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Two Swedish researchers whose work has led to sometimes controversial conclusions about schizophrenia and the brain were the recipients last month of the $50,000 Lieber Prize for Outstanding Achievement in Schizophrenia Research from the National Alliance for Research on Schizophrenia and Depression (NARSAD).
Goran Sedvall, M.D., Ph.D., and Lars Farde, M.D., Ph.D., who received the prize at NARSAD’s annual symposium in New York City, spoke with Psychiatric News about their research developing a method of determining when the brain’s dopamine and serotonin receptors are fully occupied. The research has helped clinicians better determine what constitutes an optimal dose of a neuroleptic based on full receptor occupancy.
It has also demonstrated convincingly that all antipsychotic drugs, with the exception of clozapine, target the same receptors, despite assertions by pharmaceutical companies that newer neuroleptics have significantly different modes of action, said Farde. Further, it shows that use of more than one neuroleptic drug at a time serves no therapeutic purpose, Farde said.
Although the technique for determining optimal dose is complex and costly, and hence not a practical day-to-day clinical tool, their work has spurred many clinicians to use lower doses, according to Sedvall.
"There are many exciting aspects" to their research, added Farde. But it has been especially heartening to do such highly technical work and "immediately see it has a clinical consequence" that will improve the treatment of patients. As a consequence of their work there is "a worldwide trend toward lower doses," said Farde.
But the researchers are concerned about the continued use of multiple neuroleptics in the same patient. Such polypharmacy continues as a result of "rigidity and ignorance," said Farde. In Sweden, where their work has had a major impact, average doses of neuroleptics are lower than anywhere else in the world, he noted. He and Sedvall are campaigning to get psychiatrists to stop using more than one neuroleptic at a time.
Sedvall began his career at Sweden’s Karolinska Institute in Stockholm before receiving a Fulbright scholarship to work at the National Institute of Mental Health (NIMH) in the late 1960’s. There he worked with other scientists to develop methods of measuring dopamine synthesis in the brain. It was at that time that he started looking at how antipsychotic drugs affected dopamine in the brain.
After returning to Sweden in the 1970’s, Sedvall began to investigate dopamine metabolites in cerebrospinal fluid of people with schizophrenia. In the early 1980’s he began developing a quantitative approach for imaging neuroreceptors using PET (positron emission tomography) in combination with radioactively tagged ligands - molecules that bind to neuroreceptors allowing the receptors to be identified. It was at this time that he met Farde at the Karolinska Institute, serving as supervisor for Farde’s doctoral thesis on dopamine receptor characteristics in the living human brain. That research, published in Science in 1986, was the first quantitative in vivo study of any neuroreceptor in the living human brain, according to Sedvall.
Farde "has broadened the approach to imaging both dopamine and serotonin systems," said Sedvall. "Our approach today is to examine in detail these receptor mechanisms in schizophrenia and try to identify if there are subtle differences" in the brains of people with schizophrenia compared with normal subjects.
Farde is also looking into another controversial area - the correlation between receptor density and personality traits in normal people. A study on that subject was published in Nature earlier this year.
"He has actually found correlation between numbers of receptors in the brain and personality characteristics," Sedvall commented. That research "is certainly controversial, which is why it’s so important to have some hard data when talking about it," observed Sedvall.
Farde has focused on the dimension of personality called "detachment," which resembles some of the negative symptoms of schizophrenia such as anhedonia and social withdrawal. "We are very much aware that this is a reductionistic approach, but still the data are there," remarked Sedvall. Those with a high degree of detachment have low numbers of D2 dopamine receptors in the basal ganglia, which is the only place the researchers have measured them so far, explained Sedvall. Future research will measure receptors in other parts of the brain, he said.
"We know that neuroleptics are not very useful in treating negative symptoms," added Farde. "[Neuroleptic] drugs block dopamine receptors." If, as their research suggests, a low number of such receptors is correlated with negative symptoms, it makes sense that conventional neuroleptics would not lessen these symptoms, he explained.
Clozapine, however, is unique among all antipsychotic drugs in that it occupies a very low fraction of D2 receptors at normal clinical doses. This may explain why it works for some people not helped by other antipsychotic drugs. Clozapine also occupies a subtype of serotonin receptor at high density, which suggests that this receptor may play a larger role in schizophrenia than has been assumed, said Farde.
The "general aim of our research is to find some kind of objective criteria about what are the malfunctioning systems that lead to schizophrenia," said Farde. As the tools to do so have become available, he and Sedvall are looking at "many more systems and regions in the brain" than before, he noted.
They are also comparing the postmortem brains of people with and without schizophrenia. They have already looked at about 30 normal brains and are beginning to examine the brains of people who had schizophrenia.
Such research is costly, he noted. "The recognition of our work by NARSAD will help us to raise more grant money," said Farde. Both he and Sedvall were surprised to receive the award, and neither of them knew they had been nominated.