Project 2 ACISR

项目2 ACISR

• 批准号: 8377191
• 负责人: SERGE SEVY
• 金额: $ 8.32万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8377191
• 关键词: Acute; Addictive Behavior; Adherence; Adverse effects; Adverse event; Age; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol or Other Drugs use; Alcohols; Amphetamines; Anhedonia; Animals; Antidepressive Agents; Antipsychotic Agents; Attenuated; Biological Markers; Brain; Cannabis; Cardiovascular system; Categories; Clinical; Cocaine; Cocaine Dependence; Cocaine-Related Disorders; Cognitive; Data; Dependence; Dextroamphetamine; Diagnosis; Disease; Dopamine; Dopamine Receptor; Dose; Double-Blind Method; Drug Addiction; Emotional; Environment; Ethanol; FDA approved; Failure; Functional disorder; Generations; Genetic; Guidelines; Hallucinogens; Human; Image; Individual; Inhalant dose form; Intoxication; Life; Maintenance; Major Depressive Disorder; Marijuana Smoking; Measures; Metabolic; Metabolic syndrome; Modeling; Moods; Motor; Mus; Opiates; Outcome; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Placebos; Population; Prevalence; Prolactin; Property; Psychotic Disorders; Quality of life; Randomized; Recurrence; Relapse; Reporting; Research; Rewards; Risk; Risperidone; Sampling Studies; Schizoaffective Disorders; Schizophrenia; Schizophreniform Disorder; Severities; Social Functioning; Specific qualifier value; Stimulus; Substance Addiction; Substance Use Disorder; Substance abuse problem; Symptoms; Testing; Therapeutic Effect; Time; Urine; Weight Gain; Withdrawal; aged; alcohol effect; alcohol use disorder; aripiprazole; comparative efficacy; compare effectiveness; craving; depressive symptoms; disorder later incidence prevention; experience; first episode psychosis; first episode schizophrenia; flexibility; hazard; high risk; human subject; improved; indexing; male; meetings; olanzapine; open label; outcome forecast; placebo controlled study; prevent; response; sex; sobriety; treatment effect

Acute psychotic episodes have been associated with alcohol, hallucinogen, cannabis, or cocaine/stimulant use. Currently, there are no guidelines for the pharmacological treatment of individuals with psychosis associated with substance use beyond the acute episode, and specifically, no studies assessing the long-term efficacy of second generation antipsychotics in this population. Among the second generation antipsychotics, aripiprazole may be the optimal choice for long-term treatment of these subjects for the following reasons: 1) Its antipsychotic efficacy is similar to other second generation antipsychotics. 2) It is a prime candidate for the treatment of dopaminergic dysfunction found in addictive behaviors. It is the only approved D2 partial agonist available in the U.S. and has a modulating effect on dopaminergic function, i.e., acts as a D2 antagonist in dopamine-rich environment and D2 agonist in dopamine-poor environment (Travis et al. 2005). Converging evidence from animal and human studies suggests that dysfunction of the dopaminergic brain reward circuit is involved in the various aspects of drug addiction, including reinforcing responses to drugs during intoxication, activation during craving, and deactivation during withdrawal (Kalivas 2002). It has been suggested that decreases in dopamine receptors and dopamine release may induce a decreased sensitivity of reward circuits to stimulation by natural rewards (Noble et al. 1991; Volkow et al. 2002). In mice, aripiprazole antagonizes ethanol-, amphetamine-, and cocaine-induced locomotor stimulation, which suggest that aripiprazole decreases drug-induced hyperdopaminergia (Jerihag 2008; Leite et al. 2008). In human subjects, aripiprazole attenuates the discriminative-stimulus, cardiovascular effects, and subjectrated effects of d-amphetamine (Lile et al. 2005; Stoops et al. 2006). 3) Several studies suggest that it decreases substance use in subjects without and with psychosis. Martinotti et al (2007) reported on thirteen detoxified alcohol-dependent subjects who were treated with flexible doses of aripiprazole for 16 weeks. All subjects experienced reduced craving and a decrease ofthe SCL-90 General Severity Index with 6 patients maintaining sobriety during the study. Anton et al (2008) conducted a 12-week double-blind placebo-controlled study in 295 subjects with alcohol dependence. Compared to subjects on placebo, subjects treated with aripiprazole reported more positive subjective treatment effects and less overall severity of alcohol dependence at the end of the study. Kranzler et al (2008) found that aripiprazole decreases the euphoric effect of alcohol in 18 healthy subjects. Deseilles et al (2008) reported a decrease in cannabis use in one non-psychotic subject treated with aripiprazole. Beresford et al (2005) conducted a 8-week, open-label trial in 10 poorly compliant subjects with schizophrenia and co-occuring cocaine dependence and alcohol abuse. Six subjects completed the trial and had decreased positive urine tests for cocaine, and decreased craving for cocaine and alcohol. In Brown et al (2005), 20 antipsychotic-treated subjects were switched to 12- week open-label aripiprazole. Alcohol dependent subjects (n=17) had a decrease in dollars spent on alcohol and in craving. Subjects with cocaine-related disorders (n=9) had decreased cocaine craving. 5) Aripiprazole has antidepressant properties and is approved by the FDA as augmentation therapy in major depression (Berman et al. 2007). Subjects with psychotic disorders and co-occurring substance use disorders are prone to anhedonia, emotional flattening and low mood, increasing the risk of relapse to substance abuse, low adherence rates and poorer clinical outcomes. Hence, we hypothesize that aripiprazole will improve mood in subjects with psychotic episodes associated with substance use. 5) It has a relatively favorable side effect profile, including less risk of metabolic syndrome, prolactin elevation, and QTc interval prolongation compared to other atypicals (Chen et al. 2007; El-Sayeh et al. 2006). PRELIMINARY DATA From 2001 to 2007, we conducted a study comparing the effectiveness of randomly assigned open-label flexible dose treatment with olanzapine (2.5 to 20 mg per day) or risperidone (1 to 6 mg) in subjects aged 16 to 40 with a first episode of schizophrenia (75%), schizoaffective disorder (17%), or schizophreniform disorder (8%). The final study sample consisted of 112 subjects (70% male; mean age 23.3 (SD = 5.1) years). Lifetime prevalence rates of abuse or dependence were the highest for cannabis (44%), followed by alcohol (22%), and cocaine (4%). Nineteen subjects with cannabis use disorders (abuse or dependence; CUD) (39%) had alcohol use disorders (abuse or dependence) and seven CUD subjects (14%) had other substance use disorders (cocaine, n=5; hallucinogens, n=2; opiates, n=1; inhalants, n=1). 49.1% (95% Cl: 38.7%, 59.6%) of patients met response criteria. However, thirty percent (95% Cl: 13.5%, 46.2%) of subjects who met response criteria failed to maintain response. Marijuana use and alcohol use during treatment were significantly correlated and associated with failure to maintain response. Using a composite measure for our multivariate model, which included sex and medication assignment, both the composite substance use measure (hazard ratio=1.48; 95% Cl=1.04, 2.10; p<0.04) and poor premorbid social functioning (hazard ratio=1.14; 95% Cl=1.02, 1.28; p<0.03) were significant predictors of response instability. We also assessed if olanzapine (n=28) was more effective than risperidone (n=21) in first-episode patients with cannabis use disorders. Response rates of positive symptoms were 45% (95% Cl: 25%, 65%) with olanzapine and 54% (95% Cl: 29%, 79%) with risperidone. Survival curves did not differ between groups (log-rank test; p < 0.95) and there were no differences between treatment groups for cannabis use (56% in the olanzapine group vs. 35% in the risperidone group, p < 0.16) or alcohol use (52% in the olanzapine group vs. 40% in the risperidone group, p < 0.42). Thus, our results suggest that (1) olanzapine and risperidone have similar efficacy on psychotic symptoms and cannabis or alcohol use in subjects with cannabis use disorders and a first episode of psychosis; and (2) cannabis and alcohol use during treatment increases the risk of not sustaining response. These preliminary studies also demonstrate our ability to use second generation antipsychotics for treating psychotic patients with co-occurring substance use disorders during and after the acute episode.

急性精神病发作与酒精、致幻剂、大麻或可卡因/兴奋剂的使用有关。目前，对于与急性发作后的物质使用相关的精神病个体的药物治疗尚无指南，特别是，没有研究评估长期影响 第二代抗精神病药物对该人群的疗效。在第二代抗精神病药中，阿立哌唑可能是这些受试者长期治疗的最佳选择，原因如下：1）其抗精神病疗效与其他第二代抗精神病药相似。 2) 它是治疗成瘾行为中多巴胺能功能障碍的主要候选药物。它是美国唯一批准的 D2 部分激动剂，对多巴胺能功能具有调节作用，即在多巴胺丰富的环境中充当 D2 拮抗剂，在多巴胺缺乏的环境中充当 D2 激动剂 （特拉维斯等人，2005）。来自动物和人类研究的综合证据表明，多巴胺能大脑奖励回路的功能障碍与药物成瘾的各个方面有关，包括在中毒期间增强对药物的反应、在渴望期间激活以及在戒断期间失活（Kalivas） 2002）。有人提出，多巴胺受体和多巴胺释放的减少可能会导致奖赏回路对自然奖赏刺激的敏感性降低（Noble 等人，1991 年；Volkow 等人，2002 年）。在小鼠中，阿立哌唑拮抗乙醇、安非他明和可卡因诱导的运动刺激， 这表明阿立哌唑可减少药物引起的多巴胺能亢进（Jerihag 2008；Leite et al. 2008）。 在人类受试者中，阿立哌唑减弱了 d-安非他明的辨别刺激、心血管效应和受试者效应（Lile 等人，2005 年；Stoops 等人，2006 年）。 3) 多项研究表明，它可以减少患有和患有精神病的受试者的物质使用。 Martinotti 等人 (2007) 报道了 13 名戒毒的酒精依赖受试者接受灵活剂量的阿立哌唑治疗 16 周。所有受试者的渴望均有所减少，SCL-90 一般严重程度指数也有所下降，其中 6 名患者在研究期间保持清醒。 Anton 等人 (2008) 对 295 名酒精依赖受试者进行了一项为期 12 周的双盲安慰剂对照研究。与服用安慰剂的受试者相比，接受阿立哌唑治疗的受试者报告了更积极的主观治疗效果，但总体治疗效果较差 研究结束时酒精依赖的严重程度。 Kranzler 等人 (2008) 发现阿立哌唑降低了 18 名健康受试者的酒精欣快效应。 Deseilles 等人 (2008) 报告称，一名接受阿立哌唑治疗的非精神病患者的大麻使用量有所减少。 Beresford 等人 (2005) 对 10 名依从性差、患有精神分裂症、同时患有可卡因依赖和酗酒的受试者进行了为期 8 周的开放标签试验。六名受试者完成了试验，可卡因尿检阳性率有所下降，对可卡因和酒精的渴望也有所下降。 Brown 等人 (2005) 将 20 名接受抗精神病药物治疗的受试者转为 12 名接受抗精神病药物治疗的受试者。 周开放标签阿立哌唑。酒精依赖受试者（n = 17）花在酒精上的美元和对酒精的渴望有所减少。患有可卡因相关疾病的受试者 (n=9) 对可卡因的渴望有所降低。 5) 阿立哌唑具有抗抑郁特性，并被 FDA 批准作为重度抑郁症的增强疗法（Berman 等人，2007 年）。患有精神障碍和同时发生的药物滥用障碍的受试者容易出现快感缺失、情绪低落和情绪低落，增加药物滥用复发的风险、低依从率和较差的临床结果。因此，我们假设阿立哌唑会改善患有与物质使用相关的精神病发作的受试者的情绪。 5) 与其他非典型药物相比，它具有相对有利的副作用，包括代谢综合征、催乳素升高和 QTc 间期延长的风险较低（Chen 等人，2007 年；El-Sayeh 等人，2006 年）。 初步数据 2001年至2007年，我们进行了一项研究，比较随机分配的开放标签灵活剂量治疗奥氮平（每天2.5至20毫克）或利培酮（1至6毫克）对16至40岁首次发作的受试者的有效性精神分裂症 (75%)、分裂情感性障碍 (17%) 或精神分裂样障碍 (8%)。最终研究样本由 112 名受试者组成（70% 为男性；平均年龄 23.3 (SD = 5.1) 岁）。大麻的终生滥用或依赖流行率最高（44%），其次是酒精（22%）和可卡因（4%）。 19 名患有大麻使用障碍（滥用或依赖；CUD）的受试者（39％）患有酒精使用障碍（滥用或依赖），7 名 CUD 受试者（14％）患有其他物质使用障碍（可卡因，n = 5；致幻剂，n = 2；阿片类药物，n=1；吸入剂，n=1)。 49.1%（95% CI：38.7%、59.6%）的患者符合缓解标准。然而，百分之三十（95％CI：13.5％，46.2％）的符合反应标准的受试者未能维持反应。治疗期间吸食大麻和饮酒显着相关，并且与未能维持反应相关。使用 我们的多变量模型的综合衡量标准，其中包括性别和药物分配、综合物质使用衡量标准（风险比=1.48；95% Cl=1.04、2.10；p<0.04）和病前社会功能不良（风险比=1.14；95） % Cl=1.02、1.28；p<0.03）是反应不稳定的显着预测因子。 我们还评估了奥氮平 (n=28) 对于首发大麻使用障碍患者是否比利培酮 (n=21) 更有效。奥氮平阳性症状的缓解率为 45%（95% CI：25%、65%），利培酮阳性症状的缓解率为 54%（95% Cl：29%、79%）。各组之间的生存曲线没有差异（对数秩检验；p < 0.95），治疗组之间在大麻使用（奥氮平组为 56%，利培酮组为 35%，p < 0.16）或酒精使用（奥氮平组为 52%，利培酮组为 40%）方面没有差异。利培酮组，p < 0.42）。因此，我们的结果表明（1）奥氮平和利培酮具有相似的作用 对患有大麻使用障碍和首次精神病发作的受试者的精神病症状和大麻或酒精使用的功效； (2) 治疗期间使用大麻和酒精会增加无法维持治疗的风险 回复。这些初步研究还证明了我们有能力使用第二代抗精神病药物来治疗急性发作期间和之后同时发生的物质使用障碍的精神病患者。