A 35-year-old woman with treatment-resistant depression has failed 2 adequate antidepressant trials. She is started on ketamine infusion. The primary mechanism by which ketamine produces rapid antidepressant effects (within hours) is:

• A Immediate reuptake inhibition of serotonin and norepinephrine
• B Inhibition of monoamine oxidase resulting in increased synaptic monoamine availability
• C NMDA receptor antagonism leading to disinhibition of AMPA signalling, BDNF release, and rapid synaptogenesis in prefrontal cortex ✓
• D Direct agonism at 5-HT2A receptors in the default mode network

Explanation

Ketamine's rapid antidepressant action (within 2–4 hours, lasting 1–2 weeks) is attributed to its NMDA receptor antagonism, particularly blockade of tonically active NMDA receptors on GABAergic interneurons. This disinhibits glutamate release onto AMPA receptors, activating the mTOR pathway, increasing BDNF production, and rapidly promoting synaptic plasticity and synaptogenesis in the prefrontal cortex and hippocampus — neural circuit changes reversed by depression. This mechanism bypasses the weeks-long delay of classic antidepressants. Esketamine (intranasal, Spravato) is FDA-approved for treatment-resistant depression and major depressive disorder with acute suicidal ideation.

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

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