The Use of Selective Estrogen Receptor Modulators in the Treatment of Schizophrenia- a Pilot Study
Condition: Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional
Phase: Phase 2

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.
    

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.
    

Intervention name(s): Raloxifene; Estradiol/dyhydroprogestrone
Intervention type(s): Drug; Drug
Intervention MeSH terms: Raloxifene Hydrochloride; Estradiol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Schizophrenia; Mental Illness; Hormone Therapy; Post-menopausal; SERM; Raloxifene