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.     

Update on atomoxetine in the treatment of attention-deficit/hyperactivity disorder

Background: Atomoxetine, an inhibitor of, the presynaptic transporter of norepinephrine, was approved for the treatment of attention-deficit/ hyperactivity disorder (ADHD) in children aged 6 years and older, adolescents and adults in the USA in 2002, and in Europe, first in the UK and then by mutual recognition in several countries during 2003 and 2004. Since that time, the use of atomoxetine has spread globally and extensive additional research has been conducted evaluating its efficacy and safety. Objective: The objective of this review is to provide a summary of the available data on atomoxetine, with an emphasis on postmarketing clinical research, which is helping to clarify the role of this agent in ADHD pharmacotherapy. Methods: Recent as well as long-term safety and efficacy data are reviewed, with an emphasis on comparison with long-acting psychostimulants, ADHD in special populations and in patients with psychiatric comorbidities. Results/conclusion: Atomoxetine is an effective acute and long-term pharmacotherapy for ADHD, and may play a particular role in the treatment of patients with comorbid disorders and those who have failed or are unable to tolerate stimulants.     

Long‐Term Pharmacotherapy of Adults With Attention Deficit Hyperactivity Disorder: A Literature Review and Clinical Study

This MiniReview reports and discusses the main findings of the author's thesis including a literature study of long‐term pharmacological treatment of adults with attention deficit hyperactivity disorder (ADHD), and a clinical study of 1‐year medication. Electronic databases were systematically reviewed for original studies on pharmacotherapy of the defined duration, 24 weeks or more. Although few trials were found with limitations such as excluding comorbidities, treatment with stimulants and atomoxetine was reported tolerated and effective compared to non‐treatment. The clinical study of the thesis was conducted on 250 medication‐naïve patients with ADHD referred to a specialized outpatient clinic. Comorbid psychiatric disorders were diagnosed among 75% of the patients. About 56% had not completed secondary school, and 51% had been unable to work the preceding year. Persisting inattentive symptoms and comorbid mental disorders in adulthood were related to long‐term work disability. In the prospective observational study of the thesis, patients were treated with methylphenidate as first‐line drug and atomoxetine or dexamphetamine as second‐line drugs, according to current treatment guidelines. At 12‐month follow‐up, 232 patients completed evaluation and 70% persisted on medication. About 80% of these used methylphenidate. Sustained improvement of symptoms and functioning was related to continued medication. Comorbid mental disorders and side effects were related to lower effectiveness and adherence, and 12% stopped medication due to side effects. Summing up the MiniReview, treatment with stimulants and atomoxetine of adults with ADHD has long‐term beneficial effects and is tolerated but more longitudinal studies should be performed. With stated limitations, the findings of the thesis should contribute to a relevant guidance for clinical practice.     

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.     

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.     

Pharmacotherapy of attention-deficit hyperactivity disorder in adolescents

Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioural disorder in children and adolescents, consisting of developmentally inappropriate levels of inattention and/or hyperactivity and impulsivity. The majority of children with ADHD will continue to experience significant ADHD symptoms as teens. ADHD in adolescents can result in significant functional impairment and poorer quality of life. Children and adolescents with ADHD are at higher risk of developing other psychiatric illnesses such as mood, conduct and substance abuse disorders. Stimulants (amphetamines and methylphenidates) and nonstimulants (atomoxetine, guanfacine extended-release (XR) and clonidine XR) have been found to be effective and are approved by the US FDA for the treatment of ADHD in adolescents in the US. Of the agents approved in the US, only guanfacine XR and clonidine XR are not approved in any other countries. There is growing evidence that treatment of ADHD with stimulants reduces the risk of development of other psychiatric co-morbidities, including substance abuse disorders. To date, all FDA-approved stimulants and nonstimulants that have been adequately studied have been demonstrated to be safe and effective in treating ADHD in both children and adolescents. Therefore, clinical decisions used in selecting pharmacotherapy to treat ADHD in children aged 6-12 years can be applied in the adolescent population.     

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.     

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.     

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.     

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.     

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.     

Drug therapy for adults with attention-deficit hyperactivity disorder

Practitioners are increasingly called upon to diagnose and treat attention deficit hyperactivity disorder (ADHD) in adults. Although the use of pharmacotherapy in children with ADHD is well studied, the use of drugs for the treatment of adults with ADHD remains less well established.A systematic review of the literature identified 15 studies (n = 482 patients) of stimulants, and 27 studies of nonstimulant medications (n = 1179 subjects) including antidepressants, norepinephrine reuptake inhibitors, antihypertensive agents, amino acids and wake-promoting agents for the treatment of ADHD in adults.Controlled clinical trials in adults showed that stimulants, antidepressants and norepinephrine reuptake inhibitors demonstrated significant short-term improvements in ADHD symptoms compared with placebo. The two longer term trials with methylphenidate in adults confirmed the ongoing effectiveness and tolerability of stimulants. The response to amphetamine and methylphenidate appears to be dose-dependent. Methylphenidate and amphetamine had an immediate onset of action, whereas responses to pemoline, antidepressants and norepinephrine reuptake inhibitors appeared delayed. Controlled data on nicotinic/cholinergic compounds appear promising. Considerable variability was found in the diagnostic criteria for ADHD in adults, drug dosages and response rates between the various studies.Under controlled conditions, the aggregate literature comprised mainly of short-term studies, shows that stimulants, norepinephrine reuptake inhibitors and specific antidepressants had clinically and statistically significant beneficial effects in the treatment of ADHD in adults. Cholinergic agents appear promising. Further studies are necessary to evaluate the long-term effectiveness and tolerability of various agents, functional and neuropsychological outcomes, and the use of various agents in specific subgroups of adults with ADHD.     

A multi-centre,randomised, open-label study of atomoxetine compared with standard current therapy in UK children and adolescents with attention-deficit/hyperactivity disorder (ADHD)*

ABSTRACT

Objective: To assess the broader efficacy (i.e., improve­ments in quality of life/functional outcomes) of atomoxetine compared with standard current therapy (SCT) in UK paediatric patients with ADHD and to explore clinician/parent/child perceptions of ADHD.

Research design and methods: A total of 201 patients with ADHD were randomised into this multi-centre, open-label study to receive atomoxetine (n = 104) or SCT (n = 97) for 10 weeks. Broader efficacy was assessed using the parent-rated Child Health and Illness Profile-Child Edition (CHIP?CE) total (global) t-score. Secondary outcome measures included the five CHIP?CE domains; parent-rated Family Burden of Illness Module (FBIM); investigator-rated ADHD?Rating Scale; investigator-rated Clinical Global Impression (CGI)-Severity/Improvement scales; and child-rated Harter Self-Perception Profile (HSPP).

Results: Quality of life of children/adolescents with ADHD was extremely compromised at baseline (CHIP?CE total t-scores: atomoxetine, 23.2 ± 12.2; SCT, 23.9 ± 11.0), and improved during the 10-week study for both groups; the CHIP?CE score was statistically significantly higher for patients treated with atomoxetine (38.4 ± 1.3) compared with SCT (30.8 ± 1.3) at week 10 (?p < 0.001). ADHD?RS, CGI-Severity, and CGI-Improvement scores were significantly different between the groups in favour of atomoxetine (?p < 0.001). There was a statistically significant difference between the groups in the HSPP Social Acceptance domain in favour of atomoxetine, but not in the five other HSPP domains or FBIM total score. Atomoxetine was well-tolerated.

Conclusions: Results from this open-label trial show that atomoxetine is superior to SCT in addressing broader efficacy and functional outcomes in UK children/adoles­cents with ADHD. This study contributes to the under­standing of broader efficacy in children with ADHD, and is timely in light of recent NICE guidance.     

Evaluation of dystonia in children and adolescents treated with atomoxetine within the Truven MarketScan database: a retrospective cohort study

Objective: Atomoxetine is a non-stimulant drug indicated for the treatment of attention-deficit/hyperactivity disorder in children aged ≥6 years, adolescents, and adults. In this retrospective cohort study, the incidence and risk of dystonia in children and adolescents treated with atomoxetine was compared to a propensity score-matched cohort of stimulant users.

Methods: Data between 1 January 2006 and 31 December 2014 from patients aged 6–17 years in the Truven Health Analytics MarketScan database were used to generate two cohorts of patients: (1) atomoxetine users and (2) stimulant (methylphenidates or amphetamines) users. A Cox proportional hazards regression model was used to compare incidence of dystonia across propensity score-matched cohorts.

Results: Of the 70,657 atomoxetine users, 70,655 users were propensity score-matched to a stimulant user. In the atomoxetine- and stimulant-treated cohorts, the crude incidence rates of dystonia were 54.9 (95% CI: 27.1–82.7) and 77.9 (95% CI: 49.1–106.8) per 100,000 person-years, respectively. The hazard ratio for occurrence of dystonia with atomoxetine use relative to stimulant use was 0.68 (95% CI: 0.36 ? 1.28; P = 0.23).

Conclusion: In this large retrospective cohort study, there was no significant difference in incidence or risk of dystonia among patients treated with atomoxetine compared to 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: a selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder

Atomoxetine (Strattera^?, Eli Lilly & Co.) is a selective noradrenaline reuptake inhibitor that has been studied for use in the treatment of attention-deficit/hyperactivity disorder (ADHD). So far, two open-label and seven randomised, double-blind, placebo-controlled, clinical trials have been published, six in youths and three in adults. Each of these trials has shown a positive response as measured by the primary efficacy measures, the ADHD-IV Rating Scale (ADHD RS) or the Conners Adult ADHD Rating Scale (CAARS). Atomoxetine has generally been well tolerated. In November of 2002 the FDA approved atomoxetine for use in the US for the treatment of ADHD in children, adolescents and adults. Atomoxetine is the first nonstimulant approved by the FDA for the treatment of ADHD and the first medication approved for the treatment of adult ADHD.     

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.     

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.     

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.     

Cardiovascular effects of atomoxetine in children, adolescents, and adults.

BACKGROUND: Atomoxetine is a highly specific presynaptic inhibitor of the noradrenaline (norepinephrine) transporter that was recently approved in the US for the treatment of patients with attention-deficit/hyperactivity disorder (ADHD). Adverse effects on the cardiovascular system, including abnormalities in heart rate, blood pressure, or cardiac rhythm have been associated with several noradrenergic medications. OBJECTIVE: To further elucidate the magnitude and impact of blood pressure and pulse elevations in patients taking atomoxetine. STUDY DESIGN: Short-term cardiovascular safety in children, adolescents, and adults with ADHD was assessed in five randomised, double-blind trials (duration up to 10 weeks) with atomoxetine (n = 612) or placebo (n = 474). Long-term cardiovascular safety in children and adolescents (n = 169) was assessed in patients who entered an open-label extension or a blinded continuation following short-term treatment. METHODS: Adverse events, blood pressure, sitting pulse, and electrocardiograms (ECGs) were collected throughout the trials. QT intervals were corrected for heart rate by a data-specific correction factor (QTcD; derived from baseline ECGs) as well as standard methods. RESULTS: Atomoxetine treatment was associated with small but statistically significant increases in mean systolic blood pressure in adults and diastolic blood pressure in children and adolescents. Mean pulse rate increased for all atomoxetine treatment groups. The increases in blood pressure and pulse tended to occur early in therapy, stabilised, and returned toward baseline upon drug discontinuation. There was no significant difference between atomoxetine and placebo treatment groups in change in QTcD interval for all study populations. Palpitations in the adult patient population were the only significant cardiovascular adverse event (p = 0.037) occurring more frequently in the atomoxetine treatment group (3.7%) than in the placebo group (0.8%). Discontinuations due to cardiovascular-related events were very uncommon in the adult group, and did not occur in the child/adolescent group.CONCLUSION: While atomoxetine has noradrenergic activity, increases in pulse and blood pressure were small and of little, if any, clinical significance. Atomoxetine was not associated with QT interval prolongation. Cardiovascular effects of atomoxetine were minimal, and atomoxetine was well tolerated in short- and long-term studies.