Brexpiprazole (Rexulti) is a medication that has similar effects to two other atypical antipsychotics, cariprazine (Vraylar) and aripiprazole (Abilify) but brexpiprazole does not have approval in the United States for treating bipolar mania. Why is this, and how should it guide clinical practice?
A recent review of all of the studies of brexpiprazole in bipolar mania that are listed on the FDA’s Clinical Trials website was published by two international experts in bipolar disorder, Gary Sachs and Eduard Vieta. In their review, the authors note that the three studies that look at this question did not show that brexpiprazole was effective in treating bipolar mania. This is a surprising finding because brexpiprazole has been shown to be effective in treating psychosis in schizophrenia, and almost every medication that has been approved for psychosis in schizophrenia has been shown to be effective in treating bipolar mania.
The authors make an important point early in their discussion, “failed” clinical trials are relatively common. Almost every medication that the FDA has approved for the treatment of unipolar depression has one or more “failed” clinical trials – meaning trials where there was no statistical difference between the medication and placebo.
Limitations of Clinical Trials
In fact the topic of failed clinical trials has been the subject of a great deal of thought in the psychiatric research community. There are many reasons why a clinical trial may not show a difference between the active medication and a placebo, but the most common reasons are:
- There was a very high response to placebo (patients got better on their own).
- Patients had a milder form of disease (which is often the cause of a high placebo response).
- The titration schedule for the medication was too conservative (it took too long to get to the full dose or many patients never got to the full dose).
- The dose was inadequate (the dose that the study sponsor thought should be the full dose was actually too low).
- The active medication was not effective.
Clinical Trials of Brexpiprazole and Bipolar Mania
Looking at the three studies, is there evidence in favor of one or more of these reasons?
There were some differences in outcomes in the two acute trials. One of these was conducted in the United States and one in Europe. In the European study there was evidence that brexpiprazole was effective on some measures, this was not true in the US study.
The authors note that there was an unusually high response to placebo, particularly in the clinical trial that took place in the United States. Also, in the US clinical trial, there were more patients who were felt to have “good insight,” which is also a marker for a milder form of bipolar mania.
The titration schedule was much slower than in comparable clinical trials for cariprazine. In fact, it took twice as long to get to the “full therapeutic dose” in the brexpiprazole studies.
Finally, there is evidence to suggest that the “therapeutic dose” for cariprazine may be higher, in terms of receptor occupancy and potential side effects than the “therapeutic dose” for brexpiprazole.
In other words, there is evidence to suggest that all of the potential causes for a “failed” clinical trial were present in the brexpiprazole mania studies.
Implications for Treatment
What should the clinician do in this situation?
The lack of evidence for effectiveness of a medication is not the same as evidence that the medication doesn’t work. It just means that we don’t know.
Unfortunately, in medicine we are often forced to make decisions when we don’t know the answers for sure.
In general, at Gateway Psychiatric, we try to “do the things that we know work before trying things that we don’t know work.” However, sometimes we have to move outside that realm. For example, treating a patient who has had a good response to aripiprazole (Abilify) for bipolar mania but has had fairly severe adverse effects and has had one failed trial of cariprazine, should we consider brexpiprazole, which is very similar to both of those medications?
I think that the answer is yes. But when doing so we should be very careful to watch for signs that the medication is not working.
Vieta, E., Sachs, G., Chang, D., Hellsten, J., Brewer, C., Peters Strickland, T., & Hefting, N. (2021). Two randomized, double-blind, placebo-controlled trials and one open-label, long-term trial of brexpiprazole for the acute treatment of bipolar mania. Journal of Psychopharmacology, , 026988112098510-269881120985102.
Brown ES, Khaleghi N, Van Enkevort E, Ivleva E, Nakamura A, Holmes T, Mason BL, Escalante C. A pilot study of brexpiprazole for bipolar depression. J Affect Disord. 2019 Apr 15;249:315-318. doi: 10.1016/j.jad.2019.02.056. Epub 2019 Feb 19. PMID: 30802696.