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Proc Natl Acad Sci U S A. 2018 Aug 21;115(34):8627-8632. doi: 10.1073/pnas.1801609115. Epub 2018 Jul 30.

Acetyl-l-carnitine deficiency in patients with major depressive disorder.

Author information

1
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; cnasca@rockefeller.edu mcewen@rockefeller.edu.
2
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065.
3
Biostatistics and Experimental Research Design, Center for Clinical and Translational Science, The Rockefeller University, New York, NY 10065.
4
Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, New York, NY 10065.
5
Department of Psychiatry, Weill Cornell Medical College, New York, NY 10065.
6
Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710.
7
Biochemical Genetics Laboratory, Duke University Health System, Durham, NC 27710.
8
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
9
Department of Clinical Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
10
Center for Neuroscience in Women's Health, Stanford University, Palo Alto, CA 94305.

Abstract

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.

KEYWORDS:

childhood trauma; epigenetic; glutamate; mGlu2; treatment-resistant depression

PMID:
30061399
PMCID:
PMC6112703
[Available on 2019-02-21]
DOI:
10.1073/pnas.1801609115
[Indexed for MEDLINE]

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