A 52-year-old man with Major Depressive Disorder has been on fluoxetine 40 mg daily for 6 weeks with partial response. His psychiatrist is considering augmentation strategies. Which of the following augmentation agents is NOT supported by robust evidence in treatment-resistant depression?

Explanation

## Augmentation Strategies in Treatment-Resistant MDD ### Evidence-Based Augmentation Agents **Key Point:** Augmentation (adding a second agent to an SSRI/SNRI) differs from switching. The three evidence-based augmentation strategies for treatment-resistant depression are: | Augmentation Agent | Evidence Level | Mechanism | Typical Dosing | | --- | --- | --- | --- | | **Aripiprazole** | Strong (RCTs) | D2/5-HT1A partial agonist | 5–15 mg/day | | **Lithium** | Strong (meta-analyses) | Enhances serotonergic neurotransmission, neuroprotection | 600–1200 mg/day (0.6–1.2 mEq/L) | | **Thyroid hormone (T3)** | Moderate–Strong | Enhances antidepressant efficacy, increases receptor sensitivity | 25–50 mcg/day | | **Benzodiazepines** | Weak (no RCT evidence) | GABA-A agonist; anxiolytic only | Variable | ### Why Benzodiazepines Are NOT Recommended for Augmentation **High-Yield:** Benzodiazepines (alprazolam, lorazepam) are NOT evidence-based augmentation agents for MDD: 1. **No RCT evidence** — No randomized controlled trials demonstrate that benzodiazepines augment SSRI efficacy for core depressive symptoms (mood, anhedonia, guilt). 2. **Symptomatic relief only** — Benzodiazepines address anxiety and insomnia (common comorbidities in MDD) but do NOT treat the underlying depressive disorder. 3. **Dependence and tolerance** — Chronic benzodiazepine use carries risks of dependence, cognitive impairment, and paradoxical depression with long-term use. 4. **Not first-line** — Current guidelines (APA, NICE) recommend aripiprazole, lithium, or T3 augmentation before considering benzodiazepines, which are reserved for acute anxiety/insomnia management. **Clinical Pearl:** A common clinical error is prescribing benzodiazepines to depressed patients with anxiety, assuming they "augment" antidepressant therapy. In reality, benzodiazepines are adjunctive for symptom control, not disease-modifying augmentation. **Warning:** Do NOT confuse "adjunctive use" (benzodiazepines for anxiety/sleep) with "evidence-based augmentation" (aripiprazole, lithium, T3 for core depression). The question asks specifically about augmentation for treatment-resistant depression, where benzodiazepines lack RCT support.