The cognitive neuroscience of ketamine in major depression

Abstract

Ketamine's potential as a rapid-acting antidepressant was first identified in 2000, despite its long-standing use as an anaesthetic agent. Clinically, ketamine alleviates depressive symptoms, including the difficult-to-treat symptom of anhedonia, within hours, with the effects of a single dose lasting for days. Since then, research has focused on uncovering the mechanisms underlying its rapid antidepressant effects in both humans and animal models. While its molecular and cellular effects have been extensively characterized, its impact on cognitive and neuropsychological mechanisms-potential mediators of its clinical efficacy-remains an area of ongoing investigation. Preclinical studies suggest that ketamine rapidly influences the lateral habenula (involved in punishment processing) and fronto-striatal (reward) systems, reverses negative affective biases in established memories, and promotes long-term stress resilience. Translating these findings to human models is crucial, and emerging evidence suggests that ketamine engages similar mechanisms in healthy volunteer and patient groups. However, its clinical application is constrained by acute side effects and an unknown long-term safety profile. Further research into ketamine's mechanisms of action will be essential to inform the development of novel, safer and more accessible rapid-acting antidepressants.

Keywords: depression; fast-acting antidepressant; ketamine; neurocognitive.

Figure 1

A schematic overview of evidence of ketamine neuropsychological mechanism of action. The figure provides a schematic representation of the neuropsychological mechanisms of ketamine’s action on reward, negative bias^, and resilience,^, as discussed in the current review. dACC = dorsal anterior cingulate cortex; DI = dominant interaction; FST = forced swim test; LHb = lateral habenula; SHAPS = Snaith and Hamilton Pleasure Scale; VS = ventral striatum.