Consilium MedicumConsilium Medicum2075-17532542-2170Consilium Medicum9686910.26442/20751753.2019.2.190304Research ArticleThe role of neurotrophic factors in development of post-stroke depressionBogolepovaAnna N.D. Sci. (Med.), Prof.annabogolepova@yandex.ruPirogov Russian National Research Medical University15022019212182319012022Copyright © 2019, Consilium Medicum2019Cerebrovascular disease is one of the most important causes of disability. Depression is reported to be the most widespread psychological disorder among stroke complications. Post-stroke depression is observed in about 1/3 of stroke survivors, the overall incidence rate is 55%. Depression that develops after stroke has a strong negative influence on the primary disease course, deteriorates functional improvement and quality of life and increases mortality rate. Depressive disorder in patients is a risk factor of additional cognitive disorders development, as much as to dementia. In recent years a lot of evidence on nerve growth factors involvement in pathogenesis of affective disorders development has been acquired. A decrease in brain-derived nerve factor (BDNF) levels was observed in patients with depressive disorders. Moreover, neurotrophic factors can be regarded as possible biomarkers not only of post-stroke depressive disorder itself but also of response to treatment with antidepressants. Acquired data show that BDNF has a key role in post-stroke depression pathophysiology. Use of medications with neurotrophic action such as cerebrolysin is an important aspect of post-stroke depression treatment. Preclinical studies showed that cerebrolysin influences levels of neurotrophic factor and demonstrated functional equivalence of cerebrolysin neuropeptides and neurotrophic factors. In clinical studies cerebrolysin effectiveness in post-stroke depression treatment was demonstrated. Positive results of cerebrolysin and antidepressants combined use were acquired.BDNFcerebrovascular pathologyischemic strokepost-stroke depressionneurotrophic factorsBDNFneuroplasticityCerebrolysinцереброваскулярная патологияишемический инсультпостинсультная депрессиянейтротрофические факторынейропластичностьцеребролизин[De Ryck A, Brouns R, Geurden M et al. Risk factors for poststroke depression: identification of inconsistencies based on a systematic review. J Geriatr Psychiatry Neurol 2014; 27 (3): 147-58.][Пирадов М.А., Максимова М.Ю., Танашян М.М. Инсульт. Пошаговая инструкция. М.: ГЭОТАР-Медиа, 2019.][Скворцова В.И. Интервью Министра Вероники Скворцовой «Независимой газете». https: //www.rosminzdrav.ru/news/2017/05/17/5449-intervyu-ministra-veroniki-skvortsovoy-nezavisimoy-gazete][Alajbegovic A, Djelilovic-Vranic J, Nakicevic A et al. Post stroke depression. Med Arch 2014; 68 (1): 47-50.][Villa R.F, Ferrari F, Moretti A. Post-stroke depression: Mechanisms and pharmacological treatment. Pharmacol. Ther 2018; 184: 131-44.][Gainotti G, Antonucci G, Marra C, Paolucci S. Relation between depression after stroke, antidepressant therapy, and functional recovery. J Neurol Neurosurg Psychiatry 2001; 7: 258-61.][Hackett M.L, Yapa C, Parag V, Anderson C.S. Frequency of depression after stroke: a systematic review of observational studies. Stroke 2005; 36: 1330-40.][Berg A, Palomaki H, Lehtihalmes M et al. Poststroke depression: an 18-month follow-up. Stroke 2003; 34: 138-43.][Robinson R.G, Jorge R.E. Post-stroke depression: A review. Am J Psychiatry 2016; 173: 221-31.][Spalletta G, Robinson R.G. How should depression be diagnosed in patients with stroke? Acta Psychiatr Scand 2010; 121 (6): 401-3.][Chau J.P, Thopson D.R, Twinn S et al. Determinants of participation restriction among community dwelling stroke survivors: a path analysis. BMC Neurol 2009; 9 (49): 1-7.][Teoh V, Sims J, Milgrom J. Psychosocial predictors of quality of life in a sample of community-dwelling stroke survivors: a longitudinal study. Top Stroke Rehabil 2009; 16 (2): 157-66.][Morris J, Oliver T, Kroll T et al. The importance of psychological and social factors in influencing the uptake and maintenance of physical activity after stroke: a structured review of the empirical literature. Stroke Res Treat 2012; 2012: 1-20.][Thilarajah S, Mentiplay B.F, Bower K.J et al. Factors Associated With Post-Stroke Physical Activity: A Systematic Review and Meta-Analysis. Arch Phys Med Rehabil 2017 (published Online First: 24 Oct 2017).][Park G-Y, Im S, Lee S-J et al. The Association between Post-Stroke Depression and the Activities of Daily Living/Gait Balance in Patients with First-Onset Stroke Patients. Psychiatry Investig 2016; 13: 659-64.][Prasomsri J, Jalayondeja C, Bovonsunthonchai S et al. Walking and stair climbing abilities in individuals after chronic stroke with and without mental health problem. J Med Assoc Thai 2014; 97 (Suppl. 7): S10-15.][Matsuzaki S, Hashimoto M, Yuki S et al. The relationship between post-stroke depression and physical recovery. J Affect Dis 2015; 176: 56-60.][Snyder H.R. Major depressive disorder is associated with broad impairments on neuropsychological measures of executive function: A meta-analysis and review. Psychol Bull 2013; 139: 81-132.][Douven E, Aalten P, Staals J et al. Co-occurrence of depressive symptoms and executive dysfunction after stroke: associations with brain pathology and prognosis. J Neurol Neurosurg Psychiatry 2018: jnnp-2017-317548 (published Online First: 14 Feb 2018).][Гусев Е.И., Боголепова А.Н. Когнитивные нарушения и деменция. М.: Группа Ремедиум, 2018.][Гусев Е.И., Бойко А.Н., Сидоренко Т.В. и др. Приверженность основной терапии у больных с постинсультной депрессией. Неврол. журн. 2011; 4: 1-6.][Brilleman S.L, Purdy S, Salisbury C et al. Implications of comorbidity for primary care costs in the UK: a retrospective observational study. Br J Gen Pract 2013; 63: 274-82.][Ayerbe L, Ayis S, Rudd A.G et al. Natural history, predictors, and associations of depression years after stroke: The South London Stroke Register. Stroke 2011; 42: 1907-11.][Cuijpers P, Beekman A.T, Reynolds C.F. Preventing depression: a global priority. JAMA 2012; 307 (10): 1033-4.][Nakase T, Tobisawa M, Sasaki M, Suzuki A. Outstanding Symptoms of Poststroke Depression during the Acute Phase of Stroke. PLoS ONE 2016; 11 (10): e0163038. DOI: 10.1371/journal. pone.0163038][Zhang Y, Zhao H, Fang Y et al. The association between lesion location, sex and poststroke depression: Meta-analysis. Brain and Behavior 2017; 7: e00788. https: //doi.org/10.1002/brb3.788][Carson A.J, MacHale S, Allen K et al. Depression after stroke and lesion location: A systematic review. Lancet 2000; 356: 122-6.][Hadidi N, Treat-Jacobson D.J, Lindquist R. Poststroke depression and functional outcome: A critical review of literature. Heart and Lung 2009; 38: 151-62.][Wei N, Yong W, Li X et al. Post-stroke depression and lesion location: A systematic review. J Neurol 2015; 262: 81-90.][Bae K.Y, Kang H.J, Kim J.W et al. Associations of white matter hyperintensities with poststroke depression: A 1-year longitudinal study. Int J Geriatr Psychiatry 2019; 34 (1): 162-8. DOI: 10.1002/gps.5005][Tsai C-S, Wu Ch-L, Hung T-H et al. Incidence and risk factors of poststroke depression in patients with acute ischemic stroke: A 1-year prospective study in Taiwan. Biomed J 2016; 39: 195-200. http: //dx.doi.org/10.1016/j.bj.2015.10.004][Salinas J, Ray R.M., Nassir R et al. Factors Associated With New-Onset Depression Following Ischemic Stroke: The Women’s Health Initiative. J Am Heart Assoc 2017; 6: e003828. DOI: 10.1161/JAHA.116.003828][Salinas J, Beiser A, Himali J.J et al. Factors Associated with New-Onset Depression After Stroke. J Neuropsychiatry Clin Neurosci 2016. DOI: 10.1176/appi.neuropsych.15110388][Park E-Y, Kim J-H. An analysis of depressive symptoms in stroke survivors: verification of amoderating effect of demographic characteristics. BMC Psychiatry 2017; 17: 132. DOI 10.1186/s12888-017-1292-4][Park E.Y, Shin I.S, Kim J.H. A meta-analysis of the variables related to depression in Korean patients with a stroke. J Korean Acad Nurs. 2012; 42 (4): 537-48.][Гусев Е.И., Боголепова А.Н. Роль процессов нейропластичности в развитии депрессивных расстройств. Трудный пациент. 2010; 10: 11-6.][Liguz-Lecznar M, Kossut M. Influence of inflammation on poststroke plasticity. Neural Plast 2013; 258582. DOI: 10.1155/2013/258582][Martin B, Wang R, Cong W. et al. Altered learning, memory, and social behavior in type 1 taste receptor subunit 3 knock-out mice are associated with neuronal dysfunction. J Biol Chem 2017; 292: 11508-30. DOI: 10.1074/jbc.M116.773820][Law H.C, Szeto S.S, Quan Q et al. Characterization of the molecular mechanisms underlying the chronic phase of stroke in a cynomolgus monkey model of induced cerebral ischemia. J Proteome Res 2017; 16: 1150-66. DOI: 10.1021/acs.jproteome. 6b00651][Klein R, Mahlberg N, Ohren M et al. The neural cell adhesion molecule-derived (NCAM)-peptide FG loop (FGL) mobilizes endogenous neural stem cells and promotes endogenous regenerative capacity after stroke. J Neuroimmune Pharmacol 2016; 11: 708-20. DOI: 10.1007/s11481-016-9694-5][Zelentsova-Levytskyi K, Talmi Z, Abboud-Jarrous G et al. Negatively regulates neural stem cell selfrenewal through Bmi-1 signaling. Front Mol Neurosci 2017; 10: 124. DOI: 10.3389/fnmol.2017.00124][Aimone J.B, Li Y, Lee S.W et al. Regulation and function of adult neurogenesis: from genes to cognition. Physiol Rev 2014; 94: 991-1026. DOI: 10.1152/physrev.00004.2014][Yang L, Zhang Z, Sun D et al. Low serum BDNF may indicate the development of PSD in patients with acute ischemic stroke. Int J Geriatr Psychiatry 2011; 26: 495-502.][Kim J.M, Stewart R, Kang H.J et al. A longitudinal study of BDNF promoter methylation and genotype with poststroke depression. J Affect Dis 2013; 149: 93-9.][Pandey G.N, Ren X, Rizavi H.S et al. Brain derived neurotrophic factor and tyrosine kinase B receptor signalling in postmortem brain of teenage suicide victims. Int J Neuropsychopharmacol 2008; 11: 1047-61. DOI: 10.1017/S1461145708009000][Karege F, Vaudan G, Schwald M et al. Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Mol Brain Res 2005; 136: 29-37. DOI: 10.1016/j.molbrainres.2004.12.020][Dwivedi Y, Rizavi H.S, Conley R.R et al. Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch General Psychiatry 2003; 60: 804-15. DOI: 10.1001/archpsyc.60.8.804][Molendijk M.L, Spinhoven P, Polak M et al. Serum BDNF concentrations as peripheral manifestations of depression: evidence froma systematic review and meta-analyses on 179 associations (N=9484). Mol Psychiatry 2014; 19: 791-800. DOI: 10.1038/mp.2013.105][Sen S, Duman R, Sanacora G. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 2008; 64: 527-32. DOI: 10.1016/j.biopsych.2008.05.005][Brunoni A.R, Lopes M, Fregni F. A systematic review and meta analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 2008; 11: 1169-80. DOI: 10.1017/S1461145708009309][Brunoni A.R, Lopes M, Fregni F. A systematic review andmeta-analysis of clinical studies onmajor depression and BDNF levels: Implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 2008; 11: 1169-80.][Sen S, Duman R, Sanacora G. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: Meta-analyses and implications. Biol Psychiatry 2008; 64: 527-32.][Pisoni A, Strawbridge R, Hodsoll J et al. Growth Factor Proteins and Treatment-Resistant Depression: A Place on the Path to Precision. Front. Psychiatry 2018; 9: 386. DOI: 10.3389/fpsyt.2018.00386][Kishi T, Yoshimura R, Ikuta T, Iwata N. Brain-Derived Neurotrophic Factor and Major Depressive Disorder: Evidence from Meta-Analyses. Front Psychiatry 2017; 8.][Zhou Z, Lu T, Xu G et al. Decreased serum brain-derived neurotrophic factor (BDNF) is associated with post-stroke depression but not with BDNF gene Val66Met polymorphism. Clin Chem Lab Med 2011; 49: 185-9.][Li Y, Peng C, Guo X et al. Expression of Brain-derived Neurotrophic Factor and Tyrosine Kinase B in Cerebellum of Poststroke Depression Rat Model. Chin Med J 2015; 128: 2926-31.][Cichoń, Bijak M, Czarny P et al. Increase in Blood Levels of Growth Factors Involved in the Neuroplasticity Process by Using an Extremely Low Frequency Electromagnetic Field in Post-stroke Patients. Front. Aging Neurosci 2018; 10: 294. DOI: 10.3389/fnagi.2018.00294][Chang W.H, Shin M.A, Lee A et al. Relationship between Serum BDNF Levels and Depressive Mood in Subacute Stroke Patients: A Preliminary Study. Int J Mol Sci 2018; 19: 3131. DOI: 10.3390/ijms19103131][Li J, Zhao Y.D, Zeng J.W et al. Serum Brain-derived neurotrophic factor levels in post-stroke depression. J Affect Dis 2014; 168: 373-9.][Xu H.B, Xu Y.H, He Y et al. Decreased Serum Brain-Derived Neurotrophic Factor May Indicate the Development of Poststroke Depression in Patients with Acute Ischemic Stroke: A Meta-Analysis. J Stroke Cerebrovasc Dis 2018; 27: 709-15.][Shimizu E, Hashimoto K, Okamura N et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003; 54 (1): 70-5.][Deyama S, Bang E, Kato T et al. Neurotrophic and Antidepressant Actions of Brain-Derived Neurotrophic Factor Require Vascular Endothelial Growth Factor. Biol Psychiatry 2018. pii: S0006-3223 (18)32099-7. DOI: 10.1016/j.biopsych.2018.12.014][Hackett M.L, Anderson C.S, House A et al. Interventions for treating depression after stroke. Cochrane Database Syst Rev 2008: CD003437.][Winstein C.J, Stein J, Arena R et al. Guidelines for Adult Stroke Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2016; 47: e98-e169.][Masliah E, Díez-Tejedor E. The pharmacology of neurotrophic treatment with Cerebrolysin: brain protection and repair to counteract pathologies of acute and chronic neurological disorders. Drugs Today (Barc) 2012; 48 (Suppl. A): 3-24. DOI: 10.1358/dot.2012.48(Suppl.A).1739716][Wronski R, Tompa P, Hutter-Paier B et al. Inhibitory effect of a brain derived peptide preparation on the Ca++-dependent protease, calpain. J Neural Transm 2000; 107: 145-57.][Hanson L.R, Liu X.F, Ross T.M et al. Cerebrolysin reduces infarct volume in a rat model of focal cerebral ischemic damage. Am J Neuroprotec Neuroregen 2009; 1: 62-8][Chen H, Tung Y.C, Li B et al. Trophic factors counteract elevated FGF-2-induced inhibition of adult neurogenesis. Neurobiol Aging 2007; 28 (8): 1148-6268.][Ubhi K, Rockenstein E, Vazquez-Roque R et al. Cerebrolysin Modulates Pronerve Growth Factor/Nerve Growth Factor Ratio and Ameliorates the Cholinergic Deficit in a Transgenic Model of Alzheimer’s Disease. J Neurosci Res 2013; 91: 167-77.][Hampson D.R, Windisch M, Baskys A. Increased binding of BDNF to TrkB induced by the antidemetia drug Cerebrolysin. Soc Neurosci 1997; 23: 1896.][Bornstein N.M, Guekht A, Vester J et al. Safety and efficacy of Cerebrolysin in early post-stroke recovery: a meta-analysis of nine randomized clinical trials. Neurol Sci 2018; 39: 629-40. https: //doi.org/10.1007/s10072-017-3214-0][Muresanu D.F, Heiss W-D, Hoemberg V et al. Cerebrolysin and Recovery After Stroke (CARS). A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial. Stroke 2015; 47: 151-9. DOI: 10.1161/STROKEAHA.115.009416][Чуканова Е.И., Гусев Е.И., Белоусов Д.Ю. и др. Результаты многоцентрового рандомизированного контролируемого клинико-экономического исследования терапии острого периода ишемического инсульта Церебролизином. Качеств. клин. практика. 2011; 3: 14-37.][Мальцева М.Н., Шмонин А.А. Использование препарата церебролизин в программе эрготерапевтической нормализации качества жизни у пациентов с депрессией, перенесших ишемический инсульт. Поликлиника. 2017; 1 (1): 12-4.][Мальцева М.Н., Шмонин А.А., Дидур М.Д., Мельникова Е.В. Церебролизин в программе эрготерапевтической коррекции у пациентов-мужчин с постинсультной депрессией. Эффективная фармакотерапия. 2017; 19: 74-9.][Ларикова Т.И., Луканин А.Н., Ужегова И.В., Яковец Ю.Е. Возможности комплексной терапии при реабилитации инсульта. Рус. мед. журн. 2007; 8: 1155-7.][Зуйкова Н.Л., Исраелян А.Ю., Гушанская Е.В., Медведев В.Э. Церебролизин в терапии депрессий. Психиатрия и психофармакотерапия. 2013; 15 (1): 41-6.][Пантелеева Г.П., Артюх В.В., Крылова Е.С. и др. Оптимизации психофармакотерапии эндогенных депрессий с помощью препарата Церебролизин®. Психиатрия и психофармакотерапия. 2012; 14 (1): 23-9.][Alvarez X.A, Sampedro C, Cacabelos R et al. Redused TNF-a and increased IGF-I levels in the serum of Alzheimer’s disease patients treated with neutrophic agent Cerebrolysin. Int J Neuropsy 2009; 12: 867-72.][Alvarez X.A, Alvarez I, Iglesias O et al. Synergistic Increase of Serum BDNF in Alzheimer Patients Treated with Cerebrolysin and Donepezil: Association with Cognitive Improvement in ApoE4 Cases. Int J Neuropsychopharmacol 2016; 19 (6): 1-6. DOI: 10.1093/ijnp/pyw024][Селянина Н.В., Каракулова Ю.В. Влияние нейротрофической терапии на динамику когнитивных функций при черепно-мозговой травме. Доктор.Ру. Неврология и Психиатрия. 2014; 6 (94): 29-32.][Шишкова В.Н., Зотова Л.И., Малюкова Н.Г. и др. Оценка влияния терапии церебролизином у пациентов с постинсультной афазией на уровень BDNF, в зависимости от наличия или отсутствия нарушений углеводного обмена. Журн. неврологии и психиатрии им. С.С.Корсакова. 2015; 106 (7): 68-70.][Шишкова В.Н., Зотова Л.И., Ременник А.Ю., Керимова Е.И. Влияние Церебролизина на постинсультную афазию и уровень фактора роста нервов при нарушениях углеводного обмена. Доктор.ру. Неврология и Психиатрия. 2015; 5-6: 25-30.][Шишкова В.Н., Зотова Л.И., Ременник А.Ю., Керимова Е.И. Динамика уровня цилиарного нейротрофического фактора у пациентов с постинсультной афазией и нарушениями углеводного обмена на фоне терапии Церебролизином, Доктор.ру. Неврология и Психиатрия. 2015; 5-6: 25-30.]