Craig A. Erickson

Gastrointestinal Symptoms in a Sample of Children with Pervasive Developmental Disorders

Objective To evaluate gastrointestinal (GI) problems in a large, well-characterized sample of children with pervasive developmental disorders (PDDs). Methods One hundred seventy two children entering one of two trials conducted by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network were assessed comprehensively prior to starting treatment and classified with regard to GI symptoms. Results Thirty nine (22.7%) were positive for GI problems, primarily constipation and diarrhea. Those with GI problems were no different from subjects without GI problems in demographic characteristics, measures of adaptive functioning, or autism symptom severity. Compared to children without GI problems, those with GI problems showed greater symptom severity on measures of irritability, anxiety, and social withdrawal. Those with GI problems were also less likely to respond to treatment.

Antipsychotics in the treatment of autism

Atypical antipsychotics have become indispensable in the treatment of a variety of symptoms in autism. They are frequently used to treat irritability and associated behaviors including aggression and self injury. They may also be efficacious for hyperactivity and stereotyped behavior. This review presents the rationale for the use of this drug class in autism and reviews the most important studies published on this topic to date. Significant adverse effects, including weight gain and the possibility of tardive dyskinesia, are reviewed. Future research directions are discussed.

Aripiprazole in Pervasive Developmental Disorder Not Otherwise Specified and Asperger's Disorder: A 14-Week, Prospective, Open-Label Study

OBJECTIVE The aim of this study was to determine the effectiveness and tolerability of aripiprazole for irritability in pervasive developmental disorder not otherwise specified (PDD-NOS) and Aspergers disorder. METHOD This is a 14-week, prospective, open-label investigation of aripiprazole in 25 children and adolescents diagnosed with PDD-NOS or Aspergers disorder. Primary outcome measures included the Clinical Global Impressions-Improvement (CGI-I) scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I). RESULTS Twenty-five subjects, ages 5-17 years (mean 8.6 years) received a mean final aripiprazole dosage of 7.8 mg/day (range 2.5-15 mg/day). Full-scale intelligence quotient (IQ) scores ranged from 48 to 122 (mean 84). Twenty-two (88%) of 25 subjects were responders in regard to interfering symptoms of irritability, including aggression, self-injury, and tantrums, with a final CGI-I of 1 or 2 (very much or much improved) and a 25% or greater improvement on the ABC-I. The final mean CGI-I was 1.6 (p <or= 0.0001). ABC-I scores ranged from 18 to 43 (mean 29) at baseline, whereas scores at week 14 ranged from 0 to 27 (mean 8.1) (p <or= 0.001). Aripiprazole was well tolerated. Mild extrapyramidal symptoms (EPS) were reported in 9 subjects. Age- and sex-normed body mass index (BMI) increased from a mean value of 20.3 at baseline to 21.1 at end point (p <or= 0.04). Prolactin significantly decreased from a mean value of 9.3 at baseline to 2.9 at end point (p <or= 0.0001). No subject exited the study due to a drug-related adverse event. CONCLUSIONS These preliminary data suggest that aripiprazole may be effective and well tolerated for severe irritability in pediatric patients with PDD-NOS or Aspergers disorder. Larger-scale placebo-controlled studies are needed to elucidate the efficacy and tolerability of aripiprazole in this understudied population.

STX209 (Arbaclofen) for Autism Spectrum Disorders: An 8-Week Open-Label Study

STX209 (arbaclofen), a selective GABA-B agonist, is hypothesized to modulate the balance of excitatory to inhibitory neurotransmission, and has shown preliminary evidence of benefit in fragile X syndrome. We evaluated its safety, tolerability, and efficacy in non-syndromic autism spectrum disorders, in an 8-week open-label trial enrolling 32 children and adolescents with either Autistic Disorder or Pervasive Developmental Disorder—Not Otherwise Specified, and a score ≥17 on the Aberrant Behavior Checklist (ABC)—Irritability subscale. STX209 was generally well-tolerated. The most common adverse events were agitation and irritability, which typically resolved without dose changes, and were often felt to represent spontaneous variation in underlying symptoms. Improvements were observed on several outcome measures in this exploratory trial, including the ABC-Irritability (the primary endpoint) and the Lethargy/Social Withdrawal subscales, the Social Responsiveness Scale, the CY-BOCS-PDD, and clinical global impression scales. Placebo-controlled study of STX209 is warranted.

Pharmacologic Treatment of Behavioral Symptoms Associated With Autism and Other Pervasive Developmental Disorders

Opinion statementPervasive developmental disorders (PDDs), including autistic disorder (autism), Asperger’s disorder, and pervasive developmental disorder not otherwise specified (PDD NOS), are neurodevelopmental disorders of childhood onset. These disorders persist throughout the lifespan of affected individuals and are characterized by impaired social behavior and communication, along with repetitive, stereotypic behaviors. Early diagnosis and subsequent behavioral therapy have been shown to improve outcomes for these individuals. Risperidone and aripiprazole have been approved by the United States Food and Drug Administration (FDA) for treatment of irritability associated with autism in children and adolescents. Despite their efficacy, use of these medications is limited by their side effects. In individuals with severe irritability, the first-line treatment is often risperidone. Because of its relatively lower risk of weight gain and metabolic side effects, aripiprazole may be used initially if there is a personal or family history of obesity or diabetes. Monitoring of body mass index and metabolic profiles is indicated with both medications. Stereotypic behaviors associated with autism, though clearly driven by neurobiologic processes, can also be understood as coping mechanisms used to decrease anxiety. From this perspective, therapies targeting reduction of these symptoms may be contraindicated. However, when these symptoms are severe and interfering, pharmacotherapy may be necessary. Serotonin reuptake inhibitors are of limited efficacy in children and adolescents, but risperidone and aripiprazole have been shown to reduce these symptoms. There remains a need for further safety and efficacy research in this area. Hyperactivity and inattention are currently treated with a variety of medications, including guanfacine, which has a relatively benign side effect profile. Stimulant medications are generally avoided as first-line treatment for hyperactivity because of concerns about increased irritability. Currently, social impairment is best addressed through behavioral therapy and social skills training. Novel pharmacotherapies to improve social impairment are in the early stages of research.

Aripiprazole in autism spectrum disorders and fragile X syndrome

SummaryAutism spectrum disorders (ASDs) are childhood onset developmental disorders characterized by impairment of social skills and repetitive behavior, and also for classic autistic disorder, a significant impairment of communication. In addition to these core symptom domains, persons with ASDs frequently exhibit interfering behavioral symptoms, including irritability marked by aggression, self-injurious behavior, and severe tantrums. Aripiprazole is an atypical or newer generation antipsychotic with a unique mechanism of action impacting dopaminergic and serotonergic neurotransmission. The drug has been found efficacious for several indications, including most recently for use targeting irritability associated with autistic disorder in youth. Fragile X syndrome is the most common inherited cause of developmental disability and the most common known single gene cause of ASDs. As in idiopathic ASDs, irritable behavior is often exhibited by persons with fragile X syndrome. However, research to date in this disorder has not focused on this target symptom cluster. An initial pilot study has begun to assess the impact of aripiprazole on irritability in youth with fragile X syndrome.

Developing Drugs for Core Social and Communication Impairment in Autism

There are many challenges to studying drug effects on core social and language impairment in autism. Drugs such as fenfluramine, naltrexone, and secretin do not appear to be efficacious for these core symptoms. Risperidone has led to improvement in some aspects of social relatedness when used to treat irritability in autism. More research is needed on the utility of selective serotonin reuptake inhibitors, cholinergic drugs, glutamatergic drugs, and oxytocin for core autistic symptoms.

Autism as early neurodevelopmental disorder: evidence for an sAPPα-mediated anabolic pathway

Autism is a neurodevelopmental disorder marked by social skills and communication deficits and interfering repetitive behavior. Intellectual disability often accompanies autism. In addition to behavioral deficits, autism is characterized by neuropathology and brain overgrowth. Increased intracranial volume often accompanies this brain growth. We have found that the Alzheimer’s disease (AD) associated amyloid-β precursor protein (APP), especially its neuroprotective processing product, secreted APP α, is elevated in persons with autism. This has led to the “anabolic hypothesis” of autism etiology, in which neuronal overgrowth in the brain results in interneuronal misconnections that may underlie multiple autism symptoms. We review the contribution of research in brain volume and of APP to the anabolic hypothesis, and relate APP to other proteins and pathways that have already been directly associated with autism, such as fragile X mental retardation protein, Ras small GTPase/extracellular signal-regulated kinase, and phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin. We also present additional evidence of magnetic resonance imaging intracranial measurements in favor of the anabolic hypothesis. Finally, since it appears that APP’s involvement in autism is part of a multi-partner network, we extend this concept into the inherently interactive realm of epigenetics. We speculate that the underlying molecular abnormalities that influence APP’s contribution to autism are epigenetic markers overlaid onto potentially vulnerable gene sequences due to environmental influence.

An Open-Label Naturalistic Pilot Study of Acamprosate in Youth with Autistic Disorder

To date, placebo-controlled drug trials targeting the core social impairment of autistic disorder (autism) have had uniformly negative results. Given this, the search for new potentially novel agents targeting the core social impairment of autism continues. Acamprosate is U.S. Food and Drug Administration-approved drug to treat alcohol dependence. The drug likely impacts both gamma-aminobutyric acid and glutamate neurotransmission. This study describes our initial open-label experience with acamprosate targeting social impairment in youth with autism. In this naturalistic report, five of six youth (mean age, 9.5 years) were judged treatment responders to acamprosate (mean dose 1,110 mg/day) over 10 to 30 weeks (mean duration, 20 weeks) of treatment. Acamprosate was well tolerated with only mild gastrointestinal adverse effects noted in three (50%) subjects.

Impact of acamprosate on plasma amyloid-β precursor protein in youth: A pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker

BACKGROUND Understanding of the pathophysiology of autism spectrum disorder (ASD) remains limited. Brain overgrowth has been hypothesized to be associated with the development of ASD. A derivative of amyloid-β precursor protein (APP), secreted APPα (sAPPα), has neuroproliferative effects and has been shown to be elevated in the plasma of persons with ASD compared to control subjects. Reduction in sAPPα holds promise as a novel molecular target of treatment in ASD. Research into the neurochemistry of ASD has repeatedly implicated excessive glutamatergic and deficient GABAergic neurotransmission in the disorder. With this in mind, acamprosate, a novel modulator of glutamate and GABA function, has been studied in ASD. No data is available on the impact of glutamate or GABA modulation on sAPPα function. METHODS Plasma APP derivative levels pre- and post-treatment with acamprosate were determined in two pilot studies involving youth with idiopathic and fragile X syndrome (FXS)-associated ASD. We additionally compared baseline APP derivative levels between youth with FXS-associated or idiopathic ASD. RESULTS Acamprosate use was associated with a significant reduction in plasma sAPP(total) and sAPPα levels but no change occurred in Aβ40 or Aβ42 levels in 15 youth with ASD (mean age: 11.1 years). Youth with FXS-associated ASD (n = 12) showed increased sAPPα processing compared to age-, gender- and IQ-match youth with idiopathic ASD (n = 11). CONCLUSIONS Plasma APP derivative analysis holds promise as a potential biomarker for use in ASD targeted treatment. Reduction in sAPP (total) and sAPPα may be a novel pharmacodynamic property of acamprosate. Future study is required to address limitations of the current study to determine if baseline APP derivative analysis may predict subgroups of persons with idiopathic or FXS-associated ASD who may respond best to acamprosate or to potentially other modulators of glutamate and/or GABA neurotransmission.