Mechanisms of ketamine and its metabolites as antidepressants

Abstract

Treating major depression is a medical need that remains unmet by monoaminergic therapeutic strategies that commonly fail to achieve symptom remission. A breakthrough in the treatment of depression was the discovery that the anesthetic (R,S)-ketamine (ketamine), when administered at sub-anesthetic doses, elicits rapid (sometimes within hours) antidepressant effects in humans that are otherwise resistant to monoaminergic-acting therapies. While this finding was revolutionary and led to the FDA approval of (S)-ketamine (esketamine) for use in adults with treatment-resistant depression and suicidal ideation, the mechanisms underlying how ketamine or esketamine elicit their effects are still under active investigation. An emerging view is that metabolism of ketamine may be a crucial step in its mechanism of action, as several metabolites of ketamine have neuroactive effects of their own and may be leveraged as therapeutics. For example, (2R,6R)-hydroxynorketamine (HNK), is readily observed in humans following ketamine treatment and has shown therapeutic potential in preclinical tests of antidepressant efficacy and synaptic potentiation while being devoid of the negative adverse effects of ketamine, including its dissociative properties and abuse potential. We discuss preclinical and clinical studies pertaining to how ketamine and its metabolites produce antidepressant effects. Specifically, we explore effects on glutamate neurotransmission through N-methyl D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), synaptic structural changes via brain derived neurotrophic factor (BDNF) signaling, interactions with opioid receptors, and the enhancement of serotonin, norepinephrine, and dopamine signaling. Strategic targeting of these mechanisms may result in novel rapid-acting antidepressants with fewer undesirable side effects compared to ketamine.

Keywords: (2R,6R)-Hydroxynorketamine; Antidepressant; Depression; Glutamate; Ketamine; NMDAR.

Figure 1:. Ketamine metabolism.

A, B) The (S) and (R) enantiomers of ketamine are rapidly and stereoselectively metabolized by liver P450 enzymes to produce their respective norketamine enantiomer via demethylation of the methyl amine and then hydroxylation of the cyclohexanone ring to produce the hydroxynorketamines (HNKs). The production of dehydroxynorketamine from norketamine is not shown as the dehydroxynorketamines do not appear to cross the blood brain barrier (Can et al., 2016). C) The HNKs (12 in total) are named based on the positioning of hydroxyl group on the cyclohexanone ring and stereochemistry of the hydroxyl and amino groups. For example, (2R,6S)-HNK denotes on the cyclohexanone ring the amino group positioned at carbon 2 in the R configuration and a hydroxyl group at carbon 6 in the S configuration. *Denotes location of a stereocenter.

Figure 2:. Model glutamatergic synapse in the prefrontal cortex (PFC) highlighting the mechanisms of ketamine action.

The actions of ketamine and its (2R,6R)-HNK metabolite have diverse actions on multiple neurotransmitter systems. Antagonism of NMDARs in GABAergic interneurons leads to a disinhibition of excitatory output due to a reduction in GABA release. Antagonism of NMDARs that prevents phosphorylation of the GluA1 subunit of AMPARs, may enhance AMPAR signaling through permitting AMPAR exchange between synaptic and extrasynaptic domains. Enhanced monoaminergic input produced by ketamine and/or (2R,6R)-HNK increases AMPAR phosphorylation at GluA1 S845 and S831 which facilitates membrane insertion, synaptic localization, and channel conductance. The BDNF receptor TrkB signals through mTOR to increase the expression of key synaptic structure proteins such as PSD95 and GluA1. Ketamine and (2R,6R)-HNK can both directly bind and activate TrkB. VTA, ventral tegmental area; DRN, dorsal raphe nucleus; LC, locus coeruleus; EPSCs, excitatory postsynaptic currents; APs, action potentials; PV, parvalbumin; PSD95, postsynaptic density-95; BDNF, brain-derived neurotrophic factor; AR, adrenergic receptor; mGluR2, metabotropic glutamate receptor 2; D1R, dopamine receptor 1; HNK, hydroxynorketamine; TrkB, tropomyosin receptor kinase B; 5-HTR, serotonin receptor; mTOR, mechanistic target of rapamycin.