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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.

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.

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.

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., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Introduction: This study conducted spectroscopic analyses using proton (1H) Magnetic Resonance Spectroscopy (at 4 Tesla) in a sample of adolescents with Attention Deficit Hyperactivity Disorder (ADHD), before and after treatment with extended release methylphenidate (OROS MPH), as compared to a sample of healthy comparators., Aims: The main aim of this study is to use 1H MRS to measure differences in brain biochemistry between adolescents with and without ADHD, and to assess changes in cerebral biochemistry, before and after stimulant treatment in ADHD youth., Results: Subjects with ADHD were medically healthy adolescents treated in an open label fashion with OROS MPH (mean dose: 54 mg/day; 0.90 mg/kg/day). Subjects with ADHD were scanned before and after OROS MPH treatment. Healthy comparators were scanned once. Magnetic resonance (MR) spectroscopy studies were performed on a 4.0 T Varian Unity/Inova MR scanner; proton spectra were acquired from the Anterior Cingulate Cortex (ACC). Data were analyzed using MANOVA and repeated measurement ANOVA. Higher metabolite ratios (Glutamate/myo-inositol, Glutamine/myo-inositol, Glutamate + Glutamine/myo-inositol) were observed in the ACC in untreated ADHD subjects as compared to controls, and to treated ADHD youth; these group differences did not reach the a priori threshold for statistical significance., Conclusions: These preliminary findings suggest the presence of glutamatergic abnormalities in adolescents with ADHD, which may normalize with MPH treatment. Larger sample, controlled studies are needed to confirm these preliminary findings., (© 2010 Blackwell Publishing Ltd.)

Objective: The main aim of this study was to examine the efficacy, tolerability, and compliance of an extended-release formulation of methylphenidate (OROS-MPH) in adults with ADHD receiving immediate-release methylphenidate (IR-MPH)., Method: Participants were outpatient adults with ADHD who were stable on IR-MPH-administered TID. Participants were randomized (4:1) to equipotent doses of OROS-MPH or to continue IR-MPH and were assessed weekly for 6 weeks with the Adult ADHD Investigator System Symptom Report Scale (AISRS)., Results: Randomization of 53 IR-MPH responders to IR- or OROS-MPH had no effect on AISRS score at endpoint (11.2 ± 6.9 vs. 10.7 ± 5.1, p = .8). Participants stabilized on IR-MPH and switched to OROS-MPH remained satisfied over 71% of the time. However, the IR-MPH group missed more doses (7.3 ± 6.8 vs. 3.3 ± 4.2, p = .02) than the OROS-MPH group., Conclusion: Findings showed that adults with ADHD can be successfully switched from an effective regimen of IR-MPH TID to once-daily OROS-MPH. Results also demonstrated better compliance with OROS-MPH than with IR-MPH treatment.

We conducted a 3-phase, double-blind, placebo-controlled, parallel study design of osmotic-release oral system (OROS)-methylphenidate (MPH) in adults (19-60 years of age) with attention deficit/hyperactivity disorder as classified by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Phase 1 of the study was a 6-week, acute efficacy trial (n = 223), phase 2 was a 24-week, double-blind continuation study of responders (n = 96), and phase 3 was a double-blind, placebo-controlled, 4-week discontinuation study (n = 23). The mean daily dosage at phase 1 endpoint was 78.4 ± 31.7 mg (0.97 ± 0.32 mg/kg) OROS-MPH and 96.6 ± 26.5 mg (1.16 ± 0.19 mg/kg) placebo (P < 0.0001). Clinical response at phase 1 endpoint was significantly greater in the OROS-MPH group (62%, n = 67 vs 37%, n = 41; P < 0.001) and was maintained throughout 24 weeks of double-blind treatment. With double-blind, placebo-controlled discontinuation, however, there was no statistically significant difference in the rate of relapse between OROS-MPH responders randomized to placebo and those randomized to continue active treatment (18%, n = 2 vs 0%, n = 0; P = 0.1). As expected, decreased appetite, insomnia, being tense/jittery, mucosal dryness, and neurological symptoms were statistically significantly associated with OROS-MPH treatment. More work is needed to be conducted with larger samples being followed to study completion to better understand the long-lasting impact of pharmacotherapy for adult attention-deficit/hyperactivity disorder.

Objective: Children with attention-deficit/hyperactivity disorder (ADHD) frequently manifest behavioral difficulties in the morning prior to school. Our aim was to examine the effects of the methylphenidate transdermal system (MTS) on before-school ADHD symptoms and functioning in children with ADHD., Method: In this randomized crossover study, conducted from May 2007 until December 2008, 6- to 12-year-old subjects with DSM-IV-defined ADHD received either MTS or a placebo transdermal system (PTS) at 10 mg for 1 week and then 20 mg for 1 week. Subjects were then crossed over directly to the other treatment for the remaining 2 weeks. The primary efficacy measure was the ADHD Rating Scale. All analyses were intent to treat, with the last observation carried forward., Results: Thirty subjects completed at least 1 week of treatment, and 26 subjects completed the entire protocol. The sample was primarily male, with a mean +/- SD age of 9.17 +/- 1.84 years. Compared to PTS, there were significant reductions with MTS in the ADHD Rating Scale score (P < .001). Adverse effects of MTS during the active (versus PTS) phase were similar to those seen in other controlled trials of MTS., Conclusions: These results show that MTS is effective not only for morning ADHD symptoms, but also in improving associated activities and functioning that occur before school in children with ADHD., Trial Registration: clinicaltrials.gov Identifier: NCT00586157., (©Copyright 2010 Physicians Postgraduate Press, Inc.)

Objective: The aim of this study was to evaluate the tolerability of adding OROS methylphenidate (MPH) to children who are partial responders to atomoxetine (ATMX) in the treatment of attention-deficit/hyperactivity disorder (ADHD)., Methods: This was a two-phase, 7-week, open study in children aged 6-17 years. Phase 1 initiated ATMX for a minimum of 4 weeks. Phase 2 entered partial responders to ATMX and added OROS MPH to their regimen. Safety was assessed using blood pressure and heart rate measurements, electrocardiogram readings, AEs, laboratories, and ATMX levels., Results: Fifty subjects who were partial responders to ATMX received the combination therapy, with 41 subjects completing the entire protocol. As reported elsewhere (Wilens et al., 2009 ), OROS MPH added to partial responders of ATMX was accompanied by a 40% reduction in the ADHD rating scale score and improvements in executive functioning. However, the combination of ATMX plus OROS MPH was associated with greater rates of insomnia, irritability, and loss of appetite compared to ATMX alone. A small significant increase in diastolic blood pressure was observed during adjunctive OROS MPH, with no clinically meaningful changes in electrocardiogram (ECG) parameters during the study. ATMX levels and liver function tests did not significantly change during the combination treatment., Conclusion: Adjunct OROS MPH in ATMX partial responders yielded an additive adverse effect burden in this short-term study. Further controlled research with larger samples of children is warranted.

Objective: This study evaluated the effectiveness of adding OROS methylphenidate (MPH) to children who are partial responders to atomoxetine (ATMX) in the treatment of attention-deficit/hyperactivity disorder (ADHD)., Methods: This is a two-phase, 7-week, open study in children aged 6-17 years. Phase I initiated ATMX for a minimum of 4 weeks. Phase II entered partial responders to ATMX and added up to 54 mg of OROS MPH to their regimen. Subjects were assessed on multiple outcomes, including ADHD, executive functioning, and adverse effects. All analyses were intent to treat, with last observation carried forward., Results: Fifty subjects who were partial responders to ATMX were treated with the combination therapy, with 41 subjects completing the entire protocol. There was a 40% reduction in their ADHD Rating Scale from the start of phase II through the end of study (from 21.14 +/- 9.9 to 12.8 +/- 9.7, t = 6.5, p < 0.0001). In addition, there was a clinically significant reduction in the Clinical Global Index of ADHD severity from moderate to mild ADHD (start of phase II, 3.7; end of phase II, 2.7, 27%, t = 6.5, p < 0.0001), as well as improvements in executive functioning., Conclusion: These results suggest that OROS MPH added to the regimen of partial responders to ATMX improves ADHD and executive functioning, necessitating further controlled trials.

Objective: To examine the effects of high doses of extended-release methylphenidate (OROS MPH) on cardiovascular variables in adolescents with attention deficit hyperactivity disorder (ADHD)., Study Design: ECG indices plus systolic blood pressure (SBP), diastolic BP (DBP) and heart rate (HR) were assessed during an open-label study of OROS MPH in 114 adolescents with ADHD (doses up to 1.5 mg/kg/d). Cardiovascular parameters were assessed at 6 weeks and 6 months., Results: Small but statistically significant changes in DBP and HR were observed at 6 weeks, without further increases up to 6 months' follow-up. A small but statistically significant increase in SBP was observed over time. Twenty-nine percent of patients had isolated elevations in BP readings prior to study entry, and 14% had >3 consecutive visits at which elevated BP were observed during OROS MPH treatment. No clinically significant changes in ECG parameters were observed. No serious cardiovascular adverse events occurred., Conclusions: Treatment with relatively high doses of OROS MPH was associated with small but statistically significant mean increases in BP and HR, primarily during the first 6 weeks of treatment, without clinically meaningful changes in ECG. These observations are consistent with previous reports using lower doses.

Background: The main aim of this study was to compare the safety and efficacy of IR MPH administered three times daily to those of once daily OROS-MPH., Methods: Subjects were outpatient adults satisfying full diagnostic criteria for DSM-IV ADHD between 19 and 60 years of age. Data from two independently conducted 6-week placebo controlled, randomized clinical trials of IR-MPH (tid) and of OROS-MPH were pooled to create three study groups: Placebo (N = 116), IR-MPH (tid) (N = 102) and OROS-MPH (N = 67)., Results: Eight-five percent (N = 99) of placebo treated subjects, 77% (N = 79) of the IR-MPH (tid) treated subjects, and 82% (N = 55) of the OROS-MPH treated subjects completed the 6-week trial. Total daily doses at endpoint were 80.9 +/- 31.9 mg, 74.8 +/- 26.2 mg, and 95.4 +/- 26.3 mg in the OROS-MPH, IR-MPH (tid), and placebo groups, respectively. At endpoint, 66% (N = 44) of subjects receiving OROS-MPH and 70% (N = 71) of subjects receiving IR-MPH (tid) were considered responders compared with 31% (N = 36) on placebo., Conclusion: Comparison of data from two similarly designed, large, randomized, placebo-controlled, trials, showed that equipotent daily doses of once daily OROS-MPH had similar efficacy to that of TID administered IR MPH.

Background: The objective of this study was to evaluate the safety and efficacy of once-daily OROS methylphenidate (MPH) in the treatment of adults with DSM-IV attention-deficit/hyperactivity disorder (ADHD)., Methods: We conducted a randomized, 6-week, placebo-controlled, parallel-design study of OROS MPH in 141 adult subjects with DSM-IV ADHD, using standardized instruments for diagnosis. OROS MPH or placebo was initiated at 36 mg/day and titrated to optimal response, depending on efficacy and tolerability, up to 1.3 mg/kg/day., Results: Treatment with OROS MPH was associated with clinically and statistically significant reductions in DSM-IV symptoms of inattention and hyperactivity/impulsivity relative to subjects treated with placebo. At endpoint, 66% of subjects (n = 44) receiving OROS MPH and 39% of subjects (n = 29) [corrected] receiving placebo attained our a priori definition of response of much or very much improved on the Clinical Global Impression-Improvement scale plus a >30% reduction in Adult ADHD Investigator System Report Scale score. OROS MPH was associated with small but statistically significant increases in systolic blood pressure (3.5 +/- 11.8 mm Hg), diastolic blood pressure (4.0 +/- 8.5 mm Hg), and heart rate (4.5 +/- 10.5 bpm)., Conclusions: These results show that treatment with OROS MPH in daily doses of up to 1.3 mg/kg/day was effective in the treatment of adults with ADHD. Because of the potential for increases in blood pressure and heart rate, subjects receiving treatment with MPH should be monitored for changes in blood pressure parameters during treatment.

Introduction: Many adults with current impairing symptoms of attention-deficit/hyperactivity disorder (ADHD) do not report an age at onset before 7 years of age and cannot, therefore, be assigned the full Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), diagnosis of ADHD. We hypothesized that treatment with oral release osmotic system (OROS) methylphenidate (MPH) will be safe and efficacious for the treatment of adults with late-onset ADHD., Method: This was a 6-week, open-label, prospective treatment study of OROS MPH monotherapy in 36 adult patients with late-onset ADHD (onset later than the required 7 years of age) using standardized instruments for diagnosis and a robust oral daily dose of up to 1.3 mg/kg/day. Symptom severity was assessed with the Adult ADHD Investigator Symptom Report Scale (AISRS) and the Clinical Global Impression (CGI) scale., Results: Subjects reported robust current symptoms of ADHD at pre-treatment baseline (11.1+/-2.8 DSM-IV symptoms), but had an atypical mean age at onset of 14.2+/-8.6 years. Treatment with OROS MPH at an average daily dose of 78.2+/-29.4 mg was associated with a statistically and clinically significant reduction in ADHD symptoms relative to baseline as assessed through the AISRS (-16.4+/-10.5; P<.001). Using a categorical definition of response (CGI-I much or very much improved), a majority (n = 26; 72%) of subjects were rated as improved at endpoint., Conclusion: These results extend previous findings in adults with full ADHD to adults meeting criteria for late-onset ADHD and support the need for further controlled clinical trials in this population.