Journal
EUROPEAN NEUROPSYCHOPHARMACOLOGY
Volume 26, Issue 12, Pages 1930-1940Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.euroneuro.2016.10.009
Keywords
Magnetic resonance imaging; Emotions; Inhibition; Raloxifene hydrochloride; Estrogen receptor alpha; Schizophrenia
Funding
- University of New South Wales School of Psychiatry
- National Health and Medical Research Council of Australia Project [568807]
- Neuroscience Research Australia
- Schizophrenia Research Institute (New South Wales Ministry of Health)
- Schizophrenia Research Institute (Macquarie Group)
- Australian Schizophrenia Research Bank - National Health and Medical Research Council of Australia
- Pratt Foundation
- Ramsay Health Care
- Viertal Charitable Foundation
- National Health and Medical Research Council (Australia) [1021970]
- Swiss National fund (SSMBS, Advanced Postdoc Mobility) [P3SMP3_148381]
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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-alpha), 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-a 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 120 mg/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. Crown Copyright (C) 2016 Published by Elsevier B.V.
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