Antipsychotic Treatments Result in Brain Structure Changes

Aristotle N. Voineskos, MD, PhD

While antipsychotic medications are beneficial in treating different mental health disorders, they can also lead to changes in a patient’s brain structure.

A team, led by Aristotle N. Voineskos, MD, PhD, Center for Addiction and Mental Health for the Department of Psychiatry at the University of Toronto, examined the association between olanzapine compared to a placebo in regard to the change in brain structure in a double-blind, randomized, placebo-controlled study.

The study took place over a 36-week period at 5 academic centers with 88 patients suffering from major depressive disorder with psychotic features between 18-85 years old. The participants were recruited from the multicenter Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II) study.

Each patient was treated with olanzapine and sertraline for a period of 12-20 weeks. This included 8 weeks of remission of psychosis and remission or near remission of depression.

The patients were then randomized to continue receiving the olanzapine regime or switched to a placebo and sertraline for a subsequent 36-week period.

Each patient also completed a MRI scan at the time of the randomization, as well as a second MRI scan at the conclusion of the 36-week study. A total of 75 patients completed the follow-up scan, 72 of which were useable for the final analysis.

The investigators sought a primary outcome of a measurement of cortical thickness in gray matter. They also sought second outcomes of the measurement of microstructural integrity of white matter.

There was a significant treatment-group by time interaction in cortical thickness (left, t &thinsp;= &thinsp;3.3; P&thinsp;=&thinsp;.001; right, t&thinsp;=&thinsp;3.6; P&thinsp;<.001), but not surface area. There was no significant interaction found for fractional anisotropy, but an interaction was found for mean diffusivity of the white matter skeleton (t&thinsp;=&thinsp;−2.6, P&thinsp;=&thinsp;.01).

When the investigators restricted the analysis to those who sustained remission, exposure to olanzapine compared to placebo was associated with significant decreases in cortical thickness in the left hemisphere (β [SE], 0.04 [0.009]; t_34.4&thinsp;=&thinsp;4.7; P&thinsp;<.001), and the right hemisphere (β [SE], 0.03 [0.009]; t_35.1&thinsp;=&thinsp;3.6; P&thinsp;<.001).

A post hoc analysis showed that those who relapsed receiving placebo experienced decreases in the cortical thickness when compared to those who sustained remission.

In the prespecified secondary analysis imaging study, which was embedded in a clinical trial with remitted psychotic depression patients, the investigators found that olanzapine exposure was linked to a decline in cortical thickness when compared to a placebo. However, illness relapse for the placebo control group was associated with a decline in cortical thickness.

“In this secondary analysis of a randomized clinical trial, antipsychotic medication was shown to change brain structure,” the authors wrote. “This information is important for prescribing in psychiatric conditions where alternatives are present. However, adverse effects of relapse on brain structure support antipsychotic treatment during active illness.”

Prescriptions for antipsychotic medications are increasingly used for many brain disorders, including off-label use in children and geriatric patients.

However, there is data from previous studies showing antipsychotic medications are linked to changes in brain structure. There has not been controlled human studies linking this class of drugs to changes in brain structure.

The study, "Effects of Antipsychotic Medication on Brain Structure in Patients With Major Depressive Disorder and Psychotic Features," was published online in JAMA Psychiatry.