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Antipsychotic Shown to Change Brain in Psychotic Depression

Antipsychotic use was associated with changes in certain brain structures among patients with psychotic depression, according to a secondary analysis of a multicenter randomized control trial.

In a group of 72 patients in remission assigned to stay on a dual therapy regimen of sertraline (Zoloft) and olanzapine (Zyprexa), or to continue with sertraline only, patients exposed to olanzapine showed significant changes in cortical thickness on neuroimaging scans, such that 36 weeks of olanzapine exposure caused a mean loss of about 1.2% of the cortex, reported Aristotle Voineskos, MD, PhD, of the Centre for Addiction and Mental Health in Toronto, Canada, and colleagues.

However, olanzapine use was not associated with significant reductions in surface area, and therefore cortical volumes, or white matter fractional anisotropy, they wrote in JAMA Psychiatry.

“For context, mean annual change in cortical thickness across the adult life span is 0.35% and 0.59% in normal aging individuals aged 60 to 91 years,” Voineskos and colleagues wrote. “Given that reductions in cortical thickness are typically interpreted in psychiatric and neurologic disorders as nondesirable, our findings could support a reconsideration of the risks and benefits of antipsychotics.”

In the parent STOP-PD trial, patients with psychotic depression in remission had significantly fewer relapses at 36 weeks with both agents than with sertraline alone. But it remained unclear whether the combined therapy should be prescribed indefinitely, and if the potential side effects — like weight gain and other biologic changes — outweighed the benefit of continued exposure.

In recent years, preclinical studies have shown first- and second-generation antipsychotics can impact brain volume, a measure derived from both cortical thickness and surface area, said Sudhakar Selvaraj, MD, PhD, of the University of Texas Health Science Center in Houston, who was not involved in this study.

Olanzapine use was only associated with one of these parameters, and it remains unclear what impact the changes observed have on cognition or behavioral function, as well as whether they can be reversed, Selvaraj commented. As such, future research should evaluate whether these effects are observed with the use of other antipsychotic medications, particularly ones without the metabolic side effects olanzapine carries, he stated.

Epiphenomenon, like psychological changes associated with olanzapine use or some other unmeasured factor, could also be behind these findings, Selvaraj added.

Voineskos’ group acknowledged the possibility that epiphenomenon impacted the MRI findings, but said that the relatively long-term exposures and focus on brain structure rendered this interpretation “unlikely.”

Overall, the decision to use olanzapine in this population is a matter of balancing the drug’s side effects with its efficacy, Selvaraj said.

“If we prevent relapse … that’s a very important thing because if you don’t treat [psychotic depression], it carries risk and further affects brain function too,” Selvaraj told MedPage Today. “If a patient relapses … a lack of social activity and things like that can have negative impacts on cortical thickness as well.”

In the STOP-PD trial, participants with non-bipolar major depressive disorder with psychotic features were assigned to 12 weeks treatment with sertraline and olanzapine to attain remission, followed by 8-weeks stabilization. Once remission was sustained, they were randomized to either stay on the dual therapy or sertraline plus placebo for 36 weeks. MRI was performed at the beginning and end of this 36-week phase.

Among the participants (mean age 55; about 55% female; >70% white), about three-quarters had experienced at least two prior depressive episodes, and had Hamilton Depression Rating Scale scores from 5-6. No demographic or clinical parameters, ranging from cholesterol, baseline cortical thickness, or other measures of depression and anxiety, significantly differed between patients who were exposed to olanzapine (38) and those who were not (34).

Overall, the treatment-group by time interaction was significant for cortical thickness in both left (t=3.3, P=0.001) and right hemispheres (t=3.6, P<0.001), the authors reported.

Among participants ages 50 or older, olanzapine exposure versus placebo was associated with significantly greater changes in cortical thickness in those who sustained remission, the authors noted, and changes in white matter mean diffusivity were also greater in this older age group.

Olanzapine exposure was associated with significant reductions in cortical thickness at 36 weeks in both hemispheres when the analysis was restricted to patients who sustained remission, they reported.

Although there were no significant effects observed in white matter fractional anisotropy, olanzapine exposure was associated with significant changes in white matter mean diffusivity (t= -2.6, P=0.01), though this was not seen when the analysis was restricted to patients who sustained remission, they added.

Finally, among patients who relapsed, the placebo group experienced greater reductions in cortical thickness compared with the olanzapine group. The placebo group also had greater reductions compared to those who sustained remission, the authors reported.

“When taken together, both olanzapine and illness relapse have an effect on brain structure,” they stated.

Since both treatment arms received sertraline, the authors said they were unable to detect what effects this drug may have had on brain structures, which is a study limitation. The authors also cautioned against generalizing these findings to other antipsychotics, and noted that MRI scanner models varied across sites.


The study was funded by the National Institute of Mental Health (NIMH). The STOP-PD trial was funded by the U.S. Public Health Service.

Voineskos disclosed support from NIMH, the Canadian Institutes of Health Research, Canada Foundation for Innovation, Centre for Addiction and Mental Health Foundation, and the University of Toronto. Co-authors disclosed support from Bristol-Myers Squibb, Eli-Lilly, Pfizer, Capital Solution Design, Allergan, Janssen, Takeda, and HAPPYneuron.