Logan K. Wink

A Systematic Review of Treatments for Anxiety in Youth with Autism Spectrum Disorders

This study systematically examined the efficacy and safety of psychopharmacological and non-psychopharmacological treatments for anxiety in youth with autism spectrum disorders (ASD). Four psychopharmacological, nine cognitive behavioral therapy (CBT), and two alternative treatment studies met inclusion criteria. Psychopharmacological studies were descriptive or open label, sometimes did not specify the anxiety phenotype, and reported behavioral activation. Citalopram and buspirone yielded some improvement, whereas fluvoxamine did not. Non-psychopharmacological studies were mainly randomized controlled trials (RCTs) with CBT demonstrating moderate efficacy for anxiety disorders in youth with high functioning ASD. Deep pressure and neurofeedback provided some benefit. All studies were short-term and included small sample sizes. Large scale and long term RCTs examining psychopharmacological and non-psychopharmacological treatments are sorely needed.

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.

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.

Drug-refractory aggression, self-injurious behavior, and severe tantrums in autism spectrum disorders: A chart review study

Aggression, self-injurious behavior, and severe tantrums are impairing symptoms frequently experienced by individuals with autism spectrum disorders. Despite US Food and Drug Administration approval of two atypical antipsychotics targeting these symptoms in youth with autistic disorder, they remain frequently drug refractory. We define drug-refractory aggression, self-injurious behavior, and severe tantrums in people with autism spectrum disorders as behavioral symptoms requiring medication adjustment despite previous trials of risperidone and aripiprazole or previous trials of three psychotropic drugs targeting the symptom cluster, one of which was risperidone or aripiprazole. We reviewed the medical records of individuals of all ages referred to our clinic for autism spectrum disorder diagnostic evaluation, as well as pharmacotherapy follow-up notes for all people meeting autism spectrum disorder criteria, for drug-refractory symptoms. Among 250 consecutively referred individuals, 135 met autism spectrum disorder and enrollment criteria, and 53 of these individuals met drug-refractory symptom criteria. Factors associated with drug-refractory symptoms included age 12 years or older (p < 0.0001), diagnosis of autistic disorder (p = 0.0139), and presence of intellectual disability (p = 0.0273). This pilot report underscores the significance of drug-refractory aggression, self-injurious behavior, and severe tantrums; suggests the need for future study clarifying factors related to symptom development; and identifies the need for focused treatment study of this impairing symptom domain.

Emerging drugs for the treatment of symptoms associated with autism spectrum disorders

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 autistic disorder (autism), Aspergers disorder and PDD not otherwise specified. 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 readers 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.

Aggression in autism spectrum disorder: presentation and treatment options.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent difficulties in social communication and social interaction, coupled with restricted, repetitive patterns of behavior or interest. Research indicates that aggression rates may be higher in individuals with ASD compared to those with other developmental disabilities. Aggression is associated with negative outcomes for children with ASD and their caregivers, including decreased quality of life, increased stress levels, and reduced availability of educational and social support. Therapeutic strategies including functional behavioral assessment, reinforcement strategies, and functional communication training may have a significant impact in reducing the frequency and intensity of aggressive behavior in individuals with ASD. Pharmacologic treatments, particularly the use of second-generation antipsychotics, may also be of some benefit in reducing aggression in individuals with ASD. With the ever-increasing rate of ASD diagnosis, development of effective therapeutic and pharmacologic methods for preventing and treating aggression are essential to improving outcomes in this disorder.

Fragile X targeted pharmacotherapy: lessons learned and future directions

Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts.

The neurobehavioral and molecular phenotype of Angelman Syndrome.

Angelman Syndrome (AS) is a rare neurodevelopmental disorder associated with developmental delay, speech impairment, gait ataxia, and a unique behavioral profile. AS is caused by loss of maternal expression of the paternally imprinted UBE3A gene. In this study we aim to contribute to understanding of the neurobehavioral phenotype of AS with particular focus on the neuropsychiatric presentation of the disorder. We also undertake initial exploration of brain‐derived neurotrophic factor (BDNF) plasma levels in AS. Twelve individuals ages 3 years or older with a confirmed genetic diagnosis of AS underwent detailed medical history, phenotypic characterization, and BDNF plasma sampling. The results of this study demonstrate that individuals with AS suffer from significant developmental delay, impaired adaptive behavior, and sleep disruption. Additionally, hyperactivity/impulsivity appears to be the primary behavioral domain noted in these individuals. The majority of individuals in this project met criteria for autism spectrum disorder on the Autism Diagnostic Observation Schedule (ADOS); however, a negative correlation was noted between ADOS score and developmental age. BDNF plasma levels in AS individuals were significantly elevated compared to neurotypical controls. This is the first report of abnormal BDNF levels in AS, and one that necessitates larger future studies. The results provide a clue to understanding abnormal neuronal development in AS and may help guide future AS research.

Paliperidone palmitate in a child with 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.