1. Heather Damhoff, PharmD Clinical Specialist – Pediatric Intensive Care Kosair Children’s Hospital PHARMACOTHERAPY OF AUTISM SPECTRUM DISORDERS: A SMALL PIECE OF THE PUZZLE

2.  Continuum of neurodevelopmental disorders characterized by deficits in:  Social communication and interactions  Restrictive, repetitive patterns of behaviors, interests, activities  Prevalence  Parent reported – 2%  CDC – 1 in every 88 children  1 in 54 males  1 in 252 females  Increase of 23% compared to 2006 WHAT IS AUTISM SPECTRUM DISORDER (ASD)? Harv Rev Psych 2014; 22(2):76-92.

3. Autism Spectrum Disorder Asperger disorderPDD Autistic disorder

4.  In addition to the core symptoms may patients with ASD experience co-occurring psychiatric and behavioral problems  Aggression  Self – injury  Impulsivity  Hyperactivity  Anxiety  Mood symptoms INDICATIONS FOR MEDICATION THERAPY Curr Opin Psychiatry 2015; 28:91-101.

5. REVIEW OF ANTIPSYCHOTIC USE

6.  FDA approved medications for irritability (aggression, self injury, severe tantrums)  Risperidone (Risperdal ® )  Aripiprazole (Abilify ® ) ANTIPSYCHOTIC USE IN ASD

7.  Mechanism of Action RISPERIDONE

8. RISPERIDONE – SHORT TERM Risperidone in Children with Autism and Serious Behavioral Problems Design Randomized, double-blind, placebo-controlled Population Children 5 – 17 years with ASD Risperidone (49), Placebo (52) Primary Outcome Score on the Irritability subscale of the Aberrant Behavior Checklist Rating on the Clinical Global Impressions (CGI-I) scale Intervention < 20 kg: 0.25 mg at bedtime 20 – 45 kg: 0.5 mg at bedtime, ↑ 0.5 mg BID on Day 4 (max: 2.5 mg/day by Day 29) > 45 kg: Accelerated dose schedule (max 2.5 mg/day) N Engl J Med 2002; 347:314-231

9. RISPERIDONE – SHORT TERM

11. Risperidone in Children with Autism and Serious Behavioral Problems Medication Dose Mean daily dose during final week: 1.8 mg (range, 0.5 – 3.5 mg) Adverse Events Increased weight Fatigue Drowsiness Conclusion Risperidone safe and effective for the short-term treatment of tantrums, aggression and self-injurious behavior in ASD Reserve for treatment of moderate-to-severe behavioral problems Am J Psychiatry 2005;162:1361-1369

12. RISPERIDONE – LONG TERM Aripiprazole in Children with Autism: Long Term Benefits Design Extension trial Population Children 5 – 17 years with ASD 63 patients from Phase 1 Primary Outcome Aberrant Behavior Checklist – Irritability Clinical Global Impression – Improvement Intervention Clinicians allowed to adjust dose for response/adverse effects 15 – 45 kg: up to 3.5 mg > 45 kg: up to 4.5 mg Am J Psychiatry 2005;162:1361-1369

13. RISPERIDONE – LONG TERM Risperidone in Children with Autism: Long Term Benefits Outcomes Irritability score: 59% reduction from mean rating at initiation of treatment CGI-I: 82.5% improved or very much improved Medication dosage Only 6% increase in mean dose over 4 month period Adverse Effects Increased appetite Tiredness Drowsiness Discontinuation Relapse rate: 62.5% in placebo-treated group, 12.5% in continued risperidone group Immediately stopped Conclusion Risperidone safe and effective up to 6 months for treatment of tantrums, aggression and self-injurious behavior in ASD Little evidence of accommodation effects Am J Psychiatry 2005;162:1361-1369

14. RISPERIDONE – CORE SYMPTOMS Risperidone for the Core Symptoms of Autism Secondary Outcomes Ritvo-Freeman Real Life Rating Scale Compulsion scale – Children’s Yale-Brown Obsessive Compulsive Scale Maladaptive behavior domain of Vineland Adaptive Behavior Scale Hypothesis Risperidone is superior to placebo for reducing repetitive behavior and improves measures of social relatedness and impaired communication Am J Psychiatry 2005; 162:1142–1148

15. RITVO-FREEMAN REAL LIFE Am J Psychiatry 2005; 162:1142–1148

16. YALE-BROWN OBSESSIVE COMPULSIVE SCALE Am J Psychiatry 2005; 162:1142–1148

17. VINELAND ADAPTIVE BEHAVIOR Am J Psychiatry 2005; 162:1142–1148

18.  Indication:  FDA approved for treatment of irritability associated with ASD in children and adolescents  Dosing:  Dosing:  Higher doses 1.25 – 1.75 mg/day have been shown to be more effective; however, lowest effective dose should be use RISPERIDONE - SUMMARY WeightInitial DoseTitration 15 – 20 kg 0.25 mg/day After ≥ 4 days increase to 0.5 mg/day After ≥ 14 days increase by 0.25 mg/day at 2 week intervals ≥ 20 kg 0.5 mg /day After ≥ 4 days increase to 1 mg/day After ≥ 14 days increase by 0.5 mg/day at 2 week intervals

19.  Adverse Effects:  Weight gain  Increased appetite  Fatigue  Drowsiness  Dizziness  Drooling  Dosage Forms:  Oral solution: 1 mg/mL  Tablets: 0.25, 0.5, 1, 2, 3, 4 mg  Dispersible tablet: 0.25, 0.5, 1, 2, 3, 4 mg RISPERIDONE - SUMMARY

20. ARIPIPRAZOLE – SHORT TERM Aripiprazole in the Treatment of Irritability in Children with ASD Design Randomized, double-blind, placebo-controlled Population Children 6 – 17 years with ASD Aripiprazole (47), Placebo (51) Primary Outcome Mean change from baseline in the Aberrant Behavior Checklist Secondary Outcome Rating on the Clinical Global Impressions (CGI-I) scale Intervention Initial dose: 2 mg Target dose: 5, 10, or 15 mg/day N Engl J Med 2002; 347:314-231

21. ARIPIPRAZOLE – SHORT TERM Pediatrics 2009;124:1533-1540.

22. ARIPIPRAZOLE – SHORT TERM Pediatrics 2009;124:1533-1540.

23. ARIPIPRAZOLE – SHORT TERM Aripiprazole in the Treatment of Irritability in Children with ASD Medication Dose 2 mg/day (5%) 5 mg/day (33%) 10 mg/day (41%) 15 mg/day (21%) Adverse Events Increased appetite Fatigue Somnolence/sedation Vomiting Conclusion Aripiprazole was efficacious and generally well tolerated in the treatment of irritability associated with ASD Long-term controlled trials are warranted Pediatrics 2009;124:1533-1540.

24. ARIPIPRAZOLE– LONG TERM Aripiprazole in Children with Autism: Long Term Benefits Design Double-blind, randomized, placebo-controlled, relapse-prevention trial Population Children 6 – 17 years with ASD Phase 1: 157 patients Phase 2: 85 patients Aripiprazole (41), Placebo (44) Primary Outcome Time from randomization to relapse Determined using ABC-I and CGI-I Intervention 2 – 15 mg/day J Clin Psychiatry 2014;75(1):22-30.

25. ARIPIPRAZOLE – LONG TERM Aripiprazole in the Treatment of Irritability in Children with ASD Primary Outcome Relapse Rates at week 16 35% for aripiprazole 52% for placebo Post-hoc NNT = 6 to prevent 1 additional relapse Adverse Events Weight gain Increased appetite Somnolence Vomiting Upper respiratory tract infection Conclusion Some patients will benefit from maintenance aripiprazole therapy J Clin Psychiatry 2014;75(1):22-30.

26.  Indication:  FDA approved for treatment of irritability associated with ASD in children and adolescents  Dosing:  Dosing:  Adverse Effects:  Weight gain  Vomiting  Increased appetite  Nasopharyngitis  Dosage Forms:  Oral solution: 1 mg/mL  Tablet: 2, 5, 10, 15, 20, 30 mg  Dispersible tablet: 10, 15 mg ARIPIPRAZOLE- SUMMARY Initial DoseTitration 2 mg/day After 7 days may increase to 5 mg/day Increase by 5 mg/day every ≥ 7 days to maximum of 15 mg/day

27. RISPERIDONE VS. ARIPIPRAZOLE Head to Head Comparison for Risperidone and Aripiprazole in ASD Design Prospective, randomized clinical trial Population 59 children and adolescents with ASD Aripiprazole (29), Risperidone (30) Primary Outcome Aberrant Behavior Checklist – Irritability subscale Clinical Global Impression – Improvement Intervention Risperidone 10 – 40 kg: 0.25 mg/day titrated to max 2 mg/day > 40 kg: 0.25 mg/day titrated to max 3 mg/day Aripiprazole < 40 kg: 1.25 mg/day titrated to max 10 mg/day > 40 kg: 1.25 mg/day titrated to max 15 mg/day Child Psychiatry Hum Dev 2014;45:185-192.

28. RISPERIDONE VS. ARIPIPRAZOLE p = 0.5 Child Psychiatry Hum Dev 2014;45:185-192.

29. RISPERIDONE VS. ARIPIPRAZOLE Head to Head Comparison for Risperidone and Aripiprazole in ASD Adverse Effects (Aripiprazole vs Risperidone) Increased appetite (34.5% vs 40%) Increased drooling (31% vs 40% Drowsiness (20.7% vs 16.7%) Conclusion Safety and efficacy of aripiprazole (mean dose 5.5 mg/day) and risperidone (1.12 mg/day) were comparable Child Psychiatry Hum Dev 2014;45:185-192.

30.  Olanzapine (Zyprexa ® )  Effective in improving behavioral measures in a RDBPC study  Significantly more weight gain than placebo  Haloperidol  Improved behavioral symptoms  Use is limited due to risk of extrapyramidal symptoms OTHER ANTIPSYCHOTICS

31. COMPLEMENTARY AND ALTERNATIVE MEDICINE (CAM) TREATMENTS

32.  Higher rates of usage in families of children with ASD  28 – 95%  Commonly used CAM treatments for ASD  Natural products: 13 – 54%  Special diet: 17 – 33%  Mind and body practices: 25 – 30%  Goals of treatment:  Relief of specific symptoms  Alleviation of side effects of conventional treatments  Philosophic reasons  Wanting greater control over health management USE OF CAM IN ASD Child Adolesc Psychiatric Clin N Am 2015;24:117-143.

33.  Gluten and/or caesin-free diets  2002 – RCT, single blind  10 pairs of autistic children  GFCF diet or normal diet  Follow up – 1 year  Observed modification of attention, social and emotional factor, cognitive level, language and motor skills  2011 – Prospective, randomized, parallel group  22 children with ASD  GFCF diet or healthy, low-sugar diet  No difference in core symptoms DIETARY INTERVENTION Nutritional Neuroscience 2002;5(4):251-261 Journal of Developmental and Physical Disabilities 2011;23(3):213-225.

34.  Reason for use:  Essential for brain development and function  Hypothesis behind use in ASD not fully formulated  Cochrane review of 2 randomized trials:  Total n = 37  Dose 1.3 – 1.5 g/day  Duration 6 – 12 weeks  No significant effect on ABC OMEGA – 3 FATTY ACIDS Cochrane Database of Systematic Reviews, vol. 11, Article ID CD007992, 2011

35.  Reason for use:  Frequently observed dietary deficiency of vitamins/micronutrients in children with ASD  Combined Vitamin B6-Magnesium  Cochrane review of 3 randomized trials:  Data could not be meta-analyzed due to significant heterogeneity  All 3 trials reported no significant difference compared to placebo  Vitamin B12  Double-blind, placebo-controlled, randomized, crossover trial  No difference from placebo  Open label trial  Significant improvement in Vineland total and subscales score VITAMIN SUPPLEMENTATION Cochrane Database of Systematic Reviews, no. 4, Article ID CD003497, 2005.. J Alt Com Med 2010;16(5):555-560. Autism Research and Treatment 2013; Article ID 609705.

36.  What is it?  Administration of chemical substances for the purpose of binding and then withdrawing specific metals from a person’s body  Why in ASD?  Theoretical basis for mercury or other heavy metals as cause of ASD  Interfere with developmental processes implicated in ASD  Examples of Chelating Agents CHELATION NameHeavy metal targetRouteCommon adverse effects DMSALead, arsenic, mercury poisoning OralRash, GI upset EDTACalciumIVFatigue, thrombophlebitis, hypocalciemia DMPSArsenic, bismuth subcitrate, mercury, Wilson’s disease (copper) IV and OralRash, nausea, dysgeusia Edetate calcium disodium LeadIV and IMFatigue, nephrotoxicity Cochrane Database Syst Rev. 2015 May 11;5:CD010766

37.  Cochrane Review  To assess evidence for the effects of pharmaceutical chelating agents for symptoms of ASD  Only 1 randomized trial included  Phase 1: 7 days glutathione lotion or placebo lotion followed by 3 days of of oral DMSA  Phase 2: 3 days of oral DMSA or placebo followed by 11 days off, cycle repeated up to 6 times  NO effect on ASD symtpoms  Review conclusion:  No clinical trial evidence that suggests chelation is an effective strategy for ASD  Risks outweigh benefits (Reported renal impairment, hypocalcemia, death) CHELATION Cochrane Database Syst Rev. 2015 May 11;5:CD010766

38. NOVEL THERAPIES FOR ASD

39. TARGETED THERAPY Exp Neurobiol 2015;24(4):301-311.

40. GABA (inhibitory) Glutamate (excitatory) GLUTAMATE/GABA AGENTS AgentStudy Outcome NAC (NMDA modulator)Improved irritability Amantadine, Memantine(NMDA antagonist) No efficacy shown alone Improvement in behavior in combination with risperidone Curr Opin Psychiatry 2015;28:91-101.

41. OXYTOCIN Oxytocin Social behaviors

42. StudyResults Watanabe et al 6 week IN oxytocin Significantly improved social reciprocity Oxytocin-induced enhancement of resting-state connectivity between anterior cingulate cortex and dorso-medial prefrontal cortex Gordon et al Functional MRI study with IN oxytocin Enhanced activity for social stimuli Attenuated response to non-social stimuli Most therapeutic when used before evidence-based behavioral treatments Enhances social learning OXYTOCIN Over a dozen clinical trials are currently recruiting! JAMA Psychiatry 2014;71:166-175. Proc Natl Acad Sci 2013;110:20953-20958.

43.  Disturbance in opiate system  Chronic elevation of endogenous opiates  self-injurious behavior and hypoalgesia  Naltrexone  Competitive antagonist at opioid receptor  Outcomes  Review of 10 RDBPC trials  May improve hyperactivity and restlessness  No evidence of impact on core symptoms NALTREXONE J Intellect Disabil Res 2014;E pub ahead of print

44.  Despite high rates of medication usage in ASD, current evidence-based pharmacotherapy options are extremely limited  Risperidone and aripiprazole are effective in reducing irritability, stereotypy and hyperactivity  Data regarding efficacy of CAM in ASD is limited  New pharmacotherapy options for severely impairing co- existing and core symptoms are in urgent need CONCLUSIONS

45. Heather Damhoff, PharmD Clinical Specialist – Pediatric Intensive Care Kosair Children’s Hospital PHARMACOTHERAPY OF AUTISM SPECTRUM DISORDERS: A SMALL PIECE OF THE PUZZLE