dimethylarginine and Depressive-Disorder--Major

L-Arginine pathway metabolites appear to play differential roles in the pathogenesis of major depressive disorder (MDD). Studies have revealed an antidepressant and anxiolytic effect of agmatine and putrescine. Possible mechanisms of these effects include inhibition of nitric oxide synthase and N-methyl-D-aspartate receptors. The present study sought to determine whether MDD is associated with altered levels of arginine metabolites and whether these metabolites are associated with depression, anxiety and stress severity. Seventy seven MDD patients 21-65 years of age with a minimum score of 18 on the Hamilton Depression Scale, and 27 age and sex matched healthy controls (HC) were included. Patients with uncontrolled physical diseases, abnormal routine lab tests, other psychiatric diagnoses, or under psychotropic medication were excluded. HC subjects were recruited from the community. Rating instruments included Hamilton Depression and Anxiety Scales, Beck Depression and Anxiety Inventory and Perceived Stress Scale. Fasting blood was drawn between 8:30 and 11:00 a.m. and High Performance Liquid Chromatography (HPLC) was used to measure plasma arginine metabolites. ADMA (Asymmetrical dimethylarginine) and putrescine were significantly lower while SDMA (Symmetric dimethylarginine), agmatine and ornithine were significantly higher in MDD patients (p˂0.05). Depression, anxiety and stress severity were negatively correlated with ADMA and putrescine (p˂0.05). Stress was positively correlated with citrulline, NOHA (N-omega-hydroxy-nor-l-arginine), SDMA, agmatine and ornithine (p˂0.05). Lower putrescine levels predicted depression diagnosis (p = 0.039) and depression severity (p = 0.003). Low ADMA level predicted depression severity as well. Arginine pathway metabolites are associated with the pathophysiology of depression. Putrescine may be a biomarker to predict MDD.

Topics: Adult; Aged; Agmatine; Anxiety; Arginine; Biomarkers; Chromatography, High Pressure Liquid; Depressive Disorder, Major; Female; Humans; Male; Middle Aged; Putrescine; Stress, Psychological; Young Adult

We investigated the relationship of serum nitric oxide (NO) and asymmetrical dimethylarginine (ADMA) levels with cognitive functioning in patients with major depressive disorder (MDD). 41 MDD patients (Beck depression scale scores>16) and 44 controls were included in the study. Rey verbal learning and memory test, auditory consonant trigram test, digit span test, Wisconsin card sorting test, continuous performance task (TOVA), and Stroop test scores were found to be impaired in patients with major depressive disorder when compared to healthy controls. There was no significant difference between patient and control groups in terms of serum NO and ADMA. Serum NO levels were correlated with TOVA test error scores and Stroop test time scores, whereas serum ADMA levels were negatively correlated with TOVA test error scores. Metabolic detriments especially in relation to NO metabolism in frontal cortex and hypothalamus, psychomotor retardation, or loss of motivation may explain these deficits.

Topics: Adult; Arginine; Attention; Biomarkers; Depressive Disorder, Major; Female; Humans; Male; Neuropsychological Tests; Nitric Oxide; Psychiatric Status Rating Scales; Young Adult

(E)-4-Hydroxy-2-nonenal (HNE) is a highly electrophilic end-product of lipid peroxidation. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase (NOS). ADMA is metabolised by dimethylarginine dimethylaminohydrolase (DDAH). DDAH contains a nucleophilic cysteine residue in its active site. There is an increase in lipid peroxidation in major depression. Major depression is associated with the development of coronary heart disease (CHD) and greatly increases morbidity and mortality. There is an increase in circulating ADMA in CHD and vascular risk factors.. To determine plasma HNE, ADME and nitric oxide (NO) concentrations in patients with major depression compared to normal volunteers and to examine the effect of HNE on ADMA formation and DDAH activity in cultured endothelial cells.. The study was conducted in 25 patients with major depression (DSM-IV criteria) and 25 healthy control subjects. Plasma concentrations of HNE were determined as the O-pentafluorylbenzyl oxime using capillary column GC-MS and deuterated HNE as the internal standard; ADME by LC-MS-MS using 13C6-L-arginine as the internal standard; and NO by GC-MS following reduction to nitrate and nitrite and derivatisation to the pentafluorobenzyl derivative using [15N]nitrate and [15N]nitrite as the internal standards. Human umbilical vein endothelial cells were incubated in serum-free medium in the presence of HNE. The concentration of ADMA in the medium was determined by LC-MS-MS. DDAH activity was determined by measuring L-citrulline in endothelial cell lysates using LC-MS.. There was a significant increase in the plasma concentration of HNE (P<0.0001) and ADMA (P<0.0002) in patients with major depression. There was a significant decrease in the plasma concentration of NO (P<0.0001). A significant positive correlation was found between the plasma concentrations of HNE and ADMA (r=0.63, P<0.0001). A significant negative correlation was detected between the plasma concentrations of ADMA and NO (r=-0.595, P<0.0001). HNE significantly increased ADMA formation (P<0.0001) and significantly decreased DDAH activity (P<0.0001) in cultured endothelial cells. The effects of HNE on DDAH activity were significantly attenuated by the addition of glutathione (P<0.0001).. No allowance was made for the phase of the menstrual cycle which could influence plasma nitric oxide concentrations.. There is an increase in circulating HNE in major depression. HNE inactivates the cysteine residue in the active site of endothelial DDAH leading to the accumulation of ADMA in the circulation. The ADMA then decreases the production of eNOS. This could reduce the amount of NO diffusing from cerebral blood vessels to nearby neurons and influence the release of neurotransmitters. ADMA also constricts cerebral blood vessels and may contribute to the decreased regional perfusion in major depression. The accumulation of ADMA could explain the increased risk of CHD in major depression. The preservation of DDAH activity and the reduction of ADMA accumulation may represent a novel therapeutic approach to the treatment of major depression.

Topics: Aldehydes; Arginine; Citrulline; Coronary Disease; Depressive Disorder, Major; Female; Glutathione; Humans; Lipid Peroxidation; Male; Middle Aged; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites