Research Questions

Journal Published
Br J Psychiatry. Nov;179:403-8

Year Published
2001

Full Article
signs_of_asphyxia_at_birth_and_risk_of_schizophrenia.pdf

Hypothesis

To assess the role of different complications, and in particular to distinguish between disordered foetal development and hypoxia at birth.

Background

• It has been suggested that foetal or neonatal damage to the central nervous system (CNS) could increase the risk of schizophrenia as an adult
• Schizophrenia is twice as likely in those with any obstetric complication. 
• Previous research has found an association between obstetric complications and schizophrenia, but in many studies the sample size was limited, and no assessment of specific exposures was possible.

Journal Published
Frontiers in Psychiatry

Year Published
2019

Abstract
AutoimmuneZDiseasesZZPsychoticZDisorders.pdf

Background

• The association between immunological processes and mental disorders was observed by doctors centuries before the immune system was discovered.
• Psychosis arising either with the occurrence or disappearance of acute fever has been described by many scientists from Hippocrates around 400 BC to Kraepelin around 1900. In the 1930s it was first hypothesized by Hermann Lehmann-Facius that schizophrenia was the product of an autoimmune reaction with antibodies attacking brain tissue 
• In the 1950s and 1960s it was noticed that celiac disease seemed to occur more often within those suffering from schizophrenia than in the general population, and conversely, that schizophrenia occurred less frequently within patients with rheumatoid arthritis.
• Additionally, autoantibodies cross-reacting with brain antigens were found in patients with schizophrenia back in the 1960s, and interest in anti-neuronal antibodies in psychotic disorders has increased during the last couple of decades, with an increasing number of reports on previously unknown antibodies with brain reactivity in patients suffering from psychosis.
• The amount of evidence supporting the notion of a link between immunological processes and psychotic disorders has increased.
• Elevated levels of inflammatory markers have been found both in the blood and CSF of patients with psychosis, with even higher levels in patients in first episode psychosis or acute relapse.
• Furthermore, some have found association between higher levels of inflammation in childhood and adolescence and increased risk of psychotic disorders, elevated inflammatory biomarkers has been associated with lack of treatment response, and anti-inflammatory treatment has been found to have especially beneficial effect in an inflamed subgroup of patients.
• Moreover, it has been suggested that schizophrenia could be an autoimmune disease, based on similarities such as the remitting-relapsing phenotype of the illness, as well as the above-mentioned immunological processes.
• Research in the field of psychoneuroimmunology is still evolving, with many different aspects being investigated.
• The notion of a role of the immune system in psychotic disorders seems evident, and understanding the link between autoimmune diseases and mental disorders may shed light on possible etiological mechanisms herein.
• Understanding how the immune system and psychotic illness interact can improve our understanding of psychosis and give rise to a wide range of new treatment options in psychiatry; amongst other the possibility to identify subgroups of patients with psychotic disorders and ongoing inflammatory processes that could benefit from more targeted treatment.
• Additionally, it is very important for clinicians to be aware of somatic comorbidities, particularly in patients with psychotic disorders, in order to improve detection and treatment, and thus the course of illness.
• The notion of immunological pathways playing a role in the etiology of a subset of psychotic disorders has received increased interest in the last decades.
• There is an apparent link between autoimmune diseases and psychotic disorders.
• This is supported by genetic findings associating immune-related genetic markers with schizophrenia and clinical studies finding increased levels of inflammatory markers in patients with psychosis.
• Several large-scale epidemiologic studies have found positive associations between autoimmune diseases and psychosis. Particularly, autoimmune diseases as multiple sclerosis and lupus are known to have higher frequencies of neuropsychiatric symptoms, including psychosis, compared to healthy controls.
• Cross sectional studies have found higher prevalence of psychiatric diagnoses among those with autoimmune diseases, and longitudinal studies have shown bidirectional associations between several autoimmune diseases and increased risks associated with schizophrenia.
• Moreover, a family history of autoimmune diseases has been shown to be associated with an increased risk of psychotic disorders and vice versa. In this review we will summarize the epidemiologic evidence on associations between autoimmune diseases seases and psychosis.
• Possible mechanisms accountable for the association will be discussed, amongst others the probable role of shared genetic risk factors, the impact of infections on both autoimmunity and the development of psychotic disorders, and the potential role of the microbiome.

School, Department or Faculty
Schizophrenia Working Group of the Psychiatric Genomics Consortium

Journal Published
Schizophrenia Bulletin

Year Published
2016

Authors / Collaborators
Pouget JG1, Gonçalves VF2, Raychaudhuri S, Kennedy JL, Knight J5.

Hypothesis

The variation in immune genes contributes to schizophrenia

Background

• There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies.
• The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis.
• However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se.

Journal Published
Methods Find Exp Clin Pharmacol.

Year Published
1984

Authors / Collaborators
Knight JG.

Background

• Autoimmunity has been shown to be the basis of an ever-increasing number of human diseases.
• Schizophrenia shares a number of genetic features with these autoimmune diseases and therefore could be an autoimmune disease itself.
• Several lines of evidence suggest that overactivity of dopaminergic pathways in some areas of the brain are involved in schizophrenia, but the apparent absence of an increase in dopamine turnover suggests that this hyperactivity could be mediated by a dopamine agonist rather than by dopamine itself.
• Schizophrenia is reviewed in the light of precedents from the field of autoimmune diseases in which autoantibodies have been shown to be able to interact with, and sometimes stimulate hormone receptors, thereby causing disease.

Journal Published
British Journal of Medical Practitioners

Year Published
2015

Authors / Collaborators
James Paul Pandarakalam

Abstract
TheZAutoimmuneZZInfectious.pdf

Hypothesis

The author has reported on a review of the literature relating to the immunity- and viral-based aetiological models of schizophrenia to gain a detailed understanding of aetiological models of a subset of schizophrenia.

Background

• A clearer understanding of the aetio-pathogenesis of schizophrenia would ultimately lead to effective treatment strategies and provide the impetus for elucidation.
• The autoimmune hypothesis promulgates that it is the auto-antibodies that are responsible for schizophrenia and, according to the viral hypothesis, it may be the body’s abnormal response to a slow viral infection or the undefeated viral antigens causing the schizophrenia pathology.
• The autoimmune and viral hypotheses are interlinked, as autoimmune disorders can be triggered by microbial infection.
• Viral aetiology is less convincing than the autoimmune model, but from a treatment perspective, the former is more promising than the latter.

Journal Published
Journal of Neuroinflammation

Year Published
2018

Authors / Collaborators
Souhel Najja , Johann Steiner , Amanda Najjar and Karl Bechter

Abstract
AZclinicalZapproachZtoZnew-onsetZpsychosis.pdf

Description

• The associations with psychotic disorders have been found for a broad range of autoimmune diseases. 
• The world-wide prevalence of schizophrenia is known to be around 1% and the prevalence of autoimmune diseases have been found in a Danish nationwide study to be 4%.
• The vast majority of epidemiological studies have found a general association between autoimmunity and psychotic disorders.
• In large-scale register-based studies from Denmark, 6% of those diagnosed with schizophrenia also had a hospital contact related to an autoimmune disease during follow-up, and a Taiwanese study found that 3.4% of persons with a hospital contact for autoimmune diseases also had a hospital contact related to schizophrenia.
• A Danish study based on 7704 patients with schizophrenia, found an increased prevalence by about 45% of the occurrence of an autoimmune disease, which was later confirmed in a Taiwanese population-based study. Regarding the risk of psychosis after an autoimmune disease diagnosis, a Danish nationwide study found this to be increased by 45%, which diminished to a 29% increased risk when excluding the effect of infections, and a very recent meta-analysis by Cullen et al. found that a diagnosis of a non-neurological autoimmune disease increased the risk of later being diagnosed with a psychotic disorder by 43%.
• Additionally, being diagnosed with schizophrenia increases the lifetime prevalence of autoimmune diseases.
• Two Danish register-based studies found that individuals with psychotic disorders had a subsequently elevated risk for autoimmune diseases by around 50%. Supporting this, the recent meta-analysis found that the risk of having an autoimmune disease was 55% higher among those with a prior diagnosis of a psychotic disorder.
• Autoimmune diseases and psychosis are not only associated on an individual level. Having a first degree relative with schizophrenia has also been found to increase the risk of autoimmune diseases with 6%, and a family history of autoimmunity has been found to increase risk of both schizophrenia and non-affective psychoses with 10%.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2018

Website
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435494/#__ffn_sectitle

Description

• The original findings from the 1950s of an association between celiac disease and schizophrenia has since been explored further.
• During the next decades it was noticed that populations with lower consumption of wheat had lower incidence rates of schizophrenia, and small studies have since found beneficial effect on psychotic symptoms of a gluten-free diet in patients suffering from both celiac disease and schizophrenia.
• One epidemiological study found no significant correlation between celiac disease and psychosis however another large-scale study found a 2.11-times increased risk of schizophrenia. 
• The recent meta-analysis also found an association with an elevated risk of schizophrenia with 53%.
•  Additionally, it has been found in a Taiwanese population, that the risk of celiac disease is increased when suffering from schizophrenia.
• When discussing epidemiological studies using health records, it is important to note that celiac disease might be majorly underdiagnosed particularly within those who have already debuted with psychotic symptoms.
• In summary, most studies found a positive association between celiac disease and psychotic disorders.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435494/pdf/fpsyt-10-00131.pdf

Description

• Multiple sclerosis (MS) is an autoimmune disease associated with many neuropsychiatric symptoms, such as depression and anxiety.
• It has been found that 4% of patients with MS experiences psychosis, a prevalence much higher than that of the general population.
• Danish register-based studies have found that having MS increases the risk of schizophrenia with up to 44%, with an even further increase in risk when having both MS and a prior hospital contact due to infection. 
• Two studies found increased risk of schizophrenia with up to 30% in individuals with a family history of MS; however, they found no associations on an individual level.
• A study from Taiwan only found a trend toward an increased risk of schizophrenia in those with a diagnosis of MS.
• On the risk of a subsequent MS diagnosis in patients with schizophrenia, contradictory results have been found between a Danish and a Swedish nationwide study, finding the risk to be respectively increased by 57% and decreased by 40%.
• Current evidence of an association between MS and psychotic disorders is limited with studies showing conflicting results.
• Many, especially sensory, symptoms of multiple sclerosis might be misinterpreted as part of the patients' psychotic disorders, complicating the diagnostic process, and psychotic symptoms in people with MS might not be diagnosed since they are considered to be delirium in relation to acute MS exacerbations.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Systemic Lupus Erythematosus (SLE) is another autoimmune disease known to have a high degree of neuropsychiatric problems, such as depression and anxiety, occurring in between 21 and 95% of patients However, it has been estimated that only 13–38%, are directly attributable to SLE, whereas the remaining is suggested to be due to for example treatment complications.
• Regarding psychosis in SLE, the prevalence ranges from 2.3 to 11% in studies.
• A study from England comprising 458 patients with SLE, found that only 2.3% experienced psychosis, while a higher prevalence of psychosis have been found in a black Caribbean study population (366 patients, 7% with psychosis) and in a Brazilian population (520 patients, 11% with psychosis).
• In those experiencing psychosis, this was one of the initial symptoms of SLE in up to 60% of these patients.
• In population-based studies, a nationwide Taiwanese study found an increased risk of schizophrenia among those with SLE
• In one Danish study the presence of both SLE and a prior hospital contact with infection resulted in an increased risk of schizophrenia.
• None of the other epidemiological studies have found significant association between psychotic disorders and SLE
• The number of cases available was very small in all studies, limiting the significance of possible findings.
• In summary, large scale studies with a greater number of cases have been able to find positive associations between SLE and psychotic disorders, while smaller studies have failed to do so.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Graves' disease, the most common cause of hyperthyroidism, is also known to be linked to neuropsychiatric issues, and some even present with psychotic disorders.
• A German study found that in a cohort of 100 patients with a schizophreniform illness, 19 had increases antithyroid autoantibodies in sera, and 13 showed signs of intrathecal synthesis hereof. 
• In epidemiological studies, both Graves' disease and thyrotoxicosis have been linked with an increased risk of schizophrenia.
• Additionally, the prevalence hereof has been found to be increased among individuals with schizophrenia, though this finding has not been replicated in all studies.
• Hence, most studies indicate a positive association between Graves' disease/thyrotoxicosis and psychotic disorders.
• No studies has been able to show a significant association between autoimmune thyroiditis and schizophrenia on an individual level, but one Danish study found an increased incidence among parents and siblings of patients with schizophrenia.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Diabetes mellitus type 1 is a disease characterized by the presence of glutamic acid decarboxylase (GAD) antibodies.
• These autoantibodies have been linked with neurological problems, and thus have shown ability to cross the blood brain barrier, making them an interesting topic in the discussion of pathophysiological mechanisms.
• However, conflicting results have been found regarding the association of type 1 diabetes and psychotic disorders. Two Danish studies found an increased risk of schizophrenia when suffering from type 1 diabetes, and one found an increased risk of type 1 diabetes after having been diagnosed with schizophrenia.
• This, however, was not replicated neither in a Swedish cohort, a Taiwanese cohort nor in the recent meta-analysis, and a Finnish study even found a negative association.
• In summary, there does not seem to be a clear association between type 1 Diabetes and psychosis.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• A disease which has consistently been found to be negatively associated with schizophrenia is rheumatoid arthritis (RA).
• This apparent “protective” effect of schizophrenia on the development of rheumatoid arthritis was investigated as early as the 1950s.
• The negative association between the two has since been backed by epidemiological studies, finding decreased risk of schizophrenia in those with RA and vice versa.
• However, some studies did not find associations, and regarding the association on the risk of psychosis after a RA diagnosis, more controversy exist, with a Danish study finding that a combined history of a hospital contact due to infection and RA increased the risk of schizophrenia and a new Taiwanese study finding an increased risk of developing schizophrenia in individuals with a history of RA.
• Moreover, a Danish study found an increased prevalence of RA in the family of those with schizophrenia.
• One explanation of the consistent finding of negative association with subsequent RA diagnosis after a schizophrenia diagnosis could be that RA tends to be underdiagnosed in those suffering from psychotic disorder, and in concordance with this, both a Swedish and Danish nationwide study has shown that the same negative association can be found with other musculoskeletal diseases.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Something that really spiked the interest in autoimmunity as a player in mental illness, was the discovery of autoimmune encephalitis.

• As a group, these diseases are characterized by the presence of neuronal surface antibodies (NSAbs) and symptoms include:

1. Psychiatric and cognitive alterations

2. Seizures and movement disorders

3. With the most commonly affected part of the brain being the limbic system.

• The most discussed antibody in psychotic disorders at the moment is the N-methyl-D-aspartate receptor (NMDA-R) antibody.

• It has been reported that as many as 74% of patients suffering from NMDA-R encephalitis experience psychotic symptoms, and a recent smaller study found that 13% were initially admitted to the hospital with a psychiatric diagnosis.

• Multiple studies have investigated the frequency of NMDA-R antibodies in schizophrenia, but so far most have only had access to serum not CSF, most have had no healthy control group, and results have varied markedly.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Associations have been found between psychotic disorders and other autoimmune diseases as well.
• The incidence of psoriasis have been found to be significantly increased in individuals with schizophrenia, but not in all studies.
• Increased incidence of psoriasis have also been found in individuals with a family history of schizophrenia
• In addition, the risk of developing schizophrenia has been found in multiple studies to be increased in those with a history of psoriasis, with an additional increase when combined with a prior hospital contact due to an infection.
• The risk of developing Guillain-Barré syndrome, an autoimmune disease attacking peripheral nerves, has been found to be increased markedly in individuals with schizophrenia, and when having both a history of a hospital contact with an infection as wells as Guillain-Barré, the risk of developing schizophrenia has also been found to be increased.
• However, one other study found no association.
• Autoimmune hepatitis has been found to be greatly associated with psychotic disorders as well, with both individual history and family history hereof increasing the risk of schizophrenia, and schizophrenia increasing the risk of autoimmune hepatitis.
• Some evidence of an association between schizophrenia and Crohn's disease has also been found, though no significantly increased risk was shown in two other studies or the recent meta-analysis.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• One potential contributing factor to the link between some autoimmune diseases with mental illness, can be the presence of neuronal surface antibodies (NSAbs).
• GAD-antibodies have been linked with multiple neurological problems, and in neuropsychiatric lupus, an increased amount of antibodies was found both in serum and CSF compared to lupus with no neuropsychiatric manifestation.
• Furthermore, gliadin antibodies, associated with celiac disease, have been found to be increased in the serum of patients with recent onset schizophrenia.
• With the discovery of NMDA-receptor encephalitis, and its ability to mimic mental disorders, the interest spiked further, and with GAD-antibodies being able to induce limbic encephalitis and antibodies reacting with the NR2 subunit of NMDA being present in some cases of lupus, a possible link emerged.
• Many studies have sought to evaluate the presence of multiple different NSAbs in mental illness, but so far, consistency in methods and assays have limited the generalization of the findings.
• Many studies have lacked a healthy control group to compare their results with, and most studies have included serum but not CSF samples.
• The relevance of circulating NSAbs in serum is still unknown, and therefore comprehensive studies including healthy controls evaluating antibodies in both CSF and serum is needed to increase knowledge further.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• A dysregulated balance between regulatory T cells and Th17 cells have been described to be essential for immunological homeostasis and have been implicated in the development of several autoimmune disorders.
• Signs of a dysregulated immune system has also been found in mental illnesses and might play a role in the association found between the two.
• A meta-analysis found that levels of several lymphocytes differed when examining patients with schizophrenia compared to healthy controls.
• Studies have linked decreased regulatory T cells with negative symptoms and cognitive deficits, as well as increased levels of Th17 with psychopathology.
• In recent years, B cells have received increasing attention in the pathology of autoimmunity, and have been implicated to play a big role in for example MS, where it has also been found that anti B-cell antigen (anti-CD20) have great efficacy in the treatment hereof.
• It has been shown that oligoclonal bands (OCBs) in the CSF, something which is found in approximately 90% of patients with MS, is a sign of ongoing stimulation and maturation of antibody-expressing B-cells.
• A recent meta-analysis found that OCBs were found in the CSF of up to 12.5% of patients with schizophrenia.

Another frequent finding in patients with schizophrenia is increased levels of pro-inflammatory and decreased levels of anti-inflammatory cytokines in serum (10). Dysregulation of the anti-inflammatory cytokine IL-10 has been found to be linked with abnormal responses to common infections, and to increase the risk of developing autoimmune diseases (69).

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• It is thought that one of the most important triggers for developing autoimmune diseases is infection (70), and it is known that infectious encephalitis, specifically with herpes-simplex virus, markedly increases the risk of developing NMDA-receptor encephalitis.
• As it was shown in a large Danish nationwide study, prior infection increased the risk of developing schizophrenia in a dose-response fashion and this finding has been repeated in other large studies.
• The effect of infection on risk of schizophrenia was present regardless of autoimmune diseases, but additionally, a significant synergy was found in those with both a history of autoimmunity and infections.
• For many of the individual autoimmune diseases, it was seen that the effect on the risk of schizophrenia increased when a prior hospital contact due to infection was also present.
• Being exposed to viral or bacterial infection is known to increase the permeability of the blood-brain-barrier (BBB), which allows the entering into the central nervous system of immune cells and pro-inflammatory cytokines.
• This in itself might allow an inflammatory state in the brain, which has been theorized to play a role in the development of psychotic disorders. It may also explain the synergistic effect on risk of schizophrenia of having both an autoimmune disease and prior infections, as BBB disruption might also allow the entering of circulating antibodies.
• Supporting the role hereof, signs of a disrupted BBB has been found in patient with schizophrenia with evidence of increased albumin CSF:plasma ratio and increased levels of circulating s100-b.
• It has also been found that infections during pregnancy increases the risk of schizophrenia in the offspring.
• On the basis hereof, it has been considered whether infections during the prenatal phase might prime the immune system, making it more vulnerable and perhaps more likely to produce abnormal responses to later infections, resulting in increased inflammation
• A new study have shown that even maternal infections before and after pregnancy increases the risk of mental illness, which could also indicate a genetic susceptibility for infections associated with mental illness.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Both schizophrenia and autoimmune diseases are known to be highly hereditable.
• The most consistent finding in genetic studies of patients with schizophrenia, are differences in genes known to be linked to the immune system, and several genetic loci that increases the risk of autoimmune diseases has been located.
• As with schizophrenia, some of the discovered genetic loci in autoimmune diseases are located in the MHC region
• However, while one study found significant overlap in genes between MS and schizophrenia (but not MS and bipolar disorder), another study found no genetic association between 25 different autoimmune diseases and schizophrenia
• Genetic pleiotropy has also been hypothesized to account for the negative association found between RA and schizophrenia, with genes found to be associated with schizophrenia possibly decreasing the risk of RA.
• Another possible role of genetics in the association of autoimmune diseases and psychotic disorders could be a hereditary susceptibility for shared risk factors.
• It has been hypothesized that some of the genetic findings associated with schizophrenia might increase the risk of having infections, that then subsequently increase the risk of both autoimmune diseases and psychotic disorders.
• Additionally, it has been theorized whether some individuals with schizophrenia, might have a genetic predisposition for an abnormal immune response to common infections and foreign pathogens, for example via differences in the HLA region and complement system, which in turn could increase the risk of developing autoimmune reactions.
• The complement system has also been implicated to play a role in neurodevelopment and -maturation, and evidence of altered complement activity in patients with schizophrenia have been found.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• The gastro-intestinal tract of humans contains vast amounts of bacteria, phyla and other microorganisms, their genes collectively known as the microbiome, containing at least 100 times more genetic material than the human genome.
• This area has received great attention in the research of many different illnesses in the last years and have been implicated as a possible etiological factor in both neuropsychiatric illnesses and autoimmune diseases.
• As early as 1953, interest in gastro-intestinal inflammation in psychosis was raised, when a group of researchers found in an autopsy study that out of 82 patients with schizophrenia, 50% had gastritis, 88% enteritis and 92% colitis.
• This study has not since been replicated, but other signs of microbiome dysbiosis in this group of patients has been found with significant difference between cases and controls in the presence of both bacteria and fungi, and bacteriophages.
• Studies so far have mainly focused on the oropharyngeal microbiome due to practical limitations.
• One study however, has looked into fecal microbiome, finding no significant difference between healthy controls and patients, but showing associations between microbiome composition and symptom severity and outcome.
• The composition of the microbiome has been hypothesized to be very important in the development of both the central nervous system and the immune system. 
• Dysbiosis of the microbiome has been shown to affect both the Th1/Th2 balance and the ratio of T regulatory and Th17 cells, impacting the immune response to foreign pathogens.
• Dysbiosis have been found to influence the T-cell mediated inflammation in MS patients, and has also been suspected to play a part in the development of celiac disease, as well as non-gastro-intestinal autoimmune diseases.
• In rodents, disruption of the microbiome has been found to impair social functioning, behavior and cognition, and induce neurodevelopmental disorders.
• An important function of the microbiome, seems to be its effect on the epithelial cells in the GI wall, with evidence implicating that the composition of the microbiome is important for the tightness of the gut-blood barrier.
• Severance et al. found markers in the serum of patients with schizophrenia indicating increased permeability, also known as “leaky gut.”
• A leaky gut allows the entrance of foreign pathogens and antigens into the blood. It has been suspected to induce systemic inflammation, and in mice it has been found to even result in neuroinflammation, both of which might increase the risk of mental illness and autoimmune diseases.
• Interestingly, both infections and the treatment hereof with antibiotics can modulate the microbiome, linking the previously mentioned epidemiological findings of the influence of infections with the microbiome theory.
• Additionally, it has been theorized that maternal infection might alter both the maternal and fetal microbiome, possibly impacting the immune system and neuropsychiatric development of the offspring.
• A few studies have tried probiotic treatment in patients with schizophrenia, but no evidence of effect hereof on psychopathology has yet been found.
• However, further research on the actual composition of the microbiome in patients with mental illness as well as the possibility of using probiotics as treatment hereof is warranted.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• Psychological stress such as sexual abuse, physical abuse, emotional/psychological abuse, neglect, parental death, and bullying, both in childhood and later on, has been associated with increased risk of psychotic disorders in multiple studies.
• A Swedish register-based study found that stress-related disorders increased the risk of subsequent development of autoimmune disorders and, accordingly, in many other studies, stress have been found to be associated with disease onset and disease exacerbations in several autoimmune conditions.
• Stress can theoretically influence many of the above-mentioned possible etiological factors.
• Acute psychological stress, even in brief episodes, have been found in a meta-analysis to increase circulating proinflammatory cytokines such as IL-6, IL-1β, and TNF-α, possibly via the sympathetic nerve system and the HPA axis, and multiple adverse life events or stressful living conditions might therefore possibly contribute to a more chronic inflammatory state with dysregulation of immune response.
• Psychological stress have been thought to influence composition of the microbiome and vice versa, as well as the microbiome's effect on peripheral inflammation.
• Additionally, it has been hypothesized to increase susceptibility to infections, with one study finding that healthy subjects with higher scores on questionnaires on psychological stress were more prone to developing clinical cold and respiratory infections after exposure to respiratory viruses
• Acute stress, for example as a result of a psychiatric disorder or hospitalization, may also lead to exacerbation in symptoms of autoimmune diseases, leading to the discovery of a disease formerly undiagnosed.

Source
Autoimmune Diseases and Psychotic Disorders

Journal
Frontiers in Psychology

Year
2019

Website
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00131/full

Description

• “Autoimmune psychosis” includes those autoimmune disorders presenting primarily with atypical psychotic features masquerading as drug-resistant primary psychosis. This term suggests that this subtype of psychosis has anatomical and immunological footprints in the brain. It also serves as a reminder not to overlook appropriate neurological workup, (such as neuroimaging, EEG testing, and CSF investigation), but rather to apply it more broadly to formulate accurate differential diagnostic considerations that entertain underlying autoimmune process among other organic etiologies. Examples of atypical psychotic presentations suggestive of organic causes are:

1. Ttypical age of onset
2. Predominance of particular symptoms such as confusion, disorientation, and language disintegration
3. Catatonia, given its diverse etiology
4. Predominance of visual or multi-modal hallucinations (visual and tactile)
5. Olfactory hallucinations suggestive of mesial temporal lobe pathology
6. Predominance of specific delusions such as those related to misidentifications (Capgras syndrome)
7. Antecedent or concurrent medical illness or systemic manifestations including significant weight loss; and
8. Lack of predisposing risk factors for primary psychosis such as a strong family history of schizophrenia, a premorbid schizoid personality, or precipitating stress for mental disorder

• Antibodies against neurotransmitter receptors and synaptic proteins in schizophrenia and newonset psychosis: the concept of autoimmune psychosis In individuals with schizophrenia suggests that autoimmunity plays a role in a subgroup of these patients, early identification of antibodies targeting neurotransmitter receptors such as: 

1. 5-hydroxytryptamine
2. 1A receptor
3. Muscarinic cholinergic receptor 1 as well as
4. Dopamine-2 receptor

• Notably, the recent discovery of antibodies against synaptic and neuronal cell membrane proteins such as antiN-methyl-D-aspartate receptor (NMDAR) and gammaaminobutyric acid beta receptor (GABAßR) provides more direct evidence etiologically linking autoimmunity-related dysregulation of glutamatergic and GABAergic neurotransmissions to subsequent hazard of psychosis 
• One meta-analysis showed that patient with psychiatric illnesses such as schizophrenia and schizoaffective disorders are about three times more likely to have NMDAR antibodies (mostly of IgA or IgM type against GluN1 (NR1) subunit), compared with healthy controls 
• Similarly, other studies reported higher, albeit variable, prevalence of IgG antibodies targeting GluN1 subunit of NMDAR in the sera of individuals with first-episode psychosis (ranging from 0 to 12%)
• Furthermore, NMDAR antibody immunofluorescence response in schizophrenia patients with past catatonia is shown to be greater than that in healthy controls.
• Additional studies revealed higher prevalence of other neuronal antibodies such as voltagegated potassium channel (VGKC)- complex antibodies in patients with schizophrenia
• On the contrary, the findings from other studies provide counterargument to the putative pathogenic significance of synaptic and neuronal antibodies in a subset of individuals with schizophrenia and new-onset psychosis.
• Several studies showed comparable prevalence of antibodies targeting synaptic and neuronal cell membrane protein among healthy and schizophrenia cohorts.
• Another recent study showed that the prevalence of these antibodies among individuals with first-episode psychosis was low and comparable to that of healthy controls.
• The mixed results and the variability in the estimates of synaptic and neuronal antibody seropositivity may in part be attributed to methodological heterogeneity (e.g., cell-based assay (CBA) using live as opposed to fixed cells) that might have influenced the sensitivity and specificity of immunostaining assays used across these studies.
• The growing human and experimental data supporting an association between autoimmunity and risk of developing psychosis have prompted some authors to use the term “autoimmune psychosis”

Source
A clinical approach to new-onset psychosis associated with immune dysregulation: the concept of autoimmune psychosis

Journal
Journal Of Neuroinflammation

Year
2018

Website
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-018-1067-y

Journal Published
Am J Psychiatry

Year Published
2002

Authors / Collaborators
Mary Cannon, Peter B. Jones, Robin M. Murray

Hypothesis

This paper reviews the literature on obstetric complications as a risk factor for schizophrenia. The authors trace the evolution of this literature through different methods and carry out a quantitative review of the results from prospective, population-based studies

Background

• The much-investigated association between obstetric complications and schizophrenia has provided crucial support for developmental and nongenetic etiological models of the disorder.  
• The first mention of an association between birth complications and schizophrenia occurred in the American Journal of Psychiatry in 1934.
• Rosanoff and colleagues published “The Etiology of So-Called Schizophrenic Psychoses” based on detailed case reports of 142 pairs of twins concordant and discordant for schizophrenia.
• The authors concluded that schizophrenia could be regarded (at least in part) as a “decerebration syndrome which may result from birth trauma.”
• Somewhat surprisingly, nothing further was published on this topic until 1956 when Pasamanick and colleagues proposed their now-classic thesis of a “continuum of reproductive casualty,” whereby pregnancy and birth complications can lead to a gradient of injury extending from fetal and neonatal death through cerebral palsy, epilepsy, mental deficiency, and behavior disorder.
• The paper by Pasamanick and colleagues initially had its greatest impact on the field of child psychiatry.
• In the early 1960s, there were reports of significant associations between pregnancy complications (particularly toxemia, bleeding, and severe maternal illness) and childhood psychosis. However, diagnostic uncertainty about the classification of childhood psychosis seems to have halted research in this area. Even though a review in 1966 concluded that “the need for further researces is strongly indicated by these findings”
• There was a gap of 10 years before a study by Torrey and colleagues reported an association between bleeding in pregnancy and childhood psychosis.

Description

• Bleeding and preeclampsia in pregnancy have been associated with psychosis since the earliest days of such research.
• Pasamanick and colleagues singled out the “anoxia-producing complications of pregnancy such as toxemia and bleeding” as most likely to be associated with behavior problems.
• Preeclampsia came to particular attention in 1996 when Kendell and colleagues reported a very strong association between preeclampsia and later schizophrenia, but, in their attempt to extend the study group and replicate this finding, a flaw in the original study design was uncovered, and a retraction was published.
• The revised analysis found no significant effect for preeclampsia.
• In the largest single population-based study to date, preeclampsia was the only obstetric risk factor that remained significant after the analysis controlled for all potentially confounding factors.
• The most popular theory at present involves the mechanism of abnormal fetal blood flow resulting in chronic fetal hypoxia or malnutrition.
• Bleeding during pregnancy has many causes. Implantation bleeding and abbreviated menses are common in the first month, and placenta praevia and premature separation of the placenta are frequent causes in the last month.
• The causes of mid-pregnancy bleeding are less well understood. In one study, two-thirds of the cases were found to be due to premature separation, placenta praevia, hydatiform moles, incompetent cervices, and other identifiable causes, while in one-third of the cases, the cause could not be determined.
• In severe cases of bleeding, the pathogenic effect on the fetus is thought to be anoxia, but, in many cases, the amount of bleeding may be slight and anoxic brain damage is unlikely.
• Another explanation is that bleeding can represent a threatened spontaneous abortion.
• The process of uterine rejection could have begun but been interrupted.
• Genetic or autoimmune factors may play a part in such a process.
• The association between diabetes in pregnancy and later schizophrenia, although strong, is based on only two studies in this analysis, neither of which provided information on the type of diabetes.
• Indirect support for the association comes from one report that high prepregnancy body mass increases the risk of schizophrenia in the offspring, since high maternal body mass index is associated with non-insulin-dependent diabetes and gestational diabetes.
• The effects on the developing brain of altered glucose metabolism are not well understood.
• Poorly controlled maternal diabetes is associated with an increased risk of congenital anomalies and impaired intellectual and psychomotor development in offspring.
• Insulin-dependent diabetes mellitus has been found to be more common among the firstdegree relatives of patients with schizophrenia than among comparison subjects, indicating that an autoimmune process might be involved.
• Autoimmune mechanisms could also be implicated in the association between rhesus incompatibility and later schizophrenia.
• Rhesus hemolytic disease of the newborn is an illness with neurological consequences secondary to effects of a maternal antibody.
• Hemolytic disease can lead to early spontaneous abortion, chronic fetal hypoxia, neonatal asphyxia and pulmonary edema, and neonatal hyperbilirubinemia and kernicterus.
• The association has independent support from a cohort study that found a twofold increase in relative risk of schizophrenia among men from rhesus-incompatible pregnancies and a report that neonatal hyperbilirubinemia is a risk factor for later mental illness.

Source
Obstetric Complications and Schizophrenia: Historical and Meta-Analytic Review

Journal
Am J Psychiatry

Year
2002

Website
https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.159.7.1080