Mechanisms and Effects of Oxytocin on Social Cognition in Schizophrenia

催产素对精神分裂症社会认知的机制和影响

• 批准号: 8443359
• 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: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443359
• 关键词: Accounting; Address; Adolescence; Affect; Amygdaloid structure; Animals; Antipsychotic Agents; Area; Attention; Behavior; Behavioral; Chronic Disease; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Communication; Cues; Data; Diagnosis; Disease; Dose; Drug abuse; Early Intervention; Emotional; Emotions; Exhibits; Eye; Face; Family; Functional Magnetic Resonance Imaging; Functional disorder; Gly-Lys-Arg-oxytocin; Goals; Health Care Costs; Healthcare Systems; Human; Hyperactive behavior; Impairment; Income; Individual; Intervention; Label; Lead; Link; Measurement; Measures; Neurobiology; Neurodevelopmental Disorder; Neuropeptides; Occupational; Outcome; Oxytocin; Parasympathetic Nervous System; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Physiological; Physiology; Placebos; Play; Population; Prefrontal Cortex; Process; Psychophysiology; Recovery of Function; Research; Resistance; Role; Schizophrenia; Series; Sinus Arrhythmia; Social Behavior; Social Development; Social Functioning; Social Network; Social isolation; Societies; Stimulus; Substance abuse problem; Support System; Symptoms; System; Testing; Training; Veterans; Work; cost; disability; improved; indexing; neural patterning; neuromechanism; neurophysiology; novel; patient population; public health relevance; relating to nervous system; remediation; research study; respiratory; response; severe mental illness; social; social cognition; socioeconomics; young adult

DESCRIPTION (provided by applicant): Schizophrenia is a devastating neurodevelopmental disorder that often emerges in young adulthood, interfering with normal social development. The diagnosis is present in 1-2% of the population and cuts across socioeconomic, demographic and national lines, affects veterans as well as civilians, shaters families, and costs society billions in lost income due to social disability. The social deficits associated with schizophrenia wreak havoc on the lives of individuals who develop the disorder, and these deficits independently predict worse clinical, functional, and occupational outcomes above and beyond positive symptoms and other cognitive deficits. Despite their clinical importance, social deficits are poorly understood and resistant to available treatment options. Furthermore, abnormal neural and autonomic responses to social stimuli appear to underlie these deficits in schizophrenia. For example, patients demonstrate decreased activity of the parasympathetic nervous system (PNS), increased activity of the amygdala, and decreased activity of the ventral prefrontal cortex (vPFC) when performing certain social tasks. The neuropeptide oxytocin plays an important role in social behavior in animals and humans, increasing pro-social behavior and improving social cognition in healthy and autistic individuals. Oxytocin has also been shown to have positive effects on neural and autonomic responses in healthy individuals. Despite its potential as a new treatment for social deficits and for remediation of neurophysiological abnormalities, few studies have examined the effects of oxytocin on social cognition and behavior or on neural and autonomic responses to social stimuli in patients with schizophrenia. We propose a series of experiments aimed at both investigating the underlying neurophysiological mechanisms of oxytocin's pro-social effects and quantifying the potentially clinically useful effects of oxytocinin patients with recent-onset schizophrenia. In order to accomplish these important goals, we will first examine the effects of a single dose of exogenous oxytocin on behavioral and psychophysiological responses using validated social cognition measures in 45 patients with recent-onset schizophrenia and 45 matched healthy comparison subjects. We will also assess PNS activity as indexed by respiratory sinus arrhythmia (RSA) in order to test the hypothesis that oxytocin promotes social behavior by increasing PNS tone. Next, we will examine if oxytocin administration normalizes neural responses to social stimuli by decreasing activity of the amygdala and increasing activity of the vPFC, using a well-studied fMRI social cognition paradigm in 36 of these patients and 36 of these healthy comparison subjects. If successful, these experiments will: 1) Provide novel and important data on the neurobiological factors that underlie social deficits in patients with schizophrenia; 2) Lead to larger clinical trials of oxytoin to improve clinical outcomes in young individuals with recent-onset schizophrenia; and 3) Provide a deeper understanding of the functional and mechanistic relationships linking interrelated neurophysiologic systems that support socially meaningful behavior in healthy and schizophrenic individuals. Studying young adult patients with recent-onset schizophrenia minimizes potential confounds of chronic illness including social isolation, drug abuse and neuroleptic use and maximizes the potential long-term impact of this intervention. Overall, this work has the potential to uncover mechanisms of social dysfunction in schizophrenia, and to identify a novel treatment for the difficult-to-treat social deficits of the illness. PUBLIC HEALTH RELEVANCE: Schizophrenia affects 1-2% of the world population, is one of the top ten causes of disability worldwide, and costs the US economy more than $63 billion yearly. The VA system treats approximately 100,000 veterans with schizophrenia each year, accounting for nearly 12% of the VA's total healthcare costs. Current treatments fail to address the social deficits of schizophrenia, which are stronger predictors of clinical outcomes than positive symptoms. A pharmacological treatment for the social deficits of schizophrenia would have considerable benefit for patients, their families, society, and the VA healthcare system. The pro-social neuropeptide oxytocin is a promising treatment for social deficits in schizophrenia. The current study will investigate the effects of oxytocin on social functioning in patients with recent-onset schizophrenia and is a critical step towards identifying whether oxytocin is a viable treatment option in schizophrenia, particularly for young veterans in the earliest phases of the illness, who have a high likelihood for functional recovery.

描述（由申请人提供）： 精神分裂症是一种毁灭性的神经发育障碍，经常在成年后出现，会干扰正常的社会发展。该诊断存在于1-2％的人口中，并且在社会经济，人口和民族方面削减了诊断，会影响退伍军人以及平民，摇晃家庭，并使社会因社会残疾而造成数十亿美元的收入损失。与精神分裂症相关的社会缺陷对发展该疾病的个体的生活造成了严重破坏，这些缺陷独立预测了临床，功能和职业结果的较差，超出了积极的症状和其他认知缺陷。尽管它们的临床重要性，但社会缺陷还是对可用治疗方案的抵抗力很差。此外，对社会刺激的异常神经和自主反应似乎是精神分裂症中这些缺陷的基础。例如，患者表现出副交感神经系统（PNS）的活性降低，杏仁核的活性增加以及执行某些社交任务时腹侧前额叶皮层（VPFC）的活性降低。神经肽催产素在动物和人类的社会行为中起着重要作用，增强了亲情的行为并改善健康和自闭症患者的社会认知。催产素也已被证明对健康个体的神经和自主反应具有积极影响。尽管具有对社会缺陷的新疗法以及对神经生理异常的修复，但很少有研究研究催产素对精神分裂症患者的社会认知和行为或对社会刺激的神经和自主反应的影响。我们提出了一系列实验，旨在研究催产素的亲社会作用的基本神经生理机制，并量化最近癌症患者催产素患者的潜在临床有用作用。为了实现这些重要目标，我们将首先检查一次剂量的外源性催产素对45例最近患有精神分裂症的患者的社会认知度量和45例健康比较受试者的社会认知度量的行为和心理生理学反应的影响。我们还将评估呼吸窦性心律失常（RSA）索引的PNS活性，以检验催产素通过增加PNS张力促进社会行为的假设。接下来，我们将使用良好的FMRI社交认知范式中的36名患者和36例健康比较主题来检查催产素的给药是否通过减少杏仁核的活性和VPFC的活动增加来归一化神经对社会刺激的反应。如果成功，这些实验将：1）提供有关精神分裂症患者社会缺陷的神经生物学因素的新颖和重要数据； 2）导致Oxytoin进行更大的临床试验，以改善近期患有精神分裂症的年轻人的临床结局； 3）对关联相互关联的神经生理系统的功能和机械关系有更深入的了解，这些神经生理系统支持健康和精神分裂症个体中具有社会意义的行为。研究年轻的成年患者近期患有精神分裂症的患者最大程度地减少了慢性疾病的潜在混杂，包括社会隔离，药物滥用和神经化的使用，并最大程度地提高了这种干预措施的潜在长期影响。总体而言，这项工作有可能发现精神分裂症中社会功能障碍的机制，并确定对难以治疗的疾病社会缺陷的新颖治疗方法。 公共卫生相关性： 精神分裂症影响着世界人口的1-2％，是全球残疾人的十大原因之一，每年损失超过630亿美元的经济。 VA系统每年对大约100,000名退伍军人进行精神分裂症，占VA总医疗保健总费用的近12％。目前的治疗方法无法解决精神分裂症的社会缺陷，这比临床结局的预测因素要比积极症状更强。精神分裂症的社会缺陷的药理治疗方法将对患者，家人，社会和VA医疗保健系统有很大的好处。亲社会神经肽催产素是精神分裂症社会缺陷的有前途的治疗方法。当前的研究将研究最近患有精神分裂症患者的催产素对社会功能的影响，这是确定催产素是否是精神分裂症的可行治疗选择的关键一步 具有功能恢复的可能性很大。