What are the recommended strategies for augmenting antidepressant therapy in patients with treatment-resistant major depressive disorder?

Augmentation Strategies for Treatment-Resistant Major Depressive Disorder

First-Line Augmentation: Atypical Antipsychotics

For patients with treatment-resistant major depressive disorder who have failed at least one adequate antidepressant trial (minimum effective dose for ≥4 weeks), augmentation with atypical antipsychotics—specifically aripiprazole or brexpiprazole—represents the primary evidence-based first-line strategy. 1, 2

Aripiprazole Augmentation

• Start aripiprazole at 2-5 mg daily and titrate to target dose of 5-10 mg daily based on response and tolerability 1
• This strategy is supported by moderate-quality evidence and has FDA approval for adjunctive treatment of MDD 2
• Ensure the current antidepressant has been at therapeutic dose for at least 4 weeks before adding aripiprazole 2

Brexpiprazole Augmentation

• Initiate brexpiprazole at 0.5-1 mg daily, titrate weekly to target dose of 2 mg daily (maximum 3 mg daily for MDD) 3
• For patients on strong CYP2D6 inhibitors (paroxetine, fluoxetine), no dose adjustment is needed as this is already factored into dosing recommendations 3
• Brexpiprazole offers an alternative atypical antipsychotic option with potentially different tolerability profile 3

Quetiapine Augmentation

• Quetiapine 150-300 mg daily is another FDA-approved augmentation option for treatment-resistant depression 1

Second-Line Augmentation: Antidepressant Add-On

If atypical antipsychotics are contraindicated, not tolerated, or patient preference dictates, augment with bupropion SR or buspirone, which have moderate-certainty evidence supporting their use. 4, 5

Bupropion Augmentation

• Add bupropion 150-300 mg daily to the existing antidepressant 1
• Bupropion decreases depression severity more effectively than buspirone and has lower discontinuation rates due to adverse events 4
• Particularly useful if the patient had any partial response to the most recent antidepressant 1

Buspirone Augmentation

• Buspirone is an alternative augmentation agent with moderate-certainty evidence 5
• Less effective than bupropion for reducing depression severity 4

Third-Line Augmentation: Lithium

Lithium augmentation remains one of the best-documented treatments for treatment-resistant depression but requires careful monitoring. 1

• Requires regular monitoring of serum lithium levels, thyroid function, and renal function 1
• Reserve for patients who have failed first- and second-line augmentation strategies

Alternative and Adjunctive Strategies

Omega-3 Fatty Acids (EPA)

• Add 1-2 g/day of EPA (pure EPA or EPA/DHA ratio >2:1) as adjunctive treatment 4
• Particularly effective when added at the beginning of treatment (acceleration) or when standing antidepressant is inadequate (augmentation) 4
• Consider especially for patients who are overweight (BMI >25) or have elevated inflammatory markers 4
• Titrate dose over 2 weeks for partial responders, up to maximum dose by 4-6 weeks if tolerable 4

Switching Strategies

• If augmentation is not preferred, switching to a different antidepressant with a different mechanism of action is an alternative 4
• Switch to mirtazapine if anxiety and insomnia are prominent, as it provides faster symptom relief than SSRIs 1
• Switch to venlafaxine (SNRI) if anxiety symptoms dominate without significant insomnia 1
• Moderate-quality evidence shows no significant difference in response rates when switching between bupropion, sertraline, or venlafaxine 4, 1

Rapid-Acting Treatments for Highly Refractory Cases

Esketamine/ketamine is recommended for highly refractory cases that have failed multiple medication trials and augmentation strategies. 2, 6, 7

• NMDA receptor antagonists like S-ketamine represent the only registered drug specifically for treatment-resistant depression 6
• Reserve for patients with severe, treatment-resistant depression after other strategies have failed 2

Non-Pharmacological Augmentation

Cognitive Behavioral Therapy

• CBT should be integrated with pharmacotherapy regardless of medication choice, as evidence shows no difference between switching to another antidepressant versus switching to cognitive therapy 4, 1, 2
• Low-quality evidence suggests CBT is as effective as medication switches 4

Transcranial Magnetic Stimulation

• Consider TMS for patients who have failed multiple medication trials 2
• Should not be an exclusion criterion for clinical trials or further treatment attempts 4

Electroconvulsive Therapy

• Reserve ECT for severe, treatment-resistant cases where pharmacological approaches continue to fail 1
• Previous ECT failure should not exclude patients from other treatment trials 4

Critical Treatment Verification Before Augmentation

Before declaring treatment resistance and initiating augmentation, verify that each prior antidepressant trial met adequate criteria: 4, 1, 2

• Minimum effective dosage (the minimal approved dosage, not necessarily maximum dose) 4
• Duration of at least 4 weeks at that dosage 4, 1, 2
• Different mechanisms of action between trials 2
• Discontinuation before 4 weeks without clear evidence of lack of response should not count as treatment failure 4

Treatment Duration and Monitoring

• Maintain augmentation therapy for a minimum of 2 months to allow adequate assessment of response 5
• Early response may occur within 2 weeks, but continue treatment for at least 2 months before declaring failure 5
• Periodically reassess to determine continued need and appropriate dosage 3

Common Pitfalls to Avoid

• Do not exclude patients based solely on number of prior medication failures—multiple-drug resistant individuals should still receive treatment 4, 2
• Do not count trials discontinued due to side effects before 4 weeks as treatment failures when establishing TRD 4
• Do not use subtherapeutic doses—ensure minimum effective dosage is reached before augmenting 4
• Do not forget to assess for bipolar depression—these patients require mood stabilizers as foundation, not unipolar depression augmentation strategies 5
• Screen for substance use disorders and personality disorders before augmentation, as these significantly impact treatment response 5