Long-term changes in management following n-of-1 trials of stimulants in attention-deficit/hyperactivity disorder

Objective Our objective was to evaluate the long-term impact of n-of-1 trials—within-patient randomised, double-blind, cross-over comparisons of stimulant versus placebo or stimulant—on ADHD management. Methods Telephone surveys at 3, 6 and 12 months. Main outcome measures included (1) changes in treatment before and after the n-of-1 trial, (2) congruence of management at follow-up with trial result, (3) reasons for any non-congruence, and (4) persistence of the joint patient-doctor decision over 12 months. Patients were children with clinically diagnosed ADHD, aged 5–16 years. Results A total of 76 patients were followed up; 12 months’ data were available for 67 (88%). Management changed from baseline for 46, 48 and 51% at 3, 6 and 12 months respectively. Most responders, 21/37 (57%), remained on the same stimulant at 12 months, compared to 9/24 (37%) non-responders. Of the remaining non-responders, 15/24 (62%) either switched (2/24, 8%) or ceased stimulants (13/24, 54%). The rate of congruence with the test result was 45/65 (69%) at 3 months, 44/67 (66%) at 6 months and 40/67 (60%) at 12 months. Persistence with the post-trial decision over 12 months was high (79–85%) whether the decision was to continue or to cease stimulants. Conclusions Although not conclusive because there was no control group, our results suggest that n-of-1 trials may improve rational treatment of ADHD.     

Atomoxetine hydrochloride in the treatment of children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: A placebo-controlled Italian study

ObjectiveThe primary aim of this study was to assess the efficacy of atomoxetine in improving ADHD and ODD symptoms in paediatric patients with ADHD and comorbid oppositional defiant disorder (ODD), non-responders to previous psychological intervention with parent support.MethodsThis was a multicentre, randomised, placebo-controlled trial conducted in patients aged 6–15 years, with ADHD and ODD diagnosed according to the DSM-IV criteria by a structured clinical interview (K-SADS-PL). Only subjects who are non-responders to a 6-week standardized parent training were randomised to atomoxetine (up to 1.2 mg/kg/day) or placebo (in a 3:1 ratio) for the following 8-week double blind phase.ResultsOnly 2 of the 156 patients enrolled for the parent support phase (92.9% of males; mean age: 9.9 years), improved after the parent training program; 139 patients were randomised for entering in the study and 137 were eligible for efficacy analysis. At the end of the randomised double blind phase, the mean changes in the Swanson, Nolan and Pelham Rating Scale-Revised (SNAP-IV) ADHD subscale were − 8.1 ± 9.2 and − 2.0 ± 4.7, respectively in the atomoxetine and in the placebo group (p < 0.001 between groups); changes in the ODD subscale were − 2.7 ± 4.1 and − 0.3 ± 2.6, respectively in the two groups (p = 0.001 between groups). The CGI-ADHD-S score decreased in the atomoxetine group (median change at endpoint: − 1.0) compared to no changes in the placebo group (p < 0.001 between groups). Statistically significant differences between groups, in favour of atomoxetine, were found in the CHIP-CE scores for risk avoidance domain, emotional comfort and individual risk avoidance subdomains. An improvement in all the subscales of Conners Parents (CPRS-R:S) and Teacher (CTRS-R:S) subscales was observed with atomoxetine, except in the cognitive problems subscale in the CTRS-R:S. Only 3 patients treated with atomoxetine discontinued the study due to adverse events. No clinically significant changes of body weight, height and vital signs were observed in both groups.ConclusionsTreatment with atomoxetine of children and adolescents with ADHD and ODD, who did not initially respond to parental support, was associated with improvements in symptoms of ADHD and ODD, and general health status. Atomoxetine was well tolerated.     

Burden of illness and health care resource utilization in adult psychiatric outpatients with attention-deficit/hyperactivity disorder in Europe

Objective: To assess the burden of illness and health care resource utilization of adult nonpsychotic psychiatric outpatients with attention-deficit/hyperactivity disorder (ADHD) in Europe.

Methods: This was a multicountry, cross-sectional, observational study where unselected routine patients from clinical psychiatric outpatient settings were screened and assessed for ADHD. Patients were evaluated using the Clinical Global Impressions of Severity (CGI-S) scale, the Sheehan Disability Scale (SDS), and the EuroQol-5 Dimensions questionnaire. Data on comorbidities, functional impairment, and health care resource utilization were captured.

Results: The study enrolled 2284 patients, of whom 1986 completed the study. The prevalence of ADHD was 17.4%, of whom 46.0% had a previous ADHD diagnosis. Patients with ADHD had a high clinical burden with psychiatric comorbidities, especially depression (43.0%) and anxiety disorders (36.4%). Substance abuse (9.2% vs. 3.4%) and alcohol abuse (10.3% vs. 5.2%) were more common in the ADHD cohort vs. the non-ADHD cohort. Only 11.5% of the patients with ADHD had no other psychiatric disorder. Various measures indicated a significantly poorer level of functioning for patients with ADHD than without ADHD, as indicated by higher scores for CGI-S (3.8 vs. 3.3) and SDS (18.9 vs. 11.6) and higher percentages of debt (35.5% vs. 24.3%) and criminality (13.8% vs. 6.1%). Lastly, the health care resource utilization was considerable and similar between adult psychiatric outpatients diagnosed and not diagnosed with ADHD.

Conclusions: Although care was taken when choosing the sites for this study, to make it representative of the general outpatient adult psychiatric population, caution should be advised in generalizing the findings of our study to the general ADHD or psychiatric outpatient population. This was an observational study, thus no inference on causality can be drawn. Having ADHD imposes a considerable health and social burden on patient and health care resource utilization comparable to other chronic psychiatric disorders.     

Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: A randomized,controlled, Phase III trial

Guanfacine extended-release (GXR), a selective α2A-adrenergic agonist, is a non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD). This study assessed the efficacy (symptoms and function) and safety of dose-optimized GXR compared with placebo in children and adolescents with ADHD. An atomoxetine (ATX) arm was included to provide reference data against placebo. Patients (6–17 years) were randomized at baseline to dose-optimized GXR (0.05–0.12 mg/kg/day – 6–12 years: 1–4 mg/day; 13–17 years: 1–7 mg/day), ATX (10–100 mg/day) or placebo for 4 or 7 weeks. The primary efficacy measure was change from baseline in ADHD Rating Scale version IV (ADHD-RS-IV). Key secondary measures were Clinical Global Impression-Improvement (CGI-I) and the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P; learning and school, and family domains). Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms and vital signs. A total of 272 (80.5%) patients from Europe, the USA and Canada completed the study. Significant differences were observed in least squares mean change from baseline in ADHD-RS-IV total score (placebo-adjusted differences) (GXR: [−8.9, p<0.001]; ATX: [−3.8, p<0.05]), the difference from placebo in the percentage of patients showing improvement (1 [‘very much improved’] or 2 [‘much improved’]) for CGI-I (GXR: [23.7, p<0.001]; ATX: [12.1, p<0.05]), WFIRS-P learning and school domain (GXR: [−0.22, p<0.01]; ATX: [−0.16, p<0.05]) and WFIRS-P family domain (GXR: [−0.21, p<0.01]; ATX: [−0.09, p=0.242]). Most common TEAEs for GXR were somnolence, headache and fatigue; 70.1% of GXR subjects reported mild-to-moderate TEAEs. GXR was effective and well tolerated in children and adolescents with ADHD.     

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。     

父母教养方式对伴与不伴对立违抗性障碍注意缺陷多动障碍患儿的影响

目的 探讨父母教养方式对伴与不伴对立违抗性障碍（ODD）的注意缺陷多动障碍（ADHD）患儿的影响。方法 选择2015年1月至2016年12月安徽省精神卫生防治中心就诊的ADHD患儿124例,根据有无ODD症状,分为单纯ADHD患儿82例,合并ODD的ADHD患儿42例,按照分层抽样的方法选取合肥某小学同时期110例健康儿童作为对照组;使用父母教养方式调查问卷（EMBU）对3组儿童目前的父母教养方式进行调查评分,比较3组对象的父亲因子、母亲因子差异。结果 3组儿童父亲因子Ⅱ、Ⅲ、Ⅴ和母亲因子Ⅱ、Ⅲ、Ⅳ的差异有统计学意义（F=32.096,11.195,10.467,13.957,7.343,29.081,P均<0.001）;单纯ADHD组患儿的父亲因子Ⅱ、Ⅲ、Ⅴ和母亲因子Ⅱ、Ⅲ、Ⅳ得分高于对照组,差异有统计学意义（t=7.481,4.479,4.406,5.252,3.847,7.292,P均<0.001）;合并ADD的ADHD组患儿的父亲因子Ⅱ、Ⅲ和母亲因子Ⅱ、Ⅳ得分高于单纯ADHD,差异有统计学意义（t=2.221,P=0.028;t=2.553,P=0.012;t=2.921,P=0.004;t=3.737,P<0.001）。结论 父母教养方式的极端化对ADHD患儿有着重要影响,惩罚严厉、过分干涉的教养方式是ADHD患儿出现ODD的危险教养方式。     

Pozanicline for the treatment of attention-deficit/hyperactivity disorder

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder occurring in childhood and often continues into adolescence and adulthood. The pathophysiology of ADHD is complex and likely involves multiple neurotransmitter systems. Medications currently used for the treatment of ADHD enhance dopaminergic and/or noradrenergic transmission. However, none of these drugs target the cholinergic system, which is also thought to play a significant role in cognitive disturbances such as those found in ADHD.

Areas covered: In this review, the authors briefly discuss the cholinergic system, including multiple neuronal nicotinic receptor (NNR) subtypes that mediate the positive and negative effects of nicotine, in the context of animal models of ADHD. They also discuss the pharmacology of the NNR pozanicline, a partial agonist with high in vitro binding affinity and selectivity for the α₄β₂ NNR subtype. Finally, the authors examine pozanicline’s clinical developments.

Expert opinion: Pozanicline was shown to be effective in a pilot study in humans with ADHD, but larger trials were negative. Developing an efficacious therapy is difficult. ADHD is a complex disorder with an unknown cause, and it is unclear, at this time, which qualities from NNR agonists are needed to treat it. It is therefore necessary to develop a more enhanced understanding of the nicotinic cholinergic system and its role in ADHD. Furthermore, new research paradigms may need to be employed to find drugs that are effective in patients with ADHD.     

Substance use disorders in association with attention-deficit/hyperactivity disorder,co-morbid mental disorders,and medication in a nationwide sample

BackgroundThe association of substance use disorders (SUD) with attention-deficit disorder (ADHD), co-morbid mental disorders, and medication has only been studied in isolation and in rather small samples.ProcedureData were based on four Danish national registers covering a total of 20,742 patients with ADHD, their dispensed medications, co-morbid mental disorders, and associated SUD between 1994 and 2010. The analyses considered the risk of various medications (methylphenidate only, antidepressants only, antipsychotic only, mixed medication) in comparison to a control group of non-medicated patients with ADHD, various co-morbid disorders, duration of medication, age at diagnosis, year of birth, and sex for developing SUD.ResultsThe observation period of the cohort ranged between 2.25 and 66.21 years and the prevalence for SUD was 9.51%. The SUD rates were significantly higher prior to, compared to following the onset of medication in the methylphenidate and the mixed medication subgroup, whereas they were significantly higher following onset of medication in the antidepressants and the antipsychotics subgroups. However, the SUD rates were significantly higher in all drug conditions except for methylphenidate after onset of medication compared to the non-medicated subgroup. Risk factors obtained by regression analysis did not include methylphenidate but did include antidepressants, antipsychotics, and mixed medications, in combination with co-morbid mood, anxiety, personality, and conduct disorders, and older age at diagnosis. Longer duration of medication and female sex were protective factors.ConclusionsThis representative study based on a large nationwide psychiatric sample provides solid evidence into the patterns of SUD in patients with ADHD based on medication use and co-morbidities.     

An examination of differences in variables maintaining smoking behavior in adult smokers with and without attention-deficit/hyperactivity disorder

Individuals with attention-deficit/hyperactivity disorder (ADHD) smoke cigarettes at higher rates and have greater difficulty quitting than their non-diagnosed peers. This study examined differences between smokers with and without ADHD on a range of smoking-related variables. Twenty-two subjects with ADHD and 22 controls completed self-report measures of withdrawal symptoms, smoking motivation, sensory experience of smoking, and positive and negative affect. Compared to control smokers, smokers with ADHD reported greater craving and negative affect; perceived smoking as providing greater enhancement of concentration and alertness, as more calming, and as providing a greater decrease in irritability; found cigarette puffs to be more enjoyable and satisfying; and rated smoking as providing greater positive and negative reinforcement and greater cognitive enhancement. Women with ADHD reported the greatest effects of smoking on improving concentration and reducing irritability. Findings support the hypothesis that smokers with ADHD may experience smoking differently than smokers without the disorder, and that they may identify different motivations for smoking.     

Neurocognitive effects of methylphenidate in adult attention-deficit/hyperactivity disorder

Rationale Features of childhood attention-deficit/hyperactivity disorder (ADHD) often persist into adulthood. It has been shown that adult ADHD is associated with various neurocognitive deficits, including impairments in spatial working memory (SWM) and attention. It is not known whether these deficits are ameliorated by methylphenidate in adult ADHD.Objectives The aim of this study was to evaluate the neurocognitive effects of a single dose of methylphenidate on SWM, visual memory, spatial span and sustained attention in adult ADHD.Methods Twenty-four adult patients, recruited from a specialised clinic for the assessment of adult ADHD, were entered into a double-blind, randomised, placebo-controlled crossover study using a single 30 mg dose of methylphenidate.Results Eighteen patients met DSM-IV criteria for adult ADHD. Methylphenidate resulted in an improvement in SWM performance and sustained attention, together with a speeding in response time, in these patients. Six patients with attentional difficulties, who did not meet a DSM-IV diagnosis of ADHD, showed a different pattern of response to methylphenidate compared to the ADHD group. For the combined group, moderate correlations were shown between childhood ratings of ADHD (both self-reported and informant ratings) and response to methylphenidate on the SWM task.Conclusions Adults with ADHD had a similar neurocognitive response to methylphenidate to that previously reported for childhood ADHD. Our results provide further support for the validity of the ADHD syndrome as defined by DSM-IV and indicate possible neurocognitive substrates for clinical improvement with chronic methylphenidate.     

The effects of methylphenidate on prepulse inhibition during attended and ignored prestimuli among boys with attention-deficit hyperactivity disorder

Abstract Rationale and objectives. The present study investigated attentional modification of prepulse inhibition of startle among boys with and without attention-deficit hyperactivity disorder (ADHD). Two hypotheses were tested: (1) whether ADHD is associated with diminished prepulse inhibition during attended prestimuli, but not ignored prestimuli, and (2) whether methylphenidate selectively increases prepulse inhibition to attended prestimuli among boys with ADHD. Methods. Participants were 17 boys with ADHD and 14 controls. Participants completed a tone discrimination task in each of two sessions separated by 1 week. ADHD boys were administered methylphenidate (0.3 mg/kg) in one session and placebo in the other session in a randomized, double-blind fashion. During each series of 72 tones (75 dB; half 1200-Hz, half 400-Hz), participants were paid to attend to one pitch and ignore the other. Bilateral eyeblink electromyogram startle responses were recorded in response to acoustic probes (50-ms, 102-dB white noise) presented following the onset of two-thirds of tones, and during one-third of intertrial intervals. Results. Relative to controls, boys with ADHD exhibited diminished prepulse inhibition 120 ms after onset of attended but not ignored prestimuli following placebo administration. Methylphenidate selectively increased prepulse inhibition to attended prestimuli at 120 ms among boys with ADHD to a level comparable to that of controls, who did not receive methylphenidate. Conclusions. These data are consistent with the hypothesis that ADHD involves diminished selective attention and suggest that methylphenidate ameliorates the symptoms of ADHD, at least in part, by altering an early attentional mechanism. Electronic Publication     

孕期被动吸烟对注意缺陷多动障碍患儿认知和行为的影响

目的研究孕期被动吸烟对注意缺陷多动障碍（ADHD）患儿认知和行为的影响。方法选取伴孕期被动吸烟ADHD患儿92例、不伴孕期被动吸烟ADHD患儿99例及正常儿童100例,通过智力测定、Stroop测验和威斯康星卡片分类评估研究对象的认知和行为能力。结果ADHD患儿言语智商（VIQ）、操作智商（HQ）和总智商（FIQ）均较较正常儿童低,其中有孕期被动吸烟史的患儿更低。ADHD患儿的A、B、C卡片耗时均较对照组患儿长,而B、C卡片正确数均较对照组患儿低,有孕期被动吸烟史的ADHD患儿更为显著。ADHD患儿的错误应答数、持续性应答数、持续性错误数、持续性错误百分数和非持续性错误数均较正常儿童高,而概念化水平均较正常儿童低,且有孕期被动吸烟史的患儿更为明显。结论孕期被动吸烟损害能加重缺陷多动障碍患儿的认知和行为的缺陷。     

Pharmacological treatment of attention-deficit/hyperactivity disorder in adults

With increased awareness that attention-deficit/hyperactivity disorder (ADHD) can persist beyond childhood, pharmacological treatment options for adults have expanded. Short-acting stimulants continue to be the first-line approach, demonstrating clinical efficacy and few adverse events in well-controlled trials, with long-acting stimulants also showing promise. Atomoxetine has also been reported to improve ADHD symptoms and associated dysfunction, although longer-term, head-to-head studies with stimulants are needed. Several antidepressants (e.g., desipramine and buproprion) appear to be effective in the treatment of adult ADHD, but to a lesser extent than stimulants. Data are limited in evaluating the impact of combining pharmacological treatments for ADHD and comorbid conditions. This paper describes the safety and efficacy of medications for treating the core symptoms, psychosocial features and cognitive dysfunctions associated with adult ADHD.     

Guanfacine ER for the treatment of adolescent attention-deficit/hyperactivity disorder

Introduction: Guanfacine extended release (GXR) is an alpha 1A noradrenergic agonist that has been approved by the FDA for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) as a monotherapy, and as an adjunctive therapy to stimulants for the treatment of ADHD in children and adolescents age 6 – 17.

Areas covered: PubMed, the Ovid Medline database, and the PsycInfo database were searched using the term ‘guanfacine'. Results were then limited to criteria such as English and human, from 1990 through December 2011. The resulting yield from the comprehensive literature search was 4391 articles. The titles and abstracts of all articles were reviewed. Studies were selected for full-text review based upon their place in the hierarchy of evidence (e.g., randomized controlled trials), relevance and quality of individual studies, and generalizability to clinical practice. The search was augmented by further search of article reference lists. A total of 15 articles were selected for full-text examination.

Expert opinion: Due to the absence of positive evidence for the efficacy of GXR for monotherapy in adolescents, clinicians should be guarded in the use of GXR for monotherapy in adolescents with ADHD. The use of GXR has considerable promise as an adjunct to stimulants for other behavioral conditions associated with ADHD.     

Long-term treatment outcomes with lisdexamfetamine dimesylate for adults with attention-deficit/hyperactivity disorder stratified by baseline severity

Abstract

Objective:

To examine the impact of baseline severity on lisdexamfetamine dimesylate (LDX) efficacy in a long-term study of adults with attention-deficit/hyperactivity disorder (ADHD).     

Atomoxetine: a selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder

Atomoxetine (Strattera^?, Eli Lilly & Co.) is a selective noradrenaline reuptake inhibitor that has been studied for use in the treatment of attention-deficit/hyperactivity disorder (ADHD). So far, two open-label and seven randomised, double-blind, placebo-controlled, clinical trials have been published, six in youths and three in adults. Each of these trials has shown a positive response as measured by the primary efficacy measures, the ADHD-IV Rating Scale (ADHD RS) or the Conners Adult ADHD Rating Scale (CAARS). Atomoxetine has generally been well tolerated. In November of 2002 the FDA approved atomoxetine for use in the US for the treatment of ADHD in children, adolescents and adults. Atomoxetine is the first nonstimulant approved by the FDA for the treatment of ADHD and the first medication approved for the treatment of adult ADHD.     

Treatment stabilization in children and adolescents with attention-deficit/hyperactivity disorder: data from the Netherlands

Abstract

Objective:

To evaluate the number of patients reaching stable treatment with a stimulant (methylphenidate or dexamphetamine) or non-stimulant (atomoxetine) attention-deficit/hyperactivity disorder (ADHD) medication approved for use in the Netherlands, and the time to treatment stabilization among children and adolescents aged 6–17 years.     

SLI381: a long-acting psychostimulant preparation for the treatment of attention-deficit hyperactivity disorder

SLI381 (Adderall-XR^®) is a longer-acting form of Adderall^®, a compound of mixed amphetamine salts that is now the most frequently prescribed brand of psychostimulant medication for attention-deficit hyperactivity disorder (ADHD) in the US [1]. It has been demonstrated to be a safe and effective treatment for ADHD in school-age children. To date, the efficacy of SLI381 has been evaluated in controlled studies of over 500 patients. The therapeutic effects of SLI381 on the core symptoms of ADHD, as well as the duration of action of the formulation, have been demonstrated to persist for 12 h, with both greater efficacy and duration of effects seen at higher doses. Both behavioural and cognitive performance measures are improved throughout the school day and into post-school activities. The incidence of common stimulant-emergent side effects with SLI381 was no different than that seen with the existing Adderall preparation. Additionally, the frequency with which most stimulant-related side effects were experienced did not demonstrate a consistent dose-related incidence, with the exception of anorexia. SLI381 received a letter of approvability in August 2001 and will probably be approved in the immediate future by the US FDA. This formulation represents a valuable addition to the available pharmacotherapeutic options for ADHD by providing an amphetamine-based stimulant offering the advantages of once-daily dosing accompanied by the clinical benefits of ADHD symptom control associated with the now widely used Adderall preparation.