Negative Symptoms in Clinical High Risk and First Episode Psychiatric Illness: Investigation of a New Candidate for Targeted Treatment.

临床高风险和首发精神疾病的阴性症状：靶向治疗新候选者的调查。

• 批准号: 9789938
• 负责人: CATHERINE L CLELLAND
• 金额: $ 24.29万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789938
• 关键词: 22q11; Advocate; Affect; Alleles; Amino Acids; Anhedonia; Antipsychotic Agents; Behavioral; Biological Assay; Blood; Brain; Catabolism; Catechol O-Methyltransferase; Catecholamines; Caucasians; Chromosomes; Chronic; Clinical; Coupled; Cox Proportional Hazards Models; Diagnosis; Dopamine; Enzymes; Erythrocytes; Ethnic Origin; Exhibits; Fasting; Genes; Genetic Markers; Genetic Polymorphism; Glutamates; Homovanillic Acid; Human; Hyperprolinemia; Impairment; Individual; Investigation; Linear Regressions; Link; Logistic Regressions; Maps; Measures; Mental disorders; Metabolism; Methyltransferase Gene; Modeling; Motivation; Mus; Neuromodulator; Neurotransmitters; Occupational; Onset of illness; Outcome; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasma; Proline; Proline Dehydrogenase; Psychotic Disorders; Public Health; Quality of life; Race; Reporting; Risk; Role; Sample Size; Schizophrenia; Schizophreniform Disorder; Sensory; Severities; Signal Transduction; Symptoms; Testing; Time; Withdrawal; Work; associated symptom; autism spectrum disorder; clinical predictors; cohort; conotruncal anomaly face syndrome; economic cost; enzyme activity; experience; first episode psychosis; functional outcomes; genetic manipulation; high risk; instrument; microdeletion; neurophysiology; neurotransmission; recruit; reduce symptoms; response; social; symptom treatment; targeted treatment; transmission process

ABSTRACT Negative symptoms such as avolition, blunted affect, anhedonia, and social withdrawal, are debilitating, persistent, and significantly contribute to the huge personal and economic cost of severe psychiatric illnesses. In recent onset (RO) patients, negative symptoms are associated with poor functional outcomes. In individuals at clinical high-risk (CHR) for psychosis, negative symptoms can predict transition, and are also associated with poor and deteriorating functioning. This is particularly significant because even though most CHR individuals do not transition to psychosis, they nonetheless exhibit substantial impairments in social and occupational functioning that considerably impact quality of life. Negative symptoms are largely unaddressed by medications. Proline is a precursor of the neurotransmitter glutamate and functions as a CNS neuromodulator. Catechol-O- methyltransferase (COMT) deactivates catecholamines including dopamine (DA). We recently found an interaction between fasting plasma proline and a functional COMT polymorphism (shown to modulate DA signaling via COMT enzyme activity:DA metabolism), significantly predicts negative symptom outcomes in chronic psychiatric patients: In patients’ predicted to have high COMT activity (and enhanced DA metabolism), high proline is protective with low negative symptom severity or a greater symptom reduction over time. Conversely, carriers of the allele encoding the low activity enzyme demonstrated significantly more negative symptoms with high proline. This negative symptom interaction effect was consistent across two psychiatric illnesses. We now hypothesize that proline level and DA metabolism (as measured by COMT activity) interact to modify negative symptom severity in CHR individuals and in those with RO. We further hypothesize a significant relationship between proline, DA metabolism, and change in negative symptoms in CHR states, as well as conversion to psychosis. Specific Aims. Aim 1A. To collect cross-sectional, fasting blood from 67 CHR individuals and 69 RO patients (<2 years from their first-episode), and measure fasting plasma proline levels plus erythrocyte COMT enzyme activity. Aim 1B. To evaluate negative symptoms and functional outcomes in the two groups using a battery of instruments including the Scale for Assessment of Negative Symptoms (SANS), and test for an interaction between DA metabolism and proline. Aim 2. To longitudinally examine the change in fasting plasma proline and negative symptoms (as assessed via the Scale for assessment of Prodromal Symptoms (SOPS)) in 60 of the CHR individuals at baseline (from 1A), at 6 months, and then 1-year post baseline, testing whether the interaction between proline x COMT activity predicts change in negative symptoms over time. Aim 3. To retrospectively test whether proline x activity predicts CHR conversion to psychosis. Impact: Our study may have implications for negative symptom treatment because proline-modulating medications exist. Modulating proline according to enzyme activity and DA metabolism may hold promise for intervening and targeting negative symptoms in high-risk or RO patients; with important public health implications.

抽象的 消极症状，如无欲、情感迟钝、快感缺乏和社交退缩，使人衰弱， 严重精神疾病造成的巨大个人和经济损失。 最近发病（RO）的患者，阴性症状与功能结果不佳有关。 精神病的临床高风险（CHR），阴性症状可以预测转变，并且也与 这一点尤其重要，因为尽管大多数 CHR 个体确实如此。 虽然没有转变为精神病，但他们在社交和职业方面表现出严重损害 严重影响生活质量的功能在很大程度上无法通过药物解决。 脯氨酸是神经递质谷氨酸的前体，具有中枢神经系统神经调节剂的作用。 甲基转移酶 (COMT) 可使包括多巴胺 (DA) 在内的儿茶酚胺失活。 空腹血浆脯氨酸与功能性 COMT 多态性（显示可调节 DA）之间的相互作用 通过 COMT 酶活性发出信号：DA 代谢），显着预测慢性病患者的阴性症状结果 精神病患者：在预计具有高 COMT 活性（和增强的 DA 代谢）的患者中，高 脯氨酸具有保护作用，阴性症状严重程度较低，或随着时间的推移，症状减轻程度更大， 编码低活性酶的等位基因携带者表现出明显更多的阴性症状 这种负面症状的相互作用在两种精神疾病中是一致的。 我们现在认为脯氨酸水平和 DA 代谢（通过 COMT 活性测量）相互作用来改变 我们进一步研究了 CHR 个体和 RO 个体的阴性症状严重程度。 脯氨酸、DA 代谢与 CHR 状态下阴性症状变化之间的关系，以及 具体目标 1A 收集 67 个 CHR 的横断面空腹血液。 个体和 69 名 RO 患者（距首次发作后不到 2 年），并测量空腹血浆脯氨酸水平以及 目的 1B 评估红细胞 COMT 酶活性。 使用一系列仪器的小组，包括阴性症状评估量表（SANS），以及 测试 DA 代谢和脯氨酸之间的相互作用 目标 2. 纵向检查 DA 代谢的变化。 空腹血浆脯氨酸和阴性症状（通过前驱症状评估量表进行评估） 60 名 CHR 个体在基线（从 1A 开始）、6 个月和一年后的症状 (SOPS) 基线，测试脯氨酸 x COMT 活性之间的相互作用是否可以预测阴性症状的变化 目标 3. 回顾性测试脯氨酸 x 活性是否可以预测 CHR 转化为精神病。 影响：我们的研究可能对阴性症状治疗有影响，因为脯氨酸调节 根据酶活性和 DA 代谢调节脯氨酸的药物可能有望实现这一目标。 高危或 RO 患者的干预和阴性目标症状；具有重要的公共卫生影响。