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

Abstract

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.

Conflict of interest statement

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.

Figures

Figure 1.. Flow of Participants in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II)

aExamples of “not appropriate for further research participation”: repeated nonadherence with research assessments or repeated nonadherence with study medications during the “open-label” acute and stabilization phases of the study.

Figure 2.. Probability of Not Experiencing a Relapse

Median length of observation was 36 weeks (interquartile range [IQR], 24.8-36) for the sertraline plus olanzapine group and 19.5 weeks (IQR, 5.3-36) for the sertraline plus placebo group. For group comparison of the proportion free of relapse, log-rank test P value <.001. The shaded area represents the 95% CIs.