Low blood levels of acetyl-L-carnitine (LAC) may be a biomarker for major depressive disorder (MDD), new research suggests. The study, which included 116 participants, showed that both men and women with MDD had significantly lower levels of LAC than their counterparts who did not have the mental disorder. In addition, secondary exploratory analyses "showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD," the investigators report. Larger LAC decreases were found in those with treatment-resistant depression (TRD) and a history of childhood trauma. "These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD," the researchers write. The study is "an exciting addition to our understanding of the mechanisms of depressive illness," co–senior author Natalie Rasgon, MD, PhD, professor of psychiatry and behavioral sciences at Stanford University School of Medicine, California, said in a press release. In an interview with Medscape Medical News, she said that although it is still early days, "it's important to keep all of this in mind and to think about understanding a little better the complexity of the pathobiology of depression. "We're just adding another piece to a large puzzle, to the big picture that is mental illness," said Rasgon, who is also a member of the Stanford Neurosciences Institute. The study was published online July 30 in the Proceedings of the National Academy of Sciences. "Critical Molecule" LAC is an endogenously produced molecule "critical for hippocampal function and several behavioral domains," write the investigators. Rasgon noted that this study is part of a collaboration with the Rockefeller University in New York City, where she is a visiting professor. Bruce McEwen, PhD, professor and chief of Rockefeller's Laboratory of Neuroendocrinology, is the current study's other co–senior author. Carla Nasca, PhD, a postdoctoral scholar at the laboratory, is the lead author. "In rodent experiments led by Dr Nasca, both here at Rockefeller and elsewhere previously, a deficiency of acetyl-L-carnitine was associated with depression-like behavior," McEwen said in the press release. "They also showed that [LAC] is one of the vital connecting biomarkers in developing depression as a reaction to stress," Rasgon added in speaking to Medscape Medical News. Interestingly, LAC supplementation administered intravenously or orally to the rats who had depression-like traits led to "rapid and lasting antidepressant-like effects." Because of these findings, the investigators sought to assess LAC levels in humans. "The animal models provide a conceptual platform that is consistent with a known role of glutamatergic dysfunction, altered trophic environment, and proinflammatory states in humans with depression," they write. For the current study in humans, the researchers enrolled 116 participants aged 20 to 70 years. Of these, 71 had a diagnosis of MDD (51% women; mean age, 40.8 years) and 45 acted as age- and sex-matched healthy control participants (49% women; mean age, 38.1 years). Of case patients, 28 had moderate MDD, and 43 had severe MDD. Lower LAC Results showed that for all patients with MDD, the mean LAC concentration was 6.1 µmol/L ± 0.3 vs 8.3 µmol/L ± 0.4 for the healthy control group (P < .0001). In addition, men with MDD had a significantly lower level of LAC than men without MDD (P = .0008), as did women with vs without MDD (P = .009). There were no significant between-group differences in free-carnitine concentrations. Within the MDD group, there was a significant association between higher severity scores on the Hamilton Depression-Rating Scale and lower LAC concentrations (P = .04), as well as a correlation between lower LAC and earlier age of disease onset (P = .04). The patients with TRD also had lower levels of LAC vs those without a history of TRD (P = .01). In patients with MDD or TRD, low LAC levels were significantly associated with a history of emotional abuse (P < .001), emotional neglect (P < .001), and physical neglect (P < .01), as reported on the Childhood Trauma Questionnaire, compared with the healthy control group. A significant association was also found between LAC concentrations and physical abuse (P = .001) and sexual abuse (P = .01), but only in the patients with TRD. Childhood emotional neglect was a predictor of decreased LAC levels in women with TRD (P = .02) but not men with TRD (P = .59). Further Exploration Needed Along with results from the earlier animal studies, "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," write the investigators. However, Rasgon noted that it is too early to recommend treatments such as LAC supplementation. "We have many previous examples of how nutritional supplements widely available over the counter and unregulated by the US Food and Drug Administration — for example, omega-3 fatty acids or various herbal substances — are touted as panaceas for you-name-it, and then don't pan out," she said in the release. "We didn't test whether supplementing with [LAC] could actually improve patients' symptoms. What's the appropriate dose, frequency, duration? We need to answer many questions before proceedings with recommendations," added Rasgon. "This is the first step toward developing that knowledge, which requires large-scale, carefully controlled clinical trials," she said. She reported that further studies are currently underway "in trying to understand the changes in the levels of this substance in patients being treated for major depression and other illnesses of the brain." "Intriguing" Findings Asked to comment by Medscape Medical News, James Potash, MD, Henry Phipps Professor and director of the Department of Psychiatry and Behavioral Sciences at Johns Hopkins Medicine, Baltimore, Maryland, called the study "intriguing" and said it was designed and conducted very well. "There's very little that we have at the moment in the way of vital markers for depression. And we have virtually nothing in the way of physical tests that can tell us much of anything about depression," he said. "That low levels of acetyl-L-carnitine might be in indicator of a particular subtype of depression is certainly interesting," he said. Potash, who is also psychiatrist-in-chief at Johns Hopkins, was not involved with this research. He noted that depression is one of the most impairing illnesses "not just in psychiatry but overall. And it's unfortunate that we don't have a better understanding of how the illness plays out in the brain. "We've known about a couple of neurotransmitters, serotonin and norepinephrine, for a long time; but there's so much that we don't know. This represents an important avenue for research that could help us understand another aspect of biochemistry of depression in the brain," he said. Echoing Rasgon, he cautioned against the idea that supplements could be efficacious — at least currently. "That's tantalizing, but at the moment, there isn't much in the way of evidence that gives us great clarity that would ultimately help," said Potash. However, "it certainly strengthens the case that there ought to be a study done," including a randomized controlled trial. "We have a lot of treatments for depression, and for the most part, they work well. That is to say, we get something like two thirds of people substantially better. But depression is so common that 30% of people not responding to treatment means an awful lot of people who aren't getting well. So we desperately need to do more and do better," Potash concluded. Source
