Recognition and management of clozapine adverse effects: A systematic review and qualitative synthesis

OBJECTIVE: Clozapine is substantially underutilized in most countries and clinician factors including lack of knowledge and concerns about adverse drug effects (ADEs) contribute strongly to treatment reluctance. The aim of this systematic review was to provide clinicians with a comprehensive information source regarding clozapine ADEs. METHODS: PubMed and Embase databases were searched for English language reviews concerned with clozapine ADEs; publications identified by the automated search were manually searched for additional relevant citations. Following exclusion of redundant and irrelevant reports, pertinent information was summarized in evidence tables corresponding to each of six major ADE domains; two authors reviewed all citations for each ADE domain and summarized their content by consensus in the corresponding evidence table. This study was conducted in accordance with PRISMA principles. RESULTS: Primary and secondary searches identified a total of 305 unique reports, of which 152 were included in the qualitative synthesis. Most clozapine ADEs emerge within 3 months, and almost all appear within 6 months, after initiation. Notable exceptions are weight gain, diabetic ketoacidosis (DKA), severe clozapine-induced gastrointestinal hypomotility (CIGH), clozapine-induced cardiomyopathy (CICM), seizures, and clozapine-induced neutropenia (CIN). Most clozapine ADEs subside gradually or respond to dose reduction; those that prompt discontinuation generally do not preclude rechallenge. Rechallenge is generally inadvisable for clozapine-induced myocarditis (CIM), CICM, and clozapine-induced agranulocytosis (CIA). Clozapine plasma levels >600-1000 μg/L appear more likely to cause certain ADEs (e.g., seizures) and, although there is no clear toxicity threshold, risk/benefit ratios are generally unfavorable above 1000 μg/L. CONCLUSION: Clozapine ADEs rarely require discontinuation.