Randomized, placebo-controlled trial of risperidone for acute treatment of bipolar anxiety

Sheehan, D. V., McElroy, S. L., Harnett-Sheehan, K., Keck, P. E., Jr, Janavs, J., Rogers, J., Gonzalez, R., Shivakumar, G., & Suppes, T. (2009). Randomized, placebo-controlled trial of risperidone for acute treatment of bipolar anxiety. Journal of affective disorders, 115(3), 376–385. https://doi.org/10.1016/j.jad.2008.10.005

This is a fascinating (if somewhat overlooked) article published back in 2009 by Sheehan and colleagues in the Journal of Affective Disorders. The study explored the use of risperidone—a second-generation antipsychotic—to treat anxiety in people with bipolar affective disorder (BPAD). Sounds promising, right?

Well, before we get too excited, it’s worth noting that most of the study’s authors had multiple pharmaceutical affiliations. In fact, only two out of the whole group were unaffiliated with industry. That’s not ideal, especially when we’re thinking about treatments for our own patients—so let’s put on our sceptic hats from the outset.

The study tackled a genuinely important clinical question. Anxiety is common in people with bipolar disorder, but treating it can be tricky. Many of the medications we commonly use for anxiety, such as SSRIs, can actually destabilise mood or worsen bipolar symptoms—leaving clinicians in a bit of a bind. The authors wondered whether risperidone might offer an alternative.

The study enrolled 111 adults with bipolar disorder and moderate to severe anxiety symptoms. Participants were randomly assigned to receive either risperidone or placebo. (Importantly, none of the participants had an intellectual disability—once again, this population was excluded, as is too often the case in clinical trials.)

A variety of scales were used to measure anxiety levels and side effects, with the goal of determining whether risperidone was more effective than placebo at reducing anxiety symptoms.

Unfortunately, there were a few issues with the sample. Patients in the risperidone group were more likely to be in a "mixed mood state" at baseline. That matters—because it means the groups weren’t exactly equivalent to begin with, leaving room for confounding factors to influence the results.

There were also high dropout rates, with only 27 participants completing the trial in the risperidone group and 36 in the placebo group—not exactly large numbers to draw robust conclusions from.

So what did they find?

Risperidone didn’t significantly reduce disability related to mental illness, nor did it show superior outcomes in depression or mania symptoms compared to placebo. There was a slight reduction in anxiety in the risperidone group, but the difference was small and could easily have been due to chance.

In the end, the authors concluded that risperidone failed to show a clear benefit over placebo in treating anxiety in bipolar disorder. To their credit, they were transparent about this result despite the industry affiliations. They also acknowledged that differences in dosing and demographic characteristics between groups may have influenced the outcome.

So—back to the drawing board with this one. While it's always worth exploring new options, this study reminds us how important it is to remain critical, especially when the evidence is sponsored.