Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor

Abstract

The discovery of robust antidepressant actions exerted by the N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine has been a crucial breakthrough in mood disorder research. (R,S)-ketamine is a racemic mixture of equal amounts of (R)-ketamine (arketamine) and (S)-ketamine (esketamine). In 2019, an esketamine nasal spray from Johnson & Johnson was approved in the United States of America and Europe for treatment-resistant depression. However, an increasing number of preclinical studies show that arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite the lower binding affinity of arketamine for the NMDAR. In clinical trials, non-ketamine NMDAR-related compounds did not exhibit ketamine-like robust antidepressant actions in patients with depression, despite these compounds showing antidepressant-like effects in rodents. Thus, the rodent data do not necessarily translate to humans due to the complexity of human psychiatric disorders. Collectively, the available studies indicate that it is unlikely that NMDAR plays a major role in the antidepressant action of (R,S)-ketamine and its enantiomers, although the precise molecular mechanisms underlying antidepressant actions of (R,S)-ketamine and its enantiomers remain unclear. In this paper, we review recent findings on the molecular mechanisms underlying the antidepressant actions of (R,S)-ketamine and its potent enantiomer arketamine. Furthermore, we discuss the possible role of the brain–gut–microbiota axis and brain–spleen axis in stress-related psychiatric disorders and in the antidepressant-like action of arketamine. Finally, we discuss the potential of arketamine as a treatment for cognitive impairment in psychiatric disorders, Parkinson’s disease, osteoporosis, inflammatory bowel diseases, and stroke.

A Multiscale View of the Mechanisms Underlying Ketamine’s Antidepressant Effects: An Update on Neuronal Calcium Signaling

“…However, ketamine plays diverse roles in the glutamatergic pathway and other neurotransmitter systems, neurogenesis, inflammation, and even body–brain crosstalk. Furthermore, several studies have suggested the distinct roles of ketamine enantiomers ([ S ]-ketamine and [ R ]-ketamine) and their metabolites ([ 2R,6R ]-HNK and [ 2S,6S ]-HNK) in plasticity and behavior ( Zanos et al, 2016 ; Yamaguchi et al, 2018 ; Hashimoto, 2019 ; Lumsden et al, 2019 ; Yokoyama et al, 2020 ; Highland et al, 2021 ; Wei et al, 2021 ). Thus, mechanisms underlying ketamine’s actions remain controversial.…”

“…AMPARs can also have several direct effects on synaptic transmission (i.e., LTP) and intracellular signals without the proper functioning of NMDARs. This NMDAR-independent and AMPAR-dependent intracellular signaling pathway is also hypothesized to underlie ketamine’s antidepressant actions ( Zanos et al, 2016 ; Duman et al, 2019 ; Wei et al, 2021 ).…”

“…Ketamine elicits robust unwanted side effects, including prepulse-inhibition deficits, cognitive deficits, and schizophrenia-like psychotic symptoms in humans ( Lahti et al, 1995 ; Chan et al, 2013 ; Giorgetti et al, 2015 ). Recent preclinical data indicate that ketamine’s enantiomer ( R )-ketamine ( Hashimoto, 2019 ; Wei et al, 2021 ) and its metabolites ( 2R, 6R )-hydroxynorketamine (HNK) ( Zanos et al, 2016 ) exert antidepressant effects with fewer adverse effects than do ketamine or ( S )-ketamine. Since potential mechanisms underlying the rapid antidepressant actions of ketamine and its metabolites have been reviewed elsewhere ( Fukumoto et al, 2017 ; Yang C. et al, 2018 ; Duman et al, 2019 ; Krystal et al, 2019 ; Sial et al, 2020 ; Highland et al, 2021 ; Shinohara et al, 2021 ; Wei et al, 2021 ; Xia et al, 2021 ), we review the recent progress in deciphering mechanisms underlying ketamine’s sustained antidepressant effects, with a particular focus on the role of calcium signaling from a multiscale perspective.…”

“…Moreover, such ketamine antidepressant effects have been observed in not only naïve, non-stressed animals but also in animals subjected to adverse stressful life events. Animals exposed to chronic stress show despair-like behavior, anhedonia, anxiety, and/or social avoidance, whereas a single injection of ketamine or its metabolites rapidly reverses these deleterious effects and exerts long-term effects ( Li et al, 2011 ; Zanos et al, 2016 ; Duman et al, 2019 ; Wei et al, 2021 ).…”

Case Report: Repeated Series of Ketamine Infusions in Patients With Treatment-Resistant Depression: Presentation of Five Cases

“…The study had three phases: with a single infusion, succeeded by six infusions thrice weekly over 2 weeks, and the maintenance phase with four once-weekly infusions. Bryant et al (20) reported a series of six geriatric patients treated with acute (5-27) ketamine infusions followed by the long-term maintenance phase (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Five of six patients showed a robust response including further improvement after the acute phase, but they lost the response over time.…”