The Major Depressive Disorder (MDD) is an important issue for public health. It often appears during the adolescence, and, among the related consequences, suicide is the second cause of death in this age group. Despite its social relevance, however, MDD is far to be understood, and there is some lack of information about its early onset.
For example, most of the studies are focused on adults, while few of them target the adolescents. Among other things, this makes difficult to establish reliable markers linked to the early onset of the illness. The aim of the study described here was to test in adolescents some biochemical markers already known in adults, and to investigate their possible role in the early stages of the MDD.
In adults, there is evidence that connects the rise of lactate levels in the brain with the manifestation of MDD. At the biochemical level, indeed, lactate is the product of glycolysis in conditions of absence of oxygen. Normally, glycolysis needs aerobic conditions in order to produce energy for the brain, but sometimes it does not occur: for instance when an inflammation process occurs.
If the immune system is somewhat dysregulated, cytokines – that are proteins involved in the inflammation process – increase their levels and act on the mitochondria, which get impaired and produce molecules that react with the oxygen. This leads to a further activation of cytokines, which act again on the mitochondria, which produce more oxidative molecules… so a recurring cycle starts, which may even lead to the cell death. Without going so far, the oxidative stress due to a mild inflammation can change the glycolysis pathway and lead to an increase in lactate production.
Therefore, the link between inflammation, hypoxia, mitochondrial dysfunction, and lactate production, already well known in the adults, has been investigated in a group of adolescents with MDD symptoms. Researchers used a magnetic resonance technique, called MRS imaging, which permits to measure the level of specific molecules in sections of the brain in vivo. They checked for lactate levels in the cerebrospinal fluid (CSF), together with other potential markers such as N-acetyl-aspartate (NAA) and choline. A decrease of NAA could be associated with the loss of function of the neurons, while higher levels of choline are associated with the cell membrane disruption after an oxidative stress.
The results actually showed higher levels of lactate in adolescents with MDD compared with a healthy group of control. However, NAA and choline levels did not change between the two groups. This suggests that the impairment of the function of neuronal mitochondria may be relatively slight.
Moreover, there was not a clear relation between the levels of the lactate and the other molecules and the assessed clinical symptoms, like fatigue and anhedonia (that is, the loss of the capacity to experience pleasure).
Therefore, it is difficult to evaluate whether the dysfunction of the activity of the mitochondria, which lead to the increase of the lactate levels, is a feature linked to the MDD, or is rather a trait of some individuals presenting that kind of vulnerability, probably but not necessarily linked to the MDD.
In conclusion, this study presents for the first time a clear correlation between CSF levels of lactate and MDD symptoms in adolescents, but it is not possible to come to further conclusions. Additional studies should be conducted with larger groups of subjects (23 adolescents participated in the study) and strict rules: for example, in this study, it was not known if the subjects had used nicotine or alcohol just before undergoing the MRS.
The levels of lactate in the CSF of adolescents at early stages of MDD are higher than normal. This suggests an impairment of mitochondrial functionality, but it is not clear whether it is related to the manifestation of the depression or is a trait of individuals predisposed to a psychopathology.
Reference: Bradley K.A.L. et al. Increased ventricular cerebrospinal fluid lactate in depressed adolescents. European Psychiatry 32 (2016) 1–8.
The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).