Abstract
Genetic factors play a crucial role for the pathophysiology of treatment-resistant depression (TRD). It has been established that Catechol-O-methyltransferase (COMT) and cyclic amp-response element-binding protein (CREB) are associated with antidepressant response. The aim of this study was to explore the association between single nucleotide polymorphisms (SNPs) in COMT and CREB1 genes and TRD in a Chinese population. We recruited 181 patients with major depressive disorder (MDD) and 80 healthy controls, including 81 TRD patients. Depressive symptoms were assessed with the Hamilton Depression Rating Scale-17 (HDRS). Genotyping was performed using mass spectrometry. Genetic analyses were conducted by PLINK Software. The distribution of COMT SNP rs4818 allele and genotypes were significantly different between TRD and controls. Statistical differences in allele frequencies were observed between TRD and non-TRD groups, including rs11904814 and rs6740584 in CREB1 gene, rs4680 and rs4818 in COMT gene. There were differences in the distribution of HDRS total scores among different phenotypes of CREB1 rs11904814, CREB1 rs6740584, COMT rs4680 and rs4818. Gene–gene interaction effect of COMT–CREB1 (rs4680 × rs6740584) revealed significant epistasis in TRD. There findings indicate that COMT and CREB1 polymorphisms influence the risk of TRD and affect the severity of depressive symptoms of MDD.
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References
Antypa N, Drago A, Serretti A (2013) The role of COMT gene variants in depression: Bridging neuropsychological, behavioral and clinical phenotypes. Neurosci Biobehav Rev. 37(8):1597–610. https://doi.org/10.1016/j.neubiorev.2013.06.006
Avinun R, Nevo A, Radtke SR, Brigidi BD, Hariri AR (2020) Divergence of an association between depressive symptoms and a dopamine polygenic score in Caucasians and Asians. Eur Arch Psychiatry Clin Neurosci. 270:229–35. https://doi.org/10.1007/s00406-019-01040-x
Benedetti F, Colombo C, Pirovano A, Marino E, Smeraldi E (2009) The catechol-O-methyltransferase Val (108/158) Met polymorphism affects antidepressant response to paroxetine in a naturalistic setting. Psychopharmacology 203:155–160. https://doi.org/10.1007/s00213-008-1381-7
Benedetti F, Dallaspezia S, Colombo C, Lorenzi C, Pirovano A, Smeraldi E (2010) Effect of catechol-O-methyltransferase Val (108/158) Met polymorphism on antidepressant efficacy of fluvoxamine. Eur Psychiatry 25:476–478. https://doi.org/10.1016/j.eurpsy.2009.12.007
Blendy JA (2006) The role of CREB in depression and antidepressant treatment. Biol Psychiat 59:1144–1150. https://doi.org/10.1016/j.biopsych.2005.11.003
Brunoni AR, Carracedo A, Amigo OM, Pellicer AL, Talib L, Carvalho AF et al (2020) Association of BDNF, HTR2A, TPH1, SLC6A4, and COMT polymorphisms with tDCS and escitalopram efficacy: ancillary analysis of a double-blind, placebo-controlled trial. Braz J Psychiatr. 42:128–35. https://doi.org/10.1590/1516-4446-2019-0620
Calabrò M, Mandelli L, Crisafulli C, Lee SJ, Jun TY, Wang SM et al (2018) Neuroplasticity, neurotransmission and brain-related genes in major depression and bipolar disorder: focus on treatment outcomes in an asiatic sample. Adv Ther 35(10):1656–70. https://doi.org/10.1007/s12325-018-0781-2
Calati R, Crisafulli C, Balestri M, Serretti A, Spina E, Calabrò M et al (2013) Evaluation of the role of MAPK1 and CREB1 polymorphisms on treatment resistance, response and remission in mood disorder patients. Prog Neuropsychopharmacol Biol Psychiatry 44:271–278. https://doi.org/10.1016/j.pnpbp.2013.03.005
Carpi FM, Di Pietro F, Vincenzetti S, Mignini F, Napolioni V (2011) Human dna extraction methods: patents and applications. Recent Patents DNA Gene Seq. https://doi.org/10.2174/187221511794839264
Carvalho AF, Berk M, Hyphantis TN, McIntyre RS (2014) The integrative management of treatment-resistant depression: a comprehensive review and perspectives. Psychother Psychosom 83:70–88. https://doi.org/10.1159/000357500
Chao JK, Yang MC, Chen CS, Wang IC, Kao WT, Shi MD (2019) A gender-specific COMT haplotype contributes to risk modulation rather than disease severity of major depressive disorder in a Chinese population. J Affect Disord 246:376–386. https://doi.org/10.1016/j.jad.2018.12.088
Chen TY, Tzeng NS (2013) Aripiprazole: a dopamine modulator that mimics methylphenidate in producing faster antidepressant effects. Med Hypotheses 81:183–185. https://doi.org/10.1016/j.mehy.2013.05.009
Chen AC, Shirayama Y, Shin KH, Neve RL, Duman RS (2001) Expression of the cAMP response element binding protein (CREB) in hippocampus produces an antidepressant effect. Biol Psychiatry. 49(9):753–62. https://doi.org/10.1016/s0006-3223(00)01114-8
Chen MH, Lin WC, Wu HJ, Cheng CM, Li CT, Hong CJ et al (2019) Antisuicidal effect, BDNF Val66Met polymorphism, and low-dose ketamine infusion: Reanalysis of adjunctive ketamine study of Taiwanese patients with treatment-resistant depression (AKSTP-TRD). J Affect Disord 251:162–169. https://doi.org/10.1016/j.jad.2019.03.075
Chiesa A, Lia L, Alberti S, Lee SJ, Han C, Patkar AA et al (2014) Lack of influence of rs4680 (COMT) and rs6276 (DRD2) on diagnosis and clinical outcomes in patients with major depression. Int J Psychiatry Clin Pract. 18:97–102. https://doi.org/10.3109/13651501.2014.894073
Dandekar MP, Luse D, Hoffmann C, Cotton P, Peery T, Ruiz C et al (2017) Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle. J Affect Disord. 217:80–88. https://doi.org/10.1016/j.jad.2017.03.074
Demyttenaere K, Van Duppen Z (2019) The impact of (the concept of) treatment-resistant depression: an opinion review. Int J Neuropsychopharmacol 22:85–92. https://doi.org/10.1093/ijnp/pyy052
Fabbri C, Porcelli S, Serretti A (2013) Genetics of Treatment-resistant Depression. Treatment-resistant Depression. Wiley, Oxford, pp 43–90. https://doi.org/10.1093/ijnp/pyy024
Fabbri C, Corponi F, Albani D, Raimondi I, Forloni G, Schruers K et al (2018) Pleiotropic genes in psychiatry: Calcium channels and the stress-related FKBP5 gene in antidepressant resistance. Prog Neuropsychopharmacol Biol Psychiatry 81:203–210. https://doi.org/10.1016/j.pnpbp.2017.10.005
Fabbri C, Kasper S, Kautzky A, Bartova L, Dold M, Zohar J et al (2019) Genome-wide association study of treatment-resistance in depression and meta-analysis of three independent samples. Br J Psychiatry 214:36–41. https://doi.org/10.1192/bjp.2018.256
Fava M (2003) Diagnosis and definition of treatment-resistant depression. Biol Psychiat 53:649–659. https://doi.org/10.1016/S0006-3223(03)00231-2
Gundersen BB, Briand LA, Onksen JL, Lelay J, Kaestner KH, Blendy JA (2013) Increased hippocampal neurogenesis and accelerated response to antidepressants in mice with specific deletion of CREB in the hippocampus: role of cAMP response-element modulator τ. J Neurosci. 33(34):13673–85. https://doi.org/10.1523/JNEUROSCI.1669-13.2013
Halaris A, Sohl E, Whitham EA (2021) Treatment-resistant depression revisited: a glimmer of hope. J Pers Med 11(2):155. https://doi.org/10.3390/jpm11020155
Hamilton M (1960) A RATING SCALE FOR DEPRESSION. J Neurol Neurosurg Psychiatry 23:56–62. https://doi.org/10.1136/jnnp.23.1.56
Hori H, Kunugi H (2013) Dopamine agonist-responsive depression: dopamine and depression. Psychogeriatrics 13:189–195. https://doi.org/10.1111/psyg.12014
Johnston KM, Powell LC, Anderson IM, Szabo S, Cline S (2019) The burden of treatment-resistant depression: a systematic review of the economic and quality of life literature. J Affect Disord 242:195–210. https://doi.org/10.1016/j.jad.2018.06.045
Juhasz G, Dunham JS, McKie S, Thomas E, Downey D, Chase D et al (2011) The CREB1-BDNF-NTRK2 pathway in depression: multiple gene-cognition-environment interactions. Biol Psychiatry 69:762–71. https://doi.org/10.1016/j.biopsych.2010.11.019
Kocabas NA, Faghel C, Barreto M, Kasper S, Linotte S, Mendlewicz J et al (2010) The impact of catechol-O-methyltransferase SNPs and haplotypes on treatment response phenotypes in major depressive disorder: a case–control association study. Int Clin Psychopharmacol 25:218–227. https://doi.org/10.1097/YIC.0b013e328338b884
Kovács KJ (2013) CRH: The link between hormonal-, metabolic- and behavioral responses to stress. J Chem Neuroanat 54:25–33. https://doi.org/10.1016/j.jchemneu.2013.05.003
Lépine JP, Briley M (2011) The increasing burden of depression. Neuropsychiatric Dis Treat 7:3. https://doi.org/10.2147/NDT.S19617
Lex H, Ginsburg Y, Sitzmann AF, Grayhack C, Maixner DF, Mickey BJ (2019) Quality of life across domains among individuals with treatment-resistant depression. J Affect Disord 243:401–407. https://doi.org/10.1016/j.jad.2018.09.062
Li M, Luo X, Rietschel M, Lewis CM, Mattheisen M, Müller-Myhsok B et al (2014) Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility. Mol Psychiatry 19:452–461. https://doi.org/10.1038/mp.2013.37
Li Z, Ruan M, Chen J, Fang Y (2021) Major depressive disorder: advances in neuroscience research and translational applications. Neurosci Bull 37:863–880
Lin Z, He H, Zhang C, Wang Z, Jiang M, Li Q et al (2015) Influence of Val108/158Met COMT gene polymorphism on the efficacy of modified electroconvulsive therapy in patients with treatment resistant depression. Cell Biochem Biophys 71:1387–1393. https://doi.org/10.1007/s12013-014-0361-2
Ma J, Wang L, Yang Y, Qiao Z, Fang D, Qiu X et al (2017) GNB3 and CREB1 gene polymorphisms combined with negative life events increase susceptibility to major depression in a Chinese Han population. PLoS One 12:e0170994. https://doi.org/10.1371/journal.pone.0170994
Malhi GS, Mann JJ (2018) Depression. The Lancet. 392:2299–312. https://doi.org/10.1016/S0140-6736(18)31948-2
Marchese E, Di Maria V, Samengo D, Pani G, Michetti F, Geloso MC (2017) Post-natal deletion of neuronal cAMP responsive-element binding (CREB)-1 promotes pro-inflammatory changes in the mouse hippocampus. Neurochem Res 42:2230–2245. https://doi.org/10.1007/s11064-017-2233-9
Murphy GM, Sarginson JE, Ryan HS, O’Hara R, Schatzberg AF, Lazzeroni LC et al (2013) BDNF and CREB1 genetic variants interact to affect antidepressant treatment outcomes in geriatric depression. Pharmacogenet Genom 23:301–313. https://doi.org/10.1097/FPC.0b013e328360b175
O’Dushlaine C, Ripke S, Ruderfer DM, Hamilton SP, Fava M, Iosifescu DV et al (2014) Rare copy number variation in treatment-resistant major depressive disorder. Biol Psychiatry. 76:536–41. https://doi.org/10.1016/j.biopsych.2013.10.028
Perlis RH, Moorjani P, Fagerness J, Purcell S, Trivedi Madhukar H, Fava M et al (2008) Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR(*)D study. Neuropsychopharmacology. 33(12):2810–9. https://doi.org/10.1038/npp.2008.6
Rafa-Zabłocka K, Kreiner G, Bagińska M, Nalepa I (2018) Selective depletion of CREB in serotonergic neurons affects the upregulation of brain-derived neurotrophic factor evoked by chronic fluoxetine treatment. Front Neurosci 12:637. https://doi.org/10.3389/fnins.2018.00637
Rosenblat JD, McIntyre RS, Alves GS, Fountoulakis KN, Carvalho AF (2015) Beyond monoamines-novel targets for treatment-resistant depression: a comprehensive review. Curr Neuropharmacol 13(5):636–655. https://doi.org/10.2174/1570159X13666150630175044
Schosser A, Serretti A, Souery D, Mendlewicz J, Zohar J, Montgomery S et al (2012) European group for the study of resistant depression (GSRD)—where have we gone so far: review of clinical and genetic findings. Eur Neuropsychopharmacol 22:453–468. https://doi.org/10.1016/j.euroneuro.2012.02.006
Seib C, Whiteside E, Voisey J, Lee K, Alexander K, Humphreys J et al (2016) Stress, COMT polymorphisms, and depressive symptoms in older Australian women: an exploratory study. Genet Test Mol Biomarkers 20:478–481. https://doi.org/10.1089/gtmb.2015.0028
Serretti A, Chiesa A, Calati R, Massat I, Linotte S, Kasper S et al (2011) A preliminary investigation of the influence of CREB1 gene on treatment resistance in major depression. J Affect Disord 128:56–63. https://doi.org/10.1016/j.jad.2010.06.025
Strawbridge R, Hodsoll J, Powell TR, Hotopf M, Hatch SL, Breen G et al (2019) Inflammatory profiles of severe treatment-resistant depression. J Affect Disord 246:42–51. https://doi.org/10.1016/j.jad.2018.12.037
Tang Z, Zhang S, Guo D, Wang H (2020) Association between COMT gene Val108/158Met and antidepressive treatment response: a meta-analysis. Gene 15(734):144333. https://doi.org/10.1016/j.gene.2020.144333
Taranu A, Asmar KE, Colle R, Ferreri F, Polosan M, David D et al (2017) The Catechol-O-methyltransferase Val(108/158)Met genetic polymorphism cannot be recommended as a biomarker for the prediction of venlafaxine efficacy in patients treated in psychiatric settings. Basic Clin Pharmacol Toxicol 121:435–441. https://doi.org/10.1111/bcpt.12827
Tenhunen J (1996) Characterization of the rat Catechol-O-Methyltransferase gene proximal promoter: identification of a nuclear protein–DNA interaction that contributes to the tissue-specific regulation. DNA Cell Biol 15:461–473. https://doi.org/10.1089/dna.1996.15.461
Tsai SJ, Gau YTA, Hong CJ, Liou YJ, Yu YWY, Chen TJ et al (2009) Sexually dimorphic effect of catechol-O-methyltransferase val158met polymorphism on clinical response to fluoxetine in major depressive patients. J Affect Disord 113:183–187. https://doi.org/10.1016/j.jad.2008.04.017
Utge S, Soronen P, Partonen T, Loukola A, Kronholm E, Pirkola S et al (2010) A population-based association study of candidate genes for depression and sleep disturbance. Am J Med Genet 153B:468–476. https://doi.org/10.1002/ajmg.b.31002
Wang P, Yang Y, Yang X, Qiu X, Qiao Z, Wang L, Ma J (2015) CREB1 gene polymorphisms combined with environmental risk factors increase susceptibility to major depressive disorder (MDD). Int J Clin Exp Pathol 8(1):906
Wolk DM, Clark AE (2018) Matrix-assisted laser desorption time of flight mass spectrometry. Clin Lab Med 38(3):471–486. https://doi.org/10.1016/j.cll.2018.05.008
Xiao X, Zhang C, Grigoroiu-Serbanescu M, Wang L, Li L, Zhou D et al (2018) The cAMP responsive element-binding (CREB)-1 gene increases risk of major psychiatric disorders. Mol Psychiatry 23:1957–1967. https://doi.org/10.1038/mp.2017.243
Xing J, Ginty DD, Greenberg ME (1996) Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science. 273(5277):959–63. https://doi.org/10.1126/science.273.5277.959
Acknowledgements
We thank all the study participants for their cooperation. These sources had no further role in this study design, data collection, and statistical analysis, drafting of the report, and submitting the paper for publication. Thanks to Jaelin Rippe for contributing to this article.
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Study concept and design: JL, SL. Acquisition of data: SL, LN, YQ, YM, SL, NG, HC. Statistical analysis: YW, SL. Drafting of the manuscript: YW, SL, JL. Study supervision: JL.
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Wang, Y., Li, S., Niu, L. et al. Polymorphisms of COMT and CREB1 are associated with treatment-resistant depression in a Chinese Han population. J Neural Transm 129, 85–93 (2022). https://doi.org/10.1007/s00702-021-02415-y
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DOI: https://doi.org/10.1007/s00702-021-02415-y