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Immune responses and inflammation in other mental disorders.

Immune responses and inflammation in other mental disorders.

There is evidence that various mental disorders can also be triggered by viruses or by the immune response to viruses. This is unlikely to be the only or the most common origin of mental symptoms, but should be considered as a possible cause.

1. Depression

1.1. Basal blood levels of cytokines

In severely depressed persons, compared to healthy persons, the basal blood values are on average (i.e. not in every affected person)

  • Significantly increased
    • IL-6 (16 studies, n = 892)1 (31 studies).2 Similarly, a recent single study in relation to subclinical depressive symptoms found that basal IL-6 but not TNF-α blood levels correlated with measures of acute (subclinical) depressed mood in remitted depressed individuals as in healthy individuals.3
      • Differently, IL-6 and sIL-6R (on an administration of interferon alpha) did not correlate with increased depression scores after MADRS. Changes in IL-6 day course had no effect on behavior.4
    • CRP (20 studies)2
  • Tends to increase, large variation in results
    • TNF
      • Increased (meta-study of 13 studies, n = 788)1
      • Increase doubtful due to large heterogeneity and inconsistency of subgroups2
      • No elevation in a recent study related to subclinical depression symptoms3
      • Basal IL-6 but not TNF-α blood levels correlated with measures of acute (subclinical) depressed mood in remitted depressives as in healthy individuals.3
  • Without differences
    • IFN-γ (4 studies)1
    • IL-1β (9 studies)12
    • IL-2 (5 studies)1
    • Il-4 (5 studies)1
    • IL-8 (4 studies)1
    • IL-10 (6 studies),1 as well as a recent study related to subclinical depression symptoms.3

1.2. Stress responses of cytokines in depression

Acutely depressed individuals (unlike healthy individuals) showed a positive correlation of the stress responses of cortisol and IL-6 and between the stress responses of epinephrine, TNF-α, and CRP. Healthy individuals showed only a significant correlation between ACTH and CRP stress responses.5
In contrast, in nondepressed as well as in remitted (recovered formerly) depressed individuals, no correlation was found between stress responses of cortisol on the one hand and cytokines on the other (IL-6, TNF-α, IL-10).3

1.3. Individual treatment options from an immunological perspective for depression

In depression, a correlation between increased IL-6 levels and thereby decreased serotonin synthesis is observed. Furthermore, increased levels of lymphocytes, phagocytes, IL-1, IL-2, INF-α, INF-γ, TNF-α, positive acute phase proteins, CRP and peripheral mononuclear cells as well as decreased levels of negative acute phase proteins have been described. In depression, preliminary studies also suggest an antidepressant effect of COX2 inhibitors (given augmentatively), which inhibit IL-1 and IL-6 and increase serotonin levels, among other effects. Diclofenac is a COX2 inhibitor, which explains the high cardiovascular risk of diclofenac,6 whereas ibuprofen and naproxen inhibit COX1 more than COX2.
Similarly, TNFantagonists appear to exert antidepressant effects. In addition, the levels of pro-inflammatory inflammatory markers decrease in conventionally successfully treated patients (including electroconvulsive therapy).7

One study reported that elevated IL-1-α levels were inhibited by supplementation of EPA or DHA, whereas elevated IL-6 and TNF-α levels were reduced (only) by EPA.8

2. Fatigue

In fatigue, a decrease in IL-6 and TNF-alpha was found in response to stress, while healthy individuals showed an increase in response to stress. In fatigue, moreover, ACTH levels and salivary cortisol levels were lower overall, while blood cortisol was lower only basally. Thus, there was a negative correlation of the IL-6 and TNF-alpha stress response to the cortisol stress response in fatigue, compared with a positive correlation in healthy individuals.9

3. Schizophrenia

Mild chronic encephalitis (inflammation of the brain) is considered in treatment-resistant schizophrenia.10 Indications for this are:

  • Activated monocytes
  • Proteome changes in the blood
  • Discrete CSF pathologies in more than 60% of treatment-resistant schizophrenic psychoses
  • Activated microglia
  • Disconnectivity in imaging modalities.

In this context, the detection of low-grade chronic inflammatory factors is a major problem.

For schizophrenia, benefits of augmentative treatment with type 1 cytokine-promoting and COX-2-inhibiting drugs have been described.7

4. Psychosis

A large cohort study of nearly 1.2 million children found slight evidence that neurotropic infections in childhood and adolescence are a risk factor for later psychosis:11

  • CMV (cytomegalovirus, a herpes virus) infections just about doubled the risk
  • Mumps virus infections increased the risk
  • Bacterial infections or urban living increased the risk very slightly
  • Enteroviruses did not increase the risk (risk ratio 1.0).

In contrast, psychosis in one parent increased the risk more than 6-fold.

Autoimmune diseases increase the risk of later schizophrenia by 45%. Conversely, 9 autoimmune diseases are more common in schizophrenia sufferers than in non-sufferers, and 12 autoimmune diseases are more common in parents of schizophrenia sufferers than in parents of non-sufferers.12 Another study also concludes that autoimmune diseases increase the risk of schizophrenia.13

5. Sleep problems

One-time as well as chronic sleep fragmentation increased mRNA and protein levels of cytokines in body tissues in mice. Changes in inflammatory responses reflected activation of stress axes with increased corticosterone and norepinephrine. Treatment with 6-OHDA significantly reduced inflammation caused by sleep fragmentation. This suggests regulation of sleep fragmentation-induced inflammation in body tissues by the autonomic nervous system (sympathetic/parasympathetic).
Chronic sleep fragmentation showed more severe consequences than single (acute) sleep fragmentation. One-week recovery from sleep fragmentation sufficiently alleviated peripheral inflammatory responses but not noradrenergic responses.14


  1. Dowlati, Herrmann, Swardfager, Liu, Sham, Reim, Lanctôt (2010): A Meta-Analysis of Cytokines in Major Depression, Biological Psychiatry, Volume 67, Issue 5, 2010, Pages 446-457, ISSN 0006-3223, https://doi.org/10.1016/j.biopsych.2009.09.033.

  2. Haapakoski, Mathieu, Ebmeier, Alenius, Kivimäki (2015): Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder, Brain, Behavior, and Immunity, Volume 49, 2015, Pages 206-215, ISSN 0889-1591, https://doi.org/10.1016/j.bbi.2015.06.001.

  3. Poidinger (2015): Immunparameter bei remittiert depressiven und gesunden Probanden unter Berücksichtigung der Reaktion auf die Exposition mit psychosozialen Stressoren. Dissertation, n = 71

  4. Raison, Borisov, Woolwine, Massung, Vogt, Miller (2010): Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol Psychiatry. 2010 May;15(5):535-47. doi: 10.1038/mp.2008.58.

  5. Weinstein, Deuster, Francis, Bonsall, Tracy, Kop (2010): Neurohormonal and inflammatory hyper-responsiveness to acute mental stress in depression, Biological Psychology, Volume 84, Issue 2, 2010, Pages 228-234, ISSN 0301-0511, https://doi.org/10.1016/j.biopsycho.2010.01.016. n = 28

  6. Mende (2018): Diclofenac – Ein Coxib undercover? Pharmazeutische Zeitung 36/2018

  7. Müller: Psychoneuroimmunologische Grundlagen psychischer Erkrankungen, in: Möller, Laux, Kapfhammer (Hrsg.) (2017): Psychiatrie, Psychosomatik, Psychotherapie, Band 1, 5. Auflage, Kapitel 11, S. 291 – 310

  8. Peng, Zhang, Yan, Zhang, Yang, Wang, Song (2020): EPA is More Effective than DHA to Improve Depression-Like Behavior, Glia Cell Dysfunction and Hippcampal Apoptosis Signaling in a Chronic Stress-Induced Rat Model of Depression. Int J Mol Sci. 2020 Mar 5;21(5):E1769. doi: 10.3390/ijms21051769. PMID: 32150824.

  9. Gaab, Rohleder, Heitz, Engert, Schad, Schürmeyer, Ehlert (2005): Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome, Psychoneuroendocrinology, Volume 30, Issue 2, 2005, Pages 188-198, ISSN 0306-4530, https://doi.org/10.1016/j.psyneuen.2004.06.008.

  10. Bechter (2013): Schizophrenie – eine milde Enzephalitis? Fortschr Neurol Psychiatr 2013; 81(5): 250-259. DOI: 10.1055/s-0033-1335253

  11. Dalman, Allebeck, Gunnell, Harrison, Kristensson, Lewis, Lofving, Rasmussen, Wicks, Karlsson (2008): Infections in the CNS During Childhood and the Risk of Subsequent Psychotic Illness: A Cohort Study of More Than One Million Swedish Subjects; American Journal of Psychiatry 2008 165:1, 59-65, https://doi.org/10.1176/appi.ajp.2007.07050740, n = 1,187 Millionen

  12. Eaton, Byrne, Ewald, Mors, Chen, Agerbo, Mortensen (2006): Association of Schizophrenia and Autoimmune Diseases: Linkage of Danish National Registers. American Journal of Psychiatry 2006 163:3, 521-528, n = 7.704 Schizophrenie-Betroffene plus deren Eltern

  13. Benros, Mortensen, Eaton (2012): Autoimmune diseases and infections as risk factors for schizophrenia. Annals of the New York Academy of Sciences, 1262: 56-66. doi:10.1111/j.1749-6632.2012.06638.x

  14. Mishra, Pullum, Thayer, Plummer, Conkright, Morris, O’Hara, Demas, Ashley (2020): Chemical sympathectomy reduces peripheral inflammatory responses to acute and chronic sleep fragmentation. Am J Physiol Regul Integr Comp Physiol. 2020 Mar 4. doi: 10.1152/ajpregu.00358.2019. PMID: 32130024.

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