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.

Ketamine: 50 Years of Modulating the Mind

“…Remarkably, this also includes the acute reduction of suicidal ideation (DiazGranados et al, 2010a; Larkin and Beautrais, 2011; Zigman and Blier, 2013; Murrough et al, 2015). Recent neuroimaging studies support potential anti-anhedonic and anti-depressant effects, demonstrating its ability to alter glucose metabolism in regions implicated in mood disorders (Lally et al, 2014, 2015; Nugent et al, 2014). Repeated ketamine doses may improve depressive symptoms comparable to—and perhaps even more rapidly than—electroconvulsive therapy (ECT; Ghasemi et al, 2014), and it may even be successful in treating ECT-resistant depression (Ibrahim et al, 2011).…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…Relapse to depression following ketamine treatment might be related to the reversal of the synaptic effects of ketamine [39]; also see Sections 4 and 5. In addition to its antidepressant actions, a single infusion of ketamine induces anti-anhedonic effects [40] and reduces suicidal ideation [29] in depressed patients with an effect commencing within a few hours of administration and lasting for up to 1 week, similar to its antidepressant time course. Importantly, the anti-suicidal actions of ketamine are partially independent of its antidepressant effects [29, 41], although further studies are required to confirm this conclusion.…”

Does Ketamine Have Anti-Suicidal Properties? Current Status and Future Directions

“…In a recent report, anhedonia levels in a sample of 36 BD patients were reduced for up to 14 days following a single infusion of ketamine (but not saline), even after controlling for total depression at each timepoint [43]. This pattern suggests a specific benefit of ketamine on anhedonia, over and above its effect on other depression symptoms, which could potentially contribute to decreased immediate suicide risk, particularly if a state of decreased anhedonia allows for greater engagement with protective factors in the environment (e.g., increased social engagement).…”