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 Impairment Repetitive Behaviors Speech/ Communication Deficits Social Phobia Asperger’s syndrome Obsessive Compulsive Disorder AUTISM Impulsivity/ Aggression Expressive/Receptive Language Disorders EEG Abnormalities ADHD Symptoms

Peter Della Bella, MD Director of Clinical Programs Premier HealthCare Treating Agitation and Aggression in People with ASDs

ADHD Symptoms and Autism Spectrum Disorders: Co-Occurrence, Phenomenology, and Treatment David Grodberg, M.D David Grodberg, M.D. Seaver Autism Center

The Treatment of Anxiety and Repetitive Behaviors in Autism Spectrum Disorders Alex Kolevzon, M.D 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 irritated c a l m agitated ATTACK coping loss of control

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 irritated c a l m agitated ATTACK

Roots of Agitation and Aggression c a l m / irritated agitated ATTACK stress, discomfort, pain

Roots of Agitation and Aggression c a l m / irritated agitated ATTACK stress, discomfort, pain 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 Irritated c a l m agitated ATTACK

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 ValproateCarbamazepine Oxcarbazepine Lithium Anti-anxiety Benzodiazepines: Clonazepam Lorazepam Diazepam BuspironeSSRIs: 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 % 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) Repetitive self-injury Motor stereotypies Sniffing/mouthing objects Touching Tapping Rubbing Higher Order (compulsive) Insistence on sameness Ritualistic behavior Circumscribed interests & preoccupation

Repetitive Behaviors Lower Order (motor/sensory) Hoarding Higher Order (compulsive) 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

Serotonin Reuptake Inhibitors

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