Polymorphism in alpha 2A adrenergic receptor gene is associated with sialorrhea in schizophrenia patients on clozapine treatment Anssi Solismaa 1,2 *, Olli Kampman 1,2 , Niko Seppälä 3 , Merja Viikki 1,4 , Kari-Matti Mäkelä 5,6 , Nina Mononen 5,6 , Terho Lehtimäki 5,6 and Esa Leinonen 1,7 1 School of Medicine, University of Tampere, Tampere, Finland 2 Department of Psychiatry, Seinäjoki Hospital District, Seinäjoki, Finland 3 Department of Psychiatry, Satakunta Hospital District, Pori, Finland 4 Tampere Mental Health Centre, Tampere, Finland 5 Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland 6 Department of Clinical Chemistry, University of Tampere, School of Medicine, Tampere, Finland 7 Department of Psychiatry, Tampere University Hospital, Tampere, Finland Objective Clozapine-induced sialorrhea (CIS) is a common, inconvenient and socially stigmatizing adverse effect. The pathophysiology of CIS may be related to the effect of clozapine on the muscarinic and adrenergic receptors as well as the disruption of the circadian rhythms. The aim of this study was to find out if polymorphisms in muscarinic M1 and M3 receptor genes (CHRM1 and CHRM3), adrenoceptor alpha 2A gene (ADRA2A) or clock circadian regulator gene (CLOCK) are associated with CIS. Methods Two hundred and thirty-seven clozapine-treated Finnish schizophrenia patients were genotyped for CHRM1, CHRM3, CLOCK and ADRA2A polymorphisms, and their salivary dysfunction was assessed with two questions. Twenty-six of these patients had previously been on medication to treat CIS. Comparisons of the genotypes between patients with excessive versus non-excessive salivation were analysed. Genotype distributions between patients and control group and haplotypes were also studied. Results CHRM1, CHRM3 and CLOCK polymorphisms and haplotypes were not associated with CIS. ADRA2A (rs1800544) genotype was associated with CIS (p = 0.029). In patients with CIS, CC genotype (n = 103) was more common than in G-allele carriers (n = 79) (p = 0.013, OR 2.13, 95% CI: 1.17–3.88). No differences were found in the distributions of genotypes between patients and controls. Conclusions ADRA2A genotype was associated with CIS. Copyright © 2014 John Wiley & Sons, Ltd. key words—clozapine; sialorrhea; ADRA2A; polymorphism; single nucleotide; drug toxicity INTRODUCTION Sialorrhea is a common and inconvenient adverse effect in clozapine treatment. Clozapine-induced sialorrhea (CIS) often develops in an early phase after the initiation of clozapine treatment. (Safferman et al., 1991; Praharaj et al., 2010) CIS occurs in approxi- mately 30% of clozapine-treated patients, although the percentage varies in the literature (Praharaj et al., 2006). Patients may experience CIS throughout the day, but it is most marked during sleep (Safferman et al., 1991; Ben-Aryeh et al., 1996). Patients complaining of sialorrhea often report a wet pillow following a night’s sleep (Praharaj et al., 2006), although objective measurements of salivary flow in clozapine-treated patients are few and inconclusive (Ekström et al., 2010a). Ben-Aryeh et al. (1996) found no difference in saliva flow rate or saliva composition in patients complaining of sialorrhea during clozapine treatment compared with healthy controls. As these patients complained of nocturnal sialorrhea, it was suggested that the sialorrhea occurring at night may instead be due to disruptions of the circadian rhythms. Salivary flow follows circadian rhythms as the salivary flow from the major glands, the parotid and submandibular glands, decreases signif- icantly during sleep (Dawes, 1972; Dawes and Ong, 1973; Ferguson et al., 1973; for a review see Thie et al., 2002). The clock mechanisms behind salivary flow still remain unclear. A recent study reports that clock gene RNAs and clock proteins were detected in salivary gland cells, especially in serous acinar and duct cells, indicating that clock genes may con- tribute to the circadian rhythms of salivary flow. (Zheng et al., 2012) *Correspondence to: A. Solismaa MD, University of Tampere, School of Medicine, 33014 University of Tampere, Finland. Tel: +358-40-8355677; Fax: +358-3-35516164 E-mail: anssi.solismaa@uta.fi Received 1 August 2013 Accepted 20 March 2014 Copyright © 2014 John Wiley & Sons, Ltd. human psychopharmacology Hum. Psychopharmacol Clin Exp 2014; 29: 336–341. Published online 19 May 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.2408