A Definitive Estrogen Patch Study (ADEPT)
Condition: Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder(Not in Manic Phase)
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional
Phase: Phase 2

Summary: 
      OBJECTIVE:

      To test the use of adjunctive estrogen in a 8 week, three-arm, double-blind,
      placebo-controlled study in the treatment of psychotic symptoms in women with schizophrenia.

      HYPOTHESIS:

      That women receiving adjunctive estrogen will demonstrate significantly greater improvements
      in the symptoms of schizophrenia than women receiving adjunctive placebo.

      STUDY POPULATION:

      180 women will be recruited over a three-year period across three sites. Participant will be
      of potential child-bearing age (Pre-menopausal and Post-menarche) with a current diagnosis of
      Schizophrenia, Schizophreniform Disorder, or Schizoaffective Disorder (not in manic
      phase)according to the Mini International Neuropsychiatric Interview (MINI).

      STUDY MEDICATION:

      Estradiol. One third of the participants (n=60) will be randomised to receive adjunctive
      100mcg Estradiol; one third of the participants (n=60) will be randomised to receive
      adjunctive 200mcg Estradiol n=60; and, one third of the participants (n=60) will be
      randomised to receive adjunctive placebo n=60). All patches will be covered with identical
      adhesive contact to ensure the "blind" is maintained.

      STUDY EVALUATIONS:

      Data will be collected over a two-month period for each participant. Visits will be performed
      at baseline, and then at weekly or fortnightly intervals. A total of six visits will be
      completed for each participant. The following evaluations will be performed:

      i) Inclusion/exclusion checklist. (Baseline visit only)

      ii) Informed consent. (Baseline visit only)

      iii)psychiatric evaluation to determine diagnosis. (Baseline visit only)

      iv) General clinical evaluation including medical history, current conditions and a
      non-invasive physical examination, body weight, vital signs. (Baseline and endpoint visits)

      v) Medication history. (Baseline and evaluation visits)

      vi) Demographics. (Baseline visits only)

      vii) The primary outcome measures will be the Positive and Negative Syndrome Scale (PANSS),
      which will be taken at weeks 1, 2, 4 and 8 of the trial. Cognitive testing will take place at
      baseline and 8 weeks. Side effects will be assessed at weeks 1, 2, 4, 6, and 8 to measure
      changes in subject's reported side effects during the trial.

      viii) Laboratory tests including; Serum levels of mood stabiliser, LH, FSH, Estrogen,
      Progesterone, Prolactin, DHEA,Testosterone and(Baseline and evaluation visits).
    

Detailed description: 
      This research protocol outlines a multi-site clinical trial of adjunctive estradiol in women
      with Schizophrenia. We propose to recruit 180 women into this study from 3 Australian sites -
      The Alfred Hospital, Barwon Health, and Dandenong Hospital.

      1.1 Literature Review

      Schizophrenia is a severe mental disorder that affects up to 2% 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 antipsychotics 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 (1990) 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. Seeman and
      Lang (1990) further hypothesised that estrogen may provide protection against early onset of
      severe treatment resistant schizophrenia through an anti-dopaminergic effect by modulating
      the sensitivity of the dopamine receptor thereby potentiating the effect of antipsychotics.

      Evidence for estrogen having a modulating effect on dopaminergic systems comes from studies
      in rats in which estrogens can enhance antipsychotic-induced cataplexy (Behrens et al. 1992;
      Fields et al 1982) and reduce amphetamine and apomorphine-induced behaviour such as
      stereotypies (Ferretti et al., 1992; Clopton et al., 1986). In humans, the presence of
      estrogen receptors in the limbic system indicates that estrogens may have a neuromodulatory
      function (Foreman, et al., 1980; Koller, et al., 1980; Gordon et al., 1980). Estrogens have
      been shown to reduce the dopamine concentration in the striatum (Dupond et al., 1981; Bedard
      et al., 1984) and modulate the sensitivity as well as the number of dopamine receptors (Di
      Paolo, et al., 1981; McDermott, et al., 1994). There are clinical case reports of women whose
      schizophrenic symptomatology is exacerbated at low estrogen phases of the menstrual cycle
      (Endo et al., 1978). Similarly there are clinical case reports of women with chronic
      schizophrenia improving during pregnancy - when estrogen levels are extremely high (Seeman,
      1986). After delivery, when estrogen levels drop, increased vulnerability to psychosis is
      observed (Seeman, 1996). A recent study investigating the relationship between schizophrenia
      psychopathology and low estrogen phases of the menstrual cycle revealed that symptoms
      improved when natural estradiol levels increased (Riecher-Rossler et al., 1994). This study
      also showed that all 32 patients studied had markedly reduced serum estradiol levels compared
      with the normal population and that fluctuations throughout the cycle were dampened.

      1.2 Justification for Project

      The findings from both basic and clinical research reviewed in section 1.1 above 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. Case reports have
      appeared in the literature in which clinicians detail improvement in one or two female
      patients following administration of synthetic combined estrogen and progesterone. A study
      conducted by Klaiber and colleagues' (1979) reported that large doses of estrogen assisted in
      the treatment of depression in women. 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 (Kulkarni et al., 1996) 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
      (Kulkarni et al., 2003), our results showed that the 100mcg estrogen adjunct afforded the
      best outcomes. We then conducted a "proof of concept" study to examine the effect of adding
      100mcg transdermal estrogen versus transdermal placebo to antipsychotic drug treatment in 90
      women with schizophrenia. For the results of this 'proof of concept' study please refer to
      Appendix G.

      1.3 Review of Estradiol and its Uses

      Estrogen is one of a group of hormonal steroid compounds that promote the development of
      female secondary sex characteristics. Human estrogen is produced by the ovaries, adrenal
      cortices, testes, and feto-placental unit. Along with progesterone, estrogen plays a major
      role in the regulation of the menstrual cycle and is regulated by levels of Luteinizing
      Hormone (LH) and Follicle Stimulating Hormone (FSH) released from the anterior pituitary
      gland in the brain. These two gonadotropin hormones are in turn regulated by the actions of
      the hypothalamus. Pharmaceutical preparations of estrogen are used in oral contraceptives, to
      palliate post-menopausal breast cancer and prostatic cancer, to inhibit lactation, and to
      treat threatened abortion, osteoporosis and ovarian disease. Estrogen is also given to
      relieve the discomforts of menopause. Types of estrogen are conjugated estrogen, esterified
      estrogen, estradiol, estriol and estrone (Mosby, 1986). Delivery of estrogen by transdermal
      patches provides more natural and physiologically equivalent replacement of estradiol levels.

      2. RESEARCH OBJECTIVES

      To conduct a three-arm, double-blind, randomized, placebo-controlled, trial across three
      sites, to investigate the 'estrogen-protection' hypothesis in women with schizophrenia. The
      study aims to:

        1. replicate previous research, thereby providing 'proof of concept' for the potential use
           of estradiol as a treatment in women with schizophrenia;

        2. investigate the effect of an increased dose of estradiol (200mcg transdermal);

        3. investigate the duration of the "antipsychotic effect" of estradiol

           The aims will be met by comparing changes in psychopathology and cognition over an
           8-week period between three groups of participants: (1) a group of participants
           receiving standard antipsychotic treatment and a placebo; (2) a matched group receiving
           standard antipsychotic treatment plus 100mcg estradiol patches; and (3) a matched group
           receiving standard antipsychotic treatment plus 200mcg estradiol patches.

           3. ETHICS REVIEW AND INFORMED CONSENT

           3.1 Ethics Review

           The protocol for this study was approved by the Alfred Research & Ethics Committee on
           6th January 2005, at the Barwon site on 01/03/2006, and at the Dandenong site on
           12/05/2006.

           3.2 Issues Related to the Use of Estradiol Skin Patches

           The study involves the addition of 100mcg/200mcg estradiol to standard antipsychotic
           treatment for 8 weeks. This dose of estradiol is commonly used in hormone replacement
           therapy for postmenopausal women, without side effects. The length of the trial is 2
           menstrual cycles, 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. Basic medical precautions will be taken prior to the
           commencement of estrogen therapy (ie. physical examination, routine investigations and
           pregnancy testing). In our large study of 90 women 100mcg transdermal estradiol was used
           and the treatment was well tolerated. Subjects will be counselled with regard to the
           lack of contraceptive effect of using estradiol patches.

           3.3 Use of a Placebo

           All subjects will be informed that there is a two-in-three chance that they will receive
           estradiol patches and a one-in-three chance they will receive placebo patches. As well
           as the study medication, all subjects will receive standard antipsychotic medication and
           thus will not be disadvantaged in any way by placement in the "placebo" group. Subjects
           who are entered into the trial will be on a relatively stable treatment regime having
           had no change of medication in the prior 30 days and there will be no future change in
           medication anticipated. By controlling this variable, we are able to create a 'true
           placebo' group as there should be no modification of antipsychotic medication over the
           trial period that could potentially affect the psychopathology results. Both subjects
           and researchers will be unaware of which group a subject is in. However, if the need
           arises researchers will be able to break the code to reveal the group to which the
           subject belongs. Subjects allocated to the placebo group will be offered open-label
           adjunctive treatment with 200mcg estradiol for two months proceeding the trial, thereby
           ensuring all participants receive the potential benefits of adjunctive estradiol.

           3.4 Standard Antipsychotic Treatment

           As the proposed study is an adjunctive trial, all participants will continue to receive
           standard antipsychotic treatment whilst in the trial. Antipsychotic medication will be
           measured in "risperidone equivalents", which involves converting the dose of their
           current antipsychotic treatment to its equivalent dose of risperidone. To be included in
           the trial participants must meet the following criteria: 2-10mg daily "risperidone
           equivalents" for at least 4 weeks with residual symptoms as defined by a PANSS positive
           score greater than 15 and/or a PANSS negative score greater than 15.

           3.5 Informed Consent

           Only participants 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. 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. Participants will be advised that
           their participation is voluntary and that they are free to withdraw from the study at
           any stage.

           3.6 Confidentiality

           Participants' identity will remain anonymous at all times. Once a participant 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. Participants' files will be stored in locked filing cabinets
           with access only available to researchers on the project. All test results will be
           shared with the participant and their family / guardian.

           4. METHOD

           4.1 Participants

           A target number of 180 participants (60 from The Alfred, 60 from Barwon and 60 from
           Dandenong) will be recruited over a three-year period with equal numbers being allocated
           to each group (100mcg Estradiol n=60; 200mcg Estradiol n=60; Placebo n=60). Participants
           will be recruited from both inpatient and outpatient settings and participants may be
           recruited from other centres providing that approval has been gained from the
           appropriate controlling bodies. The total number of subjects will allow results to be
           analysed by subgroups based on factors such as menstrual cycle phase.

           4.2 Materials

             -  demographic information

             -  diagnosis according to the Mini International Neuropsychiatric Interview (MINI) -
                modules L (psychotic disorders) and D (mania/hypomania )

             -  inclusion/exclusion criteria check

             -  medical history & non-invasive general physical examination

             -  Laboratory tests to determine pregnancy status, menstrual cycle phase and
                neuroendocrine status

             -  Breast scan (mammogram; at Alfred and Dandenong sites) or breast screens
                (ultrasounds; at Barwon site) to check for breast abnormalities in participants to
                be conducted when informed consent is provided

             -  hormone measurements of estrogen, progesterone, prolactin, testosterone, LH, FSH
                and DHEA

             -  A menstrual cycle questionnaire (MCQ) to gain a menstrual history

             -  Assessment of psychopathology (PANSS & MADRS) and cognitive function (RBANS)

           Hormone assays will be repeated at weeks 4 and 8. A menstrual calendar will be used to
           record the onset and cessation of menses during the trial. The primary outcome measures
           will be the Positive and Negative Syndrome Scale (PANSS), which will be taken at weeks
           1, 2, 4 and 8 of the trial. Cognitive testing will take place at baseline and 8 weeks.
           Side effects will be assessed at weeks 1, 2, 4, 6, and 8 to measure changes in subject's
           reported side effects during the trial.

           4.3 Procedures

           Participants will be screened as soon after identification as possible to assess
           eligibility for entry into the study. The diagnostic instrument to be used will be the
           Mini International Neuropsychiatric Interview (MINI). The details of the project and
           requirements of participation will be explained to eligible participants and a Plain
           Language Statement provided. If a potential participant is identified to be a current
           client of The Alfred Psychiatric Service, Southern Health (Dandenong site) or Barwon
           Health (Barwon site), the researcher will contact a member of the individual's treating
           team to discuss the suitability of approaching the client and to gain an indication of
           the person's ability to give informed consent. A member of the treating team will then
           approach the potential participant and ask if they are willing to talk to the researcher
           about the study. This discussion will involve providing a detailed verbal explanation of
           the study and the written Participant Information and Consent Form (PI&CF) as approved
           by the applicable Human Research Ethics Committee. The potential participant will be
           asked to read through the PI&CF or have it read to them by the researcher. The potential
           participant will be encouraged to discuss the PI&CF and the possibility of participating
           in this study with a significant other or support person.

           Once the potential participant has read the PI&CF the researcher will have another
           discussion with this person, preferably in the presence of a witness. The researcher
           will ask the potential participant to provide a verbal explanation about what they think
           the study is about and what is involved in their participation. The researcher may draw
           attention to particular parts of the PI&CF to ensure that the potential participant is
           fully aware of all aspects involved. The potential participant will be asked if he/she
           has any questions about the study, which will be answered by the researcher. At this
           point, if the researcher believes that the potential participant understands the
           information provided to them about the study, and has had the opportunity to ask
           questions and have them answered, then the consent form can be signed. The consent form
           will be signed and dated by the project participant, by the researcher who explained the
           project to the participant, and by a witness.

           Participants who provide informed, written consent will undergo a full psychiatric and
           medical history and will receive a non-invasive physical examination as well as a breast
           scan or screen (dependant on site specific regulatory advice). Baseline hormone levels
           will be measured via a blood test, and a menstrual cycle questionnaire will be
           administered to determine menstrual status. Baseline psychopathology rating scales
           (PANSS) will then be administered. After a participant has been deemed eligible to enter
           the trial and baseline measurements have been performed, the participant may be
           randomised to one of three groups for the duration of the eight-week double blind phase.
           The three groups are: (1) 100mcg estradiol patches, (2) 200mcg estradiol patches, and
           (3) placebo patches.

           Upon entry into the double-blind phase, each participant will be allocated an
           identification number and will be randomly assigned to a treatment regimen as generated
           by The Alfred Clinical Trials Pharmacy, who will be aware of which treatment group the
           participant is allocated to but will not be directly involved in the trial. The Clinical
           Trials Pharmacy coordinator will not disclose the randomisation codes to any of the
           investigators or data collectors involved with the project.

           Day one of the trial will be the first day that the participant receives the study
           medication. Study medication is dispensed via the pharmacy department at each site.
           Baseline measurements must be taken the day before the first day of the trial, and thus
           baseline is considered to be Day 0. Evaluation of adverse events and medication
           compliance will be performed at regular intervals for the duration of the trial.
           Psychopathology rating scales will be completed at baseline and weeks 1, 2, 4 and 8.
           Hormone assays will be completed at baseline and weeks 4 and 8. Cognitive assessment
           will be completed at baseline and at week 8. The week 8 visit must fall on the last day
           of the trial medication.

           4.4 Clinical Follow-up

           For ethical reasons, upon completion of the active phase of the trial each participant
           will be "unblinded" and made aware of which treatment they had received. Participants
           who were receiving placebo will be offered an "open label" trial of the 200mg estradiol
           patches. This is so that no one is disadvantaged by their participation in the trial and
           are all able to take the active medication if they so wish. Participants who opt to have
           an "open label" trial of the estradiol patches will be monitored for side effects for a
           further 8 weeks whilst they are using the patches. This data will not be included in the
           research trial database.

           All participants will be followed up for 3 months following the completion of the active
           phase of the trial (including the open-label treatment). This follow-up will consist of
           monthly telephone contact to check participant's progress as well as determine the
           duration of the "antipsychotic effect" of estrogen.

           5. STUDY MANAGEMENT

           5.1 Data Management

           Source data from each site will be transferred to The Alfred site for data entry and
           analysis. A copy of the source data for each site will be archived at each site
           according to local ethics committee guidelines. A Contract Research Organisation (CRO)
           will monitor each of the sites to ensure high quality data and adherence to study
           recruitment and retention targets. Inter-rater reliability training will be performed
           annually for all staff at each site or when new staff commence.
    

Intervention name(s): Estradiol; Estradiol; placebo
Intervention type(s): Drug; Drug; Other
Intervention description(s): 100 mcg adjunctive transdermal estradiol; 200 mcg adjunctive transdermal estradiol; adjunctive transdermal placebo
Intervention MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Schizophrenia; Estrogen; Psychosis