1. Pharmacogenetics of Antipsychotic Drug Response
Anil K. Malhotra, M.D.
Zucker Hillside Hospital
Glen Oaks, NY
Albert Einstein College of Medicine
Bronx, NY

2. 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

3. Discontinued Due to Lack of Efficacy
Chouinard et al 1993
Marder & Melbach 1997
Beasley et al 1996
Tollefson et al 1997
Arvinitis et al 1997

4. Clinical Response over 4 Weeks of Antipsychotic Drug Treatment

5. Meta-analysis of Weight Gain Following Antipsychotic Drug Treatment

6. ALOX5 Genotype and Response to Antiasthma Treatment
FEV1 % Change From Baseline
P = 0.039

7. Pharmacogenetics of Clozapine Response
Candidate Frequency of Association With
Receptor 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 III
5HT2A 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

8. 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

9. 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.

10. Pharmacogenetics of Clozapine Response: Methods
72 DSM-IIIR diagnosed schizophrenic or schizoaffective patients (52M, 20F, age = ± 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

11. -141C Ins/Del and Clozapine Response
Clozapine Clozapine
Responders Nonresponders Total
Genotypea
Del+ 2 (10%) 19 (37%) 21 (29%)
Del- 19 (90%) 32 (63%) 51 (71%)
Total
Alleleb
Del 2 (5%) 20 (20%) 22 (15%)
Ins 40 (95%) 82 (80%) 122 (85%)
Total
aFET, P = 0.015
bFET, P = 0.023

12. DRD2 -141C Ins/Del and Clozapine Response45 40
BPRS
Total 18
Del+ 35
Del- 30 25
Typical
Neuroleptic
Clozapine

13. 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/m2)

14. 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.

15. 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

16. Case-Control Association
Drug Responders
Drug Non-Responders
Measure allele frequencies in both samples, search for statistically significant differences

17. Regional Frequencies of DRD4 VNTR Alleles
Repeat

18. Transmission Disequilibrium Test (TDT)AB AC AB AE AE AE AB AC

19. Power of Case-Control vs Family-Based Association
Genetic Model Allele Frequency Case-Control Family-Based
Dominant , ,913
Recessive ,820 38,
Additive
 = 5 x 10-8.
Power = 0.80.
From Risch and Teng, 1998.

20. Number of Unlinked Markers to Detect Stratification
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
RR = 1
RR = 2
RR = 4
RR = 8
Probability
No. of Unlinked Markers

21. Whole Genome Association: A Plausible Strategy to Identify New Drug Targets?
2 - 3 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

22. Funding: NIMH, NARSAD, Stanley Foundation, Pfizer Inc.
Acknowledgments
NIMH
MPRC
Zucker Hillside
Caleb Adler
Alan Breier
Alan Clifton
Lisa Kestler
David Pickar
Walter Rooney
Robert Buchanan
Pat Ball
John Bates
Janet Lavelle
Alan Mendelowitz
Donna O’Shea
Kamran Razi
John Kane
NIAAA
David Goldman
Norio Ozaki
Chiara Mazzanti
Funding: NIMH, NARSAD, Stanley Foundation, Pfizer Inc.