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Antioxidant uric acid in treated and untreated subjects with major depressive disorder: a meta-analysis and meta-regression

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Abstract

Pathophysiological mechanisms of major depressive disorder (MDD) seem to be associated with oxidative stress pathways and altered purinergic metabolism. We conducted a systematic review and meta-analysis to estimate if subjects with MDD might have reduced levels of antioxidant uric acid, considering also potential influence of antidepressant treatment. We searched the main Electronic Databases, identifying 14 studies that met our inclusion criteria. Meta-analyses were carried out generating pooled Hedges’ g and mean differences (MDs), using random-effects models. Heterogeneity across studies and risk of publication bias were estimated using standard methods. Relevant sensitivity and meta-regression analyses were conducted. Subjects with MDD had levels of uric acid lower than healthy controls (Hedges’ g = −0.30; p = 0.003). Overall between-study heterogeneity was high (I 2 = 76.3%). The effect was significant among studies including drug naïve/free MDD individuals (Hedges’ g = −0.55; p = 0.023), but not among those involving treated subjects (Hedges’ g = −0.15; p = 0.062). Relevant quality- and heterogeneity-based sensitivity analyses, as well as meta-regressions, confirmed these findings. In addition, uric acid levels significantly, though inconsistently (I 2 = 79.2%), increased after treatment (MD = +0.71 mg/dL; p < 0.001), regardless of follow-up duration (p = 0.518). Our meta-analysis shows that subjects with MDD have lower levels of uric acid. Since antidepressant treatment seems to influence this association, our findings support the hypothesis that uric acid levels may represent a state marker of MDD. Nevertheless, the potential role of additional factors that might clarify the nature of this association deserves further research.

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References

  1. Grassi D, Ferri L, Desideri G, Di Giosia P, Cheli P, Del Pinto R, Properzi G, Ferri C (2013) Chronic hyperuricemia, uric acid deposit and cardiovascular risk. Curr Pharm Des 19(13):2432–2438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA (2005) Uric acid and oxidative stress. Curr Pharm Des 11(32):4145–4151

    Article  CAS  PubMed  Google Scholar 

  3. Sautin YY, Johnson RJ (2008) Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 27(6):608–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ames BN, Cathcart R, Schwiers E, Hochstein P (1981) Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA 78(11):6858–6862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hooper DC, Scott GS, Zborek A, Mikheeva T, Kean RB, Koprowski H, Spitsin SV (2000) Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood-CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis. FASEB J 14(5):691–698

    Article  CAS  PubMed  Google Scholar 

  6. Kean RB, Spitsin SV, Mikheeva T, Scott GS, Hooper DC (2000) The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity. J Immunol 165(11):6511–6518

    Article  CAS  PubMed  Google Scholar 

  7. Fang P, Li X, Luo JJ, Wang H, Yang XF (2013) A double-edged sword: uric acid and neurological disorders. Brain Disord Ther 2(2):109

    PubMed  PubMed Central  Google Scholar 

  8. Wen S, Cheng M, Wang H, Yue J, Wang H, Li G, Zheng L, Zhong Z, Peng F (2012) Serum uric acid levels and the clinical characteristics of depression. Clin Biochem 45(1–2):49–53

    Article  CAS  PubMed  Google Scholar 

  9. Black CN, Bot M, Scheffer PG, Cuijpers P, Penninx BW (2015) Is depression associated with increased oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology 51:164–175

    Article  CAS  PubMed  Google Scholar 

  10. 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(1):12–19

    Article  CAS  PubMed  Google Scholar 

  11. Jiménez-Fernández S, Gurpegui M, Díaz-Atienza F, Pérez-Costillas L, Gerstenberg M, Correll CU (2015) Oxidative stress and antioxidant parameters in patients with major depressive disorder compared to healthy controls before and after antidepressant treatment: results from a meta-analysis. J Clin Psychiatry 76(12):1658–1667

    Article  PubMed  Google Scholar 

  12. Ali-Sisto T, Tolmunen T, Toffol E, Viinamäki H, Mäntyselkä P, Valkonen-Korhonen M, Honkalampi K, Ruusunen A, Velagapudi V, Lehto SM (2016) Purine metabolism is dysregulated in patients with major depressive disorder. Psychoneuroendocrinology 70:25–32

    Article  CAS  PubMed  Google Scholar 

  13. Kesebir S, Tatlıdil Yaylacı E, Süner O, Gültekin BK (2014) Uric acid levels may be a biological marker for the differentiation of unipolar and bipolar disorder: the role of affective temperament. J Affect Disord 165:131–134

    Article  CAS  PubMed  Google Scholar 

  14. Kobrosly R, van Wijngaarden E (2010) Associations between immunologic, inflammatory, and oxidative stress markers with severity of depressive symptoms: an analysis of the 2005–2006 National Health and Nutrition Examination Survey. Neurotoxicology 31(1):126–133

    Article  CAS  PubMed  Google Scholar 

  15. 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(2):67–73

    Article  CAS  PubMed  Google Scholar 

  16. Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87(2):659–797

    Article  CAS  PubMed  Google Scholar 

  17. El-Yacoubi M, Costentin J, Vaugeois JM (2003) Adenosine A2A receptors and depression. Neurology 61(11 Suppl 6):S82–S87

    Article  CAS  PubMed  Google Scholar 

  18. Yamada K, Kobayashi M, Kanda T (2014) Involvement of adenosine A2A receptors in depression and anxiety. Int Rev Neurobiol 119:373–393

    Article  PubMed  Google Scholar 

  19. Bartoli F, Crocamo C, Mazza MG, Clerici M, Carrà G (2016) Uric acid levels in subjects with bipolar disorder: a comparative meta-analysis. J Psychiatr Res 81:133–139

    Article  PubMed  Google Scholar 

  20. Bartoli F, Crocamo C, Dakanalis A, Brosio E, Miotto A, Capuzzi E, Clerici M, Carrà G (2017) Purinergic system dysfunctions in subjects with bipolar disorder: a comparative cross-sectional study. Compr Psychiatry 73:1–6

    Article  PubMed  Google Scholar 

  21. Liu T, Zhong S, Liao X, Chen J, He T, Lai S, Jia Y (2015) A meta-analysis of oxidative stress markers in depression. PLoS One 10(10):e0138904

    Article  PubMed  PubMed Central  Google Scholar 

  22. 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(5):1284–1290

    Article  CAS  PubMed  Google Scholar 

  23. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) Group. JAMA 283(15):2008–2012

    Article  CAS  PubMed  Google Scholar 

  24. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sterne JA, Egger M, Moher D (2008) Addressing reporting biases. In: Higgins JP, Green S (eds) Cochrane handbook for systematic reviews of interventions: Cochrane book series. John Wiley & Sons, Ltd, Chichester

    Google Scholar 

  26. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560

    Article  PubMed  PubMed Central  Google Scholar 

  27. Patsopoulos NA, Evangelou E, Ioannidis JP (2008) Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation. Int J Epidemiol 37(5):1148–1157

    Article  PubMed  Google Scholar 

  28. Bartoli F, Crocamo C, Gennaro GM, Castagna G, Trotta G, Clerici M, Carrà G (2016) Exploring the association between bipolar disorder and uric acid: a mediation analysis. J Psychosom Res 84:56–59

    Article  PubMed  Google Scholar 

  29. Chaudhari K, 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(1):77–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Keshavarz M, Khosravizadegan F, Bibak A (2016) Serum uric acid levels in different phases of acute severe manic and depressed patients. Arch Neurosci 3(2):e30236

    Google Scholar 

  31. Peng YF, Xiang Y, Wei YS (2016) The significance of routine biochemical markers in patients with major depressive disorder. Sci Rep 6:34402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wiener C, Rassier GT, Kaster MP, Jansen K, Pinheiro RT, Klamt F, Magalhaes PV, Kapczinski F, Ghisleni G, da Silva RA (2014) Gender-based differences in oxidative stress parameters do not underlie the differences in mood disorders susceptibility between sexes. Eur Psychiatry 29(1):58–63

    Article  CAS  PubMed  Google Scholar 

  33. Yanik M, Erel O, Kati M (2004) The relationship between potency of oxidative stress and severity of depression. Acta Neuropsychiatr 16(4):200–203

    Article  PubMed  Google Scholar 

  34. Zeman M, Jirak R, Zak A, Jachymova M, Vecka M, Tvrzicka E, Vavrova L, Kodydkova J, Stankova B (2009) Features of metabolic syndrome in patients with depressive disorder. Cas Lek Cesk 148(7):309–314

    CAS  PubMed  Google Scholar 

  35. Canan F, Yildirim O, Tosun M, Kayka N, Tuman TC, Alcelik A (2014) Serum levels of omentin are not altered in drug-naive patients with major depression: a pilot study. Psychiatr Danub 26(1):34–38

    CAS  PubMed  Google Scholar 

  36. Lasic D, Bevanda M, Bosnjak N, Uglesic B, Glavina T, Franic T (2014) Metabolic syndrome and inflammation markers in patients with schizophrenia and recurrent depressive disorder. Psychiatr Danub 26(3):214–219

    PubMed  Google Scholar 

  37. Cohen J (1988) Statistical power analysis for the behavioral sciences, 2nd edn. Lawrence Earlbaum Associates, Hillsdale

    Google Scholar 

  38. Bartoli F, Carrà G, Clerici M (2017) Update on bipolar disorder biomarker candidates: what about uric acid/adenosine hypothesis? Expert Rev Mol Diagn 17(2):105–106

    Article  CAS  PubMed  Google Scholar 

  39. Bartoli F, Crocamo C, Clerici M, Carrà G (2017) Allopurinol as add-on treatment for mania symptoms in bipolar disorder: systematic review and meta-analysis of randomised controlled trials. Br J Psychiatry 210(1):10–15

    Article  PubMed  Google Scholar 

  40. Prado de Oliveira E, Burini RC (2012) High plasma uric acid concentration: causes and consequences. Diabetol Metab Syndr 4:12

    Article  Google Scholar 

  41. Forsyth AK, Williams PG, Deane FP (2012) Nutrition status of primary care patients with depression and anxiety. Aust J Prim Health 18(2):172–176

    Article  PubMed  Google Scholar 

  42. Kaner G, Soylu M, Yüksel N, Inanç N, Ongan D, Başmısırlı E (2015) Evaluation of nutritional status of patients with depression. Biomed Res Int 2015:521481

    Article  PubMed  PubMed Central  Google Scholar 

  43. Soltani Z, Rasheed K, Kapusta DR, Reisin E (2013) Potential role of uric acid in metabolic syndrome, hypertension, kidney injury, and cardiovascular diseases: is it time for reappraisal? Curr Hypertens Rep 15(3):175–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yuan H, Yu C, Li X, Sun L, Zhu X, Zhao C, Zhang Z, Yang Z (2015) Serum uric acid levels and risk of metabolic syndrome: a dose-response meta-analysis of prospective studies. J Clin Endocrinol Metab 100(11):4198–4207

    Article  CAS  PubMed  Google Scholar 

  45. Carrà G, Bartoli F, Carretta D, Crocamo C, Bozzetti A, Clerici M, Bebbington PE (2014) The prevalence of metabolic syndrome in people with severe mental illness: a mediation analysis. Soc Psychiatry Psychiatr Epidemiol 49(11):1739–1746

    Article  PubMed  Google Scholar 

  46. Bartoli F, Carrà G, Crocamo C, Carretta D, Clerici M (2013) Bipolar disorder, schizophrenia, and metabolic syndrome. Am J Psychiatry 170(8):927–928

    Article  PubMed  Google Scholar 

  47. Clerici M, Bartoli F, Carretta D, Crocamo C, Bebbington P, Carrà G (2014) Cardiovascular risk factors among people with severe mental illness in Italy: a cross-sectional comparative study. Gen Hosp Psychiatry 36(6):698–702

    Article  PubMed  Google Scholar 

  48. Serretti A, Mandelli L (2010) Antidepressants and body weight: a comprehensive review and meta-analysis. J Clin Psychiatry 71(10):1259–1272

    Article  PubMed  Google Scholar 

  49. Michel TM, Pülschen D, Thome J (2012) The role of oxidative stress in depressive disorders. Curr Pharm Des 18(36):5890–5899

    Article  CAS  PubMed  Google Scholar 

  50. Sperlagh B, Csolle C, Ando RD, Goloncser F, Kittel A, Baranyi M (2012) The role of purinergic signaling in depressive disorders. Neuropsychopharmacol Hung 14(4):231–238

    PubMed  Google Scholar 

  51. Ortiz R, Ulrich H, Zarate CA Jr, Machado-Vieira R (2015) Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics. Prog Neuropsychopharmacol Biol Psychiatry 57:117–131

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We wish to express our great appreciation to all the authors of studies included in the current meta-analysis. A special thanks to Fatih Canan (Department of Psychiatry, Akdeniz University School of Medicine, Antalya, Turkey), Gabriele Ghisleni (Department of Life and Health Sciences, Universidade Catolica de Pelotas, Pelotas, Rio Grande do Sul, Brazil), and Davor Lasic (Department of Psychiatry, University Hospital Centre Split, Split, Croatia), who provided additional, unpublished data.

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Authors and Affiliations

  1. Department of Medicine and Surgery, University of Milano Bicocca, Via Cadore 48, 20900, Monza, Italy

    Francesco Bartoli, Giulia Trotta, Cristina Crocamo, Maria Rosaria Malerba, Massimo Clerici & Giuseppe Carrà

  2. Division of Psychiatry, University College London, London, UK

    Giuseppe Carrà

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  1. Francesco Bartoli
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Correspondence to Francesco Bartoli.

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Bartoli, F., Trotta, G., Crocamo, C. et al. Antioxidant uric acid in treated and untreated subjects with major depressive disorder: a meta-analysis and meta-regression. Eur Arch Psychiatry Clin Neurosci 268, 119–127 (2018). https://doi.org/10.1007/s00406-017-0817-7

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