Psychopharmacology & Autism

1. Psychopharmacology& Autism

2. Psychopharmacology& Autism Basem K. Shlewiet, M.D. Child and Adolescent Psychiatrist Medical Director, KidsPeaceExecutive Director, KidsPeace Hospital

3. Psychopharmacology& Autism Course Outline Autism Spectrum Disorders. Pharmacology and Its Principles Neurotransmitters Medications commonly used in Autism

4. Autism is a complex developmental disability that typically appears during the first three years of life • It is widely recognized as a neurodevelopmental disorder that affects the functioning of the brain. • It is a spectrum disorder • Children with autism are unable to interpret the emotional states of others, failing to recognize anger, sorrow or manipulative intent • It impacts the normal development of the brain in the areas of social interaction and communication skills What is Autism?

5. Children and adults with autism typically have difficulties in verbal and non-verbal communication, social interactions, and leisure or play activities • Stereotypic (self-stimulatory) behaviors may be present • In some cases, aggressive and/or self-injurious behaviors might be present • It is not a behavioral, emotional or conduct disorder • There are no medical tests that can be used to diagnose autism What is Autism?

6. Autism Spectrum Disorders (ASD) Diagnostic Categories: Autism Asperger’s Disorder Pervasive Developmental Disorder – Not Otherwise Specified (PDD-NOS) Rett’s Disorder Childhood Disintegrative Disorder

7. Characteristics of ASD Neurological disorder characterized by three core areas of impairment: Social skills Verbal & non-verbal communication Restricted or repetitive behaviors and/or interests Variability of skills and deficits Life long challenges

8. Symptoms of children with autism Communication Social relationships Act as if unaware of the coming and going of others Are inaccessible, as if in a shell Fail to seek comfort Fail to develop relationships with peers Have problems seeing things from another person’s perspective, leaving the child unable to predict or understand other people’s actions Physically attack and injure others without provocation Avoid eye contact Act as if deaf Develop language, then abruptly stop talking Fail to use spoken language, without compensating by gesture Exploration of Environment Remain fixated on a single item or activity Practice strange actions like rocking or hand-flapping Sniff or lick toys Show no sensitivity to burns or bruises, and engage in self-mutilation Are intensely preoccupied with a single subject, activity or gesture Show distress over change Insist on routine or rituals with no purpose Lack fear

9. Diagnostic Criteria for Autistic Disorder Six or more items from (1), (2), and (3), with at least two from (1), and one each from (2) and (3): 1. qualitative impairment in social interaction, as manifested by at least two of the following: marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction failure to develop peer relationships appropriate to developmental level a lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by a lack of showing, bringing, or pointing out objects of interest) lack of social or emotional reciprocity

10. Diagnostic Criteria for Autistic Disorder 2. qualitative impairments in communication as manifested by at least one of the following: delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gesture or mime) in individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others stereotyped and repetitive use of language or idiosyncratic language lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level

11. Diagnostic Criteria for Autistic Disorder 3. restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following: encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus apparently inflexible adherence to specific, nonfunctional routines or rituals stereotyped and repetitive motor manners (e.g., hand or finger flapping or twisting, or complex whole-body movements) persistent preoccupation with parts of objects

12. Diagnostic Criteria for Asperger’s Disorder • Asperger’s Disorder = Autistic Disorder – Language Delay

13. What causes autism? • A specific cause is not known, but current research links autism to biological and neurological differences in the brain • Studies of twins in the UK confirm that autism has a heritable compound but suggest that environmental influences play a role as well • By examining the inheritance of the disorder, researchers have shown that autism does run in families, but not in a clear-cut way • Siblings of people with autism have a 3 to 8 percent chance of being diagnosed with the same disorder It can be safely said that: • Autism is not caused by bad parenting or ‘refrigerator mothers’ as was suggested by psychiatrist Bruno Bettelheim in the 1950s.

14. 1 in 1,000 individuals are diagnosed with “classic” autism. • 1 in 500 individuals are within the Autism Spectrum including Pervasive Developmental Disorders Autism Statistics • 1 in 110 individuals are within the Autism Spectrum including both PDD and Asperger’s Syndrome • Autism is four times more prevalent in boys than girls • Every day, 53 babies are born in the United States who will later be diagnosed with Autism Spectrum Disorders • It has no racial, ethnic or social boundaries • Family income, lifestyle, and educational levels do not affect the chance of autism’s occurrence • Research shows that 50% of children diagnosed with autism will remain mute throughout their lives. • Approximately 10% of autistic individuals have savant abilities

15. Autism Statistics

16. Autism Statistics

17. Autism Statistics

18. 2011: 1 in 110 (CDC) Increase in Prevalence 1980s: 1 in 2500

19. Increase in Prevalence

20. Medications & ASDs

21. 3 studies looking at the use of Medications in Autism • 70% in VA • 52 in MN • Medicaid nationwide study: 56% Autism Statistics

22.  The Interactive Autism Network (IAN): • Collects info from Families. • Findings Are Preliminary Autism Statistics IAN Research Findings: Medications….. April 11, 2008

23. Table 1. Psychotropic Medications Frequently Prescribed for Children with ASD Autism Statistics IAN Research Findings: Medications….. April 11, 2008

24. Table 1. Psychotropic Medications Frequently Prescribed for Children with ASD Autism Statistics IAN Research Findings: Medications….. April 11, 2008

25. Treatment information for 5,174 children with ASD. • 31% are taking at least one such medication • 6% taking three or more. • Figures vary quite a bit by age group Autism Statistics Table 2. Use of Psychotropic Medication by Children with ASD by Age Group IAN Research Findings: Medications….. April 11, 2008

26. Table 3. Parents' Evaluation of Psychotropic Medications by Category Autism Statistics IAN Research Findings: Medications….. April 11, 2008

27. General Consideratios: Prevalence -          Medication use is widespread -          Many medications have been tried, some helpful, some not helpful -          Psychotropics are costly

28. General Consideratios: Best Practices When used, Medication is only one part of a comprehensive treatment approach. “Core” vs. “target symptoms” Medical aspects should not be overseen: Pain especially when language is limited Pubertal transition, hormonal and sexual transition.

29. Target Symptoms for Psychotropic medication use in ASDs • Core symptoms Communication & Language Restrictive or repetitive behavior or interests Target Symptoms: Aggression. Self injurious behavior. Seizures. Co-occurring illness Social relationships

30. Autism might overshadow other disorders. We cannot explain all behaviors by autism. Seizures. Not uncommon to oversee other disorders: MR Depression and Anxiety. ADHD. Psychosis. Seizures (4 fold increase)

31. Ineffective Treatments Irelene Lenses. Facilitated communication Psychodynamic Psychotherapy Sacrocranial therapy Animal-assisted therapy. Le packing. Antimychotic therapy Chelation therapy. Could be dangerous and deadly. Secretin: 15 double blind, placebo controlled studies.

32. What can Medications help with Target Symptoms: Irritability, aggression, self injurious behavior, property destruction. Not very successful Hyperactivity, inattention Repetitive behavior

33. Aggression and Irritability! Typical Antipsychotics: (Haldol, Prolixin) Dopamine Antagonists Traditionally used to treat Schizophrenia Risk of tardivedyskinesia, small risk but concerning. Atypical Antipsychotics Mixed mechanism of action (Serotonin) Promising trials . Lower risk of TD

34. Anti-Psychotics: Clinical Use 2006: Risperidone was first medication to be FDA approved for treatment of irritability in children aged 5-16 with ASD 2009: Aripiprazole approved for same indication in children aged 6-17 Both available in liquid preparations

35. Neurotransmitter Clinical Highlights Dopamine • A “feel good” neurotransmitter • Release enhanced by L-dopa and amphetamines • Reuptake blocked by cocaine • Made from the amino acid tyrosine

36. Neurotransmitter Clinical Highlights Dopamine • Implicated roles in movement, attention, learning, reinforcing effects of abused drugs. • When not balanced by proper amounts of serotonin can cause addictive, compulsive behavior: “got to have it” • Drug abuse, compulsive shopping, eating, sex • May be involved in schizophrenia • Deficient in Parkinson’s disease

37. Neurotransmitter Clinical Highlights Dopamine Pathways

38. DopamineReceptors

39. Dopamine + Cocaine Cocaine: a Dopamine agonists Cocaine blocks DA transporters (Amphetamine increase DA release and reverses transporter)

40. Risperidone • Open label studies and case reports for indicate positive effects for: Autism spectrum disruptive/aggressive behavior Mental Retardation disruptive/aggressive behavior General Aggression

41. Risperidone cont’d • Double blind, placebo controlled study – Autistic Disorder with severe aggressive/disruptive behavior 101 children 5-17 yrs (mean 8.8 yrs) 49 assigned to risperidone, 51 to placebo– 0.5-3.5mg/d for 8 weeks 69% on risperidone had 25% or greater reduction in symptoms vs. 12% on placebo Effect size: 1.2 (more than 0.8 considered significant) (McCracken et al ’02, NEJM)

42. Fig 1 Irritability subscale of ABC (mean {+/-} SE) versus time profiles by treatment group Shea, S. et al. Pediatrics 2004;114:e634-e641

43. Clinical Impression Scale: CGI

44. Anti-Psychotics: Evidence of Effect • Results (at 6 months): • 63 subjects entered the 4 month open label phase • 82.5% of patients continued to be rated as “much improved” or “very much improved” on CGI-I • 6 month weight gain of 5.1 kg (0.85 kg/month) • One subject withdrew due to constipation • 6 subjects reported to have abnormal movements (none confirmed on exam)

45. 6 months after: Restricted, repetitive, & stereotypic behavior McDougle et al. Am J Psych. 2005

46. Anti-Psychotics: Evidence of Effect • Additional risperidone studies: • Shea et al, 2004: • 79 children ages 5-12 with ASD, risp or placebo for 8 weeks • 64% reduction in ABC Irritability score in risp group vs. 18% in placebo • RUPP, 2009: • 124 children ages 4-13 with PDD • Risperidone + parent training superior to risperidone alone • Aripiprazole • Owen et al, 2009: • 98 children ages 6-17 with Autistic Disorder, 8 weeks • 52% responders in aripiprazole group vs. 14% in placebo • Adverse effects: Fatigue, somnolence, weight gain, tremor

47. Anti-Psychotics: Evidence of Effect • Conclusions: • Risperidone was safe and effective for short-term treatment of tantrums, aggression, and self-injurious behavior in children with autistic disorder • Improvements also seen in hyperactivity and stereotypic behavior • Short period limits inferences about long-term efficacy and side effects

48. Atypical Antipsychotics • Risperidone • Single vs divided dose • M-tabs, oral solution (1mg/ml) • Quetiapine (Seroquel)- weak D2 affinity, sedating • Aripiprazole (Abilify) – partial D2 agonist- Comparable Efficacey to Risperdal. Less weight gain • Ziprasidone (Geodon)

49. Potential Side Effects Recommended Monitoring Anti-Psychotics: Side Effects & Monitoring • Increased appetite and weight gain • Dyslipidemia • Diabetes • Increased liver enzymes • Sedation • Constipation • Extrapyramidal symptoms • Prolactin elevation • Baseline history, PE • Baseline labs • Fasting glucose and lipids • Liver function tests • Prolactin? • Repeat labs at 12 weeks, then every 3-6 months • Monitor weight/BMI • Monitor for side effects

50. Atypical Side Effects