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

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.