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What is the effect of transdermal estradiol added to antipsychotic treatment in women of childbearing age with schizophrenia?
In this 8-week, double-blind, randomized, placebo-controlled parallel-group study of 200 women with schizophrenia randomized to a 200-μg estradiol patch or placebo added to antipsychotics, participants receiving transdermal estradiol patches had statistically significant improvements in the primary outcome measure, Positive and Negative Syndrome Scale positive subscale, as well as Positive and Negative Syndrome Scale negative subscale, general psychopathology subscale, and Positive and Negative Syndrome Scale total scores.
Estradiol might be an effective treatment for schizophrenia; these results should be viewed in the context of the differences in the natural course of schizophrenia between females and males.
Several lines of evidence suggest that estradiol influences the course of schizophrenia, and a previous randomized controlled trial demonstrated that transdermal estradiol improved symptoms in female patients of childbearing age. However, many initial positive findings in schizophrenia research are not later replicated.
To independently replicate the results of the effect of estradiol on schizophrenia in women of childbearing age.
Design, Setting, and Participants
An 8-week randomized, placebo-controlled trial performed in the Republic of Moldova between December 4, 2015, and July 29, 2016, among 200 premenopausal women aged 19 to 46 years with schizophrenia or schizoaffective disorder as defined by the DSM-5.
Patients were randomized to receive a 200-μg estradiol patch or placebo patch changed twice a week added to their antipsychotic treatment.
Main Outcomes and Measures
The primary outcome was the positive subscale of the Positive and Negative Syndrome Scale (PANSS; lower scores indicated fewer symptoms and higher scores indicated more symptoms), analyzed with mixed models for repeated measures on an intention-to-treat basis.
A total of 100 women (median age, 38 years; interquartile range, 34-42 years) were randomized to receive an estradiol patch and 100 women (median age, 38 years; interquartile range, 31-41 years) were randomized to receive a placebo patch; the median age at baseline for the entire group of 200 women was 38.0 years (range, 19.5-46.0 years). At baseline, the mean positive PANSS score was 19.6 for both groups combined; at week 8, the mean positive PANSS score was 14.4 in the placebo group and 13.4 in the estradiol group. Compared with placebo, participants receiving add-on estradiol patches had statistically significant improvements in the primary outcome measure, PANSS positive subscale points (–0.94; 95% CI, –1.64 to –0.24; P = .008; effect size = 0.38). Post hoc heterogeneity analyses found that this effect occurred almost entirely in 100 participants older than 38.0 years (46 in placebo group vs 54 in estradiol group; difference, –1.98 points on the PANSS positive subscale; 95% CI, –2.94 to –1.02; P < .001). Younger participants did not benefit from estradiol (difference, 0.08 points on the PANSS positive subscale; 95% CI, –0.91 to 1.07; P = .87). Breast tenderness was more common in the estradiol group (n = 15) than in the placebo group (n = 1) as was weight gain (14 in estradiol group vs 1 in placebo group).
Conclusions and Relevance
The results independently replicate the finding that transdermal estradiol is an effective add-on treatment for women of childbearing age with schizophrenia and extend it, finding improvements in negative symptoms and finding that the effect could be specific to those older than 38 years. The results should be viewed in the context of the differences in the natural course of schizophrenia between females and males.
ClinicalTrials.gov identifier: NCT03848234
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Accepted for Publication: May 14, 2019.
Corresponding Author: Mark Weiser, MD, Stanley Medical Research Institute, 10605 Concord St, Ste 206, Kensington, MD 20895 (firstname.lastname@example.org).
Published Online: July 31, 2019. doi:10.1001/jamapsychiatry.2019.1842
Author Contributions: Dr Weiser had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Weiser, SanGiovanni, Davidson, Burshtein, Gonen, Slobozean Pavalache, Ryan, Davis.
Acquisition, analysis, or interpretation of data: Weiser, Levi, Zamora, Biegon, SanGiovanni, Radu, Slobozean Pavalache, Nastas, Hemi, Ryan, Davis.
Drafting of the manuscript: Weiser, Levi, Zamora, Biegon, Davidson, Burshtein, Gonen, Slobozean Pavalache, Hemi, Davis.
Critical revision of the manuscript for important intellectual content: Weiser, Zamora, Biegon, SanGiovanni, Davidson, Radu, Nastas, Ryan, Davis.
Statistical analysis: Levi, Zamora, Biegon, SanGiovanni, Ryan, Davis.
Obtained funding: Weiser.
Administrative, technical, or material support: Weiser, SanGiovanni, Davidson, Burshtein, Gonen, Radu, Hemi, Davis.
Supervision: Weiser, Davidson, Gonen, Radu, Nastas, Davis.
Conflict of Interest Disclosures: Dr Davidson reported that, at the time of the trial, he owned stocks in the site management organization that supported the site conducting the trial. No other disclosures were reported.
Funding/Support: This study was funded by the Stanley Medical Research Institute (http://www.stanleyresearch.org/), a nonprofit organization based in Maryland supporting research on the causes of and treatments for schizophrenia and bipolar disorder.
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 3.
Additional Contributions: Mirit Hanochi, MSc, Institute of Endocrinology, Sheba Medical Center, assisted in measuring the levels of hormones in the sera. Mark Horowitz, MS, National Institute on Aging, National Institutes of Health, assisted with statistical programming. They were not compensated for their contributions.
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