Role of ADHD medication in children with autism spectrum disorder Pieter Hoekstra University of Groningen, Netherlands Symptoms of ADHD are highly prevalent in children with ASD Two independent chart reviews reported that 59% (Goldstein & Schwebach, 2004) and 78% (Lee & Ousley, 2006), respectively, of referred children with ASD fulfilled full DSM IV criteria for an ADHD subtype. Overlap between ADHD and Autism ADHD comorbidity in ASD needs clinical attention ASD+ADHD: – more general psychopathology (internalizing + externalizing symptoms) – more impairments on the social interaction scale of the ADI-R Holtmann et al., 2005 ADHD comorbidity in ASD needs clinical attention ADHD symptoms in children with ASD – associated with more severe oppositional, aggressive, and ASD symptoms – can interfere with ability to benefit from psychosocial treatments Gadow, DeVincent, & Pomeroy, 2006 Medication options for ADHD in ASD • • • • Alpha Agonists (clonidine) Psychostimulants Atomoxetine Antipsychotics? Clonidine • Open label retrospective study (N=19) • Improvement in reducing sleep initiation latency and night awakening, • To a less degree improvement in ADHD, mood instability, and aggressiveness Ming et al Brain & Development 30 (2008) 454–460 Clonidine cross-over with placebo • N=8 • Improvement on – – – – ABC irritability Stereotypy, Hyperactivity Inappropriate speech • Main side effects – Drowsiness – Decreased activity. Jaselskis et al (1992) J Clin Psychopharmacol. 12(5):322-7 Transdermal clonidine Plb cross-over trial • N=9 • Improvement on three subscales of the Ritvo-Freeman Real Life Rating Scale: – social relationship to people – affectual responses – sensory responses • Sedation and fatigue during the first 2 weeks of clonidine treatment Fankhauser et al, (1992). J Clin Psychiatry; 53(3):77-82 Clonidine conclusions • Very few controlled data! • Positive effects on sleep latency and hyperactivity? • Is effect sedating or truly enhancing inattention? Methylphenidate • Historical data and beliefs negative • Small studies support use of MPH in autism • Anecdotal reports of a high frequency of adverse drug reactions including stereotypies and social withdrawal Quintana et al (1995), J Autism dev Disorders Handen et al (2000), J Autism Dev Disorders RUPP Study of MPH in Children with ASD + Hyperactivity • 72 children with autism, Asperger’s, or PDDNOS and significant ADHD symptoms • Design – 7-day test dose period – 4-week double blind cross-over trial of 3 dose levels (0.125, 0.25, 0.50 mg/kg/dose) of MPH t.i.d. and placebo in random order RUPP (2005) Arch Gen Psychiatry Test-dose phase • 6 out of 72 subjects were unable to tolerate > 2 dose levels of MPH and were dropped from the study • 16 out of the remaining 66 subjects had intolerable adverse effects at the highest dose of MPH; entered modified crossover phase • Irritability was the most common reason for intolerability Cross-over phase • 58/66 subjects completed the cross-over phase • 7 subjects dropped out due to intolerable adverse effects • Significant main effect of dose of MPH on the ABC hyperactivity subscale as rated by both teacher (p=0.009) and parent (P<0.001) Cross-over phase: Other ABC Subscales • Worsening of parent-rated social withdrawal at high-dose MPH (P<0.001) • No changes in other subscales (irritability, stereotypy, inappropriate speech) Categorical response Asperger’s/ PDDNOS (N=19) Autism (N=47) Plb Low Medium High 6 (32%) 7 (37%) 7 (37%) 6 (32%) 6 (13%) 13 (28%) 15 (32%) 12 (26%) Most common side effects of MPH in ASD • • • • • Appetite decrease (24%) Difficulty falling asleep (18%) Emotional outburst (13%) Irritability (12%) Stomach discomfort (7%) Rupp, 2005 MPH RUPP summary • Methylphenidate superior to placebo (effect sizes 0.20 to 0.54) on hyperactivity ABC (MTA: 0.35-.1.31) • 35/72 (49%) responders. • Discontinuation 18% (MTA: 1.4%) • No effect on irritability, lethargy/social withdrawal, stereotypy, or inappropriate speech Methylphenidate-secondary effects • Hyperactivity and impulsivity improved more than inattention. • No effects on ODD or stereotyped and repetitive behavior • Effects on joint attention initiations, response to bids for joint attention, self-regulation, and regulated affective state (examined through direct observation) Jahromi et al, 2008; Posey et al, 2007 Atomoxetine % vs. baseline in prefrontale cortex Direct on noradrenaline, indirect on dopamine Serotonin Dopamine Noradrenaline 400 350 * P < 0.05 vs. baseline 300 250 * 200 * 150 100 50 Atomoxetine 1 mg/kg i.p. 0 -1 0 1 2 3 4 Time (hours) Data from rat study Bymaster et al.2002 Three open label studies; atomoxetine in ASD • Posey, et al; Journal of Child & Adolescent Psychopharmacology, 16, 5, 2006; 599-610 n=16, 75% improved on the CGI-I • Troost, et al; Journal of Child & Adolescent Psychopharmacology, 16, 5, 2006; 611-619 n=12 , decreased with 44% measured by the ADHDRS • Jou, et al; Journal of Child & Adolescent Psychopharmacology, 15, 2, 2005; 325-330 n=20, 60% response Placebo controlled cross-over study • 6 weeks atx vs placebo (n=16) • ATX superior to placebo (p=.043, effect size d=0.90). Arnold et al, 2006 A Randomized, Double-blind Comparison of Atomoxetine Hydrochloride and Placebo for Symptoms of AttentionDeficit/Hyperactivity Disorder in Children and Adolescents with Autism Spectrum Disorder Sponsored by Eli Lilly and company RADAR study • • • • Dutch multi-center study (n=97) Children with ASD plus ADHD Atomoxetine versus placebo (8 weeks) Open label extension (16 weeks) Study design SP I SP II SP III Atomoxetine 1.2 mg/kg/day Open-label atomoxetine* Screening / wash-out Placebo Attachment 2 3-28 days Visit 1 1 wk Visit 2 1 3 3 11 3 Visit 6 * 1.2 mg/kg/day; the dose may be lowered to 0.8 mg/kg/day 3 12 Visit 11 ADHD rating scale (p<.001) -1,2 MMRM LS-mean at endpoint (95% CI): Atomoxetine 31,6 (29,2-33,9); Placebo 38,3 (36,0 -40,6) Inattentive symptoms (p=.003) MMRM LS-mean at endpoint (95% CI): Atomoxetine 17,2 (15,9-18,4); Placebo 19,9 (18,7 -21,1) Hyperactive/impulsive symptoms (p<.001) MMRM LS-mean at endpoint (95% CI): Atomoxetine 14,5 (13,0-15,9); Placebo 18,4 (17.0 -19,7) Teacher ADHD ratings (p=.077) LOCF LS-mean at endpoint (95% CI): Atomoxetine 15,1 (13,0-17,2); Placebo 17,8 (15,7 -19,8) Teacher hyperactivity ratings (p=.024) * LOCF LS-mean at endpoint (95% CI): Atomoxetine 6,8 (5,5 - 8,0); Placebo 8,8 (7,6 -10,0) Atomoxetine categorical response ATX PLB 0% 2.2% Much + 20.9% 6.5% Minimally + 27.9% 13.0% No change 37.2% 65.2% Minimally - 9.3% 6.5% Much - 4.7% 6.5% 0% 0% Very much + Very much - Adverse events; ATX-Radar vs MPH-RUPP • Appetite decrease (27.1%) • Initial insomnia (6.3%) • Feeling abnormal (4.2%) • Agitation (2.1%) • Abdominal pain (18.8%) RADAR • Appetite decrease (24.2%) • Difficulty falling asleep (18.2%) • Emotional outburst (13.6%) • Irritability (12.1%) • Stomach or abdominal discomfort (7.6%) Rupp, 2005 Adverse events ADHD+ASD versus ADHD only • Nausea (29%) • Decreased appetite (27%) • Headache (25%) • Fatigue (23%) • Abdominal pain upper (19%) • Vomiting (15%) • Early morning awakening (10%) RADAR, 2009 • Nausea (10-11%) • Decreased appetite (16%) • Headache (19%) • Fatigue (1-10%) • Abdominal pain upper (18%) • Vomiting (10-11%) • Early morning awakening (0.1-1%) SPC Atomoxetine Main conclusions of atomoxetine trial • • • • • Atmoxetine is better than placebo Most effects in hyperactivity domain Not many true responders Less robust effects than ADHD as such Relatively well tolerated but more adverse events than in ADHD as such Conclusions • ADHD symptoms frequent in ASD • ADHD symptoms important focus for treatment in ASD • Both MPH and ATX effective treatments, but not for every child! • Children with ASD show less predictable, less robust response, and tend to experience more side effects Future focus • Effective treatments for non-responders • Identification of treatment moderators • Effectiveness of combined treatments • Better treatments!! What about antipsychotics? • Risperidone • Aripiprazole Risperidon for irritability (Rupp, 2002) • Multisite, randomized, double-blind trial of risperidone versus placebo • Autistic disorder accompanied by severe tantrums, aggression, or selfinjurious behavior • N=101 (5 to 17 years old) • Mean daily dose 1.8±0.7 mg (range, 0.5-3.5) Decrease in irritability CGI Improvement status Risperidone for core symptoms of autism? • Improvements in restricted, repetitive, and stereotyped patterns of behavior, interests, and activities • No change in social interaction and communication. McDougle et al, 2005 Risperidone effective on longer term • Double-blind discontinuation after 24 weeks of treatment; placebo switch versus continuing use of risperidone • Risperidone superior in preventing relapse: in 3 of 12 patients (25%) continuing on risperidone versus 8 of 12 (67%) switched to placebo (Troost et al, 2005) • Rupp (2005): 12.5% (risperidone) versus 62.5% (placebo) Cognitive effects of risperidone: sedation or enhancement • No deterioriation of focused attention • Improvement of divided attention Troost et al., 2006 • Better on a verbal learning task (word recognition and spatial memory task). No deterioration. Amman et al., 2008 Side effects of risperidone may be genetically based • Weight gain: – 5HT2C promoter T allele carriers (22%): 0.017 BMI z scores (1.84 + 1.51 kg) – Non-T carriers 0.64 + 0.35 z (3.23 + 1.47 kg) Hoekstra et al (under review) • Prolactin elevation: – Positively associated with number of functional CYP2D6 genes Troost et al, 2007 Aripiprazole for irritability • N=218 • 8 weeks: placebo/5/10/15 mg (fixed dose) • Decrease in ABC-I: 12.4-14.4 (5-15 mg ari) vs 8.4 (plb) • Weight gain 1.3 kg vs placebo 0.3 kg (risperidone RUPP 2.7 vs 0.8 kg) Marcus et al, 2009 Aripiprazole-flexible dose • N=98; 8 weeks • Placebo or aripirazole (5-15 mg) • 12.9 vs 5.0 decrease ABC-I (Rupp risperidone 14.9 vs 3.6) • Weight gain 2.0 vs 0.8 kg Owen et al., 2009