Advertisement

A longitudinal study of neurotrophic, oxidative, and inflammatory markers in first-onset depression in midlife women

  • Matheus A. Pasquali
  • Bernard L. Harlow
  • Claudio N. Soares
  • Michael W. Otto
  • Lee S. Cohen
  • Luciano Minuzzi
  • Daniel P. Gelain
  • Jose Claudio F. Moreira
  • Benicio N. FreyEmail author
Original Paper

Abstract

Prospective studies have shown during the years preceding and following menopause, also known as “menopause transition”, that midlife women are at higher risk for developing first-onset major depressive disorder (MDD). The biological factors associated with risk and resilience in this population are, however, largely unknown. Considering the growing body of evidence suggesting that inflammation, oxidative stress, and brain-derived neurotrophic factor (BDNF) are associated with the pathophysiology of MDD, we investigated serum levels of protein carbonyl, lipid peroxidation (thiobarbituric acid reactive substances—TBARS), thiol group content, BDNF, 3-nitrotyrosine, and heat shock protein 70 (HSP70) in a longitudinal cohort of first-onset MDD. One hundred and forty-eight women from the Harvard Study of Moods and Cycles, a prospective study of midlife women monitored throughout the transition to menopause, were studied. Within- and between-groups analyses of these peripheral markers were conducted in 37 women who developed and 111 women that did not develop MDD during the 3-year follow-up period. In women who developed MDD, HSP70 and 3-nitrotyrosine were elevated at baseline, whereas TBARS were elevated 6 months prior to development of MDD, as compared to those who did not develop MDD. Within-group analyses showed that HSP70, 3-nitrotyrosine, and BDNF decreased over time, whereas protein carbonyl was elevated only at 12 months prior to development of MDD. In women who did not develop MDD, HSP70 and thiol decreased over time. The development of MDD in midlife women may be associated with a systemic cascade of pro-oxidative and pro-inflammatory events including increased HSP70, 3-nitrotyrosine, protein carbonyl, and lipid peroxidation and decreased BDNF.

Keywords

BDNF Blood Inflammation Major depression Menopause Oxidative stress Women 

Notes

Acknowledgements

This work was supported in part by an unrestricted educational Pfizer Fellowship in Women’s Mental Health (Dr. Pasquali). Original funding for the Harvard Study of Moods and Cycles was from NIH Grants R01-MH-50013 and R01-MH-69732 from the National Institute of Mental Health.

Compliance with ethical standards

Conflict of interest

Dr. Otto has served as a paid consultant for MicroTransponder Inc., Concert Pharmaceuticals, and ProPhase; provided expert consensus opinion for Otsuka Pharmaceuticals, received royalty support for use of the SIGH-A from ProPhase, and received book royalties from Oxford University Press, Routledge, and Springer. Dr. Cohen has received research support from AstraZeneca Pharmaceuticals, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Cephalon, Inc., Forest Laboratories, Inc., GlaxoSmithKline, National Institute on Aging, National Institutes of Health, National Institute of Mental Health, Ortho-McNeil Janssen, Pfizer Inc., and Sunovion Pharmaceuticals, Inc. He has done advisory/consulting activities with Noven Pharmaceuticals, and PamLab LLC. Dr. Gelain has received grants from Foundation For Supporting Research of Rio Grande do Sul, Brazil (FAPERGS: PIPG 0427-2551/14-0; and PqG 12099/8), and National Council for Scientific and Technological Development, Brazil (PVE 400437/2013-9). Dr. Moreira has received grants from Foundation For Supporting Research of Rio Grande do Sul, Brazil (FAPERGS: PIPG 0427-2551/14-0; and FAPERGS: PG 12/1060-6), and National Council for Scientific and Technological Development, Brazil (CNPq: 470973/2012-9). Dr. Frey has received grant/research support from Alternative Funding Plan Innovations Award, Brain and Behavior Research Foundation, Canadian Institutes of Health Research, Hamilton Health Sciences Foundation, J.P. Bickell Foundation, Ontario Brain Institute, Ontario Mental Health Foundation, Society for Women’s Health Research, Eli Lilly, and Pfizer, and has received consultant and/or speaker fees from AstraZeneca, Bristol-Myers Squibb, Canadian Psychiatric Association, CANMAT, Lundbeck, Pfizer, Servier, and Sunovion. Drs. Pasquali, Harlow, Soares, and Minuzzi report no financial relationships with commercial interests.

References

  1. 1.
    Afolayan AJ, Teng RJ, Eis A, Rana U, Broniowska KA, Corbett JA, Pritchard K, Konduri GG (2014) Inducible HSP70 regulates superoxide dismutase-2 and mitochondrial oxidative stress in the endothelial cells from developing lungs. Am J Physiol Lung Cell Mol Physiol 306:L351–L360CrossRefGoogle Scholar
  2. 2.
    Asea A (2007) Mechanisms of HSP72 release. J Biosci 32:579–584CrossRefGoogle Scholar
  3. 3.
    Behr GA, Moreira JC, Frey BN (2012) Preclinical and clinical evidence of antioxidant effects of antidepressant agents: implications for the pathophysiology of major depressive disorder. Oxid Med Cell Longev 2012:609421CrossRefGoogle Scholar
  4. 4.
    Bharath S, Andersen JK (2005) Glutathione depletion in a midbrain-derived immortalized dopaminergic cell line results in limited tyrosine nitration of mitochondrial complex i subunits: implications for Parkinson’s disease. Antioxid Redox Signal 7:900–910CrossRefGoogle Scholar
  5. 5.
    Birmaher B, Ryan ND, Williamson DE, Brent DA, Kaufman J, Dahl RE, Perel J, Nelson B (1996) Childhood and adolescent depression: a review of the past 10 years. Part I. J Am Acad Child Adolesc Psychiatry 35:1427–1439CrossRefGoogle Scholar
  6. 6.
    Bocchio-Chiavetto L, Bagnardi V, Zanardini R, Molteni R, Nielsen MG, Placentino A, Giovannini C, Rillosi L, Ventriglia M, Riva MA, Gennarelli M (2010) Serum and plasma BDNF levels in major depression: a replication study and meta-analyses. World J Biol Psychiatry 11:763–773CrossRefGoogle Scholar
  7. 7.
    Boiocchi C, Osera C, Monti MC, Ferraro OE, Govoni S, Cuccia M, Montomoli C, Pascale A, Bergamaschi R (2014) Are Hsp70 protein expression and genetic polymorphism implicated in multiple sclerosis inflammation? J Neuroimmunol 268:84–88CrossRefGoogle Scholar
  8. 8.
    Brunoni AR, Baeken C, Machado-Vieira R, Gattaz WF, Vanderhasselt MA (2014) BDNF blood levels after electroconvulsive therapy in patients with mood disorders: a systematic review and meta-analysis. World J Biol Psychiatry 15:411–418CrossRefGoogle Scholar
  9. 9.
    Burkhalter J, Fiumelli H, Allaman I, Chatton JY, Martin JL (2003) Brain-derived neurotrophic factor stimulates energy metabolism in developing cortical neurons. J Neurosci 23:8212–8220CrossRefGoogle Scholar
  10. 10.
    Bus BA, Molendijk ML, Tendolkar I, Penninx BW, Prickaerts J, Elzinga BM, Voshaar RC (2015) Chronic depression is associated with a pronounced decrease in serum brain-derived neurotrophic factor over time. Mol Psychiatry 20:602–608CrossRefGoogle Scholar
  11. 11.
    Carvalho AF, Köhler CA, Fernandes BS, Quevedo J, Miskowiak KW, Brunoni AR, Machado-Vieira R, Maes M, Vieta E, Berk M (2016) Bias in emerging biomarkers for bipolar disorder. Psychol Med 46:2287–2297CrossRefGoogle Scholar
  12. 12.
    Cattaneo A, Ferrari C, Uher R, Bocchio-Chiavetto L, Riva MA, MRC ImmunoPsychiatry Consortium, Pariante CM (2016) Absolute measurements of macrophage migration inhibitory factor and interleukin-1-β mrna levels accurately predict treatment response in depressed patients. Int J Neuropsychopharmacol 19. doi: 10.1093/ijnp/pyw045 CrossRefGoogle Scholar
  13. 13.
    Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL (2006) Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry 63:385–390CrossRefGoogle Scholar
  14. 14.
    Duman RS, Aghajanian GK (2012) Synaptic dysfunction in depression: potential therapeutic targets. Science 338:68–72CrossRefGoogle Scholar
  15. 15.
    Duman RS, Li N (2012) A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos Trans R Soc Lond B Biol Sci 367:2475–2484CrossRefGoogle Scholar
  16. 16.
    Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127CrossRefGoogle Scholar
  17. 17.
    Duman RS, Heninger GR, Nestler EJ (1997) A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597–606CrossRefGoogle Scholar
  18. 18.
    Feeney MB, Schoneich C (2012) Tyrosine modifications in aging. Antioxid Redox Signal 17:1571–1579CrossRefGoogle Scholar
  19. 19.
    Fornaro M, Rocchi G, Escelsior A, Contini P, Ghio M, Colicchio S, De Berardis D, Amore M, Fornaro P, Martino M (2013) VEGF plasma level variations in duloxetine-treated patients with major depression. J Affect Disord 151:590–595CrossRefGoogle Scholar
  20. 20.
    Freeman EW, Sammel MD, Lin H, Nelson DB (2006) Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry 63:375–382CrossRefGoogle Scholar
  21. 21.
    Frey BN, Andreazza AC, Houenou J, Jamain S, Goldstein BI, Frye MA, Leboyer M, Berk M, Malhi GS, Lopez-Jaramillo C, Taylor VH, Dodd S, Frangou S, Hall GB, Fernandes BS, Kauer-Sant’Anna M, Yatham LN, Kapczinski F, Young LT (2013) Biomarkers in bipolar disorder: a positional paper from the international society for bipolar disorders biomarkers task force. Aust N Z J Psychiatry 47:321–332CrossRefGoogle Scholar
  22. 22.
    Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT (2011) Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol 14:123–130CrossRefGoogle Scholar
  23. 23.
    Gelain DP, de Bittencourt Pasquali MA, Comim CM, Grunwald MS, Ritter C, Tomasi CD, Alves SC, Quevedo J, Dal-Pizzol F, Moreira JC (2011) Serum heat shock protein 70 levels, oxidant status, and mortality in sepsis. Shock 35:466–470CrossRefGoogle Scholar
  24. 24.
    Grunwald MS, Ligabue-Braun R, Souza CS, Verli H, Gelain DP, Moreira JCF (2017) Putative model for heat shock protein 70 complexation with receptor of advanced glycation end products through fluorescence proximity assays and normal mode analyses. Cell Stress Chaperones 22:99–111CrossRefGoogle Scholar
  25. 25.
    Harlow BL, Cohen LS, Otto MW, Spiegelman D, Cramer DW (1999) Prevalence and predictors of depressive symptoms in older premenopausal women. Arch Gen Psychiatry 56:418–424CrossRefGoogle Scholar
  26. 26.
    Harlow BL, Cohen LS, Otto MW, Liberman RF, Spiegelman D, Cramer DW (2002) Demographic, family, and occupational characteristics associated with major depression: the Harvard study of moods and cycles. Acta Psychiatr Scand 105:209–217CrossRefGoogle Scholar
  27. 27.
    Janssen-Heininger YM, Mossman BT, Heintz NH, Forman HJ, Kalyanaraman B, Finkel T, Stamler JS, Rhee SG, van der Vliet A (2008) Redox-based regulation of signal transduction: principles, pitfalls, and promises. Free Radic Biol Med 45:1–17CrossRefGoogle Scholar
  28. 28.
    Kapczinski F, Frey BN, Andreazza AC, Kauer-Sant’Anna M, Cunha AB, Post RM (2008) Increased oxidative stress as a mechanism for decreased BDNF levels in acute manic episodes. Rev Bras Psiquiatr 30:243–245CrossRefGoogle Scholar
  29. 29.
    Kapur S, Phillips AG, Insel TR (2012) Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Mol Psychiatry 17:1174–1179CrossRefGoogle Scholar
  30. 30.
    Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM (2002) Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 109:143–148CrossRefGoogle Scholar
  31. 31.
    Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS, National Comorbidity Survey R (2003) The epidemiology of major depressive disorder: results from the national comorbidity survey replication (NCS-R). JAMA 289:3095–3105CrossRefGoogle Scholar
  32. 32.
    Kotan Z, Sarandol E, Kirhan E, Ozkaya G, Kirli S (2012) Serum brain-derived neurotrophic factor, vascular endothelial growth factor and leptin levels in patients with a diagnosis of severe major depressive disorder with melancholic features. Ther Adv Psychopharmacol 2:65–74CrossRefGoogle Scholar
  33. 33.
    Kuloglu M, Atmaca M, Tezcan E, Gecici O, Tunckol H, Ustundag B (2002) Antioxidant enzyme activities and malondialdehyde levels in patients with obsessive-compulsive disorder. Neuropsychobiology 46:27–32CrossRefGoogle Scholar
  34. 34.
    Lapidus KA, Gabbay V, Mao X, Johnson A, Murrough JW, Mathew SJ, Shungu DC (2014) In vivo (1)H MRS study of potential associations between glutathione, oxidative stress and anhedonia in major depressive disorder. Neurosci Lett 569:74–79CrossRefGoogle Scholar
  35. 35.
    Molendijk ML, Spinhoven P, Polak M, Bus BA, Penninx BW, Elzinga BM (2014) Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (n = 9484). Mol Psychiatry 19:791–800CrossRefGoogle Scholar
  36. 36.
    Multhoff G (2007) Heat shock protein 70 (Hsp70): membrane location, export and immunological relevance. Methods 43:229–237CrossRefGoogle Scholar
  37. 37.
    Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547CrossRefGoogle Scholar
  38. 38.
    O’Donovan A, Rush G, Hoatam G, Hughes BM, McCrohan A, Kelleher C, O’Farrelly C, Malone KM (2013) Suicidal ideation is associated with elevated inflammation in patients with major depressive disorder. Depress Anxiety 30:307–314CrossRefGoogle Scholar
  39. 39.
    Ozdemir E, Cetinkaya S, Ersan S, Kucukosman S, Ersan EE (2009) Serum selenium and plasma malondialdehyde levels and antioxidant enzyme activities in patients with obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 33:62–65CrossRefGoogle Scholar
  40. 40.
    Pae CU, Drago A, Forlani M, Patkar AA, Serretti A (2010) Investigation of an epistastic effect between a set of TAAR6 and HSP-70 genes variations and major mood disorders. Am J Med Genet B Neuropsychiatr Genet 153B:680–683CrossRefGoogle Scholar
  41. 41.
    Papakostas GI, Shelton RC, Kinrys G, Henry ME, Bakow BR, Lipkin SH, Pi B, Thurmond L, Bilello JA (2013) Assessment of a multi-assay, serum-based biological diagnostic test for major depressive disorder: a pilot and replication study. Mol Psychiatry 18:332–339CrossRefGoogle Scholar
  42. 42.
    Polyakova M, Stuke K, Schuemberg K, Mueller K, Schoenknecht P, Schroeter ML (2015) BDNF as a biomarker for successful treatment of mood disorders: a systematic & quantitative meta-analysis. J Affect Disord 174:432–440CrossRefGoogle Scholar
  43. 43.
    Sahara N, Maeda S, Yoshiike Y, Mizoroki T, Yamashita S, Murayama M, Park JM, Saito Y, Murayama S, Takashima A (2007) Molecular chaperone-mediated tau protein metabolism counteracts the formation of granular tau oligomers in human brain. J Neurosci Res 85:3098–3108CrossRefGoogle Scholar
  44. 44.
    Sarandol A, Sarandol E, Eker SS, Karaagac EU, Hizli BZ, Dirican M, Kirli S (2006) Oxidation of apolipoprotein b-containing lipoproteins and serum paraoxonase/arylesterase activities in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 30:1103–1108CrossRefGoogle Scholar
  45. 45.
    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 22:67–73CrossRefGoogle Scholar
  46. 46.
    Scaini G, Comim CM, Oliveira GM, Pasquali MA, Quevedo J, Gelain DP, Moreira JC, Schuck PF, Ferreira GC, Bogo MR, Streck EL (2013) Chronic administration of branched-chain amino acids impairs spatial memory and increases brain-derived neurotrophic factor in a rat model. J Inherit Metab Dis 36:721–730CrossRefGoogle Scholar
  47. 47.
    Schmidt HD, Duman RS (2010) Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology 35:2378–2391CrossRefGoogle Scholar
  48. 48.
    Schmidt HD, Shelton RC, Duman RS (2011) Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology 36:2375–2394CrossRefGoogle Scholar
  49. 49.
    Sen S, Duman R, Sanacora G (2008) Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 64:527–532CrossRefGoogle Scholar
  50. 50.
    Stegenga BT, King M, Grobbee DE, Torres-Gonzalez F, Svab I, Maaroos HI, Xavier M, Saldivia S, Bottomley C, Nazareth I, Geerlings MI (2012) Differential impact of risk factors for women and men on the risk of major depressive disorder. Ann Epidemiol 22:388–396CrossRefGoogle Scholar
  51. 51.
    Tang D, Kang R, Xiao W, Wang H, Calderwood SK, Xiao X (2007) The anti-inflammatory effects of heat shock protein 72 involve inhibition of high-mobility-group box 1 release and proinflammatory function in macrophages. J Immunol 179:1236–1244CrossRefGoogle Scholar
  52. 52.
    Uher R, Tansey KE, Dew T, Maier W, Mors O, Hauser J, Dernovsek MZ, Henigsberg N, Souery D, Farmer A, McGuffin P (2014) An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am J Psychiatry 171:1278–1286CrossRefGoogle Scholar
  53. 53.
    Vogelzangs N, Beekman AT, van Reedt Dortland AK, Schoevers RA, Giltay EJ, de Jonge P, Penninx BW (2014) Inflammatory and metabolic dysregulation and the 2-year course of depressive disorders in antidepressant users. Neuropsychopharmacology 39:1624–1634CrossRefGoogle Scholar
  54. 54.
    Weissman MM, Bland R, Joyce PR, Newman S, Wells JE, Wittchen HU (1993) Sex differences in rates of depression: cross-national perspectives. J Affect Disord 29:77–84CrossRefGoogle Scholar
  55. 55.
    Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG, Joyce PR, Karam EG, Lee CK, Lellouch J, Lepine JP, Newman SC, Rubio-Stipec M, Wells JE, Wickramaratne PJ, Wittchen H, Yeh EK (1996) Cross-national epidemiology of major depression and bipolar disorder. JAMA 276:293–299CrossRefGoogle Scholar
  56. 56.
    Wen S, Cheng M, Wang H, Yue J, Li G, Zheng L, Zhong Z, Peng F (2012) Serum uric acid levels and the clinical characteristics of depression. Clin Biochem 45:49–53CrossRefGoogle Scholar
  57. 57.
    Wickramaratne PJ, Weissman MM (1996) Time trends in risk of depression. J Clin Epidemiol 49:1077–1078CrossRefGoogle Scholar
  58. 58.
    Yoshida T, Ishikawa M, Niitsu T, Nakazato M, Watanabe H, Shiraishi T, Shiina A, Hashimoto T, Kanahara N, Hasegawa T, Enohara M, Kimura A, Iyo M, Hashimoto K (2012) Decreased serum levels of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder. PLoS One 7(8):e42676CrossRefGoogle Scholar
  59. 59.
    Ziegler TR, Ogden LG, Singleton KD, Luo M, Fernandez-Estivariz C, Griffith DP, Galloway JR, Wischmeyer PE (2005) Parenteral glutamine increases serum heat shock protein 70 in critically ill patients. Intensive Care Med 31:1079–1086CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Matheus A. Pasquali
    • 1
    • 2
    • 3
  • Bernard L. Harlow
    • 4
  • Claudio N. Soares
    • 5
  • Michael W. Otto
    • 6
  • Lee S. Cohen
    • 7
  • Luciano Minuzzi
    • 1
    • 2
    • 8
  • Daniel P. Gelain
    • 3
  • Jose Claudio F. Moreira
    • 3
  • Benicio N. Frey
    • 1
    • 2
    • 8
    Email author
  1. 1.Women’s Health Concerns ClinicSt. Joseph’s Healthcare HamiltonHamiltonCanada
  2. 2.Mood Disorders ProgramSt. Joseph’s Healthcare HamiltonHamiltonCanada
  3. 3.Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  4. 4.Department of EpidemiologyBoston University School of Public HealthBostonUSA
  5. 5.Department of PsychiatryQueen’s University School of MedicineKingstonCanada
  6. 6.Department of Psychological and Brain SciencesBoston UniversityBostonUSA
  7. 7.Center for Women’s Mental Health Department of Psychiatry, Massachusetts General HospitalBostonUSA
  8. 8.Department of Psychiatry and Behavioural NeurosciencesMcMaster UniversityHamiltonCanada

Personalised recommendations