What role does the (2R,6R)‐hydronorketamine metabolite play in the antidepressant‐like and abuse‐related effects of (R)‐ketamine?

Abstract

Major depressive disorder (MDD) is a major health concern in which approximately 30% of patients do not response to currently approved antidepressant medications and are classified as treatment-resistant patients. The noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine produces both rapid (<24 hr) and sustained (up to several weeks) antidepressant effects in treatmentresistant patients following acute or repeated i.v. infusions of ketamine (0.5 mg·kg −1 ), a finding that has been replicated across several clinical studies. Ketamine also has demonstrated abuse liability among illicit drug users and concerns regarding the possible neurotoxic, and psychotomimetic effects have limited ketamine's clinical use (see Hillhouse & Porter, 2015). These concerns have led to the development and evaluation of ketamine's isomers and their biologically active metabolites to assess safety concerns (i.e., reduced abuse concern), and to elucidate ketamine's mechanism of action.The recent paper by Zanos, Highland, Liu, et al. (2019) aims to fill these gaps in understanding ketamine's therapeutic potential by first examining if ketamine-associated abuse liability can be reduced. The (S)-ketamine enantiomer has higher affinity for NMDA receptors and is thought to be more responsible for the abuse-related effects of ketamine, in that preclinical data have found that (S)-ketamine produces antidepressant-like effects and abuse-related effects at comparable doses. For example, while (S)-ketamine produces antidepressantlike effects across several behavioral models at 10 mg·kg −1 ; (S)-ketamine also produces conditioned place preference (CPP), increases locomotor activity (LMA), and disrupts the startle reflex at 10 mg·kg −1 (Yang et al., 2015;Yang et al., 2017;Zanos et al., 2016;Zhang, Li, & Hashimoto, 2014). Conversely, (R)-ketamine appears to have reduced abuse liability as it failed to produce CPP, increased LMA, or disruption of the startle reflex response, although it should be noted that a limited dose range (10-20 mg·kg −1 ) was tested (Yang et al., 2015). Furthermore, results indicated that (R)-ketamine produces more potent and longer acting antidepressant-like effects, producing antidepressant-like effects as low as 5 mg·kg −1 (Zanos et al., 2016; Zanos, Highland, Liu, et al., 2019). The present study (Zanos, Highland, Liu, et al., 2019) builds upon these findings by demonstrating that (R)-ketamine produces abuse-related effects at doses four to 18 times higher than the antidepressant dose (5 mg·kg −1 ), including hyperactivity (40 mg·kg −1 ), CPP (40 mg·kg −1 ), motor impairments (20-40 mg·kg −1 ), and disrupted started reflex (90 mg·kg −1 ). In sum, the (R)-and (S)-ketamine enantiomers produce both antidepressantlike and abuse-related effects; however, the therapeutic window (i.e., antidepressant-like effects vs. abuse liability) is larger, and the antidepressant-like effects are sustained for longer periods of time for (R)ketamine, compared to (S)-ketamine. Taken together, with evidence which indic...

Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers

“…In addition, (R)-ketamine seems to be a more potent and longer acting antidepressant compared to (S)-ketamine and (R/S)ketamine (Chang et al, 2019;Hashimoto, 2019;Wei et al 2020). Furthermore, different research groups demonstrated that the active metabolite (2R,6R)-hydroxynorketamine (HNK) of (R)-ketamine might play a role in the potency and the sustained antidepressant-like effects (overview in Hashimoto, 2019 andHillhouse et al, 2019). (R)-Ketamine has approximately three to four-fold lower affinity for blocking the NMDA receptor compared to (S)-ketamine and therapeutically relevant concentrations of (2R,6R)-HNK do not bind to or directly inhibit NMDA receptors (Jelen et al, 2020).…”

Effects of (2R,6R)-hydroxynorketamine in assays of acute pain-stimulated and pain-depressed behaviors in mice

“…Lastly, and most importantly, there is a documented history of (2R,6R)-HNK producing null effects (i.e. failing to produce significant effects) in assays used to measure antidepressant effects (See our commentary for more details [31][32][33][34][35].…”

Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications

“…treatment in stresssusceptible Wistar-Kyoto rats, despite restoring novel object location recognition and Schaffer collateral LTP in vivo. However, the lack of an analysis of the doseresponse relationship (i.e., testing only a single dose) in most of these studies precludes a more informed conclusion on the functional significance of these results, which contrast those from numerous other laboratories [described above; also reviewed in Hillhouse et al (2019)].…”