Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

Abstract

The study of inflammation in fear- and anxiety-based disorders has gained interest as growing literature indicates that pro-inflammatory markers can directly modulate affective behavior. Indeed, heightened concentrations of inflammatory signals, including cytokines and C-reactive protein, have been described in posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), and phobias (agoraphobia, social phobia, etc.). However, not all reports indicate a positive association between inflammation and fear- and anxiety-based symptoms, suggesting that other factors are important in future assessments of inflammation's role in the maintenance of these disorders (ie, sex, co-morbid conditions, types of trauma exposure, and behavioral sources of inflammation). The most parsimonious explanation of increased inflammation in PTSD, GAD, PD, and phobias is via the activation of the stress response and central and peripheral immune cells to release cytokines. Dysregulation of the stress axis in the face of increased sympathetic tone and decreased parasympathetic activity characteristic of anxiety disorders could further augment inflammation and contribute to increased symptoms by having direct effects on brain regions critical for the regulation of fear and anxiety (such as the prefrontal cortex, insula, amygdala, and hippocampus). Taken together, the available data suggest that targeting inflammation may serve as a potential therapeutic target for treating these fear- and anxiety-based disorders in the future. However, the field must continue to characterize the specific role pro-inflammatory signaling in the maintenance of these unique psychiatric conditions.

Figure 1

Inflammation in fear- and anxiety-based disorders: mechanisms and consequences. Exposure to trauma and acute stressors in individuals with fear- and anxiety-based may facilitate increased immune activity in both the periphery and the central nervous system (CNS) via stress and trauma effects on neuroendocrine systems and the sympathetic nervous system (SNS). The overactivity of the SNS and decreased activity of the parasympathetic nervous system in fear- and anxiety-based disorders increases the release of pro-inflammatory cytokines. Suppressed ability of glucocorticoids to inhibit inflammatory processes in these chronic stress states also contributes to a pro-inflammatory state that can influence neurotransmitter systems, neurocircuitry, and finally, affective behavior. Cytokines may contribute to the maintenance of fear- and anxiety-based symptoms by affecting the activity and connections of regions of the brain implicated in the etiology of these disorders, including the amygdala, hippocampus, insula, medial prefrontal cortex (mPFC), and the anterior cingulate (ACC). Figure adapted from Felger et al (2016) and reproduced by permission of Oxford University Press (http://global.oup.com/?cc=us).