Serotonin toxicity caused by moclobemide too soon after paroxetine-selegiline.

Serotonin toxicity is an iatrogenic complication of serotonergic drug therapy. It is due to an overstimulation of central and peripheral serotonin receptors that lead to neuromuscular, mental and autonomic changes. Moclobemide is a reversible inhibitor of monoamine oxidase (MAO)-A, selegiline is an irreversible selective inhibitor of MAO-B, and paroxetine is a selective serotonin reuptake inhibitor. Combined use of these agents is known to cause serotonin toxicity. A 53-year-old woman had been treated with paroxetine and selegiline. After moclobemide was prescribed in place of paroxetine without a washout period, she quickly developed confusion, agitation, ataxia, diaphoresis, tremor, mydriasis, ocular clonus, hyperreflexia, tachycardia, moderately elevated blood pressure and high fever, symptoms that were consistent with serotonin toxicity. Discontinuation of the drugs, hydration and supportive care were followed by remarkable improvement of baseline status within 3 days. This case demonstrates that serotonin toxicity may occur even with small doses of paroxetine, selegiline and moclobemide in combination. Physicians managing patients with depression must be aware of the potential for serotonin toxicity and should be able to recognize and treat or, ideally, anticipate and avoid this pharmacodynamically-mediated interaction that may occur between prescribed drugs.

Serotonin toxicity: a practical approach to diagnosis and treatment.

Excess serotonin in the central nervous system leads to a condition commonly referred to as the serotonin syndrome, but better described as a spectrum of toxicity - serotonin toxicity. Serotonin toxicity is characterised by neuromuscular excitation (clonus, hyperreflexia, myoclonus, rigidity), autonomic stimulation (hyperthermia, tachycardia, diaphoresis, tremor, flushing) and changed mental state (anxiety, agitation, confusion). Serotonin toxicity can be: mild (serotonergic features that may or may not concern the patient); moderate (toxicity which causes significant distress and deserves treatment, but is not life-threatening); or severe (a medical emergency characterised by rapid onset of severe hyperthermia, muscle rigidity and multiple organ failure). Diagnosis of serotonin toxicity is often made on the basis of the presence of at least three of Sternbach's 10 clinical features. However, these features have very low specificity. The Hunter Serotonin Toxicity Criteria use a smaller, more specific set of clinical features for diagnosis, including clonus, which has been found to be more specific to serotonin toxicity. There are several drug mechanisms that cause excess serotonin, but severe serotonin toxicity only occurs with combinations of drugs acting at different sites, most commonly including a monoamine oxidase inhibitor and a serotonin reuptake inhibitor. Less severe toxicity occurs with other combinations, overdoses and even single-drug therapy in susceptible individuals. Treatment should focus on cessation of the serotonergic medication and supportive care. Some antiserotonergic agents have been used in clinical practice, but the preferred agent, dose and indications are not well defined.

Hyperthermic syndromes induced by toxins.

Normal thermogenesis requires a complex interaction between systems that generate and dissipate heat. Serving as director of thermogenesis, the hypothalamus activates the sympathetic nervous system along with the thyroid and adrenal glands to respond to changes in body temperature. Working in concert, these systems result in heat generation by uncoupling of oxidative phosphorylation, combined with impaired heat dissipation through vasoconstriction. In this article, the authors discuss serotonin and sympathomimetic syndromes, neuroleptic malignant syndrome,and malignant hyperthermia and how these syndromes affect the hypothalamic and sympathetic nervous systems, resulting at times in severe hyperthermia. Current treatment recommendations and future trends in treatment are also discussed.

Management of drug-induced hyperthermia.

PURPOSE OF REVIEW: To review the current literature describing drug-induced hyperthermia and its treatment. Specifically, five syndromes will be discussed: malignant hyperthermia, neuroleptic malignant syndrome, anticholinergic poisoning, sympathomimetic poisoning, and serotonin syndrome. RECENT FINDINGS: The most recent findings in the literature are the recognition of previously undescribed drugs or drug combinations that have lead to hyperthermia. Recent literature also attests to the potential morbidity and mortality of drug-induced hyperthermia. SUMMARY: Although the recognition of causative agents is increasing, the treatment of drug-induced hyperthermia remains unchanged and continues to be primarily supportive.

The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.

BACKGROUND: There are difficulties with the diagnosis of serotonin toxicity, particularly with the use of Sternbach's criteria. AIM: To improve the criteria for diagnosing clinically significant serotonin toxicity. DESIGN: Retrospective analysis of prospectively collected data METHODS: We studied all patients admitted to the Hunter Area Toxicology Service (HATS) following an overdose of a serotonergic drug from January 1987 to November 2002 (n = 2222). Main outcomes were: diagnosis of serotonin toxicity by a clinical toxicologist, fulfillment of Sternbach's criteria and treatment with a serotonin receptor (5-HT(2A)) antagonist. A learning dataset of 473 selective serotonin reuptake inhibitor (SSRI)-alone overdoses was used to determine individual clinical features predictive of serotonin toxicity by univariate analysis. Decision rules using CART analysis were developed, and tested on the dataset of all serotonergic overdose admissions. RESULTS: Numerous clinical features were associated with serotonin toxicity, but only clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia were needed for accurate prediction of serotonin toxicity as diagnosed by a clinical toxicologist. Although the learning dataset did not include patients with life-threatening serotonin toxicity, hypertonicity and maximum temperature > 38 degrees C were universal in such patients; these features were therefore added. Using these seven clinical features, decision rules (the Hunter Serotonin Toxicity Criteria) were developed. These new criteria were simpler, more sensitive (84% vs. 75%) and more specific (97% vs. 96%) than Sternbach's criteria. DISCUSSION: These redefined criteria for serotonin toxicity should be more sensitive to serotonin toxicity and less likely to yield false positives.

Drug interactions--friend or foe?

An explosion of knowledge about interactions of drugs with other drugs and with foods threatens to inundate clinicians. This review provides a better understanding of the cytochrome P450 system with a focus on those enzymes most involved in drug metabolism. Emphasis is placed on antidepressant medications, how they are metabolized by the P450 system, and how they alter the metabolism of other drugs. The role of antidepressants in precipitating the serotonin syndrome is also discussed.

[Pharmacologic analysis of the mechanism of development of serotonin diarrhea in the mouse]. / Farmakologicheskii analiz mekhanizma vozniknoveniia serotoninovoi diarei u myshei.

Diarrhea that arises in mice given serotonin intravenously is not suppressed by tipindolol, LSD-25, ciproheptadine in doses in which these drugs block the D and T serotonin-reactive structures, or is not reduced by hexonium, thereby providing no evidence in favour of the reflex nature of the effect. Diarrhea is suppressed by morphine and atropine, thus pointing to the responsibility for its origin of M-serotoninoreactive structures of intestinal parasympathetic ganglia with subsequent involvement of the postganglionic cholinergic link.

Volvulus of the small bowel.

Over two years in a major hospital in northern Uganda 12 cases of primary volvulus of the small bowel were seen out of a total of 65 cases of intestinal obstruction which did not include external hernias. This relatively high incidence was associated with drinking large amounts of local "kongo" beer. General systemic symptoms of circulatory collapse were conspicuous by their absence. The kongo beer was found to have a high concentration of serotonin, and this substance may have caused the volvulus of the small bowel in three quarters of the cases.