Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial

被引:843
作者
Patil, Sandeep T.
Zhang, Lu
Martenyi, Ferenc
Lowe, Stephen L.
Jackson, Kimberley A.
Andreev, Boris V.
Avedisova, Alla S.
Bardenstein, Leonid M.
Gurovich, Issak Y.
Morozova, Margarita A.
Mosolov, Sergey N.
Neznanov, Nikolai G.
Reznik, Alexander M.
Smulevich, Anatoly B.
Tochilov, Vladimir A.
Johnson, Bryan G.
Monn, James A.
Schoepp, Darryle D.
机构
[1] Lilly Med Ctr, A-1030 Vienna, Austria
[2] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA
[3] Lily Natl Univ, Singapore Ctr Clin Pharmacol, Singapore 117597, Singapore
[4] Lilly Erl Wood Manor, Windlesham GU20 6PH, Surrey, England
[5] Gatchinskiy Reg Psychiat Hosp, Nikolskoe 188357, Russia
[6] St Petersburg State Univ, St Petersburg, Russia
[7] Moscow State Univ Med & Dent, Moscow Psychiat Hosp, Moscow 115522, Russia
[8] Moscow Res Inst Psychiat, Moscow 107076, Russia
[9] Russian Acad Med Sci, State Inst Mental Hlth Sci Res Ctr, Moscow 115522, Russia
[10] VM Bekhterev Psychoneurol Res Inst, St Petersburg 192019, Russia
[11] Moscow Reg Psychiat Hosp, Khotkovo 142601, Moscow Region, Russia
[12] Mechnikov State Med Acad, St Petersburg 190121, Russia
关键词
D O I
10.1038/nm1632
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 receptors(2). LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors(3) 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.
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收藏
页码:1102 / 1107
页数:6
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