Complex ADHD Challenging Case: Managing Co-Occurring Attention-Deficit Hyperactivity Disorder and Congenital Heart Disease with a Limited Medication Formulary: A Case from Mexico.

CASE: DL is an 8-year-old Mexican boy with a posterior atrial septal defect and partial anomalous pulmonary venous return of the right lower pulmonary vein with resultant right heart dilation with normal right ventricular systolic and diastolic function and no arrhythmias. Surgical repair was deferred, and DL's condition was being medically managed with furosemide 0.5 mg/kg BID and spironolactone 0.5 mg/kg BID.DL presents for developmental assessment due to poor performance in school following a lifting of COVID-19 pandemic restrictions and return to in-person classes. He has been attending full-time classes for 3 months without improvements in math, reading, and writing skills. Current attentional concerns at school include an inability to complete tasks without getting distracted by minimal stimuli and highly impulsive behavior.At the first assessment, DL was performing below grade expectations (e.g., reading by syllable without text comprehension, demonstrating preoperational addition and subtraction skills, inability to take dictation)-all of which was viewed as negatively impacted by attentional deficits. DL met DSM-5 criteria for ADHD, predominantly inattentive type. He was started on 10-mg immediate-release methylphenidate PO at 8 am with breakfast and a second dose of 10-mg immediate-release methylphenidate PO 4 hours after the first dose.After a month, at the first follow-up consultation, improvement in attention span, impulsivity, and school performance were observed, including reading skills and math proficiency. However, DL's mother raised concerns about circumoral cyanosis and acrocyanosis in the fingers of both hands after playing outside. These signs were not previously observed. During physical examination at the same visit, heart rate, blood pressure, and oximetry were within baseline ranges and his cardiac examination was unchanged. DL's dosage of methylphenidate was lowered to 10-mg immediate-release methylphenidate PO QD in the mornings with breakfast (8 am).DL did not return to clinic for another 2 months, having discontinued the medication after 2 months of treatment given financial limitations. His mother reported that DL's exertional circumoral cyanosis and acrocyanosis resolved while he was off medication. However, she observed an increase in inattentive symptoms and impulsivity and decline in his academic skills. She asked if our team was able continue the treatment despite the drug side effects, since she believed the benefits outweighed the disadvantages.Given these concerns, the team requested an updated cardiology assessment. The Cardiologist recommended discontinuation of methylphenidate and recommended follow-up with cardiothoracic surgery for reassessment of the surgical timeline.Given the limited treatment options in Mexico, what would you do next as the treating developmental-behavioral clinician…?

Effectiveness of collaborative tele-mental health care for children with attention deficit hyperactivity disorder in United Arab Emirates.

Background: Attention deficit hyperactivity disorder is a common neurodevelopmental disorder. Accessing services for this disorder is a worldwide challenge and requires innovative interventions. Aims: We aimed to investigate the effectiveness of tele-collaborative care for attention deficit hyperactivity disorder in primary health care centres in Dubai. Methods: Six trained physicians started collaborative care clinics across Dubai. Eligible children aged 6-12 years attending primary health care centres with attention deficit hyperactivity disorder were randomly selected to receive telehealth collaborative care, or standard treatment. Baseline assessments were conducted using the Vanderbilt Behavioral Assessment Scale, the Columbia Impairment Scale, the Childhood Behavior Checklist, and the Strength and Difficulties Questionnaire. Waiting times and clinical and functional outcomes were measured in both groups and compared. Continuous variables were presented as means and standard deviations, categorical variables such as sex were presented as numbers and percentages, and continuous outcome variables were compared using the Student t-test. Results: Among the referred children (n = 112), 11 boys and 6 girls met the eligibility criteria (mean age 7.8 years). The dropout rate at 6 months in the control group was 80%, compared with 50% in the intervention group. The mean waiting time was significantly shorter in the intervention group (1.3 weeks) than the control group (7.1 weeks); P = 0.026. The mean difference in the Childhood Behavior Checklist total score over time was significantly higher in the intervention group (P = 0.042), but the mean difference in the Vanderbilt scale was not significant. Conclusion: Tele-collaborative care for children with attention deficit hyperactivity disorder within primary health care is feasible.

Cardiovascular Considerations for Stimulant Class Medications.

The cardiovascular (CV) impact of stimulants has been examined for decades, with investigations ranging from small sample targeted studies of heart rate (HR) and blood pressure (BP), to large scale epidemiologic investigations. The preponderance of evidence is reassuring, albeit generally based on healthy samples using variable methodology, excluding those at theoretic high risk (eg, comorbid cardiac illness). Screening for theoretically vulnerable patients are recommended, as well as monitoring for CV symptoms and BP/HR, with shared inquiry/further evaluation if concerned. Future investigations to support the identification of risk are needed, while attention to stimulant-associated CV risk is an opportunity for clinicians to engage in general CV risk identification and intervention.

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.

New stimulant formulations for pediatric attention-deficit/hyperactivity disorder: a case-based approach for the primary care provider.

PURPOSE OF REVIEW: To provide an up-to-date clinical review of U.S. Food and Drug Administration (FDA)-approved stimulant medications for attention-deficit/hyperactivity disorder (ADHD), including a framework for individualized treatment by primary care pediatric providers. RECENT FINDINGS: Stimulant medications are first-line agents for pediatric ADHD. Since 2012, 11 novel stimulant medications have been approved by the FDA for the treatment of ADHD. Because of an expanded formulary of available methylphenidate-based and amphetamine-based stimulants, primary care providers may be unfamiliar with some novel medications outside a select formulary. SUMMARY: The current broad formulary of methylphenidate-based and amphetamine-based stimulants provides primary care clinicians with a greater opportunity for personalized medicine within the patient-centered medical home. Through a systematic review of prior relevant medication trials, a consideration of daily symptom burden and thoughtful pragmatics, primary care providers can offer a more precise, customized stimulant treatment.

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.

Do Stimulants Reduce the Risk for Alcohol and Substance Use in Youth With ADHD? A Secondary Analysis of a Prospective, 24-Month Open-Label Study of Osmotic-Release Methylphenidate.

OBJECTIVE: The purpose of this study was to examine the impact of stimulant treatment on risk for alcohol and illicit drug use in adolescents with ADHD. METHOD: Analysis of data derived from a prospective open-label treatment study of adolescent ADHD ( n = 115, 76% male), and a historical, naturalistic sample of ADHD ( n = 44, 68% male) and non-ADHD youth ( n = 52, 73% male) of similar age and sex. Treatment consisted of extended-release methylphenidate in the clinical trial or naturalistic stimulant treatment. Self-report of alcohol and drug use was derived from a modified version of the Drug Use Screening Inventory. RESULTS: Rates of alcohol and drug use in the past year were significantly lower in the clinical trial compared with untreated and treated naturalistic ADHD comparators, and similar to rates in non-ADHD comparators. CONCLUSION: Well-monitored stimulant treatment may reduce the risk for alcohol and substance use in adolescent ADHD.

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.

A randomized controlled trial of cognitive behavioral therapy for ADHD in medication-treated adolescents.

OBJECTIVE: To test cognitive behavioral therapy (CBT) for persistent attention-deficit hyperactivity disorder (ADHD) symptoms in a sample of medication-treated adolescents. METHODS: Forty-six adolescents (ages 14-18), with clinically significant ADHD symptoms despite stable medication treatment were randomly assigned to receive CBT for ADHD or wait list control in a cross-over design. Twenty-four were randomized to CBT, 22 to wait list, and 15 crossed-over from wait list to CBT. A blind independent evaluator (IE) rated symptom severity on the ADHD Current Symptom Scale, by adolescent and parent report, and rated each subject using the Clinical Global Impression Severity Scale (CGI), a global measure of distress and impairment. These assessments were performed at baseline, 4-months (post-CBT or post wait list), and 8-months (post-treatment for those originally assigned to the wait list condition and 4-month follow-up for those originally assigned to CBT). TRIAL REGISTRATION: http://clinicaltrials.gov/show/NCT01019252. RESULTS: Using all available data, mixed effects modeling, and pooling for the wait list cross-over, participants who received CBT received a mean score 10.93 lower on the IE-rated parent assessment of symptom severity (95% CI: -12.93, -8.93; p < .0001), 5.24 lower on the IE-rated adolescent assessment of symptom severity (95% CI: -7.21, -3.28; p < .0001), and 1.17 lower IE-rated CGI (95% CI: -1.39, -.94; p < .0001). Results were consistent across 100 multiple imputations (all p < .0001). There was a greater proportion of responders after CBT by parent (50% vs. 18%, p = .00) and adolescent (58% vs. 18% p = .02) report. CONCLUSIONS: This study demonstrates initial efficacy of CBT for adolescents with ADHD who continued to exhibit persistent symptoms despite medications.

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.

An evidence-based systematic review of elderberry and elderflower (Sambucus nigra) by the Natural Standard Research Collaboration.

An evidence-based systematic review of elderberry and elderflower (Sambucus nigra) by the Natural Standard Research Collaboration consolidates the safety and efficacy data available in the scientific literature using a validated, reproducible grading rationale. This article includes written and statistical analysis of clinical trials, plus a compilation of expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

Assessment of cognitive domains during treatment with OROS methylphenidate in adolescents with ADHD.

AIM: To psychometrically assess cognitive domains in adolescents with ADHD during long-term open treatment with robust dosing of extended-release methylphenidate (OROS MPH). METHODS: Data were derived from a prospective clinical study of adolescent ADHD, employing the Cambridge Neuropsychological Test Automated Battery (CANTAB), before and after up to one year of treatment with OROS MPH. In the absence of placebo control, a similar age and gender group of youth without ADHD served as comparators. RESULTS: During the course of treatment with OROS MPH, ADHD youth's performance significantly improved across multiple CANTAB tasks, including spatial working memory, rapid visual processing, verbal recognition memory, set shifting, and inhibition/vigilance. ADHD subjects' scores in several CANTAB tasks, including spatial working memory, planning, and set shifting, were significantly more impaired at baseline compared to the non-ADHD comparison group; these significant differences were no longer seen at endpoint. CONCLUSIONS: Statistically significant improvements in multiple cognitive domains were observed in a sample of adolescents with ADHD over the course of 12 months of robust treatment with extended-release methylphenidate. Rigorous, monitored stimulant treatment may be associated with objectively determined cognitive benefits; however, practice effects in this open trial cannot be ruled out. Further study on this important topic is warranted.

Examining the nature of the association between attention-deficit hyperactivity disorder and nicotine dependence: a familial risk analysis.

OBJECTIVE: To use familial risk analysis to examine the association between attention-deficit hyperactivity disorder (ADHD) and nicotine dependence (ND). METHOD: Subjects were children with (n = 257) and without (n = 229) ADHD of both sexes ascertained from pediatric and psychiatric referral sources and their first-degree relatives (N = 1627). RESULTS: ND in probands increased the risk for ND in relatives irrespective of ADHD status. There was no evidence of cosegregation or assortative mating between these disorders. Patterns of familial risk analysis suggest that the association between ADHD and ND is most consistent with the hypothesis of independent transmission of these disorders. CONCLUSIONS: These findings may have important implications for the identification of a subgroup of children with ADHD at high risk for ND based on parental history of ND.

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.

A cardiopulmonary study of lisdexamfetamine in adults with attention-deficit/hyperactivity disorder.

OBJECTIVES: Due to concerns about the safety of stimulants for ADHD, novel assessments of the cardiopulmonary impact of these agents are needed. METHODS: An open design of lisdexamfetamine (LDX) in 15 adults with DSM-IV ADHD. Following a psychiatric evaluation and medical history, subjects underwent echocardiography (TTE) and cardiopulmonary exercise testing (CPET). LDX was titrated to 70 mg daily over 6 weeks, followed by monthly visits to 6 months. Change in TTE and CPET measures were examined following up to 6 months of LDX. RESULTS: At endpoint, there were no significant alterations in indices of cardiac systolic performance, or in metabolic and ventilatory variables at maximum exertion (P values >0.05). We found significant mean changes in resting LV systolic dimension and Doppler diastolic indices. Change in heart rate recovery at 1 min met statistical significance (P = 0.05). CONCLUSIONS: We did not detect clinically meaningful changes in cardiac structure and function or in metabolic and ventilatory variables at maximum exertion in ADHD adults receiving open LDX. The clinical significance of changes in resting LV dimension and indices of diastolic function are not in the direction of cardiomyopathy. Future large sample controlled study can examine these findings, as well as stimulants' impact on heart rate recovery.

Do stimulants reduce the risk for cigarette smoking in youth with attention-deficit hyperactivity disorder? A prospective, long-term, open-label study of extended-release methylphenidate.

OBJECTIVE: Although attention-deficit hyperactivity disorder (ADHD) is a well-known risk factor for cigarette smoking, prospective studies aimed at reducing smoking risk in this population are critically needed. STUDY DESIGN: This was a 2-year, prospective, open-label clinical trial of extended-release methylphenidate for smoking prevention in adolescents with ADHD (n = 154). Smoking outcomes were assessed with the Fagerstrom Tolerance Questionnaire. Comparisons were made using data from a historical, naturalistic sample of ADHD (n = 103) and non-ADHD comparators (n = 188) of similar age and sex assessed with the same assessment battery as that used in subjects participating in the clinical trial. RESULTS: The smoking rate at endpoint (mean, 10 months of methylphenidate treatment) was low in the clinical trial subjects and not significantly different from that in the non-ADHD comparators or the ADHD comparators receiving stimulants naturalistically (7.1% vs 8.0% vs 10.9%; P > .20). In contrast, the smoking rate was significantly lower in the clinical trial subjects than in the naturalistic sample of ADHD comparators who were not receiving stimulant treatment (7.1% vs 19.6%; P = .009 [not significant], adjusting for comorbid conduct disorder and alcohol and drug abuse). CONCLUSION: Although considered preliminary until replicated in future randomized clinical trials, the findings from this single-site, open-label study suggest that stimulant treatment may contribute to a decreased risk for smoking in adolescents with ADHD. If confirmed, this finding would have significant clinical and public health impacts.