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.     

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.     

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.     

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.     

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.     

盐酸托莫西汀治疗注意缺陷多动障碍的Meta分析

目的:采用Meta分析方法对盐酸托莫西汀治疗注意缺陷多动障碍的疗效及安全性进行评价。方法:查询Medline,EmBase,SCI,Elsevier,CBMdisc等数据库,收集盐酸托莫西汀治疗注意缺陷多动障碍的临床试验文献,提取疗效指标及安全性数据,采用Review Manager 4.2软件进行统计计算。结果:检索到年龄<18岁的儿童及青少年的随机双盲安慰剂对照临床研究文献14篇,均为国外文献(Jadad评分≥4分);样本含量1 995例;药物剂量0.5~1.8 mg.kg-1.d-1。在忽略药物剂量的条件下,盐酸托莫西汀与安慰剂相比,儿童及青少年的ADHD-RS评分和CGI-S评分平均减分值分别为[WMD-7.26(-8.28,-6.24)]和[WMD-0.62(-0.75,-0.48)](P<0.01)。试验中出现的不良反应有食欲下降[RR:4.46(2.89,6.89)]、恶心[RR:2.97(2.00,4.41)]、呕吐[RR:2.14(1.42,3.21)]及体重改变[WMD-1.88(-2.23,-1.52)]。结论:盐酸托莫西汀在改善注意缺陷多动障碍患者的核心症状方面疗效显著,耐受性良好。     

Pharmacological and clinical dilemmas of prescribing in co-morbid adult attention-deficit/hyperactivity disorder and addiction

The present article reviews whether available efficacy and safety data support the pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD) in patients with concurrent substance use disorders (SUD). Arguments for and against treating adult ADHD with active SUD are discussed. Findings from 19 large open studies and controlled clinical trials show that the use of atomoxetine or extended-release methylphenidate formulations, together with psychological therapy, yield promising though inconclusive results about short term efficacy of these drugs in the treatment of adult ADHD in patients with SUD and no other severe mental disorders. However, the efficacy of these drugs is scant or lacking for treating concurrent SUD. No serious safety issues have been associated with these drugs in patients with co-morbid SUD-ADHD, given their low risk of abuse and favourable side effect and drug–drug interaction profile. The decision to treat adult ADHD in the context of active SUD depends on various factors, some directly related to SUD-ADHD co-morbidity (e.g. degree of diagnostic uncertainty for ADHD) and other factors related to the clinical expertise of the medical staff and availability of adequate resources (e.g. the means to monitor compliance with pharmacological treatment). Our recommendation is that clinical decisions be individualized and based on a careful analysis of the advantages and disadvantages of pharmacological treatment for ADHD on a case-by-case basis in the context of active SUD.     

Guanfacine extended-release for attention-deficit/hyperactivity disorder (ADHD)

Importance of the field: Guanfacine extended-release (GXR) is a non-stimulant approved in the US for treatment of attention deficit/hyperactivity disorder (ADHD). GXR is a ‘first in class’ α_2A-adrenoceptor agonist reformulated to optimize efficacy. GXR enters a rapidly growing but crowded ADHD market as an alternative not only to psychostimulants but also to atomoxetine.

Areas covered in this review: Pharmacodynamics, pharmacokinetics, clinical efficacy and safety of GXR are covered based on a literature review (MEDLINE and EMBASE) from 1980 to 2010. Two large pivotal controlled trials are reviewed along with companion safety studies over 24 months. Collateral studies in ADHD children with oppositional symptoms and combination use of GXR in psychostimulant partial-responders are featured.

What the reader will gain: Novel aspects of apparent GXR mechanism of action may complement existing treatments. Study evidence indicates that GXR is a well-tolerated and effective treatment for children and adolescents with ADHD, and appears efficacious to reduce oppositional symptoms in children with these complicating features. The GXR safety database reflects mild and asymptomatic decreases in both blood pressure and heart rate throughout, with most adverse events being somnolence-related and time-limited.

Take home message: This review of GXR will allow the reader to determine the place for GXR in the ADHD treatment landscape.     

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.     

OROS methylphenidate hydrochloride for adult patients with attention deficit/hyperactivity disorder

Introduction: Attention deficit/hyperactivity disorder (ADHD) is estimated to affect 4 – 5% of adults. Impairment across multiple domains of daily living can be mild to serious. OROS methylphenidate (MPH) was evaluated in two large adult clinical trials, and in 2008 it was approved in the USA to treat ADHD in adults aged up to 65 years.

Areas covered: Products approved for adult ADHD; chemistry, pharmacodynamics, pharmacokinetics, metabolism, efficacy, safety, tolerability, abuse liability, regulatory affairs, and relative merits and limitations associated with OROS MPH; and complexities associated with diagnosis and treatment of ADHD are discussed in this review. The reader will gain an introduction to the epidemiology, features and special issues regarding clinical management of ADHD in adults. Key features and development of OROS MPH are presented, and unique characteristics of the delivery system and their implications for clinical use of the drug are discussed.

Expert opinion: The OROS system delivers MPH in a highly consistent manner using osmotic pressure at a controlled rate over a 12-h duration of effect. Compared with immediate-release MPH, it provides a smoother pharmacokinetic curve, and it may show greater patient compliance, fewer missed doses and reduced abuse liability.     

Guanfacine extended release for the treatment of attention-deficit/hyperactivity disorder in children and adolescents

Introduction: Guanfacine extended release (GXR) is a selective α_2A-adrenoreceptor agonist originally developed as an antihypertensive agent and now FDA approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) as monotherapy and as adjunctive to psychostimulants in children and adolescents 6 – 17 years old.

Areas covered: Search of the PubMed and PsycInfo databases from 1990 to 2014 using the search term ‘guanfacine’. Studies selected for review were either controlled or open trials of guanfacine or GXR. Shire Pharmaceuticals, Inc. was contacted and supplied a synopsis of all available ADHD studies on GXR for review.

Expert opinion: GXR is an evidence-based treatment for ADHD in children and adolescents. Because this compound has a smaller effect size than psychostimulants for the symptoms of ADHD, it is generally considered a second-line treatment after the psychostimulants or in combination with psychostimulants. Evidence for efficacy is more robust in children than for adolescents. Because of its pharmacodynamic actions in prefrontal cortex, GXR shows considerable promise for other behavioral conditions frequently comorbid with ADHD and potential promise for emotional and behavioral dysregulation secondary to traumatic stress.     

小儿智力糖浆联合哌甲酯治疗注意力缺陷多动障碍的系统评价

目的 评价小儿智力糖浆联合哌甲酯治疗注意力缺陷多动障碍的临床疗效及安全性。方法 计算机检索中国学术期刊全文数据库（CNKI）、中国生物医学文献数据库（CBM）、维普中文期刊全文数据库（VIP）、万方数据库、the Cochrane Library、PubMed和Web of Science中英文数据库,收集各数据库建库起至2021年12月26日小儿智力糖浆联合哌甲酯治疗注意力缺陷多动障碍的临床随机对照试验（RCT）。由两位研究人员独立筛选文献、提取资料,使用RevMan 5.4软件分析数据。结果 共纳入9项RCTs、包括861例患儿。Meta分析结果显示：小儿智力糖浆联合哌甲酯组在多动指数评分[MD=-0.32,95% CI（-0.40,-0.23）,P<0.000 01]、冲动行为评分[MD=-0.38,95% CI（-0.48,-0.29）,P<0.000 01]、学习行为评分[MD=-0.36,95% CI（-0.43,-0.29）,P<0.000 01]、不良反应率[RR=0.64,95% CI（0.46,0.89）,P=0.009]方面,与对照组比较,差异均有统计学意义。结论 小儿智力糖浆联合哌甲酯治疗注意力缺陷多动障碍的疗效优于单用哌甲酯,且更安全。     

Effects of stimulant medications on the EEG of children with attention-deficit/hyperactivity disorder

Abstract Rationale. Stimulant medications are the most commonly used treatments for attention deficit/hyperactivity disorder (ADHD) in North America and Australia, although it is still not entirely known how these medications work. Objectives. This study aimed to investigate the effects of stimulant medications on the EEG of children with the Combined subtype of ADHD. Method. An initial EEG was recorded during an eyes-closed resting condition and Fourier transformed to provide absolute and relative power estimates for the delta, theta, alpha and beta bands. Theta/alpha and theta/beta ratios were also calculated. Subjects were placed on a 6-month trial of a stimulant and a second EEG was recorded at the end of the trial. Results. The ADHD group had significantly greater absolute delta and theta, less posterior absolute beta, more relative theta, and less relative alpha than the control group, which is typical of EEG studies of children with ADHD. The use of stimulant medications resulted in normalisation of the EEG, primarily evident in changes in the theta and beta bands. Conclusions. These results suggest that stimulants act to increase cortical arousal in children with ADHD, normalising their brain activity. Electronic Publication     

小儿黄龙颗粒对注意力缺陷多动障碍模型大鼠注意定势转移能力的影响

目的 建立注意力缺陷多动障碍（ADHD）大鼠模型,观察小儿黄龙颗粒对ADHD模型大鼠的注意定势转移能力的影响。方法 采用自发性高血压大鼠（SHR）作为ADHD模型大鼠,将32只健康SHR随机分为模型组、哌甲酯（阳性药,给予盐酸哌甲酯缓释片6.75 mg·kg^-1）组和小儿黄龙颗粒低、高剂量（1.875、3.75 g·kg^-1）组,每组8只,另分别设WKY大鼠组和Wistar大鼠组（作为对照）,每组8只。各给药组按10 mL·kg^-1体质量ig给药,模型组、对照组ig生理盐水,每天2次,连续给药21 d。检测各组大鼠在注意定势转移任务（AST）中各阶段［简单辨别（SD）阶段、复杂辨别（CD）及其反向阶段、内维度转换（IDS）及其反向阶段、逆反学习（RL）及其反向阶段、外维度转换（EDS）及其反向阶段］的错误次数和错误率。结果 模型组SHR在CD、IDS、RL阶段的错误次数及错误率显著高于Wistar大鼠（P＜0.05、0.01）;在IDS反向阶段,模型组大鼠的错误率较Wistar大鼠显著增加（P＜0.05）,其他阶段SHR的错误次数及错误率较Wistar大鼠呈增加趋势。小儿黄龙颗粒各剂量组各阶段的错误次数及错误率较模型组大鼠有不同程度的减少,其中小儿黄龙颗粒高剂量组在CD阶段的错误次数及错误率,低剂量组在IDS正向阶段的错误次数与错误率,高剂量组在IDS正向阶段的错误次数,低、高剂量组在RL正向阶段的错误次数,与模型组大鼠相比有显著差异（P＜0.05、0.01）。结论 小儿黄龙颗粒能够提高ADHD大鼠的注意定势转移能力,治疗ADHD。     

Ganglionic nicotinic acetylcholine receptor activation by the novel agonist ABT-418

ABT-418 was functionally characterized as a neuronal nicotinic acetylcholine receptor (nAChR) channel agonist using preparations that contain nAChRs characteristic of the ganglionic subtypes. In PC12 cells, ABT-418, like (?)nicotine, activated an inward current that decayed within seconds in the continued presence of agonist. ABT-418 was 4-fold less potent than (?)nicotine (EC₅₀ = 214 ± 30 μM and 52 ± 4 μM, respectively) while the efficacy of ABT-418 was not significantly different from (?)nicotine when the peak response amplitude was measured. Responses to 300 μM ABT-418 were reversibly inhibited 81 ± 3% by 10 μM mecamylamine, 38 ± 1% by 10 μM dihydro-β-erythroidine, and 82 ± 2% by 100 μM dihydro-β-erythroidine. These nAChR antagonists affected the response to (?)nicotine similarly. Furthermore, responses to maximal concentrations of ABT-418 (3 mM) and (?)nicotine (1 mM) were not additive, consistent with ABT-418 and (?)nicotine acting through the same receptor(s). However, the Hill coefficient for ABT-418 (1.18 ± 0.20) was smaller than that for (?)nicotine (1.77 ± 0.18), and high concentrations of ABT-418 appeared to elicit a more rapidly decaying response than did (?)nicotine. In the rat superior cervical sympathetic ganglion also, ABT-418 was 2.5-fold less potent than (?)nicotine in blocking nicotinic transmission, presumably through nicotinic receptor desensitization. These studies provide the most direct evidence that ABT-418 activates nicotinic cholinergic channels, and suggest that ABT-418 would have reduced potency compared to (?)nicotine in peripheral ganglia, consistent with the reduced side effect liability of this novel nAChR agonist. © Wiley-Liss, Inc.     

Impulsive behavior and nicotinic acetylcholine receptors

Higher impulsivity is thought to be a risk factor for drug addiction, criminal involvement, and suicide. Excessive levels of impulsivity are often observed in several psychiatric disorders including attention-deficit/hyperactivity disorder and schizophrenia. Previous studies have demonstrated that nicotinic acetylcholine receptors (nAChRs) are involved in impulsive behavior. Here, we introduce recent advances in this field and describe the role of the following nAChR-related brain mechanisms in modulating impulsive behavior: dopamine release in the ventral striatum; α4β2 nAChRs in the infralimbic cortex, which is a ventral part of the medial prefrontal cortex (mPFC); and dopamine release in the mPFC. We also suggest several potential therapeutic drugs to address these mechanisms in impulsivity-related disorders and explore future directions to further elucidate the roles of central nAChRs in impulsive behavior.     

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.     

儿童注意缺陷-多动障碍中药新药临床试验设计与评价技术指南

《儿科常见疾病中药新药临床试验设计与评价技术指南》是中华中医药学会儿科分会临床评价学组制定的、指导儿科中药Ⅱ期、Ⅲ期临床试验和上市后有效性再评价方案设计的、具有病种特色的系列临床评价技术指南,旨在推动儿科中药临床试验设计与评价水平的提高,并为临床提供安全有效的儿童用药.采用世界卫生组织(WHO)推荐的"共识会议法"和美国国立卫生研究院(NIH)发展共识方案(GPP)有关原则,国内全部18个国家药物临床试验机构中医儿科专业的临床儿科专家以及国内相关临床评价专家参加了急性上呼吸道感染、急性支气管炎、支气管哮喘、反复呼吸道感染、厌食、轮状病毒性肠炎、注意缺陷-多动障碍、抽动障碍、遗尿症、手足口病、湿疹11个儿科常见病种指南的起草或多次提出修改建议,历经3年反复完善,最终形成共识,并由中华中医药学会儿科分会于2013年10月发布.本指南从研究背景、研究目标、总体设计、诊断标准、受试者的选择、给药方案、安全性评价、有效性评价、试验流程、数据管理与统计分析、质量保证、相关伦理学要求、试验结束后的医疗措施、资料保存等方面阐述了儿童注意缺陷-多动障碍中药新药临床试验的设计与评价技术要点,期望能为申办者与研究者在临床试验方案设计中提供指导.