Details for This Review

Study Population: Nine randomized controlled trials from 16 high-income countries, including 3,424 adults with treatment-resistant depression (lack of response after at least two trials of antidepressant monotherapy) who met the Diagnostic and Statistical Manual of Mental Disorders, 4th and 5th eds., criteria for major depressive disorder and were having a current depressive episode

Efficacy End Points: Primary outcome: response to treatment (greater than 50% improvement in depressive symptoms on validated depression score) at eight weeks; secondary outcomes: response to treatment after two and 18 weeks, remission after eight weeks, social functioning or adjustment, health-related quality of life

Harm End Points: Primary outcomes: dropouts due to any cause or adverse effects at eight weeks; secondary outcomes: any adverse effects, specific adverse effects (e.g., akathisia [restlessness], weight gain)

Narrative: Major depressive disorder affects more than 300 million people of all ages worldwide.¹ Depression is a leading cause of disability, impairs quality of life and psychosocial development, and increases morbidity and mortality.^1,2 Major depressive disorder is severe and episodic, with episodes lasting six to 12 months on average.³ Approximately 50% of patients do not achieve remission with first-line treatments, including selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, and about two-thirds of patients require further trials of antidepressant therapies to achieve remission.^2,4

Treatment-resistant depression is defined by chronic and persistent symptoms of low mood and repeated major depressive disorder episodes after at least two adequate antidepressant treatment trials.^2,4 Treatment-resistant depression occurs in up to 60% of patients with a major depressive disorder.² Differentiating treatment-resistant depression from persistent depressive disorder (low mood occurring for at least two years without repeated major depressive disorder episodes) is essential because up to 40% of dysthymic symptoms are considered treatment resistant. This is key because studies have shown that antidepressants and psychotherapy are less effective for persistent depressive disorder than for nonchronic major depressive disorder, including treatment-resistant depression.³

This Cochrane review focused on the effectiveness of brexpiprazole (Rexulti) as an adjunctive therapy for treatment of treatment-resistant depression.4 Brexpiprazole is a second-generation antipsychotic that functions as a partial agonist of dopamine and serotonin receptors. Second-generation antipsychotics are often preferred over first-generation medications because they have a lower risk of extrapyramidal symptoms. However, adverse effects can include metabolic disturbances such as weight gain, hyper-lipidemia, and hyperglycemia.⁵

The Cochrane review included patients with a history of nonresponse to one or more antidepressant monotherapies and compared brexpiprazole as adjunct treatment with placebo or another antidepressant (e.g., duloxetine [Cymbalta], escitalopram, fluoxetine, paroxetine, sertraline, extended-release venlafaxine). Inclusion criteria for all studies required a diagnosis of major depressive disorder with a current episode. Primary outcomes were response to treatment (defined as greater than 50% improvement in depressive symptoms on a validated depression score), number of dropouts due to any cause, and number of dropouts due to adverse effects—all measured at eight weeks. Secondary outcomes included response to treatment after two and 18 weeks, remission after eight weeks, social functioning or adjustment, and health-related quality of life.

High-certainty evidence in the Cochrane review showed better treatment response (odds ratio [OR] = 1.47; 95% CI, 1.23 to 1.75; absolute risk difference [ARD] = 6.3%; number needed to treat [NNT] = 16) and increased remission rates (OR = 1.46; 95% CI, 1.19 to 1.79; ARD = 4.6%; NNT = 22) at eight weeks with brexpiprazole adjunctive therapy compared with placebo.⁴ High-certainty evidence also demonstrated that brexpiprazole reduced depressive symptoms compared with placebo (mean difference = 1.39; 95% CI, 1.96 to 0.82). The review did not find adequate evidence to draw conclusions about treatment outcomes at two or 18 weeks, social functioning or adjustment, or health-related quality of life.

High-certainty evidence in the review showed that, compared with placebo, participants receiving brexpiprazole adjunctive therapy were more likely to withdraw due to any cause (OR = 1.37; 95% CI, 1.02 to 1.83; ARD = 2.6%; number needed to harm [NNH] = 38) or due to adverse effects (OR = 2.88; 95% CI, 1.37 to 6.05; ARD = 1.7%; NNH = 58) at eight weeks.

In the Cochrane review, moderate-certainty evidence demonstrated that, compared with placebo, participants receiving brexpiprazole adjunctive therapy were more likely to have akathisia (OR = 2.95; 95% CI, 2.06 to 4.21; ARD = 4.9%; NNH = 20) or weight gain (OR = 3.14; 95% CI, 2.19 to 4.49; ARD = 5%; NNH = 20) at the end of the trial. The review did not find adequate evidence to draw conclusions about the total number of adverse effects between groups.

Caveats: Limitations of this review include lack of generalizability in children/adolescents and the geriatric population. In addition, only one study had a follow-up period longer than 12 weeks, limiting long-term data.

Gender is a key demographic in major depressive disorder because the condition is more common in women than in men. Women reportedly comprised most of the participants (67.5%) in the review; however, there was no mention of how gender was identified, male and female were the binary options described, and the authors did not report on differences in response.⁶

Additionally, studies with more than 20% of participants with a diagnosis of bipolar depression or psychotic depression were excluded, limiting generalizability across commonly associated behavioral health diagnoses. Response to treatment outcomes in general can also be considered arbitrary or subjective and naturally has some inter- and intrarater variability. Patient-oriented outcomes, such as suicide rate, were not included. Finally, no studies included brexpiprazole as monotherapy, used dual therapy as comparators, or evaluated patients unresponsive to only one antidepressant trial.

Overall, although broader age range and long-term data are lacking and the comparisons included placebo instead of dual therapy (e.g., escitalopram and bupropion), the review presents moderate- to high-certainty data that brexpiprazole is effective as an adjunct for treatment-resistant depression in adults 18 to 65 years of age. Based on these results and limitations, we have assigned a color recommendation of yellow (uncertain benefits). Brexpiprazole improved depressive symptoms and induced remission in a significant number of patients in the acute treatment period. Withdrawal rates due to adverse effects were low, and, given the effects within eight weeks, long-term treatment may not be needed.

Counseling on the adverse effects of akathisia and weight gain is warranted. Further data are needed to determine the effectiveness in children, adolescents, and older populations; to evaluate brexpiprazole as monotherapy compared with dual-therapy regimens; and to assess long-term effectiveness.