An investigation of the a 1A -adrenergic receptor gene and antipsychotic-induced side-effects Pilar A. Saiz 1,2 , Margaret T. Susce 3 , Dan A. Clark 1 , Robert W. Kerwin 1,y , Patricio Molero 1,4 , Maria J. Arranz 1 * and Jose de Leon 3 1 Clinical Neuropharmacology, Institute of Psychiatry—King’s College, London, UK 2 Department of Psychiatry, University of Oviedo, Oviedo, Spain 3 University of Kentucky, Mental Health Research Center at Eastern State Hospital, Lexington, Kentucky, USA 4 Department of Psychiatry, Clinica Universitaria, University of Navarra, Pamplona, Spain Antipsychotic treatment is hampered by the induction of side-effects such as tardive dyskinesia (TD), weight gain, sedation and extrapyramidal side-effects (EPS). Identification of the factors related to their development would facilitate their avoidance and the improvement of antipsychotic treatment. It has been hypothesised that genetic variants in drug targeted receptors may contribute to the development of side-effects. In this study, we have investigated the possible influence of genetic variants (-563-C/T, -4155-G/C and -4884-A/G) of the a 1A -adrenergic receptor, an important target of atypical antipsychotic drugs, and development of side-effects after antipsychotic medication in a sample of N ¼ 427 US Caucasian patients. We found several marginal associations ( p < 0.05) between a 1A -adrenergic genetic variants and antipsychoti- c-induced side-effects which did not reach statistical significance after corrections for multiple analyses. These results do not support a major role of a 1A -adrenergic genetic variants in obesity and other side-effects observed after prolonged treatment with antipsychotic medications. Copyright # 2007 John Wiley & Sons, Ltd. key words — a 1A -adrenergic receptor; side-effects; risperidone; genetic association INTRODUCTION Antipsychotic drugs are indicated for the treatment of schizophrenia, bipolar disorder and psychotic depres- sion but are widely used in many other psychiatric disorders in adults (Buckley 2001) and even fre- quently prescribed in children (Olfson et al., 2006). Antipsychotic treatment is hampered by the incidence of side-effects. Treatment-related side-effects such as reversible extrapyramidal side-effects (EPS), tardive dyskinesia (TD), weight gain and sedation make a sizeable contribution to poor treatment compliance (Kane 1999). The considerable variation in the incidence of side-effects between individuals cannot be accounted for by the type of antipsychotic alone (Morgenstern and Glazer 1993) implying that there are other factors influencing their incidence. In recent years, significant associations have been made between several genetic polymorphisms and the incidence of motor side-effects (namely TD or EPS) (Muller et al., 2004; Ohmori et al., 2003; Segman and Lerer 2002). These include poly- morphisms in metabolic enzymes (CYP2D6 and CYP1A2 genes) (Inada et al., 2003; Patsopoulos et al., 2005; Schillevoort et al., 2002; Scordo et al., 2000), drug-targeted receptors (Bakker et al., 2006; Lerer et al., 2002, 2005; Nakazono et al., 2005) and variants in enzymes involved in oxidative stress (de Leon et al., 2005b). Whilst the newer generation atypical antipsycho- tics are recognised to reduce the incidence of motor side-effects (such as TD and EPS), their use is hindered by other side-effects such as weight gain and sedation (Basile et al., 2001). A number of genetic studies have linked polymorphisms in genes coding for metabolic enzymes and neurotransmitter receptors human psychopharmacology Hum. Psychopharmacol Clin Exp 2008; 23: 107–114. Published online 30 October 2007 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/hup.903 *Correspondence to: Dr M. J. Arranz, P.O. Box 51, Clinical Neuropharmacology, Institute of Psychiatry—King’s College, London SE5 8AF, UK. Tel: 00 44 207 848 0343. E-mail: m.arranz@iop.kcl.ac.uk y Professor Kerwin passed away during the completion of this work. Copyright # 2007 John Wiley & Sons, Ltd. Received 30 April 2007 Accepted 19 September 2007