No influence of adrenergic receptor polymorphisms on schizophrenia and antipsychotic response A.A. Bolonna, M.J. Arranz * , J. Munro, S. Osborne, M. Petouni, M. Martinez, R.W. Kerwin Section of Clinical Neuropharmacology, Department of Psychological Medicine, Institute of Psychiatry, Denmark Hill, London, SE5 8AF, UK Received 10 November 1999; received in revised form 10 December 1999; accepted 15 December 1999 Abstract The adrenergic system plays an important role in psychiatric disorders such as depression and schizophrenia. Antag- onism of the adrenergic receptor subtypes a 1A and a 2A has been found to have an antipsychotic effect. Genetic mutations in these receptors could be related to the alterations in the adrenergic system observed in psychiatric patients and to failure to respond to drug antagonism. We have studied one polymorphism in the a 1A –adrenergic receptor (Arg492Cys) and two polymorphisms in the promoter region of the a 2A –adrenergic receptor (-1291-C/G and -261-G/A) in a sample of clozapine-treated schizophrenic patients and controls. No clear differences were observed between the different groups suggesting that these polymorphisms did not play an important role in the aetiology of the disorder or in determining antipsychotic response. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Adrenergic receptors; Clozapine response; Pharmacogenetics; Schizophrenia Dysfunction of noradrenergic transmission plays an important role in several neuropsychiatric disorders such as depression, suicide, cognitive disorders and schizophre- nia. Significant increase in plasma norepinephrine in chil- dren with attention-deficit hyperactivity disorder (ADHD) and cognitive disabilities has been reported [1,9]. Altered sensitivity [7,13,15] and increased density of adrenergic receptors (AR) in central brain regions [5,17] was measured in depressed and suicide victims. Alpha-2A dysregulation has also been observed in panic disorder [8]. Of the different subtypes of alpha (a ) adrenergic recep- tors identified (a 1A,1B, 1D and a 2A,2B,2C ), two of them, a 1A and a 2A , have been implicated in mediating antipsychotic response [10,12]. Antagonism of adrenergic receptors has been proved to have antipsychotic action when coupled to neuroleptic treatment in patients with schizophrenia [12]. In addition, it has been postulated that adrenergic antagonism contributes to the superior efficacy of clozapine, an atypical antipsychotic drug with high success rates in the treatment of schizophrenic patients refractory to other drugs [3,14,16]. Clozapine displays high affinity for the a 1A receptor subtype, similar to that of 5-HT receptors, and lower affinity for the a 2A subtype [20]. Genetic mutations in drug targeted receptors have been hypothesised to influence treatment response [2]. According to this hypothesis, clozapine mechanism of action can be influenced by mutations in targeted receptors. Although in previous studies associa- tions have been reported between 5-HT 2A and 5-HT 2C genetic variants and clozapine response [2,19], other targeted proteins including adrenergic receptors may still contribute to treatment response. As a result, new antipsy- chotic drugs such as risperidone, olanzapine, quetiapine and sertindole include adrenergic antagonism amongst their mechanism of action. Considering the biological and pharmacological evidence, adrenergic receptors have been postulated as candidate aetiological and antipsychotic factors in schizo- phrenia and depression. DNA polymorphisms in genes coding for receptor proteins may account for some of the alterations observed in the adrenergic system in psychiatric patients or be related to resistance to drug treatment. To determine the aetiological and pharmacological relevance of DNA alterations in these receptors, we investigated two polymorphisms in the promoter region of the alpha-2A (a 2A ) adrenergic receptor gene (-1291-C/G and -261-G/A) [4,11] and an alpha-1A (a 1A ) structural polymorphism (Arg492Cys) [18] in a sample of clozapine treated patients Neuroscience Letters 280 (2000) 65–68 0304-3940/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(99)01000-9 www.elsevier.com/locate/neulet * Corresponding author. Tel.: 144-207-848-0343; fax: 144-207- 848-0051. E-mail address: spjumja@iop.kcl.ac.uk (M.J. Arranz)