Microsoft word - 280529-pharmacotherapy for autism.doc

PL Detail-Document #280529
−This PL Detail-Document gives subscribers additional insight related to the Recommendations published in− PHARMACIST’S LETTER / PRESCRIBER’S LETTER
Management of Autism-Related Symptoms
The prevalence of Autistic Spectrum Disorders (ASD) is on the rise, with the latest CDC statistics citing one in 88 children in the U.S. are diagnosed with ASD.1 Autistic Spectrum Disorders (i.e., autism, Asperger's disorder, pervasive developmental disorder not otherwise specified [PDD-NOS], Rett disorder, and childhood disintegrative disorder) are characterized by impaired socialization, delayed and unusual communication, and repetitive behaviors and/or restricted interests.2-4 In addition to these core characteristics of autism, many patients also have behavioral symptoms such as hyperactivity, aggression, tantrums, self-injury, and other undesirable behaviors.4 Intensive behavioral and educational therapy are the backbone of autism treatment.2,3 Although there is no cure for ASD, several psychotropic agents have been used off-label to manage dysfunctional behaviors associated with autism when behavioral therapy is not enough. Children with autistic spectrum disorders are more sensitive to the effects of drugs. It is important to initiate therapy at the lowest dose possible and titrate dosing slowly as necessary. Since children with autistic spectrum disorders have limited communication skills, it is important to closely monitor response and adverse effects associated with drug therapy. Information about medications that have been used to manage symptoms associated with ASD is listed in the chart below. If parents ask about secretin, explain there is no evidence that it’s helpful for autism. A Cochrane review shows it doesn’t work.17 Abbreviations: ASD=Autistic Spectrum Disorder; GI=gastrointestinal; SSRI=selective serotonin
reuptake inhibitor.
NOTE: Weight-based doses should not exceed the normal adult dose.
Drug or Drug Class Target Symptoms4-7,10
Guanfacine is well tolerated and effective for
hyperactivity and inattention.4,5 Guanfacine is less sedating than clonidine and may be better tolerated.5 Clonidine has sedative effects and has been shown to
reduce sleep latency and nighttime waking in children with ASD in addition to decreasing irritability, hyperactivity, inappropriate speech, and oppositional Side effects of alpha-agonists include sedation,
hypotension, rebound hypertension if discontinued abruptly, dry mouth, dizziness, irritability, increased aggression and self-injury, decreased appetite, sleep disturbance. Blood pressure and heart rate should be monitored at each visit.4,5 Amantadine 5 mg/kg/day has been shown to modestly improve hyperactivity and inappropriate speech in children and adolescents with autism in a small
double-blind, placebo-controlled study.11 It is thought
to work by modulating glutamatergic activity.11
Side effects include orthostatic hypotension, anxiety,
depression, fatigue, irritability, etc.16
Copyright 2012 by Therapeutic Research Center P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 ~ ~ (PL Detail-Document #280529: Page 2 of 6)
Drug or Drug Class Target Symptoms4-7,10
Divalproex sodium (Depakote) has been shown to
improve repetitive behaviors in children with ASD in a small, randomized trial.4,7 Mean doses studied were 500 mg to 1500 mg/day (usually given in divided
doses).7 Divalproex sodium can potentially improve
affective instability, impulsivity, and aggression
associated with ASD.11
Levetiracetam (Keppra) was found to be beneficial in
reducing hyperactivity, impulsivity, aggression, and
affective lability in a small (n=12) open-label study.11
Side effects include dizziness, headache, somnolence,
Overall effect in children with ASD and symptoms of ADHD is smaller than for children with isolated
Side effects include GI symptoms, fatigue, sleep
problems, mood swings, suicidal ideation, dizziness,
and change in appetite.4
Aripiprazole (Abilify) and risperidone (Risperdal) are the only FDA-approved agents for treatment of irritability, self-injurious, and aggressive behaviors in irritability, hyperactivity, children with ASD. These agents are not approved for ASD in Canada, but are often used off-label. Risperidone is approved in the U.S. for treatment of
irritability associated with ASD in children aged five to 16 years.8 The target dose is 0.5 mg/day (<20 kg) Aripiprazole is approved in the U.S. for treatment of
irritability associated with ASD in children aged six to 17 years.9 The recommended target dose is 5 mg to 10 mg/day, with an initial dose of 2 mg/day and maximum dose of 15 mg/day.9 Olanzapine (Zyprexa) has been shown to improve disruptive behaviors in children with ASD in several small prospective studies (only one was blinded).4 Evidence supporting the use of clozapine (Clozaril), quetiapine (Seroquel), and ziprasidone (Geodon) are primarily open-label studies or case series. More research is needed before they can be recommended for use in the treatment of disruptive behavior in children with ASD.4 Side effects include weight gain, hyperglycemia, and
hyperlipidemia, extrapyramidal symptoms,
drowsiness, lethargy, drooling, etc.4,8-10,15
Copyright 2012 by Therapeutic Research Center P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 ~ ~ (PL Detail-Document #280529: Page 3 of 6)
Drug or Drug Class Target Symptoms4-7,10
Several small, prospective studies suggest that buspirone may improve anxiety, irritability, tantrums, and hyperactivity in patient ASD.11 Doses studied were between 10 mg to 45 mg/day (usually given in divided doses).11 Side effects include dizziness, drowsiness, headache,
nervousness, etc.16
Preliminary data suggest cholinesterase inhibitors (donepezil [Aricept], galantamine [Razadyne (U.S.); Reminyl ER (Canada)], tacrine [Cognex, U.S. only], and rivastigmine [Exelon]) show some benefit for dysfunctional behaviors, hyperactivity, and expressive speech in patients with ASD.6,11 Until more data are available, it is uncertain whether these drugs have any role in the treatment of social and language impairment associated with ASD.6 The use of clomipramine for repetitive behaviors in children with ASD is based on its effect in individuals with OCD.4 However, studies of clomipramine for repetitive behaviors in children with ASD have shown inconsistent results.4 Side effects include lethargy, tremors, tachycardia,
insomnia, diaphoresis, nausea, decreased appetite,
urinary retention, and severe constipation.4
Randomized controlled trials suggest haloperidol is effective in reducing behavioral symptoms.4,10 However, it is less effective than risperidone.4 irritability, hyperactivity, Doses ranging from 0.25 mg/day to 4 mg/day (usually social withdrawal, and given in divided doses) have been found to be effective in children ages 2 to 7.5 years old.12 Haloperidol at an average dose of 1.7 mg/day (usually given in divided doses) resulted in significant improvement in withdrawal and stereotypy in children >4.5 years old.10 Side effects include sedation, extrapyramidal
symptoms (dystonias, withdrawal dyskinesias), which
develop in about one-third of the patients.4,10
Lithium Aggression Lithium has been shown to be effective for manic
symptoms, aggression, and self-injury associated with ASD in case reports.20 Side effects include diarrhea, nausea, vomiting, dry
mouth, somnolence, etc.16
Copyright 2012 by Therapeutic Research Center P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 ~ ~ (PL Detail-Document #280529: Page 4 of 6)
Drug or Drug Class Target Symptoms4-7,10
Melatonin can potentially improve sleep onset and maintenance in children with ASD.4 Recommend 0.5 mg to 1 mg/day taken 30 to 60 minutes before bedtime and increase dose by 1 mg as needed to a maximum of 10 mg/day.4 Side effects include daytime drowsiness, headache,
dizziness, etc.19
In controlled studies, naltrexone has been shown to have some positive effect on hyperactivity but not self-harming behaviors.11 However, naltrexone is not commonly used in ASD.11 The use of an SSRI for repetitive behaviors in children with ASD is based on data of SSRIs in the treatment of OCD.4 Positive effects in ASD is not significant when adjusted for publication bias.13 Expect modest, There are no randomized trials assessing the anxiolytic effect of SSRIs in children with ASD. However, SSRIs have been shown to be effective in reducing the core symptoms of anxiety in children and adolescents without ASD.4 Fluoxetine (Prozac) has the most evidence in
reducing repetitive behaviors in children and
adolescents with ASD.4 A mean dose of
9.9 + 4.35 mg/day was found to be effective in a
placebo-controlled trial.14 In another open-label trial
0.2 mg to 1.4 mg/kg/day was tried.18
Fluvoxamine (Luvox) was found to improve
repetitive thoughts and behavior, maladaptive
behavior and repetitive language usage in adults, but
not in children.6
Citalopram (Celexa) did not improve repetitive
behaviors and was associated with an increased risk of
side effects such as impulsivity, decreased
concentration, hyperactivity, stereotypy, diarrhea, and
insomnia in children with ASD.4,7
Escitalopram (Lexapro [U.S.]; Cipralex [Canada])
was shown to somewhat improve irritability, lethargy,
stereotypy, hyperactivity, and inappropriate speech in
an open-label trial.4
Sertraline (Zoloft), in open-label trials, has been
shown to improve repetitive and disruptive behaviors
in adults with ASD.4

Side effects
of SSRIs include sedation, anorexia,
agitation, headaches, aggression, anxiety, activation,
insomnia, GI upset, and drowsiness.4
Copyright 2012 by Therapeutic Research Center P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 ~ ~ (PL Detail-Document #280529: Page 5 of 6)
Drug or Drug Class Target Symptoms4-7,10
Methylphenidate has been shown to improve
hyperactivity and inattention in children with ASD in randomized crossover trials.4,5,7 However, the
response rate to methylphenidate is lower in children
with ASD vs children with ADHD without ASD.4,5
Effective doses ranged from 0.25 mg/kg/day to
0.5 mg/kg/day.7 Methylphenidate also may have
beneficial effects on social communication and self-
Though frequently used in clinical practice, studies on
amphetamines are lacking and it is unclear whether
results from trials of methylphenidate can be
generalized to amphetamines.4
Side effects of stimulants include sleep disturbance,
decreased appetite, irritability, tics, sadness, dullness,
and social withdrawal. Children with ASD are more
prone to stimulant side effects than children without

Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other
necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our
editors have researched the information with input from experts, government agencies, and national organizations.
Information and internet links in this article were current as of the date of publication.

Copyright 2012 by Therapeutic Research Center P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 ~ ~ (PL Detail-Document #280529: Page 6 of 6)
Project Leader in preparation of this PL Detail-
9. Product information for Abilify. Bristol-Myers Document: Wan-Chih Tom, Pharm.D.
Squibb. Otsuka America Pharmaceutical, Inc. 10. Kaplan G, McCracken JT. Psychopharmacology of References
Autism Spectrum Disorders. Pediatr Clin North Am 1. CDC Press Release. CDC estimates 1 in 88 children in the United States has been identified as having an autism spectrum disorder. March 29, behavioral symptoms in autism and pervasive developmental disorders. J Clin Psychiatry tism_disorder.html. (Accessed April 15, 2012). 12. Anderson LT, Campbell M, Adams P, et al. The 2. Agency for HealthCare Research and Quality. effects of haloperidol on discrimination learning and Therapies for children with autism spectrum behavioral symptoms in autistic children. J Autism disorders: comparative effectiveness review No. Dev Disord 1989;19:227-39. [Abstract] 26. Executive summary. April 2011. AHRQ Pub. Pharmacologic treatment of repetitive behaviors in autism spectrum disorders: evidence of publication ts/106/651/Autism_Disorder_exec-summ.pdf. bias. Pediatrics. Published online, April 23, 2012. 3. Warren Z, Veenstra-Vander-Weele J, Stone W, et 14. Hollander E, Phillips A, Chaplin W, et al. A placebo al. Therapies for children with autism spectrum controlled crossover trial of liquid fluoxetine on disorders. Comparative effectiveness review No. repetitive behaviors in childhood and adolescent 26. (prepared by the Vanderbilt Evidence-based autism. Neuropsychopharmacology 2005;30:582- Practice Center under Contract No. 290-2007- 10065-I). AHRQ Publication No. 11-EHC029-EF. 15. PL Detail-Document, Atypical Antipsychotics in Rockville, MD: Agency for Healthcare Research Kids. Pharmacist’s Letter/Prescriber’s Letter. 16. Lexicomp Online. Hudson, OH: Lexi-Comp, Inc. (Accessed April 25, 2012). 17. Williams K, Wray JA, Wheeler DM. Intravenous secretin for autism spectrum disorders (ASD) Autism spectrum disorders in children and Updated. Cochrane Summaries. Published online: adolescents: pharmacologic interventions. Last reviewed April 29, 2011. Literature review current ous-secretin-for-autism-spectrum-disorders-asd. (Accessed April 6, 18. Stigler KA, Posey DJ, McDougle CJ. Drug therapy 5. Murray MJ. Attention-deficit/hyperactivity disorder algorithms target autism’s problem behaviors. in the context of autism spectrum disorders. Curr 19. Jellin JM, Gregory PJ, et al. Natural Medicines 6. Posey DJ, Erickson CA, McDougle CJ. Developing (Accessed April impairment in autism. Child Adolesc Psychiatr Clin 20. McDougle CJ, Stigler KA, Posey DJ. Treatment of 7. Nazeer A. Psychopharmacology of autistic aggression in children and adolescents with autism spectrum disorders in children and adolescents. and conduct disorder. J Clin Psychiatry Janssen Pharmaceuticals Inc. Titusville, NJ 08560. September 2011.
Cite this document as follows: PL Detail-Document, Management of Autism-Related Symptoms. Pharmacist’s
Letter/Prescriber’s Letter. May 2012.

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