Antipsychotic exposure and regional brain volume changes in schizophrenia: Dose-related associations.
Khalilullah Arsyi, Artha M T Simanjuntak, Juwita Saragih et al.
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In 30 seconds
This systematic review and meta-analysis examined associations between cumulative antipsychotic exposure, expressed as chlorpromazine equivalents, and MRI-measured brain structure in people with schizophrenia. Across 19 studies involving 1607 patients, greater 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). Negative associations were also reported for cortical thickness and several regional or total brain volumes, while white matter volume was not significantly associated. The observational results do not establish that medication caused the structural differences.
Key findings
- Cumulative exposure was inversely associated with global gray matter volume (10 studies, n = 993; r = -0.259, 95% CI -0.337 to -0.179; p < 0.001).
- Negative associations were reported 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 was positively associated with exposure (r = 0.228); white matter volume was not significantly associated.
- The gray matter association was consistent across study designs and illness stages, with no significant subgroup differences.
Why it matters
The findings highlight a relationship between cumulative antipsychotic exposure and several MRI measures of brain structure, relevant to interpreting long-term imaging changes in schizophrenia. Because exposure is closely linked to illness progression, the observed associations cannot distinguish medication effects from disease-related changes. The results therefore underscore the need for cautious interpretation rather than a causal conclusion.
What to keep in mind
The evidence is observational and cannot establish causality. Publication bias was detected for global gray matter volume; the authors also note few studies and heterogeneity across secondary outcomes.