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A new meta-analysis by Cullen and colleagues finds an association between psychosis and non-neurological autoimmune disorders (NNAI).1 NNAI are those autoimmune disorders that affect mainly the peripheral systems, as opposed to the brain (e.g., type 1 diabetes).
Background
Previous research has uncovered a link between schizophrenia and certain autoimmune disorders. For example, Eaton and colleagues, using the data from the Danish Psychiatric Register (which included information on all people diagnosed with schizophrenia in Denmark during the 1981-1998 period), concluded that people with a history of autoimmune disease had a 45% increase risk for schizophrenia.2
Specifically, the following autoimmune disorders had a higher prevalence in people with schizophrenia: Acquired hemolytic anemia (a rare blood disease), alopecia areata (spot baldness), chronic active hepatitis (liver disease), intestinal malabsorption, interstitial cystitis (a bladder condition), myositis (muscle inflammation), polymyalgia rheumatica (an inflammatory disorder associated with muscle pain and stiffness), Sjögren’s syndrome (a condition which causes dry eyes/mouth), and thyrotoxicosis (a condition caused by excess thyroid hormones).
Another study (also using Danish registers) found that autoimmune disease increased the risk for schizophrenia by 30 percent, and the mere history of hospitalization with any infection was associated with an increased risk of 60 percent.3
Research conducted in Taiwan (on 11,000 in-patients with schizophrenia) showed similar results;4 specifically, schizophrenia patients had an increased risk of the following conditions:
Coeliac disease (an illness related to an abnormal intestinal reaction to Gluten), Graves’ disease (a common cause of overproduction of thyroid), hypersensitivity vasculitis (related to inflammation of blood vessels), pernicious anaemia (common cause of vitamin B12 deficiency), and psoriasis (a skin condition).
The Present Study
Cullen and colleagues conducted a meta-analysis of 31 studies (covering research that was published prior to April 2018). These studies, which included 107 effect sizes, all together comprised data for over 25 million people.
The results of the meta-analysis showed a positive association between psychosis and coeliac disease, Graves’ disease, pernicious anemia, pemphigoid (a rare skin disease), and psoriasis. There was also a negative association between psychosis and ankylosing spondylitis (a type of spine arthritis) and rheumatoid arthritis (a disease affecting mainly the joints).1
The overall effect size (odds ratio of 1.26) was rather small, but consistent across all research designs.
A temporal analysis showed that psychosis and autoimmune diseases not only co-occurred, but that the presence of psychosis increased the risk for NNAI disorders, and NNAI disorders also increased the risk for psychosis.
Explanation of Link Between NNAI and Psychosis
How can we explain such consistent association between NNAI and psychosis? No single agreed-upon explanation exists. Indeed, different pathways have been implicated. One involves infectious agents; these agents might cause psychosis directly (by affecting the neurons and the brain) or indirectly (by activating the immune system).
Another pathway involves autoimmune mechanisms, and the production of immune system proteins that attack body’s organs, causing inflammation of blood vessels, for instance.5
A third possibility implicates a complex “immune-mediated developmental two-hit model.”
According to this model, in the genetically vulnerable, early environmental factors like stress or infection result in brain abnormalities and vulnerabilities. That is the first hit. The second hit refers to environmental or internal changes (involving puberty, stress, or bacteria/viruses) which occur later, and result in problems with the neuronal circuits, and in some cases, give rise to psychosis.5
There has been significant support for the inflammation hypothesis of schizophrenia, given that, for instance, the complement system (a component of the immune response) is more active in both autoimmune disorders and schizophrenia. There is also support for shared genetic link between NNAI and psychosis because research shows a strong association between genes that play a role in immune regulation and in schizophrenia.4
Psychosis Essential Reads
As can be seen, despite support for different views, there is no agreement on the specific processes that underlie the link between autoimmune disorders and psychosis; which is why Cullen et al hesitate to offer treatment recommendations.
The authors do, however, suggest that it is a good idea to carefully monitor people with certain autoimmune diseases―especially anaemia, pemphigoid, and Graves’ disease―for early signs of psychotic disorders.
References
1. Cullen, A. E., Holmes, S., Pollak, T. A., Blackman, G., Joyce, D. W., Kempton, M. J., ...Mondelli V. (in press). Associations between non-neurological autoimmune disorders and psychosis: A Meta-Analysis. Biological Psychiatry. doi: 10.1016/j.biopsych.2018.06.016.
2. Eaton, W. W, Byrne, M., Ewald, H., Mors, O., Chen, C. Y., Agerbo, E., Mortensen, P. B. (2006). Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. American Journal of Psychiatry, 163, 521–528.
3. Benros, M. E., Nielsen, P. R., Nordentoft, M., Eaton, W. W., Dalton, S. O., and Mortensen, P. B. (2011). Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. American Journal of Psychiatry, 168, 1303–1310.
4. Chen, S. J., Chao, Y. L., Chen, C. Y., Chang, C. M., Wu, E. C., Wu, C. S.,...Tsai, H. J., 2012. Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study. British Journal of Psychiatry, 200, 374–380.
5. Bergink, V., Gibney, S. M., Drexhage, H. A. (2014). Autoimmunity, inflammation and psychosis: a search for peripheral markers. Biological Psychiatry, 75, 324–331.
