A 45-year-old woman with treatment-resistant MDD is prescribed esketamine nasal spray (Spravato). Its rapid antidepressant effect, occurring within hours, is mechanistically attributed to:
- A NMDA receptor blockade leading to disinhibition of AMPA receptor-mediated BDNF-mTORC1 synaptic plasticity ✓
- B Opioid mu receptor agonism causing rapid mood elevation independent of glutamate
- C Serotonin 5-HT2A receptor antagonism normalizing default mode network activity
- D GABA-A receptor potentiation at extrasynaptic delta-containing subunits producing anxiolysis
Explanation
Esketamine (S-ketamine) blocks NMDA receptors, particularly those on GABAergic interneurons; this disinhibition increases burst firing of glutamatergic pyramidal neurons, causing a transient increase in synaptic glutamate acting on AMPA receptors. AMPA activation triggers BDNF release, which activates TrkB receptors, stimulating the mTORC1 pathway to synthesize synaptic proteins and rapidly restore synaptic connections in mood-regulating circuits like the prefrontal cortex. This synaptic plasticity mechanism explains the onset within hours, unlike monoamine-based antidepressants that take weeks.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.