Treatment-Resistant Depression: Evidence-Based Management
Augmentation with atypical antipsychotics, specifically aripiprazole, represents the primary first-line strategy for treatment-resistant depression after failure of at least two adequate antidepressant trials with different mechanisms of action. 1, 2, 3
Defining Treatment-Resistant Depression
Before initiating treatment, confirm the diagnosis of TRD by verifying:
- Failure of at least two adequate antidepressant trials with different mechanisms of action (according to Neuroscience-based Nomenclature) in the current depressive episode 4, 1
- Each trial must be at minimum effective dosage (the minimal approved dosage) for at least 4 weeks duration 4, 1
- Only treatment failures within the past 2 years should be considered for prolonged current episodes 1, 2
- Discontinuation before 4 weeks due to side effects should not count as treatment failure unless there is clear evidence of non-response 4
Treatment Algorithm
First-Line: Atypical Antipsychotic Augmentation
The evidence base supporting augmentation with atypical antipsychotics (aripiprazole, quetiapine, and olanzapine) is the most extensive and rigorous of all pharmacological approaches in TRD. 3, 5
Aripiprazole augmentation is recommended after inadequate response to at least one antidepressant at adequate dose for ≥4 weeks 1, 2, 3:
- Aripiprazole was the first medication approved by the FDA specifically as adjunctive therapy for treatment-resistant depression 3, 6
- Doses are slightly lower than those used for schizophrenia or bipolar disorder 6
- Alternative atypical antipsychotics with strong evidence include quetiapine extended-release and olanzapine-fluoxetine combination 3, 7, 8
Olanzapine-fluoxetine combination is FDA-approved for TRD 3:
- Starting dose: 5 mg olanzapine with 20 mg fluoxetine once daily in the evening 3
- Dose range: olanzapine 5-20 mg with fluoxetine 20-50 mg 3
- Critical caveat: Metabolic monitoring is essential; use may be limited by metabolic side-effects including weight gain 3, 7
- Consider fluoxetine's long half-life and cytochrome P450 enzyme inhibition, which can prolong effects for weeks 1, 3
Second-Line: Alternative Augmentation Strategies
If atypical antipsychotics are not tolerated or effective, consider:
- Lithium augmentation - well-studied with established efficacy 3, 7, 9
- Liothyronine (T3) augmentation - effective thyroid hormone strategy 3, 7, 9
- Lamotrigine augmentation - supported by evidence 3, 7
- Antidepressant combinations: bupropion, tricyclics, or mirtazapine added to current antidepressant 3, 7
Third-Line: Rapid-Acting Treatments for Highly Refractory Cases
Esketamine (SPRAVATO) or ketamine should be reserved for highly refractory cases who have failed multiple augmentation strategies 1, 2, 3, 7:
- FDA-approved indication: TRD in adults as monotherapy or in conjunction with an oral antidepressant 10
- Dosing for TRD 10:
- Induction Phase (Weeks 1-4): 56 mg or 84 mg twice weekly
- Maintenance Phase (Weeks 5-8): 56 mg or 84 mg once weekly
- Week 9 and after: 56 mg or 84 mg every 2 weeks or once weekly
- Critical safety requirements 10:
- Must be administered under direct healthcare provider supervision
- Monitor for sedation, dissociation, and respiratory depression for at least 2 hours post-administration
- Assess blood pressure before dosing and at approximately 40 minutes post-dose
- Available only through REMS program due to risks of sedation, dissociation, respiratory depression, and abuse potential
- Patients cannot drive until the next day following restful sleep
- Common adverse reactions (≥5% and twice placebo rate): dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increase, vomiting, feeling drunk 10
- May help reduce suicidal ideation, though effectiveness in preventing suicide has not been demonstrated 3, 10
Fourth-Line: Neuromodulation
Transcranial magnetic stimulation (TMS) should be considered for patients who have failed medication trials 1, 2:
- Non-invasive brain stimulation option 4
- Failure of TMS or electroconvulsive therapy (ECT) should not exclude patients from further treatment trials 4
Electroconvulsive therapy (ECT) remains an option for severe, refractory cases 4, 9:
- Particularly for patients with high scores on staging tools predicting poor response 4
Adjunctive Psychotherapy
Cognitive behavioral therapy should be used in conjunction with pharmacotherapy throughout treatment 1, 5:
- Psychotherapy failure does not count toward defining TRD but should be documented 4
- Manual-based psychotherapies, particularly CBT, have compelling evidence in TRD 5
Critical Pitfalls to Avoid
Do not escalate antidepressant doses beyond minimum effective dosage - most studies show no benefit with increased risk of side effects and discontinuation 4:
- Exception: Some evidence suggests higher doses may have superior efficacy in select cases 4
Do not exclude patients based on number of prior medication failures - multiple-drug resistant individuals should not be excluded from treatment trials 4, 1:
- Document all prior treatments for staging purposes 4
Do not exclude patients with depression specifiers - all specifiers (melancholic, atypical, anxious, psychotic, mixed) should be considered within TRD, except bipolar depression which should be excluded 4
Avoid switching strategies after partial response - combination/augmentation strategies are preferred when partial response was achieved, as switching may lose achieved improvements 9:
- Switching has limited effectiveness in achieving remission compared to augmentation 9
Do not use inadequate trial duration - while initial response may be seen at 2 weeks, stable response/remission typically requires 4 weeks minimum 4:
- Complete remission may not be detectable until 6-14 weeks for some patients 4
Staging and Documentation
Use the Maudsley Staging Method (MSM) for structured documentation - it is the preferred staging instrument 1: