Adjunctive selective estrogen receptor modulator increases neural activity in the hippocampus and inferior frontal gyrus during emotional face recognition in schizophrenia.

E Ji,A J Skilleter,C S Weickert,R Lenroot,A Vercammen,R E Gur,J Kindler,C White,T W Weickert

doi:10.1038/tp.2016.59

Abstract

Estrogen has been implicated in the development and course of schizophrenia with most evidence suggesting a neuroprotective effect. Treatment with raloxifene, a selective estrogen receptor modulator, can reduce symptom severity, improve cognition and normalize brain activity during learning in schizophrenia. People with schizophrenia are especially impaired in the identification of negative facial emotions. The present study was designed to determine the extent to which adjunctive raloxifene treatment would alter abnormal neural activity during angry facial emotion recognition in schizophrenia. Twenty people with schizophrenia (12 men, 8 women) participated in a 13-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment (120 mg per day orally) and performed a facial emotion recognition task during functional magnetic resonance imaging after each treatment phase. Two-sample t-tests in regions of interest selected a priori were performed to assess activation differences between raloxifene and placebo conditions during the recognition of angry faces. Adjunctive raloxifene significantly increased activation in the right hippocampus and left inferior frontal gyrus compared with the placebo condition (family-wise error, P<0.05). There was no significant difference in performance accuracy or reaction time between active and placebo conditions. To the best of our knowledge, this study provides the first evidence suggesting that adjunctive raloxifene treatment changes neural activity in brain regions associated with facial emotion recognition in schizophrenia. These findings support the hypothesis that estrogen plays a modifying role in schizophrenia and shows that adjunctive raloxifene treatment may reverse abnormal neural activity during facial emotion recognition, which is relevant to impaired social functioning in men and women with schizophrenia.

Highlights

Schizophrenia is a disabling psychiatric disorder, with a 70–80% unemployment rate,[1] associated with multifaceted deficits in cognitive function[2,3] and emotion processing.[4,5] antipsychotics are the first line of treatment for schizophrenia, these medications are often limited in their effectiveness and leave many patients with residual symptoms while producing unwanted side effects.[6]
The men and women with schizophrenia in this sample were chronically ill, treated primarily with secondgeneration antipsychotics, and displayed mild-to-moderate symptom severity based on Positive and Negative Syndrome Scale (PANSS) scores
The main aim of the present study was to determine the extent to which raloxifene would influence neural activity associated with recognition of faces with a negative valence in men and women with schizophrenia

Summary

Introduction

Schizophrenia is a disabling psychiatric disorder, with a 70–80% unemployment rate,[1] associated with multifaceted deficits in cognitive function[2,3] and emotion processing.[4,5] antipsychotics are the first line of treatment for schizophrenia, these medications are often limited in their effectiveness and leave many patients with residual symptoms while producing unwanted side effects.[6]. The onset of the disease typically occurs during adolescence[7] and the clinical presentation, response to treatment and symptom severity can differ between men and women.[8,9,10] Schizophrenia occurs less frequently and has a later average age of onset in women.[11,12]. Women tend to experience a less-severe course of the disease compared with men.[9] Studies have found lower estrogen levels in women with schizophrenia relative to healthy women, relapses are more frequent when estrogen levels are low, such as during the early follicular phase of the menstrual cycle, postpartum and after menopause when there is a second peak of illness onset and a more severe course of illness.[13,14,15,16,17,18] These findings support the estrogen hypothesis of schizophrenia that posits that estrogen may have a neuroprotective effect against the disease.[19]

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