Extended Antidepressant Therapy Curbs Relapses in Bipolar Disorder

Summary: Researchers lead a global clinical trial suggesting that long-term use of modern antidepressants could reduce depressive relapses in patients with bipolar disorder.

This challenges current clinical practice guidelines and might significantly change how bipolar depression is treated worldwide. The study found that those who continued antidepressant treatment over a year were significantly less likely to experience a depressive relapse.

These findings could lead to a revision of current bipolar treatment guidelines and potentially offer a life-saving treatment approach for bipolar patients.

Key Facts:

Source: University of British Columbia

Treatment with modern antidepressants may help prevent patients with bipolar disorder from relapsing into a depressive episode, according to an international clinical trial led by researchers at the University of British Columbia.

The findings, published today in the New England Journal of Medicine, challenge current clinical practice guidelines and could change how bipolar depression is managed globally.

“Treating depression in bipolar disorder is challenging and the depressive episodes can be quite devastating for patients and their families,” said Dr. Lakshmi Yatham, professor and head of the department of psychiatry at UBC, and the study’s lead author.

“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.”

Patients with bipolar disorder experience extreme changes in their emotional state that cycle through periods of intense highs (mania or hypomania) and lows (depression). During depressive episodes, patients can experience feelings of sadness, hopelessness and loss of interest or pleasure in activities, in addition to trouble sleeping, changes in appetite and suicidal thoughts.

Antidepressant adjunctive therapy – in which antidepressants are prescribed alongside mood stabilizers and/or second-generation antipsychotic medications – is a commonly used strategy by clinicians to treat depressive episodes.

However, the duration of this therapy is hotly debated due to a lack of evidence and concerns that antidepressants may induce mania, mixed states or rapid cycling between mania and depression.

Practice guidelines for the management of bipolar disorder published by the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) currently recommend discontinuing antidepressant treatment eight weeks after remission of depression.

“It’s an area that hasn’t been widely studied and there is not a lot of consensus among experts,” said Dr. Yatham. “Some studies have shown that up to 80 per cent of patients continue receiving antidepressants for six months or longer.”

Now, results from the world’s first randomized clinical trial assessing the duration of adjunctive antidepressant therapy suggest that extending the treatment period beyond current guidelines may help prevent depressive relapses.

The clinical trial, conducted at sites in Canada, South Korea and India, involved 178 patients with bipolar I disorder who were in remission from a depressive episode following treatment with modern antidepressant drugs (escitalopram or bupropion XL). The patients were randomly assigned to either continue antidepressant treatment for 52 weeks, or begin tapering off antidepressants at six weeks and switch to a placebo at eight weeks.

Over the year-long study, 46 per cent of patients in the placebo group experienced a relapse of a mood event, compared to only 31 per cent in the group that continued antidepressant treatment.

While this primary outcome was not found to be statistically significant, the comparison included relapses that occurred during the first six weeks of the study when both groups were receiving the same treatment.

However, in an analysis from week six onward, when treatment between the two groups differed, patients that continued antidepressant treatment were 40 percent less likely to experience a relapse of any mood event, and 59 percent less likely to experience a depressive episode relative to the placebo group.

There was no significant difference in the rate of manic episodes or the rate of adverse events between groups.

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

Patients with bipolar I disorder experience depressive symptoms three times more frequently than manic symptoms. Previous studies have shown that suicide attempts and suicide deaths are at least 18 times more common during depressive episodes compared to during manic episodes.

“Stabilizing patients and keeping them stable by preventing relapse is critical and can quite literally be lifesaving,” said Dr. Yatham.

“Future revisions of bipolar guidelines will incorporate the evidence from this study and contribute to changes in clinical practice on how antidepressants will be used to manage patients with bipolar disorder.”

The study was a collaboration between researchers at UBC and other study sites in Canada, India and South Korea. It was supported by the Canadian Institutes of Health Research.

Author: Alex WallsSource: University of British ColumbiaContact: Alex Walls – University of British ColumbiaImage: The image is credited to Neuroscience News

Original Research: Closed access.“Duration of Adjunctive Antidepressant Maintenance in Bipolar I Depression” by Lakshmi Yatham et al. NJEM

Abstract

Duration of Adjunctive Antidepressant Maintenance in Bipolar I Depression

Antidepressants are used to treat acute depression in patients with bipolar I disorder, but their effect as maintenance treatment after the remission of depression has not been well studied.

We conducted a multisite, double-blind, randomized, placebo-controlled trial of maintenance of treatment with adjunctive escitalopram or bupropion XL as compared with discontinuation of antidepressant therapy in patients with bipolar I disorder who had recently had remission of a depressive episode. Patients were randomly assigned in a 1:1 ratio to continue treatment with antidepressants for 52 weeks after remission or to switch to placebo at 8 weeks. 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. Key secondary outcomes included the time to an episode of mania or hypomania or depression.

Of 209 patients with bipolar I disorder who participated in an open-label treatment phase, 150 who had remission of depression were enrolled in the double-blind phase in addition to 27 patients who were enrolled directly. A total of 90 patients were assigned to continue treatment with the prescribed antidepressant for 52 weeks (52-week group) and 87 were assigned to switch to placebo at 8 weeks (8-week group). The trial was stopped before full recruitment was reached owing to slow recruitment and funding limitations. At 52 weeks, 28 of the patients in the 52-week group (31%) and 40 in the 8-week group (46%) had a primary-outcome event. The hazard ratio for time to any mood episode in the 52-week group relative to the 8-week group was 0.68 (95% confidence interval [CI], 0.43 to 1.10; P=0.12 by log-rank test). A total of 11 patients in the 52-week group (12%) as compared with 5 patients in the 8-week group (6%) had mania or hypomania (hazard ratio, 2.28; 95% CI, 0.86 to 6.08), and 15 patients (17%) as compared with 35 patients (40%) had recurrence of depression (hazard ratio, 0.43; 95% CI, 0.25 to 0.75). The incidence of adverse events was similar in the two groups.

In a trial involving patients with bipolar I disorder and a recently remitted depressive episode, adjunctive treatment with escitalopram or bupropion XL that continued for 52 weeks did not show a significant benefit as compared with treatment for 8 weeks in preventing relapse of any mood episode. The trial was stopped early owing to slow recruitment and funding limitations. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00958633. opens in new tab.)

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