Neuropharmacology of Ketamine and Its Use in the Treatment of Major Depressive Disorder: A Review.

Depression is a common yet potentially debilitating mood disorder with complex neurobiological underpinnings, including deficiencies in monoaminergic and glutamatergic signaling, overactivity of the lateral habenula, and dysregulation of brain-derived neurotrophic factor (BDNF) signaling. Ketamine has emerged as a mechanistically novel, effective, and rapidly acting antidepressant. Ketamine's primary effects are due to N-methyl-D-aspartate receptor (NMDAR) antagonism, although hypotheses regarding the importance of its impact on monoaminergic signaling (preclinical evidence), BDNF signaling (preclinical evidence), opioid receptor agonism (preclinical evidence), and neuroinflammation (clinical evidence) have gained traction. Compared to selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), ketamine demonstrates greater efficacy, a significantly faster onset of action, and generally more tolerable side effects. However, its benefits are offset by a far shorter duration of antidepressant effects and accessibility limitations. In a head-to-head trial, compared to electroconvulsive therapy (ECT), ketamine showed similar efficacy in non-psychotic depression while providing clinically significant relief more rapidly. While promising, further research is needed to optimize ketamine's dosing regimen, enhance its accessibility, and better understand potential drawbacks such as bladder toxicity and addiction potential. Additionally, studying the mechanisms behind ketamine's antidepressant action may provide deeper insight into the neurobiology of depression.