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
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Nat Med. 2007 Sep;13(9):1102-7. doi: 10.1038/nm1632. Epub 2007 Sep 2.
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.
精神分裂症是一种慢性、复杂且异质性的精神障碍，其病理特征为大脑边缘结构内神经元兴奋性和可塑性的破坏。这些病理特征在行为上表现为阳性症状（包括幻觉、妄想和思维紊乱）、阴性症状（如社交退缩、冷漠和情感迟钝）以及其他精神病理症状（如精神运动迟缓、缺乏洞察力、注意力不集中和冲动控制能力差）。数十年来，谷氨酸神经传递的改变一直与精神分裂症有关，但所有常用的抗精神病药物都作用于多巴胺受体。LY404039是代谢型谷氨酸2/3（mGlu2/3）受体的选择性激动剂，在动物研究中已显示出抗精神病潜力。基于啮齿动物的数据，我们提供了新的证据，表明mGlu2/3受体激动剂的作用机制与奥氮平不同。为了在临床上验证这一机制，在一项随机、三臂、双盲、安慰剂对照研究中，以奥氮平作为活性对照，对LY404039的口服前体药物（LY2140023）在精神分裂症患者中进行了评估。与奥氮平治疗一样，LY2140023治疗安全且耐受性良好；与安慰剂相比，接受治疗的患者在精神分裂症的阳性和阴性症状方面均有统计学意义的改善（第4周时P<0.001）。值得注意的是，接受LY2140023治疗的患者在催乳素升高、锥体外系症状或体重增加方面与接受安慰剂治疗的患者没有差异。这些数据表明，mGlu2/3受体激动剂具有抗精神病特性，可能为精神分裂症的治疗提供一种新的选择。
