Study IDs Potential New Drug Target for Schizophrenia

Study IDs Potential New Drug Target for Schizophrenia

Japanese researchers have discovered a deficiency in the brains of people with schizophrenia. The findings could lead to the development of new drug therapies.

For the study, researchers at the RIKEN Center for Brain Science (CBS) in Japan conducted post-mortem exams (autopsies) and discovered that schizophrenia was linked to lower-than-normal levels of S1P, a type of fatty molecule found in the white matter of the brain.

In recent years, drug therapy for schizophrenia has come to a halt. Most schizophrenia drugs currently available are based on dopamine, but they are ineffective in about one out of every three patients. The researchers believe that preventing S1P degradation might be a new target for drug development.

“Because we don’t have another angle on what causes schizophrenia, many pharmaceutical companies are pulling out of schizophrenia-related drug development,” says Takeo Yoshikawa, team leader at RIKEN CBS. “Hopefully, our findings can provide the new angle with a new target for drug development.”

Although schizophrenia is a well-researched mental disorder, the mechanisms behind it remain a mystery. Scientists have known for some time that the brains of people with schizophrenia have less white matter than normal brains.

White matter is produced by oligodendrocytes, special cells that wrap around the parts of neurons that carry outgoing signals, which help them communicate with each other. The psychotic symptoms of schizophrenia include hallucinations and delusions — the inability to distinguish reality from fantasy — which might originate in white matter abnormalities that cause irregular communication between neurons.

Led by Takeo Yoshikawa, the team at RIKEN CBS investigated sphingolipids, a group of lipids known to have many functions, some related to white matter. In cadavers of schizophrenia patients, the researchers conducted an analysis of the large white matter tract that connects the left and right sides of the brain. In doing so, they found a severe deficiency in S1P, a sphingolipid necessary for oligodendrocyte production.

Further research showed that although normal amounts of S1P had been produced, it was metabolized and broken down when it should not have been.

“Drugs that prevent S1P degradation could be particularly effective in treating schizophrenia,” says Kayoko Esaki, first author and postdoctoral research scientist.

Although the experiment sounds simple, measuring S1P levels in the brains of cadavers was a big challenge and required interdisciplinary expertise in chemistry — specifically mass spectrometry — that was brought to the team by Esaki.

“This was the first psychiatric study of the postmortem brain to use mass spectroscopic analysis, and our discovery would not have been possible without our newly established comprehensive technique for screening sphingolipids,” says Yoshikawa.

After discovering S1P sphingolipid deficiency in schizophrenia brains, the researchers then examined postmortem brains of people with bipolar disorder or major depressive disorder. They found that S1P levels did not differ from what they found in normal brains, indicating that the problem is specific for schizophrenia, and not a common feature of mental disorders.

Before schizophrenia-specific clinical trials can begin, studies in animals will be necessary. “The next important step,” says Yoshikawa, “is to determine precisely which S1P receptor-acting drugs are effective in experimental animals. Although the new blockbuster drug fingolimod works at the S1P receptor and is effective at treating multiple sclerosis, we do not yet know how effective it would be for schizophrenia.”

The findings are published in the journal Schizophrenia Bulletin.

Source: RIKEN

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