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 Department of Psychiatry � Janssen - ended � Other Financial Interests � Roche - ended � Regrettably, none University of California, San Francisco � Speaker Bureaus � Family Financial Interest � None � All my children are employed � Consulting Relationships � Honorarium � Janssen/J&J � No STAR.ucsf.edu � Off Label Meds Developmental Disabilities: Update for Health Professionals � Travel � Yes, of course UCSF San Francisco, CA � Too much; no conflict 3 March 2017 What is a Neurodevelopmental Disorder? (1) ASD – Usually Syndromal Autism Spectrum Disorder – Pediatric Onset – Affecting Brain Function The Paradigmatic – Clinical Effects on Neurodevelopmental Disorder • Emotion • Cognition • Behavior
What is a What is a Neurodevelopmental Disorder? (3) Neurodevelopmental Disorder? (4) per DSM5 Consider Other Neurodevelopmental Disorders: 1. Intellectual Disability (ID) � OCD 11. Other Specified Attention-Deficit (Intellectual Development Disorder) Hyperactivity Disorder � Eating Disorders 2. Global Development Delay 12. Unspecified Attention-Deficit � Mood Disorders 3. Unspecified Intellectual Disability Hyperactivity Disorder � Bipolar Disorder (Intellectual Developmental Disorder) 13. Specific Learning Disorder 4. Language Disorder � Major Depressive Disorder 14. Developmental Coordination Disorder 5. Speech Sound Disorder 15. Stereotypic Movement Disorder � Substance Abuse 6. Childhood-Onset Fluency Disorder 16. Tic Disorder � Schizophrenia (Stuttering) 17. Other Specified Tic Disorder � Trauma related disorders 7. Social Pragmatic Communication 18. Unspecified Tic Disorder Disorder (SCD) � Epilepsy 19. Other Specified Neurodevelopmental 8. Unspecified Communication Disorder Disorder � Alzheimer’s Disease 9. Autism Spectrum Disorder(ASD) 20. Unspecified Neurodevelopmental Disorder 10. Attention Deficit Hyperactivity Disorder (ADHD) 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
Leo Kanner (1894-1981) “Autistic Disturbances of Affective Contact” The Nervous Child , 1943 New Yorker 12/27/93 Oliver Sacks. Anthropologist from Mars 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 Wild Boy of Aveyron Jean Marc Gaspard Itard (1774-1838) everyday functioning. (1801 Memoire , 1806 Rapport Sur Victor de l’Aveyron)
DSM 5 Social Communication Disorder Autism Spectrum Disorders (ASD) A. Social Communication Disorder (SCD)is an impairment of pragmatics – � A Syndrome – diagnosed based on difficulty in the social uses of verbal and nonverbal communication � The 2 “D’s” = Delay & Deviations B. Low social communication abilities � Domains of Impairment – result in functional limitations a. Social Development • C. Rule out Autism Spectrum Disorder Joint Attention • Theory of Mind • D. Symptoms must be present in early childhood Reciprocity b. Communication Development c. Restricted/Repetitive & Stereotyped Patterns of Interests and Activities (including IS) What are the Spectra or Axes Autism & Autistic Spectrum Disorders in Autism Spectrum Disorders (ASD)? (ASD) Few Autism Symptoms Lower Cognitive Function • Course a. Consistent over time b. Some symptoms decrease Fluent Language Poor Social Skills a. Stereotypies b. Visual regard ASD c. Some symptoms persist Good Social Skills Poor/No Language - Lack of social reciprocity - Language abnormalities - Restrictive and repetitive behaviors/IS Higher Cognitive Function Many Autism Symptoms HIGH Functioning> > > > > > > > > > > > > > > > > > > > > > > > > > > LOW Functioning
Autism Etiology Appropriate Assessment What Causes ASD? is the • Chromosomal (syndromic) – fragile- X syndrome, tuberous sclerosis Starting Point for Treatment • Genetic - increased risk in twins, siblings – small chromosomal deletions or duplications (i.e., copy number variation or CNV.) of • Structural Brain Disruption – anatomic, cellular Autism • Others – Environmental/toxic – Immunologic – gastrointestinal, – etc Factors That Predict Autism Outcome Sources of Informatiom 1. Expressive Language • Screening • Adaptive Function - Communicative speech by age 5 • Clinical Interview – Vineland 2. Language Comprehension – ABC – History - Spoken language by age 5 • Physical Examination – Direct Observation 3. Intellectual Capacity – Neurological • Standard Diagnostics - Non-verbal intelligence – Sensory Exam – ADI 4. Adaptive Function • Laboratory – ADOS 5. Severity of Autism symptoms – CARS – Only as indicated a. Social deficits b. Restricted, Repetitive Behaviors c. Aggression
Environmental Interventions: RRB’s How Early? How Often? Restrictive and Repetitive • Speech & Language Therapy • Educational Programming Behaviors • Behavior Therapy 1. Stereotypies – ABA – DTT 2. Insistence on sameness – Pivotal Response Training – ESDM • Family Interventions 3. “Stimming” – Education – Parent Training 4. Habits • Individual Psychotherapy • Pharmacotherapy 5. Tics SSRI’s ollander Fig 1-YBOCS Compulsion Score Serotonin Reuptake Inhibitors* • fluoxetine (Prozac) • sertraline (Zoloft) • paroxetine (Paxil) • fluvoxamine (Luvox) • citalopram (Celexa) • escitalopram (Lexapro) • clorimpramine (Anafranil) CY-BOCS Compulsion Score *Note: FDA Warning about suicidality Hollander, et al. Neuropsychopharm (2004) pp1-8
Fluoxetine/Placebo Side Effects Hollander Fig 3 – CGI Global Improvement -Composite 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] CGI Global Improvement - Composite Hollander, et al. Neuropsychopharm (2004) pp1-8 Hollander, et al. Neuropsychopharm (2004) pp1-8 Traditional Neuroleptics • haloperidol (Haldol) Aggression & Irritability • trifluoperazine (Stelazine) • fluphenazine (Prolixin)
Primary Endpoint Analysis Aberrant Behavior Checklist - Irritability Atypical Neurolpeptics After 8 weeks of treatment, the risperidone group had a 56.9% improvement compared to a 14.1% improvement in the placebo group. 30 • clozapine (clozaril) Placebo (n=52) Mean ABC Irritability Total Score 25 Risperidone (n=49) • risperidone (Risperdal)* 20 Improvement • olanzepine (Zyprexa) 15 * • quetiapine (Seroquel) * 10 * * • ziprasadone (Geodon) 5 BL (RIS)=26.2 BL (PBO)=25.5 Mean Daily Dose at Week 8 (RIS)=11.3 Week 8 (PBO)=21.9 Week 8 RIS = 1.8 mg 0 • aripiperazole (Abilify)* 0 2 4 6 8 • Others Time in Weeks LOCF analysis; * P <0.001 vs. PBO *FDA Approved for irritability in ASD RUPP Autism Network. N Engl J Med. 2002;347:314-321. Primary Endpoint Analysis Secondary Endpoint Analysis Clinical Global Impression - Improvement Aberrant Behavior Checklist Subscales “ Much Improved” or “Very Much Improved” on CGI-I by group Change in ABC-Subscale scores from baseline to endpoint Baseline 75.5% risperidone (n=49) 90 Hyperactivity Stereotypy 8-weeks * Percentage of Subjects with CGI-I < 3 Placebo (n=52) 80 P <0.001 vs placebo P <0.001 vs placebo 35 12 32.3 31.8 70 10.6 * 30 27.6 10 60 9.0 ABC-Hyperactivity Score ABC-Stereotypy Score 25 50 8 7.3 40 20 5.8 17.0 6 30 15 11.5% 4 20 10 10 2 Mean Daily Dose at 5 Week 8 RIS= 1.8 mg 0 0 0 0 1 2 3 4 5 6 7 8 Risperidone Placebo Risperidone Placebo Time in Weeks * P <0.001 vs. placebo at weeks 4 and 8 RUPP Autism Network. N Engl J Med. 2002;347:314-321. RUPP Autism Network. N Engl J Med. 2002;347:314-321.
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