Association of DNA methylation in BDNF with escitalopram treatment response in depressed Chinese Han patients
The neurotrophin brain-derived neurotrophic factor (BDNF) has been found to be associated with both the pathophysiology of depression and antidepressants response. Gene expression differences were partly mediated by SNP, which might be identified as a predictor of antidepressant response. In the present study, we attempt to identify whether DNA methylation, another factor known to affect gene transcription, might also predict antidepressant response.
A total of 85 depressed Chinese Han patients were followed-up 8 weeks after initiating escitalopram treatment. Treatment response was assessed by changes in the Hamilton Depression Rating Scale-17 (HAMD-17) score. The Life Events Scale (LES) and the Childhood Trauma Questionnaire (CTQ) were utilized as the assessment of previous life stress. The bisulfate sequencing was used to assess DNA methylation. Four single nucleotide polymorphisms (SNPs) in the BDNF gene were genotyped using PCR-RFLP or PCR sequencing.
We identified a DNA methylation predictor (P = 0.006–0.036) and a DNA methylation by LES interaction predictor (OR = 1.442 [1.057–1.968], P = 0.021) of general antidepressant treatment response. Lower mean BDNF DNA methylation was associated with impaired antidepressant response. Furthermore, the present data indicated that age, life stress, and SNPs genotype might be likely related to DNA methylation status. Average DNA methylation of BDNF at baseline was significantly lower than that at endpoint after 8 weeks of escitalopram treatment, which was based only on a subset of cases (n = 44).
Our results suggest that BDNF DNA hypomethylation and its interaction with lower LES score might result in impaired antidepressant treatment response. The pharmacoepigenetic study could eventually help in finding epigenetic biomarkers of antidepressant response.
KeywordsMajor depressive disorder Escitalopram Brain-derived neurotrophic factor Polymorphism DNA methylation
We gratefully acknowledge the data analysis support of Dr. Caifu Xue.
Weimin Cai, Zhenghui Yi, and Peipei Wang conceived and designed the study. Peipei Wang and Weimin Cai wrote the manuscript. Peipei Wang contributed to the data analysis. Peipei Wang, Cuizhen Zhang, Qinyu Lv, Yiru Fang, and Zhenghui Yi collected the samples. Peipei Wang, Hong Sun, Cuizhen Zhang, and Guo Ma contributed to the reagents, materials, and analysis tools. All the authors read and approved the final manuscript.
This work was supported by the National Key R&D Program of China (2016YFC1307100, 2016YFC1305904), the National Basic Research Program of China (Precision Psychiatry Program 2016YFC0906402), the National Natural Science Foundation of China (81671326), the CAS Key Laboratory of Mental Health (KLMH2018K02), the combination of traditional Chinese and Western medicine in Shanghai general hospital in 2017 (ZHYY-ZXYJHZX-2-201708), and the Shanghai Science and Technology Commission Foundation (17411970000).
Compliance with ethical standards
The study was approved by the ethics committees of Shanghai Mental Health Center (2012-26R) and performed according to the Declaration of Helsinki and the International Conference on Harmonization-Good Clinical Practice standards. All participating subjects received a description of the study and gave informed written consent.
The authors declare that they have no conflict of interest.
- 1.Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE, Flaxman AD, Johns N, Burstein R, Murray CJL, Vos T (2013) Global burden of disease attributable to mental and substance use disorders: findings from the global burden of disease study 2010. Lancet 382(9904):1575–1586. https://doi.org/10.1016/S0140-6736(13)61611-6 CrossRefPubMedGoogle Scholar
- 10.Chiara F, Stefano P, Alessandro S (2014) From pharmacogenetics to pharmacogenomics: the way toward the personalization of antidepressant treatment. Can J PsychiatrGoogle Scholar
- 15.Molendijk ML, Bus BA, Spinhoven P, Penninx BW, Kenis G, Prickaerts J, Voshaar RC, Elzinga BM (2011) Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry 16(11):1088–1095. https://doi.org/10.1038/mp.2010.98 CrossRefPubMedGoogle Scholar
- 16.Hochberg Z, Feil R, Constancia M, Fraga M, Junien C, Carel JC, Boileau P, Le Bouc Y, Deal CL, Lillycrop K, Scharfmann R, Sheppard A, Skinner M, Szyf M, Waterland RA, Waxman DJ, Whitelaw E, Ong K, Albertsson-Wikland K (2011) Child health, developmental plasticity, and epigenetic programming. Endocr Rev 32(2):159–224. https://doi.org/10.1210/er.2009-0039 CrossRefPubMedGoogle Scholar
- 17.Shimada-Sugimoto M, Otowa T, Miyagawa T, Umekage T, Kawamura Y, Bundo M, Iwamoto K, Tochigi M, Kasai K, Kaiya H, Tanii H, Okazaki Y, Tokunaga K, Sasaki T (2017) Epigenome-wide association study of DNA methylation in panic disorder. Clin Epigenetics 9(1). https://doi.org/10.1186/s13148-016-0307-1
- 18.Kember RL, Dempster EL, Lee THA, Schalkwyk LC, Mill J, Fernandes C (2012) Maternal separation is associated with strain-specific responses to stress and epigenetic alterations to Nr3c1, Avp, and Nr4a1 in mouse. Brain Behav 2(4):455. https://doi.org/10.1002/brb3.69 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Tadić A, Müller-Engling L, Schlicht KF, Kotsiari A, Dreimüller N, Kleimann A, Bleich S, Lieb K, Frieling H (2013) Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression. MOL PSYCHIATR 19(3):281–283. https://doi.org/10.1038/mp.2013.58 Google Scholar
- 20.Okada S, Morinobu S, Fuchikami M, Segawa M, Yokomaku K, Kataoka T, Okamoto Y, Yamawaki S, Inoue T, Kusumi I, Koyama T, Tsuchiyama K, Terao T, Kokubo Y, Mimura M (2014) The potential of SLC6A4 gene methylation analysis for the diagnosis and treatment of major depression. J Psychiatr Res 53:47–53. https://doi.org/10.1016/j.jpsychires.2014.02.002 CrossRefPubMedGoogle Scholar
- 21.Domschke K, Tidow N, Schwarte K, Deckert J, Lesch K, Arolt V, Zwanzger P, Baune BT (2014) Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response. Int J Neuropsychopharmacol 17(08):1167–1176. https://doi.org/10.1017/S146114571400039X CrossRefPubMedGoogle Scholar
- 23.Gass P, Rodr Guez N, Bl Zquez A, Monteagudo A, Boloc D, Plana MT, Lafuente A, Zaro L, Arnaiz JA, Mas S (2017) Epigenetic and genetic variants in the HTR1B gene and clinical improvement in children and adolescents treated with fluoxetine. Prog Neuro-Psychopharmacol Biol Psychiatry 75:28–34. https://doi.org/10.1016/j.pnpbp.2016.12.003 CrossRefGoogle Scholar
- 25.McDade TW, Ryan C, Jones MJ, MacIsaac JL, Morin AM, Meyer JM, Borja JB, Miller GE, Kobor MS, Kuzawa CW (2017) Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood. Proc Natl Acad Sci 114(29):7611–7616. https://doi.org/10.1073/pnas.1620661114 CrossRefPubMedGoogle Scholar
- 26.Gao X, Thomsen H, Zhang Y, Breitling LP, Brenner H (2017) The impact of methylation quantitative trait loci (mQTLs) on active smoking-related DNA methylation changes. Clin Epigenetics 9(1). https://doi.org/10.1186/s13148-017-0387-6
- 27.Walker RM, Christoforou AN, McCartney DL, Morris SW, Kennedy NA, Morten P, Anderson SM, Torrance HS, Macdonald A, Sussmann JE, Whalley HC, Blackwood DHR, McIntosh AM, Porteous DJ, Evans KL (2016) DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder. Clin Epigenetics 8(1). https://doi.org/10.1186/s13148-016-0171-z
- 30.Heaton P, Davis RE, Happ FGE (2008) Research note: exceptional absolute pitch perception for spoken words in an able adult with autism. Neuropsychologia 46(7):2095–2098. https://doi.org/10.1016/j.neuropsychologia.2008.02.006 CrossRefPubMedGoogle Scholar
- 32.Bauer M, Whybrow P, Angst J, Versiani M, Moller H (2002) World Federation of Societies of biological psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: acute and continuation treatment of major depressive disorder. World J Biol Psychiatry 3(1):5–43CrossRefPubMedGoogle Scholar
- 34.Häuser W, Hoffmann E, Wolfe F, Worthing A, Stahl N, Rothenberg R, Walitt B (2015) Self-reported childhood maltreatment, lifelong traumatic events and mental disorders in fibromyalgia syndrome: a comparison of US and German outpatients. Clin Exp Rheumatol 33(1 Suppl 88):S86–S92PubMedPubMedCentralGoogle Scholar
- 37.Kurita M, Nishino S, Kato M, Numata Y, Sato T (2012) Plasma brain-derived neurotrophic factor levels predict the clinical outcome of depression treatment in a naturalistic study: e39212. PLoS One 7(6). https://doi.org/10.1371/journal.pone.0039212
- 41.Domschke K, Tidow N, Schwarte K, Ziegler C, Lesch K, Deckert JR, Arolt V, Zwanzger P, Baune BT (2015) Pharmacoepigenetics of depression: no major influence of MAO-A DNA methylation on treatment response. J Neural Transm 122(1):99–108. https://doi.org/10.1007/s00702-014-1227-x CrossRefPubMedGoogle Scholar
- 44.Domschke K, Tidow N, Schrempf M, Schwarte K, Klauke B, Reif A, Kersting A, Arolt V, Zwanzger P, Deckert JR (2013) Epigenetic signature of panic disorder: a role of glutamate decarboxylase 1 (GAD1) DNA hypomethylation? Prog Neuro-Psychopharmacol Biol Psychiatry 46:189–196. https://doi.org/10.1016/j.pnpbp.2013.07.014 CrossRefGoogle Scholar