The cognitive neuroscience of ketamine in major depression.
Sara Costi, Chloe Wigg, Erdem Pulcu, Susannah E Murphy, Catherine J Harmer
Brain : a journal of neurology June 30, 2025 DOI: 10.1093/brain/awaf242 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Topics | Depression Ketamine Esketamine |
| Keywords | Fast-acting antidepressant Ketamine treatment Ketamine therapy Ketamine medication Ketamine drug Ketamine antidepressant Depression therapy Depression treatment Depression medication Mental health treatment Antidepressant therapy Neurocognitive impact Neurocognitive effects Brain effects Cognitive changes Neurological impact Rapid antidepressant Quick antidepressant Fast-acting medication |
| Citations | 3 |
| Key findings | Ketamine rapidly alleviates depressive symptoms including anhedonia within hours, with effects lasting days, and preclinical evidence suggests it influences punishment- and reward-related brain systems and reverses negative affective biases. |
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.