When is Rexulti (brexpiprazole) indicated for treatment of major depressive disorder in adults?

When is Rexulti (Brexpiprazole) Indicated for Major Depressive Disorder?

Rexulti is indicated as adjunctive therapy to antidepressants in adults with major depressive disorder who have demonstrated an inadequate response to prior antidepressant treatment. 1

Specific Clinical Criteria for Use

Treatment-Resistant Depression Definition:

• Brexpiprazole should be considered when patients have failed to achieve adequate response after 1-3 adequate antidepressant trials in the current depressive episode 1
• An adequate trial requires sufficient dose and duration (minimum 4-6 weeks at therapeutic doses) before determining inadequate response 2
• The FDA approval was based on studies where patients demonstrated persistent symptoms without substantial improvement throughout 8 weeks of prospective antidepressant treatment with SSRIs or SNRIs (escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, or venlafaxine) 1

When to Initiate Brexpiprazole

Primary Indication:

• Add brexpiprazole when patients continue to have unresolved depressive symptoms despite ongoing antidepressant monotherapy at adequate doses for 6-8 weeks 1, 3
• The drug is specifically approved for adjunctive use—it must be added to an existing antidepressant, not used as monotherapy 1

Timing in Disease Course:

• Brexpiprazole is effective both earlier and later in the disease course, with treatment effects ranging from -1.79 to -2.92 points on MADRS across different patient subgroups 4
• There is no advantage to delaying brexpiprazole treatment once inadequate response to antidepressant monotherapy is established 4

Dosing Strategy

FDA-Approved Regimen:

• Start at 0.5 mg once daily for Week 1 1
• Increase to 1 mg once daily at Week 2 1
• Titrate to target dose of 2-3 mg once daily from Week 3 onwards based on tolerability and response 1
• The 2 mg and 3 mg daily doses demonstrated statistically significant superiority over placebo plus antidepressant in pivotal trials 1

Evidence of Efficacy

Clinical Trial Results:

• In two 6-week randomized controlled trials, brexpiprazole 2-3 mg daily plus antidepressant produced placebo-subtracted differences of -3.2 points (2 mg) and -2.0 points (3 mg) on the MADRS scale 1
• Approximately 50% of adults with MDD fail to achieve adequate response to first-line antidepressant treatment, establishing the clinical need for augmentation strategies 5

Critical Considerations Before Prescribing

Verify Treatment Resistance:

• Before adding brexpiprazole, confirm that the current antidepressant trial has been adequate in both dose and duration (minimum 6-8 weeks) 2, 1
• Document medication adherence, as up to 50% of patients with MDD demonstrate non-adherence, which can masquerade as treatment resistance 2
• Consider checking plasma antidepressant levels if adherence is uncertain 2

Alternative First-Line Augmentation:

• The American College of Physicians strongly recommends adding Cognitive Behavioral Therapy (CBT) to pharmacotherapy for treatment-resistant depression, which produces superior outcomes compared to antidepressant monotherapy alone (remission rates 57.5% vs 31.0%, P < 0.001) 2
• Consider CBT augmentation before or concurrent with brexpiprazole, particularly in severe depression 2

Common Pitfalls to Avoid

• Premature initiation: Do not add brexpiprazole before completing an adequate 6-8 week trial of the current antidepressant at therapeutic doses 2, 1
• Monotherapy use: Brexpiprazole is not approved as monotherapy for MDD and must be used adjunctively with an antidepressant 1
• Inadequate monitoring: Assess for akathisia (6.7% incidence), weight gain (mean 2.7-3.2 kg), and metabolic effects during treatment 6

Safety Profile

Most Common Adverse Events (≥5%):

• Weight increase (17.7%), somnolence (8.0%), headache (7.2%), akathisia (6.7%), increased appetite (6.3%), insomnia (6.3%), and fatigue (6.1%) 6
• Most adverse events are mild to moderate in severity 6
• Brexpiprazole has a lower potential than aripiprazole to cause activation-like adverse effects due to its unique receptor binding profile and low intrinsic D2 activity 3