What Causes Schizophrenia?

Many people with schizophrenia experience psychosis: hallucinations, delusions, paranoia, or even catatonia. However, symptoms can vary wildly among patients in their presentation and severity. For some, the disease is only a small setback in an otherwise fully functional life.

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Like autism, schizophrenia is diagnosed based on symptoms alone. “Schizophrenia may represent a common clinical syndrome that most likely represents many different diseases,” explained neuroscience expert Stuart C. Sealfon M.D., Chairman of Neurology at the Icahn School of Medicine at Mount Sinai, in an interview with Healthline.

The standard treatment for schizophrenia is antipsychotic drugs. These drugs can carry a range of nasty side effects, and they help some patients much more than others.

Read About Different Types of Schizophrenia and How to Treat Them »

Inflammation on the Brain

A researcher at the University of Oxford, Belinda Lennox, and her team may have found one of the diseases that’s currently misdiagnosed as schizophrenia: encephalitis, or inflammation of the brain.

The team examined 46 patients who had experienced their first episode of psychosis. In three of the people—around six percent—they found antibodies that specifically target nerve cells. Antibodies direct the body’s immune system, telling white blood cells what to attack and what to leave alone. Normally, antibodies target viruses and bacteria, allowing the immune system to fight off infections. But in the case of autoimmune diseases, the antibodies target the body’s own cells for destruction.

In this case, the antibodies were attacking a structure called the NMDA receptor, an important protein found on the surface of many nerve cells that allows them to receive signals from other nerve cells. The receptor is found throughout the brain and is involved in the formation of new memories. When the immune system attacks the NMDA receptor, it becomes inflamed, and one of the possible symptoms is psychosis.

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Clean the Blood, Protect the Brain

To test this theory—and to help their patient—the team treated one man with plasmapheresis, a procedure that filters antibodies out of the blood. They also gave him prednisone, a steroid medication that suppresses the immune system. His psychotic symptoms improved without any antipsychotic drugs.

“This is the first case description, to our knowledge, of a patient with NMDA [receptor] antibodies and a purely psychiatric presentation responding to immunotherapy,” Lennox wrote.

Other data suggest that for this treatment to work, the psychosis has to be caught early. A larger study of people with chronic schizophrenia didn’t find the NMDA receptor antibodies, leading to two possible conclusions. Either the antibodies fade from the bloodstream over time, leaving behind the damage they’ve caused, or these patients have schizophrenia due to other causes.

Since then, Lennox has been screening incoming early-psychosis patients for the anti-NMDA antibodies and treating those who test positive. “I'm cautious to claim any results because it hasn’t been done in a randomized controlled way,” she said in an interview with The Naked Scientists. “But we have treated about 20 patients now, and each patient has improved with the psychiatric symptoms so far.” 

Read More: What Causes Schizophrenia? »

Uniting the Brain and Body

Lennox worries that people with symptoms of schizophrenia will be treated solely as psychiatric patients, rather than as patients with any other medical condition.

“Psychiatry has been progressively de-medicalized,” she wrote. “The speciality has separated from the rest of medicine. This is an untenable position, when there is the potential for detecting such a treatable disorder in a percentage of our patients. The physical and cultural separation of psychiatry from the rest of medicine makes it difficult for us now to adequately investigate and manage our patients.”

Rather than viewing this cause of psychosis as a subtype of schizophrenia, Sealfon suggests that anti-NMDA receptor encephalitis is simply its own disease, which, due to its symptoms, has been placed in the schizophrenia grab-bag.

“As schizophrenia is diagnosed on clinical grounds, it is likely that occasional cases of schizophrenia, especially newly diagnosed diseases, are actually variants of anti-NMDA antibody encephalitis,” he told Healthline. “Antibody-mediated disease causes a syndrome that is clinically indistinguishable from schizophrenia, but this is probably not the same disease. Whether these antibodies can cause the same disease as schizophrenia requires further study.”

Sealfon referred to another study, which examined the blood of 459 people with schizophrenia, bipolar disorder, or major depression, plus healthy controls. The study found that 10 percent of those with an initial diagnosis of schizophrenia carried anti-NMDA receptor antibodies. Looking more closely, they re-diagnosed two of the patients with NMDA antibody encephalitis.

As for the rest? Although they carried antibodies for NMDA, they were of the wrong type. “Acutely ill patients with an initial schizophrenia diagnosis show an increased prevalence of NMDA [receptor] antibodies,” the researchers wrote. “The repertoire of antibody subtypes in schizophrenia is different from that with NMDA [receptor] encephalitis.”

Because of this difference in antibody types, Sealfon advises caution in drawing any conclusions about the connection between the antibody signature and psychosis. “These antibodies may sometimes cause schizophrenia, predispose to it, be a marker of the disease without being causative, or be unrelated,” he said.

Still, the discovery of NMDA antibody encephalitis offers new hope for the treatment of some cases of what’s currently called schizophrenia. “Identifying any possible cause for a small percentage of patients presenting with schizophrenia is an important advance in improving diagnosis and developing specific and individualized therapeutic approaches,” Sealfon said.

Related News: Why Are Schizophrenics More Likely to Be Left-Handed? »