Ketamine and its metabolites: Potential as novel treatments for depression.

Summary

Ketamine can rapidly relieve depressive symptoms within hours of a single dose, even in patients who do not respond to traditional antidepressants, which often take weeks to work. However, the specific mechanisms behind this rapid effect are not fully understood, and ketamine is associated with serious side effects like dissociative symptoms, cognitive impairment, and abuse potential. This review examines ketamine's pharmacological properties and proposed mechanisms of action, including the disinhibition hypothesis, synaptogenesis, and downstream pathways such as enhanced brain-derived neurotrophic factor signaling and activation of mechanistic target of rapamycin complex 1. (R)-ketamine may offer a safer alternative with fewer adverse effects, and understanding these mechanisms could help develop new rapid antidepressants that maximize benefits while minimizing risks.

Study at a glance

Abstract

Depression is a well-known serious mental illness, and the onset of treatment using traditional antidepressants is frequently delayed by several weeks. Moreover, numerous patients with depression fail to respond to therapy. One major breakthrough in antidepressant therapy is that subanesthetic ketamine doses can rapidly alleviate depressive symptoms within hours of administering a single dose, even in treatment-resistant patients. However, specific mechanisms through which ketamine exerts its antidepressant effects remain elusive, leading to concerns regarding its rapid and long-lasting antidepressant effects. N-methyl-d-aspartate receptor (NMDAR) antagonists like ketamine are reportedly associated with serious side effects, such as dissociative symptoms, cognitive impairment, and abuse potential, limiting the large-scale clinical use of ketamine as an antidepressant. Herein, we reviewed the pharmacological properties of ketamine and the mechanisms of action underlying the rapid antidepressant efficacy, including the disinhibition hypothesis and synaptogenesis, along with common downstream effector pathways such as enhanced brain-derived neurotrophic factor and tropomyosin-related kinase B signaling, activation of the mechanistic target of rapamycin complex 1 and transforming growth factor β1. We focused on evidence supporting the relevance of these potential mechanisms of ketamine and its metabolites in mediating the clinical efficacy of the drug. Given its reported antidepressant efficacy in preclinical studies and limited undesirable adverse effects, (R)-ketamine may be a safer, more controllable, rapid antidepressant. Overall, understanding the potential mechanisms of action of ketamine and its metabolites in combination with pharmacology may help develop a new generation of rapid antidepressants that maximize antidepressant effects while avoiding unfavorable adverse effects.