1. Master Slide Current Trends in the Pharmacological Treatment of Autism Alexander Kolevzon, MD Peter Della Bella, MD David Grodberg, MD Charles Cartwright, MD

2. 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

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

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

5. The Treatment of Anxiety and Repetitive Behaviors in Autism Spectrum Disorders Alex Kolevzon, M.D Alex Kolevzon, M.D. Clinical Director, Seaver Autism Center

6. Future Directions Targeting Novel Neurotransmitter and Hormonal Systems In Autism Charles Cartwright, MD Director, YAI Autism Center

7. Master Slide Agitation and Aggression Peter Della Bella, MD

8. What is Agitation? An inability to cope causing distress… and losing control Precursors: Irritability, anxiety, fatigue… The worry: add a trigger and…

9. What is Aggression? (Latin) Attack Premeditated vs. loss of impulse control

10. Understanding the Roots of Agitation and Aggression

11. Roots of Irritability & Agitation - the Fight or Flight Response Sources: Babble.com; Brain-trainer.com; quantumlearningblog

12. Roots of Agitation and Aggression irritated c a l m agitated ATTACK coping loss of control

13. Roots of Agitation and Aggression Survival instinct (“Boxed into a corner”) Pain/physical discomfort (sensory integration) Psychic discomfort (stress, change, frustration)

14. Roots of Agitation and Aggression irritated c a l m agitated ATTACK

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

16. Roots of Agitation and Aggression c a l m / irritated agitated ATTACK stress, discomfort, pain cultural, behavioral, “medical” factors

17. 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)

18. Roots of Agitation and Aggression Irritated c a l m agitated ATTACK

19. 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

20. FDA approved for autism…

21. 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

22. What are the pros and cons of using medications?

23. Master Slide Attention Deficit and Hyperactivity David Grodberg, MD

24. 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 41- 78% of children with ASD

25. 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

26. 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

27. TREATMENT OF ADHD SYMPTOMS IN ASD Strongest evidence: methylphenidate –2 placebo-controlled trials –retrospective and prospective effectiveness study

28. Methylphenidate Increases NE and DA by blocking reuptake

29. 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

30. 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

31. Guanfacine Alpha 2A agonist. Enhances prefrontal cortical function

32. Atomoxetine Increases NE and DA in prefrontal cortex.

33. TREATMENT OF ADHD SYMPTOMS IN ASD Weak Support: clonidine, donepezil –very small studies

34. Clonidine Nonselective alpha2 agonist. More sedating/hypotensive.

35. Donepezil Acetyl Cholinesterase inhibitor

36. 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

37. 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.

38. Master Slide Anxiety and Repetitive Behaviors Alexander Kolevzon, MD

39. 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)

40. 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

41. Repetitive Behaviors Lower Order (motor/sensory) Hoarding Higher Order (compulsive) Obsessions Anagnostou et al, 2005

42. Serotonin System  Critical to neurodevelopment  Directs neuronal growth, proliferation, differentiation  Widely expressed in emotional centers of brain

43. Emotional Center of Brain

44. Serotonin Pathways

45. Serotonin System in Autism

46. Serotonin Reuptake Inhibitors

47. Serotonergic Medications

48. Medication Open Label Controlled fluoxetine + + + + + + -- fluvoxamine+ sertraline + + + citalopram+-- escitalopram+ venlafaxine + + clomipramine+ buspirone

49. Study of Fluoxetine in Autism (SOFIA) N=158

50. Atypical Antipsychotics - Risperidone McDougle et al, 2005

51. Atypical Antipsychotics – Abilify Marcus et al, 2009

52. 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

53. IV Oxytocin Challenge  need to know  repeating  ordering  need to tell  self-injury  touching Hollander et al, 2003

54. Master Slide Future Directions Charles Cartwright, MD

55. All Treatments Discussed are Off Label and do not have FDA Approval for the Treatment of Autism

56. The Glutamate System

57. Machado-Vieira et al, 2009

58. Glutamate Modulating Treatments

59. D-Cycloserine

60. D-Cycloserine in the Treatment of Autism Posey et al, 2004

61. Riluzole

62. Riluzole in the Treatment of OCD Coric et al, 2005

63. N-acetylcysteine

64. N-acetylcysteine in the Treatment of Trichotillomania Grant et al, 2009

65. Treatments that involve Hormones

66. Oxytocin

67. Andari et al, 2010

68. Caution Demonstrate Safety and Efficacy

69. Master Slide THANK YOU