Cristan Farmer

Huntington’s disease A randomized, controlled trial using the NMDA-antagonist amantadine

ObjectiveTo examine the acute effects of the NMDA receptor antagonist amantadine on motor and cognitive function in Huntington’s disease (HD). Background Chorea in HD and in the levodopa-induced dyskinesias of PD may be clinically indistinguishable. In PD, hyperphosphorylation of NMDA receptors expressed on striatal medium spiny neurons contributes to peak-dose dyskinesias, and drugs that block these receptors can diminish chorea severity. Because these spiny neurons are the primary target of the neurodegenerative process in HD, sensitization of NMDA receptors on residual striatal neurons might also participate in the generation of motor dysfunction in HD. Methods To evaluate this possibility, 24 patients with HD entered a double-blind placebo-controlled crossover study of amantadine with two 2-week arms. Results Chorea scores were lower with amantadine (usually 400 mg/d) than placebo, with a median reduction in extremity chorea at rest of 36% (p = 0.04) for all 22 evaluable patients and of 56% in the 10 individuals with the highest plasma drug levels. Improvement correlated with plasma amantadine concentrations (p = 0.01) but not CAG repeat length. Parkinsonian rating scores did not worsen and there was no consistent change in cognitive measures. Adverse event profile was benign. Conclusions Results suggest that NMDA receptor supersensitivity may contribute to the clinical expression of choreiform dyskinesias in HD and that selective antagonists at that site can safely confer palliative benefit.

Development of the Children's Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP)

Whereas some scales exist for assessing aggression in typically developing children, they do not give a detailed analysis, and none is available for populations with developmental disabilities (DD). Parents of 365 children with DD completed the Childrens Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP), which surveys the severity of aggressive and hostile behaviors (Problem Scale) in addition to their proactive or reactive qualities (the Provocation Scale). Factor analysis yielded a 5-factor solution: I. Verbal Aggression (12 items), II. Bullying (12 items), III. Covert Aggression (11 items), IV. Hostility (9 items), and V. Physical Aggression (8 items). Coefficient alpha ranged from moderate (0.74, Physical Aggression) to high (0.92, Verbal Aggression). General validity was supported by expected differences between age and gender groups. Preliminary normative data were presented. The C-SHARP appears to be a promising tool for assessing aggression and hostility in children with DD.

The ADOS calibrated severity score: relationship to phenotypic variables and stability over time.

Measurement of the severity of autism at a single time point, and over time, is a widespread challenge for researchers. Recently, Gotham, Pickles, and Lord published a severity metric (calibrated severity scores; CSS) that takes into account age and language level and is based on raw total scores of the Autism Diagnostic Observation Schedule (ADOS), a standardized measure commonly used in autism diagnosis. The present study examined psychometric characteristics of the CSS compared to raw scores in an independent sample of 368 children aged 2 to 12 years with autism, pervasive developmental disorder‐not otherwise specified (PDD‐NOS), non‐spectrum delay, or typical development. Reflecting the intended calibration, the CSS were more uniformly distributed within clinical diagnostic category and across ADOS modules than were raw scores. Cross‐sectional analyses examining raw and severity scores and their relationships to participant characteristics revealed that verbal developmental level was a significant predictor of raw score but accounted for significantly less variance in the CSS. Longitudinal analyses indicated overall stability of the CSS over 12 to 24 months in children with autism. Findings from this study support the use of the CSS as a more valid indicator of autism severity than the ADOS raw total score, and extend the literature by examining the stability over 12 to 24 months of the CSS in children with ASD. Autism Res 2012, 5: 267–276.

Treatment of Inattention, Overactivity, and Impulsiveness in Autism Spectrum Disorders

We reviewed the recent literature on medicines used to manage inattention, impulsiveness, and overactivity in children with pervasive developmental disorders (autistic disorder, pervasive developmental disorder not otherwise specified, Aspergers disorder) using computer searches of pharmacologic studies. A substantial number of reports were identified and summarized. The literature tends to be dominated by uncontrolled studies, although the number of controlled trials is growing. Findings are described for psychostimulants, noradrenergic reuptake inhibitors, antipsychotics, alpha adrenergic agonists, antidepressants, anxiolytics, cholinesterase inhibitors, N-methyl-D-aspartate receptor blockers, and antiepileptic mood stabilizers. Evidence for a positive effect is strongest for psychostimulants, noradrenergic reuptake inhibitors, antipsychotics, and alpha adrenergic agonists. Evidence for efficacy seems weakest for newer antidepressants, anxiolytics, and mood stabilizers.

Risperidone Added to Parent Training and Stimulant Medication: Effects on Attention-Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, Conduct Disorder, and Peer Aggression

OBJECTIVE In this study, we aimed to expand on our prior research into the relative efficacy of combining parent training, stimulant medication, and placebo (Basic therapy) versus parent training, stimulant, and risperidone (Augmented therapy) by examining treatment effects for attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) symptoms and peer aggression, symptom-induced impairment, and informant discrepancy. METHOD Children (6-12 years of age; N = 168) with severe physical aggression, ADHD, and co-occurring ODD/CD received an open trial of parent training and stimulant medication for 3 weeks. Participants failing to show optimal clinical response were randomly assigned to Basic or Augmented therapy for an additional 6 weeks. RESULTS Compared with Basic therapy, children receiving Augmented therapy experienced greater reduction in parent-rated ODD severity (p = .002, Cohens d = 0.27) and peer aggression (p = .02, Cohens d = 0.32) but not ADHD or CD symptoms. Fewer children receiving Augmented (16%) than Basic (40%) therapy were rated by their parents as impaired by ODD symptoms at week 9/endpoint (p = .008). Teacher ratings indicated greater reduction in ADHD severity (p = .02, Cohens d = 0.61) with Augmented therapy, but not for ODD or CD symptoms or peer aggression. Although both interventions were associated with marked symptom reduction, a relatively large percentage of children were rated as impaired for at least 1 targeted disorder at week 9/endpoint by parents (Basic 47%; Augmented 27%) and teachers (Basic 48%; Augmented 38%). CONCLUSION Augmented therapy was superior to Basic therapy in reducing severity of ADHD and ODD symptoms, peer aggression, and symptom-induced impairment, but clinical improvement was generally context specific, and effect sizes ranged from small to moderate. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study); http://clinicaltrials.gov/; NCT00796302.

Pharmacotherapy for the Core Symptoms in Autistic Disorder: Current Status of the Research

The current review covers extant literature on pharmacotherapy for core symptoms of autism. The core symptoms of autism include impairments in social interaction and communication, as well as the presence of restricted and repetitive behaviors. There are no known efficacious treatments for the core social symptoms, although effects on repetitive behaviors are indicated with some data. While studies of fenfluramine, secretin, opiates, and mood stabilizers generally find no effect, mixed results suggest more research is needed on antidepressants and atypical antipsychotics. Newer lines of research, including cholinergic and glutamatergic agents and oxytocin, will be of considerable interest in the future. However, research on the treatment of core symptoms is plagued by limitations in study design, statistical power, and other issues inherent to the study of treatments for autism (e.g., heterogeneity of the disorder) that continue to prevent the elucidation of efficacious treatments.

Serum Ferritin and Amphetamine Response in Youth with Attention-Deficit/Hyperactivity Disorder

INTRODUCTION Iron deficiency (ID) has been associated with attention and behavioral problems, in general, and with attention-deficit/hyperactivity disorder (ADHD), in particular. The study aim was to explore whether iron stores, as reflected by serum ferritin concentration, predicted response to psychostimulants. METHODS Six- to 14-year-old children with ADHD enrolled in a multiphase, double-blind, randomized, placebo-controlled trial investigating zinc supplementation in treating ADHD and optimizing response to psychostimulants. The Swanson, Nolan, and Pelham (SNAP) ADHD rating scale was the primary clinical instrument. Serum ferritin concentration was obtained at baseline and 8 weeks later. Partial correlations, adjusting for age and sex, were computed. RESULTS Fifty-two participants (83% males) had a mean age of 10 years. Their ADHD symptoms were moderately severe at baseline (SNAP item mean = 2.1). Their mean ferritin concentration was 18.4  ng/mL, with 23% of the participants having a level below 7, the assay-defined threshold for ID. Serum ferritin was inversely correlated with baseline inattention, hyperactivity/impulsivity, and total ADHD symptom scores (Partial Spearmans r = -0.31, p = 0.04; r = -0.42, p < 0.006; and r = -0.43, p < 0.004, respectively) and with the weight-adjusted dose of amphetamine used to optimize clinical response (Partial Spearmans r = -0.45, p < 0.007). Psychotropic-treatment history moderated some, but not all, of these associations, with previously medicated children showing a stronger association between ferritin concentration and ADHD symptom severity. CONCLUSION These findings add to the growing literature implicating ID in ADHD. The prediction of amphetamine optimal dose by ferritin concentration suggests that iron supplementation should be investigated as a potential intervention to optimize response to psychostimulants at a lower dose in individuals with low iron stores and ADHD.

The Treatment of Severe Child Aggression (TOSCA) Study: Design Challenges

BackgroundPolypharmacy (the concurrent use of more than one psychoactive drug) and other combination interventions are increasingly common for treatment of severe psychiatric problems only partly responsive to monotherapy. This practice and research on it raise scientific, clinical, and ethical issues such as additive side effects, interactions, threshold for adding second drug, appropriate target measures, and (for studies) timing of randomization. One challenging area for treatment is severe child aggression. Commonly-used medications, often in combination, include psychostimulants, antipsychotics, mood stabilizers, and alpha-2 agonists, which vary considerably in terms of perceived safety and efficacy.ResultsIn designing our NIMH-funded trial of polypharmacy, we focused attention on the added benefit of a second drug (risperidone) to the effect of the first (stimulant). We selected these two drugs because their associated adverse events might neutralize each other (e.g., sleep delay and appetite decrease from stimulant versus sedation and appetite increase from antipsychotic). Moreover, there was considerable evidence of efficacy for each drug individually for the management of ADHD and child aggression. The study sample comprised children (ages 6-12 years) with both diagnosed ADHD and disruptive behavior disorder (oppositional-defiant or conduct disorder) accompanied by severe physical aggression. In a staged sequence, the medication with the least problematic adverse effects (stimulant) was openly titrated in 3 weeks to optimal effect. Participants whose behavioral symptoms were not normalized received additional double-blind medication, either risperidone or placebo, by random assignment. Thus children whose behavioral symptoms were normalized with stimulant medication were not exposed to an antipsychotic. All families participated in an empirically-supported parent training program for disruptive behavior, so that the actual comparison was stimulant+parent training versus stimulant+antipsychotic+parent training.ConclusionsWe hope that the resolutions of the challenges presented here will be useful to other investigators and facilitate much-needed research on child psychiatric polypharmacy.Trial RegistrationClinicalTrials.gov NCT00796302

12-Week, Placebo-Controlled Trial of Add-on Riluzole in the Treatment of Childhood-Onset Obsessive–Compulsive Disorder

Many children with childhood-onset obsessive–compulsive disorder (OCD) fail to respond adequately to standard therapies. Evidence from preclinical and clinical studies suggests that the glutamatergic neurotransmitter system might be an alternative treatment target. This study examined the efficacy of riluzole, a glutamatergic modulator, as an adjunctive therapy for children with treatment-resistant OCD. In a 12-week, double-blind, placebo-controlled study, 60 treatment-resistant children and adolescents (mean age=14.5±2.4 years), with moderate to severe OCD (mean Children’s Yale-Brown Obsessive–Compulsive Scale (CY-BOCS)=28.2±3.7), 17 of whom also had concomitant autism spectrum disorder, were randomized to receive riluzole (final dose of 100 mg/day) or placebo in addition to the existing treatment regimen. Fifty-nine subjects completed the randomized trial. Primary outcome measures were changes on the CY-BOCS, the Clinical Global Impressions Scale, and the Children’s Global Assessment Scale. Riluzole was fairly well tolerated, although it was associated with one case of pancreatitis and five instances of slight increases in transaminases. All subjects showed significant reductions in CY-BOCS scores during treatment; however, there was no significant difference between placebo and riluzole on any of the primary or secondary outcome measures. The study failed to demonstrate superiority of riluzole over placebo as an adjunctive treatment for children with childhood-onset OCD. However, future studies may show benefits for less treatment-refractory children with fewer concomitant medications.

Dietary adequacy of children with autism compared with controls and the impact of restricted diet.

Objective: Children with autism (AUT) may consume a restricted diet relative to typical peers, whether due to therapeutic measures or sensory sensitivities. The objective of this study was to compare children with AUT with both typically developing (TYP) and developmentally delayed children on nutrient and food group intake and overall diet quality and to evaluate the impact of diet restriction. Methods: Three-day food records and interview information were analyzed from 69 children with AUT, 14 children with developmental delay, and 37 TYP children, drawn from a larger longitudinal study. Results: Children with AUT did not differ significantly from children with other developmental delays on any dietary measures. Although there were differences in the average intake of some nutrients between AUT and typical controls, only calcium and dairy were also less likely to be consumed in adequate amounts by the AUT group. Intentional diet restriction accounted for most of the differences between AUT and typical controls. On average, all groups had inadequate fiber, vitamin D, and vegetable intake. Inadequate intake of folate, grains, and dairy was noted for the AUT subgroup with intentional diet restrictions. Children in the AUT group not following a restricted diet received significantly worse Healthy Eating Index-2005 scores than those following a restricted diet and typical controls. These differences were not nutritionally significant. Conclusions: When evaluating nutritional adequacy of children with AUT, special consideration should be given to calcium, folate, dairy, and grains. Diets of all children with AUT should be evaluated for idiosyncratic deficiencies because of unique dietary patterns.