Neural correlates of change in major depressive disorder anhedonia following open-label ketamine

This open-label study (n=52) investigated the effects of ketamine (35mg/70kg) with regard to the neural correlates related to the remission of anhedonia in major depressive disorder (MDD). Ketamine infusion rapidly reduced anhedonia, a trend that was sustained for three days and correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC).

Abstract

Introduction: Anhedonia is a cardinal symptom of major depression and is often refractory to standard treatment, yet no approved medication for this specific symptom exists.

Methods: In this exploratory re-analysis, we assessed whether administration of rapid-acting antidepressant ketamine was associated specifically with reduced anhedonia in medication-free treatment-refractory patients with major depressive disorder in an open-label investigation. Additionally, participants received either oral riluzole or placebo daily beginning 4 hours post-infusion. A subgroup of patients underwent fluorodeoxyglucose positron emission tomography scans at baseline (1–3 days pre-infusion) and 2 hours post-ketamine infusion.

Results: Anhedonia rapidly decreased following a single ketamine infusion; this was sustained for up to three days, but was not altered by riluzole. Reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC). The tentative relationship between change in anhedonia and glucose metabolism remained significant in dACC and OFC, and at trend level in the hippocampus, a result not anticipated, when controlling for change in total depression score.

Discussion: Results, however, remain tenuous due to the lack of a placebo control for ketamine. In addition to alleviating overall depressive symptoms, ketamine could possess anti-anhedonic potential in major depressive disorder, which speculatively, may be mediated by alterations in metabolic activity in the hippocampus, dACC and OFC.”

Authors: David J. Nutt, Pierre Blier, Níall Lally, Allison C. Nugent, David A. Luckenbaugh, Mark J. Niciu, Jonathan P. Roiser & Carlos A. Zarate

Summary

Introduction

Anhedonia is a principal symptom of major depression and is associated with more severe depression and poorer treatment response in patients treated with standard medications. Additionally, mounting evidence suggests that standard antidepressants may possess minimal efficacy in relieving anhedonia.

The treatment of anhedonia in patients with depression has been proposed to be feasible through manipulating signalling within the dopaminergic system, but few studies have tested this proposal directly. However, recent evidence suggests that targeting the glutamatergic system may provide fast-acting treatments for general depressive symptomatology.

Ketamine, a rapid-acting antidepressant, was found to reduce anhedonia in medication-free treatment-refractory patients with major depressive disorder. This effect was sustained for up to three days and was correlated with changes in glucose metabolism in the hippocampus, dACC and OFC.

Evidence suggests that disruption in glutamatergic signalling may be particularly important in maintaining anhedonia. Ketamine, an NMDA antagonist, was shown to ameliorate anhedonia in rodent models of depression, and glucose metabolism was increased in the dorsal anterior cingulate cortex.

In this study, patients with MDD received a single open-label dose of intravenous ketamine followed by oral riluzole or placebo for 28 days. Anhedonia levels were assessed using the Snaith-Hamilton Pleasure Scale and FDG-PET was used to assess underlying neural correlates of the effect of ketamine on anhedonia.

Participants

Fifty-two patients with treatment-refractory MDD without psychotic features were recruited to participate in this inpatient trial at the National Institute of Mental Health, Bethesda, MD, USA. The study was approved by the Combined Neuroscience Institutional Review Board.

Trial design

After a 2-week drug-free period (5 weeks for fluoxetine), patients received a single open-label infusion of ketamine hydrochloride over 40 minutes via a Baxter infusion pump, and were randomized to receive either riluzole or placebo twice a day for 4 weeks.

Rating scales were administered at baseline, 40, 80, 120 and 230 minutes post-infusion, and thereafter daily for the subsequent 28 days. Anhedonia was measured using the SHAPS, a 14-item self-administered questionnaire, with higher scores indicating greater anticipatory, not consummatory, anhedonia.

PET acquisition and analysis

A subgroup of 20 patients underwent two FDG-PET scans, one at baseline and another beginning 2 hours and ending 3.5 hours post-ketamine infusion (but prior to riluzole/placebo randomization). The precise details of the imaging parameters have been reported elsewhere.

A cardiac input function was calculated from dynamic cardiac imaging, and venous blood samples were used to assess the blood pool radioactivity. MRI images were acquired to allow anatomical localization of PET activity.

PET analyses comprised both region of interest (ROI) and whole-brain investigations. ROIs were selected based on extant literature implicating these structures in depression and reward processing, and 152 template-defined ROIs were applied to rCMRGlu PET images.

A whole-brain analysis of FDG and PET images was performed using Statistical Parametric Mapping (SPM5) within Matlab. The difference image was created by normalizing the PET images by the SPM5-calculated global mean and subtracting the baseline image from the post-ketamine image.

The percentage change in SHAPS levels between baseline and 230 minutes post-ketamine infusion was calculated and used as a regression variable. The 230-minute time point was selected for inclusion in the analysis because it was free from the acute psychotomimetic effects of ketamine.

Statistical analyses

The statistical analysis was performed using SPSS 21 and two-tailed significance was determined as p .05. Adjustment for multiple comparisons was not conducted for this analysis.

We compared MADRS scores, and specifically the MADRS anhedonia question, between consensus ratings and the baseline (60 minutes pre-ketamine infusion) using paired-samples t-tests.

We estimated linear mixed models using a restricted maximum likelihood procedure and used an autoregressive moving averages covariance structure to examine the change in the total SHAPS score over time. Riluzole had no effect on anhedonia levels, so we explored the change following ketamine only.

A model including total MADRS score as a time point-specific covariate was constructed to explore whether the change in anhedonia levels following ketamine occurred over and above the effect on other depressive symptoms. However, the lack of a placebo-controlled comparison precluded accurate estimation.

We performed secondary analyses to explore whether ketamine exerted specific anti-anhedonic effects. We found that the diagnosis of melancholic MDD subtype, comorbid diagnosis of anxiety and family history of alcohol use disorder were associated with enhanced anti-anhedonic response to ketamine.

We assessed whether rCMRGlu in the VS and OFC was related to hedonic capacity at baseline and the change following ketamine. We performed small volume correction on the whole-brain images discussed directly below.

PET imaging was used to examine the relationship between baseline rCMRGlu and baseline SHAPS score, and to examine the relationship between change in SHAPS score and change in rCMRGlu, across the whole brain, in SPM5.

Psychometrics

Almost all patients reported clinically significant levels of anhedonia at baseline, and there was a significant positive correlation between total SHAPS score and MADRS score at baseline.

Primary analyses

We investigated the effect of riluzole on anhedonia levels on days 1 – 28 and found no effect of drug or interaction between time and drug. We found that there was a significant effect of time on anhedonia following a single ketamine infusion, with anhedonia being reduced at 40, 80, 120 and 230 minutes post-ketamine, and on days 1, 2 and 3 following the single ketamine infusion.

Secondary analyses

There was no significant main effect of depression subtype or comorbid anxiety diagnosis, and no significant interaction between anxiety diagnosis and time. However, there was a significant main effect of family history of alcohol use disorder.

PET imaging

Due to technical difficulties, only 19 patients had venous blood samples taken, and ROI modelling could not be completed for one patient. However, a trend towards a negative association between increased rCMRGlu and decreased anhedonia was found in the VS.

Based on our recent report, increased rCMRGlu in the dACC was associated with decreased anhedonia levels following ketamine. This association remained significant when controlling for change in total MADRS.

In the whole brain, there was no significant relationship between baseline levels of SHAPS and baseline glucose metabolism, nor was baseline rCMRGlu predictive of the anti-anhedonic response to ketamine. However, increased glucose metabolism in the right hippocampus was associated with decreased anhedonia.

Discussion

A single open-label intravenous infusion of ketamine reduced levels of anhedonia in patients with medication-refractory MDD. Ketamine was associated with increases in the hippocampus and dACC, and decreases in the OFC, but not with baseline glucose metabolism.

Given the prevalence and debilitating nature of anhedonia across neuropsychiatric disorders, the absence of approved treatments for this symptom is surprising. Ketamine was shown to have a rapid and sustained anti-anhedonic effect in treatment-resistant patients diagnosed with MDD.

Ketamine enhanced the anti-anhedonic response in patients with a family history of an alcohol use disorder, which supports the hypothesis of a biological disposition to NMDA receptor antagonists associated with a family history of an alcohol use disorder.

The present study identified specific neurobiological correlates of anhedonia in patients with MDD disjunct to the previous broad-spectrum investigation of the anti-depressive effects of ketamine in MDD. These correlates were consistent with the notion that anhedonia has a neural basis distinct from that of other depressive symptoms.

The hippocampus is involved in reward processing, motivation and learning. Stimulation of the subiculum causes an increase in dopamine levels in the nucleus accumbens, but this increase is not linear and may explain why changes in VS rCMRGlu were not significantly associated with changes in anticipatory anhedonia levels.

The OFC is critical for reward processing and may have distinct functional specializations, with the medial area being responsible for reward and the lateral area being responsible for punishment. Patients with MDD have been found to exhibit both hyposensitivity to reward and hypersensitivity to punishment.

In BD, dACC rCMRGlu was negatively correlated with the anti-anhedonic response to ketamine. This finding is consistent with the finding that increased glucose metabolism in the dACC is associated with increased reward anticipation.

We found no association between rCMRGlu and anhedonia, nor was baseline metabolism predictive of the anti-anhedonic response to ketamine. This may be because there was not enough variance in our sample at baseline.

This study has several limitations that need to be addressed by future research. It was not possible to appropriately estimate the independence of the change in anhedonia levels from the change in total depression score due to the lack of a placebo control for ketamine.

The validity of the antianhedonic reduction induced by ketamine at 40 minutes post-infusion commencement is questionable, as the patients who experienced the most dissociation at 40 minutes post-infusion had the greatest reduction in depressive symptoms at 230 minutes and 7 days post-infusion.

While we attempted to control for total depression score in our study, it is possible that our results reflect alterations in variables not assessed by the MADRS. Furthermore, replication and extension of our brain imaging findings are required.

Ketamine is potentially efficacious in treating anhedonia in MDD, and riluzole was not found to be an effective adjunctive anhedonia treatment post-ketamine. These findings add increasing weight to the promise of NMDA receptor antagonists and other glutamatergic compounds in treating cardinal symptoms of depression.

Study details

Topics studied
Depression

Study characteristics
Placebo-Controlled Open-Label

Participants
52

Authors

Authors associated with this publication with profiles on Blossom

Mark Niciu
Mark Niciu is an Assistant Professor of Psychiatry at the University of Iowa. Mark and his team are interested in the therapeutic effects of ketamine.

David Nutt
David John Nutt is a great advocate for looking at drugs and their harm objectively and scientifically. This got him dismissed as ACMD (Advisory Council on the Misuse of Drugs) chairman.

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