Downloaded from https://journals.lww.com/psychopharmacology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3be73+7zLk/Sq+y6koaZl6Ep8oGuop87+8AoBvh7J400mYizg71tReg== on 05/03/2018 Genetic Polymorphisms Associated With Constipation and Anticholinergic Symptoms in Patients Receiving Clozapine Anssi Solismaa, MD,*† Olli Kampman, MD, PhD,*† Leo-Pekka Lyytikäinen, MD,*‡ Niko Seppälä, MD, PhD,§ Merja Viikki, MD, PhD,* Nina Mononen, PhD,*‡ Terho Lehtimäki, MD, PhD,*‡ and Esa Leinonen, MD, PhD*§ Abstract: Background: Clozapine impairs gastrointestinal motility owing to its an- ticholinergic and antiserotonergic properties. This commonly leads to con- stipation and potentially to more severe complications such as bowel obstruction and ischemia. The aim of this study was to determine whether genetic variations in the genes encoding muscarinic and serotonergic re- ceptors (CHRM2, CHRM3, HTR2, HTR3, HTR4, and HTR7) explain the variations in incidence of constipation and anticholinergic symptoms dur- ing clozapine treatment. Genes associated with opiate-induced constipation were also included in this analysis (TPH1, OPRM1, ABCB1, and COMT). Procedures: Blood samples from 176 clozapine-treated, Finnish, white patients with schizophrenia were genotyped. Constipation and anticholin- ergic symptoms were rated using the Liverpool University Neuroleptic Side Effect Rating Scale self-report questionnaire. In total, 192 single- nucleotide polymorphisms (SNPs) were detected and grouped to formulate a weighted genetic-risk score (GRS). Results: No significant associations between individual SNPs or GRSs and constipation or laxative use were observed. A GRS of 19 SNPs in CHRM2, CHRM3, HTR3C, HTR7, ABCB1, OPRM1, and TPH1 was asso- ciated with anticholinergic symptoms in a generalized linear univariate model, with body mass index, clozapine monotherapy, and GRS as explaining vari- ables (permuted P = 0.014). Generalized linear univariate model analysis per- formed on the opiate-induced constipation–associated SNPs and a single CHRM3 SNP revealed an association between anticholinergic symptoms and a score of 8 SNPs (adjusted P = 0.038, permuted P = 0.002). Conclusions: Two GRSs are able to predict the risk of anticholinergic symptoms in patients receiving clozapine and possibly an increased risk of gastrointestinal hypomotility. Key Words: adverse effects, antipsychotics, constipation, clozapine, polymorphism (J Clin Psychopharmacol 2018;38: 193–199) C onstipation is a common adverse effect of clozapine that is re- ported to occur in 14% to 60% of patients receiving treatment with this drug, 1,2 often leading to increased use of laxative medi- cation. 3 The impairment of gastrointestinal motility associated with clozapine can also result in severe complications such as dysphagia, ileus, intestinal obstruction, bowel ischemia, and megacolon. Among clinicians, these risks seem to be less well known than clozapine- induced agranulocytosis, despite clozapine-induced gastrointesti- nal hypomotility and agranulocytosis having similar prevalence rates (4.0%–8.0% vs 3.8%–8.0%). Furthermore, clozapine- induced gastrointestinal hypomotility is associated with a greater risk of mortality, and careful monitoring of patients receiving clozapine for symptoms of gastrointestinal hypomotility is recommended. 4,5 Clozapine-induced constipation seems to be associated with the anticholinergic and antiserotonergic properties of this agent. 5,6 In the absence of clozapine, acetylcholine stimulates muscarinic receptors in both smooth muscle cells and the interstitial cells of Cajal of the gastrointestinal tract, the latter of which function as the pacemaker cells of the gastrointestinal tract. 7 Muscarinic re- ceptors (of the M 2 and M 3 subtypes) are expressed in interstitial cells of Cajal and smooth muscle cells of the gastrointestinal tract. 8 However, other anticholinergic agents with an efficacy sim- ilar to that of clozapine have much lower risks of gastrointestinal hypomotility. For example, the risk of constipation associated with use of clozapine is 3 times greater than that associated with chlor- promazine. 9 Treatment with clozapine is also associated with a higher risk of ileus than that of other antipsychotics, as demon- strated by data from a large European study. 10 This increase in risk is proposed to be caused by the antiserotonergic effects of cloza- pine. 5 Clozapine is an antagonist of several 5-hydroxytryptamine receptors (5-HT 2 , 5-HT 3 , 5-HT 6 , and 5-HT 7 ). 11 Serotonin also has a complex and crucial but still controversial role in gut function. Data from many studies have suggested that 5-HT receptors, espe- cially 5-HT 3 and 5-HT 4 , have an important role in the regulation of gut motility. 5,12 5-HT 2 receptors have been suggested to modulate visceral sensation, and 5-HT 7 receptors might be involved in medi- ating relaxation of gastrointestinal smooth muscle. Furthermore, inhibition of 5-HT 3 receptors has been reported to reduce the rate of colon transit, inhibit gastrocolic reflexes, increase the level of colonic compliance, and possibly reduce intestinal sensitivity to distension. 5 The aim of this study was to determine the influence of ge- netic variations in different subtypes of muscarinic and serotoner- gic receptors and whether such variations can explain the variable incidence of constipation or anticholinergic symptoms during clo- zapine treatment. Interactions between such variations and the risk of constipation or anticholinergic symptoms caused by antipsy- chotic medications have not been studied previously. All muscarinic and serotonergic subtypes that have been previously suggested to have a role in regulating gut motility were included in this study. Single-nucleotide polymorphisms (SNPs) in the genes encoding the M 2 and M 3 muscarinic receptors (CHRM2, CHRM3) and the 5-HT 2 , 5-HT 3 , 5-HT 4 , and 5-HT 7 receptors (HTR2, HTR3, HTR4, and HTR7) were extracted. Additional analyses were per- formed, including SNPs in TPH1, OPRM1, ABCB1, CHRM3, and COMT , which have all previously been suggested to contribute to the variability in incidence of constipation among patients with cancer receiving treatment with opioids. 13 TPH1 encodes tryptophan From the *Faculty of Medicine and Life Sciences, University of Tampere, Tampere; †Department of Psychiatry, Seinäjoki Hospital District, Seinäjoki; and ‡Fimlab Laboratories, Pirkanmaa Hospital District; and §Department of Psychiatry, Tampere University Hospital, Tampere, Finland. Received November 15, 2017; accepted after revision February 28, 2018. Reprints: Anssi Solismaa, MD, University of Tampere, School of Medicine, 33014 Tampere, Finland (e‐mail: asolismaa@gmail.com). The study has been funded by Medical Research Fund of Tampere University Hospital (Competitive State Research Financing, 9R028), Satakunta Hospital District Research Fund (EVO-funding), and Seinäjoki Hospital District Research Fund (EVO1114). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000885 ORIGINAL CONTRIBUTION Journal of Clinical Psychopharmacology • Volume 38, Number 3, June 2018 www.psychopharmacology.com 193 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.