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

## TL;DR

This paper reviews how ketamine works in the brain and its potential as a fast-acting treatment for depression.

## Contribution

The paper provides a comprehensive review of ketamine's neuropharmacological mechanisms and clinical efficacy for depression.

## Key findings

- Ketamine acts as an NMDAR antagonist and may influence monoaminergic, BDNF, and opioid signaling.
- Ketamine shows faster onset and better tolerability compared to SSRIs and TCAs.
- Ketamine is as effective as ECT for non-psychotic depression but has shorter-lasting effects.

## Abstract

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.