Ketamine and the Disinhibition Hypothesis: Neurotrophic Factor-Mediated Treatment of Depression

Abstract

Ketamine is a promising alternative to traditional pharmacotherapies for major depressive disorder, treatment-resistant depression, and other psychiatric conditions that heavily contribute to the global disease burden. In contrast to the current standard of care medications for these disorders, ketamine offers rapid onset, enduring clinical efficacy, and unique therapeutic potential for use in acute, psychiatric emergencies. This narrative presents an alternative framework for understanding depression, as mounting evidence supports a neuronal atrophy and synaptic disconnection theory, rather than the prevailing monoamine depletion hypothesis. In this context, we describe ketamine, its enantiomers, and various metabolites in a range of mechanistic actions through multiple converging pathways, including N-methyl-D-aspartate receptor (NMDAR) inhibition and the enhancement of glutamatergic signaling. We describe the disinhibition hypothesis, which posits that ketamine's pharmacological action ultimately results in excitatory cortical disinhibition, causing the release of neurotrophic factors, the most important of which is brain-derived neurotrophic factor (BDNF). BDNF-mediated signaling along with vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF-1) subsequently give rise to the repair of neuro-structural abnormalities in patients with depressive disorders. Ketamine's efficacious amelioration of treatment-resistant depression is revolutionizing psychiatric treatment and opening up fresh vistas for understanding the underlying causes of mental illness.

Keywords: arketamine; brain-derived growth factor; esketamine; ketamine; major depressive disorder; synaptogenesis; treatment-resistant depression.

Figure 1

Intermediates in the metabolism of ketamine enantiomers. Cytochrome P450 (CYP) enzymes in the liver N-demethylate ketamine or hydroxyketamine to produce norketamine or hydroxynorketamine, respectively. The oxidation of norketamine to produce dehydronorketamine also occurs. CYP enzymes can hydroxylate ketamine and norketamine to produce hydroxyketamine and hydroxynorketamine, respectively. (A) depicts the metabolism of (S)-ketamine (esketamine), while (B) depicts the metabolism of (R)-ketamine (arketamine). All structures are derived from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/, accessed on 3 May 2023). The overall figure is adapted from [72,73].

Figure 2

Model of the disinhibition hypothesis. A. Ketamine’s antidepressant mechanism of action primarily depends on the antagonism of NMDARs (N-methyl-D-aspartate receptors) on GABAergic interneurons preventing GABA release. B. The inhibition of GABA release prevents the inhibition of pyramidal glutamatergic neurons. This allows for the release of glutamate and the downstream effects of the subsequent glutamate surge. C. Glutamate binds to post-synaptic AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), allowing for calcium influx. D. Calcium influx leads to the calcium-dependent release of BDNF from the post-synaptic membrane. NOTE: the model shows the post-synaptic release of BDNF, though an immunofluorescent localization study has suggested that the pre-synaptic release of BDNF at the downstream synaptic cleft is involved [112]. E. Autocrine signaling of BDNF leads to downstream signaling through the MAPK, PLC-γ, and PI3K-Akt signaling pathways. The MAPK and PLC-γ pathway are primarily implicated in synaptic plasticity, while the PI3k-Akt pathway leads to anti-apoptotic signaling and cell survival. Signaling through mTORC1 has also been implicated in synaptic plasticity and neuritogenesis. NOTE: As mentioned previously, autocrine signaling is shown, but paracrine signaling may be involved based on the location of BNDF-containing vesicles in immunofluorescence studies [112]. Some graphic components from Servier Medical Art were used to draw parts of this model. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/, accessed 3 May 2023).