PM389. Preliminary Genetic Model Predicting Clozapine Response

Objective: Pharmacotherapy by antipsychotics has been the main therapy for schizophrenia. However, how antipsychotics improve symptoms is unknown and evaluating the therapeutic effect objectively is still difficult. Many studies have suggested abnormalities of auditory processing in schizophrenia, which may be associated with clinical symptoms such as auditory hallucinations and is expected to be the index for the treatment. To find the measurable indicators for the therapeutic effect, we explored the relationship between pharmacotherapy and brain function in schizophrenia by fMRI. Methods: We recruited 11 schizophrenia patients (SZs) and 6 healthy controls (HCs). We used a mismatch negativity (MMN) task and an auditory verbal working memory (VWM) task to assess auditory processing functions. Participants also underwent the resting-state fMRI session. 2 schizophrenia patients underwent the examination twice before and after medication. Results: During the MMN task, HCs demonstrated significantly larger activation in the left temporo-parietal junction for deviant relative to standard stimuli than SZs. In one SZ patient, decreased activation of the left temporal gyrus was not normalized after medication (P<0.05). During the VWM task, in the rehearsal condition, HCs showed significantly larger activation in the left temporo-parietal junction than SZs. After medication, 2 patients showed the increased activation in the left temporoparietal junction, but the activation of overall brain decreased. During the resting-state, SZs showed increased functional connectivity between the left inferior frontal gyrus and the left supramarginal gyrus and the increased connectivity was normalized after medication (p<0.001). Conclusion: These results suggest that antipsychotics may improve the function of the left temporoparietal junction but may reduce overall brain activation during the VWM task. It is also suggested that functional connectivity between the left inferior frontal gyrus and the left supramarginal gyrus may be increased in schizophrenia during the resting-state and antipsychotics may normalize the abnormality. PM389 Preliminary Genetic Model Predicting Clozapine Response Eric Huang1, James Kennedy1, Jeffrey Lieberman2, Herbert Meltzer3, Steven Potkin4, Arun Tiwari1, Clement Zai1 1Centre for Addiction and Mental Health, Canada, 2Columbia University Medical Center, USA, 3Northwestern University, USA, 4University of California, USA Abstract Objectives: Despite its clinical utility, a pharmacogenetic test for response to the antipsychotic clozapine has yet to be developed. Thus, we sought to create a preliminary genetic model for response. Multiple genetic variants from different systems (e.g. dopamine, serotonin) have been linked with clozapine response. Previous work by our group has implicated multiple dopamine D2 receptor (DRD2) genetic variants, including the genomewide significant schizophrenia risk variant rs2514218. Thus, we focused our model on dopamine system-related gene variants. Methods: We analyzed genetic variants in dopamine systemrelated genes in relation to clozapine response. The sample consisted of 151 Caucasian schizophrenia (DSM-III) patients treated with clozapine for six months. Response was assessed using the Brief Psychiatric Rating Scale (BPRS), and evaluated based upon absolute score change and binary response (Kane et al. 1988 criteria). Variants showing at least a nominal statistical trend (p>0.1) were included in the model. The mode of inheritance of all single nucleotide polymorphisms (SNPs) was determined and risk scores for each SNP calculated using standard procedures. Results: Five SNPs were included in the model: DRD2 rs2514218, rs1799978 and rs2242531, COMT rs4680, and BDNF rs6265. We observed a significant association between total risk score with BPRS score change (p=0.029, Adjusted R2=0.41) and binary response (p=0.013, Nagelkerke R2=0.30). Individuals with the lowest risk score experienced the smallest decrease in BPRS score. Conclusions: We have developed a preliminary genetic model for clozapine response, and are currently assembling a replication sample for further testing. The fact that a model based upon dopamine system genetic variants may explain variation in clozapine response indicates that the drug’s therapeutic effect depends in part on its effects on dopaminergic activity in multiple brain regions. These include direct effects on D1 and D4 receptors, and indirect ones through activity at 5-HT2A and 5-HT1A receptors. PM390 Comparison of Fast Versus Slow Strategy in Switching Schizophrenia Patients to Aripiprazole from Other Antipsychotics Tzung-Jeng Hwang, MD, PhD,* Hung-Yu Chan, MD, PhD,*‡ ChingFeng Lin, PhD,†ǁ Ming H. Hsieh, MD, PhD,* Chen-Chun Liu, MD, PhD,* Chih-Min Liu, MD, PhD,* Ching-Hua Kuo, PhD,§ Wei J. Chen, MD,