Depression and immune function

Major depression is often associated or correlated with immune function dysregulation,[1][2][3][4][5][6]and the two are thought to share similar physiological pathways and risk factors.[1][7] 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.[2][8] 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.[9][10][11][12]

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.[13][14][15]

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.[2][8][1][5][3] 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.[2][16][17] Despite these symptoms overlapping with major depression, they are insufficient to result in a diagnosis on their own,[1][18] with their connection to inflammation being better understood than their connection to depression.[19]

The relationship between inflammation and depression is also seen across the lifespan, with inflammation at one point being associated with increased risk of depression later in life.[8] 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.[8][11][20] 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 increased risk of depression as an adult.[21][22][23] 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.[4]

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.[8] 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.[8] 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.[24][25]

Comorbidity

Although not as strong as a risk factor as social adversity,[26] 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.[9][27] 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.[26] 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.[10][28]

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.[29] For example, asthma,[30] diabetes,[31][32][33] obesity,[34] heart disease,[35][36] and rheumatoid arthritis[37][38] are all often co-morbid with depression and characterized by seemingly excessive inflammatory responses.[39] Although much of these symptoms overlap both sickness behavior and depression, symptoms associated with solely with depression are also often found, with suicidal ideation and increased anxiety being common in individuals with autoimmune disorders.[40]

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.[8][41][42][43] While depression symptoms tend to be sensitive to placebo responses,[44] 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.[8][45] In addition, statins, poly-unsaturated fatty acids, corticosteroids, and anti-inflammatories aimed at specific illnesses all have been shown to has positive effects on depression but in a lesser number of studies.[8][42]

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.[8][46] The use of NSAIDs in particular, has been cautioned due to concerns over potential side-effects[8][47] and their potential the limit the effectiveness of certain antidepressants.[48]

Antidepressants

Similar to findings that anti-inflammatories may reduce depression symptoms, antidepressants have been shown to reduce inflammation levels.[8][49] In particular, both selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are often reported to come with both anti-inflammatory and anti-oxidative effects in clinical trials.[50] 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.[50][51]

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.[39][15] Of the possible types of stressors, those involving social adversity tend to be the most likely to result in depression[26][52][53] and are significant predictors of inflammation levels in both experimental and observational studies.[39][15] This is often seen short term, with inflammation markers often being found to be elevated in response to negative social outcomes[54][55][56] and throughout the course of one's depression, with bereaved individuals often experiencing greater inflammation than non-grieving individuals.[57][58]

Both one's risk of depression[53][59] and inflammation levels [39][55][12] have also been found to be higher in adults who experienced childhood adversity. Similarly, these individuals also face increased risk of autoimmune diseases,[12] which are both indicative of greater inflammatory responses and risk factors for depression.[60][61] 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.[60] 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.[60]

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 [30][62] and heart disease,[63] while also being associated with decreased levels of inflammatory markers as a whole following negative social interactions.[39][64]

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.[7] 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.[7][65][66]

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.[7][65] 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.[7][65] Due to this sensitivity and NLPR3's role in triggering cytokine release, NLPR3 is thought to be a key component in sterile inflammatory responses,[7] 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.[7][65][67]

Macrophages

It has been argued that depression may be the result of macrophage activity as part of the process of inflammation.[68][41][69][70]

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.[7][71][72]

Despite cytokines often being too large to pass through the blood-brain barrier alone,[72] 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.[7][65] 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.[65][73]

Once peripheral cytokines initially communicate the existence of inflammation outside of the CNS, microglia and astrocytes within the CNS are activated and release additional cytokines and chemokines, which then results in the production of neurotransmitters that can contribute to sickness behavior or depression.[39][74] Although the possibility of maladptive outcomes due to dysregulation, this connection is largely thought to be adaptive due to the benefits of coordinating the CNS with broader immune processes [74][75] and due to the role immune function in the brain has in facilitating learning and memory.[76]

Incomplete connection

Despite being associated in many ways, the connection between depression and inflammation is not complete.[1] This is seen in that immune activity does not appear to be enough on its own to cause depression.[39] Evidence for this comes primarily from treatments that involve the pro-inflammatory IFN-α, which is commonly used in treating viral infections but only results in major depression in about one third of patients.[39][77][78][79] Of the reasons why this might be, one suggestion is that symptoms relating to low mood and anxiety are brought about less in patients relative to increases in symptoms relating to reduced activity and appetite suppression, which tend to almost always occur.[9] This has been seen to indicate that depression as a whole cannot be seen as sickness behavior.[1] However, others have suggested the need for approaches that include illness symptoms as a sub-type of depression, with certain types being more connected to inflammation.[35]

In addition to evidence suggesting that inflammation is not sufficient for the development of major depression, evidence for a lack of complete overlap also comes from findings that depression often occurs without existing immune challenges, with social adversity appearing to cause depression without the requirement of underlying inflammation.[1][28] Similarly, the existence of variation in the degree to which depressed individuals experience inflammation has also been seen to suggest that it is possible that some instances of depression may occur without inflammation.[39] However, it is possible that all instances of depression involve increased inflammation, something which is consistent with the idea that depression may have evolved through the co-option of sickness behavior.[14]

In animals

Although major depression is primarily studied in humans, there is evidence that depression-like symptoms beyond sickness behavior are also seen in non-human animals and that these symptoms often are accompanied by increased inflammation.[13][14][80]  Primarily seen in experimental studies, these symptoms often take the form of states that appear similar to the helplessness, anxiety, anhedonia, and weight change seen in human depression.[13][81][82][83] However, the degree to which these symptoms are comparable to human symptoms is unknown, with the full suite of cognitive symptoms associated with depression having yet to be found in any study of non-human animals.[80]

Compared to the uncertainty about how the behaviors observed in non-human animals are experienced cognitively, there is much more evidence supporting the connection between inflammation and sickness behavior in non-human animals.[82] As with humans, this is mainly seen experimentally, with injections of pro-inflammatory cytokines often resulting in sickness behavior and occasionally other depression-like symptoms.[84] Likewise, the ability for anti-inflammatories to reduce these symptoms is also seen in experimental studies as is seen in humans.[13][85][86]

Medical explanations

From immune response

One explanation for the connection between inflammation and depression symptoms, is that depression is a disorder that stems from immune responses across the body.[13]  Due in large part to the systems that bring them about both involving the same pro-inflammatory cytokines, the suggestion is that strong or prolonged immune responses allow for those with susceptibilities to depression to experience it outside of experiences with any other risk factors.[1][13] Of the ways this might happen, one is that those whose immune responses have been shifted to be pro-inflammatory without sufficient anti-inflammatory compensation have elevated risk of experiencing inflammation intense enough to cause depression.[13] Another suggestion is that variation in neurotransmitter production or receptors may also play a role in one's risk of experiencing inflammation-based depression if certain combinations result in increased risk of inflammation, similarly putting them at risk of maladaptive changes in brain chemistry.[13]

However, findings that depression and pro-inflammatory responses do not require the presence of the other for one to develop have led others to argue that the two conditions are often distinct,[39] something which has been suggested to reduce the explanation's appeal to psychiatrists.[13]

Evolutionary explanations

Pathogen host defense hypothesis

One explanation that sees the connection between depression and inflammation as the result of adaptations is the Pathogen Host Defense Hypothesis (PATHOS-D), which proposes that depression is directly tied to immune responses.[15] From this perspective, depression-like symptoms are thought to reduce energy consumption and reallocate resources so that one can mount a stronger immune defense, thereby reducing the organism's risk of death.[15] In addition to this, both the reduction in activity and social withdrawal that often accompanies depression are also suggested to provide benefits by decreasing one's risk of encountering new pathogens or exposing kin or cooperative partners to one's illness, although they are likely of secondary importance.[2][15]

Beyond serving as an explanation for the connection between depression and inflammation, PATHOS-D was also designed to account for the connection between social stressors and depression.[15] By viewing social adversity as a recurrent cue of likely injury and infection risk across human evolutionary history, social stressors are incorporated into the hypothesis with the expectation that their presence can be used to inform the need to up-regulate immune function before the actual injury or infection risk occurs. As the risk of death in these situations was high ancestrally, false alarms in which social adversity results in one experiencing the costs of depression without any pathogen threat are expected to be common due to the greater costs of failing to respond to an actual threat. Therefore, the benefits of depression in terms of reduced mortality are expected to outweigh the costs of depression throughout our evolutionary history both in terms of false alarms and the costs of depression in general.

Although serving as an explanation for the association between depression and increased inflammation levels, the host-defense hypothesis cannot currently explain many of the symptoms outside of reduced activity or social withdrawal.[2] For example, both depression's connection to suicidality and the fact that depression symptoms often persist outside of illness or after a pathogen has been dealt with suggest that there is more to depression than its role as a coordinated immune defense.[2] However, the host-defense hypothesis is not mutually exclusive with other explanations for these occurrences,[2] and it is possible that illness symptoms can be co-opted for other purposes,[14][16][44] such as signaling weakness and need for help.[44]

Social signal transduction theory

Closely related to the host-defense hypothesis, the Social Signal Transduction Theory of Depression also directly incorporates social stressors into its explanation for the connection between depression and up-regulated immune responses.[39] However, compared to PATHOS-D, it emphasizes the role of depression as the body's way to prepare itself for the threat of future infection to a greater degree. It also differs in that while PATHOS-D still allows for many cases of depression to be adaptive in Western, Industrialized societies, the Social Signal Transduction Theory expects most instances to be maladaptive.[39] This is due to the expectation that much of the cues indicating risk of injury are less relevant now due to both their lesser connection with violence and the fact that modern medicine has greatly reduced one's risk of death or long-term damage from infection.

However, like PATHOS-D, the Social Signal Transduction Theory of Depression has been suggested to be compatible with other explanations, with there being potential for both the cognitive and inflammatory symptoms of depression to be functional in times of social adversity.[87]

Immune dysregulation hypothesis

Another explanation for the connection between depression and inflammation that emphasizes the role of environmental mismatch is the Immune Dysregulation Hypothesis.[4] The Immune Dysregulation hypothesis is based on the old friends hypothesis, which suggests that Western, sanitary environments fail to provide sufficient microorganism exposure to train the immune system to tolerate safe or difficult to eradicate microorganisms, thereby resulting in greater prevalence of the pro-inflammatory phenotypes that typify autoimmune diseases.[2][4] As depression is also associated with pro-inflammatory responses, the suggestion is that the causes of depression are little different from the causes of the autoimmune diseases it is largely co-morbid with, with sanitary environments increasing the risk of excessive inflammation in response to psychosocial stressors just as it is thought to with otherwise harmless microorganisms.[4]

However, evidence of increased inflammation among depressed individuals is also seen among the Tsimané, which has been presented as challenge for the Immune Dysregulation Hypothesis' expectation that this association is restricted to Western environments.[2]

Co-opted sickness behavior

An additional explanation for the overlap in symptoms shared by depression and sickness behavior is that the neurobiology associated with sickness behavior was co-opted to result in melancholic symptoms outside of illness by other adaptations.[14] Based largely on the degree of overlap in symptoms major depression, sickness behavior, and starvation depression share, the argument is that sickness behavior likely evolved first due to its prevalence across animal species and the role infection plays as a major fitness threat.[14] However, once the ability to down-regulate behavior to divert resources for immune function existed, the underlying mechanisms could then be used by other systems. This is thought to then allow for additional adaptations that add cognitive symptoms unique to melancholic depression to those stemming from normal sickness behavior.[14]

Although likely consistent with any explanation of the evolution as major depression as the result of psychological adaptations, Andrews and Durisko present the co-option hypothesis as mainly consistent with the analytical rumination hypothesis.[14][88] From this perspective, major depression is thought to often result in improved problem solving due to the redistribution of energy away from physical activity for increased rumination. As this is thought to be energetically costly, it therefore functions very similarly to sickness behavior with it both being adaptive for redistributing energy flows, differing primarily in whether increasing energy goes to cognition or immune defense.

See also

References
  1. Valkanova V, Ebmeier KP, Allan CL (September 2013). "CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies". Journal of Affective Disorders. 150 (3): 736–44. doi:10.1016/j.jad.2013.06.004. PMID 23870425.
  2. Stieglitz J, Trumble BC, Thompson ME, Blackwell AD, Kaplan H, Gurven M (October 2015). "Depression as sickness behavior? A test of the host defense hypothesis in a high pathogen population". Brain, Behavior, and Immunity. 49: 130–9. doi:10.1016/j.bbi.2015.05.008. PMC 4567437. PMID 26044086.
  3. Dantzer R (May 2009). "Cytokine, sickness behavior, and depression". Immunology and Allergy Clinics of North America. 29 (2): 247–64. doi:10.1016/j.iac.2009.02.002. PMC 2740752. PMID 19389580.
  4. Raison CL, Lowry CA, Rook GA (December 2010). "Inflammation, sanitation, and consternation: loss of contact with coevolved, tolerogenic microorganisms and the pathophysiology and treatment of major depression". Archives of General Psychiatry. 67 (12): 1211–24. doi:10.1001/archgenpsychiatry.2010.161. PMC 3724429. PMID 21135322.
  5. Drevets, Wayne C.; Wittenberg, Gayle M.; Bullmore, Edward T.; Manji, Husseini K. (2022-01-17). "Immune targets for therapeutic development in depression: towards precision medicine". Nature Reviews Drug Discovery. 21 (3): 224–244. doi:10.1038/s41573-021-00368-1. ISSN 1474-1784. PMC 8763135. PMID 35039676.
  6. Lee, Chieh-Hsin; Giuliani, Fabrizio (2019). "The Role of Inflammation in Depression and Fatigue". Frontiers in Immunology. 10: 1696. doi:10.3389/fimmu.2019.01696. ISSN 1664-3224. PMC 6658985. PMID 31379879.
  7. Fleshner M, Frank M, Maier SF (January 2017). "Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders". Neuropsychopharmacology. 42 (1): 36–45. doi:10.1038/npp.2016.125. PMC 5143484. PMID 27412959.
  8. Kohler O, Krogh J, Mors O, Benros ME (2016-08-26). "Inflammation in Depression and the Potential for Anti-Inflammatory Treatment". Current Neuropharmacology. 14 (7): 732–42. doi:10.2174/1570159X14666151208113700. PMC 5050394. PMID 27640518.
  9. Capuron L, Miller AH (December 2004). "Cytokines and psychopathology: lessons from interferon-alpha". Biological Psychiatry. 56 (11): 819–24. doi:10.1016/j.biopsych.2004.02.009. PMID 15576057. S2CID 54345505.
  10. Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J, Mortensen PB (August 2013). "Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study". JAMA Psychiatry. 70 (8): 812–20. doi:10.1001/jamapsychiatry.2013.1111. PMID 23760347.
  11. Gimeno D, Kivimäki M, Brunner EJ, Elovainio M, De Vogli R, Steptoe A, et al. (March 2009). "Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study". Psychological Medicine. 39 (3): 413–23. doi:10.1017/S0033291708003723. PMC 2788760. PMID 18533059.
  12. Miller GE, Chen E (June 2010). "Harsh family climate in early life presages the emergence of a proinflammatory phenotype in adolescence". Psychological Science. 21 (6): 848–56. doi:10.1177/0956797610370161. PMC 3207635. PMID 20431047.
  13. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW (January 2008). "From inflammation to sickness and depression: when the immune system subjugates the brain". Nature Reviews. Neuroscience. 9 (1): 46–56. doi:10.1038/nrn2297. PMC 2919277. PMID 18073775.
  14. Andrews PW, Durisko Z (2016-01-19). DeRubeis RJ, Strunk DR (eds.). "The Evolution of Depressive Phenotypes". The Oxford Handbook of Mood Disorders. Oxford University Press. 1: 23–36. doi:10.1093/oxfordhb/9780199973965.013.3. ISBN 978-0-19-997396-5.
  15. Raison CL, Miller AH (January 2013). "The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D)". Molecular Psychiatry. 18 (1): 15–37. doi:10.1038/mp.2012.2. PMC 3532038. PMID 22290120.
  16. Tiokhin, Leonid (2016). "Do Symptoms of Illness Serve Signaling Functions? (Hint: Yes)". The Quarterly Review of Biology. 91 (2): 177–195. doi:10.1086/686811. ISSN 0033-5770. PMID 27405223. S2CID 25776913.
  17. Hennessy MB, Deak T, Schiml PA (March 2014). "Sociality and sickness: have cytokines evolved to serve social functions beyond times of pathogen exposure?". Brain, Behavior, and Immunity. 37: 15–20. doi:10.1016/j.bbi.2013.10.021. PMC 3951666. PMID 24184399.
  18. "What Is Depression?". www.psychiatry.org. Retrieved 2019-04-23.
  19. Pariante CM (June 2017). "Why are depressed patients inflamed? A reflection on 20 years of research on depression, glucocorticoid resistance and inflammation". European Neuropsychopharmacology. 27 (6): 554–559. doi:10.1016/j.euroneuro.2017.04.001. PMID 28479211.
  20. Matthews KA, Chang YF, Thurston RC, Bromberger JT (February 2014). "Child abuse is related to inflammation in mid-life women: role of obesity". Brain, Behavior, and Immunity. 36: 29–34. doi:10.1016/j.bbi.2013.09.013. PMC 3947183. PMID 24076375.
  21. Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB (October 2014). "Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study". JAMA Psychiatry. 71 (10): 1121–8. doi:10.1001/jamapsychiatry.2014.1332. PMC 4561502. PMID 25133871.
  22. Goodwin RD (November 2011). "Association between infection early in life and mental disorders among youth in the community: a cross-sectional study". BMC Public Health. 11 (1): 878. doi:10.1186/1471-2458-11-878. PMC 3248872. PMID 22103993.
  23. Pasco JA, Nicholson GC, Williams LJ, Jacka FN, Henry MJ, Kotowicz MA, et al. (November 2010). "Association of high-sensitivity C-reactive protein with de novo major depression". The British Journal of Psychiatry. 197 (5): 372–7. doi:10.1192/bjp.bp.109.076430. PMID 21037214.
  24. Krogh J, Benros ME, Jørgensen MB, Vesterager L, Elfving B, Nordentoft M (January 2014). "The association between depressive symptoms, cognitive function, and inflammation in major depression". Brain, Behavior, and Immunity. 35: 70–6. doi:10.1016/j.bbi.2013.08.014. PMID 24016864. S2CID 41758614.
  25. Howren MB, Lamkin DM, Suls J (February 2009). "Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis". Psychosomatic Medicine. 71 (2): 171–86. doi:10.1097/psy.0b013e3181907c1b. PMID 19188531. S2CID 10130027.
  26. Kendler KS, Karkowski LM, Prescott CA (June 1999). "Causal relationship between stressful life events and the onset of major depression". The American Journal of Psychiatry. 156 (6): 837–41. doi:10.1176/ajp.156.6.837. PMID 10360120.
  27. Evans DL, Staab JP, Petitto JM, Morrison MF, Szuba MP, Ward HE, et al. (1999). "Depression in the medical setting: biopsychological interactions and treatment considerations". The Journal of Clinical Psychiatry. 60 Suppl 4: 40–55, discussion 56. PMID 10086482.
  28. Raison CL, Miller AH (December 2011). "Is depression an inflammatory disorder?". Current Psychiatry Reports. 13 (6): 467–75. doi:10.1007/s11920-011-0232-0. PMC 3285451. PMID 21927805.
  29. Evans DL, Charney DS, Lewis L, Golden RN, Gorman JM, Krishnan KR, et al. (August 2005). "Mood disorders in the medically ill: scientific review and recommendations". Biological Psychiatry. 58 (3): 175–89. doi:10.1016/j.biopsych.2005.05.001. PMID 16084838. S2CID 23834820.
  30. Chen E, Miller GE (November 2007). "Stress and inflammation in exacerbations of asthma". Brain, Behavior, and Immunity. 21 (8): 993–9. doi:10.1016/j.bbi.2007.03.009. PMC 2077080. PMID 17493786.
  31. Holt RI, de Groot M, Golden SH (June 2014). "Diabetes and depression". Current Diabetes Reports. 14 (6): 491. doi:10.1007/s11892-014-0491-3. PMC 4476048. PMID 24743941.
  32. Bădescu SV, Tătaru C, Kobylinska L, Georgescu EL, Zahiu DM, Zăgrean AM, Zăgrean L (2016). "The association between Diabetes mellitus and Depression". Journal of Medicine and Life. 9 (2): 120–5. PMC 4863499. PMID 27453739.
  33. Gendelman N, Snell-Bergeon JK, McFann K, Kinney G, Paul Wadwa R, Bishop F, et al. (April 2009). "Prevalence and correlates of depression in individuals with and without type 1 diabetes". Diabetes Care. 32 (4): 575–9. doi:10.2337/dc08-1835. PMC 2660458. PMID 19171719.
  34. Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers P, Penninx BW, Zitman FG (March 2010). "Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies". Archives of General Psychiatry. 67 (3): 220–9. doi:10.1001/archgenpsychiatry.2010.2. PMID 20194822.
  35. Baune BT, Stuart M, Gilmour A, Wersching H, Heindel W, Arolt V, Berger K (March 2012). "The relationship between subtypes of depression and cardiovascular disease: a systematic review of biological models". Translational Psychiatry. 2 (3): e92. doi:10.1038/tp.2012.18. PMC 3309537. PMID 22832857.
  36. Celano CM, Huffman JC (2011). "Depression and cardiac disease: a review". Cardiology in Review. 19 (3): 130–42. doi:10.1097/CRD.0b013e31820e8106. PMID 21464641. S2CID 205567046.
  37. Margaretten M, Julian L, Katz P, Yelin E (2011). "Depression in patients with rheumatoid arthritis: description, causes and mechanisms". International Journal of Clinical Rheumatology. 6 (2): 617–623. doi:10.2217/ijr.11.6. PMC 3247620. PMID 22211138.
  38. Isik A, Koca SS, Ozturk A, Mermi O (June 2007). "Anxiety and depression in patients with rheumatoid arthritis". Clinical Rheumatology. 26 (6): 872–8. doi:10.1007/s10067-006-0407-y. PMID 16941197. S2CID 20831139.
  39. Slavich GM, Irwin MR (May 2014). "From stress to inflammation and major depressive disorder: a social signal transduction theory of depression". Psychological Bulletin. 140 (3): 774–815. doi:10.1037/a0035302. PMC 4006295. PMID 24417575.
  40. Pryce CR, Fontana A (2016). Dantzer R, Capuron L (eds.). "Depression in Autoimmune Diseases" (PDF). Current Topics in Behavioral Neurosciences. Springer International Publishing. 31: 139–154. doi:10.1007/7854_2016_7. ISBN 9783319511511. PMID 27221625.
  41. Kopschina Feltes P, Doorduin J, Klein HC, Juárez-Orozco LE, Dierckx RA, Moriguchi-Jeckel CM, de Vries EF (September 2017). "Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy". Journal of Psychopharmacology. 31 (9): 1149–1165. doi:10.1177/0269881117711708. PMC 5606303. PMID 28653857.
  42. Fond G, Hamdani N, Kapczinski F, Boukouaci W, Drancourt N, Dargel A, et al. (March 2014). "Effectiveness and tolerance of anti-inflammatory drugs' add-on therapy in major mental disorders: a systematic qualitative review". Acta Psychiatrica Scandinavica. 129 (3): 163–79. doi:10.1111/acps.12211. PMID 24215721. S2CID 23482349.
  43. Husain MI, Strawbridge R, Stokes PR, Young AH (September 2017). "Anti-inflammatory treatments for mood disorders: Systematic review and meta-analysis". Journal of Psychopharmacology. 31 (9): 1137–1148. doi:10.1177/0269881117725711. PMID 28858537. S2CID 6639590.
  44. Steinkopf, Leander (2015). "The Signaling Theory of Symptoms: An Evolutionary Explanation of the Placebo Effect". Evolutionary Psychology. 13 (3): 147470491560055. doi:10.1177/1474704915600559. ISSN 1474-7049.
  45. Köhler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O, Krogh J (December 2014). "Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials". JAMA Psychiatry. 71 (12): 1381–91. doi:10.1001/jamapsychiatry.2014.1611. PMID 25322082.
  46. Anglin R, Moayyedi P, Leontiadis GI (May 2015). "Anti-inflammatory Intervention in Depression". JAMA Psychiatry. 72 (5): 512. doi:10.1001/jamapsychiatry.2014.3246. PMID 25945487.
  47. Browning CH (1996). "Nonsteroidal anti-inflammatory drugs and severe psychiatric side effects". International Journal of Psychiatry in Medicine. 26 (1): 25–34. doi:10.2190/1B32-79EA-B6H5-395V. PMID 8707453. S2CID 24252939.
  48. Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P (May 2011). "Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans". Proceedings of the National Academy of Sciences of the United States of America. 108 (22): 9262–7. Bibcode:2011PNAS..108.9262W. doi:10.1073/pnas.1104836108. PMC 3107316. PMID 21518864.
  49. Belmaker RH, Agam G (January 2008). "Major depressive disorder". The New England Journal of Medicine. 358 (1): 55–68. doi:10.1056/NEJMra073096. PMID 18172175.
  50. Gałecki P, Mossakowska-Wójcik J, Talarowska M (January 2018). "The anti-inflammatory mechanism of antidepressants - SSRIs, SNRIs". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 80 (Pt C): 291–294. doi:10.1016/j.pnpbp.2017.03.016. PMID 28342944. S2CID 34055415.
  51. Lindqvist D, Dhabhar FS, James SJ, Hough CM, Jain FA, Bersani FS, et al. (February 2017). "Oxidative stress, inflammation and treatment response in major depression". Psychoneuroendocrinology. 76: 197–205. doi:10.1016/j.psyneuen.2016.11.031. PMC 5272818. PMID 27960139.
  52. Mazure, Carolyn M. (1998). "Life Stressors as Risk Factors in Depression". Clinical Psychology: Science and Practice. 5 (3): 291–313. doi:10.1111/j.1468-2850.1998.tb00151.x.
  53. Hammen C (2005). "Stress and depression". Annual Review of Clinical Psychology. 1 (1): 293–319. doi:10.1146/annurev.clinpsy.1.102803.143938. PMID 17716090. S2CID 17119300.
  54. Slopen N, Kubzansky LD, McLaughlin KA, Koenen KC (February 2013). "Childhood adversity and inflammatory processes in youth: a prospective study". Psychoneuroendocrinology. 38 (2): 188–200. doi:10.1016/j.psyneuen.2012.05.013. PMC 3632283. PMID 22727478.
  55. Slopen N, Koenen KC, Kubzansky LD (February 2012). "Childhood adversity and immune and inflammatory biomarkers associated with cardiovascular risk in youth: a systematic review". Brain, Behavior, and Immunity. 26 (2): 239–50. doi:10.1016/j.bbi.2011.11.003. PMID 22138616. S2CID 28740445.
  56. Segerstrom SC, Miller GE (July 2004). "Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry". Psychological Bulletin. 130 (4): 601–30. doi:10.1037/0033-2909.130.4.601. PMC 1361287. PMID 15250815.
  57. Schultze-Florey CR, Martínez-Maza O, Magpantay L, Breen EC, Irwin MR, Gündel H, O'Connor MF (October 2012). "When grief makes you sick: bereavement induced systemic inflammation is a question of genotype". Brain, Behavior, and Immunity. 26 (7): 1066–71. doi:10.1016/j.bbi.2012.06.009. PMC 3601554. PMID 22735772.
  58. O'Connor MF, Wellisch DK, Stanton AL, Olmstead R, Irwin MR (May 2012). "Diurnal cortisol in Complicated and Non-Complicated Grief: slope differences across the day". Psychoneuroendocrinology. 37 (5): 725–8. doi:10.1016/j.psyneuen.2011.08.009. PMC 3258306. PMID 21925795.
  59. Duncan RD, Saunders BE, Kilpatrick DG, Hanson RF, Resnick HS (July 1996). "Childhood physical assault as a risk factor for PTSD, depression, and substance abuse: findings from a national survey". The American Journal of Orthopsychiatry. 66 (3): 437–48. doi:10.1037/h0080194. PMID 8827267.
  60. Euesden J, Danese A, Lewis CM, Maughan B (2017-03-06). Hashimoto K (ed.). "A bidirectional relationship between depression and the autoimmune disorders - New perspectives from the National Child Development Study". PLOS ONE. 12 (3): e0173015. Bibcode:2017PLoSO..1273015E. doi:10.1371/journal.pone.0173015. PMC 5338810. PMID 28264010.
  61. Benros ME (November 2016). "Autoimmune diseases can be associated with depression". Evidence-Based Mental Health. 19 (4): e27. doi:10.1136/eb-2016-102417. PMID 27729383. S2CID 45199547.
  62. Smith A, Nicholson K (May 2001). "Psychosocial factors, respiratory viruses and exacerbation of asthma". Psychoneuroendocrinology. 26 (4): 411–20. doi:10.1016/S0306-4530(00)00063-9. PMC 7125531. PMID 11259860.
  63. Knox SS, Uvnäs-Moberg K (November 1998). "Social isolation and cardiovascular disease: an atherosclerotic pathway?". Psychoneuroendocrinology. 23 (8): 877–90. doi:10.1016/S0306-4530(98)00061-4. PMID 9924742. S2CID 28094733.
  64. Kiecolt-Glaser JK, Loving TJ, Stowell JR, Malarkey WB, Lemeshow S, Dickinson SL, Glaser R (December 2005). "Hostile marital interactions, proinflammatory cytokine production, and wound healing". Archives of General Psychiatry. 62 (12): 1377–84. doi:10.1001/archpsyc.62.12.1377. PMID 16330726.
  65. Kaufmann FN, Costa AP, Ghisleni G, Diaz AP, Rodrigues AL, Peluffo H, Kaster MP (August 2017). "NLRP3 inflammasome-driven pathways in depression: Clinical and preclinical findings". Brain, Behavior, and Immunity. 64: 367–383. doi:10.1016/j.bbi.2017.03.002. PMID 28263786. S2CID 205866721.
  66. Alcocer-Gómez E, Cordero MD (February 2017). "NLRP3 inflammasome: common nexus between depression and cardiovascular diseases". Nature Reviews. Cardiology. 14 (2): 124. doi:10.1038/nrcardio.2016.214. PMID 28054580.
  67. Iwata M, Ota KT, Duman RS (July 2013). "The inflammasome: pathways linking psychological stress, depression, and systemic illnesses". Brain, Behavior, and Immunity. 31: 105–14. doi:10.1016/j.bbi.2012.12.008. PMC 4426992. PMID 23261775.
  68. Abbott, Alison (2018-05-29). "Depression: the radical theory linking it to inflammation". Nature. 557 (7707): 633–634. Bibcode:2018Natur.557..633A. doi:10.1038/d41586-018-05261-3. S2CID 44128017.
  69. Dey A, Hankey Giblin PA (June 2018). "Insights into Macrophage Heterogeneity and Cytokine-Induced Neuroinflammation in Major Depressive Disorder". Pharmaceuticals. 11 (3): 64. doi:10.3390/ph11030064. PMC 6160985. PMID 29941796.
  70. Gałecki P, Talarowska M (June 2018). "Inflammatory theory of depression". Psychiatria Polska. 52 (3): 437–447. doi:10.12740/PP/76863. PMID 30218560.
  71. Liongue C, Sertori R, Ward AC (July 2016). "Evolution of Cytokine Receptor Signaling". Journal of Immunology. 197 (1): 11–8. doi:10.4049/jimmunol.1600372. PMID 27317733.
  72. Corwin EJ (July 2000). "Understanding cytokines. Part I: Physiology and mechanism of action". Biological Research for Nursing. 2 (1): 30–40. doi:10.1177/109980040000200104. PMID 11232509. S2CID 28608400.
  73. Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O (April 2013). "Neuroinflammation and psychiatric illness". Journal of Neuroinflammation. 10 (1): 43. doi:10.1186/1742-2094-10-43. PMC 3626880. PMID 23547920.
  74. Tian L, Ma L, Kaarela T, Li Z (July 2012). "Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases". Journal of Neuroinflammation. 9 (1): 155. doi:10.1186/1742-2094-9-155. PMC 3410819. PMID 22747919.
  75. Nesse, Randolph M.; Williams, George C.. (2012). Why We Get Sick The New Science of Darwinian Medicine. Knopf Doubleday Publishing Group. ISBN 9780307816009. OCLC 1090912898.{{cite book}}: CS1 maint: multiple names: authors list (link)
  76. Yirmiya R, Goshen I (February 2011). "Immune modulation of learning, memory, neural plasticity and neurogenesis". Brain, Behavior, and Immunity. 25 (2): 181–213. doi:10.1016/j.bbi.2010.10.015. PMID 20970492. S2CID 13826202.
  77. Krishnan V, Nestler EJ (October 2008). "The molecular neurobiology of depression". Nature. 455 (7215): 894–902. Bibcode:2008Natur.455..894K. doi:10.1038/nature07455. PMC 2721780. PMID 18923511.
  78. Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, et al. (March 2001). "Paroxetine for the prevention of depression induced by high-dose interferon alfa". The New England Journal of Medicine. 344 (13): 961–6. doi:10.1056/NEJM200103293441303. PMID 11274622.
  79. Loftis JM, Hauser P (October 2004). "The phenomenology and treatment of interferon-induced depression". Journal of Affective Disorders. 82 (2): 175–90. doi:10.1016/j.jad.2004.04.002. PMID 15488246.
  80. Czéh B, Fuchs E, Wiborg O, Simon M (January 2016). "Animal models of major depression and their clinical implications". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 64: 293–310. doi:10.1016/j.pnpbp.2015.04.004. PMID 25891248. S2CID 207410936.
  81. Gibney SM, McGuinness B, Prendergast C, Harkin A, Connor TJ (February 2013). "Poly I:C-induced activation of the immune response is accompanied by depression and anxiety-like behaviours, kynurenine pathway activation and reduced BDNF expression". Brain, Behavior, and Immunity. 28: 170–81. doi:10.1016/j.bbi.2012.11.010. PMID 23201589. S2CID 2133286.
  82. Merali Z, Brennan K, Brau P, Anisman H (February 2003). "Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for "free chow" and "earned" sucrose intake". Psychopharmacology. 165 (4): 413–8. doi:10.1007/s00213-002-1273-1. PMID 12459927. S2CID 23685138.
  83. Wang Q, Timberlake MA, Prall K, Dwivedi Y (July 2017). "The recent progress in animal models of depression". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 77: 99–109. doi:10.1016/j.pnpbp.2017.04.008. PMC 5605906. PMID 28396255.
  84. Haapakoski R, Ebmeier KP, Alenius H, Kivimäki M (April 2016). "Innate and adaptive immunity in the development of depression: An update on current knowledge and technological advances". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 66: 63–72. doi:10.1016/j.pnpbp.2015.11.012. PMC 4736094. PMID 26631274.
  85. Yirmiya R, Weidenfeld J, Pollak Y, Morag M, Morag A, Avitsur R, et al. (1999). "Cytokines, "depression due to a general medical condition," and antidepressant drugs". Advances in Experimental Medicine and Biology. 461: 283–316. doi:10.1007/978-0-585-37970-8_16. ISBN 978-0-306-46135-4. PMID 10442179.
  86. Amani M, Shokouhi G, Salari AA (April 2019). "Minocycline prevents the development of depression-like behavior and hippocampal inflammation in a rat model of Alzheimer's disease". Psychopharmacology. 236 (4): 1281–1292. doi:10.1007/s00213-018-5137-8. PMID 30515523. S2CID 54446076.
  87. Hagen EH, Thornhill R (2017). "Testing the psychological pain hypothesis for postnatal depression: Reproductive success versus evidence of design". Evolution, Medicine, and Public Health. 2017 (1): 17–23. doi:10.1093/emph/eow032. PMC 5224882. PMID 28073826.
  88. Andrews PW, Thomson JA (July 2009). "The bright side of being blue: depression as an adaptation for analyzing complex problems". Psychological Review. 116 (3): 620–54. doi:10.1037/a0016242. PMC 2734449. PMID 19618990.
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