Ketamine, a racemic mixture consisting of ()- and ()-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine's pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of -methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high-frequency correlated activity in mood-relevant regions of the forebrain. Negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses. Because α5 subunits display a restricted expression in the forebrain, we predicted that α5 GABA-NAMs would produce activation of principle neurons but exert fewer side effects than ketamine. We tested this hypothesis in male mice and observed that the α5 GABA-NAM MRK-016 exerted an antidepressant-like response in the forced swim test at 1 and 24 h after administration and an anti-anhedonic response after chronic stress in the female urine sniffing test (FUST). Like ketamine, MRK-016 produced a transient increase in EEG γ power, and both the increase in γ power and its antidepressant effects in the forced swim test were blocked by prior administration of the AMPA-type glutamate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Unlike ketamine, however, MRK-016 produced no impairment of rota-rod performance, no reduction of prepulse inhibition (PPI), no conditioned-place preference (CPP), and no change in locomotion. α5 GABA-NAMs, thus reproduce the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor (AMPAR)-dependent increase in coherent neuronal activity, but display fewer potential negative side effects. These compounds thus demonstrate promise as clinically useful fast-acting antidepressants.

Currently approved antidepressant drugs often take months to take full effect, and ∼30% of depressed patients remain treatment resistant. In contrast, ketamine, when administered as a single subanesthetic dose, exerts rapid and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant drug candidate with limited dissociation properties and abuse potential. We assessed the role of group II metabotropic glutamate receptor subtypes 2 (mGlu 2 ) and 3 (mGlu 3 ) in the antidepressant-relevant actions of (2R,6R)-HNK using behavioral, genetic, and pharmacological approaches as well as cortical quantitative EEG (qEEG) measurements in mice. Both ketamine and (2R,6R)-HNK prevented mGlu 2/3 receptor agonist (LY379268)induced body temperature increases in mice lacking the Grm3, but not Grm2, gene. This action was not replicated by NMDA receptor antagonists or a chemical variant of ketamine that limits metabolism to (2R,6R)-HNK. The antidepressant-relevant behavioral effects and 30-to 80-Hz qEEG oscillation (gamma-range) increases resultant from (2R,6R)-HNK administration were prevented by pretreatment with an mGlu 2/3 receptor agonist and absent in mice lacking the Grm2, but not Grm3 −/− , gene. Combined subeffective doses of the mGlu 2/3 receptor antagonist LY341495 and (2R,6R)-HNK exerted synergistic increases on gamma oscillations and antidepressant-relevant behavioral actions. These findings highlight that (2R,6R)-HNK exerts antidepressant-relevant actions via a mechanism converging with mGlu 2 receptor signaling and suggest enhanced cortical gamma oscillations as a marker of target engagement relevant to antidepressant efficacy. Moreover, these results support the use of (2R,6R)-HNK and inhibitors of mGlu 2 receptor function in clinical trials for treatment-resistant depression either alone or in combination. ketamine | hydroxynorketamine | antidepressant | mGlu 2 receptor |

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.

Background: (R,S)-ketamine has gained attention for its rapid-acting antidepressant actions in patients with treatment-resistant depression. However, widespread use of ketamine is limited by its side effects, abuse potential, and poor oral bioavailability. The ketamine metabolite, (2R,6R)hydroxynorketamine, exerts rapid antidepressant effects, without ketamine's adverse effects and abuse potential, in rodents. Methods: We evaluated the oral bioavailability of (2R,6R)-hydroxynorketamine in three species (mice, rats, and dogs) and also evaluated five candidate prodrug modifications for their capacity to enhance the oral bioavailability of (2R,6R)-hydroxynorketamine in mice. Oral administration of (2R,6R)hydroxynorketamine was assessed for adverse behavioral effects and for antidepressant efficacy in the mouse forced-swim and learned helplessness tests. Results: (2R,6R)-hydroxynorketamine had absolute bioavailability between 46-52% in mice, 42% in rats, and 58% in dogs. Compared to intraperitoneal injection in mice, the relative oral bioavailability of (2R,6R)-hydroxynorketamine was 62%, which was not improved by any of the candidate prodrugs tested. Following oral administration, (2R,6R)-hydroxynorketamine readily penetrated the brain, with brain to plasma ratios between 0.67-1.2 in mice and rats. Oral administration of (2R,6R)-hydroxynorketamine to mice did not alter locomotor activity or precipitate behaviors associated with discomfort, sickness, or stereotypy up to a dose of 450 mg/kg. Oral (2R,6R)-hydroxynorketamine reduced forced-swim test immobility time (15-150 mg/kg) and reversed learned helplessness (50-150 mg/kg) in mice. Conclusions: These results demonstrate that (2R,6R)-hydroxynorketamine has favorable oral bioavailability in three species and exhibits antidepressant efficacy following oral administration in mice.

The following authors declare competing financial interests: R.M. and C.A.Z. are listed as co-inventors on a patent for the use of (2R,6R)hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro-and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain. P.Z., R.M., P.M., C.T., C.A.Z., and T.G. are listed as co-inventors on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. R.M., P.M., C.A.Z., and C.T. have assigned their patent rights to the United States government but will share a percentage of any royalties that may be received by the government. P.Z. and T.G. have assigned their patent rights to the University of Maryland Baltimore but will share a percentage of any royalties that may be received by the University of Maryland Baltimore. T.D.G. has received research funding from Allergan and Roche Pharmaceuticals and has served as a consultant for FSV7, LLC, during the preceding 3 years. All other authors declare no competing interests.

No abstract

Stress is a leading risk factor for the onset and recurrence of major depression. Enhancing stress resilience may be a therapeutic strategy to prevent the development of depression in at-risk populations or its recurrence in depressed patients. Group II metabotropic glutamate receptor (mGlu 2/3) antagonists have been recognized for antidepressant-like actions in preclinical models, but have not been evaluated for prophylactic effects. We assessed the role of mGlu 2/3 in modulating stress resilience using subtypespecific knockout mice lacking mGlu 2 (Grm2 −/−) or mGlu 3 (Grm3 −/−), and pharmacological manipulations of mGlu 2/3 activity during or prior to the induction and reinstatement of stress-induced behavioral deficits. Grm2 −/− , but not Grm3 −/− , mice exhibited reduced forced-swimming test immobility time and were resilient to developing inescapable shock (IES)-induced escape deficits. Grm2 −/− mice were also resilient to developing corticosterone (CORT)-induced escape deficits and chronic social defeat stressinduced anhedonia. Pharmacological blockade of mGlu 2/3 with the antagonist LY341495 during stress prevented the development of IES-and CORT-induced escape deficits, while activation with the agonist LY379268 increased susceptibility to escape deficits. Prophylactic treatment with the LY341495, both systemically and via microinjection into the medial prefrontal cortex (mPFC), up to 7 days before IES, prevented both the induction of escape deficits and their reinstatement by brief re-exposure to IES up to 20 days after treatment. Overall, blockade of mGlu 2/3 enhanced stress resilience and deletion of mGlu 2 , but not mGlu 3 , conferred a stressresilient phenotype, indicating that prophylactic treatments reducing mGlu 2 activity may protect against stress-induced changes underlying the development or recurrence of stress-induced disorders, including depression.