title: Raloxifene increases prefrontal activity during emotional inhibition in schizophrenia based on estrogen receptor genotype.
abstract: People with schizophrenia show decreased prefrontal cortex (PFC) activity during emotional response inhibition, a cognitive process sensitive to hormonal influences. Raloxifene, a selective estrogen receptor modulator, binds estrogen receptor alpha (ESR-α), improves memory, attention and normalizes cortical and hippocampal activity during learning and emotional face recognition in schizophrenia. Here, we tested the extent to which raloxifene restores neuronal activity during emotional response inhibition in schizophrenia. Since genetic variation in estrogen receptor alpha (ESR-1) determines cortical ESR-α production and correlates with cognition, we also predicted that genetic ESR-1 variation would differentially relate to increased cortical activity by raloxifene administration. Thirty people with schizophrenia participated in a thirteen-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of raloxifene administered at 120mg/day. Effects of raloxifene on brain activation were assessed based on ESR-1 genotype using functional magnetic resonance imaging during emotional word inhibition. Raloxifene increased PFC activity during inhibition of response to negative words and the raloxifene related increased PFC activity was greater in patients homozygous for ESR-1 rs9340799 AA relative to G carriers. Comparison to 23 healthy controls demonstrated that PFC activity of people with schizophrenia receiving raloxifene was more similar to controls than to their own brain activity during placebo. Estrogen receptor modulation by raloxifene restores PFC activity during emotional response inhibition in schizophrenia and ESR-1 genotype predicts degree of increased neural activity in response to raloxifene. While these preliminary results require replication, they suggest the potential for personalized pharmacotherapy using ESR-1 and estrogen receptor targeting compounds in schizophrenia.
authors.affiliation: School of Psychiatry, University of New South Wales, Randwick, NSW 2031 Australia; Neuroscience Research Australia, Randwick, NSW 2031, Australia; University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, 3000 Bern 60, Switzerland.
authors.forename: Jochen
authors.initials: J
authors.lastname: Kindler
authors.affiliation: School of Psychiatry, University of New South Wales, Randwick, NSW 2031 Australia; Neuroscience Research Australia, Randwick, NSW 2031, Australia; Schizophrenia Research Institute, Randwick, NSW 2031 Australia.
authors.forename: Cynthia Shannon
authors.initials: CS
authors.lastname: Weickert
authors.affiliation: Neuroscience Research Australia, Randwick, NSW 2031, Australia; Schizophrenia Research Institute, Randwick, NSW 2031 Australia; School of Medical Sciences, University of New South Wales, Randwick, Australia.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Schofield
authors.affiliation: School of Psychiatry, University of New South Wales, Randwick, NSW 2031 Australia; Neuroscience Research Australia, Randwick, NSW 2031, Australia; Schizophrenia Research Institute, Randwick, NSW 2031 Australia.
authors.forename: Rhoshel
authors.initials: R
authors.lastname: Lenroot
authors.affiliation: School of Psychiatry, University of New South Wales, Randwick, NSW 2031 Australia; Neuroscience Research Australia, Randwick, NSW 2031, Australia; Schizophrenia Research Institute, Randwick, NSW 2031 Australia. Electronic address: t.weickert@unsw.edu.au.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Weickert
mesh_terms: D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004644:Emotions / Q000187:drug effects*; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007266:Inhibition, Psychological; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000187:drug effects*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D012559:Schizophrenia / Q000235:genetics*; D012565:Schizophrenic Psychology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride
keywords: Emotions; Estrogen receptor alpha; Inhibition; Magnetic resonance imaging; Raloxifene hydrochloride; Schizophrenia