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）的共病非常普遍，超过33%的SZ