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S.07.04 Towards pharmacogenomics: A large-scale association study on response to haloperidol
s112
I
S 07 04
S.07.
Towards association
pharmacogenomics: study on response
The impact
of genomics
A large-scale to haloperidol
D. Rujescu’ , I. Giegliug’ , M. Schafe?, N. Dahmeu3, T. Sauder4, A. Szegedi3, M.R. Toliat4, H.-J. Moller’ , B. Boudy’ , A.M. Hartmamr’ , H.H. Stasseu5. ‘Ludwig-Maximilians University, Dep. of Psychiatry, Munich, Germany; 2HumDoldt University, Dept. of Psychiatry of the Charite, Berlin, Germany; 3University of Mainz, Dept. of Psychiatry, Mainz, Germany; 4A4ax-Delb-iick-Centel; Berlin, Germany; ‘Psychiatric University Hospital, Research department, Zurich, Switzerland
It is well known that patients display marked differences in response to drugs, which may be partially attributed to genetic predisposition wesell, 2000). G emetic variatious responsible for iuterindividual differences in response to treatment affect drug metabolism (pharmacokiuetic level) or drug targets (pharmacodyuamic level) (Cichou et al., 2000). For response to autipsychotic treatment, the munber of susceptibility loci, the attributable risk conferred by each locus, aud the degree of iuteractiou betweeu loci remail1 uuknown Thus, fiudiug genes that iuflueuce response to treatment presents a major challenge, giveu that the biological mechanisms responsible for response to autipsychotics are far from being understood. In spite of these difficulties, two maiu approaches have beeu used in the search for susceptibility genes: linkage studies, which do uot have to rely ou specific biological hypotheses, seek to identify chromosomal regions coutaiuiug susceptibility loci; aud association studies, which are sensitive enough to detect small geue effects, but have to relay ou the choice of plausible candidate genes. So far, uo linkage study ou response to autipsychotics has beeu published, since this approach is virtually uot applicable for treatment response due to the fact, that standardized data ou respouse in multiplex families are needed. Case control association studies provide au alternative aud powerful approach of ideutifyiug such genes in feasible sample sizes. Most candidate geue studies focused ou neurotransmitter receptors aud metabolisiug enzymes. Haloperidol is highly efficient in the treatment of acute psychosis, especially wheu severe symptoms predominate. The dopamiue hypothesis of schizophrenia as well as the fact that dopamiue receptors are the primary targets in the treatment of schizophrenia, prompted the iuvestigatiou of genes involved in dopamiue ueurotrausmissiou in response to treatment. We could recently demo&rate that response to haloperidol, a typical autipsychotic, is associated with au SNP in the 3’ region of the dopamiue D2 receptor @RD2) geue (Schafer et al., 2001), although schizophrenia per se is uot associated with this single uucleotide polymorphism (SNP). This study investigates the associatiou of response to short-term haloperidol treatment with 120 microsatellites aud 200 SNPs in various candidate genes selected based ou their role in ueurotrausmission Oue hundred patients with acute psychosis (schizophrenia, schizoaffective, brief psychotic, aud substance-induced psychotic disorder) were treated with haloperidol for up to 28 days. Diaguosis was established by applying the SCID I aud II iuterview. Patients were assessed at baseline aud ou days 3, 7, 14, 21 aud 28. Improvement aud response were measured by using the Positive aud Negative Syudrome Scale. Haloperidol plasma levels were also obtained. We will present data ou this ougoiug largescale association study ou response to haloperidol. Geuotypiug of further 400 SNPs is uuder way.
in schizophrenia
References
[l]
Cichon S, Nothen MM, Rietschel M, Propping P. (2000) Pharmacogenetics of schizophrenia. Am. J. Med. Genet. 97:9%106. [2] Schafer M, Rujescu D, Giegling I, Guntermann A, Erfurth A, Bandy B, Moller HJ. (2001) Association of short-term response to haloperidol treatment with a polymorphism in the dopamine D(2) receptor gene. Am J Psychiatry 158(5):802-4. [3] Vesell ES (2000) Advances in pharmacogenetics and pharmacogenomics. J. Clin. Pharmacol. 40:93&938.
I S 07 05
Advances of clozapine
R.W. Kerwin Neuropharmacology,
Institute
in the pharmacogenetic response of London,
prediction
Psychiatry, Clinical United Kingdom
In the last decade, the candidate geue strategy has succeeded in the ideutificatiou of genetic variants with significant iuflueuce in treatment response. Association studies comparing mutations in candidate genes of individuals preseutiug differeut response to a particular treatment have helped to identify mutations in ueurotrausmitter receptors aud metabolic enzymes associated with response to psychiatric drugs. Genetic variants in 5-HT2A receptors have beeu associated with long-tenn response to the autipsychotic clozapiue. Iuterestiugly, dopamiuergic variants have beeu associated with early response to ueuroleptics, suggesting that differeut systems may contribute to therapeutic response at differeut stages of treatment. Polymorphisms in the serotouiu transporter have also beeu associated with poor response to autidepressaut drugs. Association studies have proved to be a useful tool for the ideutificatiou of single genes with a major or moderate coutributiou to response variability. However, these fiudiugs, takeu individually, are of limited clinical value. Response variability is a complex trait, very likely controlled by a core of genes with a major effect aud additioual coutributious from other genes with a miiior role. Theoretically, combined iufonnatiou from key response-related genes could be used to fonn the basis of prediction tests. This hypothesis was put to test in a study iuvestigatiug mutations in drug-targeted receptor genes ou a sample of clozapiue treated patients. We reported that a combiuatiou of polymorphisms in six key genes (5-HT2A, 5-HT2C, 5-HTT aud H2) resulted in the correct prediction of response in more thau 76% of cases. This significant prediction is being improved with the iucorporatiou of additioual polymorphisms in response related genes in the prediction equation Although the same equation will uot be applicable to differeut ethnic groups, adjustment according to the local frequencies of the predictor mutations cau result in similar prediction tests. Additionally, these predictor genes may also be important for other autipsychotic drugs with similar pharmacological profiles. For example, response to olauzapiue, au atypical autipsychotic that resembles clozapiue in its strong affinity for serotouergic receptors, cau also be predicted by the same serotouiu polymorphisms used for the prediction of clozapine. The iucorporatiou of dopamiue 3 variants in the prediction equation resulted in au improvement in the level of prediction (76% correctly classified). In summary, it is expected that, after validatiou in appropriate clinical samples, the first prediction tests for autipsychotic response will be available for clinical use in 335 years. Similar prediction methods could be developed for other autipsychotic drugs leading to individually tailored autipsychotic treatment.
I
S 07 04
S.07.
Towards association
pharmacogenomics: study on response
The impact
of genomics
A large-scale to haloperidol
D. Rujescu’ , I. Giegliug’ , M. Schafe?, N. Dahmeu3, T. Sauder4, A. Szegedi3, M.R. Toliat4, H.-J. Moller’ , B. Boudy’ , A.M. Hartmamr’ , H.H. Stasseu5. ‘Ludwig-Maximilians University, Dep. of Psychiatry, Munich, Germany; 2HumDoldt University, Dept. of Psychiatry of the Charite, Berlin, Germany; 3University of Mainz, Dept. of Psychiatry, Mainz, Germany; 4A4ax-Delb-iick-Centel; Berlin, Germany; ‘Psychiatric University Hospital, Research department, Zurich, Switzerland
It is well known that patients display marked differences in response to drugs, which may be partially attributed to genetic predisposition wesell, 2000). G emetic variatious responsible for iuterindividual differences in response to treatment affect drug metabolism (pharmacokiuetic level) or drug targets (pharmacodyuamic level) (Cichou et al., 2000). For response to autipsychotic treatment, the munber of susceptibility loci, the attributable risk conferred by each locus, aud the degree of iuteractiou betweeu loci remail1 uuknown Thus, fiudiug genes that iuflueuce response to treatment presents a major challenge, giveu that the biological mechanisms responsible for response to autipsychotics are far from being understood. In spite of these difficulties, two maiu approaches have beeu used in the search for susceptibility genes: linkage studies, which do uot have to rely ou specific biological hypotheses, seek to identify chromosomal regions coutaiuiug susceptibility loci; aud association studies, which are sensitive enough to detect small geue effects, but have to relay ou the choice of plausible candidate genes. So far, uo linkage study ou response to autipsychotics has beeu published, since this approach is virtually uot applicable for treatment response due to the fact, that standardized data ou respouse in multiplex families are needed. Case control association studies provide au alternative aud powerful approach of ideutifyiug such genes in feasible sample sizes. Most candidate geue studies focused ou neurotransmitter receptors aud metabolisiug enzymes. Haloperidol is highly efficient in the treatment of acute psychosis, especially wheu severe symptoms predominate. The dopamiue hypothesis of schizophrenia as well as the fact that dopamiue receptors are the primary targets in the treatment of schizophrenia, prompted the iuvestigatiou of genes involved in dopamiue ueurotrausmissiou in response to treatment. We could recently demo&rate that response to haloperidol, a typical autipsychotic, is associated with au SNP in the 3’ region of the dopamiue D2 receptor @RD2) geue (Schafer et al., 2001), although schizophrenia per se is uot associated with this single uucleotide polymorphism (SNP). This study investigates the associatiou of response to short-term haloperidol treatment with 120 microsatellites aud 200 SNPs in various candidate genes selected based ou their role in ueurotrausmission Oue hundred patients with acute psychosis (schizophrenia, schizoaffective, brief psychotic, aud substance-induced psychotic disorder) were treated with haloperidol for up to 28 days. Diaguosis was established by applying the SCID I aud II iuterview. Patients were assessed at baseline aud ou days 3, 7, 14, 21 aud 28. Improvement aud response were measured by using the Positive aud Negative Syudrome Scale. Haloperidol plasma levels were also obtained. We will present data ou this ougoiug largescale association study ou response to haloperidol. Geuotypiug of further 400 SNPs is uuder way.
in schizophrenia
References
[l]
Cichon S, Nothen MM, Rietschel M, Propping P. (2000) Pharmacogenetics of schizophrenia. Am. J. Med. Genet. 97:9%106. [2] Schafer M, Rujescu D, Giegling I, Guntermann A, Erfurth A, Bandy B, Moller HJ. (2001) Association of short-term response to haloperidol treatment with a polymorphism in the dopamine D(2) receptor gene. Am J Psychiatry 158(5):802-4. [3] Vesell ES (2000) Advances in pharmacogenetics and pharmacogenomics. J. Clin. Pharmacol. 40:93&938.
I S 07 05
Advances of clozapine
R.W. Kerwin Neuropharmacology,
Institute
in the pharmacogenetic response of London,
prediction
Psychiatry, Clinical United Kingdom
In the last decade, the candidate geue strategy has succeeded in the ideutificatiou of genetic variants with significant iuflueuce in treatment response. Association studies comparing mutations in candidate genes of individuals preseutiug differeut response to a particular treatment have helped to identify mutations in ueurotrausmitter receptors aud metabolic enzymes associated with response to psychiatric drugs. Genetic variants in 5-HT2A receptors have beeu associated with long-tenn response to the autipsychotic clozapiue. Iuterestiugly, dopamiuergic variants have beeu associated with early response to ueuroleptics, suggesting that differeut systems may contribute to therapeutic response at differeut stages of treatment. Polymorphisms in the serotouiu transporter have also beeu associated with poor response to autidepressaut drugs. Association studies have proved to be a useful tool for the ideutificatiou of single genes with a major or moderate coutributiou to response variability. However, these fiudiugs, takeu individually, are of limited clinical value. Response variability is a complex trait, very likely controlled by a core of genes with a major effect aud additioual coutributious from other genes with a miiior role. Theoretically, combined iufonnatiou from key response-related genes could be used to fonn the basis of prediction tests. This hypothesis was put to test in a study iuvestigatiug mutations in drug-targeted receptor genes ou a sample of clozapiue treated patients. We reported that a combiuatiou of polymorphisms in six key genes (5-HT2A, 5-HT2C, 5-HTT aud H2) resulted in the correct prediction of response in more thau 76% of cases. This significant prediction is being improved with the iucorporatiou of additioual polymorphisms in response related genes in the prediction equation Although the same equation will uot be applicable to differeut ethnic groups, adjustment according to the local frequencies of the predictor mutations cau result in similar prediction tests. Additionally, these predictor genes may also be important for other autipsychotic drugs with similar pharmacological profiles. For example, response to olauzapiue, au atypical autipsychotic that resembles clozapiue in its strong affinity for serotouergic receptors, cau also be predicted by the same serotouiu polymorphisms used for the prediction of clozapine. The iucorporatiou of dopamiue 3 variants in the prediction equation resulted in au improvement in the level of prediction (76% correctly classified). In summary, it is expected that, after validatiou in appropriate clinical samples, the first prediction tests for autipsychotic response will be available for clinical use in 335 years. Similar prediction methods could be developed for other autipsychotic drugs leading to individually tailored autipsychotic treatment.