Clinically Meaningful Improvements in Early Morning and Late Afternoon/Evening Functional Impairment in Children with ADHD Treated with Delayed-Release and Extended-Release Methylphenidate.

OBJECTIVE: The Before School Functioning Questionnaire and Parent Rating of Evening and Morning Behavior-Revised assess early morning (BSFQ, PREMB-R AM subscale) and late afternoon/evening (PREMB-R PM subscale) functional impairment in children with ADHD. Clinically meaningful improvements were identified and applied to a trial of delayed-release and extended-release methylphenidate (DR/ER-MPH) in children with ADHD (NCT02520388) to determine if the statistically-determined improvements in functional impairment were also clinically meaningful. METHOD: Clinically meaningful improvements in BSFQ/PREMB-R were established post hoc by receiver operating characteristics curves, using anchors of Clinical Global Impression-Improvement (CGI-I) = 1 and CGI-I ≤ 2. Percentages of participants achieving these thresholds were calculated. RESULTS: Thresholds for CGI-I = 1/CGI-I ≤ 2, respectively, were 27/20 (BSFQ), 5/3 (PREMB-R AM), and 9/5 (PREMB-R PM)-point decreases. More children achieved clinically meaningful improvements with DR/ER-MPH versus placebo (all p < .05). CONCLUSION: DR/ER-MPH increased proportions of children achieving clinically meaningful improvements in BSFQ and PREMB-R.

Assessment and Treatment of a Young Adult with Congenital Heart Disease and ADHD.

CASE: Phillip is a young man born with hypoplastic left heart syndrome referred to your practice for a range of mental health concerns. He underwent palliation to an extracardiac Fontan in infancy and experienced multiple complications over the next decade including valvular regurgitation and arrhythmias necessitating a pacemaker. Phillip continued to have systolic heart failure with New York Heart Association class II symptoms, managed with 4 medications and anticoagulation.Despite this complex history, Phillip had intact cognitive abilities, achieved typical milestones, and performed well academically in secondary school. His first year of college proved to be more challenging, and Phillip presented to the outpatient psychiatry service with an acute depressive episode. His family history included depression, without known attention-deficit/hyperactivity disorder (ADHD). Treatment, including a selective serotonin reuptake inhibitor, cognitive behavioral therapy, and family support, led to near resolution of his symptoms of depression.In subsequent appointments, Phillip described a long history of inattention and disorganization with onset in childhood. This contributed to the decision to leave college, despite remission of symptoms of depression. Phillip was unable to study for any extended period without "perfect conditions," described as the absence of potential distractions except for background music. Despite attempts to maintain "perfect conditions," Phillip was often off task and "hyperfocusing" on irrelevant topics. Phillip struggled with planning and time management and would misplace items daily. Moreover, although the importance of self-care was well understood, Phillip often forgot to take his cardiac medication or to exercise, and he admitted to inconsistent sleep habits because of losing track of time.Based on a comprehensive psychiatric evaluation including retrospective report from a parent, Phillip was diagnosed with ADHD, coexisting with major depressive disorder, in remission. Significant ADHD symptoms were documented by interview, self-report, and administration of an abbreviated neuropsychological battery.Considering concerns regarding use of stimulants in a patient with congenital heart disease, including death, stroke, and myocardial infarction,1,2 how would you assess the risks-benefits of use of stimulants with Phillip? REFERENCES: 1. Wilens TE, Prince JB, Spencer TJ, et al. Stimulants and sudden death: what is a physician to do? Pediatrics. 2006;118:1215-1219.2. Zito JM, Burcu M. Stimulants and pediatric cardiovascular risk. J Child Adolesc Psychopharmacol. 2017;27:538-545.

Reliability and Validity of the Before-School Functioning Scale in Children With ADHD.

OBJECTIVE: Children with ADHD frequently manifest behavioral difficulties in the morning prior to school. We sought to assess the reliability and validity of the Before-School Functioning Questionnaire (BSFQ) as a measure of morning behaviors impaired by ADHD. METHOD: We used pre-treatment data from a randomized crossover study of 6- to 12-year-old participants comparing the methylphenidate transdermal delivery system (MTS) with a placebo transdermal system (PTS) for a total of 4 weeks. RESULTS: The BSFQ investigator-rated scale shows very good internal homogeneity (Cronbach's α = .91), good test-retest reliability ( r = .60), good concurrent validity ( r range = .42-.86), and a strong treatment effect (effect size = -.93). The self-rated BSFQ showed lower levels of reliability and validity. CONCLUSION: The investigator-rated BSFQ should be used in future trials of ADHD medications aimed at assessing efficacy in the morning before school.

Treatment of Attention-Deficit/Hyperactivity Disorder in Adolescents: A Systematic Review.

IMPORTANCE: Although attention-deficit/hyperactivity disorder (ADHD) is highly prevalent in adolescents and often persists into adulthood, most studies about treatment were performed in children. Less is known about ADHD treatment in adolescents. OBJECTIVE: To review the evidence for pharmacological and psychosocial treatment of ADHD in adolescents. EVIDENCE REVIEW: The databases of CINAHL Plus, MEDLINE, PsycINFO, ERIC, and the Cochrane Database of Systematic Reviews were searched for articles published between January 1, 1999, and January 31, 2016, on ADHD treatment in adolescents. Additional studies were identified by hand-searching reference lists of retrieved articles. Study quality was rated using McMaster University Effective Public Health Practice Project criteria. The evidence level for treatment recommendations was based on Oxford Centre for Evidence-Based Medicine criteria. FINDINGS: Sixteen randomized clinical trials and 1 meta-analysis, involving 2668 participants, of pharmacological and psychosocial treatments for ADHD in adolescents aged 12 years to 18 years were included. Evidence of efficacy was stronger for the extended-release methylphenidate and amphetamine class stimulant medications (level 1B based on Oxford Centre for Evidence-Based Medicine criteria) and atomoxetine than for the extended-release α2-adrenergic agonists guanfacine or clonidine (no studies). For the primary efficacy measure of total symptom score on the ADHD Rating Scale (score range, 0 [least symptomatic] to 54 [most symptomatic]), both stimulant and nonstimulant medications led to clinically significant reductions of 14.93 to 24.60 absolute points. The psychosocial treatments combining behavioral, cognitive behavioral, and skills training techniques demonstrated small- to medium-sized improvements (range for mean SD difference in Cohen d, 0.30-0.69) for parent-rated ADHD symptoms, co-occurring emotional or behavioral symptoms, and interpersonal functioning. Psychosocial treatments were associated with more robust (Cohen d range, 0.51-5.15) improvements in academic and organizational skills, such as homework completion and planner use. CONCLUSIONS AND RELEVANCE: Evidence supports the use of extended-release methylphenidate and amphetamine formulations, atomoxetine, and extended-release guanfacine to improve symptoms of ADHD in adolescents. Psychosocial treatments incorporating behavior contingency management, motivational enhancement, and academic, organizational, and social skills training techniques were associated with inconsistent effects on ADHD symptoms and greater benefit for academic and organizational skills. Additional treatment studies in adolescents, including combined pharmacological and psychosocial treatments, are needed.

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.

Do stimulants improve functioning in adults with ADHD? A review of the literature.

ADHD is prevalent in adulthood and stimulant pharmacotherapy is the primary treatment for uncomplicated presentations. ADHD is associated with significant functional impairment in major life roles. Measurement of the efficacy of stimulant treatment for adult ADHD therefore should include assessment of improvement in role function. A literature search was conducted to identify studies that measured change in function with stimulant treatment in adult ADHD using measures other than global clinical impression or global assessment of function ratings. Five studies were identified that met our search criteria. Evidence of functional improvement with stimulant treatment was found with the following validated self-report measures of functional wellbeing employed across these studies: the Medical Outcome Study 36-item Short Form Health Survey; ADHD Impact Module for Adults; Quality of Life Enjoyment and Satisfaction scale-Short Form; Sheehan Disability Scale, and Social Adjustment Scale-Self-Report. We conclude that investigations using self-report scales provide evidence that stimulant treatment translates into measurable improvement in daily function for adults with ADHD. Further investigation could better characterize the mediators and moderators of individual improvement, an important step towards the personalization of treatment for ADHD in adulthood.

A pilot open label prospective study of memantine monotherapy in adults with ADHD.

OBJECTIVES: Available pharmacotherapies treat some adults with ADHD inadequately. A small literature suggests that glutamate modulation could have effects on ADHD. METHODS: Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, was titrated to a maximum dose of 10 mg BID in 34 adult subjects aged 18-55 who met DSM-IV criteria for ADHD or ADHD NOS on structured interview. Twenty-eight subjects completed 12 weeks exposure. The Adult ADHD Investigator Symptom Report (AISRS), Clinical Global Impression (CGI), a neuropsychological battery sensitive to domains of executive function, and the CANTAB cognitive battery were administered. Paired t-tests compared treated and baseline scores. RESULTS: At week 12, AISRS data showed reduction in total symptoms (-17.5, P < 0.001), inattentive symptoms (-10.6, P < 0.001), and hyperactive symptoms (-6.9, P < 0.01). A total of 44% of subjects had CGI ratings of much or very much improved. Cognitive performance improved in measures of attention, working memory, and other selected executive domains by weeks 6 and 12 (each P < 0.05); simple reaction time declined by week 12 (P < 0.05). There were no severe adverse events, but mild adverse events were common and six subjects discontinued due to adverse effects. CONCLUSIONS: Memantine was largely well-tolerated and associated with improvement in ADHD symptoms and neuropsychological performance. Randomized studies are indicated to confirm whether memantine is a novel therapy for ADHD across the lifespan.

Cardiovascular risk of stimulant treatment in pediatric attention-deficit/hyperactivity disorder: update and clinical recommendations.

OBJECTIVE: This review provides an update on the cardiovascular impact of therapeutic stimulant-class medication for children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHOD: Relevant clinical literature was ascertained using PubMed searches limited to human studies and the English language as of May 2011. Current practice guidelines and consensus statements also were reviewed. RESULTS: Stimulant-class medications for healthy children and adolescents with ADHD are associated with mean elevations in blood pressure (≤5 mmHg) and heart rate (≤10 beats/min) without changes in electrocardiographic parameters. A subset (5-15%) of children and adolescents treated may have a greater increase in heart rate or blood pressure at a given assessment or may report a cardiovascular-type complaint during stimulant treatment. It is extremely rare for a child or adolescent receiving stimulant medication to have a serious cardiovascular event during treatment, with the risk appearing similar to groups of children not receiving stimulant medication. CONCLUSIONS: Clinicians should adhere to current recommendations regarding the prescription of stimulant medications for youth with ADHD. Scientific inquiry is indicated to identify patients at heightened risk and to continue surveillance for the longer-term cardiovascular impact of these agents.

Adult attention-deficit/hyperactivity disorder treatment and cardiovascular implications.

Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder afflicting adults worldwide. This article is an update on the evidence supporting medications for adult ADHD, with particular emphasis on cardiovascular implications. Relevant clinical literature was sought using PubMed searches, with an emphasis on new reports from April 2009 to April 2011. This review describes the efficacy and general tolerability of stimulant and nonstimulant medications for adults with ADHD as seen in contemporary clinical trials. Cardiovascular response to medications for ADHD is primarily seen in heart rate and blood pressure elevations, while less is known about the etiology of rare cardiovascular events or long-term sequelae. Further research is indicated to delineate clinical and functional outcomes for adults with ADHD, as well as long-term safety of medication treatment.

An open-label study of the tolerability of mixed amphetamine salts in adults with attention-deficit/hyperactivity disorder and treated primary essential hypertension.

OBJECTIVE: To evaluate the short-term tolerability of an extended-release preparation of the stimulant medication mixed amphetamine salts (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD) whose hypertension has been successfully treated with antihypertensive medications. METHOD: An 8-week, 2-phase, open-label study design was implemented. All adults had ADHD (DSM-IV diagnosis) and essential hypertension and were required to be normotensive (blood pressure < 135/85 mm Hg, treated) for at least 4 weeks at entry into the study. MAS XR was given for a 6-week period, titrated once each week to a target maximum dose of 60 mg/day given once daily in the morning (phase 1), and then discontinued for 2 weeks at the end of the study (phase 2). At baseline, subjects underwent a comprehensive clinical assessment, medical history, vital signs assessment, and electrocardiogram (ECG). Rating scales were used throughout the study to assess response to treatment, and blood pressure was measured manually at each study visit. The primary outcome was the effect of MAS XR on blood pressure and the development of hypertension. RESULTS: Thirteen subjects receiving antihypertensive therapy were entered and placed on MAS XR treatment and completed the trial. There were no serious adverse events. No sustained elevated blood pressure (> 140/90 mm Hg at 2 consecutive visits) was observed in the subjects treated with MAS XR. Similar rates of single episodes of hypertension were observed in phases 1 and 2. Similarly, there was no group mean increase in systolic or diastolic blood pressure or pulse during treatment with MAS XR. No clinically significant changes in the ECG were observed. During the 6-week medication phase, significant improvement was found on rating scales assessing ADHD symptoms and severity that reversed with discontinuation of MAS XR. CONCLUSION: The results of this open study suggest that adults with ADHD and controlled hypertension can be safely treated with MAS XR.

Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the effects of medications used in the treatment of adults with attention-deficit/hyperactivity disorder (ADHD) on blood pressure and pulse. METHOD: Subjects were those with DSM-III-R-/DSM-IV-diagnosed ADHD enrolled in placebo-controlled studies of 5 different medications for ADHD. Cardiovascular data from these studies of both stimulants (methylphenidate, amphetamine compounds, pemoline) and nonstimulants (bupropion, desipramine) were reanalyzed for baseline-to-endpoint active-treatment or placebo effects on blood pressure and heart rate. RESULTS: There were 125 subjects with a mean +/- SD age of 39 +/- 9 years. In general, active drug treatment for ADHD compared to baseline was associated with several statistically significant changes in systolic blood pressure (bupropion: +5.9 mm Hg, p < .05 by paired t test; amphetamine: +5.4 mm Hg, p < .05), diastolic blood pressure (desipramine: +7.1 mm Hg, p < .05), and heart rate (bupropion: +6.9 mm Hg, p < .05; amphetamine: +7.3 mm Hg, p < .05; methylphenidate: +4.5 mm Hg, p < .05). New-onset cases of systolic or diastolic hypertension (blood pressure > or = 140/90) were recorded in 8% (7/89) of placebo-treated subjects and 10% (9/89) of subjects receiving active medication, regardless of the class (stimulant, nonstimulant). CONCLUSION: Both stimulant and nonstimulant catecholaminergic medications used in adults with ADHD are associated with minor, but statistically significant, changes in heart rate and blood pressure that were often observed in those receiving placebo. Given the minor pressor and chronotropic effect of these medications, adults with ADHD should have their blood pressure and heart rate checked at baseline and periodically during treatment.