Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk.

Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-profile approach, we examined 18 major white matter tracts in 38 offspring of BD parents, 36 offspring of comparison parents with non-BD psychopathology (depression, attention-deficit/hyperactivity disorder), and 41 offspring of healthy parents. Both at-risk groups showed significantly lower fractional anisotropy (FA) in left-sided tracts (cingulum, inferior longitudinal fasciculus, forceps minor), and significantly greater FA in right-sided tracts (uncinate fasciculus and inferior longitudinal fasciculus), relative to offspring of healthy parents (P < 0.05). These abnormalities were present in both healthy and affected youth in at-risk groups. Only offspring (particularly healthy offspring) of BD parents showed lower FA in the right superior longitudinal fasciculus relative to healthy offspring of healthy parents (P < 0.05). We show, for the first time, important similarities, and some differences, in white matter structure between offspring of BD and offspring of non-BD parents. Findings suggest that lower left-sided and higher right-sided FA in tracts important for emotional regulation may represent markers of risk for general, rather than BD-specific, psychopathology. Lower FA in the right superior longitudinal fasciculus may protect against development of BD in offspring of BD parents.

Reward-related neural activity and structure predict future substance use in dysregulated youth.

BACKGROUND: Identifying youth who may engage in future substance use could facilitate early identification of substance use disorder vulnerability. We aimed to identify biomarkers that predicted future substance use in psychiatrically un-well youth. METHOD: LASSO regression for variable selection was used to predict substance use 24.3 months after neuroimaging assessment in 73 behaviorally and emotionally dysregulated youth aged 13.9 (s.d. = 2.0) years, 30 female, from three clinical sites in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Predictor variables included neural activity during a reward task, cortical thickness, and clinical and demographic variables. RESULTS: Future substance use was associated with higher left middle prefrontal cortex activity, lower left ventral anterior insula activity, thicker caudal anterior cingulate cortex, higher depression and lower mania scores, not using antipsychotic medication, more parental stress, older age. This combination of variables explained 60.4% of the variance in future substance use, and accurately classified 83.6%. CONCLUSIONS: These variables explained a large proportion of the variance, were useful classifiers of future substance use, and showed the value of combining multiple domains to provide a comprehensive understanding of substance use development. This may be a step toward identifying neural measures that can identify future substance use disorder risk, and act as targets for therapeutic interventions.

Predicting clinical outcome from reward circuitry function and white matter structure in behaviorally and emotionally dysregulated youth.

Behavioral and emotional dysregulation in childhood may be understood as prodromal to adult psychopathology. Additionally, there is a critical need to identify biomarkers reflecting underlying neuropathological processes that predict clinical/behavioral outcomes in youth. We aimed to identify such biomarkers in youth with behavioral and emotional dysregulation in the Longitudinal Assessment of Manic Symptoms (LAMS) study. We examined neuroimaging measures of function and white matter in the whole brain using 80 youth aged 14.0 (s.d.=2.0) from three clinical sites. Linear regression using the LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection was used to predict severity of future behavioral and emotional dysregulation measured by the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M)) at a mean of 14.2 months follow-up after neuroimaging assessment. Neuroimaging measures, together with near-scan PGBI-10M, a score of manic behaviors, depressive behaviors and sex, explained 28% of the variance in follow-up PGBI-10M. Neuroimaging measures alone, after accounting for other identified predictors, explained ~1/3 of the explained variance, in follow-up PGBI-10M. Specifically, greater bilateral cingulum length predicted lower PGBI-10M at follow-up. Greater functional connectivity in parietal-subcortical reward circuitry predicted greater PGBI-10M at follow-up. For the first time, data suggest that multimodal neuroimaging measures of underlying neuropathologic processes account for over a third of the explained variance in clinical outcome in a large sample of behaviorally and emotionally dysregulated youth. This may be an important first step toward identifying neurobiological measures with the potential to act as novel targets for early detection and future therapeutic interventions.

Behavioral and emotional dysregulation trajectories marked by prefrontal-amygdala function in symptomatic youth.

BACKGROUND: Neuroimaging measures of behavioral and emotional dysregulation can yield biomarkers denoting developmental trajectories of psychiatric pathology in youth. We aimed to identify functional abnormalities in emotion regulation (ER) neural circuitry associated with different behavioral and emotional dysregulation trajectories using latent class growth analysis (LCGA) and neuroimaging. METHOD: A total of 61 youth (9-17 years) from the Longitudinal Assessment of Manic Symptoms study, and 24 healthy control youth, completed an emotional face n-back ER task during scanning. LCGA was performed on 12 biannual reports completed over 5 years of the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M), a parental report of the child's difficulty regulating positive mood and energy. RESULTS: There were two latent classes of PGBI-10M trajectories: high and decreasing (HighD; n=22) and low and decreasing (LowD; n=39) course of behavioral and emotional dysregulation over the 12 time points. Task performance was >89% in all youth, but more accurate in healthy controls and LowD versus HighD (p<0.001). During ER, LowD had greater activity than HighD and healthy controls in the dorsolateral prefrontal cortex, a key ER region, and greater functional connectivity than HighD between the amygdala and ventrolateral prefrontal cortex (p's<0.001, corrected). CONCLUSIONS: Patterns of function in lateral prefrontal cortical-amygdala circuitry in youth denote the severity of the developmental trajectory of behavioral and emotional dysregulation over time, and may be biological targets to guide differential treatment and novel treatment development for different levels of behavioral and emotional dysregulation in youth.

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.

Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.

Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies.

Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10(-6)), CNR1 (P=9.6 × 10(-5)) and the leptin (LEP) promoter (P=1.4 × 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event.

The Home Situations Questionnaire-PDD version: factor structure and psychometric properties.

BACKGROUND: The Home Situations Questionnaire (HSQ) is a caregiver-rated scale designed to assess behavioural non-compliance in everyday settings that has been used in several studies in typically developing children. Currently there is no accepted measure of behavioural non-compliance in children with pervasive developmental disorders (PDDs). METHODS: Investigators of the Research Units on Pediatric Psychopharmacology Autism Network modified the HSQ for children with PDDs by adding five items (making 25 total items), and used it as the primary outcome measure in a clinical trial. In the current investigation, we examined the factor structure and psychometric properties of the modified scale, the HSQ-PDD. RESULTS: An exploratory factor analysis with oblique rotations yielded two factors: 'Socially Inflexible' (14 items) and 'Demand-Specific' (six items). Item content of both factors appeared to fit well with the rubric of PDDs. Internal consistency, using Cronbach's alpha statistic, was 0.90 for 'Socially Inflexible', and 0.80 for 'Demand-Specific.' The obtained sub-scales and HSQ-PDD Total score showed moderate correlations with selected sub-scales of the Aberrant Behavior Checklist, Child and Adolescent Symptom Inventory, and Children's Yale-Brown Obsessive Compulsive Scale, and low correlations with the Vineland Adaptive Behavior sub-scales. CONCLUSIONS: The HSQ-PDD appears to be well suited for children with PDDs, although the Demand-Specific sub-scale may benefit from addition of more items. We provided sub-scale means and standard deviations for this relatively severe group of children with PDDs, and discussed the factor structure with respect to previous research.

Switching from oral extended-release methylphenidate to the methylphenidate transdermal system: continued attention-deficit/hyperactivity disorder symptom control and tolerability after abrupt conversion.

OBJECTIVE: To evaluate symptom control and tolerability after abrupt conversion from oral extended-release methylphenidate (ER-MPH) to methylphenidate transdermal system (MTS) via a dose-transition schedule in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: In a 4-week, prospective, multisite, open-label study, 171 children (164 intent-to-treat) with diagnosed ADHD aged 6-12 years abruptly switched from a stable dose of oral ER-MPH to MTS in nominal dosages of 10, 15, 20, and 30 mg using a predefined dose-transition schedule. After the first week on the scheduled dose, the dose was titrated to optimal effect. The primary effectiveness outcome was the change from baseline (while taking ER-MPH) to week 4 in ADHD-Rating Scale-IV (ADHD-RS-IV) total scores. Adverse events (AEs) were assessed throughout the study. RESULTS: Most subjects (58%) remained on the initial MTS dose defined by the dose-transition schedule; 38% increased and 4% decreased their MTS dose for optimization. MTS dose optimization resulted in significantly better ADHD-RS-IV total (mean +/- SD) scores at week 4 than at baseline (9.9 +/- 7.47 vs. 14.1 +/- 7.48; p < 0.0001). The most commonly reported AEs included headache, decreased appetite, insomnia, and upper abdominal pain. Four subjects (2.3%) discontinued because of application site reactions and three discontinued because of other AEs. CONCLUSIONS: Abrupt conversion from a stable dose of oral ER-MPH to MTS was accomplished using a predefined dose-transition schedule without loss of symptom control; however, careful titration to optimal dose is recommended. Most AEs were mild to moderate and, with the exception of application site reactions, were similar to AEs typically observed with oral MPH. Limitations of this study included its open-label sequential design without placebo, which could result in spurious attribution of improvement to the study treatment and precluded superiority determinations of MTS over baseline ER-MPH treatment. The apparent superiority of MTS was likely due to more careful titration and clinical monitoring rather than the product itself. ClinicalTrials.gov: NCT00151983.

Prenatal cocaine exposure alters potassium-evoked dopamine release dynamics in rat striatum.

The emerging profile for the effects of prenatal cocaine exposure presents two prominent features in the exposed offspring: cognitive/attention deficits and an age-associated trend toward motor/tone abnormalities up to 2 years of age. One candidate mechanism underlying these clinical features is long-lasting alterations to dopamine (DA) neuron function. However, the impact of prenatal cocaine exposure on DA release in dopaminergic terminal fields in vivo in mature offspring is poorly understood. Long-Evans female rats were implanted with an i.v. access port, bred, and given saline or cocaine-HCl (3 mg/kg/ml) for gestational days (GD) 8-14 (1x/day), GD 15-21 (2x/day), or GD 8-21 (1x/day-GD 8-14, 2x/day-GD 15-21). Using in vivo high-speed chronoamperometric recordings, potassium-stimulated DA release was measured in striatum of anesthetized male offspring 90-150 days after birth. There was a trend toward increased potassium-evoked DA signal amplitudes in offspring exposed to cocaine at any time period examined. In offspring exposed to cocaine during GD 8-21 and GD 15-21, but not at GD 8-14, there were significant decreases in the clearance capacity of the potassium-evoked DA signal compared with control offspring. The time required to clear 80% of the evoked DA signal (T(80)) in striatum for DA was significantly prolonged (approximately 150% of control) and this effect was further increased in the mean-evoked DA concentration range for these two groups. We also measured total dopamine transporter (DAT) and tyrosine hydroxylase protein levels in these offspring by blot immunolabeling and found a small, but significant, decrease in DAT protein in striatum from offspring exposed at GD 8-21 and GD 15-21. Collectively, these data demonstrate that prenatal cocaine exposure during dopamine neuron neurogenesis has long-lasting effects on DA neuron function lasting into early adulthood which may be related in part to steady state DAT protein levels. These molecular events may be associated with established cognitive deficits and perhaps the trends seen in altered motor behavior.

Alternative treatments for adults with attention-deficit hyperactivity disorder (ADHD).

A previous review of alternative treatments (Tx) of ADHD--those other than psychoactive medication and behavioral/psychosocial Tx--was supplemented with an additional literature search focused on adults with ADHD. Twenty-four alternative Tx were identified, ranging in scientific documentation from discrediting controlled studies through mere hypotheses to positive controlled double-blind clinical trials. Many of them are applicable only to a specific subgroup. Although oligoantigenic (few-foods) diets have convincing double-blind evidence of efficacy for a properly selected subgroup of children, they do not appear promising for adults. Enzyme-potentiated desensitization, relaxation/EMG biofeedback, and deleading also have controlled evidence of efficacy. Iron supplementation, magnesium supplementation, Chinese herbals, EEG biofeedback, massage, meditation, mirror feedback, channel-specific perceptual training, and vestibular stimulation all have promising prospective pilot data, many of these tests reasonably controlled. Single-vitamin megadosage has some intriguing pilot trial data. Zinc supplementation is hypothetically supported by systematic case-control data, but no systematic clinical trial. Laser acupuncture has promising unpublished pilot data and may be more applicable to adults than children. Essential fatty acid supplementation has promising systematic case-control data, but clinical trials are equivocal. RDA vitamin supplementation, non-Chinese herbals, homeopathic remedies, and antifungal therapy have no systematic data in ADHD. Megadose multivitamin combinations are probably ineffective for most patients and are possibly dangerous. Simple sugar restriction seems ineffective. Amino acid supplementation is mildly effective in the short term, but not beyond 2-3 months. Thyroid treatment is effective in the presence of documented thyroid abnormality. Some alternative Tx of ADHD are effective or probably effective, but mainly for certain patients. In some cases, they are the Tx of choice, and initial evaluation should consider the relevant etiologies. A few have failed to prove effective in controlled trials. Most need research to determine whether they are effective and/or to define the applicable subgroup. Some of them, although not safer than standard Tx, may be preferable for an etiologic subgroup.

Findings from the NIMH Multimodal Treatment Study of ADHD (MTA): implications and applications for primary care providers.

In 1992, the National Institute of Mental Health and 6 teams of investigators began a multisite clinical trial, the Multimodal Treatment of Attention-Deficit Hyperactivity Disorder (MTA) study. Five hundred seventy-nine children were randomly assigned to either routine community care (CC) or one of three study-delivered treatments, all lasting 14 months. The three MTA treatments-monthly medication management (usually methylphenidate) following weekly titration (MedMgt), intensive behavioral treatment (Beh), and the combination (Comb)-were designed to reflect known best practices within each treatment approach. Children were assessed at four time points in multiple outcome. Results indicated that Comb and MedMgt interventions were substantially superior to Beh and CC interventions for attention-deficit hyperactivity disorder symptoms. For other functioning domains (social skills, academics, parent-child relations, oppositional behavior, anxiety/depression), results suggested slight advantages of Comb over single treatments (MedMgt, Beh) and community care. High quality medication treatment characterized by careful yet adequate dosing, three times daily methylphenidate administration, monthly follow-up visits, and communication with schools conveyed substantial benefits to those children that received it. In contrast to the overall study findings that showed the largest benefits for high quality medication management (regardless of whether given in the MedMgt or Comb group), secondary analyses revealed that Comb had a significant incremental effect over MedMgt (with a small effect size for this comparison) when categorical indicators of excellent response and when composite outcome measures were used. In addition, children with parent-defined comorbid anxiety disorders, particularly those with overlapping disruptive disorder comorbidities, showed preferential benefits to the Beh and Comb interventions. Parental attitudes and disciplinary practices appeared to mediate improved response to the Beh and Comb interventions.

Turn-of-the-century ethical issues in child psychiatric research.

National concern in 2000 about increased psychoactive drug prescription for preschoolers accentuated the 1990s thrust for more pharmacologic research in children. Preschoolers are prescribed potent drugs without adequate evidence for efficacy or safety at this plastic age of the rapidly developing brain. Implementation of needed preschool research poses special ethical complications. Children with mental disorder qualify for special protection under both rubrics. Parental informed consent is crucial for preschoolers, who appear incapable of assent because of their preoperational, magical, animistic, egocentric thinking, with inability to comprehend relative risks and benefits. Whether they can dissent is an open question. Possibly for research with direct benefit outweighing the risk, parental permission/consent could override attempted preschooler dissent. Subject recompense should be adjusted for age differences in perception of amount, although parent reimbursement needs to be realistic. Insurance for research risk is desirable. Placebo controls appear justified for preschoolers because there is little evidence base to say that a proven effective treatment already exists. Disruptive behavior disorders, including attention-deficit/hyperactivity, have enough evidence of preschool diagnostic validity to justify therapeutic trials. In preschool pharmacologic research, a brief trial of a nonpharmacologic treatment should precede the drug trial to ensure that placebo responders and responders to the alternative treatment are not exposed to drug risk.

Symptom profiles in children with ADHD: effects of comorbidity and gender.

OBJECTIVE: To examine ratings and objective measures of attention-deficit/hyperactivity disorder (ADHD) symptoms to assess whether ADHD children with and without comorbid conditions have equally high levels of core symptoms and whether symptom profiles differ as a function of comorbidity and gender. METHOD: Four hundred ninety-eight children from the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were divided into comorbid groups based on the parent Diagnostic Interview Schedule for Children and assessed via parents' and teachers' Swanson, Nolan, and Pelham (SNAP) ratings and a continuous performance test (CPT). Comorbidity and gender effects were examined using analyses of covariance controlled for age and site. RESULTS: CPT inattention, impulsivity, and dyscontrol errors were high in all ADHD groups. Children with ADHD + oppositional defiant or conduct disorder were rated as more impulsive than inattentive, while children with ADHD + anxiety disorders (ANX) were relatively more inattentive than impulsive. Girls were less impaired than boys on most ratings and several CPT indices, particularly impulsivity, and girls with ADHD + ANX made fewer CPT impulsivity errors than girls with ADHD-only. CONCLUSIONS: Children with ADHD have high levels of core symptoms as measured by rating scales and CPT, irrespective of comorbidity. However, there are important differences in symptomatology as a function of comorbidity and gender.

ADHD comorbidity findings from the MTA study: comparing comorbid subgroups.

OBJECTIVES: Previous research has been inconclusive whether attention-deficit/hyperactivity disorder (ADHD), when comorbid with disruptive disorders (oppositional defiant disorder [ODD] or conduct disorder [CD]), with the internalizing disorders (anxiety and/or depression), or with both, should constitute separate clinical entities. Determination of the clinical significance of potential ADHD + internalizing disorder or ADHD + ODD/CD syndromes could yield better diagnostic decision-making, treatment planning, and treatment outcomes. METHOD: Drawing upon cross-sectional and longitudinal information from 579 children (aged 7-9.9 years) with ADHD participating in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), investigators applied validational criteria to compare ADHD subjects with and without comorbid internalizing disorders and ODD/CD. RESULTS: Substantial evidence of main effects of internalizing and externalizing comorbid disorders was found. Moderate evidence of interactions of parent-reported anxiety and ODD/CD status were noted on response to treatment, indicating that children with ADHD and anxiety disorders (but no ODD/CD) were likely to respond equally well to the MTA behavioral and medication treatments. Children with ADHD-only or ADHD with ODD/CD (but without anxiety disorders) responded best to MTA medication treatments (with or without behavioral treatments), while children with multiple comorbid disorders (anxiety and ODD/CD) responded optimally to combined (medication and behavioral) treatments. CONCLUSIONS: Findings indicate that three clinical profiles, ADHD co-occurring with internalizing disorders (principally parent-reported anxiety disorders) absent any concurrent disruptive disorder (ADHD + ANX), ADHD co-occurring with ODD/CD but no anxiety (ADHD + ODD/CD), and ADHD with both anxiety and ODD/CD (ADHD + ANX + ODD/CD) may be sufficiently distinct to warrant classification as ADHD subtypes different from "pure" ADHD with neither comorbidity. Future clinical, etiological, and genetics research should explore the merits of these three ADHD classification options.

Multimodal treatment of ADHD in the MTA: an alternative outcome analysis.

OBJECTIVE: To conduct a post hoc investigation of the utility of a single composite measure of treatment outcome for the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) at 14 months postbaseline. BACKGROUND: Examination of multiple measures one at a time in the main MTA intent-to-treat outcome analyses failed to detect a statistically significant advantage of combined treatment (Comb) over medication management (MedMgt). A measure that increases power and precision using a single outcome score may be a useful alternative to multiple outcome measures. METHOD: Factor analysis of baseline scores yielded two "source factors" (parent and teacher) and one "instrument factor" (parent-child interactions). A composite score was created from the average of standardized parent and teacher measures. RESULTS: The composite was internally consistent (alpha = .83), reliable (test-retest over 3 months = 0.86), and correlated 0.61 with clinician global judgments. In an intent-to-treat analysis, Comb was statistically significantly better than all other treatments, with effect sizes ranging from small (0.28) versus MedMgt, to moderately large (0.70) versus a community comparison group. CONCLUSIONS: A composite of ADHD variables may be an important tool in future treatment trials with ADHD and may avoid some of the statistical limitations of multiple measures.

Clinical relevance of the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment.

OBJECTIVES: To develop a categorical outcome measure related to clinical decisions and to perform secondary analyses to supplement the primary analyses of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA). METHOD: End-of-treatment status was summarized by averaging the parent and teacher ratings of attention-deficit/hyperactivity disorder and oppositional defiant disorder symptoms on the Swanson, Nolan, and Pelham, version IV (SNAP-IV) scale, and low symptom-severity ("Just a Little") on this continuous measure was set as a clinical cutoff to form a categorical outcome measure reflecting successful treatment. Three orthogonal comparisons of the treatment groups (combined treatment [Comb], medication management [MedMgt], behavioral treatment [Beh], and community comparison [CC]) evaluated hypotheses about the MTA medication algorithm ("Comb + MedMgt versus Beh + CC"), multimodality superiority ("Comb versus MedMgt"), and psychosocial substitution ("Beh versus CC"). RESULTS: The summary of SNAP-IV ratings across sources and domains increased the precision of measurement by 30%. The secondary analyses of group differences in success rates (Comb = 68%; MedMgt = 56%; Beh = 34%; CC = 25%) confirmed the large effect of the MTA medication algorithm and a smaller effect of multimodality superiority, which was now statistically significant (p < .05). The psychosocial substitution effect remained negligible and nonsignificant. CONCLUSION: These secondary analyses confirm the primary findings and clarify clinical decisions about the choice between multimodal and unimodal treatment with medication.

Methylphenidate dosage for children with ADHD over time under controlled conditions: lessons from the MTA.

OBJECTIVES: To examine the trajectory of methylphenidate (MPH) dosage over time, following a controlled titration, and to ascertain how accurately the titration was able to predict effective long-term treatment in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: Using the 14-month-treatment database of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), the outcome of the initial placebo-controlled, double-blind, randomized daily switch titration of MPH was compared with the subsequent maintenance pharmacotherapy. Children received monthly monitoring visits and, when needed, medication adjustments. RESULTS: Of the 198 children for whom MPH was the optimal treatment at titration (mean +/- SD dose: 30.5 +/- 14.2 mg/day), 88% were still taking MPH at the end of maintenance (mean dose 34.4 +/- 13.3 mg/day). Titration-determined dose and end-of-maintenance dose were significantly correlated (r = 0.52-0.68). Children receiving combined pharmacotherapy and behavioral treatment ended maintenance on a lower dose (31.1 +/- 11.7 mg/day) than did children receiving pharmacotherapy only (38.1 +/- 14.2 mg/day). Of the 230 children for whom titration identified an optimal treatment, 17% continued both the assigned medication and dosage throughout maintenance. The mean number of pharmacological changes per child was 2.8 +/- 1.8 (SD), and time to first change was 4.7 months +/- 0.3 (SE). CONCLUSIONS: For most children, initial titration found a dose of MPH in the general range of the effective maintenance dose, but did not prevent the need for subsequent maintenance adjustments. For optimal pharmacological treatment of ADHD, both careful initial titration and ongoing medication management are needed.

Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial.

OBJECTIVE: Results of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were analyzed to determine whether a double-blind, placebo-controlled methylphenidate (MPH) titration trial identified the best MPH dose for each child with attention-deficit/hyperactivity disorder (ADHD). METHOD: Children with ADHD assigned to MTA medication treatment groups (n = 289) underwent a controlled 28-day titration protocol that administered different MPH doses (placebo, low, middle, and high) on successive days. RESULTS: A repeated-measures analysis of variance revealed main effects for MPH dose with greater effects on teacher ratings of impairment and deportment (F3 = 100.6, n = 223, p = .0001; effect sizes 0.8-1.3) than on parent ratings of similar endpoints (F3 = 55.61, n = 253, p = .00001; effect sizes 0.4-0.6). Dose did not interact with period, dose order, comorbid diagnosis, site, or treatment group. CONCLUSIONS: The MTA titration protocol validated the efficacy of weekend MPH dosing and established a total daily dose limit of 35 mg of MPH for children weighing less than 25 kg. It replicated previously reported MPH response rates (77%), distribution of best doses (10-50 mg/day) across subjects, effect sizes on impairment and deportment, as well as dose-related adverse events.

Methodological issues in designing a multisite trial of risperidone in children and adolescents with autism.

OBJECTIVE: To describe the methodological challenges and decisions made in developing a multisite, controlled study of risperidone in children and adolescents with autism. METHODS: Review the design considerations for clinical trials in children with autistic disorder accompanied by severe tantrums, aggressive and/or self-injurious behaviors. These design considerations include the definition of inclusion criteria that are relevant to clinical practice and matching study design to the goal of evaluating short- and long-term effects. Additional ethical and scientific issues concern the length of trial and sample size. RESULTS: We undertook a short-term, placebo-controlled study to evaluate the efficacy and safety of risperidone in children and adolescents with autistic disorder. This trial design was followed by an extended open-label maintenance on risperidone to confirm durability of treatment effects and to monitor safety. Finally, a placebo-controlled discontinuation study tested the need for continuous treatment. CONCLUSIONS: In the absence of standard pharmacological treatment for children with autistic disorder, a placebo-controlled study remains the most appropriate method of testing efficacy and safety. The clinical relevance of this study is enhanced by the addition of an extended maintenance phase followed by a placebo discontinuation.

Psychosocial treatment strategies in the MTA study: rationale, methods, and critical issues in design and implementation.

The Collaborative Multimodal Treatment Study of Children with Attention Deficit Hyperactivity Disorder (ADHD), the MTA, is the first multisite, cooperative agreement treatment study of children, and the largest psychiatric/psychological treatment trial ever conducted by the National Institute of Mental Health. It examines the effectiveness of Medication vs. Psychosocial treatment vs. their combination for treatment of ADHD and compares these experimental arms to each other and to routine community care. In a parallel group design, 579 (male and female) ADHD children, aged 7-9 years, 11 months, were randomly assigned to one of the four experimental arms, and then received 14 months of prescribed treatment (or community care) with periodic reassessments. After delineating the theoretical and empirical rationales for Psychosocial treatment of ADHD, we describe the MTA's Psychosocial Treatment strategy applied to all children in two of the four experimental arms (Psychosocial treatment alone; Combined treatment). Psychosocial treatment consisted of three major components: a Parent Training component, a two-part School Intervention component, and a child treatment component anchored in an intensive Summer Treatment Program. Components were selected based on evidence of treatment efficacy and because they address comprehensive symptom targets, settings, comorbidities, and functional domains. We delineate key conceptual and logistical issues faced by clinical researchers in design and implementation of Psychosocial research with examples of how these issues were addressed in the MTA study.