Han La

Background:   Major depressive disorder (MDD) and treatment-resistant depression (TRD) represent significant global health burdens, with conventional antidepressants often failing to produce rapid or sustained relief¹. Ketamine, an NMDA receptor antagonist, has garnered considerable attention for its rapid-onset and potent antidepressant and antisuicidal effects². Despite its growing clinical use, the molecular mechanisms underlying these powerful effects remain incompletely characterized. Emerging evidence implicates several pathways, including autophagy regulation, inflammasome signaling, neuroinflammatory pathways, and synaptic plasticity as central mediators of ketamine’s rapid acting and potent therapeutic profile.

Objective: This review aims to synthesize the current mechanistic evidence surrounding ketamine’s antidepressant, neuroprotective, and anti-inflammatory effects. More specifically, particular focus was placed on the complex interplay between the AMPK/mTOR axis, HMGB1-RAGE signaling, NLRP3 inflammasome suppression, and AMPAR-BDNF-mTORC1-D3R neuroplasticity pathways.

Research Methods: A literature search was conducted in the PubMed database using the following terms: “ketamine,” “antidepressant mechanism,” “autophagy,” “mTOR,” “NLRP3 inflammasome,” “HMGB1-RAGE,” and “neuroplasticity,”. Studies were selected based on relevance to ketamine’s molecular mechanisms in preclinical and clinical models. Five primary sources published between 2018 and 2022 were included, comprising in vivo murine models, in vitro cellular studies, and a randomized controlled human trial.

Results: The reviewed studies collectively support a multi-pathway model of ketamine’s action. It is demonstrated that ketamine activates AMPK and inhibits mTOR phosphorylation in LPS-induced acute lung injury, enhancing autophagy and reducing apoptosis in alveolar epithelial cells³. Additionally, studies also showed that sub-anesthetic ketamine upregulates autophagy flux, which in turn suppresses NLRP3 inflammasome components (NLRP3, ASC, caspase-1) and restores BDNF-mediated neuroplasticity in a chronic restraint stress model; whereas co-administration of the autophagy inhibitor Baf A1 blocked these effects⁴. The HMGB1-RAGE axis also acts as a critical upstream regulator⁵. Studies find that ketamine prevents HMGB1 translocation and RAGE upregulation, thereby unblocking lysosomal dysfunction-driven autophagy flux impairment and shifting microglial polarization from M1 to M2 states⁵. Comprehensively, an established a downstream neuroplasticity pathway in dopaminergic neurons was outlined, where NMDAR blockade leads to AMPAR activation, subsequent BDNF release, TrkB engagement, and D3R-dependent PI3K-mTORC1 activation, culminating in dendritic arborization². Moreover, a clinical trial confirmed ketamine’s rapid antisuicidal effect peaking at 24 hours post-infusion in TRD patients, though adjunctive rapamycin-mediated mTORC1 inhibition did not significantly extend this benefit⁶.

Conclusion: Ketamine exerts its therapeutic effects through convergent regulation of autophagy, neuroinflammation, and synaptic plasticity. The AMPK/mTOR, HMGB1-RAGE, and NLRP3 pathways collectively mediate its anti-inflammatory and antidepressant properties, while AMPAR-BDNF-mTORC1-D3R signaling underlies structural neuroplasticity and further enhancing its antidepressant effects. These findings support ketamine as a mechanistically rich compound and highlight autophagy flux restoration and D3R signaling as promising targets for next-generation antidepressant development.

Work Cited

1. Aref SK, Habib MZ, Eid DM, et al. Cognitive and psychotic effects of ketamine “short- vs. long-term” therapy in a rat model of depression: Hippocampal TrkB/Akt/GSK-3β/mTOR/autophagy trajectories. Prog Neuropsychopharmacol Biol Psychiatry. 2025;142:111503. doi:10.1016/j.pnpbp.2025.111503
2. Cavalleri L, Merlo Pich E, Millan MJ, et al. Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling. Mol Psychiatry. 2018;23(4):812-823. doi:10.1038/mp.2017.241
3. Cao J, Mai H, Chen Y, et al. Ketamine Promotes LPS-Induced Pulmonary Autophagy and Reduces Apoptosis through the AMPK/mTOR Pathway. Contrast Media Mol Imaging. 2022;2022:8713701. doi:10.1155/2022/8713701
4. Lyu D, Wang F, Zhang M, et al. Ketamine induces rapid antidepressant effects via the autophagy-NLRP3 inflammasome pathway. Psychopharmacology (Berl). 2022;239(10):3201-3212. doi:10.1007/s00213-022-06201-w
5. Wu M, Zhao L, Wang Y, et al. Ketamine Regulates the Autophagy Flux and Polarization of Microglia through the HMGB1-RAGE Axis and Exerts Antidepressant Effects in Mice. J Neuropathol Exp Neurol. 2022;81(11):931-942. doi:10.1093/jnen/nlac035
6. Averill LA, Averill CL, Gueorguieva R, et al. mTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression. J Affect Disord. 2022;303:91-97. doi:10.1016/j.jad.2022.01.104