Eli Lilly researchers believe they have discovered a new class of schizophrenia medication that avoids key adverse effects seen in current treatments, not least the firm’s own blockbuster Zyprexa.

A clinical trial in the September issue of Nature Medicine describes a drug, LY2140023, that works effectively in people with schizophrenia by targeting glutamate-mediated neurotransmission. All current drugs target dopamine receptors, and it is this mode of action that is thought to be responsible for unpleasant extrapyramidal side effects such as involuntary movement – effects that cause some psychotic patients to shun their medication.

Previously, glutamate neurotransmission has been touted as an important factor in schizophrenia but evidence thus far has been scarce. In the latest study, however, researchers report that a selective agonist of a specific subtype of glutamate receptor, known as mGlu2/3, has antipsychotic effects in schizophrenic patients.

Sandeep Patil of Lilly Research Laboratories in Indianapolis, who led the research, said: "The results from this study indicate mGlu2/3 receptor agonists have antipsychotic properties and represent the first credible alternative treatment for schizophrenia that does not target dopamine."

Safe and well-tolerated

His team tested LY2140023 in a double-blind, placebo-controlled trial of 196 patients with schizophrenia, and compared how well it worked versus Zyprexa (olanzapine), which targets dopamine receptors. Patients treated with LY2140023 showed improvements in both positive (hallucinations, delusions and thought disorder) and negative (social withdrawal, apathy and emotional blunting) symptoms of schizophrenia compared to placebo after four weeks of treatment. Treatment with LY2140023 was safe and well-tolerated.

"Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain," said Dr Patil. Most adverse events linked to LY2140023, typically insomnia, nausea, headache and somnolence, were mild to moderate in severity and not treatment-limiting.

Because this was a proof-of-concept study designed to test the efficacy of LY2140023 in the treatment of schizophrenia, no rigorous comparison was made against olanzapine in terms of efficacy. The researchers note, however, that "exploratory post-hoc analysis" suggested there was no statistically significant difference between the effectiveness of the two treatments. They further note that an optimal dose of LY2140023 has not yet been determined.

The authors call for larger and longer-term studies that focus on this novel approach for the treatment of schizophrenia, which is a major burden on health services around the world. The overall cost of schizophrenia to the USA in 2002 was estimated to be $62.7 billion, with $22.7 billion excess direct healthcare expenses.