Fifty Years of Research on Schizophrenia: The Ascendance of the Glutamatergic Synapse.
Fifty Years of Research on Schizophrenia: The Ascendance of the Glutamatergic Synapse.
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DOI：
10.1176/appi.ajp.2020.20101481
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发表时间：
2020-12-01
期刊：
影响因子：
--
通讯作者：
Balu DT
中科院分区：
文献类型：
--
作者：
Coyle JT;Ruzicka WB;Balu DT
1976年，我（JTC）完成了我的精神病学住院医师实习，获得了我的第一个国立卫生研究院的资助，开设了我的实验室，并负责约翰霍普金斯菲普斯诊所的精神分裂症门诊，这是我的第一个学术临床责任。那一年是精神病学科学发展的关键点，精神分裂症的多巴胺假说（1）被提出，精神分裂症的突触神经化学病理学的第一份报告出现（2），Eve Johnstone和同事首次使用计算机轴向断层扫描证明了精神分裂症的皮质萎缩（3）。在这篇综述文章中，我们回顾了过去50年来从根本上改变了我们对精神分裂症和相关严重精神障碍病因学的理解的开创性进展，这将改变精神病的诊断和治疗。20世纪70年代见证了从精神分析的霸权过渡到“生物”精神病学的兴起，在美国，几乎每一个精神病学学术部门的主席都是精神分析师。然而，生物精神病学可能更准确地指定为“精神药理学”精神病学，因为偶然发现的药物被发现是治疗严重精神障碍（包括精神分裂症）的相对有效的药物。（精神抑制剂），双相情感障碍（锂），抑郁症（三环类药物）和焦虑症（苯并二氮杂卓），基本上指导研究的是一个不言而喻的假设，即这些药物的作用机制与疾病的病理生理学密切相关。紊乱值得注意的是，这十年是由诺贝尔奖授予Julius Axelrod（我的博士后导师）带来的，因为他发现三环类抗抑郁药抑制去甲肾上腺素进入去甲肾上腺素能突触末梢的摄取（4）-因此去甲肾上腺素成为“抑郁”神经递质（5）。例如，抗精神病药物的原型氯丙嗪最初是作为麻醉的辅助药物开发的。法国精神病学家Delay和Deniker（6）注意到氯丙嗪对手术患者的镇静作用，在精神分裂症患者中进行了一项氯丙嗪的临床试验，并描述了与镇静无关的思维和行为的显着改善。制药业在实验动物中进行研究，以确定氯丙嗪抗精神病作用的行为“特征”，以筛选具有不同副作用的更有效的药物。在接下来的十年里，几种更有效的抗精神病药物，具有不同的化学结构，如氟哌啶醇，吗茚酮和氟奋乃静，被引入[7]。1963年，瑞典药理学家Arvid Carlsson发现抗精神病药物干扰大鼠基底神经节中的多巴胺信号，并提出其治疗作用机制是通过阻断多巴胺受体[8]。1976年，所罗门斯奈德建立在这一观察基础上，表明抗精神病药物的临床疗效与其对大脑多巴胺D2受体的亲和力之间存在高度显著的相关性（9）。这一观察结果是“精神分裂症的多巴胺假说”的基础，该假说提出，
In 1976, I (JTC) finished my psychiatric residency, received my first National Institutes of Health grant, opened my laboratory, and took responsibility for the Schizophrenia Outpatient Clinic at the Johns Hopkins Phipps Clinic, my first academic clinical responsibility. That year was a pivotal point in the evolution of scientific psychiatry, as the dopamine hypothesis of schizophrenia (1) was proposed, the first report of synaptic neurochemical pathology of schizophrenia appeared (2), and Eve Johnstone and colleagues first demonstrated cortical atrophy in schizophrenia using computerized axial tomography (3). In this overview article, we review the seminal advances that have fundamentally transformed how we understand the etiology of schizophrenia and related serious mental disorders over the past 50 years, which will thus transform psychiatric diagnosis and treatment. The 1970s witnessed the transition from the hegemony of psychoanalysis, with virtually every chairperson of an academic department of psychiatry in the United States being a psychoanalyst, to the rise of “biologic” psychiatry. However, biologic psychiatry might be more accurately designated “psychopharmacologic” psychiatry, as serendipitously discovered drugs found to be relatively effective treatments for serious mental disorders, including schizophrenia (neuroleptics), bipolar disorder (lithium), depression (tricyclics), and anxiety disorders (benzodiazepines), essentially guided research with an unspoken assumption that the mechanism of action of these drugs was closely linked to the pathophysiology of the disorders. Notably, the decade was ushered in by the award of the Nobel Prize to Julius Axelrod (my postdoctoral mentor) for the discovery that tricyclic antidepressants inhibit the uptake of norepinephrine into noradrenergic synaptic terminals (4)—and thus norepinephrine became the “depression” neurotransmitter (5). For example, chlorpromazine, the prototype antipsychotic, was initially developed as an adjunct to anesthesia. Noting its calming effects on surgical patients, the French psychiatrists Delay and Deniker (6) carried out a clinical trial of chlorpromazine in patients with schizophrenia and described striking improvements in thinking and behavior unrelated to sedation. Thepharmaceuticalindustryundertookstudiesinexperimental animals to identify the behavioral “signature” for the antipsychotic action of chlorpromazine to screen for more potent drugs with different side effect profiles. Over the next decade, several more potent antipsychotics, with different chemical structures, such as haloperidol, molindone, andfluphenazine, were introduced (7).In 1963, the Swedish pharmacologist Arvid Carlsson discovered that antipsychotic drugs interfere with dopamine signaling in the rat basal ganglia and proposed that their mechanism of therapeutic action is through blocking the dopamine receptor (8). In 1976, Solomon Snyder built on this observation to show that there is highly significant correlation between antipsychotics’ efficacy in the clinic and their affinity for the brain’s dopamine D2 receptor (9). This observation was the basis for the “dopamine hypothesis of schizophrenia,” which proposed that do-
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影响因子：
46.9
作者：
Ball, Madeleine P.;Li, Jin Billy;Gao, Yuan;Lee, Je-Hyuk;LeProust, Emily M.;Park, In-Hyun;Xie, Bin;Daley, George Q.;Church, George M.
通讯作者：
Church, George M.
影响因子：
10.6
作者：
Balu DT;Presti KT;Huang CCY;Muszynski K;Radzishevsky I;Wolosker H;Guffanti G;Ressler KJ;Coyle JT
通讯作者：
Coyle JT
影响因子：
168.9
作者：
BIRD, ED;BARNES, J;SHEPHERD, M
通讯作者：
SHEPHERD, M
影响因子：
11
作者：
Basu, A. C.;Tsai, G. E.;Coyle, J. T.
通讯作者：
Coyle, J. T.
影响因子：
4.2
作者：
Balu DT;Coyle JT
通讯作者：
Coyle JT