Antidepressants and seizures: emphasis on newer agents and clinical implications

Montgomery, Stuart

doi:10.1111/j.1368-5031.2005.00731.x

Cited by 111 publications

(71 citation statements)

References 33 publications

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“…In animal studies using atomoxetine or reboxetine, convulsions were observed only at extremely high doses (Wong et al, 2000;Wernicke et al, 2007). The incidence of seizures during treatment with NRIs has been reportedly rare (Montgomery, 2005;Wernicke et al, 2007). Brain levels of the drugs in overdose cases may be considerably higher than levels during treatment at therapeutic doses (Poggesi et al, 2000;Kiyono et al, 2004Kiyono et al, , 2008Garside et al, 2006;Kanegawa et al, 2006), suggesting that potent inhibition of neuronal GIRK channels by atomoxetine and reboxetine after overdose may contribute to increased seizure activity.…”

Section: Discussionmentioning

confidence: 99%

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

Kobayashi

Washiyama

Ikeda

2010

Neuropsychopharmacol

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Atomoxetine and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attentiondeficit/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 concentrationdependent, 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 A 1 adenosine receptors or by intracellularly applied GTPgS, 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.

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Section: Discussionmentioning

confidence: 99%

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

Kobayashi

Washiyama

Ikeda

2010

Neuropsychopharmacol

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“…Since then drugs such as the SSRIs have been prescribed in increasing quantity, in part because of a lower risk of seizures both in normal use and after overdose (Montgomery, 2005). In turn they have featured more prominently in fatal poisoning data (Table 2).…”

Section: Selective Serotonin Reuptake Inhibitorsmentioning

confidence: 99%

Fatal toxicity of drugs used in psychiatry

Flanagan

2007

Hum. Psychopharmacol. Clin. Exp.

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Certified deaths from fatal poisoning (accidents, suicides and open verdicts) in England and Wales have declined steadily (from 3952 in 1979 to 2565 in 2004). There was also a small annual reduction in suicides in males and in females over this period. In 2004, self-poisoning accounted for 25% of suicides and open verdicts in males (n ¼ 862) and 45% in females (n ¼ 540).Poisoning death rates per million prescriptions were about 10 times higher for tricyclic antidepressants (TCAs) than for selective serotonin reuptake inhibitors (SSRIs), England and Wales, 1993-2004. However, despite the increased prescription of SSRIs and related compounds in recent years, there has been only a slight decrease (some 10%) in the annual number of antidepressant-related poisoning deaths, in line with the reduction in suicides (all methods) over this period. Citalopram appears to have higher overdose toxicity than other SSRIs. Of newer non-SSRI antidepressants, the overdose toxicity of venlafaxine, although lower than that of TCAs, appears to be higher than that of SSRIs, with seizures, serotonin syndrome, rhabdomyolysis, renal failure and hepatic failure having been reported.Poisoning deaths involving antipsychotics either alone, or with other drugs and/or alcohol are many fewer than those involving antidepressants (713 and 5602 deaths, respectively, England and Wales, 1993-2004). Following the restriction on thioridazine usage (2000), thioridazine-associated fatal poisoning fell to zero by 2002, but this was balanced by an increase in deaths associated with atypical antipsychotics, most notably clozapine, olanzapine and quetiapine. Antipsychotic-related poisoning deaths were higher in 2004 than at any time since 1993.

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“…35 There is also some evidence from animal models that during adolescence susceptibility to seizures is increased 36,37 and reported annual incidence rates of epilepsy are higher in patients of 10-19 years of age than in adults. 38 Ingested dose and probability of seizures Dose-dependency of occurrence of seizures is well-known in cases of drug overdose 34 venlafaxine. 19 The results in the literature and of our study support the mechanistic view of the pathophysiology of seizures in overdose which are thought to be provoked by overexcitation of the brain by different pathways in a dose-dependent manner.…”

Section: 3034mentioning

confidence: 99%

Seizures after single-agent overdose with pharmaceutical drugs: Analysis of cases reported to a poison center

Reichert

Monnet‐Tschudi

et al. 2014

Clinical Toxicology

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CONTEXT Seizures during intoxications with pharmaceuticals are a well-known complication. However, only a few studies report on drugs commonly involved and calculate the seizure potential of these drugs. OBJECTIVES To identify the pharmaceutical drugs most commonly associated with seizures after single-agent overdose, the seizure potential of these pharmaceuticals, the age-distribution of the cases with seizures and the ingested doses. METHODS A retrospective review of acute single-agent exposures to pharmaceuticals reported to the Swiss Toxicological Information Centre (STIC) between January 1997 and December 2010 was conducted. Exposures which resulted in at least one seizure were identified. The seizure potential of a pharmaceutical was calculated by dividing the number of cases with seizures by the number of all cases recorded with that pharmaceutical. Data were analyzed using descriptive statistics. RESULTS We identified 15,441 single-agent exposures. Seizures occurred in 313 cases. The most prevalent pharmaceuticals were mefenamic acid (51 of the 313 cases), citalopram (34), trimipramine (27), venlafaxine (23), tramadol (15), diphenhydramine (14), amitriptyline (12), carbamazepine (11), maprotiline (10), and quetiapine (10). Antidepressants were involved in 136 cases. Drugs with a high seizure potential were bupropion (31.6%, seizures in 6 of 19 cases, 95% CI: 15.4-50.0%), maprotiline (17.5%, 10/57, 95% CI: 9.8-29.4%), venlafaxine (13.7%, 23/168, 95% CI: 9.3-19.7%), citalopram (13.1%, 34/259, 95% CI: 9.5-17.8%), and mefenamic acid (10.9%, 51/470, 95% CI: 8.4-14.0%). In adolescents (15-19y/o) 23.9% (95% CI: 17.6-31.7%) of the cases involving mefenamic acid resulted in seizures, but only 5.7% (95% CI: 3.3-9.7%) in adults ( 20y/o; p < 0.001). For citalopram these numbers were 22.0% (95% CI: 12.8-35.2%) and 10.9% (95% CI: 7.1-16.4%), respectively (p = 0.058). The probability of seizures with mefenamic acid, citalopram, trimipramine, and venlafaxine increased as the ingested dose increased. CONCLUSIONS Antidepressants were frequently associated with seizures in overdose, but other pharmaceuticals, as mefenamic acid, were also associated with seizures in a considerable number of cases. Bupropion was the pharmaceutical with the highest seizure potential even if overdose with bupropion was uncommon in our sample. Adolescents might be more susceptible to seizures after mefenamic acid overdose than adults. "Part of this work is already published as a conference abstract for the Reichert, C; Reichert, P; Monnet-Tschudi, F; Kupferschmidt, H; Ceschi, A; Rauber-Lüthy, C (2014 However, only a few studies report on drugs commonly involved and calculate the seizure potential of these drugs. Objectives. To identify the pharmaceutical drugs most commonly associated with seizures after single-agent overdose, the seizure potential of these pharmaceuticals, the age-distribution of the cases with seizures and the ingested doses. (11), maprotiline (10) and quetiapine (10). Antidepressants were involved in 136 cases. D...

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Antidepressants and seizures: emphasis on newer agents and clinical implications

Cited by 111 publications

References 33 publications

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

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

Fatal toxicity of drugs used in psychiatry

Seizures after single-agent overdose with pharmaceutical drugs: Analysis of cases reported to a poison center

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