Decision Making and Antipsychotic Medication Treatment for Youth With Autism Spectrum Disorders: Applying Guidelines in the Real World

Decision Making and Antipsychotic Medication Treatment for Youth With Autism Spectrum Disorders: Applying Guidelines in the Real World

Stephanie H. Ameis, MD, MSc; Patricia Corbett-Dick, RN, MS, PNP, PMH NP; Lynn Cole, RN, MS, PNP; and Christoph U. Correll, MD

Autism spectrum disorder (ASD) is a diagnosis that is characterized by varying degrees of (1) impairment in social reciprocity, (2) impairment in social communication, and (3) repetitive, restrictive, stereotyped patterns of interests, activities, and behaviors.1 While ASD prevalence varies across regions, recent prevalence rates range from 1:88 children in the United States2 to 1:160 children worldwide.3

Currently, only 2 atypical antipsychotics, risperidone (in 5- to 16-year-olds) and aripiprazole (in 6- to 17-year-olds), are approved by the US Food and Drug Administration (FDA) for treatment of significant irritability (aggression toward others, deliberate self-injuriousness, temper tantrums, and labile moods) associated with ASD. In a recent report on 2,843 children and adolescents (collectively referred to here as youth) with ASD, 4% of 3- to 5-year-olds, 14% of 6- to 11-year-olds, and 23% of 12- to 17-year-olds were treated with atypical antipsychotics.4 The frequent use of atypical antipsychotics in youth with ASD necessitates careful evaluation of the indication, benefits, and risks of these agents. This is especially important since youth with ASD may be at greater risk for atypical antipsychotic-related significant weight gain (≥ 7% of pretreatment weight in short-term studies) compared to youth with schizophrenia or bipolar disorder5 (although this result may be due to reduced prior atypical antipsychotic exposure in youth with ASD6). In this article, we review treatment strategies for youth with ASD, focusing on the adaptation of monitoring and management guidelines for atypical antipsychotic-related adverse effects.

EVALUATION AND MANAGEMENT OF ASD

The gold-standard ASD diagnosis is made by a team of specialists using standardized diagnostic tools (Autism Diagnostic Observation Schedule,7 Autism Diagnostic Interview-Revised8) in combination with clinical judgment.9 Assessment challenges include determining functional abilities in cognitive, language, and social domains; contribution of genetic/metabolic etiologies; and presence of comorbid medical/neurologic disorders (eg, epilepsy) and comorbid psychiatric symptoms/disorders requiring clinical intervention (eg, irritability, inattention, impulsivity, anxiety, depression, sleep disruption).9 Primary treatment for core ASD symptoms centers on evidence-based educational and behavioral interventions.10

While pharmacologic agents do not treat core ASD symptoms, certain agents are useful in reducing comorbid symptoms that impair functioning and interfere with therapeutic and scholastic progress.11 A small number of well-powered randomized controlled trials (RCTs) in youth with ASD demonstrated the efficacy of (1) risperidone and aripiprazole in treating significant irritability (with additional positive effects on hyperactivity and stereotypy)12-15; (2) haloperidol (typical antipsychotic) in reducing symptoms of negativism (angry/labile affect),16 although adverse effects (dystonias, withdrawal dyskinesias) limit its use17; and (3) methylphenidate in treating hyperactivity and impulsiveness, although effect sizes may be lower and adverse effects higher in youth with ASD compared to youth with primary attention-deficit/hyperactivity disorder.18 Conversely, 2 large RCTs19,20 failed to demonstrate the efficacy of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and citalopram in reducing repetitive behaviors in ASD. No RCT has yet examined the effect of SSRIs on mood and anxiety symptoms in ASD; therefore, evidence of efficacy for these indications is currently lacking.

MONITORING AND MANAGEMENT OF ADVERSE EFFECTS IN ATYPICAL ANTIPSYCHOTIC-TREATED YOUTH AND ADAPTATION TO ASD

Youth treated with atypical antipsychotics are at increased risk of developing extrapyramidal symptoms (EPS; parkinsonism and dystonia), withdrawal dyskinesias, prolactin-related adverse effects, dyslipidemia, and weight gain compared to adults.5,21,22 Below, we summarize guidelines for adverse effect monitoring and management in atypical antipsychotic-treated youth23-25 and provide recommendations for overcoming clinical challenges to applying these guidelines to youth with ASD.

Monitoring During Atypical Antipsychotic Use in Youth (adapted from references 22-24)

• Baseline and annually: Assess personal/family history (cardiovascular/metabolic illness, seizures/other neurologic disorder, past treatment response/adverse effects, lifestyle factors [diet/exercise]) and current treatments/potential interaction effects with atypical antipsychotics (eg, fluoxetine and paroxetine may inhibit hepatic metabolism of aripiprazole and risperidone, resulting in increased blood levels of atypical antipsychotic).
• Every visit: Monitor (1) treatment efficacy, (2) basic clinical measures (height, weight, body mass index [BMI] percentile [assessing overweight or obese status], BMI z-score [tracking sex- and age-adjusted body weight trends over time], blood pressure), (3) lifestyle factors, (4) somnolence/sedation, (5) prolactin-related adverse effects (eg, galactorrhea, gynecomastia, oligorrhea/amenorrhea; measure blood prolactin levels if adverse effects are present), and (6) new medications and interaction effects with atypical antipsychotics.
• Baseline, 3 and 6 months on treatment, and every 6 months thereafter: Perform blood work to monitor liver function, fasting glucose, glycosylated hemoglobin, and lipids. Use clinical judgment to assess whether less-frequent monitoring (ie, baseline, 6 months, annually) is appropriate in patients with low adverse effect risk or when significant barriers to more-frequent blood draws are present.
• Baseline, during titration, and every 3 months thereafter: Monitor for movement disorders with objective rating scales (eg, Abnormal Involuntary Movement Scale,26 Simpson-Angus Rating Scale27).

Adverse Effect Management During Atypical Antipsychotic Use in Youth (adapted from references 22 and 28)

Weight gain and metabolic abnormalities.

• At treatment initiation: Provide healthy lifestyle counseling/intervention, begin with an atypical antipsychotic with low adverse effect risk.
• If adverse effect occurs: Provide healthy lifestyle/weight-loss counseling/intervention, switch to lower-risk atypical antipsychotic.
• If adverse effect progresses: Provide healthy lifestyle or weight-loss counseling/intervention, switch to lower-risk atypical antipsychotic. Consider targeted treatment for abnormal weight, laboratory value, or blood pressure value (eg, lipid-lowering diet for dyslipidemia)29 and specialist referral.

Neuromotor adverse effects.

• General: “Start low, go slow, but go” regarding atypical antipsychotic use.
• Parkinsonism, dystonia (EPS): Reduce dose, add anticholinergic medication, switch to lower-risk agent.
• Akathisia: Reduce dose, add benzodiazepine or β-blocker, switch to lower-risk agent.
• Dyskinesia: Review indication/consider stopping, switch to lower-risk agent.

Other adverse effects.

• General: “Start low, go slow, but go”; adjust dose; switch to lower-risk agent.

Adaptations for Atypical Antipsychotic Use
in Youth With ASD

Complementary information for the adaptations outlined in this section can be found in 2 freely available clinical resources: the Autism Speaks Autism Treatment Network (ATN) series of tool kits on Challenging Behaviors, Visual Supports, Blood Draws, Safe and Effective Medicine Use, and Medication Decision Aid30 (http://www.autismspeaks.org/family-services/tool-kits) and the Treatment of Maladaptive Aggression in Youth (T-MAY) Tool Kit28,31 (http://www.thereachinstitute.org/tmay.html).

Determining whether atypical antipsychotic treatment is needed.

• Assess meaning, origin, and impact of the treatment target:
• Assess potential medical (ie, pain), psychiatric (ie, anxiety), and situational factors/triggers (ie, sensitivity to transitions or sensory stimuli, exposure to bullying) contributing to target symptom expression.
• Establish the function of behavior (eg, escape, avoidance, attention), evaluating antecedents, behaviors, and consequences (“ABCs”).
• Compare “ABCs” across settings, using collateral information.
• Use behavioral interventions to help youth identify alternative/more rewarding ways to communicate needs (see ATN Challenging Behaviors Tool Kit30).
• Atypical antipsychotics are indicated for irritability in ASD; however, stereotypy, hyperactivity, tics, and sleep may also improve with atypical antipsychotic treatment.
• Clearly explain to families the benefits and risks of various treatment options. Decision aids can be used to help families improve knowledge regarding treatment options and the benefits and risks and reach choices that are consistent with their values32 (see ATN Medication Decision Aid and Autism and Medication Tool Kit30 and reference 33).

Identifying and tracking target symptoms.

• Use objective measures at baseline to establish target symptom frequency, intensity, and duration across settings (home/school/community).
• Establish treatment response expectations in advance and review regularly.
• Use brief objective rating scales in the clinic to monitor symptom severity and frequency (see T-MAY Tool Kit28,31).
• Consider commonly occurring sensory sensitivities in youth with ASD (eg, sensitivity to taste or to swallowing pills) to improve medication adherence. Aripiprazole and risperidone are available as disintegrating oral tablets and liquid, which can be mixed with soft food (eg, applesauce). Youth can also practice pill swallowing with candies or using a pill-swallowing cup.30

Monitoring/managing cardiometabolic adverse effects.

• Obtaining basic clinical measures (height, weight, blood pressure) and regular bloodwork may pose unique challenges in youth with ASD. Every effort should be made to ensure that metabolic monitoring is completed with minimal distress. Simple behavior supports such as visual schedules, use of simple language (eg, “First….then….”), behavior modeling, and inclusion of families in procedures promote cooperation in the clinic (see ATN Visual Supports Tool Kit30).
• The ATN Blood Draw Tool Kit30 provides strategies to parents and providers for completing successful blood draws in youth with ASD, including instructions regarding relaxation and distraction, topical anesthetics, reinforcements, and visual supports.
• Weight management may be challenging in youth with ASD due to dietary selectivity or presence of hypotonia/motor delays that interfere with physical activity. Families often benefit from consultation regarding portion size and healthy food choices with a registered dietician. Support around developing/implementing an exercise program across settings may be helpful.30

Monitoring movement abnormalities/disorders.

• Monitoring for movement disorders in youth with ASD can be challenging, as baseline stereotypic and repetitive behaviors can be mistaken for atypical antipsychotic-related neuromotor adverse effects.
• Comprehensively assess abnormal movements at baseline and follow-up, using objective rating scales26,27 (individualized strategies and family member participation may be required for compliance).
• Record all repetitive and stereotyped behaviors present at baseline. If families consent, video recordings can be helpful to refer back to if motor symptoms arise during atypical antipsychotic treatment.

CONCLUSION

Youth with ASD require careful diagnostic evaluation to rule out addressable environmental causes of problem behaviors. Although the atypical antipsychotics risperidone and aripiprazole are currently the only FDA-approved treatments for youth with ASD, atypical antipsychotics target irritability, not core ASD deficits. Given the related adverse effects, atypical antipsychotics should be reserved for youth with severe symptoms not responding to nonpharmacologic interventions or lower-risk medication options. Clinicians must help families to carefully weigh risks and benefits of atypical antipsychotics prior to treatment initiation. Advanced treatment planning including ASD-specific adaptations will help facilitate successful treatment, adverse effect monitoring, and management in youth with ASD.

Author affiliations: The Centre for Addiction and Mental Health and the Hospital for Sick Children, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (Dr Ameis); Division of Neurodevelopmental and Behavioral Pediatrics, University of Rochester Medical Center, University of Rochester School of Nursing, Rochester (Mss Corbett-Dick and Cole); Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, and Hofstra North Shore—Long Island Jewish School of Medicine, Hempstead (Dr Correll), New York.

Potential conflicts of interest: Dr Ameis receives financial support from an Ontario Mental Health Foundation Research Training Fellowship. Dr Correll has been a consultant and/or advisor to or has received honoraria from Actelion, Alexza, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, GersonLehrman Group, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, Janssen/Johnson & Johnson, Novartis, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva, and Vanda and has received grant support from Bristol-Myers Squibb, Ortho-McNeil/Janssen/Johnson & Johnson, and Otsuka. Mss Corbett-Dick and Cole have no conflict of interest to disclose.

Funding/support: No funding support was received for this article.

Disclaimer: The views expressed in this publication do not necessarily reflect the views of Autism Speaks, Inc.

Acknowledgments: This research was conducted as part of the Autism Speaks Autism Treatment Network (ATN) and with input from the ATN Psychopharmacology Committee. Further support came from a cooperative agreement (UA3 MC 11054) from the US Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Research Program, to the Massachusetts General Hospital.

Corresponding author: Christoph U. Correll, MD, Division of Psychiatry Research, The Zucker Hillside Hospital, 75-59 263rd St, Glen Oaks, NY 11004 ([email protected]).

REFERENCES

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC: American Psychiatric Association; 2013.

2. Centers for Disease Control and Prevention. Prevalence of Autism Spectrum Disorders among multiple areas of the United States in 2008. Community Report From the Autism and Developmental Disabilities Monitoring (ADDM) Network, 2012. http://www.cdc.gov/ncbddd/autism/documents/ADDM-2012-Community-Report.pdf. Accessed July 18, 2013.

3. Elsabbagh M, et al. Autism Res. 2012;5(3):160-179. doi:10.1002/aur.239 PubMed

4. Coury DL, et al. Pediatrics. 2012;130(suppl 2):S69-S76. doi:10.1542/peds.2012-0900D PubMed

5. De Hert M, et al. Eur Psychiatry. 2011;26(3):144-158. doi:10.1016/j.eurpsy.2010.09.011 PubMed

6. Correll CU, et al. JAMA. 2009;302(16):1765-1773. doi:10.1001/jama.2009.1549 PubMed

7. Lord C, et al. J Autism Dev Disord. 2000;30(3):205-223. doi:10.1023/A:1005592401947 PubMed

8. Lord C, et al. J Autism Dev Disord. 1994;24(5):659-685. doi:10.1007/BF02172145 PubMed

9. Johnson CP, et al. Pediatrics. 2007;120(5):1183-1215. doi:10.1542/peds.2007-2361 PubMed

10. Myers SM, et al. Pediatrics. 2007;120(5):1162-1182. doi:10.1542/peds.2007-2362 PubMed

11. Siegel M, Beaulieu AA. J Autism Dev Disord. 2012;42(8):1592-1605. doi:10.1007/s10803-011-1399-2 PubMed

12. McCracken JT, et al. N Engl J Med. 2002;347(5):314-321. doi:10.1056/NEJMoa013171 PubMed

13. Shea S, et al. Pediatrics. 2004;114(5):e634-e641. doi:10.1542/peds.2003-0264-F PubMed

14. Marcus RN, et al. J Am Acad Child Adolesc Psychiatry. 2009;48(11):
1110-1119. doi:10.1097/CHI.0b013e3181b76658 PubMed

15. Owen R, et al. Pediatrics. 2009;124(6):1533-1540. doi:10.1542/peds.2008-3782 PubMed

16. Anderson LT, et al. Am J Psychiatry. 1984;141(10):1195-1202. PubMed

17. Campbell M, et al. J Am Acad Child Adolesc Psychiatry. 1997;36(6):835-843. doi:10.1097/00004583-199706000-00022 PubMed

18. Research Units on Pediatric Psychopharmacology Autism Network. Arch Gen Psychiatry. 2005;62(11):1266-1274. doi:10.1001/archpsyc.62.11.1266 PubMed

19. King BH, et al. Arch Gen Psychiatry. 2009;66(6):583-590. doi:10.1001/archgenpsychiatry.2009.30 PubMed

20. Autism Speaks ATN. Autism Speaks announces results reported for the Study of Fluoxetine in Autism (SOFIA). 2009. www.autismspeaks.org/about-us/press-releases/autism-speaks-announces-results-reported-study-fluoxetine-autism-sofia. Accessed July 18, 2013.

21. Correll CU, et al. Child Adolesc Psychiatr Clin N Am. 2006;15(1):177-206. doi:10.1016/j.chc.2005.08.007 PubMed

22. Correll CU. J Am Acad Child Adolesc Psychiatry. 2008;47(1):9-20. doi:10.1097/chi.0b013e31815b5cb1 PubMed

23. Findling R, Drury S, Jensen P, et al; AACAP Committee on Quality Issues. Practice parameters for the use of atypical antipsychotic medications in children and adolescents 2011. http://www.aacap.org/App_Themes/AACAP/docs/practice_parameters/Atypical_Antipsychotic_Medications_Web.pdf. Accessed July 18, 2013.

24. Panagiotopoulos C, et al. J Can Acad Child Adolesc Psychiatry. 2010;19(2):124-137. PubMed

25. Pringsheim T, et al. Paediatr Child Health (Oxford). 2011;16(9):581-589. PubMed

26. National Institute of Mental Health. Psychopharmacol Bull. 1985;21:1077-1080.

27. Simpson GM, Angus JW. Acta Psychiatr Scand suppl. 1970;212(S212):11-19. doi:10.1111/j.1600-0447.1970.tb02066.x PubMed

28. Scotto Rosato N, et al. Pediatrics. 2012;129(6):e1577-e1586. doi:10.1542/peds.2010-1361 PubMed

29. De Hert M, et al. Nat Rev Endocrinol. 2012;8(2):114-126. doi:10.1038/nrendo.2011.156 PubMed

30. Autism Speaks ATN. Tool kits. http://www.autismspeaks.org/family-services/tool-kits.

31. Knapp P, et al. Pediatrics. 2012;129(6):e1562-e1576. doi:10.1542/peds.2010-1360 PubMed

32. Stacey D, et al. Med Decis Making. 2012;32(3):E22-E33. doi:10.1177/0272989X12443311 PubMed

33. US Dept Health and Human Services, Substance Abuse and Mental Health Services Administration. Shared decision making in mental health. http://store.samhsa.gov/shin/content/SMA09-4371/SMA09-4371.pdf.

J Clin Psychiatry 2013;74(10):1022-1024 (doi:10.4088/JCP.13ac08691)

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