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Higher BDNF plasma levels are associated with a normalization of memory dysfunctions during an antidepressant treatment

  • Jan EngelmannEmail author
  • Stefanie Wagner
  • Daniel Wollschläger
  • Sabine Kaaden
  • Konrad F. Schlicht
  • Nadine Dreimüller
  • Dieter F. Braus
  • Marianne B. Müller
  • Oliver Tüscher
  • Helge Frieling
  • André Tadić
  • Klaus Lieb
Original Paper

Abstract

One important symptom of patients with major depressive disorder (MDD) is memory dysfunction. However, little is known about the relationship between memory performance and depression severity, about the course of memory performance during antidepressant treatment as well as about the relationship between memory performance and brain-derived neurotrophic factor (BDNF). Memory function [learning and delayed recall) was assessed in 173 MDD patients (mean age 39.7 ± 11.3 years] treated by a pre-defined treatment algorithm within the early medication change (EMC) study at baseline, days 28 and 56. Depression severity was assessed in weekly intervals, BDNF plasma levels were measured at baseline, days 14 and 56, BDNF exon IV and p11 methylation status at baseline. Linear mixed regression models revealed that the course of depression severity was not associated with the course of learning or delayed recall in the total group. 63 (36%) of the investigated patients showed memory deficits (percent range ≤ 16) at baseline. Of those, 26(41%) patients experienced a normalization of their memory deficits during treatment. Patients with a normalization of their delayed recall performance had significantly higher plasma BDNF levels (p = 0.040) from baseline to day 56 than patients with persistent deficits. Baseline BDNF exon IV promoter and p11 gene methylation status were not associated with memory performance. Our results corroborate a concomitant amelioration of learning and delayed recall dysfunctions with successful antidepressant therapy in a subgroup of patients and support a role of BDNF in the neural mechanisms underlying the normalization of memory dysfunctions in MDD. ClinicalTrials.gov number: NCT00974155; EudraCT: 2008-008280-96.

Keywords

Major depressive disorder Brain-derived neurotrophic factor Memory BDNF exon IV and p11 promoter methylation Antidepressant therapy 

Notes

Acknowledgements

The authors are grateful to the members of the EMC Study Group, who were involved in the acquisition of data for this additional scientific investigation. These members are: Univ.-Prof. Dr. Klaus Lieb, PD Dr. André Tadić, Univ.-Prof. Christoph Hiemke, Dr. Nadine Dreimüller, Dr. Ömür Baskaya, Dr. Danuta Krannich, Dr. Sonja Lorenz, Annette Bernius, Dr. Tillmann Weichert, Dr. Markus Lorscheider, Dr. Martin Kloß, Dr. Dipl.-Psych. Isabella Helmreich, Dipl.-Psych. Karen Grüllich, Elnaz Ostad Haji, Yvonne Lober, Danuta Weichert, Dr. Konrad Schlicht, Dr. Christina Weigert, Dr. Jana Maurer (Department of Psychiatry and Psychotherapy, University Medical Centre Mainz); Dr. Konstantin Mayer (Sana Klinikum Offenbach, 65346 Offenbach, Germany); Prof. Dr. Dieter F. Braus, Dr. Julia Reiff, Dr. Christoph Kindler, Dr. Svenja Davis, Dr. Claudia Ginap, Dipl.-Psych. Julia Kraus, Dipl.-Psych. Sabine Kaaden, Dr. Dipl.-Psych. Jelena Janzen, Dipl.-Psych. Nina Löffler, Caterina Topaloglu, Elitza Klutscher (Clinic for Psychiatry and Psychotherapy, Wiesbaden).

Funding

The EMC trial was funded by the German Federal Ministry for Education and Research (BMBF Grant no.: 01 KG 0906; applicants: KL, AT, CH, ND, KK); the herein presented additional investigations are not part of the funding. The BMBF had no role in the conception of the study design, in the writing of the manuscript or the decision to submit the manuscript for publication.

Compliance with ethical standards

Conflict of interest

PD Dr. André Tadic is designated as inventor of the European patent number 12171541.1–2404 ‘Method for predicting response or non-response to a mono-aminergic antidepressant’. He has received in the last five years consultancy fees from Janssen and Novartis. Prof. Dr. Klaus Lieb is designated as inventor of the European patent number 12171541.1-2404 ‘Method for predicting response or non-response to a mono-aminergic antidepressant’. Prof. Dr. Dieter F. Braus has received in the last 5 years fees for unrestricted educational lectures from Lilly, Janssen, Bayer, Lundbeck, Servier, Shire, TAD Pharma. None of the authors (JE, SW, DW, SK, KFS, ND, MM, OT) has relevant financial interests in this manuscript.

Ethical standards statement

All patients gave their written informed consent to participate in the study after a complete and extensive description. All study components were approved by the local ethical committee of the Landesärztekammer Rheinland-Pfalz [study code no. 837.166.09 (6671)] and are compliant with the Code of Ethics of the World Medical Association (Declaration of Helsinki) in its current version.

Supplementary material

406_2019_1006_MOESM1_ESM.doc (67 kb)
Supplementary material 1 (DOC 67 kb)

References

  1. 1.
    Bortolato B, Carvalho AF, McIntyre RS et al (2014) Cognitive dysfunction in major depressive disorder: a state-of-the-art clinical review. CNS Neurol Disord Drug Targets 13(10):1804–1818CrossRefGoogle Scholar
  2. 2.
    Beblo T, Sinnamon G, Baune BT et al (2011) Specifying the neuropsychology of affective disorders: clinical, demographic and neurobiological factors. Neuropsychol Rev 21:337–359CrossRefGoogle Scholar
  3. 3.
    Bora E, Harrison BJ, Yücel M et al (2013) Cognitive impairment in euthymic major depressive disorder: a meta-analysis. Psychol Med 43:2017–2026CrossRefGoogle Scholar
  4. 4.
    Trivedi MH, Greer TL (2014) Cognitive dysfunction in unipolar depression: implications for treatment. J Affect Disord 152–154:19–27CrossRefGoogle Scholar
  5. 5.
    Marazziti D, Consoli G, Picchetti M et al (2010) Cognitive impairment in major depression. Euro J Pharmacol 626:83–86CrossRefGoogle Scholar
  6. 6.
    Herrera-Guzmán I, Gudayol-Ferré E, Herrera-Guzmán D et al (2009) Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. J Psychiatr Res 43:855–863CrossRefGoogle Scholar
  7. 7.
    Deuschle M, Kniest A, Niemann H et al (2004) Impaired declarative memory in depressed patients is slow to recover: clinical experience. Pharmacopsychiatry 37:147–151CrossRefGoogle Scholar
  8. 8.
    Boeker H, Schulze J, Richter A et al (2012) Sustained cognitive impairment after clinical recovery of severe depression. J Nerv Ment Dis 200:773–776CrossRefGoogle Scholar
  9. 9.
    Paelecke-Habermann Y, Pohl J, Leplow B (2005) Attention and executive functions in remitted major depression patients. J Affect Disord 89:125–135CrossRefGoogle Scholar
  10. 10.
    Delaloye C, Moy G, de Bilbao F et al (2010) Neuroanatomical and neuropsychological features of elderly euthymic depressed patients with early- and late-onset. J Neurol Sci 299(1–2):19–23CrossRefGoogle Scholar
  11. 11.
    Molendijk ML, Bus BA, Spinhoven P et al (2011) Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry 16:1088–1095CrossRefGoogle Scholar
  12. 12.
    Polyakova M, Stuke K, Schuemberg K et al (2015) BDNF as a biomarker for successful treatment of mood disorders: a systematic and quantitative meta-analysis. J Affect Disord 174:432–440CrossRefGoogle Scholar
  13. 13.
    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
  14. 14.
    Adlam J, Zaman R (2015) The role of BDNF and memory in major depressive disorder. Psychiatr Danub 25:368–369Google Scholar
  15. 15.
    Bocchio-Chiavetto L, Bagnardi V, Zanardini R et al (2010) Serum and plasma BDNF levels in major depression: a replication study and meta-analyses. World J Biol Psychiatry 11:763–773CrossRefGoogle Scholar
  16. 16.
    Mamounas LA, Blue ME, Siuciak JA et al (1995) Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. J Neurosci 15:7929–7939CrossRefGoogle Scholar
  17. 17.
    Mossner R, Mikova O, Koutsilieri E et al (2007) Consensus paper of the WFSBP Task Force on Biological Markers: biological markers in depression. World J Biol Psychiatry 8:141–174CrossRefGoogle Scholar
  18. 18.
    Jehn CF, Becker B, Flath B et al (2015) Neurocognitive function, brain-derived neurotrophic factor (BDNF) and IL-6 levels in cancer patients with depression. J Neuroimmunol 287:88–92CrossRefGoogle Scholar
  19. 19.
    Lu Y, Christian K, Lu B (2008) BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 89:312–323CrossRefGoogle Scholar
  20. 20.
    Oral E, Canpolat S, Yildirim S et al (2012) Cognitive functions and serum levels of brain-derived neurotrophic factor in patients with major depressive disorder. Brain Res Bull 88:454–459CrossRefGoogle Scholar
  21. 21.
    Dols A, Thesing CS, Bondlaert F et al (2015) BDNF serum levels are not related to cognitive functioning in older depressed patients and controls. Int Psychogeriatr 27:649–656CrossRefGoogle Scholar
  22. 22.
    Wagner S, Kayser S, Engelmann J et al (2018) High plasma BDNF levels predict the recovery of executive dysfunctions in patients with major depressive disorder. World J Biol Psychiatry 2:1–12CrossRefGoogle Scholar
  23. 23.
    Stelzhammer V, Guest PC, Rothermundt M et al (2013) Electroconvulsive therapy exerts mainly acute molecular changes in serum of major depressive disorder patients. Eur Neuropsychopharmacol 23:1199–1207CrossRefGoogle Scholar
  24. 24.
    Bumb JM, Aksay SS, Janke C (2015) Focus on ECT seizure quality: serum BDNF as a peripheral biomarker in depressed patients. Eur Arch Psychiatry Clin Neurosci 265:227–232CrossRefGoogle Scholar
  25. 25.
    Biedermann SV, Bumb JM, Demirakca T et al (2016) Improvement in verbal memory performance in depressed in-patients after treatment with electroconvulsive therapy. Acta Psychiatr Scand 134:461–468CrossRefGoogle Scholar
  26. 26.
    Zheleznyakova GY, Cao H, Schioth HB (2016) BDNF DNA methylation changes as a biomarker of psychiatric disorders: literature review and open access database analysis. Behav Brain Funct 12:17CrossRefGoogle Scholar
  27. 27.
    Svenningsson P, Kim Y, Warner-Schmidt J et al (2013) p11 and its role in depression and therapeutic responses to antidepressants. Nat Rev Neurosci 14:673–680CrossRefGoogle Scholar
  28. 28.
    Warner-Schmidt JL, Chen EY, Zhang X et al (2010) A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiatry 68:528–535CrossRefGoogle Scholar
  29. 29.
    Tadic A, Muller-Engling L, Schlicht KF (2014) Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression. Mol Psychiatry 19:281–283CrossRefGoogle Scholar
  30. 30.
    Day JJ, Sweatt JD (2011) Epigenetic mechanisms in cognition. Neuron 70:813–829CrossRefGoogle Scholar
  31. 31.
    Day JJ, Sweatt JD (2012) Epigenetic treatments for cognitive impairments. Neuropsychopharmacology 37:247–260CrossRefGoogle Scholar
  32. 32.
    Rudenko A, Tsai LH (2014) Epigenetic modification in the nervous system and their impact upon cognitive impairments. Neuropharmacology 80:70–82CrossRefGoogle Scholar
  33. 33.
    Tadic A, Gorbulev S, Dahmen N et al (2010) Rationale and design of the randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with major depressive disorder–the EMC trial. Trials 11:21CrossRefGoogle Scholar
  34. 34.
    Tadic A, Wagner S, Gorbulev S et al (2011) Peripheral blood and neuropsychological markers for the onset of action of antidepressant drugs in patients with major depressive disorder. BMC Psychiatry 11:16CrossRefGoogle Scholar
  35. 35.
    Tadic A, Wachtlin D, Berger M, Braus DF, van Calker D, Dahmen N, Dreimuller N, Engel A, Gorbulev S, Helmreich I et al (2016) Randomized controlled study of early medication change for non-improvers to antidepressant therapy in major depression–the EMC trial. Eur Neuropsychopharmacol 26:705–716CrossRefGoogle Scholar
  36. 36.
    Nicod J, Wagner S, Vonberg F et al (2016) The amount of mitochondrial DNA in blood reflects the course of a depressive episode. Biol Psychiatry 80:e41–42CrossRefGoogle Scholar
  37. 37.
    American Psychiatric Association (2010) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Press, WashingtonGoogle Scholar
  38. 38.
    Ackenheil M, Stotz G, Dietz-Bauer R et al (1998) M.I.N.I: international neuropsychiatric interview—German Version 5.0.0. Deutschland, MünchenGoogle Scholar
  39. 39.
    Wittchen HU, Zaudig M, Fydrich T (1996) SKID-I/-II: Strukturiertes klinisches Interview für DSM-IV. Hogrefe Verlag, GöttingenGoogle Scholar
  40. 40.
    Hamilton M (1960) Hamilton depression rating scale—a rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62CrossRefGoogle Scholar
  41. 41.
    Wagner S, Helmreich I, Lieb K et al (2011) Standardized rater training for the Hamilton Depression Rating Scale (HAMD-17) and the inventory of depressive symptoms [IDS(C30)]. Psychopathology 44:68–70CrossRefGoogle Scholar
  42. 42.
    Helmstädter C, Lendt M, Lux S (2001) Verbaler Lern- und Merkfähigkeitstest. Beltz Test GmbH, GöttingenGoogle Scholar
  43. 43.
    Lehrl S (1969) Mehrfachwahl-Wortschatz-Intelligenztest (MWT-B). Perimed Fachbuch Verlagsgesellschaft mbH, ErlangenGoogle Scholar
  44. 44.
    Lewin J, Schmitt AO, Adorjan P et al (2004) Quantitative DNA methylation analysis based on four-dye trace data from direct sequencing of PCR amplificates. Bioinformatics 20:3005–3012CrossRefGoogle Scholar
  45. 45.
    Kenward MG, Roger JH (1997) Small sample inference for fixed effects from restricted maximum likelihood. Biometrics 53:983–997CrossRefGoogle Scholar
  46. 46.
    Nakagawa S, Schielzeth H (2013) A general and simple method for obtaining R 2 from generalized linear mixed-effects models. Methods Ecol Evol 4:133–142CrossRefGoogle Scholar
  47. 47.
    R Core Team (2017) A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/
  48. 48.
    Bates D, Maechler M, Bolker B et al (2015) Fitting linear mixed-effects models using lme4. J Stat Softw 67:1–48CrossRefGoogle Scholar
  49. 49.
    Halekoh U, Højsgaard SA (2014) Kenward–Roger approximation and parametric bootstrap methods for tests in linear mixed models—the R package pbkrtest. J Stat Softw 58:1–30Google Scholar
  50. 50.
    Reppermund S, Ising M, Lucae S et al (2009) Cognitive impairment in unipolar depression is persistent and non-specific: further evidence for the final common pathway disorder hypothesis. Psychol Med 39:603–614CrossRefGoogle Scholar
  51. 51.
    Christensen H, Griffiths K, Mackinnon A et al (1997) A quantitative review of cognitive deficits in depression and Alzheimer-type dementia. J Int Neuropsychol Soc 3:631–651Google Scholar
  52. 52.
    Bearden CE, Glahn DC, Monkul ES et al (2006) Patterns of memory impairment in bipolar disorder and unipolar major depression. Psychiatry Res 142:139–150CrossRefGoogle Scholar
  53. 53.
    Hasselbalch BJ, Knorr U, Kessing LV (2011) Cognitive impairment in the remitted state of unipolar depressive disorder: a systematic review. J Affect Disord 134:20–31CrossRefGoogle Scholar
  54. 54.
    Hinkelmann K, Moritz S, Botzenhardt J et al (2012) Changes in cortisol secretion during antidepressive treatment and cognitive improvement in patients with major depression: a longitudinal study. Psychoneuroendocrinology 37:685–692CrossRefGoogle Scholar
  55. 55.
    Taliaz D, Loya A, Gersner R et al (2011) Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor. J Neurosci 31:4475–4483CrossRefGoogle Scholar
  56. 56.
    Elzinga BM, Molendijk ML, Oude Voshaar RC (2011) The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val66Met. Psychopharmacology 214:319–328CrossRefGoogle Scholar
  57. 57.
    Colle R, Trabado S, Rotenberg S et al (2016) Tobacco use is associated with increased plasma BDNF levels in depressed patients. Psychiatry Res 246:370–372CrossRefGoogle Scholar
  58. 58.
    Begliuomini S, Lenzi E, Ninni F et al (2008) Plasma brain-derived neurotrophic factor daily variations in men: correlation with cortisol circadian rhythm. J Endocrinol 197:429–435CrossRefGoogle Scholar
  59. 59.
    Piccinni A, Marazziti D, Del Debbio A et al (2008) Diurnal variation of plasma brain-derived neurotrophic factor (BDNF) in humans: an analysis of sex differences. Chronobiol Int 25:819–826CrossRefGoogle Scholar
  60. 60.
    Cain SW, Chang AM, Vlasac I et al (2017) Circadian rhythms in plasma brain-derived neuritrophic factor differ in men and women. J Biol Rhythms 32:75–82CrossRefGoogle Scholar
  61. 61.
    Archer T, Josefsson T, Lindwall M (2014) Effects of physical exercise on depressive symptoms and biomarkers in depression. CNS Neurol Disord: Drug Targets 13:1640–1653CrossRefGoogle Scholar
  62. 62.
    Kerling A, Kück M, Tegtbur U et al (2017) Exercise increases serum-brain-derived neurotrophic factor in patients with major depressive disorder. J Affect Disord 215:152–155CrossRefGoogle Scholar
  63. 63.
    Jeon YK, Ha CH (2017) The effect of exercise intensity on brain derived neurotrophic factor and memory in adolescents. Environ Health Prev Med 22:27CrossRefGoogle Scholar
  64. 64.
    Pius-Sadowska E, Machalinski B (2017) BDNF—a key player in cardiovascular system. J Mol Cell Cardiol 110:54–60CrossRefGoogle Scholar
  65. 65.
    Linn BS, Linn MW, Gurel L (1968) Cumulative illness rating scale. J Am Geriatr Soc 16:622–626CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jan Engelmann
    • 1
    Email author
  • Stefanie Wagner
    • 1
  • Daniel Wollschläger
    • 2
  • Sabine Kaaden
    • 3
  • Konrad F. Schlicht
    • 1
    • 4
  • Nadine Dreimüller
    • 1
  • Dieter F. Braus
    • 3
  • Marianne B. Müller
    • 5
  • Oliver Tüscher
    • 1
  • Helge Frieling
    • 6
  • André Tadić
    • 1
    • 7
  • Klaus Lieb
    • 1
  1. 1.Department of Psychiatry and PsychotherapyUniversity Medical Center of the Johannes-Gutenberg-University MainzMainzGermany
  2. 2.Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI)University Medical CenterMainzGermany
  3. 3.Department of Psychiatry and PsychotherapyHELIOS Dr. Horst-Schmidt-KlinikenWiesbadenGermany
  4. 4.Department of NeurologyUniversity Medical Center MainzMainzGermany
  5. 5.Experimental Psychiatry, Department of Psychiatry and Psychotherapy and Focus Program Translational NeuroscienceUniversity Medical CenterMainzGermany
  6. 6.Molecular Neuroscience Laboratory, Department of Psychiatry, Social Psychiatry and PsychotherapyMedical SchoolHannoverGermany
  7. 7.Department of Psychiatry, Psychosomatics and PsychotherapyAgaplesion ElisabethenstiftDarmstadtGermany

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