Study: Continuing Antipsychotic Combination Therapy Reduces Relapse in Psychotic Depression


A randomized clinical trial found that among patients with psychotic depression in remission, continuing sertraline plus olanzapine reduced the risk of relapse over 36 weeks when compared with sertraline plus a placebo.

A randomized trial found that among patients with psychotic depression in remission, continuing sertraline plus olanzapine reduced the risk of relapse over 36 weeks when compared with sertraline plus a placebo.

Published this month in JAMA, the 36-week study took place at 4 academic medical centers from November 2011 to June 2017. It observed patients aged 18 years or older who had 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 trial.

Prior meta-analyses support the use of either electroconvulsive therapy or pharmacotherapy with the combination of an antidepressant and an antipsychotic agent for treatment of psychotic depression.

Based on previous research, it is understood that the antidepressant medication needs to be continued in order to prevent relapse and recurrence of depression. It was previously unknown, however, whether antipsychotic medication needs to be continued once an episode of psychotic depression has responded to combined antidepressant-antipsychotic treatment.

When the study began, 350 patients consented to participate and were assessed for eligibility. Throughout the 3 phases—acute, stabilization, and randomization—that number decreased to 126 individuals, who were finally randomized. Of those 126 individuals, 64 received sertraline and olanzapine, while 62 received sertraline and a placebo.

A relapse occurred in 20.3% of the participants in the sertraline-olanzapine group, and in 54.8% of the sertraline-placebo group. Among those who continued taking olanzapine, 6 were hospitalized for depression, psychosis, suicidality, mania, or hypomania, while 11 of those receiving the placebo were hospitalized for 1 or more of the same symptoms.

While the data suggests that continuation of olanzapine reduces the risk of relapsing psychotic depression, the researchers noted that the continuation must be balanced with an understanding of tolerability and adverse effects.

Weight gain was the most common adverse effect, whereas discontinuation of olanzapine was associated with weight loss. Mean total cholesterol decreased in both groups, but the rate of decline was more significant in the placebo group. There was no significant difference between groups in the trajectory of triglyceride, glucose, or HbA1c values.

Although several other antipsychotics are associated with less weight gain that olanzapine, other adverse effects are possible, including akathisia, parkinsonism, and insomnia, which can all be potentially problematic in the treatment of psychotic depression.

The study did have several limitations, most especially that more research is needed to establish whether or not the findings are generalizable to other antipsychotic medications. The researchers chose a 4-week taper of antipsychotic medications based on previous data, but it is also possible that a slower taper would have been associated with a lower relapse rate. Finally, the findings suggest a need to identify clinical and biological predictors of relapse following antipsychotic discontinuation, which would allow for more precision when deciding which individuals can be safely withdrawn from antipsychotic medications.


Flint AJ, Meyers BS, Rothschild AJ, et al. Effect of continuing olanzapine vs placebo on relapse among patients with psychotic depression in remission. Jama. 2019;322(7). doi:10.1001/jama.2019.10517.

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