What antidepressant would be recommended for a patient with treatment-resistant Major Depressive Disorder (MDD) and anxiety, who has previously failed Lexapro (escitalopram), Wellbutrin (bupropion), and Cymbalta (duloxetine)?

Recommended Antidepressant for Treatment-Resistant MDD with Anxiety

For a patient with treatment-resistant depression and anxiety who has failed escitalopram, bupropion, and duloxetine, augmentation with aripiprazole (2-20 mg/day) added to a current antidepressant is the strongest evidence-based recommendation, with superior remission rates and rapid onset of benefit. 1, 2

Primary Recommendation: Aripiprazole Augmentation

• Aripiprazole augmentation demonstrates superior remission rates of 55.4% compared to bupropion augmentation at 34.0% in treatment-resistant depression 1
• The National Institute of Mental Health specifically recommends augmentation with atypical antipsychotics such as aripiprazole or quetiapine for partial responders 1
• Aripiprazole produces a two-fold higher remission rate (36.8%) compared to placebo (18.9%) when added to ongoing antidepressant therapy 2
• Response occurs rapidly, with significant improvement from week 1 through endpoint, using mean daily doses of 6.9 mg 3
• Discontinuation rates due to adverse events are low (5.7-6.2%), with completion rates of 83-87% 3, 2

Alternative First-Line Antidepressant Options

Mirtazapine

• The American College of Physicians recommends mirtazapine for rapid symptom relief in treatment-resistant depression, with statistically significantly faster onset of action compared to SSRIs 1, 4
• Particularly beneficial for comorbid anxiety and insomnia due to sedating properties 1
• Response rates equalize with SSRIs after 4 weeks, but earlier onset provides clinical advantage 4

Venlafaxine (SNRI)

• The American Psychiatric Association suggests venlafaxine has superior efficacy compared to fluoxetine for treating anxiety symptoms in patients with depression and anxiety 1
• May offer advantages in presentations with prominent anxiety symptoms and melancholia 4
• Approximately 25% of patients achieve remission after switching to venlafaxine from failed SSRI therapy 4

Treatment Algorithm for This Patient

Step 1: Define Treatment Resistance Status

• This patient meets criteria for Treatment-Resistant Depression (TRD) with three failed antidepressant trials of different mechanisms (SSRI, NDRI, SNRI) 5
• Each medication should have been administered at minimum licensed dose for at least 4 weeks with <25% improvement 5
• All three failures should be within the current episode and past two years 5

Step 2: Choose Augmentation Strategy

• Add aripiprazole 2-5 mg/day initially, titrating to 6-20 mg/day based on response to the most recently tolerated antidepressant 3, 2
• Aripiprazole is effective even in patients who failed previous atypical antipsychotic augmentation 6
• Monitor for akathisia, sedation, and metabolic effects, though these occur at low rates with low-dose aripiprazole 3

Step 3: Alternative if Augmentation Fails or Not Tolerated

• Switch to mirtazapine 15-45 mg/day for rapid symptom relief, particularly given comorbid anxiety and likely sleep disturbance 1, 4
• Consider venlafaxine XR if anxiety symptoms are prominent, though patient already failed duloxetine (another SNRI) 1, 4

Important Clinical Caveats

Monitoring Requirements

• Close monitoring for suicidal ideation is essential, as approximately 38% of patients do not achieve response with second-generation antidepressants alone 1
• Patients treated with SSRIs are at increased risk for nonfatal suicide attempts, especially during dose adjustments 1
• The American Medical Association requires minimum 4 weeks at adequate dosing to define treatment failure 1

What NOT to Do

• Do not switch to another SSRI (sertraline, fluoxetine) as monotherapy—only 25% achieve remission with this strategy after multiple SSRI failures 4
• Bupropion augmentation is inferior to aripiprazole augmentation (34% vs 55.4% remission) and patient already failed bupropion monotherapy 1
• Buspirone augmentation is inferior to bupropion augmentation with higher discontinuation rates 5, 1

Exclusion Criteria to Verify

• Exclude bipolar disorder, as this patient would require different treatment 5
• Exclude severe active substance use disorder not in remission 5
• Confirm medication adherence through pharmacy records or plasma levels if available, as up to 50% of apparent TRD cases represent non-adherence 5