Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 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

Carla Nasca  1 , Benedetta Bigio  2   3 , Francis S Lee  4   5 , Sarah P Young  6   7 , Marin M Kautz  8 , Ashly Albright  5 , James Beasley  7 , David S Millington  6   7 , Aleksander A Mathé  9 , James H Kocsis  5 , James W Murrough  8 , Bruce S McEwen  1 , Natalie Rasgon  2   10
Affiliations
Clinical Trial

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

Carla Nasca et al. Proc Natl Acad Sci U S A. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Decreased Acetyl-l-carnitine (LAC) Levels in patients with MDD compared with HC. (A) Schematic model featuring our innovative framework: 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 accompanied by abnormal hippocampal glutamatergic function, decreased expression of the neurotrophic factor BDNF, and dendritic plasticity as well as by systemic inflammation, including insulin resistance. LAC supplementation rescues those deficits and induces rapid and lasting epigenetic antidepressant-like effects via acetylation of histones. (B and C) Plasma LAC (B) and free-carnitine (C) concentrations in HC and in patients with MDD in acute depressive episodes during study participation as assessed by ultraperformance liquid chromatography–electrospray–tandem mass spectrometry (UPLC-MS/MS). See also SI Appendix, Figs. S1 and S3 *Significant comparisons with HC. ***P < 0.001 in Student’s two-tailed t tests (α = 0.05). Dashed bars indicate group mean.
Fig. 2.
Fig. 2.
LAC levels differ between HC and MDD groups in two independent study centers. Plasma LAC levels were similarly decreased in patients with MDD compared with age- and sex-matched HC in both study centers (C, Cornell; S, Sinai) as assessed by UPLC-MS/MS. *Significant comparisons with HC. **P < 0.01 in Student’s two-tailed t tests (α = 0.05). Dashed bars indicate group mean.
Fig. 3.
Fig. 3.
The LAC deficiency is greater in patients with MDD and history of treatment-resistant depression (TRD). Plasma LAC concentrations across HC, patients with MDD without history of TRD (MDD non-TRD), and patients with MDD and with history of TRD for study center S. F(2, 53) = 4.3, P = 0.01. *Significant comparisons with HC. *P < 0.05, **P < 0.01 in Student’s two-tailed t tests (α = 0.05). Dashed bars indicate group mean. SI Appendix, Fig. S7 also shows a consistency of this stepwise in study center C.
Fig. 4.
Fig. 4.
LAC as potential moderator of sex-specific effects of childhood trauma in patients with MDD with or without history of treatment-resistant depression (TRD). (A–H) History of childhood trauma as assessed by the Childhood Trauma Questionnaire (CTQ) with individual areas, including psychical abuse (A), sexual abuse (B), emotional abuse (C), physical neglect (D), and emotional neglect (E) in HC (n = 19), in patients with MDD non-TRD (n = 16), and in patients with TRD (n = 18) that reported childhood trauma as assessed using by the CTQ at study center S. Data are presented as mean ± SEM. (F) Multiple regression analysis of LAC by emotional neglect and sex in patients with TRD. In the x axis: LAC concentrations as predicted by the model; in the y axis: LAC concentrations as measured in patients with TRD. (G and H) Models stratified by sex in women (G) and men (H) with TRD. *Significant comparisons with HC; #Significant comparison with MDD non-TRD. *P < 0.05, **P < 0.01, ***P < 0.001 in Student’s two-tailed t tests (α = 0.05) or using multiple regression analysis for the predictive model.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annu Rev Public Health. 2013;34:119–138. - PMC - PubMed
    1. Friedrich MJ. Depression is the leading cause of disability around the world. JAMA. 2017;317:1517. - PubMed
    1. Rasgon NL, McEwen BS. Insulin resistance: A missing link no more. Mol Psychiatry. 2016;21:1648–1652. - PubMed
    1. McIntyre RS, et al. Metabolic syndrome and major depressive disorder: Co-occurrence and pathophysiologic overlap. Curr Diab Rep. 2009;9:51–59. - PubMed
    1. Nemeroff CB. Paradise lost: The neurobiological and clinical consequences of child abuse and neglect. Neuron. 2016;89:892–909. - PubMed

Publication types

LinkOut - more resources

  NODES
chat 1
twitter 2