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

摘要 消极的症状，如贪婪、迟钝的情感、快感缺失和社交退缩，都会让人虚弱， 持续存在，并极大地造成严重精神疾病的巨大个人和经济代价。在……里面 新近发病(RO)的患者，阴性症状与功能预后不良有关。在个人中， 临床高风险(CHR)精神病，阴性症状可以预测转变，也与 功能不佳且不断恶化。这一点特别重要，因为尽管大多数CHR个人都是这样做的 他们没有转变为精神病，但在社会和职业方面表现出严重的障碍 对生活质量有重大影响的功能。阴性症状在很大程度上不能通过药物来解决。 脯氨酸是神经递质谷氨酸的前体，起着中枢神经调节剂的作用。邻苯二酚-O- 甲基转移酶(COMT)使包括多巴胺(DA)在内的儿茶酚胺失活。我们最近发现了一个 空腹血浆脯氨酸与功能性COMT多态(显示为调节DA)之间的相互作用 通过COMT酶活性传递信号：DA代谢)，显著预测慢性阻塞性肺疾病的阴性症状结局 精神病患者：在预计COMT活性高(和DA代谢增强)的患者中， 脯氨酸具有保护性，阴性症状严重程度较低，或者随着时间的推移，症状会有较大程度的减轻。相反， 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 高脯氨酸。这种消极症状的交互作用在两种精神疾病中是一致的。 我们现在假设，脯氨酸水平和DA代谢(通过COMT活性来衡量)相互作用，以修改 慢性阻塞性肺病患者和RO患者的阴性症状严重程度。我们进一步假设一个重要的 脯氨酸、多巴胺代谢与慢性阻塞性肺疾病阴性症状变化的关系 转化为精神病。明确的目标。目标1 A。从67小时内采集空腹横断面血液 个人和69名RO患者(从他们第一次发病起两年)，并测量空腹血浆脯氨酸水平加 红细胞COMT酶活性。目标1B。评估两组患者的阴性症状和功能结果 使用包括阴性症状量表(SANS)在内的一系列工具的小组，以及 测试多巴胺代谢和脯氨酸之间的相互作用。目标2.纵向考察 空腹血浆脯氨酸和阴性症状(通过前驱症状评估量表评估 症状(SOP)在基线(从1A开始)、6个月和1年后的60名CHR患者中 基线，测试Pro x COMT活性之间的相互作用是否可以预测阴性症状的变化 随着时间的推移。目的3.回溯性检验Pro-x活性是否能预测CHR转化为精神病。 影响：我们的研究可能对阴性症状的治疗有启示，因为 药物是存在的。根据酶活性和DA代谢调节脯氨酸可能有希望 干预和针对高危或RO患者的阴性症状；具有重要的公共卫生影响。

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.