Sertraline Plus Olanzapine Reduces Relapse Risk in Psychotic Depression

Sertraline and adjunctive olanzapine reduced the risk for relapse in patients with psychotic depression; however, patients experienced such adverse effects of olanzapine as weight gain.

Sertraline plus olanzapine compared with sertraline plus placebo reduced the risk for relapse among patients with psychotic depression in remission, according to study data published in JAMA1.

The STOP-PD II study was a 36-week randomized clinical trial conducted at four medical centers in the United States and Canada. Participants were adult patients (≥18 years) who had an episode of psychotic depression acutely treated with sertraline plus olanzapine for up to 12 weeks. Patients met criteria for remission of psychosis and remission or near remission of depressive symptoms for eight weeks before trial entry. Participants were randomly assigned to continue sertraline plus olanzapine (n=64) or to switch to sertraline plus placebo (n=62). Study assessments were conducted weekly for the first eight weeks and then once every four weeks thereafter until week 36, relapse, or early termination.

Related Articles

Risk for relapse was the primary outcome measure, assessed using clinical measures of depression, psychosis, suicidal ideation, and mania/hypomania. As secondary outcome measures, weight and waist circumference were measured at each study visit. Cox proportional hazard models were used to estimate the hazard ratio (HR) of relapse across treatment groups. Linear mixed models were used to analyze anthropometric and metabolic measures; specifically, the treatment-by-time interactions.

Among 126 participants, 114 (90.5%) completed the trial. The mean (standard deviation [SD]) age of the baseline cohort was 55.3 (14.9) years, and 78 (61.9%) were women. At the time of randomization, median sertraline dose was 150 mg/day and median olanzapine dose was 15 mg/day. Relapse was observed in 13 (20.3%) patients randomly assigned to olanzapine and 34 (54.8%) patients randomly assigned to placebo (HR, 0.25; 95% CI, 0.13-0.48; P <.001).

Investigators noted that the effect of olanzapine on the daily rate of anthropometric and metabolic measures was significantly higher than placebo for weight (0.13 pounds; 95% CI, 0.11-0.15 pounds; P <.001), waist circumference (0.009 inches; 95% CI, 0.004-0.014 inches; P =.002), and total cholesterol (0.29 mg/dL; 95% CI, 0.13-0.45 mg/dL; P =.003).

The daily rate was not sufficiently different for low density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, glucose, or hemoglobin A1C levels.

Per these data, investigators endorsed continuing sertraline plus olanzapine for 36 weeks after response in patients with psychotic depression. The optimal duration of olanzapine treatment, however, remains unclear; an editorial companion piece published in JAMA recommended a gradual tapering off olanzapine, with immediate reintroduction at the first signs of relapse.2

Given the effects of olanzapine on body weight and metabolic measures, the editorial piece also recommended aripiprazole, another alternative second-generation antipsychotic agent with less likelihood to promote weight gain. Together, the STOP-PD II study data and the accompanying editorial endorse the initial use of antipsychotic combination therapy for psychotic depressive disorders, with careful discontinuation after remission is achieved.


1. Coryell WH. Maintenance treatment for psychotic depressive disorders: progress and remaining challenges. JAMA. 2019;322(7):615-617.

2. Flint AJ, Meyers BS, Rothschild AJ, et al. Effect of continuing olanzapine vs placebo on relapse among patients with psychotic depression in remission: the STOP-PD II randomized clinical trial. JAMA. 2019;322(7):622-631.