(R)‐Ketamine exerts antidepressant actions partly via conversion to (2R,6R)‐hydroxynorketamine, while causing adverse effects at sub‐anaesthetic doses

Abstract

Background and Purpose (R)‐Ketamine (arketamine) may have utility as a rapidly acting antidepressant. While (R)‐ketamine has lower potency than (R,S)‐ketamine to inhibit NMDA receptors in vitro, the extent to which (R)‐ketamine shares the NMDA receptor‐mediated adverse effects of (R,S)‐ketamine in vivo has not been fully characterised. Furthermore, (R)‐ketamine is metabolised to (2R,6R)‐hydroxynorketamine (HNK), which may contribute to its antidepressant‐relevant actions. Experimental Approach Using mice, we compared (R)‐ketamine with a deuterated form of the drug (6,6‐dideutero‐(R)‐ketamine, (R)‐d2‐ketamine), which hinders its metabolism to (2R,6R)‐HNK, in behavioural tests predicting antidepressant responses. We also examined the actions of intracerebroventricularly infused (2R,6R)‐HNK. Further, we quantified putative NMDA receptor inhibition‐mediated adverse effects of (R)‐ketamine. Key Results (R)‐d2‐Ketamine was identical to (R)‐ketamine in binding to and functionally inhibiting NMDA receptors but hindered (R)‐ketamine's metabolism to (2R,6R)‐HNK. (R)‐Ketamine exerted greater potency than (R)‐d2‐ketamine in several antidepressant‐sensitive behavioural measures, consistent with a role of (2R,6R)‐HNK in the actions of (R)‐ketamine. There were dose‐dependent sustained antidepressant‐relevant actions of (2R,6R)‐HNK following intracerebroventricular administration. (R)‐Ketamine exerted NMDA receptor inhibition‐mediated behaviours similar to (R,S)‐ketamine, including locomotor stimulation, conditioned‐place preference, prepulse inhibition deficits, and motor incoordination, with approximately half the potency of the racemic drug. Conclusions and Implications Metabolism of (R)‐ketamine to (2R,6R)‐HNK increases the potency of (R)‐ketamine to exert antidepressant‐relevant actions in mice. Adverse effects of (R)‐ketamine require higher doses than those necessary for antidepressant‐sensitive behavioural changes in mice. However, our data revealing that (R)‐ketamine's adverse effects are elicited at sub‐anaesthetic doses indicate a potential risk for sensory dissociation and abuse liability.

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

“…These findings suggest that production of (2 R ,6 R )‐HNK from ( R,S )‐ketamine is not essential for the antidepressant effects of ( R,S )‐ketamine (or ( R )‐ketamine). A recent study by Zanos et al . demonstrated that ( R )‐ketamine may exert antidepressant actions partly via conversion to (2 R ,6 R )‐HNK.…”

“…demonstrated that ( R )‐ketamine may exert antidepressant actions partly via conversion to (2 R ,6 R )‐HNK. Thus, the word essential was changed to the word partly in their conclusion …”

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

“…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 ).…”

“…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.…”

“…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.…”