A pharmaco-imaging approach to predicting social functioning and clinical responses to oxytocin administration in schizophrenia

预测精神分裂症患者对催产素给药的社会功能和临床反应的药物成像方法

• 批准号: 10041700
• 负责人: Josh Woolley
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10041700
• 关键词: Acute; Address; Adherence; Affect; Antipsychotic Agents; Behavior; Behavioral; Brain; Chronic; Clinical; Clinical Trials; Communities; Data; Dose; Double-Blind Method; Emotional; Expressed Emotion; Functional Magnetic Resonance Imaging; General Population; Hypothalamic structure; Image; Impairment; Individual; Interpersonal Relations; Knowledge; Laboratories; Learning; Link; Literature; Measures; Medical; Methodology; Methods; Mind; Monitor; Motivation; Neuropeptides; Neurosciences; Outcome; Outcome Measure; Oxytocin; Parietal; Participant; Patients; Peptides; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phase; Placebos; Play; Population; Protocols documentation; Quality of life; Randomized; Resistance; Role; Sample Size; Scanning; Schizophrenia; Secure; Self Administration; Severities; Social Behavior; Social Functioning; Social isolation; Standardization; Stress; Symptoms; Task Performances; Testing; Therapeutic; Translational Research; Unemployment; Veterans; base; clinical practice; clinical predictors; clinically relevant; cognitive function; cost; disabling symptom; dosage; economic cost; effective therapy; functional outcomes; imaging approach; imaging study; improved; mental state; neuroimaging; neuromechanism; novel; personalized medicine; placebo group; preclinical study; predicting response; primary outcome; relating to nervous system; response; social; social cognition; social relationships; social skills; theories; treatment response

Schizophrenia is a devastating illness that is characterized by deficits in social functioning. Social ability deficits, such as poor verbal and nonverbal social skills, negative symptoms, such as decreased motivation and emotional expressivity, and impaired theory of mind (ToM), the ability to understand the mental states of others, contribute to poor social functioning and are unresponsive to antipsychotic medications. Oxytocin (OT), a neuropeptide known to play a key role in social behavior, has shown promise as a potential treatment for these deficits. However, trials conducted thus far have yielded mixed findings, stalling translation of research into clinical practice. This is likely because these trials 1) have been underpowered and limited by use of a single dosage of OT, 2) have sub-optimally assessed negative symptoms, 3) have not focused on clinically relevant deficits such as social functioning and ToM outside of positive and negative symptoms, 4) have lacked standardized drug administration and adherence monitoring protocols, and 5) have failed to account for variability in factors that moderate OT effects at the individual level. Furthermore, we do not understand the neural mechanisms of OT effects, which impairs our ability to predict who will respond to OT. The proposed study will address each of these limitations to rigorously determine the ability of OT to improve real-world social functioning in patients with schizophrenia. Adequate power, including two dosages of OT, state of the art outcome measures, remote administration and adherence monitoring, and moderator analyses will address methodological shortcomings in the extant literature. In addition, the proposed study will provide critical information regarding the neural mechanisms of OT effects. Preliminary results show that a single intranasal dose of OT improves ToM and negative symptoms in patients with schizophrenia. Furthermore, hypo-activation in the right temporo-parietal junction (rTPJ) during ToM correlates with negative symptom severity in patients with schizophrenia. Acute OT administration increases both rTPJ activation and behavioral performance during ToM tasks and these increases are correlated. Thus, OT-induced rTPJ activation increases during ToM tasks may be the mechanism of OT's effects on social functioning. The proposed study aims are to: 1) compare the acute effects of a single administration of two dosages of OT, relative to placebo, on fMRI rTPJ activity and behavioral accuracy during ToM task performance in SZ, 2) compare the clinical and behavioral effects of two dosages of chronic OT treatment, relative to placebo, in SZ patients, and 3) determine if acute fMRI rTPJ responses to a single OT administration predicts clinical responses to chronic OT treatment in SZ patients. One hundred and fifty veterans will be randomized to receive either 20IU or 40IU of OT in a placebo-controlled, within-subject, pharmaco-fMRI study in which their neural responses on OT and placebo will be quantified during two ToM tasks. After imaging, participants will be randomized to receive either the same dosage of OT they received in the fMRI portion of the study or placebo twice daily for three weeks. Social functioning (primary outcome), social ability, negative symptoms, and ToM ability will be quantified using well-validated measures at baseline and after three weeks of OT or placebo administration. The proposed study represents a significant advance in the field for several reasons. One, it is the largest study to date and the only to simultaneously examine two dosages of OT in a single study. Two, it uses state-of-the-art assessment methodologies that are focused on the most promising outcomes based on laboratory pre-clinical studies. Three, it uses video calls to directly observe drug administration adherence. Four, it will quantify individual- level variables hypothesized to moderate OT effects in schizophrenia. Five, it will use a novel pharmaco- neuroimaging paradigm to maximize the knowledge generated from the clinical trial. The proposed study represents an important step towards developing a precision, neuroscience-informed treatment that normalizes aberrant neural processing in order to improve social functioning deficits in schizophrenia.

精神分裂症是一种毁灭性的疾病，其特征是社会功能的缺陷。社会能力 缺陷，如语言和非语言社交技能差，阴性症状，如动机下降 和情感表达能力，以及受损的心理理论（ToM），理解心理状态的能力， 其他人则导致社会功能低下，对抗精神病药物无反应。催产素（OT）， 一种已知在社会行为中起关键作用的神经肽，已经显示出作为一种潜在的治疗方法的希望。 这些赤字。然而，迄今为止进行的试验得出了不同的结果，阻碍了研究的翻译 临床实践。这可能是因为这些试验1）一直动力不足，并受到使用 单剂量OT，2）具有次优评估的阴性症状，3）未关注临床 相关的缺陷，如社会功能和心理理论以外的积极和消极的症状，4）缺乏 标准化的药物管理和依从性监测方案，以及5）未能说明 在个体水平上调节OT效应的因素的可变性。此外，我们不了解 OT效应的神经机制，这削弱了我们预测谁会对OT做出反应的能力。拟议 研究将解决这些限制，以严格确定OT改善现实世界社会的能力 在精神分裂症患者中发挥作用。足够的功率，包括两剂OT，最新技术水平 结果测量、远程管理和依从性监测以及主持人分析将解决 现存文献中的方法论缺陷。此外，拟议的研究将提供关键的 关于OT效应的神经机制的信息。初步结果显示， 剂量OT改善精神分裂症患者的心理理论和阴性症状此外，低活化 在患者中，ToM期间右侧颞顶交界处（rTPJ）的活动与阴性症状严重程度相关 精神分裂症急性OT给药增加rTPJ激活和行为表现， ToM任务和这些增加是相关的。因此，OT诱导的rTPJ激活在ToM任务期间增加 可能是OT影响社会功能的机制。本研究的目的是：1）比较 相对于安慰剂，单次给予两种剂量的OT对fMRI rTPJ活性的急性影响， 行为准确性在心理理论任务的表现在深圳，2）比较临床和行为的影响， SZ患者中相对于安慰剂的慢性OT治疗剂量，以及3）确定急性fMRI rTPJ 对单次OT给药的反应预测SZ患者对长期OT治疗的临床反应。 150名退伍军人将随机接受20 IU或40 IU的OT， 受试者内药物fMRI研究，其中将量化OT和安慰剂的神经反应 在两个任务中。成像后，参与者将随机接受相同剂量的OT 他们在研究的fMRI部分或安慰剂每天两次，持续三周。社会功能 （主要结局）、社交能力、阴性症状和心理理论能力将使用经过充分验证的 在基线和OT或安慰剂给药三周后测量。拟议的研究是一项 这一领域的重大进展有几个原因。第一，这是迄今为止规模最大的研究，也是唯一一项 在一项研究中同时检查两种剂量的OT。第二，它采用最先进的评估方法 这些方法侧重于基于实验室临床前研究的最有希望的结果。 第三，它使用视频通话直接观察药物给药依从性。第四，它将量化个人- 水平变量假设中度OT对精神分裂症的影响。第五，它将使用一种新的药物- 神经影像学范式，以最大限度地从临床试验产生的知识。拟定研究 这是朝着开发一种精确的、神经科学知情的治疗方法迈出的重要一步， 异常的神经处理，以改善精神分裂症的社会功能缺陷。