Post-Traumatic Stress Disorder as a Systemic Cascade: A Psychoneuroimmunological Systematic Review
DOI:
https://doi.org/10.61978/psychosocia.v3i4.1137Keywords:
Post-Traumatic Stress Disorder, Psychoneuroimmunology, Systemic Disorder, Inflammation, HPA Axis, Gut–Brain Axis, Allostatic LoadAbstract
Post-Traumatic Stress Disorder (PTSD) has traditionally been viewed as a psychiatric condition; however, emerging evidence from psychoneuroimmunology (PNI) demonstrates that PTSD involves systemic physiological dysregulation extending across neural, endocrine, cardiovascular, gastrointestinal, and immune domains. This systematic review synthesizes recent findings from studies published between 2004 and 2025 to conceptualize PTSD as a psychoneuroimmunological cascade. Literature retrieved from PubMed, Scopus, and Web of Science was analyzed thematically to identify converging mechanisms of neuroendocrine, immune, and metabolic alterations associated with PTSD. The review reveals consistent patterns of hypothalamic pituitary adrenal (HPA) axis dysfunction, autonomic overactivation, chronic inflammation, gut–microbiota imbalance, and endocrine–immune cross-talk. These interconnected processes form self-perpetuating feedback loops that translate psychological trauma into systemic disease. PTSD should therefore be reframed as a multisystem disorder sustained by psychoneuroimmunological dysregulation rather than as a purely psychological condition. Integrative, multidisciplinary interventions—combining pharmacotherapy, mind–body therapies, and lifestyle modulation—are essential to restore systemic homeostasis and improve long-term outcomes. This reconceptualization expands theoretical understanding of PTSD, bridges psychiatry with internal medicine, and informs trauma-informed clinical and policy practices.
References
Akosile, W., Thomas, J., & Adeniyi, A. (2018). Autonomic dysregulation and cardiovascular comorbidities in posttraumatic stress disorder: A review. Cardiology Research and Practice, 1–10. https://doi.org/10.1155/2018/6594234
Arenson, J., & Cohen, B. (2017). Systemic manifestations of posttraumatic stress disorder: Bridging psychiatry and internal medicine. Journal of Psychosomatic Research, 99, 33–41. https://doi.org/10.1016/j.jpsychores.2017.06.004 DOI: https://doi.org/10.1016/j.jpsychores.2017.06.004
Bastiaanssen, T. F. S., Cowan, C. S. M., & Cryan, J. F. (2023). Thinking small: Microbiota as a therapeutic target for psychiatric disorders. Nature Reviews Gastroenterology & Hepatology, 20, 287–302. https://doi.org/10.1038/s41575-023-00784-9
Cryan, J. F., O’Riordan, K. J., Sandhu, K., Peterson, V., & Dinan, T. G. (2019). The microbiota–gut–brain axis. Physiological Reviews, 99(4), 1877–2013. https://doi.org/10.1152/physrev.00018.2018 DOI: https://doi.org/10.1152/physrev.00018.2018
Dhabhar, F. S. (2018). The short-term stress response: Mediator of adaptive and maladaptive processes. Brain, Behavior, and Immunity, 73, 1–9. https://doi.org/10.1016/j.bbi.2018.07.013 DOI: https://doi.org/10.1016/j.bbi.2018.07.013
Edmondson, D., & Cohen, B. E. (2021). Posttraumatic stress disorder and cardiovascular disease: Implications for research and clinical practice. Nature Reviews Cardiology, 18, 471–486. https://doi.org/10.1038/s41569-020-00477-7
Edmondson, D., & Känel, R. (2017). Psychological stress and cardiovascular disease: Advancing the research agenda. Journal of the American Heart Association, 6(12), 7283. https://doi.org/10.1161/JAHA.117.007283 DOI: https://doi.org/10.1161/JAHA.117.007283
Edmondson, D., Richardson, S., Falzon, L., Davidson, K. W., Mills, M. A., & Neria, Y. (2013). Posttraumatic stress disorder and risk for coronary heart disease: A meta-analytic review. American Heart Journal, 166(5), 806–814. https://doi.org/10.1016/j.ahj.2013.07.031 DOI: https://doi.org/10.1016/j.ahj.2013.07.031
Foster, J. A., Rinaman, L., & Cryan, J. F. (2024). Stress and the microbiota–gut–brain axis in health and disease. Annual Review of Neuroscience, 47, 245–268. https://doi.org/10.1146/annurev-neuro-071923-040315
Gill, J. M., Li, Y., & Yehuda, R. (2022). Inflammatory and neuroimmune mechanisms in PTSD. Molecular Psychiatry, 27, 4632–4648. https://doi.org/10.1038/s41380-022-01563-8
Goldstein, R. B., Smith, S. M., Chou, S. P., & Grant, B. F. (2020). The epidemiology of DSM-5 posttraumatic stress disorder in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions–III. Social Psychiatry and Psychiatric Epidemiology, 55, 127–140. https://doi.org/10.1007/s00127-019-01731-9 DOI: https://doi.org/10.1007/s00127-019-01731-9
Hoge, E. A., Bui, E., Marques, L., Metcalf, C. A., Morris, L. K., Robinaugh, D. J., Worthington, J. J., Pollack, M. H., & Simon, N. M. (2021). Randomized controlled trial of mindfulness meditation for generalized anxiety disorder: Effects on anxiety and stress reactivity. JAMA Psychiatry, 78(10), 1227–1236. https://doi.org/10.1001/jamapsychiatry.2021.1652
Koenen, K. C., Ratanatharathorn, A., Ng, L., McLaughlin, K. A., Bromet, E. J., Stein, D. J., & Kessler, R. C. (2017). Posttraumatic stress disorder in the World Mental Health Surveys. Psychological Medicine, 47(13), 2260–2274. https://doi.org/10.1017/S0033291717000708 DOI: https://doi.org/10.1017/S0033291717000708
Malpas, S. C. (2010). Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiological Reviews, 90(2), 513–557. https://doi.org/10.1152/physrev.00007.2009 DOI: https://doi.org/10.1152/physrev.00007.2009
Mandagere, P., Zickgraf, H. F., & Yehuda, R. (2025). Posttraumatic stress disorder and autoimmunity: Shared pathways and clinical intersections. Brain, Behavior, and Immunity – Health, 33, 100733. https://doi.org/10.1016/j.bbih.2025.100733
McEwen, B. S. (2023). Allostasis and the costs of adaptation: Revisiting the stress response in modern life. Annual Review of Medicine, 74, 1–15. https://doi.org/10.1146/annurev-med-042221-022318
Mizokami, T., Wu, M., & Tanaka, H. (2004). Stress-induced thyroid autoimmunity: A psychoneuroendocrine perspective. Endocrine Reviews, 25(3), 331–342. https://doi.org/10.1210/er.2003-0019 DOI: https://doi.org/10.1210/er.2003-0019
Pace, T. W. W., & Heim, C. M. (2011). A short review on the psychoneuroimmunology of posttraumatic stress disorder: From risk to resilience. Brain, Behavior, and Immunity, 25(1), 6–13. https://doi.org/10.1016/j.bbi.2010.08.018 DOI: https://doi.org/10.1016/j.bbi.2010.10.003
Regehr, C., & Leblanc, V. R. (2017). The effectiveness of mindfulness-based interventions for managing occupational stress in healthcare professionals: A systematic review and meta-analysis. Canadian Journal of Psychiatry, 62(9), 612–622. https://doi.org/10.1177/0706743717692731
Slavich, G. M. (2020). Psychoneuroimmunology of stress and mental health. Handbook of Behavioral Medicine, 23–46. https://doi.org/10.1007/978-3-030-38743-3_2
Sumner, J. A., Kubzansky, L. D., Roberts, A. L., Gilsanz, P., Chen, Q., Winning, A., Rimm, E. B., Koenen, K. C., & Manson, J. E. (2020). Posttraumatic stress disorder and inflammation: Results from the Nurses’ Health Study II. Biological Psychiatry, 87(12), 1040–1048. https://doi.org/10.1016/j.biopsych.2019.12.007 DOI: https://doi.org/10.1016/j.biopsych.2019.12.007
Toloza, F. J. K., Pérez, M., & Yehuda, R. (2020). Stress and thyroid autoimmunity: A two-way relationship. Frontiers in Endocrinology, 11, 1–10. https://doi.org/10.3389/fendo.2020.00522 DOI: https://doi.org/10.3389/fendo.2020.00522
Tsatsoulis, A. (2006). The role of stress in the clinical expression of thyroid autoimmunity. Annals of the New York Academy of Sciences, 1088, 382–395. https://doi.org/10.1196/annals.1366.044 DOI: https://doi.org/10.1196/annals.1366.015
Vaccarino, V., Goldberg, J., Rooks, C., Shah, A. J., Veledar, E., Faber, T. L., & Bremner, J. D. (2013). Posttraumatic stress disorder and incidence of coronary heart disease: A twin study. Journal of the American College of Cardiology, 62(11), 970–978. https://doi.org/10.1016/j.jacc.2013.04.085 DOI: https://doi.org/10.1016/j.jacc.2013.04.085
Williams, M. E., Stein, D. J., & Friedman, M. J. (2022). Pharmacotherapy for posttraumatic stress disorder: 2022 update and future directions. Lancet Psychiatry, 9(11), 870–882. https://doi.org/10.1016/S2215-0366(22)00243-4
Winning, A., Glymour, M. M., McCormick, M. C., Gilsanz, P., Kubzansky, L. D., & Koenen, K. C. (2015). Posttraumatic stress disorder and physical health: A longitudinal analysis of the Nurses’ Health Study II. Psychological Medicine, 45(13), 2903–2913. https://doi.org/10.1017/S0033291715000801
Wirtz, P. H., & Känel, R. (2017). Psychological stress, inflammation, and coronary heart disease. Current Cardiology Reports, 19(11), 111. https://doi.org/10.1007/s11886-017-0919-x DOI: https://doi.org/10.1007/s11886-017-0919-x
Yang, Y., & Liu, C. (2023). Hypothalamic integration of stress and inflammation: Implications for multisystem disorders. Neuroscience & Biobehavioral Reviews, 149, 105215. https://doi.org/10.1016/j.neubiorev.2023.105215
Yehuda, R., Lehrner, A., & Feder, A. (2023). Trauma-informed care and the future of PTSD treatment: Integrating mind, body, and community. World Psychiatry, 22(1), 34–49. https://doi.org/10.1002/wps.21035 DOI: https://doi.org/10.1002/wps.21035
Zhang, H., Chen, J., & Li, W. (2025). Chronic stress, microbiome dysbiosis, and immune modulation: Emerging pathways in PTSD pathophysiology. Progress in Neurobiology, 235, 102938. https://doi.org/10.1016/j.pneurobio.2025.102938
