Alcoholism and Schizophrenia: A Translational Approach to Treatment

描述(由申请人提供)：酒精使用障碍(AUD)，在精神分裂症(SCZ)中比普通人群中常见三倍，加剧了这种严重的精神障碍的病程。因此，AUD和SCZ并存是一个重要的公共卫生问题。虽然大多数可用的抗精神病药物并没有限制SCZ患者的酒精使用，但非典型的抗精神病药物氯氮平(CLOZ)似乎做到了这一点。然而，由于CLOZ有重要的副作用，其临床应用仅限于最严重的SCZ患者。因此，需要找到治疗SCZ和AUD的新药，这些药物在限制这些患者酗酒方面至少与CLOZ一样有效，但比CLOZ更安全。我们已经开发了CLOZ在SCZ和AUD患者中作用的神经生物学配方，我们已经在喜欢饮酒的啮齿动物群体中测试了这种配方，以开始寻找能够治疗SCZ和AUD患者的药物。这一神经生物学公式表明，酒精可能会增强SCZ患者调节失调的多巴胺介导的皮质边缘中脑奖赏回路的功能，这是他们使用酒精的基础。此外，这一配方还表明，CLOZ通过对多巴胺和去甲肾上腺素能系统的不同影响，能够减少酒精使用，因为它改善了这些患者功能失调的大脑奖赏回路。本课题组最近对嗜酒仓鼠和大鼠的研究表明，当具有多巴胺D2受体拮抗作用、去甲肾上腺素a2受体拮抗作用和去甲肾上腺素再摄取抑制作用的药物联合使用时，CLOZ的作用可以复制。这些研究表明，非典型抗精神病药物利培酮(Risp)，一种在多巴胺d2受体和去甲肾上腺素a2受体产生拮抗作用的药物，本身对SCZ患者或嗜酒啮齿动物减少饮酒的能力微乎其微，当与去甲肾上腺素再摄取抑制剂地昔帕明(Dmi)联合使用时，将减少啮齿动物的饮酒。这项拟议的R21概念翻译验证临床试验试图将这些动物研究的结果扩展到SCZ和AUD患者。我们在这份重新提交的申请中的目标是开始评估RISP与DMI联合使用是否会限制这些患者的酒精使用。我们的具体目标是：(1)确定RISP联合DMI治疗的受试者是否比单独接受RISP治疗的患者饮酒更少(饮酒天数更少；大量饮酒天数更少)；(2)探讨两组患者的症状(SCZ和抑郁)：与单独接受RISP治疗的患者相比，接受RISP联合DMI治疗的患者；以及(3)探讨两组患者的药物副作用负担：与单独接受RISP治疗的患者相比，接受RISP联合DMI治疗的患者的副作用负担。在这项翻译概念验证试验中开发的信息将使我们能够确定是否应该在SCZ和AUD患者中进行RISP和DMI的更大规模的临床试验。 与公共卫生相关：酒精使用障碍在精神分裂症患者中很常见，它会恶化这种严重的精神障碍的病程。这项基于动物研究的转化性研究提案试图开始评估两种常用药物利培酮和地昔帕明的联合使用是否会限制精神分裂症和酒精使用障碍患者的酒精使用。寻找能够限制酒精使用从而减少精神分裂症患者不良后果的药物具有非常重要的公共卫生意义。

DESCRIPTION (provided by applicant): Alcohol use disorder (AUD), which is three times more common in schizophrenia (SCZ) than in the general population, worsens the course of this severe psychiatric disorder. Thus, the co-occurrence of AUD and SCZ is an important public health problem. While most available antipsychotic medications do not limit alcohol use in patients with SCZ, the atypical antipsychotic clozapine (CLOZ) appears to do so. However, because CLOZ has important side effects, its clinical use is limited to only the most severely ill patients with SCZ. Thus, new medications for the treatment of SCZ and AUD, medications at least as effective as CLOZ for limiting alcohol abuse in these patients, but safer than CLOZ, need to be found. We have developed a neurobiologic formulation of the action of CLOZ in patients with SCZ and AUD, and we have tested this formulation in groups of alcohol preferring rodents to begin to search for medications able to treat patients with SCZ and AUD. This neurobiologic formulation suggests that alcohol may enhance the functioning of a dysregulated dopamine- mediated mesocorticolimbic brain reward circuitry in patients with SCZ that underpins their use of alcohol. Further, this formulation also proposes that CLOZ, through its diverse effects on both dopaminergic and noradrenergic systems, is able to decrease alcohol use because it ameliorates the dysfunctional brain reward circuit in these patients. Recent studies by our group in alcohol-preferring hamsters and rats have suggested that the effect of CLOZ can be duplicated when medications possessing dopamine D2 receptor antagonism, norepinephrine a2 receptor antagonism and norepinephrine reuptake inhibition are combined together. These studies have indicated that the atypical antipsychotic risperidone (RISP), a medication producing antagonism at the dopamine D2 receptor and the norepinephrine a2 receptor, which by itself has a minimal ability to decrease alcohol drinking in patients with SCZ or in alcohol-preferring rodents, will decrease alcohol drinking in rodents when combined with the norepinephrine reuptake inhibitor desipramine (DMI). This proposed translational proof of concept R21 clinical trial seeks to extend the results of these animal studies into patients with SCZ and AUD. Our goal in this resubmitted application is to begin to assess whether RISP in combination with DMI will limit alcohol use in these patients. Our Specific Aims are: (1) To determine whether subjects who are treated with RISP in combination with DMI have less alcohol use (fewer drinking days; fewer heavy drinking days) than do patients who are treated with RISP alone; (2) To explore symptoms (of SCZ and of depression) in the two groups of patients: those treated with RISP in combination with DMI, as compared to those treated with RISP alone; and (3) To explore the medication side effect burden in the two groups of patients: those treated with RISP in combination with DMI, as compared to those treated with RISP alone. Information developed during this translational proof of concept trial will allow us to determine whether a larger clinical trial of RISP in combination with DMI should be undertaken in patients with SCZ and AUD. PUBLIC HEALTH RELEVANCE: Alcohol use disorder, which is common in patients with schizophrenia, worsens the course of this severe psychiatric disorder. This translational research proposal, based on studies in animals, seeks to begin to assess whether the combination of two commonly used medications, risperidone and desipramine, will limit alcohol use in patients with co-occurring schizophrenia and alcohol use disorder. Finding medications that may be able to limit alcohol use and thereby reduce adverse outcomes in patients with schizophrenia is of great public health importance.