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

Abbreviations

BDNF

brain‐derived neurotrophic factor

CPP

conditioned place preference

CSDS

chronic social defeat stress

FST

forced swim test

HNK

hydroxynorketamine

LMA

locomotor activity

MDD

Major depressive disorder

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 treatment‐resistant 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 antidepressant‐like 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 antidepressant‐like 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 indicates (S)‐ketamine is more potent at NMDA receptors, these findings question the role of NMDA receptor antagonism in the antidepressant‐like effects of ketamine. Moreover, these results also suggest that (R)‐ketamine may be a safer compound to use in clinical populations, but it is not totally devoid of safety concerns.

Second, Zanos, Highland, Liu, et al., 2019 and Zanos et al., 2016 examined the underlying mechanisms responsible for ketamine's unique antidepressant effects. Zanos et al. (2016) demonstrated that the metabolites for (R,S)‐ketamine, (2S,6S;2R,6R)‐hydroxynorketamine (HNK), played a role in the sustained antidepressant‐like effects of ketamine by deuterating (R,S)‐ketamine at the C6 position, rendering ketamine metabolically inert—thus, preventing conversion of ketamine to (2R,6R)‐ketamine. Moreover, (2R,6R)‐HNK, an active metabolite of (R)‐ketamine, was found to be ~2.5 times more potent and produced sustained antidepressant‐like effects as compared to (2S,6S)‐HNK, an active metabolite of (S)‐ketamine. The present study (Zanos, Highland, Liu, et al., 2019) reported that (R)‐ketamine displayed greater antidepressant potency than that of a deuterated version of (R)‐ketamine, indicating that the (2R,6R)‐HNK metabolite plays a role in the potency and possibly the sustained antidepressant‐like effects of (R)‐ketamine. Importantly, therapeutically relevant concentrations of (2R,6R)‐HNK do not bind to or directly inhibit NMDA receptors or activate α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors (Lumsden et al., 2019; Shaffer et al., 2019). The antidepressant‐like effects associated with the (2R,6R)‐HNK are likely dependent upon synaptogenesis caused by increased AMPA receptor activity, brain‐derived neurotrophic factor (BDNF) release, mGlu₂ receptor inhibition, and/or other downstream signaling pathways such as mechanistic target of rapamycin (mTOR). For example, the AMPA receptor antagonist NBQX and mGlu₂ receptor agonist LY379268 attenuate the antidepressant‐like effects of (R,S)‐ketamine, (R)‐ketamine, (S)‐ketamine, and (2R,6R)‐HNK (Chou et al., 2018; Fukumoto et al., 2019; Yang et al., 2015; Zanos et al., 2016; Zanos, Highland, Stewart, et al., 2019). Additionally, (2R,6R)‐HNK does not produce abuse‐related effects up to concentrations 25 times greater than antidepressant doses, and it failed to substitute for (R,S)‐ketamine in the drug discrimination or self‐administration paradigms (Zanos et al., 2016). This reduction in abuse liability can be attributed to the inability of (2R,6R)‐HNK to bind or inhibit NMDA receptors (Lumsden et al., 2019; Shaffer et al., 2019; Zanos et al., 2016).

To date, four different research groups have published data demonstrating that (2R,6R)‐HNK produces rapid and/or sustained antidepressant‐like effects across a number of preclinical models that include forced swim test (FST), learned helplessness, novelty suppressed feeding, chronic restraint stress, and chronic social defeat stress (CSDS; Chou et al., 2018; Fukumoto et al., 2019; Highland et al., 2018; Lumsden et al., 2019; Pham et al., 2018; Zanos et al., 2016; Zanos, Highland, Liu, et al., 2019; Zanos, Highland, Stewart, et al., 2019). The Hashimoto and Chaki research group, however, has failed to replicate these antidepressant‐like effects of (2R,6R)‐HNK but have demonstrated antidepressant‐like effects of (R)‐ketamine in their studies (Shirayama & Hashimoto, 2018; Xiong et al., 2019; Yamaguchi et al., 2018; Yang et al., 2017; Zhang, Fujita, & Hashimoto, 2018). One possible explanation for these findings may be related to the limited dose range (typically a single dose) and behavioural assays used by the Hashimoto/Chaki group. First, the Hashimoto/Chaki group in all but one paper has tested only 10 mg·kg⁻¹ (2R,6R)‐HNK. While 10 mg·kg⁻¹ (2R,6R)‐HNK has been shown to produce antidepressant‐like effects in the standard models above, it is possible that there is a shift in the potency of (2R,6R)‐HNK in their studies that typically use a CSDS model that is followed by the tail suspension test, FST, and sucrose preference test as the dependent variables, such that 10 mg·kg⁻¹ (2R,6R)‐HNK does not produce antidepressant effects. (2R,6R)‐HNK (10 mg·kg⁻¹) has been shown to produce antidepressant‐like effects in a CSDS model when susceptibility was confirmed and social interaction was the dependent variable (Zanos et al., 2016). Additionally, the Hashimoto/Chaki group failed to find antidepressant‐like effects of (2R,6R)‐HNK in lipopolysaccharide‐induced depression of FST in mice (10 mg·kg⁻¹) and learned helplessness in rats (20 and 40 mg·kg⁻¹). We would urge the Hashimoto/Chaki group to test a full (2R,6R)‐HNK dose effect curve in these models, as well as in multiple depression models that have been reported to show positive results. This would help determine if the lack of antidepressant‐like effects of (2R,6R)‐HNK by this group is dose or model specific or something else. Together, these conflicting reports provide more evidence for using full dose effect curves and multiple behavioural models in each manuscript rather than relying on one dose or model. It is important to note that the Hashimoto/Chaki research group and the Gould research group each hold patents for (R)‐ketamine and (2R,6R)‐HNK/(2S,6S)‐HNK, respectively.

To date, these studies provide strong evidence that both (R)‐ketamine and (2R,6R)‐HNK metabolite may have potential as therapeutically efficacious drugs for treatment‐resistant patients. However, the present study by Zanos, Highland, Liu, et al. (2019) and studies from other labs strongly suggest that the (2R,6R)‐HNK metabolite may represent the best clinical drug candidate out of the ketamine family (i.e., (S)‐ketamine, (R)‐ketamine, and (2S,6S)‐HNK), as (2R,6R)‐HNK provides the largest therapeutic window and does not inhibit NMDA receptors (which is thought to be responsible for the psychotomimetic effects). The recent approval of (S)‐ketamine (Spravato™; esketamine) by the United States Food and Drug Administration (FDA) in March 2019, for treatment‐resistant patients raises some concerns, as data from several laboratories indicate that (S)‐ketamine is less potent at producing antidepressant effects and has a higher potential for abuse liability than (R)‐ketamine or (2R,6R)‐HNK. There was little to no evidence provided to the FDA (based on available documentation) that the (S)‐ketamine enantiomer or route of administration (intranasal) reduced the abuse liability. While we understand that there is a need to help treatment‐resistant patients, scientific evidence should be the basis of these decisions.

1.1. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 (Alexander, Christopoulos et al., 2017; Alexander, Fabbro et al., 2017; Alexander, Peters et al., 2017).

Hillhouse TM, Rice R, Porter JH. What role does the (2R,6R)‐hydronorketamine metabolite play in the antidepressant‐like and abuse‐related effects of (R)‐ketamine? Br J Pharmacol. 2019;176:3886–3888. 10.1111/bph.14785