Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression

INTRODUCTION

Over half of patients diagnosed with bipolar disorder (BD) suffer from significant levels of anhedonia, 1 defined as loss of enjoyment in, or desire to engage in, previously pleasurable activities.Notably, anhedonic patients with affective disorders have a poorer treatment prognosis than their non-anhedonic counterparts.Indeed, accumulating evidence suggests that standard treatments for depression do little to alleviate anhedoniaand may even cause reward and emotional blunting,sexual anhedoniaand anorgasmia.Furthermore, the presence of anhedonia in a major depressive episode (MDE) is a predictor of proximal suicide completion.Critically, no US Food and Drug Administrationapproved treatment currently exists specifically for anhedonia. The Diagnostic and Statistical Manual-5 (ref. 14) identifies anhedonia as one of two cardinal symptoms in the diagnosis of an MDE in both major depressive disorder (MDD) and BD. Anhedonia can be subdivided into consummatory (subjective pleasure, for example, enjoying food) and motivational components (anticipation of and drive towards rewarding stimuli, for example, planning and looking forward to a vacation) that have distinct biological bases.Indeed, research suggests that currently depressed MDD and BD patients may possess a substantial deficit in motivational, but not consummatory, reward behaviors.Studies using the sweet taste test-a task that mirrors preclinical assessments of consummatory anhedonia in rodents-found that patients with MDD demonstrated the same preference for sucrose water concentrations as healthy volunteers.Furthermore, Sherdell et al.found that MDD patients experienced the same levels of pleasure as healthy volunteers while viewing humorous cartoons in a computer task, but were not willing to exert as much effort to gain access to these stimuli; the results suggest intact consummatory processes, but attenuated motivational ones. In another study, Etain et al.found no evidence for consummatory anhedonia in BD patients. Although research pertaining to BD patients in particular is lacking, overall, the extant evidence suggests that anhedonia in depression is primarily associated with a deficit in non-consummatory reward behaviors. 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 the anticipation, motivation and learning related to pleasurable stimuli, but not to their consumption.Phasic bursts in dopaminergic neurons in the ventral tegmental area (VTA) have reliably been shown to co-occur with violations in reward expectancy,underscoring the evidence for dopaminergic signalling in reward learning. Furthermore, dopamine signalling in the nucleus accumbens, an area of dense dopaminergic projections from the VTA, has been strongly associated with reward motivation in rodents.Functional neuroimaging in humans indicates that structures such as the VTA,substantia nigra,amygdala,putamen,caudate,ventral striatum,and orbitofrontal cortex-all of which receive innervation from or project to dopaminergic nuclei-are recruited during reward anticipation. Despite the abnormalities in motivational behaviors seen in affective disorders, there is a dearth of robust evidence pertaining to any direct dopaminergic signaling deficit in patients with depression.The strongest indirect evidence for dopaminergic dysfunction in depression comes from pharmacological treatment studies. For instance, the dopamine D2 receptor agonist pramipexole improved levels of depression in both MDDand BDpatients after several weeks of daily administration. A study of Parkinson's disease patients with co-occurring depression used the Snaith-Hamilton Pleasure Scale (SHAPS), and found that pramipexole treatment decreased anticipatory anhedonia levels by 25% across the entire sample; 37 however, it is unknown whether this reduction occurred as a function of improvement in mood, Parkinson's symptomatology or hedonic capacity. It is presently unclear whether anhedonic symptoms in depression improve faster with dopaminergic-enhancing medications than with standard treatments. Furthermore, because improvements in self-reported levels of anhedonia are reportedly the last symptom to improve with selective serotonin reuptake inhibitors,there is a critical unmet need for rapid-acting treatments for anhedonia. The fact that standard antidepressants lack any proven anti-anhedonic efficacy, particularly in conjunction with the deleterious side effects associated with these agents, requires novel pharmacotherapeutic approaches. The noncompetitive N-Methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown remarkable consistency in rapidly ameliorating depressive symptoms in both MDDand BD.However, it is unknown whether ketamine also possesses any specific anti-anhedonic efficacy. Given the likely mechanistic heterogeneity of depression, it is critical to understand the specific targets of treatment response at both the clinical and neural levels, as outlined in the research domain criteria.Ketamine acts directly on the glutamatergic system, which appears to be critical in depression;however, little is known about the specificity of the relationship between commonly occurring symptoms during an MDE (for instance, anhedonia, anxiety) and particular biological phenotypes. In a small sample investigation, Walter et al.found that MDD patients with high levels of anhedonia had lower levels of glutamine, but not glutamate, than healthy controls, but only a trend towards lower glutamine than MDD patients with low levels of anhedonia, who did not differ from controls. Preclinical evidence suggests that blockade of astrocytic glutamate reuptake in rodents can induce anhedonia-like behaviors,particularly in the prefrontal cortex.In addition, ketamineand other NMDA antagonists (for example, MK-801and memantine) have been shown to reverse anhedonic phenotypes in rodents. However, preclinical evidence typically classifies anhedonia as a decrease in consummatory behavior; although anticipatory and consummatory behaviors likely interact, extrapolating from rodent behaviors to clinical patient symptoms is not straightforward. Sub-anesthetic doses of ketamine acutely increase glutamatergic and dopaminergic signaling in the prefrontal cortex of rats.Given the apparent role of dopaminergic and glutamatergic signaling in mediating anhedonia and the reported pharmacological effects in both rodents and humans, ketamine may be ideally suited to specifically ameliorate anticipatory anhedonia in currently depressed patients. This randomized, double-blind, placebo-controlled, crossover 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 were also measured in a subsample of these patients using [ 18 F] fluorodeoxyglucose (FDG) positron emission tomography (PET).FDG-PET measures glucose metabolism, which is primarily determined by glial uptake of glucose in response to glutamate release from neurons, and principally reflects glutamatergic neurotransmitter release and cycling.It is important to note that approximately all glucose entering the central nervous system is transformed into glutamate.Thus,FDG-PET provides an indirect quantitative measure of cerebral glutamate metabolism throughout the entire brain. The effects of ketamine on general depressive symptoms in the majority of BD subjects presented here (33/36, 92%) were previously reported,together with neurobiological correlates of mood improvement derived fromFDG-PET.The present study specifically explores the previously unaddressed issue of ketamine's anti-anhedonic effects and its neural correlates in this sample.