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 HEALTH10.31363/2313-7053-2021-57-4-8-14bekhterev-616Research ArticleПРОБЛЕМНЫЕ СТАТЬИPROBLEM-S0LVING ARTICLESВлияние антидепрессантов на микробиоту: неочевидные возможностиThe antidepressants effects on microbiota: unobvious possibilities Research articlehttps://orcid.org/0000-0002-5282-2036РукавишниковГ. В.RukavishnikovG. V.

Рукавишников Григорий Викторович—к.м.н., старший научный сотрудник отделения трансляционной психиатрии

192019, г. Санкт-Петербург, ул. Бехтерева д. 3

Grigory V. Rukavishnikov

Saint-Petersburg

grigory_v_r@mail.ruhttps://orcid.org/0000-0001-6565-6594ЛеоноваЛ. В.LeonovaL. V.

Леонова Любовь Вячеславовна—ординатор отделения трансляционной психиатрии

192019, г. Санкт-Петербург, ул. Бехтерева д. 3

Lubov V. Leonova

Saint-Petersburg

leonovalv@yandex.ruhttps://orcid.org/0000-0002-4658-2195КасьяновЕ. Д.KasyanovE. D.

Касьянов Евгений Дмитриевич—аспирант, младший научный сотрудник отделения трансляционной психиатрии

192019, г. Санкт-Петербург, ул. Бехтерева д. 3

Evgeny D. Kasyanov

Saint-Petersburg

ohkasyan@yandex.ruhttps://orcid.org/0000-0001-5618-4206НезнановН. Г.NeznanovN. G.

Незнанов Николай Григорьевич—д.м.н., профессор, директор ФГБУ «Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева» Минздрава России; заведующий кафедрой психиатрии и наркологии ГБОУП ВПО МЗ РФ «Первый Санкт-Петербургский государственный медицинский университет им.акад. И.П. Павлова»

192019, г. Санкт-Петербург, ул. Бехтерева д. 3; 197022, г. Санкт-Петербург, ул. Льва Толстого, д. 6-8

Nikolay G. Neznanov

Saint-Petersburg

spbinstb@bekhterev.ruhttps://orcid.org/0000-0001-7036-5927МазоГ. Э.MazoG. E.

Мазо Галина Элевна—д.м.н., зам. директора по инновационному развитию, руководитель отделения трансляционной психиатрии

192019, г. Санкт-Петербург, ул. Бехтерева д. 3

Galina E. Mazo

Saint-Petersburg

galina-mazo@yandex.ruНациональный медицинский исследовательский центр психиатрии и неврологии им. В.М. БехтереваРоссияV.M. Bekhterev National Medical Research Center for Psychiatry and NeurologyRussian FederationНациональный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева; Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. ПавловаРоссияV.M. Bekhterev National Medical Research Center for Psychiatry and Neurology; I.P. Pavlov First Saint-Petersburg State Medical UniversityRussian Federation202129122021554814Copyright © Рукавишников Г.В., Леонова Л.В., Касьянов Е.Д., Незнанов Н.Г., Мазо Г.Э., 20212021Рукавишников Г.В., Леонова Л.В., Касьянов Е.Д., Незнанов Н.Г., Мазо Г.Э.Rukavishnikov G.V., Leonova L.V., Kasyanov E.D., Neznanov N.G., Mazo G.E.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/616

Несмотря на появление новых антидепрессантов с различными механизмами действия, сохраняется большое число проблем антидепрессивной терапии. Учитывая известную антимикробную активность антидепрессантов, представляет интерес роль микробиоты в тимоаналептической активности этих препаратов. В последние годы получены важные данные о роли кишечной микробиоты в регуляции поведения и патофизиологии ряда психических расстройств, включая депрессию. Особый интерес представляет оценка роли представителей нормальной микробиоты кишечника на ход терапевтического процесса. Возникающее двунаправленное взаимодействие лекарств и микроорганизмов может иметь решающее значение для персонализированного подхода к выбору препаратов и будущих разработок лекарств.Однако, в настоящее время эта проблема остается малоизученной. Предлагаемая статья артикулирует основные направления, которые имеют клиническое значение и могут стать объектом для дальнейшего изучения в этой области. Результаты исследований указывают на то, что влияние антидепрессантов на микробиоту—многообещающее направление, изучение которого может дать много важных для клинической практики находок. Данный тип терапевтической манипуляции может предоставить возможность вмешательства в качестве потенцирования активности антидепрессантов или минимизации побочных эффектов. Проблема с этим способом вмешательства заключается в огромной сложности, когда манипуляции могут иметь как положительные, так и отрицательные эффекты одновременно в зависимости от различных штаммов микроорганизмов, влияющих на различные терапевтические эффекты. Необходимы дополнительные исследования для понимания, какие изменения происходят в микробиоме при остром и хроническом введении конкретных антидепрессантов. Возможно, это будет способствовать разработке микробиомомодулирующих тактик для индивидуализированных вмешательств.

Despite the emergence of new antidepressants with different mechanisms of action, a large number of problems in antidepressant therapy remain. Considering the known antimicrobial activity of antidepressants, the role of the microbiota in the thymoanaleptic activity of these drugs is of high interest. In recent years, important data have been obtained on the role of the gut microbiota in the regulation of behavior and the pathophysiology of a number of mental disorders, including depression. Of particular interest is the assessment of the normal intestinal microbiota role in the course of the therapeutic process. The emerging bi-directional interactions between drugs and microorganisms may be critical for personalized drug selection and future drug development. However, at the present time, this problem remains poorly understood. The proposed manuscript articulates the main directions that are of clinical importance and can become an object for further study in this area.The research results indicate that the effect of antidepressants on the microbiota is a promising area, the study of which could provide many important findings for clinical practice. This type of therapeutic manipulation can provide an opportunity for intervention in order to potentiate the activity of antidepressants or to minimize side effects. The problem with this method of intervention is enormous complexity, when manipulations can have both positive and negative effects simultaneously, depending on different strains of microorganisms influencing different therapeutic effects. More research is needed to understand what changes occur in the microbiome with acute and chronic administration of specific antidepressants. Perhaps this will contribute to the development of microbiomodulatory tactics for individualized interventions.

антидепрессантымикробиотафармакомикробиомикапре-/пробиотические эффектыantidepressantsmicrobiotapharmacomicrobiomicspre-/probiotic effectsReferencesНезнанов Н.Г., Леонова Л.В., Рукавишников Г.В., и соавт. Микробиота кишечника как объект для изучения при психических расстройствах. Успехи физиологических наук. 2021; 52(1):64-76. https://doi.org/10.31857/S0301179821010069Neznanov NG, Leonova LV, Rukavishnikov GV, et al. Enteric microbiota as a research object in mental disorders. Uspehi fiziologicheskih nauk. 2021; 52(1):64-76. (In Russ.). https://doi.org/10.31857/S0301179821010069Ahmed AI, van der Heijden FM, van den Berkmortel H, Kramers K. A man who wanted to commit suicide by hanging himself: an adverse effect of cip- rofloxacin. Gen Hosp Psychiatry. 2011; 33(1):5-82. https://doi.org/10.1016/j.genhosppsych.2010.07.002Ahmed AI, van der Heijden FM, van den Berkmortel H, Kramers K. A man who wanted to commit suicide by hanging himself: an adverse effect of ciprofloxacin. Gen Hosp Psychiatry. 2011; 33(1):5-82. https://doi.org/10.1016/j.genhosppsych.2010.07.002Barrett E, Ross RP, O’Toole PW, Fitzgerald GF, Stanton C. γ-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol. 2012; 113(2):411-417. https://doi.org/10.1111/j.1365-2672.2012.05344.xBarrett E, Ross RP, O’Toole PW, Fitzgerald GF, Stanton C. γ-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol. 2012; 113(2):411-417. https://doi.org/10.1111/j.1365-2672.2012.05344.xBravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011; 108(38):16050-16055. https://doi.org/10.1073/pnas.1102999108Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011; 108(38):16050-16055. https://doi.org/10.1073/pnas.1102999108Cenit MC, Sanz Y, Codoñer-Franch P. Influence of gut microbiota on neuropsychiatric disorders. World J Gastroenterol. 2017; 23(30):5486-5498. https://doi.org/10.3748/wjg.v23.i30.5486Cenit MC, Sanz Y, Codoñer-Franch P. Influence of gut microbiota on neuropsychiatric disorders. World J Gastroenterol. 2017; 23(30):5486-5498. https://doi.org/10.3748/wjg.v23.i30.5486Cohen BM, Baldessarini RJ. Tolerance to therapeu- tic effects of antidepressants. Am J Psychiatry. 1985; 142(4):489-490. https://doi.org/10.1176/ajp.142.4.489Cohen BM, Baldessarini RJ. Tolerance to therapeutic effects of antidepressants. Am J Psychiatry. 1985; 142(4):489-490. https://doi.org/10.1176/ajp.142.4.489Currò D. The role of gut microbiota in the modulation of drug action: a focus on some clinically significant issues. Expert Rev Clin Pharmacol. 2018; 11(2):171-183. https://doi.org/10.1080/17512433.2018.1414598Currò D. The role of gut microbiota in the modulation of drug action: a focus on some clinically significant issues. Expert Rev Clin Pharmacol. 2018; 11(2):171-183. https://doi.org/10.1080/17512433.2018.1414598Cussotto S, Clarke G, Dinan TG, Cryan JF. Psychotropics and the Microbiome: a Chamber of Secrets… Psychopharmacology (Berl). 2019; 236(5):1411-1432. https://doi.org/10.1007/s00213-019-5185-8Cussotto S, Clarke G, Dinan TG, Cryan JF. Psychotropics and the Microbiome: a Chamber of Secrets… Psychopharmacology (Berl). 2019; 236(5):1411-1432. https://doi.org/10.1007/s00213-019-5185-8Dinan TG, Borre YE, Cryan JF. Genomics of schizophrenia: time to consider the gut microbiome?. Mol Psychiatry. 2014; 19(12):1252-1257. https://doi.org/10.1038/mp.2014.93Dinan TG, Borre YE, Cryan JF. Genomics of schizophrenia: time to consider the gut microbiome?. Mol Psychiatry. 2014; 19(12):1252-1257. https://doi.org/10.1038/mp.2014.93El-Mallakh RS, Gao Y, Jeannie Roberts R. Tardive dysphoria: the role of long term antidepressant use in-inducing chronic depression. Med Hypotheses. 2011; 76(6):769-773. https://doi.org/10.1016/j.mehy.2011.01.020El-Mallakh RS, Gao Y, Jeannie Roberts R. Tardive dysphoria: the role of long term antidepressant use in-inducing chronic depression. Med Hypotheses. 2011; 76(6):769-773. https://doi.org/10.1016/j.mehy.2011.01.020ElRakaiby M, Dutilh BE, Rizkallah MR, Boleij A, Cole JN, Aziz RK. Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics. OMICS. 2014; 18(7):402-414. https://doi.org/10.1089/omi.2014.0018ElRakaiby M, Dutilh BE, Rizkallah MR, Boleij A, Cole JN, Aziz RK. Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics. OMICS. 2014; 18(7):402-414. https://doi.org/10.1089/omi.2014.0018Fava GA. Can long-term treatment with antidepressant drugs worsen the course of depression?. J Clin Psychiatry. 2003; 64(2):123-133. https://doi.org/10.4088/jcp.v64n0204Fava GA. Can long-term treatment with antidepressant drugs worsen the course of depression?. J Clin Psychiatry. 2003; 64(2):123-133. https://doi.org/10.4088/jcp.v64n0204Flowers SA, Evans SJ, Ward KM, McInnis MG, Ellingrod VL. Interaction Between Atypical An- tipsychotics and the Gut Microbiome in a Bi- polar Disease Cohort. Pharmacotherapy. 2017; 37(3):261-267. https://doi.org/10.1002/phar.1890Flowers SA, Evans SJ, Ward KM, McInnis MG, Ellingrod VL. Interaction Between Atypical An- tipsychotics and the Gut Microbiome in a Bi- polar Disease Cohort. Pharmacotherapy. 2017; 37(3):261-267. https://doi.org/10.1002/phar.1890Fornaro M, Anastasia A, Novello S, et al. The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications. Pharmacol Res. 2019; 139:494-502. https://doi.org/10.1016/j.phrs.2018.10.025Fornaro M, Anastasia A, Novello S, et al. The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications. Pharmacol Res. 2019; 139:494-502. https://doi.org/10.1016/j.phrs.2018.10.025Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015; 528(7581):262-266. https://doi.org/10.1038/nature15766Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015; 528(7581):262-266. https://doi.org/10.1038/nature15766Freedberg DE, Toussaint NC, Chen SP, et al. Proton Pump Inhibitors Alter Specific Taxa in the Human Gastrointestinal Microbiome: A Crossover Trial. Gastroenterology. 2015; 149(4):883-885. https://doi.org/10.1053/j.gastro.2015.06.043Freedberg DE, Toussaint NC, Chen SP, et al. Proton Pump Inhibitors Alter Specific Taxa in the Human Gastrointestinal Microbiome: A Crossover Trial. Gastroenterology. 2015; 149(4):883-885. https://doi.org/10.1053/j.gastro.2015.06.043Getachew B, Aubee JI, Schottenfeld RS, Csoka AB, Thompson KM, Tizabi Y. Ketamine interactions with gut-microbiota in rats: relevance to its anti- depressant and anti-inflammatory properties. BMC Microbiol. 2018; 18(1):222. https://doi.org/10.1186/s12866-018-1373-7Getachew B, Aubee JI, Schottenfeld RS, Csoka AB, Thompson KM, Tizabi Y. Ketamine interactions with gut-microbiota in rats: relevance to its anti- depressant and anti-inflammatory properties. BMC Microbiol. 2018; 18(1):222. https://doi.org/10.1186/s12866-018-1373-7Hu Y, Yang X, Qin J, et al. Metagenome-wide analysis of antibiotic resistance genes in a large cohort of human gut microbiota. Nat Commun. 2013; 4:2151. https://doi.org/10.1038/ncomms3151Hu Y, Yang X, Qin J, et al. Metagenome-wide analysis of antibiotic resistance genes in a large cohort of human gut microbiota. Nat Commun. 2013; 4:2151. https://doi.org/10.1038/ncomms3151Karine de Sousa A, Rocha JE, Gonçalves de Souza T, Sampaio de Freitas T, Ribeiro-Filho J, Melo Coutinho HD. New roles of fluoxetine in pharmacology: Antibacterial effect and modulation of antibiotic activity. Microb Pathog. 2018; 123:368-371. https://doi.org/10.1016/j.micpath.2018.07.040Karine de Sousa A, Rocha JE, Gonçalves de Souza T, Sampaio de Freitas T, Ribeiro-Filho J, Melo Coutinho HD. New roles of fluoxetine in pharmacology: Antibacterial effect and modulation of antibiotic activity. Microb Pathog. 2018; 123:368-371. https://doi.org/10.1016/j.micpath.2018.07.040Kastl AJ Jr, Terry NA, Wu GD, Albenberg LG. The Structure and Function of the Human Small Intestinal Microbiota: Current Understanding and Future Directions. Cell Mol Gastroenterol Hepatol. 2020; 9(1):33-45. https://doi.org/10.1016/j.jcmgh.2019.07.006Kastl AJ Jr, Terry NA, Wu GD, Albenberg LG. The Structure and Function of the Human Small Intestinal Microbiota: Current Understanding and Future Directions. Cell Mol Gastroenterol Hepatol. 2020; 9(1):33-45. https://doi.org/10.1016/j.jcmgh.2019.07.006Kaur K, Fayad R, Saxena A, et al. Fluoroquinolone-related neuropsychiatric and mitochondrial toxicity: a collaborative investigation by scientists and members of a social network. J Community Support Oncol. 2016; 14(2):54-65. https://doi.org/10.12788/jcso.0167Kaur K, Fayad R, Saxena A, et al. Fluoroquinolone-related neuropsychiatric and mitochondrial toxicity: a collaborative investigation by scientists and members of a social network. J Community Support Oncol. 2016; 14(2):54-65. https://doi.org/10.12788/jcso.0167Klaassen CD, Cui JY. Review: Mechanisms of How the Intestinal Microbiota Alters the Effects of Drugs and Bile Acids. Drug Metab Dispos. 2015; 43(10):1505-1521. https://doi.org/10.1124/dmd.115.065698Klaassen CD, Cui JY. Review: Mechanisms of How the Intestinal Microbiota Alters the Effects of Drugs and Bile Acids. Drug Metab Dispos. 2015; 43(10):1505-1521. https://doi.org/10.1124/dmd.115.065698Ko CY, Lin HV, Tsai GJ. Gamma-aminobutyric acid production in black soybean milk by Lactobacillus brevis FPA 3709 and the antidepressant effect of the fermented product on a forced swimming rat model. Process Biochemistry. 2013; 48(4):559-568. https://doi.org/10.1016/j.procbio.2013.02.021Ko CY, Lin HV, Tsai GJ. Gamma-aminobutyric acid production in black soybean milk by Lactobacillus brevis FPA 3709 and the antidepressant effect of the fermented product on a forced swimming rat model. Process Biochemistry. 2013; 48(4):559-568. https://doi.org/10.1016/j.procbio.2013.02.021Koller MM, Purushotham KR, Maeda N, Scarpace PJ, Humphreys-Beher MG. Desipramine induced changes in salivary proteins, cultivable oral microbiota and gingival health in aging female NIA Fischer 344 rats. Life Sci. 2000; 68(4):445-455. https://doi.org/10.1016/s0024-3205(00)00951-6Koller MM, Purushotham KR, Maeda N, Scarpace PJ, Humphreys-Beher MG. Desipramine induced changes in salivary proteins, cultivable oral microbiota and gingival health in aging female NIA Fischer 344 rats. Life Sci. 2000; 68(4):445-455. https://doi.org/10.1016/s0024-3205(00)00951-6Lee JH, Lee J. Indole as an intercellular signal in microbial communities. FEMS Microbiol Rev. 2010; 34(4):426-444. https://doi.org/10.1111/j.1574-6976.2009.00204.xLee JH, Lee J. Indole as an intercellular signal in microbial communities. FEMS Microbiol Rev. 2010; 34(4):426-444. https://doi.org/10.1111/j.1574-6976.2009.00204.xLi H, He J, Jia W. The influence of gut microbiota on drug metabolism and toxicity. Expert Opin Drug Metab Toxicol. 2016; 12(1):31-40. https://doi.org/10.1517/17425255.2016.1121234Li H, He J, Jia W. The influence of gut microbiota on drug metabolism and toxicity. Expert Opin Drug Metab Toxicol. 2016; 12(1):31-40. https://doi.org/10.1517/17425255.2016.1121234Li G, Young KD. Indole production by the tryptophanase TnaA in Escherichia coli is determined by the amount of exogenous tryptophan. Microbiology (Reading). 2013; 159(Pt 2):402-410. https://doi.org/10.1099/mic.0.064139-0Li G, Young KD. Indole production by the tryptophanase TnaA in Escherichia coli is determined by the amount of exogenous tryptophan. Microbiology (Reading). 2013; 159(Pt 2):402-410. https://doi.org/10.1099/mic.0.064139-0Lieb J, Balter A. Antidepressant tachyphylaxis. Med Hypotheses. 1984; 15(3):279-291. https://doi.org/10.1016/0306-9877(84)90018-Lieb J, Balter A. Antidepressant tachyphylaxis. Med Hypotheses. 1984; 15(3):279-291. https://doi.org/10.1016/0306-9877(84)90018-Lyte M, Daniels KM, Schmitz-Esser S. Fluoxetineinduced alteration of murine gut microbial community structure: evidence for a microbial endocrinology-based mechanism of action responsible for fluoxetine-induced side effects. PeerJ. 2019; 7:6199. https://doi.org/10.7717/peerj.6199Lyte M, Daniels KM, Schmitz-Esser S. Fluoxetineinduced alteration of murine gut microbial community structure: evidence for a microbial endocrinology-based mechanism of action responsible for fluoxetine-induced side effects. PeerJ. 2019; 7:6199. https://doi.org/10.7717/peerj.6199Macedo D, Filho AJMC, Soares de Sousa CN, et al. Antidepressants, antimicrobials or both? Gut microbiota dysbiosis in depression and possible implications of the antimicrobial effects of antidepressant drugs for antidepressant effectiveness. J Affect Disord. 2017; 208:22-32. https://doi.org/10.1016/j.jad.2016.09.012Macedo D, Filho AJMC, Soares de Sousa CN, et al. Antidepressants, antimicrobials or both? Gut microbiota dysbiosis in depression and possible implications of the antimicrobial effects of antidepressant drugs for antidepressant effectiveness. J Affect Disord. 2017; 208:22-32. https://doi.org/10.1016/j.jad.2016.09.012Magnúsdóttir S, Ravcheev D, de Crécy-Lagard V, Thiele I. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes. Front Genet. 2015; 6:148. https://doi.org/10.3389/fgene.2015.00148Magnúsdóttir S, Ravcheev D, de Crécy-Lagard V, Thiele I. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes. Front Genet. 2015; 6:148. https://doi.org/10.3389/fgene.2015.00148Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018; 555(7698):623-628. https://doi.org/10.1038/nature25979Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018; 555(7698):623-628. https://doi.org/10.1038/nature25979Molendijk ML, Bus BA, Spinhoven P, et al. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry. 2011; 16(11):1088-1095. https://doi.org/10.1038/mp.2010.98Molendijk ML, Bus BA, Spinhoven P, et al. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry. 2011; 16(11):1088-1095. https://doi.org/10.1038/mp.2010.98Munoz-Bellido JL, Munoz-Criado S, Garcìa-Rodrìguez JA. Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors. Int J Antimicrob Agents. 2000; 14(3):177-180. https://doi.org/10.1016/s0924-8579(99)00154-5Munoz-Bellido JL, Munoz-Criado S, Garcìa-Rodrìguez JA. Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors. Int J Antimicrob Agents. 2000; 14(3):177-180. https://doi.org/10.1016/s0924-8579(99)00154-5Nierenberg AA, Alpert JE. Depressive breakthrough. Psychiatr Clin North Am. 2000; 23(4):731-742. https://doi.org/10.1016/s0193-953x(05)70194-5Nierenberg AA, Alpert JE. Depressive breakthrough. Psychiatr Clin North Am. 2000; 23(4):731-742. https://doi.org/10.1016/s0193-953x(05)70194-5Posternak MA, Zimmerman M. Dual reuptake inhibitors incur lower rates of tachyphylaxis than selective serotonin reuptake inhibitors: a retrospective study. J Clin Psychiatry. 2005; 66(6):705-707. https://doi.org/10.4088/jcp.v66n0605Posternak MA, Zimmerman M. Dual reuptake inhibitors incur lower rates of tachyphylaxis than selective serotonin reuptake inhibitors: a retrospective study. J Clin Psychiatry. 2005; 66(6):705-707. https://doi.org/10.4088/jcp.v66n0605Raboni S, Bettati S, Mozzarelli A. Tryptophan synthase: a mine for enzymologists. Cell Mol Life Sci. 2009; 66(14):2391-2403. https://doi.org/10.1007/s00018-009-0028-0Raboni S, Bettati S, Mozzarelli A. Tryptophan synthase: a mine for enzymologists. Cell Mol Life Sci. 2009; 66(14):2391-2403. https://doi.org/10.1007/s00018-009-0028-0Rogers MA, Greene MT, Young VB, et al. Depression, antidepressant medications, and risk of Clostridium difficile infection. BMC Med. 2013; 11:121. https://doi.org/10.1186/1741-7015-11-121Rogers MA, Greene MT, Young VB, et al. Depression, antidepressant medications, and risk of Clostridium difficile infection. BMC Med. 2013; 11:121. https://doi.org/10.1186/1741-7015-11-121Saad R, Rizkallah MR, Aziz RK. Gut Pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes. Gut Pathog. 2012; 4(1):16. https://doi.org/10.1186/1757-4749-4-16Saad R, Rizkallah MR, Aziz RK. Gut Pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes. Gut Pathog. 2012; 4(1):16. https://doi.org/10.1186/1757-4749-4-16Selwyn FP, Cui JY, Klaassen CD. RNA-Seq Quantification of Hepatic Drug Processing Genes in GermFree Mice. Drug Metab Dispos. 2015; 43(10):1572- 1580. https://doi.org/10.1124/dmd.115.063545Selwyn FP, Cui JY, Klaassen CD. RNA-Seq Quantification of Hepatic Drug Processing Genes in GermFree Mice. Drug Metab Dispos. 2015; 43(10):1572- 1580. https://doi.org/10.1124/dmd.115.063545Sharma V. Loss of response to antidepressants and subsequent refractoriness: diagnostic issues in a retrospective case series. J Affect Disord. 2001; 64(1):99-106. https://doi.org/10.1016/s0165-0327(00)00212-3Sharma V. Loss of response to antidepressants and subsequent refractoriness: diagnostic issues in a retrospective case series. J Affect Disord. 2001; 64(1):99-106. https://doi.org/10.1016/s0165-0327(00)00212-3Sharma V. Treatment resistance in unipolar depression: Is it an iatrogenic phenomenon caused by antidepressant treatment of patients with a bipolar diathesis?. Med Hypotheses. 2006; 67(5):1142-1145. https://doi.org/10.1016/j.mehy.2006.04.058Sharma V. Treatment resistance in unipolar depression: Is it an iatrogenic phenomenon caused by antidepressant treatment of patients with a bipolar diathesis?. Med Hypotheses. 2006; 67(5):1142-1145. https://doi.org/10.1016/j.mehy.2006.04.058Sjöstedt P, Enander J, Isung J. Serotonin Reuptake Inhibitors and the Gut Microbiome: Significance of the Gut Microbiome in Relation to Mechanism of Action, Treatment Response, Side Effects, and Tachyphylaxis. Front Psychiatry. 2021; 12:682868. https://doi.org/10.3389/fpsyt.2021.682868Sjöstedt P, Enander J, Isung J. Serotonin Reuptake Inhibitors and the Gut Microbiome: Significance of the Gut Microbiome in Relation to Mechanism of Action, Treatment Response, Side Effects, and Tachyphylaxis. Front Psychiatry. 2021; 12:682868. https://doi.org/10.3389/fpsyt.2021.682868Targum SD. Identification and treatment of antidepressant tachyphylaxis. Innov Clin Neurosci. 2014; 11(3-4):24-28.Targum SD. Identification and treatment of antidepressant tachyphylaxis. Innov Clin Neurosci. 2014; 11(3-4):24-28.Vogelzangs N, Duivis HE, Beekman AT, et al. Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Transl Psychiatry. 2012; 2(2):79. https://doi.org/10.1038/tp.2012.8Vogelzangs N, Duivis HE, Beekman AT, et al. Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Transl Psychiatry. 2012; 2(2):79. https://doi.org/10.1038/tp.2012.8Vreeburg SA, Hoogendijk WJ, van Pelt J, et al. Major depressive disorder and hypothalamic-pituitaryadrenal axis activity: results from a large cohort study. Arch Gen Psychiatry. 2009; 66(6):617-626. https://doi.org/10.1001/archgenpsychiatry.2009.50Vreeburg SA, Hoogendijk WJ, van Pelt J, et al. Major depressive disorder and hypothalamic-pituitaryadrenal axis activity: results from a large cohort study. Arch Gen Psychiatry. 2009; 66(6):617-626. https://doi.org/10.1001/archgenpsychiatry.2009.50

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