Richard Harper, Jon Erickson, and Daniel Robertson/Eli Lilly and Co.

New target.
Drug molecules interact with rat version of a human glutamate receptor.

Schizophrenia Treatment Without Side Effects?

Scientists are excited over what they see as a possible breakthrough in the treatment of schizophrenia: the first human trials showing efficacy for a completely new class of antipsychotic drugs. The study represents the "leading edge of a new generation of medications" for schizophrenia, says Yale University drug researcher John Krystal.

Over the past half-century, many drugs have been introduced to treat schizophrenia, which afflicts about 1% of the population. But all of them have activity at the same target: the D2 dopamine receptor. The "dopamine hypothesis" is based on the fact that excess dopamine causes psychosis.

In recent years, however, scientists have been probing another theory, the "glutamate hypothesis." Glutamate is the brain's main excitatory neurotransmitter and activates other neurochemicals. The theory is that low activity in a certain type of glutamate receptor (NMDA) paradoxically leads to excess glutamate elsewhere, damaging brain connections. This results in psychosis, thought disorder, and the dulling of emotions associated with schizophrenia. In animal studies, compounds that act on glutamate receptors seem to block the effects of psychosis-mimicking amphetamines better than do most conventional drugs.

In a paper published online Sunday in Nature Medicine, researchers from Eli Lilly and Co. in Indianapolis, Indiana, have shown that these compounds work in humans as well.

The team, led by Sandeep Patil and Darryle Schoepp, compared a compound called LY140023 with both a placebo and with the conventional antipsychotic olanzapine. The randomized trial included 118 schizophrenic patients who spent 4 weeks closely monitored in the hospital. More than one-third of the patients in the two treatment groups responded with a 25% or more reduction in symptoms according to a standard scale--compared with only 3% of the placebo group. The difference between the treatment groups was not statistically significant; however, those taking LY140023 did not show Parkinsonian movement problems or weight gain, two side effects from conventional antipsychotic drugs.

"I could not overstate how exciting that breakthrough is," says Jeffrey Conn of Vanderbilt University in Nashville, Tennessee, who formerly worked on schizophrenia drugs for Merck & Co. "It is the first clear demonstration that you can achieve antipsychotic efficacy without inhibiting D2 dopamine receptors." Conn says the new drug may be targeting brain pathways "downstream" of those acted on by conventional antipsychotic drugs. Thus, he says, the drug "could be getting closer to the primary pathology" of schizophrenia.

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