Treatment-Resistant Depression: FDA-Approved Options

Clinical Context

The American College of Cardiology is not relevant here, however, the patient meets criteria for treatment-resistant depression (TRD), defined as failure to respond to at least two adequate antidepressant trials of different mechanisms of action, with atypical features, poor tolerability to multiple antidepressant classes, and one-year duration with significant functional impairment 1, 2, 3

Augmentation with atypical antipsychotics is the primary first-line FDA-approved strategy after inadequate response to at least one antidepressant at adequate dose for ≥4 weeks, according to the treatment guidelines 1
The evidence base supporting augmentation with atypical antipsychotics (aripiprazole, quetiapine, and olanzapine) is the most extensive and rigorous of all pharmacological approaches in TRD, with aripiprazole being the first medication approved by the FDA specifically as adjunctive therapy for treatment-resistant depression 1, 2

The FDA-approved treatment olanzapine combined with fluoxetine is recommended for treatment-resistant depression, with a starting dose of 5 mg olanzapine with 20 mg fluoxetine once daily in the evening, and a dose range of olanzapine 5-20 mg with fluoxetine 20-50 mg, according to the FDA label 1, 3
Metabolic monitoring is essential when using olanzapine-fluoxetine combination, and drug interactions should be considered, particularly with fluoxetine's long half-life and inhibition of cytochrome P450 enzymes 1
Alternative augmentation strategies with strong evidence include lithium, liothyronine (T3), lamotrigine, or combination with bupropion, tricyclics, or mirtazapine, but atypical antipsychotics have the most extensive evidence base 1
Ketamine and esketamine are recommended for highly refractory cases and may help reduce suicidal ideation, but are typically reserved for patients who have failed multiple augmentation strategies 1

The American College of Physicians-supported study demonstrated that bupropion is an effective alternative augmentation strategy for treatment-resistant depression, with strong evidence supporting its use in combination therapy, particularly when added to SSRIs or SNRIs in patients who have failed initial antidepressant monotherapy 4
The STAR*D trial showed that switching to bupropion sustained-release achieved remission in 1 in 4 patients whose initial therapy failed, with no significant difference compared to sertraline or venlafaxine extended-release, indicating its efficacy as an augmentation option 4

Bupropion is associated with significantly lower rates of sexual adverse events compared to SSRIs, making it particularly valuable when sexual side effects limit adherence, as supported by the American College of Physicians 5

The American Psychiatric Association defines treatment-resistant depression as failure to respond to at least two adequate antidepressant trials of different mechanisms of action in the current episode, with an adequate trial requiring the minimal approved dosage administered for at least 4 weeks 6, 7, 8
Discontinuation before 4 weeks due to side effects should not count as treatment failure unless there is clear evidence of non-response, and confirm adequate adherence to prior antidepressant trials before diagnosing treatment resistance 6, 8

The treatment algorithm for brexpiprazole augmentation involves confirming treatment-resistant depression diagnosis, initiating brexpiprazole augmentation at 0.5 mg once daily, increasing to 1 mg at Week 2, then to target dose of 2 mg from Week 3 onwards, monitoring response, optimizing dosing, and monitoring safety 6, 7, 8
Do not escalate antidepressant doses beyond minimum effective dosage, as most studies show no benefit with increased risk of side effects and discontinuation, and do not declare treatment failure before completing at least 4 weeks at adequate dosage 6, 8

The American Psychiatric Association recommends evidence-based psychotherapies specifically for treatment-resistant depression, in conjunction with pharmacotherapy, as an effective treatment approach 9, 10

The Depression and Anxiety journal suggests verifying adequate prior treatment trials, with minimum effective dosage for ≥4 weeks duration, and confirmed adherence, before proceeding with new treatment strategies 10, 11