1. COMT and Response to Antipsychotics in First Episode Psychosis Jeffrey R. Bishop, PharmD, MS, BCPP Assistant Professor UIC Dept of Pharmacy Practice UIC Center for Cognitive Medicine

2. Goal and Objective Goal: PGx program development –Symptom and cognition response to antipsychotic medications Objective: To study the relationship between an important functional variant in the catechol-o-methyltransferase (COMT) gene and symptom improvement in first episode psychosis patients treated with antipsychotic medications

3. Background COMT is an important regulator of dopamine (DA) metabolism –Breaks down DA –Expressed throughout the brain Predominantly expressed in prefrontal cortex Genetic variation in COMT (e.g. Val158Met) results in thermo-labile form of COMT enzyme –Valine: less DA (↑ DA metabolism) –Methionine: more DA (↓ DA metabolism)

5. Background Candidate gene selection: why COMT? –Regulates DA disposition in the brain –+/- associations with disease and symptoms –+/- associations with antipsychotic response No PGx studies in “First Episode” –+ associations with “cognition” – e.g. working memory, processing Meyer-Lindenberg and Weinberger. Nat Rev Neurosci. 2006; 7:818-827

6. Study Design Pharmacogenetic candidate gene association study Participants: current and past participants of the UIC and Pittsburgh (WPIC) First Episode studies –Inclusion criteria: DSM-IV dx schizophreniform, schizophrenia, schizoaffective disorder, bipolar disorder with psychosis <12 weeks total lifetime exposure to antipsychotics –Exclusion criteria: Previous brain injury, neurological disorder, substance dependence in the past 6 mo Treatment –3-5 day washout if on antipsychotic or mood stabilizing medications –6 weeks of antipsychotic treatment Open label flexible dosing design Risperidone (n=49), haloperidol (n=8), olanzapine (n=5), ziprasidone (n=1), fluphenazine (n=1)

7. Study Design Assessments: –Pre/post treatment clinical ratings BPRS Total – Primary outcome for PGx symptom response –Pre/post neuropsych WRAT, Trails A/B, CVLT, Digits F/B –Pre/post saccade studies –Pre/post fMRI –Consensus DSMIV diagnosis w/ SCID –DNA –Serum Risperidone/9-OH-Risperidone Hormone Changes Currently being scored…for future analyses

8. Results N=84 participants – 64 completed pre/post clinical ratings Mean age = 24.5±8 yrs 68% male Race/Ethnicity: –Caucasian: 47% –African American: 37% –Asian: 6% –Hispanic: 8% –Unknown: 1% Baseline BPRS Total: 49.9±9.7 Baseline BPRS Positive: 13.0±7 Baseline BPRS Negative: 11.0±6.5

9. Results VariableSchiz- Spectrum (n=54) Bipolar (n=10) All BPRS Total Change 11.2±12.513.7±4.311.5±12.6 BPRS Pos Change 1.3±3.94.2±6.31.8±4.5 BPRS Neg Change 3.9±4.61.6±3.93.5±4.5 20% Improvement 52%40%50% Changes significant from baseline Not statistically different between diagnostic groups Age, medication, race, gender not significantly associated with symptom change

10. Results Genotypes did not deviate from Hardy- Weinberg Equilibrium (HWE) Met/Met (n=16) Val/Met (n=44) Val/Val (n=24) 0.550.45 COMT Val158Met Allele Frequencies

11. Results: All Participants BPRS Change scores (Time1-Time2) for all participants together All p’s>0.18 Conclusion: COMT not associated with symptom improvement

12. Results: Schizophrenia Spectrum BPRS Change scores (Time1-Time2) for schizophrenia spectrum participants –Schizophrenia + Schizoaffective All p’s>0.26 Conclusion: COMT not associated with symptom improvement

13. Results: Replication in Previously Ascertained Dataset Genotyped previously described sample 1,2 N=42 subjects with schizophrenia (~2/3 first episode) Predominantly male Caucasians 4-7 day washout prior to 6 wks of fixed dose olanzapine Results: No difference in BPRS change scores over time (p=0.92) Conclusion: COMT not associated with symptom improvement 1.Ellingrod et al. Psychopharm Bull. 2003; 37:109-112 2.Bishop et al. Schizophr Res 2005; 77:253-260

14. Results In Progress: Cognitive Biomarkers Visually guided saccade latencies –Time taken to shift eye focus to new location –Measure of mental processing speed –Speeded saccadic responses to visual targets consistent with impairment of attentional regulation of sensorimotor systems 1 Significantly different across COMT Val158Met genotype groups (p=0.01) 1. Reilly JL et al. Biol Psychiatry. 2005; 57:145-154

15. Conclusion and Future Direction Conclusion: COMT Val158Met genotype is not associated with symptom response in patients with schizophrenia Future Directions: –Investigation of gene-gene interactions –Focus on relationship of variants in genes regulating dopamine, glutamate, and serotonin disposition with symptom and cognition response to antipsychotic medications

16. Acknowledgements Study Participants Funding: –ACCP Investigator Development Award (Bishop PI) –NIMH R01MH062134 (Sweeney PI) UIC Pharmacogenomics Laboratory –Michael Akroush UIC Center for Cognitive Medicine –John Sweeney, PhD –Robert Marvin, MD –Cherise Rosen, PhD –James Reilly, PhD –Margret Harris, MA –Scot Hill, PhD –Sarah Keedy, PhD –Jennifer Barrett –Nick Navarro –Mark Schneiderhan, PharmD, BCPP University of Pittsburgh Department of Psychiatry First Episode Program –Vishwajit Nimgaonkar, MD, PhD –Konasale Prasad, MD –Matcheri S. Keshevan, MD

17. Thank You