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Original Investigation
July 31, 2019

Effect of Adjunctive Estradiol on Schizophrenia Among Women of Childbearing Age: A Randomized Clinical Trial

Author Affiliations
  • 1Stanley Medical Research Institute, Kensington, Maryland
  • 2Department of Psychiatry, Sheba Medical Center, Tel Hashomer, Israel
  • 3Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
  • 4Department of Psychiatry, University of North Carolina, Chapel Hill
  • 5Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
  • 6Department of Radiology, Stony Brook University Medical School, Stony Brook, New York
  • 7Department of Neurology, Stony Brook University Medical School, Stony Brook, New York
  • 8Section on Nutritional Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
  • 9Department of Biochemistry and Molecular & Cellular Biology, Georgetown School of Medicine, Washington, DC
  • 10University of Nicosia Medical School, Engomi, Cyprus
  • 11Tangent Alzheimer Care, Breaza, Romania
  • 12Republican Psychiatric Hospital, Chișinău, Moldova
  • 13Psychiatry, Narcology, and Medical Psychology, State University of Medicine and Pharmaceuticals, “Nicolae Testemianu,” Chisinau, Moldova
  • 14Institute of Endocrinology, Sheba Medical Center, Tel Hashomer, Israel
  • 15Department of Psychiatry, University of Illinois, Chicago
  • 16Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland
JAMA Psychiatry. 2019;76(10):1009-1017. doi:10.1001/jamapsychiatry.2019.1842
Key Points

Question  What is the effect of transdermal estradiol added to antipsychotic treatment in women of childbearing age with schizophrenia?

Findings  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.

Meaning  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.

Abstract

Importance  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.

Objective  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.

Intervention  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.

Results  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.

Trial Registration  ClinicalTrials.gov identifier: NCT03848234

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