Pharmacologic Interventions for Core Social and Communication Impairment in Autism

Betty Lau, MD Child and Adolescent Psychiatry Fellow

Presentation Outline
Autism Terminology Challenges to Drug Development Risperidone indirectly improves

social impairment in Autism Lessons from failed trials of Fenfluramine, Naltrexone and Secretin Ongoing research involving SSRIs, cholinergic drugs, glutmatergic agents and oxytocin.

What is Autism?
Autism Spectrum Disorders are a

group of neurodevelopmental disorders that affect a childs social skills, communication skills and has characteristic repetitive behaviors, interests, and activities. Persist throughout the lifespan of affected individuals.

Autism Video
Towle, P. Autism Spectrum

Disorder in Young Children: A Visual Guide. Westchester Institute for Human Development.

Why Study Autism?

PDDs are present in 1 in 166

preschool children. Cerebral Palsy is in 1 in 303. Though the rate of narrowly defined autism may still be 1 in 500.
Chakrabarti S. Pervasive developmental disorders in preschool children. JAMA Jun 27; 2001 285 (24):3093-3099 [PubMed 11427137]

DSM IV

What about DSM-V?

Autism Spectrum Disorder now

encompasses the previous DSM-IV autistic disorder (autism), Aspergers disorder, childhood disintegrative disorder, and PDD NOS. 1) deficits in social interaction and communication 2) restricted repetitive behaviors, interests, and activities (RRBs). Social Communication Disorder is diagnosed if no restricted repetitive behaviors are present.

What are the Core Symptoms Autism?

Socialization impairment i.e. eye

to eye gaze, trouble sharing joy and interests with others. Communication impairment language delay and echolalia.

Top 25 Behavior Problems Rated as Moderate of Severe in PDD (n=487)

1 2 3 4 5 6 7 8 9 10 11 12 13 Easily frustrated Easily distracted Short attention span Stubborn Difficulty concentration High energy level Fidgety Overactive Repeats over and over Isolates self Overly sensitive Fails to finish things Repeatedly flaps Parent Teacher 62% 54% 60% 60% 54% 47% 51% 44% 49% 50% 44% 30% 42% 44% 41% 29% 41% 25% 36% 36% 32% 22% 31% 27% 31% 26%

Top 25 Behavior Problems Rated as Moderate of Severe in PDD (n=487)

Current Standard of Care

Applied Behavioral Analysis (ABA)

Dawson, G. Randomized Control Trial of an Intervention with Toddlers with Autism: The Early Start Denver Model. Pediatrics 2010; 125;e17 DOI:10.1542/peds.2009

derived therapies to improve overall functioning. Increase in IQ of 17.6 points, bulk due to gains in receptive and expressive language. ABA group able to keep pace with normative population in adaptive behavior, whereas the control group continued to fall behind.

Current Standard of Care

Applied Behavioral Analysis (ABA)

allowed more children to shed the diagnosis of Autistic Disorder and progress to PDD NOS. In 2011 systemic review of 34 major studies revealed no dramatic gains in functioning.
Dawson, G. Randomized Control Trial of an Intervention with Toddlers with Autism: The Early Start Denver Model. Pediatrics 2010; 125;e17 DOI:10.1542/peds.2009

Aggression and Irritability

Risperidone is a first line medication,

FDA approved for management of aggression in patients with ASD. Effect size for aggression in ASD as high as 1.2. Response was defined as 50% reduction in irritability on Aberrant Behavior Checklist. 69% subjects responded on risperidone compared to 16% placebo. Research Units in Pediatric Psychopharmacology Autism Network . 2002. Risperidone in
children with autism and serious behavioral problems. New Engl. J. Med. 347:314 321.

ADHD Symptoms
Methylphenidate used as first line in

autism population though not as effective as for children without ASD. Clonidine and guanfacine are acceptable first line agents for hyperactivity in ASD population.

Treating Comorbid Conditions

Case reports that diagnosis and

treatment of Bipolar Disorder improved social reciprocity. Symptoms of Bipolar Disorder in ASD population do respond to appropriate treatments such as Lithium and Valproic acid.

Core Social Impairment

Isolates self and Socially Withdrawn

Some individuals may have little or

no interest in establishing friendships. Echolalia is a common problem. Difficulty with conversational or pragmatic language.

Challenges to Drug Development

While Autism is highly heritable, its

basic pathophysiology is still poorly understood. Lack of reproducible neurobiological findings. Phenotypic heterogeneity. Moving developmental target.

Risperidone
Some families reported

improvement in social interaction. Canadian study of 79 children with a mean age of 7.5 years on 8 weeks of risperidone showed that social withdrawal decreased by 63% compared with 40% in the placebo group.

Risperidone
Risperidone may have modest

benefits for reducing social withdrawal, repetitive language in children with PDD exhibiting high levels of baseline irritability. It is unclear whether risperidone improves these symptoms in the absence of irritability.
Research Units in Pediatric Psychopharmacology Autism Network . 2002. Risperidone in children with autism and serious behavioral problems. New Engl. J. Med. 347:314 321.

Other Atypical Antipsychotics

Olanzapine effective when

disruptive behavior and irritability was an entry criterion, but response took 3 months when it was not. Excessive weight gain was prominent in all four studies. Aripiprazole, quetiapine and ziprasidone have only open labeled studies. Placebo controlled trials

Presentation Outline
Autism Terminology Challenges to Drug Development Risperidone indirectly improves

social impairment in Autism Lessons from failed trials of Fenfluramine, Naltrexone and Secretin Ongoing research involving SSRIs, cholinergic drugs, glutmatergic agents and oxytocin.

Drugs Not Effective for Social and Communication Impairment

Fenfluramine decreases 5-HT

blood levels. Naltrexone may be good for self injurious behaviors by decreasing endorphin modulated perpetuation. Secretin - one of the best studied treatment for autism following a well publicized case report.

Selective Serotonin Reuptake Inhibitors

12 week double blind study of

adults with autism, Fluvoxamine 8 out of 15 treated subjects were rated as responders. However, study in 34 children only 1 of 18 subjects treated were responders. High rate of adverse events including insomnia, hyperactivity,

Selective Serotonin Reuptake Inhibitors Hollander et al. administered fluoxetine to 39 children (mean age of 8.2 years) during a 20 week (8 weeks on drug) placebo controlled cross over study. Maximal target dose of 2.4 to 20mg /day. Fluoxetine was significantly better than placebo for reducing repetitive behaviors.

Selective Serotonin Reuptake Inhibitors

There was NO improvement on

measures of speech or social interaction. Other studies demonstrated improvements most commonly reported in symptoms of anxiety, mood disturbance, aggression and repetitive behavior, but NOT in social or language impairment.

Cholinesterase Inhibitors
Donepezil (Aricept) had some

reports of improvement with receptive and expressive language. Subsequent double blind placebo trials showed improvement on ABC ratings of irritability and hyperactivity, but not social withdrawal, inappropriate speech, or stereotypy.

Glutamatergic drugs
D-Cycloserine initially investigated

for the negative symptoms of schizophrenia. A statistically significant improvement was seen on the ABC Social Withdrawal subscale. Awaiting replication.

Glutamatergic drugs
Memantine (Namenda )is FDA

approved for treatment of Alzheimers. 151 patients with PDDS. Improvement on the CGI-I scale for language was noted in 70% of study participants. Adverse effects most common were increased irritability and worsening behaviors.

Oxytocin
Hollander et al. infused synthetic

oxytocin in to 15 adults with ASD during a comprehension task to identify the affect (happy, indifferent, angry and sad) of an audiotapped speaker making neutral statements. Those receiving oxytocin first maintained improvement at the time of the next baseline assessment.

Summary
Risperidone - indirectly improves

social impairment in Autism, likely through improvement in aggression and irritability. Standard dose: 0.5 mg to 3.5 mg per day. Fenfluramine, Naltrexone and Secretin are not effective after through investigation.

Summary
SSRIs Fluoxetine demonstrated

marginal decrease in repetitive behaviors and no significant side effects. Mean dose 9.9 mg per day. Cholinesterase Inhibitor - Donepezil showed improvement in ABC ratings of irritability and hyperactivity, but not social withdrawal.

Summary
Glutamatergic agent Memantine

demonstrated improvement on the CGI-I scale for language was noted in 70% of study participants. Oxytocin IV infusion demonstrated improvement in affective speech comprehension.