The Use of Selective Estrogen Receptor Modulators in the Treatment of Schizophrenia- a Pilot Study
Information source: The Alfred
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder
Intervention: Raloxifene (Drug); Estradiol/dyhydroprogestrone (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: The Alfred Official(s) and/or principal investigator(s):
Jayashri Kulkarni, MBBS, MPM, FRANZCP, PHD, Principal Investigator, Affiliation: Bayside Health; Alfred Hospital
Summary
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 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 3 month duration study
comparing the psychotic symptom response between three groups of postmenopausal women with
schizophrenia. One group will receive standard antipsychotic medication plus 60mg Raloxifene,
the second group receives standard antipsychotic medication plus Hormone Therapy(estradiol
2mg oral per day + dyhydroprogesterone 10mg oral per day) and the third group receives
standard antipsychotic medication plus oral placebo. Hypothesis 1: That the women receiving
adjunctive raloxifene or HT 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 other two groups.
Clinical Details
Official title: The Use of Selective Estrogen Receptor Modulators in the Treatment of Schizophrenia- a Pilot Study
Study design: Treatment, Randomized, Double-Blind, Active 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 (12 weeks) Adverse Symptom Checklist score at trial completion (12 weeks) Hormone level change over study period (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 8 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 have conducted a 4 week double blind, placebo controlled study using 100
microgram estradiol skin patch. We found that the 12 pre-menopausal 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. (Kulkarni et al 2000).
The major potential risks in using estrogen as a longer-term adjunctive treatment in
pre-menopausal 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 8 week or 4 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.
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 of developing a novel, safe
adjunctive treatment for women with schizophrenia to improve their quality of life.
Eligibility
Minimum age: 45 Years.
Maximum age: 70 Years.
Gender(s): Female.
Criteria:
Inclusion Criteria:
- Female aged over 45 years
- Current diagnosis of DSM-IV Schizophrenia, Schizoaffective or Schizophreniform
Disorder
- Symptom rating greater than 60 on the PANSS at baseline/screening
- Patient able to give informed consent
- Patient post menopausal (confirmed by hormone assay and Greene Climacteric Scale plus
Menstrual Cycle Questionnaire)
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 patient's psychotic illness is directly related to illicit substance abuse or has a
history of substance abuse or dependence in the past 6 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 (3 standard drinks)per day.
Locations and Contacts
Alfred Psychiatry Research Centre, Alfred Hospital, Melbourne, Victoria 3181, Australia
Additional Information
Starting date: October 2002
Ending date: April 2007
Last updated: April 20, 2007
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