Pharmacology of Pervasive Developmental Disorders December 4, 2008 W. David Lohr, M.D. email@example.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.
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