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Impact of ACE2 genetic variant on antidepressant efficacy of SSRIs

Published online by Cambridge University Press:  04 October 2021

Negar Firouzabadi Open the ORCID record for Negar Firouzabadi [Opens in a new window] ,
Parisa Farshadfar ,
Maral Haghnegahdar ,
Ali Alavi-Shoushtari  and
Vahid Ghanbarinejad
Negar Firouzabadi*
Affiliation:
Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
Parisa Farshadfar
Affiliation:
Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
Maral Haghnegahdar
Affiliation:
Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
Ali Alavi-Shoushtari
Affiliation:
Department of Psychiatry, UCLA-Kern, Bakersfield, CA, USA Department of Psychiatry, School of Medicine, Hafez Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
Vahid Ghanbarinejad
Affiliation:
Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
*
Author for correspondence: Negar Firouzabadi, Emails: [email protected], [email protected]
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Abstract

Identification of a new axis of angiotensin-converting enzyme 2 (ACE2)/angiotensin (1–7)/Mas receptor, in the renin-angiotensin system (RAS), has opened a new insight regarding the role of RAS and angiotensin in higher brain functions. ACE2 catabolizes angiotensin II and produces angiotensin (1–7), an agonist of Mas receptor. Mice lacking the Mas receptor (angiotensin 1–7 receptor) exhibit anxiety-like behaviours. The present study was conducted to test the hypothesis of the involvement of ACE2 genetic variant (G8790A) on response to selective serotonin reuptake inhibitors (SSRIs). In a randomised control trial, 200 newly diagnosed Iranian patients with major depressive disorder completed 6 weeks of fluoxetine or sertraline treatment. Patients with a reduction of 50% or more in the Hamilton Rating Scale for Depression score were considered responsive to treatment. G8790A polymorphism was determined in extracted DNAs using restriction fragment length polymerase chain reaction method. Our results show that the A allele and AA and GA genotypes were significantly associated with better response to SSRIs (p = 0.008; OR = 3.4; 95% CI = 1.4–8.5 and p = 0.027; OR = 3.3, 95% CI = 1.2–9.2, respectively). Moreover, patients with GA and AA genotypes responded significantly better to sertraline (p = 0.0002; OR = 9.1; 95% CI = 2.4–33.7). The A allele was significantly associated with better response to sertraline (p = 0.0001; OR = 7.6; 95% CI = 2.5–23.3). In conclusion, our results confirm the role of G8790A in response to some SSRIs.

Keywords

major depressive disordergenetic polymorphismsingle nucleotide polymorphismfluoxetinesertraline
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 34 , Issue 1 , February 2022 , pp. 30 - 36
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Copyright
© The Author(s), 2021. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology

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References

Alenina, N and Klempin, F (2015) The role of serotonin in adult hippocampal neurogenesis. Behavioural Brain Research 277(5), 49–57.CrossRefGoogle ScholarPubMed
Almeida-Santos, AF, Kangussu, LM, Moreira, FA, Santos, RA, Aguiar, DC and Campagnole-Santos, MJ (2016) Anxiolytic-and antidepressant-like effects of angiotensin-(1-7) in hypertensive transgenic (mRen2) 27 rats. Clinical Science 130(14), 1247–1255.CrossRefGoogle Scholar
Arroll, B, Macgillivray, S, Ogston, S, Reid, I, Sullivan, F, Williams, B and Crombie, I (2005) Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. The Annals of Family Medicine 3(5), 449–456.CrossRefGoogle ScholarPubMed
Baghai, T, Binder, E, Schule, C, Salyakina, D, Eser, D, Lucae, S, Zwanzger, P, Haberger, C, Zill, P, Ising, M (2006) Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism. Molecular Psychiatry 11, 1003.CrossRefGoogle ScholarPubMed
Baghai, TC, Schule, C, Zill, P, Deiml, T, Eser, D, Zwanzger, P, Ella, R, Rupprecht, R and Bondy, B (2004) The angiotensin I converting enzyme insertion/deletion polymorphism influences therapeutic outcome in major depressed women, but not in men. Neuroscience Letters 363(1), 38–42.CrossRefGoogle Scholar
Bahramali, E, Firouzabadi, N, Yavarian, I, Shayesteh, MRH, Erfani, N, Shoushtari, AA and Asadpour, R (2016) Influence of ACE gene on differential response to sertraline versus fluoxetine in patients with major depression: a randomized controlled trial. European Journal of Clinical Pharmacology 72(9), 1059–1064.CrossRefGoogle ScholarPubMed
Bondy, B, Baghai, TC, Zill, P, Schule, C, Eser, D, Deiml, T, Zwanzger, P, Ella, R and Rupprecht, R (2005) Genetic variants in the angiotensin I-converting-enzyme (ACE) and angiotensin II receptor (AT1) gene and clinical outcome in depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 29(6), 1094–1099.CrossRefGoogle ScholarPubMed
Braszko, JJ, Karwowska-Polecka, W, Halicka, D and Gard, PR (2003) Captopril and enalapril improve cognition and depressed mood in hypertensive patients. Journal of Basic and Clinical Physiology and Pharmacology 14(4), 323–344.CrossRefGoogle ScholarPubMed
Chrissobolis, S, Luu, A, Waldschmidt, R, Yoakum, M and D’souza, MS (2020) Targeting the renin angiotensin system for the treatment of anxiety and depression. Pharmacology Biochemistry and Behavior 199(10), 173063.CrossRefGoogle ScholarPubMed
Ciobica, A, Bild, W, Hritcu, L and Haulica, I (2009) Brain renin-angiotensin system in cognitive function: pre-clinical findings and implications for prevention and treatment of dementia. Acta Neurologica Belgica 109, 171.Google ScholarPubMed
Cowen, PJ (2008) Serotonin and depression: pathophysiological mechanism or marketing myth? Trends in Pharmacological Sciences 29(9), 433–436.CrossRefGoogle ScholarPubMed
de Melo, LA and Almeida-Santos, AF (2020) Neuropsychiatric properties of the ACE2/Ang-(1-7)/Mas pathway: a brief review. Protein and Peptide Letters 27(6), 476–483.CrossRefGoogle ScholarPubMed
Diniz, CR, Casarotto, PC, Fred, SM, Biojone, C, Castrén, E and Joca, SR (2018) Antidepressant-like effect of losartan involves TRKB transactivation from angiotensin receptor type 2 (AGTR2) and recruitment of FYN. Neuropharmacology 135(10), 163–171.CrossRefGoogle ScholarPubMed
Doobay, MF, Talman, LS, Obr, TD, Tian, X, Davisson, RL and Lazartigues, E (2007) Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 292(1), R373–R381.CrossRefGoogle ScholarPubMed
Faul, F, Erdfelder, E, Lang, A-G and Buchner, A (2007) G* Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods 39(2), 175–191.CrossRefGoogle ScholarPubMed
Firouzabadi, N, Ghazanfari, N, Alavi Shoushtari, A, Erfani, N, Fathi, F, Bazrafkan, M and Bahramali, E (2016) Genetic variants of angiotensin-converting enzyme are linked to autism: a case-control study. PLOS ONE 11(4), e0153667.CrossRefGoogle ScholarPubMed
Firouzabadi, N, Shafiei, M, Bahramali, E, Ebrahimi, SA, Bakhshandeh, H and Tajik, N (2012) Association of angiotensin-converting enzyme (ACE) gene polymorphism with elevated serum ACE activity and major depression in an Iranian population. Psychiatry Research 200(2-3), 336–342.CrossRefGoogle Scholar
Gard, PR, Mandy, A and Sutcliffe, MA (1999) Evidence of a possible role of altered angiotensin function in the treatment, but not etiology, of depression. Biological Psychiatry 45(8), 1030–1034.CrossRefGoogle Scholar
Gard, PR, Mandy, A, Whiting, JM, Nickels, DP and Meakin, AJ (1994) Reduction of responses to angiotensin II by antidepressant drugs. European Journal of Pharmacology 264(3), 295–300.CrossRefGoogle ScholarPubMed
Georgiev, V, Stancheva, S, Kambourova, T and Getova, D (1990) Effect of angiotensin II on the Vogel conflict paradigm and on the content of dopamine and noradrenaline in rat brain. Acta Physiologica et Pharmacologica Bulgarica 16, 32–37.Google ScholarPubMed
Han, W, Wei, Z, Dang, R, Guo, Y, Zhang, H, Geng, C, Wang, C, Feng, Q and Jiang, P (2020) Angiotensin-II and angiotensin-(1-7) imbalance affects comorbidity of depression and coronary heart disease. Peptides 131(6), 170353.CrossRefGoogle ScholarPubMed
Joffe, R, Sokolov, S and Streiner, D (1996) Antidepressant treatment of depression: a metaanalysis. The Canadian Journal of Psychiatry 41(10), 613–616.CrossRefGoogle ScholarPubMed
Kalra, J, Prakash, A, Kumar, P and Majeed, ABA (2015) Cerebroprotective effects of RAS inhibitors: beyond their cardio-renal actions. Journal of the Renin-Angiotensin-Aldosterone System 16(3), 459–468.CrossRefGoogle ScholarPubMed
Kangussu, LM, Almeida-Santos, AF, Bader, M, Alenina, N, Fontes, MAP, Santos, RA, Aguiar, DC and Campagnole-Santos, MJ (2013) Angiotensin-(1-7) attenuates the anxiety and depression-like behaviors in transgenic rats with low brain angiotensinogen. Behavioural Brain Research 257(1 Pt 2), 25–30.CrossRefGoogle ScholarPubMed
Kangussu, LM, Almeida-Santos, AF, Moreira, FA, Fontes, MA, Santos, RA, Aguiar, DC and Campagnole-Santos, MJ (2017) Reduced anxiety-like behavior in transgenic rats with chronically overproduction of angiotensin-(1-7): role of the Mas receptor. Behavioural Brain Research 331(5), 193–198.CrossRefGoogle ScholarPubMed
Kawajiri, M, Mogi, M, Higaki, N, Matsuoka, T, Ohyagi, Y, Tsukuda, K, Kohara, K, Horiuchi, M, Miki, T, Kira, JI (2009) Angiotensin-converting enzyme (ACE) and ACE2 levels in the cerebrospinal fluid of patients with multiple sclerosis. Multiple Sclerosis 15(2), 262–265.CrossRefGoogle ScholarPubMed
King, M, Davidson, O, Taylor, F, Haines, A, Sharp, D and Turner, R (2002) Effectiveness of teaching general practitioners skills in brief cognitive behaviour therapy to treat patients with depression: randomised controlled trial. British Medical Journal 324(7343), 947–947.CrossRefGoogle ScholarPubMed
Klempin, F, Beis, D, Mosienko, V, Kempermann, G, Bader, M and Alenina, N (2013) Serotonin is required for exercise-induced adult hippocampal neurogenesis. Journal of Neuroscience 33(19), 8270–8275.CrossRefGoogle ScholarPubMed
Klempin, F, Mosienko, V, Matthes, S, Villela, DC, Todiras, M, Penninger, JM, Bader, M, Santos, RA and Alenina, N (2018) Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response. Cellular and Molecular Life Sciences 75(19), 3625–3634.CrossRefGoogle ScholarPubMed
Kramkowski, K, Mogielnicki, A and Buczko, W (2006) The physiologic significance of the alternative. Journal of Physiology and Pharmacology 57, 529–539.Google Scholar
Lazaroni, TL, Raslan, ACS, Fontes, WR, de Oliveira, ML, Bader, M, Alenina, N, Moraes, MF, dos Santos, RA and Pereira, GS (2012) Angiotensin-(1-7)/Mas axis integrity is required for the expression of object recognition memory. Neurobiology of Learning and Memory 97(1), 113–123.CrossRefGoogle ScholarPubMed
Levinson, DF (2006) The genetics of depression: a review. Biological Psychiatry 60(2), 84–92.CrossRefGoogle ScholarPubMed
Levinson, DF, Mostafavi, S, Milaneschi, Y, Rivera, M, Ripke, S, Wray, NR and Sullivan, PF (2014) Genetic studies of major depressive disorder: why are there no GWAS findings, and what can we do about it? Biological Psychiatry 76(7), 510–512.CrossRefGoogle Scholar
Lovren, F, Pan, Y, Quan, A, Teoh, H, Wang, G, Shukla, PC, Levitt, KS, Oudit, GY, Al-Omran, M, Stewart, DJ (2008) Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis. American Journal of Physiology-Heart and Circulatory Physiology 295(4), H1377–H1384.CrossRefGoogle ScholarPubMed
Luo, H, Wu, P-F, Cao, Y, Jin, M, Shen, T-T, Wang, J, Huang, J-G, Han, Q-Q, He, J-G, Deng, S-L (2020) Angiotensin-converting enzyme inhibitor rapidly ameliorates depressive-type behaviors via bradykinin-dependent activation of mTORC1. Biological Psychiatry 88(5), 415–428.CrossRefGoogle Scholar
Mckay, KM, Imel, ZE and Wampold, BE (2006) Psychiatrist effects in the psychopharmacological treatment of depression. Journal of Affective Disorders 92(2-3), 287–290.CrossRefGoogle ScholarPubMed
Milak, MS, Parsey, RV, Keilp, J, Oquendo, MA, Malone, KM and Mann, JJ (2005) Neuroanatomic correlates of psychopathologic components of major depressive disorder. Archives of General Psychiatry 62(4), 397–408.CrossRefGoogle ScholarPubMed
Miller, S, Dykes, D and Polesky, H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Research 16(3), 1215.CrossRefGoogle ScholarPubMed
Moura Santos, D, Ribeiro Marins, F, Limborço-Filho, M, de Oliveira, ML, Hamamoto, D, Xavier, CH, Moreira, FA, Santos, RAS, Campagnole-Santos, MJ and Peliky Fontes, MA (2017) Chronic overexpression of angiotensin-(1-7) in rats reduces cardiac reactivity to acute stress and dampens anxious behavior. Stress-the International Journal on the Biology of Stress 20(2), 189–196.CrossRefGoogle ScholarPubMed
Mullins, N and Lewis, CM (2017) Genetics of depression: progress at last. Current Psychiatry Reports 19(8), 43.CrossRefGoogle ScholarPubMed
Murck, H, Schüssler, P and Steiger, A (2012) Renin-angiotensin-aldosterone system: the forgotten stress hormone system: relationship to depression and sleep. Pharmacopsychiatry 45(3), 83–95.Google ScholarPubMed
Newhouse, PA, Krishnan, K, Doraiswamy, PM, Richter, EM, Batzar, ED and Clary, CM (2000) A double-blind comparison of sertraline and fluoxetine in depressed elderly outpatients. The Journal of Clinical Psychiatry 61(8), 559–568.CrossRefGoogle ScholarPubMed
Niu, W, Qi, Y, Hou, S, Zhou, W and Qiu, C (2007) Correlation of angiotensin-converting enzyme 2 gene polymorphisms with stage 2 hypertension in Han Chinese. Translational Research 150(6), 374–380.CrossRefGoogle ScholarPubMed
Ormel, J, Hartman, CA and Snieder, H (2019) The genetics of depression: successful genome-wide association studies introduce new challenges. Translational Psychiatry 9(1), 1–10.CrossRefGoogle ScholarPubMed
Østergaard, SD, Jensen, S and Bech, P (2011) The heterogeneity of the depressive syndrome: when numbers get serious. Acta Psychiatrica Scandinavica 124(6), 495–496.CrossRefGoogle ScholarPubMed
Ripke, S, Wray, NR, Lewis, CM, Hamilton, SP, Weissman, MM, Breen, G, Byrne, EM, Blackwood, DH, Boomsma, DI, Cichon, S (2013) A mega-analysis of genome-wide association studies for major depressive disorder. Molecular Psychiatry 18(4), 497–511.Google ScholarPubMed
Saab, YB, Gard, PR, Yeoman, MS, Mfarrej, B, El-Moalem, H and Ingram, MJ (2007) Renin-angiotensin-system gene polymorphisms and depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 31(5), 1113–1118.CrossRefGoogle ScholarPubMed
Saavedra, JM, Sánchez-Lemus, E and Benicky, J (2011) Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: therapeutic implications. Psychoneuroendocrinology 36(1), 1–18.CrossRefGoogle ScholarPubMed
Santos, RA, Silva, E, A.C., S, Maric, C, Silva, DM, Machado, RP, de Buhr, I, Heringer-Walther, S, Pinheiro, SVB, Lopes, MT and Bader, M (2003) Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proceedings of The National Academy of Sciences of The United States of America 100(14), 8258–8263.CrossRefGoogle ScholarPubMed
Sarokhani, D, Parvareh, M, Dehkordi, AH, Sayehmiri, K and Moghimbeigi, A (2018) Prevalence of depression among Iranian elderly: systematic review and meta-analysis. Iranian Journal of Psychiatry 13, 55.Google ScholarPubMed
Skidgel, RA and Erdös, EG (2004) Angiotensin converting enzyme (ACE) and neprilysin hydrolyze neuropeptides: a brief history, the beginning and follow-ups to early studies. Peptides 25(3), 521–525.CrossRefGoogle ScholarPubMed
Strafella, C, Caputo, V, Termine, A, Barati, S, Gambardella, S, Borgiani, P, Caltagirone, C, Novelli, G, Giardina, E, Cascella, R (2020) Analysis of ACE2 genetic variability among populations highlights a possible link with COVID-19-related neurological complications. Genes 11(7), 741.CrossRefGoogle ScholarPubMed
Tsai, S and Hong, C (2003) Pharmacogenetics of selective serotonin reuptake inhibitor response in major depression. Current Pharmacogenomics 1(1), 1–7.CrossRefGoogle Scholar
Vadgama, N, Kreymerman, A, Campbell, J, Shamardina, O, Brugger, C, Lee, RT, Penkett, CJ, Gifford, CA, Mercola, M, Nasir, J (2021) SARS-CoV-2 susceptibility and ACE2 gene variations within diverse ethnic backgrounds. medRxiv.CrossRefGoogle Scholar
Vangjeli, C, Dicker, P, Tregouet, D-A, Shields, DC, Evans, A, Stanton, AV and (for the MORGAM project*) (2011) A polymorphism in ACE2 is associated with a lower risk for fatal cardiovascular events in females: the MORGAM project. Journal of the Renin-Angiotensin-Aldosterone System 12(4), 504–509.CrossRefGoogle ScholarPubMed
Vian, J, Pereira, C, Chavarria, V, Köhler, C, Stubbs, B, Quevedo, J, Kim, S-W, Carvalho, AF, Berk, M, Fernandes, BS (2017) The renin-angiotensin system: a possible new target for depression. BMC Medicine 15(1), 144.CrossRefGoogle ScholarPubMed
Voigt, J-P, Hörtnagl, H, Rex, A, Van Hove, L, Bader, M and Fink, H (2005) Brain angiotensin and anxiety-related behavior: the transgenic rat TGR (ASrAOGEN) 680. Brain Research 1046(1-2), 145–156.CrossRefGoogle ScholarPubMed
Wakefield, JC, Schmitz, MF, First, MB and Horwitz, AV (2007) Extending the bereavement exclusion for major depression to other losses: evidence from the National Comorbidity Survey. Archives of General Psychiatry 64(4), 433–440.CrossRefGoogle ScholarPubMed
Wray, NR, Lee, SH, Mehta, D, Vinkhuyzen, AA, Dudbridge, F and Middeldorp, CM (2014) Research review: polygenic methods and their application to psychiatric traits. Journal of Child Psychology and Psychiatry 55(10), 1068–1087.CrossRefGoogle ScholarPubMed
Wu, YH, Li, JY, Wang, C, Zhang, LM and Qiao, H (2017) The ACE 2 G8790A polymorphism: involvement in type 2 diabetes mellitus combined with cerebral stroke. Journal of Clinical Laboratory Analysis 31, e22033.CrossRefGoogle Scholar
Yang, M, Zhao, J, Xing, L and Shi, L (2015) The association between angiotensin-converting enzyme 2 polymorphisms and essential hypertension risk: a meta-analysis involving 14,122 patients. Journal of the Renin-Angiotensin-Aldosterone System 16(4), 1240–1244.CrossRefGoogle Scholar
Yi, L, Gu, Y, Wang, X, An, L, Xie, X, Shao, W, Ma, L, Fang, J, An, Y, Wang, F (2006) Association of ACE, ACE2 and UTS2 polymorphisms with essential hypertension in Han and Dongxiang populations from north-western China. Journal of International Medical Research 34(3), 272–283.CrossRefGoogle Scholar
Zhong, J, Yan, Z, Liu, D, Ni, Y, Zhao, Z, Zhu, S, Tepel, M and Zhu, Z (2006) Association of angiotensin-converting enzyme 2 gene A/G polymorphism and elevated blood pressure in Chinese patients with metabolic syndrome. Journal of Laboratory and Clinical Medicine 147(2), 91–95.CrossRefGoogle ScholarPubMed