Best Augmentation Strategy for Treatment-Resistant Depression
The most effective augmentation strategies for treatment-resistant depression are atypical antipsychotics (particularly aripiprazole) and lithium, which should be added to the current antidepressant regimen if partial response has been achieved. 1
Defining Treatment-Resistant Depression First
Before implementing augmentation, confirm true treatment resistance by ensuring:
- At least two prior adequate antidepressant trials have failed (minimum standard for TRD diagnosis) 2, 3
- Each trial was at adequate dose for minimum 4 weeks duration 3, 4
- Rule out pseudo-resistance from misdiagnosis, comorbid medical/psychiatric conditions, or inadequate prior treatment 5, 4, 6
When to Choose Augmentation Over Switching
Augmentation is the preferred strategy when:
- The current antidepressant has produced partial response (some symptom improvement but not remission) 7, 1
- Tolerability to the original agent is acceptable 7
- You want to build upon achieved improvements rather than risk losing partial gains by switching 1
Evidence-Based Augmentation Options (In Order of Strength)
First-Line Augmentation Agents
Atypical Antipsychotics:
- Aripiprazole is FDA-approved for augmentation in TRD and has the strongest evidence base 1
- Olanzapine combined with fluoxetine (OFC) is also FDA-approved with demonstrated efficacy 1
Lithium:
- Well-studied augmentation agent with established efficacy, though underutilized in clinical practice 1
- Particularly important for bipolar depression, where mood stabilizers should be the foundation 8
- Monitor therapeutic blood levels (for nortriptyline augmentation, maintain 50-150 ng/mL window) 3
Second-Line Augmentation Agents
Thyroid hormones have established evidence as augmenting agents 1
Experimental/Less-Studied Options
The following have limited evidence and should be considered only after first-line options fail: pindolol, inositol, CNS stimulants, omega-3 fatty acids, S-adenosyl-L-methionine, folic acid, lamotrigine, modafinil 1
Note: Gabapentin is NOT recommended for TRD as clinical practice guidelines do not include it among recommended treatments, and controlled studies have not found it helpful for mood disorders 9
Critical Factors to Consider Before Augmentation
Six essential confounders must be evaluated: 2
- Depressive severity at baseline
- Duration of current episode
- Prior treatment intolerance
- Prior augmentation or combination therapy attempts
- Prior psychotherapy trials
- Psychiatric comorbidities (especially substance use and personality disorders) 8
Treatment Duration Requirements
Maintain augmentation therapy for adequate duration:
- Minimum 2 months to allow adequate dose titration and assessment of response 2
- For more severely resistant patients, longer trials may be needed given increased relapse risk 2
- For bipolar depression with mood stabilizers, maintain for at least 2 years after last episode 8
Common Pitfalls to Avoid
Do not exclude patients from augmentation trials who have failed multiple prior medications, as long as they meet TRD criteria 8
Do not overlook that switching strategies have limited effectiveness in achieving remission compared to combination approaches 1
Recognize the disadvantages of combination therapy: multiple medications, broader range of adverse events, and higher costs must be weighed against potential benefits 1
Ensure systematic approach: Apply treatment algorithms systematically rather than haphazardly trying different agents, which leads to therapeutic nihilism 5, 6
Monitoring Treatment Response
Track depressive symptoms with standardized measurement tools throughout treatment to identify incomplete remission and guide modifications 7
Key outcomes to monitor include: 2
- Depressive severity
- General psychiatric status
- Functional impairment
- Quality of life
- Suicidality reduction
- Medication adherence