KETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID-ACTING ANTIDEPRESSANTS

Abstract

Major depressive disorder (MDD) is a common and debilitating psychiatric disorder. Traditional antidepressants are of limited efficacy and take weeks to months to yield full therapeutic effects. Thus, there is a clear need for effective rapid-acting antidepressant medications. The N-methyl-d-aspartate receptor (NMDA-R) antagonist, ketamine, has received a great deal of attention over the last 20 years due to the discovery that a single subanesthetic dose leads to a rapid antidepressant effect in individuals with treatment-resistant depression. Animal and human research suggest that ketamine's antidepressant effects are mediated by a glutamate surge that leads to a cascade of events that result in synaptogenesis and reversal of the negative effects of chronic stress and depression, particularly within the prefrontal cortex (PFC). Preclinical and clinical data have provided compelling insights into the mechanisms underlying the rapid-acting antidepressant effects of ketamine. This review discusses stress-related neurobiology of depression and the safety, tolerability, and efficacy of ketamine for MDD, along with a review of ketamine's mechanism of action and prospective predictors of treatment response. Research limitations and future clinical prospects are also discussed.

Keywords: antidepressants; biological markers; depression; stress; treatment resistance.

Figure 1. A schematic model depicting stress-induced neuronal atrophy and its normalization following ketamine treatment

Chronic stress causes excess extracellular glutamate, and subsequent excitoxicity, leading to dendritic retraction, reduced dendritic arborization and spine density (A & B). Twenty-four hours post-treatment, subanesthetic dose of ketamine reverses the chronic stress-induced structural deficits culminating in rapid increases in spine density (C & D).

Figure 2. Mechanism of action of ketamine’s rapid antidepressant effects

It is proposed that subanesthetic doses of ketamine will simultaneously activate the “GO”, and inhibits the “STOP”, pathways. The ketamine-induced alterations of both pathways converge to increase BDNF, protein synthesis, synaptic strength, and synaptogenesis. In this model, ketamine activates the “GO” pathway by A-1) preferentially blocking of NMDA receptors located on a subpopulation of interneurons, A-2) disinhibiting pyramidal neurons, A-3) generating a transient glutamate surge and AMPA receptors activation, A-4) stimulating BDNF release, A-5) activating TrkB receptors, A-6) stimulating the mTORC1 signaling, A-7) inducing BDNF translation, and A-8) increasing protein synthesis, AMPA cycling, and synaptogenesis. In parallel, ketamine blocks the “STOP” pathway by B-1) blocking extrasynaptic NMDA receptors, B-2) disinhibiting eEF2, B-3) inducing BDNF translation, and B-4) increasing protein synthesis, AMPA cycling, and synaptogenesis. Abbreviations: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA); brain derived neurotrophic factor (BDNF); mammalian target of rapamycin complex 1 (mTORC1); Tyrosine kinase B (TrkB); eukaryotic elongation factor 2 (eEF2); N-methyl-D-aspartate (NMDA); gamma-aminobutyric acid (GABA); glutamate (Glu).