An Epigenetic Biomarker for Depression and Trait of Childhood Trauma With Sex-Specific Effects

Nasca C, Bigio B, Lee FS, Kautz M, Young S, Cochran A, Beasley J, Millington D, Kocsis J, Murrough J, McEwen B, Rasgon N
American College of Neuropsychopharmacology. 2017.


Background: Development of diagnostics and more effective treatments for major depressive disorders (MDD) can be guided by mechanistic insights from animal studies. These are urgent medical and public health needs given that MDD is now the leading cause of illness and disability worldwide with a large economic burden. There is a broad literature from our and other groups supporting rapid antidepressant effects of the epigenetic modulator of glutamatergic function with insulin-sensitizing properties, acetyl-L-carnitine (LAC), across animal models. A common trait of such animal models with depressive and metabolic-like dysfunction was an endogenous reduction in LAC levels in the plasma and in mood regulatory brain regions, such as the hippocampus and prefrontal cortex. Therefore, based upon several converging preclinical evidence, we started by investigating the association between LAC and MDD in humans with a targetedoriented and mechanistic-driven approach.
Methods: Plasma distribution of LAC and the internal control free-carnitine were determined in 45 healthy controls (HC) and 71 patients suffering with MDD using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and stable isotope dilution electrospray-tandem mass spectrometry (ESI-MS/MS). Study participants were recruited at two independent sites, the Weill Cornell Medicine and the Mount Sinai Icahn School of Medicine. The psychiatric examination included the Structured Clinical Interview for DSM-IV (SCID, MINI), the two psychiatric scales, HDRS-17 and MADRS. Study participants completed the Childhood Trauma Questionnaire (CTQ) to assess the effects of childhood traumatic experiences, i.e., physical, sexual and emotional abuse and physical and emotional neglect. All patients with MDD were in an acute episode during study participation. Two-tailed t-tests, chisquare, Pearson correlations and multiple regression were used as appropriate to specific analyses.
Results: HC and patients with MDD did not differ on any demographic and clinical characteristics, except that, as expected, patients with MDD had significantly higher depression severity scores as assessed with the two psychiatric scales, HAM-17 and MADRS (Ham-17: HC = 0.6+/-1.1, MDD = 20.2+/-3.3, po0.0001; MADRS: HC= 1.4 +/-2.4, MDD = 32.9+/-4.7, po0.0001). Supported by validation and replication data, our findings show that LAC (and not free-carnitine) is significantly lower in patients with MDD compared to HC (po0.0001, power 0.99, effect size= 0.8). Within the group of patients with MDD, LAC was lower in patients who exhibited greater severity and earlier age of onset of MDD, independently of psychotropic drug treatment. These correlations remained significant controlling for number of past episodes, length of current episode, sex, and age. Consistent with lower LAC levels in a more severe clinical phenotype of MDD (i.e., greater severity, earlier age of onset), we report that in those patients with treatment resistant depression (TRD), reduced LAC was predicted by emotional neglect, and being a female.
Conclusions: Our new findings suggest a role for LAC, an epigenetic modulator of glutamatergic function with insulinsensitizing properties, as marker to delineate a biologicallydefined MDD phenotype, providing a potential biological target for a precision medicine approach and rational path forward for development of novel pharmaceutical agents. Future studies will test whether such severe phenotype of MDD could benefit by treatment with LAC. Given our earlier reported association of reduced LAC with IR in animals with depressive-like behaviors, it will also be important to study if LAC acts as a gating biomarker for depression encompassing other disease targets.