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

Abstract

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

Figure 1

Anti-anhedonic effect of ketamine and corresponding regression analyses with cerebral glucose metabolism. (a) Snaith–Hamilton Pleasure Scale (SHAPS) estimated scores from linear mixed model 1 (M1) indicating a significant reduction in anhedonia levels following ketamine (red) compared with placebo (blue). (b) Model 2 (M2) is the same as model 1 (M1) but has total depression score (as assessed by the Montgomery–Åsberg Depression Rating Scale (MADRS) minus item 8) entered as a covariate and still reveals a main effect of drug, thus underscoring the unique anti-anhedonic effect of ketamine administration. Asterisks indicate Bonferonni-corrected comparisons at P<0.05 for both A and B. (c) Region of interest analysis with ventral striatum (VS) demonstrating a significant association between anti-anhedonic response to ketamine and increased glucose metabolism in the VS. Changes in anhedonia levels no longer significantly predicted VS change when change in overall depressive symptoms were controlled for. (d, e) Whole-brain corrected relationship between the anti-anhedonic effects of ketamine and (d) dorsal anterior cingulate cortex (dACC), cerebellum, (e) right putamen, VS and medial posterior orbitofrontal cortex increases in glucose metabolism. (f) Whole-brain corrected relationship between SHAPS score orthogonalized against MADRS score indicating that a significant increase in dACC metabolism was associated specifically with anti-anhedonic response to ketamine independent of overall change in depressive symptoms. Error bars represent standard errors. PET images are presented (d and e, P<0.025 uncorrected; f, P<0.05 uncorrected) such that only clusters surviving family-wise error correction are shown. Color bars indicate positive t-values associated with increasing glucose metabolism. ket, ketamine; pla, placebo; rCMRGlu, regional cerebral metabolic rate for glucose metabolism.