pharmacogenetics of antipsychotic drug response
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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Pharmacogeneticsof Antipsychotic Drug
Response
Anil K. Malhotra, MDThe Zucker Hillside Hospital
Glen Oaks, New YorkThe 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
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Pharmacogenetics ofClozapine Response
Candidate Frequency of Association WithReceptor 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;
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Dopamine D2 Receptor Blockade and Antipsychotic
Potency
Seeman et al 1975
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5’
1
-141C Ins/Del
2 543 6 8
Taq1 B
7
Ser311Cys
0.91 Kb
0.2 Kb
0.14 Kb
-50 Kb
-10 Kb
25.5 Kb
A-241G
Taq1 D TaqI A
3’
DRD2 (11q22-q23): Candidate Gene for Antipsychotic Drug
Response
6
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
7
Del-
Del+
BP
RS
tota
l 18
Baseline Week 10 Clozapine
25
30
35
40
45
DRD2 -141C Ins/Del and Clozapine Response
BPRS=Brief Psychiatric Rating Scale.
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Dopamine D2 Receptor Upregulation after
Antipsychotic Treatment
Silvestri et al. 2000
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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.
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DRD2 -141C Ins/Del and Response
to Atypical Antipsychotics
Del+ (n=30)
Del- (n=31)
Log rank=5.0, df=1, P=.025.
Time (wk)
1614121086420Init
iati
ng
su
sta
ined
resp
on
se (
%)
Modified from Lencz T et al. Am J Psychiatry. 2006;163:529-531.
100
90
80
70
60
50
40
30
20
100
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DRD2 -141C Ins/Del and Antipsychotic Response: Meta –
Analytic Results
Study or Subgroup
Lencz 2006Malhotra 1999Shen 2008Wu 2005Xing 2007Yamanouchi 2003
Total (95% CI)
Total eventsHeterogeneity: Chi² = 9.23, df = 5 (P = 0.10); I² = 46%Test for overall effect: Z = 2.13 (P = 0.03)
Events
52
138
184
50
Total
302130292841
179
Events
1019505354
9
195
Total
315198
10697
125
508
Weight
13.5%16.5%21.9%27.2%14.2%
6.6%
100.0%
M-H, Fixed, 95% CI
0.42 [0.12, 1.42]0.18 [0.04, 0.85]0.73 [0.32, 1.67]0.38 [0.16, 0.94]1.43 [0.60, 3.42]1.39 [0.41, 4.79]
0.65 [0.43, 0.97]
Del Carrier Ins/Ins Odds Ratio Odds RatioM-H, Fixed, 95% CI
0.05 0.2 1 5 20Favours Ins/Ins Favours Del Carrier
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DRD2 -141C Ins/Del and Antipsychotic Response: Meta –
Analytic Results
Study or Subgroup
Lencz 2006Wu 2005Yamanouchi 2003
Total (95% CI)
Total eventsHeterogeneity: Chi² = 2.90, df = 2 (P = 0.23); I² = 31%Test for overall effect: Z = 2.00 (P = 0.05)
Events
584
17
Total
302930
89
Events
10539
72
Total
3110690
227
Weight
28.7%57.7%13.6%
100.0%
M-H, Fixed, 95% CI
0.42 [0.12, 1.42]0.38 [0.16, 0.94]1.38 [0.39, 4.87]
0.53 [0.28, 0.99]
Del Carrier Ins/Ins Odds Ratio Odds RatioM-H, Fixed, 95% CI
0.05 0.2 1 5 20Favours experimental Favours control
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DRD2 Predicts Acute Weight Gain
OLZRIS
6-W
EE
K W
T G
AIN
(P
OU
ND
S) 26
24
22
20
18
16
14
12
10
8
6
4
2
0
DRD2 DEL-141C
Non-Carrier
Carrier
MED p<.05
DRD2 p<.05
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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
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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).
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Treatment Response Phenotype in Phase I Whole
Genome Analyses
Clozapine(n = 62)
Non-Clozapine(n = 110)
P Value
Age 37.10 ± 10.38
38.47 ± 10.62 0.41
% Female 29.03% 39.10% 0.19
Age of Onset
20.89 ± 5.41 20.69 ± 6.49 0.84
% Positive Family History
31.58% 20.21% 0.12
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Treatment Responsive vs. Treatment Nonresponsive:
Phase I Results
P = 5*10-6
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Genes Associated with Treatment Response: Affy
500K Phase I Results
Chrom Gene (Function) P value3p Axonal cell
adhesion4.6*10-7
19p SNARE-related 9.4*10-7
8q Neuroreceptor (cannabinoid)
2.2*10-6
5q Lipid transport 3.0*10-6
8p Protein phosphatase
subunit
3.2*10-6
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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