Ketamine, a dissociative anaesthetic and antidepressant, produces its rapid antidepressant effect (within hours) by a mechanism distinct from monoamine-based antidepressants. The most widely accepted mechanism is:

• A Inhibition of monoamine oxidase A, acutely raising synaptic serotonin
• B Direct activation of mu-opioid receptors in the nucleus accumbens
• C Selective serotonin 5-HT1A receptor agonism in the prefrontal cortex
• D Blocking NMDA receptors on GABAergic interneurons (disinhibition), triggering glutamate burst → AMPA receptor activation → BDNF release → synaptogenesis via mTOR pathway ✓

Explanation

Ketamine's rapid antidepressant effect involves blocking NMDA receptors on tonically active GABAergic interneurons in the prefrontal cortex. This disinhibition permits a burst of glutamatergic transmission from pyramidal neurons, activating postsynaptic AMPA receptors. AMPA activation triggers synaptic BDNF release, activating TrkB receptors, which signal through the mTOR pathway to initiate rapid synaptogenesis — restoring lost synaptic connections in prefrontal cortex layers associated with depression. This mechanism explains the hours-scale antidepressant effect compared to weeks for monoamine-based antidepressants, and its efficacy in treatment-resistant depression.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.