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This study was a 10-week double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in youth with autism spectrum disorder (ASD). Participants were ages 5 to 17 years with ASD and clinically significant anxiety (Pediatric Anxiety Rating Scale [PARS] score ≥10). Thirty participants were randomized to mirtazapine (7.5–45 mg/day) or placebo in a 2:1 ratio. The co-primary outcome measures were the PARS and the Clinical Global Impressions-Improvement subscale (CGI-I). Mirtazapine resulted in a statistically significant within group decrease in anxiety on the PARS (ES 1.76, p

Individuals diagnosed with autism spectrum disorders (ASD) often exhibit serious behavioral disturbance (irritability) including severe tantrums, aggression, and self-injury that requires pharmacologic management. Research focused on the treatment of severe irritability has primarily involved the atypical antipsychotics, including risperidone and aripiprazole. Anticonvulsants have also been investigated for targeting serious behavioral disturbance; however findings have been mixed. Advances in the pharmacotherapy of irritability in ASD continue to inform practice. Research is needed to develop safer and more effective drug treatments for serious behavioral disturbance in this population. Language: en

Current observational inventories used to diagnose autism spectrum disorders (ASD) apply similar criteria to females and males alike, despite developmental differences between the sexes. Recent work investigating the chronology of diagnosis in ASD has raised the concern that females run the risk of receiving a delayed diagnosis, potentially missing a window of opportunity for early intervention. Here, we retake this issue in the context of the objective measurements of natural behaviors that involve decision-making processes. Within this context, we quantified movement variability in typically developing (TD) individuals and those diagnosed with ASD across different ages. We extracted the latencies of the decision movements and velocity-dependent parameters as the hand movements unfolded for two movement segments within the reach: movements intended toward the target and withdrawing movements that spontaneously, without instruction, occurred incidentally. The stochastic signatures of the movement decision latencies and the percent of time to maximum speed differed between males and females with ASD. This feature was also observed in the empirically estimated probability distributions of the maximum speed values, independent of limb size. Females with ASD showed different dispersion than males with ASD. The distinctions found for females with ASD were better appreciated compared with those of TD females. In light of these results, behavioral assessment of autistic traits in females should be performed relative to TD females to increase the chance of detection.

Autism spectrum disorder (ASD) is a group of heterogeneous developmental disorders manifesting in early childhood. They are associated with a range of core and associated symptoms, including repetitive behaviors, hyperactivity and irritability. This review will describe the current evidence for psychopharmacological management of individuals with ASD. Additionally, some of the future treatment prospects will be discussed. Safety issues, adverse effects and limitations of the current literature will also be highlighted.

Numerous studies have examined the brain bases of autism; few, however, have specifically examined the neurobiology of speech and language impairments in children and adults on the spectrum, especially those characterized as low functioning or minimally verbal, due to compliance issues. With exciting new advances in the development of paradigms and tools, and the ability to image children at risk for autism as young as 6 months of age, functional neuroimaging (EEG, magnetoencephalography and functional MRI) holds tremendous promise. Findings of reduced activation and structural and functional connectivity in the language network, together with deficits in social reciprocity and motivation, and a preference for visual over verbal information, appear to be carving out a neurobiological profile for the impaired social–communication brain in autism.

A Structured Observational Analog Procedure (SOAP), an analogue measure of parent-child interactions, was used to assess treatment outcome in children with Autism Spectrum Disorder and serious behavior problems. It served as a secondary outcome measure in a 24-week, randomized trial of risperidone (MED; N = 49) versus risperidone plus parent training (COMB; n = 75) (ages 4–13 years). At 24-weeks, there was 28 % reduction in child inappropriate behavior during a Demand Condition (p = .0002) and 12 % increase in compliance to parental requests (p = .004) for the two treatment conditions combined. Parents displayed 64 % greater use of positive reinforcement (p = .001) and fewer repeated requests for compliance (p

Objective To follow up on a three-site, 24-week randomized clinical trial (N = 124) comparing antipsychotic medication alone (MED) with antipsychotic medication plus parent training in the behavior management (COMB) of children with autism spectrum disorders and severe behavior problems. The COMB treatment had shown a significant advantage for child behavioral noncompliance ( p = .006, d = 0.34), irritability ( p = .01, d = 0.48), and hyperactivity/noncompliance ( p = .04, d = 0.55) with a lower medication dose. Method One year after each participant's termination, the authors mailed an assessment packet with a return-addressed envelope; a telephone call alerted the family. Failure to return packets within 1 month elicited another contact and offers to resend. Results Eighty-seven of 124 families (70.2%) participated in the follow-up. The improvement difference between treatments attenuated from after treatment to follow-up for noncompliance ( d = 0.32 to 0.12) and irritability ( d = 0.46 to 0.03). The follow-up differences were nonsignificant (the noncompliance difference also was nonsignificant after treatment for these 87 families). Sixty-seven percent of the COMB group and 53% of the MED group were still taking risperidone, the original study medication. Most needed dose adjustments or additional medication, and the COMB group no longer had a significantly lower dose. All COMB families but only 39% of MED families reported seeking parent training after treatment. Improvements in daily living skills during treatment predicted noncompliance improvement at follow-up for the COMB children, but noncompliance deterioration and especially hyperactivity/noncompliance deterioration for the MED children. Conclusions The study treatment experience/familiarity greatly influenced the follow-up treatment: those who had received parent training reported seeking it, whereas those who had not received it tended not to seek it. The superiority of COMB over MED after treatment attenuated by more than half at follow-up.

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, QT(c), 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 QT(c) intervals after aripiprazole therapy. Also, there was no significant correlation between the dose given and the percent change in the QT(c). No post-treatment QT(c) 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.

Individuals with autistic disorder (autism) frequently exhibit significant irritability marked by severe tantrums, aggression, and self-injury. Despite advances in the treatment of this symptom domain in autism, there remains an ongoing need for more effective and better tolerated pharmacotherapies. The aim of this study is to determine the effectiveness and tolerability of paliperidone for irritability in autism. This is a prospective, 8-week open-label study of paliperidone in 25 adolescents and young adults with autism. Primary outcome measures included the Clinical Global Impressions-Improvement (CGI-I) Scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I). Concomitant medications (except antipsychotics) were permitted if dosages were stable for ≥2 months. Twenty-one (84 %) of 25 subjects ages 12–21 years (mean 15.3 years) responded to paliperidone, based on a CGI-I Scale score of 1 or 2 (very much or much improved) and ≥25 % improvement on the ABC-I. The mean final dosage of paliperidone was 7.1 mg/day (range 3–12 mg/day). Two subjects discontinued paliperidone prior to study completion (moderate sedation, n = 1; nonresponse, n = 1). Mild-to-moderate extrapyramidal symptoms were recorded in four subjects. A mean weight gain of 2.2 ± 2.6 kg (range −3.6 to +7.9 kg) was recorded. Mean age- and sex-normed body mass index increased from 23.6 to 24.2 (p ≤ 0.001). Mean serum prolactin increased from 5.3 to 41.4 ng/mL (p ≤ 0.0001). Paliperidone treatment was associated with significant improvement in irritability and was generally well tolerated. Larger scale, placebo-controlled studies are needed to elucidate the efficacy and tolerability of paliperidone in this population.

Objective Children with Pervasive Developmental Disorders (PDDs) have social interaction deficits, delayed communication, and repetitive behaviors as well as impairments in adaptive functioning. Many children actually show a decline in adaptive skills compared with age mates over time. Method This 24-week, three-site, controlled clinical trial randomized 124 children (4 through 13 years of age) with PDDs and serious behavioral problems to medication alone (MED; n=49; risperidone 0.5 to 3.5 mg/day; if ineffective, switch to aripiprazole was permitted) or a combination of medication plus parent training (PT) (COMB; n=75). Parents of children in COMB received an average of 11.4 PT sessions. Standard scores and Age-Equivalent scores on Vineland Adaptive Behavior Scales were the outcome measures of primary interest. Results Seventeen subjects did not have a post-randomization Vineland assessment. Thus, we used a mixed model with outcome conditioned on the baseline Vineland scores. Both groups showed improvement over the 24-week trial on all Vineland domains. Compared with MED, Vineland Socialization and Adaptive Composite Standard scores showed greater improvement in the COMB group ( p = .01 and .05, and effect sizes=0.35 and 0.22, respectively). On Age Equivalent scores, Socialization and Communication domains showed greater improvement in COMB versus MED ( p = .03 and 0.05, and effect sizes=0.33 and 0.14, respectively). Using logistic regression, children in the COMB group were twice as likely to make at least 6 months' gain (equal to the passage of time) in the Vineland Communication Age Equivalent score compared with MED ( p = .02). After controlling for IQ, this difference was no longer significant. Conclusion Reduction of serious maladaptive behavior promotes improvement in adaptive behavior. Medication plus PT shows modest additional benefit over medication alone. Clinical trial registration information–RUPP PI PDD: Drug and Behavioral Therapy for Children With Pervasive Developmental Disorders; http://www.clinicaltrials.gov; NCT00080145.

Objective. Glutamatergic dysregulation is implicated in the pathophysiology of fragile X syndrome (FXS). Riluzole is hypothesized to have an inhibitory effect on glutamate release, block excitotoxic effects of glutamate, and potentiate postsynaptic GABA(A) receptor function. Extracellular signal-related kinase (ERK) activation is known to be delayed in humans with FXS and knockout animal models of FXS. Correction of delayed ERK activation is a potential biomarker of treatment response in FXS. We conducted a six-week open-label prospective pilot study of riluzole (100 mg/day) in six adults with FXS. Methods. Riluzole was started at 50 mg every evening and then increased to 50 mg twice daily at week 2. The dose was kept constant for the final 4 weeks of the trial. Clinical response was determined by a score of 1 “very much improved” or 2 “much improved” on the Clinical Global Impressions Improvement (CGI-I) scale and a ≥ 25% improvement on the Children's Yale-Brown Obsessive Compulsive Scale modified for Pervasive Developmental Disorders. The primary target of treatment in this study was repetitive, compulsive behavior that commonly occurs in persons with FXS. The study incorporated an ERK activation biomarker assay. Potential adverse effects were assessed in a systematic manner at all clinic visits and by phone between visits. Results. Riluzole treatment was associated with clinical response in 1 of 6 subjects (17%). Among a number of secondary outcome measures employed, significant improvement was only noted on the ADHD Rating Scale-IV (became non-significant when corrected for multiple comparisons). Riluzole use was associated with significant correction in ERK activation time in all subjects (mean change from 3.82 ± 0.27 (baseline) to 2.99 ± 0.26 (endpoint) minutes; p = 0.007). Riluzole was well tolerated; mean increases in liver function tests occurred but drug discontinuation was not required. Conclusion. Overall, riluzole use was not associated with significant clinical improvement despite uniform correction of peripheral ERK activation. Future directions of study include testing of riluzole in animal models of FXS and assessment of psychotropic monotherapy on ERK activation.

Fragile X syndrome (FXS) is the most common inherited form of developmental disability and most common single gene cause of autism. Persons with FXS frequently exhibit irritable behavior marked by aggression, self-injury, and severe tantrums. Despite frequent clinical use of atypical antipsychotic drugs to target this behavioral cluster, no systematic trials to date have assessed the efficacy and safety of these drugs in persons with FXS. We conducted a prospective open-label 12-week trial of aripiprazole in 12 persons aged 6–25 years (mean age, 14.3 years) with FXS who were free of concomitant psychoactive drugs. Aripiprazole use (mean dose, 9.8 mg/day) was associated with treatment response (defined by a Clinical Global Impressions-Improvement scale score of much improved or very much improved and a ≥25% improvement on the Aberrant Behavior Checklist-Irritability subscale) in 10 of 12 (87%) persons. Two individuals (13%) discontinued aripiprazole prior to study completion due to adverse events. One discontinuation was due to akathisia, mild drooling, and mild tiredness and the other due to moderate tiredness and moderate drooling. No significant changes in vital signs including weight or laboratory measures occurred during treatment with aripiprazole. Aripiprazole was generally safe and well tolerated and was associated with significant improvement in irritable behavior. Given these findings, a double-blind, placebo-controlled study of aripiprazole in FXS is warranted.

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.

Cases of autistic disorder (autism) have frequently been reported in association with congenital rubella and other infections. These observations stimulated further investigation into markers of immune function in autism. Postinfectious and autoimmune mechanisms of pathophysiology have been proposed. This review comprehensively addresses immune findings to date, including the role of viruses, neuroimmune factors, cellular and humoral immunity, immunogenetics, and immunotherapy in relation to autism. Although numerous immune abnormalities have been identified in autism, inconsistent results have often been reported. To date, research in this area has largely involved small, uncontrolled studies. In order to bring clarity to this field, high-quality, systematic research is needed to explore the role of neuroimmunologic factors in autism.

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 (por= 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) (por= 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 (por= 0.04). Prolactin significantly decreased from a mean value of 9.3 at baseline to 2.9 at end point (por= 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.

Children and adolescents diagnosed with autism and related pervasive developmental disorders (PDDs) often sustain irritability, including aggression, self-injurious behavior, and tantrums. Research to date supports the use of the atypical antipsychotics as a first-line pharmacologic treatment for this target symptom domain in PDDs. Currently, the atypical antipsychotic risperidone is the only medication approved by the US Food and Drug Administration for irritability in youth with autism. Additional large-scale, placebo-controlled studies of other medications are needed to determine their efficacy for the treatment of irritability in this diagnostic group.

Background 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. Methods 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. Results Inter-rater reliability (intraclass correlation coefficient [ICC] = .79) and temporal stability (average ICC = .86) were excellent. The 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 Aberrant Behavior Checklist–I (r = −.71) and Global Impressions Scale–I (r = −.52). The pre-post DD-CGAS change had an effect size of .72. Conclusions The DD-CGAS is a reliable instrument with apparent convergent validity for measuring global functioning of children with PDD in treatment studies.

The purpose of this review is to discuss the pharmacology of autistic disorder (autism) and other pervasive developmental disorders (PDDs) from the perspective of specific target symptom domains of behavior. Drug treatment strategies directed toward the following target symptom domains are included: motor hyperactivity and inattention; interfering stereotypical and repetitive behavior; aggression and self-injurious behavior (SIB); and the core social impairment of autism and other PDDs. For motor hyperactivity and inattention, studies have indicated that the α2 adrenergic agonists, clonidine and guanfacine, are useful. A placebo-controlled study by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network found methylphenidate to be efficacious in 49% of subjects with various PDDs for these target symptoms. Preliminary data with the norepinephrine reuptake inhibitor atomoxetine are encouraging. For interfering stereotypical and repetitive behavior, controlled studies of the selective serotonin reuptake inhibitor fluvoxamine found the drug to be more efficacious and better tolerated in adults than children with autism and other PDDs. A recent controlled study of low-dose liquid fluoxetine found the drug more efficacious than placebo for interfering repetitive behavior and well tolerated. A large placebo-controlled study of the atypical antipsychotic risperidone found the drug to be efficacious for reducing aggression, SIB and tantrumming in 70% of children with autism and that the response was maintained for up to 6 months. Open-label studies of other atypical antipsychotics are generally encouraging. A small, single-blind study of the glutamatergic agent d -cycloserine showed significant benefit for the social withdrawal of autism. Future directions include studying coactive pharmacological treatment strategies utilizing more than one drug to target more than one target symptom domain in individuals with autism and other PDDs.

Interest in the gastrointestinal (GI) factors of autistic disorder (autism) has developed from descriptions of symptoms such as constipation and diarrhea in autistic children and advanced towards more detailed studies of GI histopathology and treatment modalities. This review attempts to critically and comprehensively analyze the literature as it applies to all aspects of GI factors in autism, including discussion of symptoms, pathology, nutrition, and treatment. While much literature is available on this topic, a dearth of rigorous study was found to validate GI factors specific to children with autism.

The aim of this study was to obtain preliminary data regarding the effectiveness and tolerability of aripiprazole in the treatment of children and adolescents with a pervasive developmental disorder (PDD).Five youths (mean age, 12.2 years; range, 5-18 years) meeting Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criteria for a PDD received a naturalistic, open-label trial of aripiprazole (mean dosage, 12.0 mg/day; range, 10-15 mg/day) for a minimum of 8 weeks (mean duration, 12 weeks; range, 8-16 weeks).All 5 patients were judged to be responders, as determined by a Clinical Global Impressions-Improvement (CGI-I) scale rating of "much improved" or "very much improved." Aripiprazole was well tolerated. No extrapyramidal symptoms or clinically significant changes in heart rate or blood pressure occurred during the short-term trials. Two of 5 patients experienced mild somnolence. Two subjects lost weight, 2 subjects had no change, and 1 subject gained weight (mean change, -8.2 lbs; range, -30 to +1 lb). The weight loss was likely the result of the discontinuation of atypical antipsychotics that had led to significant weight gain.This case series describes the effectiveness of aripiprazole in the treatment of maladaptive behaviors in 5 patients with a PDD. No significant adverse effects emerged during these short-term trials. Additional research is needed to support these preliminary findings.

We set out to examine the effectiveness and tolerability of psychostimulants in children and adolescents with pervasive developmental disorders (PDDs).Medical records of all patients with PDDs treated with a stimulant were retrospectively reviewed. Demographics, stimulant type, drug dosage, trial duration, and adverse effects were recorded. Global improvement, focused on symptoms of hyperactivity and inattention, was measured by the Clinical Global Impressions-Improvement scale, with positive response defined by a rating of much improved or very much improved.Of 195 patients (174 males, 21 females; mean age +/- SD = 7.26 +/- 3.45 years, range 2-19 years), 61 had more than one trial, resulting in a total of 274 separate stimulant trials. It was discovered that 24.6%, 23.2%, and 11.1% of patients with a history of one, two, or three stimulant trials, respectively, responded to their first stimulant trial. Among first trial nonresponders, 6 (14.0%) of 43 patients responded to a second trial. Of those who did not respond to their first or second stimulant trial, 2 (14.3%) of 14 patients responded to a third trial. Patients with Asperger's disorder, in contrast to those with autistic disorder or PDD not otherwise specified, were significantly more likely to respond to a stimulant trial (p0.01). Use of concomitant medication (p0.007) positively affected response, whereas no association was found between stimulant type and IQ and response. Adverse effects, including agitation, dysphoria, and irritability, often occurred (154 [57.5%] of 268 trials, with 6 missing values).Overall, stimulants appeared ineffective and poorly tolerated for the majority of patients with PDDs. Response may differ with PDD subtype. Controlled studies are needed to further evaluate these preliminary findings in a systematic manner.

Pervasive developmental disorders (PDDs) are profound neuropsychiatric conditions characterized by impairments in social interaction and communication, as well as restricted patterns of behavior, interests, and activities. In addition to these core criteria, interfering behaviors including aggression, self–injury, agitation, hyperactivity, and repetitive phenomena are commonly observed. Although a nonpharmacologic approach is frequently utilized in the management of maladaptive behavior, medications are often necessary to diminish severe target symptoms in individuals with PDDs. This review will address recent advances in the pharmacotherapy of PDDs, with an emphasis on well–designed trials.

Objective To understand patient perceptions of p.r.n. medication for agitation used in institutional settings. Method A questionnaire was administered to child and adolescent psychiatric inpatients within 12 hours of their receiving p.r.n. medication for agitation and repeated 4 hours later. Research staff completed a form to rate each patient's comprehension and behavior in completing the questionnaire. Results Forty-two patients completed the survey: 38 males and 4 females, aged 7 to 17 years (mean age 12.19 years, median age 12 years). Patients requested the p.r.n. medication in 30% of episodes and assisted with the decision in an additional 10%. The p.r.n. was perceived for loss of control in more than half the cases. About 50% of the youngsters felt that the p.r.n. they received was the “best” for them. Only 30% answered that “something” could have been done by themselves or by staff to avoid requiring a p.r.n. medication. About 65% felt that “something good” happened from receiving the medication. The test-retest reliability of all but one question by κ statistic was p ≤ .001. Conclusions Hospitalized children and adolescents perceive p.r.n. medication as useful. The instrument used allows them to share their views in a reliable manner.

Since their introduction in the 1950s, antipsychotics have been used in the pharmacotherapy of a variety of neuropsychiatric conditions. The typical antipsychotics revolutionized psychiatry by introducing a biological treatment modality for psychiatric illness in adults, as well as in children and adolescents. However, their efficacy in decreasing target symptoms was frequently overshadowed by the development of significant adverse effects. Cognitive impairments were commonly observed with the low–potency antipsychotics, whereas acute dystonic reactions and dyskinesias (including withdrawal) were often reported with the administration of the high–potency agents. Ongoing concerns regarding the tolerability of this class of drugs led to the development of the atypical antipsychotics. Their profile of potent antagonism at serotonin (5–hydroxytryptamine, 5–HT) and dopamine (DA) receptors resulted in an improved tolerability profile, particularly regarding a lower incidence for tardive dyskinesia (TD). The currently available atypical antipsychotics in the United States include: clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. Although the atypical antipsychotics are formally approved for adult patients, the authors will review findings from well–designed trials regarding their efficacy and tolerability in the pediatric population.

This review examines the most recent evidence for the pharmacologic management of severe maladaptive behaviors often observed in patients with autistic disorder. Although a multimodal approach is imperative in the management of autism, medications are frequently required for the individual to benefit from behavioral and educational interventions. Several classes of medications appear helpful in diminishing specific target symptoms and include the atypical antipsychotics, selective serotonin reuptake inhibitors, mirtazapine, mood stabilizers and alpha(2)-adrenergic agonists. Controlled research and longitudinal studies are needed to expand the knowledge base of these compounds as well as other medications under investigation. It is anticipated that future research regarding neuroimmunology, as well as the cholinergic and glutamatergic neurotransmitter systems, will contribute to our understanding of the pathophysiology of autistic disorder.

To the Editor: Autistic disorder (autism) is a neuropsychiatric disorder characterized by impairments in social interaction, communication, and stereotyped behaviors and interests (American Psychiatric Association 2000). Individuals with this disorder often exhibit associated interfering symptoms including irritability, hyperactivity, and inattention. Irritability, defined as aggression, severe tantrums, and self-injury, is a particularly limiting symptom with the capacity to diminish the quality of life for both the affected individual and their caregivers. Historically, antipsychotics have been the pharmacologic treatment of choice for irritability in youth with autism. Early research focused on typical antipsychotics such as haloperidol (Cohen et al. 1980; Anderson et al. 1984). Atypical antipsychotics have a lower rate of side effects such as dyskinesias and are currently considered first-line choice for treatment of irritability associated with autistic disorder (Erickson et al. 2007; Blankenship et al. 2010). Both risperidone and aripiprazole were approved by the U.S. Food and Drug Administration (FDA) to treat irritability in youth with autism aged 5–16 and 6–17 years, respectively. Multiple double-blind, placebo-controlled studies have demonstrated the efficacy of risperidone (Research Units on Pediatric Psychopharmacology Autism 2002; Shea et al. 2004) and aripiprazole (Marcus et al. 2009; Owen et al. 2009) for the treatment of this symptom domain. Paliperidone is the active metabolite of risperidone and was approved by FDA to treat schizophrenia and schizoaffective disorder in adults. Stigler et al. (2010) recently described the effectiveness of paliperidone in treating irritability in two individuals with autism. A 16-year-old female patient and a 20-year-old male patient, both diagnosed with autism, were treated with paliperidone (3 and 12 mg/day, respectively) after they demonstrated a lack of adequate improvement on other medication regimens. Both were judged to have significant improvement in their symptoms, including aggression and tantrums, with paliperidone treatment. No adverse events were reported. Both individuals lost weight and experienced improvements in their fasting lipid profiles while taking paliperidone. In 2009, the FDA approved a sustained-release intramuscular (IM) formulation of paliperidone, paliperidone palmitate, for the treatment of adults with schizophrenia. In this report, we demonstrate the successful use of paliperidone palmitate for the treatment of irritability in a child with autism who was unable to tolerate oral medications.

This chapter will focus on the pharmacologic treatment of adolescents (12–18 years) and adults with autism spectrum disorders (ASDs). Research on the pharmacotherapy of associated symptoms of autism, such as interfering repetitive behaviors, irritability (tantrums, aggression, self-injury), and hyperactivity will be reviewed. In addition, the available literature on drug treatment of psychiatric comorbidities in ASDs will be covered, including mood and anxiety disorders, among others. This chapter will cover the available literature in adolescents and adults with ASDs. Because research to date in ASDs has largely focused on the treatment of children, key double-blind, placebo-controlled studies in this population will be summarized where applicable. Further, many studies of pharmacotherapy include children as well as adolescents and/or adults, making it difficult to generalize the results to any population.

Francisco Aboitiz*, F. Xavier Castellanos and Ximena Carrasco Departamento de Psiquiatria, Facultad de Medicina, and Centro Interdisciplinario de Neurociencia, Pontificia Universidad Catolica de Chile, Santiago, Chile New York University Child Study Center, Nathan Kline Institute for Psychiatric Research, New York, NY, USA Servicio de Neurologia y Psiquiatria infantil, Hospital Luis Calvo Mackenna Facultad de Medicina, Universidad de Chile, Santiago, Chile

Antipsychotics are frequently used in the treatment of a variety of neuropsychiatric conditions in children and adolescents. Atypical antipsychotics have come to the forefront in child psychiatry due largely to their tolerability profiles as well as their efficacy. Potential treatment options include clozapine, risperidone, olanzapine, quetiapine and ziprasidone. A number of studies investigating the use of clozapine have been published in children; however, owing to the frequent monitoring required for agranulocytosis, the use of clozapine may be restricted to patients with treatment-refractory disease. With accumulating data on the development of glucose intolerance in adults receiving clozapine, closer monitoring of bodyweight and fasting blood glucose is imperative. Clozapine also has an increased seizure risk, therefore a baseline electroencephalogram should be performed, as well as continued vigilance for this adverse effect. Risperidone is an atypical antipsychotic that is generally well tolerated and numerous studies have been published investigating this drug in children. Unlike clozapine, its receptor interaction profile lends itself toward increased risk of extrapyramidal symptoms (EPS) and hyperprolactinaemia. Bodyweight gain is a common adverse effect, although somewhat less than that reported with olanzapine. Baseline liver function studies prior to initiation of this medication are recommended. Risperidone-induced mania has been reported in adults and, therefore, increased caution should be used when deciding to treat children and adolescents with risperidone, particularly in those with a predisposition toward mania. Olanzapine, like risperidone, has also been associated with onset of mania in adults. Olanzapine has a receptor profile that results in significant risk for bodyweight gain and sedation. Furthermore, this drug has been linked to the development of glucose intolerance; thus, it is important to monitor bodyweight and fasting blood glucose on a frequent basis. Less information is known about quetiapine in children and adolescents. Reports about its efficacy and tolerability vary. Quetiapine appears to have increased risk for sedation and bodyweight gain, albeit less than that of olanzapine. The compound appears to be less likely to induce EPS. Finally, ziprasidone has recently been approved for use in the adult population. This compound, in terms of its receptor profile, has more in common with risperidone. This suggests a potential for increased risk of EPS and hyperprolactinaemia. It also has an increased risk of QTc prolongation; thus, a baseline electrocardiogram is suggested, particularly in those patients with a history of cardiovascular illness. Lack of evidence for bodyweight gain with ziprasidone is a considerable advantage.

Patients with autism spectrum disorders and intellectual disability can be clinically complex and often have limited access to psychiatric care. Because little is known about post-graduate clinical education in autism spectrum disorder and intellectual disability, we surveyed training directors of child and adolescent psychiatry fellowship programs. On average, child and adolescent psychiatry directors reported lectures of 3 and 4 h per year in autism spectrum disorder and intellectual disability, respectively. Training directors commonly reported that trainees see 1–5 patients with autism spectrum disorder or intellectual disability per year for outpatient pharmacological management and inpatient treatment. Overall, 43% of directors endorsed the need for additional resources for training in autism spectrum disorder and intellectual disability, which, coupled with low didactic and clinical exposure, suggests that current training is inadequate.

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 current assessment of behaviors in the inventories to diagnose autism spectrum disorders (ASD) focus on observation and discrete categorizations. Behaviors require movements, yet measurements of physical movements are seldom included. Their inclusion however, could provide an objective characterization of behavior to help unveil interactions between the peripheral and the central nervous systems (CNSs). Such interactions are critical for the development and maintenance of spontaneous autonomy, self-regulation, and voluntary control. At present, current approaches cannot deal with the heterogeneous, dynamic and stochastic nature of development. Accordingly, they leave no avenues for real time or longitudinal assessments of change in a coping system continuously adapting and developing compensatory mechanisms. We offer a new unifying statistical framework to reveal re-afferent kinesthetic features of the individual with ASD. The new methodology is based on the non-stationary stochastic patterns of minute fluctuations (micro-movements) inherent to our natural actions. Such patterns of behavioral variability provide re-entrant sensory feedback contributing to the autonomous regulation and coordination of the motor output. From an early age, this feedback supports centrally driven volitional control and fluid, flexible transitions between intentional and spontaneous behaviors. We show that in ASD there is a disruption in the maturation of this form of proprioception. Despite this disturbance, each individual has unique adaptive compensatory capabilities that we can unveil and exploit to evoke faster and more accurate decisions. Measuring the kinesthetic re-afference in tandem with stimuli variations we can detect changes in their micro-movements indicative of a more predictive and reliable kinesthetic percept. Our methods address the heterogeneity of ASD with a personalized approach grounded in the inherent sensory-motor abilities that the individual has already developed.

Structural and functional magnetic resonance imaging (MRI) research has significantly contributed to our understanding of the neurobiology of autism spectrum disorders (ASD). Structural MRI studies have demonstrated increased total brain volume, as well as an atypical trajectory of neurodevelopment in children with ASD. Differences in cortical gray and white matter volume have also been recorded in affected individuals, with diffusion tensor imaging revealing decreased white matter integrity at a microstructural level. Functional MRI research has found abnormalities in cortical activation and connectivity in ASD via task-based approaches. In addition, resting state studies have revealed atypical patterns of connectivity in the default-mode network. Despite these encouraging findings, additional large-scale neuroimaging studies are needed to further inform the neurobiological underpinnings of ASD.

The Research Units on Pediatric Psychopharmacology--Autism Network reported additional benefit when adding parent training (PT) to antipsychotic medication in children with autism spectrum disorders and serious behavior problems. The intent-to-treat analyses were rerun with putative predictors and moderators. The Home Situations Questionnaire (HSQ) and the Hyperactivity/Noncompliance subscale of the Aberrant Behavior Checklist were used as outcome measures. Candidate predictors and moderators included 21 demographics and baseline measures of behavior. Higher baseline HSQ scores predicted greater improvement on the HSQ regardless of treatment assignment, but no other predictors of outcome were observed. None of the variables measured in this study moderated response to PT. Antipsychotic medication plus PT appears to be equally effective for children with a wide range of demographic and behavioral characteristics.

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.

To the Editor: Pervasive developmental disorders (PDDs) are characterized by impairment in social interactions, deficits in communication, and repetitive behaviors/interests. Individuals with PDDs commonly exhibit other interfering symptoms, including inattention, hyperactivity, and impulsivity (American Psychiatric Association 2000). A study by Lecavalier (2006) with 487 nonclinically referred children and adolescents with PDDs (mean age 9.6 years) found that ∼50% exhibited moderate to severe hyperactivity and/or inattention. For typical children with attention-deficit/hyperactivity disorder (ADHD), methylphenidate (MPH) is the psychopharmacologic treatment of choice (Greenhill et al. 2002). However, the data for prescribing medication to children with PDDs and other developmental disabilities who exhibit inattention and hyperactivity are not as clear. Early studies concluded that children and adolescents with autistic disorder or intellectual disability responded poorly to stimulant medication (Aman 1982). However, more recently, a randomized, controlled, crossover trial of MPH in children with PDDs was performed by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network (RUPP 2005). They found that 35 of the 72 (49%) children were responders as judged by the Aberrant Behavior Checklist Hyperactivity subscale and the Clinical Global Impressions-Improvement (CGI-I) scale. Thirteen of the 72 (18%) individuals discontinued the study due to side effects, most commonly irritability. Based upon the modest efficacy and relatively poor tolerability of MPH, other agents used to treat inattention and hyperactivity in this population have been studied. Guanfacine immediate release (IR) is FDA approved to treat hypertension in adolescents and adults. This short acting form of guanfacine has been used clinically (“off-label”) for the treatment of ADHD in typical developing children and for treating inattention and hyperactivity in PDDs (Posey and McDougle 2007). There are three published trials of guanfacine IR in children with PDDs. One was retrospective in nature, one prospective and open-label, and one was double blind and placebo controlled. These trials describe improvement in inattention and hyperactivity in some children (Posey et al. 2004; Scahill et al. 2006; Handen et al. 2008). Although guanfacine IR appears to be helpful for these symptoms, its use may be limited, at times, by a side effect profile that includes irritability and sedation. Concerns regarding hypotension should also be considered. Guanfacine IR is dosed two to four times daily due to a rapid peak plasma concentration and a precipitous decline (Sallee 2009). The half-life ranges from 10 to 30 hours with an average half-life of 17 hours (Merck 2010). Recently, the FDA has approved guanfacine extended release (GXR) for the treatment of ADHD in children and adolescents. GXR can be prescribed alone or in combination with atomoxetine or stimulant medication to treat residual symptoms of inattention, hyperactivity, and impulsivity (Sallee 2009). The pharmacokinetics of GXR differ from those of guanfacine IR. GXR has a sustained release mechanism that helps to provide a steady plasma concentration over a longer period. When compared with guanfacine IR, GXR offers reduced peak-to-trough fluctuations that can improve tolerability and symptom control. The decreased frequency of dosing (once daily) may also increase compliance with medication. GXR has a half-life of 16 hours (Merck 2010). Three randomized, controlled studies with GXR have been performed, all finding it effective for treating symptoms of ADHD (Biederman et al. 2008; Conner et al. 2009; Sallee et al. 2009). Biederman et al. (2008) performed an 8-week double-blind, placebo-controlled, fixed dose (2, 3, 4 mg) escalation study of GXR in 345 children aged 6–17 years with a diagnosis of ADHD. All groups of children receiving GXR showed improvement compared with the placebo group on the hyperactivity/impulsivity and inattentiveness subscales of the Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV), CGI-I, the Parent's Global Assessment and the Conners' Parent and Teacher Rating Scale-Revised: Short Form. Common side effects included headache, somnolence, fatigue, abdominal pain, and sedation. Conner et al. (2009) performed an 8-week, double-blind, placebo-controlled, flexible-dose (1–4 mg/day) study of GXR in 217 children aged 6–12 years with a primary diagnosis of ADHD along with oppositional symptoms. The group of children receiving GXR showed improvement compared with placebo as judged by the ADHD-RS-IV and the Conners' Parent Rating Scale-Revised: Long Form oppositional subscale. The most common side effects reported included somnolence, headache, sedation, abdominal pain, and fatigue. Sallee et al. (2009) performed a 9-week, double-blind, placebo-controlled, dose-ranging study with GXR (1–4 mg/day) in children aged 6–17 years with ADHD. Statistically significant reductions in ADHD-RS-IV scores were noted in all groups receiving GXR as compared with the placebo group. Common side effects included somnolence, headache, fatigue, sedation, dizziness, irritability, abdominal pain, and nausea. In these studies, GXR was considered well tolerated and efficacious compared with placebo. In summary, individuals with PDDs commonly exhibit inattention, hyperactivity, and impulsivity that interfere with their quality of life. Given that guanfacine IR has shown some promise in the PDD population, it would seem that GXR could also reduce interfering symptoms in this population as well. Research to date suggests that in ADHD, GXR has a mild side effect profile, once daily dosing, and a more consistent plasma concentration as compared to guanfacine IR. In this report, we describe our clinical experience with GXR in 2 patients with PDD whom we treated.

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 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.

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.