Antipsychotic exposure and regional brain volume changes in schizophrenia: Dose-related associations

The long-term effects of antipsychotic treatment on brain structure in schizophrenia remain uncertain. Previous meta-analyses have primarily compared patients with controls rather than examining dose-related associations between cumulative exposure and brain structure.

To quantify the association between cumulative antipsychotic exposure (chlorpromazine equivalents) and structural brain changes measured by MRI in patients with schizophrenia.

Following prospective registration (PROSPERO CRD420261352526), 19 studies involving 1607 patients were included. Pearson's r or standardized β coefficients were pooled using random-effects models with the DerSimonian-Laird estimator. Subgroup analyses were conducted for the primary outcome.

Higher cumulative antipsychotic exposure was associated with lower global gray matter volume (10 studies, n = 993; r = -0.259, 95% CI -0.337 to -0.179; p < 0.001). Publication bias was detected for this outcome (Egger's test p = 0.00574). Negative associations were also observed for global cortical thickness (r = -0.293), frontal lobe volume (r = -0.339), temporal lobe volume (r = -0.351), and total brain volume (r = -0.310). Lateral ventricular volume showed a positive association (r = 0.228), whereas white matter volume was not significantly associated. The dose-related association with gray matter volume was consistent across study designs and illness stages, with no significant subgroup differences.

Higher cumulative antipsychotic exposure was modestly associated with greater structural brain alterations. However, these observational findings do not establish causality because medication exposure is closely linked to illness progression. Interpretation is further limited by publication bias, the small number of studies, and heterogeneity across secondary outcomes. Well-designed prospective longitudinal studies are needed to better distinguish medication effects from disease-related changes.