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.     

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.     

Compliance with stimulants for attention-deficit/hyperactivity disorder: issues and approaches for improvement

Attention-deficit/hyperactivity disorder (ADHD) affects approximately 8-10% of school-aged children in the US and for many individuals persists into adolescence and adulthood. Both pharmacological and nonpharmacological (behavioural) therapies are used to treat individuals with ADHD. Treatment with stimulant medications, which include methylphenidate and amphetamine, typically requires multiple daily doses to maintain efficacy. The frequency of treatment, coupled with the importance of timing of doses and the long-term nature of treatment, make noncompliance a particular issue in the treatment of ADHD. Studies report noncompliance rates of 20-65% with stimulant treatment, although there are only limited published studies and these show considerable individual variation. Noncompliance can arise through inadequate supervision of those receiving medication, leading to delayed or missed doses, or through the reluctance of individuals to take medication, which is influenced by a number of factors (e.g. social attitudes, pressures or worries surrounding medication use and the inconvenience of multiple daily doses). Two approaches are likely to increase compliance with stimulant treatment: effective once-daily formulations of medication and improved treatment information. The development of effective once-daily formulations for stimulant treatments removes the need for multiple daily doses, with the associated problems of ensuring adequate treatment supervision and personal privacy. Improved provision of education and information for individuals with ADHD, as well as their families and teachers, should help them address the issues surrounding stimulant medication and allow full participation in the treatment process. Together, these strategies should improve treatment compliance for individuals with ADHD.     

Understanding the Effects of Stimulant Medications on Cognition in Individuals with Attention-Deficit Hyperactivity Disorder: A Decade of Progress

The use of stimulant drugs for the treatment of children with attention-deficit hyperactivity disorder (ADHD) is one of the most widespread pharmacological interventions in child psychiatry and behavioral pediatrics. This treatment is well grounded on controlled studies showing efficacy of low oral doses of methylphenidate and amphetamine in reducing the behavioral symptoms of the disorder as reported by parents and teachers, both for the cognitive (inattention and impulsivity) and non-cognitive (hyperactivity) domains. Our main aim is to review the objectively measured cognitive effects that accompany the subjectively assessed clinical responses to stimulant medications. Recently, methods from the cognitive neurosciences have been used to provide information about brain processes that underlie the cognitive deficits of ADHD and the cognitive effects of stimulant medications. We will review some key findings from the recent literature, and then offer interpretations of the progress that has been made over the past decade in understanding the cognitive effects of stimulant medication on individuals with ADHD.     

Attention deficit and hyperactivity disorder: controversies of diagnosis and safety of pharmacological and nonpharmacological treatment

Attention-Deficit and Hyperactivity Disorder (ADHD) is a condition that presents with a variety of behavioral and social problems. The objective of this review was to examine the evidence concerning the controversies surrounding the diagnosis of ADHD and the safety of pharmacological and nonpharmacological treatment. A MEDLINE search was conducted using MeSH terms ADHD, children, treatments or behavioral therapy. The search was limited to January 1990 to present, randomized clinical trials, retrospective studies and English. Fifty-seven articles were selected for review. Controversies exist regarding the diagnosis: variations exist by gender, across countries and by method of diagnosis. These issues are currently unresolved. The interventions with the most data concerning their safety and efficacy in children were stimulant medications. Children with ADHD who took stimulant medications showed the greatest improvement in behavior when compared to other interventions such as behavior therapy or family counseling. Limitations of behavior therapy included that it is often a difficult process to continue on an ongoing basis and only a portion of the therapy stimulated the child's natural reward system. However, a combination of both stimulant medication and behavior therapy demonstrated synergistic efficacy. Care must be taken to insure that issues of gender and race, as well as the adverse effects of treatment options, are adequately taken into account by the treating clinician.     

Lisdexamfetamine dimesylate: a new therapeutic option for attention-deficit hyperactivity disorder

Attention-deficit hyperactivity disorder (ADHD) is associated with substantial functional, clinical and economic burdens. It is among the most common psychiatric disorders in children and adolescents, and often persists into adulthood. Both medication and psychosocial interventions are recommended for the treatment of ADHD. However, ADHD treatment practices vary considerably, depending on medication availability, reimbursement and the evolution of clinical practice in each country. In Europe, stimulants and atomoxetine are widely available medications for the treatment of ADHD, whereas in the US approved treatment options also include extended-release formulations of clonidine and guanfacine. Lisdexamfetamine dimesylate (lisdexamfetamine) is a long-acting, prodrug formulation of dexamfetamine. It is currently licensed in the US, Canada and Brazil, and is undergoing phase III studies in Europe. We performed a PubMed/MEDLINE search looking for recent (2005-2012) scientific papers regarding the pharmacokinetics, pharmacodynamics, efficacy and safety of lisdexamfetamine. The lisdexamfetamine molecule is therapeutically inactive and is enzymatically hydrolysed, primarily in the blood, to the active dexamfetamine. This conversion is unaffected by gastrointestinal pH and variations in normal transit times. Lisdexamfetamine was developed with the goal of providing an extended duration of effect that is consistent throughout the day. Clinical trials have demonstrated robust clinical efficacy of lisdexamfetamine in the treatment of children, adolescents and adults with ADHD with dose-dependent improvements in the core symptoms of ADHD. Studies have further shown that the duration of action of lisdexamfetamine continues for 13 hours post-dosing in children and for 14 hours in adults. The tolerability profile of lisdexamfetamine is consistent with those of other stimulant medications, with decreased appetite, insomnia, abdominal pain and irritability among the more frequent treatment-emergent adverse events, most of which are mild to moderate in intensity and transient in nature. There are currently no parallel-group, head-to-head trial data comparing the efficacy and safety of lisdexamfetamine with other medications for ADHD. However, the available data, including a large effect size and consistent plasma concentrations throughout the day, suggest that lisdexamfetamine is a useful treatment option for patients with ADHD.     

Pharmacotherapy of adolescent attention deficit hyperactivity disorder: challenges, choices and caveats

A recent increase in stimulant treatment of adolescents with attention deficit hyperactivity disorder (ADHD) has been documented. Challenges in treating adolescent ADHD with methylphenidate or dextroamphetamine include compliance with frequent dosing, abuse potential and wear-off or rebound effects. Co-morbid anxiety, occurring in at least 30 percent of ADHD youths, is associated with lower rate of response to stimulants. The effective alternatives, tricyclic antidepressants or pemoline, are each associated with rare but serious toxicity. Bupropion has recently proven effective in controlled trials. Other noradrenergic or dopamine-enhancing agents such as venlafaxine and nicotine show some benefit in open trials. The need for more options in pharmacotherapy of ADHD is evidenced by rapid adoption in clinical practice of alternative and adjunctive medication despite lack of controlled research on efficacy and safety. The indications for long-term stimulant treatment of ADHD present some controversy, and highlight a need for more research on safety and efficacy through the lifespan. Thresholds for diagnosis are much lower with DSM than with ICD, and thresholds for treatment are contentious, given the performance-enhancing effects of stimulants in normal students. The endpoint for treatment is unclear, as stimulants are also effective in adult ADHD. Based on short- and intermediate-term studies to date, stimulant medication is clearly more efficacious than cognitive and behavioral strategies for the symptoms of ADHD. Longer term research is needed to determine whether sustained stimulant therapy will reduce the adverse emotional, behavioral and academic consequences of inattention and impulsivity in adolescents and adults.     

Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: A review of controlled and naturalistic studies

Attention-deficit/hyperactivity disorder (ADHD) is a common disorder of childhood that often persists into adulthood. Although stimulant medications are recommended as the first-line treatment for ADHD because of their documented short-term effects in children and adults, less is known about their effects on long-term outcome in adults. Here we review the long-term efficacy and safety of the stimulant drugs methylphenidate and amphetamine, as well as the related compound atomoxetine. We performed a systematic review to identify direct and indirect effects of stimulant therapy on long-term outcome in adults. Five randomized controlled trials (RCTs), and 10 open-label extension studies of initial short-term RCTs, with total follow-up of at least 24 weeks, were identified. All these RCTs found that medication was significantly more efficacious than placebo in treating ADHD in adults, and the extension studies showed that this favorable effect of medication was maintained during the open-label follow-up period. However, since the maximum duration of these pharmacological trials was 4 years, we also reviewed 18 defined naturalistic longitudinal and cross-sectional studies, to provide more information about longer term functional outcomes, side effects and complications. These observational studies also showed positive correlations between early recognition of the disorder, stimulant treatment during childhood and favorable long-term outcome in adult ADHD patients. In conclusion, stimulant therapy of ADHD has long-term beneficial effects and is well tolerated. However, more longitudinal studies of long duration should be performed. In addition, the ethical issues involved in performing double blind RCTs of many years duration should be further explored.     

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.     

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.     

Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge

Attention-deficit hyperactivity disorder (ADHD), a common neurobehavioural disorder characterized by inattention, hyperactivity and impulsivity, is a chronic disorder and often persists into adulthood. CNS stimulants have been the most well known treatment for ADHD for several decades due to their high effectiveness, good safety profiles and relatively minor adverse effects. Non-stimulant agents, including atomoxetine, extended-release guanfacine and extended-release clonidine (US FDA approved), and several non-FDA-approved agents, such as bupropion and tricyclic antidepressants (TCAs), were recently proven to be effective alternatives to the stimulants in several open-label and placebo-controlled trials. However, most medication trials for ADHD have been short term and thus have not provided information on the long-term outcomes of ADHD treatment. Since the medical treatment of many children with ADHD, especially those with more severe symptoms or co-morbid disorders, has to be continued for several years, recent studies have shifted their focus from the acute effectiveness of stimulants or non-stimulant drugs to the long-term outcomes of medications for ADHD. Evidence has shown that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for 24-month treatment periods with few and tolerable adverse effects.     

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.     

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.     

Cerebellar Morphology and the Effects of Stimulant Medications in Youths with Attention Deficit-Hyperactivity Disorder

The cerebellum is emerging as a key anatomical structure underlying normal attentional and cognitive control mechanisms. Dysregulation within cerebellar circuits may contribute to the core symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). In the present study we aimed to characterize surface morphological features of the cerebellum in ADHD and healthy comparison youths. Further, we studied the association of cerebellar morphology with the severity of ADHD symptoms and the effects of stimulant treatment. We examined 46 youths with ADHD and 59 comparison youths 8–18 years of age in a cross-sectional, case–control study using magnetic resonance imaging. Measures of cerebellar surface morphology were the primary outcome. Relative to comparison participants, youths with ADHD exhibited smaller regional volumes corresponding to the lateral surface of the left anterior and the right posterior cerebellar hemispheres. Stimulant medication was associated with larger regional volumes over the left cerebellar surface, whereas more severe ADHD symptoms were associated with smaller regional volumes in the vermis. We used optimized measures of morphology to detect alterations in cerebellar anatomy specific to ADHD, dimensions of symptomology, and stimulant treatment. Duration of treatment correlated positively with volumes of specific cerebellar subregions, supporting a model whereby compensatory morphological changes support the effects of stimulant treatment.     

Adverse effects of pharmacotherapies for attention-deficit hyperactivity disorder: epidemiology, prevention and management

Medication for the treatment of attention-deficit hyperactivity disorder (ADHD) is in widespread use globally. There is considerable data suggesting that overall, the adverse effect burden from this use is dose dependent and is in the mild to moderate category, but few comprehensive reviews exist of the epidemiology of adverse effects alone. This review provides a general and systems-specific summary of the scientific literature regarding adverse effect data for the drugs in general use for the treatment of ADHD.Although several areas lack definitive data, current evidence suggests that, for the majority of those treated for ADHD, the medications currently available pose little in the way of risk of significant harm. Epidemiological data suggest a low incidence of serious adverse effects, whilst the less serious adverse effects, such as insomnia and anorexia, are relatively common. Also, some specific areas of study suggest lower risks of harm than previously thought, e.g. tic disorders and seizures. However, pre-existing conditions and other interindividual differences may raise the risk of harmful adverse effects, which adds emphasis to the need for careful pretreatment assessment and monitoring. Potential but unlikely long-term treatment effects need to be investigated as carefully as possible, particularly with regard to cardiac sequelae and carcinogenesis. There are both overlaps and differences between the adverse effects of stimulants and nonstimulants, such as atomoxetine. For example, the latter shares the stimulant group's potential for changing cardiovascular parameters, but may not cause insomnia.     

Substance abuse in patients with attention-deficit hyperactivity disorder : therapeutic implications

Attention-deficit hyperactivity disorder (ADHD) is a common disorder in children that frequently persists into adulthood. Studies have found that substance use disorders (SUD) are seen more commonly in those with ADHD than the general population. Although treatment with stimulant medications has been shown to be effective for individuals with ADHD, concern about the use of these agents in this population persists. This review article highlights the research in this area with a focus on the treatment of individuals who present with concomitant ADHD and SUD. Although stimulants can be abused, studies have shown that adolescents who are prescribed stimulants for ADHD have lower rates of SUD than those who are not treated with stimulants. It may be particularly difficult to evaluate adults for the diagnosis of ADHD when SUD is a co-morbid factor. Studies show that 20--30% of adults presenting with SUD have concomitant ADHD and approximately 20--40% of adults with ADHD have histories of SUD. Therefore, it is critical to perform careful diagnostic interviews to discern if patients have either or both of these disorders. Many clinical experts suggest that adults with ADHD and active SUD be treated for the SUD until a period of sobriety persists prior to initiation of specific treatment for ADHD. Since individuals with ADHD and active SUD are more likely to have more severe SUD and a worse prognosis, this approach may not serve many patients, as they relapse prior to obtaining ADHD treatment. Therefore, research has been directed towards determining if the treatment of ADHD with stimulant medications can be safe and effective for the individual with active SUD and concomitant ADHD. An initial trial of methylphenidate in a population of adults with active cocaine dependence and ADHD indicates that this is the case. Individuals with ADHD and SUD can present difficult diagnostic and therapeutic challenges. It appears that the most effective treatment option is to create a programme that uses the most effective treatment modalities available, including both behavioural and medical therapies, along with close supervision and monitoring. Newer medical treatment options of long-acting stimulants and non-stimulants (e.g. atomoxetine) offer effective treatment with a lower risk of abuse potential.     

The safety of non-stimulant agents for the treatment of attention-deficit hyperactivity disorder

Due to their well-established efficacy and safety, stimulants are the drugs of first choice if medication for attention-deficit hyperactivity disorder (ADHD) is required. Nevertheless, for some individuals other, non-stimulant treatments are needed for several reasons. If so, atomoxetine is recommended as a second-line treatment. In addition, several tricyclic antidepressants, such as desipramine or imipramine, as well as alpha-2 agonists, especially clonidine or bupropion, might be efficient in treating ADHD, in particular in specific co-morbid conditions. Despite the fact that non-stimulant treatments in ADHD are usually well-tolerated with side effects being mostly moderate and transient, special safety aspects and precautions, specific for each drug, have to be considered whenever a non-stimulant treatment is chosen. This review focuses on the tolerability, occurrence of adverse events, precautions required to prevent severe adverse events, and essential pharmacological interaction in the treatment of ADHD symptoms by non-stimulants.     

Effectiveness of one-year pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD): An open-label prospective study of time in treatment,dose, side-effects and comorbidity

How to generalize from randomized placebo controlled trials of ADHD drug treatment in adults to ‘real-world’ clinical practice is intriguing. This open-labeled prospective observational study examined the effectiveness of long-term stimulant and non-stimulant medication in adult ADHD including dose, side-effects and comorbidity in a clinical setting.A specialized ADHD outpatient clinic gave previously non-medicated adults (n=250) with ADHD methylphenidate as first-line drug according to current guidelines. Patients who were non-tolerant or experiencing low efficacy were switched to amphetamine or atomoxetine. Primary outcomes were changes of ADHD-symptoms evaluated with the Adult ADHD Self-Report Scale (ASRS) and overall severity by the Global Assessment of Functioning (GAF). Secondary outcomes were measures of mental distress, and response on the Clinical-Global-Impressions-Improvement Scale. Data at baseline and follow-ups were compared in longitudinal mixed model analyses for time on-medication, dosage, comorbidity, and side-effects.As results, 232 patients (93%) completed examination at the 12 month endpoint, and 163 (70%) remained on medication. Compared with the patients who discontinued medication, those still on medication had greater percentage reduction in ASRS-scores (median 39%, versus 13%, P<0.001) and greater improvement of GAF (median 20% versus 4%, P<0.001) and secondary outcomes. Continued medication and higher cumulated doses showed significant associations to sustained improvement. Conversely, psychiatric comorbidity and side-effects were related to lower effectiveness and more frequent termination of medication.Taken together, one-year treatment with stimulants or atomoxetine was associated with a clinically significant reduction in ADHD symptoms and mental distress, and improvement of measured function. No serious adverse events were observed.     

Safety of therapeutic methylphenidate in adults: a systematic review of the evidence

Attention deficit hyperactivity disorder (ADHD) often persists into adulthood. Stimulant drugs, including methylphenidate, have showed efficacy in trials for ADHD in adults. Adult psychiatrists are likely to encounter increasing numbers of adult patients who may benefit from methylphenidate. A systematic review of the literature was made to examine the evidence on the safety of methylphenidate, when used therapeutically in adults. Twenty-six placebo-controlled trials were found, in which 811 adults received methylphenidate for ADHD and other conditions. In the short term, methylphenidate was well tolerated and no serious side effects were observed. There is little information on the long-term safety of methylphenidate in adults, although the number of serious adverse effects reported to regulatory authorities has, so far, been low. Methylphenidate is associated with a modest rise in blood pressure and heart rate. Surveys of stimulant use in US universities show that misuse of prescribed medication, for recreation or to enhance study, is fairly common although the level of harm that arises from this practice is unclear.     

Management of treatment refractory attention-deficit/hyperactivity disorder in children and adolescents

Psychostimulants are the first-line treatment for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. A minimum of two psychostimulant trials should be instituted before a child's symptoms of ADHD are considered treatment refractory. Clinical issues of diagnostic accuracy, comorbid disorders, psychosocial factors, medication compliance, symptoms across settings, and behavioral treatment should be addressed before initiating alternative medication trials. With the exception of tricyclic antidepressants, there is a paucity of controlled studies with adequate sample size to support the efficacy and safety of nonstimulant medications for the treatment of childhood ADHD. In this article, data on medications for treatment refractory ADHD in children and adolescents are presented and treatment strategies are discussed.