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NIHR Signal Combined drug therapy for at least 36 weeks reduces relapse after psychotic depression

Published on 21 November 2019

doi: 10.3310/signal-000843

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.

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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.

Bibliography

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.

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.

Bibliography

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.

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

Published on 21 November 2019

Flint, A. J.,Meyers, B. S.,Rothschild, A. J.,Whyte, E. M.,Alexopoulos, G. S.,Rudorfer, M. V.,Marino, P.,Banerjee, S.,Pollari, C. D.,Wu, Y.,Voineskos, A. N.,Mulsant, B. H.

Jama Volume 322 Issue 7 , 2019

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.

Expert commentary

Psychotic depression is not uncommon, but there has been far less evidence for its longer-term management than either psychosis or depression. In particular, patients and clinicians have been uncertain how long to continue any antipsychotic medication, a crucial issue given its propensity for side-effects.

This trial helps inform practice by showing that the continuation of antipsychotic medication after recovery had superior outcomes to its discontinuation once individuals were well, with fewer subsequent episodes of relapse.

Helpfully, the study followed up participants for over half a year, though of course in real-world settings such medications can be continued for years.

Dr Derek Tracy, Consultant Psychiatrist and Clinical Director, Oxleas NHS Foundation Trust, London; Senior Lecturer, King's College London

The commentator declares no conflicting interests