1
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
3
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
5
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.
8
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