Optimal Dosing of Antipsychotic Drugs in Late Life

晚年抗精神病药物的最佳剂量

• 批准号: 8213776
• 负责人: david mamo
• 金额: $ 14.39万
• 依托单位: CENTRE FOR ADDICTION AND MENTAL HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-24 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213776
• 关键词: Accounting; Address; Adult; Adverse effects; Advocate; Age; Aging; Am 80; Antipsychotic Agents; Binding; Biological Assay; Brain; Chronic Schizophrenia; Clinical; Clinical Trials; Consensus; Corpus striatum structure; Data; Deterioration; Dopamine; Dose; Drug Kinetics; Drug effect disorder; Elderly; Ethics; Future; Goals; Guidelines; Impaired cognition; Knowledge; Laboratories; Life; Link; Maintenance; Measures; Methodology; Modeling; Monitor; Morbidity - disease rate; Outcome; Patients; Pharmaceutical Preparations; Plasma; Population; Positron-Emission Tomography; Process; Psychopharmacology; Psychotic Disorders; Public Health; Raclopride; Recruitment Activity; Relapse; Reporting; Research Personnel; Risk; Risperidone; Sampling; Scanning; Schizoaffective Disorders; Schizophrenia; Subgroup; Symptoms; Therapeutic; Therapeutic Effect; Titrations; Tort; Toxic effect; Translating; abnormal involuntary movement; base; clinical practice; design; drug sensitivity; early onset; middle age; mortality; older patient; prevent; prospective; public health relevance; receptor; receptor density; response; young adult

DESCRIPTION (provided by applicant): This application from a new independent investigator seeks support for a study that addresses an important problem in geriatric psychopharmacology. Schizophrenia is a life-long illness requiring daily treatment with antipsychotic medication. In contrast to antipsychotic dosing in younger patients, the minimal therapeutic dose in older patients remains unknown. Clinical guidelines based primarily on expert consensus have recommended the use of lower antipsychotic doses in older patients with schizophrenia, and dose reduction has been advocated for patients stable on higher doses. However these guidelines are based on limited empirical data that do not take into account mechanistic processes involved in drug sensitivity associated with aging. Previous Positron Emission Tomography (PET) studies in young and mid-life patients with schizophrenia have established a therapeutic window of antipsychotic drug occupancy at striatal dopamine D2/3 receptors which has been successfully employed in predicting the clinically effective doses for new and established antipsychotic drugs in younger patients. Towards the goal of establishing the lowest effective maintenance dose of antipsychotic medication in older patients with early-onset schizophrenia, we propose a PET study using a prospective within-subject design. We will determine an estimate of risperidone D2/3 occupancy associated with maintenance of response in 40 patients 60 years and older with onset of schizophrenia before the age of 45 years and maintained on a single antipsychotic (risperidone) at a steady high dose of > 3.5 mg per day for at least one year. They will undergo a gradual dose reduction up to 40% of their baseline dose to a target dose not lower than the recommended dose range of 1.25 - 3.5 mg/day. A [11C]raclopride PET scan will be completed at baseline and after dose reduction. They will then be followed for 6 months to determine clinical outcome. If they show signs of clinical deterioration, they will have their dose titrated up until clinical response is restored, and then undergo a third PET scan to establish the drug binding at the clinically effective dose. The results of this study will be used in future studies incorporating population pharmacokinetic methodology, translating the drug occupancy data collected in this to individualized dosing of risperidone for older patients with schizophrenia. This can be achieved in clinical practice using little more than standard laboratory assays to determine the lowest effective antipsychotic dose necessary for maintenance of therapeutic effect in older patients with schizophrenia, a clinical question of major public health significance. PUBLIC HEALTH RELEVANCE: Schizophrenia is a life-long condition that requires long-term treatment with antipsychotic medications to prevent relapse of psychotic symptoms. As patients with schizophrenia become older, they become more sensitive to medication side effects and require a reduction of antipsychotic dose. However, since the minimal effective dose of antipsychotic medications in older patients is not known, most of them are treated with doses that are too high. Studying the extent of antipsychotic drug binding to brain receptors using positron emission tomography (PET) will allow for the prediction of the lowest effective dose required to maintain wellness in older patients.

描述（由申请人提供）：一位新的独立研究者提出的这份申请寻求对一项研究的支持，该研究解决了老年精神药理学的一个重要问题。精神分裂症是一种终生疾病，需要每天使用抗精神病药物治疗。与年轻患者的抗精神病药物剂量相比，老年患者的最小治疗剂量仍然未知。主要基于专家共识的临床指南建议对老年精神分裂症患者使用较低的抗精神病药物剂量，并主张对高剂量治疗稳定的患者减少剂量。然而，这些指南基于有限的经验数据，没有考虑与衰老相关的药物敏感性所涉及的机械过程。先前对年轻和中年精神分裂症患者的正电子发射断层扫描 (PET) 研究已经建立了纹状体多巴胺 D2/3 受体上抗精神病药物占据的治疗窗口，该窗口已成功用于预测新的和已建立的抗精神病药物的临床有效剂量在年轻患者中。为了确定老年早发性精神分裂症患者抗精神病药物的最低有效维持剂量，我们提出了一项采用前瞻性受试者内设计的 PET 研究。我们将确定 40 名 60 岁及以上、45 岁之前精神分裂症患者的反应维持相关的利培酮 D2/3 占用率估计值，并以 > 3.5 的稳定高剂量维持单一抗精神病药（利培酮）。每天毫克，持续至少一年。他们将逐渐将剂量减少至基线剂量的 40%，直至目标剂量不低于推荐剂量范围 1.25 - 3.5 毫克/天。 [11C]雷氯必利 PET 扫描将在基线时和剂量减少后完成。然后他们将被跟踪 6 个月以确定临床结果。如果他们出现临床恶化的迹象，他们将逐步调整剂量，直到临床反应恢复，然后进行第三次 PET 扫描以确定临床有效剂量的药物结合。这项研究的结果将用于未来结合群体药代动力学方法的研究，将本研究中收集的药物占用数据转化为老年精神分裂症患者的利培酮个体化剂量。这可以在临床实践中实现，只需使用标准实验室测定来确定维持老年精神分裂症患者治疗效果所需的最低有效抗精神病药物剂量，这是一个具有重大公共卫生意义的临床问题。 公共卫生相关性：精神分裂症是一种终生疾病，需要长期使用抗精神病药物治疗以防止精神病症状复发。随着精神分裂症患者年龄的增长，他们对药物副作用变得更加敏感，需要减少抗精神病药物的剂量。然而，由于老年患者抗精神病药物的最低有效剂量尚不清楚，因此大多数患者接受的治疗剂量过高。使用正电子发射断层扫描（PET）研究抗精神病药物与大脑受体的结合程度将有助于预测老年患者维持健康所需的最低有效剂量。