A new drug can block schizophrenia-like symptoms in rats, without apparent side effects. The work, described in tomorrow's Science, suggests a new approach to schizophrenia drugs that may someday lead to better therapies for the condition, which afflicts 1% of the population of the United States alone.
Such drugs are badly needed. Current schizophrenia medications, known as neuroleptics, aim to alleviate the symptoms of the disease by blocking the action of one of the brain's chemical signals, the neurotransmitter dopamine. But while patients who take them often see reductions in paranoia and hallucinations, the drugs offer little relief from other symptoms, such as poor attention spans, jumbled thoughts, and difficulty interacting with other people. What's more, the neuroleptics often cause troubling side effects, including uncontrollable tremors similar to those in Parkinson's patients.
The psychoactive drug phencyclidine, or PCP, offered tantalizing hints that a different approach might work: blocking the activity of another neurotransmitter called glutamate. PCP induces schizophrenia-like symptoms in healthy people. Following up on those observations, neuroscientists Bita Moghaddam and Barbara Adams of Yale University School of Medicine and Veterans Administration Medical Center in West Haven, Connecticut, administered PCP to rats, which develop symptoms such as frantic running and head-turning thought to parallel psychotic symptoms in humans, and examined what happens to brain glutamate levels in the animals. Although the earlier work suggested that they should go down in response to PCP, the Yale workers found instead that they surged. Moghaddam then speculated, she recalls, that "if we block glutamate activation, maybe we can block these behavioral effects."
To avoid side effects, Moghaddam and Adams wanted to block glutamate activity only in those parts of the brain where it might be elevated. So, they turned to a drug called LY354740 that is under development at Eli Lilly & Co. in Indianapolis for other psychiatric disorders such as anxiety. By binding to the so-called metabotropic glutamate receptor on glutamate-releasing nerve terminals, LY354740 dampens output of the neurotransmitter, but only when its levels get too high. When Moghaddam and Adams gave rats the Lilly drug before administering PCP, they found that glutamate levels no longer went up in the prefrontal cortex, one of the brain regions that goes haywire in schizophrenia. The six LY354740-treated rats also stayed calm and showed little head-shaking behavior, compared to controls who got only PCP.
Encouraging results in rats don't guarantee that the approach will work in humans. Still, says schizophrenia researcher Jon Horvitz of Columbia University in New York City, "it's impressive work. This is a promising avenue for a drug that attenuates schizophrenic symptoms."