A Study on the Efficacy, Pharmacokinetics and Adverse Effects of Paliperidone ER
试验速览
- 阶段
- 4 期
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- Pharmacogenetic factor on response rate: BDNF
研究概览
简要总结
Background Paliperidone is an active metabolite of risperidone, both of which are antipsychotic agents for treatment of schizophrenia and related psychotic disorders. Pharmacogenetic studies have revealed that the efficacy and side effects of antipsychotic agents are related to polymorphisms of specific genes, however, there are just a few related studies on paliperidone. The current study aims to evaluate whether pharmacogenetic markers related to risperidone and genetic markers associated with schizophrenia have effects on the clinical effectiveness of paliperidone treatment. The study also uses changes of event-related potentials (ERP) as indices for clinical efficacy.
Methods It is a prospective, open-label, non-randomized and uncontrolled clinical trial to study the efficacy and side effects of 6-week paliperidone ER treatment for patients with schizophrenia or schizoaffective disorder. The first three weeks of treatment has to be inpatient treatment. In the first two weeks, participants will take 9 mg paliperidone ER daily. Then the dose of paliperidone can be adjusted to within the range of 6-12 mg per day. Efficacy indicators include symptom severity, global functioning, and ERP. Side effect indicators include common side effect evaluate, extrapyramidal symptoms, metabolic profiles, hormonal change, and bone metabolism indices. Participants will also receive examinations for blood drug concentration, genetic polymorphisms, and epigenetic markers.
详细描述
A. Background Schizophrenia is a heterogeneous disorder whose pathophysiology is not yet understood clearly. The treatment of schizophrenia remains suboptimal. Take risperidone for example, response rate of a patient is around only 60% to 80%. The second-generation or atypical antipsychotics are widely used. Apart from dopamine D2 receptor, they also target on 5-HT2 receptors and receptors of other neurotransmission systems. However, these second-generation antipsychotics still result in other common side effects. Therefore, finding predictors for clinical efficacy and side effect profile is a necessary task. Up to date, several genetic and non-genetic factors have been suggested related to the efficacy and side effects of antipsychotics. Noteworthy, pharmacokinetics as indicated by the temporal change of antipsychotics blood levels is usually overlooked. It might be a contributing factor why results from pharmacogenetic studies were usually difficult to be replicated.
Paliperidone (9-hydroxy-risperidone) is an active metabolite of the second-generation antipsychotics risperidone. Pharmacogenetic studies have found polymorphisms of some genes to be related to blood risperidone concentration, side effects and treatment response. Comparing to risperidone, paliperidone has less metabolic side effects, probable faster occurrence of efficacy, and better tolerance for subjects with hepatic insufficiency. Further, paliperidone is more sensitive to P-glycoprotein. There are just a few pharmacogenetic studies on paliperidone and P-glycoprotein. Therefore, one aim of this proposed study is to examine the pharmacogenetic effects on paliperidone extended release (paliperidone ER) for acute treatment of schizophrenia and schizoaffective disorder. The electrophysiological abnormalities as measured by event-related potentials (ERP) are characteristics features of several neuropsychological disorders. For schizophrenia, deficits in mismatch negativity, P50, and auditory steady state response have been frequently reported. Therefore, besides from clinical improvements, the investigators are also interested whether paliperidone treatment can alter the deficits in mismatch negativity, P50, and ASSR.
B. Study aims
- To study the association of candidate genes, which are related to pharmacodynamics and pharmacokinetics of risperidone, with paliperidone pharmacokinetics and clinical response
- To evaluate the impact of pharmacodynamics on the efficacy (including ERP change and cognitive function) and side effects of paliperidone ER for acute treatment of schizophrenia
- To evaluate whether the paliperidone pharmacodynamics is related to the metabolic, hormonal, and bone turnover profiles
- To evaluate whether paliperidone ER treatment will influence epigenetic markers
- To evaluate whether paliperidone ER treatment will influence event-related potentials and performance in neurocognitive tests
C. Study design It is a 6-week, prospective, open-label, uncontrolled and non-randomized trial of paliperidone ER for patients with schizophrenia or schizoaffective disorder in an acute episode. A total of 40 subjects will be recruited.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Paliperidone ER
Six-week paliperidone ER
干预措施: Paliperidone ER (Drug)
结局指标
主要结局
Pharmacogenetic factor on response rate: BDNF
时间窗: day 42
Whether dinucleotide repeat (GT)n of the BDNF gene is associated with the clinical response rate on day 42.
Pharmacogenetic factor on response rate: DRD3
时间窗: day 42
Whether Ser9Gly of the DRD3 gene is associated with the clinical response rate on day 42.
Pharmacogenetic factor on response rate: 5HTR2C
时间窗: day 42
Whether 995G/A of the 5HTR2C gene is associated with the clinical response rate on day 42.
Pharmacogenetic factor on response rate: COMT
时间窗: day 42
Whether val108/158Met of the COMT gene is associated with the clinical response rate on day 42.
Pharmacogenetic factor on response rate: RGS4
时间窗: day 42
Whether polymorphisms of RGS4 gene is associated with the clinical response rate on day 42.
Pharmacodynamics factor on response rate
时间窗: day 42
Whether the concentration of blood paliperidone is related to the clinical response rate on day 42. Clinical response is defined as achieving 50% or more improvement in terms of PANSS total score: \[(PANSS at evaluation - PANSS at baseline)/ (PANSS at baseline - 30)\]\*100% ≥ 50%
Pharmacogenetic factor on response rate: ABCB1
时间窗: day 42
Whether 1236C/T of the ABCB1 gene is associated with the clinical response rate on day 42.
Pharmacogenetic factor on response rate: DRD2
时间窗: day 42
Whether Ser311Cys of the DRD2 gene is associated with the clinical response rate on day 42.
Pharmacogenetic factor on response rate: 5HTR2A
时间窗: day 42
Whether 102T/C of the 5HTR2A gene is associated with the clinical response rate on day 42.
Pharmacogenetic factor on response rate: 5HTR6
时间窗: day 42
Whether 267T/C of the 5HTR6 gene is associated with the clinical response rate on day 42.
次要结局
- Change in executive function as measured by Wisconsin Card Sorting Test (WCST)(day 42)
- Change in performance on Trail-A test(day 42)
- Change in performance on Trail-B test(day 42)
- Effects on blood intact osteocalcin level(day 42)
- Effects on blood progesterone level(day 42)
- Change in person and social function(day 4, day 7, day14, day 28, and day 42)
- Change in performance on Digit Span(day 42)
- Severity of side effects(day 4, day 7, day14, day 28, day 42)
- Effects on blood HDL-cholesterol level(day 14 and day 42)
- Change in attention as measured by Continuous Performance Test (CPT)(day 42)
- Change in performance on verbal fluency test(day 42)
- Change in global impression of the patient(day 4, day 7, day14, day 28, and day 42)
- Change in auditory steady state response(day 42)
- Effects on blood leptin level(day 14 and day 42)
- Effects on blood oestradiol level(day 42)
- Effects on blood FSH level(day 42)
- Change in mismatch negativity(day 42)
- Change in P50(day 42)
- Change in performance on Arithmetic(day 42)
- Severity of extrapyramidal symptoms(day 4, day 7, day14, day 28, day 42)
- Effects on blood cholesterol level(day 14 and day 42)
- Effects on blood prolactin level(day 14 and day 42)
- Effects on adiponectin level(day 14 and day 42)
- Effects on blood phosphate level(day 42)
- Effects on blood bone-specific alkaline phosphatase level(day 42)
- Pharmacodynamics and pharmacogenetics factors on response rate(day 4, day 7, day14, day 28)
- Effects on blood glucose level(day 14 and day 42)
- Effects on blood triglyceride level(day 14 and day 42)
- Effects on blood alkaline phosphatase level(day 42)
- Effects on blood calcium level(day 42)
- Effects on blood LH level(day 42)
- Effects on blood testosterone level(day 42)
- Effects on blood uric acid level(day 14 and day 42)