Individuals with major depressive disorder (MDD) have relatively low levels of arginine, which impairs production of nitric oxide (NO) and leads to an increase in oxidative stress, new research shows.
Finnish investigators studied serum levels of three amino acids — arginine, citrulline, and ornithine — in patients with MDD and found lower arginine levels and a lower global arginine bioavailability ratio (GABR) in those with MDD in comparison with control participants who did not have MDD.
“We did not anticipate that arginine levels would have been decreased, but at the same time, we were not particularly surprised, as we expected to find something of interest,” lead author Toni Ali-Sisto, a doctoral candidate at the Institute of Clinical Medicine/Psychiatry, University of Eastern Finland, Kuopio, told Medscape Medical News.
“We know that depression, as well as any other illness or disorder, has several physiological changes related to it, but just don’t yet know all of them and how they are related to each other — although depression-induced inflammatory response may lead to reduced arginine levels,” he said.
The study was published in March in the Journal of Affective Disorders.
Novel, Improved Approach
Some studies have suggested that aberrant NO-related pathways may be implicated in MDD, the investigators note.
NO “modulates vasodilation and neuronal functions, and inhibits the aggregation of platelets, adhesion of monocytes and leucocytes, proliferation of smooth muscle cells, oxidation of low density lipoprotein cholesterol (LDL), and vascular inflammation by suppressing chemokines and adhesion molecules,” they write.
Because there are no methods to directly and reliably measure levels of NO, the only possibility is to measure the bioavailability of arginine, which is its precursor and is also the limiting factor for the synthesis of NO.
The GABR is a “novel and improved approach used to measure the capacity of a system to produce NO, and has also been used as biomarker for endothelial dysfunction and cardiovascular risk factors,” the investigators add.
GABR is calculated as the serum level of arginine divided by the sum of ornithine plus citrulline. This calculation yields a more precise estimation of the bioavailability of arginine and thus the capacity to produce NO.
In a previous study, the bioavailability of arginine was found to be decreased in patients with MDD. In addition, “decreased activity of the endothelial isoform of nitric oxide synthase (eNOS) in platelets has been observed in MDD,” the authors state.
The present study compared serum levels of arginine, citrulline, and ornithine in fasting glucose samples and calculated GABR for a group of adults (aged 20 to 71 years; n = 99) who had MDD as well as a control group of persons who did not hve depression (n = 253).
The investigators analyzed the levels of asymmetric dimethylarginine (ADMA), which is an endogenous competitive inhibitor of NOS, and symmetric dimethylarginine (SDMA), which has been thought to compete with the transportation of arginine through cell membranes.
In addition, they investigated whether these concentrations were similar in patients whose MDD was in remission (n = 33) and in patients whose MDD was not in remission (n = 45). They also studied whether these concentrations changed from baseline to 8-month follow-up in both groups.
The diagnosis of MDD was confirmed via the Structured Clinical Interview for DSM-IV, which was also used to determine remission status. Remission status was determined using the Beck Depression Inventory (BDI).
The investigators took into account frequency of physical exercise, smoking, alcohol use, marital status, educational level, and the presence of hypertension. They also measured high-density lipoprotein cholesterol (HDLC) and glycated hemoglobin (HbA1c).
At baseline, 48.5% of patients were taking antipsychotic medication, and 84.8% were taking antidepressant medication (selective serotonin reuptake inhibitors [SSRIs; 42%], venlafaxine [21.2%], mirtazapine [13.1%], duloxetine [12.1%], moclobemide [8.9%], bupropion [6.1%], and trazodone [1.0%]).
Control persons, who did not have depression, were drawn from a population-based longitudinal cohort study of individuals living in Lapinlahti, Finland.
Contrary Findings
GABR and the serum levels of arginine and SDMA were lower in participants with MDD, compared to control persons (calculated effect sizes [Cohen’s d] for group differences: 0.48 for GABR [P < .001], 0.68 for arginine [P < .001], 0.16 for citrulline [P = .259], 0.08 for ornithine [P = .460], 0.32 for SDMA [P = .045], and 0.18 for ADMA [P = .460]).
These results persisted after adjusting for age, sex, alcohol use, regular smoking, physical exercise, HbA1C levels, and HDL-C levels.
Although age and GABR correlated in the MDD group, there was no correlation in the control group.
At the time of follow-up, 45 (57.7%) patients still fulfilled the criteria for MDD, compared to 33 (42.3%) patients whose MDD was in remission. Participants whose MDD was not in remission had higher baseline BDI scores and were less likely to engage in regular exercise compared to those whose MDD was in remission.
With respect to the metabolites that were investigated, as well as GABR, there were no significant differences on follow-up between patients whose MDD was in remission and patients whose depression was not in remission. These findings remained after potential confounders were taken into account.
The findings ran “contrary” to their hypothesis, the authors note.
Within both the group of patients whose MDD was in remission and the group of patients whose depression was not in remission, GABR and the levels of arginine increased during the follow-up period, whereas the levels of ornithine decreased. However, the increase in GABR was greater in the patients whose depression was in remission than in those whose depression was not in remission.
In the MDD group, GABR was lower and ornithine levels were higher in those with hypertension (n = 32) than in those without, although there was no correlation between HDL levels and the measured metabolites or GABR.
In the MDD group, the use of duloxetine was associated with higher levels of citrulline (P = .034), and the use of bupropion was associated with higher levels of arginine and ornithine (P = .011 and P = .033, respectively). The use of mirtazapine was associated with lower GABR (P = .038).
The use of an SSRI, venlafaxine, any antidepressant medication, or any antipsychotic medication was not associated with alterations in the metabolite levels.
These findings persisted in a multivariate model in which users of duloxetine, bupropion, or mirtazapine were excluded.
Clinicians should not conclude from this study that arginine supplements should be recommended for patients suffering from depression, Al-Sisto commented.
“These results raise a question whether increase arginine intake through food or supplements would help to cure depressive symptoms, but that remains to be further studied in the future,” he said.
However, “as lower arginine levels have been previously reported to be associated with higher cardiovascular risks, patients with chronic depression should be helped to lower other risk factors for cardiovascular diseases,” he said.
Antidepressant Use a Confounder?
Commenting on the study for Medscape Medical News, Jean-Michel Le Mellédo, MD, professor of psychiatry, University of Alberta in Edmonton, Canada, said that the study’s main strength was its large sample size.
However, he regarded the use of antidepressants in study participants as the study’s “main flaw,” because “antidepressants have been shown to affect the NO pathway” and “low levels of L-arginine have been reported in unmedicated patients with major depression.”
Future studies should assess longitudinally the impact of various classes of antidepressants on L-arginine levels, he said.
The authors acknowledge that “having access to a medication-free MDD sample would have allowed possible medication effects on NO metabolism to be excluded.”
Nevertheless, they note that their observations “remained unaltered after the exclusion of participants using medications that demonstrated association with alterations in the investigated metabolites.”
The work of coauthor Soili M. Lehto, MD, PhD, was supported by the Finnish Cultural Foundation. Toni Ali-Sisto and Dr Le Mellédo have disclosed no relevant financial relationships.
J Affect Disord. 2018;229:145-151. Abstract
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