Editor’s Note: Adjunctive Antidepressant Use in Bipolar Depression

Norman Sussman, MD, DFAPA

Editor, Primary Psychiatry and Psychiatry Weekly, Professor of Psychiatry, New York University School of Medicine

The use of antidepressants to treat patients with bipolar depression can be problematical, mainly because these drugs can induce switching patients into hypomania or mania. In addition, there is anecdotal evidence that antidepressants are less likely to maintain their effectiveness over time in this population. A large study has examined the relative acute and long-term effects of bupropion, sertraline, and venlafaxine when used as adjuncts to mood stabilizers in the treatment of patients who were currently in the depressed phase of bipolar I or bipolar II disorder.

The Study

Patients were initially enrolled in a 10-week, out-patient trial. Those treated were diagnosed with bipolar disorder and were randomly treated with a flexible dose of one of the antidepressants or as adjuncts to mood stabilizers. Some patients were then followed for up to one year.

Results

During short-term treatment of bipolar disorder, the response and remission rates were comparable among the three drugs, but there was a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine, when compared with bupropion or sertraline.

Those continued on antidepressant treatment of bipolar depression for up to 1 year were monitored for antidepressant response and the occurrence of subthreshold brief hypomania.

Nearly 33% of patients with bipolar I disorder exhibited threshold switches compared to just under 20% in patients with bipolar II disorder.

As in the acute phase, the rate of threshold switches to subthreshold brief hypomanias was higher in both the acute and continuation trials of venlafaxine than in the acute and continuation trials of bupropion and sertraline.

The study also found that antidepressants often fail to maintain their effect in the bipolar population. Of the patients in the original acute antidepressant trial, only 23.3% had a sustained antidepressant response in the continuation phase, this being so even in the absence of a threshold switch.

Implications

Of the three antidepressants included in the study, venlafaxine was associated with the highest relative risk of switching and bupropion with the lowest risk. Results of the study strongly suggest that clinicians not use venlafaxine as a first choice adjunctive treatment of bipolar depression. Duloxetine, like venlafaxine, a serotonin-norepinephrine reuptake inhibitor, has not been systematically studied as an adjunctive therapy in bipolar disorder. As with other antidepressant drugs, clinical trials of duloxetine in patients with major depressive disorder, excluded subjects with a history of bipolar disorder, and no significant activation of mania or hypomania was reported. However, activation of mania/hypomania may be more likely to occur in drugs that affect both serotonin and norepinephrine—the tricyclics being the most notable examples—and until proven otherwise, duloxetine should be used cautiously in patients with a history of mania.

It is important to point out that for some patients, venlafaxine may still be an appropriate choice, particularly if it is the only antidepressant that is effective for an individual patient. However, based on this and other evidence, bupropion is least likely to induce cycling or switching.

Disclosure: Dr. Sussman reports no affiliations with or financial interests in any organization that may pose a conflict of interest.