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BMC Psychiatry
Published in: BMC Psychiatry 1/2018

Open Access 01-12-2018 | Research article

Effects of ABCB1 gene polymorphisms on autonomic nervous system activity during atypical antipsychotic treatment in schizophrenia

Authors: Saki Hattori, Akira Suda, Ikuko Kishida, Masatoshi Miyauchi, Yohko Shiraishi, Mami Fujibayashi, Natsuki Tsujita, Chie Ishii, Norio Ishii, Toshio Moritani, Masataka Taguri, Yoshio Hirayasu

Published in: BMC Psychiatry | Issue 1/2018

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Abstract

Background

There are interindividual differences in the adverse effects of atypical antipsychotics, which include autonomic nervous system (ANS) dysfunction. Accordingly, to clarify the interindividual differences in the adverse effects of specific atypical antipsychotics in schizophrenia, we investigated the association between ANS dysfunction and ATP-binding cassette transport sub-family B member 1 (ABCB1) gene polymorphisms in patients with schizophrenia.

Methods

In total, 233 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 89 participants received risperidone, 69 olanzapine, 48 aripiprazole, and 27 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. Four single nucleotide polymorphisms (SNPs) in ABCB1 (rs1045642, rs1128503, rs2032582, and rs2235048) were genotyped using the TaqMan method.

Results

For aripiprazole, sympathetic and total autonomic nervous activities were significantly lower in the rs1045642 T allele carrier–rs2235048 C allele carrier group than in the rs1045642 non-T allele carrier–rs2235048 non-C allele carrier group. In addition, in the aripiprazole group, the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582) was associated with decreased ANS activity. However, there were no significant associations between ANS activity and ABCB1 gene polymorphisms in the risperidone, olanzapine, and quetiapine groups. Multiple regression analysis revealed that sympathetic and total nervous activities were significantly associated with the ABCB1 rs1045642–rs2235048 genotype and the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582).

Conclusion

We suggest that ABCB1 genetic polymorphisms affect aripiprazole-related ANS dysfunction but do not affect risperidone-, olanzapine-, or quetiapine-related ANS dysfunction.
Literature
1.
Clamor A, Lincoln TM, Thayer JF, Koenig J. Resting vagal activity in schizophrenia: meta-analysis of heart rate variability as a potential endophenotype. Br J Psychiatry. 2016;208(1):9–16.CrossRefPubMed
2.
Quintana DS, Westlye LT, Kaufmann T, Rustan OG, Brandt CL, Haatveit B, Steen NE, Andreassen OA. Reduced heart rate variability in schizophrenia and bipolar disorder compared to healthy controls. Acta Psychiatr Scand. 2016;133(1):44–52.CrossRefPubMed
3.
Agelink MW, Majewski T, Wurthmann C, Lukas K, Ullrich H, Linka T, Klieser E. Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine. J Clin Psychopharmacol. 2001;21(1):8–13.CrossRefPubMed
4.
Birkhofer A, Geissendoerfer J, Alger P, Mueller A, Rentrop M, Strubel T, Leucht S, Forstl H, Bar KJ, Schmidt G. The deceleration capacity – a new measure of heart rate variability evaluated in patients with schizophrenia and antipsychotic treatment. Eur Psychiatry. 2013;28(2):81–6.CrossRefPubMed
5.
Cohen H, Loewenthal U, Matar M, Kotler M. Association of autonomic dysfunction and clozapine. Heart rate variability and risk for sudden death in patients with schizophrenia on long-term psychotropic medication. Br J Psychiatry. 2001;179(2):167–71.CrossRefPubMed
6.
Huang WL, Chang LR, Kuo TB, Lin YH, Chen YZ, Yang CC. Impact of antipsychotics and anticholinergics on autonomic modulation in patients with schizophrenia. J Clin Psychopharmacol. 2013;33(2):170–7.CrossRefPubMed
7.
Ieda M, Miyaoka T, Wake R, Liaury K, Tsuchie K, Fukushima M, Araki T, Ezoe S, Inagaki T, Horiguchi J. Evaluation of autonomic nervous system by salivary alpha-amylase level and heart rate variability in patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2014;264(1):83–7.CrossRefPubMed
8.
Iwamoto Y, Kawanishi C, Kishida I, Furuno T, Fujibayashi M, Ishii C, Moritani T, Taguri M, Hirayasu Y. Dose-dependent effect of antipsychotic drugs on autonomic nervous system activity in schizophrenia. BMC Psychiatry. 2012;12:199.CrossRefPubMedPubMedCentral
9.
Kim JH, Yi SH, Yoo CS, Yang SA, Yoon SC, Lee KY, Ahn YM, Kang UG, Kim YS. Heart rate dynamics and their relationship to psychotic symptom severity in clozapine-treated schizophrenic subjects. Prog Neuro-Psychopharmacol Biol Psychiatry. 2004;28(2):371–8.CrossRef
10.
Thayer JF, Yamamoto SS, Brosschot JF. The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors. Int J Cardiol. 2010;141(2):122–31.CrossRefPubMed
11.
Hattori S, Kishida I, Suda A, Miyauchi M, Shiraishi Y, Fujibayashi M, Tsujita N, Ishii C, Ishii N, Moritani T, Taguri M, Hirayasu Y. Effects of four atypical antipsychotics on autonomic nervous system activity in schizophrenia. Schizophr Res. 2018;193:134–8.CrossRefPubMed
12.
Boulton DW, DeVane CL, Liston HL, Markowitz JS. In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci. 2002;71(2):163–9.CrossRefPubMed
13.
Kirschbaum KM, Uhr M, Holthoewer D, Namendorf C, Pietrzik C, Hiemke C, Schmitt U. Pharmacokinetics of acute and sub-chronic aripiprazole in P-glycoprotein deficient mice. Neuropharmacology. 2010;59(6):474–9.CrossRefPubMed
14.
Wang JS, Zhu HJ, Donovan JL, Yuan HJ, Markowitz JS, Geesey ME, Devane CL. Aripiprazole brain concentration is altered in P-glycoprotein deficient mice. Schizophr Res. 2009;110(1–3):90–4.CrossRefPubMed
15.
Suzuki Y, Tsuneyama N, Fukui N, Sugai T, Watanabe J, Ono S, Saito M, Someya T. Impact of the ABCB1 gene polymorphism on plasma 9-Hydroxyrisperidone and active moiety levels in Japanese patients with schizophrenia. J Clin Psychopharmacol. 2013;33(3):411–4.CrossRefPubMed
16.
Suzuki T, Mihara K, Nakamura A, Kagawa S, Nagai G, Nemoto K, Kondo T. Effects of genetic polymorphisms of CYP2D6, CYP3A5, and ABCB1 on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients with schizophrenia. Ther Drug Monit. 2014;36(5):651–5.CrossRefPubMed
17.
Bozina N, Kuzman MR, Medved V, Jovanovic N, Sertic J, Hotujac L. Associations between MDR1 gene polymorphisms and schizophrenia and therapeutic response to olanzapine in female schizophrenic patients. J Psychiatr Res. 2008;42(2):89–97.CrossRefPubMed
18.
Furukori Y, Tsuchimine S, Saito M, Nakagami T, Sato Y, Kaneko S. Association between major multidrug resistance 1 (MDR1) gene polymorphisms and plasma concentration of prolactin during risperidone treatment in schizophrenic patients. Prog Neuro-Psychopharmacol Biol Psychiatry. 2007;31(6):1230–4.CrossRef
19.
Kuzman MR, Medved V, Bozina N, Grubisin J, Jovanovic N, Sertic J. Association study of MDR1 and 5-HT2C genetic polymorphisms and antipsychotic-induced metabolic disturbances in female patients with schizophrenia. The Pharmacogenomics Journal. 2011;11(2):35–44.CrossRefPubMed
20.
Suzuki Y, Tsuneyama N, Fukui N, Sugai T, Watanabe J, Ono S, Saito M, Inoue Y, Someya T. Effect of risperidone metabolism and P-glycoprotein gene polymorphism on QT interval in patients with schizophrenia. The Pharmacogenomics Journal. 2014;14(5):452–6.CrossRefPubMed
21.
Xing Q, Gao R, Li H, Feng G, Xu M, Duan S, Meng J, Zhang A, Qin S, He L. Polymorphisms of the ABCB1 gene are associated with the therapeutic response to risperidone in Chinese schizophrenia patients. Pharmacogenomics. 2006;7(7):987–93.CrossRefPubMed
22.
Xu Q, Wu X, Li M, Huang H, Minica C, Yi Z, Wang G, Shen L, Xing Q, Shi Y, He L, Qin S. Association studies of genomic variants with treatment response to risperidone, clozapine, quetiapine and chlorpromazine in the Chinese Han population. The Pharmacogenomics Journal. 2016;16(4):357–65.CrossRefPubMed
23.
Hattori S, Suda A, Kishida I, Miyauchi M, Shiraishi Y, Fujibayashi M, Tsujita N, Ishii C, Ishii N, Moritani T, Taguri M, Hirayasu Y. Associations of ABCB1 gene polymorphisms with aripiprazole-induced autonomic nervous system dysfunction in schizophrenia. Schizophrenia Resarch. 2017; https://​doi.​org/​10.​1016/​j.​schres.​2017.​11.​020.
24.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, fourth ed. Washington, DC: APA; 1994.
25.
Kay SR, Fiszbein A, Ople LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–76.CrossRefPubMed
26.
Inada T, Inagaki A. Psychotropic dose equivalence in Japan. Psychiatry Clin Neurosi. 2015;69(8):440–7.CrossRef
27.
Fujibayashi M, Matsumoto T, Kishida I, Kimura T, Ishii C, Ishii N, Moritani T. Autonomic nervous system activity and psychiatric severity in schizophrenia. Psychiatry Clin Neurosci. 2009;63(4):538–45.CrossRefPubMed
28.
Kimura T, Matsumoto T, Akiyoshi M, Owa Y, Miyasaka N, Aso T, Moritani T. Body fat and blood lipids in postmenopausal women are related to resting autonomic nervous system activity. Eur J Appl Physiol. 2006;97(5):542–7.CrossRefPubMed
29.
Matsumoto T, Miyawaki T, Ue H, Kanda T, Zenji C, Moritani T. Autonomic responsiveness to acute cold exposure in obese and non-obese young women. Int J Obes Relat Metab Disord. 1999;23(8):793–800.CrossRefPubMed
30.
Matsumoto T, Ushiroyama T, Morimura M, Moritani T, Hayashi T, Suzuki T, Tatsumi N. Autonomic nervous system activity in the late luteal phase of eumenorrheic women with premenstrual symptomatology. J Psychosom Obstet Gynaecol. 2006;27(3):131–9.CrossRefPubMed
31.
Moritani T, Kimura T, Hamada T, Nagai N. Electrophysiology and kinesiology for health and disease. J Electromyogr Kinesiol. 2005;15(3):240–55.CrossRefPubMed
32.
Akselrod S, Gorden D, Ubel FA, Shannon DC, Berger AC, Cohen RJ. Power spectrum analysis of heart of fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science. 1981;213(4504):220–2.CrossRefPubMed
33.
Pagani M, Lombardi F, Guzzeti S, Rimoldi O, Furlan R, Pizzinelli P, Sandrone G, Malfatto G, Dell’Orto S, Piccaluga E, et al. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res. 1986;59(2):178–93.CrossRefPubMed
34.
Pomeranz B, Macaulay RJ, Caudill MA, Kutz I, Adam D, Gordon D, Kilborn KM, Barger AC, Shannon DC, Cohen RJ. Assessment of autonomic function in humans by heart rate spectral analysis. Am J Phys. 1985;248(1 Pt 2):H151–3.
35.
Rompelman O, Coenen AJ, Kitney RI. Measurement of heart-rate variability: part 1-comparative study of heart-rate variability analysis methods. Med Biol Eng Comput. 1977;15(3):233–9.CrossRefPubMed
36.
Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000;97(7):3473–8.CrossRefPubMedPubMedCentral
37.
Mi W, Liu F, Liu Y, Du B, Xiao W, Li L, Huang L, Lu T, He J, Shi L, Yue W, Zhang H. Association of ABCB1 gene polymorphisms with efficacy and adverse reaction to risperidone or Paliperidone in Han Chinese schizophrenic patients. Neurosci Bull. 2016;32(6):547–9.CrossRefPubMedPubMedCentral
38.
39.
40.
Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21(2):263–5.CrossRefPubMed
41.
Gottesman MM, Hrycyna CA, Shoenlein PV, Germann UA, Pastan I. Genetic analysis of the multidrug transporter. Annu Rev Genet. 1995;29:607–49.CrossRefPubMed
42.
Sakaeda T, Nakamura T, Horinouchi M, Kakumoto M, Ohmoto N, Sakai T, Morita Y, Tamura T, Aoyama N, Hirai M, Kasuga M, Okumura K. MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res. 2001;18(10):1400–4.CrossRefPubMed
43.
Rafaniello C, Sessa M, Bernardi FF, Pozzi M, Cheli S, Cattaneo D, Baldelli S, Molteni M, Bernardini R, Rossi F, Clementi E, Bravaccio C, Radice S, Capuano A. The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions. Pharmacogenomics J. 2017; https://​doi.​org/​10.​1038/​tpj.​2017.​38.
44.
Choo EF, Leake B, Wandel C, Imamura H, Wood AJ, Wilkinson GR, Kim RB. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos. 2000;28(6):655–60.PubMed
45.
Basic S, Hajnsek S, Bozina N, Filipcic I, Sporis D, Mislov D, Posavec A. The influence of C3435T polymorphisms of ABCB1 gene on penetration of phenobarbital across the blood-brain barrier in patients with generalized epilepsy. Seizure. 2008;17(6):524–30.CrossRefPubMed
46.
Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MMA. "Silent" polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315(5811):525–8.CrossRefPubMed
47.
Soranzo N, Cavalleri GL, Weale ME, Wood NW, Depondt C, Marguerie R, Sisodiya SM, Goldstein DB. Identifying candidate causal variants responsible for altered activity of the ABCB1 multidrug resistance gene. Genome Res. 2004;14(7):1333–44.CrossRefPubMedPubMedCentral
48.
Nagasaka Y, Oda K, Iwatsubo T, Kawamura A, Usui T. Effects of aripiprazole and its active metabolite dehydroaripiprazole on the activities of drug efflux transporters expressed both in the intestine and at the blood-brain barrier. Biopharm Drug Dispos. 2012;33(6):304–15.CrossRefPubMed
49.
Kim KA, Joo HJ, Lee HM, Park JY. Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers. Pharmacogenet Genoimcs. 2014;24(1):35–42.CrossRef
50.
Vandenberghe F, Guidi M, Choong E, von GA, Conus P, Csajka C, Eap CB. Genetics-based population pharmacokinetics and pharmacodynamics of risperidone in a psychiatric cohort. Clin Pharmacokinet. 2015;54(12):1259–72.CrossRefPubMed
51.
Hung CC, Chiou MH, Teng YN, Hsieh YW, Huang CL, Lane HY. Functional impact of ABCB1 variants on interactions between P-glycoprotein and methadone. PLoS One. 2013;8(3):e59419.CrossRefPubMedPubMedCentral
Metadata
Title
Effects of ABCB1 gene polymorphisms on autonomic nervous system activity during atypical antipsychotic treatment in schizophrenia
Authors
Saki Hattori
Akira Suda
Ikuko Kishida
Masatoshi Miyauchi
Yohko Shiraishi
Mami Fujibayashi
Natsuki Tsujita
Chie Ishii
Norio Ishii
Toshio Moritani
Masataka Taguri
Yoshio Hirayasu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Psychiatry / Issue 1/2018
Electronic ISSN: 1471-244X
DOI
https://doi.org/10.1186/s12888-018-1817-5

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