Can Rexulti (brexpiprazole) be used to help manage acute exacerbations of intrusive thoughts and obsessive-compulsive disorder (OCD) tendencies in an adult patient with a history of mental health treatment, who is currently taking Prozac (fluoxetine) and experiencing anxiety and depression?

Rexulti (Brexpiprazole) for Acute OCD Exacerbations with Prozac

Brexpiprazole augmentation of fluoxetine (Prozac) is a promising and evidence-based strategy for treatment-resistant OCD with intrusive thoughts, showing 50-70% response rates in recent studies, and should be considered after optimizing fluoxetine dosing to 60-80 mg daily for at least 8-12 weeks. 1, 2, 3

First: Optimize Your Current SSRI Regimen

Before adding brexpiprazole, ensure fluoxetine is optimized:

• Increase fluoxetine to 60-80 mg daily if not already at this dose, as OCD requires higher SSRI doses than depression or anxiety disorders 1, 4, 5
• Wait a full 8-12 weeks at maximum dose before declaring treatment failure—this is critical, as premature dose changes are a common pitfall 1, 4, 6
• Monitor for early predictors of response: nervousness or insomnia in the first weeks paradoxically predict better outcomes with fluoxetine 7

When to Add Brexpiprazole

Add brexpiprazole augmentation if:

• Less than 25% improvement in OCD symptoms (measured by obsession/compulsion severity) after 8-12 weeks of fluoxetine 60-80 mg daily 2, 3
• Patient cannot access or tolerate CBT with exposure and response prevention (ERP), which remains the gold standard psychotherapy 1, 4
• Moderate to severe symptoms persist despite adequate SSRI trial 1

Brexpiprazole Dosing Protocol

Start brexpiprazole at 1 mg daily and titrate based on response:

• Week 1-2: 1 mg daily 2, 3
• Week 3-4: Increase to 2 mg daily if tolerated 2, 3
• Week 5-12: May increase to 3 mg daily based on clinical response and tolerability 8, 3
• Assess response at 12 weeks: 50-70% of treatment-resistant OCD patients achieve ≥25% symptom reduction 2, 3

Evidence Supporting This Approach

Recent high-quality studies demonstrate brexpiprazole's efficacy:

• A 2025 Italian study showed 70% of treatment-resistant OCD patients responded (≥25% Y-BOCS reduction) with brexpiprazole augmentation, with 50% achieving robust response (≥35% reduction) 3
• A 2024 study confirmed 50% response rate in SRI-resistant OCD patients with excellent tolerability 2
• Brexpiprazole's unique mechanism—partial agonism at D2, D3, and 5-HT1A receptors—may address the dopaminergic dysregulation implicated in treatment-resistant OCD 2, 3

Managing Comorbid Anxiety and Depression

Brexpiprazole is FDA-approved for adjunctive treatment of major depression, making it particularly suitable for your patient's presentation:

• The drug demonstrated statistically significant improvement in depression symptoms when added to antidepressants (including fluoxetine) in two large trials 8
• Mean improvement of 3.2 points on depression scales beyond antidepressant alone at 2 mg daily 8
• This dual benefit addresses both OCD and depressive symptoms simultaneously 8, 2

Alternative Augmentation Strategies

If brexpiprazole is unavailable or not tolerated, consider these evidence-based alternatives in order:

1. Aripiprazole 5-15 mg daily: Similar mechanism to brexpiprazole with established efficacy in treatment-resistant OCD 9, 4
2. N-acetylcysteine: Glutamatergic agent with evidence in treatment-resistant OCD (three of five RCTs positive) 9, 1
3. Memantine: Multiple RCTs support efficacy as SSRI augmentation 9, 1

Critical Role of Psychotherapy

Do not rely on medication alone—CBT with ERP is essential:

• CBT with ERP has superior effect size (NNT = 3) compared to SSRIs alone (NNT = 5) 1, 6
• 10-20 sessions are recommended, deliverable in-person or via internet-based protocols 4, 6
• Between-session homework adherence is the strongest predictor of good outcomes 1, 6
• Combined treatment (medication + CBT) is optimal and should be pursued even if medication shows partial response 1, 6, 10

Monitoring and Safety Considerations

Watch for these adverse effects with brexpiprazole:

• Mild sedation and weight gain reported in 20-55.9% of patients, generally not requiring discontinuation 2, 3
• Monitor for akathisia (restlessness), particularly in first 2-4 weeks 8
• Assess for metabolic changes: weight, glucose, lipids at baseline and 12 weeks 8
• Screen for suicidal ideation at every visit, especially given comorbid depression and anxiety (FDA boxed warning through age 24) 6

Common Pitfalls to Avoid

• Do not add brexpiprazole before optimizing fluoxetine dose and duration—this wastes time and exposes patients to unnecessary polypharmacy 1, 4
• Do not assess response before 12 weeks of brexpiprazole augmentation—earlier assessment leads to premature abandonment of effective treatment 2, 3
• Do not neglect CBT with ERP—medication alone is suboptimal, and psychotherapy has larger effect sizes 1, 6
• Do not use subtherapeutic fluoxetine doses—40 mg daily is insufficient for OCD; 60-80 mg is the target range 6, 7

Long-Term Management

If remission is achieved:

• Continue combined treatment for 12-24 months due to high OCD relapse rates (up to 67% without maintenance therapy) 6
• Taper brexpiprazole cautiously after 6-12 months of sustained remission, monitoring closely for symptom return 6
• Maintain monthly CBT booster sessions for 3-6 months after acute response to prevent relapse 4