For more than 70 years, doctors have treated the symptoms of schizophrenia—delusions, hallucinations, and cognitive impairment—with antipsychotic drugs. Prevailing theories suggest that increased dopamine signaling in the brain leads to schizophrenia, so these antipsychotics provide relief by dampening dopamine activity. However, it was never completely clear how can These drugs block dopamine activity. And because of their nature, these drugs can affect other parts of the body and cause unwanted side effects, including weight gain, constipation, and drowsiness. Moreover, nearly one-third of patients do not respond to two or more antipsychotic treatments.
What if there was a better way to treat the more than 24 million people worldwide with schizophrenia? A new study conducted by researchers in Japan and published earlier this year Cell Reports Medicine For at least a significant proportion of patients, the immune system mistakenly suggests that it is attacking a protein in the brain—which may be the actual mechanism that causes schizophrenia symptoms in the first place.
This study is also the tip of the iceberg.
“We don’t know what causes schizophrenia,” Roger McIntyre, a psychiatrist and professor of psychiatry and pharmacology at the University of Toronto (not involved in the case), told the Daily Beast. “Hard scientific studies have been conducted and they have concluded that for some people, some of the symptoms of schizophrenia may be the result of a malfunction of the immune-inflammatory system.”
“The most debilitating thing is the cognitive symptoms: it affects your concentration, concentration, memory, processing speed, as well as the so-called negative symptoms. In other words, people with schizophrenia often have a lack of motivation.“
— Roger McIntyre, University of Toronto
That, in turn, could open the door to an entirely new way of treating schizophrenia—one that doesn’t get rid of the problems that hold current antipsychotics back.
The team behind the new study analyzed the blood of nearly 200 schizophrenia patients and compared it with blood samples from more than 200 healthy individuals. In about 6 percent of schizophrenia patients, the researchers found high levels of antibodies targeting NCAM1, a protein important for cell communication in the brain. None of the healthy subjects in the study produced these antibodies.
This is a surprising finding, but are these antibodies responsible for the symptoms themselves? Or another symptom of the condition?
The scientists isolated the antibodies and injected them into mice. In addition to causing cognitive impairment and other behaviors characteristic of schizophrenia, NCAM1 autoantibodies reduced the number of connections in the brain.
“Even though the mice had these autoantibodies in their brains for only a short time, they had changes in their behavior and synapses similar to people with schizophrenia,” said Hidehiko Takahashi, a psychiatry and schizophrenia researcher in Tokyo. University of Medicine and Dentistry and author of the new study, said in a press release.
McIntyre added that there are other connections between schizophrenia and the immune system, including a subset of patients with antibodies against other brain proteins such as the NMDA receptor or other markers of immune dysregulation. “People living with schizophrenia or bipolar disorder or depression have a higher risk of getting sick with COVID-19, being hospitalized, and dying,” he said, referring to a previous study published by his research group. JAMA Psychiatry.
A 2018 study found that people with autoimmune diseases are more than 70 percent more likely to develop schizophrenia. This is not surprising given that the major genetic risk factors for the disease appear as mutations in a gene locus known as the major histocomplex. This complex is important for teaching the immune system the difference between the body’s own proteins and invading pathogens.
And the immune system-schizophrenia evidence goes beyond genetics. Resident immune cells of the brain, microglia, are also involved in the development and pathology of the disease.
“There are certain types of breast cancer that you can genotype someone and determine whether they will respond to certain drugs, for example, for breast cancer, based on the genotype. We’re not there yet in psychiatry, but that’s the direction people want to go.“
— Roger McIntyre, University of Toronto
Microglia of the brain are avid plant-enthusiasts and gardeners. As neurons grow early, microglia take care of severing unused or unwanted connections. They then provide ongoing support to fight pathogens and infections, clear waste products, and get rid of dysfunctional cells. Like the handiwork of the dreaded gardener, microglia can leave a trail of chaos.
Maternal infection during pregnancy increases the risk of developing schizophrenia – animal models implicate microglia as a mediator of this effect. In post-mortem studies, the researchers found activated levels of microglia, which “attack” other brain cells.
And that’s not all—they secrete and respond to many signaling proteins called cytokines, which also play a role in schizophrenia. In 2011, researchers found that levels of several cytokines were either higher or lower than in healthy individuals. Certain cytokines, including interleukin-1β and interleukin-6, were elevated after a first psychotic episode as well as in patients who experienced a recurrence of symptoms. Antipsychotic treatment also reduced the levels of these proteins, supporting the idea that these cytokines are targets for new treatments.
All of these studies lead to a very important question: Can drugs that reduce inflammation or target specific cytokines enhance the response to antipsychotic drugs?
Results from 2014 showed that a common approach to treating common inflammation in patients with schizophrenia is to take aspirin, estrogen, or medications called antioxidants. Do not-Acetylcysteine had a small but significant effect on symptom severity in addition to antipsychotic drugs. By zeroing in on microglia, other researchers found in 2017 that taking antipsychotics, along with minocycline, which inhibits microglia activation, improved overall symptoms.
According to McIntyre, minocycline is often prescribed as an off-label treatment. “You don’t see minocycline as a recommended treatment because it’s too much of a routine practice,” he said. “But clinicians spend a lot of time treating patients who don’t benefit from conventional practice.”
Because people with schizophrenia can experience a wide range of symptoms and pathologies, scientists are working to develop specific, personalized treatments. “We really think that schizophrenia is a group of diseases with different biological causative pathways,” McIntrye said, noting that many people who don’t benefit from current antipsychotic drugs show symptoms strongly linked to immune dysregulation.
This treatment may have a stronger effect on people who have been hospitalized with schizophrenia, as well as those who have not responded to current treatment.
“The most debilitating thing is the cognitive symptoms: it’s your focus, your concentration, your memory, your processing speed, as well as what’s called negative symptoms,” McIntyre said. “In other words, people with schizophrenia often have a lack of motivation.”
In 2014, two treatment-resistant patients received antibodies against the interferon gamma-1b protein, which is responsible for boosting the body’s immune response. Both patients showed improvement in symptoms within seven weeks.
Two years later, researchers conducted an eight-week clinical trial and found that tocilizumab, a type of antibody-based anti-inflammatory drug approved to treat arthritis, improved cognitive symptoms in patients with schizophrenia. The drug based on antibodies works by blocking the activity of the interleukin-6 receptor, preventing the activation of the body’s inflammatory response. But a 2018 study of 36 patients found no improvement with tocilizumab.
However, more trials are underway to recruit more patients to test immune-modulating drugs for schizophrenia. An antibody-based drug targeting interleukin-6 may enhance the effect of antipsychotic treatment. Another target, activated microglia, is also being tested in early trials. McIntyre expects the new treatment could be approved by the FDA in the next five or 10 years.
Despite everything we know so far, developing better treatments is still difficult. The immune system is complex and there are many different ways it can be compromised. NCAM1 autoantibodies were present in only about 6 percent of people with schizophrenia in the study. Individualized approaches to the treatment of schizophrenia may target specific aspects of the immune system that are dysfunctional, be it autoantibodies, microglia, or specific cytokines.
“There are certain types of breast cancer that you can genotype someone and, based on the genotype, determine whether they will respond to certain drugs in particular, for example, breast cancer,” McIntyre said. “We’re not there yet in psychiatry, but that’s the direction people want to go.”