, ∼50% of ADHD patients had BRIEF-AS (Behavior Rating Inventory of Executive Function-Adult Version Self-Report) Emotional control subscores between 21 and 30, compared with ∼10% of normative subjects in the BRIEF-A manual. At endpoint, in the placebo-controlled population, atomoxetine led to a small (effect size 0.19) but significant (P=0.013) treatment effect for emotional control. The effect size was 0.32 in patients with BRIEF-AS Emotional control scores>20 at baseline. Improvements in emotional control correlated with improvements in the core ADHD symptoms and quality-of-life. As deficient emotional control is associated with impaired social, educational and occupational functioning over and above that explained by core ADHD symptoms alone, improvements in emotional control may be clinically relevant. At baseline, adults with ADHD were more likely to have impaired emotional control than normative subjects. In the adult ADHD patients, atomoxetine treatment was associated with improvements in emotional control, as well as in core ADHD symptoms and quality-of-life. Copyright © 2015. Published by Elsevier Masson SAS.

  6. Effects of stimulants and atomoxetine on emotional lability in adults: A systematic review and meta-analysis.

    Science.gov (United States)

    Moukhtarian, T R; Cooper, R E; Vassos, E; Moran, P; Asherson, P

    2017-07-01

    Emotional lability (EL) is an associated feature of attention-deficit/hyperactivity disorder (ADHD) in adults, contributing to functional impairment. Yet the effect of pharmacological treatments for ADHD on EL symptoms is unknown. We conducted a systematic review and meta-analysis to examine the effects of stimulants and atomoxetine on symptoms of EL and compare these with the effects on core ADHD symptoms. A systematic search was conducted on the databases Embase, PsychInfo, and Ovid Medline ® and the clinicaltrials.gov website. We included randomised, double-blind, placebo-controlled trials of stimulants and atomoxetine in adults aged 18-60 years, with any mental health diagnosis characterised by emotional or mood instability, with at least one outcome measure of EL. All identified trials were on adults with ADHD. A random-effects meta-analysis with standardised mean difference and 95% confidence intervals was used to investigate the effect size on EL and compare this to the effect on core ADHD symptoms. Of the 3,864 publications identified, nine trials met the inclusion criteria for the meta-analysis. Stimulants and atomoxetine led to large mean weighted effect-sizes for on ADHD symptoms (n=9, SMD=-0.8, 95% CI:-1.07 to -0.53). EL outcomes showed more moderate but definite effects (n=9, SMD=-0.41, 95% CI:-0.57 to -0.25). In this meta-analysis, stimulants and atomoxetine were moderately effective for EL symptoms, while effect size on core ADHD symptoms was twice as large. Methodological issues may partially explain the difference in effect size. Reduced average effect size could also reflect heterogeneity of EL with ADHD pharmacotherapy responsive and non-responsive sub-types. Our findings indicate that EL may be less responsive than ADHD symptoms overall, perhaps indicating the need for adjunctive psychotherapy in some cases. To clarify these questions, our findings need replication in studies selecting subjects for high EL and targeting EL as the primary

  7. Long-Term Treatment with Atomoxetine for Attention-Deficit/Hyperactivity Disorder Symptoms in Children and Adolescents with Autism Spectrum Disorder : An Open-Label Extension Study

    NARCIS (Netherlands)

    Harfterkamp, Myriam; Buitelaar, Jan K.; Minderaa, Ruud B.; van de Loo-Neus, Gigi; van der Gaag, Rutger-Jan; Hoekstra, Pieter J.

    Objective: The efficacy and tolerability of long-term treatment with atomoxetine for symptoms of attention-deficit/hyperactivity disorder (ADHD) in children with autism spectrum disorder (ASD) has not been established. Methods: In this study, 88 patients 6-17 years of age, with ADHD and ASD, were

  8. A randomized double-blind study of atomoxetine versus placebo for attention-deficit/hyperactivity disorder symptoms in children with autism spectrum disorder.

    NARCIS (Netherlands)

    Harfterkamp, M.; Loo-Neus, G. van de; Minderaa, R.B.; Gaag, R.J. van der; Escobar, R.; Schacht, A.; Pamulapati, S.; Buitelaar, J.K.; Hoekstra, P.J.

    2012-01-01

    OBJECTIVE: The efficacy of atomoxetine as treatment of symptoms of attention-deficit/hyperactivity disorder (ADHD) in patients with autism spectrum disorder (ASD) has not been established. METHOD: In this study, 97 patients aged 6 to 17 years with ADHD and ASD were randomly assigned to double-blind

  9. A Randomized Double-Blind Study of Atomoxetine Versus Placebo for Attention-Deficit/Hyperactivity Disorder Symptoms in Children With Autism Spectrum Disorder

    NARCIS (Netherlands)

    Harfterkamp, Myriam; van de Loo-Neus, Gigi; Minderaa, Ruud B.; van der Gaag, Rutger-Jan; Escobar, Rodrigo; Schacht, Alexander; Pamulapati, Sireesha; Buitelaar, Jan K.; Hoekstra, Pieter J.

    Objective: The efficacy of atomoxetine as treatment of symptoms of attention-deficit/hyperactivity disorder (ADHD) in patients with autism spectrum disorder (ASD) has not been established. Method: In this study, 97 patients aged 6 to 17 years with ADHD and ASD were randomly assigned to double-blind

  10. Saturated norepinephrine transporter occupancy by atomoxetine relevant to clinical doses: a rhesus monkey study with (S,S)-[{sup 18}F]FMeNER-D{sub 2}

    Energy Technology Data Exchange (ETDEWEB)

    Takano, Akihiro; Gulyas, Balazs; Varrone, Andrea; Halldin, Christer [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Stockholm (Sweden); Maguire, Ralph Paul [Pfizer Global Research and Development, New London, CT (United States); Novartis Institutes for BioMedical Research, Basel (Switzerland)

    2009-08-15

    In a previous PET study on norepinephrine transporter (NET) occupancy in the nonhuman primate brain, the relationship between NET occupancy and atomoxetine plasma concentration, and occupancies among different brain regions, were not demonstrated adequately. It may therefore be difficult to translate the results to the clinical situations. In the present study, the detailed change of NET occupancy was investigated among a wider range of doses in a more advanced manner. Two rhesus monkeys were examined using a high-resolution PET system with (S,S)-[{sup 18}F]FMeNER-D{sub 2} under baseline conditions and after steady-state infusion of different doses of atomoxetine (0.003 to 0.12 mg/kg per hour). NET occupancy of the thalamus, brainstem and anterior cingulate cortex was calculated using BP{sub ND} obtained with the simplified reference tissue model. NET occupancy increased regionally and uniformly as the plasma concentration of atomoxetine increased. The estimated Kd value (the amount to occupy 50% of NET) in the thalamus was 16 ng/ml. The results indicate that clinical doses of atomoxetine would occupy NET almost completely. (orig.)

  11. Efficacy of Atomoxetine for the Treatment of ADHD Symptoms in Patients with Pervasive Developmental Disorders: A Prospective, Open-Label Study

    Science.gov (United States)

    Fernandez-Jaen, Alberto; Fernandez-Mayoralas, Daniel Martin; Calleja-Perez, Beatriz; Munoz-Jareno, Nuria; Campos Diaz, Maria del Rosario; Lopez-Arribas, Sonia

    2013-01-01

    Objective: Atomoxetine's tolerance and efficacy were studied in 24 patients with pervasive developmental disorder and symptoms of ADHD. Method: Prospective, open-label, 16-week study was performed, using the variables of the Clinical Global Impression Scale and the Conners' Scale, among others. Results: A significant difference was found between…

  12. Comparison of Symptomatic versus Functional Changes in Children and Adolescents with ADHD during Randomized, Double-Blind Treatment with Psychostimulants, Atomoxetine, or Placebo

    Science.gov (United States)

    Buitelaar, Jan K.; Wilens, Timothy E.; Zhang, Shuyu; Ning, Yu; Feldman, Peter D.

    2009-01-01

    Background: This meta-analysis was designed to determine the relationship between reduction of attention-deficit/hyperactivity disorder (ADHD) symptoms and improvement in functioning by examining short-term changes in functional and symptomatic scores in children and adolescents with ADHD. Methods: Search of atomoxetine's clinical trial database…

  13. Saturated norepinephrine transporter occupancy by atomoxetine relevant to clinical doses: a rhesus monkey study with (S,S)-[18F]FMeNER-D2

    International Nuclear Information System (INIS)

    Takano, Akihiro; Gulyas, Balazs; Varrone, Andrea; Halldin, Christer; Maguire, Ralph Paul

    2009-01-01

    In a previous PET study on norepinephrine transporter (NET) occupancy in the nonhuman primate brain, the relationship between NET occupancy and atomoxetine plasma concentration, and occupancies among different brain regions, were not demonstrated adequately. It may therefore be difficult to translate the results to the clinical situations. In the present study, the detailed change of NET occupancy was investigated among a wider range of doses in a more advanced manner. Two rhesus monkeys were examined using a high-resolution PET system with (S,S)-[ 18 F]FMeNER-D 2 under baseline conditions and after steady-state infusion of different doses of atomoxetine (0.003 to 0.12 mg/kg per hour). NET occupancy of the thalamus, brainstem and anterior cingulate cortex was calculated using BP ND obtained with the simplified reference tissue model. NET occupancy increased regionally and uniformly as the plasma concentration of atomoxetine increased. The estimated Kd value (the amount to occupy 50% of NET) in the thalamus was 16 ng/ml. The results indicate that clinical doses of atomoxetine would occupy NET almost completely. (orig.)

  14. Atomoxetine in autism spectrum disorder: no effects on social functioning; some beneficial effects on stereotyped behaviors, inappropriate speech, and fear of change

    NARCIS (Netherlands)

    Harfterkamp, M.; Buitelaar, J.K.; Minderaa, R.B.; Loo-Neus, G. van de; Gaag, R.J. van der; Hoekstra, P.J.

    2014-01-01

    Abstract Objective: The objective of this study was to investigate the short-term treatment effects of atomoxetine on autism spectrum disorder (ASD) symptoms in children and adolescents with both ASD and attention-deficit/hyperactivity disorder (ADHD). METHODS: A total of 97 patients 6-17 years of

  15. Atomoxetine in Autism Spectrum Disorder : No Effects on Social Functioning; Some Beneficial Effects on Stereotyped Behaviors, Inappropriate Speech, and Fear of Change

    NARCIS (Netherlands)

    Harfterkamp, Myriam; Buitelaar, Jan K.; Minderaa, Ruud B.; van de Loo-Neus, Gigi; van der Gaag, Rutger-Jan; Hoekstra, Pieter J.

    2014-01-01

    Objective: The objective of this study was to investigate the short-term treatment effects of atomoxetine on autism spectrum disorder (ASD) symptoms in children and adolescents with both ASD and attention-deficit/hyperactivity disorder (ADHD). Methods: A total of 97 patients 6-17 years of age, with

  16. Long-Term, Open-Label Safety and Efficacy of Atomoxetine in Adults with ADHD: Final Report of a 4-Year Study

    Science.gov (United States)

    Adler, Lenard A.; Spencer, Thomas J.; Williams, David W.; Moore, Rodney J.; Michelson, David

    2008-01-01

    Objective: Previously, data from 97 weeks of open-label atomoxetine treatment of adults with attention-deficit/hyperactivity disorder (ADHD) were reported. This final report of that study presents results from over 4 years of treatment. Method: Results were derived from the study of 384 patients (125 patients remaining in the open-label trial…

  17. A review of the efficacy of atomoxetine in the treatment of attention-deficit hyperactivity disorder in children and adult patients with common comorbidities

    Directory of Open Access Journals (Sweden)

    Clemow DB

    2017-02-01

    Full Text Available David B Clemow,1 Chris Bushe,2 Michele Mancini,3 Michael H Ossipov,4 Himanshu Upadhyaya1 1Eli Lilly and Company, Indianapolis, IN, USA; 2Eli Lilly, Windlesham, UK; 3Eli Lilly Italia S.p.A., Sesto Fiorentino, Italy; 4inVentiv Health Clinical, LLC, Blue Bell, PA, USA Abstract: Attention-deficit hyperactivity disorder (ADHD is a common neuropsychiatric disorder that is often diagnosed during childhood, but has also increasingly been recognized to occur in adults. Importantly, up to 52% of children (including adolescents and 87% of adults with ADHD also have a comorbid psychiatric disorder. The presence of a comorbid disorder has the potential to impact diagnosis and could affect treatment outcomes. Atomoxetine is a nonstimulant treatment for ADHD. Despite numerous published studies regarding efficacy of atomoxetine in the treatment of ADHD in patients with comorbid disorders, there is limited information about the impact of individual common comorbid disorders on the efficacy of atomoxetine for ADHD, especially with regard to adults. Moreover, a cumulative review and assessment of these studies has not been conducted. For this reason, we performed a literature review to find, identify, and cumulatively review clinical studies that examined the efficacy of atomoxetine in the treatment of patients with ADHD and comorbid psychiatric disorders. We found a total of 50 clinical studies (37 in children; 13 in adults that examined the efficacy of atomoxetine in patients with ADHD and a comorbid disorder. The comorbidities that were studied in children or in adults included anxiety, depression, and substance use disorder. Overall, the presence of comorbidity did not adversely impact the efficacy of atomoxetine in treatment of ADHD symptoms in both patient populations. In the studies identified and assessed in this review, atomoxetine did not appear to exacerbate any of the comorbid conditions and could, therefore, be an important therapy choice for the

  18. Atomoxetine hydrochloride in the treatment of children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: A placebo-controlled Italian study.

    Science.gov (United States)

    Dell'Agnello, Grazia; Maschietto, Dino; Bravaccio, Carmela; Calamoneri, Filippo; Masi, Gabriele; Curatolo, Paolo; Besana, Dante; Mancini, Francesca; Rossi, Andrea; Poole, Lynne; Escobar, Rodrigo; Zuddas, Alessandro

    2009-11-01

    The primary aim of this study was to assess the efficacy of atomoxetine in improving ADHD and ODD symptoms in paediatric patients with ADHD and comorbid oppositional defiant disorder (ODD), non-responders to previous psychological intervention with parent support. This was a multicentre, randomised, placebo-controlled trial conducted in patients aged 6-15 years, with ADHD and ODD diagnosed according to the DSM-IV criteria by a structured clinical interview (K-SADS-PL). Only subjects who are non-responders to a 6-week standardized parent training were randomised to atomoxetine (up to 1.2 mg/kg/day) or placebo (in a 3:1 ratio) for the following 8-week double blind phase. Only 2 of the 156 patients enrolled for the parent support phase (92.9% of males; mean age: 9.9 years), improved after the parent training program; 139 patients were randomised for entering in the study and 137 were eligible for efficacy analysis. At the end of the randomised double blind phase, the mean changes in the Swanson, Nolan and Pelham Rating Scale-Revised (SNAP-IV) ADHD subscale were -8.1+/-9.2 and -2.0+/-4.7, respectively in the atomoxetine and in the placebo group (patomoxetine group (median change at endpoint: -1.0) compared to no changes in the placebo group (patomoxetine, were found in the CHIP-CE scores for risk avoidance domain, emotional comfort and individual risk avoidance subdomains. An improvement in all the subscales of Conners Parents (CPRS-R:S) and Teacher (CTRS-R:S) subscales was observed with atomoxetine, except in the cognitive problems subscale in the CTRS-R:S. Only 3 patients treated with atomoxetine discontinued the study due to adverse events. No clinically significant changes of body weight, height and vital signs were observed in both groups. Treatment with atomoxetine of children and adolescents with ADHD and ODD, who did not initially respond to parental support, was associated with improvements in symptoms of ADHD and ODD, and general health status. Atomoxetine

  19. Use of atomoxetine and suicidal ideation in children and adolescents: Results of an observational cohort study within general practice in England.

    Science.gov (United States)

    Davies, M; Coughtrie, A; Layton, D; Shakir, S A S

    2017-01-01

    To investigate the association between atomoxetine, a drug used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and suicidal ideation, within a cohort of 2-18-year-old patients in England. The study was conducted using the observational cohort technique of Modified prescription event monitoring (M-PEM). Patients prescribed atomoxetine were identified from dispensed prescriptions issued by primary care physicians. A customised postal GP questionnaire was used to capture outcome data for suicidal ideation. A matched pair cohort analysis was performed within patients to compare the risk of suicidal ideation in the period after starting atomoxetine with the risk prior to starting atomoxetine; this was stratified by age and concomitant use of methylphenidate. Additional information on patient characteristics, and events of interest was also collected; individual cases of suicidal ideation were qualitatively assessed for drug relatedness. Of the final cohort (n=4509); 85.5% male (n=3857), median age 11 years (IQR: 9,14). Primary prescribing indication for atomoxetine was ADHD (n=4261, 94.6%). Almost a quarter of the cohort had been co-prescribed methylphenidate. Results of the matched pair cohort analysis indicated that the period after starting atomoxetine was not associated with an increase in the incidence of suicidal ideation compared to the period prior to starting treatment (RR: 0.71; CI: 0.48-1.07; P-value: 0.104). Individual case assessment of suicidal ideation suggested a causal association within a number of cases. This study found no evidence of an increased risk of suicidal ideation during treatment with atomoxetine, compared to the period prior to starting treatment. Amongst age specific subgroups, this risk may change. Nonetheless, individual case assessment suggested a causal relationship in some patients, hence physicians need to be aware of the possibility of developing this event, and furthermore consider how best to detect it in

  20. Two-week administration of the combined serotonin-noradrenaline reuptake inhibitor duloxetine augments functioning of mesolimbic incentive processing circuits

    NARCIS (Netherlands)

    Ossewaarde, Lindsey; Verkes, Robbert J.; Hermans, Erno J.; Kooijman, Sabine C.; Urner, Maren; Tendolkar, Indira; van Wingen, Guido A.; Fernández, Guillén

    2011-01-01

    Anhedonia and lack of motivation are core symptoms of major depressive disorder (MDD). Neuroimaging studies in MDD patients have shown reductions in reward-related activity in terminal regions of the mesolimbic dopamine (DA) system, such as the ventral striatum. Monoamines have been implicated in

  1. Two-week administration of the combined serotonin-noradrenaline reuptake inhibitor duloxetine augments functioning of mesolimbic incentive processing circuits

    NARCIS (Netherlands)

    Ossewaarde, L.; Verkes, R.J.; Hermans, E.J.; Kooijman, S.C.; Urner, M.; Tendolkar, I.; Wingen, G.A. van; Fernandez, G.S.E.

    2011-01-01

    BACKGROUND: Anhedonia and lack of motivation are core symptoms of major depressive disorder (MDD). Neuroimaging studies in MDD patients have shown reductions in reward-related activity in terminal regions of the mesolimbic dopamine (DA) system, such as the ventral striatum. Monoamines have been

  2. A randomised trial of the effect of the glycine reuptake inhibitor Org 25935 on cognitive performance in healthy male volunteers.

    Science.gov (United States)

    Christmas, David; Diaper, Alison; Wilson, Sue; Rich, Ann; Phillips, Suzanne; Udo de Haes, Joanna; Sjogren, Magnus; Nutt, David

    2014-03-01

    Cognitive impairment is integral to many neurological illnesses. Specific enhancement of glutamatergic transmission may improve memory and learning. Org 25935 increases the synaptic availability of glycine, an obligate co-agonist with glutamate at N-methyl-D-aspartate receptors. We hypothesised that Org 25935 would acutely improve the learning and memory of healthy volunteers. A randomised, double-blind, parallel-group, single-dose study of Org 25935 and placebo was carried out. Thirty-two healthy male volunteers took either 12-mg Org 25935 or matching placebo and were later assessed with the manikin task, digit span and verbal memory tests. Systematic assessments of cardiovascular and adverse events were also taken. There was no effect of Org 25935 on reaction time, number of correct responses or learning (greater or slower improvement over successive tasks) compared with placebo. Org 25935 caused significantly more dizziness and drowsiness compared with placebo; these side effects were mainly mild. A single dose of Org 25935 does not improve learning or memory in healthy male individuals. However, the drug was well tolerated, and it remains to be seen whether it would have a positive effect on cognition in patient groups with pre-existing cognitive deficits.

  3. Premature Ejaculation, Selective Serotonin Reuptake Inhibitor (ssri) Induced Delayed Ejaculation In The Framework Of The Emotional Motor System

    NARCIS (Netherlands)

    Waldinger, Marcel D; Berendsen, Hemmie H.G.; Blok, Bertil F.M.; Olivier, Berend; Holstege, Gert

    1998-01-01

    Premature ejaculation has generally been considered a psychosexual disorder with psychogenic aetiology. Although still mainly treated by behavioural therapy, in recent years double-blind studies have indicated the beneficial effects of some of the serotonergic anti depressants (SSRIs) in delaying

  4. An analysis of psychotropic drug sales. Increasing sales of selective serotonin reuptake inhibitors anre closely related to number of products

    DEFF Research Database (Denmark)

    Nielsen, Margrethe; Gøtzsche, Peter C.

    2011-01-01

    used data from various sources to establish the sales curves of psychotropic drugs in the period 1970 to 2007, based on the Anatomic Therapeutic Classification system and Defined Daily Doses. RESULTS: Fluctuations in sales of psychotropic drugs that cannot be explained by disease prevalence were caused...

  5. Prediction of clinical response based on pharmacokinetic/pharmacodynamic models of 5-hydroxytryptamine reuptake inhibitors in mice

    DEFF Research Database (Denmark)

    Kreilgaard, Mads; Smith, D. G.; Brennum, L. T.

    2008-01-01

    Bridging the gap between preclinical research and clinical trials is vital for drug development. Predicting clinically relevant steady-state drug concentrations (Css) in serum from preclinical animal models may facilitate this transition. Here we used a pharmacokinetic/pharmacodynamic (PK...

  6. Selective Serotonergic (SSRI) Versus Noradrenergic (SNRI) Reuptake Inhibitors with and without Acetylsalicylic Acid in Major Depressive Disorder.

    Science.gov (United States)

    Zdanowicz, Nicolas; Reynaert, Christine; Jacques, Denis; Lepiece, Brice; Dubois, Thomas

    2017-09-01

    Antidepressant medication efficacy remains a major research challenge. Here, we explored four questions: whether noradrenergic antidepressants are more effective than serotonergic antidepressants; whether the addition of 100 mg acetylsalicylic acid (ASA) changes antidepressant efficacy; whether the long-term efficacy differs depending on the antidepressant and the addition of ASA; and whether serum levels of brain-derived neurotrophic factor (BDNF) are clinically informative. In a two-year study, forty people with major depressive disorder were randomly assigned to groups that received an SSRI (escitalopram) or an SNRI (duloxetine), each group received concomitant ASA (100 mg) or a placebo. Sociodemographic data were recorded and patients under went regular assessments with the Hamilton depression scale (HDS) and clinical global impression (CGI) scale. Serum levels of BDNF were measured four times per year. There was no significant difference in efficacy between the two antidepressants or between antidepressant treatment with and without ASA. However, subgroup comparisons revealed that the duloxetine + ASA (DASA) subgroup showed a more rapid improvement in HDS score as early as 2 months (t=-3.114, p=0.01), in CGI score at 5 months (t=-2.119, p=0.05), and a better remission rate (χ 2 =6.296, p 0.012) than the escitalopram + placebo (EP) subgroup. Serum BDNF before treatment was also higher in the DASA subgroup than in the EP subgroup (t=3.713; p=0.002). This suggest two hypotheses: either a noradrenergic agent combined with ASA is more effective in treating depression than a serotonergic agent alone, or the level of serum BDNF before treatment is a precursor marker of the response to antidepressants. Further research is needed to test these hypotheses.

  7. Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine.

    Science.gov (United States)

    Swalve, Natashia; Smethells, John R; Zlebnik, Natalie E; Carroll, Marilyn E

    2016-06-01

    Two repurposed medications have been proposed to treat cocaine abuse. Progesterone, a gonadal hormone, and atomoxetine, a medication commonly used to treat attention deficit/hyperactivity disorder, have both been separately shown to reduce cocaine self-administration and reinstatement (i.e., relapse). The goal of the present study was to examine sex differences in the individual effects of PRO and ATO as well as the combination PRO+ATO treatment on cocaine (COC), caffeine (CAF), and/or cue-primed reinstatement of cocaine-seeking. Adult male and female Wistar rats lever-pressed under a FR 1 schedule for cocaine infusions (0.4mg/kg/inf). After 14 sessions of stable responding in daily 2-h sessions, rats underwent a 21-day extinction period when no drug or drug-related stimuli were present. Rats were then separated into four groups that received PRO (0.5mg/kg) alone (PRO+SAL), ATO (1.5mg/kg) alone (VEH+ATO), control (VEH+SAL) or combination (PRO+ATO) treatments prior to the reinstatement condition. Reinstatement of cocaine-seeking to cues and/or drug injections of cocaine or caffeine was tested after extinction. During maintenance, females self-administered more cocaine than males, but no sex differences were seen during extinction. Females showed greater cocaine-seeking than males after a CAF priming injection. Individual treatment with ATO did not decrease reinstatement under any priming condition; however, the combination treatment decreased cocaine-seeking under the COC+CUES priming condition in males, and both PRO alone and the combination treatment decreased cocaine-seeking in the CAF+CUES condition in females. Overall, PRO alone was only effective in reducing reinstatement in females, while the combination treatment was consistently effective in reducing reinstatement in both sexes. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Driving performance in adults with ADHD: results from a randomized, waiting list controlled trial with atomoxetine.

    Science.gov (United States)

    Sobanski, E; Sabljic, D; Alm, B; Dittmann, R W; Wehmeier, P M; Skopp, G; Strohbeck-Kühner, P

    2013-08-01

    To investigate effects of a 12-week treatment with atomoxetine (ATX) on driving performance in real traffic, driving-related neuropsychological performance tests and self-evaluation of driving in adult patients with ADHD compared to an untreated control group with ADHD. Parallel group design with an ATX and a waiting list group. At baseline and endpoint patients were evaluated with a standardized on-road driving test (SDBO), a driving-related neuropsychological test battery (Act and React Test System [ART2020]), and subjective measures of driving performance (one-week driving diary, Driver Coping Questionnaire). Forty-three of the 64 included patients completed the study (n=22 ATX, n=21 controls). Mean intervention period was 11.9±3.0 weeks, mean daily ATX dosage was 71.6±14.9mg. At endpoint, 60.1% of patients treated with ATX and 0% of waiting list group had reduced ADHD symptoms by greater or equal to 30%. In SDBO, ATX group reduced driving errors in three of four driving performance categories (attention, Pself-control, Pdriving errors remained stable in control group. At endpoint, 47.6% of control group and 18.2% of ATX group (Pdriving fitness criteria according to German Guidelines (percentile rank less or equal to 16 in one or more subtests in ART2020). Total number of self-reported critical traffic situations decreased from 12.0 to 6.8 per week in ATX group (Ptraffic situations did not change within both groups. Our study provides first evidence that treatment with ATX improves driving performance in real traffic in adults with ADHD. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  9. Improvement by methylphenidate and atomoxetine of social interaction deficits and recognition memory impairment in a mouse model of valproic acid-induced autism.

    Science.gov (United States)

    Hara, Yuta; Ago, Yukio; Taruta, Atsuki; Katashiba, Keisuke; Hasebe, Shigeru; Takano, Erika; Onaka, Yusuke; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

    2016-09-01

    Rodents exposed prenatally to valproic acid (VPA) show autism-related behavioral abnormalities. We recently found that prenatal VPA exposure causes a reduction of dopaminergic activity in the prefrontal cortex of male, but not female, mice. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA-treated mice. In the present study, we examined whether the attention deficit/hyperactivity disorder drugs methylphenidate and atomoxetine (which increase dopamine release in the prefrontal cortex, but not striatum, in mice) could alleviate the behavioral abnormalities and changes in dendritic spine morphology induced by prenatal VPA exposure. We found that methylphenidate and atomoxetine increased prefrontal dopamine and noradrenaline release in VPA-treated mice. Acute treatment with methylphenidate or atomoxetine did not alleviate the social interaction deficits or recognition memory impairment in VPA-treated mice, while chronic treatment for 2 weeks did. Methylphenidate or atomoxetine for 2 weeks also improved the prenatal VPA-induced decrease in dendritic spine density in the prefrontal cortex. The effects of these drugs on behaviors and dendritic spine morphology were antagonized by concomitant treatment with the dopamine-D1 receptor antagonist SCH39166 or the dopamine-D2 receptor antagonist raclopride, but not by the α2 -adrenoceptor antagonist idazoxan. These findings suggest that chronic treatment with methylphenidate or atomoxetine improves abnormal behaviors and diminishes the reduction in spine density in VPA-treated mice via a prefrontal dopaminergic system-dependent mechanism. Autism Res 2016, 9: 926-939. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

  10. A controlled study of a serotonin reuptake blocker, zimelidine, in the treatment of chronic pain.

    Science.gov (United States)

    Gourlay, G K; Cherry, D A; Cousins, M J; Love, B L; Graham, J R; McLachlan, M O

    1986-04-01

    Zimelidine inhibits the central neuronal reuptake of serotonin and has undergone clinical evaluation as an antidepressant. Twenty patients with chronic pain of non-malignant origin (mean duration 15.8 years) were entered into a double blind cross-over study of the analgesic efficacy of zimelidine and placebo. The duration of each treatment phase was 6 weeks and there was a comprehensive assessment of each patient prior to the commencement and at the completion of the study, during a brief period of hospitalisation. Zimelidine was superior (P less than 0.05) to placebo with respect to pain relief based on a global assessment (by the clinical investigators) performed at the completion of each treatment phase. However, there was no significant difference in analgesic efficacy between the zimelidine and placebo treatment phases based on the following criteria: (a) changes in the minimum effective blood concentration of pethidine necessary to provide pain relief in each patient, measured during a pethidine infusion of 1.67 mg/min for 60 min; (b) changes in pain scores estimated by patients using the visual analogue pain scale (VAPS); (c) changes in patients' estimates of pain intensity associated with various daily activities. Significant pain relief was apparent within 2-3 days in those patients who had a beneficial effect, which contrasts with the documented 3-4 weeks for maximal antidepressant effects. The results of this study suggest that serotonin reuptake blockers do not provide consistent pain relief in patients with chronic pain, but may contribute an analgesic effect in the treatment of some patients.

  11. Atomoxetine, Parent Training, and Their Combination in Children With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder.

    Science.gov (United States)

    Handen, Benjamin L; Aman, Michael G; Arnold, L Eugene; Hyman, Susan L; Tumuluru, Rameshwari V; Lecavalier, Luc; Corbett-Dick, Patricia; Pan, Xueliang; Hollway, Jill A; Buchan-Page, Kristin A; Silverman, Laura B; Brown, Nicole V; Rice, Robert R; Hellings, Jessica; Mruzek, Daniel W; McAuliffe-Bellin, Sarah; Hurt, Elizabeth A; Ryan, Melissa M; Levato, Lynne; Smith, Tristram

    2015-11-01

    Impairments associated with attention-deficit/hyperactivity disorder (ADHD) and noncompliance are prevalent in children with autism spectrum disorder (ASD). However, ADHD response to stimulants is well below rates in typically developing children, with frequent side effects. Group studies of treatments for noncompliance are rare in ASD. We examined individual and combined-effectiveness of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance. In a 3-site, 10-week, double-blind, 2 × 2 trial of ATX and PT, 128 children (ages 5-14 years) with ASD and ADHD symptoms were randomized to ATX, ATX+PT, placebo+PT, or placebo. ATX was adjusted to optimal dose (capped at 1.8 mg/kg/day) over 6 weeks and maintained for 4 additional weeks. Nine PT sessions were provided. Primary outcome measures were the parent-rated DSM ADHD symptoms on the Swanson, Nolan and Pelham (SNAP) scale and Home Situations Questionnaire (HSQ). On the SNAP, ATX, ATX+PT and placebo+PT were each superior to placebo (effect sizes 0.57-0.98; p values of .0005, .0004, and .025, respectively). For noncompliance, ATX and ATX+PT were superior to placebo (effect sizes 0.47-0.64; p values .03 and .0028, respectively). ATX was associated with decreased appetite but was otherwise well tolerated. Both ATX and PT resulted in significant improvement on ADHD symptoms, whereas ATX (both alone and combined with PT) was associated with significant decreases on measures of noncompliance. ATX appears to have a better side effects profile than psychostimulants in the population with ASD. Atomoxetine, Placebo and Parent Management Training in Autism; http://clinicaltrials.gov/; NCT00844753. Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

  12. Treatment outcomes after methylphenidate in adults with attention-deficit/hyperactivity disorder treated with lisdexamfetamine dimesylate or atomoxetine

    Directory of Open Access Journals (Sweden)

    Joseph A

    2016-03-01

    Full Text Available Alain Joseph,1 Martin Cloutier,2 Annie Guérin,2 Roy Nitulescu,2 Vanja Sikirica3 1Global HEOR and Epidemiology, Shire, Zählerweg, Zug, Switzerland; 2Analysis Group, Inc., Montreal, Quebec, Canada; 3Global HEOR and Epidemiology, Shire, Wayne, PA, USA Purpose: To compare treatment adherence, discontinuation, add-on, and daily average consumption (DACON among adults with attention-deficit/hyperactivity disorder receiving second-line lisdexamfetamine dimesylate (LDX or atomoxetine (ATX, following methylphenidate.Patients and methods: A retrospective cohort study using US commercial claims databases (Q2/2009–Q3/2013.Results: At month 12, the LDX cohort (N=2,718 had a higher adherence level (proportion of days covered: 0.48 versus 0.30, P<0.001 and was less likely to discontinue (Kaplan–Meier estimate: 63% versus 85%, P<0.001 than the ATX cohort (N=674. There were no statistical differences in treatment add-on rates between cohorts (Kaplan–Meier estimate: 26% versus 25%, P=0.297. The LDX cohort had a lower DACON (1.10 versus 1.31, P<0.001 and was less likely to have a DACON >1 (adjusted odds ratio: 0.20, 95% confidence interval: 0.15–0.25, P<0.001 than the ATX cohort.Conclusion: Adults with attention-deficit/hyperactivity disorder treated with LDX following methylphenidate had a higher treatment adherence and lower discontinuation and DACON relative to those treated with ATX following methylphenidate. Keywords: ADHD, adult, adherence, lisdexamfetamine dimesylate, atomoxetine

  13. Quantification of Methylphenidate, Dexamphetamine, and Atomoxetine in Human Serum and Oral Fluid by HPLC With Fluorescence Detection.

    Science.gov (United States)

    Stegmann, Benedikt; Dörfelt, Anett; Haen, Ekkehard

    2016-02-01

    For psychostimulants, a marked individual variability in the dose-response relationship and large differences in plasma concentrations after similar doses are known. Therefore, optimizing the efficacy of these drugs is at present the most promising way to exploit their full pharmacological potential. Moreover, it seems important to examine oral fluid as less invasive biological matrix for its benefit in therapeutic drug monitoring for patients with hyperkinetic disorder. A high-performance liquid chromatography method for quantification of methylphenidate (MPH), dexamphetamine (DXA), and atomoxetine in serum and oral fluid has been developed and validated. The analytical procedure involves liquid-liquid extraction, derivatization with 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoyl chloride as a label and chromatographic separation on a Phenomenex Gemini-NX C18 analytical column using gradient elution with water-acetonitrile. The derivatized analytes were detected at 330 nm (excitation wavelength) and 440 nm (emission wavelength). To examine the oral fluid/serum ratios, oral fluid samples were collected simultaneously to blood samples from patients with hyperkinetic disorder. The method allows quantification of all analytes in serum and oral fluid within 16 minutes under the same or similar conditions. Oral fluid/serum ratios for MPH and DXA were highly variable and showed an accumulation of these drugs in oral fluid. The developed method covers the determination of MPH, DXA, and atomoxetine concentrations in serum and oral fluid after the intake of therapeutic doses. Oral fluid samples are useful for the qualitative detection of MPH and DXA.

  14. Methylphenidate and Atomoxetine-Responsive Prefrontal Cortical Genetic Overlaps in "Impulsive" SHR/NCrl and Wistar Rats.

    Science.gov (United States)

    Dela Peña, Ike; Dela Peña, Irene Joy; de la Peña, June Bryan; Kim, Hee Jin; Shin, Chan Young; Han, Doug Hyun; Kim, Bung-Nyun; Ryu, Jong Hoon; Cheong, Jae Hoon

    2017-09-01

    Impulsivity, the predisposition to act prematurely without foresight, is associated with a number of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Identifying genetic underpinnings of impulsive behavior may help decipher the complex etiology and neurobiological factors of disorders marked by impulsivity. To identify potential genetic factors of impulsivity, we examined common differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of adolescent SHR/NCrl and Wistar rats, which showed marked decrease in preference for the large but delayed reward, compared with WKY/NCrl rats, in the delay discounting task. Of these DEGs, we examined drug-responsive transcripts whose mRNA levels were altered following treatment (in SHR/NCrl and Wistar rats) with drugs that alleviate impulsivity, namely, the ADHD medications methylphenidate and atomoxetine. Prefrontal cortical genetic overlaps between SHR/NCrl and Wistar rats in comparison with WKY/NCrl included genes associated with transcription (e.g., Btg2, Fos, Nr4a2), synaptic plasticity (e.g., Arc, Homer2), and neuron apoptosis (Grik2, Nmnat1). Treatment with methylphenidate and/or atomoxetine increased choice of the large, delayed reward in SHR/NCrl and Wistar rats and changed, in varying degrees, mRNA levels of Nr4a2, Btg2, and Homer2, genes with previously described roles in neuropsychiatric disorders characterized by impulsivity. While further studies are required, we dissected potential genetic factors that may influence impulsivity by identifying genetic overlaps in the PFC of "impulsive" SHR/NCrl and Wistar rats. Notably, these are also drug-responsive transcripts which may be studied further as biomarkers to predict response to ADHD drugs, and as potential targets for the development of treatments to improve impulsivity.

  15. Atomoxetine and Parent Training for Children With Autism and Attention-Deficit/Hyperactivity Disorder: A 24-Week Extension Study.

    Science.gov (United States)

    Smith, Tristram; Aman, Michael G; Arnold, L Eugene; Silverman, Laura B; Lecavalier, Luc; Hollway, Jill; Tumuluru, Rameshwari; Hyman, Susan L; Buchan-Page, Kristin A; Hellings, Jessica; Rice, Robert R; Brown, Nicole V; Pan, Xueliang; Handen, Benjamin L

    2016-10-01

    The authors previously reported on a 2-by-2 randomized clinical trial of individual and combined treatment with atomoxetine (ATX) and parent training (PT) for attention-deficit/hyperactivity disorder (ADHD) symptoms and behavioral noncompliance in 128 5- to 14-year-old children with autism spectrum disorder. In the present report, they describe a 24-week extension of treatment responders and nonresponders. One-hundred seventeen participants from the acute trial (91%) entered the extension; 84 of these were in 2 subgroups: "treatment responders" (n = 43) from all 4 groups in the acute trial, seen monthly for 24 weeks, and "placebo nonresponders" (n = 41), treated with open-label ATX for 10 weeks. Participants originally assigned to PT continued PT during the extension; the remainder served as controls. Primary outcome measurements were the parent-rated Swanson, Nolan and Pelham ADHD scale and the Home Situations Questionnaire. Sixty percent (26 of 43) of treatment responders in the acute trial, including 68% of responders originally assigned to ATX, still met the response criteria at the end of the extension. The response rate of placebo nonresponders treated with 10-week open-label ATX was 37% (15 of 41), similar to the acute trial. Children receiving open-label ATX + PT were significantly more likely to be ADHD responders (53% versus 23%) and noncompliance responders (58% versus 14%) than those receiving open-label ATX alone. Most ATX responders maintained their responses during the extension. PT combined with ATX in the open-label trial appeared to improve ADHD and noncompliance outcomes more than ATX alone. Clinical trial registration information-Atomoxetine, Placebo and Parent Management Training in Autism (Strattera); http://clinicaltrials.gov; NCT00844753. Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

  16. Effect of Atomoxetine Treatment on Reading and Phonological Skills in Children with Dyslexia or Attention-Deficit/Hyperactivity Disorder and Comorbid Dyslexia in a Randomized, Placebo-Controlled Trial.

    Science.gov (United States)

    Shaywitz, Sally; Shaywitz, Bennett; Wietecha, Linda; Wigal, Sharon; McBurnett, Keith; Williams, David; Kronenberger, William G; Hooper, Stephen R

    2017-02-01

    Evaluated the effects of atomoxetine on the reading abilities of children with dyslexia only or attention-deficit/hyperactivity disorder (ADHD) and comorbid dyslexia. Children aged 10-16 years (N = 209) met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for dyslexia only (n = 58), ADHD and comorbid dyslexia (n = 124), or ADHD only (n = 27) and were of normal intelligence. Patients were treated with atomoxetine (1.0-1.4 mg/kg/day) or placebo in a 16-week, randomized, placebo-controlled, double-blind trial. The dyslexia-only and ADHD and comorbid dyslexia groups were randomized 1:1; the ADHD-only group received atomoxetine in a blinded manner. Reading abilities were measured with the Woodcock Johnson III (WJIII), Comprehensive Test of Phonological Processing (CTOPP), Gray Oral Reading Tests-4, and Test of Word Reading Efficiency. Atomoxetine-treated dyslexia-only patients compared with placebo patients had significantly greater improvement (p atomoxetine-treated ADHD and comorbid dyslexia group, improvement on the CTOPP Elision measure (ES = 0.50) was significantly greater compared with placebo (p atomoxetine-treated ADHD and comorbid dyslexia group compared with placebo, and from baseline in the ADHD-only group (p ≤ 0.02). ADHD symptom improvements in the ADHD and comorbid dyslexia group were not correlated with improvements in reading. Atomoxetine treatment improved reading scores in patients with dyslexia only and ADHD and comorbid dyslexia. Improvements for patients with dyslexia only were in critical components of reading, including decoding and reading vocabulary. For patients with ADHD and comorbid dyslexia, improvements in reading scores were distinct from improvement in ADHD inattention symptoms alone. These data represent the first report of improvements in reading measures following pharmacotherapy treatment in patients with dyslexia only evaluated in a randomized

  17. Utilization of Stimulants and Atomoxetine for Attention-Deficit/Hyperactivity Disorder among 5.4 Million Children Using Population-Based Longitudinal Data

    DEFF Research Database (Denmark)

    Furu, Kari; Karlstad, Øystein; Zoëga, Helga

    2017-01-01

    Use of stimulants to treat attention-deficit/hyperactivity disorder (ADHD) has increased over the past two decades and varies substantially between countries. The objective of this multinational population-based study was to examine utilization of ADHD drugs (stimulants and atomoxetine) including...... the importance of close monitoring of treatment for ADHD among children.......Use of stimulants to treat attention-deficit/hyperactivity disorder (ADHD) has increased over the past two decades and varies substantially between countries. The objective of this multinational population-based study was to examine utilization of ADHD drugs (stimulants and atomoxetine) including...... comedication with other psychotropic drugs in the entire child population in the five Nordic countries. We included longitudinal data on dispensed ADHD drugs from five Nordic prescription registers during 2008-2012, which in 2012 comprised 48,296 individuals among 5.42 million inhabitants aged 0-17 years...

  18. A Systematic Review of Combination Therapy with Stimulants and Atomoxetine for Attention-Deficit/Hyperactivity Disorder, Including Patient Characteristics, Treatment Strategies, Effectiveness, and Tolerability

    Science.gov (United States)

    Gau, Susan Shur-Fen; Méndez, Luis; Montgomery, William; Monk, Julie A.; Altin, Murat; Wu, Shenghu; Lin, Chaucer C.H.; Dueñas, Héctor J.

    2013-01-01

    Abstract Objective The purpose of this article was to systematically review the literature on stimulant and atomoxetine combination therapy, in particular: 1) Characteristics of patients with attention-deficit/hyperactivity disorder (ADHD) given combination therapy, 2) treatment strategies used, 3) efficacy and effectiveness, and 4) safety and tolerability. Methods Literature databases (MEDLINE®, EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index Expanded, and SciVerse Scopus) were systematically searched using prespecified criteria. Publications describing stimulant and atomoxetine combination therapy in patients with ADHD or healthy volunteers were selected for review. Exclusion criteria were comorbid psychosis, bipolar disorder, epilepsy, or other psychiatric/neurologic diseases that could confound ADHD symptom assessment, or other concomitant medication(s) to treat ADHD symptoms. Results Of the 16 publications included for review, 14 reported findings from 3 prospective studies (4 publications), 7 retrospective studies, and 3 narrative reviews/medication algorithms of patients with ADHD. The other two publications reported findings from two prospective studies of healthy volunteers. The main reason for prescribing combination therapy was inadequate response to previous treatment. In the studies of patients with ADHD, if reported, 1) most patients were children/adolescents and male, and had a combined ADHD subtype; 2) methylphenidate was most often used in combination with atomoxetine for treatment augmentation or switch; 3) ADHD symptom control was improved in some, but not all, patients; and 4) there were no serious adverse events. Conclusions Published evidence of the off-label use of stimulant and atomoxetine combination therapy is limited because of the small number of publications, heterogeneous study designs (there was only one prospective, randomized controlled trial), small sample sizes, and geographic bias. Existing

  19. Atomoxetine effects on executive function as measured by the BRIEF--a in young adults with ADHD: a randomized, double-blind, placebo-controlled study.

    Directory of Open Access Journals (Sweden)

    Lenard A Adler

    Full Text Available To evaluate the effect of atomoxetine treatment on executive functions in young adults with attention-deficit/hyperactivity disorder (ADHD.In this Phase 4, multi-center, double-blind, placebo-controlled trial, young adults (18-30 years with ADHD were randomized to receive atomoxetine (20-50 mg BID, N = 220 or placebo (N = 225 for 12 weeks. The Behavior Rating Inventory of Executive Function-Adult (BRIEF-A consists of 75 self-report items within 9 nonoverlapping clinical scales measuring various aspects of executive functioning. Mean changes from baseline to 12-week endpoint on the BRIEF-A were analyzed using an ANCOVA model (terms: baseline score, treatment, and investigator.At baseline, there were no significant treatment group differences in the percentage of patients with BRIEF-A composite or index T-scores ≥60 (p>.5, with over 92% of patients having composite scores ≥60 (≥60 deemed clinically meaningful for these analyses. At endpoint, statistically significantly greater mean reductions were seen in the atomoxetine versus placebo group for the BRIEF-A Global Executive Composite (GEC, Behavioral Regulation Index (BRI, and Metacognitive Index (MI scores, as well as the Inhibit, Self-Monitor, Working Memory, Plan/Organize and Task Monitor subscale scores (p<.05, with decreases in scores signifying improvements in executive functioning. Changes in the BRIEF-A Initiate (p = .051, Organization of Materials (p = .051, Shift (p = .090, and Emotional Control (p = .219 subscale scores were not statistically significant. In addition, the validity scales: Inconsistency (p = .644, Infrequency (p = .097, and Negativity (p = .456 were not statistically significant, showing scale validity.Statistically significantly greater improvement in executive function was observed in young adults with ADHD in the atomoxetine versus placebo group as measured by changes in the BRIEF-A scales.ClinicalTrials.gov NCT00510276.

  20. Atomoxetine Effects on Executive Function as Measured by the BRIEF-A in Young Adults with ADHD: A Randomized, Double-Blind, Placebo-Controlled Study

    Science.gov (United States)

    Adler, Lenard A.; Clemow, David B.; Williams, David W.; Durell, Todd M.

    2014-01-01

    Objective To evaluate the effect of atomoxetine treatment on executive functions in young adults with attention-deficit/hyperactivity disorder (ADHD). Methods In this Phase 4, multi-center, double-blind, placebo-controlled trial, young adults (18–30 years) with ADHD were randomized to receive atomoxetine (20–50 mg BID, N = 220) or placebo (N = 225) for 12 weeks. The Behavior Rating Inventory of Executive Function-Adult (BRIEF-A) consists of 75 self-report items within 9 nonoverlapping clinical scales measuring various aspects of executive functioning. Mean changes from baseline to 12-week endpoint on the BRIEF-A were analyzed using an ANCOVA model (terms: baseline score, treatment, and investigator). Results At baseline, there were no significant treatment group differences in the percentage of patients with BRIEF-A composite or index T-scores ≥60 (p>.5), with over 92% of patients having composite scores ≥60 (≥60 deemed clinically meaningful for these analyses). At endpoint, statistically significantly greater mean reductions were seen in the atomoxetine versus placebo group for the BRIEF-A Global Executive Composite (GEC), Behavioral Regulation Index (BRI), and Metacognitive Index (MI) scores, as well as the Inhibit, Self-Monitor, Working Memory, Plan/Organize and Task Monitor subscale scores (patomoxetine versus placebo group as measured by changes in the BRIEF-A scales. Trial Registration ClinicalTrials.gov NCT00510276 PMID:25148243

  1. Effect of Atomoxetine on the Cognitive Functions in Treatment of Attention Deficit Hyperactivity Disorder in Children with Congenital Hypothyroidism: A Pilot Study.

    Science.gov (United States)

    Yang, Rongwang; Gao, Weijia; Li, Rong; Zhao, Zhengyan

    2015-04-19

    With early initiation of thyroxine supplementation, children with congenital hypothyroidism (CH) retain some subtle deficits, such as attention and inhibitory control problems. This study assessed the effects of atomoxetine on cognitive functions in treatment of attention deficit hyperactivity disorder (ADHD) symptoms in children with CH. In a 6-month, open-labeled pilot study, 12 children were recruited and received atomoxetine. The measures of efficacy were scores on the Swanson, Nolan and Pelham Teacher and Parent Rating Scale, version IV (SNAP-IV) and Clinical Global Impression-Severity scale (CGI-S). The cognitive functions were evaluated with the Wechsler Intelligence Scale for Chinese Children, Digit Span, Wisconsin Card Sorting Test, and Stroop test. A statistically significant difference was found between the mean CGI-S and SNAP-IV scores before and after treatment (p Atomoxetine appears to be useful in improving ADHD symptoms, as well as cognitive functions, in children with CH. Larger, randomized, double-blinded, clinical trials are required to replicate these results. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  2. Atomoxetine Increased Effect over Time in Adults with Attention-Deficit/Hyperactivity Disorder Treated for up to 6 Months: Pooled Analysis of Two Double-Blind, Placebo-Controlled, Randomized Trials.

    Science.gov (United States)

    Wietecha, Linda A; Clemow, David B; Buchanan, Andrew S; Young, Joel L; Sarkis, Elias H; Findling, Robert L

    2016-07-01

    Changes in the magnitude of efficacy throughout 26 weeks of atomoxetine treatment, along with impact of dosing, were evaluated in adults with ADHD from two randomized, double-blind, placebo-controlled studies. Pooled placebo (n = 485) and atomoxetine (n = 518) patients, dosed 25, 40, 60, 80 (target dose), or 100 mg daily, were assessed. Change from baseline in Conners' Adult ADHD Rating Scale-Investigator Rated Scale: Screening Version (CAARS) total ADHD symptoms score and Adult ADHD Investigator Symptom Rating Scale (AISRS) total score were analyzed using mixed-model repeated measures, with least squares mean change, effect size, and response rate calculated at 1, 2, 4, 8, 12, 16, 22, and 26 weeks. Decreases on CAARS for atomoxetine- versus placebo-treated patients were consistently statistically significantly greater at every time point beginning at one week (P ≤ 0.006, 0.28 effect size). By 4 weeks, comparison was -13.19 compared with -8.84 (P Atomoxetine response rate (CAARS 50% decrease) continued to increase throughout 26 weeks. Atomoxetine treatment in adults with ADHD was associated with small effect sizes after 4 weeks and moderate effect sizes by 6 months of treatment. The data support increased effect size and response rate over time during longer-term treatment at target dose. © 2016 Eli Lilly and Company. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

  3. Differential therapeutic effects of 12-week treatment of atomoxetine and methylphenidate on drug-naïve children with attention deficit/hyperactivity disorder: A counting Stroop functional MRI study.

    Science.gov (United States)

    Chou, Tai-Li; Chia, Seng; Shang, Chi-Yung; Gau, Susan Shur-Fen

    2015-12-01

    Methylphenidate and atomoxetine are effective in treating attention-deficit/hyperactivity disorder (ADHD) with underlying distinct pharmacological mechanisms. To relate neural mechanisms to clinical response, we conducted a comparative trial to differentiate the changes in brain activation of drug-naïve children with ADHD when performing neuropsychological tasks after 12 weeks of pharmacotherapy. We randomized 50 drug-naïve children with ADHD, aged 7-17, to treatment with methylphenidate (n=25) or atomoxetine (n=25). These children were scanned twice with functional magnetic resonance imaging (fMRI) during the counting Stroop task before and after treatment. Focused attention and impulsivity were assessed twice by using the Conner's Continuous Performance Test (CCPT). The final sample for fMRI analysis comprised 20 in the methylphenidate group and 22 in the atomoxetine group. Atomoxetine decreased activations in the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex, which correlated with improvement in focused attention assessed by the CCPT. In contrast, methylphenidate increased activations in the inferior frontal gyrus, which correlated with the decreasing severity of impulsivity assessed by the CCPT. The current findings suggest that differential therapeutic effects on neuronal changes induced by 12-week treatment atomoxetine and methylphenidate may contribute to behavioral improvement. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  4. Atomoxetine-Related Change in Sluggish Cognitive Tempo Is Partially Independent of Change in Attention-Deficit/Hyperactivity Disorder Inattentive Symptoms.

    Science.gov (United States)

    McBurnett, Keith; Clemow, David; Williams, David; Villodas, Miguel; Wietecha, Linda; Barkley, Russell

    2017-02-01

    To evaluate effects of atomoxetine versus placebo on sluggish cognitive tempo (SCT) and determine factors affecting improvement of SCT in children with attention-deficit/hyperactivity disorder (ADHD) with dyslexia (ADHD+D) or dyslexia only. This is a post hoc analysis of a 16-week placebo-controlled, double-blind randomized phase of a previously reported atomoxetine study in children aged 10-16 years with ADHD+D, Dyslexia-only, or ADHD-only (no placebo arm). Least squares mean changes from baseline to endpoint for atomoxetine versus placebo on the Kiddie-Sluggish Cognitive Tempo Interview (K-SCT) (Parent, Teacher, and Youth) were analyzed using analysis of covariance and multiple regression (partial R 2 ) analyses to test contributions of ADHD and dyslexia to improvements in K-SCT scores. Results were examined for the three informants within the three diagnostic groups (nine outcomes). Atomoxetine treatment was associated with significant reductions from baseline in seven of the nine outcomes using the p = 0.05 significance level, appropriate for exploratory analysis. When change in ADHD symptom severity was controlled, all of the seven SCT outcomes remained significant; changes in effect sizes were minimal. Regression analyses using SCT change as the criterion found a significant contribution by inattention change only for parent report, whereas, baseline SCT severity was a significant predictor in the randomized groups with the exception of teacher report in the Dyslexia-only group. Given that controlling for change in ADHD symptoms had little effect on change in SCT scores, findings suggest that change in SCT is substantially independent of change in ADHD. By inference, SCT and its response to treatment is a partially distinct phenomenon from ADHD response. Regression analyses did not reveal global effects of inattention change on SCT change; instead, baseline SCT severity was the strongest predictor of placebo-controlled treatment effect on SCT. Atomoxetine

  5. Patterns of long-term and short-term responses in adult patients with attention-deficit/hyperactivity disorder in a completer cohort of 12 weeks or more with atomoxetine.

    Science.gov (United States)

    Sobanski, E; Leppämäki, S; Bushe, C; Berggren, L; Casillas, M; Deberdt, W

    2015-11-01

    Atomoxetine is a well-established pharmacotherapy for adult ADHD. Long-term studies show incremental reductions in symptoms over time. However, clinical experience suggests that patients differ in their response patterns. From 13 Eli Lilly-sponsored studies, we pooled and analyzed data for adults with ADHD who completed atomoxetine treatment at long-term (24 weeks; n=1443) and/or short-term (12 weeks; n=2830) time-points, and had CAARS-Inv:SV total and CGI-S data up to or after these time-points and at Week 0 (i.e. at baseline, when patients first received atomoxetine). The goal was to identify and describe distinct trajectories of response to atomoxetine using hierarchical clustering methods and linear mixed modelling. Based on the homogeneity of changes in CAARS-Inv:SV total scores, 5 response clusters were identified for patients who completed long-term (24 weeks) treatment with atomoxetine, and 4 clusters were identified for patients who completed short-term (12 weeks) treatment. Four of the 5 long-term clusters (comprising 95% of completer patients) showed positive trajectories: 2 faster responding clusters (L1 and L2), and 2 more gradually responding clusters (L3 and L4). Responses (i.e.≥30% reduction in CAARS-Inv:SV total score, and CGI-S score≤3) were observed at 8 and 24 weeks in 80% and 95% of completers in Cluster L1, versus 5% and 48% in Cluster L4. While many adults with ADHD responded relatively rapidly to atomoxetine, others responded more gradually without a clear plateau at 24 weeks. Longer-term treatment may be associated with greater numbers of responders. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  6. Atomoxetine Treatment Strengthens an Anti-Correlated Relationship between Functional Brain Networks in Medication-Naïve Adults with Attention-Deficit Hyperactivity Disorder: A Randomized Double-Blind Placebo-Controlled Clinical Trial.

    Science.gov (United States)

    Lin, Hsiang-Yuan; Gau, Susan Shur-Fen

    2015-09-16

    Although atomoxetine demonstrates efficacy in individuals with attention-deficit hyperactivity disorder, its treatment effects on brain resting-state functional connectivity remain unknown. Therefore, we aimed to investigate major brain functional networks in medication-naïve adults with attention-deficit hyperactivity disorder and the efficacy of atomoxetine treatment on resting-state functional connectivity. After collecting baseline resting-state functional MRI scans from 24 adults with attention-deficit hyperactivity disorder (aged 18-52 years) and 24 healthy controls (matched in demographic characteristics), the participants with attention-deficit hyperactivity disorder were randomly assigned to atomoxetine (n=12) and placebo (n=12) arms in an 8-week, double-blind, placebo-controlled trial. The primary outcome was functional connectivity assessed by a resting-state functional MRI. Seed-based functional connectivity was calculated and compared for the affective, attention, default, and cognitive control networks. At baseline, we found atypical cross talk between the default, cognitive control, and dorsal attention networks and hypoconnectivity within the dorsal attention and default networks in adults with attention-deficit hyperactivity disorder. Our first-ever placebo-controlled clinical trial incorporating resting-state functional MRI showed that treatment with atomoxetine strengthened an anticorrelated relationship between the default and task-positive networks and modulated all major brain networks. The strengthened anticorrelations were associated with improving clinical symptoms in the atomoxetine-treated adults. Our results support the idea that atypical default mode network task-positive network interaction plays an important role in the pathophysiology of adult attention-deficit hyperactivity disorder. Strengthening this atypical relationship following atomoxetine treatment suggests an important pathway to treat attention-deficit hyperactivity

  7. [Syk inhibitors].

    Science.gov (United States)

    Kimura, Yukihiro; Chihara, Kazuyasu; Takeuchi, Kenji; Sada, Kiyonao

    2013-07-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in the University of Fukui in 1991. Syk is known to be essential for the various physiological functions, especially in hematopoietic lineage cells. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Recently, novel Syk inhibitors were developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure, and function of Syk, and then describe the novel Syk inhibitors and their current status. Furthermore, we will introduce our findings of the adaptor protein 3BP2 (c-Abl SH3 domain-binding protein-2), as a novel target of Syk.

  8. Syk inhibitors.

    Science.gov (United States)

    Chihara, Kazuyasu; Kimura, Yukihiro; Honjo, Chisato; Takeuchi, Kenji; Sada, Kiyonao

    2013-01-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in University of Fukui in 1991. Syk is most highly expressed by haemopoietic cells and known to play crucial roles in the signal transduction through various immunoreceptors of the adaptive immune response. However, recent reports demonstrate that Syk also mediates other biological functions, such as innate immune response, osteoclast maturation, platelet activation and cellular adhesion. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Because of its critical roles on the cellular functions, the development of Syk inhibitors for clinical use has been desired. Although many candidate compounds were produced, none of them had progressed to clinical trials. However, novel Syk inhibitors were finally developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure and function of Syk, and then the novel Syk inhibitors and their current status. In addition, we will introduce our research focused on the functions of Syk on Dectin-1-mediated mast cell activation.

  9. Academic outcomes in Asian children aged 8-11 years with attention-deficit/hyperactivity disorder treated with atomoxetine hydrochloride.

    Science.gov (United States)

    Mendez, Luis; Singh, Pritibha; Harrison, Gavan; Huang, Yu-Shu; Jin, Xingming; Cho, Soo Churl

    2011-06-01

    To investigate the relationship between changes in attention-deficit/hyperactivity disorder (ADHD) core symptoms and changes in academic outcome of Asian children treated with atomoxetine. This open-label study enrolled patients aged 8-11 years with DSM-IV-TR-defined ADHD, who were naïve to ADHD medications and met the symptomatic severity threshold of 1.5 standard deviations above the age and gender norm for the ADHDRS-IV-Parent:Inv (ADHDRS) total score. Data collection occurred for 24 weeks and included academic outcome, measured by the school grade average (SGA). Of 228 patients enrolled from China (n = 82), Taiwan (n = 76), and Korea (n = 70), 77.2% completed the study. Statistically significant (P < 0.001) baseline to last observation improvements in ADHDRS and SGA scores were observed. However, no linear correlation between change in ADHDRS total score and SGA (-0.083, P = 0.293) was observed. Despite significant independent improvements in core ADHD symptoms and academic grades over 24 weeks, the mean improvements observed in these measures did not appear to be correlated.

  10. Development and validation of a stability-indicating RP-HPLC method for determination of atomoxetine hydrochloride in tablets.

    Science.gov (United States)

    Patel, Sejal K; Patel, Natvarlal J

    2010-01-01

    This paper describes the development of a stability-indicating RP-HPLC method for the determination of atomoxetine hydrochloride (ATX) in the presence of its degradation products generated from forced decomposition studies. The drug substance was subjected to stress conditions of acid, base, oxidation, wet heat, dry heat, and photodegradation. In stability tests, the drug was susceptible to acid, base, oxidation, and dry and wet heat degradation. It was found to be stable under the photolytic conditions tested. The drug was successfully separated from the degradation products formed under stress conditions on a Phenomenex C18 column (250 x 4.6 mm id, 5 microm particle size) by using acetonitrile-methanol-0.032 M ammonium acetate (55 + 05 + 40, v/v/v) as the mobile phase at 1.0 mL/min and 40 degrees C. Photodiode array detection at 275 nm was used for quantitation after RP-HPLC over the concentration range of 0.5-5 microg/mL with a mean recovery of 100.8 +/- 0.4% for ATX. Statistical analysis demonstrated that the method is repeatable, specific, and accurate for the estimation of ATX. Because the method effectively separates the drug from its degradation products, it can be used as a stability-indicating method.

  11. Capillary electrophoresis coupled with electrochemiluminescence for determination of atomoxetine hydrochloride and the study on its interactions with three proteins.

    Science.gov (United States)

    Zeng, Hua-jin; Yang, Ran; Zhang, Ying; Li, Jian-jun; Qu, Ling-bo

    2015-03-01

    A simple, rapid and sensitive method for the determination of atomoxetine hydrochloride (AH) by capillary electrophoresis with electrochemiluminescence detection (CE-ECL) using tris(2,2'-bipyridyl) ruthenium (II) was developed. Under optimized conditions, the determinations of AH in capsules and rat plasmas and the study on its interactions with three plasma proteins, including bovine serum albumin, cytochrome c and myoglobin were performed successfully. Relative to some previous studies, in this paper the methodologies for the determination of AH in aqueous solution and spiked plasma systems were established, respectively. By comparing the difference between the two work curves of two systems, the matrix effect in plasma samples on the determination of AH by the CE-ECL method was discussed in detail. The results indicated that the effect of the matrix in plasma samples should not be ignored even if no obvious interference was found in the electropherograms and the establishment of method validation in complex samples by the CE-ECL method was necessary. Copyright © 2014 John Wiley & Sons, Ltd.

  12. Adverse Events of Atomoxetine in a Double-Blind Placebo-Controlled Study in Children with Autism.

    Science.gov (United States)

    Tumuluru, Rameshwari V; Corbett-Dick, Patricia; Aman, Michael G; Smith, Tristram; Arnold, L Eugene; Pan, Xueliang; Buchan-Page, Kristin A; Brown, Nicole V; Ryan, Melissa M; Hyman, Susan L; Hellings, Jessica; Williams, Craig; Hollway, Jill A; Lecavalier, Luc; Rice, Robert R; McAuliffe-Bellin, Sarah; Handen, Benjamin L

    2017-10-01

    Attention-deficit/hyperactivity disorder (ADHD) symptoms, including inattention and over activity, occur in approximately one-third of children with autism spectrum disorder (ASD). We describe the rate and duration of adverse events in a randomized controlled trial of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance in children with ASD. We conducted a 10-week, double-blind, 2 × 2 trial of ATX and PT with 128 children (ages 5-14) randomized to ATX alone, ATX+PT, placebo+PT, or placebo alone. For 6 weeks, ATX (or placebo) doses were clinically adjusted to a maximum of 1.8 mg/(kg·day) and maintained for an additional 4 weeks. An average of seven PT sessions were conducted in the two PT arms. Adverse events (AEs) were assessed through parent ratings of common symptoms on a seven-point Likert severity scale and through direct interviews with study medical staff. ATX was associated with decreased appetite and fatigue, but was otherwise well tolerated. Most reported AEs lasted 4 weeks or less. Unlike reports with typically developing (TD) children, there were no concerns with QTc changes or suicidal ideation. This study extends the findings of previous studies of ATX in ASD by documenting that the type of AEs was similar to that of TD children, with no significant safety concerns.

  13. Post Hoc Analysis of Potential Predictors of Response to Atomoxetine for the Treatment of Adults with Attention-Deficit/Hyperactivity Disorder using an Integrated Database.

    Science.gov (United States)

    Bushe, Chris; Sobanski, Esther; Coghill, David; Berggren, Lovisa; De Bruyckere, Katrien; Leppämäki, Sami

    2016-04-01

    Responses to atomoxetine vary for individual patients with attention-deficit/hyperactivity disorder (ADHD). However, we do not know whether any factors can be used to reliably predict how individuals with ADHD will respond to treatment. Our objective was to evaluate background variables that facilitate early identification of those adults with ADHD who are likely to respond to treatment with atomoxetine. We pooled data for atomoxetine-treated adults with ADHD from 12 clinical trials for a short-term (10-week) analysis, and from 11 clinical trials for a long-term (24-week) analysis. Patients not meeting a response definition [≥30 % reduction in Conners' Adult ADHD Rating Scales-Investigator Rated: Screening Version (CAARS-Inv:SV) total score and Clinical Global Impressions of ADHD Severity Scale (CGI-S) score ≤3 at endpoint], or who discontinued, were defined as non-responders. Another definition of response (≥30 % reduction in CAARS-Inv:SV total score at endpoint) was also used in these analyses; only the results with the former definition are shown in this abstract, as the same conclusions were gained with both definitions. A treatment-specified subgroup detection tool (a resampling-based ensemble tree method) was used to identify predictors of response. Of 1945 adults in the long-term analysis, 548 (28.2 %) were responders to atomoxetine at week 24; 65.2 % of 1397 non-responders had discontinued. Of 4524 adults in the short-term analysis, 1490 (32.9 %) were responders at week 10; 33.2 % of 1006 non-responders had discontinued. No analyzed baseline parameters (age, sex, prior stimulant use, ADHD subtype, CAARS-Inv:SV, CGI-S) were statistically significant predictors of response. Reductions in CAARS-Inv:SV total, CAARS-Inv:SV subscores, and CGI-S at week 4 in the short-term analysis, and at weeks 4 or 10 in the long-term analysis, were statistically significant predictors of response, i.e., patients with versus without these reductions early in

  14. Relative bioequivalence evaluation of two oral atomoxetine hydrochloride capsules: a single dose, randomized, open-label, 2-period crossover study in healthy Chinese volunteers under fasting conditions.

    Science.gov (United States)

    Shang, D-W; Guo, W; Zhou, F-C; Wang, X-P; Li, A-N; Zhang, L; Li, W-B; Lu, W; Wang, C-Y

    2013-11-01

    To evaluate the bioequivalence of a new formulation of atomoxetine hydrochloride (CAS 82248-59-7) capsules (test) and an available branded capsules (reference) after administration of a single 40 mg dose, randomized, open-label, 2-period crossover study was conducted in 22 healthy male Chinese subjects with a 1-week wash-out period. This study was designed for/the Honglin Pharmaceutical Co. Ltd and contracted to be done by the Beijing Anding Hospital in order to satisfy Chinese regulatory requirements to allow marketing of this generic product and performed according to the criteria of SFDA. Blood samples were collected before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16 and 24 h after drug administration. Plasma concentrations were determined by high-performance liquid chromatography (HPLC) with UV detection. A non-compartmental method was used to calculate the pharmacokinetic parameters and evaluate bioequivalence of the 2 formulations. The 90% confidence interval (CI) of the ratios (test/reference) of atomoxetine for AUC0-24, AUC0-∞ and Cmax were 100.9% (93.6-108.8%), 103.1% (95.1-111.7%) and 105.2% (92.8-119.4%), respectively, which fell within the interval of 80-125% and 75-133%. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. From these results it can be concluded that the test formulation of atomoxetine capsules met the regulatory criterion for bioequivalence to the reference formulation. © Georg Thieme Verlag KG Stuttgart · New York.

  15. Dopamine/noradrenaline reuptake inhibition in women improves endurance exercise performance in the heat.

    Science.gov (United States)

    Cordery, P; Peirce, N; Maughan, R J; Watson, P

    2017-11-01

    Catecholamine reuptake inhibition improves the performance of male volunteers exercising in warm conditions, but sex differences in thermoregulation, circulating hormones, and central neurotransmission may alter this response. With local ethics committee approval, nine physically active women (mean ± SD age 21 ± 2 years; height 1.68 ± 0.08 m; body mass 64.1 ± 6.0 kg; VO 2peak 51 ± 7 mL/kg/min) were recruited to examine the effect of pre-exercise administration of Bupropion (BUP; 4 × 150 mg) on prolonged exercise performance in a warm environment. Participants completed a VO 2peak test, two familiarization trials, and two randomized, double-blind experimental trials. All trials took place during the first 10 days of the follicular phase of the menstrual cycle. Participants cycled for 1 h at 60% VO 2peak followed by a 30-min performance test. Total work done was greater during the BUP trial (291 ± 48 kJ) than the placebo trial (269 ± 46 kJ, P = 0.042, d = 0.497). At the end of the performance test, core temperature was higher on the BUP trial (39.5 ± 0.4 °C) than on the placebo trial (39.2 ± 0.6 °C, P = 0.021; d = 0.588), as was heart rate (185 ± 9 vs 179 ± 13, P = 0.043; d = 0.537). The results indicate that during the follicular phase of the menstrual cycle, an acute dosing protocol of BUP can improve self-regulated performance in warm conditions. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Substrate and Inhibitor-Specific Conformational Changes in the Human Serotonin Transporter Revealed by Voltage-Clamp Fluorometry

    DEFF Research Database (Denmark)

    Söderhielm, Pella C; Andersen, Jacob; Munro, Lachlan

    2015-01-01

    of TM6, Ala419 in the interface between TM8 and extracellular loop (EL) 4, and Leu481 in EL5. The reporter positions were used for time-resolved measurement of conformational changes during 5-HT transport and binding of cocaine and the selective serotonin reuptake inhibitors fluoxetine and escitalopram...... changes overall, which included movements within or around TM1b, EL4, and EL5. Taken together, our data lead us to suggest that competitive inhibitors stabilize hSERT in a state that is different from the apo outward-open conformation as well as inward-facing conformations....

  17. Combination use of atomoxetine hydrochloride and olanzapine in the treatment of attention-deficit/hyperactivity disorder with comorbid disruptive behavior disorder in children and adolescents 10-18 years of age.

    Science.gov (United States)

    Holzer, Barry; Lopes, Vasco; Lehman, Robert

    2013-08-01

    The aim of this study was to assess the use of atomoxetine and olanzapine in combination to treat attention-deficit/hyperactivity disorder (ADHD) and comorbid disruptive behaviors in children and adolescents 10-18 years of age. Eleven subjects ages 10-18 received open-label atomoxetine and olanzapine for a 10 week treatment period. Patients were assessed at baseline, 2 weeks, 4 weeks, 6 weeks, and 10 weeks (posttreatment). ADHD improvement was measured through the ADHD Rating Scale (ADHD-RS) (Investigator and Parent ratings). Aggression was measured through the Modified Overt Aggression Scale (MOAS). The combined use of atomoxetine and olanzapine resulted in statistically significant improvement in ADHD symptoms and overt aggression from baseline to posttreatment. As evidenced by a 33% reduction in symptoms on the ADHD-RS-I and the MOAS, 73% of patients were considered responders to ADHD treatment, whereas 55% responded to treatment for aggression. Both medications were generally well tolerated. Olanzapine treatment was associated with significant weight gain. Patients gained, on average, 3.9 kg. throughout the treatment period. These data provide initial evidence that combination use of atomoxetine and olanzapine for the treatment of ADHD and comorbid disruptive behaviors was effective in reducing ADHD symptoms and aggressive behavior in a 10 week treatment period.

  18. Differential impact of methylphenidate and atomoxetine on sustained attention in youth with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Bédard, Anne-Claude V; Stein, Mark A; Halperin, Jeffrey M; Krone, Beth; Rajwan, Estrella; Newcorn, Jeffrey H

    2015-01-01

    This study examined the effects of atomoxetine (ATX) and OROS methylphenidate (MPH) on laboratory measures of inhibitory control and attention in youth with attention-deficit/hyperactivity disorder (ADHD). It was hypothesized that performance would be improved by both treatments, but response profiles would differ because the medications work via different mechanisms. One hundred and two youth (77 male; mean age = 10.5 ± 2.7 years) with ADHD received ATX (1.4 ± 0.5 mg/kg) and MPH (52.4 ± 16.6 mg) in a randomized, double-blind, crossover design. Medication was titrated in 4-6-week blocks separated by a 2-week placebo washout. Inhibitory control and attention measures were obtained at baseline, following washout, and at the end of each treatment using Conners' Continuous Performance Test II (CPT-II), which provided age-adjusted T-scores for reaction time (RT), reaction time variability (RT variability), and errors. Repeated-measures analyses of variance were performed, with Time (premedication, postmedication) and Treatment type (ATX, MPH) entered as within-subject factors. Data from the two treatment blocks were checked for order effects and combined if order effects were not present. Clinicaltrials.gov: NCT00183391. Main effects for Time on RT (p = .03), RTSD (p = .001), and omission errors (p = .01) were significant. A significant Drug × Time interaction indicated that MPH improved RT, RTSD, and omission errors more than ATX (p attention in youth with ADHD. However, the dissociation of cognitive and behavioral change with treatment indicates that CPT measures cannot be considered proxies for symptomatic improvement. Further research on the dissociation of cognitive and behavioral endpoints for ADHD is indicated. © 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.

  19. Effects of Atomoxetine in Individuals with Attention-Deficit/Hyperactivity Disorder and Low-Functioning Autism Spectrum Disorder.

    Science.gov (United States)

    Kilincaslan, Ayse; Mutluer, Tuba Duzman; Pasabeyoglu, Basak; Tutkunkardas, Mustafa Deniz; Mukaddes, Nahit Motavalli

    2016-11-01

    This naturalistic, retrospective study investigated the effects of atomoxetine (ATX) on attention-deficit/hyperactivity disorder (ADHD) symptoms and autistic features in children with autism spectrum disorders (ASDs) and intellectual disability (ID). Participants (n = 37, age range 6-17 years, mean: 10.16 ± 3.60) were assessed at baseline, 4th and 12th weeks using Clinical Global Impressions (CGI) scales, DSM-IV-based ADHD-rating scale (ADHD-RS), and amended Turkish version of Aberrant Behavior Checklist (ABC). The primary outcome measure was a treatment response defined by a CGI-improvement score of 1 or 2 together with a decrease of at least 25% in the parent-rated ADHD-RS total score at the end of 12th week. Five patients (13.5%) stopped medication at 4 weeks due to ineffectivity (2) and intolerable side effects (increased motor activity and talkativeness [n = 1], irritability [n = 2], temper outbursts [n = 2], and increased blood pressure [n = 1]). Sixteen patients (43.2%) were judged to be responders according to primary outcome measure. Improvement rate on CGI scale was 48.8%. On ADHD-RS, there were significant reductions between baseline and 4th week and between baseline and 12th week in both hyperactivity and inattention, and between baseline and 12th week in impulsivity scores. Decrease was significant in hyperactivity and social withdrawal subscales of the parent-reported ABC. Responders based on primary outcome measure were not significantly different from nonresponders in terms of sociodemographic features or clinical parameters, including intellectual, language, autism symptom, and ADHD symptom levels. In this chart review, ATX appears to be safe and effective for social withdrawal and ADHD symptoms in children with ASD and ID.

  20. Atomoxetine once daily for 24 weeks in adults with attention-deficit/hyperactivity disorder (ADHD): impact of treatment on family functioning.

    Science.gov (United States)

    Wietecha, Linda; Young, Joel; Ruff, Dustin; Dunn, David; Findling, Robert L; Saylor, Keith

    2012-01-01

    To assess the efficacy of atomoxetine (ATX) and impact of treatment on family functioning in adults with ADHD. Adults with attention-deficit/hyperactivity disorder (ADHD) having both a spouse/partner and child were randomized to placebo (n = 234) or ATX (n = 268) for 24 weeks. Attention-deficit/hyperactivity disorder measures included the Conners Adult ADHD Rating Scale total ADHD Symptoms score and Clinical Global Impression-ADHD-Severity. Marital measures included the Dyadic Adjustment Scale and the Family Assessment Measure Dyadic Relationship Scale (FAM III). Parenting measures included the Parenting Stress Index, Alabama Parenting Questionnaire, and Parenting Sense of Competence Scale (PSCS). Improvement was greater with ATX over placebo at 24 weeks on the Conners Adult ADHD Rating Scale (-16.43 vs -8.65; P ADHD yielded significant interaction and treatment differences for the FAM III Task Accomplishment and the FAM III and Dyadic Adjustment Scale affective expression items, PSCS total score, Alabama Parenting Questionnaire Corporal Punishment, and Parenting Stress Index attachment items. Atomoxetine demonstrated significant ADHD symptom reduction over 24 weeks. Although both groups demonstrated baseline-to-end point changes on many marital and parenting measure items, there were no treatment differences. Maladaptive behaviors of long-standing ADHD may benefit from both medication and behavioral-psychosocial intervention.

  1. Effect of atomoxetine on quality of life and family burden: results from a randomized, placebo-controlled, double-blind study in children and adolescents with ADHD and comorbid oppositional defiant or conduct disorder.

    Science.gov (United States)

    Wehmeier, Peter M; Schacht, Alexander; Dittmann, Ralf W; Helsberg, Karin; Schneider-Fresenius, Christian; Lehmann, Martin; Bullinger, Monika; Ravens-Sieberer, Ulrike

    2011-06-01

    To evaluate the effect of atomoxetine on quality of life (QoL) and family burden in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid oppositional defiant (ODD) or conduct disorder (CD). This secondary analysis was based on a randomized, double-blind, 9-week study of atomoxetine (target dose 1.2 mg/kg body weight) versus placebo. The study included 180 patients (atomoxetine 121, placebo 59), aged 6-17 years. QoL was measured using the KINDL-R questionnaire. The total score encompasses six dimensions (or subscales) measuring QoL in terms of "physical well-being", "emotional well-being", "self-esteem", "friends", "family", and "school". Family burden of illness was measured using the FaBel questionnaire. With atomoxetine, the KINDL-R total score improved significantly (P = 0.021) more than with placebo. This improvement also applied to the subscales except for "physical well-being" (opposite effect) and "school" (no effect). No significant treatment group differences were seen on the FaBel questionnaire. No differences were found between the fast and slow titration groups in terms of ADHD, ODD, and disruptive behavior severity. Furthermore, no such differences were observed for QoL and family burden. This study suggests positive effects of atomoxetine on quality of life, as measured by the KINDL-R scores on emotional well-being, self-esteem, friends and family, in children and adolescents with ADHD and comorbid ODD/CD. No significant treatment effects were seen on family burden, as measured by FaBel total score.

  2. Emotional well-being in children and adolescents treated with atomoxetine for attention-deficit/hyperactivity disorder: Findings from a patient, parent and physician perspective using items from the pediatric adverse event rating scale (PAERS

    Directory of Open Access Journals (Sweden)

    Dittmann Ralf W

    2008-05-01

    Full Text Available Abstract Background The objective of this analysis was to measure changes in items on the Pediatric Adverse Event Rating Scale (PAERS that relate to emotional well-being of children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD during treatment with atomoxetine for up to 24 weeks from the perspective of the patient, the parent, and the physician. Methods Patients aged 6–17 years with ADHD were treated with atomoxetine (target dose 1.2 mg/kg/day. In the two studies on which this secondary analysis is based the PAERS was used to assess the tolerability of atomoxetine in children and adolescents. This scale has a total of 48 items. The ten items that reflect emotional well-being were selected to measure changes over time from a patient, parent, and physician perspective. Results 421 patients were treated with atomoxetine. 355 patients completed the 8-week treatment period, and 260 patients completed the 24-week treatment period. The ten items that reflect emotional well-being were grouped in five dimensions: depressed mood, self-harm, irritability/agitation, drowsiness, and euphoria. The scores of these dimensions decreased over time, both from a patient as well as from a parent and physician perspective. Only the dimension self-harm was extremely low at baseline and stayed low over time. The mean scores for the ten items depended on the rater perspective. Conclusion The emotional well-being of children and adolescents with ADHD improved in terms of depressed mood, irritability/agitation, drowsiness, and euphoria during treatment with atomoxetine for up to 24 weeks.

  3. Atomoxetine could improve intra-individual variability in drug-naïve adults with attention-deficit/hyperactivity disorder comparably with methylphenidate: A head-to-head randomized clinical trial.

    Science.gov (United States)

    Ni, Hsing-Chang; Hwang Gu, Shoou-Lian; Lin, Hsiang-Yuan; Lin, Yu-Ju; Yang, Li-Kuang; Huang, Hui-Chun; Gau, Susan Shur-Fen

    2016-05-01

    Intra-individual variability in reaction time (IIV-RT) is common in individuals with attention-deficit/hyperactivity disorder (ADHD). It can be improved by stimulants. However, the effects of atomoxetine on IIV-RT are inconclusive. We aimed to investigate the effects of atomoxetine on IIV-RT, and directly compared its efficacy with methylphenidate in adults with ADHD. An 8-10 week, open-label, head-to-head, randomized clinical trial was conducted in 52 drug-naïve adults with ADHD, who were randomly assigned to two treatment groups: immediate-release methylphenidate (n=26) thrice daily (10-20 mg per dose) and atomoxetine once daily (n=26) (0.5-1.2 mg/kg/day). IIV-RT, derived from the Conners' continuous performance test (CCPT), was represented by the Gaussian (reaction time standard error, RTSE) and ex-Gaussian models (sigma and tau). Other neuropsychological functions, including response errors and mean of reaction time, were also measured. Participants received CCPT assessments at baseline and week 8-10 (60.4±6.3 days). We found comparable improvements in performances of CCPT between the immediate-release methylphenidate- and atomoxetine-treated groups. Both medications significantly improved IIV-RT in terms of reducing tau values with comparable efficacy. In addition, both medications significantly improved inhibitory control by reducing commission errors. Our results provide evidence to support that atomoxetine could improve IIV-RT and inhibitory control, of comparable efficacy with immediate-release methylphenidate, in drug-naïve adults with ADHD. Shared and unique mechanisms underpinning these medication effects on IIV-RT awaits further investigation. © The Author(s) 2016.

  4. Serotonin enhances the impact of health information on food choice.

    Science.gov (United States)

    Vlaev, Ivo; Crockett, Molly J; Clark, Luke; Müller, Ulrich; Robbins, Trevor W

    2017-06-01

    Serotonin has been implicated in promoting self-control, regulation of hunger and physiological homeostasis, and regulation of caloric intake. However, it remains unclear whether the effects of serotonin on caloric intake reflect purely homeostatic mechanisms, or whether serotonin also modulates cognitive processes involved in dietary decision making. We investigated the effects of an acute dose of the serotonin reuptake inhibitor citalopram on choices between food items that differed along taste and health attributes, compared with placebo and the noradrenaline reuptake inhibitor atomoxetine. Twenty-seven participants attended three sessions and received single doses of atomoxetine, citalopram, and placebo in a double-blind randomised cross-over design. Relative to placebo, citalopram increased choices of more healthy foods over less healthy foods. Citalopram also increased the emphasis on health considerations in decisions. Atomoxetine did not affect decision making relative to placebo. The results support the hypothesis that serotonin may influence food choice by enhancing a focus on long-term goals. The findings are relevant for understanding decisions about food consumption and also for treating health conditions such as eating disorders and obesity.

  5. Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats.

    Science.gov (United States)

    Ulak, Güner; Mutlu, Oguz; Akar, Füruzan Yildiz; Komsuoğlu, F Ipek; Tanyeri, Pelin; Erden, B Faruk

    2008-10-01

    Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10-50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.

  6. Photoaffinity labeling of the dopamine reuptake carrier protein with 3-azido 3H GBR-12935

    International Nuclear Information System (INIS)

    Berger, S.P.; Martenson, R.E.; Laing, P.; Thurkauf, A.; Decosta, B.; Rice, K.C.; Paul, S.M.

    1991-01-01

    A high affinity tritiated azido-diphenylpiperazine derivative, 3-azido 3 H GBR-12935, was synthesized as a potential photoaffinity probe of the dopamine transporter. Initially, the reversible binding of 3-azido 3 H GBR-12935 to crude synaptosomal membranes from the rat striatum was characterized. Specific binding was sodium dependent and inhibited by a variety of drugs that are known to potently inhibit dopamine uptake. Other neurotransmitter uptake inhibitors, as well as cis-flupenthixol, a potent inhibitor of 3 H GBR-12935 binding to piperazine binding sites, failed to inhibit specific binding at concentrations of less than or equal to 10 microM. A good correlation was observed between the relative potencies of these drugs in inhibiting dopamine uptake into synaptosomes and in inhibiting specific 3-azido 3 H GBR-12935 binding to rat striatal membranes. These data suggest that 3-azido 3 H GBR-12935, like other diphenylpiperazines such as 3 H GBR-12935 and 3 H GBR-12909, binds primarily to the dopamine transporter under defined assay conditions. After UV photolysis of crude synaptosomal membranes preincubated with 3-azido 3 H GBR-12935 (1-2 nM), a single radiolabeled polypeptide with an apparent molecular mass of 80 kDa was observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography. Photoincorporation of 3-azido 3 H GBR-12935 into this polypeptide was inhibited selectively by compounds that inhibit the uptake of dopamine and was completely dependent on the presence of Na+. No photolabeled proteins were observed when cerebellar membranes were substituted for striatal membranes. Essentially complete adsorption of the radiolabeled 80-kDa polypeptide to wheat germ agglutinin and elution with N-acetyl-D-glucosamine strongly suggest that the dopamine transporter polypeptide photolabeled by 3-azido 3 H GBR-12935 is glycosylated

  7. 17β-Estradiol augments antidepressant efficacy of escitalopram in ovariectomized rats: Neuroprotective and serotonin reuptake transporter modulatory effects.

    Science.gov (United States)

    Ibrahim, Weam W; Safar, Marwa M; Khattab, Mahmoud M; Agha, Azza M

    2016-12-01

    The prevalence or recurrence of depression is seriously increased in women during the transition to and after menopause. The chronic hypo-estrogenic state of menopause may reduce the response to antidepressants; however the influence of estrogen therapy on their efficacy is still controversial. This study aimed at investigating the effects of combining escitalopram with 17β-estradiol on depression and cognitive impairment induced by ovariectomy, an experimental model of human menopause. Young adult female Wistar rats were subjected to either sham operation or ovariectomy. Ovariectomized animals were treated chronically with escitalopram (10mg/kg/day, i.p) alone or with four doses of 17β-estradiol (40μg/kg, s.c) given prior to the behavioral tests. Co-administration of 17β-estradiol improved escitalopram-induced antidepressant effect in forced swimming test verified as more prominent decrease in the immobility time without opposing its memory enhancing effect in Morris water maze. 17β-estradiol augmented the modulatory effects of escitalopram on the hippocampal levels of brain-derived neurotrophic factor and serotonin reuptake transporter as well as tumor necrosis factor-alpha without altering its effects on the gene expressions of serotonin receptor 1A, estrogen receptors alpha and beta, or acetylcholinestearase content. This combined therapy afforded synergistic protective effects on the brain histopathological architecture, particularly, the hippocampus. The antidepressant effect of 17β-estradiol was abolished by pretreatment with estrogen receptor antagonist, tamoxifen (10mg/kg, p.o). In conclusion, 17β-estradiol-induced antidepressant effect was confined to intracellular estrogen receptors activation. Moreover, 17β-estradiol enhanced escitalopram's efficiency in ameliorating menopausal-like depression, via exerting synergistic neuroprotective and serotonin reuptake transporter modulatory effects, without impeding escitalopram-mediated cognitive

  8. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis

    DEFF Research Database (Denmark)

    Jakobsen, Janus Christian; Katakam, Kiran Kumar; Schou, Anne

    2017-01-01

    depressive disorder. We searched for eligible randomised clinical trials in The Cochrane Library's CENTRAL, PubMed, EMBASE, PsycLIT, PsycINFO, Science Citation Index Expanded, clinical trial registers of Europe and USA, websites of pharmaceutical companies, the U.S. Food and Drug Administration (FDA...

  9. A combined α7 nicotinic acetylcholine receptor agonist and monoamine reuptake inhibitor, NS9775, represents a novel profile with potential benefits in emotional and cognitive disturbances

    DEFF Research Database (Denmark)

    Andreasen, Jesper T; Redrobe, John P; Nielsen, Elsebet Ø

    2013-01-01

    also improve by nicotinic acetylcholine receptor (nAChR) activation. Preclinical studies have corroborated this and also demonstrated a synergistic antidepressant-like action when nAChR agonists and MRIs are combined. Here, we present the in vitro and in vivo profile of NS9775, a combined full α7 n...

  10. Effects of selective serotonin reuptake inhibitors on three sex steroids in two versions of the aromatase enzyme inhibition assay and in the H295R cell assay

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Hansen, Cecilie Hurup; Nellemann, Christine

    2015-01-01

    shown to inhibit the aromatase enzyme in both types of aromatase assays. The IC50 values ranged from 3 to 600μM. All five SSRIs, were further investigated in the H295R cell line. All compounds altered the steroid secretion from the cells, the lowest observed effect levels were 0.9μM and 3.1μ....... In this study we investigated whether the endocrine effect due to SSRI exposure could be detected in well adopted in vitro steroidogenesis assays, two versions of the aromatase enzyme inhibition assay and the H295R cell assay. The five drugs citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, were......M for sertraline and fluvoxamine, respectively. In general the H295R cell assay was more sensitive to SSRI exposure than the two aromatase assays, up to 20 times more sensitive. This indicates that the H295R cell line is a better tool for screening endocrine disrupting effects. Our findings show that the endocrine...

  11. Insight into synergetic mechanisms of tetracycline and the selective serotonin reuptake inhibitor, sertraline, in a tetracycline-resistant strain of Escherichia coli

    DEFF Research Database (Denmark)

    Li, Lili; Kromann, Sofie; Olsen, John Elmerdahl

    2017-01-01

    further decreases pH, resulting in cell death. This study shows that sertraline interacts with tetracycline in a synergistic and AcrAB-TolC pump-independent manner. The combinational treatment was further shown to induce many changes in the global transcriptome, including altered tetA and tetR expression......Sertraline, an antidepressive drug, has been reported to inhibit general bacterial efflux pumps. In the present study, we report for the first time a synergistic effect of sertraline and tetracycline in a TetA-encoded tetracycline-resistant strain of Escherichia coli. Synergy between sertraline...... '1). RNA data suggest changes in respiration that is likely to decrease intracellular pH and thereby the proton-motive force, which provides the energy for the tetracycline efflux pump. Furthermore, sertraline and tetracycline may induce a change from oxidation to fermentation in the E.coli, which...

  12. Residual sleep disturbance and risk of relapse during the continuation/maintenance phase treatment of major depressive disorder with the selective serotonin reuptake inhibitor fluoxetine

    Directory of Open Access Journals (Sweden)

    McGrath Patrick J

    2010-02-01

    Full Text Available Abstract Background Relapse of major depressive disorder (MDD is a common clinical problem. This study was designed to determine whether residual sleep disturbance (insomnia and hypersomnia predict risk of relapse during the continuation and maintenance treatment of MDD. Methods A total of 570 patients with MDD were treated with open-label, flexible dose fluoxetine (range 20 to 60 mg; mean dose = 45.8 mg/day; SD = 15.1 for 12 weeks. Under double blind conditions, 262 patients who achieved clinical response were randomly assigned to continue fluoxetine or to switch to placebo for 52 weeks or until relapse. Residual sleep disturbance during the baseline visit of the double-blind phase was assessed using items 4, 5, 6 (insomnia and 22, 23, 24 (hypersomnia of the Hamilton Depression Rating Scale (HDRS. Survival analysis was utilized to determine the effect of residual sleep disturbance on risk of relapse. Results The severities of early (P > 0.05, middle (P > 0.05, late (P > 0.05, or total (P > 0.05 residual insomnia were not found to significantly predict risk of relapse during continuation and maintenance-phase treatment. Similarly, the severities of early bedtime (P > 0.05, oversleeping (P > 0.05, napping (P > 0.05, or total (P > 0.05 residual hypersomnia were not found to significantly predict risk of relapse during continuation and maintenance-phase treatment. Conclusion The present study did not identify the severity of residual sleep disturbance among fluoxetine responders to predict risk of MDD relapse. The size of our sample may have precluded us from identifying more modest effects of residual sleep disturbance on the risk of relapse in MDD patients. Future studies are needed to further explore the relationship between residual sleep disturbance and relapse in MDD. Trial Registration ClinicalTrials.gov Identifier: NCT00427128

  13. Infant and childhood neurodevelopmental outcomes follow