Master Slide
Current Trends in the
Pharmacological Treatment of Autism
Alexander Kolevzon, MD
Peter Della Bella, MD
David Grodberg, MD
Charles Cartwright, MD
Symptom Domains and
Associated Features of ASD
Social
Phobia
ADHD
Symptoms
Social
Impairment
Asperger’s
syndrome
AUTISM
Speech/
Repetitive
Communication
Behaviors
Deficits
Expressive/Receptive
Language Disorders
EEG
Abnormalities
Impulsivity/
Aggression
Obsessive
Compulsive
Disorder
Treating Agitation and
Aggression
in People with ASDs
Peter Della Bella, MD
Director of Clinical Programs
Premier HealthCare
ADHD Symptoms and Autism
Spectrum Disorders:
Co-Occurrence,
Phenomenology, and
Treatment
David Grodberg, M.D.
Seaver Autism Center
The Treatment of Anxiety
and Repetitive Behaviors in
Autism Spectrum Disorders
Alex Kolevzon, M.D.
Clinical Director, Seaver Autism Center
Future Directions
Targeting
Novel Neurotransmitter and
Hormonal Systems
In Autism
Charles Cartwright, MD
Director, YAI Autism Center
Master Slide
Agitation and Aggression
Peter Della Bella, MD
What is Agitation?
An inability to cope
causing distress…
and losing control
Precursors: Irritability, anxiety, fatigue…
The worry: add a trigger and…
What is Aggression?
(Latin) Attack
Premeditated vs. loss of impulse control
Understanding the Roots of
Agitation and Aggression
Roots of Irritability & Agitation
- the Fight or Flight Response
Sources: Babble.com; Brain-trainer.com; quantumlearningblog
Roots of Agitation and Aggression
ATTACK
loss of
control
agitated
irritated
calm
coping
Roots of Agitation and Aggression
• Survival instinct
(“Boxed into a corner”)
• Pain/physical discomfort
(sensory integration)
• Psychic discomfort
(stress, change, frustration)
Roots of Agitation and Aggression
ATTACK
agitated
irritated
calm
Roots of Agitation and Aggression
stress, discomfort, pain
ATTACK
agitated
c a l m / irritated
Roots of Agitation and Aggression
stress, discomfort, pain
ATTACK
agitated
c a l m / irritated
cultural, behavioral, “medical” factors
What do you do?
• Survival instinct…….. take care of the threat
• Treat sources of physical discomfort, side effects… proper
medical evaluation
sensory
integration principles
• Treat sources of psychic discomfort…..
soften the blow of change
address stress (sleep, food, downtime, fun)
Roots of Agitation and Aggression
ATTACK
agitated
Irritated
calm
When do you use meds?
• When there are underlying biological factors.
Let the
symptoms guide you!
•
•
•
•
•
Anxiety Disorder
Depression
ADHD
Psychosis
Seizure
• Otherwise, MEDICATION IS A LAST RESORT
FDA approved for autism…
So what do we use?
Antipsychotics
Risperidone, aripiprazole
Olanzapine
Quetiapine
Chlorpromazine
Haloperidol
Thioridazine
Clozapine
Anti-Fight or Flight
Meds
Clonidine
Guanfacine
Beta-blockers:
propranolol
Anti-epileptics
& Mood Stabilizer
Valproate
Carbamazepine
Oxcarbazepine
Lithium
Anti-anxiety
Benzodiazepines:
Clonazepam
Lorazepam
Diazepam
Buspirone
SSRIs:
Fluoxetine
Paroxetine
Sertraline
Fluvoxamine
Citalopram/
Escitalopram
What are the pros and cons
of using medications?
Master Slide
Attention Deficit and Hyperactivity
David Grodberg, MD
ADHD SYMPTOMS IN ASD
• DSM-IV TR prohibits diagnosis of ADHD and ASD in the same
individual
• Clinic based surveys indicate that Sx c/w ADHD present in 4178% of children with ASD
ADHD SYMPTOMS IN ASD
• Asperger’s Disorder, PDD-NOS who meet full criteria for
ADHD
• Autistic Disorder with ADHD-like symptoms, which are part of
core features of autism
• Autistic Disorder with increased motor activity, impulsivity,
inattention
ADHD SYMPTOMS IN ASD
• Inattention to social stimuli but good sustained focus on
interests or objects. NOT ADHD.
• Hyperactivity as a manifestation of motor stereotypy, social
anxiety, agitation, or medication side effects. NOT ADHD
TREATMENT OF ADHD
SYMPTOMS IN ASD
• Strongest evidence: methylphenidate
– 2 placebo-controlled trials
– retrospective and prospective effectiveness
study
Methylphenidate
Increases NE and DA by blocking reuptake
Methylphenidate
ASD+ADHD tolerated stimulants generally well
ASD+ADHD had dysphoria and obsessionality
- initiate methylphenidate in ASD at lower dose
and increase dose slowly with frequent
monitoring for side effects
TREATMENT OF ADHD
SYMPTOMS IN ASD
• Moderate Level Evidence: guanfacine
– chart review study
– small open-label trial
• Moderate Level Evidence: atomoxetine
– small open label study
– small placebo controlled study
Guanfacine
Alpha 2A agonist. Enhances prefrontal cortical function
Atomoxetine
Increases NE and DA in prefrontal cortex.
TREATMENT OF ADHD
SYMPTOMS IN ASD
• Weak Support: clonidine, donepezil
– very small studies
Clonidine
Nonselective alpha2 agonist. More sedating/hypotensive.
Donepezil
Acetyl Cholinesterase inhibitor
SUMMARY
• Children with ADHD symptoms and ASD are
difficult to treat
• stimulants (methylphenidate), atomoxetine,
alpha-agonists are effective
• SSRIs and atypical neuroleptics are used to
address other types of symptoms
CLINICAL PEARLS
• If a child with ADHD is referred with poor response to
meds and/or significant side effects (anxiety, stereotypy,
aggression) - look for evidence of previously unrecognized ASD
• If a stimulant is helpful but side effects of anxiety emerge,
can switch to atomoxetine or add SSRI.
• Monitor closely for behavioral disinhibition
– hyperactivity, impulsivity, new odd/disorganized behavior, SI.
Master Slide
Anxiety and Repetitive Behaviors
Alexander Kolevzon, MD
Repetitive Behaviors
A preoccupation with stereotyped and restricted
patterns of interest
Inflexibility in adhering to routines and rituals
Stereotyped and repetitive motor mannerisms
Persistent preoccupation with parts of objects
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)
Repetitive Behaviors
Lower Order (motor/sensory) Higher Order (compulsive)
Repetitive self-injury
Motor stereotypies
Sniffing/mouthing objects
Touching
Tapping
Rubbing
Insistence on sameness
Ritualistic behavior
Circumscribed interests &
preoccupation
Repetitive Behaviors
Lower Order (motor/sensory) Higher Order (compulsive)
Hoarding
Obsessions
Anagnostou et al, 2005
Serotonin System
Critical to neurodevelopment
Directs neuronal growth,
proliferation, differentiation
Widely expressed in
emotional centers of
brain
Emotional Center of Brain
Serotonin Pathways
Serotonin System in Autism
Figure 1.
Developmental Patterns of Serotonin Synthesis
Rate of 5HT synthesis
0.016
0.014
Controls
0.012
Autistic
0.01
0.008
0.006
0.004
0.002
0
1
3
5
Based on Chugani et al., 1999
7
9
11 13
Age, years
15
17
19
Serotonin Reuptake Inhibitors
Serotonergic Medications
Serotonergic Medications
Medication
Open Label
Controlled
fluoxetine
++++
+ + --
fluvoxamine
+
+ + --
sertraline
+++
citalopram
+
escitalopram
+
venlafaxine
++
clomipramine
buspirone
--
+
++
Study of Fluoxetine in
Autism (SOFIA)
N=158
Atypical Antipsychotics Risperidone
McDougle et al, 2005
Atypical Antipsychotics – Abilify
Marcus et al, 2009
Novel Therapeutics - Oxytocin
Widely distributed in Central Nervous System;
especially emotional centers
Peripheral release is important for delivery and
lactation
Central release is important for social cognition
(recognition and memory); trust; social
attachment; maternal bonding
IV Oxytocin Challenge
 need to know
 repeating
 ordering
 need to tell
 self-injury
 touching
Hollander et al, 2003
Master Slide
Future Directions
Charles Cartwright, MD
All Treatments Discussed are Off
Label and do not have FDA Approval
for the Treatment of Autism
The Glutamate System
Machado-Vieira et al, 2009
Glutamate Modulating Treatments
D-Cycloserine
D-Cycloserine in the Treatment of Autism
Posey et al, 2004
Riluzole
Riluzole in the Treatment of OCD
Coric et al, 2005
N-acetylcysteine
N-acetylcysteine in the Treatment of
Trichotillomania
Grant et al, 2009
Treatments that involve Hormones
Oxytocin
Andari et al, 2010
Caution
Demonstrate Safety and Efficacy
Master Slide
THANK YOU