An Objective Assessment of Effect of Stimulants on Attention in Individuals With ADHD.

INTRODUCTION: Currently, assessing ADHD treatment response to stimulants relies on rating scales and subjective questionnaires and sometimes a CPT. Such tools fall short of objective, quantifiable measurement of effect, especially in natural settings and can result in inconsistent treatment. METHOD: We report results from two studies using a novel proof-of-concept approach. A preliminary trial of 10 individuals used a high-fidelity eye tracker; a second study of 100 individuals used webcams at the participants' homes. RESULTS: Both studies evaluated stimulant effect using reading behavior analysis, being an ADHD symptom that stimulants affect and a major symptom patients want to improve. Both showed a significant change in reading behavior related to medication state, suggesting a clear, objective measure of stimulant effect. CONCLUSION: Using ubiquitous hardware, investigators created a user-friendly treatment assessment platform where individuals can collect their own objective data within minutes in any setting where they have access to a web camera and computer.

Annual variation in attentional response after methylphenidate treatment.

Prevalence rates of attention-deficit/hyperactivity disorder (ADHD) differ with geographical areas varying in sunlight intensity. Sun- or daylight reaching the retina establishes entrainment of the circadian clock to daylight. Changes herein, hence, alterations in clock alignment, could be reflected indirectly in inattention via sleep duration. We here studied (1) annual variation in inattention at treatment initiation; (2) annual variation in response to ADHD treatment [methylphenidate (MPH)] by day of treatment initiation; and (3) dose dependence. We predicted least baseline inattention during a period of high sunlight intensity implying more room for improvement (i.e., a better treatment response) when sunlight intensity is low. These hypotheses were not confirmed. High-dose treated patients, however, had significantly better attention after treatment than low-dosed treated patients, only when treated in the period from winter to summer solstice. Change in solar irradiance (SI) during low-dosed treatment period was negatively related to attentional improvement. The above described findings were primarily found in inattention ratings and replicated in omission errors on a continuous performance task. Daylight and inattention have been proposed to be related via mediation of the circadian system. One mechanism of MPH may be to enhance sensitivity to the diurnal entrainment to sunlight and the question can be raised whether appropriate lighting could potentiate the effects of stimulants.

Electroencephalographic biomarkers as predictors of methylphenidate response in attention-deficit/hyperactivity disorder.

EEG biomarkers have shown promise in predicting non-response to stimulant medication in ADHD and could serve as translational biomarkers. This study aimed to replicate and extend previous EEG biomarkers. The international Study to Predict Optimized Treatment for ADHD (iSPOT-A), a multi-center, international, prospective open-label trial, enrolled 336 children and adolescents with ADHD (11.9 yrs; 245 males; prescribed methylphenidate) and 158 healthy children. Treatment response was established after six weeks using the clinician rated ADHD-Rating Scale-IV. Theta/Beta ratio (TBR) and alpha peak frequency (APF) were assessed at baseline as predictors for treatment outcome. No differences between ADHD and controls were found for TBR and APF. 62% of the ADHD group was classified as a responder. Responders did not differ from non-responders in age, medication dosage, and baseline severity of ADHD symptoms. Male-adolescent non-responders exhibited a low frontal APF (Fz: R = 9.2 Hz vs. NR = 8.1 Hz; ES = 0.83), whereas no effects were found for TBR. A low APF in male adolescents was associated with non-response to methylphenidate, replicating earlier work. Our data suggest that the typical maturational EEG changes observed in ADHD responders and controls are absent in non-responders to methylphenidate and these typical changes start emerging in adolescence. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov; NCT00863499 (https://clinicaltrials.gov/ct2/show/NCT00863499).

Cognitive Testing to Identify Children With ADHD Who Do and Do Not Respond to Methylphenidate.

OBJECTIVE: To explore the utility of cognitive measures for predicting response of children and adolescents to methylphenidate (MPH). METHOD: Participants from the International Study to Predict Optimized Treatment-in ADHD (iSPOT-A) completed a cognitive test battery prior to receiving 6 weeks of MPH. The responder criterion was a 25% reduction in ADHD-Rating Scale-IV scores. Receiver Operator Characteristics (ROC) classified non-responders from responders with maximal sensitivity and specificity. RESULTS: Overall, 62% of participants responded to MPH. Response rates for ROC-identified groups ranged from 18% to 85%. Non-responders showed compromised cognition related to switching of attention, sustained attention, planning, and impulsivity. One group of responders were 10 years of age or older and had impaired switching of attention and impulsivity; a second group had enhanced switching of attention, normal or higher Continuous Performance Task (CPT) scores, and above average scores on digit span. CONCLUSION: Cognitive tests may provide a simple, low-cost tool for treatment planning for children and adolescents with ADHD.

Tetrahydrobiopterin as a treatment for autism spectrum disorders: a double-blind, placebo-controlled trial.

OBJECTIVE: The purpose of this study was to determine if tetrahydrobiopterin (BH4) reduced core symptoms of autism spectrum disorder (ASD). METHOD: In this study, 46 children, 3-7 years of age diagnosed with an ASD were randomly assigned to double-blind treatment with 20 mg/kg/day BH4 or placebo for 16 weeks. The primary outcome measure was the Clinical Global Impressions Improvement and Severity Scales (CGI-I and CGI-S); secondary outcomes were the Preschool Language Scale-4 (PLS-4), Social Responsiveness Scale (SRS), Aberrant Behavior Checklist (ABC), and Vineland Adaptive Behavior Scales (Vineland). RESULTS: Overall, no differences were found on global improvement as measured with the CGI-I or CGI-S. Secondary measures indicated significant improvements for BH4 relative to placebo with regard to social awareness, autism mannerisms, hyperactivity, and inappropriate speech. Side effects were minimal and similar between both active medication and placebo. CONCLUSIONS: These results indicate that BH4 offers promise in reducing symptoms of ASD. Clinical Trials.gov Identifier: NCT00850070.

Blood pressure and heart rate over 10 years in the multimodal treatment study of children with ADHD.

OBJECTIVE: It is unknown whether prolonged childhood exposure to stimulant medication for the treatment of attention deficit hyperactivity disorder (ADHD) increases the risk for developing abnormalities in blood pressure or heart rate. The authors examined the association between stimulant medication and blood pressure and heart rate over 10 years. METHOD: A total of 579 children, ages 7­9, were randomly assigned to 14 months of medication treatment, behavioral therapy, the combination of the two, or usual community treatment. The controlled trial was followed by naturalistic treatment with periodic assessments. Blood pressure and heart rate data were first analyzed with linear regression models based on an intent-to-treat approach, using raw data and the blood pressure categories of prehypertension and hypertension. Currently medicated patients were then compared with never or previously medicated patients. Associations between cumulative stimulant exposure and blood pressure or heart rate were assessed. RESULTS: No treatment effect on either systolic or diastolic blood pressure could be detected. Children who were treated with stimulants had a higher heart rate (mean=84.2 bpm [SD=12.4] on medication alone and mean=84.6 bpm [SD=12.2] on medication plus behavioral therapy) than those who were treated with behavioral therapy alone (mean=79.1 bpm [SD=12.0]) or those who received usual community treatment (mean=78.9 bpm [SD=12.9]) at the end of the 14-month controlled trial, but not thereafter. Stimulant medication did not increase the risk for tachycardia, but greater cumulative stimulant exposure was associated with a higher heart rate at years 3 and 8. CONCLUSIONS: Stimulant treatment did not increase the risk for prehypertension or hypertension over the 10-year period of observation. However, stimulants had a persistent adrenergic effect on heart rate during treatment.

Pharmacological cognitive enhancers: comment on Smith and Farah (2011).

Smith and Farah (2011) provided a thought-provoking and perhaps deliberately provocative literature review of the use of stimulants to improve cognitive functioning in humans. They addressed the apparently increasing willingness of individuals mostly in the United States to use stimulants for this purpose and then summarized published literature that explores whether stimulants actually improve specific aspects of neurocognitive function. Although calling for more research, they tentatively concluded that stimulants indeed may be "smart pills" for some people under certain circumstances. This comment emphasizes that they never actually defined the desired qualities of a smart pill, seemed to accept the unproven axiom that slight improvements in specific tests constitute meaningful enhancement of intelligence, and failed to consider the possible costs to individuals and to society of promoting the use of this class of medications for such a purpose.

Psychopharmacology of depression in children and adolescents.

Although much debate continues about the prevalence of depressive disorders in prepubertal children, depression clearly is common in adolescents, increasing rapidly throughout the teen years. All physicians who work with young patients must to be able to recognize and treat these disorders. This article provides a brief overview of depressive disorders in children and adolescence, including their clinical presentation, prevalence, etiology, course, and prognosis. Psychopharmacological treatment options are reviewed in detail, including practical information for medication management including patient education, making the decision to treat with medication, selection of specific medications, strategies for nonresponsive patients, and decisions about stopping medication.

Tetrahydrobiopterin as a novel therapeutic intervention for autism.

Tetrahydrobiopterin (BH(4)) is an essential cofactor for several critical metabolic pathways that have been reported to be abnormal in autism spectrum disorder (ASD). In addition, the cerebrospinal fluid concentration of BH(4) is reported to be depressed in children with ASD. Over the past 25 years, several clinical trials have suggested that treatment with BH(4) improves ASD symptomatology in some individuals. Two ongoing clinical protocols may help further define the efficacy of BH(4) treatment in children with ASD. First, children with ASD who had low concentrations of cerebrospinal fluid or urine pterins were treated in an open-label manner with 20 mg/kg per day of BH(4). The majority of children (63%) responded positively to treatment, with minimal adverse events (AEs). Second, a double-blind placebo-controlled study examining the efficacy of 20 mg/kg per day of BH(4) treatment in children with ASD is currently underway. Safety studies from the commercially available forms of BH(4) document the low incidence of AEs, particularly serious AEs. Studies have also documented the ability of BH(4) to cross the blood-brain barrier. Based on the importance of BH(4) in neurodevelopmental metabolic pathways, the safety of BH(4) treatment, and the evidence for a therapeutic benefit of BH(4) treatment in children with ASD, we conclude that BH(4) represents a novel therapy for ASD, one that may gain wider use after further clinical studies have established efficacy and treatment guidelines.

Evidence for glutamate, GABA and NO in coordinating behaviour in the sponge, Ephydatia muelleri (Demospongiae, Spongillidae).

The view that sponges lack tissue level organisation, epithelia, sensory cells and coordinated behaviour is challenged by recent molecular studies showing the existence in Porifera of molecules and proteins that define cell signalling systems in higher order metazoans. Demonstration that freshwater sponges can contract their canals in an organised manner in response to both external and endogenous stimuli prompted us to examine the physiology of the contraction behaviour. Using a combination of digital time-lapse microscopy, high-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis, immunocytochemistry and pharmacological manipulations, we tested the role of the diffusible amino acids glutamate and gamma-aminobutyric acid (GABA) and a short-lived diffusible gas, nitric oxide (NO), in triggering or modulating contractions in Ephydatia muelleri. We identified pools of glutamate, glutamine and GABA used to maintain a metabotropic glutamate and GABA receptor signalling system. Glutamate induced contractions and propagation of a stereotypical behaviour inflating and deflating the canal system, acting in a dose-dependent manner. Glutamate-triggered contractions were blocked by the metabatropic glutamate receptor inhibitor AP3 and by incubation of the sponge in an allosteric competitive inhibitor of glutamate, Kynurenic acid. Incubation in GABA inhibited glutamate-triggered contractions of the sponge. Nitric oxide synthase, involved in the formation of the diffusible gas NO, was localised using NADPH-diaphorase to mesenchyme cells in the osculum and pinacoderm. A cGMP assay showed the same cells were labelled suggesting that the NO system is functional. Our findings suggest sponges coordinate behaviour using chemical messenger systems common to other animals.

The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study.

OBJECTIVES: To determine any long-term effects, 6 and 8 years after childhood enrollment, of the randomly assigned 14-month treatments in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA; N = 436); to test whether attention-deficit/hyperactivity disorder (ADHD) symptom trajectory through 3 years predicts outcome in subsequent years; and to examine functioning level of the MTA adolescents relative to their non-ADHD peers (local normative comparison group; N = 261). METHOD: Mixed-effects regression models with planned contrasts at 6 and 8 years tested a wide range of symptom and impairment variables assessed by parent, teacher, and youth report. RESULTS: In nearly every analysis, the originally randomized treatment groups did not differ significantly on repeated measures or newly analyzed variables (e.g., grades earned in school, arrests, psychiatric hospitalizations, other clinically relevant outcomes). Medication use decreased by 62% after the 14-month controlled trial, but adjusting for this did not change the results. ADHD symptom trajectory in the first 3 years predicted 55% of the outcomes. The MTA participants fared worse than the local normative comparison group on 91% of the variables tested. CONCLUSIONS: Type or intensity of 14 months of treatment for ADHD in childhood (at age 7.0-9.9 years) does not predict functioning 6 to 8 years later. Rather, early ADHD symptom trajectory regardless of treatment type is prognostic. This finding implies that children with behavioral and sociodemographic advantage, with the best response to any treatment, will have the best long-term prognosis. As a group, however, despite initial symptom improvement during treatment that is largely maintained after treatment, children with combined-type ADHD exhibit significant impairment in adolescence. Innovative treatment approaches targeting specific areas of adolescent impairment are needed.

Coordinated contractions effectively expel water from the aquiferous system of a freshwater sponge.

In response to mechanical stimuli the freshwater sponge Ephydatia muelleri (Demospongiae, Haplosclerida, Spongillidae) carries out a series of peristaltic-like contractions that is effective in expelling clumps of waste material from the aquiferous system. Rates of contraction depend on the region of tissue they are propagating through: 0.3-1 microm s(-1) in the peripheral canals, 1-4 microm s(-1) in central canals, and 6-122 microm s(-1) in the osculum. Faster events include twitches of the entire sponge choanosome and contraction of the sheet-like apical pinacoderm that forms the outer surface of the animal. Contraction events are temporally and spatially coordinated. Constriction of the tip of the osculum leads to dilation of excurrent canals; fields of ostia in the apical pinacoderm close in unison just prior to contraction of the choanosome, apical pinacoderm and osculum. Relaxation returns the osculum, canals and the apical pinacoderm to their normal state, and three such coordinated 'inflation-contraction' responses typically follow a single stimulus. Cells in the mesohyl arrest crawling as a wave of contraction passes, suggesting an extracellular signal may pass between cells. Bundles of actin filaments traverse endopinacocytes of the apical pinacoderm. Actin-dense plaques join actin bundles in adjacent pinacocytes to form continuous tracts spanning the whole sponge. The orchestrated and highly repeatable series of contractions illustrates that cellular sponges are capable of coordinated behavioural responses even in the absence of neurons and true muscle. Propagation of the events through the pinacocytes also illustrates the presence of a functional epithelium in cellular sponges. These results suggest that control over a hydrostatic skeleton evolved prior to the origin of nerves and true muscle.

3-year follow-up of the NIMH MTA study.

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.

Secondary evaluations of MTA 36-month outcomes: propensity score and growth mixture model analyses.

OBJECTIVE: To evaluate two hypotheses: that self-selection bias contributed to lack of medication advantage at the 36-month assessment of the Multimodal Treatment Study of Children With ADHD (MTA) and that overall improvement over time obscured treatment effects in subgroups with different outcome trajectories. METHOD: Propensity score analyses, using baseline characteristics and severity of attention-deficit/hyperactivity disorder symptoms at follow-up, established five subgroups (quintiles) based on tendency to take medication at the 36-month assessment. Growth mixture model (GMM) analyses were performed to identify subgroups (classes) with different patterns of outcome over time. RESULTS: All five propensity subgroups showed initial advantage of medication that disappeared by the 36-month assessment. GMM analyses identified heterogeneity of trajectories over time and three classes: class 1 (34% of the MTA sample) with initial small improvement followed by gradual improvement that produced significant medication effects; class 2 (52%) with initial large improvement maintained for 3 years and overrepresentation of cases treated with the MTA Medication Algorithm; and class 3 (14%) with initial large improvement followed by deterioration. CONCLUSIONS: We failed to confirm the self-selection hypothesis. We found suggestive evidence of residual but not current benefits of assigned medication in class 2 and small current benefits of actual treatment with medication in class 1.

Effects of stimulant medication on growth rates across 3 years in the MTA follow-up.

OBJECTIVE: To evaluate the hypothesis of stimulant medication effect on physical growth in the follow-up phase of the Multimodal Treatment Study of Children With ADHD. METHOD: Naturalistic subgroups were established based on patterns of treatment with stimulant medication at baseline, 14-, 24-, and 36-month assessments: not medicated (n = 65), newly medicated (n = 88), consistently medicated (n = 70), and inconsistently medicated (n = 147). Analysis of variance was used to evaluate effects of subgroup and assessment time on measures of relative size (z scores) obtained from growth norms. RESULTS: The subgroup x assessment time interaction was significant for z height (p <.005) and z weight (p <.0001), due primarily to divergence of the newly medicated and the not medicated subgroups. These initially stimulant-naïve subgroups had z scores significantly >0 at baseline. The newly medicated subgroup showed decreases in relative size that reached asymptotes by the 36-month assessment, when this group showed average growth of 2.0 cm and 2.7 kg less than the not medicated subgroup, which showed slight increases in relative size. CONCLUSIONS: Stimulant-naïve school-age children with Combined type attention-deficit/hyperactivity disorder were, as a group, larger than expected from norms before treatment but show stimulant-related decreases in growth rates after initiation of treatment, which appeared to reach asymptotes within 3 years without evidence of growth rebound.

Delinquent behavior and emerging substance use in the MTA at 36 months: prevalence, course, and treatment effects.

OBJECTIVE: To compare delinquent behavior and early substance use between the children in the Multimodal Treatment Study of Children With ADHD (MTA; N = 487) and those in a local normative comparison group (n = 272) at 24 and 36 months postrandomization and to test whether these outcomes were predicted by the randomly assigned treatments and subsequent self-selected prescribed medications. METHOD: Most MTA children were 11 to 13 years old by 36 months. Delinquency seriousness was coded ordinally from multiple measures/reporters; child-reported substance use was binary. RESULTS: Relative to local normative comparison group, MTA children had significantly higher rates of delinquency (e.g., 27.1% vs. 7.4% at 36 months; p = .000) and substance use (e.g., 17.4% vs. 7.8% at 36 months; p = .001). Children randomized to intensive behavior therapy reported less 24-month substance use than other MTA children (p = .02). Random effects ordinal growth models revealed no other effects of initial treatment assignment on delinquency seriousness or substance use. By 24 and 36 months, more days of prescribed medication were associated with more serious delinquency but not substance use. CONCLUSIONS: Cause-and-effect relationships between medication treatment and delinquency are unclear; the absence of associations between medication treatment and substance use needs to be re-evaluated at older ages. Findings underscore the need for continuous monitoring of these outcomes as children with attention-deficit/hyperactivity disorder enter adolescence.

Treatment-related changes in objectively measured parenting behaviors in the multimodal treatment study of children with attention-deficit/hyperactivity disorder.

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.

Altered neural substrates of cognitive control in childhood ADHD: evidence from functional magnetic resonance imaging.

OBJECTIVE: The study compared the neural bases of two cognitive control operations, interference suppression and response inhibition, between children with and children without attention deficit hyperactivity disorder (ADHD). METHOD: Ten children (7-11 years of age) with combined-type ADHD and 10 comparison subjects matched for age and gender underwent rapid event-related functional magnetic resonance imaging (fMRI) during performance of a modified flanker task. Functional maps were generated through group averaging and performance-based correlational analyses. RESULTS: Interference suppression in ADHD subjects was characterized by reduced engagement of a frontal-striatal-temporal-parietal network that subserved healthy performance. In contrast, response inhibition performance relied upon different regions in the two groups, frontal-striatal in comparison subjects but right superior temporal in ADHD children. CONCLUSIONS: Alteration in the neural basis of two cognitive control operations in childhood ADHD was characterized by distinct, rather than unitary, patterns of functional abnormality. Greater between-group overlap in the neural network activated for interference suppression than in response inhibition suggests that components of cognitive control are differentially sensitive to ADHD. The ADHD children's inability to activate the caudate nucleus constitutes a core abnormality in ADHD. Observed functional abnormalities did not result from prolonged stimulant exposure, since most children were medication naive.

Peer-assessed outcomes in the multimodal treatment study of children with attention deficit hyperactivity disorder.

Peer-assessed outcomes were examined at the end of treatment (14 months after study entry) for 285 children (226 boys, 59 girls) with attention deficit hyperactivity disorder (ADHD) who were rated by their classmates (2,232 classmates total) using peer sociometric procedures. All children with ADHD were participants in the Multimodal Treatment Study of Children with ADHD (MTA). Treatment groups were compared using the orthogonal treatment contrasts that accounted for the largest amount of variance in prior MTA outcome analyses: Medication Management + Combined Treatment versus Behavior Therapy + Community Care; Medication Management versus Combined Treatment; Behavior Therapy versus Community Care. There was little evidence of superiority of any of the treatments for the peer-assessed outcomes studied, although the limited evidence that emerged favored treatments involving medication management. Post hoc analyses were used to examine whether any of the four treatment groups yielded normalized peer relationships relative to randomly selected-classmates. Results indicated that children from all groups remained significantly impaired in their peer relationships.