A Definitive Estrogen Patch Study (ADEPT)
A Definitive Estrogen Patch Study (ADEPT)
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).
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.
Inclusion Criteria:

 -  Female participants of potential child-bearing age (Pre-menopausal and Post-menarche)

 -  Female participants who meet the MINI (Mini International Neuropsychiatric Interview
 for DSM-IV) diagnostic criteria for current psychotic disorder or have a current
 DSM-IV diagnosis of Schizophrenia, Schizophreniform Disorder, or Schizoaffective
 Disorder (not in manic phase).

 -  Female participants with a PANSS positive score greater than 15 and/or a PANSS
 negative score greater than 15.

 -  Female participants who are able to give informed consent

 -  Female participants receiving 2-20mg daily Risperidone equivalents for at least 4
 weeks.

 Exclusion Criteria:

 -  Female participants who are pregnant or lactating.

 -  Female participants with known severe abnormalities in the hypothalamo-pituitary
 gonadal axis, thyroid dysfunction, central nervous system tumours, history of
 thromboembolic disorders, severe renal failure, severe hepatic failure, cardiac
 disease, epilepsy or other serious medical conditions which would contraindicate
 estrogen use.

 -  Female participants already taking oral estrogen preparations containing greater then
 30mcg estradiol.

 -  Post-menopausal or pre-menarche female participants.

 -  Female participants whose psychotic illness meets DSM-IV criteria for
 substance-induced psychotic disorder.

 -  Female participants who have a current diagnosis of Schizoaffective Disorder and are
 in a manic phase.