Pharmacology  ·  CNS

Ketamine and Esketamine: Rapid-Acting Antidepressant Mechanisms

Module 6 — Chapter 17: Antidepressant Drugs

Abbreviations: NMDA = N-methyl-D-aspartate  ·  AMPA = alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid  ·  mTOR = mechanistic target of rapamycin  ·  BDNF = brain-derived neurotrophic factor  ·  TrkB = tropomyosin receptor kinase B  ·  HNK = hydroxynorketamine  ·  TRD = treatment-resistant depression  ·  MDD = major depressive disorder  ·  REMS = Risk Evaluation and Mitigation Strategy  ·  LH = lateral habenula  ·  GABA = gamma-aminobutyric acid

Rapid Antidepressant Mechanism — From NMDA Block to Synapse Formation
Step 1
NMDA Receptor Blocked
Open-channel block at rest; reduces tonic inhibition
→
Step 2
AMPA Signaling Disinhibited
AMPA/NMDA ratio increases in prefrontal cortex
→
Step 3
BDNF Released; mTOR Activated
TrkB signaling → protein synthesis initiated
→
Hours Later
New Synapses Formed
Dendritic spine restoration in prefrontal cortex; antidepressant effect
Ketamine versus Esketamine — Practical Comparison
Feature Racemic Ketamine (R,S) Esketamine (S-enantiomer)
NMDA receptor potency Lower (mix of enantiomers) ~4× more potent than R-enantiomer
Route IV infusion (off-label for depression) Intranasal (FDA-approved)
FDA approval Anesthesia only; off-label for TRD TRD + oral antidepressant; MDD with acute suicidal ideation
REMS program No Yes — certified healthcare setting only; 2-hour monitoring
DEA schedule Schedule III Schedule III
Typical dosing (depression) 0.5 mg/kg IV over 40 minutes; twice weekly 56 or 84 mg intranasally; twice weekly ×4 weeks, then taper
Open Questions and Circuit Mechanisms
Active Metabolite Debate
(2R,6R)-Hydroxynorketamine
  • Zanos et al. (Nature 2016): (2R,6R)-HNK produces antidepressant effects in mice without blocking NMDA receptors
  • Proposed mechanism: AMPA receptor potentiation directly
  • Would separate antidepressant effect from dissociative/abuse-related NMDA block
  • Clinical relevance in humans remains unresolved
  • Casarotto et al. (Cell 2021): antidepressants also act directly on TrkB receptors — further complexity
Neural Circuit Mechanism
Lateral Habenula Silencing
  • Lateral habenula: reward-prediction error center; "disappointment" encoding
  • Hyperactive in depression → suppresses dopamine and serotonin release
  • Ketamine rapidly silences lateral habenula burst firing
  • Mechanism: NMDA block prevents burst initiation
  • Provides circuit explanation for rapid antidepressant effect independent of synaptic plasticity
Esketamine REMS Requirements

Administered only in certified healthcare settings (certified pharmacy, healthcare provider, and healthcare facility). Patient must be monitored for at least 2 hours after each dose for sedation, dissociation, and blood pressure changes. Cannot be dispensed for home use. Patient cannot drive or operate machinery on the day of treatment. No evidence it prevents relapse if discontinued; used as bridge while oral antidepressant takes effect.

Suggested References

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Katzung BG, ed.Basic and Clinical Pharmacology. 15th ed.McGraw-Hill; 2021
Brunton LL, Knollmann BC, eds.Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed.McGraw-Hill; 2023
Duman RS, Aghajanian GK, Sanacora G, Bhatt DL.Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants.Nat Med. 2016;22(3):238–249
Li N, Lee B, Liu RJ, et al.mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.Science. 2010;329(5994):959–964
Zanos P, Moaddel R, Morris PJ, et al.NMDAR inhibition-independent antidepressant actions of (R,S)-ketamine metabolites.Nature. 2016;533(7604):481–486
Zanos P, Moaddel R, Morris PJ, et al.Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms.Pharmacol Rev. 2018;70(3):621–660
Zarate CA Jr, Singh JB, Carlson PJ, et al.A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.Arch Gen Psychiatry. 2006;63(8):856–864
Daly EJ, Singh JB, Fedgus M, et al.Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression.JAMA Psychiatry. 2018;75(2):139–148
Casarotto PC, Girych M, Fred SM, et al.Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.Cell. 2021;184(5):1299–1313
Zhu ZD, Xu Y, Gao Y, et al.Lateral habenula in the pathophysiology of depression.Front Cell Neurosci. 2021;15:666988
Murrough JW, Iosifescu DV, Chang LC, et al.Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.Am J Psychiatry. 2013;170(10):1134–1142
U.S. Food and Drug Administration.Spravato (esketamine) prescribing information. Revised 2023.FDA; 2023