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，其特征是社会功能缺陷。社会能力 缺陷，例如言语和非语言社交技能不良，负面症状，例如动机减少 情感表达和心理理论受损（汤姆），理解心理状态的能力 其他人则导致社会功能不佳，对抗精神病药物没有反应。催产素（OT）， 已知在社会行为中发挥关键作用的神经肽已显示出有望作为潜在的治疗方法 这些赤字。但是，迄今为止进行的试验产生了混杂的发现，使研究的翻译失速 进入临床实践。这很可能是因为这些试验1）通过使用A的功能不足和限制 OT的单一剂量，2）具有亚最佳评估的负面症状，3）尚未集中于临床上 相关的缺陷，例如社交功能和汤姆（Tom），在积极和负面症状之外，4）缺乏 标准化药物管理和依从性监测方案，5）未能说明 在单个级别上效应的因素的变异性。此外，我们不了解 OT效应的神经机制，这会损害我们预测谁将对OT做出反应的能力。提议 研究将解决这些限制中的每一个，以严格确定OT改善现实世界社会 精神分裂症患者的功能。足够的力量，包括两种OT剂量 结果指标，远程管理和依从性监控以及主持人分析将解决 现有文献中的方法论缺点。此外，拟议的研究将提供关键 有关OT效应的神经机制的信息。初步结果表明单个鼻内 精神分裂症患者的OT剂量可改善TOM和负面症状。此外，低激活 在TOM期间，在右颞顶连接（RTPJ）中，患者的症状严重程度与负面症状相关 精神分裂症。急性OT给药增加了RTPJ激活和行为性能 TOM任务和这些增加是相关的。因此，在TOM任务中，OT诱导的RTPJ激活增加 可能是OT对社会功能的影响的机制。拟议的研究目的是：1）比较 相对于安慰剂，单次给药的急性影响对fMRI RTPJ活性和 SZ中TOM任务表现期间的行为准确性，2）比较两个的临床和行为影响 相对于安慰剂，在SZ患者中，慢性OT治疗的剂量，3）确定急性fMRI RTPJ是否是 对单一OT给药的反应预测了SZ患者对慢性OT治疗的临床反应。 一百五十名退伍军人将被随机分配以在安慰剂控制中接收20IU或40IU的OT， 受试者内的药物-FMRI研究，其中将量化其对OT和安慰剂的神经反应 在两个汤姆任务中。成像后，参与者将被随机接受相同剂量的OT 他们每天两次在研究的功能磁共振成像部分或安慰剂中接受三周。社会功能 （主要结果），社会能力，负面症状和TOM能力将使用良好的验证来量化 基线和安慰剂给药三周后进行措施。拟议的研究代表 该领域的重大进展是有几个原因的。第一，它是迄今为止最大的研究，唯一 在一项研究中同时检查了两次OT剂量。第二，它使用最先进的评估 基于实验室临床前研究的最有希望的结果的方法。 第三，它使用视频呼叫直接观察药物管理依从性。四，它将量化个体 - 水平变量假设精神分裂症中的中度OT效应。五，它将使用一种新颖的药物 - 神经影像学范式最大化临床试验产生的知识。拟议的研究 代表着开发精确的，神经科学知识的治疗的重要一步 异常的神经加工，以改善精神分裂症的社会功能缺陷。