Impact of clozapine on the proteome: A systematic review and functional analyses

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia (TRS), yet its use is limited by potentially life-threatening adverse effects including myocarditis, agranulocytosis and pneumonia. Improved mechanistic understanding may facilitate safer prescribing. We conducted the first systematic review integrating proteomic findings associated with clozapine exposure. Following PRISMA guidelines, PubMed, Embase and Scopus were searched for clozapine-associated proteomic studies in animal, human and cell-based models. Differentially expressed proteins were mapped to Reactome pathways using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). Using the same approach, analyses stratified all proteins by model type and replicated proteins by exposure duration and biological system. Replicated proteins were further analysed using QIAGEN Ingenuity Pathway Analysis (IPA). Across studies, 1070 unique proteins changed following clozapine exposure (603 increased, 394 decreased, 73 discordant). Of these, 152 were identified in ≥2 studies, with 79 showing concordant directionality. Nine were replicated in ≥3 studies with consistent direction. Overall STRING analysis identified recurrent immune/inflammatory, cellular-stress and neuronal pathway enrichment, with stratified analyses providing partial support for these and related metabolic processes across model types, exposure duration and biological system. IPA highlighted necrosis-related processes and downstream disease effects involving cardiovascular, hepatic and renal systems. These findings suggest that immune, inflammatory and regulated cell-death pathways may contribute to clozapine-associated adverse effects, although their relationship to treatment response remains unknown. Limited time series data directly compare brain and peripheral blood changes. Prospective longitudinal proteomic studies during clozapine initiation are warranted to identify early biomarkers and intervention windows.