Kidambi Neil, Elsayed Omar H, El-Mallakh Rif S
Mood Disorders Research Program, Depression Center, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
Neuropsychiatr Dis Treat. 2023 May 10;19:1145-1151. doi: 10.2147/NDT.S406371. eCollection 2023.
Schizophrenia is a severe mental illness that has its onset in late adolescence or early adulthood and is associated with significant dysfunction across multiple domains. The pathogenesis of schizophrenia remains unknown, but physiologic understanding of the illness has been driven by the dopamine hypothesis. However, acetylcholine (ACh) clearly plays a role with mixed results regarding effect on psychosis. Selective muscarinic M and M agonists, such as xanomeline, originally developed to aid in cognitive loss with Alzheimer's, showed promise in proof-of-concept study in 20 patients with schizophrenia. Unfortunately, tolerability problems made muscarinic agonists impractical in either condition. However, coadministration of trospium, a lipophobic, non-selective muscarinic antagonist previously used for the treatment of overactive bladder, with xanomeline resulted in a significant reduction of cholinergic adverse effects. A recent randomized, placebo-controlled study of the antipsychotic effects of this combination in 182 patients with acute psychosis revealed improved tolerability with 80% of subjects staying to the end of the 5 weeks study. At the end of the trial, the treatment group saw a -17.4 change in the positive and negative symptom scale (PANSS) score from baseline compared to a -5.9 change in the placebo arm ( < 0.001). Furthermore, the negative symptom subscore, was also superior in the active arm ( < 0.001). These early studies are exciting because they suggest that the cholinergic system may be recruited to treat a severe and disabling disorder with suboptimal treatment options. Xanomeline-trospium combination is currently in phase III studies.
精神分裂症是一种严重的精神疾病，发病于青春期后期或成年早期，与多个领域的显著功能障碍有关。精神分裂症的发病机制尚不清楚，但对该疾病的生理学理解一直受多巴胺假说驱动。然而，乙酰胆碱（ACh）显然发挥了作用，但其对精神病的影响结果不一。选择性毒蕈碱M和M激动剂，如原用于辅助治疗阿尔茨海默病认知功能减退的占诺美林，在一项针对20名精神分裂症患者的概念验证研究中显示出前景。不幸的是，耐受性问题使毒蕈碱激动剂在这两种情况下都不实用。然而，将先前用于治疗膀胱过度活动症的亲脂性、非选择性毒蕈碱拮抗剂曲司氯铵与占诺美林联合使用，可显著减少胆碱能不良反应。最近一项针对182名急性精神病患者的该组合抗精神病作用的随机、安慰剂对照研究表明，耐受性有所改善，80%的受试者完成了为期5周的研究。在试验结束时，治疗组的阳性和阴性症状量表（PANSS）评分与基线相比变化了-17.4，而安慰剂组变化了-5.9（<0.001）。此外，主动治疗组的阴性症状子评分也更高（<0.001）。这些早期研究令人兴奋，因为它们表明胆碱能系统可能被用于治疗一种治疗选择欠佳的严重致残性疾病。占诺美林-曲司氯铵组合目前正处于III期研究阶段。
