Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
PHARMACOTHERAPY OF AUTISM SPECTRUM DISORDERS: A SMALL PIECE OF THE PUZZLE Heather Damhoff, PharmD C l i n i c al S p e c i al i s t – Pe d i a t r i c I n te n s i v e C a r e Ko s a i r C h i l d r e n ’ s H o s p i t al WHAT IS AUTISM SPECTRUM DISORDER (ASD)? 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 Harv Rev Psych 2014; 22(2):76-92. Autism Spectrum Disorder Asperger disorder PDD Autistic disorder INDICATIONS FOR MEDICATION THERAPY 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 Curr Opin Psychiatry 2015; 28:91-101. REVIEW OF ANTIPSYCHOTIC USE ANTIPSYCHOTIC USE IN ASD FDA approved medications for irritability (aggression, self injury, severe tantrums) Risperidone (Risperdal ® ) Aripiprazole (Abilify ® ) RISPERIDONE Mechanism of Action 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 RISPERIDONE – SHORT TERM RISPERIDONE – SHORT TERM RISPERIDONE – SHORT TERM 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 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 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 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 RITVO-FREEMAN REAL LIFE Am J Psychiatry 2005; 162:1142–1148 YALE-BROWN OBSESSIVE COMPULSIVE SCALE Am J Psychiatry 2005; 162:1142–1148 VINELAND ADAPTIVE BEHAVIOR Am J Psychiatry 2005; 162:1142–1148 RISPERIDONE - SUMMARY Indication: FDA approved for treatment of irritability associated with ASD in children and adolescents Dosing: Dosing: Weight Initial Dose Titration 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 Higher doses 1.25 – 1.75 mg/day have been shown to be more effective; however, lowest effective dose should be use RISPERIDONE - SUMMARY Adverse Ef fects: 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 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 ARIPIPRAZOLE – SHORT TERM Pediatrics 2009;124:1533-1540. ARIPIPRAZOLE – SHORT TERM Pediatrics 2009;124:1533-1540. 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. 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. ARIPIPRAZOLE – LONG TERM Aripiprazole in the Treatment of Irritability in Children with ASD • 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 Primary Outcome • J Clin Psychiatry 2014;75(1):22-30. ARIPIPRAZOLE- SUMMARY Indication: FDA approved for treatment of irritability associated with ASD in children and adolescents Dosing: Dosing: Initial Dose 2 mg/day Titration • • After 7 days may increase to 5 mg/day Increase by 5 mg/day every ≥ 7 days to maximum of 15 mg/day Adverse Ef fects: 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 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. RISPERIDONE VS. ARIPIPRAZOLE p = 0.5 Child Psychiatry Hum Dev 2014;45:185-192. 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. OTHER ANTIPSYCHOTICS 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 COMPLEMENTARY AND ALTERNATIVE MEDICINE (CAM) TREATMENTS USE OF CAM IN ASD 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 Child Adolesc Psychiatric Clin N Am 2015;24:117-143. DIETARY INTERVENTION 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 Nutritional Neuroscience 2002;5(4):251-261 Journal of Developmental and Physical Disabilities 2011;23(3):213-225. OMEGA – 3 FATT Y ACIDS 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 Cochrane Database of Systematic Reviews, vol. 11, Article ID CD007992, 2011 VITAMIN SUPPLEMENTATION 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 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. CHELATION 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 A gents Name Heavy metal target Route Common adverse effects DMSA Lead, arsenic, mercury poisoning Oral Rash, GI upset EDTA Calcium IV Fatigue, thrombophlebitis, hypocalciemia DMPS Arsenic, bismuth subcitrate, mercury, Wilson’s disease (copper) IV and Oral Rash, nausea, dysgeusia Edetate calcium disodium Lead IV and IM Fatigue, nephrotoxicity Cochrane Database Syst Rev. 2015 May 11;5:CD010766 CHELATION 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) Cochrane Database Syst Rev. 2015 May 11;5:CD010766 NOVEL THERAPIES FOR ASD TARGETED THERAPY Exp Neurobiol 2015;24(4):301-311. GLUTAMATE/GABA AGENTS GABA (inhibitory) Glutamate (excitatory) Agent Study Outcome NAC (NMDA modulator) Improved irritability Amantadine, Memantine(NMDA antagonist) • • Curr Opin Psychiatry 2015;28:91-101. No efficacy shown alone Improvement in behavior in combination with risperidone OXY TOCIN Oxytocin Social behaviors OXY TOCIN Study Results 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 • • • • • • Over a dozen clinical trials are currently recruiting! JAMA Psychiatry 2014;71:166-175. Proc Natl Acad Sci 2013;110:20953-20958. NALTREXONE Disturbance in opiate system Chronic elevation of endogenous opiates self-injurious behavior and hypoalgesia J Intellect Disabil Res 2014;E pub ahead of print Naltrexone Competitive antagonist at opioid receptor Outcomes Review of 10 RDBPC trials May improve hyperactivity and restlessness No evidence of impact on core symptoms CONCLUSIONS Despite high rates of medication usage in ASD, current evidence-based pharmacotherapy options are extremely limited Risperidone and aripiprazole are ef fective in reducing irritability, stereotypy and hyperactivity Data regarding ef ficacy of CAM in ASD is limited New pharmacotherapy options for severely impairing co existing and core symptoms are in urgent need PHARMACOTHERAPY OF AUTISM SPECTRUM DISORDERS: A SMALL PIECE OF THE PUZZLE Heather Damhoff, PharmD C l i n i c al S p e c i al i s t – Pe d i a t r i c I n te n s i v e C a r e Ko s a i r C h i l d r e n ’ s H o s p i t al