Background: Despite advances in schizophrenia treatment, nearly 30% ofpatients do not respond to atypical antipsychotic agents, such as olanzapine. Furthermore, 30-60% ofpatients will gain significant weight during the course of olanzapine therapy. Little research has beendone to investigate the relationship between antipsychotic treatment outcomes and genetic variabilityin second messengers coupled to serotonin (5HT) receptors. The purpose of this investigation was examineassociations between the second messenger G-Protein Beta3 Subunit Gene (GNB3) C825T polymorphism andolanzapine response and weight gain treatment. Material/Methods: We conducted a pharmacogenetic associationstudy to examine GNB3 genotypes in relation to olanzapine clinical response (as measured by the BriefPsychiatric Rating Scale or Scale for the Assessment of Negative Symptoms) or weight gain. Subjects includedforty-two individuals meeting DSM-IV criteria for schizophrenia that started olanzapine, were titratedto a fixed dose for 6 weeks, and subsequently genotyped for this investigation. Results: No statisticallysignificant associations existed between our outcome variables and GNB3 genotypes. However we did observetrends suggesting a potential relationship between the TT genotype, response, and weight gain that warrantfurther investigation. Conclusions: Preliminary results showed no statistical relationship between theC825T polymorphism and olanzapine response or weight gain. Numerical differences in outcome measuresbetween the TT vs. CT/CC genotype groups indicate that G-protein second messenger systems variabilitycoupled to primary targets of atypical antipsychotics may relate to clinical outcomes in persons withschizophrenia and that future research in this area is warranted.

Keywords: Antipsychotic Agents - therapeutic use, Base Sequence, Benzodiazepines - therapeutic use, DNA - genetics, Heterotrimeric GTP-Binding Proteins - genetics, Obesity - pathology, Pilot Projects, Polymorphism, Single Nucleotide, Protein Subunits - genetics, Schizophrenia - genetics, Serotonin Uptake Inhibitors - therapeutic use, Weight Gain - genetics