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1.  ADHD in children and adolescents 
Clinical Evidence  2008;2008:0312.
Introduction
Prevalence estimates of attention deficit hyperactivity disorder (ADHD) vary according to the diagnostic criteria used and the population sampled. DSM-IV prevalence estimates among school children in the US are 3-5%, but other estimates vary from 1.7% to 16.0%. No objective test exists to confirm the diagnosis of ADHD, which remains a clinical diagnosis. Other conditions frequently co-exist with ADHD.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of pharmacological treatments for ADHD in children and adolescents? What are the effects of psychological treatments for ADHD in children and adolescents? What are the effects of combination treatments for ADHD in children and adolescents? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 34 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: atomoxetine, bupropion, clonidine, dexamfetamine sulphate, homeopathy, methylphenidate, modafinil, omega 3-polyunsaturated fatty acids, and psychological/behavioural treatment (either alone or in combination with a drug treatment).
Key Points
Core symptoms of ADHD are inattention, hyperactivity, and impulsiveness, although other conditions frequently coexist with ADHD, including developmental disorders (especially motor, language, social communication, and specific learning disabilities) and psychiatric disorders (especially oppositional defiant and conduct disorder, anxiety, and depressive disorders). Symptoms must be present for at least 6 months, are generally observed in children before the age of 7 years, and cause clinically important impairment in social, academic, or occupational functioning which must be evident in more than one setting.Formal diagnostic criteria are most applicable to boys aged 6-12 years, and most research data relate to this group. Preschool children, adolescents, and females may present less-typical features, but similar levels of impairment. Prevalence estimates among school children range from 3% to 5%.
Methylphenidate improves core symptoms and school performance in children with ADHD when used alone.
Dexamfetamine and atomoxetine may also reduce symptoms of ADHD.
We don't know how effective any treatment for ADHD is in the long term; people with ADHD may require treatment for many years.
CAUTION: Atomoxetine may cause rare but serious liver injury.
Clonidine and modafinil may improve symptoms of ADHD compared with placebo, but are associated with an increased risk of adverse effects compared with methylphenidate, dexamfetamine, and atomoxetine.
We don't know whether homeopathy, bupropion, or polyunsaturated fatty acids are beneficial in the treatment of symptoms of ADHD.
We don't know how effective psychological/behavioural treatments alone are compared with each other or with pharmacological treatments, as we found few high-quality studies. The combination of methylphenidate plus psychological treatment may enhance effectiveness of methylphenidate alone or behavioural treatment alone, but we don't know whether dexamfetamine plus psychological treatment is effective in treatment of ADHD compared with either intervention alone. Long-term outcome for both drug treatment alone and combination treatments is uncertain.We don't know whether parent training in conjunction with teacher involvement is more effective than parent training alone.
PMCID: PMC2907929  PMID: 19445793
2.  ADHD in children and adolescents 
Clinical Evidence  2011;2011:0312.
Introduction
Prevalence estimates of attention deficit hyperactivity disorder (ADHD) vary according to the diagnostic criteria used and the population sampled. DSM-IV prevalence estimates among school children in the US are 3% to 5%, but other estimates vary from 1.7% to 16.0%. No objective test exists to confirm the diagnosis of ADHD, which remains a clinical diagnosis. Other conditions frequently co-exist with ADHD.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of pharmacological treatments for ADHD in children and adolescents? What are the effects of psychological treatments for ADHD in children and adolescents? What are the effects of combination treatments for ADHD in children and adolescents? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 70 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: atomoxetine, bupropion, clonidine, dexamfetamine sulphate, homeopathy, methylphenidate, modafinil, omega-3 polyunsaturated fatty acids, and psychological/behavioural treatment (either alone or in combination with a drug treatment).
Key Points
Core symptoms of ADHD are inattention, hyperactivity, and impulsiveness, although other conditions frequently co-exist with ADHD, including developmental disorders (especially motor, language, social communication, and specific learning disabilities) and psychiatric disorders (especially oppositional defiant and conduct disorder, anxiety, and depressive disorders). Symptoms must be present for at least 6 months, are generally observed in children before the age of 7 years, and cause clinically important impairment in social, academic, or occupational functioning that must be evident in more than one setting.Formal diagnostic criteria are most applicable to boys aged 6 to 12 years, and most research data relate to this group. Pre-school children, adolescents, and females may present less typical features, but similar levels of impairment. Prevalence estimates among school children range from 3% to 5%.
Methylphenidate improves core symptoms in children with ADHD when used alone.
Dexamfetamine and atomoxetine may also reduce symptoms of ADHD.
We don't know how effective any treatment for ADHD is in the long term; people with ADHD may require treatment for many years.
CAUTION: Atomoxetine may cause rare but serious liver injury.
Clonidine and modafinil may improve symptoms of ADHD compared with placebo, but are associated with an increased risk of adverse effects compared with methylphenidate, dexamfetamine, and atomoxetine.
We don't know whether homeopathy, bupropion, or omega-3 polyunsaturated fatty acids are beneficial in the treatment of symptoms of ADHD.
We don't know how effective psychological/behavioural treatments alone are compared with each other or with pharmacological treatments, as we found few high-quality studies. The combination of methylphenidate plus psychological treatment may enhance effectiveness of methylphenidate alone or behavioural treatment alone, but we don't know whether dexamfetamine plus psychological treatment is effective in treatment of ADHD compared with either intervention alone. Long-term outcome for both drug treatment alone and combination treatments is uncertain.We don't know whether parent training in conjunction with teacher involvement is more effective than parent training alone.
PMCID: PMC3217800  PMID: 21718557
3.  Management of adult attention deficit hyperactivity disorder in UK primary care: a survey of general practitioners 
Background
Compared to existing literature on childhood attention deficit hyperactivity disorder (ADHD), little published adult data are available, particularly outside of the United States. Using General Practitioner (GP) questionnaires from the United Kingdom, this study aimed to examine a number of issues related to ADHD in adults, across three cohorts of patients, adults who received ADHD drug treatment in childhood/adolescence but stopped prior to adulthood; adults who received ADHD drug treatment in childhood/adolescence and continued treatment into adulthood and adults who started ADHD drug treatment in adulthood.
Methods
Patients with a diagnosis of ADHD and prescribed methylphenidate, dexamfetamine or atomoxetine were identified using data from The Health Improvement Network (THIN). Dates when these drugs started and stopped were used to classify patients into the three cohorts. From each cohort, 50 patients were randomly selected and questionnaires were sent via THIN to their GPs.
GPs returned completed questionnaires to THIN who forwarded anonymised copies to the researchers. Datasets were analysed using descriptive statistics.
Results
Overall response rate was 89% (133/150). GPs stated that in 19 cases, the patient did not meet the criteria of that group; the number of valid questionnaires returned was 114 (76%). The following broad trends were observed: 1) GPs were not aware of the reason for treatment cessation in 43% of cases, 2) patient choice was the most common reason for discontinuation (56%), 3) 7% of patients who stopped pharmacological treatment subsequently reported experiencing ADHD symptoms, 4) 58% of patients who started pharmacological treatment for ADHD in adulthood received pharmacological treatment for other mental health conditions prior to the ADHD being diagnosed.
Conclusion
This study presents some key findings relating to ADHD; GPs were often not aware of the reason for patients stopping ADHD treatment in childhood or adolescence. Patient choice was identified as the most common reason for treatment cessation. For patients who started pharmacological treatment in adulthood, many patients received pharmacological treatment for comorbidities before a diagnosis of ADHD was made.
doi:10.1186/1477-7525-11-22
PMCID: PMC3598717  PMID: 23432851
Attention deficit hyperactivity disorder; Adult; Stimulant; Primary care; General practitioner
4.  Five-Fold Increase in National Prevalence Rates of Attention-Deficit/Hyperactivity Disorder Medications for Children and Adolescents with Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder, and other Psychiatric Disorders: A Danish Register-Based Study 
Abstract
Objective
The purpose of this study was to estimate the prevalence and time trends in prescriptions of methylphenidate, dexamphetamine, and atomoxetine in children and adolescents, within three diagnostic groups: 1) autism spectrum disorder (ASD), 2) attention-deficit/hyperactivity disorder (ADHD), and 3) other psychiatric disorders.
Methods
Data from six different national registers were used and merged to identify a cohort of all children and adolescents born in Denmark between 1990 and 2001 (n=852,711). Sociodemographic covariates on cohort members and their parents and lifetime prescriptions of methylphenidate, dexamphetamine, and atomoxetine were extracted from the registers. Prescriptions were also stratified by duration (<6 months. vs.≥6 months).
Results
Sixteen percent of 9698 children and adolescents with ASD (n=1577), 61% of 11,553 children and adolescents with ADHD (n=7021) and 3% of 48,468 children and adolescents with other psychiatric disorders (n=1537) were treated with one or more ADHD medications. There was a significant increase in prescription rates of these medications for all three groups. From 2003 to 2010, youth 6–13 years of age with ASD, ADHD, and other psychiatric disorders had 4.7-fold (4.4–4.9), 6.3-fold (6.0–6.4), and 5.5-fold (5.0–5.9) increases, respectively, in prescription rates of ADHD medications.
Conclusion
This is the largest study to date assessing stimulant treatment in children and adolescents with ASD, and is the first prospective study quantifying the change over time in the prevalence of treatment with ADHD medications in a population-based national cohort of children and adolescents with ASD. The prevalence of stimulant treatment in youth with ASD of 16% is consistent with earlier studies. The past decade has witnessed a clear and progressive increase in the prescription rates of medications typically used to treat ADHD in children and adolescents in Denmark. This increase is not limited to only those with ADHD, but includes others with neuropsychiatric disorders, including ASD. The risks and benefits of this practice await further study.
doi:10.1089/cap.2012.0111
PMCID: PMC3778945  PMID: 24015896
5.  Epidemiology of Treated Attention-Deficit/Hyperactivity Disorder (ADHD) across the Lifespan in Taiwan: A Nationwide Population-Based Longitudinal Study 
PLoS ONE  2014;9(4):e95014.
Objectives
We used insurance claims of a nationally representative population-based cohort to assess the longitudinal treated prevalence and incidence of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents and adults.
Methods
Participants were identified from among National Health Insurance enrollees in Taiwan from 1999 to 2005. We identified study subjects who had at least one service claim during these years with a principal diagnosis of ADHD. A total of 6,173 patients were recorded in the treated ADHD cohort during the 6-year study.
Results
There was a significant increase in the treated prevalence rate of ADHD during the study period, from 64.65 per 100,000 in 2000 to 145.40 per 100,000 in 2005 (p = .001). An increase in the treated incidence rate of ADHD, from 44.67 per 100,000 in 2000 to 81.20 per 100,000 in 2005, was also observed (p = .013). However, the treated prevalence of ADHD was still lower than that of the community data in Taiwan. The peak treated prevalence of ADHD was at age 7–12 years for both males and females, and the peak treated incidence of ADHD was at age 0–6 for females and age 7–12 for males. Overall, the treated incidence and prevalence rates dropped abruptly after age 13–18 (both p<.001) for males and females (p<.001 for both). Male vs. female ratios of treated prevalence and incidence were both above 1 before age 25–30 years, but below 1 thereafter.
Conclusion
Although an increasing number of people with ADHD sought treatment during 1999–2005 in Taiwan, the treated prevalence of ADHD was still lower than that of the community data. The treated incidence and prevalence of ADHD fell dramatically after age 13–18. However, more women than men sought treatment in adulthood. There may be under-diagnosis and under-treatment of ADHD, especially among females and adults.
doi:10.1371/journal.pone.0095014
PMCID: PMC3988191  PMID: 24736469
6.  Persistence of pharmacological treatment into adulthood, in UK primary care, for ADHD patients who started treatment in childhood or adolescence 
BMC Psychiatry  2012;12:219.
Background
ADHD guidelines in the UK suggest that children and adults who respond to pharmacological treatment should continue for as long as remains clinically effective, subject to regular review. To what extent patients persist with treatment from childhood and adolescence into adulthood is not clear. This study aims to describe, in UK primary care, the persistence of pharmacological treatment for patients with ADHD who started treatment aged 6–17 years and to estimate the percentage of patients who continued treatment from childhood and adolescence into adulthood.
Methods
The Health Improvement Network (THIN) database was used to identify patients with ADHD who received their first prescription for methylphenidate/ dexamfetamine/atomoxetine, aged 6–17 years. Patients were monitored until their ‘censored date’ (the earliest of the following dates: date the last prescription coded in the database ended, end of the study period (31st December 2008), date at which they transferred out of their practice, date of death, the last date the practice contributed data to the database). Persistence of treatment into adulthood was estimated using Kaplan Meier analysis.
Results
610 patients had follow-up data into adulthood. 213 patients (93.4% male) started treatment between 6–12 years; median treatment duration 5.9 years. 131 (61.5%) stopped before 18 years, 82 (38.5%) were still on treatment age ≥18 years. 397 patients (86.4% male) started treatment between 13–17 years; median treatment duration was 1.6 years. 227 (57.2%) stopped before 18 years, 170 (42.8%) were still on treatment age ≥18 years. The number of females in both age categories was too small to formally test for differences between genders in persistence of treatment.
Conclusion
Persistence of treatment into adulthood is lower (~40%) compared with published rates of persistence of the condition (~65% when symptomatic definition of remission used). Due to the limited number of patients with data past 18 years, it is important that ongoing monitoring of prescribing into later adulthood is undertaken, particularly to observe the effects of recommendations in new guidelines.
doi:10.1186/1471-244X-12-219
PMCID: PMC3570395  PMID: 23216881
Attention deficit hyperactivity disorder; Pharmacological treatment; Stimulants; Persistence; Adulthood
7.  Less discontinuation of ADHD drug use since the availability of long-acting ADHD medication in children, adolescents and adults under the age of 45 years in the Netherlands 
Treatment options for ADHD in the Netherlands have increased with the introduction of the extended-release formulations of methylphenidate (MPH ER, Concerta®) in 2003 and atomoxetine (ATX, Strattera®) in 2005, but data on the effect on drug usage patterns are scarce. The objective of the present study was to describe changes in the patterns of ADHD medication use and determinants thereof among children, adolescents and adults (<45 years) starting ADHD medication since the introduction of MPH ER and ATX. Data were obtained from Dutch community pharmacies as collected by the Foundation for Pharmaceutical Statistics, covering 97% of all dispenses for prescription medicines to outpatients in the Netherlands. Usage patterns (continuation, discontinuation, switching and addition) of ADHD drugs were evaluated at 3, 6 and 12 months after initiation for three separate time cohorts (patients starting ADHD medication in Jan-Dec 2002, Jan 2003–June 2004, respectively July 2004–Dec 2005). It was found that between 2002 and 2006, most ADHD drug users were initiated on methylphenidate IR. Discontinuation of any ADHD drug treatment decreased over time partly in favour of switching and addition. Discontinuation at 3 months decreased from around 33% to around 25%, at 6 months from less than 50% to almost 35%, and at 12 months from just fewer than 60% to less than 45%. Discontinuation was higher among females and in adults >18 years. After the introduction of MPH ER and ATX (time cohort III), 16.5% of the incident ADHD drug users switched their medication and almost 9% added an ADHD drug to the prior ADHD drug. In conclusion, discontinuation of incident ADHD drug use is high after 3, 6 and 12 months. During the study period, the incidence of discontinuation decreased because of the availability of extended-release methylphenidate and atomoxetine.
doi:10.1007/s12402-010-0044-9
PMCID: PMC3000908  PMID: 21258431
Immediate-release methylphenidate; Extended-release methylphenidate; Atomoxetine; Continuation; Discontinuation; Switching; Addition; Child; Adolescent; Adult; Psychostimulant; Attention deficit hyperactivity disorder
8.  Treatment Response and Remission in a Double-Blind, Randomized, Head-to-Head Study of Lisdexamfetamine Dimesylate and Atomoxetine in Children and Adolescents with Attention-Deficit Hyperactivity Disorder 
CNS Drugs  2014;28(11):1059-1069.
Objectives
A secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactivity disorder (ADHD) and an inadequate response to methylphenidate (MPH). The primary efficacy and safety outcomes of the study, SPD489-317 (ClinicalTrials.gov NCT01106430), have been published previously.
Methods
In this 9-week, double-blind, active-controlled study, patients aged 6–17 years with a previous inadequate response to MPH were randomized (1:1) to dose-optimized LDX (30, 50 or 70 mg/day) or ATX (patients <70 kg: 0.5–1.2 mg/kg/day, not to exceed 1.4 mg/kg/day; patients ≥70 kg: 40, 80 or 100 mg/day). Treatment response was a secondary efficacy outcome and was predefined as a reduction from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score of at least 25, 30 or 50 %. Sustained response was predefined as a reduction from baseline in ADHD-RS-IV total score (≥25, ≥30 or ≥50 %) or a Clinical Global Impressions (CGI)–Improvement (CGI–I) score of 1 or 2 throughout weeks 4–9. CGI–Severity (CGI–S) scores were also assessed, as an indicator of remission.
Results
A total of 267 patients were enrolled (LDX, n = 133; ATX, n = 134) and 200 completed the study (LDX, n = 99; ATX, n = 101). By week 9, significantly (p < 0.01) greater proportions of patients receiving LDX than ATX met the response criteria of a reduction from baseline in ADHD-RS-IV total score of at least 25 % (90.5 vs. 76.7 %), 30 % (88.1 vs. 73.7 %) or 50 % (73.0 vs. 50.4 %). Sustained response rates were also significantly (p < 0.05) higher among LDX-treated patients (ADHD-RS-IV ≥25, 66.1 %; ADHD-RS-IV ≥30, 61.4 %; ADHD-RS-IV ≥50, 41.7 %; CGI–I, 52.0 %) than among ATX-treated individuals (ADHD-RS-IV ≥25, 51.1 %; ADHD-RS-IV ≥30, 47.4 %; ADHD-RS-IV ≥50, 23.7 %; CGI–I, 39.3 %). Finally, by week 9, 60.7 % of patients receiving LDX and 46.3 % of those receiving ATX had a CGI–S score of 1 (normal, not at all ill) or 2 (borderline mentally ill), and greater proportions of patients in the LDX group than the ATX group experienced a reduction from baseline of at least one CGI–S category.
Conclusions
Both LDX and ATX treatment were associated with high levels of treatment response in children and adolescents with ADHD and a previous inadequate response to MPH. However, within the parameters of the study, LDX was associated with significantly higher treatment response rates than ATX across all response criteria examined. In addition, higher proportions of patients in the LDX group than the ATX group had a CGI–S score of 1 or 2 by week 9, indicating remission of symptoms. Both treatments were generally well tolerated, with safety profiles consistent with those observed in previous studies.
doi:10.1007/s40263-014-0188-9
PMCID: PMC4221603  PMID: 25038977
9.  Drug Treatment Patterns of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents in Germany: Results from a Large Population-Based Cohort Study 
Abstract
Objective
Despite a substantial increase in total methylphenidate (MPH) prescriptions in Germany over the last 20 years, and the introduction of modified release MPH (MR MPH) and atomoxetine (ATX), remarkably little is known about treatment patterns of attention- deficit/hyperactivity disorder (ADHD) in individual patients.
Methods
Usage patterns of ADHD drugs in children and adolescents in Germany were analyzed using data from one large German health insurance including >7,200,000 members. Of those, 6210 ADHD patients newly diagnosed in 2005 were followed for a maximum of 4 years. Kaplan–Meier estimates were calculated for onset and discontinuation of ADHD drug treatment. Predictors of time until drug treatment initiation were assessed by Cox regression.
Results
During follow-up, 52.0% of ADHD subjects (53.4% of boys, 47.5% of girls) received ADHD drug treatment. The majority of them (91.6%) were started on MPH, with immediate release MPH (IR MPH) being the initial treatment choice in 75.3%. In these subjects, change to drug treatment with MR MPH in the first year occurred in 48% by switch or addition. Significant predictors of drug treatment were behavioral and emotional disorders (HR=1.13; 95% CI 1.03–1.24) and a diagnosis of ADHD with conduct disorder (HR=1.21, 95% CI 1.12–1.32), whereas young age showed a protective effect. After 6, 12, and 24 months of treatment initiation, 22.4%, 43.4%, and 66.3% of treated girls, and 17.8%, 36.1%, and 54.1% of treated boys had discontinued ADHD treatment.
Conclusion
Drug treatment of ADHD was relatively common in Germany and more frequent in boys than in girls. IR MPH was the predominant treatment choice at treatment initiation. Approximately 20% of treated subjects discontinued drug treatment within the first 6 months, with girls stopping drug treatment earlier than boys. The reasons for early drug discontinuation need to be further explored.
doi:10.1089/cap.2012.0022
PMCID: PMC3523251  PMID: 23234588
10.  A systematic review of the safety information contained within the Summaries of Product Characteristics of medications licensed in the United Kingdom for Attention Deficit Hyperactivity Disorder. how does the safety prescribing advice compare with national guidance? 
Background
The safety of paediatric medications is paramount and contraindications provide clear pragmatic advice. Further advice may be accessed through Summaries of Product Characteristics (SPCs) and relevant national guidelines. The SPC can be considered the ultimate independent guideline and is regularly updated. In 2008, the authors undertook a systematic review of the SPC contraindications of medications licensed in the United Kingdom (UK) for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). At that time, there were fewer contraindications reported in the SPC for atomoxetine than methylphenidate and the specific contraindications varied considerably amongst methylphenidate formulations. In 2009, the European Medicines Agency (EMA) mandated harmonisation of methylphenidate SPCs. Between September and November 2011, there were three changes to the atomoxetine SPC that resulted in revised prescribing information. In addition, Clinical Guidance has also been produced by the National Institute for Health and Clinical Excellence (NICE) (2008), the Scottish Intercollegiate Guidelines Network (SIGN) (2009) and the British National Formulary for Children (BNFC).
Methods
An updated systematic review of the Contraindications sections of the SPCs of all medications currently licensed for treatment of ADHD in the UK was undertaken and independent statements regarding contraindications and relevant warnings and precautions were then compared with UK national guidance with the aim of assessing any disparity and potential areas of confusion for prescribers.
Results
As of November 2011, there were seven medications available in the UK for the treatment of ADHD. There are 15 contraindications for most formulations of methylphenidate, 14 for dexamfetamine and 5 for atomoxetine. Significant differences exist between the SPCs and national guidance part due to the ongoing reactive process of amending the former as new information becomes known. In addition, recommendations are made outside UK SPC licensed indications and a significant contraindication for methylphenidate (suicidal behaviours) is missing from both the NICE and SIGN guidelines. Particular disparity exists relating to monitoring for suicidal and psychiatric side effects. The BNFC has not yet been updated in line with the European Union (EU) Directive on methylphenidate; it does not include any contraindications for atomoxetine but describes contraindications for methylphenidate that are no longer in the SPC.
Conclusion
Clinicians seeking prescribing advice from critical independent sources of data, such as SPCs and national guidelines, may be confused by the disparity that exists. There are major differences between guidelines and SPCs and neither should be referred to in isolation. The SPC represents the most relevant source of safety data to aid prescribing of medications for ADHD as they present the most current safety data in line with increased exposure. National guidelines may need more regular updates.
doi:10.1186/1753-2000-6-2
PMCID: PMC3317854  PMID: 22234242
ADHD; guidelines; summary of product characteristics; drug safety; NICE; SIGN
11.  A Post Hoc Comparison of the Effects of Lisdexamfetamine Dimesylate and Osmotic-Release Oral System Methylphenidate on Symptoms of Attention-Deficit Hyperactivity Disorder in Children and Adolescents 
CNS Drugs  2013;27(9):743-751.
Introduction
There are limited head-to-head data comparing the efficacy of long-acting amfetamine- and methylphenidate-based psychostimulants as treatments for individuals with attention-deficit hyperactivity disorder (ADHD). This post hoc analysis provides the first parallel-group comparison of the effect of lisdexamfetamine dimesylate (lisdexamfetamine) and osmotic-release oral system methylphenidate (OROS-MPH) on symptoms of ADHD in children and adolescents.
Study Design
This was a post hoc analysis of a randomized, double-blind, parallel-group, dose-optimized, placebo-controlled, phase III study.
Setting
The phase III study was carried out in 48 centres across ten European countries.
Patients
The phase III study enrolled children and adolescents (aged 6–17 years) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for a primary diagnosis of ADHD and who had a baseline ADHD Rating Scale IV (ADHD-RS-IV) total score of 28 or higher.
Intervention
Eligible patients were randomized (1:1:1) to receive a once-daily, optimized dose of lisdexamfetamine (30, 50 or 70 mg/day), placebo or OROS-MPH (18, 36 or 54 mg/day) for 7 weeks.
Main Outcome Measures
In this post hoc analysis, efficacy was assessed using the ADHD-RS-IV and Clinical Global Impressions-Improvement (CGI-I) scale. Responders were defined as those achieving at least a 30 % reduction from baseline in ADHD-RS-IV total score and a CGI-I score of 1 (very much improved) or 2 (much improved). The proportion of patients achieving an ADHD-RS-IV total score less than or equal to the mean for their age (based on normative data) was also determined. Endpoint was the last on-treatment visit with a valid assessment. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs.
Results
Of the 336 patients randomized, 332 were included in the safety population, 317 were included in the full analysis set and 196 completed the study. The mean (standard deviation) ADHD-RS-IV total score at baseline was 40.7 (7.31) for lisdexamfetamine, 41.0 (7.14) for placebo and 40.5 (6.72) for OROS-MPH. The least-squares (LS) mean change (standard error) in ADHD-RS-IV total score from baseline to endpoint was −24.3 (1.16) for lisdexamfetamine, −5.7 (1.13) for placebo and −18.7 (1.14) for OROS-MPH. The difference between lisdexamfetamine and OROS-MPH in LS mean change (95 % confidence interval [CI]) in ADHD-RS-IV total score from baseline to endpoint was statistically significant in favour of lisdexamfetamine (−5.6 [−8.4 to −2.7]; p < 0.001). The difference between lisdexamfetamine and OROS-MPH in the percentage of patients (95 % CI) with a CGI-I score of 1 or 2 at endpoint was 17.4 (5.0–29.8; p < 0.05; number needed to treat [NNT] 6), and the difference in the percentage of patients (95 % CI) achieving at least a 30 % reduction in ADHD-RS-IV total score and a CGI-I score of 1 or 2 was 18.3 (5.4–31.3; p < 0.05; NNT 6). The difference between lisdexamfetamine and OROS-MPH in the percentage of patients (95 % CI) with an ADHD-RS-IV total score less than or equal to the mean for their age at endpoint was 14.0 (0.6–27.4; p = 0.050). The overall frequency of TEAEs and the frequencies of decreased appetite, insomnia, decreased weight, nausea and anorexia TEAEs were greater in patients treated with lisdexamfetamine than in those treated with OROS-MPH, whereas headache and nasopharyngitis were more frequently reported in patients receiving OROS-MPH.
Conclusions
This post hoc analysis showed that, at the doses tested, patients treated with lisdexamfetamine showed statistically significantly greater improvement in symptoms of ADHD than those receiving OROS-MPH, as assessed using the ADHD-RS-IV and CGI-I. The safety profiles of lisdexamfetamine and OROS-MPH were consistent with the known effects of stimulant medications.
doi:10.1007/s40263-013-0086-6
PMCID: PMC3751426  PMID: 23801529
12.  Atomoxetine Improved Attention in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Dyslexia in a 16 Week, Acute, Randomized, Double-Blind Trial 
Abstract
Objective
The purpose of this study was to evaluate atomoxetine treatment effects in attention-deficit/hyperactivity disorder (ADHD-only), attention-deficit/hyperactivity disorder with comorbid dyslexia (ADHD+D), or dyslexia only on ADHD core symptoms and on sluggish cognitive tempo (SCT), working memory, life performance, and self-concept.
Methods
Children and adolescents (10–16 years of age) with ADHD+D (n=124), dyslexia-only (n=58), or ADHD-only (n=27) received atomoxetine (1.0–1.4 mg/kg/day) or placebo (ADHD-only subjects received atomoxetine) in a 16 week, acute, randomized, double-blind trial with a 16 week, open-label extension phase (atomoxetine treatment only). Changes from baseline were assessed to weeks 16 and 32 in ADHD Rating Scale-IV-Parent-Version:Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv); ADHD Rating Scale-IV-Teacher-Version (ADHDRS-IV-Teacher-Version); Life Participation Scale—Child- or Parent-Rated Version (LPS); Kiddie-Sluggish Cognitive Tempo (K-SCT) Interview; Multidimensional Self Concept Scale (MSCS); and Working Memory Test Battery for Children (WMTB-C).
Results
At week 16, atomoxetine treatment resulted in significant (p<0.05) improvement from baseline in subjects with ADHD+D versus placebo on ADHDRS-IV-Parent:Inv Total (primary outcome) and subscales, ADHDRS-IV-Teacher-Version Inattentive subscale, K-SCT Interview Parent and Teacher subscales, and WMTB-C Central Executive component scores; in subjects with Dyslexia-only, atomoxetine versus placebo significantly improved K-SCT Youth subscale scores from baseline. At Week 32, atomoxetine-treated ADHD+D subjects significantly improved from baseline on all measures except MSCS Family subscale and WMTB-C Central Executive and Visuo-spatial Sketchpad component scores. The atomoxetine-treated dyslexia-only subjects significantly improved from baseline to week 32 on ADHDRS-IV-Parent:Inv Inattentive subscale, K-SCT Parent and Teacher subscales, and WMTB-C Phonological Loop and Central Executive component scores. The atomoxetine-treated ADHD-only subjects significantly improved from baseline to Week 32 on ADHDRS-Parent:Inv Total and subscales, ADHDRS-IV-Teacher-Version Hyperactive/Impulsive subscale, LPS Self-Control and Total, all K-SCT subscales, and MSCS Academic and Competence subscale scores.
Conclusions
Atomoxetine treatment improved ADHD symptoms in subjects with ADHD+D and ADHD-only, but not in subjects with dyslexia-only without ADHD. This is the first study to report significant effects of any medication on SCT.
Clinical Trials Registration
This study was registered at: http://clinicaltrials.gov/ct2/home, NCT00607919.
doi:10.1089/cap.2013.0054
PMCID: PMC3842866  PMID: 24206099
13.  A Systematic Review of Combination Therapy with Stimulants and Atomoxetine for Attention-Deficit/Hyperactivity Disorder, Including Patient Characteristics, Treatment Strategies, Effectiveness, and Tolerability 
Abstract
Objective
The purpose of this article was to systematically review the literature on stimulant and atomoxetine combination therapy, in particular: 1) Characteristics of patients with attention-deficit/hyperactivity disorder (ADHD) given combination therapy, 2) treatment strategies used, 3) efficacy and effectiveness, and 4) safety and tolerability.
Methods
Literature databases (MEDLINE®, EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index Expanded, and SciVerse Scopus) were systematically searched using prespecified criteria. Publications describing stimulant and atomoxetine combination therapy in patients with ADHD or healthy volunteers were selected for review. Exclusion criteria were comorbid psychosis, bipolar disorder, epilepsy, or other psychiatric/neurologic diseases that could confound ADHD symptom assessment, or other concomitant medication(s) to treat ADHD symptoms.
Results
Of the 16 publications included for review, 14 reported findings from 3 prospective studies (4 publications), 7 retrospective studies, and 3 narrative reviews/medication algorithms of patients with ADHD. The other two publications reported findings from two prospective studies of healthy volunteers. The main reason for prescribing combination therapy was inadequate response to previous treatment. In the studies of patients with ADHD, if reported, 1) most patients were children/adolescents and male, and had a combined ADHD subtype; 2) methylphenidate was most often used in combination with atomoxetine for treatment augmentation or switch; 3) ADHD symptom control was improved in some, but not all, patients; and 4) there were no serious adverse events.
Conclusions
Published evidence of the off-label use of stimulant and atomoxetine combination therapy is limited because of the small number of publications, heterogeneous study designs (there was only one prospective, randomized controlled trial), small sample sizes, and geographic bias. Existing evidence suggests, but does not confirm, that this drug combination may benefit some, but not all, patients who have tried several ADHD medications without success.
doi:10.1089/cap.2012.0093
PMCID: PMC3696926  PMID: 23560600
14.  Atomoxetine for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children with ADHD and dyslexia 
Background
The objective of this study was to assess the effects of atomoxetine on treating attention-deficit/hyperactivity disorder (ADHD), on reading performance, and on neurocognitive function in youth with ADHD and dyslexia (ADHD+D).
Methods
Patients with ADHD (n = 20) or ADHD+D (n = 36), aged 10-16 years, received open-label atomoxetine for 16 weeks. Data from the ADHD Rating Scale-IV (ADHDRS-IV), Kaufman Test of Educational Achievement (K-TEA), Working Memory Test Battery for Children (WMTB-C), and Life Participation Scale for ADHD-Child Version (LPS-C) were assessed.
Results
Atomoxetine demonstrated significant improvement for both groups on the ADHDRS-IV, LPS-C, and K-TEA reading comprehension standard and composite scores. K-TEA spelling subtest improvement was significant for the ADHD group, whereas the ADHD+D group showed significant reading decoding improvements. Substantial K-TEA reading and spelling subtest age equivalence gains (in months) were achieved for both groups. The WMTB-C central executive score change was significantly greater for the ADHD group. Conversely, the ADHD+D group showed significant phonological loop score enhancement by visit over the ADHD group. Atomoxetine was well tolerated, and commonly reported adverse events were similar to those previously reported.
Conclusions
Atomoxetine reduced ADHD symptoms and improved reading scores in both groups. Conversely, different patterns and magnitude of improvement in working memory component scores existed between ADHD and ADHD+D patients. Though limited by small sample size, group differences in relation to the comparable changes in improvement in ADHD symptoms could suggest that brain systems related to the therapeutic benefit of atomoxetine in reducing ADHD symptoms may be different in individuals with ADHD+D and ADHD without dyslexia.
Trial Registration
Clinical Trial Registry: ClinicalTrials.gov: NCT00191048
doi:10.1186/1753-2000-3-40
PMCID: PMC2805604  PMID: 20003507
15.  Pharmacological interventions for adolescents and adults with ADHD: stimulant and nonstimulant medications and misuse of prescription stimulants 
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by symptoms of inattention, hyperactivity, and impulsivity that cause functional impairment. Recent research indicates that symptoms persist into adulthood in the majority of cases, with prevalence estimates of approximately 5% in the school age population and 2.5%–4% in the adult population. Although students with ADHD are at greater risk for academic underachievement and psychosocial problems, increasing numbers of students with ADHD are graduating from high school and pursuing higher education. Stimulant medications are considered the first line of pharmacotherapy for individuals with ADHD, including college students. Although preliminary evidence indicates that prescription stimulants are safe and effective for college students with ADHD when used as prescribed, very few controlled studies have been conducted concerning the efficacy of prescription stimulants with college students. In addition, misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well. The purpose of the present systematic review was to investigate the efficacy of prescription stimulants for adolescents and young adults with ADHD and the nonmedical use and misuse of prescription stimulants. Results revealed that both prostimulant and stimulant medications, including lisdexamfetamine dimesylate, methylphenidate, amphetamines, and mixed-amphetamine salts, are effective at reducing ADHD symptoms in adolescents and adults with ADHD. Findings also suggest that individuals with ADHD may have higher rates of stimulant misuse than individuals without the disorder, and characteristics such as sex, race, use of illicit drugs, and academic performance are associated with misuse of stimulant medications. Results also indicate that individuals both with and without ADHD are more likely to misuse short-acting agents than long-acting agents. These findings have implications for intervention, prevention, and future research.
doi:10.2147/PRBM.S47013
PMCID: PMC4164338  PMID: 25228824
ADHD symptomatology; pharmacotherapy; nonmedical stimulant use; lisdexamfetamine; methylphenidate; amphetamine
16.  Acute atomoxetine treatment of younger and older children with ADHD: A meta-analysis of tolerability and efficacy 
Background
Atomoxetine is FDA-approved as a treatment of attention-deficit/hyperactivity disorder (ADHD) in patients aged 6 years to adult. Among pediatric clinical trials of atomoxetine to date, six with a randomized, double-blind, placebo-controlled design were used in this meta-analysis. The purpose of this article is to describe and compare the treatment response and tolerability of atomoxetine between younger children (6–7 years) and older children (8–12 years) with ADHD, as reported in these six acute treatment trials.
Methods
Data from six clinical trials of 6–9 weeks duration were pooled, yielding 280 subjects, ages 6–7 years, and 860 subjects, ages 8–12 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-diagnosed ADHD. Efficacy was analyzed using the ADHD Rating Scale-IV (ADHD-RS), Conners' Parent Rating Scale-revised (CPRS-R:S), and the Clinical Global Impression of ADHD Severity (CGI-ADHD-S).
Results
Atomoxetine was superior to placebo in both age categories for mean (SD) change in ADHD-RS total, total T, and subscale scores; 3 CPRS-R:S subscales; and CGI-ADHD-S from baseline. Although there were no significant treatment differentials between the age groups for these efficacy measures, the age groups themselves, regardless of treatment, were significantly different for ADHD-RS total (younger: ATX = -14.2 [13.8], PBO = -4.6 [10.4]; older: ATX = -15.4 [13.2], PBO = -7.3 [12.0]; p = .001), total T (younger: ATX = -15.2 [14.8], PBO = -4.9 [11.2]; older: ATX = -16.4 [14.6], PBO = -7.9 [13.1]; p = .003), and subscale scores (Inattentive: younger: ATX = -7.2 [7.5], PBO = -2.4 [5.7]; older: ATX = -8.0 [7.4], PBO = -3.9 [6.7]; p = .043; Hyperactive/Impulsive: younger: ATX = -7.0 [7.2], PBO = -2.1 [5.4]; older: ATX = -7.3 [7.0], PBO = -3.4 [6.3]; p < .001), as well as the CGI-ADHD-S score (younger: ATX = -1.2 [1.3], PBO = -0.5 [0.9]; older: ATX = -1.4 [1.3], PBO = -0.7 [1.1]; p = .010). Although few subjects discontinued from either age group due to adverse events, a significant treatment-by-age-group interaction was observed for abdominal pain (younger: ATX = 19%, PBO = 6%; older: ATX = 15%, PBO = 13%; p = .044), vomiting (younger: ATX = 14%, PBO = 2%; older: ATX = 9%, PBO = 6%; p = .053), cough (younger: ATX = 10%, PBO = 6%; older: ATX = 3%, PBO = 9%; p = .007), and pyrexia (younger: ATX = 5%, PBO = 2%; older: ATX = 3%, PBO = 5%; p = .058).
Conclusion
Atomoxetine is an effective and generally well-tolerated treatment of ADHD in both younger and older children as assessed by three recognized measures of symptoms in six controlled clinical trials.
Trial Registration
Not Applicable.
doi:10.1186/1753-2000-2-25
PMCID: PMC2556311  PMID: 18793405
17.  The Safety and Efficacy of Methylphenidate and Dexmethylphenidate in Adults with Attention Deficit/Hyperactivity Disorder 
Objective
To review the literature on the safety and efficacy of methylphenidate, OROS-methylphenidate, methylphenidate ER, and dexmethylphenidate in adults with Attention-Deficit/Hyperactivity Disorder (ADHD). To analyze the effects of different doses of methylphenidate, it’s various formulations, and methylphenidate on efficacy and safety in this population.
Data sources
Literature retrieval was performed through Pubmed/MEDLINE (Up to May 2010) using the terms methylphenidate, dexmethylphenidate, and attention-deficit hyperactivity disorder. In addition, reference citations from publications identified were reviewed.
Study selection and data extraction
Double-blinded, placebo-controlled clinical trials, as well as crossover and open-label trials found using the search criteria listed above were included for review. Case reports were not included in this review.
Data synthesis
Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric condition that is commonly seen in children and adolescents, that persists into adulthood for about 50% of patients. Methylphenidate and dexmethylphenidate are often prescribed to treat the symptoms associated with ADHD. The literature validating the safety and efficacy of methylphenidate and dexmethylphenidate in children and adolescents with ADHD is substantial. However, the literature specifically addressing the safety and efficacy of these medications in the adult population is less extensive and prescribing is often anecdotal based on child and adolescent data. Understanding the literature regarding methylphenidate and dexmethylphenidate and its effects in adults can enhance evidence-based medicine (EBM) and improve treatment outcomes
Conclusion
Methylphenidate and dexmethylphenidate are safe and effective medications to treat the symptoms of ADHD in adults. Based on the literature, increased doses are associated with better treatment response with moderate safety concerns. The different dosage forms available enable individualization of treatment.
PMCID: PMC3661236  PMID: 23861628
methylphenidate; dexmethylphenidate; ADHD; pharmacological treatment
18.  Influence of relative age on diagnosis and treatment of attention-deficit/hyperactivity disorder in children 
Background:
The annual cut-off date of birth for entry to school in British Columbia, Canada, is Dec. 31. Thus, children born in December are typically the youngest in their grade. We sought to determine the influence of relative age within a grade on the diagnosis and pharmacologic treatment of attention-deficit/hyperactivity disorder (ADHD) in children.
Methods:
We conducted a cohort study involving 937 943 children in British Columbia who were 6–12 years of age at any time between Dec. 1, 1997, and Nov. 30, 2008. We calculated the absolute and relative risk of receiving a diagnosis of ADHD and of receiving a prescription for a medication used to treat ADHD (i.e., methylphenidate, dextroamphetamine, mixed amphetamine salts or atomoxetine) for children born in December compared with children born in January.
Results:
Boys who were born in December were 30% more likely (relative risk [RR] 1.30, 95% confidence interval [CI] 1.23–1.37) to receive a diagnosis of ADHD than boys born in January. Girls born in December were 70% more likely (RR 1.70, 95% CI 1.53–1.88) to receive a diagnosis of ADHD than girls born in January. Similarly, boys were 41% more likely (RR 1.41, 95% CI 1.33–1.50) and girls 77% more likely (RR 1.77, 95% CI 1.57–2.00) to be given a prescription for a medication to treat ADHD if they were born in December than if they were born in January.
Interpretation:
The results of our analyses show a relative-age effect in the diagnosis and treatment of ADHD in children aged 6–12 years in British Columbia. These findings raise concerns about the potential harms of overdiagnosis and overprescribing. These harms include adverse effects on sleep, appetite and growth, in addition to increased risk of cardiovascular events.
doi:10.1503/cmaj.111619
PMCID: PMC3328520  PMID: 22392937
19.  A retrospective claims analysis of combination therapy in the treatment of adult attention-deficit/hyperactivity disorder (ADHD) 
Background
Combination therapy in managing psychiatric disorders is not uncommon. While combination therapy has been documented for depression and schizophrenia, little is known about combination therapy practices in managing attention-deficit/hyperactivity disorder (ADHD). This study seeks to quantify the combination use of ADHD medications and to understand predictors of combination therapy.
Methods
Prescription dispensing events were drawn from a U.S. national claims database including over 80 managed-care plans. Patients studied were age 18 or over with at least 1 medical claim with a diagnosis of ADHD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 314.0), a pharmacy claim for ADHD medication during the study period July2003 to June2004, and continuous enrollment 6 months prior to and throughout the study period. Dispensing events were grouped into 6 categories: atomoxetine (ATX), long-acting stimulants (LAS), intermediate-acting stimulants (IAS), short-acting stimulants (SAS), bupropion (BUP), and Alpha-2 Adrenergic Agonists (A2A). Events were assigned to calendar months, and months with combined use from multiple categories within patient were identified. Predictors of combination therapy for LAS and for ATX were modeled for patients covered by commercial plans using logistic regression in a generalized estimating equations framework to adjust for within-patient correlation between months of observation. Factors included age, gender, presence of the hyperactive component of ADHD, prior diagnoses for psychiatric disorders, claims history of recent psychiatric visit, insurance plan type, and geographic region.
Results
There were 18,609 patients identified representing a total of 11,886 months of therapy with ATX; 40,949 months with LAS; 13,622 months with IAS; 38,141 months with SAS; 22,087 months with BUP; and 1,916 months with A2A. Combination therapy was present in 19.7% of continuing months (months after the first month of therapy) for ATX, 21.0% for LAS, 27.4% for IAS, 23.1% for SAS, 36.9% for BUP, and 53.0% for A2A.
For patients receiving LAS, being age 25–44 or age 45 and older versus being 18–24 years old, seeing a psychiatrist, having comorbid depression, or having point-of-service coverage versus a Health Maintenance Organization (HMO) resulted in odds ratios significantly greater than 1, representing increased likelihood for combination therapy in managing adult ADHD.
For patients receiving ATX, being age 25–44 or age 45 and older versus being 18–24 years old, seeing a psychiatrist, having a hyperactive component to ADHD, or having comorbid depression resulted in odds ratios significantly greater than 1, representing increased likelihood for combination therapy in managing adult ADHD.
Conclusion
ATX and LAS are the most likely drugs to be used as monotherapy. Factors predicting combination use were similar for months in which ATX was used and for months in which LAS was used except that a hyperactive component to ADHD predicted increased combination use for ATX but not for LAS.
doi:10.1186/1472-6963-9-95
PMCID: PMC2702287  PMID: 19505334
20.  Combination and Switching of Stimulants in Children and Adolescents with Attention Deficit/Hyperactivity Disorder in Quebec 
Objective:
To assess the one-year period prevalence of stimulant combination therapy and switching in children/ adolescents with attention deficit/hyperactivity disorder (ADHD) in Quebec, Canada.
Method:
Patients aged 6–17 years, with at least two ADHD diagnosis codes documented in different visits and at least 30 days’ supply of a stimulant during their most recent one-year observation period were selected from the Regie de l’assurance maladie du Quebec database (03/2007–02/2012). Combination therapy was defined as at least 30 consecutive days of concomitant use of multiple stimulants with different active moieties, or use of a stimulant and another psychotropic medication. Therapy switching was defined as a prescription claim for a new psychotropic medication less than 30 days before or after the end of supply of a stimulant. The one-year period prevalence of therapy combination and switching was calculated.
Results:
The one-year period prevalence of combination therapy and switching among 9,431 children and adolescents with ADHD treated with stimulants was 19.8% and 18.7%, respectively. The most frequent combination categories were atypical antipsychotics (AAP: 10.8%), atomoxetine (ATX: 5.5%) and clonidine (5.3%). The most frequent switched-to categories were other stimulants (7.9%), AAP (5.5%) and ATX (4.7%).
Conclusions:
Approximately one in five children/adolescents with ADHD on a stimulant experienced combination therapy or therapy switching; however, the majority of the medications used in combination or switching were not label-indicated for the treatment of ADHD in Canada. These results highlight the need for further research to evaluate the risk-benefit of stimulant combination and switching in children and adolescents with ADHD.
PMCID: PMC4197516  PMID: 25320609
combination therapy; ADHD; RAMQ; switching; stimulants; traitement par combinaison; TDAH; RAMQ; changement; stimulants
21.  Efficacy of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder previously treated with methylphenidate: a post hoc analysis 
Background
Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral psychiatric disorder that afflicts children, with a reported prevalence of 2.4% to 19.8% worldwide. Stimulants (methylphenidate [MPH] and amphetamine) are considered first-line ADHD pharmacotherapy. MPH is a catecholamine reuptake inhibitor, whereas amphetamines have additional presynaptic activity. Although MPH and amphetamine can effectively manage ADHD symptoms in most pediatric patients, many still fail to respond optimally to either. After administration, the prodrug stimulant lisdexamfetamine dimesylate (LDX) is converted to l-lysine and therapeutically active d-amphetamine in the blood. The objective of this study was to evaluate the clinical efficacy of LDX in children with ADHD who remained symptomatic (ie, nonremitters; ADHD Rating Scale IV [ADHD-RS-IV] total score > 18) on MPH therapy prior to enrollment in a 4-week placebo-controlled LDX trial, compared with the overall population.
Methods
In this post hoc analysis of data from a multicenter, randomized, double-blind, forced-dose titration study, we evaluated the clinical efficacy of LDX in children aged 6-12 years with and without prior MPH treatment at screening. ADHD symptoms were assessed using the ADHD-RS-IV scale, Conners' Parent Rating Scale-Revised short form (CPRS-R), and Clinical Global Impressions-Improvement scale, at screening, baseline, and endpoint. ADHD-RS-IV total and CPRS-R ADHD Index scores were summarized as mean (SD). Clinical response for the subgroup analysis was defined as a ≥ 30% reduction from baseline in ADHD-RS-IV score and a CGI-I score of 1 or 2. Dunnett test was used to compare change from baseline in all groups. Number needed to treat to achieve one clinical responder or one symptomatic remitter was calculated as the reciprocal of the difference in their proportions on active treatment and placebo at endpoint.
Results
Of 290 randomized participants enrolled, 28 received MPH therapy at screening, of which 26 remained symptomatic (ADHD-RS-IV > 18). ADHD-RS-IV total scores, changes from baseline, clinical responsiveness, and rates of symptomatic remission in this subgroup were comparable to the overall population. The safety and tolerability profiles for LDX were comparable to other stimulants currently available.
Conclusion
In this analysis, children with significant clinical ADHD symptoms despite MPH treatment improved during treatment with LDX and experienced similar improvements in their symptoms as the overall study population.
Trial Registration
ClinicalTrials.gov: NCT00556296
doi:10.1186/1753-2000-5-35
PMCID: PMC3225298  PMID: 22054243
Attention-deficit/hyperactivity disorder (ADHD); lisdexamfetamine dimesylate (LDX); methylphenidate; children; efficacy
22.  Osmotic release oral system-methylphenidate improves neural activity during low reward processing in children and adolescents with attention-deficit/hyperactivity disorder☆ 
NeuroImage : Clinical  2013;2:366-376.
Attention-deficit/hyperactivity disorder (ADHD) is neurobehavioral disorder characterized by inattention, hyperactivity/impulsivity and impaired reward system function, such as delay aversion and low reward sensitivity. The pharmacological treatment for ADHD includes methylphenidate (MPH), or osmotic release oral system-MPH (OROS-MPH), which increases extrasynaptic dopamine and noradrenaline levels by blocking their reuptake. Although previous functional magnetic resonance imaging (fMRI) studies revealed that acute treatment with MPH alters activation of the nucleus accumbens during delay aversion in children and adolescents with ADHD, the effects a relatively long period of OROS-MPH treatment on delay aversion as well as reward sensitivity remain unclear. Thus, we evaluated brain activation with fMRI during a reward sensitivity paradigm that consists of high monetary reward and low monetary reward conditions before and after a 3-month treatment with OROS-MPH in 17 children and adolescents with ADHD (mean age, 13.3 ± 2.2) and 17 age- and sex-matched healthy controls (mean age, 13.0 ± 1.9). We found that before treatment there was decreased activation of the nucleus accumbens and thalamus in patients with ADHD during only the low monetary reward condition, which was improved to same level as those of the healthy controls after the treatment. The observed change in brain activity was associated with improved ADHD symptom scores, which were derived from Japanese versions of the ADHD rating scale-IV. These results suggest that treatment with OROS-MPH for a relatively long period is effective in controlling reward sensitivity in children and adolescents with ADHD.
Highlights
•Attention deficit/hyperactivity disorder (ADHD) has low reward sensitivity.•Activity in thalamus and nucleus accumbens was decreased in low monetary reward.•Osmotic release oral system-methylphenidate (OROS-MPH) is a medication for ADHD.•Brain activity and ADHD symptoms were improved by 3-month treatment with OROS-MPH.•OROS-MPH treatment for long periods may change brain activity of pediatric ADHD.
doi:10.1016/j.nicl.2013.03.004
PMCID: PMC3777787  PMID: 24179790
Attention deficit/hyperactivity disorder; Dopamine; Functional magnetic resonance imaging; Osmotic release oral system-methylphenidate; Reward sensitivity
23.  Efficacy and Safety of Lisdexamfetamine Dimesylate and Atomoxetine in the Treatment of Attention-Deficit/Hyperactivity Disorder: a Head-to-Head, Randomized, Double-Blind, Phase IIIb Study 
CNS Drugs  2013;27(12):1081-1092.
Objectives
The aim of this study was to compare the efficacy and safety of the prodrug psychostimulant lisdexamfetamine dimesylate (LDX) and the non-stimulant noradrenergic compound atomoxetine (ATX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) who had previously responded inadequately to methylphenidate (MPH).
Methods
This 9-week, head-to-head, randomized, double-blind, active-controlled study (SPD489-317; ClinicalTrials.gov NCT01106430) enrolled patients (aged 6–17 years) with at least moderately symptomatic ADHD and an inadequate response to previous MPH therapy. Patients were randomized (1:1) to an optimized daily dose of LDX (30, 50 or 70 mg) or ATX (patients <70 kg, 0.5–1.2 mg/kg with total daily dose not to exceed 1.4 mg/kg; patients ≥70 kg, 40, 80 or 100 mg). The primary efficacy outcome was time (days) to first clinical response. Clinical response was defined as a Clinical Global Impressions-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved). Secondary efficacy outcomes included the proportion of responders at each study visit and the change from baseline in ADHD Rating Scale (ADHD-RS-IV) and CGI-Severity scores. Tolerability and safety were assessed by monitoring treatment-emergent adverse events (TEAEs), height and weight, vital signs and electrocardiogram parameters. Endpoint was defined as the last post-baseline, on-treatment visit with a valid assessment.
Results
Of 267 patients randomized (LDX, n = 133; ATX, n = 134), 200 (74.9 %) completed the study. The median time to first clinical response [95 % confidence interval (CI)] was significantly shorter for patients receiving LDX [12.0 days (8.0–16.0)] than for those receiving ATX [21.0 days (15.0–23.0)] (p = 0.001). By week 9, 81.7 % (95 % CI 75.0–88.5) of patients receiving LDX had responded to treatment compared with 63.6 % (95 % CI 55.4–71.8) of those receiving ATX (p = 0.001). Also by week 9, the difference between LDX and ATX in least-squares mean change from baseline (95 % CI) was significant in favour of LDX for the ADHD-RS-IV total score [−6.5 (−9.3 to −3.6); p < 0.001; effect size 0.56], inattentiveness subscale score [−3.4 (−4.9 to −1.8); p < 0.001; effect size 0.53] and the hyperactivity/impulsivity subscale score [−3.2 (−4.6 to −1.7); p < 0.001; effect size 0.53]. TEAEs were reported by 71.9 and 70.9 % of patients receiving LDX and ATX, respectively. At endpoint, both treatments were associated with mean (standard deviation) increases in systolic blood pressure [LDX, +0.7 mmHg (9.08); ATX, +0.6 mmHg (7.96)], diastolic blood pressure [LDX, +0.1 mmHg (8.33); ATX, +1.3 mmHg (8.24)] and pulse rate [LDX, +3.6 bpm (10.49); ATX, +3.7 bpm (10.75)], and decreases in weight [LDX, −1.30 kg (1.806); ATX, −0.15 kg (1.434)].
Conclusions
LDX was associated with a faster and more robust treatment response than ATX in children and adolescents with at least moderately symptomatic ADHD who had previously responded inadequately to MPH. Both treatments displayed safety profiles consistent with findings from previous clinical trials.
doi:10.1007/s40263-013-0104-8
PMCID: PMC3835923  PMID: 23959815
24.  Impact of Attention-Deficit/Hyperactivity Disorder (ADHD) on prescription dug spending for children and adolescents: increasing relevance of health economic evidence 
Background
During the last decade, pharmaceutical spending for patients with attention-deficit-hyperactivity disorder (ADHD) has been escalating internationally.
Objectives
First, to estimate future trends of ADHD-related drug expenditures from the perspectives of the statutory health insurance (SHI; Gesetzliche Krankenversicherung, GKV) in Germany and the National Health Service (NHS) in England, respectively, for children and adolescents age 6 to 18 years. Second, to evaluate the budgetary impact on individual prescribers (child and adolescent psychiatrists and pediatricians treating patients with ADHD) in Germany.
Methods
A model was developed to predict plausible scenarios of future pharmaceutical expenditures for treatment of ADHD. Model inputs were derived from demographic and epidemiological data, a literature review of past spending trends, and an analysis of new pharmaceutical products in development for ADHD. Only products in clinical development phase III or later were considered. Uncertainty was addressed by way of scenario analysis. For each jurisdiction, five scenarios used different assumptions of future diagnosis prevalence, treatment prevalence, rates of adoption and unit costs of novel drugs, and treatment intensity.
Results
Annual ADHD pharmacotherapy expenditures for children and adolescents will further increase and may exceed €310 m (D; E: ₤78 m) in 2012 (2002: ~€21.8 m; ~₤7.0 m). During this period, overall drug spending by individual physicians may increase 2.3- to 9.5-fold, resulting from the multiplicative effects of four variables: increased number of diagnosed cases, growing acceptance and intensity of pharmacotherapy, and higher unit costs of novel medications.
Discussion
Even for an extreme low case scenario, a more than six-fold increase of pharmaceutical spending for children and adolescents is predicted over the decade from 2002 to 2012, from the perspectives of both the NHS in England and the GKV in Germany. This budgetary impact projection represents a partial analysis only because other expenditures are likely to rise as well, for instance those associated with physician services, including diagnosis and psychosocial treatment. Further to this, by definition budgetary impact analyses have little to nothing to say about clinical appropriateness and about value of money.
Conclusion
Providers of care for children and adolescents with ADHD should anticipate serious challenges related to the cost-effectiveness of interventions.
doi:10.1186/1753-2000-1-13
PMCID: PMC2216002  PMID: 18005403
25.  A systematic review of randomized controlled trials of bupropion versus methylphenidate in the treatment of attention-deficit/hyperactivity disorder 
Background
Some trials have suggested that bupropion, as well as methylphenidate, is beneficial in the treatment of attention‐deficit/hyperactivity disorder (ADHD).
Objectives
The purpose of this systematic review was to summarize the efficacy, acceptability, and tolerability of bupropion in comparison with methylphenidate for ADHD treatment. Included studies were randomized controlled trials (RCTs) that compared bupropion and methylphenidate. Clinical studies conducted between January 1991 and January 2014 were reviewed.
Data sources
MEDLINE®, EMBASE™, CINAHL, PsycINFO®, and the Cochrane Controlled Trials Register were searched in January 2014. Additionally, clinical trials were identified from the databases of ClinicalTrials.gov and the EU Clinical Trials Register.
Study eligible criteria, participants, and interventions
All RCTs of bupropion and methylphenidate reporting final outcomes relevant to 1) ADHD severity, 2) response or remission rates, 3) overall discontinuation rate, or 4) discontinuation rate due to adverse events. Language restriction was not applied.
Study appraisal and synthesis methods
The relevant clinical trials were examined and the data of interest were extracted. Additionally, the risks of bias were also inspected. The efficacy outcomes were the mean changed scores of ADHD rating scales, the overall response rate, and the overall remission rates. The overall discontinuation rate and the discontinuation rate due to adverse events were determined. Relative risks and weighted mean differences or standardized mean differences with 95% confidence intervals were estimated using a random effect model.
Results
A total of 146 subjects in four RCTs comparing bupropion with methylphenidate in the treatment of ADHD were included. The pooled mean changed scores of the Iowa–Conner’s Abbreviated Parent and Teacher Questionnaires and the ADHD Rating Scale‐IV for parents and teachers of children and adolescents with ADHD in the bupropion‐ and methylphenidate‐treated groups were not significantly different. Additionally, the pooled mean changed score in adult ADHD between the two groups, measured by the ADHD Rating Scale‐IV and the Adult ADHD Rating Scale, was also not significantly different. The pooled rates of response, overall discontinuation, and discontinuation due to adverse events between the two groups were not significantly different.
Conclusion
Based on limited data from this systematic review, bupropion was as effective as methylphenidate for ADHD patients. Additionally, tolerability and acceptability were also comparable. However, these findings should be considered as very preliminary results. To confirm this evidence, further studies in this area should be conducted.
doi:10.2147/NDT.S62714
PMCID: PMC4128852  PMID: 25120365
bupropion; methylphenidate; systematic review; ADHD; acceptability; tolerability

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