An update on ketamine and its two enantiomers as rapid-acting antidepressants

ABSTRACT

Introduction: Depression is one of the most disabling diseases worldwide. Approximately one-third of depressed patients are treatment-resistant to the currently available antidepressants and there is a significant therapeutic time lag of weeks to months. There is a clear unmet need for rapid-acting and more efficacious treatments. (R,S)-ketamine, an old anesthetic drug, appears now to be going through a renaissance.

Areas covered: This paper reviews recent literature describing the antidepressant effects of ketamine and its enantiomer (S)-ketamine in patients with major depressive disorder (MDD) and bipolar disorder (BD). Furthermore, the authors discuss the therapeutic potential of (R)-ketamine, another enantiomer of (R,S)-ketamine, and (S)-norketamine.

Expert commentary: A number of clinical studies have demonstrated that (R,S)-ketamine has rapid-acting and sustained antidepressant activity in treatment-resistant patients with MDD, BD, and other psychiatric disorders. Off-label use of ketamine for mood disorders is proving popular in the United States. Meanwhile, preclinical data suggests that (R)-ketamine can exert longer-lasting antidepressant effects than (S)-ketamine in animal models of depression, and (R)-ketamine may have less detrimental side effects than (R,S)-ketamine and (S)-ketamine. Additionally, (S)-norketamine exhibits rapid and sustained antidepressant effects, with a potency similar to that of (S)-ketamine. Unlike (S)-ketamine, (S)-norketamine does not cause behavioral and biochemical abnormalities and could be a safer than (S)-ketamine too.

KEYWORDS:

• Rapid-acting antidepressant
• depression
• suicide
• ketamine
• (R)-ketamine (or arketamine)
• (S)-ketamine (or esketamine)
• (S)-norketamine
• (2R,6R)-hydroxynorketamine (HNK)

Declaration of interest

K Hashimoto is the inventor of filed patent applications on “The use of R-ketamine in the treatment of psychiatric diseases’ and ‘(S)-norketamine and salt thereof as pharmaceutical’ by the Chiba University. K Hashimoto also declares that he has received research support from Dainippon Sumitomo, Otsuka, and Taisho. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was supported by the grants from: AMED, Japan to K Hashimoto (grant no. JP18dm0107119), the National Nature Science Foundation of China (81801341), the Medical and Public Health Technology Research Projects of Wuxi Technology Bureau (CSE31N1723; CSE31N1613) and the Wuxi Municipal Health and Family Planning Commission research project (MS201704).