REVIEW OF: Vieta E et al, J Psychopharmacol 2021;35(8):971–982

TYPE OF STUDY: Phase III randomized controlled trials

Brexpiprazole is FDA approved in schizophrenia and as an adjunct for major depression and is one of the better-tolerated antipsychotics. Like aripiprazole, it is a partial D2 and 5-HT1A agonist. Unlike most antipsychotics, brexpiprazole has never been studied in acute mania, so these two recently published industry-sponsored trials give us the first glimpse of its antimanic potential.

The trials employed similar designs. Both were large, randomized, placebo-controlled trials that compared brexpiprazole with placebo over three weeks in acute bipolar I mania. The participants were drawn from US and European sites and had a Young Mania Rating Scale (YMRS) score over 24 at entry. Brexpiprazole was started at 2 mg/day and titrated up to 4 mg/day as tolerated. No other medication was allowed except lorazepam on an as-needed basis. The trials enrolled 654 patients, over 75% of whom completed the acute phase.

After three weeks, YMRS scores were about the same for drug and placebo, although the brexpiprazole group scored a little better on the secondary Clinical Global Impression—Bipolar Disorder (CGI-BD) measure.

Both trials included an open-label, long-term phase where symptoms were treated with brexpiprazole for another six months if the investigators thought patients would benefit from continued treatment. Outcome measures over the 26 weeks of this phase showed gradual decreases in YMRS and CGI-BD scores, but the changes were not dramatic and there was no control arm to compare them to.

Brexpiprazole was well tolerated, with akathisia the most commonly reported adverse effect. During the open-label extension, six patients became manic, five became depressed, and four developed suicidal ideation, but these events lacked a placebo arm for comparison.

The multicenter design may have obscured the drug-placebo difference. There are more investigators per patient in multicenter trials, increasing the attention each patient receives and amplifying the placebo effect. However, other antipsychotics have overcome this and yielded positive results in mania during multicenter trials.

The authors conducted a secondary analysis in an attempt to salvage some signal of response in these patients. Based on earlier evidence that poor insight predicts a better response to antipsychotics in mania (Welten CCM et al, J Clin Psychopharmacol 2016;36(1):71–76), they reanalyzed the data and found that poorer insight was associated with a statistically significant improvement on brexpiprazole relative to placebo (odds ratio 2.2, CI 1.1–4.4).

TCPR’s Take
The atypical antipsychotics are a varied class, and we can’t conclude all of them work in acute mania. Stick with those that are FDA approved in mania (aripiprazole, asenapine, cariprazine, olanzapine, quetiapine, risperidone, and ziprasidone), as the others in this class are either untested (eg, lumateperone, lurasidone) or have negative results in this condition (eg, paliperidone).