Evolution of the treatment of attention-deficit/hyperactivity disorder in children: a review

BACKGROUND: Efficacious and well-tolerated medications are available for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulants such as methylphenidate (MPH) and amphetamines are the most widely used medications approved by the US Food and Drug Administration for the treatment of ADHDin children. OBJECTIVE: This article reviews the literature on the development and use of medications for the treatment of ADHD in children. METHODS: A search of MEDLINE was conducted toidentify relevant studies and critical reviews on the treatment of ADHD in children.The main criteria for inclusion of a study were that it have a controlled design, enroll >100 subjects if a clinical trial and >20 subjects if a classroom study, assess symptoms with the most widely used scales and tests,and be published from 2000 to 2008.A few older pivotal studies were also included. RESULTS: Many studies have reported the long-term efficacy and tolerability of immediate-release formulations of MPH. The disadvantages of such formulations include the need for multiple daily dosing and a potential for abuse. Various extended-release formulations of MPH have been found effective in controlled studies enrolling large numbers of children with ADHD. The efficacy and tolerability of dexmethylphenidate, the active D-isomer of MPH, in an extended-release formulation have also been reported. An extended-release formulation of mixed amphetamine salts (MMAS-XR) that is dosed once daily has been found to be efficacious and well tolerated. The non-stimulant atomoxetine has been reported to be well tolerated and efficacious, although it may not be as effective as stimulants; this formulation is, however, less likely than stimulants to be associated with abuse and diversion. A recently approved prodrug stimulant, lisdexamfetamine dimesylate (LDX), was developed to provide a long duration of effect that is consistent throughout the day, with a reduced potential for abuse. In a placebo-controlled study in children with ADHD, less intersubject variability in T(max), C(max), and AUC from time zero to the last quantifiable concentration was seen in the 8 subjects who received LDX (percent coefficient of variation, 15.3, 20.3, and 21.6, respectively) compared with the 9 subjects who received MAS-XR (52.8, 44.0, and 42.8).In 2 clinical trials, significantly greater improvements in teacher and parent ratings of ADHD symptoms were seen with LDX compared with placebo (P<0.001).A study of the abuse potential of LDX evaluated subjective responses to the effects of oral LDX and immediate-release d-amphetamine in adults with a history of stimulant abuse. LDX was associated with a significantly lower abuse-related liking effect than d-aamphetamine (P = 0.039). CONCLUSIONS: Currently available treatments for ADHD in children are efficacious and well tolerated, but many of them are limited by the requirement for multiple daily dosing and abuse potential. LDX, a long-acting prodrug of d-amphetamine, has been reported to be effective and appears to overcome some of these limitations.     

Evaluation and treatment of ADHD

Symptoms of attention-deficit/hyperactivity disorder (ADHD) are present in as many as 9 percent of school-age children. ADHD-specific questionnaires can help determine whether children meet diagnostic criteria for the disorder. The recommended evaluation also includes documenting the type and severity of ADHD symptoms, verifying the presence of normal vision and hearing, screening for comorbid psychologic conditions, reviewing the child's developmental history and school performance, and applying objective measures of cognitive function. The stimulants methylphenidate and dextroamphetamine remain the pharmacologic agents of first choice for the management of ADHD. These agents are equally effective in improving the core symptoms of the disorder, but individual children may respond better to one stimulant medication than to another. Achievement of maximal benefit may require titration of the initial dosage and dosing before breakfast, before lunch and in the afternoon. The family physician should tailor the treatment plan to meet the unique needs of the child and family. Psychosocial, behavioral and educational strategies that enhance specific behaviors may improve educational and social functioning in the child with ADHD.     

White noise as a possible therapeutic option for children with ADHD

Attention deficit/hyperactivity disorder (ADHD) is a condition that affects many children and adults throughout the world. ADHD symptoms have been associated with changes in catecholamine release. Current therapies for ADHD have a variety of limitations that invite additional therapeutic options. White noise therapy has previously been utilized to improve sleep and aspects of cognition in a variety of patient populations. Through a proposed phenomenon called stochastic resonance, white noise may have the ability to improve symptoms in children with ADHD. Empirically, white noise therapy has been able to improve certain tasks affected by ADHD symptoms, including speech recognition and reading and writing speed. Not all tasks affected by ADHD are improved, however, and significant logistical challenges remain before this therapy could be realistically implemented. In this review, there appears to be evidence that white noise therapy could be beneficial for patients with ADHD, and therefore further research is encouraged to establish parameters for maximum therapeutic benefit.     

Attention-deficit hyperactivity disorder in adults.

It has been estimated that 30% to 70% of children who are diagnosed as having attention-deficit hyperactivity disorder (ADHD) will continue to show symptoms of the condition as adults. Since the prevalence of ADHD among school children may be 3% or more, its prevalence among adults may be 1% or 2%. The third revised edition of the Diagnostic and Statistical Manual (1987) of the American Psychiatric Association lists three essential features for the diagnosis of ADHD: "developmentally inappropriate inattention, impulsiveness, and hyperactivity." Other conditions associated with ADHD in adults include learning disabilities (or their sequelae), general anxiety disorder, drug and alcohol abuse, and dysthymic and cyclothymic disorders. Strong correlations have been found between ADHD and oppositional defiant and conduct disorders in children and an increased risk for antisocial disorders in adults. A combination of genetic, biologic, and environmental factors appears to be implicated in the etiology of ADHD. The management of adult ADHD requires a multimodal approach. The patient needs to be informed of the cause of his or her impulsive and often self-destructive behavior. Many patients will have learning difficulties that require evaluation and remediation by specialists in learning disabilities. Psychotherapy can help the patients resolve disturbances in perceptions of self and others and family therapy can address difficulties in the adult's relationships with family members. Pharmacotherapy of adult ADHD includes the use of central nervous system stimulants, such as methylphenidate, dextroamphetamine, and pemoline, of the tricyclic antidepressants imipramine and desimipramine, and of other antihypertensive, analgesic, and antimanic drugs.     

Attention deficit hyperactivity disorder: An update

Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder, affecting 3% to 5% of school-aged children. Of the 3 subtypes—predominantly inattentive, predominantly hyperactive/impulsive, and a combined subtype—the latter is the most commonly represented group, accounting for 50% to 70% of all ADHD individuals. Stimulant medication is the cornerstone of management; however, stimulants with a short duration of action have been problematic for some patients. Recent technologic advances in delivery systems offer many patients the option of a once-daily dosage.     

Adult ADHD: evaluation and treatment in family medicine

Attention-deficit/hyperactivity disorder (ADHD) affects 30 to 50 percent of adults who had ADHD in childhood. Accurate diagnosis of ADHD in adults is challenging and requires attention to early development and symptoms of inattention, distractibility, impulsivity and emotional lability. Diagnosis is further complicated by the overlap between the symptoms of adult ADHD and the symptoms of other common psychiatric conditions such as depression and substance abuse. While stimulants are a common treatment for adult patients with ADHD, antidepressants may also be effective. Cognitive-behavioral skills training and psychotherapy are useful adjuncts to pharmacotherapy.     

Assessing the value of atomoxetine in treating children and adolescents with ADHD in the UK

Background: Economic evaluation of healthcare technologies is becoming increasingly relevant, enabling decision makers to assess and compare treatments within the context of costs and outcomes. Moreover, it is increasingly important for clinicians and prescribers to have some understanding of economic evaluation. For attention‐deficit/hyperactivity disorder (ADHD), economic evaluations have largely focused on pharmacotherapy, and results indicate that such treatments are cost‐effective compared with other interventions. Aims: This review provides an overview of ADHD, its consequences and pharmacotherapy; describes the principles of health economic analysis, health‐related quality of life (HRQL) and a cost‐effectiveness model of atomoxetine for ADHD treatment; and outlines guidance from the National Institute for Health and Clinical Excellence on ADHD pharmacotherapy. Methods: The cost‐effectiveness of atomoxetine for children with ADHD in the UK was compared with treatment alternatives using an economic model with Markov processes. The model evaluated atomoxetine in five patient subgroups according to treatment history and comorbidities precluding stimulants. Incremental cost per quality‐adjusted life‐year (QALY) was calculated and compared between treatment algorithms. The Markov process incorporated 18 health states, representing a range of outcomes across the treatments. Utility values were derived from a survey of 83 parents of children with ADHD, and treatment efficacy and safety were based on a review of controlled clinical trials and literature, and validated by international experts. Costs and outcomes were estimated using Monte Carlo simulation over 1‐year. Results: Atomoxetine was a cost‐effective treatment across the whole ADHD population, with incremental cost‐effectiveness ratios ranging from £11,500 to £15,900 per QALY, compared with alternative pharmacotherapies, which are within UK and rest of Europe acceptability limits. Higher utility values achieved treating ADHD with atomoxetine, compensate for the relatively higher acquisition cost compared with stimulants. Conclusions: Atomoxetine is cost‐effective and may have advantages over stimulants, including benefits to HRQL and no abuse liability and is the only treatment in the UK licensed for continued treatment into adulthood in adolescents who have shown a response from treatment.     

The Role of Alpha2-Adrenergic Agonists in Attention-Deficit/Hyperactivity Disorder

Abstract

Psychostimulants are first-line therapy for patients with attention-deficit/hyperactivity disorder (ADHD). However, some patients are not optimal responders to monotherapy or present as comorbid for a variety of other disorders that either preclude the use of stimulants or produce a symptom complex that is resistant to monotherapy. Unfortunately, there are few agents well studied in combination with psychostimulants for patients with ADHD. The combination of psychostimulants with alpha₂-adrenergic agonists may offer a complementary approach to treating such complex patients. The rationale for combination therapy is that the primary effects of stimulants and alpha₂-adrenergic agonists are mediated by different but complementary mechanisms of action, emphasizing different neurotransmitter systems, which together modulate prefrontal cortex functioning. Although immediate-release clonidine and guanfacine have long been studied in ADHD, their usage has been limited by rapid absorption and clearance, negative side effects, and reduced efficacy compared with stimulants. New controlled-release formulations of the alpha₂-adrenergic agonists have overcome some of these limitations, with recent clinical trials demonstrating their enhanced tolerability and effectiveness for treatment of ADHD in children and adolescents. Studies with each of these new formulations (ie, guanfacine extended release and clonidine hydrochloride extended-release tablets) in combination with psychostimulants have demonstrated that the addition of an alpha₂-adrenergic agonist to psychostimulant therapy significantly enhances efficacy without compromising safety. This review will encompass the clinical study database for novel formulations of alpha₂-adrenergic agonists, enabling the reader to appreciate their place in ADHD treatment as well as the potential utility of a combination approach with psychostimulants for patients with complex ADHD.     

Attention-deficit/hyperactivity disorder in adults: evidence-based recommendations for management

Attention-deficit/hyperactivity disorder (ADHD) is associated with impairments in educational, occupational, neuropsychological, and social functioning in adults. Successful diagnosis and treatment of the disorder in adults can be a challenge because recent and integrative clinical guidelines are lacking and diagnostic criteria are based on making a retrospective diagnosis of childhood-onset ADHD. To develop evidence-based recommendations for the treatment of ADHD in adults, the scientific literature was reviewed, including primary clinical studies, meta-analyses, and available clinical guidelines. Studies show that stimulant therapy is highly effective and safe in the management of ADHD in adults, with similar response rates to those reported in children at doses that are equivalent on a mg/kg basis. Long-acting stimulants, such as OROS methylphenidate (OROS MPH, Concerta), dexmethylphenidate (d-MPH, Focalin), and mixed amphetamine salts extended release (MAS XR, Adderall XR), have durations of action of up to 10 to 12 hours, which permit once-daily dosing. For adults with ADHD who do not respond to stimulant therapy or who have a comorbid condition in which a stimulant is contraindicated, the nonstimulant atomoxetine (Strattera) may be an appropriate alternative. For many adults, cognitive-behavioral therapy in addition to pharmacotherapy may improve treatment response. Attention-deficit/hyperactivity disorder medications may increase blood pressure and heart rate in adults, so patients should be monitored.     

亲子互动疗法在学龄前ADHD儿童中的应用效果

近年来,国内外关于学龄前注意缺陷多动障碍(ADHD)儿童的家庭干预得到了越来越多研究者的关注和重视,因其效果显著而被众多诊疗指南认定为学龄前ADHD儿童的一线治疗方法。亲子互动疗法(PCIT)是一种主要针对学龄前儿童问题行为的家庭养育行为干预方法,其中现场实时指导、亲子共同参与、科学严谨的评估等要素保证了干预效果。该方法能有效减轻ADHD儿童的核心症状和家长的育儿压力,增强亲子关系和提升家庭功能。本文对PCIT的独特优势、实施流程、影响机制等进行综述,以期为今后我国学龄前ADHD儿童PCIT的研究设计、本土化治疗方案的研发和临床应用提供参考和依据。     

Stimulant drugs in the developmental disabilities revisited

In this paper, I attempt to update the evidence for a conceptual model published some years ago (Aman, 1982) that strived to account for variable responses to stimulant medication in children with normal IQ and in those with developmental disabilities. This model accounted for such variations in terms of differences in breadth of attention across clinical groups. Recent reports on the use of stimulant drugs in subjects with developmental disabilities were reviewed. The evidence shows that children with mental retardation and ADHD often benefit from such medication, although their response rate seems to be somewhat lower than that of ADHD children of normal IQ. There is a paucity of stimulant drug research with children having autism, but it is clear that some of them also benefit from stimulant medication. However, there are also reports of adverse behavioral reactions to the stimulants in some children with autism or PDD. Several studies examining predictor variables were reviewed. Breadth of attention, IQ, and mental age have been useful in predicting outcome in a number of studies, and I argue that this supports the model. There is a continuing need for stimulant drug research in children with developmental disabilities, especially in those with autism. There is also merit in assessing cognitive variables suggested by the model as well as demographic and clinical variables for their ability to predict clinical response in these children.     

Methylphenidate Facilitates Hypnotizability in Adults With ADHD: A Naturalistic Cohort Study

Impaired attention may impede learning of adaptive skills in ADHD. While manipulations that reduce competition between attentional processes, including hypnosis, could boost learning, their feasibility in ADHD is unknown. Because hypnotic phenomena rely on attentional mechanisms, the authors aimed to assess whether stimulants could enhance hypnotizability in ADHD. In the current study, stimulant-naïve patients seeking treatment for ADHD-related symptoms were assessed with the Stanford Hypnotic Susceptibility Scale (SHSS) at baseline and during methylphenidate treatment. Methylphenidate dose and SHSS increase were negatively correlated with baseline SHSS scores. Upon reaching effective doses, mean SHSS scores increased significantly. All patients who had been poorly hypnotizable at baseline demonstrated moderate-to-high hypnotizability at follow-up. The data support methylphenidate enhancement of hypnotizability in ADHD, thus highlighting novel treatment approaches for this disabling disorder.     

Symptoms of Attention Deficit Hyperactivity Disorder in Children and Adults with Intellectual Disability: A Review

Background Despite a reported excess of attention deficit hyperactivity disorder (ADHD) symptoms in individuals with intellectual disability, it has been argued that ADHD symptoms have been under diagnosed and inadequately treated in individuals with intellectual disability. Materials and methods Published studies focussing on the level of ADHD symptoms in children and adults with intellectual disability are reviewed. Issues around screening for ADHD symptoms in individuals with intellectual disability and the validity of the diagnosis of ADHD are considered. Interventions including pharmacological studies are discussed with respect to published research. Results Reported prevalence rates of ADHD symptoms in individuals with intellectual disability vary significantly depending on instruments and diagnostic practices employed. Published research on interventions for individuals with ADHD has primarily focussed on pharmacological interventions. Conclusion Much less is known about ADHD in individuals with intellectual disability than about ADHD in individuals without intellectual disability. There is an urgent need to clarify baseline rates of ADHD in individuals with intellectual disability and to develop efficacious interventions to support affected individuals and their families.     

The Diagnosis and Management of Anxiety in Adolescents With Comorbid ADHD

Among adolescents suffering from attention-deficit/hyperactivity disorder (ADHD), comorbid anxiety disorders are common, and symptoms need to be recognized early to minimize the potential impact on their quality of life. Anxiety disorders are recognized by using validated screening tools such as the Screen for Child Anxiety Related Emotional Disorders and the Spence Children’s Anxiety Scale. Clinicians should first optimize ADHD therapy to ensure anxiety is not related to uncontrolled ADHD. This population benefits greatest from family-based cognitive behavioral therapy; however, best results are seen with the addition of pharmacotherapy. Pharmacological regimens include switching from stimulants to atomoxetine or the addition of selective serotonin reuptake inhibitors.     

Self-concept in children and adolescents with attention deficit hyperactivity disorder

Children with attention deficit hyperactivity disorder (ADHD) struggle with behavioral symptoms, yet little research has provided information about how behavioral symptoms impact their self-concept, especially in terms of gender, age, and ethnicity. Data were collected from 145 children and adolescents with ADHD and their mothers. African Americans, Hispanic Americans, and Caucasians were nearly equally represented in the sample, with approximately one third each. The Child Behavior Checklist was used to assess ADHD symptom severity, and Piers--Harris Children's Self-Concept Scale was used to measure self-concept. Older ages and more internalizing behavior problems predicted lower self-concept. There were no significant differences between ethnic groups on behavior problem and self-concept scores, although post hoc analyses revealed a trend for Caucasian children with ADHD to have lower self-concept scores than those of African American or Hispanic children. The findings indicate that there is a need to assess self-concept in children and adolescents with ADHD, especially those who are older and have comorbid conditions of anxiety and depression.     

Attention-deficit/hyperactivity disorder: is it time to reappraise the role of sugar consumption?

Attention-deficit/hyperactivity disorder (ADHD) affects nearly 10% of children in the United States, and the prevalence of this disorder has increased steadily over the past decades. The cause of ADHD is unknown, although recent studies suggest that it may be associated with a disruption in dopamine signaling whereby dopamine D2 receptors are reduced in reward-related brain regions. This same pattern of reduced dopamine-mediated signaling is observed in various reward-deficiency syndromes associated with food or drug addiction, as well as in obesity. While genetic mechanisms are likely contributory to cases of ADHD, the marked frequency of the disorder suggests that other factors are involved in the etiology. In this article, we revisit the hypothesis that excessive sugar intake may have an underlying role in ADHD. We review preclinical and clinical data suggesting overlaps among ADHD, sugar and drug addiction, and obesity. Further, we present the hypothesis that the chronic effects of excessive sugar intake may lead to alterations in mesolimbic dopamine signaling, which could contribute to the symptoms associated with ADHD. We recommend further studies to investigate the possible relationship between chronic sugar intake and ADHD.     

Transitioning Youth With Attention Deficit Hyperactivity Disorder to Adult Health Care

Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood neurodevelopmental diseases and nearly two thirds of children with ADHD have symptoms that persist into adulthood. Approximately 750,000 children with special health care needs transition from pediatric to adult health care annually in the United States. For youth with ADHD, organized, coordinated, and systematic care transition from pediatric to adult health care providers is essential to prevent negative consequences related to unmanaged ADHD symptoms and to optimize health and promote maximum functioning. The Got Transition model's 6 core elements provide a guide to support successful transition for adolescents with ADHD.     

Attention-deficit/hyperactivity disorder

ADHD continues to be one of the most common psychiatric disorders in children and is recognized increasingly as a common psychiatric disorder in adults. Diagnosis of the disorder requires careful consideration of other psychiatric and medical disorders that may mimic symptoms of ADHD. Comorbid disorders are common in patients with ADHD and require careful attention. A recommended diagnostic evaluation for children and adults includes the completion of a psychiatric interview, rating scales from multiple informants, and often individually tailored psychologic testing. Pharmacologic treatment options include the first-line stimulant agents for adults and children and TCAs and atypical antidepressants as second-line agents. Behavioral interventions may help reduce ADHD symptoms and address comorbid conditions in children. Future research is needed to identify the optimal psychosocial treatment for adults with ADHD.