Mark Weiser1,2,3, Linda Levi2, Daisy Zamora4,5, Anat Biegon6,7, John Paul SanGiovanni8,9, Michael Davidson2,10, Shimon Burshtein2, Ilan Gonen11, Paull Radu11, Kristina Slobozean Pavalache12, Igor Nastas13, Rina Hemi14, Timothy Ryan15, John M Davis15,16. 1. Stanley Medical Research Institute, Kensington, Maryland. 2. Department of Psychiatry, Sheba Medical Center, Tel Hashomer, Israel. 3. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 4. Department of Psychiatry, University of North Carolina, Chapel Hill. 5. Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. 6. Department of Radiology, Stony Brook University Medical School, Stony Brook, New York. 7. Department of Neurology, Stony Brook University Medical School, Stony Brook, New York. 8. Section on Nutritional Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland. 9. Department of Biochemistry and Molecular & Cellular Biology, Georgetown School of Medicine, Washington, DC. 10. University of Nicosia Medical School, Engomi, Cyprus. 11. Tangent Alzheimer Care, Breaza, Romania. 12. Republican Psychiatric Hospital, Chișinău, Moldova. 13. Psychiatry, Narcology, and Medical Psychology, State University of Medicine and Pharmaceuticals, "Nicolae Testemianu," Chisinau, Moldova. 14. Institute of Endocrinology, Sheba Medical Center, Tel Hashomer, Israel. 15. Department of Psychiatry, University of Illinois, Chicago. 16. Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland.
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 patchand 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 placebogroup 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 inplacebogroup 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 estradiolgroup (n = 15) than in the placebogroup (n = 1) as was weight gain (14 in estradiolgroup 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.
RCT Entities:
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.
Authors: M van der Werf; M Hanssen; S Köhler; M Verkaaik; F R Verhey; R van Winkel; J van Os; J Allardyce Journal: Psychol Med Date: 2012-12-17 Impact factor: 7.723
Authors: J Kulkarni; A Riedel; A R de Castella; P B Fitzgerald; T J Rolfe; J Taffe; H Burger Journal: Arch Womens Ment Health Date: 2002-11 Impact factor: 3.633
Authors: T J Key; P N Appleby; G K Reeves; R C Travis; A J Alberg; A Barricarte; F Berrino; V Krogh; S Sieri; L A Brinton; J F Dorgan; L Dossus; M Dowsett; A H Eliassen; R T Fortner; S E Hankinson; K J Helzlsouer; J Hoff man-Bolton; George W Comstock; R Kaaks; L L Kahle; P Muti; K Overvad; P H M Peeters; E Riboli; S Rinaldi; D E Rollison; F Z Stanczyk; D Trichopoulos; S S Tworoger; P Vineis Journal: Lancet Oncol Date: 2013-07-24 Impact factor: 41.316