Jury Still Out on Maintenance Therapy for Bipolar Depression

The first randomized controlled trial testing the safety and efficacy of long-term antidepressant maintenance therapy after remission of a depressive episode in adults with bipolar I disorder has yielded mixed results.

Continuing antidepressant therapy for 52 weeks, as opposed to stopping it at 8 weeks, was not more beneficial with regard to the primary outcome of occurrence of any mood episode.

However, a prespecified sensitivity analysis of the primary outcome and of the secondary analyses suggests that continuing antidepressant therapy for 52 weeks may prolong the time to a depressive relapse.

“Because the primary outcome is negative and the prespecified sensitivity analysis is positive and the secondary outcomes are positive, some clinicians will pick the position that they work and some that they don’t work,” lead investigator Lakshmi Yatham, MBBS, with University of British Columbia (UBC) in Vancouver, Canada, told Medscape Medical News.

The study was published online August 3 in the New England Journal of Medicine.

Controversial Issue

Adjunctive antidepressant therapy — alongside mood stabilizers and/or second-generation antipsychotic medications — are often used to treat acute depressive episodes in patients with bipolar I disorder.

Currently, the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) advise discontinuing antidepressant treatment 8 weeks after remission of depression.

Yet, the duration of antidepressant therapy for bipolar depression is “highly controversial,” due to a lack of evidence and concerns that antidepressants may induce mania, mixed states, or rapid cycling between mania and depression, Yatham told Medscape Medical News.

Yatham and colleagues assessed the safety and efficacy of continuing adjunctive antidepressant treatment (escitalopram or bupropion XL) for 52 weeks after remission, compared with discontinuing antidepressant therapy at 8 weeks after remission.

The final analysis included 177 patients (mean age 41 years, 48% men) with bipolar I disorder who had remission of depression; 90 patients continued treatment with an antidepressant for 52 weeks and 87 were switched to placebo at 8 weeks. All were taking a mood stabilizer or a second-generation antipsychotic, or both.

The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide.

At 52 weeks, 28 patients (31%) in the 52-week group had experienced any mood episode (primary outcome) compared with 40 patients (46%) in the 8-week group.

The primary outcome did not reach statistical significance (hazard ratio [HR] 0.68; 95% CI, 0.43 – 1.10; P = .12).

The researchers note that the decision by the study team to include relapses that occurred during the first 6 weeks of the study may have affected the primary outcome.

“During the first 6 weeks, both groups were getting the same treatment and we thought there shouldn’t be any difference in relapse, but sadly, there were more relapses in the 52-week group even though the treatments were identical,” Yatham told Medscape Medical News.

However, in a sensitivity analysis of the primary outcome after week 6, when treatment between the two groups differed, patients continuing antidepressant treatment were 40% less likely to experience a relapse of any mood event (HR, 0.60) and 59% less likely to experience a depressive episode (HR, 0.41) relative to the placebo group.

“From the point where the two groups began receiving different treatments, we see a significant benefit for patients who continued treatment with antidepressants,” Yatham said in a news release.

“Treating depression in bipolar disorder is challenging. Reducing the risk of relapse is important because it can provide patients with a great deal of stability that ultimately lets them get back to the activities they enjoy and can greatly improve their quality of life,” he added.

Although fewer patients in the 52-week group than 8-week group had a depressive episode within 52 weeks (17% vs 40%; HR, 0.43), more had a manic or hypomanic event (12% vs 6%; HR, 2.28).

The estimated probability of remaining free of a depressive episode at 52 weeks was 72% in the 52-week group vs 53% in the 8-week group. The estimated probability of remaining free of a manic episode at 52 weeks was 81% and 92%, respectively.

The incidence of adverse events was similar in the two groups, with a low rate of discontinuation due to adverse events and no serious adverse events. Clinically significant weight gain (≥7% increase in body weight) was observed in 14% of patients in the 52-week group and 7% of patients in the 8-week group.

Limitations of the trial include the fact that it was stopped early, before the planned sample size was reached, owing to slow recruitment and funding issues.

Other limitations include a lack of ethnic diversity (only 12% were White and < 1% Black) and over-representation of patients from India, which may limit generalizability. 

In addition, the findings may not be applicable to treatment with antidepressants other than escitalopram and buproprion XL. Finally, the study population was also enriched for patients who responded to these antidepressants.

Need for an Individualized Approach

Commenting on the study for Medscape Medical News, Roger McIntyre, MD, professor of psychiatry in pharmacology, University of Toronto, Canada, noted the study was not easy to conduct and the investigators should be credited for conducting a maintenance study in bipolar depression.

“Although the study reports, as it should, that there is no evidence of maintenance effect, the secondary analysis, which was not adjusted for multiplicity, does suggest that there is a benefit,” said McIntyre, who was not associated with this research.

“However, the authors are also correct in stating that one cannot draw a conclusion because it was not the primary question and was not adjusted for multiplicity,” he added.

“If anything,” said McIntyre, “what these results do support is the notion that antidepressants are unlikely to destabilize all patients. Instead, the risk of destabilization seems to be largely limited to some persons, and there is a suggestion, based on the secondary outcome of this study, that maintenance antidepressant benefits can be seen in some people. But again that’s a testable hypothesis.”

Also weighing in on the research, Madhukar H. Trivedi, MD, professor of psychiatry and director, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas, said the study is “interesting,” adding that it was “unfortunate that the researchers had to curtail recruitment and reduce the size of the trial.”

“But the main finding is indeed that there was no significant advantage with 52 [weeks] continuation, except maybe increasing time to relapse. There are indeed a number of interesting findings in the secondary analyses but sample size may have limited certainty,” Trivedi told Medscape Medical News.

“It seems that the results would not suggest a change in the current guidelines and yet we have to also mention that, for now, one has to make individual decisions and maybe recommend a more definitive complete trial,” added Trivedi, who was not involved in the study.

The study was supported by the Canadian Institutes of Health Research. Bausch Health (formerly Valeant), Lundbeck, and Lupin provided trial medications but were not involved in the design or conduct of the trial, data collection or analyses, writing of the manuscript, or decision to submit the manuscript for publication. Disclosures for authors are available at the conclusion of the original article.

N Engl J Med. Published online August 3, 2023. Abstract

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