Acetyl- l -carnitine deficiency in patients with major depressive disorder
Open accessAbstract
The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of ill health and disability. The endogenously produced molecule acetyl-l-carnitine (LAC) is critical for hippocampal function and several behavioral domains. In rodents with depressive-like traits, LAC levels are markedly decreased and signal abnormal hippocampal glutamatergic function and dendritic plasticity. LAC supplementation induces rapid and lasting antidepressant-like effects via epigenetic mechanisms of histone acetylation. This mechanistic model led us to evaluate LAC levels in humans. We found that LAC levels, and not those of free carnitine, were decreased in patients with MDD compared with age- and sex-matched healthy controls in two independent study centers. Secondary exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD. Moreover, these analyses showed that the decrease in LAC was larger in patients with a history of treatment-resistant depression (TRD), among whom childhood trauma and, specifically, a history of emotional neglect and being female, predicted the decreased LAC. These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD characterized by decreased LAC, greater severity, and earlier onset as well as a history of childhood trauma in patients with TRD. Together with studies in rodents, these translational findings support further exploration of LAC as a therapeutic target that may help to define individualized treatments in biologically based depression subtype consistent with the spirit of precision medicine.
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Maladaptive epigenetic changes can be reversed or normalized by psychological interventions such as cognitive behavioral therapy (CBT) and mindfulness.
“maladaptive epigenetic changes can be reversed or normalized by psychological interventions such as cognitive behavioral therapy (CBT) and mindfulness”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [57]
The Abstract discusses epigenetic effects of acetyl-L-carnitine supplementation in rodent models, not psychological interventions. Searches for CBT, mindfulness, and reversal or normalization of epigenetic changes found no passage addressing the claim. (LLM, conf=0.72)
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- Authors
- Nasca, C., Bigio, B., Lee, F. S., Young, S. P., Kautz, M. M., Albright, A., Beasley, J., Millington, D. S., Mathé, A. A., Kocsis, J. H., Murrough, J. W., McEwen, B. S., & Rasgon, N.
- Affiliations
- Rockefeller University (US)
- Weill Cornell Medicine (US)
- Duke University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Duke University Health System (US)
- Karolinska Institutet (SE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-07-30
- Volume
- 115
- Issue
- 34
- Pages
- 8627-8632
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6112703
- OpenAlex
- W2886666079
- Cited by
- 152
- References
- 45
- Citations by year
- 2026: 9 · 2025: 23 · 2024: 15 · 2023: 11 · 2022: 23 · 2021: 26 · 2020: 24 · 2019: 14 · 2018: 7
- FWCI
- 11.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Robertson Foundation (NA)
- Hope for Depression Research Foundation (NA)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- acetyl-L-carnitine, major depressive disorder, treatment-resistant depression, biomarkers, hippocampal function, histone acetylation, childhood trauma, emotional neglect, depression severity, age of onset, precision medicine, antidepressant-like effects
- MeSH terms
- Acetylcarnitine, Adult, Age Factors, Aged, Carnitine, Depressive Disorder, Major, Major Depressive Disorder, Female, Humans, Male, Middle Aged, Sex Factors
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