Comorbidity Factors and Brain Mechanisms Linking Chronic Stress and Systemic Illness

Abstract

Neuropsychiatric symptoms and mental illness are commonly present in patients with chronic systemic diseases. Mood disorders, such as depression, are present in up to 50% of these patients, resulting in impaired physical recovery and more intricate treatment regimen. Stress associated with both physical and emotional aspects of systemic illness is thought to elicit detrimental effects to initiate comorbid mental disorders. However, clinical reports also indicate that the relationship between systemic and psychiatric illnesses is bidirectional, further increasing the complexity of the underlying pathophysiological processes. In this review, we discuss the recent evidence linking chronic stress and systemic illness, such as activation of the immune response system and release of common proinflammatory mediators. Altogether, discovery of new targets is needed for development of better treatments for stress-related psychiatric illnesses as well as improvement of mental health aspects of different systemic diseases.

Figure 1

Bidirectional relationship between systemic illness and psychiatric disorders. Physical and/or psychological stress associated with systemic illness can lead to activation of immune response system resulting in increased local and systemic release of proinflammatory cytokines. Increased levels of inflammatory mediators in the CNS are potentially key contributors to the damaging cellular and morphological adaptations that underlie development of comorbid mental illness.

Figure 2

Role of microglia and inflammasome complex in development of inflammatory responses. Systemic disorders and pathological states can induce activation of microglial cells leading to a local release of proinflammatory cytokines (PICs). This process includes stimulation of microglial P2X7 receptors and downstream activation of the NLRP3 inflammasome. Consequent systemic increases in circulating PICs may signify one of the fundamental mechanisms responsible for initiation of molecular and functional alteration within the CNS that underlie development of mental illness. Interleukin (IL), tumor necrosis factor alpha (TNFα), reactive oxygen species (ROS), NOD-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), N-methyl-D-aspartate receptor (NMDAR), and purinergic type 2X7 (P2X7).