Pharmacokinetics & Mechanism

Ketamine (C13H16ClNO) is a dissociative anesthetic that functions primarily as a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor. Unlike traditional SSRIs which operate on the serotonin system, Ketamine directly modulates the Glutamate system—the brain's primary excitatory neurotransmitter.

The Glutamate Surge: By blocking NMDA receptors on GABAergic interneurons, Ketamine disinhibits the release of glutamate. This surge stimulates post-synaptic AMPA receptors, triggering the release of Brain-Derived Neurotrophic Factor (BDNF) and activating the mTORC1 signaling pathway. This cascade results in rapid synaptogenesis (dendritic spine growth) in the Prefrontal Cortex, effectively repairing neural circuitry atrophied by chronic stress or depression.

Figure 1.1: The mTOR Cascade
NMDA Blockade

Ketamine binds to the PCP site within the NMDA channel, preventing calcium influx.

BDNF Release

AMPA activation leads to protein synthesis key for synaptic plasticity.

The Infusion Protocol

We adhere to the Yale/NIMH standard protocol for psychiatric indications, utilizing sub-anesthetic dosing to maximize neuroplasticity while maintaining patient safety.

1. Dosing Strategy

Initial Dose: 0.5 mg/kg administered intravenously over 40 minutes.
Titration: Dosage is titrated in subsequent sessions (up to 0.75 mg/kg or 1.0 mg/kg) based on patient tolerability and dissociation depth. Bioavailability via IV infusion is 100%, ensuring precise control over plasma concentrations compared to oral or intranasal routes.

2. The Acute Phase

The standard induction course consists of 6 infusions administered over a 2-3 week period. This frequency is critical to sustain the initial spike in BDNF and stabilize the new synaptic connections. "One-off" sessions are rarely effective for long-term remission.

Patient Safety & Contraindications

While safe at sub-anesthetic doses, Ketamine increases sympathetic output. We strictly monitor hemodynamic stability.

  • Hypertension: Transient BP elevation is common. We exclude patients with uncontrolled hypertension (>150/90 mmHg).
  • Psychosis: History of Schizophrenia or active psychotic symptoms is an absolute contraindication due to potential exacerbation by dopaminergic modulation.
  • Active Substance Abuse: Patients must be screened for recent recreational drug use to prevent interactions.