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

Disclaimer

• I have no financial or research interests in any of the medications

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

Introduction

• ASD are a heterogeneous group of disorders– Clinical manifestations vary

in presentation & intensity• Treatments must be

individualized– Weigh potential risks &

benefits

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

Introduction

• Medications available do not directly treat core features of autism – i.e. social-communication impairments

• Treat behavioral manifestations of the underlying brain pathology

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

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

Target Symptoms

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

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

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

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

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

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

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

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

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

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

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

Other Antiepileptics•Carbamazepine (Tegretol) •Gabapentin (Neurontin)•Lamotrigine (Lamictal)•Topiramate (Topamax)•Oxcarbazepine (Trileptal)•Levetiracetam (Keppra)

Aggression, Irritability & Self-Injury

• 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

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)

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

• 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

• 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

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

Other Agents•Hollander E, et al, 2006

– Small RCT (13 individuals) of Valproate– Showed significant improvement of

RRBs/rigidity vs. placebo

Repetitive Behaviors & Rigidity

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

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

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

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

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

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

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

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

Hyperactivity & Inattention

Other Agents•Valproate•Topiramate•Lamotrigine

• 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

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

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

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

Sleep Disturbance

Other Agents

•Risperidone

•Clonidine

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

Side-effects

Side-effects: Antipsychotics

• Neuroleptic malignant syndrome• Extra-pyramidal symptoms• Agranulocytosis• Cardiovascular changes• Galactorrhea• Weight gain & metabolic disorder• Sedation

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 ???

Side-effects: Stimulants

• Appetite supression

• Irritability

• Sleep disturbance

• Dullness/social withdrawal

• Headaches

• Tremors/tics

• Cardiovascular symptoms

Side-effects: Alpha-Agonists

• Sedation (especially clonidine)

• Aggression/irritability

• Dry mouth

• Constipation

• Nocturnal enuresis

• Dizziness

• Hypotension & bradycardia

General Guidelines

“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

“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

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

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

Case 3

• 14 yo female with ASD and severe intellectual disability

• Frequent aggression & self-injury• Prior trials of Adderall, Concerta & Zoloft

worsened behaviors

• 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

• 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

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

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

Choosing a Medication

• Likelihood of improvement in target symptoms

• Potential adverse effects

• Practical considerations – Formulations– Dosing schedule– Lab monitoring

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

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