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

This double-blind, placebo-controlled study (n=37) found that ketamine improved responses to rewards two hours after depressed patients had received ketamine (35mg/70kg) treatment. This correlated with neurological observations (increases in activation of NAc, the putamen, the insula, and the caudate).

Abstract

“Background Ketamine as an antidepressant improves anhedonia as early as 2h post-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.

Methods We examined ketamine’s effects during the anticipation and receipt of expected rewards on pre-defined brain areas, namely the dorsal and ventral striatum, the ventral tegmental area, the amygdala and the insula. We have recruited 37 male and female participants who remitted from depression and were free from symptoms and antidepressant treatments at the time of the scan. Participants were scanned, 2h after drug administration, in a double-blind cross over design (ketamine:0.5mg/kg and placebo) while performing a monetary reward task.

Results A significant main effect of ketamine, across all ROIs, 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, which showed increased activation upon the receipt of smaller rewards compared to neutral. The levels of (2R,6R)-HNK, 2h post-infusion, significantly correlated with the activation observed in the ventral tegmental area for that contrast.

Conclusions 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.”

Authors: Vasileia Kotoula, Argyris Stringaris, Nuria Mackes, Ndabezinhle Mazibuko, Peter C. T. Hawkins, Maura Furey, H. Valerie Curran & Mitul A. Mehta

Summary

Ketamine improves anhedonia as early as 2h post-infusion, and affects reward-related brain areas. The drug effects were particularly prominent in the nucleus accumbens and putamen, which showed increased activation upon the receipt of smaller rewards compared to neutral.

Ketamine, an NMDA receptor antagonist, improves anhedonia, a symptom of Major Depressive Disorder that is resistant to standard anti-depressant treatment. We examined whether ketamine 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.

The ventral striatum, the caudate and the putamen are involved in reward processing in healthy volunteers, but are decreased in activation during the anticipation phase of the MID task in depression.

In depression, reward processing areas are hypoactivated, and this hypoactivation persists in remission. Compounds that target reward processing areas are considered promising candidates for alleviating depression. Ketamine improves anhedonia as early as two hours after a single infusion, and its effects are correlated with increased glucose metabolism in the dACC and hippocampus. Research in non-human primates suggests that ketamine treatment can ameliorate blunted anticipatory responses to appetitive stimuli by normalizing brain activation in the sub-genual anterior cingulate cortex (sgACC). However, the effects of ketamine on reward-related brain regions during the emergent period are not known.

Ketamine and its main metabolite, norketamine, activate post-synaptic AMPA receptors and trigger plasticity-related molecular processes, which have been linked to the antidepressant effects of the drug. In this study, we aimed to examine the effects of ketamine on task performance and functional brain response to the MID task in a cohort of participants who remitted from depression.

Ketamine increased activation in areas associated with reward in a whole brain analysis, and its metabolites correlated with activation in reward processing brain areas.

37 remitted depressed volunteers took part in a randomised double-blind, placebo controlled, cross-over study. They were assessed using the MINI International Neuropsychiatric Interview and gave written informed consent for the study.

Participants were randomized to receive ketamine or placebo during a 40min steady state infusion. The Psychotomimetic States Inventory and Snaith-Hamilton Pleasure Scale were used to assess anhedonia and psychotomimetic symptoms.

All scans were acquired using a GE MR750 3-Tesla scanner and a 16-channel head coil. The structural and functional data were analysed using SPM-12 and no significant differences were found between the ketamine and placebo conditions.

The MID task consisted of 96 trials of different 10 reward magnitudes, signalled by the initial cue. Three regressors were created for the anticipation phase of the task, one for low win anticipation, one for high win anticipation and one for low no-win anticipation. We defined regions of interest (ROIs) in the amygdala, ventral and dorsal striatum, the VTA and the insula, and thresholded for grey matter with a minimal probability index set at 20%. We analysed the ROI values in SPSS version 25.

Ketamine, norketamine, and the two isoforms of hydroxynorketamine were measured in blood samples and correlated with brain activations induced by ketamine.

The overall effect of ketamine treatment on each task contrast was examined using a mixed-effects model in SPSS. The ketamine metabolite levels, 2h post infusion, were predicted by robust regressions.

Subjective effects of ketamine were as expected, and placebo effects were low. The SHAPS indicated very low levels of anhedonia pre-infusion, which remained unchanged after ketamine.

The total amount of money won during the task did not significantly differ between the ketamine and placebo sessions, and there was no interaction with drug. The brain activations during the anticipation and feedback phases of the MID task were aligned with expectations based on previous studies.

Ketamine increased activity in the NAc and caudate during the anticipation phase of all win trials compared to neutral trials, and in the NAc and putamen during the feedback phase of low win trials compared to neutral trials.

Ketamine caused a main effect in all predefined ROIs when no-win trials were contrasted to neutral trials, and no single ROI showed a significant change by itself after correction for multiple comparisons. Ketamine did not affect the activation of the sgACC in any of the task contrasts that were examined, nor did it produce any significant changes in the activation of the VTA, norketamine and (2R, 6R)-HNK plasma levels.

Ketamine can modulate reward-related neural processes, producing differential effects depending on the task contrast, 2h after its administration, without concurrent changes in depressive symptoms and the confounding effects of antidepressant treatment.

Ketamine increased activation of the NAc, the putamen, the insula and the caudate in the MID task, and this may contribute to the blunted responses to positive feedback that characterise remitted depressed individuals. Ketamine altered the activation within the mesolimbic reward pathway, which provides a plausible mechanism by which ketamine could modulate abnormal responses to positive and negative feedback. Additionally, ketamine increased the salience of no win trials in our remitted depressed cohort, which could be beneficial for anhedonia.

In our study, we found that the levels of an active metabolite of ketamine, (2R, 6R)-HNK, correlated with the changes in brain activity during the feedback phase of low win trials. Ketamine’s antidepressant action might be due to increased plasticity in the brain, which is mediated by AMPA receptors. PET studies support this conclusion by showing increased glucose metabolism, which correlates with improvements in depression symptoms and anhedonia.

This study has a number of limitations, such as the absence of a healthy volunteer group, and no other study exists looking at the effects of ketamine in reward processing. Ketamine effects were observed during the feedback phase of the MID task, and these effects may be related to the drug’s effects during anticipation. In our study, ketamine had differential effects during the feedback phase of win and no win trials, potentially indicating that the drug might produce more profound effects during no win condition or even punishment.

In summary, this study demonstrated that ketamine, 2h post administration, could produce detectable changes in brain areas that are part of the mesolimbic pathway involved in reward processing. These findings support a model whereby ketamine improves reward processing deficits via enhanced anticipation of reward and modulation of responses to negative feedback. Disclosures: The journal pre-proof consulted for Janssen on esketamine, and Dr Mehta has received funding from J&J, Lundbeck and Takeda.

The activation of the ventral tegmental area and the dorsal striatum/putamen were significantly increased 2h post ketamine compared to placebo, and this result survived Bonferroni correction for multiple comparisons. The blood concentrations of ketamine and its main metabolites were measured at the end of the 40min infusion and 2h post.