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Disentangling sex differences in PTSD risk factors

Nature Mental Health (2024)Cite this article

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Abstract

Despite extensive research on sex/gender differences in posttraumatic stress disorder (PTSD), underlying mechanisms are still not fully understood. Here we present a systematic overview of three sex/gender-related risk pathways. We assessed 16 risk factors as well as 3 month PTSD severity in a prospective cohort study (n = 2924) of acutely traumatized individuals and investigated potential mediators in the pathway between sex assigned at birth and PTSD severity using multiple mediation analysis with regularization. Six risk factors were more prevalent/severe in women, and none was more pronounced in men. Analyses showed that acute stress disorder, neuroticism, lifetime sexual assault exposure, anxiety sensitivity and pretrauma anxiety symptoms fully mediated and uniquely contributed to the relationship between sex assigned at birth and PTSD severity. Our results demonstrate different risk mechanisms for women and men. Such knowledge can inform targeted interventions. Our systematic approach to differential risk pathways can be transferred to other mental disorders to guide sex- and gender-sensitive mental health research.

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Fig. 1: Possible pathways of how risk factors can contribute to sex differences in PTSD.
Fig. 2: Flowchart of AURORA participants included in the present analysis.
Fig. 3: Multiple mediation model for PTSD severity comparing female and male participants.

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Data availability

Data and/or research tools used in the preparation of this manuscript were obtained from the NDA. The NDA is a collaborative informatics system created by the National Institutes of Health to provide a national resource to support and accelerate research in mental health. Dataset identifier(s) at the NDA Digital Object identifier via https://doi.org/10.15154/c01s-jy79 (ref. 55). This manuscript reflects the views of the authors and may not reflect the opinions or views of the National Institutes of Health (NIH) or of the submitters submitting original data to NDA.

Code Availability

An R-based html markup document, which reproduces our analyses and results, is publicly available in a public OSF repository at https://osf.io/v3euk/ (ref. 54).

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Acknowledgements

AURORA is supported by grant U01MH110925 from the National Institute of Mental Health (NIMH) to S.A.M, R.C.K., K.C.K. and K.J.R., the US Army Medical Research and Material Command, the One Mind Foundation and The Mayday Fund. Verily Life Sciences and Mindstrong Health provided some of the hardware and software used to perform study assessments. S.H.’s time is supported by a PhD scholarship of ‘Stiftung der Deutschen Wirtschaft’ (to S.H.). The funding sources 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. The authors thank A. Williams, X. Yao and the other members of the University of North Carolina Institute for Trauma Recovery for their efforts and aide in this research. We also thank the research staff at McLean Hospital, Emory University, Temple University and Wayne State University for their efforts and aide. We further express our gratitude to the participants and their families for their willingness to participate in this research. The investigators wish to thank the trauma survivors participating in the AURORA study. Their time and effort during a challenging period of their lives make our efforts to improve recovery for future trauma survivors possible. This project was supported by the NIMH under U01MH110925, the US Army MRMC, One Mind and The Mayday Fund. The content is solely responsibility of the authors and does not necessarily represent the official views of any of the funders. Verily Life Sciences and Mindstrong Health provided some of the hardware and software used to perform study assessments. The Many Brains Project provided software for neurocognitive assessments.

Author information

Author notes

  1. These authors contributed equally: Abigail Powers, Jennifer S. Stevens.

Authors and Affiliations

  1. Department of Education and Psychology, Clinical Psychological Intervention, Freie Universität Berlin, Berlin, Germany

    Stephanie Haering

  2. Charité Center for Health and Human Sciences, Gender in Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Stephanie Haering

  3. Department of Psychiatry, McLean Hospital, Belmont, MA, USA

    Antonia V. Seligowski & Scott L. Rauch

  4. Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Sarah D. Linnstaedt & Xinming An

  5. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    Vasiliki Michopoulos, Abigail Powers & Jennifer S. Stevens

  6. Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Stacey L. House

  7. Department of Epidemiology, Brown University, Providence, RI, USA

    Francesca L. Beaudoin

  8. Department of Emergency Medicine, Brown University, Providence, RI, USA

    Francesca L. Beaudoin

  9. Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, USA

    Thomas C. Neylan

  10. Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA

    Gari D. Clifford

  11. Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, USA

    Laura T. Germine & Scott L. Rauch

  12. The Many Brains Project, Belmont, MA, USA

    Laura T. Germine

  13. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Laura T. Germine & Scott L. Rauch

  14. Department of Emergency Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA

    John P. Haran

  15. Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Alan B. Storrow

  16. Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, USA

    Christopher Lewandowski

  17. Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Paul I. Musey Jr

  18. Department of Emergency Medicine, University of Florida College of Medicine Jacksonville, Jacksonville, FL, USA

    Phyllis L. Hendry & Sophia Sheikh

  19. Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, USA

    Christopher W. Jones

  20. Department of Emergency Medicine, Ohio State University College of Medicine, Columbus, OH, USA

    Brittany E. Punches

  21. College of Nursing, Ohio State University, Columbus, OH, USA

    Brittany E. Punches

  22. Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, USA

    Robert A. Swor

  23. Department of Emergency Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA

    Nina T. Gentile

  24. Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Lauren A. Hudak

  25. Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA

    Jose L. Pascual

  26. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Jose L. Pascual & Mark J. Seamon

  27. Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, USA

    Mark J. Seamon

  28. Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, USA

    Claire Pearson

  29. Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA

    David A. Peak

  30. Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Roland C. Merchant & Leon D. Sanchez

  31. Department of Emergency Medicine, Trinity Health at Ann Arbor, Ypsilanti, MI, USA

    Robert M. Domeier

  32. Department of Emergency Medicine, University of Massachusetts Medical School at Baystate, Springfield, MA, USA

    Niels K. Rathlev

  33. Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, USA

    Brian J. O’Neil

  34. Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA

    Leon D. Sanchez

  35. Department of Psychological Sciences, University of Missouri at St. Louis, St. Louis, MO, USA

    Steven E. Bruce

  36. Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, USA

    Steven E. Harte

  37. Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, USA

    Steven E. Harte

  38. Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Samuel A. McLean

  39. Institute for Trauma Recovery, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Samuel A. McLean

  40. Department of Health Care Policy, Harvard Medical School, Boston, MA, USA

    Ronald C. Kessler

  41. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA

    Karestan C. Koenen

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  1. Stephanie Haering
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S.A.M., R.C.K., K.C.K., S.H., A.P., J.S.S., A.V.S., S.D.L. and V.M. conceptualized the study. S.L.H., F.L.B., X.A., J.S.S., T.C.N., G.D.C., S.D.L., L.T.G., S.L.R., S.A.M., R.C.K. and K.C.K. performed the methodology. Formal analysis was done by S.H., A.P., J.S.S. S.L.H., F.L.B., X.A., J.S.S., T.C.N., G.D.C., S.D.L., L.T.G., S.L.R., J.P.H., A.B.S., P.I.M.Jr, P.L.H., S.S., C.W.J., B.E.P., R.A.S., N.T.G., L.A.H., J.L.P., M.J.S., C.P., D.A.P., R.C.M., R.M.D., N.K.R., B.J.O., L.D.S., S.E.B., S.A.M., R.C.K. and K.C.K. performed the investigation. S.L.H., F.L.B., X.A., J.S.S., T.C.N., G.D.C., S.D.L., L.T.G., S.L.R., J.P.H., A.B.S., P.I.M.Jr, P.L.H., S.S., C.W.J., B.E.P., R.A.S., N.T.G., L.A.H., J.L.P., M.J.S., C.P., D.A.P., R.C.M., R.M.D., N.K.R., B.J.O., L.D.S., S.E.B., S.A.M., R.C.K. and K.C.K. collected resources. The data curation was done by S.L.H., F.L.B., X.A., J.S.S., T.C.N., G.D.C., S.D.L., L.T.G., S.L.R., S.A.M., R.C.K. and K.C.K. Writing—original draft—was done by S.H., A.P. and J.S.S. Writing—review and editing—was done by A.V.S., S.D.L., V.M., S.L.H., F.L.B., X.A., T.C.N., G.D.C., L.T.G., S.L.R., J.P.H., A.B.S., C.L., P.I.M.Jr, P.L.H., S.S., C.W.J., B.E.P., R.A.S., N.T.G., L.A.H., J.L.P., M.J.S., C.P., D.A.P., R.C.M., R.M.D., N.K.R., B.J.O., L.D.S., S.E.B., S.E.H. S.A.M., R.C.K., K.C.K., J.S.S. and A.P. Visualization was done by S.H., A.P. and J.S.S. S.A.M., R.C.K., K.C.K., S.H., J.S.S. and A.P. supervised the study. Project administration was done by S.L.H., F.L.B., J.S.S., J.P.H., A.B.S., P.I.M.Jr, P.L.H., S.S., C.W.J., B.E.P., R.A.S., N.T.G., L.A.H., J.L.P., M.J.S., C.P., D.A.P., R.C.M., R.M.D, N.K.R., B.J.O., L.D.S., S.E.B., S.A.M., R.C.K. and K.C.K. Funding acquisition was done by S.A.M., R.C.K. and K.C.K. All authors revised the paper critically for important intellectual context and approved the final manuscript.

Corresponding author

Correspondence to Jennifer S. Stevens.

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Competing interests

T.C.N. has received research support from NIH, VA and Rainwater Charitable Foundation and consulting income from Jazz Pharmaceuticals. In the last 3 years, G.D.C. has received research funding from the NSF, NIH and LifeBell AI and unrestricted donations from AliveCor Inc., Amazon Research, the Center for Discovery, the Gates Foundation, Google, the Gordon and Betty Moore Foundation, MathWorks, Microsoft Research, Nextsense Inc., One Mind Foundation, the Rett Research Foundation and Samsung Research. G.D.C. has financial interest in AliveCor Inc. and Nextsense Inc. He also is the CTO of MindChild Medical and CSO of LifeBell AI and has ownership in both companies. These relationships are unconnected to the current work. L.T.G. receives funding from the National Institute of Mental Health (R01 MH121617) and is on the board of the Many Brains Project. L.T.G.’s family also has equity in Intelerad Medical Systems, Inc. S.L.R. reports grants from NIH during the conduct of the study; personal fees from the Society of Biological Psychiatry paid role as secretary, other from Oxford University Press royalties, other from the American Psychiatric Publishing Inc. royalties, other from the Veterans Administration per diem for oversight committee and other from Community Psychiatry/Mindpath Health paid board service, including equity outside the submitted work; other from National Association of Behavioral Healthcare for paid Board service; other from Springer Publishing royalties; and Leadership roles on Board or Council for Society of Biological Psychiatry, Anxiety and Depression Association of America and National Network of Depression Centers. C.W.J. has no competing interests related to this work, though he has been an investigator on studies funded by AstraZeneca, Vapotherm, Abbott and Ophirex. S.E.H. has no competing interest related to this work, though in the last 3 years he has received research funding from Aptinyx and Arbor Medical Innovations and consulting payments from Indiana University and Memorial Sloan Kettering Cancer Center. S.A.M. served as a consultant for Walter Reed Army Institute for Research and for Arbor Medical Innovations. In the past 3 years, R.C.K. was a consultant for Cambridge Health Alliance, Canandaigua Veterans Administration Medical Center, Holmusk, Partners Healthcare, Inc., RallyPoint Networks, Inc. and Sage Therapeutics. He has stock options in Cerebral Inc., Mirah, PYM and Roga Sciences. K.C.K.’s research has been supported by the Robert Wood Johnson Foundation, the Kaiser Family Foundation, the Harvard Center on the Developing Child, Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, the National Institutes of Health, One Mind, the Anonymous Foundation and Cohen Veterans Bioscience. She has been a paid consultant for Baker Hostetler, Discovery Vitality and the Department of Justice. She has been a paid external reviewer for the Chan Zuckerberg Foundation, the University of Cape Town and Capita Ireland. She has had paid speaking engagements in the last 3 years with the American Psychological Association and European Central Bank. Sigmund Freud University—Milan, Cambridge Health Alliance and Coverys. She receives royalties from Guilford Press and Oxford University Press. The remaining authors declare no competing interests.

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Nature Mental Health thanks Hannah Schumm, Saurabh Shaw and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Distribution of PTSD symptoms 3-months post-trauma by sex.

Density and boxplot for the distribution of 3-month PTSD symptoms as measured by the PCL-5, including n = 1818 women and n = 1124 men. The boxplot indicates the median as well as the 25th and 75th percentiles. Whiskers indicate 1.5 times the inter-quartile range.

Supplementary information

Supplementary Information

Supplementary information on measures included in this study. Supplementary Tables 1–5.

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Haering, S., Seligowski, A.V., Linnstaedt, S.D. et al. Disentangling sex differences in PTSD risk factors. Nat. Mental Health (2024). https://doi.org/10.1038/s44220-024-00236-y

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