Continuing adjunctive antidepressant treatment for up to a year following remission of an acute Depressive Episode in patients with bipolar I disorder showed no significant benefit for preventing relapse, a randomized trial showed.

At 52 weeks, 31% of patients treated with maintenance escitalopram (Lexapro) or bupropion XL (Wellbutrin XL) for that duration of time experienced a subsequent mood episode, as compared with 46% of those who switched to placebo at 8 weeks (HR 0.68, 95% CI 0.43-1.10, P=0.12), reported Lakshmi N. Yatham, MBBS, of the University of British Columbia in Vancouver, and co-authors.

Fewer patients in the 52-week group had recurrence of depression versus the 8-week group (17% vs 40%; HR 0.43, 95% CI 0.25-0.75), but more had mania or hypomania (12% vs 6%; HR 2.28, 95% CI 0.86-6.08), they detailed in the New England Journal of Medicine.

Notably, the researchers ended the trial before full enrollment was achieved due to slow recruitment and funding limitations, which they acknowledged may have affected the Primary Outcome of the study. And Yatham suggested that early differences in relapse, when both groups were on treatment, may have played a role as well.

“Because the treatments were identical in the first 6 weeks, we were not expecting any differences between the two groups in those first 6 weeks,” Yatham told MedPage Today. “By some random noise, there was a difference in the first 6 weeks.”

Four patients in the 52-week maintenance group and one in the 8-week group relapsed at 6 weeks, the point at which patients in the 8-week group underwent dose reductions before switching to placebo. “That kind of messed up our analysis,” he said.

Yatham noted that he and his team had debated whether to include the initial 6-week period in the primary outcome analysis, but decided it would likely not affect the overall data because the treatments were the same. When the outcomes during that period proved to be different, the group also analyzed the primary outcome without the confounding data from that initial period of the trial to show the contrast.

In the sensitivity analysis of outcomes after 6 weeks, the HR for time to any mood episode was 0.60 (95% CI 0.37-0.98).

“When you do look at when the treatments are different, the group that continued antidepressant therapy, the 52-week group, did significantly better in terms of time to any mood episode, and in particular time to depressive episode without increasing risk of mania,” Yatham said.

Patients in the 52-week group were 59% less likely to experience a depressive episode after the first 6 weeks (HR 0.41, 95% 0.23-0.72) when compared with the 8-week group.

“Although our primary outcome, which was confounded by the random noise, was negative, most clinicians are going to look at this study and say, antidepressant adjunctive therapy is beneficial for at least some bipolar patients, and we do need to continue them for a longer period of time,” he noted.

For this multisite, double-blind trial, the researchers recruited patients with bipolar I disorder who had recently had remission of a depressive episode and were treated with adjunctive escitalopram (10-30 mg daily) or bupropion XL (150-450 mg daily) in the previous 16 weeks at sites in Canada, Korea, and India.

All patients were also taking a mood stabilizer or a second-generation antipsychotic agent (or a combination of the two).

Of 177 patients with bipolar I disorder who had remission of depression included in the final analysis, 90 were assigned to continue treatment and 87 were assigned to switch to placebo. Most of the participants were recruited in India; 87% were Asian, and 12% were white. Mean age was 41, and 48% were men.

The primary outcome was assessed in a time-to-event analysis. Mood episode was 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.

The incidence of adverse events was similar between the two groups. 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.