ASD Usually Syndromal Autism Spectrum Disorder Pediatric Onset - - PowerPoint PPT Presentation

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ASD Usually Syndromal Autism Spectrum Disorder Pediatric Onset - - PowerPoint PPT Presentation

Oct 18, 2022 203 likes •364 views

D ISCLOSURE of I NTERESTS Psychopharmacology and Bennett L. Leventhal, MD Autism Spectrum Disorder Sources of Research Support Stock and Investments Bennett L. Leventhal, MD NIH Sadly, no Professor Simons Foundation

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SLIDE 1

Psychopharmacology

and

Autism Spectrum Disorder

Bennett L. Leventhal, MD Professor Department of Psychiatry University of California, San Francisco

Developmental Disabilities: Update for Health Professionals UCSF San Francisco, CA 3 March 2017

STAR.ucsf.edu

DISCLOSURE of INTERESTS

Bennett L. Leventhal, MD

Sources of Research Support NIH Simons Foundation Janssen - ended Roche - ended Speaker Bureaus None Consulting Relationships Janssen/J&J Off Label Meds Yes, of course Stock and Investments Sadly, no Other Financial Interests Regrettably, none Family Financial Interest All my children are employed Honorarium No Travel Too much; no conflict

ASD Autism Spectrum Disorder

The Paradigmatic Neurodevelopmental Disorder

What is a Neurodevelopmental Disorder?(1)

–Usually Syndromal –Pediatric Onset –Affecting Brain Function –Clinical Effects on

  • Emotion
  • Cognition
  • Behavior
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SLIDE 2

What is a Neurodevelopmental Disorder? (3)

1. Intellectual Disability (ID) (Intellectual Development Disorder) 2. Global Development Delay 3. Unspecified Intellectual Disability (Intellectual Developmental Disorder)

  • 4. Language Disorder
  • 5. Speech Sound Disorder
  • 6. Childhood-Onset Fluency Disorder

(Stuttering)

  • 7. Social Pragmatic Communication

Disorder (SCD)

  • 8. Unspecified Communication Disorder

9. Autism Spectrum Disorder(ASD)

  • 10. Attention Deficit Hyperactivity Disorder

(ADHD) 11. Other Specified Attention-Deficit Hyperactivity Disorder 12. Unspecified Attention-Deficit Hyperactivity Disorder 13. Specific Learning Disorder 14. Developmental Coordination Disorder 15. Stereotypic Movement Disorder 16. Tic Disorder 17. Other Specified Tic Disorder 18. Unspecified Tic Disorder 19. Other Specified Neurodevelopmental Disorder 20. Unspecified Neurodevelopmental Disorder

per DSM5

What is a Neurodevelopmental Disorder?

(4)

Consider Other Neurodevelopmental Disorders:

OCD Eating Disorders Mood Disorders

Bipolar Disorder Major Depressive Disorder

Substance Abuse Schizophrenia Trauma related disorders Epilepsy Alzheimer’s Disease

Autism/ASD – A syndrome

  • Syndrome

– Group of symptoms that tend to cluster together and share a common natural history/course

  • Disease

– A syndrome for which there is:

  • A known etiology (or cause)
  • A known pathophysiological process
  • Both
  • ASD is not so unusual because:

– Like the most medical conditions, ASD is a syndrome

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SLIDE 3

New Yorker 12/27/93 Oliver Sacks. Anthropologist from Mars

Leo Kanner

(1894-1981)

“Autistic Disturbances of Affective Contact” The Nervous Child, 1943

Wild Boy of Aveyron Jean Marc Gaspard Itard (1774-1838) (1801 Memoire, 1806 Rapport Sur Victor de l’Aveyron)

DSM 5: ASD

  • A. Persistent deficits in social communication

and social interaction across contexts, not accounted for by general developmental delays

  • B. Restricted, repetitive patterns of behavior,

interests, or activities

  • C. Symptoms must be present in early

childhood

  • D. Symptoms together limit and impair

everyday functioning.

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SLIDE 4

DSM 5 Social Communication Disorder

  • A. Social Communication Disorder (SCD)is

– an impairment of pragmatics – diagnosed based on difficulty in the social uses of verbal and nonverbal communication

  • B. Low social communication abilities

– result in functional limitations

  • C. Rule out Autism Spectrum Disorder
  • D. Symptoms must be present in early childhood

Autism Spectrum Disorders (ASD)

  • A Syndrome
  • The 2 “D’s” = Delay & Deviations
  • Domains of Impairment

a. Social Development

  • Joint Attention
  • Theory of Mind
  • Reciprocity

b. Communication Development c. Restricted/Repetitive & Stereotyped Patterns of Interests and Activities (including IS)

Autism & Autistic Spectrum Disorders (ASD)

  • Course
  • a. Consistent over time
  • b. Some symptoms decrease

a. Stereotypies b. Visual regard

c. Some symptoms persist

  • Lack of social reciprocity
  • Language abnormalities
  • Restrictive and repetitive behaviors/IS

What are the Spectra or Axes in Autism Spectrum Disorders (ASD)?

Poor/No Language Fluent Language Few Autism Symptoms Many Autism Symptoms Good Social Skills Lower Cognitive Function Poor Social Skills Higher Cognitive Function

ASD

HIGH Functioning> > > > > > > > > > > > > > > > > > > > > > > > > > > LOW Functioning

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SLIDE 5

Autism Etiology What Causes ASD?

  • Chromosomal (syndromic)

– fragile- X syndrome, tuberous sclerosis

  • Genetic - increased risk in twins, siblings

– small chromosomal deletions or duplications (i.e., copy number variation or CNV.)

  • Structural Brain Disruption

– anatomic, cellular

  • Others

– Environmental/toxic – Immunologic – gastrointestinal, – etc

Appropriate Assessment is the Starting Point for Treatment

  • f

Autism

Sources of Informatiom

  • Screening
  • Clinical Interview

– History – Direct Observation

  • Standard Diagnostics

– ADI – ADOS – CARS

  • Adaptive Function

– Vineland – ABC

  • Physical Examination

– Neurological – Sensory Exam

  • Laboratory

– Only as indicated

Factors That Predict Autism Outcome

  • 1. Expressive Language
  • Communicative speech by age 5
  • 2. Language Comprehension
  • Spoken language by age 5
  • 3. Intellectual Capacity
  • Non-verbal intelligence
  • 4. Adaptive Function
  • 5. Severity of Autism symptoms
  • a. Social deficits
  • b. Restricted, Repetitive Behaviors
  • c. Aggression
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SLIDE 6

Environmental Interventions:

How Early? How Often?

  • Speech & Language Therapy
  • Educational Programming
  • Behavior Therapy

– ABA – DTT – Pivotal Response Training – ESDM

  • Family Interventions

– Education – Parent Training

  • Individual Psychotherapy
  • Pharmacotherapy

RRB’s Restrictive and Repetitive Behaviors

  • 1. Stereotypies
  • 2. Insistence on sameness
  • 3. “Stimming”
  • 4. Habits
  • 5. Tics

SSRI’s Serotonin Reuptake Inhibitors*

  • fluoxetine (Prozac)
  • sertraline (Zoloft)
  • paroxetine (Paxil)
  • fluvoxamine (Luvox)
  • citalopram (Celexa)
  • escitalopram (Lexapro)
  • clorimpramine (Anafranil)

*Note: FDA Warning about suicidality

Hollander, et al. Neuropsychopharm (2004) pp1-8

  • llander Fig 1-YBOCS Compulsion Score

CY-BOCS Compulsion Score

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SLIDE 7

Hollander, et al. Neuropsychopharm (2004) pp1-8

Hollander Fig 3 – CGI Global Improvement -Composite

CGI Global Improvement - Composite

Hollander, et al. Neuropsychopharm (2004) pp1-8

Symptom Fluoxetine Placebo Anxiety/Nervousness 15.9% [ 6/39] 33.3% [12/36] Insomnia 35.9% [14/39] 47.2% [16/36] Drowsiness/Fatigue/Sedation 17.9% [ 7/39] 11.1% [ 4/36] Agitation 46.2% [18/39] 44.4% [16/36] Diarrhea 5.1% [ 2/39] 19.4% [ 7/36] Anorexia 15.4% [ 6/39] 11.1% [ 4/36] URI 10.3% [ 4/39] 19.4% [ 7/36] Weight Gain 0% [ 0/39] 2.8% [ 1/36]

Fluoxetine/Placebo Side Effects

Aggression & Irritability

Traditional Neuroleptics

  • haloperidol (Haldol)
  • trifluoperazine (Stelazine)
  • fluphenazine (Prolixin)
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SLIDE 8

Atypical Neurolpeptics

  • clozapine (clozaril)
  • risperidone (Risperdal)*
  • olanzepine (Zyprexa)
  • quetiapine (Seroquel)
  • ziprasadone (Geodon)
  • aripiperazole (Abilify)*
  • Others

*FDA Approved for irritability in ASD

Primary Endpoint Analysis Aberrant Behavior Checklist - Irritability

LOCF analysis; *P<0.001 vs. PBO BL (RIS)=26.2 BL (PBO)=25.5 Week 8 (RIS)=11.3 Week 8 (PBO)=21.9

Risperidone (n=49) Placebo (n=52)

*

Time in Weeks 5 10 15 20 25 30 2 4 6 8 Mean ABC Irritability Total Score Improvement

* * *

RUPP Autism Network. N Engl J Med. 2002;347:314-321.

After 8 weeks of treatment, the risperidone group had a 56.9% improvement compared to a 14.1% improvement in the placebo group.

Mean Daily Dose at Week 8 RIS = 1.8 mg

Primary Endpoint Analysis Clinical Global Impression - Improvement

“Much Improved” or “Very Much Improved” on CGI-I by group

Time in Weeks risperidone (n=49) Placebo (n=52)

*P<0.001 vs. placebo at weeks 4 and 8 RUPP Autism Network. N Engl J Med. 2002;347:314-321.

10 20 30 40 50 60 70 80 90 1 2 3 4 5 6 7 8 Percentage of Subjects with CGI-I < 3 75.5% 11.5%

* *

Mean Daily Dose at Week 8 RIS= 1.8 mg

Secondary Endpoint Analysis Aberrant Behavior Checklist Subscales

Change in ABC-Subscale scores from baseline to endpoint

Stereotypy

10.6 9.0 5.8 7.3 2 4 6 8 10 12 Risperidone Placebo ABC-Stereotypy Score

P<0.001 vs placebo RUPP Autism Network. N Engl J Med. 2002;347:314-321.

Baseline 8-weeks

31.8 32.3 17.0 27.6 5 10 15 20 25 30 35 Risperidone Placebo ABC-Hyperactivity Score

Hyperactivity

P<0.001 vs placebo

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SLIDE 9

Change in ABC-Subscale scores from baseline to endpoint

*Scores for Social Withdrawal and Inappropriate Speech did not differ significantly from placebo after the Bonferroni correction (NS indicates not significant) RUPP Autism Network. N Engl J Med. 2002;347:314-321.

Baseline 8-weeks

4.8 6.5 3.0 5.9 1 2 3 4 5 6 7 Risperidone Placebo ABC-Inappropriate Speech Score

Inappropriate Speech

NS vs. placebo*

16.4 16.1 8.9 12.0 2 4 6 8 10 12 14 16 18 Risperidone Placebo ABC-Social Withdrawl Score

Social Withdrawal

NS vs. placebo*

RUPP Autism Secondary Endpoint Analysis Aberrant Behavior Checklist (ABC) Scales

RUPP Autism Study: Adverse Events

Adverse event risperidone n = 49 n (%) Placebo n = 52 n (%) P-value† Increased appetite Mild 24 (49) 13 (25) 0.03 Moderate 12 (24) 2 (4) 0.01 Fatigue 29 (59) 14 (27) 0.003 Drowsiness 24 (49) 6 (12) <0.001 Drooling 13 (27) 3 (6) 0.02 Tremor Dizziness Constipation Tachycardia 7 (14) 8 (16) 14 (29) 6 (12) 1 (2) 2 (4) 6 (12) 1 (2) 0.06 0.05 0.06 0.06 Weight gain in kg 2.7 ± 2.9 0.8 ± 2.2 <0.001

*

RUPP Autism Network. N Engl J Med. 2002;347:314-321.

Lithium Lithium Carbonate

propranolol

Inderal [β-adrenergic blocker]

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SLIDE 10

Attention Deficits

Stimulants

  • Amphetamines

– Dexedrine (DEX) – Methamphetamine – Adderall – Adderall XR – Vyvanse

  • Methylphenidates (MPH)

– Ritalin (and other short acting MPH) – Ritalin SR – Ritalin LA – Concerta – Focalin (dex MPH) – Metadate CD – Methylin ER – MPH patch – Quillivant XR (liquid)

Mean Parent & Teacher Rated ABC Hyperactivity Subscale Scores During Crossover & Open Label Phase

RUPP, Arch Gen Psychiatry, 62 (11) 1266-1274 (2005)

Non-Stimulant ADHD Treatments

  • Cylert (pemoline)
  • Tricyclic

Antidepressants

  • Atypical

Antidepressants – Buproprion

  • Welbutrin

– Venlafaxine

  • Effexor
  • SSRI’s
  • NE Agents

– Atomoxetine (Strattera)

  • Alpha Adrenergic

Agonists – Clonodine

  • Catapres
  • Kapvay

– Guanfacine

  • Tenex
  • Intuniv
  • Atypical Neuroleptics

– Risperdal – Zyprexa – Geodon

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SLIDE 11

Mood Disturbance Irritability

SSRI’s Serotonin Reuptake Inhibitors*

  • fluoxetine (Prozac)
  • sertraline (Zoloft)
  • paroxetine (Paxil)
  • fluvoxamine (Luvox)
  • citalopram (Celexa)
  • escitalopram (Lexapro)
  • clorimpramine (Anafranil)

*Note: FDA Warning about suicidality

Anticonvulsants (mood stabilizers)

  • valproate (Depakote)
  • carbamazepine (Tegretol)
  • lamotragine (Lamictal)
  • neurotonin (Neurontin)
  • gabapentin (Gabatril)
  • Others

Anxiety

  • 1. Anti-anxiety medications
  • Benzodiazepines
  • 2. SSRI’s*

fluoxetine (Prozac) sertraline (Zoloft) paroxetine (Paxil) fluvoxamine (Luvox) citalopram (Celexa) escitalopram (Lexapro) clorimpramine (Anafranil)

*Note: FDA Warning about suicidality

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SLIDE 12

New Medications

  • GABA – active agents
  • mGluR5 agonists and antagonists
  • Oxytocin
  • Vasopressin 1A antogonist
  • Others directed at evolving biology

Cognitive Enhancers?

Arricept (donepezil) Exelon (rivastigmine) Namenda (memantine) Reminyl (galantamine)

Complementary and Alternative/ Integrative Treatments - “Off-label”

  • Sleep supplements (e.g., melatonin)
  • Diets (e.g., gluten free/casein free)
  • Supplements (e.g., omega 3 fatty acids)
  • Vitamins (e.g., B6 and magnesium)
  • Allergies (e.g., lactose)
  • Anti-oxidants (e.g.,Vit E)
  • Neurotransmission Modulators (e.g., NAC)

Other Proposed Treatments

  • Vitamins
  • Minerals
  • Dietary Supplements
  • Dietary Restrictions
  • Sugar
  • Food Dyes
  • Chelation
  • Secretin
  • Steroids
  • Eye Tracking
  • Sensory Diets
  • Facilitated

Communication

  • Floor Time
  • ?
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SLIDE 13

10 20 30 40 50 60 70 80 90 100 2 4 6 8 Week Score

Secretin-Placebo ABC-C Placebo-Secretin ABC-C

Placebo Secretin Placebo Secretin

CHELATION

[The Removal of Heavy Metals]

  • Benefits
  • Removes toxic heavy metals, when present
  • Measured in blood, tissue, X-Ray
  • NOT measured in hair
  • E.g., lead, strontium
  • Risks
  • Chelating chemicals are toxic themselves
  • → Sickness & Death
  • Takes a long time
  • Remove toxin but likely will not reverse neural

damage

Change in the mean item score on the Children’s Psychiatric Rating Scale-14 (CPRS-14) with risperidone. Each line represents an individual child’s score from baseline to the end of short-term treatment.

Malone et al. JAACAP, 41:(2):140-47.February 2002

All Medications have Side Effects

A special problem in treating ASD

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SLIDE 14

Just because a small amount of medication works well, it does not mean that a lot will work better

Another special problem in treating ASD

Most children with ASD get better

  • ver time!

Our goals are: Search for etiologies that can be used to Enhance treatment Prevent ASD In the meantime: Use treatments that help individuals with ASD:

  • Acquire skills
  • Improve ability to use those skills
  • Move toward independent and semi-independent

living

QUESTIONS?

THANK YOU

Psychopharmacology

and

Autism Spectrum Disorder

Bennett L. Leventhal, MD Professor Department of Psychiatry University of California, San Francisco

Developmental Disabilities: Update for Health Professionals UCSF San Francisco, CA 3 March 2017

STAR.ucsf.edu