Npgrj_nm_1632 1102..1107

Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control)1. Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors2. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors3 and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P o 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia. The amino acid analog LY404039 is a highly selective agonist for human and rat mGlu2/3 receptors (Supplementary Table 1 online). LY404039 has no appreciable affinity for other glutamate receptor subtypes and transporters, or for nonglutamate receptors such as dopamine or serotonin that mediate the actions of atypical drugs such as olanzapine3. However, in humans, oral absorption of LY404039 was found to be low. LY2140023, a methionine amide of LY404039, was later discovered to be an effective oral prodrug in man (Supplementary Fig. 1 online). Once absorbed, LY2140023 is efficiently hydrolyzed to produce the active mGlu2/3 receptor agonist LY404039 (Supplementary Fig. 1). This resulted in an estimated bioavailability of LY404039 49%, according to urine data. Unlike LY404039, LY2140023 has no appreciable affinity for rat or human mGlu2 or mGlu3 receptors (Supplementary Table 1) or for other central nervous system receptors. To further explore the mechanism of action of LY2140023 in rodent models, we compared the active compound LY404039 to olanzapine in the mouse phencyclidine (PCP) model (Fig. 1). We examined the drugs’ ability to block PCP-induced hyperlocomotion in both wildtype mice and mice lacking mGlu2/3 receptors. PCP treatment increased motor ambulations in both wild-type and mGlu2/3 knockout mice. LY404039 inhibited these PCP-induced effects, but this inhibition was lost in the mGlu2/3 knockouts. In contrast, olanzapine was equally effective in both wild-type and knockout animals. This shows that LY404039 exerts its effects through the activation of mGlu2/3 receptors, as opposed to the serotonergic and dopaminergic pathways used by olanzapine. In the clinical proof-of-concept study, a total of 196 patients with considerable psychopathology of schizophrenia were enrolled and randomly assigned to receive LY2140023, placebo or olanzapine in a 3:2:1 ratio. All patients were hospitalized, gradually taken off any © 20 07 N at u re P u b lis h in g G ro u p h tt p :/ /w w w .n at u re .c o m /n at u re m ed ic in e