What is an FDA-approved treatment option for a patient with treatment-resistant depression who has not responded to selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and bupropion?

Treatment-Resistant Depression: FDA-Approved Options

For this patient with treatment-resistant depression who has failed SSRIs, SNRIs, and bupropion, second-generation antipsychotics represent the FDA-approved treatment option with the strongest evidence base. 1, 2, 3

Clinical Context

This 20-year-old woman meets criteria for treatment-resistant depression (TRD), defined as failure to respond to at least two adequate antidepressant trials of different mechanisms of action. 1 Her presentation includes:

• Atypical features (hypersomnia, weight gain, interpersonal sensitivity) 1
• Poor tolerability to multiple antidepressant classes 4
• One-year duration with significant functional impairment 4

FDA-Approved Treatment: Second-Generation Antipsychotics

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. 1

Specific FDA-Approved Options

Aripiprazole is the first medication approved by the FDA specifically as adjunctive therapy for treatment-resistant depression. 5, 6 The evidence base supporting augmentation with atypical antipsychotics (aripiprazole, quetiapine, and olanzapine) is the most extensive and rigorous of all pharmacological approaches in TRD. 6

Olanzapine combined with fluoxetine is FDA-approved for treatment-resistant depression, defined as major depressive disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode. 2 The FDA label specifies:

• Starting dose: 5 mg olanzapine with 20 mg fluoxetine once daily in the evening 2
• Dose range: olanzapine 5-20 mg with fluoxetine 20-50 mg 2
• Efficacy demonstrated with olanzapine 6-18 mg and fluoxetine 25-50 mg 2

Why Not the Other Options?

Benzodiazepines are not FDA-approved for treatment-resistant depression and do not address the core depressive symptoms. 1

Deep brain stimulation is not FDA-approved for treatment-resistant depression. 4

Flooding is a behavioral therapy technique for anxiety disorders, not an FDA-approved treatment for depression. 1

Transcranial magnetic stimulation (TMS) is FDA-approved and should be considered for patients who have failed medication trials 1, 7, but second-generation antipsychotics have more extensive evidence as the primary pharmacological intervention. 6

Treatment Algorithm

1. Verify TRD diagnosis: Confirm failure of at least 2 adequate antidepressant trials with different mechanisms (SSRIs, SNRIs, bupropion in this case). 1

2. Ensure adequate trials: Each trial should be at minimum effective dosage for ≥4 weeks. 1 Discontinuation due to side effects before completing 4 weeks should not count as treatment failure. 1

3. Initiate augmentation: Add an atypical antipsychotic to the current antidepressant regimen rather than switching to another antidepressant monotherapy. 6 Augmentation with certain second-generation antipsychotics may be preferred over switching to antidepressant monotherapy. 3

4. Monitor response: The Maudsley Staging Method (MSM) is the preferred staging instrument for documenting treatment resistance, incorporating duration of illness and baseline symptom severity, correctly predicting treatment resistance in >85% of cases. 1

Important Clinical Considerations

Metabolic monitoring is essential when using olanzapine-fluoxetine combination, as metabolic side-effects may limit its use. 3 This is particularly relevant given this patient's 40-pound weight gain, though this preceded treatment initiation.

Consider drug interactions: Fluoxetine has a long half-life and inhibits cytochrome P450 enzymes, which can prolong effects and side effects for weeks. 1

Alternative augmentation strategies with strong evidence include lithium, liothyronine (T3), lamotrigine, or combination with bupropion, tricyclics, or mirtazapine. 3 However, atypical antipsychotics have the most extensive evidence base. 6

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, 7, 3