Ketamine and Esketamine: Rapid-Acting Antidepressant Pharmacology

Module 6 — Chapter 17: Antidepressant Drugs

Mechanism of Rapid Antidepressant Action
Step 1
Ketamine blocks N-methyl-D-aspartate receptors on inhibitory interneurons in prefrontal cortex
→
Step 2
Inhibitory interneurons suppressed → pyramidal neurons disinhibited → glutamate burst released
→
Step 3
Glutamate activates AMPA receptors → BDNF released → TrkB receptor activation
→
Step 4 — Hours
Rapid synaptogenesis in prefrontal circuits → antidepressant effect within hours; lasts 3–7 days
The Key Distinction

All prior antidepressants: monoamine mechanism, two-to-four-week onset. Ketamine and esketamine: N-methyl-D-aspartate glutamate receptor blockade, antidepressant effect within hours. The mechanisms are entirely different. The speed is entirely different.

Esketamine versus Intravenous Ketamine
Feature Esketamine (Spravato) Intravenous Ketamine
Regulatory status Food and Drug Administration-approved for treatment-resistant depression and major depressive disorder with acute suicidal ideation Off-label — no Food and Drug Administration approval for psychiatric indications
Formulation S-enantiomer only; intranasal spray (Spravato) Racemic mixture (R + S enantiomers); intravenous infusion 0.5 mg per kilogram over 40 minutes
Setting Risk Evaluation and Mitigation Strategy-certified healthcare setting mandatory Monitored clinical setting; no standardized regulatory requirement
Monitoring Minimum 2-hour observation after each dose; no driving day of treatment 1 to 2 hours post-infusion; no driving day of treatment
With oral antidepressant Required — esketamine is not approved as monotherapy Typically used as bridge or adjunct; no formal requirement
Insurance coverage Often covered for approved indications Rarely covered (off-label); cost is a major barrier
Safety Profile and Contraindications
Adverse Effects
Expected and Common
  • Dissociation: perceptual distortions, depersonalization, unreality — begins minutes after administration, resolves within 60 to 90 minutes; expected and dose-dependent
  • Blood pressure and heart rate elevation: transient sympathomimetic effect; monitor during session
  • Nausea and vomiting: 20 to 30 percent of patients; antiemetic pre-treatment reduces risk
  • Sedation: basis for 2-hour post-dose monitoring and no-driving restriction
Contraindications
Absolute and Clinical
  • Aneurysmal vascular disease or arteriovenous malformation — absolute
  • Intracerebral hemorrhage — absolute
  • Active psychosis or schizophrenia — clinical contraindication; may precipitate or worsen psychosis
  • Uncontrolled hypertension — relative; optimize before use
  • Schedule III controlled substance — abuse potential; chronic high-dose use associated with bladder damage (ketamine uropathy)