Major depression is often associated or correlated with immune function dysregulation, and the two are thought to share similar physiological pathways and risk factors. Primarily seen through increased inflammation, this relationship is bidirectional with depression often resulting in increased immune response and illness resulting in prolonged sadness and lack of activity. This association is seen both long-term and short-term, with the presence of one often being accompanied by the other and both inflammation and depression often being co-morbid with other conditions.
Explanations for this relationship have come from both medical and evolutionary approaches, with disagreements stemming primarily about whether the connection is functional and why depression and inflammation share similar physiological pathways.
Depression and inflammation Major depression is often associated with biomarkers indicative of inflammatory responses, with interleukin-6, interleukin-1, interleukin-2 receptor, tumor necrosis factor alpha, C-reactive protein, and monocyte chemotactic protein-1 all being found to be elevated in those with depression. Similarly, the same biomarkers are also strongly associated with sickness behavior, with both humans and non-human animals displaying decreased motor activity and lowered interest in normal activities in experimental and naturalistic studies. Despite these symptoms overlapping with major depression, they are insufficient to result in a diagnosis on their own, with their connection to inflammation being better understood than their connection to depression.
The relationship between inflammation and depression is also seen across the lifespan, with inflammation at one point being associated with an increased risk of depression later in life. This has been seen in relatively short periods with both adult men and women with high levels of inflammatory markers experiencing increased risk of depression in the following years. Similar affects are also seen over longer periods of time, with multiple longitudinal studies finding high levels of inflammation early in life to be associated with an increased risk of depression as an adult. Although less studied, evidence also exists for this relationship also being found in the opposite direction, with early experiences of major depression being associated with stronger inflammatory responses to social stressors later in life.
Despite these associations between inflammation and depression symptoms, the degree to which this relationship is causal is still largely unclear. Of the reasons for this, one is that most of the studies examining inflammation are limited to peripheral markers of inflammation, with direct examinations of their connection to processes in the brain being rare. Another is the fact that both depression and inflammation are often confounded with other conditions, allowing for the possibility they both may be caused by other variables rather than one directly causing the other. Of these potential variables, obesity has received the most attention due to findings that BMI often moderates or mediates the link between depression symptoms and inflammation.
Comorbidity Although not as strong as a risk factor as social adversity, illness is often associated with depression. Compared to the healthy portion of the US population, those experiencing illness are 5-10 times more likely to experience depression or depression-like symptoms. This association appears to often develop rapidly and is not constrained to individual with the condition, with a large-scale twin study finding that individuals with severe illness or injury had an odds ratio of 3.1 for developing major depression in the first month of their condition and those with an important member in their social network becoming severely ill having an odds ratio of 2.5 over the same time period. However, the increased association between inflammatory responses and depression is not constrained to times around illness, with both infections and autoimmune disorders increasing one's risk of depression later in life.
In addition to its association with illness in general, depression appears to be particularly connected to conditions in which inflammation makes up a substantial part of symptomology. For example, asthma, diabetes, obesity, heart disease, and rheumatoid arthritis are all often co-morbid with depression and characterized by seemingly excessive inflammatory responses. Although much of these symptoms overlap both sickness behavior and depression, symptoms associated solely with depression are also often found, with suicidal ideation and increased anxiety being common in individuals with autoimmune disorders.
Anti-inflammatories Although in the early stages of research, there are indications that anti-inflammatories can reduce symptoms in those with depression and mood disorders. While depression symptoms tend to be sensitive to placebo responses, clinical trials have shown that these benefits often outperform placebos when used on their own or in conjunction with anti-depressants, with NSAIDs and cytokine inhibitors each being shown effective by multiple trials. In addition, statins, poly-unsaturated fatty acids, corticosteroids, and anti-inflammatories aimed at specific illnesses all have been shown to have positive effects on depression but in a lesser number of studies.
However, despite initial evidence for the ability of anti-inflammatories to lessen depression symptoms, the diverse nature of methods used in these studies and the risks of side effects have been suggested to warrant caution when considering their potential as depression treatments. The use of NSAIDs in particular, has been cautioned due to concerns their potential side-effects and their potential the interact with or limit the effectiveness of certain antidepressants.
Antidepressants Similar to findings that anti-inflammatories may reduce depression symptoms, antidepressants have been shown to reduce inflammation levels. In particular, both selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) are often reported to come with both anti-inflammatory and anti-oxidative effects in clinical trials. In addition to this, a smaller number of studies have reported that those who did not respond to antidepressants had higher levels of inflammatory markers than those who the treatments worked for.
Risk factors Beyond often being associated between with one another, both depression and inflammation are similarly sensitive to external stressors, something which has been used to further argue in favor of their connection. Of the possible types of stressors, those involving social adversity tend to be the most likely to result in depression and are significant predictors of inflammation levels in both experimental and observational studies. This is often seen short term, with inflammation markers often being found to be elevated in response to negative social outcomes and throughout the course of one's depression, with bereaved individuals often experiencing greater inflammation than non-grieving individuals.
Both one's risk of depression and inflammation levels have also been found to be higher in adults who experienced childhood adversity. Similarly, these individuals also face increased risk of autoimmune diseases, which are both indicative of greater inflammatory responses and risk factors for depression. As with the relationship between depression and inflammation as a whole, this relationship is thought to be bidirectional with both depression increasing one's risk of autoimmune disease and autoimmune disease increasing one's risk of depression. However, it is also likely that this connection is also due in part to depression and inflammation sharing many risk factors that may contribute to both conditions.
Social support as a protective factor Similar to their shared risk factors, social support has been found to reduce the risk of both depression and pro-inflammatory phenotypes. This is seen with relatively high levels of social support being found to be associated with decreased risk of depression as well as asthma and heart disease, while also being associated with decreased levels of inflammatory markers as a whole following negative social interactions.
Physiological pathways Inflammasomes Of the pathways linking the non-pathogenic stressors associated with depression to inflammation, inflammasome activation has been highlighted as one of the most promising. While major depression is associated with increased inflammasome activation in general, the NLRP3 inflammasome complex has received the most attention in relation to major depression due to both its role in triggering the release of interleukin-1β and interleukin-18 and its association with depression and depression-like symptoms in both humans and non-human animals.
Compared to other inflammasomes, NLPR3 is sensitive to a greater number and variety of stressors and has been shown to result in inflammation without the presence of pathogens. This is possible due to NLPR3's sensitivity to a wide range of danger-associated molecular patterns (DAMPs), which can indicate the presence of various forms noninfectious stressors throughout the body. Due to this sensitivity and NLPR3's role in triggering cytokine release, NLPR3 is thought to be a key component in sterile inflammatory responses, something which has led to the suggestion that it is a likely mechanism linking non-pathogen induced stress to the increased inflammation that is common in depression and other forms of psychological distress.
Macrophages It has been argued that depression may be the result of macrophage activity as part of the process of inflammation.
Many of the symptoms of depression are thought to stem from the release of inflammatory cytokines by macrophages in the peripheral and central nervous systems. Cytokines have the potential to impact neural connectivity and neurotransmitter concentrations, subsequently producing physiological alterations in the nervous system and contributing to depressive symptoms. One important inflammatory cytokine, interferon-α (IFN- α), is correlated with the development of depressive symptoms through the overactivation of the hypothalamic-pituitary-adrenal axis (HPA axis) and increased levels of corticotropin-releasing factor (CRF). Increased concentrations of other inflammatory cytokines, including interleukin-1(IL-1; causes inflammatory cascade and abnormal hormone concentration), interleukin-6 (IL-6; activates HPA axis and stimulates stress reaction), and tumor necrosis factor-α (TNF-α; activates HPA axis and impacts serotonergic system), have also been found in depressed individuals.
Link between symptoms Compared to the link between external stressors and inflammation, the connection between peripheral inflammation and depression symptoms is better understood. This is due to cytokines being directly involved with inflammatory responses while also serving as a signal that can lead to changes in behavior.
Despite cytokines often being too large to pass through the blood-brain barrier alone, their effect on the central nervous system (CNS) can happen with cytokines entering the CNS in areas where the blood-brain barrier is permeable, by being carried across the blood-brain barrier, or by binding with the cerebral vascular endothelium, thereby signaling the presence of inflammation to the brain. There is also initial evidence that major depression and stress can alter the permeability of the blood-brain barrier, allowing substances which would normally not be able to pass through enter the brain, thereby increasing the ways peripheral inflammation can affect the brain.