Management of Treatment-Resistant Depression and Anxiety After Multiple SSRI Failures
For this 50-year-old patient who has failed multiple SSRIs and bupropion, augment the most recently tolerated antidepressant with aripiprazole (starting at 2 mg daily) or switch to venlafaxine ER 150-225 mg daily, as these strategies demonstrate superior outcomes in treatment-resistant depression compared to further SSRI trials. 1, 2
Primary Recommended Strategy: Augmentation with Aripiprazole
Aripiprazole augmentation of the current or most recently tolerated antidepressant is the preferred first-line approach, demonstrating 55.4% remission rates in treatment-resistant depression and significantly improving well-being scores (4.83 points improvement) compared to switching strategies (2.04 points with switch to bupropion, P=0.014). 3, 2
Start aripiprazole at 2 mg daily to minimize tremor risk, then increase by 2-3 mg every 1-2 weeks as tolerated, up to a maximum of 10-15 mg daily. 3
In older adults with treatment-resistant depression, aripiprazole augmentation improved well-being significantly more over 10 weeks than switching to bupropion and was associated with 28.9% remission rates versus 19.3% with switching. 2
Alternative Strategy: Switch to Venlafaxine ER
If augmentation is not tolerated or preferred, switch to venlafaxine ER 150-225 mg daily, as this represents a therapeutic dose with demonstrated superior efficacy for patients with comorbid depression and anxiety symptoms. 1, 4
Venlafaxine shows superior efficacy compared to fluoxetine specifically for treating anxiety symptoms in patients with comorbid depression and anxiety. 1
The STAR*D trial demonstrated that switching to venlafaxine resulted in 1 in 4 patients (25%) becoming symptom-free, with no significant difference compared to bupropion or sertraline. 1, 4
Critical caveat: Monitor blood pressure closely when using venlafaxine ER, as SNRIs can cause dose-dependent hypertension. 3
Second-Line Augmentation Options
Bupropion Augmentation
Add bupropion SR 150-300 mg to the current antidepressant if aripiprazole is not tolerated or contraindicated. 1, 3
Bupropion augmentation decreases depression severity more than buspirone augmentation, with lower discontinuation rates due to adverse events. 5, 1
In the OPTIMUM trial, bupropion augmentation achieved 28.2% remission rates, comparable to aripiprazole (28.9%) but superior to switching strategies (19.3%). 2
Important caveat: Case reports document serotonin syndrome when combining bupropion with SSRIs, likely due to bupropion's inhibition of cytochrome P450 2D6, which increases SSRI blood levels. Monitor for confusion, myoclonus, autonomic instability, and altered consciousness. 6
Lithium Augmentation
Consider lithium augmentation if aripiprazole and bupropion both fail, as lithium is one of the best-documented treatments for treatment-resistant depression. 1, 3
Start lithium carbonate 300 mg twice daily, targeting a blood level of 0.6-1.0 mEq/L. 3
Critical monitoring requirements: Weekly lithium levels initially, then monthly thyroid function (TSH) and renal function (creatinine) checks. 3
In step 2 of the OPTIMUM trial (patients who failed initial strategies), lithium augmentation achieved 18.9% remission rates with 3.17 points improvement in well-being scores. 2
Treatment Algorithm
Step 1: Initial Augmentation (Weeks 1-10)
- Augment with aripiprazole 2 mg daily, increasing by 2-3 mg every 1-2 weeks to 10-15 mg as tolerated. 3, 2
- Assess treatment response at 6-8 weeks using standardized rating scales. 3
- Monitor weekly for suicidal ideation during the first month, then at each dose adjustment. 3
Step 2: If Inadequate Response (Weeks 10-20)
- Either switch to venlafaxine ER 150-225 mg daily OR add bupropion SR 150-300 mg to the current regimen. 1, 3
- Reassess after 4-6 weeks at therapeutic dose before declaring treatment failure. 1
Step 3: If Still Inadequate Response (After Week 20)
- Add lithium carbonate 300 mg twice daily with appropriate monitoring. 3, 2
- Consider quetiapine 50-300 mg as an alternative augmentation strategy if lithium is contraindicated. 1
Critical Safety Considerations
Monitor for serotonin syndrome when combining multiple serotonergic agents, particularly with bupropion-SSRI combinations. Early manifestations (myoclonus, confusion, gait difficulties) may be misinterpreted as depression worsening. 6
Ensure adequate trial duration: A minimum of 4 weeks at therapeutic dose is required before declaring treatment failure. 1
Assess for suicidal ideation weekly during the first month, then at each dose adjustment. 3
Common pitfall: Declaring treatment failure prematurely before reaching therapeutic doses or adequate trial duration. Many patients are maintained on subtherapeutic doses (e.g., venlafaxine 37.5 mg is inadequate for depression or anxiety). 1
Psychotherapy Integration
Add cognitive-behavioral therapy (CBT) to pharmacotherapy, as augmentation with CBT shows comparable efficacy to pharmacologic augmentation strategies. 5, 7
Low-quality evidence shows no difference in response or remission when switching from one antidepressant to another compared with switching to cognitive therapy. 5
Preferred psychotherapy techniques include cognitive-behavioral therapy, supportive psychotherapy, problem-solving psychotherapy, and interpersonal psychotherapy. 7