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

Abstract

We thank Lindeman et al.¹ for their response to our review on the management of serotonin toxicity and providing their opinion on the potential role of olanzapine as an antidote. We wish to clarify that our position is not one of pessimism but rather an emphasis on the critical importance of early resuscitative and supportive care as the cornerstone of management of severe serotonin toxicity, and the requirement for a clinically evidence-based approach to the use of antidotes.²

The pharmacodynamic arguments presented for olanzapine's receptor-binding properties are of interest but without robust clinical evidence beyond anecdotal reports, only provide the basis for clinical studies. While receptor occupancy studies of olanzapine suggest binding and high occupancy at 5-HT2 receptors, this is not evidence that it will decrease high concentrations of serotonin in the central nervous system or decrease the resultant clinical effects. Further, the study by Kapur et al. only examined 17 people receiving varying doses of olanzapine (5–60 mg/day) after treatment for at least 5 days,³ which cannot be translated to the single administration of olanzapine to treat serotonin toxicity. In fact, the data presented in your table would suggest that risperidone is a better agent.

Before an antidote is recommended, it is essential to assess the risk of adverse effects, compared to supportive care alone. A major drawback with chlorpromazine is the high risk of hypotension, particularly in a critically unwell patient with severe serotonin toxicity requiring intubation. A similar risk assessment would be required for olanzapine in serotonin toxicity. Numerous studies have demonstrated that olanzapine is often associated with anticholinergic effects and delirium.⁴

With the limited clinical reports of olanzapine use in serotonin toxicity, we encourage the authors to publish their experience. Interestingly, a study in overdose patients demonstrated that olanzapine and risperidone co-ingestion with a serotonergic agent reduced the risk of serotonin toxicity, with the lowest risk observed with risperidone.⁵ Even better would be to undertake a controlled trial of olanzapine versus placebo in serotonin toxicity to avoid the low-level evidence available for other antidotes. Until more evidence is available, we maintain that early recognition, withdrawal of serotonergic agents, and effective resuscitative and supportive measures remain the foundation of serotonin toxicity management.

Sincerely,

The authors have no conflicts of interest to declare.