Background,clinical features and treatment of attention deficit hyperactivity disorder in children

Introduction: Attention deficit hyperactivity disorder (ADHD) is an early onset, clinically heterogeneous, complex neurobiological disorder, defined by symptoms of inattention and hyperactivity/impulsivity and has been associated with a broad range of impairments for those affected. Additionally, ADHD in children and adolescents is frequently associated with psychiatric comorbidities. This review provides an overview of the epidemiology, neurobiology, genetics, diagnosis and most recent pharmacological approaches for treatment with a focus on safety and efficacy and describes the use of medications used to treat ADHD in special populations.

Areas covered: PubMed, Cochrane database, Essential Evidence and Uptodate were searched for relevant articles about stimulant and non-stimulant pharmacological approaches in ADHD.

Expert opinion: Data supporting the safety and efficacy of both stimulant and non-stimulant formulations have significantly grown over the past decade and more efforts are being made to tailor medications to the needs of the patients and their families. Pharmacogenomics research is evolving, but predictors of treatment response and side effects remain largely unknown. Other unmet clinical needs include long-term follow-up studies of the safety and efficacy of medications for those with ADHD alone, or with comorbidities and in special populations including preschoolers.     

Lisdexamfetamine dimesylate: a new option in stimulant treatment for ADHD

Importance of the field: Attention deficit/hyperactivity disorder (ADHD), a prevalent disorder in children and adults, presents a substantial societal burden in both monetary cost and human suffering. Characterized by significant difficulties in maintaining attention, completing tasks, motor control, and appropriate social engagement, the disorder begins early in life and results in significant impairment across domains of functioning, including social, educational, and occupational achievement. The condition also carries heightened risk of substance use and dependence, and criminal activity. Pharmacologic treatment is a key component of ADHD management and has been found to be cost effective and generally well tolerated. However, despite increasing options for medication therapy, community management of ADHD is suboptimal. This review assesses current research on lisdexamfetamine dimesylate (LDX), a relatively recent addition to the range of treatment options.

Areas covered in this review: This review summarizes peer-reviewed literature on LDX published 2003 – 2010.

What the reader will gain: The reader will gain insight into the efficacy and safety of LDX in the treatment of ADHD, and its place in the clinical armamentarium.

Take home message: LDX is a useful addition to the formulary, showing similar efficacy and safety profiles to other stimulants.     

Attention-deficit/hyperactivity disorder treatment: what are the long-term cardiovascular risks?

Introduction: This drug safety review provides an update on the long-term cardiovascular risks of therapeutic stimulant class medication for children and adults with attention-deficit/hyperactivity disorder (ADHD).

Areas covered: Relevant literature on the long-term (defined as ≥ 12 months) cardiovascular effects of stimulant class medications for ADHD was sought using PubMed searches for clinical literature, epidemiological reports, as well as reviews of post-marketing data and clinical guidelines/consensus statements. Comparison was made to the non-stimulant atomoxetine.

Expert opinion: Long-term cardiovascular risks of stimulants for healthy children and adults with ADHD are limited to minor mean elevations in blood pressure (≤ 7 mmHg) and heart rate (≤ 10 bpm). In a sizeable minority of individuals these elevations are greater and/or reach a clinical threshold. Subjective complaints may also be anticipated during long-term treatment, yet without an increase in serious cardiac outcomes above background rates per age. Future research is needed on possible latent or cumulative cardiovascular risks in healthy individuals, as well as the longer-term cardiovascular safety in vulnerable populations.     

Impact of Central Nervous System Stimulant Medication Use on Growth in Pediatric Populations with Attention-Deficit/Hyperactivity Disorder: A Review

Central nervous system stimulants are a commonly used first-line treatment option for attention-deficit/hyperactivity disorder (ADHD). Stimulants are generally well tolerated, with anorexia and insomnia the most common adverse effects. However, there are some concerns with long-term use of stimulants, such as potential growth delay. Historically, data regarding this long-term adverse effect have been conflicting. In this article, we review the newer data surrounding the effects of central nervous system stimulants on growth parameters in children with ADHD. We conducted a literature search of the PubMed database; only articles using ADHD criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, were included to ensure the most up-to-date review of literature. Nine articles were identified for relevance and quality and are discussed in this review, describing clinical observations of height and weight of adolescent or pediatric patients receiving stimulant medications for ADHD therapy. In summary, this review points toward potential associations between duration of treatment and higher doses of stimulants with decreased weight and body mass index. Furthermore, this review demonstrates that evidence is still conflicting regarding the relationship between stimulant use and significant height decreases. Future studies with higher quality of evidence are needed to observe this potential adverse effect of stimulants in children and adolescents.     

Stimulant Medication for ADHD in Opioid Maintenance Treatment

Objective: The use of central stimulant medication in adults with attention deficit hyperactivity disorder (ADHD) who receive opioid maintenance treatment remains controversial and empirical evidence is limited. Because of the abuse potential of stimulant drugs, Norway has restrictions on prescribing central stimulants to individuals who have substance use disorders or who are on opioid maintenance treatment. In this naturalistic study, we describe experiences from a program through which central stimulant medication was administered to patients with ADHD receiving opioid maintenance treatment. Methods: This report is based on a program evaluation of a combined treatment project designed to provide stimulant medication to patients with adult ADHD who were receiving opioid maintenance treatment. As part of the clinical treatment, patients were monitored closely for any medical issues or adverse medication reactions and provided regular urine samples for analysis and information regarding demographics, treatment goals, legal involvement, diagnoses, substance abuse, and ADHD symptoms. Monitoring occurred at baseline, at 2 months (after patients being stabilized on the central stimulant), and again at 3, 6 and 24 months. Results: Among 42 patients initially offered the combined treatment, 24 were actually eligible, 20 started the combined treatment, and 10 stayed in the program. We were not able to identify a single major cause of treatment dropout. Patients reported significantly fewer symptoms of ADHD at the 6- to 8-week point, regardless of whether the data were analyzed using an intent-to-treat (all participants) or per-protocol (only those with complete data at all points) method. Even though self-assessed ADHD scores dropped significantly during treatment, the scores still remained fairly high, suggesting persistent functional impairment. Neither severe complications nor increase in substance abuse were observed during treatment with central stimulants. Conclusions: These findings show some promise with regard to the safety and utility of central stimulant medications for patients with ADHD who are receiving opioid maintenance treatment. Our study has methodological limitations, and systematic, well-designed clinical investigations are needed to increase the knowledge base.     

Current Investigational Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder

Introduction: Symptoms of attention-deficit/hyperactivity disorder (ADHD) were first described more than 100 years ago. It is a common neurobehavioral disorder that begins in childhood and often persists into adulthood. Treatment for ADHD has been available since Bradley first prescribed amphetamines for hyperkinetic boys more than 70 years ago. Although multiple effective medications for the treatment of ADHD are on the market, all have limitations. Stimulants are controlled substances and may not be effective or tolerable for all patients. The non-stimulants are not as effective as stimulants and have their own side effect profiles.

Areas Covered: In this review, the limitations of currently available medications including methylphenidates, amphetamines, atomoxetine, extended-release guanfacine and extended-release clonidine are considered and drugs in development for the treatment of ADHD are examined. Although the main focus is on phase I and II trials, drugs which may soon be marketed are also discussed.

Expert opinion: Multiple drugs are currently in development, with several targeting novel receptors originally identified using animal models. Since ADHD appears to be complex disorder associated with multiple genes, these models have often not predicted effectiveness in humans. Until there is a better understanding of the genetics of ADHD, drug development will remain challenging.     

Evaluation of the current data on guanfacine extended release for the treatment of ADHD in children and adolescents

ABSTRACT

Introduction: Attention-deficit/hyperactivity disorder (ADHD) commonly occurs in children, adolescents, and adults. Although symptoms of ADHD often respond robustly to treatment with stimulants (amphetamine or methylphenidate), not all patients are appropriate candidates for treatment with these drugs. Guanfacine extended-release (GXR) is a non-stimulant alternative drug approved for the treatment of ADHD in the United States (U.S.), Canada, and Europe.

Areas covered: The chemistry, pharmacokinetics, mechanism of action and dosage of GXR are presented. Efficacy and safety data obtained in clinical trials with subjects aged 6–17 years for both GXR monotherapy and use in combination with stimulants are described. Meta-analyses comparing GXR to other drugs are presented. MedWatch surveillance data collected for GXR since approval in the U.S. are also discussed.

Expert opinion: Although GXR is effective for the treatment of ADHD and has a different side effect profile than stimulants, it is not as impressive in reducing symptoms. Despite the availability of multiple pharmacological treatments for ADHD, there remains an unmet need for formulations as potent as stimulants but with fewer adverse effects. Several pharmacological agents for ADHD treatment are in development. It is not clear that any of these compounds will replace currently available formulations as first-line alternatives.     

Pediatric pharmacoepidemiology - safety and effectiveness of medicines for ADHD

Introduction: Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder in children and adolescents that comprises core symptoms of developmentally inappropriate levels of inattention and/or hyperactivity and impulsivity. Stimulant (methylphenidate, amphetamines) and non stimulant (atomoxetine, clonidine and guanfacine) are the treatment usually prescribed for ADHD.

Area covered: This review covers the safety of ADHD medications in children and adolescents.

MEDLINE, EMBASE and PsycINFO databases were searched with the aim to retrieve prospective studies that monitored the incidence of adverse events (AEs) in children receiving drug therapy for ADHD. Many of the studies investigated the risk of specific AEs. In particular, the cardiovascular safety, the impact on growth and on sleep pattern, the risk of substance use disorders and of suicidal ideation are among the topics more studied.

Expert opinion: Effective drugs for ADHD appears to be safe and well tolerated. Most of the adverse events reported in the randomised controlled trials are mild and transient. Decreased appetite, growth decrease and the impact on sleep (insomnia for stimulants and somnolence for alpha2-agonists) are among the most common events. Concerns exist about cardiovascular and psychiatric AEs, even if the available evidence does not support an association with medications.     

A qualitative review of issues arising in the use of psycho­stimulant medications in patients with ADHD and co‑morbid substance use disorders

ABSTRACT

Objective: This review addresses the relationship between attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs), with an emphasis on factors that determine the potential for psychostimulant abuse. Strategies for identification and treatment of patients with ADHD who are at risk for, or have, co-morbid SUD are also addressed.

Research design and methods: The article was based on a qualitative review of current literature addressing co-morbid ADHD and SUD.

Discussion: Adolescent and adult patients with ADHD are at increased risk for SUD, as well as a number of other psychiatric disorders. Psychostimulant agents like methyl­phenidate (MPH) and mixed amphetamine salts (MAS) are effective first-line pharmacotherapies for ADHD; however, they are Schedule II controlled substances with a potential for abuse. Evidence suggests that treatment of ADHD during childhood with stimulant agents may reduce the risk of developing SUD later on. Factors associated with the highest risk of SUD in patients with ADHD include co-morbid antisocial personality disorder, bipolar disorder, an eating disorder, severe ADHD and/or antisocial behavior symptoms, and dropping out of school. Treatment initiation during adolescence or young adulthood also has been linked to increased risk of polydrug use and non-medical stimulant use, a pattern of behavior consistent with a risk of SUD development. Treatment plans for patients with ADHD and co-morbid SUD should include behavioral interventions, careful monitoring, and when appropriate, pharmacotherapy. When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD. Long-acting stimulant formulations and non-stimulants, like atomoxetine or bupropion, have a lower potential for abuse, and provide several safe and effective treatment options for the development of a comprehensive manage­ment plan for patients with co-morbid ADHD and SUD.

Conclusions: The present review is neither exhaustive nor systematic. Moreover, the reviewed studies vary wide­ly with regards to methodology and patient populations. In light of these limitations, several conclusions are still warranted. Patients with ADHD are at increased risk for SUD. Under certain conditions, psychostimulants may be a pharmacologic option in the treatment of patients with co-morbid ADHD and SUD. However, clinicians should be mindful of the risks and benefits of this treatment approach in a high-risk population and should also bear in mind the labeling guidelines when working with this co-morbidity.     

Current and emerging pharmacotherapy for the treatment of adult attention deficit hyperactivity disorder (ADHD)

ABSTRACT

Introduction: ADHD is characterized by a developmentally inappropriate level of inattentiveness, impulsivity and/or hyperactivity. In adults, the disorder is frequently accompanied by Emotional Dysregulation (ED), associated to a variety of related psychiatric comorbidities, complicating its recognition and treatment management.

Areas covered: This paper reviews randomized active comparator-controlled or placebo-controlled trials evaluating the use of pharmacotherapy in adults with ADHD and ED, other neurodevelopmental disorders, Bipolar Disorder (BD) and Anxiety Disorders (ADs). When controlled data are unavailable, the authors have included open-label and observational studies.

Expert opinion: ED in adult patients with ADHD is a very common and impairing problem that can be treated with stimulants or atomoxetine. ADHD studies in adults with other neurodevelopment disorders are scarce; stimulants seem to be the most effective and safe drugs in treating ADHD symptoms, without worsening the core features of other neurodevelopmental disorders. In patients with ADHD and comorbid BD, the treatment of BD alone may result in residual symptoms of ADHD. Patients should be treated hierarchically: BD should be treated first, while ADHD should be treated combining ADHD medications and mood stabilizers after mood stabilization. The available evidence for treating patients with ADHD and comorbid ADs in adults supports the idea of an anti-anxiety/ADHD-specific treatment association.     

Dexmethylphenidate for attention deficit hyperactivity disorder

Background: Dexmethylphenidate is a single-isomer stimulant medication approved for the treatment of attention deficit hyperactivity disorder (ADHD). Single-isomer drugs have the potential for decreased undesired effects and improved therapeutic efficacy. Stimulant medications have been the mainstay treatments for ADHD for fifty years, and ability to reduce their adverse effects would be useful in promoting patient compliance with treatment. Objective: To review the literature on the safety and efficacy of dexmethylphenidate. Methods: MedLine, PubMed search of dexmethylphenidate research. Results/conclusions: Dexmethylphenidate is a safe and effective treatment for ADHD. Its overall safety and tolerability profile is similar to other members of the psychostimulant class.     

Efficacy and tolerability of pharmacotherapies for attention-deficit hyperactivity disorder in adults

This review examines the evidence regarding the efficacy and tolerability of long- and short-acting stimulant medications, as well as the non-stimulant medications atomoxetine and bupropion in the treatment of adult attention-deficit hyperactivity disorder (ADHD). Effect sizes in adults appear to be of almost the same magnitude as in school-age children when robust doses are used. There are adequate data demonstrating short-term efficacy and safety of medication in ADHD during adulthood but long-term studies are lacking, particularly in view of concerns regarding cardiovascular adverse events. There is some evidence that stimulant medication can improve driving performance in adults with ADHD. The extent to which medication may improve academic, occupational and social functioning in adults with ADHD is unclear, and future research should investigate these outcomes. Medication treatment of adults with ADHD in sports is controversial. Both stimulant and non-stimulant medications seem to be well tolerated. Monitoring of pulse and blood pressure is recommended with these drugs because of their cardiovascular effects. There have been extremely rare case reports of sudden death in adults and children treated with stimulants and atomoxetine, but it is difficult to clearly establish causality. In view of reports of treatment-related suicide-related behaviour with atomoxetine, it is recommended that adults should be observed for agitation, irritability, suicidal thinking, self-harming or unusual behaviour, particularly in the first months of treatment, or after a change of dose. ADHD in adults continues to remain an under-recognized disorder in many parts of the world and there is a lack of specialist clinics for assessment and treatment of adult ADHD. Studies to date have failed to show efficacy of medications in the treatment of ADHD in the substance misuse population. There is little evidence so far to suggest an increased misuse of stimulants or diversion amongst substance misusers; however, data are insufficient to draw firm conclusions. Further work is necessary to evaluate effective treatments in subgroups such as the substance misuse population, those with multiple co-morbidities and different ADHD subtypes.     

The use of stimulants and atomoxetine in adults with comorbid ADHD and bipolar disorder

Introduction: Attention deficit/hyperactivity disorder (ADHD) persists into adulthood in about 50% of the affected children, with high rates of comorbidity with bipolar disorder (BD). Stimulants and atomoxetine (ATX) are effective treatments for ADHD, but their use in adults with comorbid BD (ADHD-BD) has not been extensively studied and may be problematic.

Areas covered: The aim of the paper is to summarize the available literature regarding the use of these medications in ADHD-BD adult patients. Results of randomized-controlled and open-label trials, case reports, and case series are reviewed. We also reviewed data relative to some specific issues of this comorbidity in adults, especially substance use disorder, malingering, and stimulants misuse.

Expert opinion: ADHD-BD may be associated with more severe symptoms, course, and worst outcome of both conditions. The frequent coexistence with alcohol and substance abuse may further complicate treatment management. Stimulants are the most effective medications for ADHD, but their use may be contraindicated in the presence of a comorbid drug abuse or in patients that simulate or exaggerate ADHD symptoms in order to obtain stimulants for diversion or abuse. ATX may be effective in the treatment of ADHD symptoms in BD patients, with a modestly increased risk of (hypo)manic switches and destabilization of the mood disorder when utilized in association with mood stabilizers. In the majority of the cases, a hierarchical approach is desirable, with mood stabilization preceding the treatment of ADHD symptoms. Although systematic trials on the use of stimulants and ATX in ADHD-BD comorbidity in adulthood are necessary, both treatments should be considered possible options to be carefully evaluated once the patient has been stabilized.     

The safety of extended-release drug formulations for the treatment of ADHD

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder affecting millions of patients worldwide. Effective treatments have been available for more than 60 years in the form of immediate-release (IR) stimulants However, stimulants have a high risk for abuse and are associated with adverse effects Including elevated blood pressure and heart rate, insomnia and decreased appetite. IR formulations also require multiple daily dosing. The search for improved safety, tolerability and convenience has led to the development of multiple extended-release (ER) stimulant and non-stimulant formulations.

Areas covered: Adverse effects of (ER) products including amphetamine, methylphenidate, clonidine and guanfacine will be reviewed and their significance discussed.

Expert opinion: Limitations of currently marketed medications have led to the search for drugs with efficacy comparable to ER stimulants and a more favorable adverse event profile. Several are in development, but their potential utility is not yet known. Current research is also focused on finding specific genetic defects in patients with ADHD. Exciting progress has been made with the identification of mGluR receptor defects in some patients. However because of the heterogeneity of the disorder, effective targeted treatments for the majority of patients with ADHD does not appear likely in the near future.     

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     

Aripiprazole for the treatment of bipolar disorder: a review of current evidence

Introduction: Several medications are available for the treatment of different phases of bipolar disorder, yet many of the drugs that are currently approved carry a substantial burden of side effects or do not lead all treated patients to remission.

Areas covered: This paper comprises a review and commentary regarding the use of oral and intramuscular aripiprazole in the acute and maintenance phases of bipolar disorder. Basic principles in dosing, switching, management of side effects and co-administration of aripiprazole with other medications are provided. This paper presents practical strategies to translate the data from clinical research into clinical practice.

Expert opinion: Aripiprazole has proven to be an effective medication for the acute treatment of manic and mixed episodes, as well as for the prophylactic–maintenance phase of bipolar disorder in patients recovering from a manic/mixed episode. Choosing the appropriate dosing and tapering strategy, addressing the side effects, controlling withdrawal symptoms from previous medications and using adjunctive medications when necessary are key to successful treatment with aripiprazole.     

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.     

Symptoms of Depression and ADHD in Relation to Stimulant Medication Misuse Among College Students

Background: The misuse of stimulant medications, commonly used for the treatment of attention-deficit/hyperactivity disorder (ADHD), is a concern on college campuses. Objective: This study sought to examine the relations between the misuse of stimulant medications and symptoms of depression and ADHD. Method: Eight hundred and ninety students ages 18–26 from one public university took a web-based survey including rating scales measuring symptoms of depression and ADHD. Results: The prevalence rate of misuse in the past year was 23%. Symptoms of depression were significantly related to misuse; however, once symptoms of ADHD were included in the analysis, depression was no longer a significant predictor. Further, there was not a significant interaction between ADHD and depression, but symptoms of ADHD were significantly related to misuse. Conclusions/Importance: Results suggest that attention difficulties may be one of the most important factors in predicting stimulant medication misuse. Therefore, prevention efforts to reduce the misuse of stimulant medication would be most successful when targeting students with symptoms of inattention.     

Long-term use of stimulants in children with attention deficit hyperactivity disorder: safety, efficacy, and long-term outcome

The purpose of this review is to summarize existing data on the long-term safety and efficacy of stimulant treatment, and how long-term stimulant treatment of children with attention deficit hyperactivity disorder (ADHD) affects their outcome. Existing controlled studies of children with ADHD treated and untreated with stimulants, as well as long-term prospective follow-up studies, are reviewed. Children with ADHD treated with stimulants for as long as 2 years continue to benefit from the treatment, with improvements observed in ADHD symptoms, comorbid oppositional defiant disorder, and academic and social functioning, with no significant problems of tolerance or adverse effects. Long-term, prospective follow-up studies into adulthood show that stimulant treatment in childhood has slight benefits regarding social skills and self-esteem. Long-term adverse effects from stimulant treatment in childhood regarding adult height or future substance abuse have not been supported by existing studies.     

Review of lisdexamfetamine dimesylate in children and adolescents with attention deficit/hyperactivity disorder

Abstract

Objective

Lisdexamfetamine dimesylate is a stimulant prodrug with low abuse and diversion potential that is used in treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults. This current literature review article aims to examine safety and efficacy of LDX in children and adolescents for the treatment of ADHD based on currently available data.