Neural correlates of change in major depressive disorder anhedonia following open-label ketamine

Summary

Anhedonia, a core symptom of major depression that often resists standard treatment, rapidly decreased after a single infusion of the antidepressant ketamine in medication-free patients with treatment-refractory major depressive disorder, and the reduction lasted up to three days. Adding daily oral riluzole or placebo did not alter this effect. In a subgroup, reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex. The relationship remained significant in the dorsal anterior cingulate cortex and orbitofrontal cortex, and at trend level in the hippocampus, when controlling for total depression score. Results are tenuous due to the lack of a placebo control for ketamine.

Study at a glance

Abstract

Anhedonia is a cardinal symptom of major depression and is often refractory to standard treatment, yet no approved medication for this specific symptom exists. In this exploratory re-analysis, we assessed whether administration of rapid-acting antidepressant ketamine was associated specifically with reduced anhedonia in medication-free treatment-refractory patients with major depressive disorder in an open-label investigation. Additionally, participants received either oral riluzole or placebo daily beginning 4 hours post-infusion. A subgroup of patients underwent fluorodeoxyglucose positron emission tomography scans at baseline (1-3 days pre-infusion) and 2 hours post-ketamine infusion. Anhedonia rapidly decreased following a single ketamine infusion; this was sustained for up to three days, but was not altered by riluzole. Reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC). The tentative relationship between change in anhedonia and glucose metabolism remained significant in dACC and OFC, and at trend level in the hippocampus, a result not anticipated, when controlling for change in total depression score. Results, however, remain tenuous due to the lack of a placebo control for ketamine. In addition to alleviating overall depressive symptoms, ketamine could possess anti-anhedonic potential in major depressive disorder, which speculatively, may be mediated by alterations in metabolic activity in the hippocampus, dACC and OFC.