生物谷報(bào)道：一項(xiàng)臨床試驗(yàn)發(fā)現(xiàn)，一種以谷氨酸調(diào)控的神經(jīng)傳遞素為靶標(biāo)的新藥能有效地治療精神分裂癥,，新成果發(fā)表在9月號(hào)的《自然—醫(yī)學(xué)》期刊上,。
以前的研究反復(fù)顯示,，谷氨酸調(diào)控神經(jīng)傳遞素的變異與精神分裂癥相關(guān)，但一直缺少這種關(guān)聯(lián)性的有力證據(jù),。對(duì)精神分裂癥而言,，所有常用的處方安定藥均以多巴胺受體為靶標(biāo)。如今,，Sandeep Patil和同事報(bào)告：一種特別的谷氨酸受體亞型mGlu2/3是一種選擇性激動(dòng)素,，它對(duì)精神分裂癥患者有安定作用。
在一組雙盲,、安慰劑控制的試驗(yàn)中,，他們?cè)囼?yàn)其新藥LY2140023對(duì)精神分裂癥患者的作用，并將這種新藥的療效與最常用的安定藥奧氮平進(jìn)行了比較,，奧氮平是以多巴胺受體為靶標(biāo)的精神分裂癥治療藥物,。錯(cuò)覺、幻覺,、思維混亂,、社交退縮、冷漠和情感遲鈍均是精神分裂癥患者的主要癥狀，經(jīng)過(guò)4個(gè)星期的治療后,，Patil和同事發(fā)現(xiàn),，接受LY2140023治療的患者在這些方面的表現(xiàn)有明顯提高。
目前,，多巴胺是治療精神分裂癥的唯一靶標(biāo),，新研究表明，mGlu2/3受體激動(dòng)素具有安定特性,，可成為精神分裂癥治療的第一個(gè)替代靶標(biāo),。（科學(xué)時(shí)報(bào)）
原始出處:
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: [email protected]
Correspondence to: James A Monn1 e-mail: [email protected]
