🧪 History of Ketamine

• Discovered in 1962 by Calvin Stevens at Parke-Davis Laboratories as a derivative of phencyclidine (PCP).

• Initially developed as a safer anesthetic alternative with shorter action and fewer psychotomimetic effects.

• First used in humans in 1964, FDA-approved in 1970.

• Widely used in field anesthesia, particularly during the Vietnam War.

• Its dissociative properties made it popular in emergency, pediatric, and veterinary anesthesia.

Shift to psychiatry:

• In 2000, Berman et al. published the first controlled study demonstrating rapid antidepressant effects.

• Subsequent NIH studies (e.g., Zarate et al., 2006) confirmed benefits in treatment-resistant depression (TRD).

• Since then, it has become one of the most exciting innovations in neuropsychiatry.

🧬 Mechanism of Action

Ketamine’s antidepressant effect is multifactorial and distinct from monoaminergic agents (e.g., SSRIs).

1. NMDA Receptor Antagonism

• Noncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptor.

• Blocks excitatory glutamate input, paradoxically enhancing glutamate transmission at AMPA receptors.

2. Enhanced Synaptic Plasticity

• Disinhibition leads to increased AMPA receptor activity → boosts downstream signaling.

• Activates BDNF (Brain-Derived Neurotrophic Factor) and mTOR (mechanistic target of rapamycin) pathways.

• Results in increased synaptogenesis, especially in prefrontal cortex and hippocampus.

3. Other effects:

• Modulates opioid receptors, dopamine, serotonin, and inflammatory cytokines (e.g., IL-6, TNF-α).

• Influences default mode network (DMN) activity during dissociation.

💥 Psychotropic & Antidepressant Effects

📍 Routes of Administration in Psychiatry

• IV infusion (most studied): 0.5 mg/kg over 40 minutes

• Intramuscular (IM): convenient, especially in resource-limited settings

• Intranasal (IN): FDA-approved esketamine (Spravato) in the U.S.

• Sublingual / Oral: lower bioavailability, slower onset

⚠️ Side Effects and Risks

Note: At sub-anesthetic psychiatric doses, most side effects are mild and self-limiting.

🧠 Role in Psychiatry

✅ Evidence-Based Indications

1. Treatment-Resistant Depression (TRD)

   • Most robust evidence.

   • IV or IN protocols used across major studies.

   • Often requires 6–8 sessions over 2–3 weeks followed by maintenance doses.

2. Acute Suicidal Ideation

   • Rapid reduction in suicidality seen within 4–24 hours.

   • Used in emergency psychiatry and inpatient settings.

3. Bipolar Depression

   • Caution advised; shown efficacy in depressive phase (not during mania).

4. Post-Traumatic Stress Disorder (PTSD)

   • Emerging evidence; especially when combined with psychotherapy (KAP).

5. Obsessive-Compulsive Disorder (OCD), Anxiety Disorders

   • Early-phase trials ongoing; variable response.

💬 Psychotherapeutic Integration: Ketamine-Assisted Psychotherapy (KAP)

• Combines dissociative experience of ketamine with structured psychotherapy.

• Helps patients revisit painful memories or shift rigid cognitive patterns.

• Particularly used in PTSD, existential distress, end-of-life anxiety.

🏥 Clinical Use: Safety Essentials

• Patient selection: Screen for cardiovascular risk, psychosis, substance use.

• Monitoring: Vitals, oxygen saturation, mental status pre/post session.

• Informed consent: Must discuss off-label use, side effects, and alternatives.

• Emergency support: Trained staff, basic life support (BLS), crash cart if IV.

📚 Key Clinical Trials

🔮 Future Directions

• Biomarkers of response (e.g., EEG, fNIRS)

• Home-based protocols for SL use (controversial)

• Novel glutamatergic agents (e.g., rapastinel, apimostinel)

• Integration with psychedelics and MDMA-based therapies

🧾 Summary

Ketamine represents a watershed moment in psychiatry, challenging the monoaminergic orthodoxy and offering hope for rapid relief in severe depression and suicidality. While its use must be clinically cautious and ethically grounded, the therapeutic potential is undeniable.

For India and other emerging economies, this is an opportunity to build cost-effective, psychiatrist-led protocols that expand access while ensuring safety.