Selective Estrogen Receptor Modulators - A Potential Treatment for Psychotic Symptoms of Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional
Phase: Phase 4

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. 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.
    

Intervention name(s): Raloxifene hydrochloride; Lactose Capsules
Intervention type(s): Drug; Other
Intervention description(s): 120 mg per capsule (1 tablet daily); 1 tablet daily for 12 weeks
Intervention MeSH terms: Raloxifene Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Schizophrenia; Mental Illness; SERM; Raloxifene; Cognition