Official Title: “Selective Estrogen Receptor Modulators - A Potential Treatment for Psychotic Symptoms of Schizophrenia?”

The aim of the project is to investigate the use of Raloxifene (a new form of estrogen) as a treatment for schizophrenia in postmenopausal women. Raloxifene is a Selective Estrogen Receptor Modulator (SERM), which means that it can affect the central nervous system (CNS) effects of estrogen (eg. improving emotional symptoms, memory, information processing and concentration), without adversely affecting reproductive tissue/organs such as breast, uterus and ovaries. We are conducting a double-blind, placebo controlled, three month study comparing the psychotic symptom response between two groups of postmenopausal women with schizophrenia. One group will receive standard antipsychotic medication plus 120mg Raloxifene, while the second group will receive standard antipsychotic medication plus oral placebo.

Hypothesis 1: That the women receiving adjunctive Raloxifene would have a quicker recovery from psychotic symptoms, as measured on the rating scales, compared with the women receiving adjunctive placebo.

Hypothesis 2: That the Raloxifene group would have better cognitive improvement than the placebo group.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Efficacy Study

Estrogen is hypothesised to be protective for women against early onset of severe symptoms of schizophrenia (Hafner, 1991; Seeman, 1992). This 'estrogen hypothesis' was derived from epidemiological, clinical and animal studies. Following the results of such studies, we conducted a study (Kulkarni et al 1996) in which a group of premenopausal women with schizophrenia were given 0.02mg oral estradiol as an adjunct to antipsychotic drug treatment for eight weeks, and compared their progress with a similar group who received antipsychotic drugs only. The group receiving estrogen made a significantly more rapid recovery from acute psychotic symptoms and also reported improvement in their general health status.

Subsequently, we conducted a four week double-blind, placebo-controlled study, using 100mcg estradiol skin patches. We found that the 12 premenopausal women who received the estradiol adjunct had a significantly lower total PANSS and BPRS score than 12 women who received placebo patches plus antipsychotic medication.

The major potential risks in using estrogen as a longer term adjunctive treatment in premenopausal women with schizophrenia appear to be the potential harmful effects of estrogen itself in its action on breast and uterine tissue. Our studies were brief for this reason, in that we used estrogen without progesterone over an eight week or four week period.

With the recent advent of Selective Estrogen Receptor Modulators, in particular Raloxifene Hydrochloride, there is the potential to harness the positive estrogenic effect on CNS neurotransmitter systems without affecting breast or uterine tissue. While the CNS effects of Raloxifene have not been fully studied, its actions are mediated through binding to estrogen receptors and can thereby regulate gene expression that is ligand, tissue or gene specific. By inference then, Raloxifene would be expected to impact on dopamine and serotonin pathways in a similar fashion to conjugated estrogen. A study (Nickleisen et al 1999) on the effect of Raloxifene on cognition in healthy, postmenopausal women found a slight increase in verbal memory performance after one month of high dose treatment, while no other differences were found after 12 months of treatment. There are no studies in women with cognitive impairment where a treatment effect would be more likely to be apparent. Similarly, there are no clinical studies to date investigating the effect of Raloxifene on psychotic symptoms.

To this end, we are putting forward an investigator initiated clinical trial proposal to investigate the effect of adjunctive Raloxifene on psychotic symptoms in women with schizophrenia. This is, therefore, a study to follow our Pilot Study in the same area, but with an increase of Raloxifene from 60mg to 120mg daily.

The aim of this project is to study the effect of Raloxifene as an adjunct to antipsychotic medication in postmenopausal women with schizophrenia as a means to developing a novel, safe adjunctive treatment for women with schizophrenia to improve their quality of life.

Intervention(s) in this Clinical Trial

• Drug: Raloxifene hydrochloride

Primary Measures

• PANSS score at trial completion (12 weeks)

Secondary Measures

• MADRS score at trial completion (12 weeks)
• Cognitive Test scores at trial completion (12weeks)
• Adverse Symptom Checklist score at trial completion (12 weeks)
• Hormone level change over study duration (12 weeks)

Inclusion Criteria:

• Female, 45 years and over
• Current diagnosis of DSM-IV Schizophrenia, Schizoaffective Disorder or Schizophreniform Disorder
• Symptom rating greater than 60 on the PANSS at baseline/screening
• Patient is able to give informed consent
• Patient post-menopausal (confirmed by Hormone Assay, Greene Climacteric Scale and Menstrual Cycle Interview)

Exclusion Criteria:

• Clinically significant concomitant medical or neurological condition or history of venous thromboembolic event
• High suicide/aggression risk in the opinion of the investigator
• If participant's illness is directly related to illicit substance abuse or has a history of substance abuse or dependence in the past six months
• Smoking more than 20 cigarettes per day
• Use of any form of hormones or hormone therapy
• Illness causing immobilisation
• Undiagnosed postmenopausal vaginal bleeding
• Consumption of more than 30gm of alcohol (three standard drinks) per day

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 45 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: The Alfred

Overall Clinical Trial Officials and Contacts

Jayashri Kulkarni, MBBS, MPM, FRANZCP, PhD Principal Investigator Bayside Health, Alfred Hospital  

Overall Contact: Jayashri Kulkarni, MBBS, MPM, FRANZCP, PhD +61 3 9276 6564 J.Kulkarni@alfred.org.au

Information obtained from ClinicalTrials.gov on October 07, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00361543

Study ID Number: APRC 94/06

ClinicalTrials.gov Identifier: NCT00361543

Health Authority: Australia: Human Research Ethics Committee