Conflict Between Available Data and the Real World of Bipolar Depression Treatment

In a session at the American Psychiatric Association 2023 Annual Meeting titled “Treatment of Bipolar Depression,” Michael Jay Gitlin, MD, gave an overview of agents used in bipolar depression treatment, including mood stabilizers, second-generation antipsychotics, and antidepressants. In his presentation, he also paid special attention to issues with the available clinical data on many treatments.

Dr. Gitlin qualified that, while mania is the defining pole of bipolar disorder, depression is the dominant pole. He cited data showing patients with bipolar disorders spend approximately three times more time depressed than they spend manic or hypomanic. Despite this fact, there are far more studies on mania than there are on depression.

Dr. Gitlin also highlighted an “obsession” among colleagues over the clinical differences between major depression and bipolar depression. While there are some differences, the similarities far outweigh the differences, he said, and any feature you can see in bipolar depression, you can see in unipolar depression.

Compared with treating unipolar depression, Dr. Gitlin noted treatments for bipolar depression are tricker due to different efficacy factors and considerations for rates of switching and rapid cycling—whether formal episodes or just mood instability.

Lithium is the oldest mood stabilizer used in bipolar disorder, Dr. Gitlin said. While there is published evidence on lithium’s antidepressant effects, there is a “startling” lack of published controlled trials on lithium for bipolar depression. Likewise, carbamazepine is only explored in a few trivial studies with no great data, according to Dr. Gitlin.

As another example of issues in the published evidence, Dr. Gitlin pointed to valproate, which had four, small, double-blind, randomized, controlled trials that showed it was more effective than placebo in acute bipolar depression.

If that is the case, Dr. Gitlin said, why isn’t valproate used more frequently? He then noted that real-world use eventually revealed that valproate could lead to serious fertility problems, including serious teratogenicity, in younger women.

Lamotrigine, which Dr. Gitlin called one of the darlings of bipolar disorder treatment, is unique among mood stabilizers for having a greater impact in preventing lows rather than preventing highs; however, it does not have an indication for acute bipolar depression.

Of the five double-blind trials on lamotrigine, only one was positive. Subsequent analyses reported some increased efficacy after stratifying patients by greater disease severity, but Dr. Gitlin went on to point out that the finding was due to a decrease in placebo response rather than an increase in treatment response.

Nonetheless, Dr. Gitlin said he believes lamotrigine works for bipolar depression, and he uses it fairly regularly. However, he emphasized that, from a strictly data point of view, it’s difficult to approach the treatment from a strictly evidence-based perspective.