Beyond NMDA Receptors: A Narrative Review of Ketamine's Rapid and Multifaceted Mechanisms in Depression Treatment

Abstract

The rising prevalence of depression, with its associated suicide risk, demands effective fast-acting treatments. Ketamine has emerged as promising, demonstrating rapid antidepressant effects. While early studies show swift mood improvements, its precise mechanisms remain unclear. This article aims to compile and synthesize the literature on ketamine's molecular actions. Ketamine primarily works by antagonizing NMDA receptors, reducing GABAergic inhibition, and increasing glutamate release. This enhanced glutamate activates AMPA receptors, triggering crucial downstream cascades, including BDNF-TrkB and mTOR pathways, promoting synaptic proliferation and regeneration. Moreover, neuroimaging studies have demonstrated alterations in brain networks involved in emotional regulation, including the Default Mode Network (DMN), Central Executive Network (CEN), and Salience Network (SN), which are frequently disrupted in depression. Despite the promising findings, the literature reveals significant inaccuracies and gaps in understanding the full scope of ketamine's therapeutic potential. For instance, ketamine engages with opioid receptors, insinuating a permissive role of the opioid system in amplifying ketamine's antidepressant effects, albeit ketamine does not operate as a direct opioid agonist. Further exploration is requisite to comprehensively ascertain its safety profile, long-term efficacy, and the impact of genetic determinants, such as BDNF polymorphisms, on treatment responsiveness.

Keywords: BDNF; NMDA antagonist; antidepressant; depression; ketamine; mechanism of action; neuroplasticity; opioid system; triple network dysfunction.

Figure 1

Flowchart of search strategy. * Due to frequent gaps in the PubMed database regarding selected molecular aspects, we included older studies if, after consultation between three authors, the study was deemed crucial (three authors indicated “yes” during the inclusion voting (“yes” or “no”). Additionally, we used ResearchGate for topics that were not sufficiently covered by data exclusively from PubMed. ** In this step, despite excluding studies that did not meet our inclusion criteria, we removed duplicate studies missed by the automated tool.

Figure 2

Pathway of 1 phase ketamine metabolism. Ketamine (both isomers) is metabolized through N-demethylation by liver cytochrome P450 enzymes (primarily by CYP3A4 and CYP2B6), resulting in the formation of norketamine. Norketamine is then mainly converted by CYP2B6, CYP3A5 and CYP2A6 through hydroxylation to hydroxynorketamine (right path) and by CYP2B6 through dehydrogenation to dehydronorketamine (left path).

Figure 3

Ketamine blocks NMDA receptors on GABA-releasing interneurons (A), reducing GABA release from presynaptic glutamatergic neuron (B). Reduction in HCN1 activity promotes increased glutamate release. Glutamate activates AMPA receptors at a postsynaptic neuron (C), which initiates a cascade of intracellular events involving the mTOR pathway, elevating BDNF levels. The activation of mTOR is linked to increased phosphorylation of the proteins 4E-BP1 and p70S6K. Elevated BDNF levels activate TrkB receptors, activating TRPC3 through the TrkB-PLCγ pathway. Additionally, BDNF indirectly triggers rapid activation of the PI3K-Akt pathway, stabilizing the interaction between PSD-95 and TrkB to facilitate synaptic connectivity. TrkB modulates NMDA receptor activity by dissociating RasGrf1 from NR2B, reducing NMDA receptor signaling associated with LTD. Blockade of NMDA receptors also reduces phosphorylation of eEF2, which, in turn, enhances BDNF expression. Akt activation further influences cellular processes by inhibiting the TSC2 protein, releasing mTORC1 from regulatory constraints, and enhancing mTORC1 signaling. (2R,6R)-HNK dissociates TrkB from PTPσ, restoring juvenile-like plasticity in the brain. Additionally, ketamine administration restores GLT-1 levels in astrocytes (D), supporting glutamate reuptake and regulation. Activation of the ERα receptor initiates a positive feedback loop in which ketamine enhances the effects of its metabolites by increasing the activity of the enzymes CYP2A6 and CYP2B6.