Maintenance Antipsychotic Lowers Risk of Psychotic Depression Relapse

A study published August 20 in JAMA supports the use of the selective serotonin reuptake inhibitor sertraline and the antipsychotic olanzapine for the maintenance treatment of psychotic depression.

As indicated by the name, psychotic depression involves the onset of a depressive episode accompanied by delusions and/or (less frequently) hallucinations.

Previous studies show that the use of a combined antidepressant/antipsychotic treatment is effective at reducing psychotic depression symptoms in the short term, but there has been little data on the best long-term strategy for these patients. Available evidence points to maintaining antidepressant use to prevent depression relapse, since future depressive episodes are also likely to include psychotic symptoms. But what about maintenance antipsychotic treatment?

To explore this question, investigators at the University of Toronto and colleagues conducted a nine-month study involving 126 patients with psychotic depression who had achieved remission while taking sertraline in combination with olanzapine. After 36 weeks, patients were far less likely to relapse if they continued taking these medications compared with those who switched to sertraline plus a placebo.

The study investigators, led by Alistair Flint, M.B., a professor of psychiatry at the University of Toronto, cautioned that the observed benefits of maintaining antipsychotic treatment need to be weighed against the risks of greater weight gain and potential metabolic problems; however, they also noted that many incidents of relapse in their study resulted in admission to a psychiatric hospital. This highlights the severity and cost of a psychotic relapse.

“[T]his is an important study that addresses a deadly illness that is more common than people think,” said Alan Schatzberg, M.D., the Kenneth T. Norris Jr. Professor of Psychiatry and Behavioral Sciences at Stanford University and past APA president. Schatzberg noted that people who experience psychotic depression are at elevated risk of suicide as well as many medical problems related to excess production of the stress hormone cortisol.

The findings come from a large clinical trial known as the Study of the Pharmacotherapy of Psychotic Depression, Part 2 (STOP-PD II). The original STOP-PD trial, which was published in 2009, established that a combination therapy of sertraline plus olanzapine was more likely to lead to remission of psychotic depression than olanzapine alone over 12 weeks of therapy.

For this follow-up study, 259 adults aged 18 and older who were experiencing depression accompanied by at least one delusion received up to 12 weeks of sertraline (150 mg/day to 200 mg/day) and olanzapine (15 mg/day to 20 mg/day) combination therapy. Any participant who had achieved remission or “near remission” of their symptoms during this period was enrolled in the long-term phase of this study. Remission was defined as the absence of any psychotic symptoms as well as a score of 10 or less on the Hamilton Depression Rating Scale (HDRS) for two consecutive weeks. Near remission was defined as the absence of psychotic symptoms, an HDRS score of 11 to 15 and drop in HDRS score of 50% from baseline, and being rated as “very much improved” or “much improved” on the Clinical Global Impression scale.

After remaining on both medications for eight additional weeks to ensure symptoms were stable, 126 patients who achieved near remission or remission were randomly assigned to continue their combination therapy or have their olanzapine pills gradually switched over to placebo pills. The participants were then monitored for up to 36 additional weeks to assess relapse and other health outcomes.

At the end of the 36-week maintenance phase, 20% of patients randomized to olanzapine and 54% randomized to placebo experienced at least one relapse. A patient was considered to have relapsed if at least one of the following scenarios occurred: depression symptoms returned; delusions or hallucinations returned; and/or patient experienced suicide ideation/attempt, emergence of manic symptoms, or a hospitalization in a psychiatric unit.

Most relapses in patients taking placebo occurred within the first 12 weeks after randomization, or within 20 weeks after their remission. This corresponds to previous analyses that found that patients with psychotic depression should stay on antipsychotics for at least four months once their symptoms improve.

In terms of side effects, the participants who continued to take olanzapine gained an average of six pounds over the 36-week period, after gaining an average of 12 pounds during the 20-week period prior to the maintenance phase. (The participants who switched to placebo lost about three pounds on average after they switched.) Patients who switched to placebo also experienced greater improvements in their cholesterol levels than those taking olanzapine over the course of the study. Other metabolic parameters like triglycerides, glucose, or HbA1c levels did not significantly differ between the patients taking olanzapine compared with placebo.

Schatzberg noted that the study enrolled an older population (the average age of participants was 55), which might skew some of these findings. “Metabolic problems are less of an issue for older adults, so the results showing small metabolic differences between olanzapine and placebo may not be uniform across all ages,” he said.

Before thinking about maintenance treatment or even immediate treatment, it is imperative to diagnose psychotic depression correctly, Schatzberg continued. “Many clinicians may misdiagnose because they think that feelings of guilt or paranoia are natural for someone with severe depression, and they don’t probe to see how distorted these feelings are,” he said. He advised physicians to ask patients and their family members about potential delusions as soon as possible if there is any hint of unusual thoughts related to guilt, shame, inadequacy, or persecution.

STOP-PD II was supported by grants from the National Institute of Mental Health. Eli Lily and Pfizer provided the olanzapine and sertraline used in the study, respectively. ■

“Effect of Continuing Olanzapine vs Placebo on Relapse Among Patients With Psychotic Depression in Remission: The STOP-PD II Randomized Clinical Trial” is posted here. An accompanying editorial, “Maintenance Treatment for Psychotic Depressive Disorders: Progress and Remaining Challenges” is posted here.