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Patients with psychotic depression who achieve remission benefit from continuing the antipsychotic drug olanzapine, alongside the antidepressant sertraline for at least a further four months, a North American trial has found.

Patients who reduced and stopped olanzapine when their condition stabilised were more than twice as likely to relapse when compared with those who continued combined drug therapy. The majority of relapses occurred within two months of withdrawing olanzapine.

This was a randomised control trial, with 126 participants. By 36 weeks from stabilisation, 13 people (20.3%) who were taking sertraline plus olanzapine and 34 people (54%) who were taking sertraline plus placebo experienced a relapse.

These results suggest that continuation of combined drug therapy for these patients may help reduce the risks of potentially life-threatening relapse. The benefit needs to be balanced against the adverse effects of olanzapine, which include weight gain.

Why was this study needed?

Psychotic depression is one of the most serious mental illnesses, with a high risk of suicide. It is usually treated with a combination of an antidepressant and an antipsychotic drug, plus psychological and social support.

There is evidence that continuing to take antidepressant medication, once treatment has been effective, can help to prevent a relapse. However, it’s not known how long an antipsychotic drug should be continued once an episode of psychotic depression has responded to combined treatment.

The STOP-PD II trial aimed to assess the risks and benefits of continuing antipsychotic medication in patients with psychotic depression after the patient has responded to treatment with sertraline plus olanzapine.

What did this study do?

This randomised controlled trial was conducted at four medical centres in the US and Canada between November 2011 and June 2017.

Participants aged between 18 and 85 were enrolled in the ‘acute’ phase of the study after experiencing a major depressive episode with at least one associated delusion. People were excluded if they had any other lifetime or current psychotic disorder.

All participants received sertraline (150-200mg per day) plus olanzapine (15-20mg per day). Once they were in or close to remission, they entered the ‘stabilisation’ phase.

Patients who then went on to have an eight-week period without relapses were randomised into two groups: 64 were prescribed sertraline plus olanzapine for nine months and 62 were prescribed sertraline plus placebo.

This was a well-designed, though relatively small, trial and the results should be reliable.

What did it find?

  • A relapse occurred in 13 out of 64 participants (20.3%) in the sertraline-plus-olanzapine group and 34 out of 62 (54.8%) of the sertraline-plus-placebo group (hazard ratio 0.25, 95% confidence interval 0.13 to 0.48).
  • Relapses in the placebo group mainly occurred during the first 12 weeks, whereas relapses among the sertraline-olanzapine group were distributed throughout the 36-week period.
  • In the randomised phase, those in the combined therapy group gained an average of 2.6kg (5.7lbs); while those in the placebo group lost on average 1.4kg (3.1lbs). This was in addition to the average 5.4kg (12lbs) patients gained in the acute and stabilisation treatment phases.
  • The mean total cholesterol decreased in both groups, but this decrease was sharper in the placebo group.

What does current guidance say on this issue?

NICE guidance (CG90, updated April 2018) recommends that patients diagnosed with severe depression that includes psychotic symptoms are referred to specialist mental health services.

For these patients, the NICE guideline states that pharmacological treatment with antidepressants augmented with antipsychotics such as olanzapine, should be considered, but point out that the optimum dose and duration of treatment is not known.

What are the implications?

These results provide good evidence that combination therapy may be continued for at least six months after achieving remission where appropriate. Since 1 in 5 patients in the combined drug group also relapsed, we are still in need of research to find more effective treatments in this area.

Since this study ended at 36 weeks, it does not tell us the optimal duration of treatment with olanzapine following remission of psychotic depression but does usefully highlight the risks of withdrawing this medication too soon.

Citation and Funding

Flint AJ, Meyers B, 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).622-31.

This study was funded by the United States National Institute for Health.



NHS website. Psychotic depression. London: Department of Health and Social Care; updated 2016.

NICE. Depression in adults: recognition and management. CG90. London: National Institute for Health and Care Excellence; updated April 2018.

Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre


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