Comment: Serotonin Syndrome, Mydriasis, and Cyproheptadine

TO THE EDITOR: In the July/August issue, McDaniel reported four cases of alleged serotonin syndrome that were treated with cyproheptadine.1 He suggested that the relatively moderate pupillary constriction that occurred following the administration of cyproheptadine was a useful measure of suppression of the syndrome.1 This is a rather ambitious hypothesis based on a small number of cases. It is therefore important to clarify the clinical features of serotonin syndrome and their time course. McDaniel included an unusual list of clinical features for serotonin syndrome. It is better described as a triad of clinical features: (1) autonomic signs; (2) neuromuscular changes; and (3) altered mental status.2 Important omissions in the author’s list1 are the neuromuscular features of clonus, ocular clonus, and hyperreflexia. Severe serotonin toxicity causes hyperthermia, increased tone that may lead to respiratory failure, and rhabdomyolysis, but fatal tachyarrhythmias are rarely reported.2 It has been previously suggested that the condition is more consistent with a spectrum of toxicity,3-5 rather than a distinct syndrome. Mydriasis is not a universal finding in serotonin syndrome and is not included in either Sternbach’s criteria6 or in other scoring systems.7 In presentations to the Hunter Area Toxicology Service (HATS), Australia, mydriasis occurs in less than one-half of patients with serotonin toxicity. Of 8542 admissions to the HATS in the last 12 years, 1204 had mydriasis from any cause of poisoning (14.1%). In the same time period, 149 patients were diagnosed with serotonin toxicity by the attending clinical toxicologist, and 41.6% of these had mydriasis. Thus, the use of mydriasis to identify cases of serotonin toxicity is limited as it occurs in <50% of cases. Mydriasis is far more common with anticholinergic toxicity, which is an important differential diagnosis in these cases — and may also satisfy Sternbach’s criteria, which, therefore, are not completely specific. McDaniel attempts to provide a mechanistic explanation for serotonin toxicity based on the few cases described and the resolution of mydriasis with cyproheptadine. Unfortunately, the explanation is based on cases with atypical serotonergic features and the false premise that mydriasis occurs in all cases of serotonin syndrome. There is considerable animal work that supports the involvement of 5-HT2A, rather than 5-HT1A, receptors in serotonin syndrome.8,9 There is also increasing clinical evidence that serotonin toxicity can be reversed by nonspecific 5-HT2 receptor antagonists, such as cyproheptadine and chlorpromazine.4,10 Although the author suggests that the time course of serotonin syndrome is of the order of several days,1 this is not supported in the literature.2,4 In all but the most severe cases, the condition resolves within 24 hours after the cessation of the implicated agent.2 The rapid onset and progression of severe serotonin syndrome and its rapid resolution are important features that differentiate it from other conditions, such as neuroleptic malignant syndrome.2,4 Cyproheptadine appears to be a useful treatment in serotonin toxicity based on the limited evidence available. If used appropriately, it appears to shorten the course of the illness, although this has not been tested in controlled trials. In a case of serotonin toxicity due to the interaction between dexamphetamine and venlafaxine,11 there was a clear reduction in tachycardia, tremor, neuromuscular features, and anxiety over the course of four hours. This is similar to other reports of cyproheptadine use in serotonin toxicity.10 Cyproheptadine is an appropriate early treatment for serotonin toxicity, as the author suggested. However, it should be titrated against both the neuromuscular and autonomic features to determine a clinical response, not solely mydriasis. If there is minimal or no response over a period of hours, then other diagnoses should be revisited; in severe cases with hyperthermia and sustained clonus, further therapies such as paralysis and sedation in an intensive care unit should be undertaken.