Clozapine-Associated Serotonin Syndrome: A Case Report and Literature Review

Serotonin syndrome (SS) is a rare but potentially life-threatening condition resulting from increased serotoninergic activity in the central nervous system, either from exposure to a serotonin agonist or from withdrawal of a serotonin antagonist. Clozapine withdrawal has been implicated in cases of serotonin syndrome; however, clozapine exerts both agonist and antagonist properties at the serotonin receptor. We present the case of a 37-year-old male with unspecified psychosis and a structural neurological deficit who developed SS according to the Hunter Criteria while on a regimen of clozapine, paliperidone, and prednisone taper. Within an hour of receiving 400 mg of clozapine, the patient developed fever, tachycardia, diaphoresis, tremor, hyperreflexia, and inducible clonus. His symptoms resolved with supportive care, including intravenous fluids, benzodiazepines, and acetaminophen. We speculate that clozapine exerted its serotoninergic properties to induce SS symptoms in our patient, although alternative considerations and etiologies are discussed. We also include a review of the literature on cases of serotonin syndrome associated with clozapine. Five case reports were identified, all of which described SS occurring in the context of clozapine withdrawal or discontinuation. To our knowledge, ours is the first case suggestive of clozapine-induced SS. This case highlights the importance of considering SS in patients receiving clozapine, especially when concomitant medications may amplify serotoninergic effects. In addition, clinicians should exercise caution when using clozapine in patients with complex neurological conditions or in those with atypical psychiatric presentations. Close monitoring is needed when clozapine dose adjustments are made.