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
  • 1.2. Stress responses of cytokines in depression
  • 1.3. Individual treatment options from an immunological perspective for depression
• 2. Fatigue
• 3. Schizophrenia
• 4. Psychosis
• 5. Sleep problems

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 individuals³
    • 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-α
    • 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, TNF-α antagonists 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¶

Single 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