Department of Psychiatry, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Neuropharmacology. 2012 Jun;62(7):2137-53. doi: 10.1016/j.neuropharm.2012.01.015. Epub 2012 Jan 28.
Current psychiatric diagnostic schema segregate symptom clusters into discrete entities, however, large proportions of patients suffer from comorbid conditions that fit neither diagnostic nor therapeutic schema. Similarly, psychotropic treatments ranging from lithium and antipsychotics to serotonin reuptake inhibitors (SSRIs) and acetylcholinesterase inhibitors have been shown to be efficacious in a wide spectrum of psychiatric disorders ranging from autism, schizophrenia (SZ), depression, and bipolar disorder (BD) to Alzheimer's disease (AD). This apparent lack of specificity suggests that psychiatric symptoms as well as treatments may share aspects of pathophysiology and mechanisms of action that defy current symptom-based diagnostic and neuron-based therapeutic schema. A myelin-centered model of human brain function can help integrate these incongruities and provide novel insights into disease etiologies and treatment mechanisms. Available data are integrated herein to suggest that widely used psychotropic treatments ranging from antipsychotics and antidepressants to lithium and electroconvulsive therapy share complex signaling pathways such as Akt and glycogen synthase kinase-3 (GSK3) that affect myelination, its plasticity, and repair. These signaling pathways respond to neurotransmitters, neurotrophins, hormones, and nutrition, underlie intricate neuroglial communications, and may substantially contribute to the mechanisms of action and wide spectra of efficacy of current therapeutics by promoting myelination. Imaging and genetic technologies make it possible to safely and non-invasively test these hypotheses directly in humans and can help guide clinical trial efforts designed to correct myelination abnormalities. Such efforts may provide insights into novel avenues for treatment and prevention of some of the most prevalent and devastating human diseases.
目前的精神疾病诊断模式将症状群分为离散实体，但很大比例的患者患有既不符合诊断也不符合治疗模式的共病。同样，从锂和抗精神病药到 5-羟色胺再摄取抑制剂 (SSRIs) 和乙酰胆碱酯酶抑制剂在内的各种精神药物治疗方法已被证明在从自闭症、精神分裂症 (SZ)、抑郁症和双相情感障碍 (BD) 到阿尔茨海默病 (AD) 等广泛的精神疾病中有效。这种明显缺乏特异性表明，精神症状以及治疗方法可能具有一些病理生理学和作用机制方面的共同点，这些共同点与当前基于症状的诊断和基于神经元的治疗模式相矛盾。以髓鞘为中心的人脑功能模型可以帮助整合这些不和谐之处，并为疾病病因和治疗机制提供新的见解。本文整合了现有数据，表明从抗精神病药和抗抑郁药到锂和电惊厥疗法等广泛使用的精神药物治疗方法共享 Akt 和糖原合成酶激酶-3 (GSK3) 等复杂信号通路，这些信号通路影响髓鞘形成、其可塑性和修复。这些信号通路对神经递质、神经营养因子、激素和营养物质作出反应，构成复杂的神经胶质通讯，并且通过促进髓鞘形成，可能对当前治疗方法的作用机制和广泛疗效做出重大贡献。成像和遗传技术使我们能够安全、无创地在人体中直接测试这些假设，并有助于指导旨在纠正髓鞘异常的临床试验努力。这些努力可能为一些最常见和最具破坏性的人类疾病的治疗和预防提供新的途径。
