What are the benefits and harms of brexpiprazole, a new antipsychotic medication, for the treatment of depression when compared to dummy tablets or antidepressants?

Key messages

– Brexpiprazole added to an antidepressant is better at reducing the symptoms of depression than placebo (dummy tablet) added to an antidepressant.

– Brexpiprazole might be more commonly associated with weight gain and akathisia (a feeling of restlessness that causes a compelling need to move all the time).

What is depression?

Depression is a common mental health condition which leads to low mood, inability to experience pleasure, sleep disruption, weight loss, fatigue or low energy, slower speech and movements, feeling worthless or excessively guilty, being unable to concentrate and having thoughts of committing suicide. To be diagnosed with depression, a person should experience five or more of these symptoms, including low mood or loss of sense of pleasure for at least two weeks.

How is the condition treated?

Unless the symptoms of depression are mild, the first option for treatment is an antidepressant medication, but antidepressants only help in half of cases when prescribed for the first time. When an antidepressant is not enough to treat depression, one available option is to add another medication to help the effects of the antidepressant. Other options include changing the antidepressant to another antidepressant, talking therapy or stimulation of the brain through electrical pulses. Brexpiprazole is a new medication which can be added to an antidepressant that has not worked by itself. Brexpiprazole can be prescribed in doses from 0.5 mg to 3 mg for the treatment of depression. It has also been approved for the treatment of schizophrenia.

What did we want to find out?

We wanted to examine the effects of brexpiprazole in the treatment of depression when prescribed by itself or when added to another antidepressant and how its effects compare to the effects of antidepressants or placebo. To do so we explored several effects. First, we looked into how well brexpiprazole decreased the symptoms of depression. Second, we explored how many participants gave up taking part in the studies for any reason. Third, we investigated how many stopped participating because of the unwanted effects they experienced. Fourth, we explored what unwanted effects emerged with the use of brexpiprazole. We also wanted to know how brexpiprazole affected the quality of life of the participants and how it affected the way they functioned in their everyday lives.

What did we do?

We searched scientific databases for studies that reported the effects of brexpiprazole versus placebo or antidepressants for depression. We included only studies in which the participants were assigned randomly to one or the other treatment. Neither them nor the team that was evaluating the effects of the treatment knew what was prescribed and this helped to objectively evaluate the results without the knowledge of what was prescribed impacting on the outcome. We compared and summarised the results and evaluated how confident we were that the results of the studies represented the real effects of the medication. We based our confidence on different factors such as the size of the effects, the methods used, and what and how the results were reported.

What did we find and what were the limitations of our findings?

We found nine studies, which included 3424 participants; two-thirds of them were women and one-third were men.

We only found studies in which brexpiprazole was added after the participants had tried treatment with two or more antidepressants on their own. We have a high level of confidence that brexpiprazole added to an antidepressant reduced the symptoms of depression more after eight weeks of treatment than placebo added to an antidepressant. Brexpiprazole was also more likely to lead to no symptoms of depression than placebo when either of them was added to an antidepressant. We are moderately confident that brexpiprazole caused weight gain or subjective feelings of restlessness more often than placebo. We are less confident about the results around these unwanted effects as we could not find information about how they were measured and whether all studies used the same methods to measure them.

What did we fail to find?

We found no studies that explored how brexpiprazole would work for children or older people who have depression. We wanted to find how brexpiprazole would work when given for depression for longer periods of time, such as 18 to 24 weeks, but we found only one study and its results were not enough to draw a conclusion.

How up-to-date is this evidence?

Our evidence is up-to-date to 1 November 2021.

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.

Read the full abstract...

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).


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 strategy: 

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 results: 

We 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.