Acetyl-L-carnitine deficiency in patients with major depressive disorder: Implications for treatment resistant depression
Nasca C, Bigio B, Lee FS, Young S, Kautz M, Cochran A, Beasley J, Mathes AA, Kocsis J, Murrough J, McEwen BS, Rasgon NL
Society for Neuroscience. 2018.
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. Converging evidence has demonstrated that supplementation with LAC has rapid antidepressant responses via epigenetic regulation of hippocampal glutamatergic function in rodents with a deficiency in the levels of the endogenously-produced LAC in plasma and mood regulatory brain regions. Responses to standard antidepressant medications required repeated weeks of administration in the experimental models. This mechanistic model led us to evaluate LAC levels in humans with major depressive disorder (MDD). Our data show that LAC levels, and not the levels of free-carnitine, were decreased in patients with MDD as compared to age- and sex-matched healthy controls in two independent study centers. Furthermore, the degree of LAC deficiency reflected both the severity and age of onset of MDD. In a subgroup of patients defined for history of treatment resistant depression (TRD), we find that decrease in LAC was larger and was associated with history of childhood trauma, and specifically emotional neglect. Supported by an initial validation in two independent cohorts, these findings suggest that the LAC deficiency may aid with the diagnosis of a clinical phenotype of depression. Further studies of LAC as a therapeutic target may help to define individualized treatments in biologically-based depression subtype consistent with the spirit of precision medicine.