Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

Abstract

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers.

Figure 1

Inflammation causes sickness and depression. This Figure shows the theory that acute triggers cause inflammation and increased production of pro-inflammatory cytokines (PICs), which is associated with the onset of sickness behavior and clinical depression.

Figure 2

This figure shows the functions of acute inflammation-induced sickness behavior: a) energy saving by protecting the organism from the energy consuming effects of inflammation (through somnolence, lethargy, sleepiness, hyperalgesia, reduction of motor activity, exploration and grooming, cognitive deficits, loss of libido, anhedonia, disinterest in social interactions with the environment, and anxiety); b) anti-inflammatory effects (through anorexia, weight loss); and c) pathogen-directed effects (through pyrexia).

Figure 3

This figure compares sickness behavior with clinical depression. Sickness behavior is energy saving, helps to eradicate the trigger, and has anti-inflammatory effects and as such enhances recovery and is part of a compensatory (anti)-inflammatory reflex system (CIRS). Increases in pro-inflammatory cytokines (PICs) underpin both sickness behavior and clinical depression and thus may explain the partial phenomenological overlap. Depression, however, is a chronic disorder with a specific course and pathophysiology and the presence of a CIRS that downregulates the primary inflammatory response. Disorders in tryptophan catabolites (TRYCATs), cell-mediated immune (CMI) activation, and oxidative and nitrosative stress (O&NS), and, in particular, their sequelae (O&NS damage, sensitization, autoimmunity and neuroprogression) are the specific organic substrates of depression. While sickness behavior is a behavioral response to acute triggers, the onset of depression is associated with multiple less-well defined trigger factors, for example, brain disorders, such as Alzheimer (AD), Huntington (HD), and Parkinson (PD) disorder, stroke and multiple sclerosis (MS); systemic disorders, such as cardio-vascular disorder (CVD), chronic obstructive pulmonary disorder (COPD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disorder (IBD), diabetes, metabolic syndrome, HIV infection, cancer, bacterial translocation; and conditions, such as postpartum period, hemodialysis, and interferon-(IFN)α based immunotherapy.