Can I add brexpiprazole (Rexulti) to citalopram (Celexa) for major depressive disorder?

Adding Rexulti (Brexpiprazole) to Celexa (Citalopram) for Depression

Yes, you can add brexpiprazole to citalopram for major depressive disorder, but only after citalopram has been tried at an adequate dose for 6-8 weeks without sufficient response. This combination is FDA-approved and supported by high-quality evidence demonstrating superior efficacy compared to continuing antidepressant monotherapy alone 1.

When to Consider Adding Brexpiprazole

Timing is critical. The American College of Physicians strongly recommends modifying treatment only after inadequate response to pharmacotherapy within 6-8 weeks of initiation 2. Do not add brexpiprazole prematurely—patients need an adequate trial of citalopram monotherapy first at therapeutic doses 2.

Definition of Inadequate Response

• Persistent depressive symptoms without substantial improvement throughout 6-8 weeks of treatment 1
• Less than 50% reduction in depressive symptoms on standardized scales 3
• Continued functional impairment in work, social, or home responsibilities despite treatment 4

Evidence Supporting This Combination

The FDA approval of brexpiprazole for adjunctive treatment is based on two pivotal 6-week trials that specifically included patients on SSRIs like citalopram (as well as other antidepressants) 1. In these studies:

• Brexpiprazole 2 mg daily added to antidepressants showed a placebo-subtracted difference of -3.2 points on the MADRS scale (95% CI: -4.9 to -1.5) 1
• Brexpiprazole 3 mg daily showed a difference of -2.0 points (95% CI: -3.4 to -0.5) 1
• Benefits were seen regardless of whether patients had minimal response (>0% to <25% improvement) or partial response (≥25% to <50% improvement) to their antidepressant 3

Importantly, efficacy was demonstrated in patients with anxiety symptoms comorbid with depression, with a placebo-subtracted difference of -3.00 points in patients with anxious distress 5.

Dosing Strategy

Start low and titrate slowly:

• Week 1: Initiate brexpiprazole at 0.5 mg once daily 1
• Week 2: Increase to 1 mg once daily 1
• Week 3 onward: Increase to target dose of 2 mg once daily, or up to 3 mg once daily if needed 1
• Continue citalopram at the same stable dose throughout 1

The target dose is typically 2 mg daily, which showed the strongest evidence in the pivotal trial 1.

Safety Considerations and Monitoring

Monitor closely in the first 1-2 weeks for worsening depression, suicidal thoughts, agitation, irritability, or unusual behavioral changes 2. This is standard for all antidepressant therapy modifications.

Common Adverse Events to Anticipate

The most frequent treatment-emergent adverse events with adjunctive brexpiprazole include 4, 6:

• Headache (21.3%)
• Weight increase (17.0%)—clinically relevant weight gain (≥7%) occurred in 10.5% of patients
• Somnolence (17.0%)
• Fatigue (15.2% in elderly patients)
• Akathisia (6.4%—notably low compared to other antipsychotics)
• Restlessness (12.9%)

Akathisia rates are relatively low compared to other atypical antipsychotics used for depression augmentation, making brexpiprazole a favorable option from a tolerability standpoint 4, 5.

Special Populations

In elderly patients (≥65 years), long-term treatment with adjunctive brexpiprazole was generally well tolerated over 26 weeks, with no consistent clinically relevant findings on movement disorder scales 6.

Advantages Over Alternative Augmentation Strategies

Brexpiprazole has specific advantages compared to augmenting with another antidepressant:

• The American College of Physicians found that augmenting citalopram with bupropion showed no difference in response or remission compared to augmenting with buspirone, though bupropion decreased depression severity more 2
• However, these older guidelines predate brexpiprazole's FDA approval and the robust evidence now available 1
• Brexpiprazole demonstrated efficacy specifically in patients who failed adequate antidepressant trials, which is the exact clinical scenario you're addressing 1, 3

Duration of Treatment

Once you achieve satisfactory response with the combination:

• Continue treatment for 4-9 months after response in first-episode depression 2
• For patients with 2 or more prior episodes, even longer duration may be beneficial 2

Common Pitfalls to Avoid

1. Don't add brexpiprazole too early—ensure citalopram has had an adequate 6-8 week trial at therapeutic doses first 2
2. Don't start at too high a dose—begin at 0.5 mg to minimize adverse events, particularly akathisia 1
3. Don't forget to monitor weight—10.5% of patients experience clinically significant weight gain 4
4. Don't discontinue citalopram—brexpiprazole is adjunctive therapy, not replacement therapy 1

Functional Outcomes

Beyond symptom reduction, adjunctive brexpiprazole improves real-world functioning. In young adults (18-35 years) who were working or studying, adjunctive brexpiprazole significantly improved:

• Sheehan Disability Scale scores (LS mean change -11.2, p<0.0001) 4
• Work Limitations Questionnaire scores (p<0.0001) 4
• Effects on work/school, social life, and home responsibilities 4

This functional improvement translates to reduced socioeconomic burden and is particularly relevant for patients whose depression impacts their productivity 4.

Bottom Line Algorithm

Follow this stepwise approach:

1. Ensure citalopram has been tried for 6-8 weeks at adequate dose 2
2. Confirm inadequate response (persistent symptoms, <50% improvement, functional impairment) 1, 3
3. Add brexpiprazole 0.5 mg daily for Week 1 1
4. Increase to 1 mg daily at Week 2 1
5. Increase to 2 mg daily (target dose) at Week 3 1
6. Monitor for response over 6 weeks and assess tolerability 1
7. If response achieved, continue combination for 4-9 months minimum 2