New Treatments for Refractory Depression
For treatment-resistant depression, add either aripiprazole or quetiapine augmentation to the existing antidepressant, or add cognitive behavioral therapy—both strategies provide similar efficacy with relatively rapid onset of action. 1, 2
Defining Treatment-Resistant Depression
Before pursuing new treatments, confirm true treatment resistance by verifying:
- Minimum of two failed antidepressant trials with <25% improvement, each at adequate dose (minimum approved dosage) for at least 4 weeks 3
- Exclude inadequate dosing or duration—the most common cause of apparent treatment resistance 4
- Rule out undiagnosed medical conditions, comorbid psychiatric disorders (especially "secret" comorbidities like substance use or personality disorders), and depression subtypes requiring modified approaches 4
First-Line Augmentation Strategies
Pharmacologic Augmentation
Add second-generation antipsychotics to the current antidepressant:
- Aripiprazole (FDA-approved for adjunctive treatment) or quetiapine provide relatively rapid onset of action 1, 2
- Both agents show similar symptomatic relief when used as augmentation 2
- Monitor metabolic effects closely: weight gain, lipid changes, glucose abnormalities 1
- Bupropion SR offers lower discontinuation rates due to adverse events compared to other augmentation options 2
Psychological Augmentation
Add cognitive behavioral therapy (CBT) to ongoing antidepressant:
- CBT augmentation provides similar efficacy to medication augmentation but may offer more sustainable long-term outcomes 1, 2
- Problem-solving therapy represents an alternative evidence-based psychological option 2
- Interpersonal therapy and acceptance and commitment therapy also have supporting evidence 2
The choice between medication and psychological augmentation should be based on adverse effect profiles, patient preferences, cost, and accessibility 5
Second-Line Strategies: Switching Antidepressants
If augmentation fails or is not tolerated:
- Switch to a different SSRI (escitalopram, fluoxetine) or SNRI (venlafaxine, duloxetine) 1
- Different switching strategies provide similar symptom relief, so selection should prioritize adverse event profiles and patient-specific factors 2
- No significant differences exist between various pharmacologic switch strategies (bupropion SR, escitalopram, duloxetine, sertraline, venlafaxine, vortioxetine) 3
Complementary and Alternative Approaches
Evidence supports several complementary options as adjunctive therapies:
- Acupuncture combined with antidepressants achieves higher remission rates (35.7% vs. 26.1%) than antidepressant monotherapy 3
- Omega-3 fatty acids (EPA and DHA), particularly for patients with comorbid coronary heart disease 2
- S-adenosyl-L-methionine (SAMe) demonstrates efficacy as adjunctive treatment 2
- St. John's wort shows evidence for efficacy but requires caution regarding drug interactions 2
- Supervised aerobic exercise (minimum 30 minutes of moderate-intensity activity on most days) shows no difference in remission compared to sertraline, with numerically lower discontinuation rates 3, 2
- Meditation and yoga represent additional evidence-based options 2
Treatment Duration and Monitoring
- Continue augmentation strategy for at least 4-9 months after achieving satisfactory response 1
- For recurrent depression (≥2 episodes), longer treatment duration is beneficial 1
- Assess response at 4 and 8 weeks using validated instruments 2
- Monitor treatment adherence and adverse events throughout 2
Critical Caveats
The certainty of evidence for most treatment comparisons is low, with limitations including high dropout rates, dosing inequalities, and small sample sizes 2, 5. Despite this, the strategies above represent the best available evidence-based approaches for refractory depression.
Exclude patients with bipolar depression from unipolar TRD protocols, as all depression specifiers (melancholic, atypical, anxious, psychotic, mixed) should be considered within TRD definitions except bipolar depression 3