The Bidirectional Relationship of Depression and Inflammation: Double Trouble

Abstract

Depression represents the number one cause of disability worldwide and is often fatal. Inflammatory processes have been implicated in the pathophysiology of depression. It is now well established that dysregulation of both the innate and adaptive immune systems occur in depressed patients and hinder favorable prognosis, including antidepressant responses. In this review, we describe how the immune system regulates mood and the potential causes of the dysregulated inflammatory responses in depressed patients. However, the proportion of never-treated major depressive disorder (MDD) patients who exhibit inflammation remains to be clarified, as the heterogeneity in inflammation findings may stem in part from examining MDD patients with varied interventions. Inflammation is likely a critical disease modifier, promoting susceptibility to depression. Controlling inflammation might provide an overall therapeutic benefit, regardless of whether it is secondary to early life trauma, a more acute stress response, microbiome alterations, a genetic diathesis, or a combination of these and other factors.

Figure 1.. Symptoms of Depression Associated with Different Immunological Changes

Monoamine neurotransmitters have been associated with various symptoms of depression as depicted in each oval. Some symptoms are dependent on multiple neurotransmitters, such as psychomotor retardation that is regulated by serotonin, dopamine, norepinephrine, and glutamate. Each box represents the different immunological changes (e.g., cytokines, immune cell, and others) associated with each symptom.

Figure 2.. Timeline of Discoveries Associating Depression with Immunological and Inflammatory Changes

This timeline depicts the origins of psychoneuroimmunology (Ader and Cohen, 1975), and several prominent inflammatory theories related to depression, starting with the cell immunosuppression theory initiated by Dvorakova et al., 1980, followed by the sickness behavior hypothesis (reviewed in Dantzer et al., 2008) and the theory of hyperactivation of the immune system (initiated by Smith, 1991, and reviewed by Raison et al., 2006) and ending with more recent findings, such as possible effects of changes in the microbiome in MDD patients.

Figure 3.. Diagram of Potential Immune Response Dysregulations in MDD Patients

Stress induces the production of alarmins, molecules that trigger the production of proinflammatory cytokines by innate immune cells that promotes depressive-like behaviors in rodents. Genetically mediated susceptibility, a history of infection, and autoimmune diseases also can prime the immune system’s response to stress, through both the innate and adaptive immune systems. Infection and autoimmune diseases, for example, may act on T helper cells and affect cytokine production and antibody production. The proinflammatory cytokines are thought to promote depression, whereas the role of anti-inflammatory cytokines is less understood, and it remains to be determined whether anti-inflammatory cytokines induce cell immunosuppression or tolerance, and whether the hypothalamic-pituitary-adrenal axis (HPA) and/or the sympathetic nervous system (SNS) axis are implicated in this phenomena.

Figure 4.. Multiple Mechanisms May Contribute to the Dysregulation of Cytokines in MDD

Immune cell production of cytokines is regulated by multiple mechanisms, including anti-inflammatory actions by glucocorticoids, and vagus nerve pathways, and proinflammatory actions influenced by the microbial composition and stress-induced DAMPs involving both the inflammasome and the NF-κB pathways. Ach, acetylcholine; ATP, adenosine triphosphate; DAMP, danger-associated molecular pattern; GR, glucocorticoid receptor; GSK3, glycogen synthase kinase-3; HMGB1, high-mobility group binding protein-1; IL, interleukin; NF-κB, nuclear factor-kappa B; TLR, Toll-like receptor; TGF, transforming growth factor; TNF, tumor necrosis factor

Figure 5.. Where the Field Is Going

Historically many studies of immunological factors that may affect MDD focused on a single component, such as genetic variables, cytokines, immune cell types or actions, and the microbiome composition. With technological advances that have recently become available, or are under development, we envision that researchers will be able to apply a more integrated approach to analyze multiple parameters in each individual subject to obtain a more complete and integrated picture of genetic, microbial, and immunological factors that influence the onset, course, and treatment response of MDD patients.