Global arginine bioavailability ratio is decreased in patients with major depressive disorder

Major depressive disorder (MDD) has been associated in some studies with abnormal nitric oxide (NO)-related pathways. Nitric oxide is a signaling molecule that is synthesized from the amino acid arginine. Production of NO is catalyzed by one of 3 isoforms of nitric oxide synthase (NOS): inducible NOS (iNOS), neuronal NOS (nNOS), and endothelial NOS (eNOS). There is no reliable way to directly measure NO levels because it is synthesized at local sites and has a short half-life. One way to estimate the ability to produce NO is to measure the global arginine bioavailability ratio (GABR), defined as the serum level of arginine divided by the sum of ornithine plus citrulline.  


A study conducted in Finland evaluated GABR in 2 population samples: 99 patients with MDD and 253 non-depressed controls.

Nitric oxide is synthesized from arginine, an amino acid found in nuts, seeds, and legumes.


After adjusting for confounding variables, baseline levels of GABR and serum arginine were significantly lower in patients with MDD than in non-depressed controls (OR of having MDD for each unit increase in GABR = 0.51; 95 % CI, 0.32-0.80; p=.003). Over a mean follow-up of 8 months, patients with MDD who went into remission experienced a greater increase in GABR over time than those who did not go into remission, but the difference between groups was not significant. 

The authors of the study propose 2 mechanisms to explain the relationship between decreased GABR and MDD: it could mean that low arginine supply compromises the ability to produce NO or that rapid production of NO depletes arginine supplies. The first mechanism (compromised NO production) would compromise the neuronal functions of NO, which include activation of the N-methyl-D-aspartate (NMDA) receptor—a target of some pharmacological treatments for depression. The second mechanism (increased production of NO) could be induced by chronic inflammation. Low-grade inflammation is characteristic of MDD, and inflammatory cytokines activate the iNOS enzyme (converting arginine to NO) and also the arginase enzyme (converting arginine to ornithine). 


This study demonstrates a significant association between decreased arginine availability and MDD. Further studies are needed to understand the precise mechanisms of this association and whether nutritional therapies can be implemented to support related biochemical pathways.

Ali-Sisto, T., Tolmunen, T., Viinamäki, H., Mäntyselkä, P., Valkonen-Korhonen, M., Koivumaa-Honkanen, H., … Lehto, S.M. (2018). Global arginine bioavailability ratio is decreased in patients with major depressive disorder. Journal of Affective Disorders, 229, 145-151.