Patil ST et al. (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med 13: 1102–1107

Antipsychotics commonly used in the treatment of schizophrenia target dopamine receptors, but there is growing evidence that altered glutamate transmission is important in the pathophysiology of the disease. Researchers have developed a new drug, dubbed LY2140023, which is converted to a selective agonist of metabotropic glutamate 2/3 (mGlu2/3) receptors once absorbed. In a mouse study, the active mGlu2/3 receptor agonist was shown to inhibit phencyclidine-induced hyperlocomotion via a mechanism different to that of olanzapine. A double-blind, placebo-controlled phase II study was undertaken to test the clinical usefulness of LY2140023.

Patil et al. randomized 196 patients with schizophrenic psychopathology to receive either LY2140023 (40 mg twice daily), olanzapine (15 mg once daily) or placebo in a 3:1:2 ratio; 118 patients completed the planned 4 weeks of treatment. Positive and Negative Symptom Scale (PANSS) scores improved significantly from baseline in patients treated with LY2140023 and olanzapine (P <0.001 for both). The onset of efficacy was rapid in both groups, with significant effects apparent at 1 week (P <0.05) and maintained until the end of the study period. LY2140023 was generally well-tolerated, and, notably, did not result in elevated prolactin levels, worsening of extrapyramidal symptoms or weight gain compared with placebo.

This study provides conclusive evidence of a role for glutamate in the pathophysiology of schizophrenia, and indicates that mGlu2/3 receptor agonism could be a valid therapeutic approach in the disease.