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

精神分裂症是一种以社会功能缺陷为特征的破坏性疾病。社交能力 缺陷，如语言和非语言社交技能差，消极症状，如动力减弱 情感表现力和心理理论受损(TOM)，即理解人的心理状态的能力 其他人，导致社交功能不佳，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，已显示出作为一种潜在的治疗方法的前景 这些赤字。然而，到目前为止，进行的试验结果喜忧参半，阻碍了研究的翻译 进入临床实践。这很可能是因为这些试验1)动力不足，而且由于使用了 单剂量催产素，2)有次优评估的阴性症状，3)没有集中在临床上 积极症状和消极症状之外的相关缺陷，如社会功能和心理健康状况，4)缺乏 标准化的药物管理和依从性监测方案，以及5)没有考虑到 在个体层面上缓和加班效应的因素的可变性。此外，我们不理解 OT效应的神经机制，这削弱了我们预测谁将对OT做出反应的能力。建议数 研究将解决这些限制中的每一个，以严格确定OT改善现实社会的能力 精神分裂症患者的功能。充足的能量，包括两剂OT，最先进的 成果衡量、远程管理和遵守情况监测以及主持人分析将涉及 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，单次鼻腔注射 剂量OT可改善精神分裂症患者的TOM和阴性症状。此外，低活性 TOM患者右侧颞顶交界区与阴性症状严重程度的相关性 患有精神分裂症。急性给予OT可同时增加rTPJ激活和行为表现 TOM任务和这些增加是相关的。因此，在TOM任务中，OT诱导的rTPJ激活增加 可能是催产素影响社会功能的机制。建议的研究目的是：1)比较 与安慰剂相比，一次给药两种剂量的OT对fMRI rTPJ活性和 深圳心理理论任务执行中的行为准确性，2)比较两种方法的临床和行为效果 SZ患者的慢性OT治疗剂量，相对于安慰剂，以及3)决定急性fMRI rTPJ 对单次OT给药的反应可预测SZ患者对慢性OT治疗的临床反应。 150名退伍军人将随机接受20IU或40IU的OT，对照组为安慰剂， 受试者内，药物-功能磁共振研究，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，参与者将被随机接受相同剂量的OT 他们在研究的fMRI部分接受了为期三周的每天两次的fMRI或安慰剂治疗。社会功能 (主要结果)、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 在基线和服用OT或安慰剂三周后进行测量。拟议的研究代表了一项 在该领域取得重大进展有几个原因。其一，这是迄今为止规模最大的研究，也是唯一 在一项研究中同时检查两种剂量的OT。第二，它使用了最先进的评估 注重基于实验室临床前研究的最有希望的结果的方法学。 第三，它使用视频电话直接观察药物给药的遵守情况。第四，它将量化个人- 假设精神分裂症的催产素效应为中度的水平变量。第五，它将使用一种新的药物- 神经成像范式，以最大限度地利用临床试验产生的知识。建议进行的研究 代表着朝着开发一种精确的、神经科学知情的治疗方法迈出了重要的一步 为改善精神分裂症患者的社会功能缺陷而进行的神经加工异常。

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.