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Pharmacology of Autism

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Pharmacology of Autism Powered By Docstoc
					Pharmacology of Pervasive
 Developmental Disorders
                    December 4, 2008
                   W. David Lohr, M.D.
                david.lohr@lohrmd.com
Clinical Director, Adolescent Treatment Services, OLOP
                  Autistic Disorder

• A. A total of 6 or more items from categories
  1, 2, or 3 with at least 2 from category 1.
  – 1.    impaired social interaction
     •   a. marked impairment in nonverbal behavior
     •   b. deficient peer relationships
     •   c. lack of spontaneous seeking to share emotions
     •   d. lack of social or emotional reciprocity
              Autistic Disorder
• 2. impaired communication
  – a. delayed or absent spoken language
  – b. inability to sustain a conversation with others
  – c. stereotyped and repetitive use of language
  – d. lack of make-believe or social imitative play
             Autistic Disorder
• 3. restricted, repetitive, and stereotyped
  behaviors
  – a. Preoccupation with restricted patterns of
    interest
  – b. inflexible routines or rituals
  – c. stereotypical and repetitive motor movements
  – d. preoccupation with parts of objects.
• Delays in at least one area must onset before
  3 years of age.
            Asperger’s Disorder

• Impaired social interaction, (2 items)
• Restricted, repetitive, and stereotypical
  behaviors, (1 item)
• Clinically significant dysfunction
• No delay in language
• No mental retardation
              Rett’s Disorder
• Normal development through 5 months of age
• Deceleration of head growth between ages 5
  and 48 months of age
• Loss of previously acquired hand function with
  onset of stereotypical hand movements
• Loss of social engagement
• Poorly coordinated gait or trunk movements
• Severely impaired language
 Childhood Disintegration Disorder
• Normal development until at least 2 years of
  age
• Loss of skills before age of 10
  – Language
  – Social function
  – Bowel or bladder control
  – Play
  – Motor skills
   Childhood Disintegration Disorder

• Abnormal function in at least 2 areas
  – Social function
  – Language
  – Repetitive and stereotypical patterns of interest
             The Evaluation Process

• Make a clear diagnosis for yourself
• Detailed psychiatric assessment
  – Historical information
     •   Pregnancy, Neonatal, Developmental History
     •   Medical History
     •   Family and Psychosocial Factors
     •   Treatment History
        The Evaluation Process
• Mental Status Examination
  – Social Interaction
  – Communication Skills
  – Play
  – Restricted Interests and Unusual Behaviors
  – Specific Target Symptoms
        The Evaluation Process
• Medical Assessment
  – Rule out medical conditions associated with
    autism
  – Audiological and Visual Examinations
  – Neurologic Exam
  – Lab Studies
  – Consultations with other professionals
        The Evaluation Process
• Psychological Assessments
  – IQ
  – Adaptive Skills
  – Language and Vocabulary
  – Oral-Motor Skills
  – Social Function
• OT and PT Assessments
                 Treatment Plan

• Educational and Vocational Interventions
  – Foster social, communicative and cognitive skills
• Behavioral Interventions
  – ABA
  – Social Skills Training
• Family Intervention
  – Education and Support
  – Parent Management Training
            Pharmacotherapy
• Core Symptoms vs. Target Symptoms
• Target symptoms must be indentified
  – Establish a hierarchy of target symptoms which
    may be consolidated
• Target symptoms include aggression, SIB,
  hyperactivity, and repetitive behaviors
• Role in the overall treatment plan
  – Adjunctive and after environmental treatment
    efforts
            Pharmacotherapy
• Risk/Benefit Ratio
  – Monitor for side effects
• Assess Change
  – Efficacy based on report from parents, teachers,
    staff
  – Rating scales
• 34 – 55 % of children with autism are treated
  with medications
 Background support for Intervention

• Increased platelet 5-HT levels found in 40% of
  autistic population, Ritvo 1970; Rolf 1993.
• PET imaging showed difference in serotonin
  synthesis capacity in autism
• Serotonin transporter gene SCL6A4 is a candidate
  gene in autism
• Cholinergic abnormalities also noted
  – Basal forebrain cholinergic neuron abnormalities
  – Postmortem changes in cholinergic pathways in
    autism
 Background support for Intervention
• Target symptoms for serotonin drugs are
  irritability, aggression, and compulsive
  behavior
• Studies support an association between
  dopaminergic system and aggression and SIB
      Antipsychotics in Autism
• Risperidone approved by FDA for use in
  children with autism for treatment of
  irritability, aggression, and SIB
• Combined dopamine and serotonin antagonist
           Risperidone in Autism
                RUPP 2002
• DBPC study in 101 children aged 5 – 17 years,
  mean age 8.8 years
• Risperidone mean dose of 1.8 mg/day for 8
  weeks
• Greater reductions in Irritability subscale of ABC,
  57% vs. 14%, compared to placebo, effect size 1.2
• Significant improvement in stereotypy and
  hyperactivity subscales of ABC and repetitive
  behavior on CY-BOCS
           Risperidone in Autism
                RUPP 2002
• No improvement in social withdrawal or
  inappropriate speech
• 69% vs. 12% had a positive response
• No EPS
• Significant increase in weight, mild to moderate
  increases in appetite in 73%, fatigue 59%,
  drowsiness 49%, drooling 27%, dizziness 16%
• Parents reported most benefit in reducing SIB and
  aggression
         Risperidone in Autism
• Shea 2004 DBPC parallel-group, 8 weeks
• 80 children aged 5 -12 years with PDD, mean
  dose of risperidone 1.17 mg/day
• Measures of irritability and conduct problems
  significantly decreased in risperidone
• No difference in EPS
• Significant more weight gain, 2.7 kg, in active
  treatment
            Risperidone
      RUPP 2005 Extension Study
• 4 month open-label phase then 8-week DBPC
  parallel group discontinuation trial
• 32 subject completed this trial
• Relapse rate 62.5% in placebo vs. 12.5% in
  risperidone
• Early termination by NIMH
• Only responders to risperidone were included
  in extension study
   Risperidone for core symptoms of
                autism
• RUPP 2005. Significant improvements in
  restricted, repetitive, and stereotyped
  behaviors
• No improvement in social interactions and
  communication
• Ritvo-Freeman Real Life Rating Scale, CY-BOCS
  compulsive scale, maladaptive behavioral
  domain of Vineland Adaptive Behavior Scale
         Risperidone in Autism
• Troost 2005, 36 subjects with autism, 24-week
  open label phase, 24 responders entered into 8-
  week DBPC discontinuation phase
• Mean dose 1.81 mg/day
• Relapse = 25% increase in ABC-I, or CGI clinician
  rating
• Relapse in 67% of placebo vs. 25% in risperidone
• Support effectiveness in reducing tantrums,
  aggression, and SIB
           Risperidone in Autism

• Solid support of improved aggression,
  irritability, SIB, temper tantrums, mood lability
  in DBPC trials
• Well tolerated and effective for up to 6
  months
• Monitor for involuntary movements, weight
  gain, metabolic syndrome
          Olanzapine in autism
• Malone, 2001. open label study compared to
  olanzapine to haloperidol, 6 subjects in each
  group
• Mean dose of zyprexa 7.9 mg/day vs. 1.4 mg/day
  for haloperidol, 6 week study
• CGI, Children’s Psychiatric Rating Scale
• 5/6 of olanzapine vs. 3/6 of haloperidol subjects
  rated as responder
• Olanzapine had significantly increased weight
  gain, no motor side effects
          Haloperidol in Autism
• Campbell’s 1978-1984 controlled studies showed
  haloperidol to significant to placebo in effect on
  affective lability, anger, temper outbursts
• 1978 PC 12 week study of haloperidol in 40
  children found effectiveness in attention and
  retention of learned materials and decreased
  stereotypies and withdrawal
• Frequent acute dystonic reactions and sedation
         Haloperidol in Autism
• Remington 2001 compared haloperidol,
  clomipramine, and placebo in 36 subjects with
  autism, 7 weeks, DBPC crossover design.
• Mean dose of haloperidol 1.3 mg/day
• No difference in aggression and SIB in
  haloperidol vs. placebo
• 10/33 subjects discontinued haloperidol due
  adverse effects mostly fatigue/lethargy
         Haloperidol in Autism
• 12 of 60 patients developed dyskinesia in a 6-
  month study, 9 upon withdrawal
• 34% of 118 children have withdrawal
  dyskinesia, 9 developed tardive dyskinesia
       Antipsychotics in Autism
• Evidence for efficacy with Risperdidone
• Limited evidence for other atypical
  antipsychotics
• ? Abilify
• Typical antipsychotics associated with greater
  movement abnormalities
  – ?CATIE study lessons
               SSRI and Autism
• Used widely in autism, 21.4%
  – Serotonin dysfunction in autism
     • Elevated levels of serotonin
     • PET imaging differences in serotonin synthesis
     • Serotonin transporter gene
  – Similarity of symptoms to OCD
  – some studies in adults with autism
       Fluvoxamine and Autism
• McDougle 2000 study of 34 subjects, mean
  age 9.5 years. 12 week DB parallel group
  comparison with placebo, mean dose 106.9
  mg/day
• 1 of 18 fluvoxamine responders vs. 0 of 16
  placebo subjects
       Fluvoxamine and Autism
• McDougle 1996 study of 30 adults, 12 week,
  DBPC.
• 8 of 15 subjects rated as responders vs. 0/15
  placebo treated subjects
• Improvements in repetitive behaviors,
  maladaptive behavior, repetitive language
• Mild side effects – sedation, nausea
         Fluoxetine and Autism
• Hollander 2005 study of 39 children, mean
  age 8.2 years, 20 week, PC crossover study vs.
  placebo, two 8-week phases of active vs.
  placebo with 4-week washout
• Mean dose 9.9 mg/day
• Significant response in reducing repetitive
  behavior on CY-BOCS
• No change in speech or social function
• No significant difference in side effects
         Fluoxetine and Autism
• Cook 1992. Fluoxetine found effective in
  15/23 subjects age 7-28 years with autism.
  – 6/23 subjects discontinued due to side effects
• DeLong 2002. Positive response with
  fluoxetine in 89/129, 69%, in children aged 2-8
  years, duration 5-76 months. Variable dosing
  noted
           SSRI and Autism
• No PC studies of sertraline in PDD, only open
  label studies in adults
• Case reports only for paroxetine in child and
  adolescents
• Couturier 2002 Retrospective study of
  citalopram, mean dose 19.7 mg/day in 17
  children aged 4-15 years.
  – 10/15 subjects improved
  – Anxiety and aggression were most responsive
        Fluoxetine and Autism
• Buchsbaum 2001. Placebo controlled
  crossover study of 6 adults. 8 week study, max
  dose 40 mg. Unclear methodology
• Significant improvements in anxiety.
• No data on side effects
               SSRI and Autism
• Namerow 2003 study in 15 children aged 6-16
  years, mean dose 16.9 mg/day of citalopram
  – 11/15 rated as improved
  – 2/15 discontinued study early due to side effects
• Owley 2005 10-week open label study of 28
  subjects and escitalopram, mean dose 11.1
  mg/day
  – 17/28, 61%, rated as 50% reduction in parent rated
    ABC-irritability subscale
  – 10/28, 36%, couldn’t tolerate 10 mg/day
             SSRI and Autism
• Limited display of effectiveness.
• Fluoxetine has 2 placebo-controlled trials to
  support its use.
• Reduction in repetitive behaviors noted
• No improvement in core symptoms of autism
  of communication or socialization
           SSRI and Autism
• Global improvements and improvements in
  anxiety and mood symptoms
• Common side effects included agitation,
  aggression, hyperactivity, insomnia
• Risk/benefit ratio, target symptoms
• No long-term data
      Clomipramine and Autism
• Remington 2001 RCT, standardized outcome
  measure of aggression, 36 subjects, 7 weeks,
  DBPC crossover
• Average dose 128.4 mg/day, ABC-Irritability
  subscale
• No significant difference with placebo
• Poor tolerability
  – 20 subjects discontinued clomipramine
  – Fatigue/lethargy, behavioral problems
       Clomipramine and Autism
• Gordon 1993 compared clomipramine vs.
  placebo and desipramine, randomized crossover
  study
• 24 subjects with autism, children and young
  adults
• Significant reductions in anger, sterotypies,
  compulsive behaviors, and hyperactivity vs.
  placebo
• Adverse effects ECG changes, seizures, irritability,
  aggression
     Clomipramine and Autism
• No advantage shown to SSRI
• Increased risk
          Stimulants in Autism
• Increase availability of dopamine in striatum,
  enhancing prefrontal cortical function
• Parents and teachers of autistic children
  report moderate to severe problems with
  concentration, attention span, distraction,
  fidgeting and wiggling
          Stimulants in Autism
• Campbell 1972 PC study comparing T3 and
  dextroamphetamine, mean dosage 4.8
  mg/day
• 16 children aged 3 – 6 years with diagnosis of
  autism, schizophrenia, organic brain syndrome
• All groups worsened with dextroamphetamine
• Common adverse effects of hyperactivity,
  stereotypy, irritability, reduced appetite
         Stimulants in Autism
• Campbell 1976 DB crossover comparison of
  levoamphetamine and levodopa
• 12 children, aged 3 – 12 years with
  schizophrenia with autistic symptoms
• Levoamphetamine, mean dose 13.4 mg,
  worsened symptoms
• Increased stereotypy in 82%
            Stimulants in autism

• Quintana 1995 study of methylphenidate
  – DBPC cross-over design, 4 weeks
  – 10 subjects with autism, age 7 to 11
  – Divided doses 20 and 40 mg/day
  – Significant improvements in irritability subscale of
    ABC, modest benefit over placebo
  – No significant differences in side effects
          Stimulants in Autism
• Handen 2000 study of methylphenidate
  – DBPC crossover design, 7 days
  – 13 subjects, age 5.6 – 11 years
  – Low and high doses bid or tid
  – 62% showed reduced hyperactivity and
    inattention
  – Significant improvement in irritability subscale of
    ABC and aggression subscale of IOWA CTRS.
  – 5 children had severe side effects, 3 subjects
    discontinued active treatment
          Stimulants in Autism
• Nickels 2008 retrospective study of population-
  based cohort of children with autism
• 52% of all children were treated with stimulants,
  methylphenidate most common
• 69% favorable response rate
• 66% of subjects experienced side effects, 17% of
  treatment episodes had a side effect, 22%
  discontinued treatment
• Median duration of treatment 3.1 years
           Stimulants in Autism
                  RUPP
• RUPP Autism Network 2005 Study of
  methylphenidate
• DBPC, crossover design with open-label
  continuation
• 1 week test dose phase, 1 week each of
  placebo or low, medium, or high dose
  – 0.125, 0.25, and 0.5 mg/kg/dose. Tid dosing
• 8 week open-label continuation
           Stimulants in Autism
                  RUPP
• 72 subjects aged 5 – 14 years, 66 tolerated
  test dose
• Overall 49% of 72 subjects responded to
  active dose. Determination of best dose was
  20% placebo, 25% low, 32% medium, and 23%
  high dose.
• Significant effect on teacher and parent rated
  hyperactivity.
• Overall modest effect sizes 0.25 – 0.50
            Stimulants in Autism
                   RUPP
• Significant worsening of parent-rated
  lethargy/social withdrawal and inappropriate
  speech
• Methylphenidate did not improve ABC
  subscale ratings for irritability, lethargy/social
  withdrawal, stereotypy, inappropriate speech
            Stimulants in Autism
                   RUPP
• Response rate lower than 75% in typical
  children with ADHD
• 18% discontinued active medication due to
  side effects
  – Irritability most common, decreased appetite,
    difficulty falling asleep, and emotional outbursts
    were more frequent
  – Higher rate of side effects compared with 4%
    discontinuation in MTA study.
           Stimulants in Autism

• Lower response rates and higher side effects
  than in non-autistic population
• Modest benefits in hyperactivity, inattention,
  and irritability
• No effect on core symptoms
• Should we expect more for longer acting
  stimulants?
         Clonidine and autism
• Individuals with autism studied to show hyper
  arousal in response to stimuli
• Clonidine et al lower production of
  catecholamines as alpha-2 adrenergic agonists
          Clonidine and autism
• Jaselskis 1992 study of 8 males age 5-13.4
  years, 6 weeks, DBPC cross-over design, mean
  dose 0.15-0.20 mg/day
• Significantly, 33%, lower irritability subscale
  of ABC as rated by teacher, no change in
  clinician ratings
  – Also improvement in hyperactivity and
    stereotypies
  – 4/6 relapsed in a follow up study
         Clonidine and Autism
• Frankhauser 1992 placebo vs. clonidine in 7
  males ages 5-33 years.
• Significant improvements in clinician and
  parent global scales
• No improvement in parent Conners ratings
        Guanfacine and autism
• Posey 2004 retrospective review of 80
  children age 3-18 years, mean dose of 2.6 mg
• Considered effective in 24% to reduce
  hyperactivity, inattention, impulsivity
       Atomoxetine and autism
• Selective inhibition of presynaptic NE
  transporter, selective dopamine effect in
  frontal lobe
• Retrospective improvement in 20
  child/adolescents with open treatment of 18-
  60 mg/day
  – 60% response via CGI
  – Parent ratings for conduct, hyperactivity,
    inattention, learning
           Atomoxetine and autism
                Arnold 2006
• DBPC crossover trial of 16 children age 5-15 years, 6
  week study, 1 week washout, mean dose 44.2 mg/day
• Significant improvement on hyperactivity scale of ABC,
  ratings of DSM-IV hyperactive/impulsive symptoms,
  CGI
• Significant improvement in lethargy/social withdrawal
• All 16 subject showed upper GI symptoms, significant
  side effects also included fatigue, racing heart
   – 1/16 terminated early due to aggression and psychosis
         Atomoxetine and autism
              Arnold 2006
• Overall response rate of 57% rated by parents
  and 43% rated by teachers
  – Lower than in typical population
  – Similar to stimulants in RUPP
• Lower rate of side effect than stimulant
  studies.
  – Allowed concomitant medication
      Mood stabilizers in autism
• 1/3 patients with autism have seizures
• Antiaggressive effects of valproate
• Kindling theory
           Valproate in autism
• Hellings 2005 DBPC parallel-group design, 8
  weeks, age 6-20 years, 30 subjects PDD-NOS
  with significant aggression, dose 20
  mg/kg/day, mean level 77.7
• No significant differences on irritability
  subscale of ABC or Overt Aggression Scale
• Significant side effect of increased appetite
         Valproate in autism
• Hollander 2006 8-week DBPC study of 13
  patients, mean age 9 years with ASD, mean
  dose 833.9 mg/day
• Improved repetitive behaviors measured by
  CY-BOCS
       Lamotrigine and autism
• Belsito DBPC parallel group design in 35
  youths age 3-11 years, 18 weeks, 8 week
  titration to 5 mg/kg/day then maintained for 4
  weeks. 2 week taper then 4 week drug free
  phase
• No significant difference in the irritability
  subscale of ABC
• No preselection for aggression
• No significant difference in side effects
      Levetiracetam and autism
• Wasserman 2006 DBPC parallel-group study of
  20 children with ASD, mean age 8.7 years,
  mean dose of 862.5 mg/day
• No significant differences in parent ratings of
  irritability, ABC-I
• Teacher ratings showed increased irritability in
  levetiracetam
• No statistical analysis of side effects
        Naltrexone and autism
• Endogenous opioid system involved in
  aggression
• Elevated levels of beta-endorphin in some
  youths with autism
  – SIB maintained by need to attenuate pain
• Long acting opiate antagonist
         Naltrexone and autism
• Campbell 1993, 41 children with autism, DBPC,
  parallel-group, 4 weeks, mean age 4.9 years
• Dose was 0.5 mg/kg for 1 week, then 1 mg/kg for
  2 weeks, then 1 week placebo phase
• No significant improvements in severity of SIB or
  aggression, significant improvement in
  hyperactivity
• No difference in side effects
• No preselection for aggression
        Naltrexone and autism
• Willemsen-Swinkels 1995 DBPC study of 20
  children with autism, single-dose crossover
  design, mean age 5.5 years
• Single dose of 40 mg
• Significant reduction in ABC-I
        Naltrexone and autism
• Willemsen-Swinkels 1996 extension DBPC
  crossover design with 4 weeks in each
  treatment
• Doses from 0.74 to 1.18 mg/kg/day
• No significant differences in parent rated ABC-
  I
• Significant differences in teacher rated ABC-I
• No serious adverse effects
• Only 2/20 subjects had “mild SIB” at baseline
        Naltrexone and Autism
• Further blinded studies of 13 children aged 3-
  8 years show improvements in hyperactivity
  and restlessness on teacher and parent rated
  scales
• No significant differences in an extension
  study
• Overall modest effects on hyperactivity and
  restlessness, no efficacy in core social and
  cognitive symptoms or SIB
           Other medications
• Secretin failed to show significant differences
  from placebo in 5 DBPC trials
• Omega-3 fatty acid failed to show significance
  in one small DBPC study of 13 youths
                   Conclusions
• Careful diagnosis and evaluation
• Pharmacotherapy is only part of an overall
  approach
  – Target symptoms not core symptoms
• Go slow, go low
  – Side effects
• Study the data
                 References
Aman, M. “Management of Hyperactivity and Other
  Acting-Out Problems in Patients with Autism
  Spectrum Disorder”, Seminars in Pediatric
  Neurology 11:225-228, 2004.
Dinca, O. et al, “Systematic review of randomized
  controlled trials of atypical antipsychotics and
  selective serotonin reuptake inhibitors for
  behavioral problems associated with pervasive
  developmental disorders”, Journal of
  Psychopharmacology 19(5) (2005) 521-532.
                References
• Parikh et al, “Psychopharmacology of
  Aggression in Children and Adolescents with
  Autism: A Critical Review of Efficacy and
  Tolerability”, Journal of Child and Adolescent
  Psychopharmacology vol 18, no 2, 2008.
• Posey et al, “The Use of Selective Serotonin
  Reuptake Inhibitors in Autism and Related
  Disorders”, Journal of Child and Adolescent
  Pyschopharmacologyvol 16, no 1 and 2, 2006.