Dynamics of the systemic inflammatory response surrounding stressors and the association with neuropsychiatric and somatic outcomes

TY - JOUR

T1 - Dynamics of the systemic inflammatory response surrounding stressors and the association with neuropsychiatric and somatic outcomes

AU - Berlot, Rok

AU - Ipavic, Ester

AU - Lynch-Kelly, Katharine

AU - Hafeez, Danish

AU - Nicholson, Timothy R

AU - Edwards, Mark J

AU - Pollak, Thomas A

N1 - Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2026/7/6

Y1 - 2026/7/6

N2 - Acute and chronic stressors contribute to neuropsychiatric disorders. However, the role of inflammatory dynamics around stress exposure remains unclear. Using TriNetX, an international electronic health records database, we examined how systemic inflammatory activity and its temporal dynamics relate to risk of mental illness and somatic symptoms. We compared 44,904 individuals with records of accidents and leukocytosis in the surrounding period with matched individuals with normal leukocyte counts, and performed analogous comparisons for socioeconomic and psychosocial stressors in cohorts of 100,855 individuals with leukocytosis and matched controls. To contrast dynamic with static inflammatory responses, we compared cohorts exhibiting leukocyte count changes with those maintaining persistently normal or elevated counts around stressor exposure. Incidence of psychiatric and somatic symptom diagnoses were evaluated within two years of the stressor. Following acute stressors, leukocytosis (compared with normal leukocyte counts) was associated with lower rates of anxiety disorders (Odds Ratio 0.88, 95% Confidence Interval 0.83-0.93), depression (0.92, 0.86-0.98), cognitive symptoms (0.86, 0.81-0.92) and several somatic symptoms, with similar reductions in anxiety (0.92, 0.88-0.95) and depression (0.92, 0.89-0.96) observed after chronic stressors. A dynamic inflammatory response was associated with the most favourable outcomes, with lower rates of anxiety, depression, cognitive difficulties, fatigue, and pain-related symptoms compared to persistently lower or higher inflammation, and lower rates of functional neurological disorder compared to low inflammation. Our findings suggest that patterns of inflammatory response to stressors are associated with diverse mental health and somatic outcomes, with transient immune activation showing a more favourable outcome profile.

AB - Acute and chronic stressors contribute to neuropsychiatric disorders. However, the role of inflammatory dynamics around stress exposure remains unclear. Using TriNetX, an international electronic health records database, we examined how systemic inflammatory activity and its temporal dynamics relate to risk of mental illness and somatic symptoms. We compared 44,904 individuals with records of accidents and leukocytosis in the surrounding period with matched individuals with normal leukocyte counts, and performed analogous comparisons for socioeconomic and psychosocial stressors in cohorts of 100,855 individuals with leukocytosis and matched controls. To contrast dynamic with static inflammatory responses, we compared cohorts exhibiting leukocyte count changes with those maintaining persistently normal or elevated counts around stressor exposure. Incidence of psychiatric and somatic symptom diagnoses were evaluated within two years of the stressor. Following acute stressors, leukocytosis (compared with normal leukocyte counts) was associated with lower rates of anxiety disorders (Odds Ratio 0.88, 95% Confidence Interval 0.83-0.93), depression (0.92, 0.86-0.98), cognitive symptoms (0.86, 0.81-0.92) and several somatic symptoms, with similar reductions in anxiety (0.92, 0.88-0.95) and depression (0.92, 0.89-0.96) observed after chronic stressors. A dynamic inflammatory response was associated with the most favourable outcomes, with lower rates of anxiety, depression, cognitive difficulties, fatigue, and pain-related symptoms compared to persistently lower or higher inflammation, and lower rates of functional neurological disorder compared to low inflammation. Our findings suggest that patterns of inflammatory response to stressors are associated with diverse mental health and somatic outcomes, with transient immune activation showing a more favourable outcome profile.

UR - https://www.scopus.com/pages/publications/105044081861

U2 - 10.1016/j.bbi.2026.106893

DO - 10.1016/j.bbi.2026.106893

M3 - Article

C2 - 42409181

SN - 0889-1591

VL - 138

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

M1 - 106893

ER -