Nitric Oxide-Related Biological Pathways in Patients with Major Depression

Abstract

BackgroundMajor depression is a well-known risk factor for cardiovascular diseases and increased mortality following myocardial infarction. However, biomarkers of depression and increased cardiovascular risk are still missing. The aim of this prospective study was to evaluate, whether nitric-oxide (NO) related factors for endothelial dysfunction, such as global arginine bioavailability, arginase activity, L-arginine/ADMA ratio and the arginine metabolites asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) might be biomarkers for depression-induced cardiovascular risk.MethodsIn 71 in-patients with major depression and 48 healthy controls the Global Arginine Bioavailability Ratio (GABR), arginase activity (arginine/ornithine ratio), the L-arginine/ADMA ratio, ADMA, and SDMA were determined by high-pressure liquid chromatography. Psychiatric and laboratory assessments were obtained at baseline at the time of in-patient admittance and at the time of hospital discharge.ResultsThe ADMA concentrations in patients with major depression were significantly elevated and the SDMA concentrations were significantly decreased in comparison with the healthy controls. Even after a first improvement of depression, ADMA and SDMA levels remained nearly unchanged. In addition, after a first improvement of depression at the time of hospital discharge, a significant decrease in arginase activity, an increased L-arginine/ADMA ratio and a trend for increased global arginine bioavailability were observed.ConclusionsOur study results are evidence that in patients with major depression ADMA and SDMA might be biomarkers to indicate an increased cardiovascular threat due to depression-triggered NO reduction. GABR, the L-arginine/ADMA ratio and arginase activity might be indicators of therapy success and increased NO production after remission.

Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects

“…1). The lower circulating levels of threonine (82.5 ± 22.5 μM vs 96.7 ± 27.4 uM) and citrulline (19.2 ± 5.2 μM vs 23.8 ± 7.2 μM) in MDD patients relative to healthy controls are consistent with those of previous reports (Baranyi et al 2015; Hess et al 2017). …”

“…These results are consistent with previous reports (Baranyi et al 2015; Hess et al 2017, Ali-Sisto et al 2018), where the authors showed decreased circulating levels of arginine and citrulline in MDD patients. No differences were observed for citrulline or arginine when comparing treatment with ketamine to placebo in healthy controls or MDD patients.…”

“…Comparing patients with MDD and healthy controls at baseline, no metabolite was significantly different ( q -value < 0.1). A contributing factor to difference observed from previous studies that demonstrated statistically significant differences for certain metabolites between MDD subjects and healthy controls (Steffens et al 2010, Baranyi et al 2015, Hess et al 2017) may be that in our study the MDD patients were both treatment resistant and not on medication during the study. In addition, the lack of differences in circulating amino acids was also consistent with a report by Maes et al, where the authors also did not observe changes in serum amino acid levels (Maes et al 1998).…”

“…Multiple factors affect NO levels including arginase activity, amino acid levels, NOS activity, and the presence of specific endogenous NOS inhibitors, such as asymmetric dimethylarginine (ADMA). Arginase activity, determined by the arginine/ ornithine ratio, had higher changes with responders relative to non-responders ( p = 0.044) at 230 min when adjusted for base-line levels, indicating the increased bioavailability of arginine may result from decreased arginase activity, similar to what was found in a recent study, where they also observed a decrease in arginase activity after first improvement of depression (Baranyi et al 2015; Hess et al 2017). A novel approach for a more precise measurement of the bioavailability of arginine and NO production is the Global Arginine Bioavailability Ratio (GABR) which is calculated as arginine/(citrulline + ornithine) (Baranyi et al 2015, Ali-Sisto et al 2018).…”

“…Arginase activity, determined by the arginine/ ornithine ratio, had higher changes with responders relative to non-responders ( p = 0.044) at 230 min when adjusted for base-line levels, indicating the increased bioavailability of arginine may result from decreased arginase activity, similar to what was found in a recent study, where they also observed a decrease in arginase activity after first improvement of depression (Baranyi et al 2015; Hess et al 2017). A novel approach for a more precise measurement of the bioavailability of arginine and NO production is the Global Arginine Bioavailability Ratio (GABR) which is calculated as arginine/(citrulline + ornithine) (Baranyi et al 2015, Ali-Sisto et al 2018). Lower GABR has been associated with increased risk in cardiovascular disease (Sourij et al 2011), has been shown to be lower in PTSD subjects (Bersani et al 2016) and MDD subjects (Ali-Sisto et al 2018), and was negatively associated with PTSD symptom severity and was inversely correlated with inflammation markers IL-6 and TNF-α (Bersani et al 2016).…”