Selective Estrogen Receptor Modulators - A Potential Treatment for Psychotic Symptoms of Schizophrenia

Condition(s) targeted: Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder

Intervention: Raloxifene hydrochloride (Drug); Gelatine Capsules (Other)

Phase: Phase 4

Status: Recruiting

Sponsored by: The Alfred

Official(s) and/or principal investigator(s):
Jayashri Kulkarni, MBBS, MPM, FRANZCP, PhD, Principal Investigator, Affiliation: Bayside Health, Alfred Hospital

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

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.

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

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

Primary outcome: PANSS score at trial completion (12 weeks)

Secondary outcome:

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)

Detailed description: 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.

Minimum age: 45 Years. Maximum age: 70 Years. Gender(s): Female.

Criteria:

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

Jayashri Kulkarni, MBBS, MPM, FRANZCP, PhD, Phone: +61 3 9276 6564, Ext: 6564, Email: J.Kulkarni@alfred.org.au

Alfred Psychiatry Research Centre, Melbourne, Victoria 3004, Australia; Recruiting
Jayashri Kulkarni, MBBS, MPM, FRANZCP, PhD, Phone: + 61 3 9276 6564, Ext: 6564, Email: J.Kulkarni@alfred.org.au
Anthony de Castella, DipAppSci, BA, MA, Phone: +61 3 9276 6564, Ext: 6564, Email: A.Decastella@alfred.org.au
Paul Fitzgerald, MBBS, MPM, FRANZCP, PhD, Sub-Investigator
Anthony de Castella, DipAppSci, BA, MA, Sub-Investigator
Susan Davis, MBBS, FRANZCP, PhD, Sub-Investigator
Emorfia Gavrilidis, BAAppScience, Sub-Investigator
Heather Gilbert, RN Division 1/Research Nurse, Sub-Investigator

Starting date: August 2006
Ending date: January 2011
Last updated: February 4, 2009