What would be the next best medication for a woman with Major Depressive Disorder (MDD) and anxiety who has failed Lexapro (escitalopram), Wellbutrin (bupropion), and Cymbalta (duloxetine)?

Next-Line Treatment for Treatment-Resistant MDD

After failing multiple antidepressants including an SSRI (Lexapro), SNRI (Cymbalta), and atypical antidepressant (Wellbutrin), the most evidence-based next step is augmentation with aripiprazole added to the current antidepressant rather than switching to another monotherapy agent. 1, 2

Rationale for Augmentation Over Switching

• Moderate-quality evidence from the STAR*D trial demonstrates no superiority when switching between different antidepressants after multiple failures, with equivalent response rates whether switching to bupropion, sertraline, or venlafaxine 1
• After failing medications from three different mechanistic classes (SSRI, SNRI, and dopamine-norepinephrine reuptake inhibitor), continuing to switch within these classes offers no clear advantage 3
• Augmentation strategies become more appropriate than switching after 2-3 failed antidepressant trials 1

Primary Recommendation: Aripiprazole Augmentation

Add aripiprazole 2.5-15 mg/day (mean effective dose 9 mg/day) to the current or most recently tolerated antidepressant. 4

Supporting Evidence

• Aripiprazole is FDA-approved specifically for adjunctive treatment of MDD based on two large randomized, double-blind, placebo-controlled trials 2
• In older adults with MDD who failed both SSRI and SNRI trials, aripiprazole augmentation achieved 50% remission rates with good tolerability 4
• Only 6-8% discontinuation rates due to adverse effects (primarily sedation and akathisia) 4
• Demonstrates efficacy even in the absence of psychotic symptoms 2

Dosing Strategy

• Start aripiprazole at 2.5 mg/day 4
• Titrate to 5 mg/day after one week if tolerated 4
• Further increase by 2.5-5 mg increments every 1-2 weeks based on response and tolerability 4
• Target dose range: 5-15 mg/day (mean effective dose 9 mg/day) 4

Alternative Option: Combination Antidepressant Therapy

If aripiprazole is declined or not tolerated, consider adding bupropion to an SSRI (not Wellbutrin alone, but in combination). 5

Evidence for This Approach

• The combination of escitalopram plus bupropion-SR achieved 62% response and 50% remission rates in patients with chronic/recurrent MDD 5
• Only 6% discontinuation due to side effects 5
• Low-quality evidence shows bupropion augmentation of citalopram reduces depression severity more than buspirone augmentation, though response/remission rates are similar 1, 6
• Bupropion augmentation has significantly better tolerability than buspirone (12.5% vs 20.6% discontinuation rates; P < 0.001) 6

Important Caveat

Since this patient already failed Wellbutrin (bupropion) monotherapy, the combination approach adds a different mechanism (SSRI serotonergic activity) rather than simply retrialing the same failed agent 5

Third-Line Consideration: Cognitive Behavioral Therapy

If pharmacological augmentation fails or is declined, switch to or add CBT. 1

• Low-quality evidence shows no difference in response or remission when switching to CBT versus switching to another antidepressant 1, 3
• CBT augmentation provides sustained long-term benefits with lower discontinuation rates compared to pharmacological augmentation 6

Critical Monitoring Parameters

First 24-48 Hours After Any Change

• Mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity (signs of serotonin syndrome if overlapping serotonergic agents) 3
• Suicidal thoughts and behaviors, particularly given multiple treatment failures 6, 7

Ongoing Monitoring for Aripiprazole

• Akathisia and sedation (most common side effects) 4
• Vital signs including blood pressure and heart rate 7
• Weight and metabolic parameters (though aripiprazole has lower metabolic risk than other atypical antipsychotics) 4

If Using Bupropion Combination

• Seizure risk factors (avoid if history of epilepsy or eating disorders) 7
• Blood pressure (avoid in uncontrolled hypertension) 7
• Ensure 14-day washout if patient was on MAOIs 7

What NOT to Do

• Do not simply switch to another SSRI or SNRI monotherapy - moderate-quality evidence shows no benefit after multiple failures within these classes 1
• Do not use buspirone for augmentation - inferior to bupropion in reducing depression severity and has worse tolerability 1, 6
• Do not combine multiple serotonergic agents without careful monitoring for serotonin syndrome risk 3