A 40-year-old man with treatment-resistant depression (failed 3 SSRIs, 1 SNRI, augmentation) is offered ketamine infusion. Ketamine's antidepressant mechanism is PRIMARILY through:

• A Serotonin reuptake inhibition at 5-HT transporters
• B NMDA receptor antagonism leading to glutamate burst and AMPA receptor-mediated BDNF/mTOR signaling ✓
• C Mu-opioid receptor agonism in limbic regions
• D Dopamine D3 receptor agonism in the reward circuit

Explanation

Ketamine is an NMDA (N-methyl-D-aspartate) glutamate receptor antagonist. Its rapid antidepressant effect (within hours) is thought to result from: NMDA blockade on GABAergic interneurons → disinhibition of pyramidal neurons → burst of glutamate → AMPA receptor activation → downstream signaling cascade including BDNF release and mTOR pathway activation → rapid synaptogenesis in the prefrontal cortex and hippocampus, reversing the synaptic deficits in depression. This glutamate hypothesis of depression (rather than the classical monoamine hypothesis) explains ketamine's rapid, distinct mechanism from traditional antidepressants.

Reference: Kaplan & Sadock's Synopsis of Psychiatry, 11th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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