Is Rexulti (brexpiprazole) effective for treating bipolar depression?

Rexulti (Brexpiprazole) for Bipolar Depression

Rexulti (brexpiprazole) is not recommended as a first-line treatment for bipolar depression as there is insufficient evidence supporting its efficacy for this indication, with only a small pilot study showing potential benefit.

Evidence for Brexpiprazole in Bipolar Depression

• A small pilot study from 2019 showed that brexpiprazole reduced depressive symptoms and increased quality of life in patients with bipolar depression 1
• However, this was an open-label study with only 21 participants, limiting the strength of its conclusions
• Brexpiprazole is FDA-approved only for:
  • Adjunctive therapy with antidepressants in major depressive disorder (MDD) 2, 3
  • Monotherapy for schizophrenia 3
• It is not FDA-approved for any phase of bipolar disorder

Recommended Treatments for Bipolar Depression

According to the American Academy of Child and Adolescent Psychiatry guidelines 4, 5, the following medications have stronger evidence for bipolar depression:

1. Lamotrigine:

   • Particularly effective for bipolar depression with anxiety 5
   • FDA-approved for maintenance therapy in adults 4
   • Has a relatively safe side effect profile 5

2. Lithium:

   • FDA-approved for ages 12+ for acute mania and maintenance therapy 4
   • Less effective for preventing depression than mania 5
   • Requires regular monitoring of serum levels, thyroid and renal function 5

3. Olanzapine-fluoxetine combination:

   • FDA-approved specifically for bipolar depression in adults 4

4. Valproate:

   • Effective for mixed episodes 5
   • Requires monitoring of liver function, complete blood counts, and pregnancy tests 5

Cautions with Antipsychotics in Bipolar Disorder

• Atypical antipsychotics as a class are associated with significant weight gain and metabolic problems (type 2 diabetes, hyperlipidemia) 4
• Monitoring requirements include:
  • Baseline body mass index, waist circumference, blood pressure, fasting glucose, and lipid panel
  • Monthly BMI follow-up for 3 months, then quarterly
  • Blood pressure, fasting glucose, and lipids after 3 months and then yearly 4

Treatment Algorithm for Bipolar Depression

1. First-line options:

   • Lamotrigine (especially for predominant anxiety with depression)
   • Lithium
   • Olanzapine-fluoxetine combination

2. Second-line options:

   • Valproate
   • FDA-approved atypical antipsychotics with evidence in bipolar disorder

3. Consider brexpiprazole only if:

   • Patient has failed first and second-line treatments
   • Patient has shown good response to brexpiprazole for other indications
   • Close monitoring for side effects is implemented

Important Considerations

• Antidepressants (including when combined with brexpiprazole) may destabilize mood or trigger manic episodes in bipolar patients 4, 5
• Unlike aripiprazole (which has been studied extensively in bipolar disorder but found ineffective for bipolar depression 6), brexpiprazole has minimal evidence in bipolar disorder
• Brexpiprazole has a unique receptor binding profile with low intrinsic D2 activity that may result in fewer activation-like adverse effects such as akathisia compared to aripiprazole 2

Until larger, controlled studies are conducted specifically evaluating brexpiprazole in bipolar depression, clinicians should rely on treatments with established efficacy and FDA approval for this indication.