Effects of Early Life Adversities on Acetylcarnitine Deficiency and Insulin Resistance in Patients With Major Depression
Nasca C, Bigio B, Lin KW, Dobbin J, Kautz M, Cochran A, Robakis T, Myoraku A, Beasley J, Wroolie T, Young S, Mathe A, Kocsis J, Murrough J, Lee FS, McEwen BS, Ragson NL
American College of Neuropsychopharmacology. 2018.
Background: The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of disability and risk factor for suicide. Early life adversities (ELA), such as childhood trauma, are risk factors for poor mental health outcomes in adulthood. The biological pathways leading from risk to outcomes are yet-to-be fully elucidated. The endogenously produced molecule acetyl-L-carnitine (LAC) is an epigenetic modulator of central glutamatergic function and a candidate biomarker of insulin resistance (IR). In rodents with depressive-like traits and peripheral IR, LAC levels are markedly decreased and signal decreased acetylation of histones underlying transcriptional regulation of the metabotropic glutamate receptors mGluR2 in the ventral hippocampus and corresponding dendritic plasticity. We evaluated here a role of LAC and IR in in patients with MDD and history of ELA.
Methods: Study participants were recruited at three independent sites, the Weill Cornell Medicine, the Mount Sinai Icahn School of Medicine and Stanford University. Plasma distribution of LAC and the internal control free-carnitine were determined in 45 healthy controls (HC) and 116 patients with MDD using UPLC-MS/MS and ESI-MS/MS; insulin resistance and sensitive was assessed by fasting plasma glucose (FPG) and insulin (FPI) levels, body mass index (BMI), weight and HOMA, Matsuda index and glucose and insulin responses to oral glucose challenges. Depression severity was assessed with the HDRS-21. Physical, sexual and emotional abuses as well as physical and emotional neglect were assessed with the Childhood Trauma Questionnaire. Two-tailed t-tests, chi-square, Pearson correlations and multiple regression were used as appropriate to specific analyses.
Results: LAC (and not free-carnitine) is significantly lower in patients with MDD compared to HC (p<0.0001, power 0.99, effect size=0.8), independently of psychotropic drug treatment, as we recently reported. Within the group of patients with MDD, the LAC deficiency was greater with stronger severity, earlier disease onset and history of treatment resistant depression, which was associated with childhood trauma. Our new data in subjects screened for insulin resistance and sensitivity, show that IR was worst with higher reported rates of childhood trauma in that patients who reported higher rates of specific types of childhood trauma had higher levels of FPI and HOMA (FPI: r=0.6, p=0.004; HOMA: r=0.52, p=0.004).
Conclusions: Our new translational findings suggest that a LAC deficiency and IR may define metabolic endophenotypes of MDD with a vulnerability memory that may be tracked back to ELA. Identifying the role of ELA on metabolic risk factors contributing to behavioral states in patients with MDD can lead to a mechanistic framework for development of a precision medicine approach for preemptive tailored interventions based upon endogenous drug-targets. Studies leveraging the use of brain-derived exosomes are ongoing to evaluate the contribution of central metabolic functions on the peripheral deficiency in LAC and IR in these metabolic endophenotypes of MDD.
Supported by the Robertson Therapeutic Development Foundation (RTDF), the Hope for Depression Research Foundation (HDRF) to CN and BMC and the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by the Pritzker Neuropsychiatric Disorders Research Fund L.L.C, and 1R21 MH093948-01A1 (SPO #50260) and ADA7-09-CT-50 (SPO #43365) to NR.