During the early 1970s, a young University of Toronto researcher named Philip Seeman embarked on an experiment that some scientists dismissed as a waste of time. Doctors then knew that antipsychotic drugs could relieve some symptoms of schizophrenia. But nobody understood how they worked or believed that Seeman's innovative approach - using radioactively tagged drugs and tissue samples from schizophrenic brains - could provide the answer. Seeman persevered and, in 1974, he showed that the drugs zeroed in on a tiny brain protein that acts as a receptor for dopamine - a chemical that transmits messages inside the brain. Two decades later, Seeman - along with other leading researchers who have made Toronto's Clarke Institute of Psychiatry a world-renowned centre for the study of the disease - is still searching for, and finding, new clues to the mystery of schizophrenia. Following a series of breakthrough discoveries by the Clarke scientists, pharmaceutical companies now are working on drugs that could significantly improve the lives of schizophrenics. And some experts predict that drugs capable of suppressing the disease's symptoms completely could emerge within a few decades.
Inspired by the realization that schizophrenia is a biochemical brain disorder - and not, as doctors once believed, the result of family influences during childhood - a growing number of scientists are studying the disease. During the past five years, researchers at the Clarke Institute have isolated the genes for three types of dopamine receptors in the brain - findings that provide the pharmaceutical industry with clues for the creation of new drugs. At the same time, researchers in other Canadian laboratories are hunting for malfunctioning genes and other abnormalities that could provide clues to the underlying cause of schizophrenia. So far, what scientists do know is that dopamine is an important part of the problem - because it is an overactive dopamine system that apparently causes hallucinations and delusions in schizophrenic brains. Now, scientists are struggling to understand how dopamine receptors function - and how they go wrong. In a key finding in 1989, Seeman, now a professor of pharmacology at the University of Toronto, and other researchers discovered that normal communications between two of the receptors, called D1 and D2, apparently break down in schizophrenic brains, triggering psychotic episodes.
In a series of related breakthroughs, scientists at the Clarke and other labs have gained a deeper understanding of the dopamine receptors. In 1989, Hubert Van Tol, a Dutch-born molecular biologist working at a Portland, Ore., research institute, isolated the gene for the D2 receptor, which Seeman had identified in 1974. Two years later, after taking up a new post at the Clarke Institute, Van Tol isolated the gene for the D4 receptor, which appears to be overly abundant in people with schizophrenia. Then, in 1991 and 1992, Hyman Niznik, a molecular neuropharmacologist at the Clarke, cloned the genes for the D1 and D5 receptors.
The flurry of discoveries included one profound disappointment. Having isolated the dopamine receptor genes, scientists had hoped that at least one might turn out to be flawed - a finding that might have pointed to the cause of schizophrenia and provided a way of testing for the disease. But that hope fizzled. "It turns out," says Seeman, "that the receptor genes are basically all normal in schizophrenics." Adds James Kennedy, a neurogeneticist at the Clarke Institute: "It is as though the dopamine system was waving at us and saying, 'I'm involved.' But it won't tell us exactly how."
The failure to find a malfunctioning gene will not hold up the development of new drugs. But it does mean that a long search may lie ahead for the underlying causes of schizophrenia. Because most schizophrenics come from families with a history of the illness, scientists believe that one or more flawed genes must play a role in the disease. But if the flaw is not in the genes that determine the development of the dopamine receptors, the only other possibility is that a genetic flaw is causing problems in some other part of the brain - and setting in motion a chain of events that ultimately disrupts the dopamine system. While Seeman and scientists at the Clarke Institute struggle to unravel the riddle of the receptors, researchers at other Canadian institutions are looking for suspect genes and pursuing other avenues of inquiry. Among them:
1) Last May, Canadian researchers reported findings that demonstrated an insidious and little-recognized aspect of schizophrenia: in its inherited form, the illness becomes more serious, and the age of onset earlier, with each succeeding generation. According to Dr. Anne Bassett, a researcher at Toronto's Queen Street Mental Health Centre, that pattern may be caused by a genetic instability that increases with each generation, to the point where it interferes with the functioning of one or more genes - and triggers schizophrenia. Using genetic material and medical histories collected from 15 large families in Ontario and the Maritime provinces, Bassett and Kennedy are searching for telltale areas of instability that could help to determine which genes are affected.
2) Employing brain scanning equipment, Dr. William Honer, a University of British Columbia psychiatrist, is examining the brains of normal people and of schizophrenics who are members of the same families that are involved in Bassett and Kennedy's genetic linkage study. Honer's goal: to see whether there are significant differences in the brains of schizophrenics. So far, Honer has discovered that an area of the temporal lobe - a region of the brain involved in memory and hearing functions - appears to be affected. In schizophrenic brains, says Honer, the fluid spaces between areas of grey matter appear to be larger than in nonschizophrenic brains. That, adds Honer, may mean that the temporal lobe has not developed normally. The differences are most pronounced in a part of the temporal lobe called the Sylvian fissure - a brain region involved in the integration of language with other mental functions. "That makes sense," says Honer. "People with schizophrenia have auditory hallucinations, and they have difficulty organizing their thought processes."
3) Researchers at the Montreal Neurological Institute have discovered evidence suggesting that the brains of schizophrenics generate between 30 and 40 per cent more dopamine than the brains of people who do not have the illness. The finding is important because even though most researchers agree that dopamine plays a central role in schizophrenia, until recently there was little hard evidence to support the theory. In their study, the Montreal researchers under neurophysiologist Albert Gjedde injected schizophrenic subjects with a radioactively tagged synthetic version of dopa, the naturally occurring amino acid that the brain converts into dopamine. Using brain-scanning equipment, the researchers found that the dopamine produced in schizophrenic brains showed more prominently than in normal patients. "Seemingly, there is an increased capacity to synthesize dopamine in the brains of people with schizophrenia," says Paul Cumming, a research associate at Montreal Neurological.
Until a major breakthrough occurs in some other area of schizophrenia research, the key to treating the disease will probably remain in the complex realm of the dopamine system. Currently, most antipsychotic drugs act primarily on the D2 receptor, with limited results. But a growing knowledge of the different kinds of receptors may result in more effective drugs. Already, a number of pharmaceutical firms are working on drugs that could ease the symptoms of schizophrenia by targeting the D3 and D4 receptors. As well, several firms, including Indianapolis-based Eli Lilly and Co. and Abbott Laboratories of Chicago, are conducting trials of drugs that, like the recently introduced drug risperidone, would block the action of dopamine and another neurotransmitter - serotonin - in the brain. Some experts believe that blocking action accounts for the success of risperidone at low dosages in helping to quell psychotic symptoms in some schizophrenics - without the accompanying side-effects produced by other antipsychotics.
Once scientists understand the genetic roots of schizophrenia, firms may be able to design drugs that will, in effect, correct biological deficiencies in the brain. When will this happen? Seeman, 60, is cautiously hopeful. "In terms of better drugs, the prospects are good," he says. "In terms of understanding what causes the disease, we're getting closer - but we are not there yet." Some younger scientists are more optimistic. The Clarke's Niznik thinks that the speed at which scientists are gaining understanding of the brain means that a virtual cure for schizophrenia could appear within the next two decades. "If we know the genes for the proteins involved and understand how they work, then we can make mutations of these genes to make receptors behave," says Niznik. "It will happen. The question is when." For the legions of suffering schizophrenics, that day cannot come too soon.
Maclean's January 30, 1995