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Is Schizophrenia a Disorder of the Immune System?

October 8, 2018

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Self-portrait of a person with schizophrenia, representing that individual's perception of the distorted experience of reality in the disorder.Graphic credit: Craig Finn (schizophrenia patient) - Plos Medicine, CC0, https://commons.wikimedia.org/w/index.php?curid=1345958

Several years ago assessing data from the largest ever genetic study of schizophrenia, researchers began shedding light on the multiple roles of the immune system. It had been suspected that the illness was an autoimmune disorder like multiple sclerosis, Crohn's or rheumatoid 1) ___ where the immune system misfires and attacks the body. The international team from the University of Toronto and Lancaster University have found strong evidence that schizophrenia is different. The scientists had the idea that genetic variants influencing immune function contribute to the disease, but they found that the pattern in schizophrenia is not the same as in classic autoimmune disorders. They found that among 108 regions of the genome previously linked to the schizophrenia, only six act on both the immune system and the 2) ___.

People with 3) ___ show hallmarks of immune diseases such as prior infection and inflammation, supporting the idea that immune disturbances may play a role by disrupting the brain. However, it is not clear if these immune disturbances are a cause or a consequence of the illness and they themselves could be caused by a combination of genetic and environmental risk factors. For example, we know that schizophrenia is more likely if someone has had a severe infection requiring hospitalization. This means that the involvement of the immune system could be environmental, like being exposed to a virus as a fetus in the 4) ___. Thus, schizophrenia does not appear to be an autoimmune disease and that the illness could be caused by environmental risk factors which activate the 5) ___response, like infections or stress, although further research is needed.

A psychiatrist treating a 23 year old man, with delusions, at the Shimane University School of Medicine in Japan, eventually diagnosed paranoid schizophrenia. He then prescribed a series of antipsychotic drugs. None helped. The man's symptoms were, treatment resistant. A year later, the patient's condition worsened. He developed fatigue, fever and shortness of breath, and was diagnosed with (cancer of the blood) acute myeloid leukemia. He needed a bone-6) ___ transplant to survive. After the transplant, the man's delusions and paranoia almost completely disappeared. The paranoid schizophrenia had vanished. Now, years later, this patient is completely off all medication and shows no psychiatric symptoms. Somehow the transplant cured the man's schizophrenia. A bone-marrow transplant essentially reboots the immune system. Chemotherapy kills off your old 7) ___ blood cells, and new ones grow from the donor's transplanted blood stem cells. It may be too soon, to extrapolate too much from a single case study, and it's possible it was the drugs the man took as part of the transplant procedure that helped him. But his recovery suggests that his immune system was somehow driving his psychiatric symptoms. The idea seems bizarre, because we're only beginning to understand the enormous importance of how the immune system impacts our health. Therefore, we should question how the immune system could affect our brains.

A growing body of literature suggests that the immune system is involved in psychiatric disorders from depression to bipolar disorder to autism. The theory has a long, if somewhat overlooked, history. In the late 19th century, physicians noticed that when infections tore through psychiatric wards, the resulting fevers seemed to cause an improvement in some mentally ill and even catatonic patients. Inspired by these observations, the Austrian physician Julius Wagner-Jauregg developed a method of deliberate infection of psychiatric patients with malaria to induce fever. Some of his patients died from the treatment, but many others recovered. He won a Nobel Prize in 1927. One much more recent case study relates how a woman's psychotic symptoms from schizoaffective disorder, which combines symptoms of schizophrenia and a mood disorder such as depression, were gone after a severe infection with high fever. In today's world, it has been observed that people who suffer from certain autoimmune diseases, like lupus, can develop what looks like psychiatric illness. These symptoms probably result from the immune system attacking the central nervous system or from a more generalized inflammation that affects how the brain works.

In the past 15 years or so, a new field has emerged called autoimmune neurology. The best known disease is probably anti-NMDA-receptor encephalitis, made famous by Susannah Cahalan's memoir “Brain on Fire.“ These disorders can resemble bipolar disorder, epilepsy, even dementia - and that's often how they're diagnosed initially. But when promptly treated with powerful immune-suppressing therapies, what looks like dementia often reverses. Psychosis evaporates. Epilepsy stops. Patients who just a decade ago might have been institutionalized, or even died, get better and go home. These diseases are rare, but their existence suggests there could be other immune disorders of the brain and 8) ___ system we don't know about yet.

It has been estimated that about a third of schizophrenia patients show some evidence of immune disturbance. The role of immune activation in serious psychiatric disorders is probably the most interesting new thing to know about these disorders. Studies on the role of genes in schizophrenia also suggest immune involvement. People with schizophrenia tend not to have many children. So how have the genes that increase the risk of schizophrenia, assuming they exist, persisted in populations over time? One possibility is that we retain genes that might increase the risk of schizophrenia because those genes helped humans fight off pathogens in the past. Some psychiatric illness may be an inadvertent consequence, in part, of having an aggressive immune system. In terms of the patient in Japan mentioned above, there are other possible explanations for his recovery in that he could have suffered from a condition called paraneoplastic syndrome. That's when a cancer patient's immune system attacks a tumor, in this case the leukemia, but because some molecule in the central nervous system happens to resemble one on the tumor, the immune system also attacks the brain, causing psychiatric or neurological problems. This condition was important historically because it pushed researchers to consider the immune system as a cause of neurological and psychiatric symptoms. Eventually they discovered that the immune system alone, unprompted by malignancy, could cause psychiatric symptoms. Another case study from the Netherlands highlights this still-mysterious relationship. In this study, a man with leukemia received a bone-marrow transplant from a schizophrenic brother. He beat the cancer but developed schizophrenia. Once he had the same immune system, he developed similar psychiatric symptoms. The bigger question is this: If so many syndromes can produce schizophrenia-like symptoms, should we examine more closely the entity we call schizophrenia? Some psychiatrists long ago posited that many “schizophrenias“ existed and that different paths that led to what looked like one disorder. Perhaps one of those paths is autoinflammatory or autoimmune. If this idea pans out, what can we do about it? Bone marrow transplant is an extreme and risky intervention, and even if the theoretical basis were completely sound which it's not yet it's unlikely to become a widespread treatment for psychiatric disorders. There may be other, softer interventions. A decade ago, it was discovered by accident that when two schizophrenia patients who were both institutionalized, and practically catatonic, were treated with minocycline, an old antibiotic usually used for acne, both completely normalized. When treatment stopped, the psychosis returned. Minocycline has since been studied by others. Larger trials suggest that it's an effective add-on treatment for schizophrenia. Some have argued that it works because it tamps down inflammation in the brain. But it's also possible that it affects the microbiome the community of 9) ___ in the human body, and thus changes how the immune system works. This was recently explored with a different tool: probiotics, microbes thought to improve immune function. During manic episodes, many patients have elevated levels of cytokines, molecules secreted by immune cells. In a study, 33 mania patients who'd previously been hospitalized took a 10) ___ prophylactically. Over 24 weeks, patients who took the probiotic (along with their usual medications) were 75% less likely to be admitted to the hospital for manic attacks compared with patients who didn't. The study is preliminary, but it suggests that targeting immune function may improve mental health outcomes and that tinkering with the microbiome might be a practical, cost-effective way to do this. We now seem to have reached such a threshold with certain rare autoimmune diseases of the brain. Not long ago, they could be a death sentence or warrant institutionalization. Now, with aggressive treatment directed at the immune system, patients can recover. Does this group encompass a larger chunk of psychiatric disorders? No one knows the answer yet, but it's an exciting time to follow the research. Sources: The New York Times; ScienceDaily; nih.gov; Lancaster University; Wikipedia

ANSWERS: 1) arthritis; 2) brain; 3) schizophrenia; 4) womb; 5) immune; 6) marrow; 7) white; 8) nervous; 9) microbes; 10) probiotic

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