Clinical Estradiol Trial in Women With Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional
Phase: Phase 2

Summary: 
      To investigate the 'estrogen-protection' hypothesis by comparing changes in psychotic
      symptoms between one group of patients receiving standard antipsychotic drug treatment plus
      placebo and a second matched group receiving standard antipsychotic drug treatment plus
      100microgram estradiol patch in a double blind controlled trial.

      Hypothesis : That the women receiving adjunctive estradiol will demonstrate a more rapid and
      more substantial decrease in psychotic symptoms over the course of the study than the women
      receiving adjunctive placebo.
    

Detailed description: 
      BACKGROUND:

      Schizophrenia is a severe mental disorder that affects up to two percent of the adult
      population. Patients present with a variety of symptoms including hallucinations, delusions
      and bizarre behaviour while some develop additional "negative" symptoms such as amotivational
      states and poverty of thought. Schizophrenia is generally thought to be an organic brain
      disorder with psychosocial determinants for course and outcome. The illness appears to be
      heterogenous with groups of patients presenting with distinct and differing patterns of
      psychopathology and illness course. Part of this heterogeneity includes distinct male and
      female subtypes of schizophrenia.

      In recent times, gender differences in schizophrenia have received some attention, in
      particular from an epidemiological and psychopathological perspective. Hormonal studies have
      been utilised to investigate underlying neuroendocrine disturbances in schizophrenia, but
      information from these studies has not been used in the development of new gender specific
      treatment strategies. Overall the treatment of schizophrenia has remained gender-blind. The
      main gender differences observed in schizophrenia that have international consensus include
      the later age of onset in women, better response to neuroleptics in women, and more treatment
      resistant negative symptoms in men. Women have also demonstrated vulnerability to psychotic
      episodes during menopause, the post-partum period and at low estrogen phases of the menstrual
      cycle.

      From these clinical observations, Seeman and Lang hypothesised that estrogen may provide
      "protection" against early onset of severe schizophrenia in women, thereby accounting for
      increased vulnerability during both lifetime and monthly low estrogen phases. Findings from
      both basic and clinical research warrant further investigation of the hypothesis that
      estrogen has a protective effect in women not only over the female life cycle, but also over
      the menstrual cycle.

      We have been conducting clinical trials in patients with schizophrenia using estrogen as a
      treatment for many years, and have an international reputation for work in this area.
      Initially, we conducted an open clinical trial with acutely ill schizophrenic women and added
      0.02mg of oral estradiol to the antipsychotic drug treatment of 11 women. Their response was
      compared to seven women who received antipsychotic drugs alone. The estrogen adjunct group
      showed dramatic earlier improvement, with significant reduction in positive psychotic
      symptoms by day 3 of treatment. This suggests that estradiol may act as a catalyst for
      treatment and could prove to be an important adjunctive treatment in the therapy of
      schizophrenia. Subsequent to this early pilot study, we conducted a double blind placebo
      controlled 3-arm study of 100mcg, 50mcg estradiol and placebo transdermal adjunctive patches.
      Published in Schizophrenia Research(2001), our results showed that the 100mcg estradiol
      adjunct afforded the best outcomes.

      RESEARCH OBJECTIVES:

      To investigate the usefulness of estradiol as an adjunctive treatment in schizophrenia ,by
      comparing changes in psychopathology between one group of patients receiving standard
      antipsychotic drug treatment plus a placebo skin patch and a second matched group receiving
      standard antipsychotic drug treatment plus a 100mcg estradiol patch in a double blind, 28
      day, controlled trial.

      ETHICS REVIEW AND INFORMED CONSENT:

      The protocol for this study has been approved by the Alfred Ethics Committee.

      Only patients who are able to give informed consent, i.e. able to demonstrate an
      understanding of the objectives of the study and the implications of their role in it, will
      be recruited into the study. Patients who are extremely psychotic or disturbed will not be
      approached to enter the study. Involuntary patients who are able to give informed consent
      will be able to participate and where possible a guardian or relative will be contacted and
      notified of the patients' involvement. Patients will be advised that their participation is
      voluntary and that they are free to withdraw from the study at any stage.

      CONFIDENTIALITY:

      Patients' identity will remain anonymous at all times. Once a patient agrees to participate
      in the study, she will be assigned a code number to ensure anonymity. Information about the
      subject will be restricted to the researchers directly involved, unless there are clear
      management issues, in which case the information will be shared with the treatment team.
      Patients' files will be stored in locked filing cabinets with access available to researchers
      only. All test results will be shared with the patient and family / guardian.

      STUDY POPULATION:

      A target number of 100 patients will be recruited over a three-year period with equal numbers
      being allocated to each group. Patients will be recruited from both inpatient and outpatient
      settings and patients may be recruited from other centres providing that approval has been
      gained from the appropriate controlling bodies.

      INCLUSION CRITERIA:

      Female patients who have a current DSM 4 diagnosis of Schizophrenia, Schizoaffective or
      Schizophreniform Disorder.

      EXCLUSION CRITERIA:

        -  Female patients who are pregnant or lactating.

        -  Female patients with postpartum psychosis or related disorder

        -  Female patients with known abnormalities in the hypothalamo-pituitary gonadal-axis,
           thyroid dysfunction, central nervous system tumours.

        -  Female patients taking estrogen preparations such as the oral contraceptive pill.

        -  Female patients whose psychotic illness is directly due to illicit drugs or who have a
           history of substance abuse or dependence during the last 6 months.

      Females with any significant unstable medical illness such as cardiovascular disease, renal
      disease, Addisons disease, thromboembolic disorders, epilepsy, diabetes etc.

      - Post-menopausal or pre-menarche female patients.

      WITHDRAWAL CRITERIA:

      Patients are free to withdraw from the study at any stage without offering an explanation.

      Patients experiencing any adverse effects which, in the opinion of the investigator, are
      serious (i.e. life threatening, requiring hospitalisation or medical treatment) will be
      withdrawn from the study immediately. All patients withdrawn will be followed up until the
      adverse event has resolved.

      STUDY TREATMENTS CONCOMITANT TREATMENTS:

      All patients will participate in standard in-patient and outpatient psychosocial therapies
      and activities as advised by their treatment team. All patients will receive psychotropic and
      non-psychotropic medications as per their treatment teams orders. All medications received
      during the study will be recorded to be included in the analysis.

      STUDY MEDICATION:

      The study involves the addition of transdermal 100mcg estradiol (or transdermal placebo-
      inactive substance) to standard antipsychotic treatment for 4 weeks. The length of the trial
      is 1 menstrual cycle, which is a short period of estrogen use. Most side effects commonly
      associated with estrogen use are related to long term administration and are thus not
      applicable in this study.

      STUDY MEASUREMENTS:

      The PANSS (Kay et al. 1987) will be performed at screening/baseline and at each evaluation
      visit. The PANSS consists of a Positive Scale (7 positive symptom constructs), a Negative
      Scale (7 negative symptom constructs) and a General Psychopathology Scale (16 symptom
      constructs). This scale will be the primary outcome measure of the trial.

      In addition to the PANSS, the Adverse Symptom Checklist, Abnormal Involuntary Movement Scale,
      Simpson Angus Scale and serum hormone measurements will be completed at each visit. Cognitive
      testing will be performed monthly. Participants will be assessed at baseline, day 7, day 14,
      day 21 and day 28.

      DATA MANAGEMENT:

      All data gathered will be entered in the patients file under the patients code number. Files
      will be stored in the research unit in locked filing cabinets. Data entered on computer will
      be done so using the patients code number for identification. A separate booklet will be used
      to record data collected at screening, baseline, and evaluation visits. All files will be
      retained by the hospital for a period of 15 years after completion or discontinuation of the
      trial.
    

Intervention name(s): Estradiol
Intervention type(s): Drug
Intervention MeSH terms: Estradiol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Schizophrenia; Gender differences; Hormones; Estradiol; PANSS