Next Treatment Step for Treatment-Resistant Depression
After failing both Lexapro (escitalopram) and Prozac (fluoxetine), augment the current antidepressant with an atypical antipsychotic—specifically aripiprazole, quetiapine extended-release, or the olanzapine-fluoxetine combination—as this represents the FDA-approved first-line strategy with the most extensive evidence base for treatment-resistant depression. 1
Why Augmentation Over Switching
Your patient now meets criteria for treatment-resistant depression (TRD), defined as failure to respond to at least two adequate antidepressant trials 2, 1. At this juncture, augmentation with atypical antipsychotics has superior evidence compared to switching to another antidepressant monotherapy 1, 3. The evidence shows that switching to a third antidepressant yields response rates below 20% in many cases 2, while atypical antipsychotic augmentation has the most rigorous and extensive evidence base of all pharmacological approaches in TRD 1.
Specific FDA-Approved Options
First-Line Augmentation Choices:
Aripiprazole: The first medication specifically FDA-approved as adjunctive therapy for treatment-resistant depression 1, 4. This should be your primary consideration given its approval status and extensive evidence 5.
Quetiapine extended-release: FDA-approved for depression augmentation with strong evidence 1, 5, 3.
Olanzapine-fluoxetine combination: FDA-approved specifically for TRD, starting at 5 mg olanzapine with 20 mg fluoxetine once daily in the evening, with dose range of 5-20 mg olanzapine and 20-50 mg fluoxetine 1. Since your patient already tried Prozac (fluoxetine), this option allows you to restart fluoxetine at a therapeutic dose while adding olanzapine's augmentation benefit 3.
Brexpiprazole and cariprazine: Also FDA-approved for depression augmentation 5.
Critical Monitoring Requirements
When using atypical antipsychotics, you must implement metabolic monitoring due to risks of weight gain, metabolic syndrome, akathisia, and tardive dyskinesia 1, 5. For the olanzapine-fluoxetine combination specifically, monitor for drug interactions given fluoxetine's long half-life and cytochrome P450 enzyme inhibition 1.
Alternative Evidence-Based Strategies
If atypical antipsychotics are contraindicated or not tolerated, alternative augmentation strategies with strong evidence include 1, 3:
- Lithium augmentation: Well-established efficacy, though requires close monitoring 3
- Liothyronine (T3): Effective thyroid hormone augmentation 3
- Lamotrigine: Particularly useful in certain depression subtypes 3
- Combination with bupropion, tricyclics, or mirtazapine: Effective antidepressant combinations 3
However, note that one older study found high-dose fluoxetine (40-60 mg/day) more effective than fluoxetine plus lithium or fluoxetine plus desipramine in fluoxetine non-responders 6, though this contradicts the broader evidence base favoring augmentation strategies.
When to Consider Advanced Interventions
Reserve ketamine or esketamine for highly refractory cases after multiple augmentation strategies have failed 1. These agents may help reduce suicidal ideation but represent later-line options 1, 3.
Common Pitfall to Avoid
Do not simply switch to a third antidepressant monotherapy (such as venlafaxine, duloxetine, or mirtazapine alone) as your next step 1. While this remains the most widely used real-world practice, it yields suboptimal remission rates in TRD 5. The evidence clearly favors augmentation at this stage of treatment resistance.