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/兴奋剂使用有关。目前，没有针对与急性发作以外的药物使用相关的精神病患者的药理治疗指南，具体来说，没有评估长期的研究 第二代抗精神病药在该人群中的功效。在第二代抗精神病药中，由于以下原因，阿立哌唑可能是对这些受试者进行长期治疗的最佳选择：1）其抗精神病药疗效类似于其他第二代抗精神病药。 2）这是治疗在上瘾行为中发现多巴胺能功能障碍的主要候选者。它是美国唯一获得批准的D2部分激动剂，并且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，在多巴胺贫民环境中充当D2激动剂 （Travis等，2005）。来自动物和人类研究的融合证据表明，多巴胺能脑奖励回路的功能障碍参与药物成瘾的各个方面，包括在毒化过程中加强对药物的反应，渴望期间的激活和戒断期间的失活（kalivas（kalivas） 2002）。有人提出，多巴胺受体和多巴胺释放的降低可能会引起奖励回路对自然奖励刺激的敏感性（Noble等，1991; Volkow etal。2002）。在小鼠中，阿立哌唑拮抗乙醇，苯丙胺和可卡因诱导的运动刺激， 这表明阿立哌唑降低了药物诱导的高巴掌能（Jerihag 2008； Leite等，2008）。 在人类受试者中，阿立哌唑可减轻D-苯丙胺的歧视性刺激，心血管效应和主体效应（Lile等，2005； Stoops等，2006）。 3）几项研究表明，它可以减少没有精神病和精神病的受试者中的物质使用。 Martinotti等人（2007年）报道了13个用柔性剂量的阿哌他唑治疗的13个排毒的酒精依赖性受试者16周。所有受试者的渴望降低和SCL-90一般严重程度指数的降低，在研究期间有6例保持清醒的患者。 Anton等人（2008年）对295名酒精依赖受试者进行了为期12周的双盲安慰剂对照研究。与安慰剂上的受试者相比，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，整体效果较少 研究结束时酒精依赖的严重程度。 Kranzler等人（2008年）发现，阿立哌唑降低了18名健康受试者酒精的欣快作用。 Deseilles等人（2008年）报告说，用阿立哌唑治疗的一个非精神病患者中大麻使用的使用降低。 Beresford等人（2005年）在10名精神分裂症和共抵销可卡因依赖和酗酒的受试者中进行了为期8周的开放标签试验。六名受试者完成了该试验，并减少了可卡因的尿液测试，并降低了对可卡因和酒精的渴望。在Brown等人（2005年）中，将20名抗精神病药物治疗的受试者切换为12-- 一周的开放标签Aripiprazole。酒精依赖的受试者（n = 17）的花费下降了酒精和渴望。与可卡因相关疾病的受试者（n = 9）的渴望减少了。 5）Aripiprazole具有抗抑郁药的特性，并被FDA批准为重度抑郁症的增强疗法（Berman等，2007）。患有精神疾病和同时发生物质使用障碍的受试者容易发生抗衰变，情绪平坦和情绪低落，增加了对药物滥用，低依从性率和较差的临床结果的复发风险。因此，我们假设Aripiprazole将改善与药物使用相关的精神病发作受试者的情绪。 5）它具有相对有利的副作用特征，包括与其他非典型人相比，代谢综合征，催乳素升高和QTC间隔延长的风险较小（Chen等，2007； El-Sayeh等，2006）。 初步数据 从2001年到2007年，我们进行了一项研究，比较了与奥氮平（每天2.5至20毫克）随机分配的开放标签柔性剂量治疗的有效性，或者在16至40岁的受试者中与Schizophrenia（75％），Schizoprandrenry（17％），或Schizoplrenren Righander（17％）的16至40岁受试者（1至6 mg）的有效性（1至6 mg）（1至6 mg） （8％）。最终的研究样本包括112名受试者（70％男性；平均年龄23.3（SD = 5.1）年）。终身滥用或依赖性的患病率最高（44％），其次是酒精（22％）和可卡因（4％）。患有大麻使用障碍（滥用或依赖）（39％）的十九个受试者患有酒精使用障碍（滥用或依赖性），七个CUD受试者（14％）患有其他药物使用障碍（可卡因，n = 5;幻觉剂，n = 2; n = 2; opiates，opiates，opiates，n = 1; n = 1; inhalants n = 1），n = 1）。 49.1％（95％CL：38.7％，59.6％）符合反应标准。但是，满足反应标准的受试者中有30％（95％CL：13.5％，46.2％）未能维持反应。治疗过程中使用和饮酒的使用显着相关，并且与未能保持反应有关。使用 包括性别和药物分配在内的多元模型的综合度量，复合物质使用度量（危险比= 1.48; 95％Cl = 1.04，2.10; p <0.04）和较差的前社会功能（危险比= 1.14; 95％; 95％cl = 1.02，1.28; p <0.03; p <0.03; p <0.03; p <0.03; p <0.03）都是重要的。 我们还评估了奥氮平（n = 28）是否比利培酮（n = 21）在大麻使用障碍的第一期患者中更有效。阳性症状的反应率为45％（95％CL：25％，65％），甲氮平（54％）（95％CL：29％，79％）的利培酮。组之间的生存曲线没有差异（对数秩检验； P <0.95）且治疗组之间使用大麻的治疗组没有差异（奥氮平组为56％，在利培酮组中为35％，p <0.16）或饮酒（在奥氮平组中为52％，在瑞氏酮组中为40％，risperidone组为40％，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 精神病症状和大麻或酒精使用的功效对大麻使用障碍的受试者和精神病的第一集； （2）治疗期间的大麻和饮酒会增加不维持的风险 回复。这些初步研究还表明，在急性发作期间和之后，我们使用第二代抗精神病药治疗精神病患者的能力。