Presentation on theme: "Pharmacogenetics of Antipsychotic Drug Response"— Presentation transcript:
1Pharmacogenetics of Antipsychotic Drug Response Anil K. Malhotra, M.D.Zucker Hillside HospitalGlen Oaks, NYAlbert Einstein College of MedicineBronx, NY
2SchizophreniaChronic mental illness characterized by perceptual abnormalities, disorganized behavior, interpersonal problems and cognitive impairmentAffects approximately 1% of population worldwideAssociated with high levels of morbidity and mortality; 10% suicide rate in schizophreniaMainstay of treatment is the antipsychotic drugs
3Discontinued Due to Lack of Efficacy Chouinard et al 1993Marder & Melbach 1997Beasley et al 1996Tollefson et al 1997Arvinitis et al 1997
4Clinical Response over 4 Weeks of Antipsychotic Drug Treatment
5Meta-analysis of Weight Gain Following Antipsychotic Drug Treatment
6ALOX5 Genotype and Response to Antiasthma Treatment FEV1 % Change From BaselineP = 0.039
7Pharmacogenetics of Clozapine Response Candidate Frequency of Association WithReceptor Polymorphism Rare Allele Clozapine Response?D3 Ser9Gly 35% Yes (Shaikh et al, 1996)No (Malhotra et al, 1998)D4 16 amino acid repeat multiple alleles No (Rao et al, 1994)in exon III5HT2A T102C 45% Yes (Arranz et al, 1996)No (Malhotra et al, 1996)His452Tyr 9% No (Malhotra et al, 1996)5HT2C Cys23Ser 13% (males) Yes (Sodhi et al, 1995)24% (females) No (Malhotra et al, 1996)5HTT bp repeat in 40% No (Arranz et al, 2000)5 regulatory region
8D2 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
9Functional Effects of the DRD2 -141C Ins/Del Polymorphism 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) cellsP <0.02P <0.01PercentageFrom Arinami et al, 1997.
10Pharmacogenetics of Clozapine Response: Methods 72 DSM-IIIR diagnosed schizophrenic or schizoaffective patients (52M, 20F, age = ± 7.5 years) from the NIMH and MPRCBPRS ratings after 10 weeks of clozapine treatment (dose = 405 ± 125 mg/d)Data analysisResponder/nonresponder analysisComparison of BPRS score by genotype after clozapine treatment
12DRD2 -141C Ins/Del and Clozapine Response 4540BPRSTotal 18Del+35Del-3025TypicalNeurolepticClozapine
13Association of 5-HT2C -759C/T Polymorphism and Weight Gain Genotype was significantly associated with the increase in BMIafter 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/m2)
14Association 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 = 6.0Patients with –759C allele were far more likely to develop significant weight gain (relative risk 3.45) than those with the –759T allele.
15New Developments in (Pharmaco)Genomics Human genome sequenceMassive SNP identification efforts by industry and academiaNew genotyping technologies in biotech (Affymetrix, Sequenom, Orchid…)Currently, ~ 40 c/SNP genotypeGenomic control approaches
16Case-Control Association Drug RespondersDrug Non-RespondersMeasure allele frequencies in both samples, search for statistically significant differences
17Regional Frequencies of DRD4 VNTR Alleles Repeat
18Transmission Disequilibrium Test (TDT) ABACABAEAEAEABAC
19Power of Case-Control vs Family-Based Association Genetic Model Allele Frequency Case-Control Family-BasedDominant , ,913Recessive ,820 38,Additive = 5 x 10-8.Power = 0.80.From Risch and Teng, 1998.
20Number of Unlinked Markers to Detect Stratification 0.350.300.250.200.150.100.050.00RR = 1RR = 2RR = 4RR = 8ProbabilityNo. of Unlinked Markers
21Whole Genome Association: A Plausible Strategy to Identify New Drug Targets? 2 - 3 coding or promoter region SNP’s in every gene expressed in the CNS20, ,000 genes in the CNSCase-control association: genomic control with unlinked markers, haplotype analysisGenotyping costs50,000 SNPs1,000 patients from a clinical trial population@ 40 c/genotype = $20,000,000@ 1 c/genotype = $500,000
22Funding: NIMH, NARSAD, Stanley Foundation, Pfizer Inc. AcknowledgmentsNIMHMPRCZucker HillsideCaleb AdlerAlan BreierAlan CliftonLisa KestlerDavid PickarWalter RooneyRobert BuchananPat BallJohn BatesJanet LavelleAlan MendelowitzDonna O’SheaKamran RaziJohn KaneNIAAADavid GoldmanNorio OzakiChiara MazzantiFunding: NIMH, NARSAD, Stanley Foundation, Pfizer Inc.