Studies have suggested that depression was accompanied by oxidative stress dysregulation, including abnormal total antioxidant capacity (TAC), antioxidants, free radicals, oxidative damage and autoimmune response products. This meta-analysis aims to analyse the clinical data quantitatively by comparing the oxidative stress markers between depressed patients and healthy controls.
A search was conducted to collect the studies that measured the oxidative stress markers in depressed patients. Studies were searched in Embase, Medline, PsychINFO, Science direct, CBMDisc, CNKI and VIP from 1990 to May 2015. Data were subjected to meta-analysis by using a random effects model for examining the effect sizes of the results. Bias assessments, heterogeneity assessments and sensitivity analyses were also conducted.
115 articles met the inclusion criteria. Lower TAC was noted in acute episodes (AEs) of depressed patients (p<0.05). Antioxidants, including serum paraoxonase, uric acid, albumin, high-density lipoprotein cholesterol and zinc levels were lower than controls (p<0.05); the serum uric acid, albumin and vitamin C levels were increased after antidepressant therapy (p<0.05). Oxidative damage products, including red blood cell (RBC) malondialdehyde (MDA), serum MDA and 8-F2-isoprostanes levels were higher than controls (p<0.05). After antidepressant medication, RBC and serum MDA levels were decreased (p<0.05). Moreover, serum peroxide in free radicals levels were higher than controls (p<0.05). There were no differences between the depressed patients and controls for other oxidative stress markers.
This meta-analysis supports the facts that the serum TAC, paraoxonase and antioxidant levels are lower, and the serum free radical and oxidative damage product levels are higher than controls in depressed patients. Meanwhile, the antioxidant levels are increased and the oxidative damage product levels are decreased after antidepressant medication. The pathophysiological relationships between oxidative stress and depression, and the potential benefits of antioxidant supplementation deserve further research.
Citation: Liu T, Zhong S, Liao X, Chen J, He T, Lai S, et al. (2015) A Meta-Analysis of Oxidative Stress Markers in Depression. PLoS ONE 10(10): e0138904. https://doi.org/10.1371/journal.pone.0138904
Editor: Xiang Yang Zhang, Baylor College of Medicine, UNITED STATES
Received: April 13, 2015; Accepted: September 4, 2015; Published: October 7, 2015
Copyright: © 2015 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This work was supported by grants from the Planned Science and Technology Project of Guangdong Province, China (No:2014A020212401, 2014B020212022), the Educational Commission of Guangdong Province, China (No: 2013KJCX0025), the Humanities and Social Sciences Planning Fund (No:13YJA190008) and the Scientific Cultivation and Innovation Fund of Jinan University (No:21615466). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Depression affects millions of people and is the leading global cause of disability according to the World Health Organization . However, the psychopathological mechanisms of depression are unclear. Recently, many studies have indicated that oxidative stress might play a vital role . Some studies have demonstrated that depressed patients’ oxidative product levels in their peripheral blood [3, 4], red blood cells (RBC) , mononuclear cells , urine , cerebrospinal fluid  and postmortem brains  were abnormal. Antioxidant system disturbance in peripheral blood has also been reported . Autoimmune responses against neoepitopes induced by oxidative damage of fatty acid and protein membranes have been reported [10, 11]. Lower glutathione (GSH) levels  and a negative relationship between anhedonia severity and occipital GSH levels  were found through magnetic resonance spectroscopy (MRS).
Oxidative stress is defined as a persistent imbalance between oxidation and anti-oxidation, which leads to the damage of cellular macromolecules [14, 15]. The free radicals consist of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The main ROS includes superoxide anion, hydroxy radical and hydrogen peroxide, and the RNS consists of nitric oxide (NO), nitrogen dioxide and peroxynitrite. Nitrite is often used as a marker of NO activity. Interestingly, the brain appears to be more susceptible to the ROS/RNS because of the high content of unsaturated fatty acids, high oxygen consumption per unit weight, high content of key ingredients of lipid peroxidation (LP) and scarcity of antioxidant defence systems . The oxidative products include products of oxidative damage of LP, protein and DNA in depression. As a product of LP, abnormal malondialdehyde (MDA) levels in depression have been reported . 8-F2-isoprostane (8-iso-PGF2α) is another product of LP  that is considered to be a marker of LP because of its chemical stability . The protein carbonyl (PC), 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-oxo-7, 8-dihydroguanosine (8-oxoGuo) are the markers of protein, DNA and RNA oxidative damage, respectively [3, 20, 21]. The oxidative damage to cellular macromolecules changes the structure of original epitopes, which leads to the generation of new epitopes modified (neoepitopes). The antibodies against oxidative neoepitopes in depression have been found [10, 11, 22–24]. On the other hand, the antioxidant defence systems can be divided into enzymatic and non-enzymatic antioxidants. The non-enzymatic antioxidants include vitamins C and E, albumin, uric acid, high-density lipoprotein cholesterol (HDL-C), GSH, coenzyme Q10 (CoQ10), ceruloplasmin, zinc, selenium, and so on. The enzymatic antioxidants include superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), glutathione reductase (GR), paraoxonase 1 (PON1), and so on.
Some studies have reported that patients of depression have significant alterations in total antioxidant capacity (TAC), antioxidants, free radicals, oxidative products and antibodies against oxidative neoepitopes, but these findings were not consistent. A previous quantitative review of the association between depression and oxidative stress markers was reported, but it comprehensively analysed all oxidative stress markers at once . The objective of this study is to review the studies of each oxidative stress marker in depression and to quantify the magnitude of differences in oxidative stress markers between the depressed patients and control subjects in different sample sources (e.g., serum, plasma, RBCs) in acute episodes (AEs). Considering the effects of the treatment settings, we quantified the changes after antidepressant therapy. No differences in oxidative stress markers between serum and plasma were found in our analyses, both materials were referred to as “serum”.
Methods and Materials
We searched Medline, Embase, PsychINFO, Sciencedirect, CBMDisc, CNKI and VIP from 1990 to May 2015 using the following key words: (depression OR major depression OR unipolar depression OR major depressed disorder) AND (oxidation OR oxidative stress OR antioxidant OR antioxidant enzyme OR total antioxidant capacity OR total antioxidant potential OR free radical OR superoxide dismutase OR glutathione peroxidase OR catalase OR paraoxonase OR glutathione reductase OR vitamin C OR vitamin E OR albumin OR uric acid OR high-density lipoprotein cholesterol OR zinc OR nitric oxide OR nitrite OR peroxide OR malondialdehyde OR 8-F2-isoprostane OR protein carbonyl). We reviewed the titles and abstracts to select potentially relevant papers. If there was doubt about the suitability of the paper based on the abstract, the full text was reviewed. We manually searched the references and relevant articles for inclusion.
Studies were included in our analyses if they met the following criteria: 1) cross-sectional studies measuring oxidative stress markers in serum, plasma, or RBC of depressed patients; 2) studies that assessed oxidative stress markers in patients with an acute exacerbation of depression at baseline and again after antidepressant therapy; 3) inclusion of a depressed group as diagnosed by standard recognised criteria or screened with a standardized instrument; or 4) studies that provided subject numbers, means and standard deviations. Through our search strategy, we decided to focus on TAC, certain enzymatic antioxidants (SOD, GPX, CAT, PON and GR), non-enzymatic antioxidants (albumin, uric acid, zinc, HDL-C, vitamin C and E), free radicals (NO, nitric oxide, peroxide) and oxidative damage products (MDA, 8-iso-PGF2α, PCC), but not antibodies against oxidative neoepitopes and other oxidative stress markers because of limited studies.
Studies were excluded from our analyses if they met the following criteria: 1) reviews, conference abstracts, editorials and letters; 2) animal studies; 3) studies that reported on depressed symptoms in the context of other neuropsychiatric disorders or medical illnesses; or 4) dual publications (if the same sample was used in more than one publication, the study that provided stronger evidence was considered for analysis).
Data extraction and quality assessment
The data were extracted by two independent raters (TL and SMZ), with disagreements settled by discussion. Information was extracted in a systematic way as follows: 1) population characteristics; 2) sample types; 3) data for mean (SD); 4) diagnostic strategy; 5) treatment situations and 6) confounding factors. The quality was assessed independently by two raters by using the Newcastle-Ottawa Scale (NOS) (case control studies or cohort studies) . The NOS of case control studies assesses three components: selection, comparability and exposures, and the NOS of cohort studies assesses three components: selection, comparability and outcomes. We identified “high”-quality with a “star”. A study could be awarded a maximum of one star for each numbered item within the “selection” and “exposure or outcomes” categories. A maximum of two stars could be given for “comparability”. Studies with ≤ 4 stars were considered low quality and were excluded.
All statistical analyses were performed using the standardized mean difference (SMD) methodology in the Stata 12.0 software (StataCorp, College Station, Texas). Pooled effect sizes (ES) were calculated according to DerSimonian and Laird for the random effects model because of the diversity of methods, patients’ clinical statuses and treatments . Potential publication bias was assessed by using Egger’s test . Between-study heterogeneity (I2) was assessed as previously described by Glasziou and Sanders . Sensitivity analysis was performed by removing each study one by one and all combinations of two studies. The significance was defined as p<0.1 in Egger’s test and the significance of the other statistical tests was defined p<0.05. All comparisons were two-tailed, and 95% confidence intervals (CI) were described where applicable.
The search identified 7443 potentially relevant articles. After we removed duplicates, 6038 articles were remained. On the initial screening, 5894 were excluded based on titles and abstracts. Full-text evaluation was conducted for the remaining 144 articles, and 25 articles were excluded for not fulfilling inclusion criteria. 119 articles were remained. However, the quality of four papers was low, ranging from 3 to 4 stars in total [30–33]. Eventually, 115 articles that included 273 studies were included to our analyses [4, 9, 11, 17, 18, 20, 34–142]. 22 comparison analyses of depressed patients and healthy controls, and 14 comparison analyses of pre-and post-therapy in depressed patients were performed. Table 1 presents characteristics of included studies and meta-analyses of oxidative stress markers.
Studies of TAC
The serum TAC was lower in AEs of depressed patients than controls (p<0.05), but it did not increase after antidepressant therapy (Fig 1A). Publication bias assessed with Egger’s test was not significant for all analyses. The heterogeneity was high in the ES estimates for all analyses. Sensitivity analysis of serum TAC in the comparison of before and after the treatment (CBAT) was performed by removing two studies [34, 40], the heterogeneity was no longer significant, and the result remained unchanged. The heterogeneity was also significant for analysis of serum TAC in AEs after removing each study one by one and all combinations of two studies.
Positive effect sizes (bars go upwards) indicate that the marker levels in depressed patients were higher than controls or increased after antidepressant therapy; negative effect sizes (bars go downwards) indicate that marker levels were lower than controls or decreased after antidepressant therapy. *p < 0.05, **p < 0.01, ***p < 0.001. TAC, total antioxidant capacity; HDL-C, high-density lipoprotein cholesterol; SOD, superoxide dismutase; GPX, glutathione peroxidase; CAT, catalase; GR, glutathione reductase; PON, paraoxonase; MDA, malondialdehyde; 8-iso-PGF2α, 8-F2-isoprostanes; PCC, oxidation protein product.
Studies of non-enzymatic antioxidants
The serum uric acid, albumin, HDL-C and zinc levels were lower in AEs than controls (p<0.05), and uric acid, albumin and vitamin C levels were increased after antidepressant therapy (p<0.05). There were no differences in vitamin C and E levels between groups (Fig 1B). Publication bias was significant for vitamin C in CBAT, vitamin E in AEs, uric acid in AEs, albumin in AEs and CBAT, and HDL-C in AEs analyses (p<0.1), but not for other analyses. Heterogeneity was low for HDL-C in CBAT and moderate for vitamin C in CBAT but high in the other analyses. Sensitivity analyses showed heterogeneity was no longer significant and that vitamin C levels remained increased after antidepressant therapy after two studies were removed [34, 58] (p<0.001). There was also significant heterogeneity for other analyses that could be performed after removing each study one by one and all combinations of two studies.
Studies of enzymatic antioxidants
RBC enzymatic antioxidants.
There were no differences in all RBC enzymatic antioxidant activities in all analyses (Fig 1C). Publication bias was significant for GPX in CBAT, CAT in CBAT and GR in AEs (p<0.1), but not in other analyses. Heterogeneity was high for all enzymatic antioxidant analyses except CAT in CBAT. Sensitivity analyses showed that heterogeneity was no longer significant, SOD activity was decreased after antidepressant therapy after two studies were removed [43, 45] (p<0.05), and GPX activity was higher than controls after two studies were removed [4, 34] (p<0.05), CAT activity still didn’t differ between groups after one study was removed . There was also significant heterogeneity for other analyses after each single study and all combinations of two studies were removed.
Serum enzymatic antioxidants.
Serum PON activity was lower in AEs than controls, but it didn’t increased after antidepressant therapy. There were no differences in the other serum enzymatic antioxidant activities (Fig 1D). Publication bias was not significant for all enzymatic antioxidant analyses that could be performed. Heterogeneity was high for all analyses except PON activity in AEs and CBAT. Sensitivity analyses showed that heterogeneity was no longer significant, SOD activity was decreased after antidepressant therapy after one study was removed  (p<0.01). There was also significant heterogeneity for other analyses that could be performed after removing each study one by one and all combinations of two studies.
Studies of free radicals
The serum peroxide levels were higher in AEs than controls (p<0.05). Serum nitrite levels were decreased after antidepressant therapy (p<0.01). There were no differences in serum nitrite and NO levels between groups (Fig 1E). Publication bias was significant for peroxide levels in AEs (p<0.1), but not in any of the other analyses that could be performed. The heterogeneity was significant for nitrite, NO and peroxide levels in AEs but not for nitrite levels in CBAT. Sensitivity analyses showed that heterogeneity was no longer significant, the peroxide levels in AEs were still higher after one study was removed  (p<0.01). There was also significant heterogeneity in other analyses after removing each study one by one and all combinations of two studies.
Studies of oxidative damage products
The RBC MDA, serum MDA and 8-iso-PGF2α levels in AEs were all higher than controls (p<0.05), the RBC and serum MDA levels were decreased after antidepressant therapy (p<0.05). The serum PCC levels didn’t differ between groups in AEs (Fig 1F). Publication bias was significant for RBC and serum MDA in AEs (p<0.1), but not for other analyses. There was significant heterogeneity for all oxidative damage product analyses except the RBC MDA in CBAT. Sensitivity analyses showed that heterogeneity was no longer significant, RBC MDA levels in AEs was still higher than controls after one study was removed  (p<0.01), serum MDA levels remained decreased after antidepressant therapy after two studies were removed [4, 52] (p<0.01). Serum PCC levels in AEs still didn’t differ between groups after one study was removed . In other sensitivity analyses, the heterogeneity was also significant.
The present findings support oxidative stress may be disordered in depressed patients, which is demonstrated by abnormal oxidative stress marker levels. In this meta-analysis, at first we found in depressed patients: 1) the serum TAC, PON, uric acid, albumin, HDL-C and zinc levels were lower than controls; 2) the serum peroxide, MDA, 8-iso-PGF2α and RBC MDA levels were higher than controls. To explore the effect of the antidepressant therapy to oxidative stress markers, we reviewed the studies which had changes. And it came to the conclusions: 1) the serum uric acid, albumin, and vitamin C levels were increased; 2) the serum nitrite, RBC and serum MDA levels were decreased.
Considering the between-study heterogeneity, we performed sensitivity analyses. Following the sensitivity analyses, the heterogeneity of some oxidative markers was significantly decreased, the RBC GPX activities changed to be higher than controls, and the RBC and serum SOD activities were decreased after antidepressant therapy. However, the heterogeneity of most oxidative markers was also obvious, and even though the heterogeneity of a few studies was significantly decreased, but the results remained unchanged after one or two studies were removed. The higher RBC GPX activity could have been a compensatory mechanism for the excess production of free radicals in depressed patients . The decreased RBC and serum SOD activities could reflect a decrease in oxidative stress disturbance. PON1 is an enzymatic antioxidant that bound to HDL. Most of antioxidant activity of HDL relies on PON1 to prevent LDL and HDL oxidation . Lower PON1 activity in depressed patients may be ascribed to lower HDL-C levels.
The limitations of the present study include minor studies, publication bias and between-study heterogeneity in some analyses; thus, the results for many oxidative stress markers should be interpreted with caution. Because of the effect of the sample sources on oxidative stress markers, we quantified the magnitude of differences in different sample sources. However, there were few published oxidative stress marker studies, the number of included studies was small. Twenty-two comparison analyses of the depressed patients and healthy controls in oxidative stress markers were performed in this study, but one, four and two of the 22 comparison analyses only included 2, 3, and 4 studies, respectively. Fourteen analyses compared the effect of antidepressant therapy in depressed patients, and two, two and seven of this 14 comparison analyses only included 2, 3, and 4 studies, respectively.
It is possible that the heterogeneity could also have been attributable to many factors, including unmatched age, gender, race, ethnicity, body mass index (BMI), smoking, dietary habits, treatment settings, different assay methodologies, different phases of illness and different clinical courses of illness . By quality assessment, we eliminated a number of low-quality studies. However, most studies considered some, but not all confounding factors so that we could not exclude all of these studies. For example, 10 articles that measured serum TAC in AEs in our analyses, 9 of them considered the effects of age and gender [9, 34–36, 38–42], and only 2 articles matched BMI and smoking status [34, 39]. There are data that link oxidative stress and nicotine dependence [138, 145], but a sub-analysis was not possible for the limited number of studies that stratified by smoking status. Moreover, treatment settings factor was complex. Because most studies included patients that treated with various agents and treatment durations, the effects of specific antidepressant agents and the duration of antidepressant therapy on individual oxidative stress markers could not be evaluated exactly.
The serum antioxidant levels are significantly lower in depression in our study and previous reports, including PON, albumin, zinc, uric acid HDL-C, CoQ10  and GSH [4, 38]. Meanwhile, the oxidative damage product levels are significantly higher. The body couldn’t scavenge the excess free radicals (peroxide), leading to damages of main parts of cellular macromolecules such as fatty acids, protein, DNA, RNA and mitochondria. The longitudinal antidepressant therapy can reverse these abnormal oxidative stress parameters. It has proved these phenomena occur in depression, such as increased levels of MDA, 8-iso-PGF2α, 8-oxoGuo and 8-OHdG [3, 21]. Oxidative stress plays a crucial role in the pathophysiology of depression. Some genes may be a potential factor. Lawlor et al (2007) reported the R allele of PON1Q192R was associated with depression . In addition, poor appetite, psychological stressors, obesity, metabolic syndrome, sleep disorders, cigarette smoking and unhealthy lifestyle may also contribute to it . Furthermore, oxidative stress activates the immune-inflammatory pathways . But some studies supported decrease in albumin, zinc and HDL-C levels was probably related to increased levels of pro-inflammatory cytokines (such as interleukin-1 (IL-1) and IL-6) [59, 70–72, 117] during an acute phase response, which illustrated the activated immune-inflammatory pathways also activates the oxidative stress. These two mechanisms influence each other. On the other hand, the oxidative damage to cellular macromolecules changes the structure of original epitopes, which leads to generation of new epitopes modified (neoepitopes). Oxidative neoepitopes reported up to now include the conjugated oleic and azelaic acid, MDA, phosphatidyl inositol (Pi), NO-modified adducts and oxidized low density lipoprotein (oxLDL) [11, 22–24]. Maes et al reported the levels of serum IgG antibody against the oxLDL and IgM antibodies against the conjugated oleic and azelaic acid, MDA, Pi and NO-modified adducts were increased in depression [11, 22–24]. Depleted antioxidant defence in depression suggests that antioxidant supplements may be useful in clinical management. Preliminary evidence has indicated that patients treated with CoQ10 showed improvement in depressive symptoms and decrease in hippocampal oxidative DNA damage . In our analyses, vitamin C and E levels did not differ between depressed patients and controls, but many studies have reported that vitamin C and E supplements could improve depressive moods [150, 151].
In conclusion, we should cautiously interpret these results because the limitations of minor studies, public bias and between-study heterogeneity in our study. The results of our meta-analysis reveal that oxidative stress is disturbed in patients of depression. Further investigation needs to explore the roles of oxidative stress markers in the pathophysiology of depression and the potential benefits of antioxidant supplementation.
We would like to thank the authors of the original research studies that were included in this meta-analysis.
Conceived and designed the experiments: YBJ. Performed the experiments: TL SMZ XXL. Analyzed the data: JC TTH. Contributed reagents/materials/analysis tools: SKL. Wrote the paper: TL.
- 1. Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nature Reviews Neuroscience 7: 137–151. pmid:16429123
- 2. Maes M, Ruckoanich P, Chang YS, Mahanonda N, Berk M (2011) Multiple aberrations in shared inflammatory and oxidative & nitrosative stress (IO&NS) pathways explain the co-association of depression and cardiovascular disorder (CVD), and the increased risk for CVD and due mortality in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 35: 769–783. pmid:20561554
- 3. Forlenza MJ, Miller GE (2006) Increased serum levels of 8-hydroxy-2'-deoxyguanosine in clinical depression. Psychosom Med 68: 1–7. pmid:16449405
- 4. Rybka J, Kędziora-Kornatowska K, Banaś-Leżańska P, Majsterek I, Carvalho LA, Cattaneo A, et al. (2013) Interplay between the pro-oxidant and antioxidant systems and proinflammatory cytokine levels, in relation to iron metabolism and the erythron in depression. Free Radic Biol Med 63: 187–194. pmid:23707456
- 5. Moreno-Fernández AM, Cordero MD, Garrido-Maraver J, Alcocer-Gómez E, Casas-Barquero N, Carmona-López MI, et al. (2012) Oral treatment with amitriptyline induces coenzyme Q deficiency and oxidative stress in psychiatric patients. J Psychiatr Res 46: 341–345. pmid:22118833
- 6. Milaneschi Y, Cesari M, Simonsick EM, Vogelzangs N, Kanaya AM, Yaffe K, et al. (2013) Lipid peroxidation and depressed mood in community-dwelling older men and women. PLoS One 8: e65406. pmid:23776478
- 7. Pomara N, Bruno D, Sarreal AS, Hernando RT, Nierenberg J, Petkova E, et al. (2012) Lower CSF amyloid beta peptides and higher F2-isoprostanes in cognitively intact elderly individuals with major depressive disorder. Am J Psychiatry 169: 523–530. pmid:22764362
- 8. Gao SF, Qi XR, Zhao J, Balesar R, Bao AM, Swaab DF. (2013) Decreased NOS1 expression in the anterior cingulate cortex in depression. Cereb Cortex 23: 2956–2964. pmid:22989585
- 9. Ghodake SR, Suryakar AN, Kulhalli PM, Padalkar RK, Shaikh AK (2012) A study of oxidative stress and influence of antioxidant vitamins supplementation in patients with major depression. Current Neurobiology 3: 107–111.
- 10. Maes M, Mihaylova I, Kubera M, Leunis JC (2008) An IgM-mediated immune response directed against nitro-bovine serum albumin (nitro-BSA) in chronic fatigue syndrome (CFS) and major depression: evidence that nitrosative stress is another factor underpinning the comorbidity between major depression and CFS. Neuro Endocrinol Lett 29: 313–319. pmid:18580855
- 11. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. (2010) Increased plasma peroxides and serum oxidized low density lipoprotein antibodies in major depression: markers that further explain the higher incidence of neurodegeneration and coronary artery disease. J Affect Disord 125: 287–294. pmid:20083310
- 12. Godlewska BR, Near J, Cowen PJ (2015) Neurochemistry of major depression: a study using magnetic resonance spectroscopy. Psychopharmacology (Berl) 232(3): 501–507.
- 13. Lapidus KA, Gabbay V, Mao X, Johnson A, Murrough JW, Mathew SJ, et al. (2014) In vivo (1)H MRS study of potential associations between glutathione, oxidative stress and anhedonia in major depressive disorder. Neurosci Lett 569: 74–79. pmid:24704328
- 14. Ng F, Berk M, Dean O, Bush AI (2008) Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 11: 851–876. pmid:18205981
- 15. Hovatta I, Juhila J, Donner J (2010) Oxidative stress in anxiety and comorbid disorders. Neurosci Res 68: 261–275. pmid:20804792
- 16. Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408: 239–247. pmid:11089981
- 17. Bal N, Acar ST, Yazıcı A, Yazıcı K, Tamer L (2012) Altered Levels of Malondialdehyde and Vitamin E in Major Depressive Disorder and Generalized Anxiety Disorder. Dusunen Adam: Journal of Psychiatry & Neurological Sciences 25: 206–211.
- 18. Yager S, Forlenza MJ, Miller GE (2010) Depression and oxidative damage to lipids. Psychoneuroendocrinology 35: 1356–1362.
- 19. Praticò D, Rokach J, Lawson J, FitzGerald GA (2004) F2-isoprostanes as indices of lipid peroxidation in inflammatory diseases. Chem Phys Lipids 128: 165–171. pmid:15037161
- 20. Magalhães PV, Jansen K, Pinheiro RT, Colpo GD, da Motta LL, Klamt F, et al. (2012) Peripheral oxidative damage in early-stage mood disorders: a nested population-based case-control study. Int J Neuropsychopharmacol 8: 1043–1050.
- 21. Jorgensen A, Krogh J, Miskowiak K, Bolwig TG, Kessing LV, Fink-Jensen A, et al. (2013) Systemic oxidatively generated DNA/RNA damage in clinical depression: associations to symptom severity and response to electroconvulsive therapy. J Affect Disord 149: 355–362. pmid:23497793
- 22. Maes M, Mihaylova I, Kubera M, Leunis JC, Geffard M (2011) IgM-mediated autoimmune responses directed against multiple neoepitopes in depression: new pathways that underpin the inflammatory and neuroprogressive pathophysiology. J Affect Disord 135:414–418. pmid:21930301
- 23. Maes M, Kubera M, Mihaylova I, Geffard M, Galecki P, Leunis JC, et al. (2013) Increased autoimmune responses against auto-epitopes modified by oxidative and nitrosative damage in depression: implications for the pathways to chronic depression and neuroprogression. J Affect Disord 149:23–29. pmid:22898471
- 24. Maes M, Kubera M, Leunis JC, Berk M, Geffard M, Bosmans E. (2013) In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr Scand 127:344–354. pmid:22900942
- 25. Palta P, Samuel LJ, Miller ER 3rd, Szanton SL (2014) Depression and oxidative stress: results from a meta-analysis of observational studies. Psychosom Med 76: 12–19. pmid:24336428
- 26. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25: 603–605. pmid:20652370
- 27. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177–188. pmid:3802833
- 28. Egger M, Smith DG, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634. pmid:9310563
- 29. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50: 1088–1101. pmid:7786990
- 30. Qian ZP, Chen R, He YQ (2012) A study of correlation between serum zinc and lithium levels of depressed patients. Medical Laboratory Science and Clinics 23: 64.
- 31. Owen AJ, Batterham MJ, Probst YC, Grenyer BF, Tapsell LC (2005) Low plasma vitamin E levels in major depression: diet or disease?. Eur J Clin Nutr 59: 304–306. pmid:15508016
- 32. Chen Y, Liu SW (2010) A study of serum IL-1β, IL-6 and blood SOD levels in patients of depression. Neural Injury and Functional Reconstruction January 5: 74–75.
- 33. Narang RL, Gupta KR, Narang AP, Singh R (1991) Levels of copper and zinc in depression. Indian J Physiol Pharmacol. 35: 272–274. pmid:1812105
- 34. Kotan VO, Sarandol E, Kirhan E, Ozkaya G, Kirli S (2011) Effects of long-term antidepressant treatment on oxidative status in major depressive disorder: a 24-week follow-up study. Prog Neuropsychopharmacol Biol Psychiatry 35: 1284–1290. pmid:21515329
- 35. Gałecki P, Szemraj J, Bieńkiewicz M, Florkowski A, Gałecka E (2009) Lipid peroxidation and antioxidant protection in patients during acute depressive episodes and in remission after fluoxetine treatment. Pharmacol Rep 61: 436–447. pmid:19605942
- 36. Sarandol A, Sarandol E, Eker SS, Erdinc S, Vatansever E, Kirli S. (2007) Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative-antioxidative systems. Hum Psychopharmacol 22: 67–73. pmid:17299810
- 37. Vargas HO, Nunes SO, de Castro MR, Vargas MM, Barbosa DS, Bortolasci CC, et al. (2013) Oxidative stress and inflammatory markers are associated with depression and nicotine dependence. Neurosci Lett 544: 136–140. pmid:23583694
- 38. Mico JA, Rojas-Corrales MO, Gibert-Rahola J, Parellada M, Moreno D, Fraguas D, et al. (2011) Reduced antioxidant defense in early onset first-episode psychosis: a case-control study. BMC Psychiatry 11: 26. pmid:21320302
- 39. Yanik M, Erel O, Kati M (2004) The relationship between potency of oxidative stress and severity of depression. Blackwell Munksgaard 16: 200–203.
- 40. Selek S, Dalkilic A, Kaya MC, Savas HA, Bez Y, Celik H, et al. (2012) The relationship of oxidative metabolism to treatment response in major depression: A biological basis for treatment duration. Neurology, Psychiatry and Brain Research 18: 15–18.
- 41. Cumurcu BE, Ozyurt H, Etikan I, Demir S, Karlidag R (2009) Total antioxidant capacity and total oxidant status in patients with major depression: impact of antidepressant treatment. Psychiatry Clin Neurosci 63: 639–645. pmid:19674383
- 42. Prohan M, Amani R, Nematpour S, Jomehzadeh N, Haghighizadeh MH (2014) Total antioxidant capacity of diet and serum, dietary antioxidant vitamins intake, and serum hs-CRP levels in relation to depression scales in university male students. Redox Rep 19: 133–139. pmid:24524538
- 43. Gałecki P, Szemraj J, Bieńkiewicz M, Zboralski K, Gałecka E (2009) Oxidative stress parameters after combined fluoxetine and acetylsalicylic acid therapy in depressive patients. Hum Psychopharmacol 24: 277–286. pmid:19319921
- 44. Bilici M, Efe H, Köroğlu MA, Uydu HA, Bekaroğlu M, Değer O. (2001) Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by treatments. J Affect Disord 64: 43–51. pmid:11292519
- 45. Fadillioglu E, Kaya B, Uz E, Emre MH, Ünal S (2000) Effects of Moderate Exercise on Mild Depressive Mood, Antioxidants and Lipid Peroxidation 10: 194–200.
- 46. Hu JM, Feng DM, Li JZ (1996) Analysis of superoxide dismutase activity of red blood cell in patients with schizophrenia and depression. Chinese Journal of Nervous and Mental Diseases 22: 86–87.
- 47. Huang ZZ, Chen XW, Wu XN, Wang JL (1999) Study on lipid peroxide, superoxide dismutase and glutathione peroxidase in patients with affective disorder. Chin J Psychiatry 32: 191.
- 48. Szuster-Ciesielska A, Słotwińska M, Stachura A, Marmurowska-Michałowska H, Dubas-Slemp H, Bojarska-Junak A, et al. (2008) Accelerated apoptosis of blood leukocytes and oxidative stress in blood of patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry 32: 686–694. pmid:18083280
- 49. Herken H, Gurel A, Selek S, Armutcu F, Ozen ME, Bulut M, et al. (2007) Adenosine Deaminase, Nitric Oxide, Superoxide Dismutase, and Xanthine Oxidase in Patients with Major Depression:Impact of Antidepressant Treatment. Arch Med Res 38: 247–252. pmid:17227736
- 50. Russo AJ (2010) Increased Serum Cu/Zn SOD in Individuals with Clinical Depression Normalizes After Zinc and Antioxidant Therapy. Nutr Metab Insights 3: 37–42. pmid:23966790
- 51. Ormonde do Carmo MB, Mendes-Ribeiro AC, Matsuura C, Pinto VL, Mury WV, Pinto NO, et al. (2014) Major depression induces oxidative stress and platelet hyperaggregability. J Psychiatr Res 61: 19–24. pmid:25560770
- 52. Khanzode SD, Dakhale GN, Khanzode SS, Saoji A, Palasodkar R (2003) Oxidative damage and major depression: the potential antioxidant action of selective serotonin reuptake inhibitors. Redox Rep 8: 365–370. pmid:14980069
- 53. He J, Du CY, Gao P, Ruan QM, Wang KQ (2000) The clinical study of antioxidative capacity in psychiatry patients. Chinese Journal of Behavio ral Medical Science 9: 139–1142.
- 54. Zhang XH, Xu L, Tao SM, Tang M (1997) Changes of plasma SOD activity and MDA level in patients with depression and anxiety. Journal of Convalescen and Rehabilitation 12: 157–158.
- 55. Chen ZM, Zhang JH, Zhang XM, Fang RCh, Yu YH, Qi JY, et al. (1995) Significance of detection of lipid peroxide and glutathione peroxidase in patients with single episode depression. Journal of Xin Xiang Medical College 12: 153–155.
- 56. Barim AO, Aydin S, Colak R, Dag E, Deniz O, Sahin I. (2009) Ghrelin, paraoxonase and arylesterase levels in depressive patients before and after citalopram treatment. Clin Biochem 42: 1076–1081. pmid:19272368
- 57. Bortolasci CC, Vargas HO, Souza-Nogueira A, Barbosa DS, Moreira EG, Nunes SO, et al. (2014) Lowered plasma paraoxonase (PON)1 activity is a trait marker of major depression and PON1 Q192R gene polymorphism-smoking interactions differentially predict the odds of major depression and bipolar disorder. J Affect Disord 159:23–30. pmid:24679385
- 58. Gautam M, Agrawal M, Gautam M, Sharma P, Gautam AS, Gautam S. (2012) Role of antioxidants in generalised anxiety disorder and depression. Indian J Psychiatry 54: 244–247. pmid:23226848
- 59. Maes M, Smith R, Christophe A, Vandoolaeghe E, Van Gastel A, Neels H, et al. (1997) Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: relationship with immune inflammatory markers. Acta Psychiatr Scand 95: 212–221. pmid:9111854
- 60. Chaudhari K, Khanzode S, Khanzode S, Dakhale G, Saoji A, Sarode S. (2010) Clinical correlation of alteration of endogenous antioxidant-uric acid level in major depressive disorder. Indian J Clin Biochem 25: 77–81. pmid:23105889
- 61. Wiener C, Rassier GT, Kaster MP, Jansen K, Pinheiro RT, Klamt F, et al. (2014) Gender-based differences in oxidative stress parameters do not underlie the differences in mood disorders susceptibility between sexes. Eur Psychiatry 29: 58–63. pmid:23850061
- 62. Wen S, Cheng M, Wang H, Yue J, Wang H, Li G, et al. (2012) Serum uric acid levels and the clinical characteristics of depression. Clin Biochem 45: 49–53. pmid:22040815
- 63. Wen SL, Chen MF, Wang JF (2013) Analysis on serum levels of non-enzyme antioxidants and intelligence quotient in patients with recurrent depression. Chin Prev Med 14: 579–581.
- 64. Tao R, Li H, Zhang HM, Zhang Y, Ma HC (2014) High serum uric acid level in adolescent depressive patients. Med J Chin PAPF 24: 363–367.
- 65. Chen MF, Wang XL, Wang HL (2010) Analysis on serum levels of uric acid in patients with depression. Chin J Prev Chron Dis 18: 302.
- 66. Chen MF, Wang XL, Wang HL (2012) Plasma Non-enzyme Antioxidants Levels in the Depressive Patients with Attempted Suicide. Chin J Prev Chron Dis 20: 529–531.
- 67. Maes M, Vandewoude M, Scharpé S, De Clercq L, Stevens W, Lepoutre L, et al. (1991) Anthropometric and biochemical assessment of the nutritional state in depression: evidence for lower visceral protein plasma levels in depression. J Affect Disord 23: 25–33. pmid:1774420
- 68. Maes M, Wauters A, Neels H, Scharpé S, Van Gastel A, D'Hondt P, et al. (1995) Total serum protein and serum protein fractions in depression: relationships to depressive symptoms and glucocorticoid activity. J Affect Disord 4: 61–69.
- 69. Maes M, Wauters A, Verkerk R, Demedts P, Neels H, Van Gastel A, et al. (1996) Lower serum L-tryptophan availability in depression as a marker of a more generalized disorder in protein metabolism. Neuropsychopharmacology 15: 243–251. pmid:8873107
- 70. Maes M, Verkerk R, Vandoolaeghe E, Van Hunsel F, Neels H, Wauters A, et al. (1997) Serotonin-immune interactions in major depression: lower serum tryptophan as a marker of an immune-inflammatory response. Eur Arch Psychiatry Clin Neurosci 247: 154–161. pmid:9224908
- 71. Maes M, Vandoolaeghe E, Neels H, Demedts P, Wauters A, Meltzer HY, et al. (1997) Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness. Biol Psychiatry 42:349–358. pmid:9276075
- 72. Maes M, De Meester I, Verkerk R, De Medts P, Wauters A, Vanhoof G, et al. (1997) Lower serum dipeptidyl peptidase IV activity in treatment resistant major depression: Relationships with immune-inflammatory markers. Psychoneuroendocrinology 22: 65–78. pmid:9149329
- 73. Maes M, De Vos N, Demedts P, Wauters A, Neels H (1999) Lower serum zinc in major depression in relation to changes in serum acute phase proteins. J Affect Disord 56: 189–194. pmid:10701476
- 74. Uzbekov MG, Misionzhnik EY, Maximova NM, Vertogradova OP (2006) Biochemical profile in patients with anxious depression under the treatment with serotonergic antidepressants with different mechanisms of action. Hum Psychopharmacol 21: 109–115. pmid:16342231
- 75. Nunes SO, Reiche EM, Morimoto HK, Matsuo T, Itano EN, Xavier EC, et al. (2002) Immune and hormonal activity in adults suffering from depression. Braz J Med Biol Res 35: 581–587. pmid:12011944
- 76. Pinto VL, de Souza PF, Brunini TM, Oliveira MB, Moss MB, Siqueira MA, et al. (2012) Low plasma levels of L-arginine, impaired intraplatelet nitric oxide and platelet hyperaggregability: Implications for cardiovascular disease in depressive patients. J Affect Disord 140: 187–192. pmid:22424639
- 77. Huang TL (2002) Lower Serum Albumin Levels in Patients with Mood Disorders. Chang Gung Med J 25: 509–513. pmid:12392362
- 78. Van Hunsel F, Wauters A, Vandoolaeghe E, Neels H, Demedts P, Maes M (1996) Lower total serum protein, albumin, and beta-and gamma-globulin in major and treatment-resistant depression: Effects of antidepressant treatments. Psychiatry Res 65: 159–169. pmid:9029664
- 79. Salimi S, Kianpoor M, Abassi MR, Abdani M, Moghaddam ES (2008) Lower total serum protein, albumin and zinc in depression in an Iranian population. J Med Sci 8: 587–590.
- 80. Olusi SO, Fido AA (1996) Serum lipid concentrations in patients with major depressive disorder. Biol Psychiatry 40: 1128–1131. pmid:8931915
- 81. Lu J, Xiong SX (2010) The effect of escitalopram on serum glucose and lipids. Medical Journal of Chinese People’s Health 22:2242.
- 82. Yuan YG, Zhang XB, Wu AQ, Chen YQ (2002) Serum lipid concentrations in patients with comorbid anxiety and depression. Chin J Nerv Ment Dis 28:33–35.
- 83. Yuan YG, Ye Q, Chen Y, Li HL, Lu R, Mei G, Lu R, et al. (2006) A study of serum lipid concentrations and apolipoprotein E genotype among patients with senile depression and alzhemier disease. Chinese General Practice 9:106–108.
- 84. Yuan YG, Zhang XB, Wu AQ, Zhang SN, Chen YQ (2003) The relation ship between plasma monoamine neurotransmitters and serum lipid concentrations in depressive patients. J Clin Psychol Med 13:67–68.
- 85. Huang XB, Zhang JP, Guan NH, Wei QL, Lu JY, Gan ZY (2003) Serum lipid and catecholamin concentrations in patients with anxiety and depression. J Clin Psychol Med 13:94–95.
- 86. Zhang YN. A study of brain function, the levels of serum lipid and related psychosociological factors of depression in late life. Shandong: Taishan Medical University, 2007.
- 87. Wu MD, Yang W, Yang LW, Zhou Y (2004) A study of serum lipid concentrations in 536 patients of psychiatric disorders. Journal of Sichuan Continuing Education College of MS 23: 175–176.
- 88. Wang XH, Wang LL, Li P (2014) A study of physical function, serum lipids and cytokines in 48 uygur elderly patients with depression. Xinjiang Medical Journal 44:61–63.
- 89. Lv YC, Lv HJ, Liu BR, Qin DX, Ding YF, Li YN, et al. (2011) Analysis of suicidal behavior and detection of biological parameter in patients with depressive disorder. Journal of Medical Forum 32:7–13.
- 90. Guo XS, Xu MZ, Shi TY, Liu L (2006) Existence of lipid metabolism dysfunction in patients with endogenous depression. Laboratory Medicine 21:143–145.
- 91. Ni SL, Sun J, Shang XF, Guan CB (2011) The study of correlation between depression and metabolic syndrome in women. Guide of China Medicine 9:265–267.
- 92. Wang GH, Huang CX (2003) The levels of the cholesterol, triglyceride, lipoprotein, apolipoprotein in young depression patients. MedicaI JournaI of Wuhan University 24:174–176.
- 93. Che RP, Huang J (2014) The study on lipid metabolism in 86 patients with first episode depression. Journal of Practical Medical Techniques 21:664–665.
- 94. Zhang WJ, Zhang Fan (2012) The clinical study of serum thyroid hormone and lipid levels in patients with first episode depression. Chin J Lab Diagn 16:712–713.
- 95. Xia QC, Wang GH, Wang HL, Xie ZP, Fang Y, Li Y. (2009) Study of metabolism of glucose and lipid in patients of first-episode depressioon. J Clin Psychiatry 19:241–243.
- 96. Li CY, Hao JH, Guo YH (2011) The comparative study on serum glucose and lipids in patients with first episode depression. Medical Journal of ChinesePeople’s Health 23:1355–1356.
- 97. He WL, Xia QC (2013) Research on lipid metabolism of the first-episode patients with depression. World Health Digest Medical Periodieal 10:413–415.
- 98. Chen Y, Hong W. The relationship between the suicidal behavior of depressed patient and the level decline of serum, LDL and HDL cholesterols. Sichuan Mental Health 16:76–78.
- 99. Jiao YM, Sun LF, Wang LW, Zhang LS, Chen JH, Zhou M, et al. (2006) Fasting blood glucose and serum lipid level in patients with major depression and their relations to psychopathology. Shanghai Archives of Psychiatry 18:266–269.
- 100. Xu MZ, Guo SX, Chen ZM, Yu YH, Ji WD, Liang W, et al. (2000) Serum levels of cholesterol, lipoproteins and apolipoproteins in patients with depressive disorder and their significance. Ch in J Psychiatry 33:155–157.
- 101. Wu FX, Zang DX, Cheng ZL (1998) Depression and hemorheology. J Clin Psychol Med 8:341–343.
- 102. Canan F, Dikici S, Kutlucan A, Celbek G, Coskun H, et al. (2012) Association of mean platelet volume with DSM-IV major depression in a large community-based population: the MELEN study. J Psychiatr Res. 46: 298–302. pmid:22154758
- 103. Vargas HO, Nunes SO, Barbosa DS, Vargas MM, Cestari A, Dodd S, et al. (2014) Castelli risk indexes 1 and 2 are higher in major depression but other characteristics of the metabolic syndrome are not specific to mood disorders. Life Sci 102: 65–71. pmid:24607777
- 104. Huang TL, Wu SC, Chiang YS, Chen JF (2003) Correlation between serum lipid, lipoprotein concentrations and anxious state, depressive state or major depressive disorder. Psychiatry Res 118:147–153. pmid:12798979
- 105. Ebesunun MO, Eruvulobi HU, Olagunju T, Owoeye OA (2012) Elevated plasma homocysteine in association with decreased vitamin B(12), folate, serotonin, lipids and lipoproteins in depressed patients. Afr J Psychiatry (Johannesbg) 15:25–29.
- 106. Hocaoglu C, Kural B, Aliyazıcıoglu R, Deger O, Cengiz S (2012) IL-1β, IL-6, IL-8, IL-10, IFN-γ, TNF-α and its relationship with lipid parameters in patients with major depression. Metab Brain Dis 27:425–430. pmid:22707092
- 107. Vogelzangs N, Comijs HC, Oude Voshaar RC, Stek ML, Penninx BW (2014) Late-life depression symptom profiles are differentially associated with immunometabolic functioning. Brain Behav Immun 41:109–115. pmid:24838021
- 108. Lehto SM, Hintikka J, Niskanen L, Tolmunen T, Koivumaa-Honkanen H, Honkalampi K, et al. (2008) Low HDL cholesterol associates with major depression in a sample with a 7-year history of depressive symptoms. Prog Neuropsychopharmacol Biol Psychiatry 32:1557–1561. pmid:18583011
- 109. Lehto SM, Niskanen L, Tolmunen T, Hintikka J, Viinamäki H, Heiskanen T, et al. (2010) Low serum HDL-cholesterol levels are associated with long symptom duration in patients with major depressive disorder. Psychiatry Clin Neurosci 64:279–283. pmid:20374538
- 110. Sarandol A, Sarandol E, Eker SS, Karaagac EU, Hizli BZ, Dirican M, et al. (2006) Oxidation of apolipoprotein B-containing lipoproteins and serum paraoxonase/arylesterase activities in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 30:1103–1108. pmid:16716479
- 111. Karlović D, Buljan D, Martinac M, Marcinko D (2004) Serum lipid concentrations in Croatian veterans with post-traumatic stress disorder, post-traumatic stress disorder comorbid with major depressive disorder,or major depressive disorder. J Korean Med Sci 19:431–436. pmid:15201512
- 112. Sevincok L, Buyukozturk A, Dereboy F (2001) Serum lipid concentrations in patients with comorbid generalized anxiety disorder and major depressive disorder. Can J Psychiatry 46:68–71. pmid:11221492
- 113. Khalid A, Lal N, Trivedi JK, Dalal PK, Asthana OP, Srivastava JS, et al. (1998) Serum lipids: new biological markers in depression?. Indian J Psychiatry 40:217–223. pmid:21494476
- 114. Dimopoulos N, Piperi C, Salonicioti A, Psarra V, Mitsonis C, Liappas I, et al. (2007) Characterization of the lipid profile in dementia and depression in the elderly. J Geriatr Psychiatry Neurol 20: 138–144. pmid:17712096
- 115. Kerling A, Tegtbur U, Gützlaff E, Kück M, Borchert L, Ates Z, et al. (2015) Effects of adjunctive exercise on physiological and psychological parameters in depression: a randomized pilot trial. J Affect Disord 177:1–6. pmid:25743367
- 116. McLoughlin IJ, Hodge JS (1990) Zinc in depressive disorder. Acta Psychiatrica Scandinavica 82: 451–453. pmid:2291414
- 117. Maes M, D'Haese PC, Scharpé S, D'Hondt P, Cosyns P, et al. (1994) Hypozincemia in depression. J Affect Disord 31: 35–40.
- 118. Maes M, Christophe A, Delanghe J, Altamura C, Neels H, Meltzer HY, et al. (1999) Lowered omega 3 poly-unsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Res 85: 275–291. pmid:10333380
- 119. Yu HY, Cui C, Wang YZ, Liu LL, He BP, Zhao DS, et al. (1997) The mearsure of trace element in red blood cell and serum of depressed patients. Hebei Mental Health 10: 10–12.
- 120. Fernández-González MD, García-Unzueta MT, Herrán A, Vázquez-Barquero JL, Díez-Manrique JF, Álvarez C (1998) Trace elements in serum of psychiatric outpatients. Química Clínica 17: 208.
- 121. Nowak G, Zieba A, Dudek D, Krośniak M, Szymaczek M, Schlegel-Zawadzka M (2000) Serum Trace Elements in Animal Models and Human Depression. Part I. Zinc. Human Psychopharmacology: Clinical and Experimental 14: 83–86.
- 122. Chang XR, Wang HM, Li XH, Dai ZS, Zhao YH (2001) The mearsure of serum 14 kinds of trace element in patients of depression. Chinese Journal of Behavioral Medical Science 10: 589–590.
- 123. Yang K, Zhang ZX, Wang CH, Xie GR, Zhou WQ, Tang YQ, et al. (2005) The study of level changes of serum cytokine, C-reactive protein and zinc in patients with depression at pre- and post-treatment of Paroxetine. Chin J of Behavioral Med Sci 14: 792–794.
- 124. Crayton JW, Walsh WJ (2007) Elevated serum copper levels in women with a history of post-partum depression. J Trace Elem Med Biol 21: 17–21. pmid:17317521
- 125. Liu KB (2008) The study of the association between trace element and senile dementia/depressive disorder. Shandong: Shandong University, 2008.
- 126. Amani R, Saeidi S, Nazari Z, Nematpour S (2010) Correlation between dietary zinc intakes and its serum levels with depression scales in young female students. Biol Trace Elem Res 137: 150–158. pmid:20013161
- 127. Salustri C, Squitti R, Zappasodi F, Ventriglia M, Bevacqua MG, Fontana M, et al. (2010) Oxidative stress and brain glutamate-mediated excitability in depressed patient. J Affect Disord 127: 321–325. pmid:20547423
- 128. Guo XQ, Wang XD, Wang LW, Zhang YP (2011) A study of serum ten kinds of trace element level changes in depressed patients. China Health Monthly 1: 136–137.
- 129. Wu GF, Xiao SJ, Hu CM, Cong FY, Li YJ (2012) A study of correlation between cytokine, serum zinc level, thyroid hormone and depression. The Public Health 6: 61–62.
- 130. Arslan A, Uzun M (2008) Does the lower nitric oxide level cause cardiovascular changes inmajor depressed women?. Eur Rev Med Pharmacol Sci 12: 309–313. pmid:19024215
- 131. Yapislar H, Aydogan S, Ozüm Ü (2012) Biological understanding of the cardiovascular risk associated with major depression and panic disorder is important. Int J Psychiatry Clin Pract 16: 27–32. pmid:22122655
- 132. Chrapko WE, Jurasz P, Radomski MW, Lara N, Archer SL, Le Mellédo JM (2004) Decreased platelet nitric oxide synthase activity and plasma nitric oxide metabolites in major depressive disorder. Biol Psychiatry 56: 129–134. pmid:15231445
- 133. Suzuki E, Yagi G, Nakaki T, Kanba S, Asai M (2001) Elevated plasma nitrate levels in depressive states. J Affect Disord 63: 221–224. pmid:11246099
- 134. Kim YK, Paik JW, Lee SW, Yoon D, Han C, Lee BH (2006) Increased plasma nitric oxide level associated with suicide attempt in depressive patients. Prog Neuropsychopharmacol Biol Psychiatry 30: 1091–1096. pmid:16725247
- 135. Ikenouchi-Sugita A, Yoshimura R, Kishi T, Umene-Nakano W, Hori H, Hayashi K, et al. (2011) Three polymorphisms of the eNOS gene and plasma levels of metabolites of nitric oxide in depressed Japanese patients: a preliminary report. Hum Psychopharmacol 26: 531–534. pmid:22031268
- 136. Selley ML (2004) Increased (E)-4-hydroxy-2-nonenal and asymmetric dimethylarginine concentrations and decreased nitric oxide concentrations in the plasma of patients with major depression. J Affect Disord 80: 249–256. pmid:15207938
- 137. Talarowska M, Gałecki P, Maes M, Orzechowska A, Chamielec M, Bartosz G, et al. (2012) Nitric oxide plasma concentration associated with cognitive impairment in patients with recurrent depressive disorder. Neurosci Lett 510: 127–131. pmid:22273980
- 138. Akpinar A, Yaman GB, Demirdas A, Onal S (2013) Possible role of adrenomedullin and nitric oxide in major depression. Prog Neuropsychopharmacol Biol Psychiatry 46: 120–125. pmid:23867466
- 139. Canpolat S, KJrpJnar I, Deveci E, Aksoy H, Bayraktutan Z, Eren I, et al. (2014) Relationship of asymmetrical dimethylarginine, nitric oxide, and sustained attention during attack in patients with major depressive disorder. ScientificWorldJournal 2014: 624395. pmid:24558318
- 140. Xu XW, Pang MZ, Huang JX (2010) The mearsure of MAO, MDA, hs-CRP levels and their clinical meaning in patients of depression. Medical Innovation of Chin 7: 175–176.
- 141. Rawdin BJ, Mellon SH, Dhabhar FS, Epel ES, Puterman E, Su Y, et al. (2013) Dysregulated relationship of inflammation and oxidative stress in major depression. Brain Behav Immun 31: 143–152. pmid:23201587
- 142. Dimopoulos N, Piperi C, Psarra V, Lea RW, Kalofoutis A (2008) Increased plasma levels of 8-iso-PGF2alpha and IL-6 in an elderly population with depression. Psychiatry Res 161: 59–66. pmid:18783834
- 143. Razavi AE, Ani M, Pourfarzam M, Naderi GA (2012) Associations between high density lipoprotein mean particle size and serum paraoxonase-1 activity. J Res Med Sci 17:1020–1026. pmid:23833575
- 144. Flatow J, Buckley P, Miller BJ (2013) Meta-Analysis of Oxidative Stress in Schizophrenia. Biol Psychiatry 74: 400–409. pmid:23683390
- 145. Rytilä P, Rehn T, Ilumets H, Rouhos A, Sovijärvi A, Myllärniemi M, et al. (2006) Increased oxidative stress in asymptomatic current chronic smokers and GOLD stage 0 COPD. Respir Res 7: 69. pmid:16646959
- 146. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2009) Lower plasma Coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness. Neuro Endocrinol Lett 30:462–469. pmid:20010493
- 147. Lawlor DA, Day IN, Gaunt TR, Hinks LJ, Timpson N, Ebrahim S, et al. (2007) The association of the paraoxonase (PON1) Q192R polymorphism with depression in older women: findings from the British Women's Heart and Health Study. J Epidemiol Community Health 61:85–87. pmid:17183021
- 148. Moylan S, Berk M, Dean OM, Samuni Y, Williams LJ, O'Neil A, et al. (2014) Oxidative & nitrosative stress in depression: why so much stress?. Neurosci Biobehav Rev 45:46–62. pmid:24858007
- 149. Aboul-Fotouh S (2013) Coenzyme Q10 displays antidepressant-like activity with reduction of hippocampal oxidative/nitrosative DNA damage in chronically stressed rats. Pharmacol Biochem Behav 104: 105–112. pmid:23313551
- 150. Brody S (2002) High-dose ascorbic acid increases intercourse frequency and improves mood: a randomized controlled clinicaltrial. Biol Psychiatry 52: 371–374. pmid:12208645
- 151. Amr M, El-Mogy A, Shams T, Vieira K, Lakhan SE (2013) Efficacy of vitamin C as an adjunct to fluoxetine therapy in pediatric major depressive disorder: a randomized, double-blind, placebo-controlled pilot study. Nutr J 12: 31. pmid:23510529