title: Pharmacogenetic study of the effects of raloxifene on negative symptoms of postmenopausal women with schizophrenia: A double-blind, randomized, placebo-controlled trial.
abstract: Several double-blind clinical trials have reported improvement in positive, negative and cognitive symptoms of schizophrenia with raloxifene, a selective receptor estrogen modulator. However, there are some inconsistencies in replicating findings between studies of different countries. The failure to replicate these findings may result from genetic factors that could explain some of the variability in the treatment response. However, pharmacogenetic studies exploring this topic in women with schizophrenia are lacking. We aimed to conduct an exploratory pharmacogenetic analysis of a double-blind, randomized, parallel, placebo-controlled study of 24 weeks' duration of raloxifene aiming to improve negative symptoms in postmenopausal women with schizophrenia. Four single nucleotide polymorphisms (SNPs) were studied: rs9340799, rs2234693 and rs1801132 in the Estrogen Receptor 1 (ESR1) gene, and rs1042597 in the UDP-glucuronosyltransferase 1A8 (UGT1A8) gene. Sixty-five postmenopausal women with schizophrenia (DSM-IV) were randomized to either 60mg/day adjunctive raloxifene (36 women) or adjunctive placebo (29 women). Psychopathological symptoms were assessed at baseline and at weeks 4, 12, and 24 with the Positive and Negative Syndrome Scale (PANSS). Of the four studied SNPs, the rs1042597 variant in the UGT1A8 gene was associated with a different treatment response in negative symptoms with raloxifene treatment, whereas the rs2234693 variant in the ESR1 gene was associated with a distinct response in general psychopathology. In conclusion, our study suggests that genetic variants in UGT1A8 and ESR1 genes modulate the treatment response to adding raloxifene to antipsychotic treatment in postmenopausal women with schizophrenia.
authors.affiliation: Corporació Sanitària i Universitària Parc Taulí, Mental Health Department, Universitat Autònoma de Barcelona, Sabadell, Spain; Catalan Group in Women's Mental Health Research (GTRDSM), Barcelona, Spain; Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain. Electronic address: jlabad@tauli.cat.
authors.forename: Javier
authors.initials: J
authors.lastname: Labad
authors.affiliation: Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain; Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Martorell
authors.affiliation: Catalan Group in Women's Mental Health Research (GTRDSM), Barcelona, Spain; Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain; Parc Sanitari Sant Joan de Déu, Research and Development Unit, Sant Boi de Llobregat, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Huerta-Ramos
authors.affiliation: Corporació Sanitària i Universitària Parc Taulí, Mental Health Department, Universitat Autònoma de Barcelona, Sabadell, Spain; Catalan Group in Women's Mental Health Research (GTRDSM), Barcelona, Spain; Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Cobo
authors.affiliation: Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain; Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Vilella
authors.affiliation: Catalan Group in Women's Mental Health Research (GTRDSM), Barcelona, Spain; Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain; Parc Sanitari Sant Joan de Déu, Research and Development Unit, Sant Boi de Llobregat, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Rubio-Abadal
authors.affiliation: Catalan Group in Women's Mental Health Research (GTRDSM), Barcelona, Spain; Cap EAE Salut Mental, Andorra.
authors.forename: Gemma
authors.initials: G
authors.lastname: Garcia-Pares
authors.affiliation: Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Creus
authors.affiliation: Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain; Parc Sanitari Sant Joan de Déu, Research and Development Unit, Sant Boi de Llobregat, Spain.
authors.forename: Cristian
authors.initials: C
authors.lastname: Núñez
authors.affiliation: Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain; Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Ortega
authors.affiliation: Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain; Parc Sanitari Sant Joan de Déu, Research and Development Unit, Sant Boi de Llobregat, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Miquel
authors.affiliation: Catalan Group in Women's Mental Health Research (GTRDSM), Barcelona, Spain; Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM), Madrid, Spain; Parc Sanitari Sant Joan de Déu, Research and Development Unit, Sant Boi de Llobregat, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Usall
mesh_terms: D017668:Age of Onset; D000368:Aged; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004311:Double-Blind Method; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D010597:Pharmacogenetics; D000071185:Pharmacogenomic Testing; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017698:Postmenopause / Q000523:psychology; D020849:Raloxifene Hydrochloride / Q000009:adverse effects*; D012559:Schizophrenia; D012565:Schizophrenic Psychology; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D014453:Glucuronosyltransferase; C454320:UDP-glucuronosyltransferase, UGT1A8
keywords: Genetics; Negative symptoms; Pharmacogenetics; Postmenopause; Raloxifene; Schizophrenia