Since the initiation of antipsychotic drug therapy for schizophrenia, clinical observations and empirical studies have demonstrated that these medications bring benefit and harm. Consequently, efforts to develop new antipsychotic medications during the past 50 years have been motivated, at least partly, by the desire to enhance the benefit to harm ratio relative to existing medications. In this issue of the Archives, Ho and colleagues1 examine one arm of this ratio by asking whether antipsychotic medications contribute to progressive brain volume reductions in schizophrenia. Individuals early in the course of schizophrenia (n = 211) were treated with antipsychotic medications according to standard clinical practice and followed up longitudinally with clinical assessments and serial magnetic resonance imaging (MRI) scans (between 2 and 5 scans per individual) for a mean of 7 years. The authors found that the amount of exposure to antipsychotic medication predicted decrements in cerebral gray and white matter volumes and increased the volume of the putamen. Illness duration and severity were also associated with smaller brain volume measures, but the relationship between antipsychotic medication use and brain volume remained significant after accounting for the effects of illness severity and duration and substance abuse history. Interestingly, changes in brain volume with time were similar for all classes of antipsychotic medications (ie, typical antipsychotics, atypical [ie, excluding clozapine] antipsychotics, and clozapine).
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