THE ROLE OF BRAIN-DERIVED NEUROTROPHIC FACTOR IN THE PATHOGENESIS OF DEPRESSIVE DISORDERS

DOI: https://doi.org/10.29296/24999490-2021-03-02

I.I. Shepeleva(1, 2), I.V. Chekhonin(1), A.A. Chernysheva(1), K.Sh. Kardashova(1), E.V. Voznyakovskaya(1), O.I. Gurina(1), 1-V.P. Serbsky National Medical Research Centre for Psychiatry and Narcology, Kropotkinskiy by-street, 23, Moscow, 119034, Russian Federation; 2-N.I. Pirogov Russian National Research Medical University, Ostrovitianova str., 1, Moscow, 117997, Russian Federation E-mail: [email protected]

The neurotrophic hypothesis of depressive disorders has gained widespread recognition nowadays. This review is devoted to the brain-derived neurotrophic factor (BDNF) system in the pathogenesis of depression and major depressive disorder. We describe the structure and expression mechanisms of the BDNF gene, peculiarities of BDNF synthesis and processing, which yield not only mature BDNF but also pro-BDNF and BDNF pro-peptide. This work also summarizes BDNF signaling pathways and their long-term synaptic potentiation (mature BDNF) and long-term depression (pro-BDNF). The analyzed studies include clinical results and animal model experiments. Morphological data supports the correlation between BDNF signaling alterations and degenerative changes that are most prominent in hippocampal regions and the prefrontal cortex. Among depression mechanisms, we mention functional BDNF receptor changes (TrkB and p75NTR) and the role of BDNF gene polymorphisms. The therapeutic part of the review encompasses influences of BDNF, its processing products, and receptors in biological fluids and tissues, primarily in serum. We should conclude that BDNF system molecules have perspectives far beyond fundamental neurobiology, including depressive disorder diagnostics and treatment monitoring.
Keywords: 
BDNF, TrkB, p75NTR, depression, antidepressants, biomarkers
Список литературы: 
  1. Schulz P.E., Arora G. Depression. Continuum (Minneap Minn). 2015; 21 (3): 756–71. DOI: 10.1212/01.CON.0000466664.35650.b4.
  2. Masi G., Brovedani P. The hippocampus, neurotrophic factors and depression: possible implications for the pharmacotherapy of depression. CNS Drugs. 2011; 25 (11): 913–31. DOI: 10.2165/11595900-000000000-00000.
  3. Mondal A.C., Fatima M. Direct and indirect evidences of BDNF and NGF as key modulators in depression: role of antidepressants treatment. Int J. Neurosci. 2019; 129 (3): 283–96. DOI: 10.1080/00207454.2018.1527328.
  4. Uzun S., Kozumplik O., Topić R., Jakovljević M. Depressive disorders and comorbidity: somatic illness vs. side effect. Psychiatr Danub. 2009; 21 (3): 391–8.
  5. Novick D., Montgomery W., Vorstenbosch E., Moneta M.V., Dueñas H., Haro J.M. Recovery in patients with major depressive disorder (MDD): results of a 6-month, multinational, observational study. Patient Prefer Adherence. 2017; 11: 1859–68. DOI: 10.2147/ppa.S138750.
  6. Bjorkholm C., Monteggia L.M. BDNF - a key transducer of antidepressant effects. Neuropharmacology. 2016; 102: 72–9. DOI: 10.1016/j.neuropharm.2015.10.034.
  7. Pruunsild P., Kazantseva A., Aid T., Palm K., Timmusk T. Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics. 2007; 90 (3): 397–406. DOI: 10.1016/j.ygeno.2007.05.004.
  8. Cattaneo A., Cattane N., Begni V., Pariante C.M., Riva M.A. The human BDNF gene: peripheral gene expression and protein levels as biomarkers for psychiatric disorders. Transl Psychiatry. 2016; 6 (11): e958. DOI: 10.1038/tp.2016.214.
  9. Cortés-Mendoza J., Diaz de León-Guerrero S., Pedraza-Alva G., Pérez-Martinez L. Shaping synaptic plasticity: the role of activity-mediated epigenetic regulation on gene transcription. Int J. Dev Neurosci. 2013; 31 (6): 359–69. DOI: 10.1016/j.ijdevneu.2013.04.003.
  10. Hing B., Sathyaputri L., Potash J.B. A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder. Am J Med Genet B Neuropsychiatr Genet. 2018; 177 (2): 143–67. DOI: 10.1002/ajmg.b.32616.
  11. Egan M.F., Kojima M., Callicott J.H., Goldberg T.E., Kolachana B.S., Bertolino A., Zaitsev E., Gold B., Goldman D., Dean M., Lu B., Weinberger D.R. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003; 112 (2): 257–69. DOI: 10.1016/s0092-8674(03)00035-7.
  12. Binder D.K., Scharfman H.E. Brain-derived neurotrophic factor. Growth Factors. 2004; 22 (3): 123–31. DOI: 10.1080/08977190410001723308.
  13. Song M., Martinowich K., Lee F.S. BDNF at the synapse: why location matters. Mol Psychiatry. 2017; 22 (10): 1370–5. DOI: 10.1038/mp.2017.144.
  14. Matsumoto T., Rauskolb S., Polack M., Klose J., Kolbeck R., Korte M., Barde Y.A. Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat Neurosci. 2008; 11 (2): 131–3. DOI: 10.1038/nn2038.
  15. Nagappan G., Zaitsev E., Senatorov V.V., Jr., Yang J., Hempstead B.L., Lu B. Control of extracellular cleavage of ProBDNF by high frequency neuronal activity. Proc Natl Acad Sci U S A. 2009; 106 (4): 1267–72. DOI: 10.1073/pnas.0807322106.
  16. Sasi M., Vignoli B., Canossa M., Blum R. Neurobiology of local and intercellular BDNF signaling. Pflugers Arch. 2017; 469 (5–6): 593–610. DOI: 10.1007/s00424-017-1964-4.
  17. Begni V., Riva M.A., Cattaneo A. Cellular and molecular mechanisms of the brain-derived neurotrophic factor in physiological and pathological conditions. Clin Sci (Lond). 2017; 131 (2): 123–38. DOI: 10.1042/cs20160009.
  18. Reichardt L.F. Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci. 2006; 361 (1473): 1545–64. DOI: 10.1098/rstb.2006.1894.
  19. Phillips C. Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection. Neural Plast. 2017; 2017: 7260130. DOI: 10.1155/2017/7260130.
  20. Tsai S.J. Down-regulation of the Trk-B signal pathway: the possible pathogenesis of major depression. Med Hypotheses. 2004; 62 (2): 215–8. DOI: 10.1016/s0306-9877(03)00299-8.
  21. Meeker R.B., Williams K.S. The p75 neurotrophin receptor: at the crossroad of neural repair and death. Neural Regen Res. 2015; 10(5): 721-5. DOI: 10.4103/1673-5374.156967.
  22. Teng H.K., Teng K.K., Lee R., Wright S., Tevar S., Almeida R.D., Kermani P., Torkin R., Chen Z.Y., Lee F.S., Kraemer R.T., Nykjaer A., Hempstead B.L. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci. 2005; 25 (22): 5455–63. DOI: 10.1523/jneurosci.5123-04.2005.
  23. Kraemer B.R., Snow J.P., Vollbrecht P., Pathak A., Valentine W.M., Deutch A.Y., Carter B.D. A role for the p75 neurotrophin receptor in axonal degeneration and apoptosis induced by oxidative stress. J. Biol. Chem. 2014; 289 (31): 21205–16. DOI: 10.1074/jbc.M114.563403.
  24. Mandel A.L., Ozdener H., Utermohlen V. Identification of pro- and mature brain-derived neurotrophic factor in human saliva. Arch Oral Biol. 2009; 54 (7): 689–95. DOI: 10.1016/j.archoralbio.2009.04.005.
  25. Marsden W.N. Synaptic plasticity in depression: molecular, cellular and functional correlates. Prog Neuropsychopharmacol Biol Psychiatry. 2013; 43: 168–84. DOI: 10.1016/j.pnpbp.2012.12.012.
  26. Lisman J., Yasuda R., Raghavachari S. Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci. 2012; 13 (3): 169–82. DOI: 10.1038/nrn3192.
  27. Deogracias R., Espliguero G., Iglesias T., Rodriguez-Peña A. Expression of the neurotrophin receptor trkB is regulated by the cAMP/CREB pathway in neurons. Mol Cell Neurosci. 2004; 26 (3): 470–80. DOI: 10.1016/j.mcn.2004.03.007.
  28. Harward S.C., Hedrick N.G., Hall C.E., Parra-Bueno P., Milner T.A., Pan E., Laviv T., Hempstead B.L., Yasuda R., McNamara J.O. Autocrine BDNF-TrkB signalling within a single dendritic spine. Nature. 2016; 538 (7623): 99–103. DOI: 10.1038/nature19766.
  29. Mizui T., Ishikawa Y., Kumanogoh H., Lume M., Matsumoto T., Hara T., Yamawaki S., Takahashi M., Shiosaka S., Itami C., Uegaki K., Saarma M., Kojima M. BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met. Proc Natl Acad Sci U S A. 2015; 112 (23): 3067–74. DOI: 10.1073/pnas.1422336112.
  30. Kumar A., Pareek V., Faiq M.A., Ghosh S.K., Kumari C. ADULT NEUROGENESIS IN HUMANS: A Review of Basic Concepts, History, Current Research, and Clinical Implications. Innov Clin Neurosci. 2019; 16 (5–6): 30–7.
  31. Snapyan M., Lemasson M., Brill M.S., Blais M., Massouh M., Ninkovic J., Gravel C., Berthod F., Götz M., Barker P.A., Parent A., Saghatelyan A. Vasculature guides migrating neuronal precursors in the adult mammalian forebrain via brain-derived neurotrophic factor signaling. J Neurosci. 2009; 29 (13): 4172–88. DOI: 10.1523/jneurosci.4956-08.2009.
  32. Liu P.Z., Nusslock R. Exercise-Mediated Neurogenesis in the Hippocampus via BDNF. Front Neurosci. 2018; 12: 52. DOI: 10.3389/fnins.2018.00052.
  33. Galvão R.P., Garcia-Verdugo J.M., Alvarez-Buylla A. Brain-derived neurotrophic factor signaling does not stimulate subventricular zone neurogenesis in adult mice and rats. J. Neurosci. 2008; 28 (50): 13368–83. DOI: 10.1523/jneurosci.2918-08.2008.
  34. Taliaz D., Stall N., Dar D.E., Zangen A. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol Psychiatry. 2010; 15 (1): 80–92. DOI: 10.1038/mp.2009.67.
  35. Lohoff F.W. Overview of the genetics of major depressive disorder. Curr Psychiatry Rep. 2010; 12 (6): 539–46. DOI: 10.1007/s11920-010-0150-6.
  36. Pittenger C., Duman R.S. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology. 2008; 33 (1): 88–109. DOI: 10.1038/sj.npp.1301574.
  37. Yu H., Chen Z.Y. The role of BDNF in depression on the basis of its location in the neural circuitry. Acta Pharmacol Sin. 2011; 32(1): 3-11. DOI: 10.1038/aps.2010.184.
  38. Zhu C., Xu J., Lin Y., Ju P., Duan D., Luo Y., Ding W., Huang S., Chen J., Cui D. Loss of Microglia and Impaired Brain-Neurotrophic Factor Signaling Pathway in a Comorbid Model of Chronic Pain and Depression. Front Psychiatry. 2018; 9: 442. DOI: 10.3389/fpsyt.2018.00442.
  39. Ye Y., Wang G., Wang H., Wang X. Brain-derived neurotrophic factor (BDNF) infusion restored astrocytic plasticity in the hippocampus of a rat model of depression. Neurosci Lett. 2011; 503 (1): 15–9. DOI: 10.1016/j.neulet.2011.07.055.
  40. Rajkowska G., Stockmeier C.A. Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets. 2013; 14 (11): 1225–36. DOI: 10.2174/13894501113149990156.
  41. Schröter K., Brum M., Brunkhorst-Kanaan N., Tole F., Ziegler C., Domschke K., Reif A., Kittel-Schneider S. Longitudinal multi-level biomarker analysis of BDNF in major depression and bipolar disorder. Eur Arch Psychiatry Clin Neurosci. 2020; 270 (2): 169–81. DOI: 10.1007/s00406-019-01007-y.
  42. Duman R.S., Monteggia L.M. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006; 59 (12): 1116–27. DOI: 10.1016/j.biopsych.2006.02.013.
  43. Dwivedi Y. Brain-derived neurotrophic factor: role in depression and suicide. Neuropsychiatr Dis Treat. 2009; 5: 433–49. DOI: 10.2147/ndt.s5700.
  44. Ozan E., Okur H., Eker C., Eker O.D., Gönül A.S., Akarsu N. The effect of depression, BDNF gene val66met polymorphism and gender on serum BDNF levels. Brain Res Bull. 2010; 81 (1): 61–5. DOI: 10.1016/j.brainresbull.2009.06.022.
  45. Liu L.L., Li J.M., Su W.J., Wang B., Jiang C.L. Sex differences in depressive-like behaviour may relate to imbalance of microglia activation in the hippocampus. Brain Behav Immun. 2019; 81: 188–97. DOI: 10.1016/j.bbi.2019.06.012.
  46. Gyekis J.P., Yu W., Dong S., Wang H., Qian J., Kota P., Yang J. No association of genetic variants in BDNF with major depression: a meta- and gene-based analysis. Am J Med Genet B Neuropsychiatr Genet. 2013; 162b (1): 61–70. DOI: 10.1002/ajmg.b.32122.
  47. Harrisberger F., Smieskova R., Schmidt A., Lenz C., Walter A., Wittfeld K., Grabe H.J., Lang U.E., Fusar-Poli P., Borgwardt S. BDNF Val66Met polymorphism and hippocampal volume in neuropsychiatric disorders: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2015; 55: 107–18. DOI: 10.1016/j.neubiorev.2015.04.017.
  48. Molendijk M.L., van Tol M.J., Penninx B.W., van der Wee N.J., Aleman A., Veltman D.J., Spinhoven P., Elzinga B.M. BDNF val66met affects hippocampal volume and emotion-related hippocampal memory activity. Transl Psychiatry. 2012; 2 (1): 74. DOI: 10.1038/tp.2011.72.
  49. Zhang L., Li X.X., Hu X.Z. Post-traumatic stress disorder risk and brain-derived neurotrophic factor Val66Met. World J. Psychiatry. 2016; 6 (1): 1–6. DOI: 10.5498/wjp.v6.i1.1.
  50. Gerritsen L., Tendolkar I., Franke B., Vasquez A.A., Kooijman S., Buitelaar J., Fernández G., Rijpkema M. BDNF Val66Met genotype modulates the effect of childhood adversity on subgenual anterior cingulate cortex volume in healthy subjects. Mol Psychiatry. 2012; 17 (6): 597–603. DOI: 10.1038/mp.2011.51.
  51. Hwang J.P., Tsai S.J., Hong C.J., Yang C.H., Lirng J.F., Yang Y.M. The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiol Aging. 2006; 27 (12): 1834–7. DOI: 10.1016/j.neurobiolaging.2005.10.013.
  52. Hosang G.M., Shiles C., Tansey K.E., McGuffin P., Uher R. Interaction between stress and the BDNF Val66Met polymorphism in depression: a systematic review and meta-analysis. BMC Med. 2014; 12: 7. DOI: 10.1186/1741-7015-12-7.
  53. Verhagen M., van der Meij A., van Deurzen P.A., Janzing J.G., Arias-Vásquez A., Buitelaar J.K., Franke B. Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity. Mol Psychiatry. 2010; 15 (3): 260–71. DOI: 10.1038/mp.2008.109.
  54. Monteggia L.M., Barrot M., Powell C.M., Berton O., Galanis V., Gemelli T., Meuth S., Nagy A., Greene R.W., Nestler E.J. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci USA. 2004; 101 (29): 10827–32. DOI: 10.1073/pnas.0402141101.
  55. Schmidt H.D., Duman R.S. Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology. 2010; 35 (12): 2378–91. DOI: 10.1038/npp.2010.114.
  56. Sairanen M., Lucas G., Ernfors P., Castrén M., Castrén E. Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J. Neurosci. 2005; 25 (5): 1089–94. DOI: 10.1523/jneurosci.3741-04.2005.
  57. Toda T., Gage F.H. Review: adult neurogenesis contributes to hippocampal plasticity. Cell Tissue Res. 2018; 373 (3): 693–709. DOI: 10.1007/s00441-017-2735-4.
  58. Castrén E., Kojima M. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments. Neurobiol Dis. 2017; 97 (Pt B): 119–26. DOI: 10.1016/j.nbd.2016.07.010.
  59. Nikulina E.M., Johnston C.E., Wang J., Hammer R.P., Jr. Neurotrophins in the ventral tegmental area: Role in social stress, mood disorders and drug abuse. Neuroscience. 2014; 282: 122–38. DOI: 10.1016/j.neuroscience.2014.05.028.
  60. Rios M. BDNF and the central control of feeding: accidental bystander or essential player? Trends Neurosci. 2013; 36 (2): 83–90. DOI: 10.1016/j.tins.2012.12.009.
  61. Liu B., Liu J., Wang M., Zhang Y., Li L. From Serotonin to Neuroplasticity: Evolvement of Theories for Major Depressive Disorder. Front Cell Neurosci. 2017; 11: 305. DOI: 10.3389/fncel.2017.00305.
  62. Duman R.S., Deyama S., Fogaça M.V. Role of BDNF in the pathophysiology and treatment of depression: Activity-dependent effects distinguish rapid-acting antidepressants. Eur J. Neurosci. 2019. DOI: 10.1111/ejn.14630.
  63. Zhang Y., Shi J., Li J., Liu R., Yu Y., Xu Y. Role of brain-derived neurotrophic factor in the molecular neurobiology of major depressive disorder. Transl Perioper Pain Med. 2017; 4 (1): 20–30.
  64. Zhang Y., Gu F., Chen J., Dong W. Chronic antidepressant administration alleviates frontal and hippocampal BDNF deficits in CUMS rat. Brain Res. 2010; 1366: 141–8. DOI: 10.1016/j.brainres.2010.09.095.
  65. Balu D.T., Hoshaw B.A., Malberg J.E., Rosenzweig-Lipson S., Schechter L.E., Lucki I. Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. Brain Res. 2008; 1211: 37–43. DOI: 10.1016/j.brainres.2008.03.023.
  66. Park H.S., Kim T.W., Park S.S., Lee S.J. Swimming exercise ameliorates mood disorder and memory impairment by enhancing neurogenesis, serotonin expression, and inhibiting apoptosis in social isolation rats during adolescence. J. Exerc Rehabil. 2020; 16 (2): 132–40. DOI: 10.12965/jer.2040216.108.
  67. Damirchi A., Hosseini F., Babaei P. Mental Training Enhances Cognitive Function and BDNF More Than Either Physical or Combined Training in Elderly Women With MCI: A Small-Scale Study. Am J Alzheimers Dis Other Demen. 2018; 33 (1): 20–9. DOI: 10.1177/1533317517727068.
  68. Saarelainen T., Hendolin P., Lucas G., Koponen E., Sairanen M., MacDonald E., Agerman K., Haapasalo A., Nawa H., Aloyz R., Ernfors P., Castrén E. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J. Neurosci. 2003; 23 (1): 349–57. DOI: 10.1523/jneurosci.23-01-00349.2003.
  69. Colle R., Gressier F., Verstuyft C., Deflesselle E., Lépine J.P., Ferreri F., Hardy P., Guilloux J.P., Petit A.C., Fève B., Falissard B., Becquemont L., Corruble E. Brain-derived neurotrophic factor Val66Met polymorphism and 6-month antidepressant remission in depressed Caucasian patients. J. Affect Disord. 2015; 175: 233–40. DOI: 10.1016/j.jad.2015.01.013.
  70. Hacimusalar Y., Eşel E. Suggested Biomarkers for Major Depressive Disorder. Noro Psikiyatr Ars. 2018; 55 (3): 280–90. DOI: 10.5152/npa.2017.19482.
  71. Kishi T., Yoshimura R., Ikuta T., Iwata N. Brain-Derived Neurotrophic Factor and Major Depressive Disorder: Evidence from Meta-Analyses. Front Psychiatry. 2017; 8: 308. DOI: 10.3389/fpsyt.2017.00308.
  72. Klein A.B., Williamson R., Santini M.A., Clemmensen C., Ettrup A., Rios M., Knudsen G.M., Aznar S. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J. Neuropsychopharmacol. 2011; 14 (3): 347–53. DOI: 10.1017/s1461145710000738.
  73. Serra-Millàs M., López-Vilchez I., Navarro V., Galán A.M., Escolar G., Penadés R., Catalán R., Fañanás L., Arias B., Gastó C. Changes in plasma and platelet BDNF levels induced by S-citalopram in major depression. Psychopharmacology (Berl). 2011; 216 (1): 1–8. DOI: 10.1007/s00213-011-2180-0.
  74. Polyakova M., Stuke K., Schuemberg K., Mueller K., Schoenknecht P., Schroeter M.L. BDNF as a biomarker for successful treatment of mood disorders: a systematic & quantitative meta-analysis. J. Affect Disord. 2015; 174: 432–40. DOI: 10.1016/j.jad.2014.11.044.
  75. Fernandes B.S., Gama C.S., Kauer-Sant’Anna M., Lobato M.I., Belmonte-de-Abreu P., Kapczinski F. Serum brain-derived neurotrophic factor in bipolar and unipolar depression: a potential adjunctive tool for differential diagnosis. J. Psychiatr Res. 2009; 43 (15): 1200–4. DOI: 10.1016/j.jpsychires.2009.04.010.
  76. Xu Y., Yao S., Wei H., Zhu X., Yu M., Li Y. Application value of selected serum indicators in the differential diagnosis of geriatric depression and transient depressive state. Neuropsychiatr Dis Treat. 2018; 14: 459–65. DOI: 10.2147/ndt.S152247.
  77. Mizui T., Hattori K., Ishiwata S., Hidese S., Yoshida S., Kunugi H., Kojima M. Cerebrospinal fluid BDNF pro-peptide levels in major depressive disorder and schizophrenia. J. Psychiatr Res. 2019; 113: 190–8. DOI: 10.1016/j.jpsychires.2019.03.024.
  78. Zhou L., Xiong J., Lim Y., Ruan Y., Huang C., Zhu Y., Zhong J.H., Xiao Z., Zhou X.F. Upregulation of blood proBDNF and its receptors in major depression. J. Affect Disord. 2013; 150 (3): 776–84. DOI: 10.1016/j.jad.2013.03.002.
  79. Jiang H., Chen S., Li C., Lu N., Yue Y., Yin Y., Zhang Y., Zhi X., Zhang D., Yuan Y. The serum protein levels of the tPA-BDNF pathway are implicated in depression and antidepressant treatment. Transl Psychiatry. 2017; 7 (4): 1079. DOI: 10.1038/tp.2017.43.
  80. Zhao G., Zhang C., Chen J., Su Y., Zhou R., Wang F., Xia W., Huang J., Wang Z., Hu Y., Cao L., Guo X., Yuan C., Wang Y., Yi Z., Lu W., Wu Y., Wu Z., Hong W., Peng D., Fang Y. Ratio of mBDNF to proBDNF for Differential Diagnosis of Major Depressive Disorder and Bipolar Depression. Mol Neurobiol. 2017; 54 (7): 5573–82. DOI: 10.1007/s12035-016-0098-6.