Olanzapine After Psychotic Depression Remission Cuts Relapses

Pauline Anderson

August 23, 2019

Patients in remission from psychotic depression can benefit from continued use of an antipsychotic, but metabolic side effects may be a concern, new research suggests.

In a randomized trial of patients whose psychotic depression responded to the combination of sertraline and olanzapine, continuing olanzapine reduced the risk for a relapse compared with those who continued on sertraline plus placebo.

However, continued use of olanzapine was also associated with greater weight gain.

The study, which was led by Alastair J. Flint, MB, Toronto General Hospital, Ontario, Canada, was published in the August 20 issue of the Journal of the American Medical Association (JAMA).

Three-Phase Analysis

As reported by Medscape Medical News, the Study of the Pharmacotherapy of Psychotic Depression (STOP-PD) examined the efficacy and tolerability of a combination serotonergic antidepressant and a second-generation antipsychotic agent for the acute treatment of psychotic depression.

That analysis showed that olanzapine plus sertraline was more efficacious than olanzapine plus placebo, but both treatments were associated with an increase in weight and lipids over the 12-week study.

The primary goal of the current STOP-PD II trial was to assess the risks and benefits of continuing antipsychotic medication in younger and older patients with psychotic depression once the depressive episode had responded to treatment with sertraline plus olanzapine.

STOP-PD II included patients from four academic centers: University Health Network, Toronto; University of Massachusetts Medical School, Worcester; University of Pittsburgh School of Medicine; and Weill Cornell Medicine, New York City. The study had three phases: acute, stabilization, and randomized controlled trial (RCT).

At time of enrollment in the acute phase of the study, participants were aged 18 to 85 years, met criteria for a current major depressive episode with at least one associated delusion with or without hallucinations, and had a score of 21 or higher on the 17-item Hamilton Depression Rating Scale (HDRS).

In the open-label acute phase, participants received a combination of sertraline (target dose, 150 - 200 mg/d) plus olanzapine (target dose, 15 - 20 mg/d). Researchers chose olanzapine because it is the only antipsychotic agent with established efficacy in combination therapy in both younger and older patients with psychotic depression.

Stabilization, Randomization

Patients entered the open-label stabilization phase as soon as they met criteria for remission. This was defined as the absence of delusions and hallucinations and an HDRS score of 10 or less for 2 consecutive weeks.

Participants who met criteria for "near remission" were also eligible for the stabilization phase. This included those without delusions and hallucinations but with an HDRS score of 11 to 15, a 50% or more reduction in baseline HDRS score, and a rating of "very much improved" or "much improved" on the Clinical Global Impression scale.

At the end of the 8-week stabilization phase, participants who still met full-remission or near-remission criteria following treatment with sertraline plus olanzapine and who had a score of 24 or higher on the Mini-Mental State Examination were eligible for the 36-week RCT.

The patients continued to take open-label sertraline for the duration of the trial and were randomly assigned to continue olanzapine or switch to placebo over a 4-week taper of olanzapine.

A total of 64 patients were assigned to the sertraline-olanzapine group and 62 to the sertraline-placebo group. The mean age of these participants was 55.3 years and 61.9% were women. About 90.5% completed the trial.

The primary outcome was risk for relapse.

Fewer Relapses

Results showed that a relapse occurred in 20.3% of the sertraline-olanzapine group vs 54.8% of the sertraline-placebo group (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.13 - 0.48; P < .001).

The number needed to treat with sertraline plus olanzapine to prevent one relapse was 2.8.

For the participants taking placebo, the majority of relapses occurred within the first 12 weeks after randomization. Relapses among the sertraline-olanzapine group were distributed throughout the 36-week trial.

Relapses resulted in a high frequency of psychiatric hospitalization, highlighting the severity and cost of this disorder and the importance in preventing relapse, the researchers note.

Those in the combined treatment group had a 2.6 kg (6 lb) mean weight gain while the placebo group had a 1.4 kg (3 lb) weight loss. Those receiving olanzapine had already gained 5.4 kg (12 lb) in the acute and stabilization phases.

Mean total cholesterol decreased in both groups, but the trajectory of decline was greater in the placebo group.

In terms of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, glucose, and HbA1c levels, the effect of olanzapine was not significantly different from placebo.

The study had a number of limitations, including that no combinations other than sertraline and olanzapine were assessed. In addition, patients were not assessed for the presence of comorbid personality disorders, some of which are associated with suicide attempts and risk of hospitalization, which were criteria for relapse in the study.

The investigators note that a slower taper of antipsychotic medication than the 4 weeks used in the study may have been associated with a lower relapse rate.

The study did not include data on biomarkers of risk for relapse. The researchers report that 45% of participants who switched to placebo did not relapse and benefited from a decline in weight and lipids.

"These findings suggest the need to identify clinical and biological predictors of relapse following antipsychotic discontinuation; this would allow some precision when deciding which individuals can be safely withdrawn from antipsychotic medication after remission of psychotic depression," they write.

Important Issue

In an accompanying editorial, William H. Coryell, MD, Department of Psychiatry, University of Iowa, Iowa City, writes that the study addresses the important issue of how long an antipsychotic should be used following symptom remission.

Coryell notes that antipsychotic medications can have considerable adverse effects; chief among these are extrapyramidal symptoms and risks for tardive dyskinesia in the case of first-generation antipsychotic agents.

Weight gain, dyslipidemia, and increased risks of developing type 2 diabetes are well-recognized adverse effects of many second-generation antipsychotic agents, he adds.

Clinicians might consider using an alternative second-generation antipsychotic agent with lesser tendencies to promote weight gain, such as aripiprazole, Coryell points out.

The new findings suggest that combined treatment for an additional 4-month period after remission is "highly effective for the prevention of recurrence in psychotic depression," writes Coryell.

But what's unclear is how much longer combined treatment offers substantially more protection than monotherapy, he adds.

"Should combined treatment be prescribed indefinitely? As the authors note, the study to answer this question would require many more participants to achieve adequate power, and it is unlikely that such a study will ever be conducted," he writes.

Psychotic depression presents clinicians with the challenge of treating an illness with high potential morbidity, both from acute and lifetime perspectives Coryell notes. However, psychotic depression can be highly responsive to well-chosen treatment.

"Judicious discontinuation of antipsychotic agents followed by close vigilance over the subsequent several months is likely to be an effective strategy," Coryell writes. "For those patients who tolerate antipsychotic medications well, longer periods taking combined treatment may be preferable."

The study was funded by the US Public Health Service and the NIMH. Flint reported grants from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Canadian Institutes of Health Research, Brain Canada, the Ontario Brain Institute, and the Alzheimer's Association, as well as nonfinancial support from Eli Lilly and Pfizer. Disclosures for the other study authors are listed in the original article. Coryell has disclosed no relevant financial relationships.

JAMA. 2019;322:615-617, 622-631. Abstract, Editorial

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