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Effect of Continuing Olanzapine vs Placebo on Relapse Among Patients With Psychotic Depression in RemissionThe STOP-PD II Randomized Clinical Trial

Educational Objective
To understand risks associated with psychotic depression and its treatment.
1 Credit CME
Key Points

Question  Does continuing antipsychotic medication reduce the risk of relapse among patients with psychotic depression in remission?

Findings  In this 36-week randomized clinical trial that included 126 persons aged 18 years or older, 13 participants (20.3%) randomized to sertraline plus olanzapine and 34 (54.8%) to sertraline plus placebo experienced a relapse, a difference that was statistically significant.

Meaning  For patients with psychotic depression in remission, continuing olanzapine reduced the 36-week risk of relapse.


Importance  Psychotic depression is a severely disabling and potentially lethal disorder. Little is known about the efficacy and tolerability of continuing antipsychotic medication for patients with psychotic depression in remission.

Objective  To determine the clinical effects of continuing antipsychotic medication once an episode of psychotic depression has responded to combination treatment with an antidepressant and antipsychotic agent.

Design, Setting, and Participants  Thirty-six week randomized clinical trial conducted at 4 academic medical centers. Patients aged 18 years or older had an episode of psychotic depression acutely treated with sertraline plus olanzapine for up to 12 weeks and met criteria for remission of psychosis and remission or near-remission of depressive symptoms for 8 weeks before entering the clinical trial. The study was conducted from November 2011 to June 2017, and the final date of follow-up was June 13, 2017.

Interventions  Participants were randomized either to continue olanzapine (n = 64) or switch from olanzapine to placebo (n = 62). All participants continued sertraline.

Main Outcomes and Measures  The primary outcome was risk of relapse. Main secondary outcomes were change in weight, waist circumference, lipids, serum glucose, and hemoglobin A1c (HbA1c).

Results  Among 126 participants who were randomized (mean [SD] age, 55.3 years [14.9 years]; 78 women [61.9%]), 114 (90.5%) completed the trial. At the time of randomization, the median dosage of sertraline was 150 mg/d (interquartile range [IQR], 150-200 mg/d) and the median dosage of olanzapine was 15 mg/d (IQR, 10-20 mg/d). Thirteen participants (20.3%) randomized to olanzapine and 34 (54.8%) to placebo experienced a relapse (hazard ratio, 0.25; 95% CI, 0.13 to 0.48; P < .001). The effect of olanzapine on the daily rate of anthropometric and metabolic measures significantly differed from placebo for weight (0.13 lb; 95% CI, 0.11 to 0.15), waist circumference (0.009 inches; 95% CI, 0.004 to 0.014), and total cholesterol (0.29 mg/dL; 95% CI, 0.13 to 0.45) but was not significantly different for low-density lipoprotein cholesterol (0.04 mg/dL; 95% CI, −0.01 to 0.10), high-density lipoprotein cholesterol (−0.01 mg/dL; 95% CI, −0.03 to 0.01), triglyceride (−0.153 mg/dL; 95% CI, −0.306 to 0.004), glucose (−0.02 mg/dL; 95% CI, −0.12 to 0.08), or HbA1c levels (−0.0002 mg/dL; 95% CI, −0.0021 to 0.0016).

Conclusions and Relevance  Among patients with psychotic depression in remission, continuing sertraline plus olanzapine compared with sertraline plus placebo reduced the risk of relapse over 36 weeks. This benefit needs to be balanced against potential adverse effects of olanzapine, including weight gain.

Trial Registration  ClinicalTrials.gov Identifier: NCT01427608

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Article Information

Corresponding Author: Alastair J. Flint, MB, Toronto General Hospital, 200 Elizabeth St, 8 Eaton North Room 238, Toronto, ON, M5G 2C4, Canada (alastair.flint@uhn.ca).

Accepted for Publication: June 27, 2019.

Author Contributions: Dr Flint had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Flint, Meyers, Rothschild, Whyte, Mulsant.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Flint, Meyers, Rothschild, Whyte, Alexopoulos, Rudorfer, Marino, Banerjee, Voineskos, Mulsant.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Banerjee, Pollari, Wu.

Obtained funding: Flint, Meyers, Rothschild, Whyte, Mulsant.

Administrative, technical, or material support: Flint, Meyers, Rothschild, Whyte, Alexopoulos, Rudorfer, Marino, Voineskos, Mulsant.

Supervision: Flint, Meyers, Rothschild, Whyte, Alexopoulos, Marino, Mulsant.

The STOP-PD II Study Group:Centre for Addiction and Mental Health, Toronto: Benoit Mulsant, MD, James Kennedy, MD, Bruce Pollock, MD, PhD, and Aristotle Voineskos, MD, PhD; National Institute of Mental Health, Bethesda: Matthew Rudorfer, MD; University Health Network, Toronto: Alastair Flint, MB, Peter Giacobbe, MD, and Brenda Swampillai, BSc. University of Massachusetts Medical School and UMass Memorial Health Care, Worcester: Anthony Rothschild, MD, Kristina Deligiannidis, MD, Chelsea Kosma, MA, and Wendy Marsh, MD; Weill Medical College of Cornell University and New York Presbyterian Hospital: Barnett Meyers, MD, George Alexopoulos, MD, Samprit Banerjee, PhD, Judith English, MA, James Kocsis, MD, Barbara Ladenheim, PhD, Vassilios Latoussakis, MD, Patricia Marino, PhD, Nikhil Palekar, MD, Christina Pollari, MPH, and Yiyuan Wu, MS; Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania: Ellen Whyte, MD, Meryl Butters, PhD, Ariel Gildengers, MD, Joelle Kincman, PhD, and Michelle Zmuda, MA.

Conflict of Interest Disclosures: Dr Flint reported receiving grants from 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 and nonfinancial support from Eli Lilly and Pfizer. Dr Rothschild reported receiving grants from National Institute of Mental Health (NIMH), the Irving S. and Betty Brudnick Endowed Chair in Psychiatry, Allergan, Janssen, and Takeda; nonfinancial support from Eli Lilly and Pfizer; personal fees from Alkermes, GlaxoSmithKline, Sage Therapeutics, Sanofi-Aventis, UMass Medical School, the American Psychiatric Press, and UpToDate. Dr Whyte reported receiving grants from the NIMH, National Institutes of Health, and Health Resources and Services Administration and nonfinancial support from Pfizer and Lilly. Dr Alexopoulos reported receiving grants from the NIMH and nonfinancial support from Pfizer and Lilly; personal fees from Takeda, Lundbeck, Otsuka, Allergan, Astra Zeneca, and Sunovion. Dr Voineskos reported receiving grants from the NIMH, the Canadian Institute of Health Research, Canadian Foundation for Innovation, Centre for Addiction and Mental Health Foundation, Brain Behavior Research Foundation, and the University of Toronto. Dr Mulsant reported receiving grants from Brain Canada, Centre for Addiction and Mental Health Foundation, the Canadian Institutes of Health Research, and NIMH and nonfinancial support from Eli Lilly, Pfizer, Capital Solution Design LLC, HAPPYneuron, and General Electric. No other disclosures were reported.

Funding/Support: This study was funded by US Public Health Service grants MH 62446, MH 62518, MH 62565, and MH 62624 from the NIMH. Eli Lilly provided olanzapine and matching placebo pills and Pfizer provided sertraline; neither company provided funding for the study.

Role of the Funder/Sponsor: The NIMH participated in the implementation of this study through the U01 mechanism. Dr Rudorfer represented NIMH on the study’s steering committee and participated in the conduct of the study; interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. The NIMH did not participate in the design of the study or the collection, management, or analysis of data. A data and safety monitoring board at the NIMH provided data and safety monitoring. Neither Eli Lilly nor Pfizer participated in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Additional Contributions: We thank the members of the STOP-PD II Study Group for their contributions. Drs Butters, Pollock, and Rudofer did not receive compensation for their role in this study; each of the other named persons did receive compensation for their role in this study.

Data Sharing Statement: See Supplement 3.

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