Abstract
BackgroundKetamine as an antidepressant improves anhedonia as early as 2 hours after infusion. These drug effects are thought to be exerted via actions on reward-related brain areas—yet these actions remain largely unknown. Our study investigates 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. MethodsWe examined ketamine’s effects during the anticipation and receipt of expected rewards on predefined brain areas, namely, the dorsal and ventral striatum, ventral tegmental area, amygdala, and insula. We recruited 37 male and female participants with remitted depression who were free from symptoms and antidepressant treatments at the time of the scan. Participants were scanned 2 hours after drug administration in a double-blind crossover design (ketamine: 0.5 mg/kg and placebo) while performing a monetary reward task. ResultsA significant main effect of ketamine was observed across all regions of interest during the anticipation and feedback phases of win and no-win trials. The drug effects were particularly prominent in the nucleus accumbens and putamen, which showed increased activation on the receipt of smaller rewards compared with neutral. The levels of (2R,6R)-hydroxynorketamine 2 hours after infusion significantly correlated with the activation observed in the ventral tegmental area for that contrast. ConclusionsThese findings demonstrate that ketamine can produce detectable changes in reward-related brain areas 2 hours after infusion, which occur without symptom changes and support the idea that ketamine might improve reward-related symptoms via modulation of response to feedback.
Highlights
Ketamine as an antidepressant improves anhedonia as early as 2h postinfusion
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
We aimed to investigate the effects of ketamine on task performance and functional brain response to the monetary incentive delay (MID) task two hours post-infusion – the time at which early antidepressant effects are reported – in a cohort of participants who remitted from depression
Summary
Ketamine as an antidepressant improves anhedonia as early as 2h postinfusion These drug effects are thought to be exerted via actions on reward-related brain areas—yet, these actions remain largely unknown. In relation to reward processing, the drug improves anhedonia, a symptom known to be resistant to standard anti-depressant treatment [6]. No study has examined whether ketamine’s ability to improve anhedonia is the result of direct modulation of reward processing areas that is not secondary to changes in symptoms. We have used a well-validated fMRI task, the monetary incentive delay (MID) task [7] in order to examine whether the drug engages brain areas involved in reward processing, two hours after its administration, in a relatively large sample of treatment-free and symptom-free remitted depressed volunteers
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