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

摘要 消极症状，如无意志、情感迟钝、快感缺乏和社交退缩，会使人衰弱， 这些疾病持续存在，并大大增加了严重精神疾病的巨大个人和经济成本。在 在新近发病（RO）患者中，阴性症状与不良功能结局相关。个体中 在精神病临床高危人群中，阴性症状可以预测过渡期，并且也与 功能不佳和恶化。这一点特别重要，因为即使大多数人都这样做， 虽然没有转变为精神病，但他们在社会和职业方面表现出严重的障碍， 对生活质量有很大影响。阴性症状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，并且作为CNS神经调质起作用。邻苯二酚 甲基转移酶（COMT）使包括多巴胺（DA）的儿茶酚胺失活。我们最近发现了一个 空腹血浆脯氨酸和功能性COMT多态性之间的相互作用（显示调节DA 通过COMT酶活性的信号传导：DA代谢），显著预测慢性炎症患者的阴性症状结果。 精神病患者：在预测具有高COMT活性（和增强的DA代谢）的患者中， 脯氨酸具有保护性，其阴性症状严重程度低或随着时间的推移症状减轻更大。相反地， 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， 高脯氨酸这种消极的症状相互作用效应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活性测量）相互作用， 阴性症状的严重程度在糖尿病患者和RO患者中。我们进一步假设， 脯氨酸、DA代谢与抑郁症阴性症状变化之间的关系，以及 转化为精神病具体目标。目标1A。收集67名受试者的横断面空腹血液， 个体和69名RO患者（首次发病<2年），并测量空腹血浆脯氨酸水平， 红细胞COMT酶活性。目标1B。评估两人的阴性症状和功能结果 使用包括阴性症状评估量表（SANS）在内的一组工具，以及 测试DA代谢和脯氨酸之间的相互作用。目标2.为了纵向研究 空腹血浆脯氨酸和阴性症状（通过前驱症状评估量表评估） 在基线（从1A）、6个月和1年后， 基线，测试脯氨酸x COMT活性之间的相互作用是否预测阴性症状的变化 随着时间目标3：回顾性检验脯氨酸x活性是否可预测糖尿病向精神病的转化。 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 药物存在。根据酶活性和DA代谢调节脯氨酸可能有希望 干预和针对高风险或RO患者的阴性症状;具有重要的公共卫生意义。

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.