Koola Maju Mathew
Department of Psychiatry and Behavioral Sciences, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
Mol Neuropsychiatry. 2018 Dec;4(3):134-148. doi: 10.1159/000494495. Epub 2018 Nov 19.
Schizophrenia is, in part, a cognitive illness. There are no approved medications for cognitive impairments associated with schizophrenia (CIAS) and primary negative symptoms. Cholinergic and glutamatergic systems, alpha-7 nicotinic acetylcholine (α-7nACh) and -methyl-D-aspartate (NMDA) receptors, kynurenic acid (KYNA), and mismatch negativity have been implicated in the pathophysiology of CIAS and negative symptoms. Galantamine is an acetylcholinesterase inhibitor that is also a positive allosteric modulator at the α4β2 and α7nACh receptors. Memantine is a noncompetitive NMDA receptor antagonist. Galantamine and memantine alone and in combination were effective for cognition in animals and people with Alzheimer's disease. The objective of this article is to critically dissect the published randomized controlled trials with galantamine and memantine for CIAS to highlight the efficacy signal. These studies may have failed to detect a clinically meaningful efficacy signal due to limitations, methodological issues, and possible medication nonadherence. There is evidence from a small open-label study that the galantamine-memantine combination may be effective for CIAS with kynurenine pathway metabolites as biomarkers to detect the severity of cognitive impairments. Given that there are no available treatments for cognitive impairments and primary negative symptoms in schizophrenia, testing of this "five-pronged strategy" (quintuple hypotheses: dopamine, nicotinic-cholinergic, glutamatergic/NMDA, GABA, and KYNA) is a "low-risk high-gain" approach that could be a major breakthrough in the field. The galantamine-memantine combination has the potential to treat positive, cognitive, and negative symptoms, and targeting the quintuple hypotheses concurrently may lead to a major scientific advancement - from antipsychotic treatment to antischizophrenia treatment.
精神分裂症在一定程度上是一种认知疾病。目前尚无获批用于治疗与精神分裂症相关的认知障碍（CIAS）及原发性阴性症状的药物。胆碱能和谷氨酸能系统、α-7烟碱型乙酰胆碱（α-7nACh）和N-甲基-D-天冬氨酸（NMDA）受体、犬尿氨酸（KYNA）以及失配负波已被认为与CIAS及阴性症状的病理生理学有关。加兰他敏是一种乙酰胆碱酯酶抑制剂，同时也是α4β2和α7nACh受体的正变构调节剂。美金刚是一种非竞争性NMDA受体拮抗剂。加兰他敏和美金刚单独使用及联合使用对患有阿尔茨海默病的动物和人在认知方面均有效。本文的目的是对已发表的关于加兰他敏和美金刚治疗CIAS的随机对照试验进行批判性剖析，以突出疗效信号。由于存在局限性、方法学问题以及可能的药物不依从性，这些研究可能未能检测到具有临床意义的疗效信号。一项小型开放标签研究有证据表明，以犬尿氨酸途径代谢物作为检测认知障碍严重程度的生物标志物时，加兰他敏-美金刚联合用药可能对CIAS有效。鉴于精神分裂症的认知障碍和原发性阴性症状尚无可用治疗方法，对这种“五管齐下策略”（五个假设：多巴胺、烟碱-胆碱能、谷氨酸能/NMDA、GABA和KYNA）进行测试是一种“低风险高回报”的方法，可能成为该领域的重大突破。加兰他敏-美金刚联合用药有潜力治疗阳性、认知和阴性症状，同时针对这五个假设可能会带来重大的科学进展——从抗精神病治疗迈向抗精神分裂症治疗。
