Pharmacogenetics of Antipsychotic Drug Response

Anil K. Malhotra, M.D.Zucker Hillside HospitalGlen Oaks, NYAlbert Einstein College of MedicineBronx, 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

33%

31%

32%

21%

28%

26%

38%

17%

52%

5%

0% 10% 20% 30% 40% 50% 60%

Hal 12 mg

Qtp 750 Mg

Hal 12 mg

Olz 13 mg

Hal 15 mg

Olz 15 mg

Hal 20 mg

Risp 6 mg

Hal 20 mg

Risp 6 mgChouinard et al 1993

Arvinitis et al 1997

Tollefson et al 1997

Beasley et al 1996

Marder & Melbach 1997

Mean Total BPRS

47.68

42.4440.55

38.17 37.08

30.00

35.00

40.00

45.00

50.00

0 1 2 3 4 5

Week

Scor

eClinical Response over 4 Weeks of Antipsychotic Drug Treatment

Meta-analysis of Weight Gain Following Antipsychotic Drug Treatment

-10

-5

0

5

10

15

20

25Day 8 Day 84

Wild type:ABT-761

Wild type:placebo

Mutant:ABT-761

ALOX5 Genotype and Response to Antiasthma Treatment

FEV1 %Change

FromBaseline

P = 0.039

P = 0.026P = 0.004

P <0.001

Pharmacogenetics of Clozapine ResponseCandidate 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 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 20-34 bp repeat in 40% 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

0

50

100

150

200

250

A-241/-141C Del A-241/-141 Ins0

50

100

A-241/-141C Del A-241/-141 Ins

P <0.02 P <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, 1997.

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 21 51 72

aFET, P = 0.015bFET, P = 0.023

-141C Ins/Del and Clozapine Response

Genotypea

Clozapine ClozapineResponders Nonresponders Total

Del 2 (5%) 20 (20%) 22 (15%)Ins 40 (95%) 82 (80%) 122 (85%)Total 42 102 144

Alleleb

Del-

Del+BPRSTotal 18

Typical Neuroleptic

Clozapine25

30

35

40

45

DRD2 -141C Ins/Del and Clozapine Response

Association of 5-HT2C -759C/T Polymorphism and Weight Gain

-0.20

0.20.40.60.8

11.21.41.6

6 weeks 10 weeks

Wild-type Variant• 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)

Cha

nge

i n B

MI (

k g/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 Responders Drug Non-Responders

Measure allele frequencies in both samples, search for statistically significant differences

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

2 3 4 5 6 7 8 10

AlleleFrequencies

AfricaEurope and Middle EastEast and South AsiaPacificAmericas

Regional Frequencies of DRD4 VNTR Alleles

Repeat

Transmission Disequilibrium Test (TDT)

AB AC

AE AE AB AC

ABAE

Power of Case-Control vs Family-Based Association

Genetic Model Allele Frequency Case-Control Family-BasedDominant 0.05 207 314

0.20 158 2240.70 2,204 2,913

Recessive 0.05 28,820 38,9090.20 712 9720.70 160 199

Additive 0.05 502 7340.20 238 3330.70 530 686

= 5 x 10-8.Power = 0.80.From Risch and Teng, 1998.

Number of Unlinked Markers to Detect Stratification

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0.00

Probability

No. of Unlinked Markers0 5 10 15 20 25 30 35 40

RR = 1RR = 2RR = 4RR = 8

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 - 30,000 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.