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See Inside June/July 2008

A Novel Chemical Target

A drug for schizophrenia tweaks the brain's levels of glutamate

Antidepressants such as Prozac made serotonin a household word, and cocaine studies transformed dopamine into a synonym for pleasure. Now glutamate may finally find its fame, thanks to a new schizophrenia drug—the first ever to target this abundant neurotransmitter. The drug could usher in an era of better treatments for neurological ailments, including mood disorders, Alzheimer’s, Parkinson’s and brain damage from stroke.

Until now, clinical efforts to alter glutamate levels have failed because tinkering with this essential neurotransmitter, which excites neurons, is tricky. High concentrations of glutamate can trigger seizures or kill brain cells—and levels that dip too low can cause coma. The new agent avoids these dangers by binding only to a subset of glutamate receptors that have more nuanced effects on neurons. Researchers think it may work for schizophrenia by decreasing the abnormally high glutamate levels in certain brain areas that are associated with the disease. Restoring the glutamate balance could then reduce excessive amounts of dopamine, another key player in the disease, in a psychosis-related neuronal pathway.

Researchers hope that aiming for glutamate will help patients who do not respond to the schizophrenia medications currently in use, which target only dopamine and serotonin. The new drug, which may reach the market in as few as three years, could also be a welcome alternative for patients who cannot tolerate the other drugs’ side effects, which include involuntary repetitive movement and significant weight gain that often leads to diabetes.

Pharmaceutical companies are racing to produce more glutamate therapies. “There may be an explosion of new tools” targeting glutamate, says Darryle Schoepp, a Merck scientist who developed the novel drug while working at Eli Lilly.

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