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

January 28, 2015 updated by: Jayashri Kulkarni, Professor, The Alfred

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) in the treatment of women with schizophrenia and schizoaffective disorder. 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. The investigators are conducting a double-blind, placebo controlled, three month study comparing the psychotic symptom response of women with schizophrenia in both groups. 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 Overview

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, the investigators 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, the investigators conducted a four week double-blind, placebo-controlled study, using 100mcg estradiol skin patches. The investigators 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 the investigators 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, the investigators 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 women with schizophrenia as a means to developing a novel, safe adjunctive treatment for women with schizophrenia to improve their quality of life.

Study Type

Interventional

Enrollment (Actual)

54

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Victoria
      • Melbourne, Victoria, Australia, 3004
        • Monash Alfred Psychiatry Research Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years to 70 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Physically well.
  • A current DSM-IV diagnosis of schizophrenia or related disorder.
  • 45-70 years
  • Able to give informed consent.
  • PANSS total score > 60 (1 - 7 scale) and a score of 4 (moderate) or more on two or more of the following PANSS items: delusions, hallucinatory behaviour, conceptual disorganization or suspiciousness.
  • No abnormality observed during physical breast examination.
  • Documented normal PAP smear and pelvic examination in the preceding two years.

Exclusion Criteria:

  • Patients with known abnormalities in the hypothalamo-pituitary gonadal axis, thyroid dysfunction, central nervous system tumours, active or past history of a venous thromboembolic event, or undiagnosed vaginal bleeding.
  • Patients with any significant unstable medical illness such as epilepsy and diabetes or known active cardiac, renal or liver disease; presence of illness causing immobilisation.
  • Patients whose psychotic illness is directly related to illicit substance use or who have a history of substance abuse or dependence during the last six months, or consumption of more than 30gm of alcohol (three standard drinks) per day.
  • Smoking more than 20 cigarettes per day.
  • Use of any form of estrogen, progestin or androgen as hormonal therapy, or antiandrogen including tibolone or use of phytoestrogen supplements as powder or tablet.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: 1
Raloxifene Hydrochloride
120 mg per capsule (1 tablet daily)
PLACEBO_COMPARATOR: 2
placebo tablet
1 tablet daily for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
PANSS score at trial completion (12 weeks)
Time Frame: baseline, week 2,4,6,8,10,12
baseline, week 2,4,6,8,10,12

Secondary Outcome Measures

Outcome Measure
Time Frame
MADRS score at trial completion (12 weeks)
Time Frame: baseline, week 2,4,6,8,10,12
baseline, week 2,4,6,8,10,12
Cognitive Test scores at trial completion (12weeks)
Time Frame: baseline and week 12
baseline and week 12
Adverse Symptom Checklist score at trial completion (12 weeks)
Time Frame: baseline, week 2,4,6,8,10,12
baseline, week 2,4,6,8,10,12
Hormone level change over study duration (12 weeks)
Time Frame: baseline, weeks 4, 8, 12
baseline, weeks 4, 8, 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2006

Primary Completion (ACTUAL)

December 1, 2014

Study Completion (ACTUAL)

December 1, 2014

Study Registration Dates

First Submitted

August 7, 2006

First Submitted That Met QC Criteria

August 7, 2006

First Posted (ESTIMATE)

August 8, 2006

Study Record Updates

Last Update Posted (ESTIMATE)

January 30, 2015

Last Update Submitted That Met QC Criteria

January 28, 2015

Last Verified

January 1, 2015

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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