title: Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: Sandeep T
authors.initials: ST
authors.lastname: Patil
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Ferenc
authors.initials: F
authors.lastname: Martenyi
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lowe
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Jackson
authors.forename: Boris V
authors.initials: BV
authors.lastname: Andreev
authors.forename: Alla S
authors.initials: AS
authors.lastname: Avedisova
authors.forename: Leonid M
authors.initials: LM
authors.lastname: Bardenstein
authors.forename: Issak Y
authors.initials: IY
authors.lastname: Gurovich
authors.forename: Margarita A
authors.initials: MA
authors.lastname: Morozova
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Mosolov
authors.forename: Nikolai G
authors.initials: NG
authors.lastname: Neznanov
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Reznik
authors.forename: Anatoly B
authors.initials: AB
authors.lastname: Smulevich
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Tochilov
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Johnson
authors.forename: James A
authors.initials: JA
authors.lastname: Monn
authors.forename: Darryle D
authors.initials: DD
authors.lastname: Schoepp
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use* / Q000633:toxicity; D001569:Benzodiazepines / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use* / Q000633:toxicity; D003499:Cyclic S-Oxides / Q000627:therapeutic use* / Q000633:toxicity; D004195:Disease Models, Animal; D004311:Double-Blind Method; D006801:Humans; D000077152:Olanzapine; D010919:Placebos; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology*; D012559:Schizophrenia / Q000188:drug therapy*
chemical_list: C517803:4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; D010919:Placebos; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D001569:Benzodiazepines; D000077152:Olanzapine