Schizophrenia is a mental illness that can profoundly change an individual’s perception of reality. An estimated 2.4 million adults in the United States live with schizophrenia, which can cause symptoms such as hearing voices, struggling to organize thoughts, and having visual hallucinations and delusions.
Although society is starting to discuss mental health more openly, thanks to initiatives such as Mental Health Month, there is still a great deal of stigma around schizophrenia.
Living with schizophrenia can also be extremely challenging. Treatment options are limited, and antipsychotics, which are the standard first-line treatment, are ineffective in many patients.
Antipsychotic drugs may also have unpleasant side effects, including considerable weight gain, tiredness, and restless muscles. One study even linked first generation antipsychotic drugs to the loss of brain tissue in people with schizophrenia.
However, a new study from the RIKEN Center for Brain Science (CBS) in Japan could open up a different avenue for drug development — one that relates to changes in lipid metabolism.
The study findings feature in the journal Schizophrenia Bulletin.
The study focuses on white matter, the part of the brain comprising axons that carry nerve impulses between neurons. Research has identified a reduction in white matter in people with schizophrenia.
White matter gets its name from its light color, which is due to the lipid-dense myelin sheaths that surround axons, facilitating the rapid conduction of nerve impulses. Loss of myelin is associated with a number of neurological conditions, most notably multiple sclerosis.
Fatty molecules called sphingolipids are important in the formation of myelin, and previous studies have shown differences in the levels of these molecules in people with schizophrenia. However, many questions remain unanswered.
To look at the connection between sphingolipids and schizophrenia in more detail, the researchers behind the new study analyzed the levels of these molecules in the postmortem brain tissue of 15 people with schizophrenia. They carried out the same analysis on an equal number of age- and sex-matched controls.
The researchers used mass spectrometry, a technique typically more familiar to chemists. This technique identifies the particles present in a sample by measuring their mass, which it does by bombarding the sample with electrons.
“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,” explains Dr. Takeo Yoshikawa, team leader at RIKEN CBS.
The team found that levels of a sphingolipid called S1P were lower in people with schizophrenia than in those without this condition. Levels were lower in a region of the brain called the corpus callosum — the largest collection of white matter in the brain, which connects its two hemispheres. Abnormalities in this region could lead to irregular communication between neurons.
To determine whether this mechanism is common across mental disorders, the scientists also analyzed the brains of people with bipolar disorder and major depressive disorder.
They found that S1P levels in these people were normal, indicating that the deficiency is specific to schizophrenia.
Further experiments suggested that the problem may be due not to an impaired production of S1P but to the abnormal degradation of this lipid.
If this is the case, designing drugs to stop the breakdown of S1P could help treat schizophrenia. The team hopes that this finding will help reinvigorate drug development for the condition.
“Because we don’t have another angle on what causes schizophrenia, many pharmaceutical companies are pulling out of schizophrenia-related drug development. Hopefully, our findings can provide the new angle with a new target for drug development.”
– Dr. Takeo Yoshikawa
The researchers say that it is possible that the existing multiple sclerosis treatment fingolimod (Gilenya) — which targets the S1P receptor — could be effective, eliminating the need for a lengthy drug development process.
However, it remains unclear whether Gilenya would work as a treatment for schizophrenia, and more research is necessary to understand the exact role that S1P plays in the condition. The first step is to begin work on animals, Yoshikawa says.
“The next important step is to determine precisely which S1P receptor-acting drugs are effective in experimental animals,” he concludes.
