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

J Psychopharmacol. 2015 May;29(5):596-607. doi: 10.1177/0269881114568041. Epub 2015 Feb 17.


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.

Keywords: 18FDG-PET; Anti-anhedonic; NMDA; depression; dorsal anterior cingulate cortex; glutamate; hippocampus; orbitofrontal cortex; reward; riluzole; subiculum.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Anhedonia / drug effects*
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology
  • Depressive Disorder, Treatment-Resistant / diagnostic imaging
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Depressive Disorder, Treatment-Resistant / psychology
  • Double-Blind Method
  • Female
  • Gyrus Cinguli / diagnostic imaging
  • Hippocampus / diagnostic imaging
  • Humans
  • Ketamine / pharmacology*
  • Ketamine / therapeutic use
  • Male
  • Middle Aged
  • Radionuclide Imaging
  • Treatment Outcome


  • Antidepressive Agents
  • Ketamine