Modern antidepressants prevent relapse in patients with bipolar I disorder: NEJM

South Korea: In an international clinical trial involving patients with bipolar I disorder and a recently remitted depressive episode, treatment with modern antidepressants may help prevent patients from relapsing into a depressive episode.

In the trial published in the New England Journal of Medicine, researchers at the University of British Columbia found that adjunctive treatment with escitalopram or bupropion XL (modern antidepressant drugs) continuing for 52 weeks did not show a significant benefit versus treatment for 8 weeks in preventing relapse of any mood episode.

The findings challenge current clinical practice guidelines and could change how bipolar depression is managed globally. The trial was stopped early owing to slow recruitment and funding limitations.

“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 per cent less likely to experience a relapse of any mood event, and 59 per cent 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 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.”

Reference:

Lakshmi N. Yatham, Shyam Sundar Arumugham, Muralidharan Kesavan, Kanchana Ramachandran, Nithyananda S. Murthy, Gayatri Saraf, Yongdong Ouyang, David J. Bond, Ayal Schaffer, Arun Ravindran, Nisha Ravindran, Benicio N. Frey, DOI: 10.1056/NEJMoa2300184.