Response to: Letter regarding ‘Management of serotonin syndrome (toxicity)’

Abstract

We thank Mullins et al for your letter regarding our review article on the management of serotonin toxicity.¹ While your insights are valuable, we must clarify our stance on the use of cyproheptadine, particularly in the context of mild serotonin toxicity. We agree that the cornerstone of managing severe serotonin toxicity lies not in the administration of an ‘antidote’ but in providing effective early resuscitative and supportive care.

It is important to note that the pathophysiology of serotonin toxicity is complex, with at least seven families of 5-HT receptors and no single receptor being solely responsible for serotonin toxicity. However, the 5-HT1A and 5-HT2A receptors have been primarily implicated in serotonin toxicity.² 5-HT1A has a higher affinity for serotonin than 5-HT2A receptors, and as serotonin concentrations increase, 5-HT2A activation leads to more severe toxicity. What is still unclear is the extent of serotonin antagonism after a single dose of cyproheptadine, degree of antagonism at 5HT1A and 5HT2A receptors and the time of onset of this antagonism. Furthermore, the percentage of 5-HT blockade required to alleviate symptoms is unknown. The brief letter to the editor by Kapur, which Mullins et al reference, discusses the use of 18F-setoperone positron emission tomography (PET) in two healthy volunteers, one receiving cyproheptadine 4 mg and the other 6 mg 8 hourly for 6 days.³ This report of two patients demonstrated that cyproheptadine could block 85%–95% of 5HT2 receptors in the prefrontal cortex after 6 days of treatment.³ No data are provided after a single dose or even after 24 h of treatment.

We do not dismiss cyproheptadine as a treatment option for mild serotonin toxicity; rather, we emphasize that there is no strong evidence that cyproheptadine results in better or faster symptom resolution compared to benzodiazepines. Benzodiazepines are commonly administered to manage anxiety, agitation and other toxidromes, including sympathomimetic and anticholinergic toxicity, so clinicians are familiar with their use in neurotoxic syndromes. In our clinical practice, patients with mild serotonin toxicity typically respond well to small doses of diazepam (5–10 mg) and can be safely discharged.

Oral diazepam has a rapid onset of action within an hour, compared to cyproheptadine with an onset of 2–3 h and peak concentrations at 4 h.⁴ Relying on cyproheptadine could delay treatment, particularly if not readily available. Assertions of its rapid efficacy lack empirical support and are inconsistent with its pharmacokinetic profile.

The authors have no conflicts of interest to declare.