FKBP5 Gene Variants as Predictors for Antidepressant Response in Individuals with Major Depressive Disorder Who Have Experienced Childhood Trauma. A Systematic Review

  • Natalie Wietfeldt Saba University
  • Andrew J. Boileau Saba University School of Medicine, The Bottom, Caribbean Netherlands
Keywords: Pharmacogenetics, Depressive Disorder, Major, Adult Survivors of Child Adverse Events

Abstract

FKBP5 gene variants may predict antidepressant treatment response in individuals with Major Depressive Disorder. PubMed and Web of Science were searched systematically for articles studying individuals who had received a diagnosis of Major Depressive Disorder (MDD) and were given antidepressant treatment. Inclusion criteria were studies that researched FKBP5 and its variants and focused on antidepressant treatment response. Previous studies support a potential underlying epigenetic mechanism, demethylation at FKBP5 polymorphisms (rs1360780, rs3800373, rs9470080, and rs4713916) after experiencing childhood trauma, leading to increased hypothalamic-pituitary-adrenal (HPA) axis sensitivity and a propensity for the development of MDD. These polymorphisms informed the review, but additional polymorphisms (rs9380514, rs352428) were also considered. Studies conducted prior to 2008, reviews, meta-analyses, editorials, and non-research-based articles were excluded. Studies examined in this article suggest FKBP5 polymorphism rs4713916 and FKBP5 RNA levels may be associated with antidepressant response. Variants rs1360780, rs3800373, and rs9470080 were associated with both positive response and non-response or lack of remission. Variants rs9380514, rs352428, and rs936882 were associated with poor response to antidepressant treatment or non-remission. Further insights into the role FKBP5 plays in development and antidepressant treatment response may be aided by future studies focused on individuals who previously experienced childhood trauma and later developed MDD.

Author Biography

Andrew J. Boileau, Saba University School of Medicine, The Bottom, Caribbean Netherlands

PhD. Full Professor

References

Substance Abuse and Mental Health Services Administration. (2019). Key substance use and mental health indicators in the United States: Results from the 2018 National Survey on Drug Use and Health (HHS Publication No. PEP19-5068, NSDUH Series H-54). Rockville, MD: Center for Behavioral Health Statistics and Quality. Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data. Last updated: 2019 August 20, Cited: 2020 May 13.

Pratt LA, Brody DJ, Gu Q. Antidepressant Use among Persons Aged 12 and Over: United States, 2011-2014. NCHS Data Brief. Number 283. National Center for Health Statistics. 2017.

Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Pütz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet. 2004 Dec;36(12):1319.

Rao S, Yao Y, Ryan J, Li T, Wang D, Zheng C, Xu Y, Xu Q. Common variants in FKBP5 gene and major depressive disorder (MDD) susceptibility: a comprehensive meta-analysis. Sci Rep. 2016 Sep 7;6:32687.

Tsai SJ, Hong CJ, Chen TJ, Yu YW. Lack of supporting evidence for a genetic association of the FKBP5 polymorphism and response to antidepressant treatment. Am J Med Genet B Neuropsychiatr Genet. 2007 Dec 5;144(8):1097-8.

Zeier Z, Carpenter LL, Kalin NH, Rodriguez CI, McDonald WM, Widge AS, Nemeroff CB. Clinical implementation of pharmacogenetic decision support tools for antidepressant drug prescribing. Am J Psychiatry. 2018 Sep 1;175(9):873-86.

Ising M, Scheuer S, Belcredi P, Uhr M, Holsboer F. S74. Perspective of Personalized Drug Treatment in Depression. Biol Psychiatry. 2018 May 1;83(9):S375-6.

Tokuda T, Yoshimoto J, Shimizu Y, Okada G, Takamura M, Okamoto Y, Yamawaki S, Doya K. Identification of depression subtypes and relevant brain regions using a data-driven approach. Sci Rep. 2018 Sep 20;8(1):14082.

Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000 Nov;23(5):477.

Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008 Sep 1;31(9):464-8.

Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, Pace TW, Mercer KB, Mayberg HS, Bradley B, Nemeroff CB. Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nat Neurosci. 2013 Jan;16(1):33.

Appel K, Schwahn C, Mahler J, Schulz A, Spitzer C, Fenske K, Stender J, Barnow S, John U, Teumer A, Biffar R. Moderation of adult depression by a polymorphism in the FKBP5 gene and childhood physical abuse in the general population. Neuropsychopharmacology. 2011 Sep;36(10):1982.

Lavebratt C, Åberg E, Sjöholm LK, Forsell Y. Variations in FKBP5 and BDNF genes are suggestively associated with depression in a Swedish population-based cohort. J Affect Disord. 2010 Sep 1;125(1-3):249-55.

Tyrka AR, Ridout KK, Parade SH, Paquette A, Marsit CJ, Seifer R. Childhood maltreatment and methylation of FK506 binding protein 5 gene (FKBP5). Dev Psychopathol. 2015 Nov;27(4pt2):1637-45.

Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009 Dec 1;34:S186-95.

Farrell C, Doolin K, O’Leary N, Jairaj C, Roddy D, Tozzi L, Morris D, Harkin A, Frodl T, Nemoda Z, Szyf M. DNA methylation differences at the glucocorticoid receptor gene in depression are related to functional alterations in hypothalamic–pituitary–adrenal axis activity and to early life emotional abuse. Psychiatry Res. 2018 Jul 1;265:341-8.

Matosin N, Halldorsdottir T, Binder EB. Understanding the molecular mechanisms underpinning gene by environment interactions in psychiatric disorders: the FKBP5 model. Biol Psychiatry. 2018 May 15;83(10):821-30.

Menke A, Lehrieder D, Fietz J, Leistner C, Wurst C, Stonawski S, Reitz J, Lechner K, Busch Y, Weber H, Deckert J. Childhood trauma dependent anxious depression sensitizes HPA axis function. Psychoneuroendocrinology. 2018 Dec 1;98:22-9.

Vermeer H, Hendriks-Stegeman BI, van der Burg B, van Buul-Offers SC, Jansen M. Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential marker for glucocorticoid sensitivity, potency, and bioavailability. J Clin Endocrinol Metab. 2003 Jan 1;88(1):277-84.

Zannas AS, Wiechmann T, Gassen NC, Binder EB. Gene–stress–epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology. 2016 Jan;41(1):261.

Qiu B, Xu Y, Wang J, Liu M, Dou L, Deng R, Wang C, Williams KE, Stewart RB, Xie Z, Ren W. Loss of FKBP5 Affects Neuron Synaptic Plasticity: An Electrophysiology Insight. Neuroscience. 2019 Mar 15;402:23-36.

Grabe HJ, Wittfeld K, Van der Auwera S, Janowitz D, Hegenscheid K, Habes M, Homuth G, Barnow S, John U, Nauck M, Völzke H. Effect of the interaction between childhood abuse and rs1360780 of the FKBP5 gene on gray matter volume in a general population sample. Hum Brain Mapp. 2016 Apr;37(4):1602-13.

Tozzi L, Carballedo A, Wetterling F, McCarthy H, O'keane V, Gill M, Morris D, Fahey C, Meaney J, Frodl T. Single-nucleotide polymorphism of the FKBP5 gene and childhood maltreatment as predictors of structural changes in brain areas involved in emotional processing in depression. Neuropsychopharmacology. 2016 Jan;41(2):487.

Tozzi L, Farrell C, Booij L, Doolin K, Nemoda Z, Szyf M, Pomares FB, Chiarella J, O'Keane V, Frodl T. Epigenetic changes of FKBP5 as a link connecting genetic and environmental risk factors with structural and functional brain changes in major depression. Neuropsychopharmacology. 2018 Apr;43(5):1138.

Koenen KC, Saxe G, Purcell S, Smoller JW, Bartholomew D, Miller A, Hall E, Kaplow J, Bosquet M, Moulton S, Baldwin C. Polymorphisms in FKBP5 are associated with peritraumatic dissociation in medically injured children. Mol Psychiatry. 2005 Dec;10(12):1058.

Mehta D, Gonik M, Klengel T, Rex-Haffner M, Menke A, Rubel J, Mercer KB, Pütz B, Bradley B, Holsboer F, Ressler KJ. Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies. Arch Gen Psychiatry. 2011 Sep 5;68(9):901-10.

Roy A, Gorodetsky E, Yuan Q, Goldman D, Enoch MA. Interaction of FKBP5, a stress-related gene, with childhood trauma increases the risk for attempting suicide. Neuropsychopharmacology. 2010 Jul;35(8):1674.

Zimmermann P, Brückl T, Nocon A, Pfister H, Binder EB, Uhr M, Lieb R, Moffitt TE, Caspi A, Holsboer F, Ising M. Interaction of FKBP5 gene variants and adverse life events in predicting depression onset: results from a 10-year prospective community study. Am J Psychiatry. 2011 Oct;168(10):1107-16.

Cattaneo A, Gennarelli M, Uher R, Breen G, Farmer A, Aitchison KJ, Craig IW, Anacker C, Zunsztain PA, McGuffin P, Pariante CM. Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology. 2013 Feb;38(3):377.

Banach E, Szczepankiewicz A, Leszczynska-Rodziewicz A, Pawlak J, Dmitrzak-Weglarz M, Zaremba D, Twarowska-Hauser J. Venlafaxine and sertraline does not affect the expression of genes regulating stress response in female MDD patients. Psychiatr. Pol. 2017 Dec 30;51(6):1029-38.

Lekman M, Laje G, Charney D, Rush AJ, Wilson AF, Sorant AJ, Lipsky R, Wisniewski SR, Manji H, McMahon FJ, Paddock S. The FKBP5-gene in depression and treatment response—an association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR* D) Cohort. Biol psychiatry. 2008 Jun 15;63(12):1103-10.

Zobel A, Schuhmacher A, Jessen F, Höfels S, Von Widdern O, Metten M, Pfeiffer U, Hanses C, Becker T, Rietschel M, Scheef L. DNA sequence variants of the FKBP5 gene are associated with unipolar depression. Int J Neuropsychopharmacol. 2010 Jun 1;13(5):649-60.

Stamm TJ, Rampp C, Wiethoff K, Stingl J, Mössner R, O′ Malley G, Ricken R, Seemüller F, Keck M, Fisher R, Gaebel W. The FKBP5 polymorphism rs1360780 influences the effect of an algorithm-based antidepressant treatment and is associated with remission in patients with major depression. J Psychopharmacol. 2016 Jan;30(1):40-7.

Fabbri C, Corponi F, Albani D, Raimondi I, Forloni G, Schruers K, Kasper S, Kautzky A, Zohar J, Souery D, Montgomery S. Pleiotropic genes in psychiatry: Calcium channels and the stress-related FKBP5 gene in antidepressant resistance. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Feb 2;81:203-10.

Ellsworth KA, Moon I, Eckloff BW, Fridley BL, Jenkins GD, Batzler A, Biernacka JM, Abo R, Brisbin A, Ji Y, Hebbring S. FKBP5 genetic variation: association with selective serotonin reuptake inhibitor treatment outcomes in major depressive disorder. Pharmacogenet Genomics. 2013 Mar;23(3):156.

Hähle A, Merz S, Meyners C, Hausch F. The many faces of FKBP51. Biomolecules. 2019 Jan;9(1):35.

Ising M, Maccarrone G, Brückl T, Scheuer S, Hennings J, Holsboer F, Turck CW, Uhr M, Lucae S. FKBP5 Gene Expression Predicts Antidepressant Treatment Outcome in Depression. Int J Mol Sci. 2019 Jan;20(3):485.

Published
2020-05-22
How to Cite
Wietfeldt, N., & Boileau, A. J. (2020). FKBP5 Gene Variants as Predictors for Antidepressant Response in Individuals with Major Depressive Disorder Who Have Experienced Childhood Trauma. A Systematic Review. International Journal of Medical Students, 8(2), 126-134. https://doi.org/10.5195/ijms.2020.437
Section
Review