BioEd Online

Psychiatrists have welcomed the unveiling by a US drug company of the first new class of schizophrenia drugs since the 1950s.

According to early clinical-trial data, the prototype drug — codenamed LY2140023 and produced by Eli Lilly researchers in Indianapolis, Indiana — seems to be as effective as olanzapine, the best currently available drug. The drug's developers hope that it will offer psychiatrists a new alternative for treating their patients, and one that may offer greater benefits in relation to the side effects.

According to the World Health Organization, schizophrenia affects around 1% of the population worldwide. Its broad range of debilitating symptoms can include delusions, hallucination, disordered thinking, social withdrawal and emotional 'flatness'.

Current anti-schizophrenia drugs all work the same way, by reducing levels of the neurotransmitter dopamine in the brain. But they do not control the disease well in all patients and often have unpleasant side effects. The new drug, LY2140023, is converted in the body into a second compound, called LY404023, which acts by damping down the activity of a different neurotransmitter, glutamate.

Lilly researchers say that the trial is an important proof of principle that their new approach to the disease works, but they don't yet know if this particular compound will make it into the clinic. "Our study is the first conclusive evidence for a role of glutamate in the pathophysiology of schizophrenia," says James Monn, one of the research team.

In the trial, 196 schizophrenic patients were treated with either LY2140023, olanzapine, or a placebo for four weeks. The drugs were roughly equally effective, the researchers report in Nature Medicine¹.

New approach

"In terms of drug development this is a giant step forward — pretty much the first major step forward since 1952, when chlorpromazine was introduced," comments Solomon Snyder, a neuropharmacologist at Johns Hopkins University in Baltimore, Maryland.

Chlorpromazine, despite its serious side effects — which include lactation and uncontrolled movements — transformed the treatment of schizophrenia. Before this, most schizophrenics were doomed to lifelong incarceration. Newer drugs of the same class, such as olanzapine, have been chemically fine-tuned to minimize side effects, but many patients still do not like to take them and often abandon therapy. The side effects of LY2140023, including insomnia and emotional instability, are slightly different to those of olanzapine although they are of roughly the same overall severity — but unlike any existing antipsychotic, the new drug did not cause weight gain.

The idea that the glutamate system might be involved in schizophrenia first emerged when doctors noticed that the 1980s party drug phencyclidine (PCP) induced a temporary psychosis similar to the disease. But the new drug is the first to demonstrate that this system can be deliberately manipulated to help schizophrenics.

Monn admits that the scientists don't know exactly how the new drug produces its antipsychotic actions. But biochemically, the action is relatively subtle because it works on a particular glutamate receptor called mGlu2/3, which is involved in a feedback loop controlling glutamate release, and therefore only works when the glutamate system is very active — bouts of high activity in this system are suspected to be one of the hallmarks of the disease.