Presentation on theme: "Pharmacogenetics of Antipsychotic Drug Response Anil K. Malhotra, M.D. Zucker Hillside Hospital Glen Oaks, NY Albert Einstein College of Medicine Bronx,"— Presentation transcript:
Pharmacogenetics of Antipsychotic Drug Response Anil K. Malhotra, M.D. Zucker Hillside Hospital Glen Oaks, NY Albert Einstein College of Medicine Bronx, NY
Schizophrenia Chronic mental illness characterized by perceptual abnormalities, disorganized behavior, interpersonal problems and cognitive impairment Affects approximately 1% of population worldwide Associated with high levels of morbidity and mortality; 10% suicide rate in schizophrenia Mainstay of treatment is the antipsychotic drugs
Discontinued Due to Lack of Efficacy Chouinard et al 1993 Arvinitis et al 1997 Tollefson et al 1997 Beasley et al 1996 Marder & Melbach 1997
Clinical Response over 4 Weeks of Antipsychotic Drug Treatment
Meta-analysis of Weight Gain Following Antipsychotic Drug Treatment
ALOX5 Genotype and Response to Antiasthma Treatment FEV 1 % Change From Baseline P = P = P = P <0.001
Pharmacogenetics of Clozapine Response CandidateFrequency ofAssociation With ReceptorPolymorphismRare AlleleClozapine Response? D 3 Ser 9 Gly35%Yes (Shaikh et al, 1996) No (Malhotra et al, 1998) D 4 16 amino acid repeatmultiple allelesNo (Rao et al, 1994) in exon III 5HT 2A T 102 C 45%Yes (Arranz et al, 1996) No (Malhotra et al, 1996) His 452 Tyr9%No (Malhotra et al, 1996) 5HT 2C Cys 23 Ser13% (males)Yes (Sodhi et al, 1995) 24% (females)No (Malhotra et al, 1996) 5HTT20-34 bp repeat in40%No (Arranz et al, 2000) 5 regulatory region
D2 Receptor Gene Polymorphisms No common coding region polymorphisms (Gejman et al, 1994) Two common SNPs, -141C Ins/Del and A241G, in promoter region (Arinami, et al, 1997) -141C Ins/Del associated with schizophrenia (P <0.001) in a case-control study (N = 260) of Japanese patients
P <0.02P <0.01 Transient expression of luciferase enzymatic activity driven by the DRD2 5’-flanking 304 bp containing the A-241 and -141C Del alleles, the A-241 and -141C Ins alleles in Y79 (A) and 293 (B) cells From Arinami et al, Functional Effects of the DRD2 -141C Ins/Del Polymorphism Percentage
Pharmacogenetics of Clozapine Response: Methods 72 DSM-IIIR diagnosed schizophrenic or schizoaffective patients (52M, 20F, age = 37.2 ± 7.5 years) from the NIMH and MPRC BPRS ratings after 10 weeks of clozapine treatment (dose = 405 ± 125 mg/d) Data analysis –Responder/nonresponder analysis –Comparison of BPRS score by genotype after clozapine treatment
Del+2(10%)19(37%)21(29%) Del-19(90%)32(63%)51(71%) Total a FET, P = b FET, P = C Ins/Del and Clozapine Response Genotype a Clozapine RespondersNonrespondersTotal Del2(5%)20(20%)22(15%) Ins40(95%)82(80%)122(85%) Total Allele b
Del- Del+BPRS Total 18 Typical Neuroleptic Clozapine DRD2 -141C Ins/Del and Clozapine Response
Association of 5-HT2C -759C/T Polymorphism and Weight Gain Genotype was significantly associated with the increase in BMI –after 6 weeks (p<0.001) –and 10 weeks (p<0.001) The association between genotype and weight gain at six weeks remained in: –males (p<0.01), –females (p<0.01) and in patients receiving only: –chlorpromazine (n=69, p<0.01), –risperidone (n=46, p<0.05) Change in BMI (kg/m 2 )
Association of 5-HT2C -759C/T Polymorphism and Weight Gain Patients with clinically significant weight gain: (increase of >7%) At six weeks 27/96 (28%) wild-type and 0/27 (0%) variant cases (p=0.002) At ten weeks 46/90 (51%) wild-type and 4/27 (15%) variant cases (p=0.001) Odds ratio = 6.0 Patients with –759C allele were far more likely to develop significant weight gain (relative risk 3.45) than those with the –759T allele.
New Developments in (Pharmaco)Genomics Human genome sequence Massive SNP identification efforts by industry and academia New genotyping technologies in biotech (Affymetrix, Sequenom, Orchid…) –Currently, ~ 40 c/SNP genotype Genomic control approaches
Case-Control Association Drug RespondersDrug Non-Responders Measure allele frequencies in both samples, search for statistically significant differences
Regional Frequencies of DRD4 VNTR Alleles Repeat
Transmission Disequilibrium Test (TDT) ABAC AE ABAC AB AE
Power of Case-Control vs Family-Based Association Genetic ModelAllele FrequencyCase-ControlFamily-Based Dominant ,204 2,913 Recessive0.0528,82038, Additive = 5 x Power = From Risch and Teng, 1998.
Number of Unlinked Markers to Detect Stratification Probability No. of Unlinked Markers RR = 1 RR = 2 RR = 4 RR = 8
Whole Genome Association: A Plausible Strategy to Identify New Drug Targets? coding or promoter region SNP’s in every gene expressed in the CNS 20, ,000 genes in the CNS Case-control association: genomic control with unlinked markers, haplotype analysis Genotyping costs –50,000 SNPs –1,000 patients from a clinical trial population 40 c/genotype = $20,000,000 1 c/genotype = $500,000
Acknowledgments Caleb Adler Alan Breier Alan Clifton Lisa Kestler David Pickar Walter Rooney NIMH MPRC Robert Buchanan Pat Ball NIAAA David Goldman Norio Ozaki Chiara Mazzanti Zucker Hillside John Bates Janet Lavelle Alan Mendelowitz Donna O’Shea Kamran Razi John Kane Funding: NIMH, NARSAD, Stanley Foundation, Pfizer Inc.