Antipsychotic medication treatment, compared with placebo, as well as illness relapse while receiving placebo, were linked to decreased cortical thickness in patients with major depressive disorder (MDD) with psychotic features. The study, published in JAMA Psychiatry, highlights the potential risks and benefits of antipsychotics, which are increasingly prescribed in a range of pediatric, adult, and geriatric disorders.

The investigators assessed the association of olanzapine vs placebo with changes in cortical and subcortical gray matter structures and white matter microstructures in 72 patients (age range, 18-85 years) with psychotic depression. In the first phase, patients received 15 to 20 mg/day olanzapine and 150 to 200 mg/day sertraline for up to 12 weeks to reach remission. Phase 2 involved 8 weeks of sustained remission, and phase 3 comprised a 36-week randomized controlled trial comparing sertraline plus olanzapine (n=38) with sertraline plus placebo (n=34) in terms of relapse prevention. The investigators conducted magnetic resonance imaging scans before and after the conclusion of phase 3.

There was a significant treatment group by time interaction for the primary outcome measure: cortical thickness. Sustained use of olanzapine vs placebo was associated with potentially adverse changes in brain structure; namely, a thinning of the cortex across the 36-week period in the left (β, 0.04 [standard error, 0.009]; t34.4, 4.7; P <.001), and right (β, 0.03 [standard error, 0.009]; t35.1, 3.6; P <.001) hemispheres. No significant change was found with olanzapine vs placebo exposure in subcortical volumes or surface area. Notably, these cortical thickness changes were even more prominent in the elderly study participants, as well as mean diffusivity of white matter (t, −3.4; P =.002).

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However, participants who experienced an illness relapse while receiving placebo also had a decline in cortical thickness, emphasizing the essential role antipsychotics play in treating disorders where psychosis is present. In addition, for patients receiving olanzapine, those who sustained remission experienced significant decreases in cortical thickness compared with those who relapsed.

Limitations of the study included the inability to address any potential effects of sertraline on brain structure, as both groups received this medication, and differences in scanner models across sites, which could result in detected magnetic resonance imaging changes representing an epiphenomenon rather than actual brain alterations.

The researchers concluded that their findings “could support a reconsideration of the risks and benefits of antipsychotics” and help clinicians build “a predictive model of which patients require long-term treatment with antipsychotics and which patients can safely discontinue them.”


Voineskos AN, Mulsant BH, Dickie EW, Neufeld NH, Rothschild AJ, Whyte EM. Effects of antipsychotic medication on brain structure in patients with major depressive disorder and psychotic features: Neuroimaging findings in the context of a randomized placebo-controlled clinical trial [published online February 26, 2020]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2020.0036