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Neural correlates of change in major depressive disorder anhedonia following open-label ketamine
Open accessAbstract
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.
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“Antidepressant effects of low-dose ketamine [56] and transcranial magnetic stimulation can improve the cerebral glucose metabolism in these regions [57–60].”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [56]
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“First, among patients with TRD, a single ketamine infusion rapidly reduced anhedonic symptoms, and reduction in anhedonia correlated with decreased metabolism in the right lateral OFC (as well as increased glucose metabolism in dACC) [116].”
From Prefrontal cortex and depression (2022) · cites this paper as [116]
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“and to rapidly reduce anhedonia 25–27.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [26]
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Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms
Zanos, P., Moaddel, R., Morris, P. J., Riggs, L. M., Highland, J. N., Georgiou, P., Pereira, E. F. R., Albuquerque, E. X., Thomas, C. J., Zarate, C. A., et al. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.015198 · Cited by 1,260
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Metadata
- Authors
- Lally, N., Nugent, A. C., Luckenbaugh, D. A., Niciu, M. J., Roiser, J. P., & Zarate, C. A.
- Affiliations
- National Institutes of Health (US)
- University College London (GB)
- Corresponding author
- Lally, Níall
- Venue
- Journal of Psychopharmacology
- Publisher
- SAGE Publications
- Published
- 2015-02-17
- Volume
- 29
- Issue
- 5
- Pages
- 596-607
- ISSN
- 0269-8811 (ISSN-L)
- 1461-7285
- PMC
- PMC5116382
- OpenAlex
- W2113067674
- Cited by
- 224
- References
- 70
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 32 · 2023: 20 · 2022: 33 · 2021: 27 · 2020: 18 · 2019: 22 · 2018: 15 · 2017: 12 · 2016: 19 · 2015: 7
- FWCI
- 12.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (04-M-0222)
- National Institute of Mental Health (ZIAMH002857)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- ketamine, anhedonia, major depressive disorder, treatment-resistant depression, rapid-acting antidepressants, riluzole, glucose metabolism, hippocampus, dorsal anterior cingulate cortex, orbitofrontal cortex, inferior frontal gyrus, neural correlates, FDG-PET
- MeSH terms
- Adult, Antidepressive Agents, Major Depressive Disorder, Double-Blind Method, Female, Gyrus Cinguli, Hippocampus, Humans, Ketamine, Male, Middle Aged, Radionuclide Imaging, Treatment Outcome, Anhedonia, Depressive Disorder, Treatment-Resistant
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