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

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.

Conflict of interest statement

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.

Figures

Figure 1.. CONSORT Flow Diagram

ANCOVA indicates analysis of covariance.

Figure 2.. Outcomes Over Time in the Placebo and Estradiol Groups

Differences are calculated using mixed models for repeated measures. Decreasing score equals increasing improvement in well-being (n = 200). CGI indicates Clinical Global Impression Scale; PANSS, Positive and Negative Syndrome Scale; and MADRS, Montgomery Depression Scale.

Figure 3.. Differences in Outcome Scores Between Placebo and Estradiol Groups by Median Baseline Age

Differences are calculated using mixed models for repeated measures. A negative difference means the estradiol group improved in well-being more than the placebo group. The vertical lines at week 8 are 95% CIs. Median baseline age was 38.0 years. CGI indicates Clinical Global Impression Scale; PANSS, Positive and Negative Syndrome Scale; and MADRS, Montgomery Depression Scale.