The discovery of the antipsychotic drug chlorpromazine more than 50 years ago radically altered the treatment of schizophrenia by giving people a tool to treat the hallucinations and delusions associated with the mental illness. Yet although there are now a number of these first-generation antipsychotics on the market, the medications have limited abilities to reduce the negative symptoms of disease, such as lack of motivation or emotion. Some newer agents that address some of these problems have since been developed, but these carry their own suite of debilitating side-effects, so patients and doctors alike have desperately sought alternatives. To that end, researchers are ramping up their efforts by leveraging state-of-the art sequencing and stem cell technologies to identify better drugs for schizophrenia.
“In the next five years, we are going to understand this disease,” Edward Scolnick, director of the Stanley Center for Psychiatric Research at the Broad Institute in Cambridge, Massachusetts, told Nature Medicine. “Nothing but dollars and time stands in our way.”
At the New York Academy of Sciences’ Advancing Drug Discovery for Schizophrenia meeting earlier this month, Scolnick described the latest efforts of the International Schizophrenia Consortium initiative. Two years ago, the consortium — which includes researchers in the US, UK, Ireland and Sweden — conducted a genome-wide association study, and found thousands of common variants linked to the disease. But that analysis was based on only around 3,300 people with schizophrenia and 3,600 healthy controls. Now the group is scaling up to include an estimated 20,000 schizophrenics and 40,000 healthy people in an effort to identify pathways containing a critical subset of these genes that could be targeted to develop new therapies — a strategy that appears promising for a growing number of complex conditions including schizophrenia. Last week, for instance, a separate international team reported in Nature that a polymorphism in the neuropeptide receptor VIPR2, a potentially druggable target, confers significant risk for schizophrenia. A complementary approach using exosome sequencing is also ongoing.
In addition, the researchers are reprogramming skin cells from people with schizophrenia to create a panel of induced pluripotent stem (iPS) cells that can then be used for drug discovery. “[By] being able to look at human neurons and see how genes that are being discovered modulate those neurons.we can find chemicals that reverse those [effects] leading to new targets and new medicines for the disorder,” says consortium member Stephen Haggerty, a chemical biologist at the Massachusetts General Hospital in Boston. Just last month researchers from Johns Hopkins University in Baltimore demonstrated the feasibility of such an approach by reporting the first iPS cell lines derived from people with schizophrenia.
Scolnick estimates that the ambitious research project will cost upward of $200 million. He concedes that this is a hefty price to pay. But he argues that investing in the effort will be money well spent. “For the first time in the history of the field there is a way forward that can lead to significant improvements in diagnosis and therapy,” he says.
Image: Alex Minott