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Another Piece of the Puzzle: the Role of Medication in the Care of Individuals on the Autism Spectrum
Valentina Intagliata, MDValentina Intagliata, MD
Assistant Professor of PediatricsAssistant Professor of Pediatrics
UVa ChildrenUVa Children’’s Hospitals Hospital
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Disclaimer
• I have no financial or research interests in any of the medications
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Objectives
• Recognize target symptoms in children with ASD which can be treated with medications
• Be familiar with medications used commonly in children with ASD
• Be aware of the possible side-effects of these medications
• Case presentations
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Introduction
• ASD are a heterogeneous group of disorders– Clinical manifestations vary
in presentation & intensity• Treatments must be
individualized– Weigh potential risks &
benefits
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Introduction
• Behavioral & educational approaches are the cornerstone of comprehensive treatment for core symptoms
• Medications may be a useful
adjunct to treat common
comorbid symptoms – after
behavioral & environmental
interventions have been
maximized
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Introduction
• Medications available do not directly treat core features of autism – i.e. social-communication impairments
• Treat behavioral manifestations of the underlying brain pathology
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Introduction
• Most existing evidence on medication use is extrapolated from studies on comorbid conditions (e.g. ADHD, OCD, anxiety) in children without ASD
• Studies in children with ASD are generally small, retrospective & unblinded – Also, lack of diagnostic tools standardized in
the ASD population
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Introduction
• Most medications are not FDA-approved for use in children with ASD– Exceptions:
• Risperidone & Aripiprazole• Methylphenidate
• Many other medications are used off-label– Parents/caregivers should be informed of this
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Target Symptoms
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Target Symptoms
• Behaviors that interfere with learning, health, safety, socialization, quality of life, and/or overall functioning– Aggression, irritability & self-injury– Repetitive behaviors & rigidity– Hyperactivity & inattention– Anxiety & depression– Sleep disturbance
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Aggression, Irritability & Self-Injury
• Aggression & related disruptive behavior generally elicit the most concern in ASD
• These behaviors can lead to injury & isolation• High prevalence of these
symptoms (Kanne et al, 2011)
• 68% to caregivers • 49% to non-caregivers
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Antipsychotics•Efficacy of antipsychotics in autistic children was first documented in the 1970s• Now commonly used for ASD
– Risperidone & Aripiprazole are the only 2 FDA-approved agents for aggression
Aggression, Irritability & Self-Injury
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Antipsychotics•Anderson LT & Campbell M et al, 1984
– RCT of Haloperidol (~1.7 mg/d) – Significant improvement in aggression
(negativism, angry affect & mood lability)– However…
• Sedation common • 1/3 children developed dystonia & withdrawal
dyskinesias
Aggression, Irritability & Self-Injury
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Antipsychotics•Risperidone was first “atypical antipsychotic”•RUPP, 2005
– RCT of Risperidone (~2.08 mg/d) – Effective in decreasing moderate-severe
tantrums, aggression & self-injurious behavior– Effects stable over time w/o dose increase,
but relapse w/ medication withdrawal at 6 mos
Aggression, Irritability & Self-Injury
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Antipsychotics•Risperidone quickly
became first-line treatment•FDA approved Risperidone in 2006 for autism
– Ages 5-16 yo with max dose 3 mg/d
Aggression, Irritability & Self-Injury
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Moderators and Mediators of Risperidone Effect• Higher symptom severity associated with greater
improvement• Weight gain mediates treatment response
negatively• Socioeconomic advantage, low baseline prolactin
and absence of anxiety, bi-polar symptoms, ODD, stereotopy & hyperactivity correlates with positive outcome
• Intensive behavioral intervention in addition to risperidone resulted in the best outcome in autism with aggression
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Antipsychotics•Aripiprazole is another “atypical antipsychotic” •Marcus RN et al, 2009
– RCT of Aripiprazole (5, 10, 15 mg/d)– All doses superior to placebo– Extrapyramidal symptoms but which rarely led
to discontinuation
Aggression, Irritability & Self-Injury
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Antipsychotics•FDA approved Aripiprazole
in 2009 for autism– Ages 6-17 yo with max dose 15 mg/d
•Other antipsychotics lack large-scale RCTs– Variable benefits of Olanzapine & Zipraside
based on small open-label studies– Quetiapine does not appear to be beneficial
Aggression, Irritability & Self-Injury
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Stimulants•Methylphenidate (MPH) has been examined for Tx of aggression in ASD ages 5-11 yo•Quintana H et al, 1995; Handen BL et al, 2000
– RCTs, but small & short duration– Superiority over placebo – High rate of side-effects
Aggression, Irritability & Self-Injury
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Other Agents•Valproate showed modest superiority & min side-effects in RCT (Hollander E, et al, 2010)•Naltrexone & Clonidine showed superiority in RCT (Parikh MS et al, 2008)•Not considered first-line agents
Aggression, Irritability & Self-Injury
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Other Antiepileptics•Carbamazepine (Tegretol) •Gabapentin (Neurontin)•Lamotrigine (Lamictal)•Topiramate (Topamax)•Oxcarbazepine (Trileptal)•Levetiracetam (Keppra)
Aggression, Irritability & Self-Injury
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• No clinical algorithm exists for• Clinicians generally start with
lower risk alternatives• However, poor response &
serious symptoms, these agents are often replaced by one of two FDA-approved antipsychotics
Aggression, Irritability & Self-Injury
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Repetitive Behaviors & Rigidity
• Restricted, repetitive & stereotyped behaviors (RRBs), interests & activities (“rigidity”) are characteristic of ASDs– Lower-level motor behaviors (e.g. rocking) – Higher-level routines/rituals (e.g. insistence
on sameness)
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Selective Serotonin Reuptake Inhibitors•Initial use based on reports on serotoninergic dysfunction in ASD & shared symptomatology with OCD which responds to SSRIs •Most common class of psychotropics
for individuals with ASD– Evidence is marginal from RCTs
Repetitive Behaviors & Rigidity
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• Hollander et al, 2005– RCT of Fluoxetine (~10 mg/d)– Better than placebo – 39 children 5-16 yo
• SOFIA, 2011– RCT of Fluoxetine– No benefit over placebo over 14-wks– 158 children 5-17 yo
Repetitive Behaviors & Rigidity
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• King BH et al, 2009– Large RCT of Citalopram (2.5-20 mg/d)– No significant difference b/w Tx & control– 149 children ages 5-17 yo– 1/3 experienced serotoninergic activation
(increased activity, mood changes, insomnia)• Owley T et al, 2005
– Open-label RCT of Escitalopram – More positive effects on irritability
Repetitive Behaviors & Rigidity
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Atypical Antipsychotics•RRBs were examined as secondary outcomes in studies discussed previously
– Risperidone significantly greater reduction vs. placebo (RUPP, 2005)
– Aripiprazole significantly improved RRBs vs. placebo (Marcus RN et al, 2009)
Repetitive Behaviors & Rigidity
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Other Agents•Hollander E, et al, 2006
– Small RCT (13 individuals) of Valproate– Showed significant improvement of
RRBs/rigidity vs. placebo
Repetitive Behaviors & Rigidity
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Repetitive Behaviors & Rigidity
• RRBs/rigidity constitute frequent problematic behavior in children with ASD
• Tx choices are difficult given relative lack of support of efficacy & side-effects can be difficult to tolerate
• Clinicians advised to recognize Tx limitations & reserve medication to those with severe RRBs
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Hyperactivity & Inattention
• High prevalence of hyperactivity & inattention in children with ASD– Between 30-80% meeting criteria for ADHD
• These children have more severe difficulties vs. ASD alone
• Multiple agents have been investigated to treat these symptoms
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Stimulants
•Role of stimulants in typical children is well-documented
•Third most common class of medications used in ASD
– Methylphenidate (MPH)
is used preferentially – Studies on amphetamines are lacking
Hyperactivity & Inattention
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Stimulants•RUPP, 2005
– RCT of MPH (0.15mg/kg, 0.25mg/kg, 0.5mg/kg)– All doses superior to placebo– Even highest effect size was much lower vs.
typical children– 18% discontinued medication due to side-effects
Hyperactivity & Inattention
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Adverse Effects of Stimulants in Children with ASD• Can increase perseveration,
repetitive behaviors & irritability• May increase anxiety• May lead to increased sensory
processing difficulties• Often better tolerated & more useful
in mild range of ASD• Less effective in the presence of
significant intellectual disability
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Atypical Antipsychotics•RUPP, 2002
– RCT of Risperidone– Secondary analysis showed large reduction in
hyperactivity in children with ASD•Owen et al, 2009
– RCT of Aripiprazole– Significant improvement over placebo
Hyperactivity & Inattention
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Other Agents•Arnold LE et al, 2006
– Small, pilot placebo-controlled crossover study of Atomoxetine (1.2-1.4 mg/kg)
– Significant improvement vs. placebo– Effects comparable to MPH in ASD– Tolerable side-effects– Concomitant use of other psychotropics
Hyperactivity & Inattention
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Other Agents•Small, controlled trial of Clonidine showed superior reduction in disruptive behaviors (Jaselskis CA et al, 1992)•Small, open-label prospective study of Guanfacine showed moderate benefit (47% response) for high levels of hyperactivity & inattention (Scahill L et al, 2006)
–Well-tolerated
Hyperactivity & Inattention
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Hyperactivity & Inattention
Other Agents•Valproate•Topiramate•Lamotrigine
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• None of the highly effective Tx for ADHD (i.e. stimulants) in typically developing children have same robust response in ASD– High rate of side-effects even a low doses
• Alpha-agonists deserve more research and often form a solid second-line Tx choice
• Antipsychotics can be effective for hyperactivity, but less favored
Hyperactivity & Inattention
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Anxiety & Depression
• Research is lacking in effects of psychotropics for depression & anxiety in children with ASD
• Strong empirical support exists for SSRIs in typical children; uncertain whether this translates to those with ASD
• Some support exists for use of these medications in adults with ASD– High rate of significant adverse effects
(“activation”) in children greatly tempers enthusiasm
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Sleep Disturbance
• Children w/ ASD experience sleep disturbance at much higher rates
• Chronic sleep disturbance is disruptive to overall functioning & quality of family life
• Lack of FDA-approved medications for this problem
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Sleep Disturbance
Melatonin•RCTs of Melatonin (Sanchez-Barcelo EJ, 2011)•Up to 6 mg/d was found to be effective•No significant side-effects•Long-term Tx has not been studied
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Sleep Disturbance
Other Agents
•Risperidone
•Clonidine
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Social Deficits
• Medications that may improve social deficits in children with ASD include:– Atypical antipsychotic, SSRIs– Oxyctocin– Memantine, Amantadine– Lamotrigine, D-cycloserine– Galantamine, Rivastigmine, Donepezil– Tetrahydrobiopterin
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Side-effects
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Side-effects: Antipsychotics
• Neuroleptic malignant syndrome• Extra-pyramidal symptoms• Agranulocytosis• Cardiovascular changes• Galactorrhea• Weight gain & metabolic disorder• Sedation
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Side-effects: SSRIs
• Neuropsychiatric (10-30%)
• Especially activation (agitation, disinhibition, hyperkinesia), may be more common in younger patients
• Initial worsening of anxiety & OCD
• GI upset (10%)
• Suicidal thinking & behavior ???
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Side-effects: Stimulants
• Appetite supression
• Irritability
• Sleep disturbance
• Dullness/social withdrawal
• Headaches
• Tremors/tics
• Cardiovascular symptoms
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Side-effects: Alpha-Agonists
• Sedation (especially clonidine)
• Aggression/irritability
• Dry mouth
• Constipation
• Nocturnal enuresis
• Dizziness
• Hypotension & bradycardia
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General Guidelines
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“Rules of Thumb”
• Identify specific problematic behaviors
• Address environmental issues that may be exacerbating the behaviors
• Start low and go slow
• Address sleep difficulties early
• Change one variable at a time
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“Rules of Thumb”
• Children with ASD are more sensitive to psychotropic medications – thus more likely to have adverse effects
• It is often difficult (due to limited communication and difficulty identifying emotions) to determine the predominant target symptom & thus the best medication
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Case 1
• 3 yo male with ASD• Up all night, hyperactive, aggressive,
constantly in dangerous situations• Attends a special education pre-school
program where similar behaviors are occurring
• Family is exhausted
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Case 2
• 8 yo male with ASD
• Anxious, constant repetitive behaviors, inattentive at school, many sensory processing issues
• Prior trials of Adderall & Concerta made the situation worse
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Case 3
• 14 yo female with ASD and severe intellectual disability
• Frequent aggression & self-injury• Prior trials of Adderall, Concerta & Zoloft
worsened behaviors
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• Anderson LT, Campgell M, et al. Haloperidol in the treatment of infatile autism: effects on learning & behavioral symptoms. Am J Psychiatry 1984; 141(10):1195-202.
• Handen Bl et al. Efficacy of mehtylphenidate among children with autism and symptoms of ADHD. J Autism Dev Disord 2000;30:245-55.
• Hollander E, et al. A placebo-controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism. Neuropsychopharmacology 2005;30:582-9.
• Hollander E, et al. Divalproex sodium vs. placebo in the treatment of repetiitve behaviors in autism spectrum disorder. Int J Neuropsychopharmacol 2006;9(2):209-13.
• Hollander E, et al. Divalproex sodium vs. placebo for the treatment of irritability in cildren and adolescents with autism specrum disorders. Neuropsychopharmacology 2010;35:990-8.
• Kanne SM, Mazurek MO. Aggression in children and adolescents with ASD: prevalence and risk factors. J Autism Dev Disord 2011;41(7):926-37.
• Kaplan G & McCracken JT. Psychopharmacology of Autism Spectrum Disorders. Pediatr Clin N Am 2012;59:175-187.
• Marcus RN et al. A placebo-controlled, fixed-dose study of apriprazole in children & adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry 2009;48(11):1110-9.
References
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• Owen R, et al. Aripiprazole in the treatment of irritability of children & adolescents with autistic disorder. Pediatrics 2009;124:1533-40.
• Owley T, et al. An open-label trial of escitalopram in PDD. J Am Acad Child Adolesc Psychiatry 2005;44(4):343-8.
• Parikh MS et al. Psychopharmacology of aggression in children and adolescents with autsim: a critical review of efficacy & tolerability. J Child Adolesc Psychopharmacol 2008;18(2):157-78.
• Quintana H et al. Use of methylphenidate in the treatment of children with autistic disorder. J Autism Dev Disord 1995;25:283-94.
• RUPP. Risperidone in children with autism and serious behavioral problems. Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. N Engl J Med 2002;347:314-21.
• RUPP. Randomized, controlled, crossover trial of methylphenidate in PDD with hyperativity. Research nits on Pediatric Psychopharmacology (RUPP) Autism Network. Arch Gen Psychiatry 2005;62(11):1266-74.
• Sanchez-Barcelo EJ et al. Clinical uses of melatonin in pediatrics. Int J Pediatr 2011;89:24-26.
• SOFIA. Available at:http://wwww.autismspeaks.org/about-us/press-releases/autism-speaks-announces-results-reported-study-fluoxetine-autism-sofia.
References
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References
• Arnold LE, et al.: Moderators, mediators, and other predictors of risperidone response in children with autistic disorder and irritability. Journal of Child & Adolescent Psychopharmacology. 20(2):83-93, 2010 Apr.
• Erickson CA, et al.: A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology (2007) 191:141-147
• Findling RL: Pharmacologic treatment of behavioral symptoms in autism and pervasive developmental disorders. J Clin Psychiatry 2005;66(suppl 10):26-31
• Frazier TW, et al.: Effectiveness of medication combined with intensive behavioral intervention for reducing aggression in youth with autism spectrum disorder. Journal of Child & Adolescent Psychopharmacology. 20(3):167-77, 2010 Jun.
• Grant P, et al.: An open-label trial of riluzole, a glutamate antagonist, in children with treatment-resistant obsessive-compulsive disorder. J Child Adolescent Psychopharmacology (2007) 17(6):761-767
• King BH, et al.: Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism. Archives of general Psychiatry. 66(6):583-90, 2009 Jun.
• Mandell DS, et al.: Psychotropic medication use among Medicaid-enrolled children with autism spectrum disorders. Pediatrics 2008;121;e441-e448
• Masi G, et al., Aripiprazole monotherapy in children and young adolescents with pervasive developmental disorders: a retrospective study. CNS Drugs. 23(6):511-21, 2009
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References
• McCracken JT: Safety issues with drug therapies for autism spectrum disorders. J Clin Psychiatry 2005;66(suppl 10):32-37
• Myers SM: The status of pharmacotherapy for autism spectrum disorders. Expert Opin. Pharmacother. (2007) 8(11):1579-1603
• Nickels K, et al., Stimulant medication treatment of target behaviors in children with autism: a population-based study. Journal of Developmental & Behavioral Pediatrics. 29(2):75-81, 2008 Apr.
• Parikh MS, et al., Psychopharmacology of aggression in children and adolescents with autism: a critical review of efficacy and tolerability. Journal of Child & Adolescent Psychopharmacology. 18(2):157-78, 2008 Apr.
• Rosenberg RE, et al., Psychotropic medication use among children with autism spectrum disorders enrolled in a national registry, 2007-2008. Journal of Autism & Developmental Disorders. 40(3):342-51, 2010 Mar.
• Rossignol DA. Novel and emerging treatments for autism spectrum disorders: a systematic review. Annals of Clinical Psychiatry. 21(4):213-36, 2009 Oct-Dec.
• Rubin DM, et al., State variation in psychotropic medication use by foster care children with autism spectrum disorder. Pediatrics. 124(2):e305-12, 2009 Aug.
• Williams K, et al., Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD) (Review). The Cochrane Library 2010, Issue 8
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Choosing a Medication
• Likelihood of improvement in target symptoms
• Potential adverse effects
• Practical considerations – Formulations– Dosing schedule– Lab monitoring
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Stimulant or SSRI?
• External versus internal distractibility
• External distractibility is seen in ADHD
• Many children with ASD have a prominent ADHD component (dual diagnosis)
• Internal distractibility is a result of the anxiety and behavioral rigidity that is a part of ASDs
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Combining Medications
• Consider a phone call or referral to a sub-specialist; be willing to continue with management and monitoring
• Be wary of increased drug interactions with 3 or more medications
• Low doses of 2 medications may be better than a high dose of one