Jessica A. Hellings

SPECT brain imaging abnormalities in attention deficit hyperactivity disorder.

SPECT using N-Isopropyl I-123 IMP was performed, as part of a neuropsychiatric evaluation, on 10 patients with the DSM III-R diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) and 6 patients from a non-ADHD mixed psychiatric group used as controls for comparison. Mean regional I-123 IMP SPECT region of interest (ROI) count ratios (left to right) demonstrated that the ADHD patients had greater overall hemispheric I-123 IMP uptake asymmetry with less activity in the left frontal and left parietal regions in comparison to control patients. Both groups demonstrated similar I-123 IMP uptake asymmetry in the temporal regions. These findings are consistent with previous studies of brain physiology in ADHD implicating regional cortical perfusion and metabolism abnormalities in areas which are involved in the control of attentional processes.

Weight Gain in a Controlled Study of Risperidone in Children, Adolescents and Adults with Mental Retardation and Autism

As part of an ongoing, prospective, ABA design, double-blind crossover study of risperidone versus placebo for the treatment of aggressive, destructive and self-injurious behavior in persons aged 6-65 years with mental retardation (MR) and autism, we measured the weight of 19 subjects at each study visit. We compared mean weight gain during the 16-week acute phase and 24-week open maintenance phase with that during the initial and middle placebo phases statistically, using a linear mixed model procedure. Results of the linear mixed model analysis showed that relative weight gain observed during the acute and maintenance drug phases was significantly greater than that observed during the initial and middle placebo phases respectively (p = .0001 and p = .0001). Over approximately a year, children aged 8-12 (n = 5) gained a mean of 8.2 kg (range = 2.7-17.7 kg); adolescents (n = 6) aged 13-16 gained a mean of 8.4 kg (range 3.6-15.5 kg); adults aged 21-51 (n = 8) gained a mean of 5.4 kg (range 0-9.5 kg). Weight gain observed in this controlled study of risperidone treatment in children, adolescents, and adults with MR and autism was significant. It may be greater in this population than in others reported and in this study was not limited to an acute effect only. Rate of weight gain diminished rapidly on tapering and stopping the drug. Further studies are urgently needed, including those incorporating diet and exercise programming.

Effects of risperidone on Aberrant behavior of persons with developmental disabilities: I. A double-blind crossover study using multiple measures

The efficacy of the atypical antipsychotic risperidone was evaluated in the treatment of aberrant behavior (e.g., aggression, self-injury) in 20 individuals with developmental disabilities. A double-blind, crossover design was used to compare risperidone with placebo in a 22-week trial with a 6-month follow-up phase. Based on a 50% reduction in mean Aberrant Behavior Checklist--Community total scores, 50% of the participants were identified as responders. Naturalistic observations of a subset of five individuals showed that for 4 out of 5 participants, risperidone was effective in reducing aberrant behavior. Side effects included weight gain (84% of participants) and sedation (40% of participants). The advantages of conducting a comprehensive analysis of the effects of medication on aberrant behavior are discussed.

Effects of risperidone on destructive behavior of persons with developmental disabilities: III. Functional analysis.

Functional analyses were conducted during a double-blind, placebo-controlled study of the atypical antipsychotic medication risperidone with 13 individuals. Risperidone was effective in reducing destructive behavior (compared to placebo) for 10 participants. For 7 of these responders, an undifferentiated pattern of responding occurred across their baseline functional analysis conditions (i.e., a similar rate of responding across conditions), and risperidone treatment produced nonspecific reductions of their destructive behavior across functional analysis conditions. For the remaining 3 responders, a differentiated pattern of responding occurred across their baseline functional analysis conditions (i.e., an elevated rate of responding occurred in a specific condition), and risperidone treatment produced function-specific reductions of their destructive behavior.

Use of Functional Analysis Methodology in the Evaluation of Medication Effects

The atypical antipsychotic medication risperidone was evaluated using a double-blind, placebo-controlled design in the treatment of destructive behavior in two individuals with autism. Premedication functional analyses indicated that destructive behavior was maintained by escape from demands, attention, or access to tangible items. For both individuals, destructive behavior during the demand condition was significantly reduced during the medication phases, whereas destructive behavior continued to occur to obtain tangible items (Reggie) and attention (Sean). In addition, there appeared to be a differential effect of the medication on self-injurious behavior (SIB) versus aggression for Sean. Results of the study demonstrate how functional analysis may provide information on those conditions and behaviors that are most likely to be affected by a specific medication.

Atomoxetine, Parent Training, and Their Combination in Children With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder

OBJECTIVE Impairments associated with attention-deficit/hyperactivity disorder (ADHD) and noncompliance are prevalent in children with autism spectrum disorder (ASD). However, ADHD response to stimulants is well below rates in typically developing children, with frequent side effects. Group studies of treatments for noncompliance are rare in ASD. We examined individual and combined-effectiveness of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance. METHOD In a 3-site, 10-week, double-blind, 2 × 2 trial of ATX and PT, 128 children (ages 5-14 years) with ASD and ADHD symptoms were randomized to ATX, ATX+PT, placebo+PT, or placebo. ATX was adjusted to optimal dose (capped at 1.8 mg/kg/day) over 6 weeks and maintained for 4 additional weeks. Nine PT sessions were provided. Primary outcome measures were the parent-rated DSM ADHD symptoms on the Swanson, Nolan and Pelham (SNAP) scale and Home Situations Questionnaire (HSQ). RESULTS On the SNAP, ATX, ATX+PT and placebo+PT were each superior to placebo (effect sizes 0.57-0.98; p values of .0005, .0004, and .025, respectively). For noncompliance, ATX and ATX+PT were superior to placebo (effect sizes 0.47-0.64; p values .03 and .0028, respectively). ATX was associated with decreased appetite but was otherwise well tolerated. CONCLUSION Both ATX and PT resulted in significant improvement on ADHD symptoms, whereas ATX (both alone and combined with PT) was associated with significant decreases on measures of noncompliance. ATX appears to have a better side effects profile than psychostimulants in the population with ASD. CLINICAL TRIAL REGISTRATION INFORMATION Atomoxetine, Placebo and Parent Management Training in Autism; http://clinicaltrials.gov/; NCT00844753.

Genetics and Mitochondrial Abnormalities in Autism Spectrum Disorders: A Review

We review the current status of the role and function of the mitochondrial DNA (mtDNA) in the etiology of autism spectrum disorders (ASD) and the interaction of nuclear and mitochondrial genes. High lactate levels reported in about one in five children with ASD may indicate involvement of the mitochondria in energy metabolism and brain development. Mitochondrial disturbances include depletion, decreased quantity or mutations of mtDNA producing defects in biochemical reactions within the mitochondria. A subset of individuals with ASD manifests copy number variation or small DNA deletions/duplications, but fewer than 20 percent are diagnosed with a single gene condition such as fragile X syndrome. The remaining individuals with ASD have chromosomal abnormalities (e.g., 15q11-q13 duplications), other genetic or multigenic causes or epigenetic defects. Next generation DNA sequencing techniques will enable better characterization of genetic and molecular anomalies in ASD, including defects in the mitochondrial genome particularly in younger children.

Psychopharmacology of mood disorders in persons with mental retardation and autism

The ever-growing range of designer drugs such as selective serotonin reuptake inhibitors (SSRIs) and other new antidepressants, atypical antipsychotic agents, and antiseizure medications may improve treatment efficacy and safety for persons with mood disorders and mental retardation (MR) and autism. Mood disorders are still frequently undiagnosed or misdiagnosed, and are often chronic and atypical. Diagnosis must rely on reporting of signs of the illnesses by caregivers, rather than by self-report. A key issue guiding the use of mood stabilizers as first-line drugs instead of antidepressants is the present or past existence of manic features. Chronic and atypical forms of bipolar disorder often require multiple mood stabilizers for acute and maintenance treatment. The role of the atypical antipsychotic agents in acute and maintenance treatment of mood disorders requires further study in this population, in terms of lower long-term risk and possible beneficial cognitive effects. The SSRIs appear to be broad spectrum and offer ease of prescription, may reverse some of the core features of autism, and can be beneficial for self-injury, explosive outbursts, and depressive and anxiety symptoms and behaviors. However, in view of the risk of drug interactions, together with the often numerous physicians treating mentally retarded persons for epilepsy and psychiatric and physical illness, scrupulous attention to pharmacotherapy detail and vigilance for drug interactions is essential. Research studies are needed to better characterize the phenomenology, biology, and treatment responses in the MR population. MRDD Research Reviews 1999;5:270–278.

Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial

IMPORTANCE Atypical antipsychotic medications are indicated for the treatment of irritability and agitation symptoms in children with autism spectrum disorder (ASD). Unfortunately, these medications are associated with weight gain and metabolic complications that are especially troubling in children and with long-term use. OBJECTIVE To evaluate the efficacy of metformin for weight gain associated with atypical antipsychotic medications in children and adolescents with ASD (defined in the protocol as DSM-IV diagnosis of autistic disorder, Asperger disorder, or pervasive developmental disorder not otherwise specified), aged 6 to 17 years. DESIGN, SETTING, AND PARTICIPANTS A 16-week, double-blind, placebo-controlled, randomized clinical trial was conducted at 4 centers in Toronto, Ontario, Canada; Columbus, Ohio; Pittsburgh, Pennsylvania; and Nashville, Tennessee. In all, 209 potential participants were screened by telephone, 69 individuals provided consent, and 61 participants were randomized to receive metformin or placebo between April 26, 2013, and June 24, 2015. INTERVENTIONS Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years. MAIN OUTCOMES AND MEASURES The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication. RESULTS Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005). CONCLUSIONS AND RELEVANCE Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01825798.

Effects of Risperidone on Aberrant Behavior in Persons With Developmental Disabilities: II. Social Validity Measures

Consumer satisfaction and social validity were measured during a double-blind, placebo-controlled evaluation of the atypical neuroleptic risperidone in treating severe aberrant behavior of persons with developmental disabilities. First, a satisfaction survey was completed after a medication trial by each participants caregiver. Results showed that 100% of the caregivers felt that participation was a positive experience for themselves and participants. Second, 52 community members viewed videotapes of 5 participants during a clinical interview when they were taking either placebo or risperidone. Raters also indicated that when on the medication, participants displayed fewer aberrant behaviors, were less irritable, in a better mood, and were more responsive to their environment.