Disentangling sex differences in PTSD risk factors

Stephanie Haering^{1

2}, Antonia V Seligowski³, Sarah D Linnstaedt⁴, Vasiliki Michopoulos⁵, Stacey L House⁶, Francesca L Beaudoin^{7

8}, Xinming An⁴, Thomas C Neylan⁹, Gari D Clifford¹⁰, Laura T Germine^{11

12

13}, Scott L Rauch^{11

3

13}, John P Haran¹⁴, Alan B Storrow¹⁵, Christopher Lewandowski¹⁶, Paul I Musey Jr¹⁷, Phyllis L Hendry¹⁸, Sophia Sheikh¹⁸, Christopher W Jones¹⁹, Brittany E Punches^{20

21}, Robert A Swor²², Nina T Gentile²³, Lauren A Hudak²⁴, Jose L Pascual^{25

26}, Mark J Seamon^{27

26}, Claire Pearson²⁸, David A Peak²⁹, Roland C Merchant³⁰, Robert M Domeier³¹, Niels K Rathlev³², Brian J O'Neil³³, Leon D Sanchez^{30

34}, Steven E Bruce³⁵, Steven E Harte^{36

37}, Samuel A McLean^{38

39}, Ronald C Kessler⁴⁰, Karestan C Koenen⁴¹, Abigail Powers⁵, Jennifer S Stevens⁵

Affiliations

¹ Department of Education and Psychology, Clinical Psychological Intervention, Freie Universität Berlin, Berlin, Germany.
² Charité Center for Health and Human Sciences, Gender in Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
³ Department of Psychiatry, McLean Hospital, Belmont, MA, USA.
⁴ Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
⁶ Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁷ Department of Epidemiology, Brown University, Providence, RI, USA.
⁸ Department of Emergency Medicine, Brown University, Providence, RI, USA.
⁹ Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA.
¹¹ Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, USA.
¹² The Many Brains Project, Belmont, MA, USA.
¹³ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Emergency Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
¹⁵ Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁶ Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, USA.
¹⁷ Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁸ Department of Emergency Medicine, University of Florida College of Medicine -Jacksonville, Jacksonville, FL, USA.
¹⁹ Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, USA.
²⁰ Department of Emergency Medicine, Ohio State University College of Medicine, Columbus, OH, USA.
²¹ Ohio State University College of Nursing, Columbus, OH, USA.
²² Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, USA.
²³ Department of Emergency Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
²⁴ Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA.
²⁵ Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
²⁶ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁷ Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, USA.
²⁸ Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, USA.
²⁹ Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁰ Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³¹ Department of Emergency Medicine, Trinity Health-Ann Arbor, Ypsilanti, MI, USA.
³² Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, USA.
³³ Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, USA.
³⁴ Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA.
³⁵ Department of Psychological Sciences, University of Missouri - St. Louis, St. Louis, MO, USA.
³⁶ Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, USA.
³⁷ Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, USA.
³⁸ Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁹ Institute for Trauma Recovery, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴⁰ Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
⁴¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.

PMID: 39534178
PMCID: PMC11556219
DOI: 10.1038/s44220-024-00236-y

Disentangling sex differences in PTSD risk factors

Stephanie Haering et al. Nat Ment Health. 2024 May.

. 2024 May;2(5):605-615.

doi: 10.1038/s44220-024-00236-y. Epub 2024 Apr 19.

Authors

Affiliations

¹ Department of Education and Psychology, Clinical Psychological Intervention, Freie Universität Berlin, Berlin, Germany.
² Charité Center for Health and Human Sciences, Gender in Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
³ Department of Psychiatry, McLean Hospital, Belmont, MA, USA.
⁴ Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
⁶ Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁷ Department of Epidemiology, Brown University, Providence, RI, USA.
⁸ Department of Emergency Medicine, Brown University, Providence, RI, USA.
⁹ Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA.
¹¹ Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, USA.
¹² The Many Brains Project, Belmont, MA, USA.
¹³ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Emergency Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
¹⁵ Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁶ Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, USA.
¹⁷ Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁸ Department of Emergency Medicine, University of Florida College of Medicine -Jacksonville, Jacksonville, FL, USA.
¹⁹ Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, USA.
²⁰ Department of Emergency Medicine, Ohio State University College of Medicine, Columbus, OH, USA.
²¹ Ohio State University College of Nursing, Columbus, OH, USA.
²² Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, USA.
²³ Department of Emergency Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
²⁴ Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA.
²⁵ Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
²⁶ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁷ Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, USA.
²⁸ Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, USA.
²⁹ Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁰ Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³¹ Department of Emergency Medicine, Trinity Health-Ann Arbor, Ypsilanti, MI, USA.
³² Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, USA.
³³ Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, USA.
³⁴ Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA.
³⁵ Department of Psychological Sciences, University of Missouri - St. Louis, St. Louis, MO, USA.
³⁶ Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, USA.
³⁷ Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, USA.
³⁸ Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁹ Institute for Trauma Recovery, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴⁰ Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
⁴¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.

PMID: 39534178
PMCID: PMC11556219
DOI: 10.1038/s44220-024-00236-y

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 were more pronounced in men. Analyses showed that acute stress disorder, neuroticism, lifetime sexual assault exposure, anxiety sensitivity, and pre-trauma 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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Conflict of interest statement

Competing Interests Statement -Dr. Neylan has received research support from NIH, VA, and Rainwater Charitable Foundation, and consulting income from Jazz Pharmaceuticals. - In the last three years Dr. Clifford 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. Dr Clifford 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. - Dr. Germine receives funding from the National Institute of Mental Health (R01 MH121617) and is on the board of the Many Brains Project. Dr. Germine’s family also has equity in Intelerad Medical Systems, Inc. -Dr. Rauch reports grants from NIH during the conduct of the study; personal fees from SOBP (Society of Biological Psychiatry) paid role as secretary, other from Oxford University Press royalties, other from APP (American Psychiatric Publishing Inc.) royalties, other from VA (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 SOBP, ADAA (Anxiety and Depression Association of America), and NNDC (National Network of Depression Centers). - Dr. Jones has no competing interests related to this work, though he has been an investigator on studies funded by AstraZeneca, Vapotherm, Abbott, and Ophirex. - Dr. Harte has no competing interest related to this work, though in the last three years he has received research funding from Aptinyx and Arbor Medical Innovations, and consulting payments from Indiana University and Memorial Sloan Kettering Cancer Center. - Dr. McLean served as a consultant for Walter Reed Army Institute for Research and for Arbor Medical Innovations. - In the past 3 years, Dr. Kessler was a consultant for Cambridge Health Alliance, Canandaigua VA Medical Center, Holmusk, Partners Healthcare, Inc., RallyPoint Networks, Inc., and Sage Therapeutics. He has stock options in Cerebral Inc., Mirah, PYM, and Roga Sciences. - Dr. Koenen’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 three years with the American Psychological Association, 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.

Figures

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

**Fig. 1 |. Possible pathways of how risk factors can contribute to sex differences in posttraumatic stress disorder (PTSD)**
The figure summarizes how sex/gender-related aspects in risk factors may contribute to sex/gender differences in PTSD. Risk factors may either be sex/gender-dependent or sex/gender-specific: Sex/gender-dependent risk factors refer to quantitative differences by sex/gender, whereas sex/gender-specific risk factors refer to qualitative differeances. Sex/gender-specific risk factors are associated with risk only in one sex/gender. Sex/gender-dependent risk factors can be further classified into risk factors with prevalence or severity differences, and risk factors with vulnerability differences by sex/gender. Risk factors with prevalence or severity differences refer to predictors with sex/gender differences in the distribution within the (study) population. Risk factors associated with vulnerability differences describe predictors with sex/gender-differential effects i.e., sex/gender moderates the association between a certain risk factor and PTSD. The two sex/gender-dependent sub-groups are not mutually exclusive.

**Fig. 2 |. Multiple mediation model for PTSD severity comparing female and male participants.**
The figure shows the estimates by the multiple mediation model with regularization predicting 3-month PTSD severity. Coefficients are standardized to facilitate comparisons of mediation path direction and magnitude. *Indicates statistical significance based on 95% confidence interval.

**Fig. 3 |. Flowchart of AURORA participants included in the present analysis.**
The chart shows the flow of participants from recruitment to follow-up.

See this image and copyright information in PMC

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Disentangling sex differences in PTSD risk factors

Affiliations

Disentangling sex differences in PTSD risk factors

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources