Switching from neurostimulant therapy to atomoxetine in children and adolescents with attention-deficit hyperactivity disorder : clinical approaches and review of current available evidence

This review provides practical information on and clinical reasons for switching children and young people with attention-deficit hyperactivity disorder (ADHD) from neurostimulants to atomoxetine, detailing currently available evidence, and switching options. The issue is of particular relevance following recent guidance from the National Institute for Health and Clinical Excellence and European ADHD guidelines endorsing the use of atomoxetine, along with the stimulants methylphenidate and dexamphetamine, in the management of ADHD in children and adolescents in the UK. The selective norepinephrine (noradrenaline) reuptake inhibitor, atomoxetine, is a non-stimulant drug licensed for the treatment of ADHD in children and adolescents, and in adults who have shown a response in childhood. Following the once-daily morning dose, its therapeutic effects extend through the waking hours, into late evening, and in some patients, through to early the next morning. Atomoxetine may be considered for patients who are unresponsive or incompletely responsive to stimulant treatment, have co-morbid conditions (e.g. tics, anxiety, depression), and have sleep disturbances or eating problems, for patients in whom stimulants are poorly tolerated, and for situations where there is potential for drug abuse or diversion. Atomoxetine has been shown to be effective in relapse prevention and there is suggestion that atomoxetine may have a positive effect on global functioning; specifically health-related quality of life, self-esteem, and social and family functioning. According to one study, approximately 50% of non-responders to methylphenidate will respond to atomoxetine therapy and approximately 75% of responders to methylphenidate will also respond to atomoxetine. Atomoxetine may be initiated by a schedule of dose increases and cross-tapering with methylphenidate. A slow titration schedule with divided doses minimizes the impact of adverse events within the first several weeks of treatment. Atomoxetine may be co-administered with methylphenidate during the switching period without undue concern for adverse events, such as cardiovascular effects (although monitoring of blood pressure and heart rate is necessary). Atomoxetine may be discontinued abruptly and patients may miss the occasional dose without rebound effects or discontinuation syndrome. A trial period of at least 6-8 weeks, perhaps longer, is recommended before evaluation of the overall tolerability and efficacy of atomoxetine. We conclude that patients with ADHD can be switched from neurostimulants, specifically methylphenidate, to atomoxetine, and may benefit from symptom improvement.     

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.     

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.     

Atomoxetine: the first nonstimulant for the management of attention-deficit/hyperactivity disorder.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, drug interactions, dosage and administration, and place in therapy of atomoxetine in the treatment of attention-deficit/hyperactivity disorder (ADHD) are reviewed. SUMMARY: Atomoxetine is a methylphenoxy-benzenepropanamine derivative with antidepressant activity and is thought to enhance noradrenergic function via selective inhibition of the presynaptic norepinephrine transporter. Atomoxetine is rapidly absorbed from the gastrointestinal tract, reaching peak levels in 1.83 hours in pediatric patients and 1-1.5 hours in adults. The clinical efficacy of atomoxetine in the treatment of ADHD has been evaluated in six published clinical trials of children and adolescents and two studies enrolling only adults. Clinical trial data indicate that atomoxetine is safe and well tolerated for the treatment of ADHD; however, safety data about long-term use (greater than one year) are unavailable. Adverse events reported in clinical trials were mainly mild to moderate and transient in nature. Recommended dosing of atomoxetine is weight based, and dosages should be adjusted to a target dosage of 1.2 mg/kg/day in children and adolescents weighing 70 kg or less and to 80 mg/day in children and adolescents weighing over 70 kg and adults. While current guidelines from the American Academy of Pediatrics recommend stimulants and behavior modification as first-line therapy for the management of ADHD, atomoxetine offers those patients who do not respond to or cannot tolerate one or more stimulants an alternative treatment option. CONCLUSION: Atomoxetine, the first non-stimulant approved for the management of ADHD in children, adolescents, and adults, provides patients who have not responded to or cannot tolerate one or more stimulants an alternative treatment option.     

Current issues around the pharmacotherapy of ADHD in children and adults

Background New drugs and new formulations enter the growing market for ADHD medication. The growing awareness of possible persistence of ADHD impairment beyond childhood and adolescence resulting in increased pharmacotherapy of ADHD in adults, is also a good reason for making an inventory of the what is generally known about pharmacotherapy in ADHD. Aim To discuss current issues in the possible pharmacotherapy treatment of ADHD in children, adolescents and adults with respect to the position of pharmacotherapy in ADHD treatment guidelines, the pharmacoepidemiological trends, and current concerns about the drugs used. Methods A search of the literature with an emphasis on the position of pharmacotherapy in ADHD treatment guidelines, the pharmacoepidemiological trends, and current concerns about the drugs used in pharmacotherapy. Results According to the guidelines, the treatment of ADHD in children consists of psychosocial interventions in combination with pharmacotherapy when needed. Stimulants are the first-choice drugs in the pharmacological treatment of ADHD in children despite a number of well known and frequently reported side effects like sleep disorders and loss of appetite. With regard to the treatment of adults, stimulant treatment was recommended as the first-choice pharmacotherapy in the single guideline available. Both in children and adults, there appears to be an additional though limited role for the nonadrenergic drug atomoxetine. The increase of ADHD medication use, in children, adolescents and in adults, can not only be interpreted as a sign of overdiagnosis of ADHD. Despite the frequent use of stimulants, there is still a lack of clarity on the effects of long-term use on growth and nutritional status of children. Cardiovascular effects of both stimulants and atomoxetine are rare but can be severe. The literature suggests that atomoxetine may be associated with suicidal ideation in children. Conclusion Although pharmacotherapy is increasing common in the treatment of ADHD in both children and adults, there are still a lot of questions about side effects and how best to counter them. This suggests an important role for close monitoring of children and adults treated with stimulants or atomoxetine.     

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.     

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.     

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.     

Comparative benefits and harms of competing medications for adults with attention-deficit hyperactivity disorder: a systematic review and indirect comparison meta-analysis

Rationale Recommended medication prescribing hierarchies for adult attention-deficit hyperactivity disorder (ADHD) vary between different guideline committees. Few trials directly compare competing ADHD medications in adults and provide little insight for clinicians making treatment choices. Objective The objective of this study was to assess comparative benefits and harms of competing medications for adult ADHD using indirect comparison meta-analysis. Materials and methods Eligible studies were English-language publications of randomized controlled trials comparing ADHD drugs to placebo. Data sources were electronic bibliographic databases, Drugs@FDA, manufacturer data, and reference lists. Two reviewers independently abstracted data on design, internal validity, population, and results. Benefits and harms were compared between drug types using indirect comparison meta-regression (ratio of relative risks). Results Twenty-two placebo-controlled trials were included (n = 2,203). Relative benefit of clinical response for shorter-acting stimulants, primarily immediate release methylphenidate, was 3.26 times greater than for patients taking longer-acting stimulants (95% CI 2.03, 5.22) and 2.24 times greater than for patients taking longer-acting forms of bupropion (95% CI 1.23, 4.08). Immediate release methylphenidate is also the only drug shown to reduce ADHD symptoms in adults with substance abuse disorders. Neither non-stimulants nor longer-acting stimulants reduced adverse effects compared to shorter-acting stimulants. Key gaps in evidence were academic, occupational, social functioning, cardiovascular toxicity, and longer-term outcomes, influences of ADHD subtype and/or comorbidities, and misuse/diversion of the drugs. Conclusions Current best evidence supports using immediate release methylphenidate as first-line treatment for most adults with ADHD. Financial disclosures None of the authors or the person named in the Acknowledgments section have any financial interest in any company that makes or distributes the products reviewed in this report.     

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 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.     

Influence of stimulant and non-stimulant drug treatment on driving performance in patients with attention deficit hyperactivity disorder: A systematic review

Adults with Attention Deficit Hyperactivity Disorder (ADHD), especially teenagers and young adults, show important car driving impairments, including risky driving, accidents, fines and suspension of driver׳s license. We systematically reviewed the efficacy of stimulant and non-stimulant drugs on driving performance of ADHD patients. We searched several databases for randomized controlled trials (RCTs) published through March, 2013. Fifteen RCTs (the majority with crossover design) evaluated methylphenidate (MPH) immediate-release (MPH-IR), MPH osmotic-controlled oral system (MPH-OROS), MPH transdermal system (MTS), extended-release mixed amphetamine salts (MAS-XR); atomoxetine (ATX) and lisdexamfetamine (LDX). Methods varied widely; including simulators and/or cars and different courses and scenarios. Various outcomes of driving performance, including a ‘composite’ or ‘overall’ driving score were considered. In general, stimulants improved driving performance in ADHD patients (either in RCTs conducted in simulators and/or cars). MPH-OROS improved driving performance compared with MAS-XR, placebo, or no-drug conditions. Although MPH-OROS and MPH-IR produced similar improvements during the day, MPH-IR lost its efficacy in the evening. MAS-XR also improved driving performance, but worsened driving performance in the evening. MTS (one study) showed a positive effect, but drug compliance varied widely across patients. LDX had positive effect on driving (two studies with the same sample). Studies with ATX report conflicting results. Improvement was more consistent in teenagers and young adults. In general, treatment with psychostimulants or ATX in therapeutic dosages had no negative impact on driving performance of ADHD patients. To conclude, treatment with stimulants in therapeutic doses improves driving performance in ADHD patients, especially teenagers and young adults.     

New formulations of stimulants for attention-deficit hyperactivity disorder: therapeutic potential

New formulations of stimulant medications for the treatment of attention-deficit hyperactivity disorder (ADHD) have been an important focus for pharmaceutical industry research and development over the past decade. In this article, we review and assess the therapeutic potential of five new stimulant formulations (one immediate release and four longer-acting preparations) that have recently become available for the treatment of ADHD.While the therapeutic potential of immediate-release enantiomers of methylphenidate has not yet been clinically realised, new long-acting formulations of stimulants have changed the standard of care for children, adolescents and adults with ADHD. The longer duration of action of these once-daily compounds, and the consequent expansion of the duration of daily ADHD coverage afforded by them, has introduced the realistic possibility of reducing the overall daily burden of ADHD on affected individuals. Although more expensive, these new stimulant formulations are easier for patients to use than older stimulants, more resistant to abuse and misuse, and allow for increased privacy of ADHD treatment at school or work.     

Comparison of the inhibitory and excitatory effects of ADHD medications methylphenidate and atomoxetine on motor cortex.

Stimulant and norepinephrine (NE) reuptake inhibitor medications have different effects at the neuronal level, but both reduce symptoms of attention deficit hyperactivity disorder (ADHD). To understand their common physiologic effects and thereby gain insight into the neurobiology of ADHD treatment, we compared the effects of the stimulant methylphenidate (MPH) and NE uptake inhibitor atomoxetine (ATX) on inhibitory and excitatory processes in human cortex. Nine healthy, right-handed adults were given a single, oral dose of 30 mg MPH and 60 mg ATX at visits separated by 1 week in a randomized, double-blind crossover trial. We used paired and single transcranial magnetic stimulation (TMS) of motor cortex to measure conditioned and unconditioned motor-evoked potential amplitudes at inhibitory (3 ms) and facilitatory (10 ms) interstimulus intervals (ISI) before and after drug administration. Data were analyzed with repeated measures, mixed model regression. We also analyzed our findings and the published literature with meta-analysis software to estimate treatment effects of stimulants and NE reuptake inhibitors on these TMS measures. There were no significant pretreatment differences or effects of treatment order. Both agents produced a significant increase in facilitation and a decrease in inhibition. Effects of ATX and MPH did not differ significantly. Pooled estimates from published studies show similar results for stimulants and NE reuptake inhibitors. In conclusion, in healthy adults, both stimulant and nonstimulant medications for ADHD decrease cortical inhibition and increase cortical facilitation. Cortical inhibition, shown previously to be abnormal in ADHD, may play a key role producing behavioral pathology.     

Methylphenidate and atomoxetine increase histamine release in rat prefrontal cortex

Using microdialysis in rat prefrontal cortex, we found that 1 mg/kg of the stimulant methylphenidate and the non-stimulant atomoxetine, two widely used treatments for Attention Deficit/Hyperactivity Disorder (ADHD), produce robust increases in the extracellular levels of histamine, which plays a key role in attention, learning and memory. While the clinical response to ADHD drugs is typically attributed to modulation of norepinephrine and dopamine, this finding suggests enhanced histamine release may contribute to their efficacy as ADHD treatments.     

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.     

Atomoxetine, a novel treatment for attention-deficit-hyperactivity disorder

Atomoxetine is the first nonstimulant drug approved by the United States Food and Drug Administration (FDA) for the treatment of attention-deficit-hyperactivity disorder (ADHD), and the only agent approved by the FDA for the treatment of ADHD in adults. Atomoxetine is a norepinephrine transport inhibitor that acts almost exclusively on the noradrenergic pathway. Its mechanism of action in the control and maintenance of ADHD symptoms is thought to be through the highly specific presynaptic inhibition of norepinephrine. Clinical trials to evaluate the short-term effects of atomoxetine in children and adults have shown that atomoxetine is effective in maintaining control of ADHD. Likewise, long-term trials have determined that atomoxetine is effective in preventing relapse of ADHD symptoms without an increase in adverse effects. A comparative trial of atomoxetine with methylphenidate in school-aged children indicated similar safety and efficacy without the abuse liability associated with some psychostimulants. The most commonly reported adverse effects in children and adolescents are dyspepsia, nausea, vomiting, decreased appetite, and weight loss. The rates of adverse events in the trials were similar for both the once- and twice-daily dosing regimens. The discontinuation rate was 3.5% in patients treated with atomoxetine versus 1.4% for placebo and appeared to be dose dependent, wit a higher percentage of discontinuation at dosages greater than 1.5 mg/kg/day. In clinical trials involving adults, the emergence of clinically significant or intolerable adverse events was low. The most common adverse events in adults were dry mouth, insomnia, nausea, decreased appetite, constipation, urinary retention or difficulties with micturition, erectile disturbance, dysmenorrhea, dizziness, and decreased libido. Sexual dysfunction occurred in approximately 2% of patients treated with atomoxetine. Atomoxetine should be used with caution in patients who have hypertension or any significant cardiovascular disorder. Overall, atomoxetine therapy in patient with ADHD appears to be effective in controlling symptoms and maintaining remission, with the advantages being comparable efficacy with that of methylphenidate, a favorable safety profile, and non-controlled substance status. Additional long-term studies are needed to determine its continued efficacy for those who require lifelong treatment, and comparative trials against other stimulant and nonstimulant agents.