A patient with treatment-resistant depression fails two adequate SSRI trials. She is started on ketamine infusion. The mechanism of ketamine's rapid antidepressant effect (within hours) is distinct from SSRIs because:

• A Ketamine directly activates serotonin 5-HT2A receptors in the prefrontal cortex
• B Ketamine inhibits monoamine oxidase, causing acute elevation of all monoamines in synaptic clefts
• C Ketamine's mu-opioid agonism provides rapid mood elevation independent of glutamate pathways
• D Ketamine blocks NMDA receptors on GABA interneurons, disinhibiting glutamatergic burst signaling that activates AMPA receptors and BDNF-TrkB signaling ✓

Explanation

Ketamine's antidepressant mechanism involves NMDA receptor antagonism on GABAergic interneurons, removing tonic inhibition of pyramidal glutamatergic neurons. This results in a burst of glutamate release that activates AMPA receptors (not NMDA receptors, which remain blocked). AMPA activation triggers downstream BDNF release and TrkB signaling, promoting synaptogenesis and restoring the atrophied prefrontal cortical synaptic connections lost in depression. This explains the rapid (hours) antidepressant onset compared to weeks for SSRIs that require neuroplastic changes via different pathways.

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

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Written and medically reviewed by the StethoPrep medical team.