Optimal Dosing of Antipsychotic Drugs in Late Life

晚年抗精神病药物的最佳剂量

• 批准号: 8050586
• 负责人: david mamo
• 金额: $ 14.34万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050586
• 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）：新的独立研究者的申请寻求支持一项解决老年心理药理学重要问题的研究。精神分裂症是一种终身疾病，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剂量相反，老年患者的最低治疗剂量仍然未知。主要基于专家共识的临床指南建议在老年人的精神分裂症患者中使用较低的抗精神病药剂量，并且已经提倡减少剂量的较高剂量的患者。但是，这些准则基于有限的经验数据，这些数据没有考虑到与衰老相关的药物敏感性涉及的机械过程。先前在精神分裂症患者和中年生活患者中的正电子发射断层扫描（PET）研究已经在纹状体多巴胺D2/3受体中建立了抗精神病药药占用的治疗窗口，该窗口已成功地用于预测年轻患者的新和已建立的抗精神病药的临床有效剂量。为了在老年患者患有早期精神分裂症的老年患者中建立最低有效维持剂量的抗精神病药剂量，我们提出了一项使用前瞻性内部主体内设计的宠物研究。我们将确定利培酮D2/3占用率的估计值与40岁以上的40例患者保持45岁以前的患者，并以每天持续> 3.5 mg的稳定高剂量维持在单个抗精神病药（利培酮）上至少维持一年。他们将逐渐减少其基线剂量的40％至不低于建议剂量范围1.25-3.5 mg/天的目标剂量。 [11C] RACLOPRIDE PET扫描将在基线和减少剂量后完成。然后将遵循6个月的时间来确定临床结果。如果它们显示出临床恶化的迹象，则将其剂量滴定，直到恢复临床反应，然后进行第三次PET扫描以在临床有效剂量下建立药物结合。这项研究的结果将用于纳入种群药代动力学方法论的未来研究，将其收集的药物占用数据转化为老年患者的利培酮的个性化剂量。这可以在临床实践中使用标准实验室测定方法来确定在老年人的精神分裂症患者中维持治疗作用所需的最低有效抗精神病药剂量，这是一个具有重大公共健康意义的临床问题。 公共卫生相关性：精神分裂症是一种终身疾病，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的年龄较大，他们对药物副作用变得更加敏感，需要减少抗精神病药剂量。但是，由于尚不清楚老年患者的抗精神病药有效剂量最小，因此大多数剂量的剂量过高。使用正电子发射断层扫描（PET）研究抗精神病药与脑受体结合的程度将允许预测保持老年患者健康所需的最低有效剂量。