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Individualisation of treatment: Genetic prediction of clozapine response
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X-Y homology was predicted (Crow, 1993) on the basis of the structural brain changes associated with schizophrenia and the neuropsychological correlates of sex chromosome aneuploidies. The identification (Nanko, 1981 ) of an XX male suffering from schizophrenia provides a possible lead to the location of such a gene. We earlier reported (Laval et al., 1998) that the breakpoint was in the Xq21.3/Yp region of homology suggested by the finding of weak linkage to psychosis and to degrees of handedness. This region is of interest because it was generated after the separation of the lineages that lead to Homo sapiens and the chimpanzee. Here we report that by a combined strategy of identifying single base-pair differences between homologous STS sequences on the X and the Y chromosomes together with the use of FISH to identify Yp homologous sequences we have localized the breakpoint to approximately 50kB between the markers sY42 and 13d, a region that may be associated with recent evolutionary change. References Crow T.J. (1993) Lancet 342: 594-598. Laval S. et al. (1998) Amer J Med Genet (Neuropsychiat Genet) 81: 420-427. Nanko S. (1981) Folia Psychiat Neurol Japonica 35: 461-463.
F. P h a r m a c o g e n e t i c s A. 152. POSITIVE ASSOCIATION BETWEEN A NOVEL D I N U C L E O T I D E REPEAT POLYMORPHISM IN THE H U M A N SEROTONIN-3B RECEPTOR G E N E (5HT3B) A N D CLINICAL RESPONSE TO CLOZAPINE B. Gutirrrez, M.J. Arranz, J. Munro, S. Osborne, R.M. Murray, L. Fafianfis*, R.W. Kerwin Clinical Neuropharmacology, Dept. of Psychological Medicine, Institute of Psychiatry, London, UK. * Unitat de Biologia Humana, Dep. Biologia Animal Facultat Biologia, Universitat Barcelona, Spain Clozapine is a potent antagonist of 5HT3 receptors, which are ligand-gated ion channels that mediate rapid excitatory responses in the CNS. Recently, a new type of 5HT3 receptor subunit has been identified: 5HT3B. Gene coding for this subunit has been assigned to chromosome 11q23.1, a region which has often been linked to psychoses. In the present study, we hypothesised that clinical response to clozapine treatment may be influenced by genetic variation in the 5HT3B neurotransmitter receptor. To test this hypothesis, we genotyped a novel CA repeat polymorphism at 5HT3B gene in a sample of 140 clozapine-treated schizophrenic patients in which clinical improvement after treatment was determined by the Global Assessment Score (GAS). Allele frequencies did not differ between patients who responded (n=98, allele 1=38.27%, allele 2=61.73%) and those who did not respond to clozapine treatment (n = 42, allele 1 = 41.67%, allele 2 = 58.33%, j(2 = 0.29, p = 0.593). However, a significant association was found between clinical response and 5HT3B genotype ( ~(2= 9.54, d f = 2, p = 0.008). Homozygosity
for the 2-CA-repeat allele was more frequent in responders than in no-responders to treatment (39% versus 21% respectively, Z2 = 3.97, d f = 1, p = 0.046). Our results suggest that genetic variation at 5HT3B receptor influences clozapine response and strengthen the candidacy of this receptor as an important therapeutic target in the treatment of schizophrenia. Blanca Gutirrrez is supported by an EMBO fellowship.
A. 153. INDIVIDUALISATION OF TREATMENT: GENETIC PREDICTION OF CLOZAPINE RESPONSE M.J. Arranz, J. Munro, J. Birkett, A. Bolonna, D. Mancama, M. Sodhi, K.P. Lesch, J.F.W. Meyer, P. Sham, D. Collier, R.M. Murray, R.W. Kerwin Clinical Neuropharmacology, Dept. P. Medicine. Institute of Psyehiatrv, London, UK The aim of pharmacogenetic studies is the improvement of patient care by selection of the most beneficial drug treatment for each subject. Finding the relation between the individual's genetic profile and their clinical repsonse is the key for achieving this goal. We have investigated genetic alterations in neurotransmitter receptors targeted by the atypical antipsychotic clozapine, including 19 genetic variants in dopaminergic (D2 and D3), serotonergic (5-HT2A, 2C, 3A and 5A), adrenergic (alpha-lA and alpha-2A), and histaminergic (HI and H2) receptors on a sample of clozapine treated patients. A combination of 6 polymorphisms in 4 of the genes studied resulted in 77% success in the prediction of response (p = 0.0001). The positive predictive value (PPV) was 0.76 + 0.08 and the negative predictive value (NPV) 0.82+0.16. If replicated, these results constitute the first evidence of the use of pharmacogenetics for the prediction of antipsychotic response and will have implications for the rational use and prescribing of clozapine. The findings of this study highlight the potential of pharmacogenetic studies as the key for the future improvement and individualisation of clinical treatment.
A. 154. REVERSE PHARMACOGENETICS: MOLECULAR GENETICS IN THE PREDICTION OF RAPID RELAPSE FOLLOWING ANTIPSYCHOTIC D R U G DISCONTINUATION A.K. Malhotra, D. Goldman Hillside Hospital, Psychiatry Research, 75-59 263rd Street, Glen Oaks, N Y 11004, USA; Laboratory of Neurogenetics, National Institute on Alcoholism and Alcohol Abuse, Rockville, MD, USA A significant subgroup of patients with schizophrenia experience rapid exacerbations in clinical symptoms following anti-
X-Y homology was predicted (Crow, 1993) on the basis of the structural brain changes associated with schizophrenia and the neuropsychological correlates of sex chromosome aneuploidies. The identification (Nanko, 1981 ) of an XX male suffering from schizophrenia provides a possible lead to the location of such a gene. We earlier reported (Laval et al., 1998) that the breakpoint was in the Xq21.3/Yp region of homology suggested by the finding of weak linkage to psychosis and to degrees of handedness. This region is of interest because it was generated after the separation of the lineages that lead to Homo sapiens and the chimpanzee. Here we report that by a combined strategy of identifying single base-pair differences between homologous STS sequences on the X and the Y chromosomes together with the use of FISH to identify Yp homologous sequences we have localized the breakpoint to approximately 50kB between the markers sY42 and 13d, a region that may be associated with recent evolutionary change. References Crow T.J. (1993) Lancet 342: 594-598. Laval S. et al. (1998) Amer J Med Genet (Neuropsychiat Genet) 81: 420-427. Nanko S. (1981) Folia Psychiat Neurol Japonica 35: 461-463.
F. P h a r m a c o g e n e t i c s A. 152. POSITIVE ASSOCIATION BETWEEN A NOVEL D I N U C L E O T I D E REPEAT POLYMORPHISM IN THE H U M A N SEROTONIN-3B RECEPTOR G E N E (5HT3B) A N D CLINICAL RESPONSE TO CLOZAPINE B. Gutirrrez, M.J. Arranz, J. Munro, S. Osborne, R.M. Murray, L. Fafianfis*, R.W. Kerwin Clinical Neuropharmacology, Dept. of Psychological Medicine, Institute of Psychiatry, London, UK. * Unitat de Biologia Humana, Dep. Biologia Animal Facultat Biologia, Universitat Barcelona, Spain Clozapine is a potent antagonist of 5HT3 receptors, which are ligand-gated ion channels that mediate rapid excitatory responses in the CNS. Recently, a new type of 5HT3 receptor subunit has been identified: 5HT3B. Gene coding for this subunit has been assigned to chromosome 11q23.1, a region which has often been linked to psychoses. In the present study, we hypothesised that clinical response to clozapine treatment may be influenced by genetic variation in the 5HT3B neurotransmitter receptor. To test this hypothesis, we genotyped a novel CA repeat polymorphism at 5HT3B gene in a sample of 140 clozapine-treated schizophrenic patients in which clinical improvement after treatment was determined by the Global Assessment Score (GAS). Allele frequencies did not differ between patients who responded (n=98, allele 1=38.27%, allele 2=61.73%) and those who did not respond to clozapine treatment (n = 42, allele 1 = 41.67%, allele 2 = 58.33%, j(2 = 0.29, p = 0.593). However, a significant association was found between clinical response and 5HT3B genotype ( ~(2= 9.54, d f = 2, p = 0.008). Homozygosity
for the 2-CA-repeat allele was more frequent in responders than in no-responders to treatment (39% versus 21% respectively, Z2 = 3.97, d f = 1, p = 0.046). Our results suggest that genetic variation at 5HT3B receptor influences clozapine response and strengthen the candidacy of this receptor as an important therapeutic target in the treatment of schizophrenia. Blanca Gutirrrez is supported by an EMBO fellowship.
A. 153. INDIVIDUALISATION OF TREATMENT: GENETIC PREDICTION OF CLOZAPINE RESPONSE M.J. Arranz, J. Munro, J. Birkett, A. Bolonna, D. Mancama, M. Sodhi, K.P. Lesch, J.F.W. Meyer, P. Sham, D. Collier, R.M. Murray, R.W. Kerwin Clinical Neuropharmacology, Dept. P. Medicine. Institute of Psyehiatrv, London, UK The aim of pharmacogenetic studies is the improvement of patient care by selection of the most beneficial drug treatment for each subject. Finding the relation between the individual's genetic profile and their clinical repsonse is the key for achieving this goal. We have investigated genetic alterations in neurotransmitter receptors targeted by the atypical antipsychotic clozapine, including 19 genetic variants in dopaminergic (D2 and D3), serotonergic (5-HT2A, 2C, 3A and 5A), adrenergic (alpha-lA and alpha-2A), and histaminergic (HI and H2) receptors on a sample of clozapine treated patients. A combination of 6 polymorphisms in 4 of the genes studied resulted in 77% success in the prediction of response (p = 0.0001). The positive predictive value (PPV) was 0.76 + 0.08 and the negative predictive value (NPV) 0.82+0.16. If replicated, these results constitute the first evidence of the use of pharmacogenetics for the prediction of antipsychotic response and will have implications for the rational use and prescribing of clozapine. The findings of this study highlight the potential of pharmacogenetic studies as the key for the future improvement and individualisation of clinical treatment.
A. 154. REVERSE PHARMACOGENETICS: MOLECULAR GENETICS IN THE PREDICTION OF RAPID RELAPSE FOLLOWING ANTIPSYCHOTIC D R U G DISCONTINUATION A.K. Malhotra, D. Goldman Hillside Hospital, Psychiatry Research, 75-59 263rd Street, Glen Oaks, N Y 11004, USA; Laboratory of Neurogenetics, National Institute on Alcoholism and Alcohol Abuse, Rockville, MD, USA A significant subgroup of patients with schizophrenia experience rapid exacerbations in clinical symptoms following anti-