Precipitants and clinical features of serotonin syndrome: a systematic review with patient-level analysis of published case reports and series

Background: Serotonin syndrome (SS) is a concern for prescribers of serotonergic acting agents and mainly antidepressants, yet the implicated drug combinations and associated outcomes across clinical settings remain incompletely characterized. Methods: We performed a systematic review in PubMed/Embase, searching for SS cases in adults from the database's inception until June 2024, and conducted a patient-level and network analysis of drug co-occurrence. The quality of SS diagnoses was assessed using the Hunter Serotonin Toxicity and the Sternbach Criteria. Results: A total of 764 cases were included; 653 (85.6%) and 496 (65.0%) met the Sternbach and the Hunter Criteria, respectively. Patients with SS following suicide attempts were more frequently admitted to intensive care units with higher mortality rates than patients with SS related to regular prescriptions (79.4% vs 35.6% and 18.0% vs 5.1%, respectively, both p < 0.001). Of 645 regular prescription cases, 92.9% were drug combinations (≥ 2 agents). Monotherapy cases were milder and often occurred after initiation of a new antidepressant in younger patients. Drug combinations involved non-antidepressants in 90.7%. Network analysis identified trazodone as the most connected antidepressant, and fentanyl and tramadol as the most connected non-antidepressant nodes. We identified five SS cases following antipsychotic discontinuation while maintaining serotonergic agents. Conclusions: Non-suicidal cases of SS during regular prescription were less serious than SS cases associated with intentional overdose. The emerging role of non-antidepressant agents (e.g., several opioids and antiparkinsonian drugs) as potential precipitants support tailored interprofessional medication review in poly-medicated subjects.