Brexpiprazole versus placebo or other antidepressive agents for treating depression

Background Brexpiprazole is the newest antipsychotic drug approved as an adjunctive for treatment‐resistant depression. This systematic review provides comprehensive, high‐quality evidence for the effects of brexpiprazole in major depressive disorder (MDD) based on existing and emerging randomised controlled trials (RCTs). Objectives To evaluate the benefits and harms of brexpiprazole as monotherapy or adjunct treatment in the acute and longer‐term treatment of MDD compared to placebo or other antidepressive agents. Search methods We used standard, extensive Cochrane search methods. The latest search date was November 2021. Selection criteria We included RCTs in people with a history of non‐response to one or more antidepressant monotherapies comparing brexpiprazole as monotherapy or adjunct treatment with placebo or other antidepressive agents. Data collection and analysis We used standard Cochrane methods. Primary outcomes were 1. response to treatment, measured as number of participants who achieved 50% or more reduction of the score on a validated scale for depression, 2. dropouts due to any reason, and 3. dropouts due to adverse effects, all measured at eight weeks (acute treatment). Our secondary outcomes were 4. number of participants who responded to treatment after two and 18 weeks, number of participants who achieved remission after eight weeks, 5. total number of participants with any adverse events, 6. social functioning or adjustment, and 7. health‐related quality of life. We used GRADE to assess certainty of evidence for each outcome.Main resultsWe retrieved nine studies with 3424 participants with treatment‐resistant depression, defined as lack of response to at least two trials of antidepressant monotherapy. The age of participants was 18 to 65 years in seven studies, 18 to 75 years in one study, and older than 65 years in one study. Inclusion criteria for all studies required a diagnosis of MDD with a current major depressive episode per Diagnostic and Statistical Manual of Mental Disorders Text Revision Fourth Edition criteria and additional criteria on minimal scores on Montgomery–Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale which varied across studies. Eight studies compared brexpiprazole as adjunctive treatment to an antidepressant versus placebo as adjunctive treatment to an antidepressant. One study added brexpiprazole or placebo to a combination of antidepressant and ketamine. Four studies used fixed dosages and five studies used flexible dosages of brexpiprazole. The manufacturer sponsored eight studies and one study was independently funded.Brexpiprazole was superior in achieving response at eight weeks (odds ratio (OR) 1.47, 95% confidence interval (CI) 1.23 to 1.75; 8 studies, 3409 participants; high‐certainty evidence). More participants randomised to brexpiprazole dropped out due to any cause at eight weeks (OR 1.37, 95% CI 1.02 to 1.83; 7 studies, 2523 participants; high‐certainty evidence) or due to adverse effects (OR 2.88, 95% CI 1.37 to 6.05; 6 studies, 2472 participants; high‐certainty evidence). Brexpiprazole was superior to placebo when added to an antidepressant for achieving remission at eight weeks (OR 1.46, 95% CI 1.19 to 1.79; 7 studies, 3358 participants; high‐certainty evidence). When response was defined based on a change in the score on MADRS, brexpiprazole also demonstrated better efficacy than placebo (mean difference (MD) –1.39, 95% CI –1.96 to –0.82; 8 studies, 3263 participants; high‐certainty evidence). Compared to placebo, add‐on brexpiprazole is probably more likely to result in akathisia (OR 2.95, 95% CI 2.06 to 4.21; 7 studies, 3358 participants; moderate‐certainty evidence) and weight gain (OR 3.14, 95% CI 2.19 to 4.49; 9 studies, 3424 participants; moderate‐certainty evidence).The risk of bias varied between low and unclear for most studies. Only one study was at high risk of selective reporting bias and other bias; however, this study had a small sample size and its impact on overall risk of bias was not considered significant. The certainty of the evidence on five of the main outcomes (response to treatment, measured as number of participants who achieved response and change in depressive symptoms, remission, dropouts due to any cause, dropouts due to adverse effects) was high. The certainty of evidence for akathisia and weight gain was downgraded one level to moderate due to indirectness. Authors' conclusions Our review supports the superior efficacy of add‐on brexpiprazole in comparison to placebo in adults with treatment‐resistant depression for the short‐term and acute treatment of depression. Our findings were limited by the small number of studies and the moderate‐certainty evidence for the most common adverse effects (akathisia and weight gain). There was insufficient evidence for the effects of brexpiprazole for depression in older people or children. In addition, we found no studies that compared brexpiprazole to other antidepressants or where brexpiprazole was added after lack of response to only one antidepressant. We also lacked sufficient data to establish the long‐term efficacy of brexpiprazole as adjunctive treatment. Active comparators, long‐term studies in different age groups and cost‐effect analyses are needed to more precisely establish the clinical role of brexpiprazole in the treatment of MDD.