pharmacologic interventions for core social and communication impairment in autism

7/28/2019 Pharmacologic Interventions for Core Social and Communication Impairment in Autism

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Betty Lau, MD

Child and Adolescent Psychiatry Fellow

Pharmacologic Interventions for CoreSocial and Communication Impairment

in Autism


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Presentation Outline

Autism TerminologyChallenges to Drug DevelopmentRisperidone indirectly improves

social impairment in AutismLessons from failed trials of

Fenfluramine, Naltrexone andSecretin

Ongoing research involving SSRIs,cholinergic drugs, glutmatergicagents and oxytocin.


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What is Autism?

Autism Spectrum Disorders are agroup of neurodevelopmentaldisorders that affect a childs social

skills, communication skills andhas characteristic repetitivebehaviors, interests, and activities.

Persist throughout the lifespan of

affected individuals.


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Autism Video

Towle, P. Autism Spectrum

Disorder in Young Children: A Visual

Guide. Westchester Institute for

Human Development.


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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]


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DSM IV


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What about DSM-V?

Autism Spectrum Disordernowencompasses the previous DSM-IV autisticdisorder (autism), Aspergers disorder,

childhood disintegrative disorder, and PDDNOS. 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 arepresent.


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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.


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Top 25 Behavior Problems Rated as

Moderate of Severe in PDD (n=487)Parent Teacher

1 Easily frustrated 62% 54%

2 Easily distracted 60% 60%

3 Short attention span 54% 47%

4 Stubborn 51% 44%

5 Difficulty concentration 49% 50%

6 High energy level 44% 30%

7 Fidgety 42% 44%

8 Overactive 41% 29%

9 Repeats over and over 41% 25%10 Isolates self 36% 36%

11 Overly sensitive 32% 22%

12 Fails to finish things 31% 27%

13 Repeatedly flaps 31% 26%


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Top 25 Behavior Problems Rated as

Moderate of Severe in PDD (n=487)


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Current Standard of Care

Applied Behavioral Analysis (ABA)derived therapies to improve overallfunctioning.

Increase in IQ of 17.6 points, bulk dueto gains in receptive and expressivelanguage.

ABA group able to keep pace withnormative population in adaptivebehavior, whereas the control groupcontinued to fall behind.

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


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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 gainsin 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


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Aggression and Irritability

Risperidone is a first line medication,FDA approved for management ofaggression in patients with ASD.

Effect size for aggression in ASD ashigh 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.


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ADHD Symptoms

Methylphenidate used as first line inautism population though not as

effective as for children without

ASD.

Clonidine and guanfacine are

acceptable first line agents forhyperactivity in ASD population.


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Treating Comorbid Conditions

Case reports that diagnosis andtreatment of Bipolar Disorder

improved social reciprocity.

Symptoms of Bipolar Disorder in

ASD population do respond to

appropriate treatments such asLithium and Valproic acid.


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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 orpragmatic language.


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Challenges to Drug Development

While Autism is highly heritable, itsbasic pathophysiology is still poorly

understood.

Lack of reproducible neurobiological

findings.

Phenotypic heterogeneity.Moving developmental target.


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Risperidone

Some families reportedimprovement in social interaction.

Canadian study of 79 children with

a mean age of 7.5 years on 8weeks of risperidone showed thatsocial withdrawal decreased by

63% compared with 40% in theplacebo group.


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Risperidone

Risperidone may have modestbenefits for reducing social

withdrawal, repetitive language in

children with PDD exhibiting high

levels of baseline irritability.

It is unclear whether risperidoneimproves 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.


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Other Atypical Antipsychotics

Olanzapine effective whendisruptive 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


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Presentation Outline

Autism TerminologyChallenges to Drug DevelopmentRisperidone indirectly improves

social impairment in AutismLessons from failed trials of

Fenfluramine, Naltrexone andSecretin

Ongoing research involving SSRIs,cholinergic drugs, glutmatergicagents and oxytocin.


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Drugs Not Effective for Social and

Communication Impairment

Fenfluramine decreases 5-HTblood levels.

Naltrexone may be good for self

injurious behaviors by decreasing

endorphin modulated perpetuation.

Secretin - one of the best studiedtreatment for autism following a well

publicized case report.


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Selective Serotonin Reuptake

Inhibitors

12 week double blind study ofadults 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,


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Inhibitors

Hollander et al. administeredfluoxetine to 39 children (mean ageof 8.2 years) during a 20 week (8

weeks on drug) placebo controlledcross over study.

Maximal target dose of 2.4 to 20mg

/day.Fluoxetine was significantly better

than placebo for reducing repetitive

behaviors.


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Inhibitors

There was NO improvement onmeasures 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.


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Cholinesterase Inhibitors

Donepezil (Aricept) had somereports 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.


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Glutamatergic drugs

D-Cycloserine initially investigatedfor the negative symptoms of

schizophrenia.

A statistically significant

improvement was seen on the ABC

Social Withdrawal subscale.

Awaiting replication.


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Oxytocin

Hollander et al. infused syntheticoxytocin 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 firstmaintained improvement at the time

of the next baseline assessment.


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Summary

Risperidone - indirectly improvessocial impairment in Autism, likelythrough improvement in aggression

and irritability. Standard dose: 0.5mg to 3.5 mg per day.

Fenfluramine, Naltrexone and

Secretin are not effective afterthrough investigation.


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Summary

SSRIs Fluoxetine demonstratedmarginal 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.


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Summary

Glutamatergic agent Memantinedemonstrated improvement on the

CGI-I scale for language was noted

in 70% of study participants.

Oxytocin IV infusion

demonstrated improvement in

affective speech comprehension.


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pharmacologic interventions for core social and communication impairment in autism

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