What can be added to a patient's regimen of Cymbalta (duloxetine), Abilify (aripiprazole), and Hydroxyzine for persistent feelings of sadness?

Augmentation Strategy for Persistent Depression on Current Regimen

Add bupropion (Wellbutrin) as augmentation to the current duloxetine (Cymbalta) regimen, as this represents the most evidence-based next step for inadequate antidepressant response. 1

Rationale for This Recommendation

The patient is already on duloxetine (an SNRI), aripiprazole (an atypical antipsychotic), and hydroxyzine (for anxiety), yet continues to experience depressive symptoms. The American College of Physicians guidelines clearly state that treatment should be modified if there is inadequate response within 6-8 weeks of therapy 1. Since the patient already has aripiprazole augmentation in place and remains symptomatic, switching augmentation strategies is warranted.

Why Bupropion Specifically

• Complementary mechanism: Bupropion works primarily through dopamine and norepinephrine reuptake inhibition, providing a different mechanism than the serotonin-norepinephrine action of duloxetine 2
• Evidence for switching augmentation: When initial augmentation with one atypical antipsychotic fails, switching to a different augmentation class (rather than another antipsychotic) is supported by treatment algorithms 3
• Favorable side effect profile: Bupropion causes weight loss rather than weight gain (14-23% of patients lose >5 lbs), which contrasts with the metabolic concerns of continuing or escalating antipsychotic therapy 2
• No sexual dysfunction: Unlike SSRIs/SNRIs, bupropion does not worsen sexual side effects and may actually improve them 2

Implementation Algorithm

Step 1: Initiate Bupropion

• Start bupropion SR 150 mg once daily in the morning 2
• Continue current duloxetine dose unchanged 1
• Critical timing: Assess response at 1-2 weeks initially, then every 2-4 weeks 1, 3

Step 2: Titration (if needed after 3-4 days)

• Increase to bupropion SR 150 mg twice daily (total 300 mg/day) 2
• Maximum dose: 400 mg/day (given as 200 mg twice daily), though 300 mg/day is typically sufficient 2

Step 3: Evaluate Aripiprazole Continuation

• Consider tapering aripiprazole if adequate response occurs with bupropion augmentation, as the patient already failed this augmentation strategy 4, 5
• If keeping aripiprazole, monitor closely for akathisia (2% incidence when combined with antidepressants) and metabolic effects 2

Step 4: Response Assessment Timeline

• Partial response by 4 weeks: Continue current regimen, reassess at 8 weeks 1
• No response by 6-8 weeks: Consider switching to venlafaxine XR (different SNRI) or adding evidence-based psychotherapy 1, 3

Alternative Considerations if Bupropion Fails or Is Contraindicated

Second-Line Option: Switch Antipsychotic Augmentation

• Cariprazine has emerging evidence for treatment-resistant depression when other atypical antipsychotics fail 4
• In one case series, 7 of 10 patients who failed aripiprazole augmentation responded to cariprazine (mean HAM-D reduction from 23.9 to 14.8) 4
• Start cariprazine 1.5 mg daily, can increase to 3 mg daily 4

Third-Line Option: Switch SNRI

• Venlafaxine XR shows statistically better response and remission rates than other antidepressants in treatment-resistant cases 3
• Approximately 25% of patients become symptom-free after switching from duloxetine to venlafaxine 3

Critical Monitoring Parameters

For Bupropion Addition

• Seizure risk: Contraindicated if history of seizures, eating disorders, or abrupt alcohol/benzodiazepine discontinuation 2
• Blood pressure: Monitor for hypertension (2% incidence) 2
• Activation symptoms: Watch for insomnia (13-20%), anxiety (7%), agitation (2%), especially in first 2 weeks 2
• Suicidality monitoring: Assess every 1-2 weeks initially per ACP guidelines 1

Hydroxyzine Role

• Continue hydroxyzine as needed for acute anxiety symptoms, as it serves as a "bridging strategy" while optimizing antidepressant therapy 6
• Hydroxyzine showed superior anxiolytic effects compared to aripiprazole in preclinical studies 7

Common Pitfalls to Avoid

1. Don't add another antipsychotic: The patient already failed aripiprazole augmentation; adding or switching to quetiapine/brexpiprazole increases metabolic risk without clear benefit 5

2. Don't increase duloxetine beyond FDA maximum: There's no evidence that exceeding 60 mg daily (120 mg for some pain conditions) improves depression outcomes 1

3. Don't wait too long: The 6-8 week window for treatment modification is critical—prolonged inadequate treatment worsens outcomes 1

4. Don't ignore psychotherapy: Combined SSRI/SNRI with cognitive behavioral therapy shows superior efficacy to medication alone 3

5. Monitor drug interactions: Bupropion is metabolized by CYP2B6; hydroxyzine and aripiprazole don't significantly interact, but be aware of additive CNS effects 2

Expected Outcomes

• Response rate: Approximately 25% achieve symptom-free status with medication switching/augmentation 3
• Timeline: Initial response may occur within 2 weeks, but full evaluation requires 6-8 weeks 1
• Long-term management: If response achieved, continue combination therapy for 4-9 months minimum (longer if multiple prior episodes) 1