Antidepressants for Bipolar Depression

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.

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.

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.


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, Andrée Daigneault, Serge Beaulieu, Raymond W. Lam, Nithin Kondapuram, M.S. Reddy, R.P. Bhandary, Mysore V. Ashok, Kyooseob Ha, Yong Min Ahn, Roumen Milev, Hubert Wong, Y.C. Janardhan Reddy. Duration of Adjunctive Antidepressant Maintenance in Bipolar I Depression. New England Journal of Medicine, 2023; 389 (5): 430 DOI: 10.1056/NEJMoa2300184

University of British Columbia. (2023, August 2). Modern antidepressants may reduce risk of relapse for patients with bipolar depression. ScienceDaily. Retrieved August 3, 2023 from
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