Source: Unsplash/National Institute of Allergy and Infectious Diseases
At least since Susannah Calahan wrote the 2012 book Brain on Fire, there has been resurging speculation that psychosis might actually be a disorder of the immune system. Calahan eventually came to understand that her psychosis was the result of an autoimmune disorder, which occurs when the immune system attacks healthy cells—and interestingly, psychosis caused by autoimmune disorders is generally not responsive to psychiatric drugs.
Autoimmune responses are not the same as a healthy immune system working to counteract a foreign biological invader. Yet the study of parasites or viruses in healthy immune systems is a current interest among researchers who study the development of schizophrenia. This has led to newer studies that distinguish between autoimmune psychosis, like what Calahan experienced, and psychosis caused by immune systems working overtime to defend against biological threats.
The Immune System and Schizophrenia: A History
The idea that schizophrenia might have something to do with the immune system is not new. It has been around at least since the influenza pandemic in 1918. At that time, psychosis was thought to be caused by cerebral inflammation, called encephalitis lethargica, in which brain tissue swells and sometimes turns red, possibly due to bacterial or viral infections (like the flu).
After the widespread panic caused by the pandemic simmered down, interest in physical diseases as an influence for psychosis fell out of fashion. Instead, researchers turned to an idea called the dopamine hypothesis, which argued that schizophrenia was a result of an imbalance or dysregulation in the way dopamine was transmitted, synthesized, and used in the brain. This theory was dominant for many decades and led to the development of drugs that target dopamine.
A subsequent theory of interest was that of neurodevelopment—the idea that schizophrenia was a developmental disorder that occurred in adolescence. This would explain why schizophrenia mainly emerges in the young adult years. However, it did not adequately explain the varied causes of all the disorders on the schizophrenia spectrum.
Throughout this time, the idea that immunological disruptions could lead to schizophrenia never fully disappeared. It resurfaced again in the 1970s when the well-known psychiatrist E. Fuller Torrey—author of Surviving Schizophrenia—became interested in the possibility that schizophrenia was largely caused by infections and broadly biological factors.
How far has our knowledge come since then? In recent years, you may have seen research finding that those living with cats early in childhood might be more vulnerable to the development of schizophrenia. This is because bacteria in cat feces are capable of transmitting parasites that could affect the human brain during critical developmental stages.
Researchers in several articles this year have summarized what we know about schizophrenia spectrum disorders and the possibility that they might occur because of a disruption in the immune system.
How the Immune System Works
The immune system responds to physical, psychological, and pathogenic stress. When we have an infection in the body, the immune system responds by producing an effect called inflammation. Inflammation occurs because the body wants to protect itself and it also helps with the healing process. But it can also do slight damage to other organs since it produces redness, swelling, and other symptoms.
The central nervous system (CNS) is an extension of the immune system specifically designed to protect the brain from infection. It extracts toxins, regulates neurotransmitters, and more. Just as the body can be inflamed, the brain can also experience inflammation (known as neuroinflammation).
A substance called cerebrospinal fluid (CSF), which is a clear fluid that surrounds the brain and protects it from damage, can affect brain development through what is called the blood-brain barrier. CSF is important because whatever is in the fluid can cross over to affect brain function and activity.
Psychosis Essential Reads
There are a few possible ways that the blood-brain barrier can be weakened, including infections during pregnancy, head injuries, childhood trauma, and substance use, to name a few. When this occurs, it can leave the brain vulnerable to future pathogens and infections. In fact, changes in the immune system have been shown to affect the growth of neurons, which in turn can affect dopamine interaction.
Schizophrenia and Immunology
So, can changes in the immune system play a role in the development of schizophrenia?
In a systematic review and meta-analysis by Warren et. al, of 69 studies, 5,710 participants (3,180 of whom had been diagnosed with a schizophrenia spectrum disorder) were included to measure cerebrospinal fluid (CSF) and signs of inflammation. These signs include cytokines, proteins that communicate between cells to essentially tell the immune system to begin fighting off infections, and white blood cell count. When more cytokines and white blood cells are present in the bloodstream, for example, it usually indicates that there is a threat to the immune system and there is an increased amount of inflammation.
Overall, 3.1 percent to 23.5 percent of patients with a schizophrenia spectrum disorder had increased amounts of inflammatory proteins like cytokines. This could indicate inflammation.
However, people on antipsychotics can often experience an increase in white blood cell count while on their drugs. Information about which patients were on antipsychotics at the time of the study was not fully reported. Abnormal CSF proteins can also be present with conditions that are often diagnosed alongside schizophrenia, such as diabetes and alcohol use disorder.
Limitations and Future Studies
The studies had several limitations: Comorbidity with other behaviors and conditions that could affect CSF were not clearly defined or measured; secondary conditions like autoimmune encephalitis were not acknowledged; and long-term studies were not done often, to name a few.
The authors concluded that it is too early to say whether schizophrenia spectrum disorders more broadly, as well as the specific symptom of psychosis, are caused by immunological dysfunction. Psychosis could be similar to a fever—that is, it may simply be a symptom, the causes of which could stem from one of many underlying biological infections or disturbances. However, the authors note, the current evidence suggests that CSF abnormalities may contribute to various patients’ development of schizophrenia spectrum disorders.
Anti-inflammatory drugs have been developed to treat patients with schizophrenia, but those drugs do not necessarily cure psychosis in every patient. There is some interest in conducting future studies that target patients who specifically experience heightened abnormal CSF and psychosis.
Schizophrenia is very heterogeneous in symptoms—and current evidence suggests it could very well be heterogeneous in origin, too. As theories develop, potential sources of psychosis could be broken down with more precision, which could help patients better manage all forms of psychosis in the future.