生物谷报道：一项临床试验发现，一种以谷氨酸调控的神经传递素为靶标的新药能有效地治疗精神分裂症，新成果发表在9月号的《自然—医学》期刊上。
以前的研究反复显示，谷氨酸调控神经传递素的变异与精神分裂症相关，但一直缺少这种关联性的有力证据。对精神分裂症而言，所有常用的处方安定药均以多巴胺受体为靶标。如今，Sandeep Patil和同事报告：一种特别的谷氨酸受体亚型mGlu2/3是一种选择性激动素，它对精神分裂症患者有安定作用。
在一组双盲、安慰剂控制的试验中，他们试验其新药LY2140023对精神分裂症患者的作用，并将这种新药的疗效与最常用的安定药奥氮平进行了比较，奥氮平是以多巴胺受体为靶标的精神分裂症治疗药物。错觉、幻觉、思维混乱、社交退缩、冷漠和情感迟钝均是精神分裂症患者的主要症状，经过4个星期的治疗后，Patil和同事发现，接受LY2140023治疗的患者在这些方面的表现有明显提高。
目前，多巴胺是治疗精神分裂症的唯一靶标，新研究表明，mGlu2/3受体激动素具有安定特性，可成为精神分裂症治疗的第一个替代靶标。（科学时报）
原始出处:
Nature Medicine
Published online: 2 September 2007 | doi:10.1038/nm1632
Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial
Sandeep T Patil1,13, Lu Zhang1, Ferenc Martenyi2, Stephen L Lowe3, Kimberley A Jackson4, Boris V Andreev5, Alla S Avedisova6, Leonid M Bardenstein7, Issak Y Gurovich8, Margarita A Morozova9, Sergey N Mosolov8, Nikolai G Neznanov10, Alexander M Reznik11, Anatoly B Smulevich9, Vladimir A Tochilov12, Bryan G Johnson1, James A Monn1 & Darryle D Schoepp1,13
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 < 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.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Lilly Medical Center, Kolblgasse 8-10, A-1030 Vienna, Austria.
Lilly-National University of Singapore Centre for Clinical Pharmacology, Level 6 Clinical Research Centre (MD11), 10 Medical Drive, 117597, Singapore.
Lilly-Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK.
St. Petersburg State University, St. Petersburg and Gatchinskiy Regional Psychiatric Hospital, Nikolskoe 188357, Russia.
Serbsky State Scientific Center of Social and Forensic Psychiatry, 23, Kropotkinskiy per. Moscow 123367, Russia.
Moscow State University of Medicine and Dentistry based at Moscow Psychiatry Hospital no. 15, Moscvorechie ul. 7, Moscow 115522, Russia.
Moscow Research Institute of Psychiatry, Poteshnaya ul. 3, Moscow 107076, Russia.
State Institution "Mental Health Scientific Research Center of the Russian Academy of Medical Sciences", Kashyrskoye sh. 34, Moscow 115522, Russia.
Bekhterev Research Psychoneurological Institute, Bekhtereva ul. 3, St. Petersburg 192019, Russia.
Moscow Regional Psychiatry Hospital #5, Abramtsevskoye sh. 1a, Khotkovo, Moscow region 142601, Russia.
Mechnikov State Medical Academy, Naberezhnaya reki Mojki, 126, St. Petersburg 190121, Russia.
Present addresses: Takeda Global Research and Development Center, Inc., One Takeda Parkway, Deerfield, Illinois 60015, USA (S.T.P.); Merck and Company, Inc., 351 Sumneytown Pike, UG/4CDS013, North Wales, Pennsylvania 19454, USA (D.D.S.).
Correspondence to: Ferenc Martenyi2 e-mail: Martenyi_Ferenc@lilly.com
Correspondence to: James A Monn1 e-mail: Monn_James_A@lilly.com
