Excellent article in the NY Times on Big Pharma's newest breakthrough in schizophrenia - some very promising research. This excerpt is a good summary of the basic science leading to this new drug:

“We do not know with any of these neuropsychiatric disorders what the ultimate basis is,” Dr. Greengard says. “Let’s say you could find that too much of protein X was involved in schizophrenia. Would you then know what schizophrenia is? You would not.”

Nonetheless, the findings in rats were promising. Those studies, as well as Dr. Krystal’s tests in 2001 of volunteers given ketamine, a drug that has effects similar to PCP, hinted that the glutamate drugs might help to treat the cognitive and negative symptoms of schizophrenia. Drugs currently on the market do little to treat those symptoms.

Even before the findings at Yale, Lilly had put its first metabotropic glutamate receptor compound into human testing. Researchers initially tested the drug on patients with panic disorder, and it showed some positive results. But Lilly stopped human testing of the drug in 2001 when long-term testing in animals showed that it caused seizures.

Even so, Lilly decided that it had enough evidence to justify tests of another chemical compound, LY404039, that affected the same receptors.

“They had to take a risk on letting these drugs be tested on models or for disorders that were justified purely on pretty basic science,” Dr. Krystal says. “There is nothing with these drugs that is straightforward or makes developing them a basic path.”

When it tried to test LY404039 in humans, the company ran into yet another hurdle. The human body didn’t easily absorb it. So Lilly created a drug that the body could absorb, LY2140023, which is metabolized into LY404039 in the body.

Bingo. LY2140023 was the drug that got Dr. Schoepp jumping out of his office chair in 2006, nearly three years after the first trials in humans began. In the Lilly test, the drug was slightly less effective over all than Zyprexa, which is considered the most effective among the widely used schizophrenia treatments.

But LY2140023 also appeared to have fewer side effects than Zyprexa, which can cause severe weight gain and diabetes. The new drug also appeared to improve cognition, something that existing treatments don’t do, said Dr. Insel of the National Institute of Mental Health.