Serotonin Syndrome
Last updated: 09/30/2006
Serotonin (5-hydroxytryptamine, 5-HT) syndrome is a drug-induced syndrome typically characterized by a triad of altered mental status, neuromuscular abnormalities, and autonomic dysfunction. It is a potentially life-threatening disorder of excessive serotonergic activity. The syndrome typically occurs when two serotonergic agents are given in combination; however, it may occur with a single drug entity.
The pathophysiology of sero-tonin syndrome still remains poorly understood. It is believed to result from overstimulation of the 5-HT1a and 5-HT2 receptors caused by serotonergic drugs. The drug classes that are implicated in serotonin syndrome include serotonin precursors (eg: L-tryptophan); serotonin agonists (eg: sumatriptan); serotonin releasers (eg: amphetamines); selective serotonin reuptake inhibitors (SSRIs) (eg: fluoxetine); sero-tonin/norepinephrine reuptake inhibitors (SNRIs) (eg: venlafax-ine); monoamine oxidase inhibitors (eg: tranylcypromine); lithium, and some herbal medications (eg: St. John's Wort).
A study published in the Quarterly Journal of Medicine1 compared the relative toxicity of venlafaxine, a SNRI, and SSRIs in overdose compared to tricyclic antidepressants (TCAs). The results of the study indicated that venlafaxine is more likely to cause serotonin toxicity but less likely to cause coma when compared to the TCAs. SSRIs are less likely to cause coma, require ICU admission, or prolong the QRS interval, but are more likely to cause serotonin toxicity.
The clinical features of serotonin syndrome are highly variable. The diagnosis is determined with the presence of three major symptoms and two minor symptoms. Some major symptoms include: confusion, coma, fever or hyperthermia, diaphoresis, tremor, shivering, hyperflexia, and seizures. Some examples of minor symptoms include agitation, insomnia, tachycardia, flushing, mydriasis, and ataxia. In most cases, serotonin syndrome is a self-limiting condition and will improve once the offending agent is discontinued. Typically, mild to mod-erate cases usually resolve in 24-72 hours. In severe cases, this syndrome may be complicated due to severe hyperthermia, rhabdomyolysis, disseminated intravascular coagulation, and/or adult respiratory syndrome.
Discontinuation of the offending agent is the preferred treatment for serotonin syndrome. However, benzodiazepines may be utilized to control seizures and muscle hyperreactivity. To note, there are no published randomized clinical studies for the treatment of this syndrome. Some cases have been successfully treated with of cyproheptadine 4 to 8 mg orally, which may be repeated in two hours. If the patient has not responded after 16 mg, then cyproheptadine should be discontinued. If the patient responds, then it may be continued in divided doses up to 32 mg/day. Other drugs that have been suggested include mirtazapine, chlorpromazine, and propranolol; however these agents have contraindications and adverse effects that limit their use.
Serotonin syndrome results from an overstimulation of serotonin receptors due to drugs that may increase serotonin production, inhibit serotonin metabolism, increase serotonin release, inhibit serotonin reuptake, or stimulate serotonin receptors. The syndrome is self-limiting and will resolve spontaneously after discontinuation of the offending agent(s).
1 Whyte M, Dawson AH, and Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Quarterly Journal of Medicine, Feb 2003; 96; p. 369 ? 74.