What is the evidence for adding brexpiprazole (an atypical antipsychotic) to an antidepressant for treatment-resistant depression?

Evidence for Brexpiprazole Augmentation in Treatment-Resistant Depression

Brexpiprazole is FDA-approved and strongly recommended as adjunctive therapy to antidepressants for treatment-resistant depression, with the most extensive evidence base of all pharmacological augmentation strategies. 1, 2

FDA Approval and Regulatory Status

• Brexpiprazole received FDA approval in 2015 specifically as adjunctive therapy to antidepressants for major depressive disorder in adults who have demonstrated inadequate response to prior antidepressant treatment 2
• The FDA indication is for patients with inadequate response to 1-3 courses of antidepressant therapy in the current episode, who continue to show persistent symptoms without substantial improvement 2
• This represents the first atypical antipsychotic specifically approved by the FDA for treatment-resistant depression augmentation 1

Evidence Base from Clinical Trials

Efficacy Data

• Two pivotal 6-week, double-blind, placebo-controlled trials (Studies 1 and 2) demonstrated superiority of brexpiprazole augmentation over placebo plus antidepressant therapy 2
• In Study 1, brexpiprazole 2 mg/day plus antidepressant showed a placebo-subtracted difference of -3.2 points on the MADRS scale (95% CI: -4.9 to -1.5), representing clinically meaningful improvement 2
• In Study 2, brexpiprazole 3 mg/day plus antidepressant showed a placebo-subtracted difference of -2.0 points (95% CI: -3.4 to -0.5) 2
• The effect size (Cohen's d) was 0.41 in patients with minimal response (<25% improvement) to antidepressants and 0.28 in those with partial response (25-50% improvement) 3

Response Across Different Levels of Treatment Resistance

• Brexpiprazole demonstrates efficacy regardless of whether patients show minimal or partial response to antidepressant treatment 3
• In patients with minimal response to antidepressants (n=663), the mean MADRS improvement was -8.8 points with brexpiprazole versus -6.3 points with placebo (difference: -2.47 points, P<0.001) 3
• In patients with partial response (n=235), the mean MADRS improvement was -6.4 points with brexpiprazole versus -4.9 points with placebo (difference: -1.53 points, P=0.035) 3

Optimal Dosing Strategy

FDA-Approved Dosing

• Starting dose: 0.5 mg or 1 mg once daily 2
• Target dose: 2 mg once daily 2
• Maximum dose: 3 mg once daily 2
• Titration schedule: Start at 0.5 mg daily for Week 1, increase to 1 mg at Week 2, then increase to target dose of 2 mg or maximum of 3 mg from Week 3 onwards 2

Evidence-Based Optimal Dosing

• A dose-effect meta-analysis found that 1-2 mg daily achieves optimal balance between efficacy, tolerability, and acceptability 4
• The dose-efficacy curve showed increasing benefit up to 2 mg (OR 1.52,95% CI 1.12-2.06), with a decreasing trend at the higher licensed dose of 3 mg (OR 1.40,95% CI 0.95-2.08) 4
• This suggests that 2 mg may be the optimal dose for most patients, with 3 mg reserved for those requiring higher doses 4

Safety and Tolerability Profile

Common Adverse Events

• The most common adverse reactions in MDD trials were weight gain, somnolence, and akathisia (≥5% and at least twice the rate of placebo) 2
• In patients with minimal response to antidepressants, treatment-emergent adverse events occurred in 59.8% with brexpiprazole versus 47.8% with placebo 3
• In patients with partial response, adverse events occurred in 54.8% with brexpiprazole versus 40.8% with placebo 3
• Akathisia was reported in 8.2% of patients in open-label studies 5

Serious Safety Considerations

• Black box warning for increased mortality in elderly patients with dementia-related psychosis (though brexpiprazole is not approved for this indication) 2
• Black box warning for increased risk of suicidal thoughts and behaviors in pediatric and young adult patients 2
• Metabolic monitoring is essential, including assessment for hyperglycemia/diabetes, dyslipidemia, and weight gain 2
• Monitor for neuroleptic malignant syndrome, tardive dyskinesia, orthostatic hypotension, and seizures 2
• Pathological gambling and other compulsive behaviors have been reported; consider dose reduction or discontinuation if these occur 2

Comparative Evidence with Other Augmentation Strategies

Position in Treatment Algorithm

• Augmentation with atypical antipsychotics (including brexpiprazole, aripiprazole, and quetiapine) represents the primary first-line FDA-approved strategy after inadequate response to at least one antidepressant at adequate dose for ≥4 weeks 1, 6
• The evidence base supporting atypical antipsychotic augmentation is the most extensive and rigorous of all pharmacological approaches in treatment-resistant depression 1
• Alternative augmentation strategies with strong evidence include lithium, liothyronine (T3), lamotrigine, or combination with bupropion, tricyclics, or mirtazapine, but atypical antipsychotics have the most extensive evidence base 1

Advantages Over Other Atypical Antipsychotics

• Brexpiprazole has a considerably improved tolerability profile compared to other second-generation/atypical antipsychotics 7
• The benefits must be weighed against potential adverse events such as weight gain, akathisia, and tardive dyskinesia, which are common to the class 8

Functional Outcomes

Cognitive and Physical Functioning

• In open-label studies, patients switching to brexpiprazole augmentation showed improvements in general functioning (Sheehan Disability Scale mean change: -3.1, P<0.0001) 5
• Cognitive function improved significantly (Massachusetts General Hospital-Cognitive and Physical Functioning Questionnaire mean change: -9.2, P<0.0001) 5
• These improvements in functional outcomes occurred alongside improvements in depressive symptoms 5

Clinical Context and Definition of Treatment-Resistant Depression

When to Consider Brexpiprazole

• Treatment-resistant depression is defined as failure to respond to at least two adequate antidepressant trials of different mechanisms of action in the current episode 9, 6
• An adequate trial requires the minimal approved dosage administered for at least 4 weeks 9, 6
• Brexpiprazole can be considered after inadequate response to at least one antidepressant at adequate dose for ≥4 weeks 1, 10
• For long current episodes, only treatment failures within the last 2 years should be considered 9, 6

Important Caveats

• Discontinuation before 4 weeks due to side effects should not count as treatment failure unless there is clear evidence of non-response 9, 6
• Confirm adequate adherence to prior antidepressant trials before diagnosing treatment resistance, as non-adherence rates can exceed 50% in MDD 9
• Document prior treatment attempts with clinical records (pharmacy, hospital, or health records) rather than relying solely on patient recollection 9

Dose Adjustments for Special Populations

Hepatic Impairment

• Maximum recommended dosage is 2 mg once daily for patients with moderate to severe hepatic impairment 2

Renal Impairment

• Maximum recommended dosage is 2 mg once daily for patients with CrCl <60 mL/minute 2

Drug Interactions

• With strong CYP2D6 or CYP3A4 inhibitors: Administer half of recommended dosage 2
• With strong/moderate CYP2D6 AND strong/moderate CYP3A4 inhibitors: Administer a quarter of recommended dosage 2
• Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors: Administer a quarter of recommended dosage 2

Real-World Clinical Application

Treatment Algorithm

1. Confirm treatment-resistant depression diagnosis: Verify failure of at least two adequate antidepressant trials (minimum effective dosage for ≥4 weeks) with different mechanisms of action in the current episode 9, 6

2. Initiate brexpiprazole augmentation: Start at 0.5 mg once daily, increase to 1 mg at Week 2, then to target dose of 2 mg from Week 3 onwards 2

3. Monitor response: Assess depressive symptoms weekly using standardized scales (MADRS or similar) 2

4. Optimize dosing: If inadequate response at 2 mg after 4-6 weeks, consider increasing to 3 mg daily, though evidence suggests 2 mg may be optimal for most patients 4

5. Monitor safety: Assess for metabolic changes (weight, glucose, lipids), akathisia, and other adverse effects at each visit 2

Common Pitfalls to Avoid

• Do not escalate antidepressant doses beyond minimum effective dosage, as most studies show no benefit with increased risk of side effects and discontinuation 9, 6
• Do not declare treatment failure before completing at least 4 weeks at adequate dosage 9, 6
• Do not exclude patients based on number of prior medication failures; multiple-drug resistant individuals should not be excluded from treatment 9, 6
• Do not neglect metabolic monitoring, as weight gain and metabolic changes are common with atypical antipsychotics 2