Chemical Abnormalities Linked to Schizophrenia : The brain: Discovery that a key segment of a gene can be repeated with variations may explain why drug therapy doesn’t always work. Study opens way for new drugs.
Scientists have detected subtle chemical abnormalities in the brain that they say may make a person more susceptible to schizophrenia, manic depression and other mental disorders.
Perhaps just as important, the discovery, reported today in the British journal Nature, may explain why some people are helped by antipsychotic drugs and some are not. This information could lead to the development of new drugs as well as new ways to detect susceptibility to such disorders.
The Canadian and Oregon team found that a key segment of the gene for a crucial brain protein can be repeated two to seven times, with each variation producing slightly different characteristics of the protein. Normally, the gene is not repeated.
Researchers have recently found that such repeated gene segments are the cause of other genetic disorders, such as “fragile X syndrome,” which causes mental retardation, and the adult form of muscular dystrophy, and they speculate that the newly discovered repeat segments in the brain protein may be a cause of schizophrenia and manic depression.
The team also found that different forms of the protein interact differently with drugs. That finding may explain why certain drugs, such as the anti-schizophrenia drug clozapine, are highly effective in some patients while producing little effect in others, said molecular biologist Hubert H. M. Van Tol of the Clark Institute of Psychiatry in Toronto.
The new discovery is “an exciting finding . . . that opens up enormous possibilities for developing new treatments,” said psychopharmacologist William Potter of the National Institute of Mental Health in Bethesda, Md. “The opportunities for novel treatments could be within our grasp in the time frame of years rather than decades.”
The fact that people respond differently to such drugs as clozapine is “one of the big issues of psychiatry now,” added Dr. Solomon Snyder, a psychiatrist at the Johns Hopkins University School of Medicine in Baltimore. Van Tol’s discovery thus has “important potential implications” for the development of drugs to aid those individuals who derive no benefit from currently available drugs, he added.
Schizophrenia is the most common form of severe mental illness, affecting about 1% of the population. It is characterized by inappropriate emotions, hallucinations and disordered thought processes that cause difficulties in communication, interpersonal relationships and distinguishing between the real and the imagined. The National Academy of Sciences estimates that treatment of schizophrenia costs up to $48 billion per year.
The most effective treatment for schizophrenia is the antipsychotic drug clozapine, but it is useful in only about 60% of patients--and even among that group some patients respond better than others. Psychiatrists have had no way to predict which patients would benefit from the drug.
Clozapine targets a brain protein called the D4 dopamine receptor. Dopamine is a simple chemical that plays a key role in transmitting messages between brain cells. It binds to the D4 receptor on the surface of brain cells, triggering a response within the cell.
Previous studies have shown that excess dopamine in the brain is associated with the symptoms of schizophrenia. Clozapine counteracts the excess dopamine by binding to the D4 receptor so that dopamine cannot.
Previously, researchers had believed that only one D4 receptor existed and could not understand why clozapine did not help all schizophrenia patients. But Van Tol and his colleagues at the Clark Institute, along with molecular biologist Olivier Civelli and his colleagues at the Oregon Health Sciences University in Portland, screened more than 200 individuals--both healthy and with mental disorders--and identified seven different forms of the D4 receptor.
The different forms vary at one specific segment of the protein. In what is presumably the normal form of D4, this segment occurs once. In the less common forms, the segment is repeated two to seven times. Each of these forms, they found, binds clozapine differently. That difference in binding, Van Tol said, could easily explain the difference in therapeutic effects of the drug.
The researchers still must determine which forms of the protein are associated with a good response to drug therapy in humans. Armed with this knowledge, a simple blood test could tell psychiatrists which patients should respond to the drug. The researchers could also design drugs that interact with the forms of D4 that do not bind to clozapine.
