title: Risk genes for schizophrenia: translational opportunities for drug discovery.
abstract: Despite intensive research over many years, the treatment of schizophrenia remains a major health issue. Current and emerging treatments for schizophrenia are based upon the classical dopamine and glutamate hypotheses of disease. Existing first and second generation antipsychotic drugs based upon the dopamine hypothesis are limited by their inability to treat all symptom domains and their undesirable side effect profiles. Third generation drugs based upon the glutamate hypothesis of disease are currently under evaluation but are more likely to be used as add on treatments. Hence there is a large unmet clinical need. A major challenge in neuropsychiatric disease research is the relatively limited knowledge of disease mechanisms. However, as our understanding of the genetic causes of the disease evolves, novel strategies for the development of improved therapeutic agents will become apparent. In this review we consider the current status of knowledge of the genetic basis of schizophrenia, including methods for identifying genetic variants associated with the disorder and how they impact on gene function. Although the genetic architecture of schizophrenia is complex, some targets amenable to pharmacological intervention can be discerned. We conclude that many challenges lie ahead but the stratification of patients according to biobehavioural constructs that cross existing disease classifications but with common genetic and neurobiological bases, offer opportunities for new approaches to effective drug discovery.
authors.affiliation: Psychiatric Research Institute of Neuroscience in Glasgow (PsyRING), Universities of Glasgow and Strathclyde, Glasgow G12 8QQ, UK; CeNsUS, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK; Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Winchester
authors.affiliation: Psychiatric Research Institute of Neuroscience in Glasgow (PsyRING), Universities of Glasgow and Strathclyde, Glasgow G12 8QQ, UK; CeNsUS, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK. Electronic address: J.a.pratt@strath.ac.uk.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Pratt
authors.affiliation: Psychiatric Research Institute of Neuroscience in Glasgow (PsyRING), Universities of Glasgow and Strathclyde, Glasgow G12 8QQ, UK; Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Morris
mesh_terms: D000818:Animals; D055808:Drug Discovery; D057890:Epigenomics; D018628:Gene Dosage; D055106:Genome-Wide Association Study; D006801:Humans; D040901:Proteomics; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D049490:Systems Biology; D059467:Transcriptome
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate
keywords: Gene; Polymorphism; Schizophrenia; Stratified medicines; Therapeutics; Variant