Medication use by adolescents and adults with fragile X syndrome.

BACKGROUND: The behavioural challenges and medical conditions associated with fragile X syndrome (FXS) can lead to increased need for medications. METHOD: This longitudinal study examined the use of prescription medications for psychotropic and non-psychotropic purposes by adolescents and adults with FXS drawn from a North American community sample (N = 105). Odds and probabilities of continuing or discontinuing medication were calculated. Predictors of medication use were calculated. RESULTS: More than two-thirds took psychotropic medication, and about one-quarter took non-psychotropic medication. Over a 3-year period, those who initially took prescription medications were considerably more likely to remain on medications than to stop. Individuals with more autism symptoms, more behavioural problems, a mental health diagnosis, and greater family income were significantly more likely to use psychotropic medication 3 years later. Individuals who had more health problems, a mental health diagnosis, and were female were more likely to use non-psychotropic medication over this time period. CONCLUSIONS: Findings highlight the elevated and ongoing use of medication by individuals with FXS. Implications for social and behavioural research on FXS are discussed.

Overweight and obesity in youth with developmental disabilities: a call to action.

Elevated weight status has become a leading problem for adults and children around the world, regardless of the presence or lack of disability. Youth with intellectual and developmental disabilities are more vulnerable than the typical population to overweight in recent decades, and these individuals often experience overweight and obesity at higher rates than their typically developing peers. Young people with disabilities have many circumstances, beyond those of typically developing children, which increase their risk for greater body mass. These include greater medication use, having syndromes with obesity as an associated symptom, and possessing altered eating habits related to their disability. We discuss obesity-related health risks, possible weight management options, recommendations for weight maintenance or loss, and future research. Although most professionals who work with youth having developmental disabilities do not have great expertise in nutrition and weight management, we must collectively recognise the importance of weight issues for quality of life of these individuals and work with them in maintaining healthy lifestyles. Intervention options, both for caregivers and for health professionals, are discussed.

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.

Pharmacotherapy for hyperactivity in children with autism and other pervasive developmental disorders.

We reviewed pharmacological treatments used in children with autism and PDD-NOS who present with hyperactive symptoms. Some 41 studies were identified from the following drug categories: antipsychotics (n = 13), serotonin reuptake inhibitors (n = 3), antianxiety drugs (n = 4), psychostimulants (n = 10), alpha adrenergic agonists (n = 2), opiate blockers (n = 7), and other drugs (n = 2). Empirical evidence for significant reductions in hyperactive symptoms was strongest for the antipsychotics, psychostimulants, and naltrexone. Most studies have focused on the reduction of overactivity, and more emphasis needs to be placed on distractibility and attentional variables. A theoretical model was proposed in which participants' attentional performance may be used to predict clinical response to psychostimulants. More carefully controlled and comprehensive studies of hyperactivity are badly needed in these children.

Assessment in multisite randomized clinical trials of patients with autistic disorder: the Autism RUPP Network. Research Units on Pediatric Psychopharmacology.

Assessment of autistic disorder (autism) symptoms, primary and secondary, poses more challenging problems than ordinarily found in multisite randomized clinical trial (RCT) assessments. For example, subjects may be uncommunicative and extremely heterogeneous in problem presentation, and current pharmacological treatments are not likely to alter most core features of autism. The Autism Research Units on Pediatric Psychopharmacology (RUPP Autism Network) resolved some of these problems during the design of a risperidone RCT in children/adolescents. The inappropriateness of the usual anchors for a Clinical Global Impression of Severity (CGI-S) was resolved by defining uncomplicated autism without secondary symptoms as a CGI-S of 3, mildly ill. The communication problems, compromising use of the patient as an informant, were addressed by several strategies, including careful questioning of care providers, rating scales, laboratory tests, and physical exams. The broad subject heterogeneity requires outcome measures sensitive to individual change over a wide spectrum of treatment response and side effects. The problems of neuropsychologically testing nonverbal, lower functioning, sometimes noncompliant subjects requires careful instrument selection/adaptation and flexible administration techniques. The problems of assessing low-end IQs, neglected by most standardized test developers, was resolved by an algorithm of test hierarchy. Scarcity of other autism-adapted cognitive and neuropsychological tests and lack of standardization required development of a new, specially adapted battery. Reliability on the Autism Diagnostic Interview (currently the most valid diagnostic instrument) and other clinician instruments required extensive cross-site training (in-person, videotape, and teleconference sessions). Definition of a treatment responder required focus on individually relevant target symptoms, synthesis of possible modest improvements in many domains, and acceptance of attainable though imperfect goals. The assessment strategy developed is implemented in a RCT of risperidone (McDougle et al., 2000) for which the design and other methodological challenges are described elsewhere (Scahill et al., 2000). Some of these problems and solutions are partially shared with RCTs of other treatments and other disorders.

Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Background and rationale for an initial controlled study of risperidone.

This article has reviewed the background and rationale for the choice of risperidone as the first drug to be studied by the RUPP Autism Network. Risperidone has potent effects on 5-HT and DA neuronal systems, both of which have been implicated in the pathophysiology of autism. Unlike the typical antipsychotics, haloperidol and pimozide, which have been shown to be effective for reducing many of the maladaptive behaviors associated with autism, risperidone's 5-HT2A/DA D2 ratio of receptor blockade appears to produce a lower risk of acute and chronic extrapyramidal side effects, as well as enhanced efficacy for the "negative" symptoms of autism. Indirect clinical and preclinical evidence supports the use of risperidone to treat impaired social behavior, interfering repetitive phenomena, and aggression, targets of pharmacotherapy for many patients with autism. Numerous published open-label trials in children and adolescents with autism and related PDDs and one double-blind, placebo-controlled study in adults suggest that risperidone has promise for the treatment of children and adolescents with autism. Because most of these studies have been short-term, open-label trials in small samples, however, a large-scale controlled study of risperidone in children and adolescents with autism is needed to confirm these results. Finally, because it is likely that children who demonstrate short-term benefit from risperidone will remain on the medication indefinitely, the longer-term effectiveness and safety of risperidone in this population also needs to be determined. The design of this study and the assessments used are described separately.

Pharmacotherapy of disorders in mental retardation.

This is a review of pharmacotherapy in children and adolescents with mental retardation from the perspective of DSM and ICD disorders. The existing research is reviewed in young people with mental retardation but, when data are lacking, we examined the literature from adults with mental retardation and from typically-developing children. The literature is discussed for each of the following disorders: ADHD, anxiety disorders, bipolar disorder, conduct disorder, depression, enuresis, schizophrenia, self injury, and tics and movement disorders. With the possible exception of ADHD, there is a woeful lack of empirical data on most of these disorders in young people with mental retardation. Clinicians will often be forced to extrapolate from data on adults having mental retardation and from typically-developing children. The best policy is probably to treat such patients cautiously, while gathering data on the effects of such therapy in the hopes of beginning a data base.

Psychometric evaluation of a measure of cognitive decline in elderly people with mental retardation.

Forty elderly persons with mental retardation were assessed by their care providers on a modified version of the Short Informant Questionnaire on Cognitive Decline in The Elderly (IQCODE) an instrument designed to quantify cognitive decline in elderly people in the general population. They were also assessed for IQ, aberrant behavior, and current mental status; test-retest and interrater reliability were evaluated as well. Internal consistency, as assessed by coefficient alpha, was moderately high (alpha = .86). Test-retest reliability was mediocre and interrater reliability levels did not reach statistical significance. The Short IQCODE was not correlated with a variety of demographic features or with behavior ratings, showing evidence of divergent validity. However, the Short IQCODE was only weakly (nonsignificantly) correlated with a measure of current mental status, which challenges its concurrent validity. The Short IQCODE probably needs to be modified further for satisfactory psychometric performance in people with mental retardation. However, some features of this study may have resulted in suboptimal estimates of the Short IQCODE's psychometric characteristics.

Fenfluramine and methylphenidate in children with mental retardation and borderline IQ: clinical effects.

A double-blind, placebo-controlled, crossover study of methylphenidate (0.4 mg/kgday) and different doses of fenfluramine (1.0, 1.5, or 2.0 mg/g/day) in children with mental retardation or borderline IQ and ADHD was conducted. Parents, teachers, examiners, and physicians rated the children. There were relatively few significant drug effects by condition. When the optimal fenfluramine dose for each child was compared with placebo and methylphenidate, significant improvements occurred for fenfluramine on several parent and teacher subscales; teachers rated the children as somewhat improved with methylphenidate. The highest dose of fenfluramine produced more behavior compliance but apparently at the cost of cognitive efficiency. Most side effects (drowsiness, dizziness, anorexia) occurred with fenfluramine. Both drugs appear to be effective treatments for children with ADHD and mental retardation, although there is a possible neurotoxic action with fenfluramine. We recommend a gradual phase-in of fenfluramine dosage, up to 1.5 mg/kg/day, for most children.

The international consensus process on psychopharmacology and intellectual disability.

The present authors invited 115 scientists, practitioners and consumers from 11 nations to form an international consensus panel on best practices and clinical effects regarding psychoactive medicines and intellectual disability. Co-sponsors included the American Association on Mental Retardation, the American Psychiatric Association, the American Psychological Association, the National Institute of Mental Health, the National Association on Dual Diagnosis and The Arc of the United States. The panel developed 21 reports that were revised to reflect comments from 351 participants at a 1995 Ohio State University conference in Columbus, OH, USA. The reports will be published as chapters in a forthcoming book entitled Psychotropic Medication and Developmental Disabilities: The International Consensus Handbook. The need for research and training programmes is discussed.

Four-year follow-up of children with low intelligence and ADHD.

Twenty-six of 30 participants (87%) who took part in a medication study for treatment of ADHD were followed up 2.9 to 4.8 years (Mean = 3.9 years) later. Parent ratings on the Aberrant Behavior Checklist Community (ABC-C) indicated continued problems on the acting-out subscales, and parent assessments on the Stony Brook Checklist-3R showed a high rate of difficulty on domains called ADHD. Conduct Disorder, and Separation Anxiety Disorder. A high percentage of children (69%) were taking psychotropic drugs, substantial numbers of their families had sought nonmedical treatments, children's friendships were often rudimentary, and a significant minority of children had disciplinary problems in school or difficulty with the law. Using Pearson correlations, we identified a number of initial variables that predicted follow-up parent ratings on the ABC-C and Stony Brook. The ABC-C Irritability subscale was useful in predicting both internalizing and externalizing problems at follow-up, whereas parent and teacher hyperactivity subscales failed to predict later hyperactivity. Children identified with both low intelligence and ADHD appear to have significant behavioral and emotional problems in their early adolescence, and there may be some important qualitative differences in the outcome of these youngsters as compared with that of children identified with ADHD and normal IQ.

Parent- and self-ratings of anxiety in children with mental retardation: agreement levels and test-retest reliability.

This study examined fears in children with and without developmental disabilities. Children assigned to classes designed as developmentally handicapped (D), integrated (or mainstreamed) (I), and regular (R) were assessed. In all, 82 children were tested and retested over a 2-week interval. Self ratings and parent ratings were obtained. Three instruments were used to assess specific fears, social anxiety, social competence, and behavior problems: the Fear Survey Schedule for Children--Revised, the Social Anxiety Scale for Children, and the Child Behavior Rating Form. Correlations between parent and child ratings were fair to good. Child-parent agreement was nonsignificantly higher for children without disabilities and for children with mild handicaps integrated into regular education programs than for children in classes designated as Developmentally Handicapped. Children's test-retest reliabilities were generally higher than those of parents. Children without disabilities showed significantly higher consistency over time than children with disabilities.

The Nisonger CBRF: a child behavior rating form for children with developmental disabilities.

Although the rate of behavior and emotional problems of children with mental retardation is considerably higher than the rate among typically developing children, there is a shortage of tools for assessing persons with mental retardation. The Child Behavior Rating Form (CBRF) was modified by altering instructions and adding new items describing behavior problems known to occur in children with mental retardation. The adapted scale was named the Nisonger CBRF. Three hundred sixty-nine children being assessed at a University Affiliated Program for MR/DD were rated on the CBRF by their parents and teachers. Independent factor analyses of parent and teacher ratings produced two Social Competence subscales and six Problem Behavior subscales. These results were largely consistent across rater types and similar to prior findings with the CBRF. Internal consistency was generally high, parent-teacher agreement was satisfactory, and subscales from the Nisonger CBRF correlated highly with analogous subscales from the Aberrant Behavior Checklist. The Nisonger CBRF appears to be a promising new tool for assessing behavioral and emotional problems in children with mental retardation; however, further psychometric work is warranted.

The Nisonger Child Behavior Rating Form: age and gender effects and norms.

The Nisonger CBRF is a new informant behavior rating scale that was adapted for assessing children and adolescents with mental retardation. A total of 369 children referred to interdisciplinary diagnostic clinics for children with developmental disabilities were rated on the Nisonger Child Behavior Rating Form by their parents and teachers. Normative data (means, T scores, and percentiles) are presented Subscale scores were analyzed as a function of age and gender. Age influenced 3 of 8 subscales on the parent ratings and 1 subscale on the teacher ratings. Gender did not influence subscale scores. Age and gender results are discussed in relation to previous studies of subject variables.

Psychotropic and anticonvulsant drugs in subjects with autism: prevalence and patterns of use.

OBJECTIVE: To survey the prevalence and patterns of psychotropic and anticonvulsant medication and vitamin treatments in patients with autism. METHOD: Caregivers of 1,595 index cases were sent survey questionnaires by mail, and repeat questionnaires were sent twice if no reply was received. RESULTS: A total of 838 care providers (53%) responded to the survey. In all, 33.8% of the sample was taking some psychotropic drug or vitamin for autism or associated behavioral/psychiatric problems. A total of 19.2% reported having epilepsy, but only 13.2% were taking anticonvulsant drugs. More than 50% of the sample was taking some psychotropic, antiepileptic, vitamin, or "medical" agent. Of the agents taken, care providers were most satisfied with anticonvulsants, antidepressants, and stimulants. The use of each drug group was analyzed with respect to subject and demographic variables to evaluate medication patterns within this population. CONCLUSION: As in the often related clinical population of mental retardation, psychotropic medication appears to be heavily used in patients with autism.

The Aberrant Behavior Checklist-Community: factor validity and effect of subject variables for adults in group homes.

The factor validity of the new Aberrant Behavior Checklist-Community (ABC-C) was determined with 1,040 group home residents. Exploratory factor analysis indicated that the factor structure derived from the original ABC appears to be valid for the ABC-C when used with this population. Coefficients of congruence showed a high level of concordance with the original factor structure, and internal consistency continued to be high for each of the five subscales. Analyses for the effects of age, gender, and level of mental retardation indicated that some correction is appropriate for each of these variables when scoring the ABC-C. Further analyses explored the effects of subjects variables such as visual and auditory handicaps and the presence of epilepsy or Down syndrome. Psychotropic medication use was often associated with subscale score differences. The original ABC factor structure appears valid for scoring the ABC-C with community-based adults, at least those living in group homes.