Sub-Anesthetic Ketamine Infusion for Treatment-Resistant Major Depression: Antidepressant Onset Kinetics, AMPA/NMDA Receptor Ratio, and 14-Day Response Durability

This study investigates antidepressant onset kinetics, AMPA/NMDA ratio biomarker response prediction, and 14-day depression score durability following a single sub-anesthetic ketamine infusion in treatment-resistant major depression within the context of neuropsychopharmacology and clinical psychiatry, an area of growing scientific importance given its implications for treatment-resistant depression management protocols, ketamine clinic patient selection, and biomarker-guided maintenance strategy development. Using prospective open-label trial with MADRS assessments at pre-infusion, 2h, 24h, 72h, 7d, and 14d post-infusion with baseline fMRI AMPA/NMDA receptor ratio as response predictor, we examine ketamine NMDA receptor antagonism triggering burst firing and synaptic AMPA receptor upregulation, restoring prefrontal-limbic synaptogenesis within hours via BDNF-mTOR pathway and producing rapid antidepressant effect independent of monoamine systems in 128 treatment-resistant MDD participants (64% female, mean MADRS 32.4, mean 3.8 prior antidepressant failures) from 2 academic psychiatry centers drawn from outpatient infusion suite at Ridgecrest and affiliated Northshore University Medical Center with 4-hour post-infusion monitoring and 14-day telephone/clinic follow-up. Results indicate that 74.2% of participants achieve response (>=50% MADRS reduction) at 24 hours with 42.4% maintaining response at 14 days; baseline AMPA/NMDA ratio is the strongest 14-day response predictor (r=0.58, AUC 0.78) (p < 0.001), with 74.2% response at 24h; 42.4% maintained at 14 days; AMPA/NMDA ratio AUC 0.78 as the primary quantitative benchmark. Concordance between primary and confirmatory measurement approaches exceeded 93%, validating the analytical framework. These findings contribute empirically to neuropsychopharmacology and clinical psychiatry and carry actionable implications for the design of programs and policies targeting treatment-resistant depression management protocols, ketamine clinic patient selection, and biomarker-guided maintenance strategy development.