盐酸哌甲酯控释片治疗注意缺陷多动障碍研究进展

注意缺陷多动障碍是一种儿童期常见的精神障碍，中枢兴奋剂如盐酸哌甲酯片是临床治疗此类障碍的一线药物。然而，由于盐酸哌甲酯片疗效持续时间较短，需要每天多次服药使治疗依从性不佳。盐酸哌甲酯控释片（专注达）是每天1次服用的渗透型控释片剂，成为治疗注意缺陷多动障碍的有价值药物。现综述其药动学、药理作用、剂型特点、临床疗效和安全性研究进展。     

Effects of methylphenidate on multiple components of attention in children with attention deficit hyperactivity disorder

Rationale Methylphenidate (MPH) has been shown to be effective in the treatment of attention deficits in children with attention deficit hyperactivity disorder (ADHD). Although a variety of studies have been performed, there is little available information as to which components of attentional functioning are disturbed in ADHD.Objectives The aim of the present study was to monitor the effect of MPH on various measures of attention in children with ADHD.Methods In a double-blind, placebo-controlled, crossover study, the attentional functioning of 58 children diagnosed with ADHD without psychiatric comorbidity was examined. Assessment of attention was performed on their usual MPH treatment and following withdrawal of the drug. Furthermore, the attentional performance of 58 healthy children was assessed. The test battery consisted of reaction time tasks, including measures of alertness, vigilance, divided attention, flexibility, and aspects of selective attention such as focused attention, inhibition, and integration of sensory information.Results In comparison to the test performance of healthy children, children with ADHD displayed impairments of vigilance, divided attention, flexibility, and aspects of selective attention including focused attention, inhibition, and integration of sensory information. Statistical comparison of attentional functioning of children with ADHD on and off MPH treatment revealed that the medication resulted in an improved task accuracy regarding vigilance, divided attention, inhibition, focused attention, integration of sensory information, and flexibility. Conclusion The present findings indicate that various aspects of attention are markedly impaired in children with ADHD. Treatment with MPH was accompanied by improvements in attention functions of small to moderate sizes. Although MPH-induced improvements were observed in a broad range of attention measures, children with ADHD who were on MPH treatment nevertheless displayed serious deficits in a number of components of attention.     

Attention deficit/hyperactivity disorder: characteristics, interventions and models

An epidemiological study of Attention Deficit/Hyperactivity Disorder (ADHD) suggests that the prevalence may be two to three times higher than the figure of 3-5% often cited. In addition, the data suggest that both underdiagnosis and overdiagnosis occur frequently. Rodent animal models of ADHD, like the Spontaneously Hypertensive Rat (SHR) and other rat models such as those with chemical and radiation-induced brain lesions and cerebellar stunting, and the Coloboma mouse model exhibit clear similarities with several aspects of the human disorder and should prove useful in studying specific traits. Operant behavioral tasks that model learning, short-term memory and simple discriminations are sensitive to ADHD and methylphenidate has been shown to normalize ADHD performance in a short-term memory task. Recent findings challenge not only the current postulate that response inhibition is a unique deficit in ADHD, but also the concepts of ADHD and its treatment, which presume intact perceptual abilities. Time perception deficits may account, in part, for the excessive variability in motor response times on speeded reaction time tasks, motor control problems and motor clumsiness associated with ADHD. The Multimodality Treatment Study of ADHD (MTA) provided data suggesting that pharmacological interventions that included systematic and frequent follow-up with parents and teachers, with or without psychosocial interventions, are superior to psychosocial interventions or standard community care alone. Additionally, the MTA was one of the first studies to demonstrate benefits of multimodal and pharmacological interventions lasting longer than 1 year. Imaging studies have demonstrated differences in brain areas in children with ADHD: anterior corpus callosum, right anterior white matter, and cerebellar volumes are all decreased in children with ADHD and there is less brain asymmetry in ADHD subjects. Additionally, functional imaging studies, coupled with pharmacological manipulations, suggest decreased blood flow and energy utilization in prefrontal cortex and striatum and the dysregulation of catecholamine systems in persons with ADHD.     

Anxiety and depression symptoms and response to methylphenidate in children with attention-deficit hyperactivity disorder and tic disorder

This study examined response to methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD) and chronic multiple tic disorder. The primary goal was to determine if children with anxiety or depression symptoms showed a less favorable response to treatment. Subjects were 38 prepubertal children who participated in an 8-week, double-blind, placebo-controlled, methylphenidate crossover evaluation. Treatment effects were assessed with direct observations of child behavior in public school and clinic settings; rating scales completed by parents, teachers, and clinicians; and laboratory analogue tasks. There was little evidence (group data) that children with anxiety or depression symptoms responded in a clinically different manner to methylphenidate than youngsters who did not exhibit these symptoms, particularly in school observations of the core features of ADHD. Seeming differences between children with and without comorbid anxiety or depression symptoms and drug response are likely explained by differences in pretreatment levels of negativistic behaviors (i.e., symptoms of oppositional defiant disorder or conduct disorder). Methylphenidate appears to be effective for the management of ADHD behaviors in children with mild to moderate anxiety or depression symptoms; nevertheless, much research remains to be performed in this area.     

盐酸哌甲酯和盐酸托莫西汀在注意缺陷多动障碍儿童中的用药保留率研究（英文）

本文回顾性分析了宁波市精神病院和宁波市妇女儿童医院2018年3月至2020年9月诊断为注意缺陷多动障碍儿童的用药处方,比较了盐酸哌甲酯和盐酸托莫西汀治疗时的药物保留率情况。应用医院合理用药管理系统筛选诊断为儿童注意缺陷多动障碍的处方。在调整性别、年龄、体重以及处方费用四个系数之后,应用Kaplan-Meier回归分析比较两种用药方案的处方保留率。盐酸哌甲酯组平均年龄为8.75±2.16岁,每月处方费用为327.37±146.64元;托莫西汀组平均年龄为8.33±1.73岁,每月处方费用为363.15±154.90元。两种药物方案的入组年龄和每月处方费用存在一定的差异(均P<0.01)。对比两种治疗药物的用药保留率,盐酸哌甲酯在18个月内的用药保留率均高于盐酸托莫西汀方案,经Kaplan-Meier回归分析,这种趋势具有显著意义(Tarone-Ware,卡方值=14.893,P<0.001),处方费用可能是影响药物保留率的一个因素。本研究发现,注意缺陷多动障碍儿童应用药物治疗时,保留率逐月下降;5个月后两者的保留率分别为52.20%和41.22%,远远低于指南的推荐水平。     

No elevated genomic damage in children and adolescents with attention deficit/hyperactivity disorder after methylphenidate therapy

Background and objective

Attention-deficit/hyperactivity disorder (ADHD) is the most frequent psychiatric disorder in children and adolescents and is often treated with methylphenidate (MPH), resulting in MPH exposure in more than 1% of all children in many countries. A 2005 report on cytogenetic effects in peripheral lymphocytes from 12 ADHD children treated for 3 months with MPH raised questions about its genetic toxicity and potential carcinogenicity. In 2007, we described no elevated micronucleus frequency in 21 children after 3 months of MPH-treatment; since the difference between the two studies could not be explained we now enlarged the overall sample size, and added a healthy control group, a new chronically treated group and positive control slides. Furthermore, micronuclei were analyzed in a second tissue, buccal mucosa.

Study participants

A healthy control group (23 individuals), a chronically MPH-treated (>12 months) group (21 patients), and a drug naïve group of ADHD-affected children (26 patients), which was analyzed again after 3 months (17 patients) and 6 months (11 patients), provided samples for analysis of micronucleated lymphocytes. With inclusion of 14 previously obtained blood samples, an overall group size of 31 patients was reached for the comparison of the 3 months observation time with before for micronucleated lymphocytes. For buccal mucosa cells, an additional inclusion of 10 more chronically treated patients (no lymphocytes donated) yielded sample numbers of 22 (healthy), 17 (chronically treated), 23 (ADHD drug naïve), 14 (3 months) and 11 (6 months).

Results

No significant alteration in genomic damage as seen as micronucleus frequency in peripheral lypmphocytes or buccal mucosa cells was detected after MPH treatment.

Conclusions

No indication for genomic damage induced by MPH was obtained in this study, as in our previous study. Together with our previous study, our overall number of MPH-treated patients is now 68 (30 chronically treated, 38 prospectively followed), plus 23 healthy controls. Ongoing studies in the USA, as well as continuation of recently published epidemiological cancer incidence analysis should provide additional reassurance for MPH-treated ADHD patients.     

精苓合剂联合哌甲酯治疗儿童注意缺陷多动障碍的疗效观察

目的 探讨精苓合剂联合哌甲酯治疗儿童注意缺陷多动障碍的临床疗效。方法 选取2020年1月—2022年12月苏州市立医院北区门诊诊治的88例注意缺陷多动障碍患儿,按随机数字表法将所有患者分为对照组和治疗组,每组各44例。对照组口服盐酸哌甲酯缓释片,初始剂量18 mg/次,疗效欠佳者增加剂量18 mg至每日剂量36 mg,1次/d,温开水整片送服。治疗组在对照组治疗基础上口服精苓合剂,6岁<患儿≤9岁,6～9 mL/次;9岁<患儿≤12岁,10 mL/次;均为2次/d。两组疗程均为12周。观察两组的临床疗效,比较两组核心症状好转时间及治疗前后Swanson, Nolan and Pelham父母评定量表（SNAP）-Ⅳ、Conners父母症状问卷（PSQ）、儿童困难问卷（QCD）、Weiss功能缺陷量表（父母版）（WFIRS-P）、长处和困难问卷（SDQ）、Achenbach儿童行为量表（CBCL）评分。结果 治疗后,治疗组总有效率是95.45%,较对照组的81.82%显著提高（P<0.05）。治疗后,治疗组多动、注意缺陷、冲动的好转时间均显著短于对照组（P<0.0...     

儿童注意缺陷、多动障碍的药物治疗

注意缺陷、多动障碍 (ADHD)是儿童期最为常见的一种心理行为疾病 ,药物治疗是ADHD主要的治疗方法之一。中枢兴奋药是治疗ADHD最常用的药物 ,作用快、疗效好 ,且不良反应较少。可乐定和抗抑郁剂也有较好的治疗效果 ,可乐定主要适用于伴抽动或情绪异常的ADHD病儿 ,而抗抑郁剂多用于伴抑郁或焦虑的ADHD病儿 ,但不良反应较明显。本文还介绍了近年来出现的一些治疗AD HD的新药     

Effect of methylphenidate on attention in children with attention deficit hyperactivity disorder (ADHD): ERP evidence.

Methylphenidate is the most common treatment for attention deficit hyperactivity disorder (ADHD) and has been shown to improve attention and behaviour. However, the precise nature of methylphenidate on specific aspects of attention at different dose levels remains unclear. We studied methylphenidate effects in ADHD from a neurophysiological perspective, recording event-related potentials (ERPs) during attention task performance in normal controls and children with ADHD under different dose conditions. Twenty children with ADHD and 20 age matched controls were assessed with a continuous performance task requiring subjects to identify repeating alphabetic characters. ERPs and behavioural measures were recorded and analyzed for trials where a correct response was made. The ADHD group was assessed off drug (baseline) and on placebo, low (0.28 mg/kg) and high (0.56 mg/kg) dose levels of methylphenidate. The results showed that the ADHD group at baseline was more impulsive and inattentive than controls and had shorter P2 and N2 latencies and longer P3 latencies. Low dose methylphenidate was associated with reduced impulsivity (fewer false alarms) and decreased P3 latencies, whereas the higher dose level was associated with reduced impulsivity and less inattention (more hits), as well as increased P2 and N2 latencies and decreased P3 latencies. Amplitudes were unaffected and there were no adverse effects of the higher dose for any of the children. These results suggest differential dosage effects and a dissociation between dose levels and aspects of processing.     

Norepinephrine transporter gene (SLC6A2) is involved with methylphenidate response in Korean children with attention deficit hyperactivity disorder

The purpose of this study was to investigate the association between the methylphenidate (MPH) response and the norepinephrine transporter (NET) gene polymorphisms in Korean children with attention deficit hyperactivity disorder (ADHD). One hundred and fourteen children with ADHD (mean age 9.08 ± 1.94 years) were recruited from a child psychiatric clinic in South Korea. The genomic DNA was extracted from the blood lymphocyte. Patients were administered MPH for 8 weeks. Good response was defined as a decrease of more than 50% from the baseline ADHD rating scale-IV scores or Clinical Global Impression-Severity score was 1 or 2 after treatment. We compared the MPH response according to the genotype of G1287A of the NET gene (SLC6A2). In patients with G/G genotype, 41 patients (71.9%) showed good response and 16 patients (28.1%) showed poor response when it was measured by the ADHD rating scale-IV. In comparison, 23 patients (46.0%) with G/A genotype and four patients (57.1%) with A/A genotype showed good response (P=0.018, by the Fisher's exact test). When we compared the response of MPH between patients with G/G genotype and those without G/G genotype, 41 patients (71.9%) with G/G genotype showed good response, whereas only 27 patients (46.4%) without G/G genotype showed good response. [Pearson χ2 = 7.143, degrees of freedom (df)=1, P=0.008]. Our study found a significant association between the G1287A genotype of the NET gene and the MPH response in Korean children with ADHD. These findings support the significant role of the NET gene in ADHD treatment with MPH.