We may be treating schizophrenia wrong

For more than 70 years, doctors have treated symptoms of schizophrenia — delusions, hallucinations, and cognitive impairment — using antipsychotic medications. Prevailing theories suggest that elevated dopamine signaling in the brain leads to schizophrenia, so these antipsychotics provide relief by attenuating dopamine activity. However, it wasn’t entirely clear How These drugs calm dopamine activity. Because of their nature, these medications affect other parts of the body and promote unwanted side effects including weight gain, constipation and drowsiness. Furthermore, approximately one-third of patients do not respond to two or more common antipsychotic treatments.

What if there was a better way to treat the more than 24 million people around the world who have schizophrenia? A new study conducted by researchers in Japan and published earlier this year in Medicine Cell Reports He suggests that for at least a significant portion of patients, the immune system mistakenly attacks a protein in the brain – which may be the real mechanism that triggers schizophrenia symptoms in the first place.

This study is also the tip of the iceberg.

“We don’t know what causes schizophrenia,” Roger McIntyre, MD, a psychiatrist and professor of psychiatry and pharmacology at the University of Toronto (who was not affiliated with this work), told The Daily Beast. “The rigorous scientific studies that have been done have concluded that for some people, some symptoms of schizophrenia may be the result of a disorder in the inflammatory immune system.”

The most vulnerable are the cognitive symptoms: the ability to focus, focus, your memory, processing speed, and also the so-called negative symptoms. In other words, people with schizophrenia often experience this lack of motivation.

Roger McIntyre, University of Toronto

This, in turn, may open the door to an entirely new way to treat schizophrenia – one that is unencumbered by the challenges that current antipsychotics inhibit.

The team behind the new study analyzed blood from nearly 200 schizophrenia patients and compared it to blood samples from more than 200 healthy individuals. In about 6 percent of schizophrenia patients, researchers found elevated levels of antibodies targeting NCAM1, a protein important for cellular communication in the brain. None of the healthy individuals enrolled in the study produced this antibody.

This is a surprising finding, but was this antibody really responsible for the symptoms themselves? Or just another sign of status?

The researchers isolated the antibodies and injected them into mice. In addition to causing cognitive impairment and other behaviors characteristic of schizophrenia, NCAM1 autoantibodies also reduced the number of connections in the brain.

“Although the mice only had these autoantibodies in their brains for a short time, there were changes in their behavior and synapses that were similar to what is seen in humans with schizophrenia,” said Hidehiko Takahashi, professor of psychiatry and schizophrenia researcher at Tokyo University of Medicine and Dentistry, a co-author of the new study, said in a press release.

McIntyre added that there are other links between schizophrenia and the immune system, including a subset of patients who have antibodies against other proteins in the brain, such as NMDA receptors or other markers of immune dysregulation. He said, citing a previous study published by his research group published in Gamma Psychiatry.

A 2018 study found that people with an autoimmune disorder are 70% more likely to develop schizophrenia. This is not surprising given that the prominent genetic risk factors for the disease occur as mutations in a genetic locus called the major histocompatibility complex. This compound is important for teaching the immune system the difference between body proteins and invading pathogens.

Evidence for autoimmune schizophrenia goes beyond genetics. Brain-resident immune cells, microglia, are also implicated in disease development and disease.

There are certain forms of breast cancer, you can configure the genetic makeup of a person, and based on the genotype, you can determine whether they will respond specifically to certain drugs, for example, breast cancer. We’re not yet into psychiatry, but that’s exactly the direction people want to go.

Roger McIntyre, University of Toronto

Microglia are plant enthusiasts and gardeners in the brain. When neurons sprout and grow early in life, microglia are careful to cut off any unused or unnecessary connections. They then provide ongoing support by dealing with pathogens and infections, removing any debris, and getting rid of dysfunctional cells. Like the manual labor of a terrible gardener, microglia can leave a trail of chaos.

Maternal infection during pregnancy is known to increase the risk of schizophrenia – animal models suggest that microglia are the mediator of this effect. In post-mortem studies, researchers found elevated levels of active microglia that “attack” other cells in the brain.

And that’s not all – they also release and respond to several signaling proteins called cytokines that may also play a role in schizophrenia. In 2011, researchers discovered that levels of several cytokines are either higher or lower than levels found in healthy individuals. Some cytokines, including interleukin-1β and interleukin-6, were raised after the first psychotic episode as well as in patients who experienced relapse of symptoms. Antipsychotic treatments also lowered levels of these proteins, reinforcing the idea that these cytokines are targets for new treatments.

All of this research has led to a very important question: Can existing drugs that reduce inflammation or target specific cytokines enhance the response to antipsychotic drugs?

Results in 2014 showed that a broad approach to treating general inflammation in patients with schizophrenia found that taking aspirin, estrogen or an antioxidant called n– Acetylcysteine ​​plus antipsychotic drugs had a small but significant effect on the severity of symptoms. Other researchers discovered in 2017 that taking an antipsychotic with minocycline — a drug that prevents microglia from activating — improves symptoms overall.

According to McIntyre, minocycline is often prescribed as an off-label treatment. “You wouldn’t see minocycline as a recommended treatment because that’s outside of standard practice,” he said. “But doctors spend a lot of their time treating patients who don’t benefit from standard practice.”

Because individuals with schizophrenia can experience a wide range of symptoms and diseases, scientists are working to develop more specific and personalized treatments. “We really think that schizophrenia is a group of disorders, and there are different causative biological pathways,” McIntry said, adding that many people who do not benefit from current antipsychotic medications develop symptoms strongly related to immune dysregulation.

These treatments can have stronger effects on people with schizophrenia who are hospitalized, as well as those who do not respond to current treatments.

“The most significant impairment of cognitive symptoms is the ability to focus, focus, your memory, processing speed, and also the so-called negative symptoms,” McIntyre said. “In other words, people with schizophrenia often have this lack of motivation.”

In 2014, two treatment-resistant patients received an antibody against the interferon-gamma-1b protein – which is responsible for amplifying the body’s immune response. Both patients showed improvement in symptoms over seven weeks.

Two years later, researchers conducted an eight-week clinical trial and found that tocilizumab, a type of antibody-based drug that reduces inflammation approved to treat arthritis, improves cognitive symptoms in patients with schizophrenia. The antibody-dependent drug works by blocking the activity of the interleukin-6 receptor, which prevents the activation of the body’s inflammatory response. But a 2018 study of 36 patients found no improvement from tocilizumab.

However, further trials are underway to recruit more patients to test current immune-modifying drugs against schizophrenia. An antibody-based drug targets interleukin-6 and may increase the effects of antipsychotic treatments. Other targets activate microglia, which are also being tested in early experiments. McIntyre expects new treatments to be approved by the Food and Drug Administration in the next five to 10 years.

With everything we know so far, it’s still hard to develop better treatments. The immune system is complex and there are many different ways it can get stuck. NCAM1 autoantibodies were only present in about 6 percent of those with schizophrenia in the study. Approaches to treating schizophrenia can target specific aspects of the immune system that are not working, whether it is autoantibodies, microglia, or specific cytokines.

“There are certain forms of breast cancer, you can configure a person’s genetic makeup, and based on their genotype, you can determine if they will respond specifically to certain drugs, for example, breast cancer,” McIntyre said. “We’re not yet into psychiatry, but that’s exactly the direction people want to go.”

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