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

Oct 15, 2014Translational psychiatry

Ketamine's ability to reduce loss of pleasure and related brain changes in hard-to-treat bipolar depression

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Abstract

A single ketamine infusion rapidly reduced levels of in 36 patients with treatment-resistant bipolar depression.

Anhedonia is characterized by reduced pleasure from activities that were previously enjoyable.
Standard depression treatments often do not effectively address anhedonia and may even dull reward responses.
Over 50% of patients with bipolar disorder experience significant anhedonia during depressive episodes.
Ketamine's anti-anhedonic effects were linked to increased glucose metabolism in specific brain regions.
The reduction in anhedonia occurred independently of changes in general depressive symptoms.
The findings underscore the potential of targeting the glutamatergic system in treating symptoms of bipolar depression.

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--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.

Key numbers

14 days

Reduction in

Duration of anti-anhedonic effects following a single ketamine infusion.

Participants

Total number of treatment-resistant bipolar depression patients enrolled.

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

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