A 52-year-old man with recurrent major depressive disorder presents with passive suicidal ideation and hopelessness. He has failed trials of sertraline and escitalopram. Which agent is the preferred choice for suicide risk reduction in treatment-resistant depression?

Explanation

## Ketamine for Acute Suicidality in Treatment-Resistant Depression **Key Point:** Intravenous ketamine is the only agent with FDA approval and level-1 evidence for rapid reduction of suicidal ideation in treatment-resistant depression (TRD). It produces antisuicidal effects within hours to days, unlike conventional antidepressants which take weeks. **High-Yield:** Ketamine's rapid antisuicidal action is independent of its antidepressant effect and occurs at sub-anesthetic doses (0.5 mg/kg IV). This makes it the gold standard for acute, severe suicidality in TRD when conventional agents have failed. ### Mechanism of Antisuicidal Action 1. **NMDA receptor antagonism** → rapid glutamatergic modulation 2. **Increased BDNF** → neuroplasticity and synaptogenesis 3. **Reduced rumination and hopelessness** → within 24–72 hours 4. **Restoration of prefrontal cortex function** → improved impulse control ### Comparative Evidence in TRD-Associated Suicidality | Agent | Evidence Level | Time to Effect | Antisuicidal Efficacy | Use in TRD | |-------|----------------|-----------------|----------------------|------------| | **Ketamine (IV)** | Level 1 (RCTs) | 24–72 hours | 60–70% reduction | **First-line for acute suicidality** | | Esketamine (nasal) | Level 1 (RCTs) | 24–48 hours | 50–60% reduction | Alternative if IV unavailable | | Mirtazapine | Level 2–3 | 2–4 weeks | Modest; no acute data | Adjunctive only | | Bupropion | Level 2–3 | 2–4 weeks | Neutral to modest | Avoid (may increase agitation) | | Trazodone | Level 3 | 2–4 weeks | Limited evidence | Adjunctive for sleep only | **Clinical Pearl:** Ketamine's rapid onset makes it ideal for the "window of acute risk" — the first 24–72 hours when suicide risk is highest. Conventional antidepressants take 2–4 weeks, during which the patient remains at high risk. **Mnemonic:** **KETAMINE = Kills Emergent suicidal Thoughts And Mood-resistant Ideation Neurobiologically Expedited** — the only rapid-acting antisuicidal agent. **Warning:** Ketamine is NOT a monotherapy; it must be followed by conventional antidepressants or mood stabilizers. Esketamine (nasal spray) is an alternative if IV access is unavailable, but IV ketamine has stronger evidence in acute suicidality. [cite:Harrison 21e Ch 470; FDA Spravato approval 2019]