A Novel Personalized Approach Towards Treating Negative Symptoms and Reducing Alcohol Abuse in patients with Comorbid AUD and Schizophrenia.

一种治疗 AUD 和精神分裂症共病患者的阴性症状和减少酒精滥用的新颖个性化方法。

• 批准号: 10018457
• 负责人: CATHERINE L CLELLAND
• 金额: $ 20.11万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018457
• 关键词: Abstinence; Admission activity; Advocate; Alcohol abuse; Alcohol consumption; Alcohols; Alleles; Amino Acids; Back; Biological Assay; Blood; Brain; Catechol O-Methyltransferase; Cessation of life; Clinical; Clinical assessments; Consultations; Cox Proportional Hazards Models; Data; Diagnosis; Dopamine; Emotional; Enzymes; Exhibits; FDA approved; Fasting; Future; Gender; Genetic Polymorphism; Genotype; Glutamates; Heavy Drinking; Hospitals; Individual; Inpatients; Interview; Logistic Regressions; Measures; Mediating; Mental disorders; Metabolism; Methyltransferase Gene; Modeling; Motivation; Mus; Neuromodulator; Neurotransmitters; New York; Outcome; Outpatients; Patient Recruitments; Patients; Personal Communication; Pharmaceutical Preparations; Plasma; Population; Presbyterian Church; Proline; Psychotic Disorders; Public Health; Race; Regression Analysis; Relapse; Reporting; Research Design; Sample Size; Schizophrenia; Self Medication; Severities; Signal Transduction; Speech; Surveys; Symptoms; Tail; Testing; Time; Visit; Withdrawal; Work; alcohol comorbidity; alcohol use disorder; comorbidity; economic cost; enzyme activity; improved; innovation; interest; mortality risk; mouse model; novel; personalized approach; personalized medicine; primary outcome; programs; recruit; reduce symptoms; response; secondary outcome; social; symptomatic improvement; treatment group; trend; valproate

Comorbidity of Alcohol Use Disorder (AUD) with schizophrenia (SZ) is highly prevalent at over 33% of SZ patients. Comorbidity is associated with particularly unfavorable outcomes including increased mortality risk and treatment non-adherence. Of particular relevance, some SZ patients have reported a decrease in negative symptoms following alcohol ingestion. This is important because the negative symptoms of SZ (loss of motivation, flattening of emotional responses, decreased speech and activity, and social withdrawal), are disabling and persistent, and significantly contribute to the immense personal and economic costs of SZ. No medications are FDA-approved for treatment of negative symptoms in SZ. Proline is a precursor of the neurotransmitter glutamate and may function as a CNS neuromodulator. Elevated proline stimulates dopamine (DA) signaling in murine models. The Catechol-O-methyltransferase (COMT) enzyme catalyzes deactivation of neurotransmitters including DA. In our recent, replicated study we found that fasting plasma proline levels (which reflect CNS levels) and the COMT Val158Met functional polymorphism (a well characterized marker of DA metabolism due to the encoded high or low activity enzyme) significantly interact, predicting negative symptom outcomes in patients with severe psychiatric illness. Specifically, in Val/Val high enzyme activity patients, high proline is protective with low negative symptom severity or a greater negative symptom reduction over time. Conversely, COMT Met carriers (low activity) demonstrated the opposite: Significantly more negative symptoms or less symptom improvement as proline increased. Alcohol ingestion upregulates circulating proline in those with a current or past AUD, and thus we hypothesized that comorbid patients self-medicate with alcohol to relieve their negative symptoms; predicting more frequent comorbid AUD in Val/Val SZ patients. In a preliminary study we indeed found a strong trend for a higher proportion of AUD in Val/Val’s, as compared to Met carriers for whom alcohol-induced proline elevation would be detrimental (p=0.065 two-tailed). Taken together, our findings are important because there are medications that up-regulate proline levels, such as valproate (VPA), prescribed to ~35% of SZ inpatients. We propose that personalized VPA treatment in comorbid AUD and SZ Val/Val patients, may relieve negative symptoms and assist in maintaining abstinence due to this relief. As a necessary prerequisite to an RCT of VPA, the work described under this exploratory R21 study should allow us to move towards such a personalized treatment approach: Specific Aim 1: We will confirm our preliminary study, powered to show association of COMT with AUD in SZ; Specific Aim 2: In a naturalistic, longitudinal setting we will test the innovative hypothesis that COMT Val/Val SZ patients with co-morbid AUD, have greater negative symptom improvement if they are treated with VPA (because of significant proline elevation), compared to those without an AUD and non-VPA treatment groups; Exploratory Aim 3: To test for a VPA response on alcohol use outcomes in SZ outpatients.

酒精使用障碍 (AUD) 与精神分裂症 (SZ) 的合并症在 SZ 地区的比例超过 33% 患者。合并症与特别不利的结果相关，包括死亡风险增加 和治疗不依从。特别重要的是，一些 SZ 患者报告阴性结果有所减少 摄入酒精后的症状。这很重要，因为 SZ 的阴性症状（丧失 动机、情绪反应平缓、言语和活动减少以及社交退缩） 造成残疾和持续存在，并极大地增加了深圳巨大的个人和经济成本。不 药物已获得 FDA 批准用于治疗深圳的阴性症状。 脯氨酸是神经递质谷氨酸的前体，可作为中枢神经系统神经调节剂。高架 脯氨酸在小鼠模型中刺激多巴胺 (DA) 信号传导。儿茶酚-O-甲基转移酶 (COMT) 酶催化包括 DA 在内的神经递质失活。在我们最近的重复研究中，我们发现 空腹血浆脯氨酸水平（反映中枢神经系统水平）和 COMT Val158Met 功能多态性（a 由于编码的高活性或低活性酶，DA 代谢的良好表征标记）显着 相互作用，预测严重精神疾病患者的阴性症状结果。具体来说，在 Val/Val 高酶活性患者，高脯氨酸对低阴性症状严重程度或更高的患者具有保护作用 随着时间的推移，阴性症状会减少。相反，COMT Met 载体（低活性）证明了 相反：随着脯氨酸的增加，阴性症状显着增加或症状改善减少。 酒精摄入会上调当前或过去 AUD 患者的循环脯氨酸，因此我们假设 共病患者自我饮酒以缓解阴性症状；预测更频繁 Val/Val SZ 患者的共病 AUD。在一项初步研究中，我们确实发现了更高的强烈趋势 与酒精诱导脯氨酸升高的 Met 携带者相比，Val/Val 中 AUD 的比例 是有害的（p=0.065 双尾）。总而言之，我们的发现很重要，因为有药物 上调脯氨酸水平的药物，例如丙戊酸 (VPA)，约 35% 的深圳住院患者开出处方。我们建议 对合并 AUD 和 SZ Val/Val 患者进行个性化 VPA 治疗，可能会缓解阴性症状 由于这种缓解，有助于保持禁欲。作为 VPA RCT 的必要先决条件，该工作 这项探索性 R21 研究中描述的内容应该使我们能够迈向这种个性化治疗 方法：具体目标 1：我们将确认我们的初步研究，旨在证明 COMT 与 深圳澳元；具体目标 2：在自然主义的纵向环境中，我们将测试以下创新假设： 患有 AUD 共病的 COMT Val/Val SZ 患者如果满足以下条件，则阴性症状改善更大： 与未接受 AUD 和非 VPA 治疗的患者相比，接受 VPA 治疗的患者（因为脯氨酸显着升高） 治疗组；探索性目标 3：测试 VPA 对深圳门诊患者饮酒结果的反应。