5 May 2007. A metabotropic glutamate receptor agonist made by Eli Lilly and Company is effective in the treatment of schizophrenia and shows no evidence of major side effects, according to Phase 2 clinical trial data presented 1 April 2007 at the International Congress on Schizophrenia Research in Colorado Springs. It remains to be seen whether the drug is a viable alternative to current antipsychotic drugs, but it nonetheless represents the first clinical trial of a candidate therapy derived from basic research rather than serendipity.

The Lilly trial, presented by Bruce Kinon, builds upon a study published in Science in 1998 by Bita Moghaddam and Barbara Adams, then at Yale University. These researchers showed that regulating glutamate neurotransmission via metabotropic glutamate (mGlu) receptors, specifically types 2 and 3, could reverse some of the cognitive deficits and psychotomimetic features of phencyclidine (PCP) exposure in an animal model (Moghaddam and Adams, 1998).

"A lot of basic work will have to be done now to figure out how dopamine D2 receptor antagonists and mGlu2/3 agonists could have the same therapeutic efficacy," said Moghaddam in an interview with SRF. "We still know very little about the pathophysiology of schizophrenia, and this drug will give us a novel tool to come up with new ideas and mechanisms relevant to that pathophysiology."

A New Target in Psychosis
All current antipsychotic drugs are variations on chlorpromazine, whose efficacy against psychosis was discovered by chance more than 50 years ago. Given the limitations and side effects of these drugs, which act primarily by blocking the dopamine D2 receptor, there are constant calls for new directions in schizophrenia therapeutics. But developing new drugs requires some clear new evidence to build upon, followed by extensive testing in animals and humans.

Moghaddam and Adams provided that foundation in their 1998 study. Unlike the better known ion channel, or ionotropic, glutamate receptors (e.g., NMDA, AMPA), metabotropic receptors are linked to second messenger systems. They are found both on presynaptic membranes, where they may regulate glutamate release, and on postsynaptic membranes.

In his talk, Kinon noted that their experimental mGlu2/3 agonists appear to have high specificity for this class of mGlu receptors, with no affinity for ionotropic glutamate receptors or any effect on glutamate transporters. Similarly, there appears to be no effect on monoamine systems such as dopamine.

Kinon also noted that an obvious and appealing possibility with a new class of drugs with a different target is the potential for better tailoring of treatment. Beyond serving as an alternative choice to currently used drugs, Kinon mentioned the open question of whether the mGlu2/3 agonists could have better effectiveness against negative and cognitive symptoms, and might avoid the extrapyramidal syndrome (EPS) and metabolic side effects of currently available drugs.

Proof of Concept
In this proof-of-concept Phase 2 trial (first made public in December 2006 at the American College of Neuropsychopharmacology annual meeting in Hollywood, Florida), the Lilly researchers treated people chronically ill with schizophrenia with an mGlu2/3 agonist (the prodrug Ly2140023) for 28 days.

There was an olanzapine arm to the trial, though the study was not designed to compare these two drugs, and the olanzapine arm was included to assess the methodology. The mGlu2/3 agonist was reported to be significantly better than placebo both in terms of time to discontinuation and PANSS scores. Also encouraging was the fact that the side effects profile (EPS and metabolic indicators) of the study drug was not significantly worse than placebo.

If these results are borne out in further studies, working out the relationship between the apparently similar therapeutic effects of D2 antagonists and mGlu2/3 agonists against psychosis may allow researchers to address the question of whether the drugs could be used together, though Moghaddam is not convinced of this approach.

"Our animal data, and human studies reported by John Krystal and coworkers at Yale, showing improved cognition with this drug in PCP and ketamine models, suggest that it could be used as an adjunct," Moghaddam told SRF (see Krystal et al., 2005). "But if it works as a solo drug and does not cause any of the nasty side effects of antipsychotic drugs—motor effects, weight gain, disrupted/excess sleep—why try it as an adjunct?"—Hakon Heimer.