Only a portion of individuals experiencing chronic stress and associated increases in inflammation go on to develop pathological elevations in mood and anxiety symptoms. Some prevailing models suggest that the outcomes of chronic stress may largely depend on individual differences in perceived control. In the current study, we used this theoretical framework to disambiguate the influence of autonomic arousal and perceived control on inflammatory and psychological outcomes in a large sample of adults from the Midlife in the United States dataset (wave 2; MIDUS-2) (Final N ​= ​1030), and further replicated our approach in a second (MIDUS-Refresher) cohort (Final N ​= ​728). Using k-means clustering we created subgroups systematically differing in subjective arousal (high/low) and perceived control (low/high) and compared these subgroups on inflammatory markers and psychological outcomes. Overall results showed that individuals in the high subjective arousal subgroups had higher levels of IL-6, CRP, and FIB, independent of level of CNTL. However, distinctive, and pathological psychological symptom patterns became more apparent when individuals were characterized by both subjective arousal and perceived control. These findings suggest that subtyping individuals based on subjective arousal and perceived control can help us disentangle pathological versus adaptive mental health outcomes in those with co-occurring inflammation and may help identify those vulnerable to psychopathology in the context of physical or psychological stressor exposure.

Overactivation of proinflammatory pathways in response to stress may play an important role in the pathophysiology of psychiatric disorders such as major depressive disorder. Autonomic arousal in response to chronic stress has been mechanistically linked to the activation of proinflammatory pathways. However, not all individuals who experience chronic stress or increased inflammation develop pathological elevations in symptoms of mood and anxiety disorders. This heterogeneity poses a challenge in using inflammation as a marker of individual risk or vulnerability for related psychiatric conditions. Rodent models of pathological stress suggest that the outcomes of chronic stress may largely depend on individual differences in perceived control. In the current study, we used this theoretical framework to disambiguate the influence of autonomic arousal and perceived control on inflammatory and psychological outcomes in a large sample of adults from the Midlife in the United States dataset (wave 2; MIDUS-2) (Final N=1030), and further replicated our approach in a second (MIDUS-Refresher) cohort (Final N=728). Using k-means clustering we created subgroups systematically differing in subjective arousal (high/low) and perceived control (low/high) and compared these subgroups on inflammatory markers and psychological outcomes. Overall results showed that high subjective arousal uniquely and reliably predicted higher levels of Interleukin-6, C-Reactive Protein, and Fibrinogen. However, domain specific heterogeneity in pathological and adaptive affective outcomes, depended on both subjective arousal and perceived control. These results further extend and expand upon basic work in rodent models of stressor controllability and illustrate a useful way to probe mechanistic phenotypes in humans.