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Original Investigation
February 26, 2020

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

Author Affiliations
  • 1Kimel Family Translational Imaging-Genetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
  • 2Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
  • 3UMass Memorial Health Care, University of Massachusetts Medical School, Worcester
  • 4University of Pittsburgh, Pittsburgh, Pennsylvania
  • 5Weill Cornell Medical College, New York, New York
  • 6Nathan Kline Institute for Psychiatric Research, Orangeburg, New York
  • 7Department of Psychiatry, New York University School of Medicine, New York
  • 8Mouse Imaging Centre, The Hospital for Sick Children, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
  • 9Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, England
  • 10University Health Network, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
JAMA Psychiatry. 2020;77(7):674-683. doi:10.1001/jamapsychiatry.2020.0036
Key Points

Question  Using a double-blind, randomized, placebo-controlled design, what is the association of olanzapine vs placebo with change in brain structure in humans?

Findings  In this prespecified secondary analysis imaging study embedded in a clinical trial in people with remitted psychotic depression, olanzapine exposure vs placebo was associated with decline in cortical thickness. However, illness relapse while receiving placebo was potentially associated with a decline in cortical thickness.

Meaning  Our findings could support a reconsideration of the risks and benefits of antipsychotics and support differential effects on brain structure in those who stay well receiving placebo vs those who relapse.


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

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