The Association Between Concentrations of Arginine, Ornithine, Citrulline and Major Depressive Disorder: A Meta-Analysis

Abstract

Alterations in the peripheral (e.g., serum, plasma, platelet) concentrations of arginine and its related catabolic products (i.e., ornithine, citrulline) in the urea and nitric oxide cycles have been reported to be associated with major depressive disorder (MDD). The meta-analysis herein aimed to explore the association between the concentration of peripheral arginine, its catabolic products and MDD, as well as to discuss the possible role of arginine catabolism in the onset and progression of MDD. PubMed, EMBASE, PsycINFO and Web of Science were searched from inception to June 2020. The protocol for the meta-analysis herein has been registered at the Open Science Framework [https://doi.org/10.17605/osf.io/7fn59]. In total, 745 (47.5%) subjects with MDD and 823 (52.5%) healthy controls (HCs) from 13 articles with 16 studies were included. Fifteen of the included studies assessed concentrations of peripheral arginine, eight assessed concentrations of ornithine, and six assessed concentrations of citrulline. Results indicated that: (1) the concentrations of arginine, ornithine, and citrulline were not significantly different between individuals with MDD and HCs when serum, plasma and platelet are analyzed together, (2) in the subgroups of serum samples, the concentrations of arginine were lower in individuals with MDD than HCs, and (3) concurrent administration of psychotropic medications may be a confounding variable affecting the concentrations of arginine, ornithine, and citrulline. Our findings herein do not support the hypothesis that arginine catabolism between individuals with MDD and HCs are significantly different. The medication status and sample types should be considered as a key future research avenue for assessing arginine catabolism in MDD.

Identification of proline, 1‐pyrroline‐5‐carboxylate and glutamic acid as biomarkers of depression reflecting brain metabolism using carboxylomics, a new metabolomics method

“…Previous studies have shown that the activity of arginase is elevated in depressed patients. Furthermore, arginine is a risk factor for the progress of depression 28 . During the development of depression, the bioactivity of arginine would be decreased, this might explain the upregulated levels of arginine in our research.…”

“…Furthermore, arginine is a risk factor for the progress of depression. 28 During the development of depression, the bioactivity of arginine would be decreased, this might explain the upregulated levels of arginine in our research. The increased content of arginine might influence the production of nitric oxide, and finally enhance oxidative stress in the CNS.…”

Arginine metabolomics in mood disorders

“…A previously published systematic review and meta-analysis has investigated arginine, ornithine, and citrulline in major depressive disorder and reported no significant alterations of the three metabolites nor associations with pharmacological treatment [ 92 ]. Our meta-analysis captured a larger number of studies (20 vs. 13), which also included patients with bipolar disorders and the assessment of ADMA and SDMA, allowing a comprehensive investigation of the interplay between arginine metabolites with direct or indirect effects on NO synthesis and subtypes of mood disorder (depressive vs. bipolar).…”

Ribosomal dysregulation: A conserved pathophysiological mechanism in human depression and mouse chronic stress

“…Consequently, even simple species such as saccharomyces cerevisiae have a homeostatic mechanism during stress that halts ribosome biosynthesis via downregulation of RPGs to conserve energy (30). RPG downregulation in human MDD and mouse CVS may serve to preserve several essential amino acids, such as lysine and arginine, which are abundant in ribosomes (31,32) and whose deficiency has been functionally linked to depression (33)(34)(35). In neurons, most RPGs are found in neurites; thus, the homeostatic downregulation of RPG will decrease synaptic protein synthesis.…”