Sub-Anesthetic Ketamine Infusion for Treatment-Resistant Major Depression: Antidepressant Onset Kinetics, AMPA/NMDA Receptor Ratio, and 14-Day Response Durability
Ariel N. Shapiro, James T. McAllister, Priya V. Nair
Princeton Journal of Pre-Collegiate Research 2017 DOI: 10.67698/pjpcr.2026.0057 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Prospective open-label trial Peer reviewed |
|---|---|
| Sample size | 128 |
| Population | Adults with treatment-resistant major depressive disorder (64% female, mean MADRS 32.4, mean 3.8 prior antidepressant failures) from two academic psychiatry centers |
| Intervention | Ketamine |
| Dose | sub-anesthetic |
| Duration | 14-day follow-up after a single infusion |
| Measures | MADRS, fMRI AMPA/NMDA receptor ratio |
| Topics | Depression Esketamine Ketamine |
| Key findings | A single sub-anesthetic ketamine infusion produced response (at least 50% MADRS reduction) in 74.2% of participants at 24 hours, with 42.4% maintaining response at 14 days. Baseline fMRI AMPA/NMDA receptor ratio was the strongest predictor of 14-day response (r=0.58, AUC 0.78). The authors propose that ketamine acts via NMDA receptor antagonism, AMPA receptor upregulation, and BDNF-mTOR-dependent synaptogenesis. |
Abstract
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.
Comparable studies
Other non-randomized and open-label trials on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Rapid Resolution of Suicidal Ideation After a Single Infusion of anN-Methyl-D-Aspartate Antagonist in Patients With Treatment-Resistant Major Depressive Disorder Subjects with DSM-IV-diagnosed treatment-resistant major depressive disorder | 2010 | Open-label trial | n = 33 |
| Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression Adults (≥ 18 years) with treatment-resistant depression | 2020 | Phase 3, open-label, multicenter, long-term study | n = 802 |
| Intravenous arketamine for treatment-resistant depression: open-label pilot study Humans with treatment-resistant depression | 2020 | Open-label pilot trial | n = 7 |
| A Phase 2 Open Label Study of Efficacy, Safety, and Tolerability of SLS-002 (Intranasal Racemic Ketamine) in Adults with MDD at Imminent Risk of Suicide. Hospitalized patients with Major Depressive Disorder and acute suicidal ideation and... | 2024 | Open label study | n = 17 |
| Ketamine Safety and Tolerability in Clinical Trials for Treatment-Resistant Depression Participants with DSM-IV-defined major depressive disorder and treatment-resistant... | 2014 | Pooled analysis of three clinical trials | n = 97 |