Ketamine Modulates the Neural Correlates of Reward Processing in Unmedicated Patients in Remission from Depression

Ketamine, an antidepressant, can alter activity in brain reward areas within two hours of a single infusion, even in people who are not currently depressed. In a study of 37 remitted depression patients, ketamine increased brain responses in the nucleus accumbens and putamen during anticipation and receipt of small rewards, and the level of a ketamine metabolite (2R,6R)-HNK correlated with activation in the ventral tegmental area. These changes occurred without any changes in mood symptoms, suggesting ketamine may improve anhedonia by directly modulating how the brain processes reward feedback.

Study at a glance

Abstract

Ketamine as an antidepressant improves anhedonia, a pernicious symptom of depression as early as 2h post-infusion. The effects of ketamine on anhedonia are thought to be exerted via actions on reward-related brain areas—yet, these actions remain largely unknown. This study examines ketamine’s effects during the anticipation and receipt of an expected reward, after the psychotomimetic effects of ketamine have passed, when early antidepressant effects are reported. In order to identify brain areas that are modulated by the drug per se and are not linked to symptom changes, we have recruited 37 participants who remitted from depression and were free from symptoms and antidepressant treatments at the time of the scan. Participants were scanned while performing a monetary reward task and we examined ketamine’s effects on pre-defined brain areas that are part of the reward circuit. An overall effect of ketamine was observed during the anticipation and feedback phases of win and no-win trials. The drug effects were particularly prominent in the nucleus accumbens and putamen, upon the receipt of smaller rewards and the levels of (2R,6R)-HNK, 2h post-infusion, significantly correlated with the activation observed in the ventral tegmental area (VTA) for that contrast. These findings demonstrate that ketamine can produce detectable changes in reward-related brain areas, 2h after infusion, which occur without symptom changes and support the idea that ketamine might improve reward-related symptoms via modulation of response to feedback.