What is the best treatment plan for a patient with a history of Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD) currently taking Wellbutrin (Bupropion) 300mg daily, Buspar (Buspirone) 10mg twice daily, and Abilify (Aripiprazole) 5mg daily?

Treatment Optimization for MDD and GAD on Current Triple Therapy

Continue the current regimen of bupropion 300mg daily, buspirone 10mg BID, and aripiprazole 5mg daily, while adding evidence-based psychotherapy (CBT or interpersonal therapy) to maximize functional outcomes and quality of life. 1, 2

Current Medication Regimen Assessment

Bupropion 300mg Daily

• This is the FDA-approved target dose for MDD, established after 4 days of initial 150mg dosing 3
• Bupropion provides norepinephrine-dopamine reuptake inhibition, addressing depressive symptoms without sexual side effects common to SSRIs 1, 3
• The extended-release formulation minimizes seizure risk when dosed once daily in the morning 3

Buspirone 10mg BID (20mg total daily)

• This dose is suboptimal for GAD treatment—the FDA label and clinical trials support titration to 15-45mg/day for GAD 4, 5
• Buspirone demonstrates superior efficacy to placebo in GAD patients with coexisting mild depressive symptoms (HAM-D scores 12-17), reducing HAM-A scores by 12.4 points versus 9.5 points with placebo (p<0.03) 5
• Meta-analysis of 520 GAD patients showed 44-64% had significant coexisting depressive symptoms and responded significantly better to buspirone than placebo 6
• Consider increasing to 15mg BID (30mg daily) or 15mg TID (45mg daily) to achieve therapeutic anxiolytic effect 4, 5

Aripiprazole 5mg Daily

• Low-dose aripiprazole (2-10mg) serves as augmentation for treatment-resistant depression 2
• This dose is appropriate for augmentation purposes, though evidence for combining with bupropion specifically is limited 2

Evidence-Based Optimization Strategy

Step 1: Optimize Buspirone Dosing

• Increase buspirone to 15mg BID (30mg daily) over 1-2 weeks, monitoring for dizziness, nausea, and somnolence 4, 5
• If inadequate GAD response after 4-6 weeks, further increase to 15mg TID (45mg daily) 4, 5
• Buspirone requires 2-4 weeks for full anxiolytic effect; avoid premature discontinuation 4

Step 2: Add Evidence-Based Psychotherapy

• Moderate-quality evidence shows CBT produces equivalent response rates to SGAs (including bupropion's class) in MDD after 8-52 weeks 1
• Combination therapy (antidepressant plus CBT) showed improvement on 3 of 5 work-functioning measures compared to medication monotherapy in one trial, though clinical significance is uncertain 1
• Interpersonal therapy demonstrates no difference in response or remission compared to SGAs after 12 weeks, making it an equivalent alternative to CBT 1
• Low-quality evidence suggests psychodynamic therapy produces similar remission rates to fluoxetine after 16 weeks 1

Step 3: Monitor for Treatment Response

• Assess response at 6-8 weeks using standardized tools (PHQ-9 or HAM-D for depression; HAM-A for anxiety) 1
• Response is defined as ≥50% reduction in symptom severity scores 1
• Remission targets: HAM-D ≤7 or PHQ-9 <5 1

Alternative Augmentation Strategies if Current Regimen Fails

If Inadequate Response After Optimization

• The STAR*D trial (highest quality evidence) showed that augmenting with an SSRI (citalopram 20-40mg, sertraline 50-200mg, or escitalopram 10-20mg) produces equivalent efficacy to other augmentation strategies 2
• Bupropion augmentation with SSRIs had significantly fewer discontinuations due to adverse events (12.5%) compared to buspirone augmentation (20.6%; p<0.001) in STAR*D 2
• However, this patient is already on buspirone, making SSRI addition the logical next step if current optimization fails 2

Switching Considerations

• If switching from bupropion is necessary, the STAR*D trial showed no difference in response when switching to sertraline, venlafaxine, or cognitive therapy 2
• Cognitive therapy had numerically lower discontinuation rates (9.2%) compared to medication augmentation (18.8%) 2
• When switching bupropion formulations or discontinuing, taper from 300mg to 150mg daily before stopping to minimize withdrawal symptoms 3

Critical Drug Interactions and Safety Monitoring

Seizure Risk Management

• Bupropion 300mg daily is below the 450mg/day threshold that increases seizure risk, but avoid dose escalation beyond 300mg 3
• Do not crush, divide, or chew extended-release tablets, as this increases seizure risk 3
• Avoid alcohol and benzodiazepines, which lower seizure threshold 3

MAOI Interactions

• Allow 14 days between discontinuing an MAOI and starting bupropion, and vice versa 3
• For reversible MAOIs (linezolid, IV methylene blue), stop bupropion promptly if urgent MAOI treatment is needed, monitor for 2 weeks, then resume bupropion 24 hours after last MAOI dose 3

Buspirone-Specific Considerations

• Buspirone may interfere with urinary metanephrine/catecholamine assays, causing false-positive pheochromocytoma results—discontinue 48 hours before urine collection 4
• Buspirone does not displace tightly bound drugs (warfarin, phenytoin, propranolol), but one case report showed prolonged prothrombin time with warfarin co-administration 4
• In severe hepatic or renal impairment, buspirone administration cannot be recommended due to increased plasma levels and prolonged half-life 4

Aripiprazole Monitoring

• Monitor for akathisia, metabolic syndrome (weight gain, hyperglycemia, dyslipidemia), and extrapyramidal symptoms, though 5mg is a low dose 2

Common Pitfalls to Avoid

1. Underdosing buspirone: The current 20mg/day dose is below the therapeutic range for GAD (15-45mg/day) 4, 5
2. Premature medication switching: Allow 6-8 weeks at therapeutic doses before declaring treatment failure 1
3. Ignoring psychotherapy: Moderate-quality evidence shows CBT is equivalent to pharmacotherapy for MDD, and combination therapy may improve work functioning 1
4. Polypharmacy without optimization: Before adding a fourth medication, optimize buspirone dosing and add psychotherapy 1, 2
5. Discontinuing maintenance therapy prematurely: Meta-analysis of 31 trials supports continuation of antidepressant therapy to reduce relapse risk 1

Maintenance Phase Considerations

• Acute treatment lasts 6-12 weeks, continuation phase 4-9 months, and maintenance ≥1 year 1
• Periodically reassess the need for maintenance treatment and appropriate dosing 3
• 38% of patients do not achieve treatment response and 54% do not achieve remission with second-generation antidepressants during 6-12 weeks, necessitating augmentation or switching strategies 1