Identifying biological targets in major depressive disorder (MDD) is a critical step for development of effective mechanism-based medications. The epigenetic agent acetyl-L-carnitine (LAC) has rapid and enduring antidepressant-like effects in LAC-deficient rodents. Here, we found that LAC levels were decreased in patients with MDD versus age- and sex-matched healthy controls in two independent study centers. In subsequent exploratory analyses, the degree of LAC deficiency reflected both the severity and age of onset of MDD. Furthermore, the lowest LAC levels were found in patients with treatment-resistant depression, whereby history of emotional neglect and being female predicted decreased LAC levels. These translational findings suggest that LAC may serve as a candidate biomarker to help the diagnosis of a clinical endophenotype of MDD.
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.