The cognitive neuroscience of ketamine in major depression.
Brain : a journal of neurology – June 30, 2025
Source: PubMed
Summary
A single dose of ketamine can alleviate severe depression symptoms within hours, with effects lasting for days. This fast-acting antidepressant's neurocognitive impact is key to understanding its efficacy. Studies reveal ketamine positively influences brain reward circuits, reverses negative emotional biases, and promotes long-term stress resilience. These beneficial neurocognitive changes are observed in both healthy individuals and those with depression, offering significant promise for treatment.
Abstract
Ketamine's potential as a rapid-acting antidepressant was first identified in 2000, despite its long-standing use as an anesthetic 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.