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Pharmacopsychiatry 2025; 58(01): 25-32
DOI: 10.1055/a-2437-1751
Original Paper

ABC Family Gene Polymorphisms and Cognitive Functions Interact to Influence Antidepressant Efficacy

Meijiang Jin   #
1   Department of Psychiatry, West China Hospital of Sichuan University, Chengdu, Sichuan, China
,
Lei Ji   #
2   Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
,
Maojia Ran
1   Department of Psychiatry, West China Hospital of Sichuan University, Chengdu, Sichuan, China
,
Zhujun Wang
1   Department of Psychiatry, West China Hospital of Sichuan University, Chengdu, Sichuan, China
,
Yan Bi
2   Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
,
Hang Zhang
1   Department of Psychiatry, West China Hospital of Sichuan University, Chengdu, Sichuan, China
,
Yuanmei Tao
1   Department of Psychiatry, West China Hospital of Sichuan University, Chengdu, Sichuan, China
,
Hanmei Xu
1   Department of Psychiatry, West China Hospital of Sichuan University, Chengdu, Sichuan, China
,
Shoukang Zou
1   Department of Psychiatry, West China Hospital of Sichuan University, Chengdu, Sichuan, China
,
Hong Zhang
1   Department of Psychiatry, West China Hospital of Sichuan University, Chengdu, Sichuan, China
,
Tao Yu   *
2   Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
,
Li Yin   *
1   Department of Psychiatry, West China Hospital of Sichuan University, Chengdu, Sichuan, China
3   Institute for System Genetics, Frontiers Science Center for Disease-related Molecular Networks, Chengdu, Sichuan, China
4   Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China
› Author Affiliations Funding This work was supported by the National Key R&D program of the Chinese Science & Technology Department (2023YFE0118600), the National Natural Science Foundation of China (81801357), the Sichuan Province Science and Technology Support Program (22ZDYF1544), and the Health Commission of Sichuan province (21PJ020). The above-mentioned funding bodies had no further role in the study design, collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.
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Abstract

Introduction The importance of identifying relevant indicators of antidepressant efficacy is highlighted by the low response rates to antidepressant treatment for depression. The ABC gene family, encoding ATP-dependent transport proteins facilitating the transport of psychotropic drugs, has drawn attention. This study delved into the relationship between antidepressant efficacy and seven single nucleotide polymorphisms of ABCB1 and ABCB6 genes.

Methods A total of 549 depressed patients participated in the study, and all completed a 6-week course of antidepressant treatment. Cognitive function was assessed at baseline and post-treatment. Patients were categorized based on post-treatment HAMD-17 scores (with HAMD≤7 indicating remission), and comparisons were made between different groups in terms of allelic gene frequencies and genotypes. Logistic regression was used to explore the interaction between cognitive function and genotype on efficacy. Dual-luciferase reporter assays were performed to compare the regulatory effects of rs1109866 allele variants on the ABCB6 promoter.

Results There were no notable differences in allelic gene frequencies and genotypes between the remission and non-remission groups. Nonetheless, a significant interaction was identified between the rs1109866 genotype and language fluency-related indicators concerning efficacy (p=0.029) before correction. The dual-luciferase reporter assays demonstrated markedly higher fluorescence intensity of rs1109866-C compared to that of rs1109866-T (p<0.001).

Discussion Relying solely on genetic polymorphisms of ABC family genes as predictors of antidepressant treatment response may not be sufficient. However, the interaction between the rs1109866 and cognition plays a pivotal role. The potentially enhanced transcriptional activity of rs1109866-C might offer insight into its impact on antidepressant efficacy.

Keywords

major depression disorder - antidepression efficacy - single nucleotide polymorphism - cognitive function

# Meijiang Jin and Lei Ji are co-first authors.


* Tao Yu and Li Yin are co-corresponding authors of this paper.


Supplementary Material



Publication History

Received: 02 April 2024
Received: 03 September 2024

Accepted: 30 September 2024

Article published online:
14 November 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Charlson F, van Ommeren M, Flaxman A. et al. New WHO prevalence estimates of mental disorders in conflict settings: A systematic review and meta-analysis. Lancet 2019; 394: 240-248
    CrossrefPubMedSearch in Google Scholar
  • 2 Conejero I, Olié E, Calati R. et al. Psychological pain, depression, and suicide: Recent evidences and future directions. Curr Psychiatry Rep 2018; 20: 33
    CrossrefPubMedSearch in Google Scholar
  • 3 Walkup JT. Antidepressant efficacy for depression in children and adolescents: Industry- and NIMH-funded studies. Am J Psychiatry 2017; 174: 430-437
    CrossrefPubMedSearch in Google Scholar
  • 4 DallʼAglio L, Lewis CM, Pain O. Delineating the genetic component of gene expression in major depression. Biol Psychiatry 2021; 89: 627-636
    CrossrefPubMedSearch in Google Scholar
  • 5 Hiemke C, Bergemann N, Clement HW. et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018; 51: e1
    Thieme ConnectPubMedSearch in Google Scholar
  • 6 Maciaszek J, Pawłowski T, Hadryś T. et al. The impact of the CYP2D6 and CYP1A2 gene polymorphisms on response to duloxetine in patients with major depression. Int J Mol Sci 2023; 24
    CrossrefPubMedSearch in Google Scholar
  • 7 Thiele LS, Ishtiak-Ahmed K, Thirstrup JP. et al. Clinical impact of functional CYP2C19 and CYP2D6 gene variants on treatment with antidepressants in young people with depression: A Danish Cohort Study. Pharmaceuticals (Basel) 2022; 15: 870
    CrossrefPubMedSearch in Google Scholar
  • 8 Neuwelt E, Abbott NJ, Abrey L. et al. Strategies to advance translational research into brain barriers. Lancet Neurol 2008; 7: 84-96
    CrossrefPubMedSearch in Google Scholar
  • 9 Uhr M, Tontsch A, Namendorf C. et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron 2008; 57: 203-209
    CrossrefPubMedSearch in Google Scholar
  • 10 OʼBrien FE, Dinan TG, Griffin BT. et al. Interactions between antidepressants and P-glycoprotein at the blood-brain barrier: Clinical significance of in vitro and in vivo findings. Br J Pharmacol 2012; 165: 289-312
    CrossrefPubMedSearch in Google Scholar
  • 11 Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res 2001; 11: 1156-1166
    CrossrefPubMedSearch in Google Scholar
  • 12 Beis K. Structural basis for the mechanism of ABC transporters. Biochem Soc Trans 2015; 43: 889-893
    CrossrefPubMedSearch in Google Scholar
  • 13 Bundgaard C, Jensen CJN, Garmer M. Species comparison of in vivo P-glycoprotein-mediated brain efflux using mdr1a-deficient rats and mice. Drug Metab Dispos 2012; 40: 461-466
    CrossrefPubMedSearch in Google Scholar
  • 14 Bundgaard C, Eneberg E, Sánchez C. P-glycoprotein differentially affects escitalopram, levomilnacipran, vilazodone and vortioxetine transport at the mouse blood-brain barrier in vivo. Neuropharmacology 2016; 103: 104-111
    CrossrefPubMedSearch in Google Scholar
  • 15 Karlsson L, Carlsson B, Hiemke C. et al. Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment. Eur Neuropsychopharmacol 2013; 23: 1636-1644
    CrossrefPubMedSearch in Google Scholar
  • 16 Saiz-Rodríguez M, Ochoa D, Belmonte C. et al. Polymorphisms in CYP1A2, CYP2C9 and ABCB1 affect agomelatine pharmacokinetics. J Psychopharmacol 2019; 33: 522-531
    CrossrefPubMedSearch in Google Scholar
  • 17 Singh AB, Bousman CA, Ng CH. et al. ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression. Transl Psychiatry 2012; 2: e198
    CrossrefPubMedSearch in Google Scholar
  • 18 Schatzberg AF, DeBattista C, Lazzeroni LC. et al. ABCB1 genetic effects on antidepressant outcomes: A report from the iSPOT-D Trial. Am J Psychiatry 2015; 172: 751-759
    CrossrefPubMedSearch in Google Scholar
  • 19 Silberbauer LR, Rischka L, Vraka C. et al. ABCB1 variants and sex affect serotonin transporter occupancy in the brain. Mol Psychiatry 2022; 27: 4502-4509
    CrossrefPubMedSearch in Google Scholar
  • 20 Lynch J, Fukuda Y, Krishnamurthy P. et al. Cell survival under stress is enhanced by a mitochondrial ATP-binding cassette transporter that regulates hemoproteins. Cancer Res 2009; 69: 5560-5567
    CrossrefPubMedSearch in Google Scholar
  • 21 Liu L, Liu M, Xiu J. et al. Stimuli-responsive nanoparticles delivered by a nasal-brain pathway alleviate depression-like behavior through extensively scavenging ROS. Acta Biomater 2023; 171: 451-465
    CrossrefPubMedSearch in Google Scholar
  • 22 Liu X, Zhang R, Fan J. et al. The role of ROS/p38 MAPK/NLRP3 inflammasome cascade in arsenic-induced depression-/anxiety-like behaviors of mice. Ecotoxicol Environ Saf 2023; 261: 115111
    CrossrefPubMedSearch in Google Scholar
  • 23 Fu S, Chen H, Yang W. et al. ROS-targeted depression therapy via BSA-incubated ceria nanoclusters. Nano Lett 2022; 22: 4519-4527
    CrossrefPubMedSearch in Google Scholar
  • 24 Disner SG, Beevers CG, Haigh EAP. et al. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci 2011; 12: 467-477
    CrossrefPubMedSearch in Google Scholar
  • 25 Sun J, Wang W, Zhang R. et al. Multivariate genome-wide association study of depression, cognition, and memory phenotypes and validation analysis identify 12 cross-ethnic variants. Transl Psychiatry 2022; 12: 304
    CrossrefPubMedSearch in Google Scholar
  • 26 Qi B, Kong L, Lai X. et al. Plasma exosome proteomics reveals the pathogenesis mechanism of post-stroke cognitive impairment. Aging (Albany NY) 2023; 15: 4334-4362
    CrossrefPubMedSearch in Google Scholar
  • 27 Geers LM, Ochi T, Vyalova NM. et al. Influence of eight ABCB1 polymorphisms on antidepressant response in a prospective cohort of treatment-free Russian patients with moderate or severe depression: An explorative psychopharmacological study with naturalistic design. Hum Psychopharmacol 2022; 37: e2826
    CrossrefPubMedSearch in Google Scholar
  • 28 Huang X, Yu T, Li X. et al. ABCB6, ABCB1 and ABCG1 genetic polymorphisms and antidepressant response of SSRIs in Chinese depressive patients. Pharmacogenomics 2013; 14: 1723-1730
    CrossrefPubMedSearch in Google Scholar
  • 29 Ke X, Ding Y, Xu K. et al. The profile of cognitive impairments in chronic ketamine users. Psychiatry Res 2018; 266: 124-131
    CrossrefPubMedSearch in Google Scholar
  • 30 Mongini F, Keller R, Deregibus A. et al. Frontal lobe dysfunction in patients with chronic migraine: A clinical-neuropsychological study. Psychiatry Res 2005; 133: 101-106
    CrossrefPubMedSearch in Google Scholar
  • 31 Linari I, Juantorena GE, Ibáñez A. et al. Unveiling Trail Making Test: visual and manual trajectories indexing multiple executive processes. Sci Rep 2022; 12: 14265
    CrossrefPubMedSearch in Google Scholar
  • 32 Chu C-S, Li C-T, Brunoni AR. et al. Cognitive effects and acceptability of non-invasive brain stimulation on Alzheimerʼs disease and mild cognitive impairment: A component network meta-analysis. J Neurol Neurosurg Psychiatry 2021; 92: 195-203
    CrossrefPubMedSearch in Google Scholar
  • 33 Shan X-X, Qiu Y, Xie W-W. et al. ABCB1 gene is associated with clinical response to SNRIs in a local Chinese Han population. Front Pharmacol 2019; 10: 761
    CrossrefPubMedSearch in Google Scholar
  • 34 Dong C, Wong ML, Licinio J. Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: Association with major depression and antidepressant response in Mexican-Americans. Mol Psychiatry 2009; 14: 1105-1118
    CrossrefPubMedSearch in Google Scholar
  • 35 Breitenstein B, Scheuer S, Brückl TM. et al. Association of ABCB1 gene variants, plasma antidepressant concentration, and treatment response: Results from a randomized clinical study. J Psychiatr Res 2016; 73: 86-95
    CrossrefPubMedSearch in Google Scholar
  • 36 Lindqvist D, Dhabhar FS, James SJ. et al. Oxidative stress, inflammation and treatment response in major depression. Psychoneuroendocrinology 2017; 76: 197-205
    CrossrefPubMedSearch in Google Scholar
  • 37 Wang Y-L, Wu H-R, Zhang S-S. et al. Catalpol ameliorates depressive-like behaviors in CUMS mice via oxidative stress-mediated NLRP3 inflammasome and neuroinflammation. Transl Psychiatry 2021; 11: 353
    CrossrefPubMedSearch in Google Scholar
  • 38 Bouvier E, Brouillard F, Molet J. et al. Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression. Mol Psychiatry 2017; 22: 1701-1713
    CrossrefPubMedSearch in Google Scholar
  • 39 Mitani K, Rathnayake N, Rathnayake U. et al. Brain activity associated with the planning process during the long-time learning of the Tower of Hanoi (ToH) Task: A pilot study. Sensors (Basel) 2022; 22: 8283
    CrossrefPubMedSearch in Google Scholar
  • 40 Fansher M, Shah P, Hélie S. The effect of mode of presentation on Tower of Hanoi problem solving. Cognition 2022; 224: 105041
    CrossrefPubMedSearch in Google Scholar
  • 41 Villalobos D, Torres-Simón L, Pacios J. et al. A systematic review of normative data for verbal fluency test in different languages. Neuropsychol Rev 2023; 33: 733-764
    CrossrefPubMedSearch in Google Scholar
  • 42 Sutin AR, Stephan Y, Terracciano A. Verbal fluency and risk of dementia. Int J Geriatr Psychiatry 2019; 34: 863-867
    CrossrefPubMedSearch in Google Scholar
  • 43 Wang S, Xue Y, Zhang J. et al. Interaction between aluminum exposure and ApoEε4 gene on cognitive function of in-service workers. Chemosphere 2023; 323: 138282
    CrossrefPubMedSearch in Google Scholar
  • 44 Xu C, Sun J, Duan H. et al. Gene, environment and cognitive function: A Chinese twin ageing study. Age Ageing 2015; 44: 452-457
    CrossrefPubMedSearch in Google Scholar
  • 45 Netto MB, de Oliveira Junior AN, Goldim M. et al. Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats. Brain Behav Immun 2018; 73: 661-669
    CrossrefPubMedSearch in Google Scholar
  • 46 Hoyos CM, Stephen C, Turner A. et al. Brain oxidative stress and cognitive function in older adults with diabetes and pre-diabetes who are at risk for dementia. Diabetes Res Clin Pract 2022; 184: 109178
    CrossrefPubMedSearch in Google Scholar
  • 47 Cai Z, Qiao P-F, Wan C-Q. et al. Role of blood-brain barrier in Alzheimerʼs disease. J Alzheimers Dis 2018; 63: 1223-1234
    CrossrefPubMedSearch in Google Scholar
  • 48 Kaddoumi A, Denney TS, Deshpande G. et al. Extra-virgin olive oil enhances the blood-brain barrier function in mild cognitive impairment: A randomized controlled trial. Nutrients 2022; 14: 5102
    CrossrefPubMedSearch in Google Scholar
  • 49 Zamoscik V, Schmidt SNL, Bravo R. et al. Tryptophan-enriched diet or 5-hydroxytryptophan supplementation given in a randomized controlled trial impacts social cognition on a neural and behavioral level. Sci Rep 2021; 11: 21637
    CrossrefPubMedSearch in Google Scholar
  • 50 Zheng S, Kim H, Verhaak RGW. Silent mutations make some noise. Cell 2014; 156: 1129-1131
    CrossrefPubMedSearch in Google Scholar
  • 51 Saunders R, Deane CM. Synonymous codon usage influences the local protein structure observed. Nucleic Acids Res 2010; 38: 6719-6728
    CrossrefPubMedSearch in Google Scholar
  • 52 Bartoszewski RA, Jablonsky M, Bartoszewska S. et al. A synonymous single nucleotide polymorphism in DeltaF508 CFTR alters the secondary structure of the mRNA and the expression of the mutant protein. J Biol Chem 2010; 285: 28741-28748
    CrossrefPubMedSearch in Google Scholar
  • 53 Wang SY, Cheng YY, Liu SC. et al. A synonymous mutation in IGF-1 impacts the transcription and translation process of gene expression. Mol Ther Nucleic Acids 2021; 26: 1446-1465
    CrossrefPubMedSearch in Google Scholar