Rameshwari V. Tumuluru

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.

The effects of normal aging on amyloid-β deposition in nondemented adults with Down syndrome as imaged by carbon 11-labeled Pittsburgh compound B.

In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer‐like neuropathology.

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.

EEG abnormalities in borderline personality disorder: Specific or nonspecific☆

From the Departments of Psychiatry and Neurology, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, PA. Supported by NIMH Grant ROI MH35392 OIA2. Presented at the Society of Biological Psychiatry 40th Annual Convention and Scientific Program, 1985. Address reprint requests to Dr. Jack R. Cornelius, Room 874, Western Psychiatric Instihtte and Clinic, 3811 O:Hara Street, Pittsburgh, PA 15213. Received December 19. 1985; revised February 18, 1986. ularly in the temporal lobe) have etiological significance in the behavioral symptoms of patients with borderline personality disorder (BPD) (Andrulonis et al. 1981; Snyder et al. 1983). There are several observations and studies that support this hypothesis. For example, several symptoms are common to both temporal lobe dysrhythmias and BPD, including derealization, depersonalization, impulsivity, transient psychosis, and labile mood (Fenwick 1981). Furthermore, Snyder and Pitts (1984) reported that patients with PBD have significantly more dysrhythmias (19%

Psychopharmacological treatment of ADHD symptoms in children with autism spectrum disorder.

Abstract One of the most frequently reported behavioral concerns among children with autism spectrum disorder (ASD) is high rates of activity and inattention, symptoms that are often associated with attention deficit hyperactivity disorder (ADHD). Although there is a considerable body of research regarding the appropriate treatment of ADHD symptoms among typically developing children, the research among children with ASD is more limited. The evidence to date suggests that medication response rates among children with ASD are considerably lower than among typically developing children and that children with ASD tend to be at greater risk for experiencing side effects. The purpose of the present paper is to review the available research on the treatment of ADHD symptoms in children with ASD. This paper summarizes the data on a range of pharmacological options and provides specific recommendations for how best to clinically manage these symptoms.

A review of atomoxetine effects in young people with developmental disabilities

UNLABELLED This review summarizes the pharmacokinetic characteristics, pharmacodynamic properties, common side effects, and clinical advantages and disadvantages associated with atomoxetine (ATX) treatment in typically developing children and adults with ADHD. Then the clinical research to date in developmental disabilities (DD), including autism spectrum disorders (ASD), is summarized and reviewed. Of the 11 relevant reports available, only two were placebo-controlled randomized clinical trials, and both focused on a single DD population (ASD). All trials but one indicated clinical improvement in ADHD symptoms with ATX, although it was difficult to judge the magnitude and validity of reported improvement in the absence of placebo controls. Effects of ATX on co-occurring behavioral and cognitive symptoms were much less consistent. Appetite decrease, nausea, and irritability were the most common adverse events reported among children with DD; clinicians should be aware that, as with stimulants, irritability appears to occur much more commonly in persons with DD than in typically developing individuals. Splitting the dose initially, starting below the recommended starting dose, and titrating slowly may prevent or ameliorate side effects. Patience is needed for the slow build-up of benefit. CONCLUSIONS ATX holds promise for managing ADHD symptoms in DD, but properly controlled, randomized clinical trials of atomoxetine in intellectual disability and ASD are sorely needed. Clinicians and researchers should be vigilant for the emergence of irritability with ATX treatment. Effects of ATX on cognition in DD are virtually unstudied.

Longitudinal changes in amyloid positron emission tomography and volumetric magnetic resonance imaging in the nondemented Down syndrome population

Down syndrome (DS) arises from a triplication of chromosome 21, causing overproduction of the amyloid precursor protein and predisposes individuals to early Alzheimers disease (AD).

Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-β Burden in Down Syndrome

BACKGROUND The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimers disease (AD). OBJECTIVE The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. METHODS Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. RESULTS Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. CONCLUSIONS In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.

Leisure Activity and Caregiver Involvement in Middle-Aged and Older Adults With Down Syndrome

The present study examined leisure activity and its association with caregiver involvement (i.e., residence and time spent with primary caregiver) in 62 middle-aged and older adults with Down syndrome (aged 30-53 years). Findings indicated that middle-aged and older adults with Down syndrome frequently participated in social and passive leisure activities, with low participation in physical and mentally stimulating leisure activities. Residence and time spent with primary caregiver were associated with participation in physical leisure activity. The findings suggest a need for support services aimed at increasing opportunities for participating in physical and mentally stimulating leisure activity by middle-aged and older adults with Down syndrome. These support services should partner with primary caregivers in order to best foster participation in physical leisure activity.

ALZHEIMER-LIKE PATHOPHYSIOLOGICAL CHANGES IN THE NON-DEMENTED DOWN SYNDROME POPULATION

the activity. In AD brain, GSK-3b is truncated at the C-terminus by over-activated calpain I, leading to an increase in its activity. However, the effect of truncation on its phosphorylation is unknown.Methods:We determined themolecular mechanism bywhich the truncation of GSK3b leads to increase in its activity by usingWestern blots, immunofluorescencent staining, subcellular fractionation, in vitro dephosphorylation, and co-immunoprecipitation. Results:We found that in AD brain and in cultured cells, theC-terminally truncatedGSK-3bwas less phosphorylated at Ser9 than the full-length enzyme. The truncated GSK-3b was observed more than the full-length in the nucleus in cultured cells and in AD brain. The truncated GSK-3b interacted with protein phosphatase 2A (PP2A) more strongly and was dephosphorylated by PP2A more efficiently than the full-lengthGSK-3b.Conclusions:TheC-terminal truncation of GSK-3b promotes its nuclear translocation and enhances its interaction with and dephosphorylation by PP2A. Thus, the truncation of GSK-3b may enhance its activity through Ser9 dephosphorylation by PP2A. These findings shed a new light onto the role of calpain-GSK-3b-PP2A in tau pathogenesis in AD.