bekhterevОбозрение психиатрии и медицинской психологии имени В.М.БехтереваV.M. BEKHTEREV REVIEW OF PSYCHIATRY AND MEDICAL PSYCHOLOGY2313-70532713-055XV. M. BEKHTEREV NATIONAL RESEARCH MEDICAL CENTER FOR PSYCHIATRY AND NEUROLOGY OF THE RUSSIAN FEDERATION MINISTRY OF HEALTH10.31363/2313-7053-2019-4-1-43-47bekhterev-301Research ArticleНАУЧНО-ИССЛЕДОВАТЕЛЬСКИЕ РАБОТЫRESEARCH PAPERSТерапевтическая резистентность при депрессии с позиции генетики и фармакогенетикиTherapeutic resistance in depression from the genetics and pharmacogenetics point of viewМазоГ. Э.MazoG. E.galina-mazo@yandex.ruРукавишниковГ. В.RukavishnikovG. V.grigory_v_r@mail.ruКибитовА О.KibitovA. O.druggen@mail.ruФГБУ «Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева» Минздрава РФ; Российский национальный консорциум по психиатрической генетикеРоссияBekhterev National Medical Research Center for Psychiatry and NeurologyRussian FederationФГБУ «Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева»РоссияBekhterev National Medical Research Center for Psychiatry and NeurologyRussian FederationФГБУ «Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева»; ФГБУ «Национальный медицинский исследовательский центр психиатрии и наркологии им. В.П. Сербского»РоссияBekhterev National Medical Research Center for Psychiatry and Neurology; Serbsky National Medical Research Center on Psychiatry and AddictionsRussian Federation20190712201904-14347Copyright © Мазо Г.Э., Рукавишников Г.В., Кибитов А.О., 20192019Мазо Г.Э., Рукавишников Г.В., Кибитов А.О.Mazo G.E., Rukavishnikov G.V., Kibitov A.O.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.bekhterevreview.com/jour/article/view/301

Современные тенденции в развитии концепции терапевтически резистентных депрессий — попытки сужения весьма гетерогенной группы пациентов, которых рассматривают в ее рамках. Одним из наиболее стремительно развивающихся направлений в биологической парадигме ТРД являются генетические исследования, направленные на поиск биомаркеров прогноза терапевтического ответа при депрессии. Очевидно, что генетический риск ТР не исчерпывается комбинациями генетических вариантов генома, но имеет и фенотипические проявления на всех уровнях формирования фенотипа. По принципиальной возможности достижения ремиссионных состояний терапевтическая резистентность может быть разделена на относительную и абсолютную. В настоящее время можно говорить о том, что пациенты с относительной и абсолютной резистентностью представляют две биологически гетерогенные группы, выделение которых требует разработку специальных лабораторных подходов, которые будут способствовать разработки персонифицированного подхода к терапии.

Current trends in the concept of therapeutically resistant depression (TRD) tend to narrow its very heterogeneous group of patients. One of the most rapidly developing areas in the biological paradigm of TRD is genetic research aimed at finding biomarkers for predicting the therapeutic response. Obviously, the genetic risks of TR are not limited to combinations of genome genetic variants, but it also has phenotypic manifestations at all levels of phenotype formation. According to the fundamental possibility of achieving remission states, therapeutic resistance can be divided into relative and absolute. At present, it can be said that patients with relative and absolute resistance represent two biologically heterogeneous groups, the isolation of which requires the development of special laboratory approaches that will contribute to the development of a personalized approach to therapy.

депрессиятерапевтическая резистентностьфармакогенетикафенотипdepressiontherapeutic resistancepharmacogeneticsphenotypeReferencesВовин Р.Я, Аксёнова И.О., Затяжные депрессивные состояния. 1982; Л. Медицина. 187 c.Vovin R.Ja, Aksjonova I.O., Zatjazhnye depressivnye sostojanija. 1982; L. Medicina. 187 p. (In Russ.).Мазо Г.Э., Крижановский А.С. Специфический нейробиологический профиль терапевтически резистентной депрессии: pro et contra. Современная терапия психических расстройств. 2012;№ 1:2-7.Mazo G.Je., Krizhanovskij A.S. Specificheskij nejrobiologicheskij profil’ terapevticheski rezistentnoj depressii: pro et contra. Sovremennaja terapija psihicheskih rasstrojstv. 2012;1:2-7. (In Russ.).Мазо Г.Э., Незнанов Н.Г. Терапевтически резистентные депрессии. / Издание второе, дополненное. СПб.: Ладога; 2013. 372 с.Mazo G.E., Neznanov N.G. Terapevticheski rezistentnye depressii. / Izdanie vtoroe, dopolnennoe. SPb.: Ladoga; 2013. 372 p. (In Russ.).Мазо Г.Э., Кибитов А.О., Рукавишников Г.В. и соавт. Терапевтическая резистентность при депрессии как объект междисциплинарного биомедицинского исследования. Ж. Социальная и клиническая психиатрия. 2017;27(4):70-81.Mazo G.Je., Kibitov A.O., Rukavishnikov G.V. et al. Terapevticheskaja rezistentnost’ pri depressii kak ob#ekt mezhdisciplinarnogo biomedicinskogo issledovanija. Zh. Social’naja i klinicheskaja psihiatrija. 2017;27(4):70-81. (In Russ.).Angst J. A clinical analysis of the effects of tofranil in depression. Longitudinal and follow-up studies. Treatment of blood-relations. Psychopharmacologia. 1961;2:381–407.Angst J. A clinical analysis of the effects of tofranil in depression. Longitudinal and follow-up studies. Treatment of blood-relations. Psychopharmacologia. 1961;2:381–407.Berlim M.T., Turecki G. What is the meaning of treatment resistant/re- fractory major depression (TRD)? A systematic review of current randomized trials. Eur. Neuropsychopharmacol. 2007b;17:696– 707.Berlim M.T., Turecki G. What is the meaning of treatment resistant/re- fractory major depression (TRD)? A systematic review of current randomized trials. Eur. Neuropsychopharmacol. 2007b;17:696– 707.Bertilsson L., Dahl M. L., Dalen P. & Al-Shurbaji A. Molecular genetics of CYP2D6, clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol. 2002;53 (2):111–122.Bertilsson L., Dahl M. L., Dalen P. & Al-Shurbaji A. Molecular genetics of CYP2D6, clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol. 2002;53 (2):111–122.Cordon-Cardo C., O’Brien J.P., Casals D. et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci U S A. 1989:86(2):695– 698.Cordon-Cardo C., O’Brien J.P., Casals D. et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci U S A. 1989:86(2):695– 698.Cordon-Cardo C., O’Brien J. P., Boccia J. et al. Expression of the multidrug resistance gene prod uct (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem. 1990;38(9):1277– 1287.Cordon-Cardo C., O’Brien J. P., Boccia J. et al. Expression of the multidrug resistance gene prod uct (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem. 1990;38(9):1277– 1287.Dudek D., Rybakowski J.K., Siwek M. et al. Risk factors of treatment resistance in major depression: association with bipolarity. J. Affect. Disord. 2010;126:268–271.Dudek D., Rybakowski J.K., Siwek M. et al. Risk factors of treatment resistance in major depression: association with bipolarity. J. Affect. Disord. 2010;126:268–271.Ejsing T.B., Hasselstrom J. & Linnet K. The influence of P-glycoprotein on cerebral and hepatic concentrations of nortriptyline and its metabolites. Drug Metabol Drug Interact. 2006;21(3–4):139– 162.Ejsing T.B., Hasselstrom J. & Linnet K. The influence of P-glycoprotein on cerebral and hepatic concentrations of nortriptyline and its metabolites. Drug Metabol Drug Interact. 2006;21(3–4):139– 162.Franchini L., Serretti A., Gasperini M. & Smeraldi E. Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees. J Psychiatr Res. 1998;32(5):255–259.Franchini L., Serretti A., Gasperini M. & Smeraldi E. Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees. J Psychiatr Res. 1998;32(5):255–259.Gadad B.S., Jha M.K., Czysz A. et al. Peripheral biomarkers of major depression and antidepressant treatment response: Current knowledge and future outlooks. J Affect Disord. 2017;Jul 5. pii: S01650327(17):30671-7. doi: 10.1016/j.jad.2017.07.001.Gadad B.S., Jha M.K., Czysz A. et al. Peripheral biomarkers of major depression and antidepressant treatment response: Current knowledge and future outlooks. J Affect Disord. 2017;Jul 5. pii: S01650327(17):30671-7. doi: 10.1016/j.jad.2017.07.001.Gaynes B.N., Warden D., Trivedi M.H. et al. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr. Serv. 2009;60:1439–1445.Gaynes B.N., Warden D., Trivedi M.H. et al. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr. Serv. 2009;60:1439–1445.Hoffmeyer S., Burk O., von Richter O. et al. Functional polymorphisms of the human multidrugresistance gene, multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000;97(7):3473–3478.Hoffmeyer S., Burk O., von Richter O. et al. Functional polymorphisms of the human multidrugresistance gene, multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000;97(7):3473–3478.Jenkins E., Goldner E.M. Approaches to understanding and addressing treatment-resistant depression: a scoping review. Depress. Res. Treat. 2012; 469680.Jenkins E., Goldner E.M. Approaches to understanding and addressing treatment-resistant depression: a scoping review. Depress. Res. Treat. 2012; 469680.Nebert D.W., Dieter M.Z. The evolution of drug metabolism. Pharmacology 2000;61(3):124–135.Nebert D.W., Dieter M.Z. The evolution of drug metabolism. Pharmacology 2000;61(3):124–135.O’Reilly R.L., Bogue L. & Singh S.M. Pharmacogenetic response to antidepressants in a multicase family with affective disorder. Biol Psychiatry. 1994;36(7):467–471.O’Reilly R.L., Bogue L. & Singh S.M. Pharmacogenetic response to antidepressants in a multicase family with affective disorder. Biol Psychiatry. 1994;36(7):467–471.Pare C.M., Rees L. & Sainsbury M.J. Differentiation of two genetically specific types of depression by the response to anti-depressants. 1962;2:1340–1343.Pare C.M., Rees L. & Sainsbury M.J. Differentiation of two genetically specific types of depression by the response to anti-depressants. 1962;2:1340–1343.Perera T., George M.S., Grammer G. et al. The clinical TMS society consensus review and treat ment recommendations for TMS therapy for major depressive disorder. Brain Stimul. 2016;9:336–346.Perera T., George M.S., Grammer G. et al. The clinical TMS society consensus review and treat ment recommendations for TMS therapy for major depressive disorder. Brain Stimul. 2016;9:336–346.Pirmohamed M. Personalized pharmacogenomics: predicting efficacy and adverse drug reactions. Annu Rev Genomics Hum Genet. 2014;15:349-70. doi: 10.1146/annurev-genom-090413-025419.Pirmohamed M. Personalized pharmacogenomics: predicting efficacy and adverse drug reactions. Annu Rev Genomics Hum Genet. 2014;15:349-70. doi: 10.1146/annurev-genom-090413-025419.Schinkel A.H., Wagenaar E., Mol C.A. & van Deemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996;97(11):2517–2524.Schinkel A.H., Wagenaar E., Mol C.A. & van Deemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996;97(11):2517–2524.Schinkel A.H. & Jonker J.W. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family, an overview. Adv Drug Deliv Rev. 2003;55(1):3–29.Schinkel A.H. & Jonker J.W. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family, an overview. Adv Drug Deliv Rev. 2003;55(1):3–29.Schosser A., Serretti A., Souery D. et al. European Group for the Study of Resistant Depression (GSRD) — where have we gone so far: review of clinical and genetic findings. Eur. Neu- ropsychopharmacol. 2012;22:453–468.Schosser A., Serretti A., Souery D. et al. European Group for the Study of Resistant Depression (GSRD) — where have we gone so far: review of clinical and genetic findings. Eur. Neu- ropsychopharmacol. 2012;22:453–468.Souery D., Oswald P., Massat I. et al. Group for the Study of Resistant Depression. Clinical factors associated with treatment resistance in major depression: results from a European Multicenter Study. J. Clin. Psychiatry. 2007;68(7):1062–1070.Souery D., Oswald P., Massat I. et al. Group for the Study of Resistant Depression. Clinical factors associated with treatment resistance in major depression: results from a European Multicenter Study. J. Clin. Psychiatry. 2007;68(7):1062–1070.Staddon S., Arranz M. J., Mancama D. et al. Clinical applications of pharmacogenetics in psychiatry. Psychopharmacology (Berl). 2002;162(1):18–23.Staddon S., Arranz M. J., Mancama D. et al. Clinical applications of pharmacogenetics in psychiatry. Psychopharmacology (Berl). 2002;162(1):18–23.Steimer W., Muller B., Leucht S. & Kissling W. Pharmacogenetics, a new diagnostic tool in the management of antidepressive drug therapy. Clin Chim Acta. 2001;308(1–2):33–41.Steimer W., Muller B., Leucht S. & Kissling W. Pharmacogenetics, a new diagnostic tool in the management of antidepressive drug therapy. Clin Chim Acta. 2001;308(1–2):33–41.Thiebaut F., Tsuruo T., Hamada H. et al. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA. 1987;84(21):7735–7738.Thiebaut F., Tsuruo T., Hamada H. et al. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA. 1987;84(21):7735–7738.Uhr M., Grauer M. T. & Holsboer F. Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption. Biol Psychiatry. 2003;54(8):840–846.Uhr M., Grauer M. T. & Holsboer F. Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption. Biol Psychiatry. 2003;54(8):840–846.Uhr M., Grauer M.T., Yassouridis A. & Ebinger M. Blood-brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcb1ab) knock-out mice and controls. J Psychiatr Res. 2007;41(1–2):179–188.Uhr M., Grauer M.T., Yassouridis A. & Ebinger M. Blood-brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcb1ab) knock-out mice and controls. J Psychiatr Res. 2007;41(1–2):179–188.

The authors declare that there are no conflicts of interest present.