February 26, 2020
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Antipsychotics may change brain structure

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Antipsychotic medication may alter brain structure, according to study findings published in JAMA Psychiatry.

“In psychotic disorders, and when psychosis is present in nonpsychotic disorders, antipsychotics remain an essential treatment,” Aristotle N. Voineskos, MD, PhD, of the Centre for Addiction and Mental Health in Toronto, and colleagues wrote. “[Although] our data show that antipsychotics may cause adverse changes to brain structure, they also demonstrate that illness relapse may cause similar effects. When psychosis is present, the life-threatening effects of untreated illness outweigh any adverse effects on brain structure in clinical decision-making.”

Much of the data regarding the effects of antipsychotics on brain structure is derived from uncontrolled human studies, which suggest that both older and newer antipsychotic medications may enact changes in white matter and gray matter structure, the researchers wrote. However, these studies are confounded by patients with the greatest symptom burden typically requiring the highest antipsychotic doses, experiencing the greatest brain volume changes and being more likely to misuse substances that can affect brain structure. According to Voineskos and colleagues, a placebo-controlled trial can provide more definitive insight into these effects, but no studies of this sort have been published.

In a prespecified secondary analysis of a double-blind, randomized, placebo-controlled trial at five academic centers across 36 weeks, the researchers evaluated MRI scans of patients with major depressive disorder with psychotic features. Patients had previously enrolled in the multicenter Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II) trial. and all were prescribed olanzapine and sertraline for 12 to 20 weeks. This included 8 weeks of remission or near remission of depression and remission of psychosis. Furthermore, participants were randomly assigned to continue receiving this regimen or to switch to placebo and sertraline for a subsequent period of 36 weeks.

A subset of patients received MRI scans, with cortical thickness in gray matter as the primary outcome measure and microstructural integrity of white matter as the secondary outcome measure.

Of 88 participants aged 18 to 85 years who completed a baseline scan, 75 completed a follow-up scan, and 72 follow-ups were usable for final analyses. Voineskos and colleagues found a significant treatment-group by time interaction in cortical thickness but not surface area, as well as no significant interaction for fractional anisotropy; however, this interaction was present in mean diffusivity of the white matter skeleton. Upon restricting the analysis to participants who sustained remission, olanzapine exposure compared with placebo was associated with significant decreases in left and right hemisphere cortical thickness. Post hoc analyses revealed decreases in cortical thickness among those who relapsed receiving placebo compared with those who sustained remission.

“Given that nearly half of patients in the STOP-PD II trial sustained remission after being switched from olanzapine to placebo, future studies could provide a predictive model of which patients require long-term treatment with antipsychotics and which patients can safely discontinue them,” the researchers wrote. – by Joe Gramigna

Disclosures: Voineskos reports funding from Canada Foundation for Innovation, Canadian Institutes of Health Research, Centre for Addiction and Mental Health Foundation, NIMH and the University of Toronto. Please see the study for all other authors’ relevant financial disclosures.