Low Acetyl-L-Carnitine Levels May Be Linked to Depression

Researchers have identified a new blood-based biomarker that might improve the diagnosis and treatment of depression: acetyl-L-carnitine (LAC).  

LAC, which is naturally produced in the body, is an epigenetic modifier—it adds chemical tags to DNA to dictate which genes are turned on and off. Among LAC’s many epigenetic duties, it regulates glutamate transmission and prevents neurons from getting overexcited when activated.

A study led by a team of researchers at Stanford University School of Medicine suggests that people with major depressive disorder (MDD) have lower blood concentrations of LAC than people without depression. LAC levels were particularly low in patients whose depression was diagnosed at an early age, those with a history of childhood trauma, and those with treatment-resistant depression. These findings, posted August 21 in PNAS, point to the possibility that LAC may mediate a severe, trauma-associated depression subtype.

Senior author Natalie Rasgon, M.D., Ph.D., a professor of psychiatry and behavioral sciences at Stanford, described the findings as exciting but said these results are just the beginning of the story.

For the study, the researchers conducted clinical and psychiatric assessments of 71 adults with MDD and 45 adults without MDD. The study participants were recruited from either Weill Cornell Medicine or Mount Sinai School of Medicine. Among the 71 patients with MDD, 28 patients had moderate depression (defined as Hamilton Depression Rating Scale [HDRS] score of less than 19 or Montgomery-Åsberg Depression Rating Scale [MADRS] score of less than 34), and 43 had severe depression (HDRS scores of 19 or more/MADRS scores of 34 or more).

When the researchers compared blood samples taken from patients with MDD with those of the healthy controls, they found that LAC levels were lower in patients with MDD. There were no differences between LAC levels of men and women, regardless of age.

The researchers next compared the LAC levels in subgroups of patients with MDD. They found no association between LAC levels and depression symptoms in the patients with moderate depression; however, in patients with severe depression, higher symptom scores were linked with lower LAC. LAC levels were also linked with age of onset; the earlier depression manifested, the lower the LAC levels.

Additional analysis revealed that LAC levels of patients with treatment-resistant depression (failure to respond to at least two antidepressants) were lower than LAC levels of patients without treatment-resistant depression. Among the 18 patients with treatment-resistant depression, those who reported a childhood history of abuse, neglect, or poverty had the lowest average LAC levels.

Rasgon, who has spent years studying the role of early life adversity on depression risk, told Psychiatric News that the next step in this area of research is to try and determine at which point LAC levels change in people who develop depression. Since the current study featured only adults, many questions remain, she noted. For instance, do some people have naturally low levels of LAC that predispose them to early depression, or do traumatic childhood events lower LAC levels, which in turn increase depression risk?

Another question future studies will explore is whether raising the levels of LAC—which can be purchased as a nutritional supplement—can help patients with depression.

“[O]ur analysis looked at an endogenous substance,” she said. “We did not introduce any external carnitine into our patients, and we don’t yet know what happens when it is taken, or even what the right dose might be.”

The study was funded by the Hope for Depression Research Foundation, the Pritzker Neuropsychiatric Disorders Research Consortium, and the Robertson Foundation. ■

“Acetyl-L-Carnitine Deficiency in Patients With Major Depressive Disorder” can be accessed here.