What medication options are available for a patient with treatment-resistant depression?

Medication Options for Treatment-Resistant Depression

Augmentation with atypical antipsychotics—specifically aripiprazole, quetiapine, brexpiprazole, or the olanzapine-fluoxetine combination—represents the primary FDA-approved first-line pharmacological strategy for treatment-resistant depression after failure of at least one adequate antidepressant trial. 1

Defining Treatment-Resistant Depression

Before initiating treatment, confirm the diagnosis:

• TRD requires failure of at least two adequate antidepressant trials with different mechanisms of action in the current depressive episode 2, 3
• An adequate trial means minimum approved dosage for at least 4 weeks 2
• Discontinuation before 4 weeks due to side effects should not count as treatment failure unless there is clear evidence of non-response 2
• Verify adherence to prior trials before declaring treatment resistance 3

First-Line Pharmacological Options: Atypical Antipsychotics

The evidence base for atypical antipsychotics is the most extensive and rigorous of all pharmacological approaches in TRD, with aripiprazole being the first medication FDA-approved specifically as adjunctive therapy for treatment-resistant depression. 1

FDA-Approved Atypical Antipsychotics:

Aripiprazole:

• Start at 0.5 mg once daily, increase to 1 mg at Week 2, then target dose of 2 mg from Week 3 onwards 1
• Most extensively studied with strong evidence from multiple RCTs 1, 4

Brexpiprazole:

• Follow similar dosing algorithm as aripiprazole 1
• FDA-approved for TRD augmentation 5

Quetiapine extended-release:

• FDA-approved option 5
• Particularly beneficial when comorbid anxiety or insomnia are present 4

Olanzapine-fluoxetine combination:

• Start with 5 mg olanzapine + 20 mg fluoxetine once daily in the evening 1
• Dose range: olanzapine 5-20 mg with fluoxetine 20-50 mg 1
• Critical caveat: Requires metabolic monitoring (weight, glucose, lipids) due to significant metabolic side effects 1
• Consider fluoxetine's long half-life and cytochrome P450 enzyme inhibition when evaluating drug interactions 1

Cariprazine:

• FDA-approved for TRD 5

Important Safety Considerations:

Weigh benefits against potential adverse events including weight gain, akathisia, and tardive dyskinesia. 5

Alternative Evidence-Based Augmentation Strategies

When atypical antipsychotics are contraindicated or not tolerated:

Bupropion augmentation:

• Effective alternative with strong evidence from the STAR*D trial, achieving remission in 1 in 4 patients whose initial therapy failed 1
• Significant advantage: Lower rates of sexual adverse events compared to SSRIs, improving adherence 1
• Drug interaction caution: Bupropion inhibits CYP2D6, increasing concentrations of many antidepressants (venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics, beta-blockers, and Type 1C antiarrhythmics—consider dose reduction of these medications 6
• Avoid with MAOIs (14-day washout required) and use caution with drugs that lower seizure threshold 6

Other augmentation options with strong evidence:

• Lithium 1
• Liothyronine (T3) 1
• Lamotrigine 1
• Combination with tricyclics or mirtazapine 1

Highly Refractory Cases

Esketamine/ketamine:

• Reserved for patients who have failed multiple augmentation strategies 1, 3
• May help reduce suicidal ideation 1
• Fast-acting with different timeline than traditional antidepressants 2

Transcranial magnetic stimulation (TMS):

• Consider for patients who have failed medication trials 3, 7

Critical Treatment Algorithm

1. Verify TRD diagnosis: Confirm at least 2 adequate trials (minimum effective dosage for ≥4 weeks) with different mechanisms 3, 7
2. Do not escalate antidepressant doses beyond minimum effective dosage—most studies show no benefit with increased side effects and discontinuation risk 2, 1
3. Initiate atypical antipsychotic augmentation as first-line strategy (aripiprazole, quetiapine, brexpiprazole, or olanzapine-fluoxetine) 1
4. If atypical antipsychotics fail or are contraindicated: Consider bupropion, lithium, T3, or lamotrigine augmentation 1
5. For highly refractory cases: Esketamine/ketamine or TMS 1, 3
6. Adjunctive psychotherapy: Evidence-based psychotherapies should be used in conjunction with pharmacotherapy 3

Common Pitfalls to Avoid

• Do not declare treatment failure before completing at least 4 weeks at adequate dosage 1
• Do not exclude patients based solely on number of prior medication failures—even multi-drug resistant individuals should receive treatment 2
• Do not count discontinuation due to side effects before 4 weeks as treatment failure unless clear non-response is documented 2
• Monitor metabolic parameters closely when using olanzapine-fluoxetine combination 1
• Check for drug interactions when using bupropion augmentation, particularly with CYP2D6 substrates 6