To follow up on a 3-site 24-week randomized clinical trial (N=124) comparing antipsychotic medication alone (MED) to antipsychotic plus parent training (PT) in behavior management (COMB) for autism spectrum disorders with severe behavior problems. COMB had shown a significant advantage for child behavioral noncompliance (p=.006, d=.34), irritability (p=.01, d=.48), and hyperactivity/noncompliance (p=.04, d=.55), with a lower medication dose.
Method: A year after each participant’s termination we priority-mailed an assessment packet
with a return-addressed envelope; a phone call alerted the family. Failure to return packets within a month elicited recontact and offers to resend.
Eighty-seven of 124 families (70.2%) participated in follow-up. The improvement difference between treatments attenuated from post-treatment to follow-up for noncompliance (d=0.32 to d=0.12) and irritability (d=0.46 to d=0.03). Follow-up differences were nonsignificant. (The noncompliance difference was nonsignificant also at post-treatment for these 87.) 67% of COMB and 53% of MED were still taking risperidone, the original study medication. Most had needed dose adjustments or additional medication, and COMB no longer had a significantly lower dose. All COMB families but only 39% of MED reported seeking PT post-treatment. Daily living skills improvement during treatment predicted noncompliance improvement at follow-up for COMB, but noncompliance deterioration, and especially hyperactivity/noncompliance deterioration for MED-only children.
Study treatment experience/familiarity greatly influenced follow-up treatment: those who had received PT reported seeking it while those who had not experienced it tended not to seek it. The superiority of COMB over MED at post-treatment attenuated by over half at follow-up.
autism; antipsychotic; parent training; follow-up; clinical trial
Psychotropic medications, including the atypical antipsychotics, have historically been scrutinized for cardiac effects and risk of sudden death. Aripiprazole is an atypical antipsychotic approved for pediatric use in schizophrenia, bipolar I disorder, and autistic disorder. Adult studies have evaluated aripiprazole's effects on electrocardiograms, but no pediatric studies have been published to date.
Electrocardiographic data were collected from children and adolescents participating in a 14-week, prospective, open-label study (n=25) of aripiprazole for irritability in pervasive developmental disorder not otherwise specified and Asperger's disorder. A 12-lead electrocardiogram was obtained at the baseline and end point visits. The electrocardiograms were evaluated for abnormal findings, and the PR, QRS, QTc, and RR intervals were recorded. The QT interval was corrected using Bazett's, United States Food and Drug Administration (FDA) Pharmacology Division, and Fridericia's formulas.
Twenty-four subjects received both baseline and posttreatment electrocardiograms. The mean age was 8.6 years (range 5–17 years). The average final aripiprazole dose was 7.8 mg/day (range 2.5–15 mg/day). There were no significant differences noted with the PR, QRS, RR, and QTc intervals after aripiprazole therapy. Also, there was no significant correlation between the dose given and the percent change in the QTc. No post-treatment QTc exceeded 440 ms.
To our knowledge, this is the first systematic evaluation of the cardiac effects of aripiprazole in children and adolescents. The results are consistent with previously published literature in adults that aripiprazole has no significant cardiac effects and can be deemed a low risk for causing sudden death. It will be important to confirm these findings in a randomized controlled trial.
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.
The neurobiology of autism spectrum disorders (ASDs) has become increasingly understood since the advent of magnetic resonance imaging (MRI). Initial observations of an above-average head circumference were supported by structural MRI studies that found evidence of increased total brain volume and early rapid brain overgrowth in affected individuals. Subsequent research revealed consistent abnormalities in cortical gray and white matter volume in ASDs. The structural integrity and orientation of white matter have been further elucidated via diffusion tensor imaging methods. The emergence of functional MRI techniques led to an enhanced understanding of the neural circuitry of ASDs, demonstrating areas of dysfunctional cortical activation and atypical cortical specialization. These studies have provided evidence of underconnectivity in distributed cortical networks integral to the core impairments associated with ASDs. Abnormalities in the default-mode network during the resting state have also been identified. Overall, structural and functional MRI research has generated important insights into the neurobiology of ASDs. Additional research is needed to further delineate the underlying brain basis of this constellation of disorders.
Autism; Autism spectrum disorder; Magnetic resonance imaging; Neurobiology; Review
This review outlines pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders (ASDs) in children, adolescents, and adults. Symptom domains include repetitive and stereotyped behaviors, irritability and aggression, hyperactivity and inattention, and social impairment. Medications covered include serotonin reuptake inhibitors (SRIs), mirtazapine, antipsychotics, psychostimulants, atomoxetine, α-2 agonists, D-cycloserine, and memantine. Overall, SRIs are less efficacious and more poorly tolerated in children with ASDs than in adults. Antipsychotics are the most efficacious drugs for the treatment of irritability in ASDs, and may be useful in the treatment of other symptoms. Psychostimulants demonstrate some benefit for the treatment of hyperactivity and inattention in individuals with ASDs, but are less efficacious and associated with more adverse effects compared with individuals with ADHD. D-cycloserine and memantine appear helpful in the treatment of social impairment, although further research is needed.
autism; autism spectrum disorder; autistic disorder; pervasive developmental disorder; treatment
Importance of the Field
Autism spectrum disorders, or pervasive developmental disorders (PDDs), are neurodevelopmental disorders defined by qualitative impairment in social interaction, impaired communication, and stereotyped patterns of behavior. The most common forms of PDD are autstic disorder (autism), Asperger's disorder, and pervasive developmental disorder not otherwise specified (PDD NOS). Recent surveillance studies reveal an increase in the prevalence of autism and related PDDs. The use of pharmacologic agents in the treatment of these disorders can reduce the impact of interfering symptoms, providing relief for affected individuals and their families.
Areas Covered in this Review
This review examines results from neurobiologic research in an attempt to both elucidate the pathophysiology of autism and guide the development of pharmacologic agents for the treatment of associated symptoms. The safety and efficacy data of drugs currently in clinical use for the treatment of these symptoms, as well as pharmaceuticals currently under development, are discussed.
What the Reader will Gain
This comprehensive review will deepen the reader's current understanding of the research guiding the pharmacologic treatment of symptoms associated with autism and related PDDs. Areas of focus for future research are also discussed. The need for large-scale investigation of some commonly used pharmacologic agents, in addition to the development of drugs with improved efficacy and safety profiles, is made evident.
Take Home Message
Despite progress in the development of pharmacologic treatments for a number of interfering symptom domains associated with autism and other PDDs, a great deal of work remains.
aripiprazole; autism; autistic disorder; methylphenidate; PDDs; risperidone; treatment
Obsessive-compulsive disorder (OCD) is a chronic anxiety disorder. While medication and psychotherapy advances have been very helpful to patients, many patients do not respond adequately to initial trials of serotonergic medication or cognitive-behavioral therapy (CBT) and require multiple treatment trials or combination therapies. Comorbidity may also influence treatment response. The role of streptococcal infections in pediatric OCD has become an area of intense scrutiny and controversy. In this article, current treatment methods for OCD will be reviewed, with special attention to strategies for treating OCD in children and in patients with comorbid tic disorders. Alternative psychotherapy strategies for patients who are highly anxious about starting CBT, such as cognitive therapy or augmentation with D-cycloserine, will be reviewed. Newer issues regarding use of antibiotics, neuroleptics, and glutamate modulators in OCD treatment will also be explored.
OCD; exposure/response prevention therapy; PANDAS; tic disorder
Aripiprazole was recently US FDA-approved to treat irritability in children and adolescents with autistic disorder aged 6–17 years. There are currently only two psychotropics approved by the FDA to treat irritability in the autistic population. This drug profile will discuss available studies of aripiprazole in individuals with pervasive developmental disorders, two of which led to its recent FDA approval. We will discuss the efficacy, as well as the safety and tolerability of the drug documented in these studies. In addition, the chemistry, pharmacokinetics, metabolism and mechanism of action of aripiprazole will be reviewed.
aripiprazole; Asperger’s disorder; autistic disorder; dehyro-aripiprazole; pervasive developmental disorder; pervasive developmental disorder not otherwise specified; quinolinone antipsychotic
Autism spectrum disorders (ASDs) are childhood onset developmental disorders characterized by social skills impairment, repetitive behavior, and for classic autistic disorder, a significant communication impairment. In addition to these core symptom domains, persons with ASDs frequently exhibit interfering behavioral symptoms, including irritability marked by aggression, self-injurious behavior (SIB), 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 (FXS) is the most common inherited cause of developmental disability and most common known single gene cause of ASDs. As in idiopathic ASDs, irritable behavior is often exhibited by persons with FXS. Research to date in this disorder, however, has not focused on this target symptom cluster. Initial pilot study has begun to assess the impact of aripiprazole on irritability in youth with FXS.
aripiprazole; autistic disorder; irritability; fragile X syndrome
Guanfacine has been shown to reduce hyperactive behaviors in children with attention-deficit/hyperactivity disorder (ADHD) and possibly in children with pervasive developmental disorder (PDD) and hyperactivity. The aim of this exploratory study was to examine whether gene variants encoding the multidrug resistance protein (MDR1 or ABCB1) , a drug transporter at the blood–brain barrier, are associated with variability in the efficacy of guanfacine in children with PDD and hyperactivity.
Children with PDD who participated in an 8-week open-label trial of guanfacine were genotyped for the C3435T single-nucleotide polymorphism (SNP) variant of the MDR1 gene, a variant reported to alter function of the transporter. The decrease from baseline to 8 weeks in parent-rated Aberrant Behavior Checklist (ABC) hyperactivity and Swanson, Nolan, and Pelham (SNAP) scores were analyzed by MDR1 genotype. Response was compared between subjects homozygous for the minor allele T of the C34535T MDR1 variant (T/T) versus other genotypes (C/T and C/C).
Disruptive behavior decreased during guanfacine treatment as assessed by several end points in the 25 enrolled children (23 boys and 2 girls). Genotype data were available from 22 children. Subjects with either C/T or C/C (n = 16) genotypes showed a three-fold greater improvement than T/T MDR1 C3435T genotype (n = 6) (mean decrease of 15.1 ± 12.6, or 50.7% from baseline, versus 4.5 ± 5.1, or 15.6% from baseline) in parent-rated ABC Hyperactivity scores over 8 weeks (p = 0.03). Parent-rated ADHD SNAP scores also differed by genotype (p = 0.05).
Gene variants in MDR1 may influence guanfacine response on hyperactive-impulsive behaviors via altered membrane transport. If replicated in larger samples, additional studies would be important to clarify the mechanisms underlying this effect and to determine its clinical significance.
Observational measures of parent and child behaviours have a long history in child psychiatric and psychological intervention research, including the field of autism and developmental disability. We describe the development of the Standardised Observational Analogue Procedure (SOAP) for the assessment of parent–child behaviour before and after a structured parent training program for children with pervasive developmental disorders (PDD). We report on the use of this procedure in a pilot study of 12 participants with PDD.
Inter-rater reliability across behaviours coded ranged from 75 to 100% agreement. Blindly scored observations of behaviour showed medium effect sizes for changes in inappropriate child behaviour. Analyses of baseline scores revealed a moderate positive correlation between inappropriate child behaviours as measured in all four SOAP conditions and parent ratings of child noncompliance (rs = .66, p < .05). By contrast, the correlations of SOAP scores with parent ratings of irritability was lower (rs = .40, p > .05).
As our treatment targeted compliance, these preliminary results suggest that the SOAP provides a valid measure of noncompliant behaviour in children with PDD and is sensitive to treatment effects on inappropriate child behaviours.
pervasive developmental disorders; autism; observational measures; behaviour interventions; parent training; clinical trials
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.
The objective of this research was to explore the effects of risperidone on cognitive processes in children with autism and irritable behavior.
Thirty-eight children, ages 5–17 years with autism and severe behavioral disturbance, were randomly assigned to risperidone (0.5 to 3.5 mg/day) or placebo for 8 weeks. This sample of 38 was a subset of 101 subjects who participated in the clinical trial; 63 were unable to perform the cognitive tasks. A double-blind placebo-controlled parallel groups design was used. Dependent measures included tests of sustained attention, verbal learning, hand-eye coordination, and spatial memory assessed before, during, and after the 8-week treatment. Changes in performance were compared by repeated measures ANOVA.
Twenty-nine boys and 9 girls with autism and severe behavioral disturbance and a mental age ≥18 months completed the cognitive part of the study. No decline in performance occurred with risperidone. Performance on a cancellation task (number of correct detections) and a verbal learning task (word recognition) was better on risperidone than on placebo (without correction for multiplicity). Equivocal improvement also occurred on a spatial memory task. There were no significant differences between treatment conditions on the Purdue Pegboard (hand-eye coordination) task or the Analog Classroom Task (timed math test).
Risperidone given to children with autism at doses up to 3.5 mg for up to 8 weeks appears to have no detrimental effect on cognitive performance.
Interventions for pervasive developmental disorders (PDD) aim to alleviate symptoms and improve functioning. To measure global functioning in treatment studies, the Children’s Global Assessment Scale was modified and psychometric properties of the revised version (DD-CGAS) were assessed in children with PDD.
Developmental disabilities-relevant descriptors were developed for the DD-CGAS and administration procedures were established to enhance rater consistency. Ratings of clinical case vignettes were used to assess inter-rater reliability and temporal stability. Validity was assessed by correlating the DD-CGAS with measures of functioning and symptoms in 83 youngsters with PDD. Sensitivity to change was assessed by comparing change from baseline to post-treatment with change on the Aberrant Behavior Checklist – Irritability and Clinical Global Impressions–Improvement subscale scores in a subset of 14 children.
Inter-rater reliability (ICC=.79) and temporal stability (average ICC = .86) were excellent. DD-CGAS scores correlated with measures of functioning and symptoms with moderate to large effect sizes. Changes on the DD-CGAS correlated with changes on the ABC-I (r=.−71) and CGI-I (r=−.52). The pre-post DD-CGAS change had an effect size of .72.
The DD-CGAS is a reliable instrument with apparent convergent validity for measuring global functioning of children with PDD in treatment studies.
autism; pervasive developmental disorder; functioning; assessment; children; psychometrics
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.
Risperidone has been shown to improve serious behavioral problems in children with autism. Here we asked whether risperidone-associated improvement was related to changes in concentrations of inflammatory molecules in the serum of these subjects. Seven molecules were identified as worthy of further assessment by performing a pilot analysis of 31 inflammatory markers in 21 medication-free subjects with autism versus 15 healthy controls: epidermal growth factor (EGF), interferon-γ (IFN-γ), interleukin (IL)-13, IL-17, monocyte chemoattractant protein-1 (MCP-1), IL-1 and IL-1-receptor antagonist. Serum concentrations of these markers were then established in a different set of subjects that participated in a double-blind, clinical trial and an expanded group of healthy subjects. In the first analysis, samples obtained from subjects with autism at baseline visits were compared to visits after 8-week treatment with placebo (n=37) or risperidone (n=40). The cytokine concentrations remained stable over the 8-week period for both risperidone and placebo groups. In the second analysis, we explored further the differences between medication-free subjects with autism (n=77) and healthy controls (recruited independently; n=19). Serum levels of EGF were elevated in subjects with autism (median=103 pg/mL, n=75) in comparison to healthy controls (75 pg/mL, n=19; p<0.05), and levels of IL-13 were decreased in autism (median=0.8 pg/mL, n=77) in comparison to controls (9.8 pg/mL, n=19; p=0.0003). These changes did not correlate with standardized measures used for a diagnosis of autism. In summary, risperidone-induced clinical improvement in subjects with autism was not associated with changes in the serum inflammatory markers measured. Whether altered levels of EGF and IL-13 play a role in the pathogenesis or phenotype of autism requires further investigation.
The National Institute of Mental Health (NIMH) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network found an effect size of d = 1.2 in favor of risperidone on the main outcome measure in an 8-week double-blind, placebo-controlled trial for irritability in autistic disorder. This paper explores moderators and mediators of this effect.
Intention-to-treat (ITT) analyses were conducted with suspected moderators and mediators entered into the regression equations. MacArthur Foundation Network subgroup guidelines were followed in the evaluation of the results.
Only baseline severity moderated treatment response: Higher severity showed greater improvement for risperidone but not for placebo. Weight gain mediated treatment response negatively: Those who gained more weight improved less with risperidone and more with placebo. Compliance correlated with outcome for risperidone but not placebo. Higher dose correlated with worse outcome for placebo, but not risperidone. Of nonspecific predictors, parent education, family income, and low baseline prolactin positively predicted outcome; anxiety, bipolar symptoms, oppositional-defiant symptoms, stereotypy, and hyperactivity negatively predicted outcome. Risperidone moderated the effect of change in 5′-nucleotidase, a marker of zinc status, for which decrease was associated with improvement only with risperidone, not with placebo.
The benefit–risk ratio of risperidone is better with greater symptom severity. Risperidone can be individually titrated to optimal dosage for excellent response in the majority of children. Weight gain is not necessary for risperidone benefit and may even detract from it. Socioeconomic advantage, low prolactin, and absence of co-morbid problems nonspecifically predict better outcome. Mineral interactions with risperidone deserve further study.
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1–4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5–9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10−3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10−3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10−6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
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 Asperger's disorder.
This is a 14-week, prospective, open-label investigation of aripiprazole in 25 children and adolescents diagnosed with PDD-NOS or Asperger's disorder. Primary outcome measures included the Clinical Global Impressions–Improvement (CGI-I) scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I).
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 ≤ 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 ≤ 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 ≤ 0.04). Prolactin significantly decreased from a mean value of 9.3 at baseline to 2.9 at end point (p ≤ 0.0001). No subject exited the study due to a drug-related adverse event.
These preliminary data suggest that aripiprazole may be effective and well tolerated for severe irritability in pediatric patients with PDD-NOS or Asperger's disorder. Larger-scale placebo-controlled studies are needed to elucidate the efficacy and tolerability of aripiprazole in this understudied population.