BACKGROUND: Treatment-resistant schizophrenia (TRS) patients have been reported to exhibit distinct immunological characteristics compared with treatment-responsive patients, which have been hypothesised to relate to differential illness course or treatment response. Clozapine treatment has been associated with an increased risk of secondary antibody deficiency and a recent prospective observational study found reductions in immunoglobulin concentrations after clozapine initiation in individuals with treatment resistant schizophrenia. Researchers have hypothesised that hypogammaglobulinaemia may be associated with clozapine use in TRS, although it remains unclear whether this reflects treatment effects, underlying disease factors, or their interaction. AIMS: This systematic review primarily aimed to investigate reported associations between clozapine exposure, immunoglobulin levels, and B-lymphocyte populations in clinical studies. Preclinical findings were summarised separately. METHOD: A systematic literature search using terms related to clozapine, immunoglobulins, and B-lymphocytes was conducted on Ovid Embase Classic+Embase, Ovid Medline, Ovid APA PsycInfo, Scopus, Cochrane Library Search, and Web of Science Core Collection. Reference lists of key papers were also hand-searched for relevant studies. The search yielded 1373 records to screen. Human clinical studies, preclinical studies, and mechanistic hypotheses were analysed and discussed as separate domains. RESULTS: 16 studies were included, including 15 human clinical and 1 animal study. CLINICAL STUDIES: (1) frequently reported lower immunoglobulins, including total serum immunoglobulins and specific autoantibodies, (2) showed mixed findings for B-lymphocyte absolute counts and some evidence of subset shifts. The animal study reported lower immunoglobulin concentrations in clozapine-exposed animals relative to untreated disease-model controls. CONCLUSIONS: Current in vivo and animal studies report a diverse range of immunoglobulin and B-lymphocyte findings in clozapine-treated populations, with substantial variability and limited reproducibility across studies. Across the reviewed literature, confounding by indication remains the dominant interpretive constraint, and no immune alteration identified can be confidently ascribed to clozapine exposure independent of treatment-resistant illness. Future research should prioritise prospective human studies with baseline immune phenotyping, active comparators, longitudinal sampling, and complementary mechanistic work to evaluate whether observed immune alterations represent treatment-associated epiphenomena, illness-related features, or biologically meaningful processes, rather than inferring therapeutic mechanisms. Additional studies should also consider the relationship between these measures and changes in clinical severity scores as well as adverse effects, including infection rates and antibiotic use.
Kang et al. (Thu,) studied this question.