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

Abstract

Importance: Prescriptions for antipsychotic medications continue to increase across many brain disorders, including off-label use in children and elderly individuals. Concerning animal and uncontrolled human data suggest antipsychotics are associated with change in brain structure, but to our knowledge, there are no controlled human studies that have yet addressed this question.

Objective: To assess the effects of antipsychotics on brain structure in humans.

Design, setting, and participants: Prespecified secondary analysis of a double-blind, randomized, placebo-controlled trial over a 36-week period at 5 academic centers. All participants, aged 18 to 85 years, were recruited from the multicenter Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). All participants had major depressive disorder with psychotic features (psychotic depression) and were prescribed olanzapine and sertraline for a period of 12 to 20 weeks, which included 8 weeks of remission of psychosis and remission/near remission of depression. Participants were then were randomized to continue receiving this regimen or to be switched to placebo and sertraline for a subsequent 36-week period. Data were analyzed between October 2018 and February 2019.

Interventions: Those who consented to the imaging study completed a magnetic resonance imaging (MRI) scan at the time of randomization and a second MRI scan at the end of the 36-week period or at time of relapse.

Main outcomes and measures: The primary outcome measure was cortical thickness in gray matter and the secondary outcome measure was microstructural integrity of white matter.

Results: Eighty-eight participants (age range, 18-85 years) completed a baseline scan; 75 completed a follow-up scan, of which 72 (32 men and 40 women) were useable for final analyses. There was a significant treatment-group by time interaction in cortical thickness (left, t = 3.3; P = .001; right, t = 3.6; P < .001) but not surface area. No significant interaction was found for fractional anisotropy, but one for mean diffusivity of the white matter skeleton was present (t = -2.6, P = .01). When the analysis was restricted to those who sustained remission, exposure to olanzapine compared with placebo was associated with significant decreases in cortical thickness in the left hemisphere (β [SE], 0.04 [0.009]; t34.4 = 4.7; P <.001), and the right hemisphere (β [SE], 0.03 [0.009]; t35.1 = 3.6; P <.001). Post hoc analyses showed that those who relapsed receiving placebo experienced decreases in cortical thickness compared with those who sustained remission.

Conclusions and relevance: In this secondary analysis of a randomized clinical trial, antipsychotic medication was shown to change brain structure. 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.

Trial registration: ClinicalTrials.gov Identifier: NCT01427608.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Voineskos receives funding from the National Institute of Mental Health (NIMH), Canadian Institutes of Health Research, Canada Foundation for Innovation, Centre for Addiction and Mental Health (CAMH) Foundation, and the University of Toronto. Dr Mulsant has received research funding from Brain Canada, the CAMH Foundation, the Canadian Institutes of Health Research, and the US National Institutes of Health (NIH); research support from Bristol-Myers Squibb (medications for an NIH-funded clinical trial), Eli-Lilly (medications for an NIH-funded clinical trial), Pfizer (medications for an NIH-funded clinical trial), Capital Solution Design LLC (software used in a study funded by CAMH Foundation), and HAPPYneuron (software used in a study funded by Brain Canada). He directly owns stocks of General Electric (less than $5000). Dr Dickie receives grant support from the Brain and Behavior Research Foundation. Dr Neufeld receives grant support from the Canadian Institutes of Health Research, Physicians’ Services Incorporated Foundation, and the University of Toronto. Dr Rothschild has received grant or research support from Allergan, Janssen, the National Institute of Mental Health, Takeda, Eli-Lilly (medications for a NIH-funded clinical trial), Pfizer (medications for a NIH-funded clinical trial), and the Irving S. and Betty Brudnick Endowed Chair in Psychiatry; is a consultant to Alkermes, GlaxoSmithKline, Sage Therapeutics, and Sanofi-Aventis; and has received royalties for the Rothschild Scale for Antidepressant Tachyphylaxis; Clinical Manual for the Diagnosis and Treatment of Psychotic Depression, American Psychiatric Press, 2009; The Evidence-Based Guide to Antipsychotic Medications, American Psychiatric Press, 2010; The Evidence-Based Guide to Antidepressant Medications, American Psychiatric Press, 2012; and UpToDate. Dr Whyte receives grant support from the NIMH and Health Resources and Services Administration. Dr Meyers received research support from the NIMH at the time this work was done. Dr Alexopoulos has received NIMH grants and has served in the speakers bureau of Takeda, Lundbeck, Otsuka, Alergan, Astra/Zeneca, and Sunovion. Dr Hoptman has received NIMH grants during the conduct of this study. Dr Lerch receives grant support from Canadian Institutes of Health Research and the Ontario Brain Institute. Dr Flint has received grant support from the US National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Canadian Institutes of Health Research, Brain Canada, the Ontario Brain Institute, and Alzheimer’s Association.

Figures

Figure 1.. CONSORT Chart

This chart provides numbers regarding enrollment, allocation, follow-up, and analysis of participants initially assessed for eligibility for the neuroimaging study after consenting to the clinical trial.

Figure 2.. Change in Cortical Gray Matter Structure in the Olanzapine and Placebo Groups

Panels A and B demonstrate cortical thickness and surface area at baseline and at the time of the second scan for each participant, which occurred either at remission, relapse, or discontinuation. A significant treatment-group × time interaction for cortical thickness was found, suggesting that there was a different effect of olanzapine vs placebo if a participant sustained remission vs if there was relapse. No such effect was found for surface area. In panels C and D, the data show significant change in cortical thickness but not surface area in participants who sustained remission. These participants were scanned first at randomization and then again at approximately 36 weeks following their baseline scan. These figures show a significant decrease in cortical thickness (left and right) but not surface area in participants exposed to olanzapine over a 36-week period compared with those receiving placebo. MRI indicates magnetic resonance imaging.

Figure 3.. Change in White Matter Microstructure in the Olanzapine and Placebo Groups

Panels A and B demonstrate white matter fractional anisotropy and mean diffusivity at baseline and at the time of the second scan for each participant, respectively, which occurred either at remission, relapse, or discontinuation. A significant treatment-group by time interaction for mean diffusivity was found (but not fractional anisotropy). Panel C demonstrates no change in fractional anisotropy of the white matter skeleton, while panel D compares mean diffusivity in the white matter skeleton in the olanzapine vs placebo group over a 36-week period, which was not significant following multiple comparison correction. MRI indicates magnetic resonance imaging.