Csomor Philipp A, Preller Katrin H, Geyer Mark A, Studerus Erich, Huber Theodor, Vollenweider Franz X
Neuropsychopharmacology and Brain Imaging and Heffter Research Center, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry, Zürich, Switzerland.
Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
Neuropsychopharmacology. 2014 Sep;39(10):2485-96. doi: 10.1038/npp.2014.102. Epub 2014 May 7.
Despite advances in the treatment of schizophrenia spectrum disorders with atypical antipsychotics (AAPs), there is still need for compounds with improved efficacy/side-effect ratios. Evidence from challenge studies suggests that the assessment of gating functions in humans and rodents with naturally low-gating levels might be a useful model to screen for novel compounds with antipsychotic properties. To further evaluate and extend this translational approach, three AAPs were examined. Compounds without antipsychotic properties served as negative control treatments. In a placebo-controlled, within-subject design, healthy males received either single doses of aripiprazole and risperidone (n=28), amisulpride and lorazepam (n=30), or modafinil and valproate (n=30), and placebo. Prepulse inhibiton (PPI) and P50 suppression were assessed. Clinically associated symptoms were evaluated using the SCL-90-R. Aripiprazole, risperidone, and amisulpride increased P50 suppression in low P50 gaters. Lorazepam, modafinil, and valproate did not influence P50 suppression in low gaters. Furthermore, low P50 gaters scored significantly higher on the SCL-90-R than high P50 gaters. Aripiprazole increased PPI in low PPI gaters, whereas modafinil and lorazepam attenuated PPI in both groups. Risperidone, amisulpride, and valproate did not influence PPI. P50 suppression in low gaters appears to be an antipsychotic-sensitive neurophysiologic marker. This conclusion is supported by the association of low P50 suppression and higher clinically associated scores. Furthermore, PPI might be sensitive for atypical mechanisms of antipsychotic medication. The translational model investigating differential effects of AAPs on gating in healthy subjects with naturally low gating can be beneficial for phase II/III development plans by providing additional information for critical decision making.
尽管非典型抗精神病药物（AAPs）在精神分裂症谱系障碍的治疗方面取得了进展，但仍需要疗效/副作用比更高的化合物。激发研究的证据表明，对人类和啮齿动物中门控水平自然较低的门控功能进行评估，可能是筛选具有抗精神病特性的新型化合物的有用模型。为了进一步评估和扩展这种转化方法，对三种AAPs进行了研究。没有抗精神病特性的化合物用作阴性对照治疗。在一项安慰剂对照的受试者内设计中，健康男性分别接受单剂量的阿立哌唑和利培酮（n = 28）、氨磺必利和劳拉西泮（n = 30）、莫达非尼和丙戊酸盐（n = 30）以及安慰剂。评估了预脉冲抑制（PPI）和P50抑制。使用症状自评量表（SCL - 90 - R）评估临床相关症状。阿立哌唑、利培酮和氨磺必利增加了低P50门控者的P50抑制。劳拉西泮、莫达非尼和丙戊酸盐对低门控者的P50抑制没有影响。此外，低P50门控者在SCL - 90 - R上的得分显著高于高P50门控者。阿立哌唑增加了低PPI门控者的PPI，而莫达非尼和劳拉西泮在两组中均减弱了PPI。利培酮、氨磺必利和丙戊酸盐对PPI没有影响。低门控者的P50抑制似乎是一种对抗精神病药物敏感的神经生理学标志物。低P50抑制与更高的临床相关评分之间的关联支持了这一结论。此外，PPI可能对抗精神病药物的非典型机制敏感。通过为关键决策提供额外信息，研究AAPs对门控水平自然较低的健康受试者门控的不同影响的转化模型可能对II/III期开发计划有益。
