Beyond Ketamine: New Approaches to the Development of Safer Antidepressants

Abstract

Background: Ketamine has been reported to exert rapid and sustained antidepressant effects in patients with depression, including patients with treatment-resistant depression. However, ketamine has several drawbacks such as psychotomimetic/dissociative symptoms, abuse potential and neurotoxicity, all of which prevent its routine use in daily clinical practice.

Methods: Therefore, development of novel agents with fewer safety and usage concerns for the treatment of depression has been actively investigated. From this standpoint, searching for active substances (stereoisomers and metabolites) and agents acting on the N-methyl-D-aspartate (NMDA) receptor have recently gained much attention.

Results: The first approach includes stereoisomers of ketamine, (R)-ketamine and (S)-ketamine. Although (S)-ketamine has been considered as the active stereoisomer of racemic ketamine, recently, (R)-ketamine has been demonstrated to exert even more prolonged antidepressant effects in animal models than (S)-ketamine. Moreover, ketamine is rapidly metabolized into several metabolites, and some metabolites are speculated as being active substances exerting antidepressant effects. Of such metabolites, one in particular, namely, (2R,6R)-hydroxynorketamine, has been reported to be responsible for the antidepressant effects of ketamine. The second approach includes agents acting on the NMDA receptor, such as glycine site modulators and GluN2B subunit-selective antagonists. These agents have been tested in patients with treatment-resistant depression, and have been found to exhibit rapid antidepressant effects like ketamine.

Conclusion: The above approaches may be useful to overcome the drawbacks of ketamine. Elucidation of the mechanisms of action of ketamine may pave the way for the development of antidepressant that are safer, but as potent and rapidly acting as ketamine.

Keywords: (R)-ketamine; (S)-ketamine; 7-chlorokinurenic acid; GLYX-13; GluN2B; Ketamine; hydroxynorketamine; mGlu receptor..

Fig. (1)

Proposed mechanisms of actions of ketamine, its stereoisomers and their metabolites. Ketamine, its stereoisomers and its metabolites (norketamine and hydroxynorketamine) show different affinity for the NMDA receptor. Both racemic ketamine and (S)-ketamine have been proposed to exert antidepressant effects through blockade of the NMDA receptor, presumably on the GABA interneurons, followed by stimulation of the AMPA receptor. Both (R)-ketamine and HNKs show lower or very weak affinity for the NMDA receptor; therefore, it would appear that they stimulate the AMPA receptor through mechanisms other than NMDA receptor blockade. In any case, AMPA receptor stimulation leads to increase in synaptogenesis via BDNF/TrkB signaling, to exert rapid and sustained antidepressant activity. HNK: hydroxynorketamine.

Fig. (2)

Proposed metabolic pathways of racemic ketamine. Racemic ketamine is stereoselectively metabolized into various metabolites by multiple cytochrome P450 enzymes. Among these, ketamine, norketamine, (2S,6S;2R,6R)-HNK and their stereoisomers have been proposed to have antidepressant effects. DHNK: dehydroxynorketamine, HK: hydroxyketamine, HNK: hydroxynorketamine.

Fig. (3)

Sites of actions of agents acting on the NMDA receptor. NMDA receptors are tetramers composed of two GluN1 and two GluN2 subunits (GluN2A-GluN2D). Of these, it has been suggested that agents which selectively block the GluN2B subunit-containing NMDA receptor would be devoid of the side effects of ketamine. Similarly, despite acting on the same site of the NMDA receptor channel pore as ketamine, low trapping antagonists such as lanicemine may reduce the side effects of ketamine. Moreover, the NMDA receptor has a glycine modulatory site on GluN1, and agents acting on the glycine modulatory site may also be devoid of the side effects of ketamine. Despite the different sites of actions, these agents have been reported to mediate AMPA receptor stimulation to exert antidepressant effects.

Fig. (4)

Proposed mechanisms of actions of agents acting at the glycine modulatory site on NMDA receptor. Sarcosine, GLYX-13 and 7-CTKA, either directly or indirectly, act at the glycine modulatory site as an agonist, partial agonist and antagonist, respectively. Sarcosine indirectly stimulates the glycine modulatory site by increasing synaptic glycine level via inhibiting glycine transporter 1. Both GLYX-13 and 7-CTKA stimulate the AMPA receptor, although precise mechanisms underlying stimulation of AMPA receptor activity have not been elucidated. While sarcosine indirectly stimulates the glycine modulatory site, it also stimulates transmission at the AMPA receptor, presumably via inducing membrane translocation of GluR1. Therefore, these three agents, despite acting on the glycine modulatory site via different mechanisms, converge at increasing AMPA receptor stimulation to exert antidepressant effects. Of note, very recently, GLYX-13 has been reported to exhibit co-agonist properties at the NMDA receptor independent of the glycine modulatory sites [61], and now they claimed GLYX-13 as an NMDA receptor modulator. 7-CTKA: 7-chlorokynurenic acid.

Fig. (5)

Shared neural mechanisms of mGlu2/3 receptor antagonists and ketamine. The mGlu2/3 receptor antagonists increase glutamate release through blockade of the autoreceptor expressed at the glutamatergic terminals, while ketamine increases glutamate release, presumably by causing disinhibition of the pyramidal neurons via blockade of the NMDA receptor on the GABA interneurons. Increased glutamate release then stimulates the postsynaptic AMPA receptor, leading to BDNF/TrkB and mTOR signaling in the mPFC, eventually resulting in increased synaptogenesis.