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).
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.
Major depressive disorder is associated with altered reward processing and persistent anhedonia, deficits that can remain during remission and predict onset. Earlier work shows that ketamine produces rapid antidepressant and anti-anhedonic effects detectable as early as 2 hours after infusion, but it is unclear whether these behavioural effects reflect direct engagement of reward-processing circuitry or are secondary to symptom improvement. Neuroimaging studies have implicated striatal, insular and prefrontal nodes of the mesocorticolimbic pathway in reward anticipation and feedback, and prior PET and fMRI reports have linked early post-ketamine metabolic and activation changes in such regions to symptom change, yet the temporal and mechanistic relationships remain unsettled. Kotoula and colleagues set out to test whether a single subanaesthetic ketamine infusion (0.5 mg/kg) modulates neural responses to reward anticipation and feedback independently of concurrent symptom change. They applied a well-validated monetary incentive delay (MID) task and a pre-defined set of regions of interest (ventral and dorsal striatum, ventral tegmental area (VTA), amygdala, insula, plus an exploratory sgACC analysis), scanning participants 2 hours after infusion in a double-blind crossover design. The investigators also measured plasma concentrations of ketamine and main metabolites, including (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), to explore relationships between metabolite exposure and task-related brain activity.
The study used a double-blind, within-subject crossover design in which participants remitted from depression, free of antidepressant treatment and without current symptoms, received a single intravenous infusion of ketamine (0.5 mg/kg) in one session and saline placebo in the other. Infusions were delivered over a 40-minute steady-state period, sessions were separated by at least 7 days, and functional MRI scanning occurred 2 hours after the end of each infusion to coincide with the early antidepressant time window. Blood samples were collected pre-infusion, immediately post-infusion and 2 hours post-infusion to quantify ketamine, norketamine and two hydroxynorketamine isoforms ((2R,6R)-HNK; (2S,6S)-HNK). Behavioral measurement included the Psychotomimetic States Inventory (PSI) at the end of each infusion and the Snaith-Hamilton Pleasure Scale (SHAPS) pre-scan and 2 hours post-infusion to index psychotomimetic effects and anhedonia respectively. The cognitive probe was a MID task with 96 trials comprising high-win, low-win and neutral cues. Regressors modelled anticipation (high, low, neutral) and feedback (high win, low win, high no-win, low no-win) phases separately for each session. Imaging was performed on a 3-T scanner. Preprocessing used SPM12: realignment, coregistration to a T1 MPRAGE, DARTEL normalization and 8 mm smoothing. Motion parameters and framewise displacement were included as regressors; one participant was excluded for excessive motion. Region-of-interest (ROI) masks covered bilateral ventral striatum (nucleus accumbens), dorsal striatum (caudate, putamen), VTA, amygdala, insula and an sgACC mask used in an exploratory analysis. Mean beta estimates per ROI and contrast were extracted with MarsBar. Statistical analysis employed mixed-effects models to test overall treatment effects on each MID contrast, followed by paired t-tests for ROI comparisons and one-sample t-tests within sessions. Bonferroni correction set the ROI significance threshold at p=0.008. Robust regression assessed relationships between 2-hour metabolite levels and ketamine-induced ROI activation, with placebo beta values entered as covariates to account for individual baseline activation; false discovery rate (FDR) correction was applied to metabolite analyses.
The overall effect of treatment on each task contrast was examined using a mixedeffects model in SPSS. Each contrast was explored further by comparing the ROI activation between ketamine and placebo using a paired t-test and within each treatment session by using a one-sample t-test. Bonferroni correction for multiple comparisons was applied (p=0.008). In order to examine whether the ketamine metabolite levels, 2h post infusion, would predict the ROI activation under ketamine, we performed robust regressions. The placebo beta values were used as a covariate in this analysis to account for individual differences in brain activations and FDR correction was applied.
Ketamine, approximately 2h after its administration, modulated brain activity during the MID task, in areas that are important for reward processing. To our knowledge our study is the first to demonstrate that ketamine can produce detectable changes in the activation of brain areas that are important for reward processing and anhedonia 2h after infusion, without concurrent changes in depressive symptoms and the confounding effects of antidepressant treatment. Previous studies have shown that ketamine, 24h after its administration normalises some of the connectivity changes observed in depressionas well as reducing hyperactivation in the sgACC during a reward processing task. All these effects, at the time-point when they were observed, were accompanied by improvements in depressive symptoms and thus could either be attributed to the primary effects of the drug on neural processes that are affected in depression or could be the secondary effect of symptom changes that ketamine produces. In our cohort of remitted depressed volunteers, depressive symptoms and anhedonia were not present and did not change with ketamine suggesting that J o u r n a l P r e -p r o o f the drug can directly modulate reward-related neural processesproducing differential effects depending on the task contrast. Ketamine increased the activation of the NAc, the putamen, the insula and the caudate when the feedback phase of win and no-win trials was compared to that of neutral trials (Figure). Recent meta-analyses have shown that striatal regions present with decreased activations during the anticipation and feedback phase of the MID task in patients with a mixture of mood disorders. Moreover, striatal hypofunction persists during remissionand altered brain activations in those areas could also contribute to the blunted responses to positive feedback that characterises remitted depressed individuals. Remitted depressed and depressed individuals also demonstrate heightened neural responses to negative feedbackwhich has been related to anhedonia. The fact that ketamine, during the feedback phase of the MID task, approximately 2h post-administration, altered the activation within the mesolimbic reward pathway provides a plausible mechanism by which ketamine could modulate abnormal responses to positive and negative feedback. Additionally, ketamine's effects are more prominent for the feedback phase of no win trials which could indicate that the drug increases the salience of these trials in our remitted depressed cohort. This effect could increase motivation especially in relation to no win trials, and be beneficial for anhedonia. Several of the brain areas where ketamineinduced alterations were observed in our study are also target areas for antidepressant treatments with different pharmacologyand changes in their activation and connectivity predicts treatment response. Taken together these findings indicate that the effects observed in our study, 2h post ketamine, could be relevant to symptoms' improvement in depression. However, in order to fully understand the consequence of these changes in the J o u r n a l P r e -p r o o f modulation of specific symptoms such as anhedonia and guilt, studies in actively depressed patients will be needed. In our study, we found preliminary evidence to link the changes in brain activity with the levels of an active metabolite of ketamine, (2R, 6R)-HNK. The increases in brain activity in the VTA during the feedback phase of low win trials positively correlated with the levels of (2R, 6R)-HNK. Increased VTA activity during the feedback phase of a task that does not involve new learning is rather unexpected. It is possible, that ketamine might increase sensitivity to negative feedback. As a result, the negative outcomes of the no win trials would be perceived as unexpected and trigger new learning which would be associated with increased activation of the VTA. The increased plasticity accompanying ketamine's antidepressant action might also be contributing to that effect. It has been suggested that direct activation of AMPA receptors by (2R, 6R)-HNK triggers the plasticity-related pathways, mediating ketamine's antidepressant action. Brain areas of the mesolimbic pathway receive dense glutamatergic input and glutamate receptors of this pathway are crucial for synaptic plasticity. While there is no direct evidence of increased plasticity after ketamine in patients, PET studies support this conclusion through increased glucose metabolism, which correlates with improvements in depression symptoms and anhedonia in the VS, dACC and putamen 2h post-infusion. Taken together with studies of Lally et al, our findings demonstrate the potential value of concurrent measurement of brain metabolism, functional modulation of brain activity, symptom changes and metabolites levels in building a model of the effects of ketamine in improving specific symptoms.
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Nutt, D. J. · Journal of Psychopharmacology (2015)
Zanos, P., Moaddel, P. J., Morris, P. J. et al. · Nature (2016)
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Papers in Blossom that reference this study
Keeler, J. L., Treasure, J., Juruena, M. F. et al. · Nutrients (2021)
Participant-level and behavioural findings: Statistical degrees of freedom reported (F tests with df 1,36) indicate a sample of 37 participants entered analyses, with one excluded for motion. Ketamine produced the expected acute psychotomimetic effects: PSI total scores were substantially higher after ketamine (mean=48.4, SD=22.9) than after placebo (mean=15.1, SD=10.6). SHAPS scores were low at baseline and did not change significantly 2 hours post-ketamine, indicating no measurable change in self-reported anhedonia in this remitted cohort. Task performance did not differ between drug conditions for total money won (ketamine mean=45.1, SD=5.5; placebo mean=43.3, SD=9.1) and reaction times showed the expected main effect of reward magnitude (faster for high-win trials, F(2,36)=23.2, p<.0001) with no drug-by-reward interaction. Whole-brain analyses did not reveal significant ketamine-versus-placebo differences. ROI analyses, however, identified several treatment effects. During anticipation, a main effect of ketamine increasing activation across ROIs was observed for all win trials versus neutral (F(1,36)=9.261, p=.003). When individual ROIs were examined for high win versus neutral anticipation, increased activation was noted in the nucleus accumbens and caudate, but these did not survive correction for multiple comparisons. Effects during the feedback phase were more robust. For low win feedback versus neutral, ketamine increased activity across ROIs (F(1,36)=4.563, p<.001), and paired tests showed significant ketamine-induced increases in the nucleus accumbens and putamen that survived Bonferroni correction. No-win feedback contrasted with neutral also showed a main effect across ROIs (F(1,36)=5.467, p<.001) and, for high no-win versus neutral, F(1,36)=5.859, p=0.016, but individual ROI effects did not survive multiple-comparison correction. Comparing all win versus all no-win trials produced a main effect across ROIs (F(1,36)=5.036, p<.001) without any single ROI meeting corrected significance. Metabolite associations: In robust regression analyses (placebo beta as covariate), plasma levels of (2R,6R)-HNK at 2 hours post-infusion positively correlated with VTA activation for the contrast low win feedback versus neutral (n=22, p_FDR=0.03). A similar positive relationship between (2R,6R)-HNK and caudate activation for high no-win versus neutral was observed but did not survive multiple-comparison correction. No significant relationships emerged between ROI activation and plasma ketamine, norketamine or (2S,6S)-HNK levels. An exploratory sgACC analysis showed no significant ketamine effects for any MID contrast.
Kotoula and colleagues interpret their findings as evidence that ketamine can directly modulate reward-related neural activity within the mesolimbic pathway approximately 2 hours after administration, independent of changes in depressive symptoms or anhedonia in this remitted sample. The most consistent and robust effects were observed during the feedback phase of the MID task, with increases in nucleus accumbens and putamen activation for low-win feedback surviving correction for multiple comparisons. The authors suggest these changes could reflect enhanced sensitivity to feedback—particularly to negative or non-reward outcomes—and propose that increasing the salience of no-win trials might boost motivation and thereby be relevant to alleviating anhedonia. The reported positive correlation between (2R,6R)-HNK plasma levels and VTA activation is presented as preliminary support for a role of ketamine metabolites in modulating reward circuitry; the authors link this observation to hypotheses that (2R,6R)-HNK can directly engage AMPA receptors and trigger plasticity-related pathways. They note that such a mechanism aligns with animal-model data and PET findings of early post-ketamine metabolic changes that correlate with symptom improvement, although direct evidence for increased synaptic plasticity in humans remains indirect. Key limitations acknowledged by the investigators include the absence of a healthy control group, which prevents establishing whether ketamine normalises remitted individuals' reward responses towards healthy levels. The MID task's design emphasises anticipation and contains relatively fewer feedback trials, which constrains power for outcome-related contrasts; the task also lacked an explicit loss condition, limiting interpretation regarding punishment-specific effects. Finally, the cohort consisted of remitted, unmedicated participants, so extrapolation to acutely depressed patients requires caution. The authors recommend future, better-powered studies that include active patient samples, tasks optimised for feedback and loss conditions, and concurrent measurement of metabolism, functional responses, symptoms and metabolite levels to build a more comprehensive mechanistic model of ketamine's antidepressant and anti-anhedonic actions.