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Genetics of novel therapeutic targets in schizophrenia

Published online by Cambridge University Press:  06 August 2018

R. Kerwin  and
M. Owen
R. Kerwin*
Affiliation:
Institute of Psychiatry, London
M. Owen
Affiliation:
University of Wales College of Medicine
*
Correspondence: Professor R. Kerwin, Institute of Psychiatry, Section of Clinical Neuropharmacology, De Crespigny Park, London SE5 8AF
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Extract

For many years, following the introduction of chlorpromazine in the 1950s, little progress was made in the discovery of new drugs for schizophrenia (Reynolds, 1992). Dopamine D2 receptor blockade was recognised as the only therapeutic target for antipsychotics (Creese et al, 1976) and the inevitable consequences of striatal blockade remained problematic. However, the strategies and stimuli for discovery of new drugs changed with the introduction of new, atypical antipsychotics in the 1990s. These include clozapine, remoxipride (now withdrawn), olanzapine, risperidone and sertindole (Kerwin & Taylor, 1996). The goal of antipsychotic drug development has always been to widen the therapeutic ratio between efficacy and adverse effects. These new drugs have in the main achieved this. However, which therapeutic targets these drugs employ remains a mystery, and this information is clearly important for future research into more selectively targeted agents.

Type
Research Article
Information
The British Journal of Psychiatry , Volume 174 , Issue S38: New antipsychotics - preclinical and clinical comparisons , May 1999 , pp. 1 - 4
Copyright
Copyright © 1999 The Royal College of Psychiatrists 

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References

Arranz, M. J., Collier, D. M., Sodhi, M., et al (1995) Association between clozapine response and allelic variation in the 5HT2a receptor gene. Lancet, 346, 281–282.Google Scholar
Arranz, M. J., Collier, D. M., Munro, J., et al (1996) Analysis of a structural polymorphism in the 5HT2a receptor and clinical response to clozapine. Neuroscience Letters, 224, 95–98.Google Scholar
Ashby, C. R. Jr & Wang, R. Y. (1990) Effect of antipsychotic drugs on 5HT2 receptors in the medial prefrontal cortex. Microiontophoretic studies. Brain Research, 506, 346–348.Google Scholar
Badri, F., Masellis, M., Petronis, A., et al (1996) Dopamine and serotonin system genes may predict clinical response to clozapine. American Journal of Human Genetics, 59 (suppl. A247).Google Scholar
Barr, C. L., Kennedy, J. L., Lichter, J. B., et al (1993) Alleles at the dopamine D4 receptor locus do not contribute to the genetic susceptibility to schizophrenia in a large Swedish kindred. American Journal of Medical Genetics, 48, 218–222.CrossRefGoogle ScholarPubMed
Bennet, J. P., Enna, S. J., Bylund, D., et al (1979) Neurotransmitter receptors in frontal cortex of schizophrenics. Archives of General Psychiatry, 36, 927–934.Google Scholar
Buckland, P. R., O'Donovan, M. C. & McGuffin, P. (1993) Clozapine and sulpiride up-regulate dopamine D3 receptor mRNA levels. Neuropharmacology, 32, 901–907.CrossRefGoogle ScholarPubMed
Campion, D., d'Amato, C., Bastard, C., et al (1994) Genetic study of dopamine D1, D2 and D4 rceptors. Psychiatry Research, 51, 215–230.Google Scholar
Catalano, M., Nobile, M., Novelli, E., et al (1993) Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients. Biological Psychiatry, 34, 459–464.CrossRefGoogle ScholarPubMed
Creese, I., Burt, D. R. & Snyder, S. H. (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science, 192, 481–483.Google Scholar
Crocq, M. A., Mant, R., Asherson, P., et al (1992) Association between schizophrenia and homozygosity at the dopamine D3 receptor gene. Journal of Medical Genetics, 29, 859–860.Google Scholar
Daniels, J., Williams, J., Mant, R., et al (1994) Repeat length variation in the dopamine D4 receptor gene shows no evidence of association with schizophrenia. American Journal of Medical Genetics (Neuropsychiatric Genetics), 54, 256–258.Google Scholar
Erdmann, J., Shimron-Abarbanell, D., Rietschel, M., et al (1996) Systematic screening for mutations in the human serotonin 2A (5HT2a) receptor: identification of two naturally occurring receptor variants and association analysis in schizophrenia. Human Genetics, 97, 614–619.Google Scholar
Inayama, Y., Goneda, H., Sakai, T., et al (1996) Positive association between a DNA sequence variant in serotonin 2a receptor gene and schizophrenia. American Journal of Medical Genetics, 67, 103–105.Google Scholar
Jonsson, E., Lannfelt, L., Sokoloff, O., et al (1993) Lack of association between schizophrenia and alleles at the D3 receptor gene. Acta Psychiatrica Scandinavica, 87, 345–349.Google Scholar
Jonsson, E., Noethen, M. M., Bunzel, R., et al (1996) 5HT2A receptor T102C polymorphism and schizophrenia. Lancet, 317, 1831.Google Scholar
Kennedy, J. L., Sidenberg, D. G., Von Tol, H. H. M., et al (1993) A Hincll R7LP in the human D4 receptor locus (DRD4). Nucleic Acid Research, 19, 5801.Google Scholar
Kennedy, J. L., Petronis, A., Gao, J., et al (1994) Genetic studies of DRD4 and clinical response to neuroleptic medication. American Journal of Human Genetics, 55, 3.Google Scholar
Kerwin, R. W. & Taylor, D. (1996) New antipsychotics. A review of their current status and clinical potential. CNS Drugs, 6, 71–82.Google Scholar
Macciardi, F., Petronis, A., Van Tol, H. H. M., et al (1994) Analysis of the D4 dopamine receptor gene variant in an Italian schizophrenia kindred. Archives of General Psychiatry, 51, 288–293.Google Scholar
Malhotra, A. K., Goldman, D., Buchanan, A. B. & Pickar, D. (1996) 5HT2A receptor T102C polymorphism and schizophrenia. Lancet, 317, 1830–1831.Google Scholar
Mant, R., Williams, J., Asherson, P., et al (1994) Relationship between homozygosity at the dopamine D3 receptor gene and schizophrenia. American Journal of Medical Genetics, 54, 21–26.Google Scholar
Masellis, M., Paterson, A. D., Badri, F., et al (1995) Genetic variation of the 5HT2a receptor and response to clozapine. Lancet, 346, 908.CrossRefGoogle ScholarPubMed
Meltzer, H. (1994) Overview of the mechanism of action of clozapine. Journal of Clinical Psychiatry, 55 (suppl. B), 47–52.Google Scholar
Nanko, S., Sasaki, T., Fukuda, R., et al (1993) A study of the association between schizophrenia and the dopamine D3 receptor gene. Human Genetics, 92, 336–338.Google Scholar
Nimgaonkar, V. L., Zhang, X. R., Caldwell, J. G., et al (1993) Association study of schizophrenia with dopamine D3 receptor gene polymorphism: probable effect of family history of schizophrenia. American Journal of Medical Genetics, 48, 214–217.Google Scholar
Nimgaonkar, V. L., Zhang, Z. R., Brar, J. S., et al (1996) 5HT2 receptor gene locus: association with schizophrenia or treatment response not detected. Psychiatric Genetics, 6, 23–27.Google Scholar
Noethen, M. M., Rietschel, M., Erdmann, J., et al (1995) Genetic variation of the 5HT2a receptor and response to clozapine. Lancet, 346, 908.Google Scholar
Petronis, A., Van Tol, H. H. M. & Yang, L. (1993) Population and linkage disequilibrium analysis of new polymorphisms at the DRD4 locus. American Journal of Human Genetics, 53, 1707.Google Scholar
Pilowsky, L. S., Costa, D. C., Ell, P. J., et al (1992) Clozapine, single photon emission tomography and D2 dopamine receptor blockade hypothesis of schizophrenia. Lancet, 340, 199–202.Google Scholar
Pilowsky, L. S., Busatto, G., Taylor, M., et al (1996) Dopamine D2 receptor occupancy in vivo by the novel antipsychotic olanzapine: a 123l-IBZM single photon emission tomography study. Psychopharmacology, 124, 148–153.Google Scholar
Rao, P., Pickas, D., Gejman, P., et al (1994) Allelic variation in the D4 dopamine receptor (DRD4) gene does not predict response to clozapine. Journal of Human Genetics, 51, 912–917.Google Scholar
Reynolds, G. P. (1992) Developments in the drug treatment of schizophrenia. Trends in Neuroscience, 13, 116–121.Google Scholar
Reyntjens, A., Gelders, G. G., Hoppenbrouwers, M. J. J. A., et al (1986) Thymostemic effects of ritanserin (R55667), a centrally acting serotonin S2 blocker. Drug Development and Research, 8, 205–211.Google Scholar
Sasaki, T., Hattori, M., Fukuda, R., et al (1996) 5HT2A receptor T102C polymorphism and schizophrenia. Lancet, 347, 1832.Google Scholar
Shaikh, S., Collier, D., Kerwin, R., et al (1993) Dopamine D4 receptor subtypes and response to clozapine. Lancet, 341, 116.Google Scholar
Shaikh, S., Gill, M., Owen, M., et al (1994) Failure to find linkage between a functional polymorphism in the dopamine D4 receptor gene and schizophrenia. American Journal of Medical Genetics (Neuropsychiatric Genetics), 54, 8–11.Google Scholar
Shaikh, S., Collier, D., Sham, P., et al (1996) Allelic association between a Ser-9-Gly polymorphism in the dopamine D3 receptor gene and schizophrenia. Journal of Human Genetics, 97, 714–719.Google Scholar
Sodhi, M. S., Arranz, M. J., Curtis, D., et al (1995) Association between clozapine response and allelic variation in the 5HT2c receptor gene. Neuroreport, 7, 169–172.Google Scholar
Van Tol, H. H. M., Wu, C. M., Guan, H. C., et al (1992) Multiple dopamine D4 receptor variants in the human population. Nature, 358, 149–192.Google Scholar
Williams, J., Spurlock, G., McGuffin, P., et al (1996) Association between schizophrenia and TI02C polymorphism of the 5-hydroxytryptamine type 2a receptor gene. Lancet, 347, 1294–1296.Google Scholar
Williams, J., McGuffin, P., Nothen, M., Owen, M. J. & the EMASS Collaborative Group (1997) A meta-analysis of the association between the 5HT2a receptor TI02C polymorphism and schizophrenia. Lancet, 349, 1221.Google Scholar
Williams, J., Spurlock, G., Holmans, P., et al (1998) A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia. Molecular Psychiatry, 3, 141–149.Google Scholar
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