Glutamate Agonist LY2140023: A New Treatment for Schizophrenia?

High hopes for new schizophrenia drugs
Drug trial hailed as first major breakthrough for 50 years.

By Alison Abbott

. . .

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.

As noted by Bita Moghaddam, the "glutamate hypothesis of schizophrenia" dates back to 1980:

The idea of a glutamatergic abnormality in schizophrenia was first proposed by Kim, Kornhauber, and colleagues in 1980 (Kim et al., 1980) based on their findings of low cerebrospinal fluid (CSF) glutamate levels in patients with schizophrenia. This theory was not received well because, first, these findings could not be replicated in subsequent studies and, second, our limited knowledge of the glutamate system at the time suggested that disruptions in glutamate neurotransmission would result in overt toxicity and gross developmental abnormalities, something not seen in schizophrenia. In the last two decades, however, basic and clinical evidence has been accumulating to support the idea that aberrant NMDA receptor function subserves many aspects of molecular, cellular, and behavioral abnormalities associated with schizophrenia.

She goes on to list six lines of evidence in favor of this idea. It's definitely worth reading her review, which is freely available at the Schizophrenia Research Forum.

Reference

Patil ST, et al. (2007). Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nature Medicine. Published online: 2 September 2007.

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). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors 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 < 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.