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Infection: What Role Does it Have in Schizophrenia?

My first day back at work in 2020 was with a fantastic team of mental health housing workers. We had an extensive debate on the role of infectious diseases on mental health and I promised to present the research. So, here is a review of some fascinating research on how infectious diseases can influence the developmnet of psychotic illness.

Infection and mental illness have a long standing connection. As long ago as 1913 Noguchi and Moore established the role of syphilis as a major cause of the mental illness Paresis (click here). This connection between mental illness and infections was strengthened with the development of an antibiotic cure for the bacteria syphilis, which also cured general Paresis. This was followed by more research, notably the observation that there were increased rates of encephalitis lethargica (click here) following the influenza epidemic of 1918-1919. Interest in this area declined until a controversial paper, published in 1988, suggested increased rates of schizophrenia in Finland during an influenza pandemic in 1957. This was especially in babies being carried in the womb at this time (click here and here). This has been supported by further studies that in utero exposure to viral infections increases risk of mental illness in adult life (click here). This research, along with recent advances in understanding of how infections and the immune responses alter brain functioning, have led to increased interest once again.

An obstacle to this research had been the assumption that long term infections would always cause inflammation in the brain as an immune response. As autopsy’s on people who had lived with enduring mental illness never revealed this level of expected inflammation, it had been concluded that they had no signs of infection. However, it is now understood that infectious agents such as viruses can lie dormant within the brain for extensive periods with no inflammatory reactions. However, infection can still exert influence over other immune responses. This is consistent with recent studies that have identified substantial immune activity in the brains of those with psychiatric disorders.

Infections capable of this dormant behavior are referred to collectively as TORCH (click here) and include herpes simplex virus types 1 and 2, cytomegalovirus, and Epstein Barr virus as well as human immunodeficiency virus, measles virus, bacteria such as Chlamydiae and Borreliae, and protozoa such as Toxoplasma gondii.

To eradicate infection, the brain’s immune system relies up highly specialized cells and mechanisms not found in other parts of the body such as Microglia. Microglial cells are a specialized population of "macrophages" that are found in the central nervous system. Microglia are activated following infection through a complex and highly refined process of signalling that is governed by recognition molecules. They support the immune system by devouring cell debris, damaged cells like neurons and infectious agents like bacteria and viruses in a controlled immune response to eradicate them. They are formed during fetal development and are present from birth. Microglial activation can be measured in patients using technology such as PET scanning but a clear diagnostic protocol has not been established curtailing its use in everyday practice.

One major influence of this Microglial immune response is found in synaptic pruning. As we enter puberty, the adolescent brain undergoes a re-boot process, re-organizing synaptic pathways that link brain cells. Microgilia play a key role in this pruning process, trimming back the underutilized pathways between brain cells, giving rise to more efficient signalling in the brain. Research has identified that patients diagnosed with schizophrenia showed overactive Microglial pruning of these synapses (click here). This may account for the adolescent onset of schizophrenia. Certain antibiotics have been shown to slow this pruning process and slightly reduce the risk of developing the disorder and can be effective in reducing symptoms of psychosis in women after giving birth (click here)

The over-activation of the Microglial has been documented in a wide range of psychiatric disorders including schizophrenia, bipolar disorder and autism triggered by infectious disease dormant within the brain. Understanding how these infections produce mental health disorders challenges current medical thinking. It has long believed that every infection produces their own unique symptoms in the body. This research suggests that different kinds of infection can cause similar symptoms.

Besides antibiotic treatment, the use of medications traditionally used to treat immune disorders have also shown significant promise in reducing symptoms of schizophrenia. This includes a wide range of anti-inflammatory drugs that can be used alongside more typical psychiatric medicines (click here and here). These anti-inflammatory drugs also have few side-effects. Many anti-psychotic drugs also have anti-inflammatory properties in the brain which may partially explain their effect (click here). However, mixed outcomes for symptom reduction in studies has shown that there may be certain populations who are more responsive to anti-inflammatory medications than others, suggesting different causes for psychotic illness within what looks like a similar symptom profile (click here).

Interestingly, genetic regions associated with higher risk of mental health disorders have been shown to be related to the immune system. This suggests that genetic risk of psychiatric disorders may be partly dependent on variations in individual genetic immunity to infections. For example, not every person who is exposed to the protozoan Toxoplasma gondii is at an increased risk for a psychiatric disorder. Whilst the Epstein Barr virus increases risk of schizophrenia in those with an altered immune response to viral proteins. Equally, genetic variation within infectious diseases also seems to influence their ability to activate mental illness, with some strains of infection exerting greater risk than others.

A second advance in understanding the role of infections in brain disorders suggest the brain does not exist as an isolated organ but rather interacts with other organ systems. Numerous studies (click here) have identified the gastrointestinal tract and the brain interact in a series of networks called the “gut-brain-axis.” This has been supported by the observation that mental health patients have a high rate of gastrointestinal symptoms and this may have a role in a wide range of disorders such as anxiety and depression (click here). Equally, those with gastrointestinal problems have a higher rate of mental health symptoms. This is particularly true for those with immune-based gastrointestinal disorders such as inflammatory bowel diseases.

Changes in the immune responses in the stomach have been found in several psychiatric disorders including schizophrenia, bipolar disorder, and major depressive disorder as well as in individuals who had a recent suicide attempt. How different microbes interact with each other in the gastrointestinal tract has been characterized as the “microbiome.” This individualized ecosystem in the digestive tract is determined by genetic and environmental factors. This includes exposure to breast feeding, household contacts, exposure to viruses, allergens and diet. This balance of the microbiome can be altered by antibiotics and other pharmacological agents including many medications that are used to treat psychiatric disorders. Numerous studies have documented altered microbial composition in samples from individuals with a range of psychiatric disorders including schizophrenia, recent onset psychosis, bipolar disorder, and autism (click here or here). The microbiome can also affect the metabolism, especially how orally administered medications are digested. This could also explain why people vary in response to orally administered psychiatric medications.

The microbiome can be manipulated by adding non-toxic microorganisms such probiotics or non-digestible sugars called oligosaccharides that feed non-pathogenic bacteria. Such prebiotics can also be combined with probiotics to generate what has been characterized as synbioti preparations. One study showed that these probiotics prevented relapse in individuals discharged after hospitalization for acute mania (click here). It can also reduce inflammation in individuals with schizophrenia that reduce the negative symptoms of the disorder (click here). Additional studies are needed to define optimal dosage and composition of probiotic regimens, methods for documenting potency and shelf life of preparations are not established needed they are not currently recommended for general use in the prevention or treatment of psychiatric disorders.

Antibiotics have been shown to increase the incidence of psychiatric disorders when administered in childhood (click here or here), and the administration of antibiotics has been shown to be increased before hospital admission for a psychiatric disorder. These studies suggest that alterations in the microbiome might also have adverse effects and that the judicious use of antibiotics and the normalization of the microbiome following antibiotic use might be way to prevent some cases of psychiatric disorders.

Infectious disease is unlikely to be the sole cause of mental health disorders. The development of mental health issues is probably multi-causal with a wide range of factors influencing its development. However, it does appear that infectious diseases are one of the accumulative factors that increase people's risk. Furthermore, this research is opening new avenues of treatment which may be both effective and free of many of the side effects that make traditional anti-psychotic drugs difficult for people to tolerate. It is a new frontier in understanding mental health and so further research is necessary to understand its role and how best to progress new treatments.

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