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, 68 (2), 128-37

Long-term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First-Episode Schizophrenia


Long-term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First-Episode Schizophrenia

Beng-Choon Ho et al. Arch Gen Psychiatry.


Context: Progressive brain volume changes in schizophrenia are thought to be due principally to the disease. However, recent animal studies indicate that antipsychotics, the mainstay of treatment for schizophrenia patients, may also contribute to brain tissue volume decrement. Because antipsychotics are prescribed for long periods for schizophrenia patients and have increasingly widespread use in other psychiatric disorders, it is imperative to determine their long-term effects on the human brain.

Objective: To evaluate relative contributions of 4 potential predictors (illness duration, antipsychotic treatment, illness severity, and substance abuse) of brain volume change.

Design: Predictors of brain volume changes were assessed prospectively based on multiple informants.

Setting: Data from the Iowa Longitudinal Study.

Patients: Two hundred eleven patients with schizophrenia who underwent repeated neuroimaging beginning soon after illness onset, yielding a total of 674 high-resolution magnetic resonance scans. On average, each patient had 3 scans (≥2 and as many as 5) over 7.2 years (up to 14 years).

Main outcome measure: Brain volumes.

Results: During longitudinal follow-up, antipsychotic treatment reflected national prescribing practices in 1991 through 2009. Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid volumes. Greater intensity of antipsychotic treatment was associated with indicators of generalized and specific brain tissue reduction after controlling for effects of the other 3 predictors. More antipsychotic treatment was associated with smaller gray matter volumes. Progressive decrement in white matter volume was most evident among patients who received more antipsychotic treatment. Illness severity had relatively modest correlations with tissue volume reduction, and alcohol/illicit drug misuse had no significant associations when effects of the other variables were adjusted.

Conclusions: Viewed together with data from animal studies, our study suggests that antipsychotics have a subtle but measurable influence on brain tissue loss over time, suggesting the importance of careful risk-benefit review of dosage and duration of treatment as well as their off-label use.


Comparison of magnetic resonance imaging brain volume trajectories between tertiles of antipsychotic treatment. Tertiles were categorized as those who received the most treatment (70 patients; mean [SD] dose, 929.4 [47.7] chlorpromazine [CPZ] mg equivalents/d), intermediate treatment (70 patients; mean [SD] dose, 391.7 [77.2] CPZ mg equivalents/d), and the least treatment (71 patients; mean [SD] dose, 111.5 [87.7] CPZ mg equivalents/d). Individual patient brain volume trajectories (thin lines) and treatment tertile group mean brain volume trajectories (thick lines) are shown for total cerebral white matter (A), lateral ventricles (B), and frontal gray matter volumes (C).

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