ACE genetic variability and response to fluoxetine: lack of association in depressed patients

Document Type : Research(Original) Article


Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran


Evidences suggest that besides the neurotransmitters contributing to the development of depression, renin-angiotensin system (RAS) may also have a substantial role. Certain polymorphisms of RAS are associated with over activity of RAS & depression. Considering that antidepressants reduce the actions of angiotensin II, the main product of RAS, this may come into mind that genetic polymorphisms of the mentioned system may affect the outcome of therapy in depressed patients.In the present study, 100 newly diagnosed depressed patients, according to DSM-IV criteria, were treated with 20 mg of fluoxetine for 8-12 weeks. Patients were categorized into responsive and non-responsive groups according to 50% reduction in symptoms. Genotype frequencies of angiotensin-converting enzyme (ACE) gene [ACE (I/D, A-240T and A2350G)] were then determined in DNAs extracted from venous blood of the patients using polymerase chain reaction–restriction fragment length polymorphism (PCR– RFLP) and PCR.Results indicate that polymorphisms studied and their haplotypes were not associated with better response to fluoxetine. However, a strong association between age and treatment in depressed Iranian patients was observed (P=0.001).In conclusion, unlike previous reports, this study does not support the hypothesis of special genotypes of RAS contributing to a better response to antidepressants in depressed patients.


  1. Taylor W, Aizenstein H, Alexopoulos G. The vascular depression hypothesis: mechanisms linking vascular disease with depression. Molecular psychiatry. 2013.
  2. Malhi GS, Peter McGuffin M. The genetics of major depressive disorder. Current psychiatry reports. 2000;2(2):165-9.
  3. Alexopoulos GS. Depression in the elderly. The Lancet. 2005;365(9475):1961-70.
  4. Baghai T, Binder E, Schule C, Salyakina D, Eser D, Lucae S, et al. Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism. Molecular psychiatry. 2006;11(11):1003-15.
  5. Saab YB, Gard PR, Yeoman MS, Mfarrej B, El-Moalem H, Ingram MJ. Renin-angiotensin-system gene polymorphisms and depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2007;31(5):1113-8.
  6. Firouzabadi N, Shafiei M, Bahramali E, Ebrahimi SA, Bakhshandeh H, Tajik N. Association of angiotensin-converting enzyme (ACE) gene polymorphism with elevated serum ACE activity and major depression in an Iranian population. Psychiatry research. 2012;200(2):336-42.
  7. Jaspard E, Wei L, Alhenc-Gelas F. Differences in the properties and enzymatic specificities of the two active sites of angiotensin I-converting enzyme (kininase II). Studies with bradykinin and other natural peptides. Journal of Biological Chemistry. 1993;268(13):9496-503.
  8. Yokosawa H, Endo S, Ogura Y, Ishii Si. A new feature of angiotensin-converting enzyme in the brain: Hydrolysis of substance P. Biochemical and Biophysical Research Communications. 1983;116(2):735-42.
  9. Bohus B, de Wied D. The vasopressin deficient Brattleboro rats: a natural knockout model used in the search for CNS effects of vasopressin. Progress in Brain Research. 1999;119:555-73.
  10. Gard PR. The role of angiotensin II in cognition and behaviour. European journal of pharmacology. 2002;438(1-2):1-14.
  11. Kranzhöfer R, Schmidt J, Pfeiffer CAH, Hagl S, Libby P, Kübler W. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arteriosclerosis, thrombosis, and vascular biology. 1999;19(7):1623-9.
  12. Germain L, Chouinard G. Captopril treatment of major depression with serial measurements of blood cortisol concentrations. Biological psychiatry. 1989.
  13. Zubenko GS, Nixon RA. Mood-elevating effect of captopril in depressed patients. The American journal of psychiatry. 1984;141(1):110.
  14. Saavedra JM, Sanchez-Lemus E, Benicky J. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: therapeutic implications. Psychoneuroendocrinology. 2011;36(1):1-18.
  15. Baghai TC, Schule C, Zill P, Deiml T, Eser D, Zwanzger P, et al. The angiotensin I converting enzyme insertion/deletion polymorphism influences therapeutic outcome in major depressed women, but not in men. Neuroscience letters. 2004;363(1):38-42.
  16. Association AP, DSM-IV. APATFo. Diagnostic and statistical manual of mental disorders: DSM-IV-TR: American Psychiatric Publishing, Inc.; 2000.
  17. Hamilton M. A rating scale for depression. Journal of neurology, neurosurgery, and psychiatry. 1960;23(1):56.
  18. Miller S, Dykes D, Polesky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic acids research. 1988;16(3):1215.
  19. Rigat B, Hubert C, Corvol P, Soubrier R. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1)(dipeptidyl carboxypeptidase 1). Nucleic acids research. 1992;20(6):1433.
  20. Shanmugam V, Sell K, Saha B. Mistyping ACE heterozygotes. Genome Research. 1993;3(2):120.
  21. Hsieh YY, Chang CC, Tsai FJ, Hsu CM, Lin CC, Tsai CH. Angiotensin I-converting enzyme ACE 2350* G and ACE-240* T-related genotypes and alleles are associated with higher susceptibility to endometriosis. Molecular human reproduction. 2005;11(1):11.
  22. PERWAIZ IQBAL M, Mahmood S, Mehboobali N, Ishaq M, Fatima T, Parveen S, et al. Association study of the angiotensin-converting enzyme (ACE) gene G2350A dimorphism with myocardial infarction. Experimental and molecular medicine. 2004;36(2):110-5.
  23. Firouzabadi N, Tajik N, Shafiei M, Ebrahimi SA, Bakhshandeh H. Interaction of A-240T and A2350G related genotypes of angiotensin-converting enzyme (ACE) is associated with decreased serum ACE activity and blood pressure in a healthy Iranian population. European journal of pharmacology. 2011;668(2):241-247.
  24. Kessler RC, Demler O, Frank RG, Olfson M, Pincus HA, Walters EE, et al. Prevalence and treatment of mental disorders, 1990 to 2003. New England Journal of Medicine. 2005;352(24):2515-23.
  25. Kavari SH. A study of depression prevalence in nurses and it's effect in Shiraz Namazi hospital. Middle East J Fam Med. 2006;4(3):17-21.
  26. Marazita ML, Neiswanger K, Cooper M, Zubenko GS, Giles DE, Frank E, et al. Genetic segregation analysis of early-onset recurrent unipolar depression. The American Journal of Human Genetics. 1997;61(6):1370-8.
  27. Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: review and meta-analysis. American Journal of Psychiatry. 2000;157(10):1552.
  28. Wright JW, Harding JW. Brain renin-angiotensin--A new look at an old system. Progress in Neurobiology. 2011.
  29. Bondy B, Baghai TC, Zill P, Schule C, Eser D, Deiml T, et al. 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. 2005;29(6):1094-9.
  30. Zhu X, Bouzekri N, Southam L, Cooper RS, Adeyemo A, McKenzie CA, et al. Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. The American Journal of Human Genetics. 2001;68(5):1139-48.
  31. Wu SF, Chang JS, Peng CT, Shi YR, Tsai FJ. Polymorphism of angiotensin-1 converting enzyme gene and Kawasaki disease. Pediatric cardiology. 2004;25(5):529-33.
  32. Villard E, Tiret L, Visvikis S, Rakotovao R, Cambien F, Soubrier F. Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis. American journal of human genetics. 1996;58(6):1268.
  33. Joyce P, Mulder R, Luty S, McKenzie J, Rae A. A differential response to nortriptyline and fluoxetine in melancholic depression: the importance of age and gender. Acta Psychiatrica Scandinavica. 2003;108(1):20-3.
  34. Meltzer CC, Drevets WC, Price JC, Mathis CA, Lopresti B, Greer PJ, et al. Gender-specific aging effects on the serotonin 1A receptor. Brain research. 2001;895(1):9-17.