There have been major advances in the treatment and understanding of attention-deficit hyperactivity disorder (ADHD) in the last decade. Among these are the availability of newer stimulant ...formulations, an appreciation of the combined effects of medication and behavioural therapies, and a better understanding of the neurobiology of the disorder in children (aged 6-12 years), adolescents and adults. This article focuses on the evaluation of the efficacy and safety profiles of medications used for the management of ADHD. In assessing the various medical treatments for ADHD, certain issues and analyses have become important to address. The diagnosis, characterization and quantification of ADHD symptoms are crucial to assessing treatment effectiveness. A standardized setting for measuring the severity of ADHD symptoms is the laboratory school protocol, which simulates a school environment with tightly controlled timing of measurements. This method has been adapted successfully to the adult workplace environment to help with the evaluation of adult ADHD symptoms. Statistical analyses, such as effect size and number needed to treat, may aid in the comparison and interpretation of ADHD study results. Although an objective approach to evaluating the efficacy and safety profiles of the available medications provides necessary details about the medical options, typical clinical decisions are often based on trial and error and may be individualized based on a patient's daily routine, comorbidities and risk factors. Stimulants remain the US FDA-approved medical treatment of choice for patients with ADHD and are associated with an exceptional response rate. Findings of the Multimodal Treatment of Children With ADHD study suggest that the combination of behavioural and medical therapy may benefit most patients. Nonstimulant agents, such as atomoxetine (FDA-approved), and several non-approved agents, bupropion, guanfacine and clonidine, may offer necessary alternatives to the stimulants. This is especially important for patients who have comorbidities that are contraindicated for stimulant use based on medical issues and/or risk for stimulant abuse. Typical psychiatric comorbidities in patients with ADHD include oppositional defiant disorder, conduct disorder, major depressive disorder, bipolar disorder, anxiety, substance abuse disorder, tic disorder, and Tourette's syndrome. Although relatively safe, both stimulants and atomoxetine have class-related warnings and contraindications and are associated with adverse effects that require consideration when prescribing. Polypharmacy is a common psychiatric approach to address multiple symptoms or emergent adverse effects of necessary treatments. Future research may provide an improved understanding of polypharmacy and better characterization of the factors that influence the diagnosis and successful treatment of patients with ADHD.
The time of onset and the duration of treatment effect are important considerations in the choice of the medication to be prescribed in treating children, adolescents, and adults with ADHD. Early ...onset of effect may facilitate preparation for school, improved behavior during the trip to school, and attention during morning classes. Sustained treatment effect through afternoon and evening hours can be important because impairments associated with ADHD are not limited to the naturalistic classroom. Laboratory school protocols (LSPs) provide a simulated, rigorously controlled classroom setting environment and have proven valuable for providing pharmacokinetic and pharmacodynamic information about medications, and other treatments used in managing ADHD in school-aged children and across the lifespan.
This paper is an invited mini-review of LSPs of stimulant medication, which includes data from multiple, randomized, double-blind, and placebo-controlled medication trials for ADHD. Assessment endpoints included the permanent product measure of performance (PERMP), Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale in the preschool assessment laboratory (PAL), child/adolescent, and adult workplace environment (AWE) studies. These measures allow the study of improvement in attention and behavior in individuals with ADHD.
Analog classroom settings (LSP or AWE) have been used to assess immediate and modified-release stimulant formulations of medications to treat ADHD in multiple age groups. Results based on both subjective (e.g., SKAMP ratings) and objective (e.g., PERMP) measures are used as clinical outcomes in testing drugs currently in development for ADHD.
The LSP and its extension to PAL and AWE settings continue to be used to assess the time-course of effect of ADHD medications because they provide valuable information in their respective structured, controlled environments.
Background
Mazindol is under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD) because of its alertness-enhancing properties. A novel controlled-release (CR) ...formulation of mazindol was developed to allow once-daily dosing.
Objective
The aim of this study was to evaluate the efficacy of mazindol CR in adults with ADHD.
Design
We conducted a randomized, double-blind, placebo-controlled 6-week trial.
Methods
Subjects diagnosed with ADHD using the Mini-International Neuropsychiatric Structured Interview (MINI) and with an ADHD Rating Scale, Diagnostic and Statistical Manual of Mental Disorders 5th Edition (ADHD-RS-DSM5) score ≥ 28 were randomized to receive placebo or 1–3 mg/day of mazindol for 6 weeks. The primary endpoint was the reduction from baseline in the ADHD-RS-DSM5 score on Day 42. Secondary endpoints were response rates defined by change in ADHD-RS-DSM5 (≥ 30 or ≥ 50% reduction) and dichotomized Clinical Global Impression–Improvement (CGI-I) score (1 or 2). An exploratory endpoint of functional impairment, as measured by the Target Impairment Scale, examined individualized deficits in specific settings. Safety, tolerability, and pharmacokinetics were assessed.
Results
Eighty-five participants were randomized (
n
= 43 active, 42 placebo); 75 completed. Weekly ADHD-RS-DSM5 measurements after mazindol differed from placebo beginning at Day 7, with a least squares mean difference (active–placebo) of − 13.2 at Day 42 and an effect size of 1.09. For the 30% or more reduction in ADHD-RS-DSM5 (minimal response), a significant difference (active-placebo) was seen starting at Day 7 and continuing to Day 42. For the CGI-I (1 or 2) and for the 50% or more reduction in ADHD-RS-DSM5 (measures of excellent response), the differences began at Day 14 and continued to Day 42. Functional impairment was significantly different in the proportion achieving at least a 50% reduction in target impairment score (42.9% mazindol vs 11.9% placebo) by Day 42. Dry mouth, nausea, fatigue, heart rate (HR) increased, decreased appetite, and constipation were more prevalent for mazindol versus placebo. Overall, mazindol CR had minimal effects on blood pressure and small effects on HR.
Conclusion
Mazindol CR was efficacious in the treatment of adults with ADHD, with a large effect size, and was well tolerated, supporting the progression to phase III.
(Clinicaltrials.gov Registration No. NCT02808104)
Objective: The aim of this study is to assess the onset and duration of efficacy of multilayer-release methylphenidate (PRC-063) over 16 hr compared with placebo in adults with ADHD using the ...simulated adult workplace environment. Method: After dose-optimization with PRC-063, participants entered a double-blind, placebo-controlled, crossover phase. Primary outcome measure was the Permanent Product Measure of Performance (PERMP) total score measured pre-dose and from 1 to 16 hr post-dose. Results: Of the 59 randomized participants, 45 participants completed the study. While receiving PRC-063, adults had greater mean PERMP total scores across all time points compared with placebo (268.7 ± 11.24 vs. 255.6 ± 10.87; p = .0064). Common adverse events were decreased appetite, headache, and insomnia. There was no significant impact on overall sleep quality (p = .9542). Conclusion: PRC-063 significantly improved PERMP scores with an onset within 1 hr post-dose, and maintained improvement throughout the 16 hr post-dose study period compared with placebo in adults with ADHD.
Two phase 2 studies evaluated the efficacy and tolerability of centanafadine sustained-release (SR) for adults with attention-deficit/hyperactivity disorder (ADHD).
In a phase 2a, flexible-dose, ...single-blind study, 41 male patients (aged 18‒55 years) with a diagnosis of ADHD (based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were titrated with centanafadine-SR 200‒300, 400, or 500 mg/d for 2 weeks, and then were treated with the titrated dose for 2 weeks. In a phase 2b, randomized, double-blind, placebo-controlled, crossover study, 85 male and female patients (aged 18‒60 years) with a diagnosis of ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) were titrated to target doses of centanafadine-SR 400, 500, 600, or 800 mg/d over the course of 1 week, and then received their titrated dose for 3 weeks. The primary outcome in both studies was mean total ADHD Rating Scale-IV (ADHD-RS-IV) score.
In the phase 2a study, mean ADHD-RS-IV total score decreased by 21.41 (standard deviation 10.74) from the start of active centanafadine-SR treatment to the end of week 4 (
<0.001). In the phase 2b study, centanafadine-SR treatment resulted in a statistically significant improvement in ADHD-RS-IV from baseline to week 3 compared with placebo (least-squares mean -16.5 vs -8.4;
<0.001; effect size 0.66), with significant efficacy demonstrated as early as week 1. Centanafadine-SR was generally well tolerated at doses ≤400 mg. Most treatment-emergent adverse events (TEAEs) were mild or moderate; decreased appetite, headache, and nausea were the most frequently reported. In the 2 studies, 13 of 120 patients discontinued centanafadine-SR due to TEAEs; however, only 1 patient who received ≤400 mg discontinued due to a TEAE. No serious TEAEs were reported at any dose.
These results support the continued development of centanafadine-SR at doses up to 400 mg/d.
To assess the efficacy and safety of clonidine hydrochloride extended-release tablets (CLON-XR) combined with stimulants (ie, methylphenidate or amphetamine) for attention-deficit/hyperactivity ...disorder (ADHD).
In this phase 3, double-blind, placebo-controlled trial, children and adolescents with hyperactive- or combined-subtype ADHD who had an inadequate response to their stable stimulant regimen were randomized to receive CLON-XR or placebo in combination with their baseline stimulant medication. Predefined efficacy measures evaluated change from baseline to week 5. Safety was assessed by spontaneously reported adverse events, vital signs, electrocardiogram recordings, and clinical laboratory values. Improvement from baseline for all efficacy measures was evaluated using analysis of covariance.
Of 198 patients randomized, 102 received CLON-XR plus stimulant and 96 received placebo plus stimulant. At week 5, greater improvement from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score (95% confidence interval: -7.83 to -1.13; P = .009), ADHD-RS-IV hyperactivity and inattention subscale scores (P = .014 and P = .017, respectively), Conners' Parent Rating Scale scores (P < .062), Clinical Global Impression of Severity (P = .021), Clinical Global Impression of Improvement (P = .006), and Parent Global Assessment (P = .001) was observed in the CLON-XR plus stimulant group versus the placebo plus stimulant group. Adverse events and changes in vital signs in the CLON-XR group were generally mild.
The results of this study suggest that CLON-XR in combination with stimulants is useful in reducing ADHD in children and adolescents with partial response to stimulants.
Objective
The presence of attention‐deficit–hyperactivity disorder (ADHD) symptoms in children with congenital heart disease (CHD) was investigated.
Methods
Swanson, Nolan and Pelham teacher and ...parent rating scales, version 4 (SNAP‐IV), commonly used for assessing symptoms of ADHD, were completed by parents and counselors of children who attended a CHD summer camp. Mean scores (n = 51) were compared with two comparison groups without CHD: patients with ADHD (n = 75) and patients without ADHD (n = 41). Parent scores were also compared to previously published parent normative data.
Results
Patients with CHD were reported to have elevated SNAP‐IV scores by parents and counselors (11.8%). Parent ratings of inattention were significantly greater in CHD subjects when compared to the comparison group without ADHD (P < 0.001), and similar to the ADHD‐positive comparison group. Regarding parent ratings of hyperactivity and impulsivity, the CHD group was significantly lower than the ADHD‐positive controls (P = 0.024) but greater than the ADHD‐negative controls (P < 0.001).
Conclusion
ADHD symptoms are more prevalent in children with CHD. Parent ratings of inattention and hyperactivity symptoms in CHD patients are similar to ratings in children diagnosed with ADHD. There is a trend towards a greater prevalence of inattention symptoms in patients with cyanosis or single ventricle physiology.
The objective of this study was to evaluate differences in the pharmacodynamic (PD) profile of 2 second-generation extended-release (ER) formulations of methylphenidate (MPH): Metadate CD (MCD; ...methylphenidate HCl, US Pharmacopeia) extended-release capsules, CII, and Concerta (CON; methylphenidate HCl) extended-release tablets, CII. Little empirical information exists to help the clinician compare the PD effects of the available ER formulations on attention and behavior. Previous studies have shown that the near-equal doses of MCD and CON provide equivalent, total exposure to MPH as measured by area under the plasma concentration time curve, yet their pharmacokinetic (PK) plasma concentration versus time profiles are different. We previously offered a theoretical PK/PD account of the similarities and differences among available ER formulations based on the hypothesis that all formulations produce effects related to MPH delivered by 2 processes: 1) an initial bolus dose of immediate-release (IR) MPH that is expected to achieve peak plasma concentration in the early morning and have rapid onset of efficacy within 2 hours of dosing, which for the MCD capsule is delivered by 30% of the total daily dose as uncoated beads and for the CON tablet is delivered by an overcoat of 22% of the total daily dose; and 2) an extended, controlled delivery of ER MPH that is expected to achieve peak plasma concentrations in the afternoon to maintain efficacy for a programmed period of time after the peak of the initial bolus, which for the MCD capsule is delivered by polymer-coated beads and for the CON tablet by an osmotic-release oral system. According to this PK/PD model, clinical superiority is expected at any point in time for the formulation with the highest MPH plasma concentration.
This was a multisite, double-blind, double-dummy, 3-way crossover study of 2 active treatments (MCD and CON) and placebo (PLA). Children with confirmed diagnoses of attention-deficit/hyperactivity disorder were stratified to receive bioequivalent doses of MCD and CON that were considered to be low (20 mg of MCD and 18 mg of CON), medium (40 mg of MCD and 36 mg of CON), or high (60 mg of MCD and 54 mg of CON), and in a randomized order each of the study treatments was administered once daily in the morning for 1 week. On the seventh day of each treatment week, children attended a laboratory school, where surrogate measures of response were obtained by using teacher ratings of attention and deportment and a record of permanent product of performance on a 10-minute math test at each of the 7 classroom sessions spread across the day at 1.5-hour intervals. Safety was assessed by patient reports of adverse events, parent ratings on a stimulant side-effects scale, and measurement of vital signs.
The analyses of variance revealed large, statistically significant main effects for the within-subject factor of treatment for all 3 outcome measures (deportment, attention, and permanent product). The interactions of treatment x session were also highly significant for all 3 outcome measures. Inspection of the PD profiles for the treatment x session interactions suggested 4 patterns of efficacy across the day: 1) PLA > MCD approximately CON (PLA superiority) immediately after dosing; 2) MCD > CON > PLA during the morning (MCD superiority); 3) MCD approximately CON > PLA during the afternoon (PD equivalence of MCD and CON); and 4) CON > MCD approximately PLA in the early evening (CON superiority). The effect of site was significant, because some study centers had low and some high scores for behavior in the lab classroom, but both the low- and high-scoring sites showed similar PD patterns across the day. The interaction of dose x treatment was not significant, indicating that the pattern of treatment effects was consistent across each dose level. There were no statistically significant overall differences among the 3 treatments for the frequency of treatment-emergent adverse events, ratings of side effects, or vital signs. Two additional PK/PD questions were addressed: 1. The a priori hypothesis called for a comparison of the average of sessions (removing session as a factor) during a time period that corresponds to the length of a typical school day (from 1.5 through 7.5 hours after dosing). For the planned contrast of the 2 treatment conditions (MCD versus CON), the difference was significant, confirming the a priori hypothesis of superiority of near-equal daily doses of MCD over CON for this predefined postdosing period. 2. In the design of the study, the dose factor represented the total daily dose, consisting of 2 components: the initial bolus doses of IR MPH, which differ for the near-equal total daily doses of MCD and CON, and the reservoir doses of ER MPH, which were the same for the 2 formulations. To evaluate the moderating effects of the bolus component of dose on outcome, average effect size (ES) was calculated for the efficacy outcomes at the time of expected peak PK concentration times of the initial bolus component for each formulation at the 3 dose levels. The correlation (r) of ES with IR MPH bolus dose was significant for each of the 3 outcome measures (r approximately .9), indicating that the magnitude of effects in the early morning may be attributed to the dose administered by the IR MPH bolus of each formulation. For the 2 dose conditions with equal 12-mg IR MPH boluses (MCD 40 and CON 54), the ESs were large and indistinguishable (eg, deportment ES approximately 0.75 for both).
Once-daily doses of MCD and CON produced statistically significantly different PD effects on surrogate measures of behavior and performance among children with attention-deficit/hyperactivity disorder in the laboratory school setting. As predicted by the PK/PD model, superiority at any point in time was achieved by the formulation with the highest expected plasma MPH concentration.
ADHD is the most common neurobehavioral disorder of childhood, presenting with pervasive and impairing symptoms of inattention, hyperactivity, impulsivity, or a combination. The leading hypothesis of ...the underlying physiology of this disorder of inattention and/or hyperactivity-impulsivity is based on catecholamine dysfunction. Pharmacotherapy research indicates that psychostimulants, which are catecholamine agonists, show the greatest efficacy for treating the core symptoms of ADHD. Exercise affects the same dopaminergic and noradrenergic systems that stimulant medications target and is a stressor, which elicits measurable physiological changes. The magnitude of these peripheral alterations is posited as a potential biomarker of ADHD. The hypothesis that exercise training alters the underlying physiology present in ADHD and other medical conditions as well as conceptual issues behind its potential clinical utility is reviewed.
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