Raloxifene Augmentation in Patients With a Schizophrenia Spectrum Disorder

Rationale: Patients with a schizophrenia spectrum disorder experience substantial impairments in multiple domains of everyday life, including the ability to maintain social relationships, sustain employment, and live independently. These problems often persist, even after successful treatment of psychosis. Currently, no consistent evidence exists for the efficacy of interventions to reduce cognitive and negative symptoms, while in fact these are the factors that determine functioning to a great extent. Premenopausal women with schizophrenia have less psychotic and negative symptoms, and better cognitive and social functioning, in comparison to men and older women. This has been related to protective effects of estrogens in the brain. Administering estrogens has positive effects on psychotic symptoms, but exerts long-term side effects, especially in men. Raloxifene is a selective estrogen receptor modulator, with a beneficial side effect profile in women and in men. It has been shown to be effective in reducing symptoms in postmenopausal women with schizophrenia. Recently, positive results were found in premenopausal women and in men. It is important to replicate these results in an independent sample and to investigate the effects of raloxifene on functioning. Hypotheses: Daily treatment with raloxifene 120 milligrams (mg) in addition to antipsychotic treatment improves cognition, reduces psychotic symptoms, increases social and personal functioning and reduces health care costs, as compared to placebo. Objective: The primary objective of this trial is to investigate the hypothesized beneficial effect of raloxifene as compared to placebo when given for twelve weeks in addition to antipsychotic medication to patients with a psychotic disorder. The investigators expect lower symptom severity as measured with the Positive And Negative Symptom Scale (PANSS) and improvements of cognitive functioning as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary objectives include reducement of negative symptoms as measured with the Brief Negative Symptom Scale (BNSS), improvement of Personal and Social Performance (using the PSP-scale), reduction of thought disorder symptoms measures with the Thought And Language Disorder-scale (TALD), reduction use of health care recourses using the institute for Medical Technology Assessment's Medical Consumption Questionnaire (iMTA-MCQ), productivity using the institute for Medical Technology Assessment's Productivity Cost Questionnaire (iMTA-PCQ), improvement of quality of life using the EuroQol-5 dimensions scale (EQ-5D), improvement in both speed and error rates in the Stroop test, reduction of comorbid depression using Beck's Depression Inventory (BDI), improvement of language production and various hormonal and inflammatory parameters. Study design: Randomized placebo-controlled multicenter double-blind trial Study population: 110 men and women diagnosed with schizophrenia, schizoaffective or schizophreniform disorder, or psychotic disorder not otherwise specified (DSM-IV 295.\*) Intervention: Patients will be randomized 1:1 to either 120mg raloxifene or placebo daily for a period of 12 weeks. Identical tablets will be administered. Main study parameters/endpoints: Primary outcomes are changes in symptom severity as measured with PANSS and changes in cognition as measured with BACS. Secondary outcome are changes in negative symptoms (measured with BNSS), changes in personal and social performance (measured with PSP), change in severity of thought disorder (measured with TALD), quality of life (measured with EQ-5D), use of healthcare and non-healthcare resources, comorbid depression (measured with BDI), cognitive control (measured with a Stroop Test), language production (measured by analyzing speech samples) and hormonal and inflammatory biomarkers. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Use of raloxifene is associated with a small risk of side effects. The number of patient visits will be limited and mainly requires time invested for physical examinations, questionnaires and cognitive testing sessions (around 9 hours in total over the course of 9 months). Blood will be drawn at three occasions with negligible and known risks (e.g. irritation). The burden and risks are acceptable while the benefits are expected to be considerable.