Abstract
Background
Women are disproportionately affected by major depressive disorder (MDD). Widely used hormonal contraceptives are linked to depression and altered brain function, yet their unstudied impact on EEG-biomarkers of antidepressant response may confound efforts to develop biomarkers for women.
Methods
In 60 unmedicated premenopausal women with MDD: non-users (n = 25), combined oral contraceptive users (COC, n = 19), and progestin-only contraceptive users (POC, n = 16), we assess five EEG-biomarkers before eight weeks of 10–20 mg escitalopram: Alpha peak frequency (APF), Vigilance level, Loudness-Dependence of Auditory Evoked Potentials (LDAEP), frontal alpha asymmetry (FAA), and theta activity at the anterior cingulate cortex (tACC). Analyses include age-adjusted ANCOVAs, hierarchical logistic regression, and repeated LASSO-regressions to evaluate the effects of hormonal contraceptives on EEG-biomarkers and treatment response.
Results
No differences between contraceptive groups are found in EEG-biomarkers (ω²<0.03, p > 0.15). Adding contraceptive groups improves EEG-based predictions for all biomarkers (p < 0.044). While hierarchical regressions show no significant EEG-biomarker contraceptive-group interactions, LASSO-regressions select contraceptive status in interaction with APF and tACC in models that best predict treatment outcome. Disregarding EEG, hormonal contraceptive use is associated with treatment response (p = 0.01). COC-users exhibit lower response rates than non-users (24% vs 71%, OR = 0.14 [0.03, 0.65], p = 0.012). POC-users have a 44% response rate (p = 0.140).
Conclusions
Although hormonal contraceptive use is not associated with EEG-biomarkers in unmedicated depressed women, they may modulate links between specific EEG-biomarkers and antidepressant response. However, contraceptive use, specifically COC, is associated with worse treatment outcomes and may be critical to developing biomarkers, including EEG-based, to guide treatment in women with MDD.
Plain Language Summary
Women commonly use hormonal contraceptives, which may alter brain activity in ways that might affect how antidepressants work. We measured brain waves (EEG) in 60 women with depression before they started antidepressant treatment. The women either used combined oral contraceptives, progestin-only contraceptives, or no hormonal contraceptives. We examined five EEG-biomarkers associated with antidepressant treatment response. We found that hormonal contraceptives did not directly alter these brain wave patterns. However, women using combined oral contraceptives responded poorly to treatment compared to non-users, and knowing whether women used hormonal contraceptives helped the brain wave patterns better predict treatment success. These findings suggest that hormonal contraceptive use, particularly combined oral contraceptives, should be considered when developing personalised depression treatments for women.
Data availability
Source data for Figs. 1–3 are available in Supplementary Data 1. The analysed data is further available by application, which is reviewed by the Cimbi Database group at NRU. The application form and more detailed information are available at https://nru.dk/index.php/allcategories/category/224-cimbi. Upon approval, the Database Manager extracts the requested data. A database inventory is published in NeuroImage75.
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Acknowledgements
We gratefully acknowledge investigators from the NeuroPharm-1 study, particularly Kristin Köhler-Forsberg, collaborating general practitioners, and the Centre for Referral and Diagnostics, Mental Health Services, Capital Region of Copenhagen, for helping recruit patients. We thank Cyril Pernet for providing R code and discussing LASSO regressions, and Brice Ozenne for statistical discussions. A.K.J., M.T.A., and K.R.J. were funded by the Research Fund of the Mental Health Services—Capital Region of Denmark (R377-2021-340), and CTI by the University of Macau (SRG2023–00040-ICI and MYRG-GRG2024-00022-ICI). S.V.L. was supported by the Independent Research Fund Denmark (0134-00278B and 7025-00111B) and the Lundbeck Foundation (R450-2023-1488). The Lundbeck Foundation alliance BrainDrugs (R279-2018-1145) also funded KRJ, CTI, and VGF. The Innovation Fund Denmark (4108-00004B) supported the study.
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Contributions
Conceptualisation: K.R.J., V.G.F., M.B.J., C.T.I.; Formal Analysis: K.R.J., A.K.J., S.V.L., C.T.I.; Investigation: K.R.J., A.K.J., S.V.L., V.G.F., M.B.J., C.T.I.; Original Draft: K.R.J., A.K.J., M.B.J.; Visualisation: K.R.J., A.K.J., Review & Editing: K.R.J., A.K.J., S.V.L., M.T.A., V.G.F., M.B.J., C.T.I.; Supervision: K.R.J., V.G.F., M.B.J., C.T.I.; Administration: K.R.J., V.G.F., M.B.J.; Funding: K.R.J., V.G.F., M.B.J., C.T.I.
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Competing interests
C.T.I. is a shareholder of DeepPsy AG. K.R.J. has given talks sponsored by H. Lundbeck; all honoraria were donated to StrongMinds.org, a non-profit providing free, evidence-based mental health care to under-resourced populations. M.B.J. has given talks sponsored by H. Lundbeck and Boehringer Ingelheim. V.G.F. has served as a consultant to SAGE Therapeutics and has given lectures at seminars sponsored by Lundbeck A/S, Janssen-Cilag A/S, Gedeon-Richter A/S, and Ferring Pharmaceuticals. The other authors have nothing to disclose.
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Communications Medicine thanks Rimantė Gaižauskaitė, Paolo Benna and Ramunė Grikšienė for their contribution to the peer review of this work. A peer review file is available.
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Jensen, K.H.R., Juvik, A.K., Larsen, S.V. et al. Hormonal contraceptives and EEG biomarkers for antidepressant treatment response in women. Commun Med (2026). https://doi.org/10.1038/s43856-026-01438-4
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DOI: https://doi.org/10.1038/s43856-026-01438-4
