Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial.
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.
Patil
Sandeep T
ST
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Zhang
Lu
L
Martenyi
Ferenc
F
Lowe
Stephen L
SL
Jackson
Kimberley A
KA
Andreev
Boris V
BV
Avedisova
Alla S
AS
Bardenstein
Leonid M
LM
Gurovich
Issak Y
IY
Morozova
Margarita A
MA
Mosolov
Sergey N
SN
Neznanov
Nikolai G
NG
Reznik
Alexander M
AM
Smulevich
Anatoly B
AB
Tochilov
Vladimir A
VA
Johnson
Bryan G
BG
Monn
James A
JA
Schoepp
Darryle D
DD
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*
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