Rexulti (Brexpiprazole) for Off-Label Use in Anxiety
Brexpiprazole is not FDA-approved for primary anxiety disorders and should not be used as a first-line treatment for anxiety alone. However, it may be considered as adjunctive therapy specifically in patients with major depressive disorder (MDD) who have prominent anxiety symptoms and have failed standard antidepressant treatment.
FDA-Approved Indications
The FDA has approved brexpiprazole only for:
- Adjunctive treatment of MDD (in combination with antidepressants)
- Treatment of schizophrenia
Evidence for Anxiety Symptoms in MDD
When anxiety occurs in the context of MDD with inadequate antidepressant response, brexpiprazole shows efficacy. Clinical trials demonstrated that adjunctive brexpiprazole 2-3 mg/day improved both depressive and anxiety symptoms in patients with MDD and anxious distress 2, 3. In pooled analyses:
- Patients with anxious distress showed a placebo-subtracted difference of -2.95 to -2.81 points on depression scales (p<0.003) 3
- Benefits were seen regardless of baseline anxiety severity (mild, moderate, or severe) 4
- The drug was well-tolerated without increased activating adverse events like akathisia in anxious patients 3
Guideline-Recommended Alternatives for Primary Anxiety
For primary anxiety disorders, established first-line treatments should be used instead:
First-Line Pharmacotherapy
- SSRIs: Escitalopram, sertraline, paroxetine, fluvoxamine 5
- SNRIs: Venlafaxine 5
- Cognitive Behavioral Therapy (CBT): Structured individual or group therapy over 12-14 sessions 5
Second-Line Options
- Benzodiazepines (lorazepam, clonazepam) - time-limited use due to dependence risk 6, 5
- Pregabalin 5
- Buspirone for mild-moderate anxiety 7
When Atypical Antipsychotics Are Mentioned
Guidelines list atypical antipsychotics (quetiapine, olanzapine) only as last-line options for insomnia with comorbid conditions 8, not as primary anxiety treatments. The 2016 obesity guidelines note that maximal-dose phentermine/topiramate should be used with caution in anxiety disorders 9, but do not recommend atypical antipsychotics for primary anxiety.
Clinical Decision Algorithm
Use brexpiprazole off-label for anxiety ONLY if:
- Primary diagnosis is MDD with inadequate response to 1-3 antidepressant trials
- Prominent anxiety symptoms are present (≥2 of: tension, restlessness, poor concentration, apprehension)
- Patient is already on an antidepressant (SSRI or SNRI) that will be continued
- First-line anxiety treatments have been tried (SSRIs/SNRIs, CBT)
Do NOT use brexpiprazole if:
- Patient has primary anxiety disorder without depression
- Patient is not on a concurrent antidepressant
- First-line treatments haven't been attempted
- Patient has never tried CBT or other evidence-based psychotherapy
Dosing and Monitoring
If prescribed off-label for MDD with anxiety:
- Start 0.5 mg daily for Week 1
- Increase to 1 mg daily at Week 2
- Target dose: 2-3 mg daily from Week 3 onward 1
- Monitor for akathisia, weight gain, and metabolic effects
- Assess response at 6-8 weeks
Important Caveats
The evidence for brexpiprazole in anxiety comes exclusively from post-hoc analyses of MDD trials, not from prospective studies designed to treat anxiety 4, 2, 3. The drug has not been studied in generalized anxiety disorder, panic disorder, or social anxiety disorder as primary diagnoses. One recent review explicitly states there is "an unmet need for prospective clinical trials with anxiety-specific endpoints" 10.
Cost and insurance coverage may be problematic for off-label use, as payers typically require documented failure of multiple FDA-approved treatments first.