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。社交能力 缺陷，例如言语和非言语社交技能较差，消极症状，例如动机下降 和情绪表达能力，以及心理理论（ToM）受损，即理解他人心理状态的能力 其他人则导致社会功能较差，并且对抗精神病药物没有反应。催产素（OT）， 一种已知在社会行为中发挥关键作用的神经肽，已显示出作为潜在治疗方法的希望 这些赤字。然而，迄今为止进行的试验得出的结果好坏参半，阻碍了研究成果的转化 进入临床实践。这可能是因为这些试验 1) 动力不足并且受到使用限制 单剂量 OT，2) 未达到最佳评估的阴性症状，3) 未重点关注临床 相关缺陷，例如阳性和阴性症状之外的社会功能和 ToM，4) 缺乏 标准化药物管理和依从性监测方案，以及 5) 未能解释 在个体层面上调节 OT 影响的因素存在差异。此外，我们不明白 OT 效应的神经机制，削弱了我们预测谁会对 OT 做出反应的能力。拟议的 研究将解决这些局限性，以严格确定 OT 改善现实世界社交的能力 对精神分裂症患者起作用。足够的功率，包括两种剂量的 OT，最先进的 结果测量、远程管理和依从性监测以及主持人分析将解决 现有文献中的方法论缺陷。此外，拟议的研究将提供关键的 有关 OT 效应的神经机制的信息。初步结果表明，单次鼻内 OT 剂量可改善精神分裂症患者的 ToM 和阴性症状。此外，低激活 ToM 期间右侧颞顶交界处 (rTPJ) 的变化与患者的阴性症状严重程度相关 患有精神分裂症。急性 OT 给药可增加 rTPJ 激活和行为表现 ToM 任务和这些增加是相关的。因此，在 ToM 任务期间 OT 诱导的 rTPJ 激活增加 可能是OT影响社会功能的机制。拟议的研究目的是：1）比较 相对于安慰剂，单次施用两个剂量的 OT 对 fMRI rTPJ 活性的急性影响和 在 SZ 执行 ToM 任务期间的行为准确性，2) 比较两种方法的临床和行为效果 相对于安慰剂，SZ 患者的慢性 OT 治疗剂量，以及 3) 确定急性 fMRI rTPJ 是否 对单次 OT 给药的反应可以预测 SZ 患者对长期 OT 治疗的临床反应。 150 名退伍军人将被随机接受 20IU 或 40IU 的 OT 安慰剂对照， 受试者内药物功能磁共振成像研究，其中将量化他们对 OT 和安慰剂的神经反应 在两个 ToM 任务期间。成像后，参与者将被随机分配接受相同剂量的 OT 他们每天接受两次研究的功能磁共振成像部分或安慰剂，持续三周。社会功能 （主要结果）、社交能力、阴性症状和 ToM 能力将使用经过充分验证的方法进行量化 在基线和三周 OT 或安慰剂给药后进行测量。拟议的研究代表了 由于多种原因，该领域取得了重大进展。第一，这是迄今为止最大规模的研究，也是唯一的 在一项研究中同时检查两种剂量的 OT。二、它使用最先进的评估 专注于基于实验室临床前研究的最有希望的结果的方法。 三是通过视频通话直接观察用药依从性。第四，它将量化个人—— 假设水平变量可以减轻精神分裂症的 OT 影响。五、它将使用一种新型药物—— 神经影像范式最大限度地利用临床试验产生的知识。拟议的研究 代表着朝着开发一种精确的、基于神经科学的治疗方法迈出的重要一步，该治疗方法可以使患者正常化 异常的神经处理，以改善精神分裂症的社会功能缺陷。