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

酒精使用障碍（AUD）与精神分裂症（SZ）的共病在SZ中的患病率高达33%以上 患者合并症与特别不利的结局相关，包括死亡风险增加 和治疗不依从性。特别相关的是，一些SZ患者报告了阴性 酒精摄入后的症状这一点很重要，因为SZ的阴性症状（ 动机，情绪反应的平坦化，言语和活动减少，以及社交退缩）， 致残和持久的，并大大有助于巨大的个人和经济成本的深圳。没有 药物是FDA批准用于治疗SZ阴性症状的药物。 脯氨酸是神经递质谷氨酸的前体，并且可以作为CNS神经调质起作用。升高 脯氨酸刺激鼠模型中的多巴胺（DA）信号传导。儿茶酚-O-甲基转移酶（COMT） 酶催化包括DA在内的神经递质的失活。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CNS水平）和COMT Val 158 Met功能多态性（a 由于编码的高或低活性酶， 交互作用，预测严重精神疾病患者的阴性症状结果。具体到 瓦尔/瓦尔高酶活性患者，高脯氨酸具有保护性，阴性症状严重程度低或更高 随着时间的推移，阴性症状减少。相反，COMT Met携带者（低活性）表现出 相反：随着脯氨酸的增加，阴性症状明显增加或症状改善减少。 酒精摄入上调循环脯氨酸在那些与当前或过去的AUD，因此，我们假设 共病患者通过酒精自我抑制来缓解阴性症状;预测更频繁的 在瓦尔/瓦尔SZ患者中合并AUD。在一项初步研究中，我们确实发现了一个强烈的趋势， AUD在瓦尔/瓦尔中的比例，与酒精诱导的脯氨酸升高将 有害（p=0.065双尾）。总的来说，我们的发现很重要， 上调脯氨酸水平的药物，如丙戊酸盐（VPA），约35%的SZ住院患者使用。我们建议 合并AUD和SZ瓦尔/瓦尔患者的个性化VPA治疗可能缓解阴性症状， 帮助保持禁欲由于这种救济。作为VPA RCT的必要先决条件， 这项探索性R21研究中描述的内容应该可以让我们转向这种个性化治疗 方法：具体目标1：我们将确认我们的初步研究，有力地显示COMT与 具体目标2：在一个自然的、纵向的环境中，我们将检验创新的假设， 合并AUD的COMT瓦尔/瓦尔SZ患者的阴性症状改善更大，如果他们 与未接受AUD和非VPA治疗的患者相比，接受VPA治疗的患者（由于脯氨酸显著升高） 治疗组;探索性目的3：在SZ门诊患者中检测VPA对酒精使用结局的反应。

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.