This randomized, placebo-controlled, double-blind crossover within-subjects study (n=36) investigated the antidepressant efficacy of a single ketamine (35mg/70kg) infusion using positron emission tomography (PET) imaging on patients with bipolar depression (BD). Ketamine rapidly improved patients’ anhedonia (emotional blunting), which was linked to increased glucose metabolism in their dorsal anterior cingulate cortex and putamen.

Abstract

“Introduction: Anhedonia—which is defined as diminished pleasure from, or interest in, previously rewarding activities—is one of two cardinal symptoms of a major depressive episode. However, evidence suggests that standard treatments for depression do little to alleviate the symptoms of anhedonia and may cause reward blunting. Indeed, no therapeutics are currently approved for the treatment of anhedonia. Notably, over half of patients diagnosed with bipolar disorder experience significant levels of anhedonia during a depressive episode. Recent research into novel and rapid-acting therapeutics for depression, particularly the noncompetitive N-Methyl-D-aspartate receptor antagonist ketamine, has highlighted the role of the glutamatergic system in the treatment of depression; however, it is unknown whether ketamine specifically improves anhedonic symptoms.

Methods: The present study used a randomized, placebo-controlled, double-blind crossover design to examine whether a single ketamine infusion could reduce anhedonia levels in 36 patients with treatment-resistant bipolar depression. The study also used positron emission tomography imaging in a subset of patients to explore the neurobiological mechanisms underpinning ketamine’s anti-anhedonic effects.

Results: We found that ketamine rapidly reduced the levels of anhedonia. Furthermore, this reduction occurred independently from reductions in general depressive symptoms. Anti-anhedonic effects were specifically related to increased glucose metabolism in the dorsal anterior cingulate cortex and putamen.

Discussion: Our study emphasizes the importance of the glutamatergic system in treatment-refractory bipolar depression, particularly in the treatment of symptoms such as anhedonia.”

Authors: Níall Lally, Allison C. Nugent, D. A. Luckenbaugh, R. Ameli, J. P. Roiser & Carlos A. Zarate

Summary

INTRODUCTION

Over half of patients diagnosed with bipolar disorder (BD) suffer from significant levels of anhedonia, which is a loss of enjoyment in previously pleasurable activities. Anhedonic patients have a poorer treatment prognosis than their non-anhedonic counterparts, and no US Food and Drug Administration-approved treatment currently exists specifically for anhedonia.

Anhedonia in depression is primarily associated with a deficit in non-consummatory reward behaviors, and understanding the neural pathways that mediate anticipatory pleasure is thus a critical step towards successful treatment of anhedonia.

Dopaminergic signaling has been consistently correlated with reward anticipation, motivation and learning, but not with reward consumption. Dopaminergic neurons in the ventral tegmental area (VTA) are involved in reward learning.

There is a dearth of robust evidence for a direct dopaminergic signaling deficit in patients with depression, but pharmacological treatments have improved depression in both MDD and BD patients. It is unclear whether improvements in anhedonia improve faster with dopaminergic-enhancing medications than with standard treatments.

Ketamine, a noncompetitive NMDA receptor antagonist, has shown remarkable consistency in rapidly ameliorating depressive symptoms in both MDD and BD, but it is unknown whether ketamine also possesses any specific anti-anhedonic efficacy. Preclinical evidence suggests that blockade of astrocytic glutamate reuptake in rodents can induce anhedonia-like behaviors, and that ketamine can reverse anhedonic phenotypes in rodents. However, extrapolating from rodent behaviors to clinical patient symptoms is not straightforward.

This study assessed the anti-anhedonic efficacy of ketamine in treatment-resistant BD patients currently experiencing an MDE. Regional neural metabolism following both placebo and ketamine infusions was also measured in a subsample of these patients using [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET).

MATERIALS AND METHODS Participants

Subjects aged 18-65 with BD I or II without psychotic features were recruited through local and national media. All subjects were inpatients at the National Institutes of Health, Bethesda, MD, USA, and had failed to respond to at least one adequate antidepressant trial before hospital admission.

All participants were in good physical health and had undergone a medical examination, medical history, chest x-ray, blood laboratory tests, urinary analysis and toxicology.

Bipolar disorder patients underwent 18FDG-PET imaging and were administered a mood stabilizer, but this was not adequate to alleviate depressive symptoms. No psychotropic medication or psychotherapy was permitted in the 2 weeks before study randomization or during the 4-week study period.

Design

The study was designed as a randomized, double-blind, placebo-controlled, crossover study with two weeks between each infusion. All participants received one intravenous infusion of ketamine hydrochloride and one infusion of placebo.

The MADRS44,45 score was the primary outcome variable for antidepressant efficacy, but the main symptom of interest for this report is anhedonia, which was evaluated using the SHAPS.

Positron emission tomography acquisition and analysis

21 of 36 patients underwent two resting-state 18FDG-PET imaging scans, which were performed 2 h post infusion and ended 1.5 h later (brain emission scan). PET analyses comprised both a region of interest approach (ROI) and a whole-brain investigation.

The ROI analysis pipeline used here has been previously described. Briefly, anatomical MRI images were segmented into gray and white matter, cerebrospinal fluid, and ventral striatum, and then ROIs were applied to rCMRGlu PET images to calculate glucose metabolism rate values.

For the whole-brain investigation, 18FDG-PET images were preprocessed and analyzed using Statistical Parametric Mapping software (SPM) version 5 within the MATLAB environment. A Gaussian smoothing kernel was applied to the PET images.

Statistical analyses

Symptom rating scale analysis was conducted using IBM SPSS (Armonk, NY, USA; version 21). Linear mixed models were used to assess the effects of ketamine versus placebo on SHAPS scores over the 4-week period in this crossover design.

We conducted a multiple linear regression analysis to examine the association between ventral striatum metabolism change and overall depression score change following ketamine. We also assessed whether state-dependent anhedonia levels were associated with ROI rCMRGlu, both variables post-ketamine and post-placebo.

Complementing the ROI analysis, we performed multiple regression analyses on difference images (post-placebo – post-ketamine) and on anhedonia scores (SHAPS score orthogonalized to total MADRS score minus item 8). We report only those analyses that survived cluster correction.

Behavioral response

Ketamine significantly reduced anhedonia across time, compared with placebo, and this effect was observed at multiple times throughout the 14-day period following a single ketamine infusion.

Anhedonia levels were positively correlated with depressive symptoms at the first pre-infusion baseline, and ketamine treatment reduced anhedonia levels over-and-above its effects on other depressive symptoms.

A trend towards significance was observed with lithium being more antianhedonic than valproate. No interaction effects were noted between drug, mood stabilizer and time.

We examined whether a positive family history of alcohol use disorder was also associated with a specific enhanced anti-anhedonic response to ketamine. We found that those with a family history of alcohol use disorder had a significantly enhanced anti-anhedonic response to ketamine in comparison to those without.

PET: ROI analyses

Ketamine-induced change in ventral striatum rCMRGlu was significantly related to percent change in SHAPS score at 230 min post infusion, but not to orbitofrontal cortex rCMRGlu. However, change in MADRS score was significantly related to change in ventral striatum rCMRGlu, but not to change in SHAPS score.

PET: Whole-brain analyses

The relationship between percent improvement in SHAPS scores and rCMRGlu increases in the dorsal anterior cingulate cortex (dACC), cerebellum, and striatum was significant. The inverse contrast (the relationship between decreases in rCMRGlu and change in SHAPS score) did not yield any whole-brain corrected results.

We conducted a whole-brain analysis of metabolic changes in the ventral striatum following ketamine administration. This analysis revealed that changes in anhedonia levels were associated with increased rCMRGlu metabolism that extended into the pregenual cingulate/callosal region and the right dorsolateral prefrontal cortex.

Ketamine administration significantly reduces anhedonia levels as measured by the Snaith – Hamilton Pleasure Scale (SHAPS) and the Montgomery – sberg Depression Rating Scale (MADRS) minus item 8. The VS is a key region involved in anti-anhedonia response to ketamine. Ketamine increased glucose metabolism in the dorsal anterior cingulate cortex, cerebellum, right putamen, VS and medial posterior orbitofrontal cortex, which was associated with an anti-anhedonic response to ketamine independent of overall change in depressive symptoms.

DISCUSSION

The rapid-acting antidepressant ketamine reduced anhedonia in currently depressed treatment-resistant BD patients, and its effects lasted up to 14 days. The neurobiology of this specific anti-anhedonia effect was mediated in part by increases in glucose metabolism in the dACC and putamen, but not the ventral striatum.

Ketamine, a NMDA receptor antagonist, had rapid effects on anhedonia levels in MDD patients, but no research has been done on its effects in individuals with BD. This suggests that similar compounds may be useful in treating this debilitating symptom of depression.

We hypothesized that increased ventral striatum glucose metabolism would also be associated with improvement in anhedonia following ketamine, but found that this was not the case. The possible reasons for this include the severity of illness in these treatment-resistant BD subjects, the underlying biology of the ventral striatum or the distinct symptom assessed by the SHAPS.

The dACC and putamen are highly involved in reward processing, learning and decision-making, and the increase in glucose metabolism in the dACC and putamen seen in the present study may reflect changes in the motivation and anticipation of pleasurable events. A functional MRI study in humans found that anticipating a reward (glucose) elicited heightened activity in the right putamen compared to anticipating a punishment (salt water). Additionally, decreased anticipatory anhedonia was associated with increased glucose metabolism in the dACC and putamen.

Individuals taking lithium experienced greater antianhedonic effects than those taking valproate after the ketamine infusion. This result could be explained by either valproate causing a deficit in the anti-anhedonic effect of ketamine or lithium enhancing the anti-anhedonic effect of ketamine.

Ketamine acts by blocking the glutamatergic NMDA receptor and upregulating the -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor throughput. It may also have an effect on the dopaminergic system, which may be a potential route of the anti-anhedonic efficacy of ketamine.

The present work has several limitations, including the lack of a baseline PET image, the experiential difference between receiving ketamine and saline can be dramatic, and all participants continued to receive either lithium or valproate, which may have masked or enhanced the effect of ketamine.

Anhedonia has been suggested as a tractable endophenotype in psychiatric and neurological illnesses, and its etiology may help to clarify specific biological mechanisms mediating mental illnesses.

This study demonstrated that ketamine exerts rapid-acting anti-anhedonic effects in treatment-refractory BD patients, and that these effects are mediated by increased glucose metabolism in the dACC and putamen.

CONFLICT OF INTEREST

CAZ has submitted a patent for the use of ketamine in depression, and will share in any royalties.

ACKNOWLEDGMENTS

The authors thank Wayne Drevets MD, Maura Furey PhD, Ioline Henter MA, the 7SE research unit and staff for their support, and the Intramural Research Program at the National Institute of Mental Health.