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Pharmacogenetics of Antipsychotic Drug Response

Pharmacogenetics of Antipsychotic Drug Response. Anil K. Malhotra, MD The Zucker Hillside Hospital Glen Oaks, New York The Albert Einstein College of Medicine Bronx, New York. Dissecting the Heterogeneity of Antipsychotic Drug Response.

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Pharmacogenetics of Antipsychotic Drug Response

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  1. Pharmacogeneticsof Antipsychotic Drug Response Anil K. Malhotra, MD The Zucker Hillside Hospital Glen Oaks, New York The Albert Einstein College of Medicine Bronx, New York

  2. Dissecting the Heterogeneity of Antipsychotic Drug Response • Marked inter-individual variation in response to antipsychotic drugs • Biologic predictors of drug response (plasma HVA, prolactin, CSF metabolites) have been inconsistent • Need for molecular correlates of drug efficacy and drug-induced adverse events • Molecular correlates may suggest new targets for future drug development

  3. Pharmacogenetics ofClozapine Response Candidate Frequency of Association With Receptor Polymorphism Rare Allele Clozapine Response? D3 Ser9Gly 35% Yes (Shaikh et al, 1996)1 No (Malhotra et al, 1998)2 D4 16 amino acid repeat multiple alleles No (Rao et al, 1994)3 in exon III 5HT2A His452Tyr 45% Yes (Arranz et al, 1996)4 No (Malhotra et al, 1996)5 T102C 9% No (Malhotra et al, 1996)5 5HT2C Cys23Ser 13% (males) Yes (Sodhi et al, 1995)6 24% (females) No (Malhotra et al, 1996)7 5HTT 20-34 bp repeat in 40% No (Tsai SJ et al, 2000)8 5 regulatory region 1. Shaikh S et al. Hum Genet. 1996;97:714-719; 2. Malhotra AK et al. Mol Psychiatry. 1998;3:72-75; 3. Rao PA et al. Arch Gen Psychiatry. 1994;51:912-917; 4. Arranaz MJ et al. Neurosci Lett. 1996;217:177-178; 5. Malhotra AK et al. Am J Psychiatry. 1996;153:1092-1094; 6. Sodhi MS et al. Neuroreport. 1995;29:169-172; 7. Malhotra AK et al. Neuroreport. 1996;7:2100-2102; 8. Tsai SJ et al. Schizophr Res. 2000;44:177-181;

  4. Dopamine D2 Receptor Blockade and Antipsychotic Potency Seeman et al 1975

  5. 2 5 4 3 6 8 7 0.91 Kb 0.14 Kb -10 Kb DRD2 (11q22-q23): Candidate Gene for Antipsychotic Drug Response TaqI A -141C Ins/Del Taq1 D Taq1 B A-241G Ser311Cys 5’ 3’ 1 0.2 Kb 25.5 Kb -50 Kb

  6. Functional 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) cells P <0.02 P <0.01 Percentage From Arinami et al, 1997.

  7. DRD2 -141C Ins/Del and Clozapine Response 45 40 Del+ 35 BPRS total 18 Del- 30 25 Baseline Week 10 Clozapine BPRS=Brief Psychiatric Rating Scale.

  8. Dopamine D2 Receptor Upregulation after Antipsychotic Treatment Silvestri et al. 2000

  9. DRD2 Promoter Region Polymorphisms in First-episode Schizophrenia • 61 first-episode patients (schizophrenia/schizoaffective disorder/schizophreniform disorder) • 74% male; mean age 24±5 years, range 16-38 years • Random assignment to medication • Risperidone (1-6 mg, n=33) or olanzapine (2.5-20 mg, n=28) • Raters blind to medication and genotype • Weekly (first 4 weeks), then biweekly ratings up to 16 weeks • Response: absence of delusions, hallucinations, and substantial thought disorder • Mild (3) or less on SADS-C positive symptom items • “Much Improved” or “Very Much Improved” on CGI change item • Sustained for two or more consecutive ratings CGI=Clinical Global Impression; SADS-C=Schedule for Affective Disorders and Schizophrenia–Change Version. Lencz T et al. Am J Psychiatry. 2006;163:529-531.

  10. DRD2 -141C Ins/Del and Responseto Atypical Antipsychotics 100 90 80 Del- (n=31) 70 60 Initiating sustained response (%) 50 Del+ (n=30) 40 30 20 10 0 0 2 4 6 8 10 12 14 16 Time (wk) Log rank=5.0, df=1, P=.025. Modified from Lencz T et al. Am J Psychiatry. 2006;163:529-531.

  11. DRD2 -141C Ins/Del and Antipsychotic Response: Meta – Analytic Results

  12. DRD2 -141C Ins/Del and Antipsychotic Response: Meta – Analytic Results

  13. DRD2 Predicts Acute Weight Gain

  14. Affymetrix 500K Platform: Specifications and Quality Control • Marker spacing: 2.5kb (median); 5.8kb (mean) • Mean Call Rate = 97% (range: 90-99) • Mean heterozygosity = 27% • 22 samples repeated; all SNPs > • 1 error dropped • Concordance across 454,699 SNPs > 99% • SNPs with <85% calls excluded: 1,526 • SNPs not in HWE (p<.001) in controls: 13,662 • Total SNPs analyzed: 439,511

  15. Assessing Treatment Responsivity in Schizophrenia • Clozapine usually reserved for patients who failed two prior antipsychotic drug trials or have severe side effects. • Clozapine – treated patients are more severely ill and treatment nonresponsive. • McEvoy et al. 2006: • Patients entering CATIE CLZ trial (N=99) : 58% with > 4 prior hosps vs 48% for others (N=444) (p=0.03) • PANSS total: CLZ trial subjects: 87.6 + 20.2; Others: 77.0 +18.6 (p<0.001).

  16. Treatment Response Phenotype in Phase I Whole Genome Analyses

  17. P = 5*10-6 Treatment Responsive vs. Treatment Nonresponsive: Phase I Results

  18. Genes Associated with Treatment Response: Affy 500K Phase I Results

  19. Pharmacogenetics of Antipsychotic Drug Response: Conclusions • Multiple candidate genes have been investigated in relatively small samples with inconsistent results • DRD2: Candidate genes and meta-analytic support for role in antipsychotic efficacy • Adverse events may be more amenable for pharmacogenetic targeting • New genomic tools will markedly expand the opportunity for pharmacogenetic studies over the next few years

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