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Pharmacotherapy for Aggressive Behaviors in Persons with ASD:

Pharmacotherapy for Aggressive Behaviors in Persons with ASD:. John A. Tsiouris , M.D. Consulting Psychiatrist, IBR/Jervis Clinic Clinical Associate Professor of Psychiatry SUNY Downstate Medical Center. Autism Spectrum Disorder. Autistic Disorder Asperger’s Disorder PDD, NOS.

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Pharmacotherapy for Aggressive Behaviors in Persons with ASD:

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  1. Pharmacotherapy for Aggressive Behaviors in Persons with ASD: John A. Tsiouris, M.D. Consulting Psychiatrist, IBR/Jervis Clinic Clinical Associate Professor of Psychiatry SUNY Downstate Medical Center

  2. Autism Spectrum Disorder • Autistic Disorder • Asperger’s Disorder • PDD, NOS

  3. Spectrumof Deficits/Abilities • Relatedness (moderate-to-severe impairment) • Communication (none-to-very good) • Sameness/Stereotypies (severe-to-mild) • IQ (low-to-high) – 75% have an IQ < 70

  4. ASD is associated with: • Fragile X syndrome • PKU • Congenital Rubella • Down syndrome • X-related MR • Neurofibromatosis • Intractable Epilepsy

  5. ASD is associated with: (cont.’d) • Encephalitis, meningitis • Perinatal factors (anoxia) • Prematurity, multiple births • Medications, toxins, chemicals, etc.

  6. ASD is associated with: (cont.’d) • Parental age (old father) • Personality of parents (math/computer scientists, chemists, engineers, interior decorators, actors, etc.) • Mood and Anxiety disorder of parents • Schizophrenia and paranoid or schizoid/schizotypal personality of parents

  7. Etiology of Autism • Genetic Studies: • 12 to 15 genes implicated • Many candidate genes; few answers • Other explanatory theories • Neural synchrony vs disconnection syndrome (Geschwind & Levitt 2007; Uhlbaas & Singer 2007)

  8. Preschool Intervention Programs (Based on Brain Plasticity) • Structured teaching: TEACCH • Applied Behavior Analysis (ABA) • Discrete Trial Training (DTT) • Developmental Approaches (child-directed)

  9. Aggressive Behaviors • Verbal aggression against self • Physical aggression against self (SIB) • Verbal aggression against others • Physical aggression against others • Physical aggression toward objects (destructive)

  10. Prevalence of Challenging Behaviors in Persons with ID Point Prevalence: 15% (Holden & Gitlesen 2006) 12-month Prevalence: 52% (Crocker et al. 2006)

  11. Prevalence of Aggressive Behaviors • 30% of children and adolescents with ASD exhibit severe irritability which leads to aggression against objects, others, and/or self. (Levacalier, 2006)

  12. Incidence of Aggression Toward OthersAmong Consumers with ASD 0 10 20 30 40 50 Percentage

  13. Incidence of Aggression Toward SelfAmong Consumers with ASD 0 10 20 30 40 Percentage

  14. Incidence of Aggression Toward Objects Among Consumers with ASD 0 10 20 30 Percentage

  15. Behavior Modification for Aggressive Behaviors Published cases of successful treatment with behavior modification after a good applied behavior analysis (ABA) confirm the impact of early faulty (or only adaptive) learned patterns and the influence of the environment in maintaining such behaviors (Gardner, Carr, Mace, Foxx, and others)

  16. BehaviorModification in Practice • Lack of generalization in certain cases • Lack of good ABA • Poor behavior modification plans • Lack of implementation of plans • Has to be applied after medical and psychiatric disorders, if present, have been treated

  17. Challenging Behaviors Aggressive Behaviors are: • Normal for the chronological or mental age or the environment • Adaptive/Maladaptive • Reactive, defensive, impulsive, affective • Proactive, offensive, planned, premeditated • Have a survival value for the actor

  18. Challenging Behaviors Aggressive Behaviors have different functions at different ages, times and environments • Avoiding tasks/demands/places • Satisfying wishes and needs • Getting attention, sense of security • Communicating needs • Retaining isolation • Establishing dominance • Defending a territory

  19. Challenging Behaviors Aggressive Behaviors are associated with: • Medical/Neurological Problems • Psychiatric Disorders • Personality Disorders • Response to Environment • Phenotypes • Genotypes (Caspi et al. 2003, 2003) (temperament, family genetic make-up, learning patterns)

  20. % of Consumers with ASD for Psychiatric Disorders(N = 427)

  21. Psychiatric disorders (%) in ASD, Down’s, Fragile X, CP

  22. Other Medical Diagnoses 0 10 20 30 40 50 Percentage

  23. Most Effective Interventions 0 20 40 60 Percentage

  24. Proportion of ASD and other Consumers Receiving Medication for Challenging Behaviors

  25. Proportion of ASD and other Consumers Receiving Medication for Psychiatric Disorder

  26. Medication Tried for Autism or Challenging Behaviors of Persons with ASD • Psychotropics • Barbiturates • Antianxiety • Stimulants • Antipsychotics (typical – atypical) • Antidepressants (different types) • Mood stabilizers (anticonvulsants) • Lithium

  27. Others • Alpha2 adrenergic agonists (Clonidine) • Beta-blockers • Opioid receptor blockers (Naltrexone) • Anti-dementia drugs (Donepezil; Memantine) • ECT • Oxytocin, D-cycloserine • B6, B12, L-carnosine secretion, Dimethylglycine (DMG), Secretin • Different herbs, etc.

  28. Use of Antipsychotics in Persons with ID • Antipsychotics are estimated to be 30% of all psychotropics prescribed for persons with ID (Rinck, 1998) • 56 % are prescribed for persons with ASD (Robertson et al., 2000) • Up to 70% of all psychotropics prescribed in NYS for adults with ID are antipsychotics (Tsiouris, et al., unpublished survey data)

  29. Psychotropics in Children with ASD • 50% of children with ASD receive psychotropics • 16.5% receive antipsychotics (Aman et al., 2005) • More than 30% of psychotropics are anti-psychotics (Mandell et al., 2008

  30. Rates of Psychiatric Disorders in Persons with I.D.* Psychotic disorders 4.4% Affective Disorders 6.6% Anxiety Disorders 3.8% Organic Disorders 2.2% Pica 2.0% Other disorders 0.4 – 1.5% each OCD, substance abuse, ADHD and personality disorders Cooper, et.al. 2007 *Clinical Diagnosis

  31. Prevalence of Psychotic Disorders in Persons with ID • Estimated to be 3% (1.5- 5%)(Deb 2001; Cooper et al., 2007) • Psychosis as the only diagnosis, 7% • Psychosis with other diagnosis, 18% (Tsiouris et al., unpublished survey data)

  32. Why such a discrepancy? • Antipsychotics are used for control of aggressive behaviors and other challenging behaviors • In persons with ID • And in persons without ID, but with • Dementia • Traumatic brain injury • Personality disorders

  33. Abraham Maslow Once Said: “When the only tool you have is a hammer, you tend to treat everything as if it were a nail.”

  34. Antipsychotics used Because: • We don’t have any other tools? • We see all of them as having psychotic disorders (as in the past)? • We don’t know any better? • We prescribe what is indicated, placed in the formulary and being promoted?

  35. Psychiatric Diagnoses in Persons with I.D. Past: • Mental Retardation with behavior problems • Childhood Psychoses (children) • Schizophrenia (adults)

  36. Antipsychotics used for Aggressive Behavior 1950 – 1990 ChlorpromazineThioridazine Mesoridazine Thiothixene Perphenazine Fluphenazine and Haloperidol (the dominant one) 1990 – Present ClozapineOlanzapine QuetiapineAripiprazole Ziprasidone and Risperidone (the dominant one)

  37. Antipsychotics Are they anti-aggressive drugs? No Antipsychotics (dopamine2 receptor blockers have not proved to act as anti-aggressive drugs) deAlmeida et al 2002; Goedhard et al 2006 Do they have many side effects? Yes

  38. Dopamine and Serotonin Receptors in ASD • There is no clear evidence of abnormality in the dopamine neurotransmission in ASD (review by Posey et al., 2008) • 1/3 of children with ASD have increased serotonin levels in whole blood. (Schain & Freedman, 1961) • Acute depletion of serotonin by tryptophan revealed exacerbation of stereotypic and self-injurious behaviors (McDougle et al., 1996)

  39. Haloperidol (Haldol)(A Dopamine receptor blocker) • Decreases: irritability, agitation, stereotypies, and aggressive behaviors • Produces: sedation, acute dystonic reactions, akathisia, extrapyramidal syndrome, tardive dyskinesia, and withdrawal dyskinesias (Cohen et al., 1980; Anderson et al., 1984; Campbell et al., 1997; Shea et al., 2004)

  40. Atypical Antipsychotics(Approved by FDA for treatment of irritability associated with ASD) • Risperidone (Risperdal; Antagonist of dopamine (D2) and serotonin (5-HT2A receptors). • Aripiprazole (Abilify; partial agonist of D2 and 5-HT1A receptors and antagonist of 5-HT2A receptor)

  41. Atypical Antipsychotics(Used but not approved by the FDA) • Olanzapine (Zyprexa) • Quetiapine (Seroquel) • Ziprasidone (Geodon) • Clozapine (Clozaril) • Paliperidone (Invega) • Iloperidone (Fanapt) • Asenapine (Saphris) * All of these are D2 and 5-HT2A receptor antagonists

  42. Risperidone • Has anti-aggressive properties in animal models (developmentally immature Syrian hamsters) treated at puberty with low doses of cocaine-hydrochloride • Decreased aggression intensity but not initiation by 65% to 75% (in above animals) through blockage of D2 receptors and 5-HT 2A receptors • Ricci et al 2007 (company sponsored study)

  43. Receptors (cont.) • Activation of 5-HT2A receptors increases aggressive behavior • SaKave et al 2002 • Activation of 5-HT2C receptors reduce impulsivity • Krakowski et al 2004

  44. Receptors (cont.’d) • Activation of D2 receptors increases anxiety, social fearfulness and defensive aggression • Sweidan et al 1991 • Gendreau et al 2000

  45. Receptors relevant toaggressive behavior • 5-HT (1B) receptor subtypes and other 5-HT subtypes (1A & 2C) receptor • GABA (A) receptor modulators (Olivier & Oorschot 2005)

  46. Atypical Antipsychotics, Common Side-Effects • Weight gain  metabolic syndrome  hyperlipidemia/diabetes II • Sedation • Hyperprolactinemia (increased prolactin) • EPS, Dystonic reactions, Akathisia • Tardive and Withdrawal Dyskinesias • Seizures (lowering of seizure threshold)

  47. Side-Effects Depend On: • Their main effects on target receptors • Blockage, activation, or compensatory changes of other receptors (Histamine, α1 and α2 adrenergic and acetylcholine receptors)

  48. Past Treatments • Pain: Opioids • Fever: cold baths, blood-letting, aspirin, and others • Severe mental illness: asylum, sedatives, cold baths, etc.

  49. Current Treatments • Some of previous • But doctors are searching and treating the causes of pain or fever. • Psychiatrists make diagnoses and treat mental illness with FDA-approved psychotropics for treatment of certain psychiatric disorders

  50. Are any Changes in the Treatment of Aggression Forthcoming? Yes: In dementia, TBI, Personality Disorder No: In persons with ID & aggressive behaviors, in spite of many published guidelines and articles

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