[Skip to Content]
[Skip to Content Landing]

Effect of Adjunctive Estradiol on Schizophrenia Among Women of Childbearing AgeA Randomized Clinical Trial

Educational Objective
To examine the effect of transdermal estradiol added to antipsychotic treatment in women of childbearing age with schizophrenia.
1 Credit CME
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

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Accepted for Publication: May 14, 2019.

Corresponding Author: Mark Weiser, MD, Stanley Medical Research Institute, 10605 Concord St, Ste 206, Kensington, MD 20895 (weiserm@stanleyresearch.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.

References
1.
van Os  J, Kapur  S.  Schizophrenia.  Lancet. 2009;374(9690):635-645. doi:10.1016/S0140-6736(09)60995-8PubMedGoogle ScholarCrossref
2.
Tiihonen  J, Tanskanen  A, Taipale  H.  20-Year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia.  Am J Psychiatry. 2018;175(8):765-773. doi:10.1176/appi.ajp.2018.17091001PubMedGoogle ScholarCrossref
3.
Haukka  J, Tiihonen  J, Härkänen  T, Lönnqvist  J.  Association between medication and risk of suicide, attempted suicide and death in nationwide cohort of suicidal patients with schizophrenia.  Pharmacoepidemiol Drug Saf. 2008;17(7):686-696. doi:10.1002/pds.1579PubMedGoogle ScholarCrossref
4.
Sadock  BJ, Sadock  VA, Ruiz  P. Kaplan & Sadock's Comprehensive Textbook of Psychiatry. 10th ed. Philadelphia, PA: Wolters Kluwer; 2017.
5.
Ioannidis  JP.  Contradicted and initially stronger effects in highly cited clinical research.  JAMA. 2005;294(2):218-228. doi:10.1001/jama.294.2.218PubMedGoogle ScholarCrossref
6.
Tajika  A, Ogawa  Y, Takeshima  N, Hayasaka  Y, Furukawa  TA.  Replication and contradiction of highly cited research papers in psychiatry: 10-year follow-up.  Br J Psychiatry. 2015;207(4):357-362. doi:10.1192/bjp.bp.113.143701PubMedGoogle ScholarCrossref
7.
Kulkarni  J, Gavrilidis  E, Hayes  E, Heaton  V, Worsley  R.  Special biological issues in the management of women with schizophrenia.  Expert Rev Neurother. 2012;12(7):823-833. doi:10.1586/ern.12.62PubMedGoogle ScholarCrossref
8.
Heringa  SM, Begemann  MJ, Goverde  AJ, Sommer  IE.  Sex hormones and oxytocin augmentation strategies in schizophrenia: a quantitative review.  Schizophr Res. 2015;168(3):603-613. doi:10.1016/j.schres.2015.04.002PubMedGoogle ScholarCrossref
9.
Kulkarni  J, Riedel  A, de Castella  AR,  et al.  A clinical trial of adjunctive oestrogen treatment in women with schizophrenia.  Arch Womens Ment Health. 2002;5(3):99-104. doi:10.1007/s00737-002-0001-5PubMedGoogle ScholarCrossref
10.
Kulkarni  J, de Castella  A, Fitzgerald  PB,  et al.  Estrogen in severe mental illness: a potential new treatment approach.  Arch Gen Psychiatry. 2008;65(8):955-960. doi:10.1001/archpsyc.65.8.955PubMedGoogle ScholarCrossref
11.
Kulkarni  J, Gavrilidis  E, Wang  W,  et al.  Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age.  Mol Psychiatry. 2015;20(6):695-702. doi:10.1038/mp.2014.33PubMedGoogle ScholarCrossref
12.
Kay  SR, Fiszbein  A, Opler  LA.  The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.  Schizophr Bull. 1987;13(2):261-276. doi:10.1093/schbul/13.2.261PubMedGoogle ScholarCrossref
13.
Keefe  RS, Goldberg  TE, Harvey  PD, Gold  JM, Poe  MP, Coughenour  L.  The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery.  Schizophr Res. 2004;68(2-3):283-297. doi:10.1016/j.schres.2003.09.011PubMedGoogle ScholarCrossref
14.
Simpson  GM, Angus  JW.  A rating scale for extrapyramidal side effects.  Acta Psychiatr Scand Suppl. 1970;212(S212):11-19. doi:10.1111/j.1600-0447.1970.tb02066.xPubMedGoogle ScholarCrossref
15.
Lingjaerde  O, Ahlfors  V, Dencker  S, Elgen  K.  The UKU side effects rating scale for psychotropic drugs and a cross sectional study of side effects in antipsychotic patients.  Acta Psychiatr Scand Suppl. 1987;334:76.Google Scholar
16.
Fitzmaurice  GM, Laird  NM, Ware  JH.  Applied Longitudinal Analysis. 2nd ed. Hoboken, NJ: Wiley; 2011. doi:10.1002/9781119513469
17.
Stern  RG, Schmeidler  J, Davidson  M.  Limitations of controlled augmentation trials in schizophrenia.  Biol Psychiatry. 1997;42(2):138-143. doi:10.1016/S0006-3223(96)00295-8PubMedGoogle ScholarCrossref
18.
Häfner  H, Riecher  A, Maurer  K, Löffler  W, Munk-Jørgensen  P, Strömgren  E.  How does gender influence age at first hospitalization for schizophrenia? a transnational case register study.  Psychol Med. 1989;19(4):903-918. doi:10.1017/S0033291700005626PubMedGoogle ScholarCrossref
19.
van der Werf  M, Hanssen  M, Köhler  S,  et al; RISE Investigators.  Systematic review and collaborative recalculation of 133,693 incident cases of schizophrenia.  Psychol Med. 2014;44(1):9-16. doi:10.1017/S0033291712002796PubMedGoogle ScholarCrossref
20.
Häfner  H.  Gender differences in schizophrenia.  Psychoneuroendocrinology. 2003;28(suppl 2):17-54. doi:10.1016/S0306-4530(02)00125-7PubMedGoogle ScholarCrossref
21.
Bergemann  N, Parzer  P, Runnebaum  B, Resch  F, Mundt  C.  Estrogen, menstrual cycle phases, and psychopathology in women suffering from schizophrenia.  Psychol Med. 2007;37(10):1427-1436. doi:10.1017/S0033291707000578PubMedGoogle ScholarCrossref
22.
Hoff  AL, Kremen  WS, Wieneke  MH,  et al.  Association of estrogen levels with neuropsychological performance in women with schizophrenia.  Am J Psychiatry. 2001;158(7):1134-1139. doi:10.1176/appi.ajp.158.7.1134PubMedGoogle ScholarCrossref
23.
Gillies  GE, McArthur  S.  Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines.  Pharmacol Rev. 2010;62(2):155-198. doi:10.1124/pr.109.002071PubMedGoogle ScholarCrossref
24.
Biegon  A, Alia-Klein  N, Fowler  JS.  Potential contribution of aromatase inhibition to the effects of nicotine and related compounds on the brain.  Front Pharmacol. 2012;3:185. doi:10.3389/fphar.2012.00185PubMedGoogle ScholarCrossref
25.
Biegon  A, Kim  S-W, Logan  J, Hooker  JM, Muench  L, Fowler  JS.  Nicotine blocks brain estrogen synthase (aromatase): in vivo positron emission tomography studies in female baboons.  Biol Psychiatry. 2010;67(8):774-777. doi:10.1016/j.biopsych.2010.01.004PubMedGoogle ScholarCrossref
26.
Baker  M.  1,500 Scientists lift the lid on reproducibility.  Nature. 2016;533(7604):452-454. doi:10.1038/533452aPubMedGoogle ScholarCrossref
27.
Aarts  AA, Anderson  JE, Anderson  CJ,  et al; Open Science Collaboration.  Estimating the reproducibility of psychological science.  Science. 2015;349(6251):aac4716. doi:10.1126/science.aac4716PubMedGoogle ScholarCrossref
28.
Zhong  GC, Cheng  JH, Xu  XL, Wang  K.  Meta-analysis of oral contraceptive use and risks of all-cause and cause-specific death.  Int J Gynaecol Obstet. 2015;131(3):228-233. doi:10.1016/j.ijgo.2015.05.026PubMedGoogle ScholarCrossref
29.
Cramer  DW, Braaten  K.  Contemporary hormonal contraception and the risk of breast cancer.  N Engl J Med. 2018;378(13):1264-1268. doi:10.1056/NEJMc1800054PubMedGoogle Scholar
30.
Key  TJ, Appleby  PN, Reeves  GK,  et al; Endogenous Hormones and Breast Cancer Collaborative Group.  Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies.  Lancet Oncol. 2013;14(10):1009-1019. doi:10.1016/S1470-2045(13)70301-2PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Topics
State Requirements