Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers

Abstract

Ketamine, a drug introduced in the 1960s as an anesthetic agent and still used for that purpose, has garnered marked interest over the past two decades as an emerging treatment for major depressive disorder. With increasing evidence of its efficacy in treatment-resistant depression and its potential anti-suicidal action, a great deal of investigation has been conducted on elucidating ketamine’s effects on the brain. Of particular interest and therapeutic potential is the ability of ketamine to exert rapid antidepressant properties as early as several hours after administration. This is in stark contrast to the delayed effects observed with traditional antidepressants, often requiring several weeks of therapy for a clinical response. Furthermore, ketamine appears to have a unique mechanism of action involving glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and [Formula: see text]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity. This paper provides a brief overview of ketamine with regard to pharmacology/pharmacokinetics, toxicology, the current state of clinical trials on depression, postulated antidepressant mechanisms and potential biomarkers (biochemical, inflammatory, metabolic, neuroimaging sleep-related and cognitive) for predicting response to and/or monitoring of therapeutic outcome with ketamine.

The Oscillatory Profile Induced by the Anxiogenic Drug FG-7142 in the Amygdala–Hippocampal Network Is Reversed by Infralimbic Deep Brain Stimulation: Relevance for Mood Disorders

“…Our study agrees with animal and clinical studies that have reported similar increases in gamma power following acute ketamine administration at therapeutic levels [168][169][170][171][172][173]. Similarly to DBS, subanesthetic doses of ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, also provides a fast antidepressant action [174], being particularly effective in anxious depression [175] and it is also helpful in relieving social anxiety disorder [176]. Cornwell and colleagues found that this rise in gamma power following ketamine administration, measured in cortical magnetoencephalographic recordings, is correlated to antidepressant responses and increased in responders vs. non-responders [177].…”

Therapeutic Potentials of Ketamine and Esketamine in Obsessive–Compulsive Disorder (OCD), Substance Use Disorders (SUD) and Eating Disorders (ED): A Review of the Current Literature

“…Ketamine, an aryl cyclohexylamine derivative synthesized in 1962, was first introduced into clinical practice as an intravenous (IV) anesthetic agent in 1970 [7]. Ketamine is currently prescribed for the induction and maintenance of general anesthesia via intramuscular (IM) or IV infusion; moreover, over the past two decades, it has emerged as a promising treatment for major depressive disorder (MDD) [8,9]. In addition, increasing evidence now points to its therapeutic efficacy in treatment-resistant depression (TRD), as well as a potential agent for reducing and preventing suicide in depressed patients, as it exerts rapid antidepressant properties as early as several hours after administration.…”

The Ketamine Antidepressant Story: New Insights

“…Another study reported that a ketamine-mediated antidepressant is sexually dimorphic, but this effect was not detected in ovariectomized female rats [73]. In addition, pharmacokinetic profiling revealed that, as compared with ketamine and its other metabolites (2S,6S;2R,6R), hydroxynorketamines were metabolized in a gender-dependent manner.…”

“…Opioid (mu, delta, and kappa) receptors are also potential targets ketamine mediated rapid-antidepressant mechanisms [73]. For instance, ketamine attenuated suicidal tendencies through the modulation of opioid receptors.…”