A patient with treatment-resistant depression is started on ketamine infusions. Which intracellular signalling cascade mediates the rapid antidepressant effect observed within hours — distinct from the mechanism of traditional antidepressants?
- A Mu-opioid receptor agonism in the limbic system produces rapid anxiolysis mimicking antidepressant response
- B NMDA receptor blockade during tonic (burst-independent) firing disinhibits mTORC1, increasing BDNF synthesis and synaptic protein expression ✓
- C Serotonin reuptake inhibition via NET blockade elevates synaptic serotonin within 2 hours
- D Sigma-1 receptor agonism stabilizes IP3 receptor clusters at the mitochondria-ER junction, reducing neuronal apoptosis
Explanation
Ketamine's rapid antidepressant effect (onset within 2–4 hours, unlike 2–4 weeks for SSRIs) is primarily mediated by blockade of NMDA receptors on GABAergic interneurons during spontaneous (tonic) firing — the 'disinhibition hypothesis.' This removes inhibitory tone on glutamatergic neurons, producing a glutamate burst that activates AMPA receptors. Downstream AMPA activation triggers BDNF release and TrkB-mediated mTORC1 (mammalian target of rapamycin complex 1) signalling, leading to rapid synthesis of synaptic proteins (GluA1, PSD-95, synapsin-1) and synaptogenesis in prefrontal cortex and hippocampus. This synaptic plasticity restoration underlies the antidepressant effect that conventional monoamine-based therapies cannot rapidly replicate.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.