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

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by The Alfred
Sponsor:
Collaborators:
Stanley Medical Research Institute
National Health and Medical Research Council, Australia
Information provided by (Responsible Party):
Jayashri Kulkarni, Professor, The Alfred
ClinicalTrials.gov Identifier:
NCT00361543
First received: August 7, 2006
Last updated: January 13, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Schizophrenia
Schizoaffective Disorder
Schizophreniform Disorder
Drug: Raloxifene hydrochloride
Other: Lactose Capsules
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Selective Estrogen Receptor Modulators - A Potential Treatment for Psychotic Symptoms of Schizophrenia?

Resource links provided by NLM:


Further study details as provided by The Alfred:

Primary Outcome Measures:
  • PANSS score at trial completion (12 weeks) [ Time Frame: baseline, week 2,4,6,8,10,12 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • MADRS score at trial completion (12 weeks) [ Time Frame: baseline, week 2,4,6,8,10,12 ] [ Designated as safety issue: No ]
  • Cognitive Test scores at trial completion (12weeks) [ Time Frame: baseline and week 12 ] [ Designated as safety issue: No ]
  • Adverse Symptom Checklist score at trial completion (12 weeks) [ Time Frame: baseline, week 2,4,6,8,10,12 ] [ Designated as safety issue: No ]
  • Hormone level change over study duration (12 weeks) [ Time Frame: baseline, weeks 4, 8, 12 ] [ Designated as safety issue: No ]

Estimated Enrollment: 90
Study Start Date: August 2006
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
Raloxifene Hydrochloride
Drug: Raloxifene hydrochloride
120 mg per capsule (1 tablet daily)
Placebo Comparator: 2
placebo tablet
Other: Lactose Capsules
1 tablet daily for 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, 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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Physically well.
  • A current DSM-IV diagnosis of schizophrenia or related disorder.
  • 18- 70 years
  • Premenopausal (regular menstrual cycles and follicle stimulating hormone < 40 mIU/ml; for hysterectomised women, FSH< 40mIU/ml and estradiol> 120pmol/L)
  • Postmenopausal. The definition of postmenopausal is: more than 12 months post-amenorrhoea and FSH > 30.
  • 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 postmenopausal 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00361543

Contacts
Contact: Jayashri Kulkarni, MBBS, MPM, FRANZCP, PhD +61 3 9076 6564 ext 6564 J.Kulkarni@alfred.org.au
Contact: Anthony de Castella, DipAppSci, BA, MA +61 3 9076 6564 ext 6564 A.Decastella.@alfred.org.au

Locations
Australia, Victoria
Monash Alfred Psychiatry Research Centre Recruiting
Melbourne, Victoria, Australia, 3004
Contact: Jayashri Kulkarni, MBBS, MPM, FRANZCP, PhD    + 61 3 9076 6564 ext 6564    J.Kulkarni@alfred.org.au   
Contact: Anthony de Castella, DipAppSci, BA, MA    +61 3 9076 6564 ext 6564    A.Decastella@alfred.org.au   
Sub-Investigator: 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: Jasmin Grigg, PhD         
Sponsors and Collaborators
The Alfred
Stanley Medical Research Institute
National Health and Medical Research Council, Australia
Investigators
Principal Investigator: Jayashri Kulkarni, MBBS, MPM, FRANZCP, PhD Bayside Health, Alfred Hospital
  More Information

No publications provided

Responsible Party: Jayashri Kulkarni, Professor, Principal Investigator, The Alfred
ClinicalTrials.gov Identifier: NCT00361543     History of Changes
Other Study ID Numbers: APRC 94/06, 03T-422
Study First Received: August 7, 2006
Last Updated: January 13, 2014
Health Authority: Australia: Human Research Ethics Committee

Keywords provided by The Alfred:
Schizophrenia
Mental Illness
SERM
Raloxifene
Cognition

Additional relevant MeSH terms:
Schizophrenia
Disease
Psychotic Disorders
Schizophrenia and Disorders with Psychotic Features
Mental Disorders
Pathologic Processes
Estrogens
Raloxifene
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Estrogen Antagonists
Hormone Antagonists
Bone Density Conservation Agents

ClinicalTrials.gov processed this record on September 18, 2014