S-37-01

Effects of polymorphisms in the cytochrome p450 system on response to antipsychotics

J. Brockmrller. Abteilung Klinische Pharmakolo, Göttingen, Germany

S-37-02

Towards pharmacogenomics: A large scale association study on response to haloperidol

D. Rujescu, I. Giegling, M. Schafer, N. Dahmen, T. Sander, A. Szegedi, M. R. Toliat, B. Bondy, A. M. Hartmann, H. H. Stassen, H. J. Möller. University of Munich Dept. of Psychiatry, Munich, Germany

Haloperidol is highly efficient in the treatment of acute psychosis, especially when severe symptoms predominate. This study investigates the association of response to short-term haloperidol treatment with 120 microsatellites and 200 SNPs in various candidate genes selected based on their role in neurotransmission. One hundred patients with acute psychosis (schizophrenia, sehizoaffective, brief psychotic, and substance-induced psychotic disorder) were treated with haloperidol for up to 28 days. Diagnosis was established by applying the SCID I and II interview. Patients were assessed at baseline and on days 3, 7, 14, 21and 28. Improvement and response were measured by using the Positive and Negative Syndrome Scale. Haloperidol plasma levels were also obtained. We will present, for the first time, data on this ongoing large-scale association study on response to haloperidol. Genotyping of further 400 SNPs is under way.

S-37-03

Genetic predictors of response to clozapine and other atypical antipsychotics: Current status and implications of pharmacogenomics

M. J. Arranz, R. Kerwin. Institute of Psychiatry Clinical Neuropharmacology, London, United Kingdom

Psychopharmacogenetic research, focusing on evidence selected candidate genes, has identified several contributors to antipsychotic variability. Metabolic enzymes participating in drug biotransformation were identified as important contributors to response variability as early as the 1950s. Polymorphisms of functional significance have been described in several cytochrome P450 enzymes (Nebert, 2000) and their contribution to antipsychotic biotransformation and treatment related side-effects has been proved (Scordo et al., 2002). Additionally, genetic variants of neurotransmitter receptors and transporters have also been associated with treatment and variability. In particular, dopaminergic, serotonergic and adrenergic gene alterations may contribute to clinical outcome. Current pharmacogenetic investigations include the combination of genetic information for the selection of the most beneficial treatment according to the individual's pharrnacogenetic profile. Pharmacogenomic research, using high-throughput techniques, is aiming at better understanding the mechanism of action of psychotropic drugs. Several strategies have been developed using human or animal brains and DNA micro-array technologies for this purpose. Although still at early stages, multi-gene micro-army analyses of brains from drug-treated animals can provide information on the systems altered by antipsychotic treatment and improving our knowledge on drug mechanisms of action. By comparing results from similar studies in human brains, novel targets for antipsychotic activity can be discerned. Pharmacogenomic research will produce a wealth of information during the next decade that hopefully will serve to develop improved and safer psychotropic drugs.

S-37-04

Genetic markers and mechanisms of antipsychotic drug-induced weight gain

G. Reynolds. Queen's University Belfast Dept. of Neuroscience, Belfast, United Kingdom

Objective: Weight gain is increasingly recognised as a major problem in treatment with antipsychotic drugs, with effects on both treatment adherence and long-term morbidity. The substantial differences between individuals in the occurrence of this side effect suggests the importance of genetic factors.

Methods: We have undertaken association studies of common promoter region polymorphisms in two candidate genes, the 5- HT2C receptor and leptin, both of which are implicated in the control of feeding and body weight. These studies have been undertaken in first-episode drug-naive psychotic subjects from Chinese Han and Spanish Caucasian populations.

Results: We have reported that the -759C/T polymorphism of the 5-HT2C receptor gene strongly influences short-term treatment-induced weight gain in previously untreated Chinese patients receiving antipsychotic medication. This was also seen in a series of Spanish first-episode patients, in which the genetic effect was sustained over 9 months. In both series, we have found association of antipsychotic drug-induced weight gain with a functional polymorpbism of the leptin gene, an effect that appears to be greater in the longer term. Along with initial BMI, these two pharmacogenetic factors account for 30% of the variance in druginduced weight gain. Studies in the Spanish series demonstrate that leptin levels before treatment were strongly associated with 5- HT2C receptor genotype.

Conclusion: In addition to providing an indication of the common mechanism, effects on leptin secretion, of two genetic polymorphisms controlling drug-induced weight gain, these findings demonstrate the predictive value of pharmacogeneties in determining liability to a major side effect and indicate the potential of genetic testing in informing prescribing decisions and health and lifestyle advice for the patient and doctor.