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。     

Switching from neurostimulant therapy to atomoxetine in children and adolescents with attention-deficit hyperactivity disorder : clinical approaches and review of current available evidence

This review provides practical information on and clinical reasons for switching children and young people with attention-deficit hyperactivity disorder (ADHD) from neurostimulants to atomoxetine, detailing currently available evidence, and switching options. The issue is of particular relevance following recent guidance from the National Institute for Health and Clinical Excellence and European ADHD guidelines endorsing the use of atomoxetine, along with the stimulants methylphenidate and dexamphetamine, in the management of ADHD in children and adolescents in the UK. The selective norepinephrine (noradrenaline) reuptake inhibitor, atomoxetine, is a non-stimulant drug licensed for the treatment of ADHD in children and adolescents, and in adults who have shown a response in childhood. Following the once-daily morning dose, its therapeutic effects extend through the waking hours, into late evening, and in some patients, through to early the next morning. Atomoxetine may be considered for patients who are unresponsive or incompletely responsive to stimulant treatment, have co-morbid conditions (e.g. tics, anxiety, depression), and have sleep disturbances or eating problems, for patients in whom stimulants are poorly tolerated, and for situations where there is potential for drug abuse or diversion. Atomoxetine has been shown to be effective in relapse prevention and there is suggestion that atomoxetine may have a positive effect on global functioning; specifically health-related quality of life, self-esteem, and social and family functioning. According to one study, approximately 50% of non-responders to methylphenidate will respond to atomoxetine therapy and approximately 75% of responders to methylphenidate will also respond to atomoxetine. Atomoxetine may be initiated by a schedule of dose increases and cross-tapering with methylphenidate. A slow titration schedule with divided doses minimizes the impact of adverse events within the first several weeks of treatment. Atomoxetine may be co-administered with methylphenidate during the switching period without undue concern for adverse events, such as cardiovascular effects (although monitoring of blood pressure and heart rate is necessary). Atomoxetine may be discontinued abruptly and patients may miss the occasional dose without rebound effects or discontinuation syndrome. A trial period of at least 6-8 weeks, perhaps longer, is recommended before evaluation of the overall tolerability and efficacy of atomoxetine. We conclude that patients with ADHD can be switched from neurostimulants, specifically methylphenidate, to atomoxetine, and may benefit from symptom improvement.     

Blockade of noradrenaline re-uptake sites improves accuracy and impulse control in rats performing a five-choice serial reaction time tasks

Rationale  

Atomoxetine, reboxetine and methylphenidate all act at the noradrenaline transporter (NAT) and atomoxetine and methylphenidate are licensed for the treatment of ADHD. The five-choice serial reaction time task (5CSRTT) provides a valid model to study attention and impulsivity in rodents. Studies using this task have largely failed to demonstrate improvements in attention with atomoxetine and methylphenidate and reboxetine has not been investigated previously.     

Long‐Term Pharmacotherapy of Adults With Attention Deficit Hyperactivity Disorder: A Literature Review and Clinical Study

This MiniReview reports and discusses the main findings of the author's thesis including a literature study of long‐term pharmacological treatment of adults with attention deficit hyperactivity disorder (ADHD), and a clinical study of 1‐year medication. Electronic databases were systematically reviewed for original studies on pharmacotherapy of the defined duration, 24 weeks or more. Although few trials were found with limitations such as excluding comorbidities, treatment with stimulants and atomoxetine was reported tolerated and effective compared to non‐treatment. The clinical study of the thesis was conducted on 250 medication‐naïve patients with ADHD referred to a specialized outpatient clinic. Comorbid psychiatric disorders were diagnosed among 75% of the patients. About 56% had not completed secondary school, and 51% had been unable to work the preceding year. Persisting inattentive symptoms and comorbid mental disorders in adulthood were related to long‐term work disability. In the prospective observational study of the thesis, patients were treated with methylphenidate as first‐line drug and atomoxetine or dexamphetamine as second‐line drugs, according to current treatment guidelines. At 12‐month follow‐up, 232 patients completed evaluation and 70% persisted on medication. About 80% of these used methylphenidate. Sustained improvement of symptoms and functioning was related to continued medication. Comorbid mental disorders and side effects were related to lower effectiveness and adherence, and 12% stopped medication due to side effects. Summing up the MiniReview, treatment with stimulants and atomoxetine of adults with ADHD has long‐term beneficial effects and is tolerated but more longitudinal studies should be performed. With stated limitations, the findings of the thesis should contribute to a relevant guidance for clinical practice.     

Atomoxetine, a novel treatment for attention-deficit-hyperactivity disorder

Atomoxetine is the first nonstimulant drug approved by the United States Food and Drug Administration (FDA) for the treatment of attention-deficit-hyperactivity disorder (ADHD), and the only agent approved by the FDA for the treatment of ADHD in adults. Atomoxetine is a norepinephrine transport inhibitor that acts almost exclusively on the noradrenergic pathway. Its mechanism of action in the control and maintenance of ADHD symptoms is thought to be through the highly specific presynaptic inhibition of norepinephrine. Clinical trials to evaluate the short-term effects of atomoxetine in children and adults have shown that atomoxetine is effective in maintaining control of ADHD. Likewise, long-term trials have determined that atomoxetine is effective in preventing relapse of ADHD symptoms without an increase in adverse effects. A comparative trial of atomoxetine with methylphenidate in school-aged children indicated similar safety and efficacy without the abuse liability associated with some psychostimulants. The most commonly reported adverse effects in children and adolescents are dyspepsia, nausea, vomiting, decreased appetite, and weight loss. The rates of adverse events in the trials were similar for both the once- and twice-daily dosing regimens. The discontinuation rate was 3.5% in patients treated with atomoxetine versus 1.4% for placebo and appeared to be dose dependent, wit a higher percentage of discontinuation at dosages greater than 1.5 mg/kg/day. In clinical trials involving adults, the emergence of clinically significant or intolerable adverse events was low. The most common adverse events in adults were dry mouth, insomnia, nausea, decreased appetite, constipation, urinary retention or difficulties with micturition, erectile disturbance, dysmenorrhea, dizziness, and decreased libido. Sexual dysfunction occurred in approximately 2% of patients treated with atomoxetine. Atomoxetine should be used with caution in patients who have hypertension or any significant cardiovascular disorder. Overall, atomoxetine therapy in patient with ADHD appears to be effective in controlling symptoms and maintaining remission, with the advantages being comparable efficacy with that of methylphenidate, a favorable safety profile, and non-controlled substance status. Additional long-term studies are needed to determine its continued efficacy for those who require lifelong treatment, and comparative trials against other stimulant and nonstimulant agents.     

Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: a prospective, placebo-controlled assessment

Drugs that affect neurotransmitter release can induce changes in neuroregulation during chronic administration. Thus, in addition to recurrence of symptoms of the illness, discontinuation of treatment can be associated with clinical signs and symptoms related to these changes. Atomoxetine, a new drug approved in the United States for treatment of attention deficit/hyperactivity disorder (ADHD), is associated with blockade of the presynaptic norepinephrine transporter. Because treatment of ADHD typically involves chronic treatment, the potential for production of a discontinuation syndrome as well as recurrence of symptoms upon drug discontinuation were assessed as part of the clinical development process. The effects of discontinuation of atomoxetine were assessed in children and adults with ADHD following 9 to 10 weeks of continuous therapy in 4 large studies. Symptoms of ADHD worsened following drug discontinuation but did not return to pretreatment levels. The incidence of discontinuation-emergent adverse events was low and there were no statistically significant differences between the patients abruptly discontinuing from atomoxetine and those continuing on placebo. Discontinuation of atomoxetine did not result in the development of an acute discontinuation syndrome and was well tolerated. It appears that atomoxetine may be discontinued without risk for symptom rebound or discontinuation-emergent adverse effects. Tapering of doses is not necessary when atomoxetine is discontinued.     

Abuse liability assessment of atomoxetine in a drug-abusing population

BACKGROUND: Atomoxetine is a non-amphetamine medication approved to treat ADHD in children, adolescents, and adults. Previous studies demonstrated low abuse potential for atomoxetine in recreational drug users. This study assessed the abuse potential of atomoxetine in stimulant-preferring drug abusers compared to methylphenidate and phentermine as positive controls and desipramine and placebo as negative controls. METHODS: Forty male and female, 32-53 years old stimulant-preferring drug abusers completed this balanced Latin-square designed study. Subjects received acute, double-blind doses of placebo, desipramine (100 and 200 mg), methylphenidate (90 mg), phentermine (60 mg), and atomoxetine (45, 90, and 180 mg). Subjective and physiological effects were collected for 24 h following each drug treatment. RESULTS: Methylphenidate and phentermine were liked significantly more than placebo, atomoxetine, or desipramine. No atomoxetine dose was liked significantly more than placebo and liking scores for atomoxetine were similar to, or significantly lower than, desipramine, as assessed by the Drug Rating Questionnaire-Subject. While atomoxetine 45 and 180 mg did not significantly change any Addiction Research Center Inventory (ARCI) scores, atomoxetine 90 mg significantly increased A and BG stimulant scores of the ARCI and both methylphenidate and phentermine produced greater A and BG increases than any atomoxetine dose and also increased MBG (euphoria) scores relative to placebo. CONCLUSIONS: Atomoxetine has significantly less abuse liability than methylphenidate or phentermine and no greater abuse liability than desipramine.     

Pharmacogenetics of response to methylphenidate in adult patients with Attention-Deficit/Hyperactivity Disorder (ADHD): A systematic review

Methylphenidate (MPH) is a first line option in the psychopharmacologic treatment of adults with Attention-Deficit/Hyperactivity Disorder (ADHD). However, there is a considerable proportion of adult patients who do not respond to treatment with MPH or discontinue drug therapy. Since effects of genetic variants in the response to MPH treatment might explain these negative outcomes, we conducted an electronic systematic search of MEDLINE-indexed literature looking for articles containing information about pharmacogenetics of ADHD in adults published until January, 2012. The keywords used were ‘ADHD’, ‘Attention-Deficit/Hyperactivity Disorder’ and ‘gene’ in combination with methylphenidate, amphetamine or atomoxetine. Only 5 pharmacogenetic studies on adult ADHD met inclusion criteria. The results evidenced that most findings obtained so far are negative, and all studies focused on MPH response. There is only one positive result, for a polymorphism at the dopamine transporter gene (DAT1) gene. The current state of the art in adult ADHD implies that pharmacogenetic tests are far from routine clinical practice. However, the integration of these studies with neuroimaging and neuropsychological tests may help to understand mechanisms of drug action and the pathophysiology of ADHD.     

托莫西汀与哌甲酯治疗注意缺陷多动障碍患儿的疗效和安全性比较

目的:比较托莫西汀与哌甲酯治疗注意缺陷多动障碍患儿的疗效和安全性。方法:选择我院收治的注意缺陷多动障碍患儿共52例,随机分为托莫西汀组与哌甲酯组各26例,治疗结束后观察两组患儿的治疗有效率、ADHDRS-IV-Parent:Inv评分以及CPRS-R:S评分。结果:托莫西汀组与哌甲酯组的治疗有效率相近。治疗后托莫西汀组与哌甲酯组的ADHDRS-IV-Parent:Inv各项评分均明显下降,与治疗前比较差异均有统计学意义(P<0.05)。治疗后托莫西汀组与哌甲酯组CPRS-R:S评分的分数均明显下降,与治疗前比较差异均有统计学意义(P<0.05)。托莫西汀组的多动分变化值大于哌甲酯组,差异有统计学意义(P<0.05),两组患儿在治疗过程中均未发现严重的药物不良反应。结论:托莫西汀的疗效与哌甲酯相近,都具有良好的安全性,值得临床推广。     

One-year prospective follow-up of pharmacological treatment in children with attention-deficit/hyperactivity disorder

Objectives  

To delineate the safety and tolerability profile of methylphenidate and atomoxetine in children and adolescents with attention deficit hyperactivity disorder (ADHD) monitored for more than 1 year.     

Methylphenidate and atomoxetine normalise fronto-parietal underactivation during sustained attention in ADHD adolescents

Problems with sustained attention are a key clinical feature of Attention Deficit/Hyperactivity Disorder (ADHD) which also manifests in poor performance and abnormal fronto-striato-parietal activation during sustained attention. Methylphenidate and atomoxetine improve attention functions and upregulate abnormal fronto-cortical activation during executive function tasks in ADHD patients. Despite this, no functional Magnetic Resonance Imaging (fMRI) study has compared the effects of methylphenidate and atomoxetine on the neurofunctional substrates of sustained attention in ADHD. This randomised, double-blind, placebo-controlled, cross-over study investigated the comparative normalisation effects of methylphenidate and atomoxetine on fMRI correlates and performance in 14 ADHD adolescents relative to 27 age-matched healthy controls during a parametric sustained attention/vigilance task with progressively increasing load of sustained attention. ADHD patients were scanned three times under a single clinical dose of either methylphenidate, atomoxetine, or placebo in pseudo-randomised order. Healthy controls were scanned once and compared to patients under each drug condition to test for potential drug-normalisation effects. Relative to controls, ADHD boys under placebo were impaired in performance and had underactivation in predominantly right-hemispheric fronto-parietal, and striato-thalamic regions. Both drugs normalised all underactivations, while only methylphenidate improved performance deficits. Within patients, methylphenidate had a drug-specific effect of upregulating left ventrolateral prefrontal/superior temporal activation relative to placebo and atomoxetine, while both drugs increased activation of right middle/superior temporal cortex, posterior cingulate, and precuneus relative to placebo. The study shows shared normalisation effects of methylphenidate and atomoxetine on fronto-striato-thalamo-parietal dysfunction in ADHD during sustained attention but a drug-specific upregulation effects of methylphenidate on ventral fronto-temporal regions.     

Treatment discontinuation with methylphenidate in adults with attention deficit hyperactivity disorder: a meta-analysis of randomized clinical trials

Background

Attention deficit hyperactivity disorder (ADHD) in adulthood is increasingly diagnosed and treated. Methylphenidate is frequently advocated as a first-line pharmacological treatment.

Purpose

The aim of our study was to compare all-cause discontinuation rate of methylphenidate and its pharmaceutical presentations with placebo in adults with ADHD.

Methods

This was a systematic review and meta-analysis of randomized controlled trials comparing methylphenidate with placebo in adults with ADHD. All-cause treatment discontinuation was the primary endpoint. The efficacy in reducing ADHD symptoms and safety were the secondary endpoints.

Results

Twelve studies (2,496 patients) met the inclusion criteria. Four racemic methylphenidate and one dexmethylphenidate presentations were investigated. The rate of all-cause treatment discontinuation was greater with methylphenidate than with placebo, but this difference was not statistically significant [odds ratio (OR) 1.19, 95 % confidence interval (95 % CI) 0.82–1.74, P?=?0.37, I ²?=?64 %] This finding reached the conventional threshold of statistical significance after one outlier study was excluded (OR?1.44, 95 % CI 1.14–1.82, P?=?0.002, I ²?=?0). Methylphenidate was more efficacious than placebo for reducing ADHD symptoms and it was associated with a higher proportion of patients dropping out due to adverse effects.

Conclusions

Despite reducing ADHD symptoms, methylphenidate showed no advantage over placebo in terms of treatment discontinuation. More attention should be given in the future to the endpoint “all-cause treatment discontinuation” when making regulatory decisions and developing clinical guidelines involving the treatment of ADHD in adulthood.