Research paperDepression and anxiety symptoms are associated with prooxidant-antioxidant balance: A population-based study
Introduction
Depression and anxiety are two of the most common mental disorders and are significantly associated with systemic inflammation upregulation indicated by an increased production of pro-inflammatory cytokines and oxidative biomarkers (Duivis et al., 2013, Tayefi et al., 2017). The homeostatic buffering mechanisms regulating inflammation and oxidation in healthy individuals become dysregulated in untreated depression (Rawdin et al., 2013). In this regard, we have recently shown that depression and anxiety are associated not only with serum level of hs-CRP, but also with hematological inflammatory markers including white blood cell (WBC) count and red cell distribution width (RDW) (Shafiee et al., 2017). Such a heightened inflammatory state is accompanied by increased oxidative stress due to alterations in prooxidant-antioxidant balance (PAB), increased generation of reactive oxygen species (ROS), lipid peroxidation and decreased anti-oxidant defenses (Kawanishi et al., 2006, Valko et al., 2006).
Oxidative stress has been implicated in a variety of pathological conditions and traumatic events, including CVD, autoimmune diseases, traumatic brain injury, and others (Ehsaei et al., 2015, Heitzer et al., 2001, Sahebari et al., 2015). Oxidative stress is defined as a serious disturbance in the prooxidant-antioxidant balance in favor of the prooxidants, in which elevated levels of intracellular ROS such as hydrogen peroxide (H2O2), superoxide radical (O2°¯) or hydroxyl radical (•OH), contribute to tissue damage (Sies, 1997). Prooxidants are derived either from normal metabolic processes or from external sources such as dietary iron, cigarette smoke, and alcohol (Albano, 2006, Stone et al., 2002, van der Vaart et al., 2004). Antioxidants include the three major lipid-soluble antioxidants (e.g. α-tocopherol and vitamin A), water-soluble antioxidants (e.g. vitamin C, urate, polyphenols, and flavonoids) and the enzymatic antioxidants (e.g. catalase, peroxidase, and superoxide dismutase) (Alamdari et al., 2007). Although various methods have been developed to measure either the total oxidants [e.g. total oxidant status assays (Erel, 2005)] or antioxidants [e.g. the ferric reducing ability of plasma (Benzie and Strain, 1996)], these methods are time-consuming and imprecise due to the need for two separate tests to estimate serum prooxidant-antioxidant balance (PAB) (Alamdari et al., 2007). Therefore, we have previously developed a method in which the balance of oxidants and antioxidants can be measured using 3,3´,5,5´-tetramethylbenzidine (TMB) (Alamdari et al., 2008). The serum PAB assay has the ability to measure the prooxidant burden and the antioxidant capacity simultaneously in one assay to provide a redox index (Alamdari et al., 2008). A high serum PAB value means that the number of oxidants considerably outweigh the number of antioxidants and may reflect a higher oxidative stress state.
Considering the close association between inflammation and oxidative stress, and the fact that depression and anxiety are linked to inflammation (Berk et al., 2013, Duivis et al., 2013), we hypothesized that more severe depression/anxiety symptoms are associated with more oxidative stress reflected by higher values of serum PAB. In this regard, numerous studies have linked increased measures of oxidative stress in depression and anxiety disorders (Hovatta et al., 2010, Yanik et al., 2004). For instance, Sarandol et al. conducted a study on ninety-six patients with a diagnosis of major depressive disorder (MDD) and 54 healthy controls. Plasma malondialdehyde (MDA) and susceptibility of red blood cells (RBC) to oxidation were found to be higher in the MDD group compared with the control group. Moreover, RBC superoxide dismutase (SOD) was significantly elevated in patients with MDD (Sarandol et al., 2007). In another study, the excretion of urinary F2 isoprostane was observed to be significantly higher in patients with depression than in control subjects, even after adjustment for sex, age and body mass index (BMI) (Chung et al., 2013). Irie et al. found a significant positive correlation between depression scores and the 8-hydroxydeoxyguanosine (8-OH-dG) levels in depressed patients. Since 8-OH-dG is a product of oxidative damage to DNA, the authors suggested that clinical depression can be considered as a risk factor for cancer initiation (Irie et al., 2005). Moreover, Yanik and colleagues also investigated the relationship between the potency of oxidative stress and the severity of depression on 21 patients with MDD and 28 healthy controls. The results showed lower total antioxidant potential of plasma (TAOP) and higher oxidative stress index (OSI) in patients with depression than those in control group (Yanik et al., 2004).
Despite these observations, no studies have evaluated the association between depression/anxiety symptoms and oxidative stress using the serum PAB assay. Therefore, the primary objective of the present study was to examine the cross-sectional association between depression/anxiety symptoms and serum PAB values in a large population-based study.
Section snippets
Study population
A total of 7516 subjects [2865 (38%) males and 4651 (62%) females] were derived from a cohort of free living individuals aged 35–65 years from northeastern Iran (Ghayour-Mobarhan et al., 2015). The Mashhad Stroke and Heart Atherosclerotic Disorders (MASHAD) cohort study is a 10-year cohort, which aims to evaluate the impact of various risk factors on the incidence of cardiovascular events among a general urban population (Ghayour-Mobarhan et al., 2015). The first phase of the MASHAD cohort
Results
Among the 7516 individuals, the average age was 47.9 ± 8.1, with 62% being female. The mean age of premenopausal and menopausal women were 42.6 ± 5.1 and 55.2 ± 5.4, respectively (unshown data). Demographic and biochemical characteristics of the study population are presented in Table 1. Participants were stratified into four groups according to their depression and anxiety scores: “no or minimal”, “mild”, “moderate”, and “severe”. As given in Table 1, the number of individuals with no or
Discussion
Our results suggest that higher depression and anxiety symptoms may be associated with altered oxidative stress status, expressed by higher PAB values. However, this association was stronger for depression than in anxiety and in men than in women.
Some previous studies have reported similar association between depression and increased markers of oxidative stress including MDA (Khanzode et al., 2003, Rybka et al., 2013, Talarowska et al., 2012), isoprostanes (Dimopoulos et al., 2008, Milaneschi
Conflict of interest
None.
Authors' contributions
The work presented here was carried out in collaboration between all authors. M.G-M., S.R.A., and G.A.F. defined the research theme. M.A., S.A., and M.M., designed methods and experiments and carried out the laboratory experiments. M.T. and H.E. analysed the data and interpreted the results. M.S., N.M. and H.V. wrote the paper and revised it critically for important intellectual content.
Acknowledgments
The authors acknowledge with grateful appreciation the kind assistance provided by Mashhad University of Medical Sciences (MUMS) and Tabriz University of Medical Sciences (TUMS).
Funding
This work was supported by Mashhad University of Medical Sciences (MUMS) and Tabriz University of Medical Sciences (TUMS) (Grant number: 85134).
References (53)
- et al.
Prooxidant-antioxidant balance as a new risk factor in patients with angiographically defined coronary artery disease
Clin. Biochem.
(2008) - et al.
A novel assay for the evaluation of the prooxidant-antioxidant balance, before and after antioxidant vitamin administration in type II diabetes patients
Clin. Biochem.
(2007) - et al.
Antioxidant enzyme and malondialdehyde levels in patients with social phobia
Psychiatry Res.
(2008) - et al.
The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay
Anal. Biochem.
(1996) - et al.
Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments
J. Affect. Disord.
(2001) - et al.
Increased oxidative stress in patients with depression and its relationship to treatment
Psychiatry Res.
(2013) - et al.
Increased plasma levels of 8-iso-PGF2alpha and IL-6 in an elderly population with depression
Psychiatry Res.
(2008) - et al.
Differential association of somatic and cognitive symptoms of depression and anxiety with inflammation: findings from the Netherlands study of depression and anxiety (NESDA)
Psychoneuroendocrinology
(2013) A new automated colorimetric method for measuring total oxidant status
Clin. Biochem.
(2005)- et al.
Lipid peroxidation and antioxidant protection in patients during acute depressive episodes and in remission after fluoxetine treatment
Pharmacol. Rep.
(2009)
Oxidative stress in anxiety and comorbid disorders
Neurosci. Res.
Depression and possible cancer risk due to oxidative DNA damage
J. Psychiatr. Res.
Systemic oxidatively generated DNA/RNA damage in clinical depression: associations to symptom severity and response to electroconvulsive therapy
J. Affect. Disord.
Antioxidative enzymes and increased oxidative stress in depressive women
Clin. Biochem.
Serum selenium and plasma malondialdehyde levels and antioxidant enzyme activities in patients with obsessive-compulsive disorder
Prog. Neuro Psychopharmacol. Biol. Psychiatry
Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative
Steroids
Dysregulated relationship of inflammation and oxidative stress in major depression
Brain Behav. Immun.
Interplay between the pro-oxidant and antioxidant systems and proinflammatory cytokine levels, in relation to iron metabolism and the erythron in depression
Free Radical Biol. Med.
Depression and anxiety symptoms are associated with white blood cell count and red cell distribution width: a sex-stratified analysis in a population-based study
Psychoneuroendocrinology
The relevance of oxidative stress status in first episode and recurrent depression
J. Affect. Disord.
The influence of dietary iron and tocopherols on oxidative stress and ras-p21 levels in the colon
Cancer Detect. Prev.
Estrogens as natural antioxidants of membrane phospholipid peroxidation
FEBS Lett.
Depression and anxiety both associate with serum level of hs-CRP: a gender-stratified analysis in a population-based study
Psychoneuroendocrinology
Free radicals, metals and antioxidants in oxidative stress-induced cancer
Chem. Biol. Interact.
Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases
Front. Neuroendocrinol.
Depression and oxidative damage to lipids
Psychoneuroendocrinology
Cited by (41)
Oxidative balance scores and depressive symptoms: Mediating effects of oxidative stress and inflammatory factors
2023, Journal of Affective DisordersSkin autofluorescence of advanced glycation end products and mortality in affective disorders in the lifelines cohort study: A mediation analysis
2021, Journal of Affective DisordersCitation Excerpt :A recent experimental study demonstrated that oxidative stress mediates microvascular endothelial dysfunction in major depression (Greaney et al., 2019). Several markers of oxidative stress have been linked to both depression and anxiety (Atmaca et al., 2008; Black et al., 2015; Kuloglu et al., 2002; Shafiee et al., 2018) and natural-cause mortality (Frasure-Smith et al., 2007; Kong et al., 2015), including skin autofluorescence (SAF) levels of advanced glycation end products (AGEs) (Hagen et al., 2020; van Dooren et al., 2017; van Waateringe et al., 2019). AGEs are formed through glycation and oxidation of proteins and lipids, a process for which the degree of oxidative stress is one of the key factors (Goldin et al., 2006).
Household food insecurity is associated with depressive symptoms in the Canadian adult population
2021, Journal of Affective DisordersDietary antioxidants and fibre intake and depressive symptoms in Iranian adolescent girls
2021, Public Health Nutrition
- 1
Equally contributed as first author.