Estrogen for schizophrenia (Review)

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1 Chua WLLC, Izquierdo de Santiago A, Kulkarni J, Mortimer A This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2010, Issue 1

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 1 Mental state: 1a. Average endpoint in general mental state scores (PANSS total, high=poor) Analysis 1.4. Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 4 Mental state: 2b. Average endpoint in positive symptom scores - 50mcg estrogen (PANSS positive, high=poor) Analysis 1.6. Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 6 Mental state: 3a. Average endpoint in negative symptom scores (PANSS negative, high=poor) Analysis 1.8. Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 8 Mental state: 4a. Average endpoint in psychopathology scores (PANSS general symptoms subscale, high=poor) Analysis 1.9. Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 9 Leaving the study early: up to 8 weeks Analysis 2.1. Comparison 2 ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 1 Mental state: Average endpoint general mental state scores (PANSS, high= poor) Analysis 2.2. Comparison 2 ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 2 Leaving the study early - up to 6 months Analysis 2.3. Comparison 2 ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 3 Cognitive functioning: Average endpoint specific aspects of cognitive functioning WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT INDEX TERMS i

3 [Intervention Review] Estrogen for schizophrenia Wan Lian LC Chua 1, Angelica Izquierdo de Santiago 2, Jayashri Kulkarni 3, Ann Mortimer 4 1 Craven and Airedale Drugs and Alcohol Team, Lynfield Hospital, Bradford, UK. 2 The Mount, Leeds, UK. 3 Alfred Psychiatry Research Centre (APRC), Monash University, Melbourne, Australia. 4 Department of Psychiatry, University of Hull, Hull, UK Contact address: Wan Lian LC Chua, Craven and Airedale Drugs and Alcohol Team, Lynfield Hospital, Henry Street, Bradford, West Yorkshire, BD21 3DR, UK. Lian.Chua@bdct.nhs.uk. Editorial group: Cochrane Schizophrenia Group. Publication status and date: Edited (no change to conclusions), published in Issue 1, Review content assessed as up-to-date: 26 July Citation: Chua WLLC, Izquierdo de Santiago A, Kulkarni J, Mortimer A. Estrogen for schizophrenia. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T In terms of clinical outcomes, women with schizophrenia seem to fare better then men, but appear more vulnerable to psychotic illness in the period after birth and menopause. As these vulnerable periods to psychosis are associated with estrogen withdrawal, this hormone has been proposed as a treatment for schizophrenia. Objectives To evaluate the clinical effects of estrogens alone or in combination with progesterone, as a sole treatment or as an adjunctive therapy, for the treatment of schizophrenia or schizophrenia-like illnesses. Search methods Electronic searches of the Cochrane Schizophrenia Group s Register (October 2003) was supplemented with manual reference inspection of all identified studies. Authors of trials were contacted for further material and archive information. Selection criteria All randomised clinical trials comparing estrogens with or without progesterone, as a sole or adjunctive treatment for people with schizophrenia or other similar serious, non-affective psychotic illness. Data collection and analysis We evaluated data independently and analysed on an intention to treat basis. For binary data we calculated the fixed effect relative risk (RR) and its 95% confidence interval (CI). For continuous non-skewed data, we calculated weighted mean differences. Main results All available evidence relates to women. Four studies (n=108) compared estrogen only with placebo. Short-term scores for general mental state showed no significant difference between groups (n=24, 1 RCT, WMD PANSS for 100mcg comparison CI to 10.9). Data from all four studies showed overall loss from the studies was low (~5%), with no significant differences between groups (n=96, 4 RCTs, RR 0.95 CI 0.2 to 6.1). Skewed continuous data from two studies showed no clear differences in ratings of movement disorders. One medium-term unpublished study (n=14) compared estrogen and progesterone with placebo. Data at six months showed no difference between groups for total scores (n=9, WMD PANSS CI -51 to 0.1). For negative symptoms, results favoured the 1

4 estrogen and progesterone group (n=9, WMD PANSS negative subscale -9.0 CI -17 to -0.9). For loss to follow up there was no difference between groups (n=10, RR 0.33 CI 0.02 to 6.7). This trial used many cognitive tests and one visual retention test showed statistically significant differences favouring the treatment group: total scores (n=8, WMD -3.5 CI -5.7 to -1.3). Authors conclusions Adjunctive estrogen with or without progesterone does not appear to offer convincing advantages over placebo. Before any more research is undertaken in this area, all completed and unpublished work should be made available in order to ensure that more trials are justified. P L A I N L A N G U A G E S U M M A R Y Estrogen for schizophrenia The effects of estrogen as sole treatment or adjunctive therapy for those with schizophrenia are unclear. This review found very few relevant trials and data. The majority of results showed no effect and those that did were too weak to draw firm conclusions from. Results from unpublished trials are awaited before recommendations for more research can be made. B A C K G R O U N D The incidence of schizophrenia in men and women is approximately equal. Men and women, however, have been shown to differ in both the age of onset and the course of illness. Women have a later age of onset compared to men (Angermeyer 1988,Hafner 1997), they seem to require less antipsychotic medication (Seeman 1983), show a higher genetic loading for schizophrenia (Goldstein 1992) and have a second peak of illness onset after the menopause (Hafner 1997, McKenna 1997). To explain these differences, attention has focused on sex hormones, in particular estrogen. The estrogen theory proposes that this female hormone means that women are more protected from psychotic illnesses than men, especially during periods of high estrogen states. This protection may mean that women do not develop psychotic illnesses until later on in life or experience a less severe illness whilst pre-menopausal (Riecher-Rossler 1993). Women have been shown to be more vulnerable to psychotic breakdown at times of estrogen withdrawal, for example just after the delivery of their baby (Kendell 1987) and at the menopause. A review of 26 case reports of psychosis associated with estrogen withdrawal due to conditions unrelated to childbirth, for example post abortion and the cessation of estrogen therapy, found that these particular psychotic episodes were short and reversible and that further incidences took place estrogen withdrawal recurred (Mahe 2001). The estrogen theory is not without controversy, as a causal link has not been proven. There are arguments that marital status, premorbid personality and family history could explain gender differences in age of onset (Jablensky 1997). Others argue that there are two disease processes occurring in those suffering with schizophrenia. One may be a disease process of neurodevelopmental origin, more common in men; the other one with a stronger genetic component and a later age of onset, more common in women (Castle 1991). Paradoxically, it may also be that conventional antipsychotic medication decreases estrogen levels in some women, and yet improves psychosis (Baptista 2002). The use of oestrogen as a therapeutic intervention alone is limited to case reports (Hafner 2003, Tunde-Ayinmode 2002, Felthous 1980). Largely, the drug treatment of schizophrenia remains unaffected by the sex of the person with the illness. Estrogens are not used routinely for people with schizophrenia, and experts in the field advocate very cautious use of these hormones before the results of larger informative trials are known (Riecher-Rossler 2003). Technical information Estradiol, an oestrogen produced by the ovaries, is a reproductive hormone regulated via the gonadopituitary axis. Estrogen receptors (nowadays we can differentiate between a and ß receptors in different tissues) are not only found in the reproductive organs, but also in a variety of brain areas including the cerebral cortex, hypothalamus, pituitary and the limbic system. Estradiol modulates the dopaminergic, noradrenergic pathways in the brain and acts as a serotenergic agonist, dopamine particularly, though not exclusively, being implicated in the cause of schizophrenia (Genazzani 2002, Cyr 2002). Although estrogen is thought of as being a female sex hormone, men also produce estrogens though in a much smaller quantity, which is converted from testosterone. Men also have estrogen receptors. 2

5 Estrogen can be delivered in a variety of routes (oral tablets, patches, gels). The potency of estrogen preparations varies greatly, depending on whether they are natural or synthetic. Estrogen therapy alone in women with an intact womb would place these women at risk of endometrial cancer. To counteract this, progestogens must also be administered. Other serious adverse effects associated with estrogen therapy include venous and arterial thrombosis and breast cancer (BNF 2003). O B J E C T I V E S To evaluate the clinical effects of estrogens alone or in combination with progestogen, as a sole treatment or as an adjunctive therapy, for the treatment of schizophrenia or schizophrenia-like illnesses. M E T H O D S Criteria for considering studies for this review Types of studies We considered all relevant randomised controlled trials. If a trial was described as double blind but it was implied that the study was randomised and the participants demographic details in each group were similar, it was included. Quasi-randomised studies, in which treatment allocation was not concealed, such as those allocating by using alternate days of the week, were excluded. This is because prior knowledge of treatment allocation may lead to biased patient allocation (Schulz 1995). Types of participants Anyone with schizophrenia or similar, serious, non-affective psychosis diagnosed by any criteria irrespective of gender, age or race. If a trial included people with less serious mental illness, it was accepted for inclusion if the majority of the participants suffered from serious functional psychotic illnesses such as schizophrenia. Studies involving men, pre-menopausal women and postmenopausal women were analysed separately. Types of interventions 1. Estrogen as sole treatment: any preparation, dose and dosing schedule and any mode of administration (e.g. oral, subdermal, transdermal or nasal). 2. Estrogen as an adjunct to anti-psychotic medication (typical and atypical): any preparation, dose and dosing schedule and any mode of administration (e.g. oral, subdermal, transdermal or nasal). 3. Estrogen with progestogen as sole treatment: any preparation, dose and dosing schedule and any mode of administration (e.g. oral, subdermal, transdermal or nasal). 4. Estrogen with progestogen an adjunct to anti-psychotic medication (typical and atypical): any preparation, dose and dosing schedule and any mode of administration (e.g. oral, subdermal, transdermal or nasal). 5. Placebo: active or inactive. 6. Anti-psychotic medication: any dose or route of administration. Estradiol in its naturally occurring form is often conjugated with an ester to reduce the first passage metabolism in the liver - e.g. estradiol valerate, estradiol hemihydrate. These weaker preparations are used in hormone replacement therapy. The synthetic ethinyloestradiol, used in the oral contraceptive pill, is many times more potent than natural estradiol. Thus, it would be reasonable to distinguish between studies that used hormonal replacement therapy and contraceptive estradiol preparations. If possible, we had hoped to carry out sensitivity analyses of the following: a. high and low potency estradiol b. estradiol with and without a progestogen Types of outcome measures Where possible, outcomes were made binary by dividing them into two categories - clinically significant change and no clinically significant change. All outcomes were reported for the short term (up to 12 weeks), medium term (13 to 26 weeks), and long term (more than 26 weeks). The reviewers recognise that short, small randomised controlled trials are not the most potent methodology for investigating the prevalence of adverse effects. Ideally, large randomised studies with a long duration are more desirable for this purpose. Often these do not exist and cohort and case-control studies have to suffice. For this first phase of the review we plan to summarise only data from randomised controlled trials, see if sufficient data are present, and discuss the implications of our findings. Future updates may follow non-randomised studies, depending on the findings of this initial investigation. Primary outcomes 1. Global state 1.1 Relapse 2. Service outcomes 2.1 Hospitalisation 3. Mental state 3.1 No clinically important change in general mental state Secondary outcomes 1. Death - suicide and natural causes 3

6 2. Global state 2.1 Time to relapse 2.2 No clinically important change in global state 2.3 Not any change in global state 2.4 Average endpoint global state score 2.5 Average change in global state scores 3. Service outcomes 3.1 Time to hospitalisation 4. Mental state 4.1 Not any change in general mental state 4.2 Average endpoint general mental state score 4.3 Average change in general mental state scores 4.4 No clinically important change in specific symptoms 4.5 Not any change in specific symptoms 4.6 Average endpoint specific symptom score 4.7 Average change in specific symptom scores 5. Leaving the study early 5.1 For specific reasons 5.2 For general reasons 6. General functioning 6.1 No clinically important change in general functioning 6.2 Not any change in general functioning 6.3 Average endpoint general functioning score 6.4 Average change in general functioning scores 6.5 No clinically important change in specific aspects of functioning, such as social or life skills 6.6 Not any change in specific aspects of functioning, such as social or life skills 6.7 Average endpoint specific aspects of functioning, such as social or life skills 6.8 Average change in specific aspects of functioning, such as social or life skills 7. Behaviour 7.1 No clinically important change in general behaviour 7.2 Not any change in general behaviour 7.3 Average endpoint general behaviour score 7.4 Average change in general behaviour scores 7.5 No clinically important change in specific aspects of behaviour 7.6 Not any change in specific aspects of behaviour 7.7 Average endpoint specific aspects of behaviour 7.8 Average change in specific aspects of behaviour 8. Adverse effects 8.1 No clinically important general adverse effects 8.2 Not any general adverse effects 8.3 Average endpoint general adverse effect score 8.4 Average change in general adverse effect scores 8.5 No clinically important change in specific adverse effects* Adverse effects of the drug cam be divided broadly into three categories: Life threatening (breast cancer or endometrial cancer cerebrovascular disease, cholestatic jaundice, myocardial infarction, thromboembolic disease) Non life threatening (altered blood lipids, depression, hypersensitivity reaction, nausea and vomiting) Physiological effects of the compound (changes in libido, feminisation, pregnancy, pre-menstrual type syndrome, sodium and fluid retention) 8.6 Not any change in specific adverse effects 8.7 Average endpoint specific adverse effects 8.8 Average change in specific adverse effects 9. Engagement with services 9.1 No clinically important engagement 9.2 Not any engagement 9.3 Average endpoint engagement score 9.4 Average change in engagement scores 10. Satisfaction with treatment 10.1 Recipient of care not satisfied with treatment 10.2 Recipient of care average satisfaction score 10.3 Recipient of care average change in satisfaction scores 10.4 Carer not satisfied with treatment 10.5 Carer average satisfaction score 10.6 Carer average change in satisfaction scores 11. Quality of life 11.1 No clinically important change in quality of life 11.2 Not any change in quality of life 11.3 Average endpoint quality of life score 11.4 Average change in quality of life scores 11.5 No clinically important change in specific aspects of quality of life 11.6 Not any change in specific aspects of quality of life 11.7 Average endpoint specific aspects of quality of life 11.8 Average change in specific aspects of quality of life 12. Cognitive function 12.1 No clinically important change in general cognitive functioning 12.2 Not any change in general cognitive functioning 12.3 Average endpoint general cognitive functioning score 12.4 Average change in general cognitive functioning scores 12.5 No clinically important change in specific aspects of cognitive functioning, such as social or life skills 12.6 Not any change in specific aspects of cognitive functioning 12.7 Average endpoint specific aspects of cognitive functioning 12.8 Average change in specific aspects of cognitive functioning 13. Economic outcomes 13.1 Direct costs 13.2 Indirect costs Search methods for identification of studies Electronic searches The Cochrane Schizophrenia Group s register (October 2003) was searched with the phrase: { 4

7 [ORT* or PORT* or ERT* or hormone* or estrogen* or progesterone* or estradiol* in title or * ORT* or * PORT* or * ERT* or * hormone* or *estrogen* or *estradiol* or *progesterone* in abstract or index terms of REFERENCE] or [estradiol* or estrogen* or hormone* or progesterone* in interventions of STUDY]} The Schizophrenia groups trials register is based on regular searches of BIOSIS Inside; CENTRAL; CINAHL; EMBASE; MEDLINE and PsycINFO; the hand searching of relevant journals and conference proceedings, and searches of several key grey literature sources. A full description is given in the group s module. Searching other resources 1. Cited reference searching The references of all identified trials were also inspected for more studies. Each of the included studies was sought as a citation in the SCISEARCH (January 1974 to 2003) database. Reports of articles that had cited these studies were inspected in order to identify further trials. 2. Personal contact The primary authors of all studies initially selected for inclusion were contacted in order to identify further relevant trials. Companies producing relevant compounds were also contacted for copies of published, unpublished and archived trials. 3. Hand searching We were to have identified high yield journals and, if they were available and had not already been hand searched, we would have chosen one for a complete page by page inspection. However, no single high yield journal could be identified. Data collection and analysis 1. Resolution of disagreements between reviewers If at any stage of trial selection, data extraction or interpretation, there was disagreement between reviewers, we attempted resolution by discussion. Where this was impossible we added these studies to the list of those awaiting assessment pending further information and contacted authors for clarification before further classification. 2. Selection of trials Two reviewers (WLC, AIS) independently inspected all abstracts of studies identified by the above search terms in order to discard those that were clearly not eligible for inclusion. Full articles of relevant reports were then ordered and carefully inspected for a final decision on inclusion. Reviewers were not blinded to the names of the authors, institutions or journal of publication. 3. Assessment of trials methodological quality Two reviewers (WLC, AIS), again working independently, allocated the trials to quality categories as per the Cochrane Collaboration Handbook (Alderson 2004). The Cochrane Collaboration Handbook Criteria are based on the evidence of a strong relationship between allocation concealment and potential for bias in the results (Schulz 1995). Category A. Low risk of bias (adequate allocation concealment) Here some form of centralised randomisation scheme has been used, such as having to provide details of an enrolled participant to an office by phone in order to receive the treatment allocation. The allocation should be in identical looking numbered or coded containers and used sequentially, or in an on-site/coded computer system in a locked unreadable file. The only method of accessing this would be by inputting the characteristics of an enrolled participant. If assignment envelopes were used, the report should, at the very least, specify that they were sequentially numbered, sealed and opaque. Category A can be assigned to other combinations of described elements of the process as long as assurance is provided of adequate concealment. Category B. Moderate risk of bias (some doubt about the results) Here a list or table is used to allocate assignments of the study describes the use of envelopes or sealed envelopes. Merely stating the study as randomised with no further detail, results in a trial being assigned to Category B. Category C. High risk of bias (inadequate allocation concealment) Allocation by alternation, by reference to case record numbers, date of birth, day of the week or any other such approach, or any allocation procedure that is entirely transparent before assignment, such as open list of random numbers or assignments results in assignment to Category C. These studies were not included in this review. 4. Data extraction Each reviewer independently extracted outcome data from included trials. Details of data presented in each trial, together with reasons why some data were impossible to use in this review, were entered into the Included studies table. 5. Data management 5.1 Data extraction This was performed independently by two reviewers (WLC, AIS) and where further clarification was needed the authors of trials were contacted to provide missing data. 5.2 Intention to treat analysis Data were excluded from outcomes where more than 50% of participants in any group were lost to follow up (this did not include the outcome of leaving the study early ). In outcomes with less than 50% dropout rate, people leaving the study early were considered to have had the negative outcome, except in the event of death. The impact of including studies with high attrition rates (25-50%) was analysed in a sensitivity analysis. If inclusion of data from this latter group resulted in a substantive change in the estimate of effect their data were not added to trials with less attrition, but presented separately. 6. Data analysis 6.1 Binary data For binary outcomes a standard estimation of the random effects risk ratio (RR) and its 95% confidence interval (CI) was calculated. 5

8 The number needed to treat statistic (NNT) was also calculated as was the number needed to harm (NNH). If heterogeneity was found (see section 7), a random effects model was used. 6.2 Continuous data Skewed data: continuous data on clinical and social outcomes are often not normally distributed. To avoid the pitfall of applying parametric tests to non-parametric data, the following standards were applied to all data before inclusion: (a) standard deviations and means were reported in the paper or were obtainable from the authors, (b) when a scale started from a finite number (such as zero), the standard deviation, when multiplied by two, was less than the mean (as otherwise the mean was unlikely to be an appropriate measure of the centre of the distribution - (Altman 1996)). Endpoint scores on scales often have a finite start and end point and this rule can be applied to them Summary statistic: for continuous outcomes a weighted mean difference (WMD) between groups was estimated. Again, if heterogeneity was found (see section 5) a random effects model was used Valid scales: continuous data from rating scales were included only if the measuring instrument had been described in a peerreviewed journal (Marshall 2000) and the instrument was either a self report or completed by an independent rater or relative (not the therapist) Endpoint versus change data: where possible endpoint data were presented, and if both endpoint and change data were available for the same outcomes, then only the former were reported in this review Cluster trials: studies increasingly employ cluster randomisation (such as randomisation by clinician or practice) but analysis and pooling of clustered data poses problems. Firstly, authors often fail to account for intra class correlation in clustered studies, leading to a unit of analysis error (Divine 1992), whereby p values are spuriously low, confidence intervals unduly narrow and statistical significance overestimated which causes type I errors (Bland 1997, Gulliford 1999). Where clustering was not accounted for in primary studies, we presented the data in a table with a (*) symbol to indicate the presence of a probable unit of analysis error. In subsequent versions of this review we will seek to contact first authors of studies to obtain intra-class correlation co-efficients of their clustered data, and to adjust for this using accepted methods (Gulliford 1999). Where clustering has been incorporated into the analysis of primary studies, these data we will also be presented as if from a noncluster randomised study, but an adjustment will be made for the clustering effect. We have sought statistical advice and have been advised that the binary data as presented in a report should be divided by a design effect. This is calculated using the mean number of participants per cluster (m) and the intraclass correlation co-efficient (ICC) [Design effect = 1+(m-1)*ICC] (Donner 2002). If the ICC was not reported it was assumed to be 0.1 (Ukoumunne 1999). Where cluster studies were appropriately analysed taking into account intra-class correlation coefficients and relevant data documented in the report, synthesis with other studies was possible using the generic inverse variance technique. 7. Investigation for heterogeneity Firstly, consideration of all the included studies within any comparison was undertaken to judge clinical heterogeneity. Then visual inspection of graphs was used to investigate the possibility of statistical heterogeneity. This was supplemented by first using the I-squared statistic. This provides an estimate of the percentage of variability due to heterogeneity, rather than chance alone. Where the I-squared estimate was greater than or equal to 75%, this was interpreted as evidence of the presence of high levels of heterogeneity (Higgins 2003). If inconsistency was high, data were not summated but presented separately and reasons for heterogeneity were investigated. 8. Small study bias Data from all included trials were entered into a funnel graph (trial effect versus trial size or precision ) in an attempt to investigate the likelihood of overt small study bias which could, in turn, be a function of publication bias. A formal test of funnel plot asymmetry (suggesting potential publication bias) was undertaken where appropriate (Egger 1997). Significance levels of p < 0.1 were set a priori to accept the presence of asymmetry. 9. Sensitivity analyses If possible sensitivity analysis of primary outcomes would have been undertaken for the following: a. estradiol with and without a progestogen b. high and low potency estradiol (oral contraceptive pill and hormone replacement therapy preparations). 10. General Where possible, reviewers entered data in such a way that the area to the left of the line of no effect indicated a favourable outcome for oestrogen therapy. R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies. 1. Excluded studies We excluded 14 reports of studies; three because they were highly unlikely to be randomised (Kim 1998, Sackler 1951, Villeneuve 1980) and another two crossover design studies (Bergemann 1999, Koller 1982) because it was impossible to distinguish the precrossover from post-crossover outcome data. We have contacted the authors as there is valuable data within these trials. Two other studies did not administer estrogens (O Connor 1983, Thompson 6

9 2000). Yousef 1974 had no usable outcome measures for the purposes of this review. Three studies by the same author (Kulkarni 1999, Kulkarni 2002 and Kulkarni 2003a) all looked suitable for inclusion in terms of their methodology. Unfortunately, these were conference abstracts and the limited data presented were not usable in this review. The author informs us that these three studies have been, or are in the process of being submitted for publication. Finally, two studies (Godfrey 2002, Purdie 2000) were abandoned due to difficulties in recruiting and the authors were not able to provide us with any data. Chakos 1999 was notification of a research award, no study has been published as far as we can ascertain. 2. Awaiting assessment None identified. 3. Ongoing studies We have identified one ongoing study (Kulkarni 2003b). This is a three-month double blind, randomised, three arm comparison trial of the effects of olanzapine plus adjunctive raloxifene, estradiol 2mg plus dyhydroprogesterone or placebo in 60 postmenopausal women with schizophrenia. The study aims to compare the effects of two adjunctive estrogen treatment strategies on psychopathology, cognition and side effect burden. 4. Included studies We identified five randomised and double blind studies for inclusion in this review. One (Kulkarni 1996) was an open label trial. All were published studies with the exception of Good 1999, a conference abstract. Dr Good, when contacted, kindly provided us with unpublished data that we report in this review. 4.1 Length of trial Four studies presented short term data at less than 12 weeks. Glazer 1985 was a seven week optional crossover design. Only the pre-crossover outcome data at three weeks were used for this review. The remaining studies were for four weeks (Kulkarni 2001, Louza 2004) and eight weeks (Kulkarni 1996). Only Good 1999 presented medium term data at six months. There were no studies of longer than 6 months duration. 4.2 Participants Four studies required a diagnosis of schizophrenia or schizophreniform disorder or schizoaffective disorder, diagnosed using the Diagnostic and Statistical Manual III-R or IV (Good 1999, Kulkarni 1996, Kulkarni 2001, Louza 2004). Glazer 1985 required a diagnosis of tardive dyskinesia and not schizophrenia. However, eight out of the 10 who completed this study were also diagnosed with schizophrenia or schizoaffective disorder. As the majority of these participants had a diagnosis of schizophrenia we included this study. Kulkarni 1996, Kulkarni 2001 and Louza 2004 included pre-menopausal women in the acute phase of their illness, whereas participants in Good 1999 and Glazer 1985 were post-menopausal women in the chronic stable phase of their illness. 4.3 Setting Kulkarni 1996, Kulkarni 2001 and Louza 2004 focused on women in the acute phase of their illness and took place in a mixture of inpatient and outpatient settings. Glazer 1985 and Good 1999, however, focusing on women in the chronic stable phase, recruited their participants from the outpatient setting. 4.4 Study size All the studies were small. The largest was of 42 (Louza 2004) and the remainder ranged between 12 and 36 participants. 4.5 Interventions Estrogen was administered in different preparations, different doses and using different routes of administration in the studies. All were used within the treatment range for hormone replacement preparations. Conjugated estrogen was given orally at a dose of 0.625mcg (Louza 2004) and 1.25mg (Glazer 1985, Kulkarni 1996). Estradiol transdermal patches were administered at doses 50mcg/24 hours and 100mcg/24hours by Kulkarni 2001 (it should be noted that this was a three-arm trial comparing 100mcg, 50mcg and placebo. We could not analyse the three arms simultaneously and chose to concentrate on the data of the 100mcg data versus placebo for our comparisons, although we did present data from the 50mcg versus placebo comparison where possible. Only Good 1999 administered estrogen and progesterone (estradiol 1mg and medroxyprogesterone acetate 2.5mg, given orally). All but one open label study (Kulkarni 1996) used a placebo. All studies used estrogen or estrogen and progesterone in addition to standard treatment and antipsychotic medication. Only Louza 2004 attempted to standardise the control treatment by specifying the preparation and doses of antipsychotic medication and medication for symptomatic relief. Standard treatment was otherwise left to the discretion of the treating doctor and was subsequently variable. 4.6 Outcomes Missing outcomes None of the included studies investigated service outcomes, engagement with services, relapse, hospitalisation, patient or carer satisfaction, quality of life and economic costs. Death, suicide or self-harm were not mentioned in any of the studies Outcomes scales Several scales were used to collect data. Scales that have provided usable data for this review are listed below. a. Mental state Improvement is often defined as a 20-40% reduction on Positive and Negative Symptoms Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) scores. Brief Psychiatric Rating Scale - BPRS (Overall 1962) The BPRS is an 18-item scale measuring positive symptoms, general psychopathology and affective symptoms. The original scale has sixteen items, but a revised eighteen-item scale is commonly used. Scores can range from Each item is rated on a sevenpoint scale (1=absent; 7=extreme) with high scores indicating more severe symptoms. Positive and Negative Symptom Scale - PANSS (Kay 1987) PANSS is a 30-item rating instrument evaluating the presence/absence and severity of positive, negative and general psychopathol- 7

10 ogy of schizophrenia. All 30 items are rated on a 7-point scale (1=absent; 7=extreme). The Positive and Negative Symptom Scale was developed from the BPRS and the Psychopathology Rating Scale. It is used as a method for evaluating positive, negative and other symptom dimensions in schizophrenia. This scale can be divided into three sub-scales for measuring the severity of general psychopathology, positive symptoms (PANSS-P) and negative symptoms (PANSS-N). A high score indicates more severe symptoms. Negative symptom Rating Scale - NSRS (Iager 1985) The NSRS is a 7-point (0-6) scale with a point of absence, consisting of 10 items, conceptually sub grouped in 4 sub scales assessing: thought processes (for speech content and judgment/decision-making); cognition (for memory, attention, orientation); volition (for grooming, motivation, motion); and affect/relatedness (for emotional response and expressive relatedness). It is administered by an approximately 15-minute semi structured interview. Higher scores indicate greater deficit, more severe negative symptoms. The negative symbol (-) is written before the scores other than 0. Scale for the Assessment of Positive Symptoms - SAPS(Andreasen 1983). This is a 34-item scale for the assessment of positive symptoms in individuals with schizophrenia. It is intended to be utilised in conjunction with the scale for Assessment of Negative Symptoms also by Andreasen. It is administered via a general clinical interview, plus a series of standardised questions. Additionally any available supporting information, such as staff reports, should be utilised. Symptoms assessed include: hallucinations, delusions, bizarre behaviour and formal thought disorder. Items are scored on a sixpoint scale (0=no abnormality, 5=severe). Higher scores indicate more symptoms. b. Adverse effects Abnormal Involuntary Movement Scale - AIMS (Guy 1976) The Abnormal Involuntary Movement Scale has been used to assess abnormal involuntary movements associated with antipsychotic drugs, such as tardive dyskinesia and chronic akathisia, as well as spontaneous motor disturbance related to the illness itself. Tardive dyskinesia is a long-term, drug-induced movement disorder. However, using this scale in short-term trials may also be helpful to assess some rapidly occurring abnormal movement disorders such as tremor. Scoring consists of rating movement severity in the anatomical areas (facial/oral, extremities, and trunk) on a five point scale (0-4). A low score indicates low levels of dyskinetic movements. Simpson Angus Extrapyramidal Rating Scale - SAERS (Simpson 1970) The SAERS is a 10-item scale, used to evaluate the presence and severity of drug-induced parkinsonian symptomatology. The ten items focus on rigidity rather than bradykinesia, and do not assess subjective rigidity or slowness. Items are rated for severity on a 0-4 scale, with a scoring system of 0-4 for each item. A low score indicates low levels of parkinsonism. UKU Side Effects Rating Scale - UKU-SERS (Lingjaerd 1987) The UKU side effect rating scale is used to assess the side effects for psychotropic drugs. UKU rates four major topics: psychological side effects (10 items), neurological side effects (eight items), autonomic side effects (11 items) and other side effects (19 items). Each item is defined by means of a four-point scale where zero means-not or doubtfully present. Scoring range is from c. Cognitive functioning Benton Visual Retention Test-Revised BVRT-R (Benton 1963, Benton 1974) The purpose of this test is to assess visual memory, visual perception, and visioconstructive abilities. The drawing administrations of the test have three alternate forms, and each form is composed of 10 designs; the first two designs consist of one major geometric figure, and the other eight consist of two major figures and a smaller peripheral figure. There are different variants of administration of this test. Under the standard procedure, each design is displayed for 10 seconds and then withdrawn. Immediately after this the subject is required to reproduce the design from memory at his own pace on a blank piece of paper. Other administration modes differ in the time the design is exposed, or even copying the design without removing the stimulus card from sight. The scoring is accomplished according to explicit criteria in the manual. The number of correct reproductions is recorded accordingly. The range of scores is 0-10 as each of the 10 designs is scored on an all-or-none basis and given a credit of 1 or 0. Finger Tapping Test (Reitan 1969) The purpose of this test is to measure motor speed of the index finger of each hand. Using a specially adapted tapper, the subject is instructed to tap as rapidly as possible using the index finger of the preferred hand. A comparable set of measurement is then obtained with the non preferred hand. Five 10-second trials are normally given for each hand (up to a maximum of 10 trials can be obtained when the results are too variable). The score is computed for each hand separately and is the mean of five consecutive 10- second trials within a range of five taps or the mean of the best five trials. This examination can help to assess subtle motor and other cognitive impairment. It is sensitive to the presence of laterality of brain lesion. Tables with scores for mean performance in adults and children exist to interpret the results. Grooved Pegboard (Matthews 1964) This is part of the Wisconsin Neuropsychological Test Battery (Harley 1980) and the Lafayette Clinic Repeatable Neuropsychological Test Battery (Lewis 1977). It is a highly sensitive instrument for studying improvement in motor functions following stroke and hemispheric components of motor performance. It consists of a small board containing a 5X5 set of slotted holes angled in different directions. Each peg has a ridge along one side requiring it to be rotated into position for correct insertion. Time to completion is scored. Average scores are used as reference for different age group individuals. Scoring above the reference score would 8

11 indicate poor performance. Design Fluency Test (Jones-Gotman 1977, Jones-Gotman 1991) This test measures the production of novel abstract designs. It was developed as a nonverbal analogue to word-fluency tasks. It requires the client to generate as many different meaningless designs as possible. The test is composed of a free-response condition, lasting 5 minutes, in which few restrictions are imposed on design generation, and a fixed response condition, lasting 4 minutes, in which the client must produce designs that contain exactly four lines or components. The total score is the sum of the novel drawings minus the sum of all drawings repeated or not containing exactly four lines or components. A table of the mean acceptable novel outputs and standard deviations is available for adults (separate tables for children). Controlled Oral Word Association - COWA (Benton 1983) Other names of this test: Word fluency, FAS-test, Letter Fluency, category Fluency. The purpose of the test is to evaluate the spontaneous production of words beginning with a given letter or of a given category within a limited amount of time (verbal association fluency). This test can be found included in other examinations (e.g. The Multilingual Aphasia Examination, the Stanford-Binet test). F, A, and S are the most commonly used letters (other combinations used are CFL and PRW). For category fluency the subject is asked to produce as many animal names as possible within a limited period of time. Food names, things in a supermarket, etc, have also been used. Normative data are available in tables for the different versions of this test to help interpretation of results. People with frontal lobe dysfunction would perform poorly on this test. Rey Auditory-Verbal Learning Test - RAVLT or AVLT (Rey 1958), (English version by Taylor 1959 and Lezak 1976, Lezak 1995) There are many variations of the RAVLT. The most commonly used variant consist of 15 nouns (List A) read aloud (with 1 second interval between each word) for five consecutive trials, each followed by a free-recall test. Upon completion of Trial 5, an interference list of 15 words (List B) is presented, followed by a freerecall test of that list. Immediately following this, delayed recall of the first list is tested without further presentation of those words. Again, after a 20-minute delay period, the words from List A are required to be recalled. Finally, a story that uses all the words from List A is presented either orally or in a written form, and the patient must identify the words recognised from List A. Alternatively a matrix is presented containing all items from List A and B and 20 words phonemically and/or semantically similar. Normative data are available in tables for this test to help interpretation of the scores. A person with generalised memory deficit would perform poorly on both free recall and recognition trials. University of Pennsylvania Smell Identification Test - UPSIT ( Doty 1984) The UPSIT is a standardised scratch and sniff test of olfactory function. This self administered test requires subjects to release odours presented on a scratch card and rate each one on five nine point category scales with the following adjectives serving as anchors at their extremes; very weak-very strong; very pleasant-very unpleasant; non-irritating-irritating; very unfamiliar-very familiar; and very cool-very warm. Subjects are presented with 40-stimuli odours. Scores are correlated according to age and gender. Risk of bias in included studies 1. Randomisation All included studies were reported as randomised. None of the included studies, however, explicitly detailed the method of randomisation. Further information was gained by contacting the following authors directly. Kulkarni described using tables of random numbers (Kulkarni 1996) and coded computer generated numbers (Kulkarni 2001). Louza (Louza 2004) stated that the randomisation method was as suggested by Pocock in his book and carried out by a person not otherwise involved in the trial. In Good 1999 we know only that randomisation was undertaken in blocks of two and four by each site. We obtained no further information for Glazer Blindness One study (Kulkarni 1996) was an open label study where only the raters were blind. The remaining four studies were reported as double blind. In the case of Glazer 1985, blinding only lasted for three weeks. In response to our queries, Dr Good (Good 1999) stated that patients could have been aware that they were receiving either hormone replacement therapy or placebo. This may have been also the case in the other studies. No test for double blindness was carried out in any of the trials. No active placebos that mimicked the side effect profile of estrogen were use in any of the trials. 3. Loss to follow up Glazer 1985 and Louza 2004 described participants who left the study early and reported reasons for this. Glazer 1985 reported that one participant in the placebo group developed congestive cardiac failure and one in the estrogen group took an overdose and required psychiatric treatment for a depressive illness present at baseline that worsened following further marital discord. Communication with the author of Louza 2004 clarified that one participant in the placebo group refused to take medication and was excluded on day 3. The other participant whose symptoms of agitation, delusions and suicidal thoughts worsened belonged to the estrogen group and was excluded on day seven. Two studies did not report anyone leaving the study early (Kulkarni 1996, Kulkarni 2001). However, we have found a discrepancy with the numbers of participants recruited by Kulkarni 2001 and have sought clarification from the author. 4. Data reported Overall we found much of data could not be used because of poor reporting. Many findings presented as graphs, in percentiles, means with no standard deviation or just reported as p-values were 9

12 not amenable to further analysis. Louza 2004 stood out for the clarity of reporting. We requested further data and clarification from authors who kindly obliged when approached. We have included this data into our review and tried our best to highlight this additional information without labouring the point repeatedly. Dr Good when contacted provided unpublished data referred to in her conference abstract (Good 1999). Data collection, however, was incomplete and we have used what data we could. 5. Sensitivity analysis Sensitivity analyses were not carried out Estradiol with and without a progestogen The studies were too disparate to draw any comparisons High dose versus low dose estrogen This comparison was not possible as all included trials used low dose estrogen (i.e. hormone replacement preparations and doses as opposed to oral contraceptive doses). Effects of interventions 1. Search We identified 95 publications electronically. Many were clearly irrelevant and were discarded after we read the title and abstracts. We obtained 27 of these publications and then two reviewers independently inspected these. The publications consisted of conference abstracts, articles and research awards. In all, 19 separate studies were identified. Five of these studies, in 13 different publications, were by Professor Kulkarni. The final full inspection of these 19 studies resulted in 14 being excluded leaving for inclusion five studies, randomising a total of 122 people. 2. COMPARISON 1: ESTROGEN + STANDARD TREAT- MENT vs PLACEBO + STANDARD TREATMENT Four studies (n=108) compared estrogen only with placebo. Kulkarni 2001 was the only study, however, to present usable nonskewed data and therefore, with the exception of leaving the study early, all results are based on this one study. 2.1 Mental state Kulkarni 2001 presented non-skewed data using the PANSS. Short-term scores for general mental state showed no significant difference between groups (n=24, WMD for 100mcg comparison CI to 10.9). Similar equivocal results were found for the average endpoint scores on the negative symptoms subscale (n=24, WMD for 100mcg comparison CI -3.7 to 2.6) and psychopathology subscale (n=24, WMD for 100mcg comparison CI -7.9 to 6.2). Other studies presented skewed data for mental state using the BPRS, SAPS and NSRS and found no differences between groups. 2.2 Leaving the study early Data from all four studies showed overall loss from the studies was low (~5%), with no significant differences between groups (n=96, 4 RCTs, RR 0.95 CI 0.2 to 6.1). 2.3 Adverse effects Adverse effects: movement disorders Glazer 1985 and Louza 2004 each used different scales to measure movement disorder. Skewed data showed no clear differences in ratings of movement disorders Adverse effects: side effects Louza 2004 scored participants on the UKU side effects rating scale. This was presented as continuous data and showed no effect but again data were skewed. Mean scores were very low (1.09 in the treatment group and 3.05 for the comparison group). 3. COMPARISON 2: ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT One medium-term study (Good 1999) compared estrogen and progesterone with placebo. This study is small (n=14) and, as yet, unpublished. 3.1 Mental State: Positive and Negative Symptom Scale (PANSS) Good 1999 used the PANSS to measure mental state. Data at 6 months showed no difference between groups for positive symptoms (n=9, WMD -2.0 CI -11 to 6.5). Other results for psychopathology scores (n=9, WMD CI -29 to 0.7) and total scores (n=9, WMD CI -51 to 0.1) showed a trend appearing to favour the estrogen and progesterone group but this difference did not reach statistical significance. The only statistically significant difference between groups was found in the negative symptoms subscale. Here results favoured the estrogen and progesterone group (n=9, WMD -9.0 CI -17 to -0.9). 3.2 Loss to follow-up The 14 participants were randomised in three sites. One site failed to record which arm four participants were allocated to. We were subsequently unable to use the datacollected for these participants. Of the remaining ten participants, one participant left before the end of the trial at three months complaining of the side effect of bloating. There was no difference between groups (n=10, RR 0.33 CI 0.02 to 6.7) 3.3 Cognitive function Non-skewed data: Average endpoint scores for specific cognitive tests. Results for visual retention tests showed statistically significant differences favouring the treatment group: total scores (n=8, WMD -3.5 CI -5.7 to -1.3) and error scores (n=8, WMD CI to -6.4). Results for finger tapping were not significant with wide confidence intervals though the trend favoured the treatment group. For example, finger tapping in the dominant hand (n=9, WMD 5.10 CI -9.0 to 19) and for the non-dominant hand (n= 9, WMD 7.7 CI -8.3 to 24) Skewed data: Average endpoint scores for specific cognitive tests. Several other cognitive tests were used in this study (Verbal Fluency, Design Fluency, Auditory-Verbal Learning Test (AVLT), University of Pennsylvania Smell Test (UPSIT), and Acuity-smell sensitivity) but all data from these tests were skewed and difficult to interpret. The only conclusions we could draw were that the 10

13 confidence intervals were wide and there were no significant differences between the estrogen plus progesterone group versus the placebo group. The mean endpoint scores favoured the treatment group on Verbal Fluency, Design Fluency, Auditory-Verbal Learning Test (AVLT), University of Pennsylvania Smell Test (UPSIT), and Acuity-smell sensitivity. However, these results have large standard deviations. D I S C U S S I O N 1. Overall This review attempts to present the current evidence for estrogen as a new adjunctive treatment for schizophrenia. Results are, at the moment, unclear and there is no real evidence for or against the efficacy of adding estrogen to standard treatment for people with schizophrenia. One of the main problems was finding data. This was difficult for several reasons. 1.1 Data loss Firstly the number of trials available for analysis was small and trials currently published as conference abstracts are not yet fully published. Professor Kulkarni has published conference abstracts on at least three studies which are of interest (Kulkarni 2002, Kulkarni 1999, Kulkarni 2003a) and there is also one ongoing trial registered by the same author (Kulkarni 2003b). Conference abstracts often do not present enough data to be useful for metaanalysis. Professor Kulkarni still hopes to publish these studies, even those undertaken over five years ago. However, several follow up studies have shown that non-publication of randomised trials presented in conference proceedings is a reality and in this way much valuable randomised data are lost. We hope to update this review shortly with full data from these important trials. If presented in accordance with the CONSORT statement (Moher 2001), even conference abstracts can be a valuable source of data. Another problem was loss of data from cross-over studies. Only data from the pre-crossover arm can be used, as data from the second arm may have a carry-over effect (in that a drug may continue to have an effect even after it is stopped), and it also cannot be assumed that the condition returns to baseline state before the next intervention begins (Richens 2001, Senn 1999). Two potential trials were unusable in this review as no pre-crossover data were available. The authors have been approached and we await their response. Hopefully, as more trials become full publications and other data becomes available, this review will be updated and results more apparent. 1.2 Methodology of included trials Overall we felt the reporting of methodology was poor, with authors needing to be contacted for clarification on several issues. All five included studies were also small and unlikely to have adequate power for clinically meaningful outcomes (total n=122). Allocation of concealment was carried out adequately in only two trials (Kulkarni 2001, Louza 2004). Blinding procedures at outcome rating were also unclear. In our opinion one study, though reported as double blind (Good 1999), was effectively a single blind study. It is unlikely that over six months participants experiencing withdrawal bleeds would remain blind to their treatment allocation. There was one other single blind study reported (Kulkarni 1996) of eight weeks duration. The remaining three studies are described as double blind but no tests for blindness were carried out. We therefore suggest that all data were prone to at least a moderate degree of bias (Category B, see Methods 3). 1.3 Outcomes Only a few outcomes were adequately reported and could be included in this review. The most reported outcome was that of changes in mental state and outcomes such as hospitalisation and relapse were not a focus of these short studies. 2. COMPARISON 1: ESTROGEN + STANDARD TREAT- MENT vs PLACEBO + STANDARD TREATMENT 2.1Mental state Although all four studies rated mental state, only data from one study, Kulkarni 2001, were usable. This small study of 24 people found no short-term significant difference in the mental state of the estrogen group compared to the placebo group. PANSS total, negative and psychopathology scores were all equivocal. This result, however, is inconclusive, as data are from one small study only. 2.2 Loss to follow up In these studies there were very low attrition rates of ~5% and no significant differences between groups. This could be due to good protocol design but could also be an effect of selection bias. No studies described how recruitment was carried out. We do not know what proportion were not approached or declined to enter the trial and we do not know if the participants who entered the studies were representative or different from the population they were recruited from. 2.3 Adverse effects Movement disorders Data for this outcome were skewed. Results showed no difference between groups, with those receiving adjunctive placebo no more likely to have movement disorders than those receiving adjunctive estrogen Side effects 11

14 No specific adverse side effects were described in any of the studies. Only data involving the endpoint total scores of the scale UKU were available and these were skewed. No differences between groups were found. Care is needed in interpreting these results for estrogen s effect on adverse effect and no firm conclusion can be made until further good quality data are available. 3. COMPARISON 2: ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT 3.1 Mental State One study (Good 1999, n=14) investigated the effect of adjunct estrogen combined with progesterone compared with placebo. Scores on the PANSS total and psychopathology scale appear to favour the treatment group but were not statistically significant. There was one significant result, favouring the treatment group, on the negative sub-scale of the PANSS (n=9, WMD -9.0 CI to -0.89). These results, from such a small study need to be treated cautiously. 3.2 Loss to follow-up Although one site failed to record which arm four participants were allocated to, no differences in loss were found between groups for the remaining 10 people with usable data. 3.3 Cognitive function Good 1999 used various cognitive function tests. Five of these (Verbal Fluency, Design Fluency, Auditory-Verbal Learning Test (AVLT), University of Pennsylvania Smell Test (UPSIT), and Acuity-smell sensitivity) gave results with no significant differences between groups. Two tests (Benton Visual Retention Test (BVRT) and Finger Tapping test) presented normally distributed data. Benton Visual Retention Test showed a statistically significant result favouring the treatment group. Finger tapping results were equivocal. Again, any results from such a small study cannot carry great clinical weight and must be considered as only hypothesisgenerating. A U T H O R S C O N C L U S I O N S Implications for practice 1. For people with schizophrenia So far, these limited data apply only to women. Patients taking adjunctive estrogen in addition to their antipsychotic medication fared no better or worse than the comparison groups in terms of mental state or cognitive functioning. This intervention is likely to be offered only in trial settings. Based on the evidence so far, estrogens cannot be recommended as an adjunctive treatment for schizophrenia. 2. For clinicians Adjunctive estrogen with or without progesterone does not appear to offer significant advantages over placebo. Data are far too few to allow confident conclusions to be drawn as studies were underpowered and the women heterogeneous in age, stage of illness and interventions received. We found no clinically significant effects with regards to mental state, cognitive function or tardive dyskinesia and parkinsonian symptoms. Estrogen with or without progesterone appears to be well tolerated in the short term. The risks associated with long term use, however, cannot be ignored (CSM 2004). We cannot advocate the use of estrogen with or without progesterone as an adjunctive treatment for women with schizophrenia based on the present evidence. We have no data relevant to men with schizophrenia. 3. For funders/policy makers This review highlights that studies looking at this particular intervention exist. They are small and disparate in their methodology, intervention and outcome measures. The studies are all underpowered and the question, is estrogen a useful adjunctive treatment for schizophrenia? remains unanswered. Several studies have been funded and completed but, even years later, are not published. We are unclear if this is known by funders who expect their investment in research to have results disseminated. Implications for research 1. General As with all trials, public registration of a study before anyone is randomised would ensure that participants could be confident that people would at least know that the study had taken place. Unique study numbers would help researchers to identify single studies from multiple publications and reduce the risk of duplicating the reporting of data. Clear and strict adherence to the CONSORT statement (Moher 2001), by both reporters and editors, would help clarify methodology and many outcomes. This may have resulted in this review being more informative. 2. Specific Estrogen is an experimental intervention for schizophrenia for which the trials so far are small and the results inconclusive. We await the publication of the results of larger studies that have either been completed or are presently ongoing. It is difficult to make recommendations regarding the need for new trials until these are available. These studies mainly involve women but there are also some small trials on men. Men and women must be looked at separately and we would also expect participants in the chronic phase of their illness to be separated from those in the acute phase of their illness. Pre and post-menopausal women have been treated separately for the purposes of the trials designed so far. The different hormonal preparations used in the studies have no standardised equivalence; this makes comparisons between studies diffi- 12

15 cult. Well -designed, adequately powered studies are required if to enable definitive conclusions in this area to be drawn. Long-term trials with estrogen, however, would need to be considered carefully as a recent review has found that post-menopausal women receiving estrogen can have an increased risk of stroke disease, breast cancer and cardiovascular events (CSM 2004). Also, women with an intact uterus should receive progesterone added to estrogen to reduce the risk of endometrial cancer (CSM 2004). A C K N O W L E D G E M E N T S We would like to thank the staff at the Cochrane Schizophrenia Review Group in Leeds, especially Professor Clive Adams and John Rathbone, for all their help and support. Thanks also to Professor Kim Good who provided us with unpublished data and supporting references. R E F E R E N C E S References to studies included in this review Glazer 1985 {published data only} Glazer WM, Naftolin F, Morgenstern H. Estrogen replacement and tardive dyskinesia. Psychoneuroendocrinology 1985;10(3): [MEDLINE: ; : PMID ] Good 1999 {published and unpublished data} Good KP. . Communication with author Good KP, Kopala LC, Martzke JS, Fluker M, Seeman MV, Parish B, Shapiro H, Whitehorne L. Hormone replacement therapy in postmenopausal women with schizophrenia: preliminary findings. Schizophrenia Research 1999;12(3): 131. [: National Research Register N ] Kulkarni 1996 {published data only} Kulkarni J, de Castella A, Smith D, Taffe J, Keks N, Copolov D. A clinical trial of the effects of estrogen in acutely psychotic women. Schizophrenia Research 1996;20: [MEDLINE: ; : PMID ] Kulkarni J, de Dastella A, Smith D. Adjunctive estrogen treatment in women with schizophrenia. Schizophrenia Research 1995;15:157. [MEDLINE: ; : PMID ] Kulkarni 2001 {published and unpublished data} Kulkarni J. . Communication with author Kulkarni J, Reidel A, de Castella AR, Fitzgerald PB, Taffe J, Burger H. Estrogen - a possible role in the treatment of schizophrenia?. Schizophrenia Research 2001;49(1,2):235. [MEDLINE: ; : PMID ] Kulkarni J, Riedel A, de Castella AR, Fitzgerald PB, Rolfe TJ, Taffe J, Burger H. A clinical trial of adjunctive oestrogen treatment in women with schizophrenia. Archives of Women s Mental Health 2002;5: [MEDLINE: ; : ] Kulkarni J, Riedel A, de Castella AR, Fitzgerald PB, Rolfe TJ, Taffe J, Burger H. Estrogen - a potential treatment for schizophrenia. Schizophrenia Research 2001;48: [MEDLINE: ; : PMID ] Kulkarni J, Riedel A, decastella RA, Fitzgerald PB, Rolfe TJ, Taffe J, Burger H. Estrogen: a potential treatment for schizophrenia?. Schizophrenia Research 2000;41(1): 28. [MEDLINE: ; : Biological Abstracts ; PMID ] Louza 2004 {published and unpublished data} Louza MR. . Communication with Author Louza MR, Marques AP, Elkis H, Bassitt D, Deigoli M, Gattaz WF. Conjugated estrogens as adjuvant therapy in the treatment of acute schizophrenia; a double blind study. Schizophrenia Research 2004;66: Marques AO, Elkis H, Louza MR, Yacubian J, Diegoli MS, Gattaz WF. A double blind placebo controlled study of conjugated estrogens added to haloperidol in patients with schizophrenia. Schizophrenia Research 2001;49(12):254. [MEDLINE: ; : PMID ] References to studies excluded from this review Bergemann 1999 {published data only} Bergemann N. Estrogen as adjunct therapy of neuroleptic relapse prevention in schizophrenic women: a placebocontrolled, double-blind study. Current Opinion in Psychiatry (Abstracts of the XI World Congress of Psychiatry, Hamburg, August 6-11, 1999) 1999;12:184. [: Cochrane Library CN ] Chakos 1999 {published data only} Chakos M, Keefe R. Estrogen augmentation for women with schizophrenia. Stanley Foundation Research Awards Research Award Recipients ( accessed February 2001) [: Dissertation Abstracts (order number) AAC ] Godfrey 2002 {published data only} Godfrey E. Hormone replacement therapy as an adjunctive treatment for postmenopausal females with schizophrenia. National Research Register [: N ] Kim 1998 {published data only} Kim JS, Kwak DI, Jung IK, Joe SH. Estrogen augmentation in the female with chronic schizophrenia: a preliminary controlled study. 21st Congress of the Collegium Internationale Neuro-psychopharmacologicum; 1998 Jul 12-16; Glasgow, Scotland [: PsycINFO ] Koller 1982 {published data only} Koller WC, Barr A, Biary N. Estrogen treatment of dyskinetic disorders. Neurology 1982;32: [MEDLINE: ; : PMID ] 13

16 Kulkarni 1999 {published data only} Kulkarni J, de Castella A, Taffe J, Burger H, Reidel A. Clinical estrogen trials in patients with schizophrenia. Current Opinion in Psychiatry 1999;12(Suppl 1):S184. [: 11th World Congress of Psychiatry [CD ROM]: Conifer, Excerpta Medica Medical Communications BV, 1999 S 85 1] Kulkarni J, Riedel A, decastella RA, Fitzgerald PB, Rolfe TJ, Taffe J, Burger H. Estrogen: a potential treatment for schizophrenia?. Schizophrenia Research 2000;41(1): 28. [MEDLINE: ; : Biological Abstracts ; PMID ] Kulkarni J, Riedel A, decastella RA, Taffe J. Adjunctive estrogen in the treatment of psychotic symptoms in women: phase 2 preliminary data. Schizophrenia Research 1999;12 (3):286. [: National Research Register N ] Kulkarni 2002 {published data only} Kulkarni J, de Castella A, Downey M, Taffe J, Fitzgerald P. Estrogen-a useful adjunct in the treatment of men with schizophrenia?. Schizophrenia Research 2002;53(3 Suppl.1):10. [: 14th Congress of the European College of Neuropsychopharmacology [Congress Information System]: Conifer, Excerpta Medica Medical Communications BV, 2001 P2118#] Kulkarni J, de Castella A, Taffe J, Burger H, Reidel A. Clinical estrogen trials in patients with schizophrenia. Current Opinion in Psychiatry 1999;12(Suppl 1):S184. [: 11th World Congress of Psychiatry [CD ROM]: Conifer, Excerpta Medica Medical Communications BV, 1999 S 85 1] Kulkarni J, decastella RA, Taffe J. Clinical adjunctive estrogen trial in men with schizophrenia: a pilot study. Schizophrenia Research 1999;12(3):286. [MEDLINE: ; : PMID ] Kulkarni 2003a {published data only} Kulkarni J. Estrogen as adjunctive treatment for women with schizophrenia. Stanley Foundation Research Awards Research Award Recipients ( accessed February 2001) [: CRISP Grant Number 5R01MH ] Kulkarni J, de Castella A, Hammond J, White S, Reidel A, Taffe J, Fitzgerald P. Estrogen-further evidence for clinical usefulness in the treatment of women with schizophrenia. Schizophrenia Research 2002;53(3 Suppl.1): 10. [: 14th Congress of the European College of Neuropsychopharmacology [Congress Information System]: Conifer, Excerpta Medica Medical Communications BV, 2001 P2118#] Kulkarni J, White S, de Castella A, Fitzgerald P. Estrogen treatment in women with schizophrenia: Psychotic symptoms and cognitive response. Schizophrenia Research 2003;60:291. [MEDLINE: ; : PMID ] O Connor 1983 {published data only} O Connor M, Baker HWG. Depo-medroxy progesterone acetate as an adjunctive treatment in three aggressive schizophrenic patients. Acta Psychiatrica Scandinavica 1983; 67: [MEDLINE: ; : PMID ] Purdie 2000 {published data only (unpublished sought but not used)} Purdie D. Hrt and symptoms, bone mineral density and cognition in perimenopausal female patients with schizophrenia. National Research Register [: National Research Register N ] Sackler 1951 {published data only} Sackler MD, Sackler RR, Sackler AM, van Ophuijsen JHW. Sex steroid therapy in psychiatric disorders. Acta Psychiatrica Scandinavica 1951;26: Thompson 2000 {published data only} Thompson KN, Kulkarni J, Sergejew AA. Extrapyramidal symptoms and oestrogen. Acta Psychiatrica Scandinavica 2000;101: [MEDLINE: ; : PMID ] Villeneuve 1980 {published data only} Villeneuve A, Cazejust T, Cote M. Estrogens in tardive dyskinesia in male psychiatric patients. Neuropsychobiology 1980;6(3): [MEDLINE: ; : PMID ] Yousef 1974 {published data only} El Yousef MK, Manier D. Effects of conjugated estrogens on plasma butaperazine levels. Psychopharmacologia 1974; 39(1): [MEDLINE: ; : PsycINFO ; PMID ] References to ongoing studies Kulkarni 2003b {published data only} Kulkarni J. Three month double-blind, randomized, three arm comparison of the effects of olanzapine plus adjunctive raloxifene, estradiol 2mg plus dyhydroprogesterone or placebo in 60 post-menopausal women with schizophrenia. October Additional references Alderson 2004 Alderson P, Green S, Higgins JPT. Cochrane Reviewers Handbook [updated December 2003]. The Cochrane Library. Chichester, UK: John Wiley & Sons, Ltd, Altman 1996 Altman DG, Bland JM. Detecting skewness from summary information. BMJ 1996;313:1200. [: OLZ020600] Andreasen 1983 Andreasen NC. Negative symptoms in schizophrenia.. Archives of General Psychiatry 1983;39: Angermeyer 1988 Angermeyer MC. Gender difference in age of onset of schizophrenia: an overview. European Archive of Psychiatry and Neurological Sciences 1988;237: [MEDLINE: ] Baptista 2002 Baptista T, Beaulieu S. The hypothesis of oestrogen withdrawal associated psychoses and the paradox of antipsychotic drug-induced hypoestrogenaemia. Acta 14

17 Psychiatrica Scandinavica 2002;105(6): [MEDLINE: ] Benton 1963 Benton AL. Revised Visual Retention Test: Clinical and Experimental Applications. Third Edition. New York: Psychological Corporation, Benton 1974 Benton AL. Revised Visual Retention Test. 4th Edition. New York: The Psychological Corporation, Benton 1983 Benton AL, Hamsher K, Sivan AB. Multilingual Aphasia Examination. 3rd Edition. Iowa City, IA: AJA Associates, Bland 1997 Bland JM. Statistics notes. Trials randomised in clusters. BMJ 1997;315:600. BNF 2003 British Medical Association. British National Formulary. Royal Pharmaceutical Sociaety of Great Britian. Vol. 45, British Medical Association, March 2003: Castle 1991 Castle DJ, Murray RM. Neurodevelopmental basis of sex differences in schizophrenia. Psychological Medicine 1991; 21: CSM 2004 CSM. Review of the evidence on long-term safety of HRT. Current Problems in Pharmacovigilance 2004;30(October): 4 7. Cyr 2002 Cyr M, Calon F, Morissette M, Di Paolo T, Genazzani AR, Monteleone P, Gambacciani M. Estrogenic modulation of brain activity: implications for schizophrenia and Parkinson s disease. Journal of Psychiatry & Neuroscience 2002;27(1): [MEDLINE: ] Divine 1992 Divine GW, Brown JT, Frazier LM. The unit of analysis error in studies about physicians patient care behavior. Journal of General Internal Medicine 1992;7(6): Donner 2002 Donner A, Klar N. Issues in the meta-analysis of cluster randomized trials. Statistics in Medicine 2002;21: Doty 1984 Doty R, Shaman P, Dann M. Development of the University of Pennsylvania Smell Test: standardized microencapsulated test for olfactory function. Physiological Behaviour 1984;32: Egger 1997 Egger M, Davey-Smith G, Schneider M, Minder CSO. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;13: Felthous 1980 Felthous AR, Robinson DB, Conroy RW. Prevention of recurrent menstrual psychosis by an oral contraceptive. American Journal of Psychiatry 1980;137(2): [MEDLINE: ] Genazzani 2002 Genazzani AR, Monteleone P, Gambacciani M. Hormonal influence on the central nervous system. Maturitas 2002;43 (Suppl.1):S11 7. [MEDLINE: ] Goldstein 1992 Goldstein JM, Faraone SV, Chen WJ, Tsuang MT. Gender and the familial risk for schizophrenia. Disentangling confounding factors. Schizophrenia Research 1992;7(2): [MEDLINE: ] Gulliford 1999 Gulliford MC. Components of variance and intraclass correlations for the design of community-based surveys and intervention studies: data from the Health Survey for England American Journal of Epidemiology 1999;149: Guy 1976 Guy W. ECDEU assessment manual for psychopharmacology, revised.. Publication ADM Edition. Vol. Vol , Rockville, MD: National Institute of Mental Health, US Department of Health, Education, and Welfare., Hafner 1997 Hafner H, van der Heiden W. Epidemiology of schizophrenia. Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie 1997;42(2): [MEDLINE: ] Hafner 2003 Hafner H, Felthous AR, Robinson DB, Conroy RW. Gender differences in schizophrenia: Prevention of recurrent menstrual psychosis by an oral contraceptive. Psychoneuroendocrinology: American Journal of Psychiatry 2003;137(2): [MEDLINE: ] Higgins 2003 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327: Iager 1985 Iager AC, Kirch DG, Wyatt RC. A Negative Symptom Rating Scale. Psychiatry Res 1985;16(1): Jablensky 1997 Jablensky A, Cole SW. Is the earlier age at onset of schizophrenia in males a confounded finding?. British Journal of Psychiatry 1997;170: [MEDLINE: ] Jones-Gotman 1977 Jones-Gotman M, Milner B. Design Fluency: The invention of nonsense drawings after focal cortical lesions.. Neuropsychologia 1977;15: Jones-Gotman 1991 Jones-Gotman M. Localization of lesions by neuropsychological testing. Epilepsia 1991;32(S): Kay 1987 Kay SR Kay SR. Positive, negative symptom (PANNS) scale manual. Schizophrenia Bulletin : Postitive and negative symptoms (PANNS) scale manual.. Schizophrenia Bulletin 1987;13:

18 Kendell 1987 Kendell RE, Chalmers JC, Platz C. Epidemiology of puerperal psychoses. British Journal of Psychiatry 1987;150: [MEDLINE: ] Lezak 1976 Lezak MD. Neuropsychological Assessment. New York: Oxford University Press, Lezak 1995 Lezak MD. Neuropsychological Assessment. Third Edition. New York: Oxford University Press, Lingjaerd 1987 Lingjaerd O, Ahlfors WG, Bech P, Dencker ST, Elgen K Lingjaerd O, Ahlfors WG, Bech P, Dencker ST, Elgen K. The UKU (Udvalg for Kliniske Undersogelser) side effects rating scale. Acta Psychiatr Scandinavica 1987;76: Mahe 2001 Mahe V, Dumaine A. Oestrogen withdrawal associated psychoses. Acta Psychiatrica Scandinavica 2001;104(5): [MEDLINE: ] Marshall 2000 Marshall M, Lockwood A, Adams C, Bradley C, Joy C, Fenton M. Unpublished rating scales - a major source of bias in randomised controlled trials of treatments for schizophrenia?;176: British Journal of Psychiatry 2000;176: Matthews 1964 Matthews CG, Klove H. Instruction Manual for the Adult Neuropsychology Test Battery. Madison WI: University of Wisconsin Medical School, McKenna 1997 McKenna P. Paraphrenia and paranoia. Schizophrenia and related syndromes. Psychology Press, 1997: [: ] Moher 2001 Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials.. The Lancet 2001;357: Overall 1962 Overall JE, Gorham DR. The Brief Psychiatric Rating Scale.. Psychological Reports 1962;10: Reitan 1969 Reitan RM. Manual for Administration of Neuropsychological Test Batteries for Adults and Children. Indianapolis: n/a, Rey 1958 Rey A. L examen clinique en psychologie. Paris: Presse Universitaire de France, Richens 2001 Richens A. Proof of efficacy trials: cross-over versus parallelgroup. Epilepsy Research 2001;45: Riecher-Rossler 1993 Riecher-Rossler A, Hafner H. Schizophrenia and oestrogens - is there an association?. European Archives of Psychiatry & Clinical Neuroscience 1993;242(6): [MEDLINE: ] Riecher-Rossler 2003 Riecher-Rossler A. Oestrogen and schizophrenia. Current Opinion in Psychiatry 2003;16(2): [MEDLINE: ] Schulz 1995 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273: Seeman 1983 Seeman MV. Interaction of sex, age, and neuroleptic dose. Comprehensive Psychiatry 1983;24(2): [MEDLINE: ] Senn 1999 Senn S. Clinical cross-over trials in phase I. Statistical Methods in Medical Research 1999;8: Simpson 1970 Simpson EN, Angus JWF. A rating scale for extrapyramidal side-effects.. Acta Psychiatrica Scandinavica Supplementum 1970;212:11 9. Taylor 1959 Taylor EM. The Appraisal of Children with Cerebral Deficits. Cambridge, MA: Harvard University Press, Tunde-Ayinmode 2002 Tunde-Ayinmode M, Singh A, Marsde K. Improved functioning in a woman with schizophrenia on exclusive therapy with oestrogen pills. Australasian Psychiatry 2002; 10(4): Ukoumunne 1999 Ukoumunne OC, Gulliford MC, Chinn S, Sterne JAC, Burney PGJ. Methods for evaluating area-wide and organisation-based interventions in health and health care: a systematic review. Health Technology Assessment 1999;3(5): iii 92. [MEDLINE: ] Indicates the major publication for the study 16

19 C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of included studies [ordered by study ID] Glazer 1985 Methods Participants Interventions Outcomes Allocation: randomised. Blindness: double blind for week 1-3, thereafter open label with option to change treatments. Duration: interventions 3 weeks, followed up an additional month. Setting: outpatients tardive dyskinesia clinic. Consent: yes. Loss: described. Diagnosis: tardive dyskinesia, 8/10 completers also had diagnosis of schizophrenia or schizoaffective disorder. N=12. Sex: female. Age: >45. Inclusion criteria: post-menopausal >1 year. Exclusion criteria: received estrogen therapy in last 3 months, medical contraindications to estrogen therapy 1. Conjugated estrogen (Premarin): dose 1.25mg, oral. N=6. 2. Placebo. N=6. All continued with standard treatment including antipsychotic medication Adverse effects: AIMS. Leaving study early. Unable to use - Mental state: BPRS (no numbers reported). Acceptability of treatment: (data from only one group reported). Adverse effects: Webster scale (no numbers reported). Physiological outcomes: serum estradiol and prolactin levels (not protocol outcome) Notes Risk of bias Item Authors judgement Description Allocation concealment? Unclear B - Unclear 17

20 Good 1999 Methods Participants Interventions Outcomes Notes Allocation: randomised (in blocks of 2 and 4 by site). Blindness: double blind.* Duration: 6 months. Setting: outpatients, multicentre. Consent: yes. Loss: described. Diagnosis: schizophrenia. N=14. Age: years. Sex: female. Inclusion criteria: At least 6 months amenorrhoea, serum FSH >40IU/L, currently receiving antipsychotic medication, regularly attending an outpatient psychiatric facility Exclusion criteria: disorders that may interfere with olfactory or cognitive function, baseline hypertension, use of HRT in the last 3 months, contraindications to the use of estrogen or progestin therapy 1. Estradiol (Estrace): dose 1 mg and medroxyprogesterone acetate (Provera): dose 2.5mg, oral. N=5. 2. Placebo. N=5. All continued with standard treatment including antipsychotic medication. Four patients from a single site had no treatment assignment recorded Mental state: PANSS. Leaving study early. Cognitive Function: BVRT, AVLT, COWA, design fluency test, UPSIT, finger tapping, grooved pegboard Unable to use - Global state: CGI and GAF (data incomplete). * Some patients may have been aware of status. - Direct from Dr Good. No testing for double blindness was conducted. Treating gynaecologist and associated nurse not blind, raters were Risk of bias Item Authors judgement Description Allocation concealment? Unclear B - Unclear Kulkarni 1996 Methods Participants Allocation: randomised (using a randomly generated list of numbers). Blindness: open label but psychopathology rater was blind. Duration: 8 weeks. Setting: inpatient Consent: yes. Loss: none described. Diagnosis: schizophrenia and related psychosis. N=18. Age: childbearing age. 18

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