SchizophreniaPhase 4SERMNCT00361543
Selective Estrogen Receptor Modulators - A Potential Treatment for Psychotic Symptoms of Schizophrenia
A Phase 4 study testing Raloxifene hydrochloride and Lactose Capsules in people with Schizophrenia and Schizoaffective Disorder, run by The Alfred at 1 site in Australia.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 45 to 70 years, women only
- Conditions the study is for
- Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder
- What is being tested?
- Raloxifene hydrochloride and Lactose Capsules
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 54 participants
- Where
- 1 siteAustralia
- Study dates
- Aug 2006to Dec 2014
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 45 to 70 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
Australia1 site
Monash Alfred Psychiatry Research Centre
Melbourne, Victoria, 3004
About this study
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) 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.
Read the 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.
- Being tested
- Raloxifene hydrochloride, Lactose Capsules
- Keywords
- Schizophrenia, Mental Illness, SERM, Raloxifene, Cognition
- Medical subject headings
- Schizophrenia, Psychotic Disorders, Mental Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Raloxifene hydrochlorideDrug
120 mg per capsule (1 tablet daily)
Lactose CapsulesOther
1 tablet daily for 12 weeks
| Study group | Role | What they receive |
|---|---|---|
| 1 | Active comparator | Raloxifene Hydrochloride Receives: Drug: Raloxifene hydrochloride |
| 2 | Placebo comparator | placebo tablet Receives: Other: Lactose Capsules |
What is being measured
The primary outcome is the main question the study is designed to answer.
PANSS score at trial completion (12 weeks)
Measured: baseline, week 2,4,6,8,10,12
Secondary outcomes (4)
MADRS score at trial completion (12 weeks)
Measured: baseline, week 2,4,6,8,10,12
Cognitive Test scores at trial completion (12weeks)
Measured: baseline and week 12
Adverse Symptom Checklist score at trial completion (12 weeks)
Measured: baseline, week 2,4,6,8,10,12
Hormone level change over study duration (12 weeks)
Measured: baseline, weeks 4, 8, 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Aug 2006 (estimated)
- Study startAug 2006
- Primary completionDec 2014
- Study completionDec 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 54 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Alfred
- Sponsor type
- University, hospital or other
- Collaborators
- Stanley Medical Research Institute, National Health and Medical Research Council, Australia
- Responsible party
- Principal investigator, Jayashri Kulkarni, Professor, The Alfred
- Investigators
- Jayashri Kulkarni, MBBS, MPM, FRANZCP, PhD, Principal investigator, Bayside Health, Alfred Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00361543
- Sponsor's protocol ID
- MAPrc 94/06
- Other IDs
- 03T-422
- Acronym
- SERM
- Status last verified
- Jan 2015
- First submitted
- 7 Aug 2006
- Last updated
- 30 Jan 2015
- Results posted
- No
Publications
Thomas N, Gurvich C, Hudaib AR, Gavrilidis E, Kulkarni J. Dissecting the syndrome of schizophrenia: Associations between symptomatology and hormone levels in women with schizophrenia. Psychiatry Res. 2019 Oct;280:112510. doi: 10.1016/j.psychres.2019.112510. Epub 2019 Aug 8.
PubMed 31415936Kulkarni J, Gavrilidis E, Gwini SM, Worsley R, Grigg J, Warren A, Gurvich C, Gilbert H, Berk M, Davis SR. Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial. JAMA Psychiatry. 2016 Sep 1;73(9):947-54. doi: 10.1001/jamapsychiatry.2016.1383.
PubMed 27438995
Study at a glance
From the registry record, last updated by the sponsor on 30 Jan 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Selective Estrogen Receptor Modulators - A Potential Treatment for Psychotic Symptoms of Schizophrenia?
- ClinicalTrials.gov ID
- NCT00361543
- Acronym / sponsor ID
- SERM / MAPrc 94/06
- Keywords
- Schizophrenia, Mental Illness, SERM, Raloxifene, Cognition
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 54 participants (actual)
- Lead sponsor
- The AlfredUniversity, hospital or other
- Collaborators
- Stanley Medical Research Institute, National Health and Medical Research Council, Australia
- Study start
- Aug 2006
- Primary completion
- Dec 2014 (actual)
- Study completion
- Dec 2014 (actual)
- First posted
- 8 Aug 2006 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Active comparator | Drug: Raloxifene hydrochlorideRaloxifene Hydrochloride |
| 2 | Placebo comparator | Other: Lactose Capsulesplacebo tablet |
Who may qualify
- Ages
- 45 to 70 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Raloxifene hydrochloride120 mg per capsule (1 tablet daily) | Drug | 1 |
| Lactose Capsules1 tablet daily for 12 weeks | Other | 2 |
Primary outcome
PANSS score at trial completion (12 weeks)
Time frame: baseline, week 2,4,6,8,10,12
4 secondary outcomes
MADRS score at trial completion (12 weeks)
Time frame: baseline, week 2,4,6,8,10,12
Cognitive Test scores at trial completion (12weeks)
Time frame: baseline and week 12
Adverse Symptom Checklist score at trial completion (12 weeks)
Time frame: baseline, week 2,4,6,8,10,12
Hormone level change over study duration (12 weeks)
Time frame: baseline, weeks 4, 8, 12
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jan 2015.
- Derived from this study: PubMed 31415936Thomas N, Gurvich C, Hudaib AR, Gavrilidis E, Kulkarni J. Dissecting the syndrome of schizophrenia: Associations between symptomatology and hormone levels in women with schizophrenia. Psychiatry Res. 2019 Oct;280:112510. doi: 10.1016/j.psychres.2019.112510. Epub 2019 Aug 8.
- Derived from this study: PubMed 27438995Kulkarni J, Gavrilidis E, Gwini SM, Worsley R, Grigg J, Warren A, Gurvich C, Gilbert H, Berk M, Davis SR. Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial. JAMA Psychiatry. 2016 Sep 1;73(9):947-54. doi: 10.1001/jamapsychiatry.2016.1383.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jayashri Kulkarni, MBBS, MPM, FRANZCP, PhD principal investigator
Bayside Health, Alfred Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Raloxifene hydrochloride and Lactose Capsules in people with Schizophrenia and Schizoaffective Disorder, run by The Alfred at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Jan 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
PANSS score at trial completion (12 weeks) (time frame: baseline, week 2,4,6,8,10,12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00361543, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jan 2015.