Raloxifene augmentation in men and women with a schizophrenia spectrum disorder: A study protocol

Abstract

Although acute psychotic symptoms are often reduced by antipsychotic treatment, many patients with schizophrenia are impaired in daily functioning due to the persistence of negative and cognitive symptoms. Raloxifene, a Selective Estrogen Receptor Modulator (SERM) has been shown to be an effective adjunctive treatment in schizophrenia. Yet, there is a paucity in evidence for raloxifene efficacy in men and premenopausal women. We report the design of a study that aims to replicate earlier findings concerning the efficacy of raloxifene augmentation in reducing persisting symptoms and cognitive impairment in postmenopausal women, and to extend these findings to a male and peri/premenopausal population of patients with schizophrenia. The study is a multisite, placebo-controlled, double-blind, randomised clinical trial in approximately 110 adult men and women with schizophrenia. Participants are randomised 1:1 to adjunctive raloxifene 120 mg or placebo daily during 12 weeks. The treatment phase includes measurements at three time points (week 0, 6 and 12), followed by a follow-up period of two years. The primary outcome measure is change in symptom severity, as measured with the Positive and Negative Syndrome Scale (PANSS), and cognition, as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcome measures include social functioning and quality of life. Genetic, hormonal and inflammatory biomarkers are measured to assess potential associations with treatment effects. If it becomes apparent that raloxifene reduces psychotic symptoms and/or improves cognition, social functioning and/or quality of life as compared to placebo, implementation of raloxifene in clinical psychiatric practice can be considered.

Keywords: AE, Adverse event; AF, alkaline phosphatase; ALAT, alanine aminotransferase; ANOVA, analysis of variance; ANSS, positive and negative syndrome scale; APTT, activated partial thrombin time; ASAT, aspartate aminotransferase; Antipsychotic medication; BACS, Brief Assessment of Cognition in Schizophrenia; BDI, Beck's Depression Inventory; BNSS, Brief Negative Symptom scale; CRP, C-reactive protein; DHEA, dehydroepiandrosterone; DNA, Deoxyribonucleic acid; DSMB, Data Safety Monitoring Board; EQ-5D-5L, Euro Quality of Life 5 Dimensions 5 Levels; Estrogen; FSH, follicle stimulating hormone; GGZ Centraal, Psychiatric Center Geestelijke Gezondheidszorg Centraal; GGzE, Geestelijke Gezondheidszorg Eindhoven; HDL, high-density lipoprotein; ICH-GCP, the International Conference on Harmonization – Good Clinical Practice; IMCJE, International Committee of Medical Journal Editors; LDL, low-density lipoprotein; LHT, lithium heparin tube; MINI, Mini International Neuropsychiatric Interview Plus; PSP, Personal and Social Performance; QALYs, Quality Adjusted Life Years; Raloxifene; Randomised controlled trial; RvA, Reinier van Arkel Institute for Mental Health Care; SAE, Serious Adverse Event; SCT, sodium citrate tube; SERM, selective estrogen receptor modulator; SHBG, sex hormone-binding globulin; SMD, standard mean difference; SST, serum separator tube; SUSAR, Suspected Unexpected Serious Adverse Reaction; Schizophrenia; TALD, Thought And Language Disorder scale; ULN, upper limit of normal; UMCG, University Medical Center Groningen; UMCU, University Medical Center Utrecht; WOCBP, Women of child bearing potential; ZNA, Ziekenhuis Netwerk Antwerpen; eGFR, estimated glomerular filtration rate; iMTA-MCQ, institute for Medical Technology Assessment's Medical Consumption Questionnaire; iMTA-PCQ, institute for Medical Technology Assessment's Productivity Cost Questionnaire; psychotic disorder NOS, psychotic disorder not otherwise specified; β-HCG, beta-human chorionic gonadotropin.