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Background: Psychostimulants are considered first-line pharmacotherapy for youth with attention-deficit/hyperactivity disorder (ADHD), but questions remain regarding the comparative efficacy of amphetamine- and methylphenidate-based agents.Objective: Our objective was to describe two acute randomized, double-blind, placebo-controlled, head-to-head studies of lisdexamfetamine dimesylate (LDX) and osmotic-release oral system methylphenidate (OROS-MPH) in adolescents with ADHD.Methods: Adolescents (13-17 years) diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria were enrolled in an 8-week flexible-dose study [LDX 30-70 mg/day (n = 186 randomized); OROS-MPH 18-72 mg/day (n = 185 randomized); placebo (n = 93 randomized)] or a 6-week forced-dose study [LDX 70 mg/day (n = 219 randomized); OROS-MPH 72 mg/day (n = 220 randomized); placebo (n = 110 randomized)]. Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) total score changes from baseline (primary endpoint) at week 8 (flexible-dose study) or week 6 (forced-dose study) were assessed with mixed-effects models for repeated measures. Secondary endpoints included improvement on the dichotomized Clinical Global Impressions-Improvement scale (CGI-I; key secondary endpoint) and changes from baseline on the ADHD-RS-IV subscales. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs.Results: Least squares (LS) mean ± standard error of the mean (SEM) ADHD-RS-IV total score changes from baseline to end of treatment were -17.0 ± 1.03 with placebo, -25.4 ± 0.74 with LDX, and -22.1 ± 0.73 with OROS-MPH in the forced-dose study and -13.4 ± 1.19 with placebo, -25.6 ± 0.82 with LDX, and -23.5 ± 0.80 with OROS-MPH in the flexible-dose study. LS mean ± SEM treatment difference for the change from baseline significantly favored LDX over OROS-MPH in the forced-dose [-3.4 ± 1.04, p = 0.0013, effect size (ES) -0.33] but not the flexible-dose (-2.1 ± 1.15, p = 0.0717, ES -0.20) study. The percentage of improved participants on the dichotomized CGI-I at end of treatment was significantly greater with LDX than with OROS-MPH in the forced-dose study (81.4 vs. 71.3%, p = 0.0188) but not the flexible-dose study (LDX 83.1%, OROS-MPH 81.0%, p = 0.6165). The LS mean ± SEM treatment differences for change from baseline on the ADHD-RS-IV hyperactivity/impulsivity and inattentiveness subscales nominally favored LDX in the forced-dose study (hyperactivity/impulsivity subscale -1.3 ± 0.49, nominal p = 0.0081, ES -0.27; inattentiveness subscale -2.0 ± 0.63, nominal p = 0.0013, ES -0.33), but there were no significant differences between active treatments in the flexible-dose study. In both studies, LDX and OROS-MPH were superior to placebo for all efficacy-related endpoints (all nominal p < 0.0001; ES range -0.43 to -1.16). The overall frequency of TEAEs for LDX and OROS-MPH, respectively, were 66.5 and 58.9% in the forced-dose study and 83.2 and 82.1% in the flexible-dose study. TEAEs occurring in ≥ 5% of participants that were also reported at two or more times the rate of placebo were decreased appetite, decreased weight, insomnia, initial insomnia, dry mouth, and nasopharyngitis (LDX and OROS-MPH), irritability and dizziness (LDX only), and increased heart rate (OROS-MPH only) in the forced-dose study and decreased appetite, decreased weight, insomnia, and dizziness (LDX and OROS-MPH) and dry mouth and upper abdominal pain (LDX only) in the flexible-dose study. Mean ± standard deviation (SD) increases from baseline in vital signs (systolic and diastolic blood pressure, pulse) were observed in the forced-dose study [LDX 1.6 ± 9.65 and 3.3 ± 8.11 mmHg, 6.7 ± 12.78 beats per minute (bpm); OROS-MPH 2.6 ± 10.15 and 3.3 ± 9.13 mmHg, 7.6 ± 12.47 bpm] and the flexible-dose study (LDX 2.4 ± 9.46 and 2.8 ± 8.41 mmHg, 4.7 ± 11.82 bpm; OROS-MPH 0.4 ± 9.90 and 2.2 ± 8.64 mmHg, 6.0 ± 10.52 bpm) at the last on-treatment assessment.Conclusions: LDX was superior to OROS-MPH in adolescents with ADHD in the forced-dose but not the flexible-dose study. Safety and tolerability for both medications was consistent with previous studies. These findings underscore the robust acute efficacy of both psychostimulant classes in treating adolescents with ADHD. CLINICALTRIALS.Gov Registry Numbers: NCT01552915 and NCT01552902. [ABSTRACT FROM AUTHOR]

Background: In clinical trials of medications to treat attention-deficit/hyperactivity disorder (ADHD) in children, effects on functional impairment have been less well-studied than changes in ADHD symptoms.Objective: Data regarding functional impairment were analyzed from a multicenter, double-blind, placebo-controlled study of guanfacine extended release (GXR) in children with ADHD, using the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P). The correspondence of changes in WFIRS-P scores with symptomatic and global response to GXR treatment was also examined, with treatment response defined by scores on both the ADHD Rating Scale IV (ADHD-RS-IV) and the Clinical Global Impressions-Improvement Scale (CGI-I).Methods: In this 8-week, double-blind, placebo-controlled, dose optimization study at 47 sites across the USA and Canada, children aged 6-12 years with a diagnosis of ADHD [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, and an ADHD-RS-IV score ≥28 and CGI-Severity of Illness Scale score ≥4 at baseline], were randomized 1:1:1 into three groups: GXR AM [GXR (1-4 mg/day) in the morning, placebo in the evening], GXR PM [placebo in the morning, GXR (1-4 mg/day) in the evening], or twice-daily placebo. Parents rated their children on the WFIRS-P at screening, baseline, the end of dose optimization, and at the final on-treatment assessment.Results: The efficacy population was composed of 333 subjects (GXR AM: n = 107; GXR PM: n = 114; placebo: n = 112). At the final on-treatment assessment, there were significant improvements from baseline in the placebo-adjusted difference in least-squares (LS) mean (95 % confidence interval) WFIRS-P Total scores for both GXR treatment groups combined [GXR all-active: -0.16 (-0.25, -0.07), effect size (ES) = 0.448, P <0.001] and separately [GXR AM: -0.15 (-0.26, -0.05), ES = 0.417, P = 0.004; GXR PM: -0.18 (-0.28, -0.07), ES = 0.478, P = 0.001]. Significant improvements in WFIRS-P domain scores for Family, Learning and School (including Academic Performance and Behavior in School), Social, and Risky Behavior were found for both GXR cohorts compared with placebo. However, the Life Skills and Self-Concept domain scores of the WFIRS-P did not improve with GXR treatment. Post hoc stratification by responder status revealed that significant (P <0.001) improvements in WFIRS-P Total and all domain scores were associated with symptomatic treatment response in the GXR all-active group.Conclusions: GXR treatment in children with ADHD was associated with reductions in WFIRS-P functional impairment scores compared with placebo, regardless of time of GXR administration. Changes in WFIRS-P scores were congruent with clinical response, as determined by both ADHD symptom reduction and CGI-I scores. CLINICALTRIALS.Gov Identifier: NCT00997984. [ABSTRACT FROM AUTHOR]

Data are reported from SPD503-318, a phase 3, open-label, safety study of guanfacine extended release (GXR) in European children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Participants received dose-optimized GXR (1-7 mg/day) for up to 2 years. Of 215 enrolled participants, 214 were included in the safety population and 133 completed the study. Participants’ mean age was 11.7 years and 73.8% were male. Overall, 177 participants (82.7%) experienced a treatment-emergent adverse event (TEAE). TEAEs reported in at least 10% of participants were somnolence (36.0%), headache (28.5%), fatigue (20.1%), and nasopharyngitis (11.7%). Serious TEAEs were reported in 4.7% of participants and TEAEs leading to discontinuation were reported in 3.3% of participants. There were no deaths. Mean z-scores for BMI were stable throughout the study. The incidence of sedative TEAEs (somnolence, sedation, and hypersomnia) peaked during week 3 and decreased thereafter. Small changes from baseline to the final assessment in mean supine pulse [− 5.5 bpm (standard deviation, 12.98)] and blood pressure [systolic, 0.6 mmHg (9.32); diastolic, 0.2 mmHg (9.17)] were reported. ADHD symptoms initially decreased and remained significantly lower than baseline at study endpoint. At the final assessment, the mean change in ADHD-RS-IV total score from baseline was − 19.8 (standard error of mean, 0.84; nominal p < 0.0001). In conclusion, GXR was well tolerated and more than 60% of participants completed the 2-year study. [ABSTRACT FROM AUTHOR]

Guanfacine extended release (GXR) and atomoxetine (ATX) are nonstimulant treatments for attention-deficit/hyperactivity disorder (ADHD). As nonstimulant treatments are often used after stimulants in ADHD, GXR was assessed relative to prior stimulant treatment in a randomized controlled trial (RCT), in which ATX was included as a reference arm, and in the open-label phase of a randomized-withdrawal study (RWS). Participants were 6-17 years old with ADHD Rating Scale version IV (ADHD-RS-IV) scores =32 and Clinical Global Impressions - Severity scores =4. RCT participants received dose-optimized GXR (1-7 mg/day), ATX (10-100 mg/day), or placebo for 10-13 weeks. RWS participants received dose-optimized GXR (1-7 mg/day) for 13 weeks. Participants' last stimulant medication prior to enrolment, and reasons for stopping this medication, were collected at baseline. Change from baseline ADHD-RS-IV score and the proportion of responders were assessed by prior stimulant exposure. Of 163 RCT and 296 RWS participants who had previously received stimulant treatment, 142 and 224, respectively, had received methylphenidate (MPH); due to the low number of participants and the heterogeneity of non-MPH treatments, we only report data for prior MPH treatment. The most frequent reasons for stopping MPH were lack of effectiveness or side effects. Placebo-adjusted ADHD-RS-IV changes from baseline were significant in participants receiving GXR (prior MPH, -9.8, P<0.001, effect size [ES] 0.85; stimulant-naïve, -7.6, P<0.001, ES 0.65). In ATX-treated participants, significant placebo-adjusted differences were seen in stimulant-naïve (-5.0, P=0.022, ES 0.43) but not prior MPH-treated (-1.8, P>0.05, ES 0.15) participants. More participants met responder criteria with GXR versus placebo, regardless of prior treatment. GXR response was unaffected by prior stimulant treatment; ATX produced improvement only in stimulant-naïve participants relative to placebo. These findings may be relevant to clinical decision-making regarding sequencing of ADHD treatments. [ABSTRACT FROM AUTHOR]

Background This study examined the effects of atomoxetine ( ATX) and OROS methylphenidate ( MPH) on laboratory measures of inhibitory control and attention in youth with attention-deficit/hyperactivity disorder ( ADHD). It was hypothesized that performance would be improved by both treatments, but response profiles would differ because the medications work via different mechanisms. Methods One hundred and two youth (77 male; mean age = 10.5 ± 2.7 years) with ADHD received ATX (1.4 ± 0.5 mg/kg) and MPH (52.4 ± 16.6 mg) in a randomized, double-blind, crossover design. Medication was titrated in 4-6-week blocks separated by a 2-week placebo washout. Inhibitory control and attention measures were obtained at baseline, following washout, and at the end of each treatment using Conners' Continuous Performance Test II ( CPT- II), which provided age-adjusted T-scores for reaction time ( RT), reaction time variability ( RT variability), and errors. Repeated-measures analyses of variance were performed, with Time (premedication, postmedication) and Treatment type ( ATX, MPH) entered as within-subject factors. Data from the two treatment blocks were checked for order effects and combined if order effects were not present. Clinical trial registration: Clinicaltrials.gov: NCT00183391. Results Main effects for Time on RT ( p = .03), RTSD ( p = .001), and omission errors ( p = .01) were significant. A significant Drug × Time interaction indicated that MPH improved RT, RTSD, and omission errors more than ATX ( p < .05). Changes in performance with treatment did not correlate with changes in ADHD symptoms. Conclusions MPH has greater effects than ATX on CPT measures of sustained attention in youth with ADHD. However, the dissociation of cognitive and behavioral change with treatment indicates that CPT measures cannot be considered proxies for symptomatic improvement. Further research on the dissociation of cognitive and behavioral endpoints for ADHD is indicated. [ABSTRACT FROM AUTHOR]

Objective: To examine the efficacy and tolerability of guanfacine extended release (GXR) administered in the morning or evening in children with attention-deficit/hyperactivity disorder (ADHD). Method: In this multicenter, double-blind, placebo-controlled, dose-optimization study, children 6 to 12 years of age with ADHD were randomized to receive GXR (1-4 mg/d) in the morning and placebo in the evening (GXR AM), placebo in the morning and GXR in the evening (GXR PM), or twice-daily placebo. The primary efficacy measure was the ADHD Rating Scale-IV (ADHD-RS-IV). Results: A total of 333 child participants received study drug in the following cohorts: GXR AM (n = 107), GXR PM (n = 114), or placebo (n = 112). Mean (standard deviation) changes from baseline to week 8 (visit 10 or last observation carried forward) in ADHD-RS-IV total scores were significant for both GXR treatment groups combined (GXR all-active: -20.0 [12.97]) and separately (GXR AM: -19.8 [12.95]; GXR PM: -20.1 [13.04]) compared with placebo (-11.0 [12.93]; p < .001 for all). Most spontaneously-elicited treatment-emergent adverse events were mild or moderate in severity; the most common was somnolence (GXR all-active: 44.3%; GXR AM: 46.7%; GXR PM: 42.1%; placebo: 12.5%). Conclusions: GXR administered either in the morning or evening was associated with significant and clinically meaningful improvements in ADHD symptoms. The levels of response and tolerability observed with GXR were similar regardless of time of dosing (morning versus evening), indicating that once-daily GXR monotherapy is effective whether administered in the morning or evening. Clinical trial registration information--Tolerability and Efficacy of AM and PM Once Daily Dosing With Extended-release Guanfacine Hydrochloride in Children 6-12 With Attention-Deficit/Hyperactivity Disorder (ADHD) (The ADHD Tempo Study); http://clinicaltrials.gov/; NCT00997984. [ABSTRACT FROM AUTHOR]

The article discusses the case of a 66-year-old white woman with attention-deficit/hyperactivity disorder. Information on the results of her psychiatric interview and laboratory tests is provided. Her complaints include lack of concentration, inattention, distractibility, poor focus and procrastination. The patient's medication history included methylphenidate, mixed amphetamine salts, and nonstimulants. A cognitive-behavioral therapy combined with bupropion XL was proposed to the patient.

The article examines the brain activation changes in patients with attention-deficit/hyperactivity disorder (ADHD)using stimulant methylphenidate hydrochloride as compared to those that use nonstimulant atomoxetine hydrochloride. Youth with ADHD are presented to have evaluated using functional magnetic resonance imaging during a go/no-go test of response inhibition. Both treatments are cited to reduce bilateral motor cortex activation resulting in improvement in ADHD symptoms.

Stimulant medications, such as methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and [ 11C]raclopride (D2,/D3 receptor radioligand sensitive to competition with endogenous dopamine). Clinical responses were assessed using the Conners' Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous methylphenidate significantly increased dopamine in striatum (assessed as decreases in D2/D3 receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response [ABSTRACT FROM AUTHOR]

The article focuses on the case study of a 9-year-old boy having reactive and impulsive aggressive behavior for the last 2 years. He was treated with OROS methylphenidate by his pediatrician and moderate improvement was noted in his symptoms of attention-deficit/hyperactivity disorder (ADHD). But in his aggression, only minimal improvement occurred.

The present study examined treatment outcomes for objectively measured parenting behavior in the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (ADHD). Five hundred seventy-nine ethnically and socioeconomically diverse children with ADHD-combined type (ages 7.0–9.9 years) and their parent(s) were recruited at 6 sites in the United States and Canada and randomly assigned to 1 of 4 treatment groups for 14 months of active intervention: medication management (MedMgt), intensive behavior therapy, combination of the 2 (Comb), or a community-treated comparison (CC). Baseline and posttreatment laboratory observations of parent-child interactions were coded by observers blind to treatment condition. Comb produced significantly greater improvements in constructive parenting than did MedMgt or CC, with effect sizes approaching medium for these contrasts. Treatment effects on child behaviors were not significant. The authors discuss the importance of changes in parenting behavior for families of children with ADHD and the need for reliable and objective measures in evaluating treatment outcome. [ABSTRACT FROM AUTHOR]

Background: While studies have increasingly investigated deficits in reaction time (RT) and RT variability in children with attention deficit/hyperactivity disorder (ADHD), few studies have examined the effects of stimulant medication on these important neuropsychological outcome measures. Methods: 316 children who participated in the Multimodal Treatment Study of Children with ADHD (MTA) completed the Conners’ Continuous Performance Test (CPT) at the 24-month assessment point. Outcome measures included standard CPT outcomes (e.g., errors of commission, mean hit reaction time (RT)) and RT indicators derived from an Ex-Gaussian distributional model (i.e., mu, sigma, and tau). Results: Analyses revealed significant effects of medication across all neuropsychological outcome measures. Results on the Ex-Gaussian outcome measures revealed that stimulant medication slows RT and reduces RT variability. Conclusions: This demonstrates the importance of including analytic strategies that can accurately model the actual distributional pattern, including the positive skew. Further, the results of the study relate to several theoretical models of ADHD. [ABSTRACT FROM AUTHOR]

Objective: Attention deficit hyperactivity disorder (ADHD) is a costly public health problem. To the authors' knowledge, this is the first study on the cost-effectiveness of the major forms of ADHD treatments used in NIMH's Multimodal Treatment Study of Children With ADHD (MTA Study).Method: Five hundred seventy-nine children with ADHD, combined type, ages 7 to 9.9, were assigned to 14 months of medication management, behavioral treatment, both combined, or community care. Services were tallied throughout the study, including medication, health care visits, behavioral treatments, and rental costs. Provider specialty, total time, and number of visits with providers were used to calculate costs, adjusted to FY 2000 dollars with the consumer price index.Results: Treatment costs varied fourfold, with medication management being the least expensive, followed by behavioral treatment, and then combined treatment. Lower costs of medication treatment were found in the community care group, reflecting the less intensive (and less effective) nature of community-delivered treatment. Medical management was more effective but more costly than community care and more cost-effective than combination treatment and behavioral treatment alone. Under some conditions, combination treatment (medical management and psychotherapy) were somewhat more cost-effective, as demonstrated by lower costs per additional child "normalized" among children with multiple comorbid disorders.Conclusions: Medical management treatment, although not as effective as combined medical management and behavioral treatment, is likely to be more cost-effective in routine treatment for children with ADHD, particularly those without comorbid disorders. For some children with comorbid disorders, it may be cost-effective to provide combination treatment. [ABSTRACT FROM AUTHOR]

Objective: To examine (1) moderating effects of oppositional defiant disorder (ODD) on attention-deficit/hyperactivity disorder (ADHD) treatment response and (2) responses of ODD symptoms to atomoxetine. Method: Children and adolescents (ages 8-18) with ADHD were treated for approximately 8 weeks with placebo or atomoxetine (fixed dosing: 0.5, 1.2, or 1.8 mg/kg/day, b.i.d.) under randomized, double-blind conditions. Among patients with lifetime diagnostic information (n = 293), 39% were diagnosed with comorbid ODD and 61 % were not. Treatment-group differences and differences between patients with and without comorbid ODD were examined post hoc for changes on the Attention-Deficit/Hyperactivity Disorder Rating Scale IV-Parent version, investigator-administered and -scored; Conners' Parent Rating Scale-Revised Short Form; Clinical Global Impressions Severity of ADHD Scale; and the parent-rated Child Health Questionnaire. Results: Youths with ADHD and comorbid ODD showed statistically significant improvement in ADHD, ODD, and quality-of-life measures. Treatment response was similar in youths with and without ODD, except that the comorbid group showed improvement compared with placebo at 1.8 mg/kg/day but not 1.2 mg/kg/day. In contrast, youths without ODD showed improvement at 1.2 mg/kg/day and no incremental benefit at 1.8 mg/kg/day. Conclusions: Atomoxetine treatment improves ADHD and ODD symptoms in youths with ADHD and ODD, although the comorbid group may require higher doses. [ABSTRACT FROM AUTHOR]

We examined 9-month data from the 14-month NIMH Multimodal Treatment Study of Children with ADHD (the MTA) as a further check on the relative effect of medication (MedMgt) and behavioral treatment (Beh) for attention-deficit/hyperactivity disorder (ADHD) while Beh was still being delivered at greater intensity than at 14-month endpoint, and conversely as a check on the efficacy of the MTA behavioral generalization/maintenance procedures. Intention-to-treat analysis at 9 months showed essentially the same results as at 14 months, after Beh had been completely faded; MedMgt and the combination (Comb) of medication and Beh were significantly superior to Beh and community care (CC) for ADHD and oppositional-defiant (ODD) symptoms, with mixed results for social skills and internalizing symptoms. All treatment-group differences examined as changes in slopes from 9 to 14 months were nonsignificant (we found general improvement for all groups). Slopes from baseline to 9 months correlated highly (r > .74, p < .0001) with slopes from baseline to 14 months for all groups. The time function from baseline to 14 months showed a significant linear, but not quadratic, trend for the main outcome measure (a composite of parent- and teacher-rated ADHD and ODD symptoms) for all groups. Findings suggest that in contrast to the hypothesized deterioration in the relative benefit of Beh between 9 and 14 months (after completion of fading), the MTA Beh generalization and maintenance procedures implemented through 9 months apparently yielded continuing improvement through 14 months, with preservation of the relative position of Beh compared to other treatment strategies. [ABSTRACT FROM AUTHOR]

Current treatment algorithms recommend stimulants as the first medication option for youth with ADHD, unless there are mitigating circumstances in which case they would switch to a different stimulant or nonstimulant if treatment is unsuccessful. We compared methylphenidate (MPH) and atomoxetine (ATX) in a randomized, double-blind, cross-over study (3-6 weeks of each medication, separated by a 2-week placebo washout). [Extracted from the article]

Lisdexamfetamine dimesylate was statistically superior to osmotic controlled-release methylphenidate in a forced-dose study of adolescents with attention-deficit/hyperactivity disorder but failed to meet standards of statistical significance in a flexible-dose version of the study. [ABSTRACT FROM AUTHOR]

Objective: Aggression is a common, yet complex, behavioral complaint, and a frequent indication for referral to child and adolescent psychiatrist treatment. This article reviews the evidence supporting pharmacotherapy of aggression in youth, with a primary focus on impulsive aggression (the primary indication for this intervention). Relevant diagnostic considerations and consensus guidelines are discussed.Methods: Articles examining the role of medications in the treatment of aggression in youth with pathological aggression were identified using PubMed and MEDLINE® databases over the past 15 years (2000-2015); selected articles published prior to 2000 and deemed to be of high relevance were searched and also included. Search terms included: Aggression, aggressive, disruptive behavior, conduct, youth, children, and adolescents. Cited references were also searched for relevant articles.Results: There are a number of evidence-based medication treatments for aggression, which are generally best considered in the context of differential diagnosis and ongoing evidence-based psychosocial interventions. Impulsive aggression is generally considered the type of aggression most amenable to medication, but other aggression subtypes may also possibly respond to treatment. Medication classes with positive evidence include the psychostimulants and α-2 agonists (in the presence of attention-deficit/hyperactivity disorder [ADHD] and/or disruptive behavior disorders), mood stabilizing agents, and atypical antipsychotics. Published guidelines recommend systematic and adequate trials of medications in sequential order, to optimize response and minimize polypharmacy. Guidelines for safety monitoring are available for many of the medications used for aggression in youth, and are also discussed.Conclusions: Aggression in children carries a high risk of poor outcomes, and, therefore, a better understanding of treatment options is a high priority. The available literature points to the importance of identifying the underlying disorder, when possible, and using this information to guide treatment selection. Future studies are needed to better inform the treatment of aggression across disorders, and the treatment of different aggression subtypes. [ABSTRACT FROM AUTHOR]

Functional interactions between amygdala and prefrontal cortex provide a cortical entry point for emotional cues to bias cognitive control. Stimulation of α2 adrenoceptors enhances the prefrontal control functions and blocks the amygdala-dependent encoding of emotional cues. However, the impact of this stimulation on amygdala-prefrontal interactions and the emotional biasing of cognitive control have not been established. We tested the effect of the α2 adrenoceptor agonist guanfacine on psychophysiological interactions of amygdala with prefrontal cortex for the emotional biasing of response execution and inhibition. Fifteen healthy adults were scanned twice with event-related functional magnetic resonance imaging while performing an emotional go/no-go task following administration of oral guanfacine (1 mg) and placebo in a double-blind, counterbalanced design. Happy, sad, and neutral faces served as trial cues. Guanfacine moderated the effect of face emotion on the task-related functional connectivity of left and right amygdala with left inferior frontal gyrus compared to placebo, by selectively reversing the functional co-activation of the two regions for response execution cued by sad faces. This shift from positively to negatively correlated activation for guanfacine was associated with selective improvements in the relatively low accuracy of responses to sad faces seen for placebo. These results demonstrate the importance of functional interactions between amygdala and inferior frontal gyrus to both bottom-up biasing of cognitive control and top-down control of emotional processing, as well as for the α2 adrenoceptor-mediated modulation of these processes. These mechanisms offer a possibile method to address the emotional reactivity that is common to several psychiatric disorders. [ABSTRACT FROM AUTHOR]

Treatment studies in child and adolescent psychiatry are increasingly characterized by long-term, multisite, randomized clinical trials (RCTs). During the course of these RCTs it is common for clinical exigencies to emerge that require rapid, direct intervention. The challenge is to provide clinically appropriate responses that do not contaminate the delivery, distinctness, and interpretation of the treatments under investigation. In multisite studies, the problem is compounded by the need to minimize cross-site differences in the delivery of adjunct treatments. Such minimization requires fully operationalized and manual-based procedures for clinically mandated intervention. The NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (ADHD)--"the MTA"--is a long-term multisite collaborative study in which children with ADHD were randomly assigned to either medication management, behavioral treatment, the combination, or community-comparison assessment and referral. In designing its study, the MTA developed a manual-based set of procedures (the MTA Adjunct Services and Attrition Prevention [ASAP] Manual) for situations not covered by the protocol treatments. The majority of cases requiring adjunct services fell into two major categories: (1) crisis/emergent situations and (2) imminent risk of attrition. This report describes the ASAP guidelines for dealing with cases that required adjunct services that the MTA Steering Committee adopted before initiating the trial. Although the manual-based guidelines are especially applicable to multisite RCTs, many of the procedures in the ASAP Manual can apply to any treatment study in children. [ABSTRACT FROM AUTHOR]

Objective: Evening-dosed HLD200 is a delayed-release and extended-release methylphenidate (DR/ER-MPH) formulation consisting of uniform, dual-layered microbeads with an inner drug-loaded core. DR/ER-MPH is designed to delay the initial release of drug by 8-10 hours, and thereafter, provide a controlled, extended drug release to target onset of effect upon awakening that lasts into the evening. This phase 3 study evaluated the safety and efficacy of DR/ER-MPH on symptoms and temporal at-home functional impairment in children with attention-deficit/hyperactivity disorder (ADHD).Methods: This 3-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, forced-dose titration trial evaluated DR/ER-MPH (40-80 mg/day) in children aged 6-12 years with ADHD. Primary efficacy endpoint was the ADHD rating scale-IV (ADHD-RS-IV), and the key secondary endpoints were the Before-School Functioning Questionnaire (BSFQ), and Parent Rating of Evening and Morning Behavior-Revised, morning (PREMB-R AM) and evening (PREMB-R PM). Safety measures included spontaneously reported treatment-emergent adverse events (TEAEs) and two TEAEs of special interest, appetite suppression and insomnia (with direct questioning on sleep disturbance).Results: One hundred sixty-one participants were included in the intent-to-treat population (DR/ER-MPH, n = 81; placebo, n = 80). After 3 weeks, DR/ER-MPH achieved significant improvements versus placebo in ADHD symptoms (least-squares [LS] mean ADHD-RS-IV: 24.1 vs. 31.2; p = 0.002), and at-home early morning (LS mean BSFQ: 18.7 vs. 28.4; p < 0.001; LS mean PREMB-R AM: 2.1 vs. 3.6; p < 0.001) and late afternoon/evening (LS mean PREMB-R PM: 9.4 vs. 12.2; p = 0.002) functional impairment. Commonly reported TEAEs (≥10%) were insomnia and decreased appetite.Conclusions: DR/ER-MPH was generally well tolerated and demonstrated significant improvements versus placebo in ADHD symptoms and at-home functional impairments in the early morning, late afternoon, and evening in children with ADHD. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to evaluate the relative bioavailability and safety of a multilayer extended-release bead methylphenidate (MPH) hydrochloride 80 mg (MPH-MLR) capsule or sprinkles (37% immediate-release [IR]) versus MPH hydrochloride IR(Ritalin®) tablets, and to develop a pharmacokinetic (PK) model simulating MPH concentration-time data for different MPH-MLR dosage strengths. Methods: This was a single-center, randomized, open-label, three-period crossover study conducted in 26 fasted healthy adults (mean weight±standard deviation, 70.4±11.7 kg) assigned to single-dose oral MPH-MLR 80 mg capsule or sprinkles with applesauce, or Ritalin IR 25 mg (1×5 mg and 1×20 mg tablet) administered at 0, 4, and 8 hours. Results: MPH-MLR 80 mg capsule and sprinkles were bioequivalent; ratios for maximum concentration (Cmax), area under plasma drug concentration versus time curve (AUC)0-t, and AUC0-inf were 1.04 (95% confidence interval [CI], 96.3-112.4), 0.99 (95% CI, 95.3-102.8), and 0.99 (95% CI, 95.4-103.0), respectively. MPH-MLR capsule/sprinkles produced highly comparable, biphasic profiles of plasma MPH concentrations characterized by rapid initial peak, followed by moderate decline until 5 hours postdose, and gradual increase until 7 hours postdose, culminating in an attenuated second peak. Based on 90% CIs, total systemic exposure to MPH-MLR 80 mg capsule/sprinkles was similar to that for Ritalin IR 25 mg three times daily, but marked differences in Cmax values indicated that MPH-MLR regimens were not bioequivalent to Ritalin. MPH Cmax and total systemic exposure over the first 4 hours postdose with MPH-MLR capsule/sprinkles was markedly higher than that associated with the first dose of Ritalin. All study drugs were safe and well tolerated. The PK modeling in adults suggested that differences in MPH pharmacokinetics between MPH-MLR and Ritalin are the result of dosage form design attributes and the associated absorption profiles of MPH. Conclusions: MPH-MLR 80 mg provides a long-acting biphasic pattern of plasma MPH concentrations with one less peak and trough than Ritalin IR. [ABSTRACT FROM AUTHOR]

Abstract: Psychostimulants, such as methylphenidate, are thought to improve information processing in motivation–reward and attention-activation networks by enhancing the effects of more relevant signals and suppressing those of less relevant ones; however the nature of such reciprocal influences remains poorly understood. To explore this question, we tested the effect of methylphenidate on performance and associated brain activity in the Anticipation, Conflict, Reward (ACR) task. Sixteen healthy adult volunteers, ages 21–45, were scanned twice using functional magnetic resonance imaging (fMRI) as they performed the ACR task under placebo and methylphenidate conditions. A three-way repeated measures analysis of variance, with cue (reward vs. non-reward), target (congruent vs. incongruent) and medication condition (methylphenidate vs. placebo) as the factors, was used to analyze behaviors on the task. Blood oxygen level dependent (BOLD) signals, reflecting task-related neural activity, were evaluated using linear contrasts. Participants exhibited significantly greater accuracy in the methylphenidate condition than the placebo condition. Compared with placebo, the methylphenidate condition also was associated with lesser task-related activity in components of attention-activation systems irrespective of the reward cue, and less task-related activity in components of the reward–motivation system, particularly the insula, during reward trials irrespective of target difficulty. These results suggest that methylphenidate enhances task performance by improving efficiency of information processing in both reward–motivation and in attention-activation systems. [Copyright &y& Elsevier]

The article presents a study focusing on the prevalence, course and treatment effects on delinquent behavior and emerging substance use in the Multimodal Treatment Study of Children With Attention Deficit/Hyperactivity Disorder (ADHD) (MTA). The objective of this research is to compare delinquent behavior and substance use between the children in the MTA. It specifically focuses in a local normative comparison group at 24 and 36 months postrandomization. The study also aims to examine if the outcomes were predicted by the randomly assigned treatments and subsequent self-selected prescribed drugs. It concludes that the cause-and-effect relationships between medication treatment and delinquency are not clear. A re-evaluation of medication treatment and substance use are needed at older age.

Objective: In the intent-to-treat analysis of the Multimodal Treatment Study of Children With ADHD (MTA), the effects of medication management (MedMgt), behavior therapy (Beh), their combination (Comb), and usual community care (CC) differed at 14 and 24 months due to superiority of treatments that used the MTA medication algorithm (Comb+MedMgt) over those that did not (Beh+CC). This report examines 36-month outcomes, 2 years after treatment by the study ended.Method: For primary outcome measures (attention-deficit/hyperactivity disorder [ADHD] and oppositional defiant disorder [ODD] symptoms, social skills, reading scores, impairment, and diagnostic status), mixed-effects regression models and orthogonal contrasts examined 36-month outcomes.Results: At 3 years, 485 of the original 579 subjects (83.8%) participated in the follow-up, now at ages 10 to 13 years, (mean 11.9 years). In contrast to the significant advantage of MedMgt+Comb over Beh+CC for ADHD symptoms at 14 and 24 months, treatment groups did not differ significantly on any measure at 36 months. The percentage of children taking medication >50% of the time changed between 14 and 36 months across the initial treatment groups: Beh significantly increased (14% to 45%), MedMed+Comb significantly decreased (91% to 71%), and CC remained constant (60%-62%). Regardless of their treatment use changes, all of the groups showed symptom improvement over baseline. Notably, initial symptom severity, sex (male), comorbidity, public assistance, and parental psychopathology (ADHD) did not moderate children's 36-month treatment responses, but these factors predicted worse outcomes over 36 months, regardless of original treatment assignment.Conclusions: By 36 months, the earlier advantage of having had 14 months of the medication algorithm was no longer apparent, possibly due to age-related decline in ADHD symptoms, changes in medication management intensity, starting or stopping medications altogether, or other factors not yet evaluated. [ABSTRACT FROM AUTHOR]

The article presents a research on the effects of stimulant medication on growth rates. This aims to appraise the hypothesis of stimulant medication effect on physical growth in the follow-up of the Multimodal Treatment Study of Children With Attention Deficit/Hyperactivity Disorder (ADHD) (MTA). The method of analysis variance was utilized to assess the impact of subgroup and evaluation time on measures of relative size achieved from growth norms. The research concludes that stimulant-naive school age children with combine type ADHD were bigger expected from norms before treatment but exhibit lower stimulant-related growth rates after the start of treatment.

Objective. OROS methylphenidate HCL (MPH) is a recently developed long-acting stimulant medication used to treat attention-deficit/hyperactivity disorder (ADHD). This study was conducted to examine dosage effects on ADHD symptoms and stimulant side effects and to explore potential moderating effects of ADHD subtype. Methods. Children with ADHD combined type (ADHD-CT) or predominantly inattentive type (ADHD-PI; n = 47), ages 5 to 16 years, underwent a placebo-controlled, crossover trial using forced titration with weekly switches at 3 dosage levels. Parent and teacher ratings of ADHD symptoms were used to evaluate efficacy. In addition, vital signs and standardized measures of stimulant side effects were obtained weekly. Results. Parent ratings were more sensitive to treatment effects than teacher ratings. ADHD symptoms and Clinical Global Impressions Severity Index ratings at each dose condition differed significantly from placebo and baseline ratings, which did not differ from one another. For those with ADHD-CT, there was a clear linear dose-response relationship, with clinically significant reductions in ADHD Rating Scale-IV scores occurring in two thirds to three fourths of the subjects during either 36- or 54-mg dose conditions. Children with ADHD-PI, conversely, were more likely to respond optimally to lower doses and derived less benefit from higher doses, with 60% displaying significant improvement on the ADHD Rating Scale-IV at 36 mg or lower. Mild stimulant side effects were reported during placebo and at all dosage levels. With the exception of insomnia and decreased appetite, which were more common at higher... [ABSTRACT FROM AUTHOR]

Objective: Methylphenidate has prominent effects in the dopamine-rich striatum that are absent for the selective norepinephrine transporter inhibitor atomoxetine. This study tested whether baseline striatal activation would predict differential response to the two medications in youth with attention-deficit/hyperactivity disorder (ADHD).Method: A total of 36 youth with ADHD performed a Go/No-Go test during functional magnetic resonance imaging at baseline and were treated with methylphenidate and atomoxetine using a randomized cross-over design. Whole-brain task-related activation was regressed on clinical response.Results: Task-related activation in right caudate nucleus was predicted by an interaction of clinical responses to methylphenidate and atomoxetine (F1,30 = 17.00; p < .001). Elevated caudate activation was associated with robust improvement for methylphenidate and little improvement for atomoxetine. The rate of robust response was higher for methylphenidate than for atomoxetine in youth with high (94.4% vs. 38.8%; p = .003; number needed to treat = 2, 95% CI = 1.31-3.73) but not low (33.3% vs. 50.0%; p = .375) caudate activation. Furthermore, response to atomoxetine predicted motor cortex activation (F1,30 = 14.99; p < .001).Conclusion: Enhanced caudate activation for response inhibition may be a candidate biomarker of superior response to methylphenidate over atomoxetine in youth with ADHD, purportedly reflecting the dopaminergic effects of methylphenidate but not atomoxetine in the striatum, whereas motor cortex activation may predict response to atomoxetine. These data do not yet translate directly to the clinical setting, but the approach is potentially important for informing future research and illustrates that it may be possible to predict differential treatment response using a biomarker-driven approach.Clinical Trial Registration Information: Stimulant Versus Nonstimulant Medication for Attention Deficit Hyperactivity Disorder in Children; https://clinicaltrials.gov/; NCT00183391. [ABSTRACT FROM AUTHOR]