Child & Adolescent March 21, 2021 Sunday

ADHD comorbidity in Autism Spectrum Disorders

T. Atilla Ceranoglu, MD Assistant Professor of , Boston ADHD, ASD and Autistic Traits

• ASD and ADHD comorbid presentation • Autistic traits in ADHD • Treatment implications Neurodevelopmental Disorders(ASD and ADHD)

Shared Characteristics Distinct Symptom Triad ADHD ASD ASD ADHD Prevalence in 6-8% 2% - Impaired social interaction - Inattention Children Heritability Estimates 75% 90% - Impaired social communication - Hyperactivity Male:Female Ratio 2.5:1 4:1 Manifest early in life Yes Yes - Restricted Repetitive Behaviors - Lifelong Disorders Yes Yes

ADHD

ASD ASD & ASD Traits in ADHD

ASD Traits ASD Diagnosis Clark et al., 1999 Joshi et al., 2013 *Kochhar et al., 2011 *Cooper et al., 2014 Jensen & Steinhausen, 2014 *Grzadzinski et al., 2011 Faber et al., 2010 *Mulligan et al., 2009 Reirsen et al., 2007 Larson et al. 2011 18% - 63% *Kotte et al., 2013 Smalley et al. 2007 2% - 15% Percentage 0 10 20 30 40 50 60 70 Percentage 0 2 4 6 8 10 12 14 16 *ADHD Youth with no prior diagnosis of ASD

ASD ADHD

Comorbid ASD in up to 15% of the ADHD Populations ADHD Symptoms & Diagnosis in ASD referrals

ADHD Symptoms ADHD Diagnosis

Sverd et al., 1995 Joshi et al., 2014

Lee & Ousley, 2006 Sinzig et al., 2009

Sturm, et al., 2004 DeBruin et al., 2007 Tani et al., 2006 Mattila et al., 2010 Yoshida &… Leyfer et al., 2006 Holtmann et al.,… Gjevik et al., 2011 Goldstein &… 49% - 88% 28% - 75% Gadow et al., 2004 Simonoff et al., 2008

Percentage 0 10 20 30 40 50 60 70 80 90 100 Percentage 0 10 20 30 40 50 60 70 80 90 100

ASD ADHD

Comorbid ADHD in up to 75% of the ASD Populations ADHD Symptom Profile in ASD

ADHD+ASD ADHD * 100 * ** ** 80

60

40

Percent with Symptom 20

0 Careless/ Doesn't listen Difficulty Loses Forgetful Fidgets/ Physically On the go/ Blurts out Interrupts/ Sloppy organizing things in daily activities Squirms restless Driven by a answers Intrudes tasks/ activities motor

Inattentive Symptoms Hyperactive/Impulsive Symptoms

*p≤0.01, **p≤0.001 Profile of ADHD in ASD

Presentation of ADHD # of ADHD Symptoms 75 ** * 16 59% 14 60 57% 14 13 12 45 41% 10 33% * 8 8 8 30 6 6 5 Percentage 4 15 8% Mean # of Symptoms 2% 2 0 0

Inattentive… Combined… Inatentive… Combined… ASD+ADHD ASD+ADHD Hyperactive-Impulsive… Hyperactive-Impulsive… ADHD ADHD

More robust form of ADHD (combined) presents more frequently in ASD Additional ADHD-Related Symptoms

Control (N=106) ADHD (N=105) ADHD+CBCL-AT (N=26) a***b*** 100 a***b* a***

90 a***b* a***b*

80

70

60 a*** a***b* % 50

40 a a*** vs. Controls 30 b vs. ADHD ***p<0.001 20

10

0 Accidents Messy or Clumsy Hyperactive Equally Onset Before Fighting with Rejection by Sloppy Inattentive & Age 5 Other Peers Other Peers Hyperactive ADHD Treatment History in ASD

50 * 43% 41% 40

* 30 27% 26% 24%

20 * 18% Percentage 15%

10 5%

0 Treatment Counseling Pharmacotherapy Only Counseling + Naïve Only Pharmacotherapy ASD+ADHD ADHD

Statistical Significance: *p≤0.05, **p≤0.01, ***p≤0.001

ADHD is undertreated in youth with ASD Implications of Unrecognized Comorbidity

ADHD ASD • Impairs intellectual/school • Receive inappropriately performance aggressive treatment for psychopathology • Further compromises social functioning • Failure to recognize atypical precipitants that negatively • Interferes with ASD specific affects psychopathology behavioral interventions • • Leads to attempts to treat ADHD Failure to receive treatment specific for ASD with ASD specific interventions • • Failure to receive disorder Missed opportunity to implement early interventions for ASD specific treatment • Increased risk for developing other psychiatric conditions • disruptive behaviors • substance abuse ADHD symptoms in ASD Youth

• ADHD symptoms are common in ASD (>50%) • The clinical presentation of ADHD in ASD youth is typical of the disorder • ASD youth with ADHD have significantly more impaired psychosocial functioning • Significantly fewer ASD youth receive targeted treatment for ADHD Treatment Trials in AUTISM

IQ: Low Versus High-functioning Tx. Target: Symptoms Versus Syndromes • Hyperactivity • Irritability/Aggression • Repetitive Behaviors/Anxiety • Sleep dysregulation

Emerging Evidence: Pharmacotherapy for core features of Autism ADHD Treatment Studies in ASD

Controlled Trials ADHD Med Class Total N≥10 N<10 Stimulant Class Methylphenidate 5 5 - Non-stimulant Class 3 3 - 2 1 1 2 - 2 • One trial in adults with ASD • One trial exclusively in intellectually capable ASD (HF-ASD) • No trials on Mixed Salts in ASD CONTROLLED STUDIES for ADHD in AUTISM SPECTRUM DISORDER - Design Age Tota Dose RCT [Duration] [years] l(N) HF [mg/day] Efficacy Tolerability Comments Sign. ⇊ TEAE: Buccal-lingual All participants with speech delay Ghuman Pre- Crossover 15 ±5 Hyperactivity Movements Response less than typically expected et al., school 12 NR [4-Week] [5 – 20] - CPRS Dose-LAE: 9 (64) Improvement in social behaviors 2009 [3-5] RR: 50%; ES: 0.97 Tx-LAE: 1 (6) No worsening of ASD Pearson Sign. ⇊ ADHD TEAE: Insomnia, Typically expected response 0.35 - et al., Crossover Children - CTRS ↓Appetite D/c of MPH-IR afternoon dose d/t AEs 24 2/3rd 0.75 2013 [4-Week] [7-12] RR: 67% Dose-LAE: 5 (21) Improvement in social skills mg/kg [MPH-ER] ES: NR Tx-LAE: None No worsening of ASD, Mood, or Anxiety Sign. ⇊ TEAE: Insomnia, Majority of patients with ID & nonverbal Hyperactivity ↓Appetite, Emotional Significant level of irritability at baseline RUPP, Crossover Children 7.5 – 50 66 8% - ABC-H outburst, Irritability Response less than typically expected 2005 [4-Week] [5–13] mg RR: 49% Dose-LAE: 16 (24) ↑↑ fr. of emotional lability AE ES: 0.48 Tx-LAE: 13 (18) No worsening of ASD Sign. ⇊ Handen TEAE: P=NR Significant level of irritability at baseline Crossover Children Hyperactivity et al., 13 8% NR Dose-LAE: 2 (15) ↑↑ fr. of mood dysregulation AE [3-Week] [5-11] - CTRS-H 2000 Tx-LAE: 1 (1) No worsening of ASD RR: 61%; ES: NR Sign. ⇊ Quintana TEAE: None No mood dysregulation with Tx Crossover Children 0.4 - 0.7 Hyperactivity et al., 10 30% Dose-LAE: None No difference in HD vs. LD response [6-Week] [7-11] mg/kg - ABC-H/ CTRS-H 1995 Tx-LAE: None No worsening of ASD ES: NR NR=Not Reported; HF=High-Functioning; ID=Intellectual Disability; ES=Effect Size; RR=Response Rate; AE=Adverse Events; TEAE=Treatment Emergent AE; Dose-LAE=Dose-Limiting AE; Tx-LAE=Treatment-Limiting AE; CTRS=Conners' Teacher Rating Scale; CPRS=Conners' Parent Rating Scale; ABC-H=Aberrant Behavior Checklist-Hyperactivity subscale

Methylphenidate - RUPP Trial

Crossover RCT in ASD Youth with Hyperactivity • Diagnoses: ASD + Hyperactivity (moderate-severe) • Ages: 5-14 years (majority with Intellectual Disability)

Tolerability Phase RCT Phase Open-Label Phase • 3 Phases: 1 week; n=72 4 weeks; n=66 8 weeks; n=35

• MPH Dose (TID): • Low: 0.125mg/kg/day • Medium: 0.25 mg/kg/day • High 0.5 mg/kg/day Methylphenidate – RUPP Trial Efficacy

Crossover Phase Response: Parent-rated ABC-Hyperactivity Subscale

35 ∗ 30 p = 0.03 *p = 0.003 Effect = 0.3 p < 0.0001 Effect = 0.4 25 Effect = 0.5 *Parents reported 20 increased social 15 withdrawal on high dose of MPH 10

5

Mean ABC Hyperactivity Subscale Scores Subscale Hyperactivity ABC Mean 0 Baseline( Placebo( ______Low( Medium( High( MPH Dose Methylphenidate – RUPP Trial Efficacy

Continuation Phase Response: Informant-rated ABC-Hyperactivity Subscale

Crossover Open-Label Continuation 40

35

30

25

20

15

10 Mean ABC Hyperactivity Subscale Scores Subscale Hyperactivity ABC Mean

5 Parent Teacher

0 Baseline Crossover Phase Week 4 Week 8 @ Best Dose Methylphenidate – RUPP Trial Efficacy

ADHD Response Rate of Response: 50% 80 (≤2 CGI-I + ABC-H ⇊ >25-30%) 70%

60 Effect Size: 0.20 – 0.54 50% (vs. 0.35 – 1.31 in MTA trial) 40 ADHD response independent of:

• Level of IQ Rate of response • Subtypes of ASD 20 Additional Response* Improvement in: - Joint 0 - Self/Affect Regulation TD ASD MPH is less effective for ADHD in children with ASD than typically expected? Comorbidity unknown in a patient population predominantly with low functioning autism Methylphenidate – RUPP Trial Tolerability

Common AEs: • Decreased appetite • Initial insomnia 30 • Irritability • Emotional outbursts 25 No exacerbation of stereotypes or 20 18% repetitive behaviors 15 Dropout: 18% (13/72) 10 • All dropout d/t treatment-limiting Aes Rate of Dropout 5 • 50% (6/13) dropout d/t inability to 1.5% tolerate test dose 0 • 50% (6/13) dropout d/t irritability TD ASD MPH is associated with more frequent adverse effects in children with ASD than typically expected (comorbidities??) Methylphenidate - Extended Release

Crossover RCT in ASD Children with ADHD ASD + ADHD: N = 24 [Autistic Disorder=19/24; ADHD=19/24] Male: 79% Mean Age [Range]: 9 ±1.7 [7–12] Mean IQ [Range]: 85 ±17 [46-112] 3 Trial Phases: 1. Placebo phase: 1 Week (N=24) 2. Tolerability phase: 2 day each on test doses of 3 different strengths of MPH (N=24) 3. Crossover Phase: 3 Week (N=24) MPH-ER Dose Schedule Duration MPH Dosing Morning Afternoon [Week] (mg/Kg/day) MPH-ER dose MPH-IR dose 1 Low dose 0.2 0.15 1 Medium dose 0.35 0.25 1 High dose 0.5 0.3 Methylphenidate - Extended Release

Dose comparison, RCT in children with ASD and ADHD ASD + ADHD: N = 27

Male: 93% Mean Age [Range]: 9 ±2.9 [5-14]

Study Design - 6 weeks, flexible dosing schedule - 3 different doses: Very Low (≤10mg/day), Low (≤20 mg/day) Moderate (≤ 40 mg/day) Low dose Medium dose N=9 N=18 Mean dose 9.7mg/day Mean dose 20.28 mg/day Methylphenidate - Extended Release

Efficacy

Parent (ABC; p<0.001) and Clinician(ADHD RS-INV, p<0.001; CGI-I≤2=83%)-rated Measures: • Significant dose-related improvement in ADHD symptoms • Additional improvement in: - Irritability -Hyperactivity - Lethargy - Inappropriate Speech - Stereotypy Tolerability • No Serious or treatment limiting side effects • Common side effects: • Insomnia [13.6% total] • Loss of appetite [10.5%] • Wear off [12.3%, less in medium dose group, p=0.049] 3/20/21

OLT of MPH in Adults with HF-ASD

15 Adults aged 19-34 years (Mean age: 25 ±4.5 years) • Intact intellectual ability (IQ Range: 99 – 144) • Met the DSM-V criteria for ASD and ADHD • At least moderate level of severity for ASD and ADHD (SRS=≥85; AISRS=≥24; & respective CGI-S ≥4) • Not sign. symptoms of anxiety or mood dysregulation

Study Medication (MPH-ER Liquid Formulation: 25mg/5mL) Flexible Dose Titration Schedule Dose at Endpoint Duration QAM Dose Mean dose: 49 ±15 mg/day Initial dose: 5 mg/day 60 mg/day 08 (53%) Individual Titration phase (0-3 weeks): 5-60 mg/day 50 mg/day 02 (13%) Doses: Maintenance phase (4-6 weeks): Max. achieved dose 20-40 mg/day 05 (33%) 3/20/21

Treatment Response: ADHD Symptoms

Clinician-Rated Adult Investigator Symptom Report Scale (AISRS) Patient-Rated Adult Self-Report Scale (ASRS)

AISRS ASRS 45 41.1 ±12.1 ± 40 [MCASRS= -4.8 ±9.9; Z= -2.08; [MCASRS= -8.2 15.3; Z= -3.67; p<0.04] p<0.001] 35 LOCF [32.9 ±13.9] 36.7 ±5.4 36.3 ±13.4 30 31.8 ±13.7 25 20 18.4 ±7.9 LOCF [13.9 ±8.5] Mean Score 15 10 [MCAISRS= -18.3 ±8.2; Z=-7.10; p<0.001] 12.4 ±6.2 5 [MCAISRS= -22.8 ±8.8; Z= -9.75 0 p<0.001] 0 1 2 3 4 5 6 Week 3/20/21

Treatment Response: Response Rate

100 93% 90 80% 80% 80 70 60 50 40 30

Percent at Endpoint 20 10 0 ADHD-CGI-I ≤2 AISRS-Total Reduction ADHD - CGI - I ≤ 2 + ≥30% AISRS Reduction ≥30% 3/20/21

Treatment Response: ADHD Symptoms

AISRS % Score Reduction at Trial Completion

100% 93% 93% 89% 90% 80% 69% 69% 70% 70% 65% 63% 62% 59% 60% Reduction 54% 50% 50% 46% 44% Score

% 40% 30% AISRS 20% 8% 10% 0% Subject # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Max. daily dose (20) (20) (30) (40) (40) (50) (50) (60) (60) (60) (60) (60) (60) (60) (60) (mg/day)

Non-linear dose response 3/20/21

Treatment Response: Associated Psychopathology

[MC= -3.5 ±4.5; Z= -2.5; p=0.01] [MC= -3 ±4.5; Z= -2; p=0.06] 10 9 ±6 8.5 ±5.5 8

6 5.5 ±6 5.5 ±6.5

4 Mean Score

2

0 HAM-A HAM-D Baseline Endpoint

MC=Mean Change; HAM=A=Hamilton Anxiety Scale; HAM-D=Hamilton Depression Scale 3/20/21

MPH ER – Adverse Events

Adverse Events (Mild-Moderate Severity)

Headache 53 Insomnia 33% Anxiety 33% Decreased Appetite 27% Fatigue 13% Irritability 13%

Percentage0 10 20 30 40 50 60

Experienced any AEs: N=13 (87%) Serious AEs: N=1 (Report of OD on Benadryl [suicide attempt] at week-6. Prior h/o SI. [Upon completion continued tx. with study medication]) Treatment Limiting AEs: N=1 (Terminated at week-3 @ 20 mg/day d/t AEs: headaches, palpitations, jaw pain, & insomnia [resolved on d/c]) Titration Limiting AEs: N=7 (Headache[N=3], High Blood Pressure[N=2], Worsening of Anxiety[N=1], Nausea[N=1], Fatigue[N=1]) 3/20/21 MPH ER – Adverse Events

Baseline Endpoint Difference p-value Body weight (kg) 86 ±26.5 84.5 ±26.5 -1.45 ± 2.4 0.01 [-2.59] Pulse (bpm) 73 ±9.3 82 ±14.3 9 ±13.4 0.007 [2.69] Blood pressure (mmHg) Systolic 121.5 ±10.2 123 ±11.6 1 ±10.7 0.93 [0.08] Diastolic 78.5 ±10.0 78.7 ±11.4 0.2 ±7.6 0.71 [0.37]

Pulse & Blood Pressure 10 (heart rate >100 beats/min) Tachycardia N=3 5 5 High Blood Pressure (systolic BP ≥140 N=2 1.6 1.4 1 mm/Hg &/or diastolic BP ≥90 mm/Hg) 0 0 -1.2 No QTc prolongation on ECG observed -2.4 -1.6 (>460 or >60 ms increase from baseline) -5 -3.4 -4 -5.9 -6.5 -7 -10 -7.4

Change in Body Weight (Ibs) -15

-17 -20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Subject # Max. (20) (20) (30) (40) (40) (50) (50) (60) (60) (60) (60) (60) (60) (60) (60) daily Methylphenidate response in ASD

• Modest response, less than observed in TD children

– Less effective in treating hyperactivity symptoms

– Although dose cannot be predicted, may respond to lower dose of MPH than expected (0.3mg/kg/day)

• May also improve Social Interaction (joint attention)

• Adverse effects are more prevalent and could be dose-dependent

• ADHD Response in a carefully chosen population, screened for comorbidities is same as that in typically developing children

RUPP Autism Network, 2005; DiMartino et al., 2004; Handen et al., 2000; MTA Trial, 2001 CONTROLLED STUDIES for ADHD in AUTISM SPECTRUM DISORDER – Non-Stimulants

ATOMOXETINE Design Age Total Dose RCT [Duration] (Yrs) [N] HF (mg/day) Efficacy Tolerability Comments

Significant level of baseline irritability Handen ⇊ ADHD ↓Appetite Parallel 1.4 ±0.5 Efficacy less than typically expected et al., 5-15 128 16% (SNAP-IV) Dose-LAE: None [10-Week] mg/kg Typically expected tolerability 2015 RR 47%; ES 0.8 Tx-LAE: 5 (8) vs. 10 (16) No worsening of ASD, Mood, or SI

⇊ ADHD Nausea, ↓Appetite, Early Significant level of baseline irritability Harfterkamp Parallel 0.5-1.2 ADHD-RS [Mean↓ 8] waking, Fatigue Efficacy less than typically expected et al., 6-16 97 6% [8-Week] mg/kg RR 21% [P=NS]; Dose-LAE: None 2012 Typically expected tolerability ES NR Tx-LAE: 1 (2) vs. 0 No worsening of ASD Upset stomach, N&V, Arnold ⇊ Hyperactivity Crossover 44 ±22 Fatigue, Tachycardia Significant level of baseline irritability et al., 5-15 16 6% ABC-H [Mean↓= 5] [12-Week] 20-100 Dose-LAE: None 2006 RR 57%; ES 0.9 All participants experienced GI AEs Tx-LAE: 1 (6) vs. 0

GUANFACINE Design Age Total Dose RCT [Duration] (Yrs) [N] HF (mg/day) Efficacy Tolerability Comments Drowsiness, Fatigue, Significant level of baseline irritability ↓Appetite, Dry mouth, Scahill Chil ⇊ Hyperactivity Typically expected efficacy Emotional/ tearful, et al., Parallel dren 3 ABC-H [%↓= 44] AEs at higher frequency than typically 62 37% Irritability, Anxiety 2015 [8-Week] 5-14 1 - 4 RR 50%; ES Dose-LAE: 9 (30) vs. 5 expected [GFC-ER] 1.67 (16) Mood & anxiety related AEs Tx-LAE: 4 (13) vs. 0 No worsening of ASD NR=Not Reported; HF=High-Functioning; ES=Effect Size; RR=Response Rate; AE=Adverse Events; Dose-LAE=Dose-Limiting AE; Tx- LAE=Treatment-Limiting AE; SNAP-IV=Swanson, Nolan, & Pelham Rating Scale; ABC-H=Aberrant Behavior Checklist-Hyperactivity subscale; ADHD-RS=Attention Deficit Hyperactivity Disorder-Rating Scale

Atomoxetine

8-week RCT • 97 children with ASD + ADHD diagnoses – 6-17 years (10 ±2.5) – 37% ADHD treatment naïve – IQ: 90 ±16 (61-138) – NO concomitant psychotropic medications • Atomoxetine (BID) dosing: - Week-I: 0.5 mg/kg/day - Week-II: 0.8 mg/kg/day - Week-III:1.2 mg/kg/day Atomoxetine - Efficacy

Efficacy 45 40 35 (p < 0.001) ADHD-CGI-I ≤2

RS Mean Score 30 - ATX[21%] ⊁ PBO[9%] (p=0.14) Clinician Rated Atomoxetine

ADHD 25 Placebo 20 Baseline Week 8

Less than expected magnitude of response to atomoxetine (ADHD-RS mean reduction: ASD[8] vs. TYP[13-19]) Atomoxetine – Tolerability

- Rate of AEs: ATX 81% vs. PBO 65% - Nausea (29%ATX vs. 8%PLO; p=0.009) - Decreased appetite (27%ATX vs. 6%PLO; p=0.006) - Fatigue (22%ATX vs. 8%PLO; p=0.05) - Early Morning Awakening (10%ATX vs. 0%PLO; p=0.03) - Treatment-limiting side effect: ATX 1/48 (fatigue) vs. PBO 0/49 - No exacerbation of stereotypes or other repetitive behaviors - No serious side effects Atomoxetine is associated with more frequent adverse effects in children with ASD compared to reported rates in children with typical development Atomoxetine & Parent Training

• 10-week RCT • 128 children with ASD + ADHD – 5-14 yrs (8 ±2); 85% male – IQ 61-138 (82 ±24) – 55% with treatment-naive ADHD • Dose: – 1.2-1.8 mg/kg/day – 45 ±21mg/day – Side effects: decreased appetite, abdominal pain – No treatment related serious adverse events Atomoxetine & Parent Training

Week Group ADHD response Non-compliance Response Week ATX 47% 44% 0.003 [ES 0.64] ATX+PT 45% 23% 0.03 [ES 0.47] ADHD Response Rate: ATX > PBO [p=0.015] PT+PBO 29% 39% 0.06 ATX+PT ATX [p=NS] PBO 19% 16% Atomoxetine & Parent Training

24-week extension phase • 60% of RCT phase responders continued to meet criteria for ADHD

• Among ADHD responders: – ATX+PT 53% v ATX 23% • Among noncompliance responders: – PT+ATX 58% v ATX 14% Guanfacine ER

8-week RCT in ASD Youth with Hyperactivity

Autistic Disorder + Sign. Hyperactivity 62 (ABC-Hyperactivity score ≥24 + CGI-S ≥4) Mean Age [Range] 8.5 ±2.3 [5–14] Male 86% Drug-naive 55% Dose 3 mg/day [1 - 4]

3/19/21 EXTENDED-RELEASE GUANFACINE FOR HYPERACTIVITY IN ASD

TABLE 2. Scores on the Aberrant Behavior Checklist and ADHD Rating Scale at Baseline and Endpoint (Week 8) Guanfacine (N=30) Placebo (N=32) Raw Mean Least-Squares Meana Raw Mean Least-Squares Meana Effect Measure Baseline 95% CI Endpoint 95% CI Baseline 95% CI Endpoint 95% CI p Sizeb Aberrant Behavior Checklist Subscale Guanfacine ER - Efficacy Hyperactivityc 34.40 32.40–36.40 19.3 15.33–23.22 34.25 31.74–36.76 29.7 25.82–33.53 ,0.0001 1.67 Irritability 20.30 16.79–23.81 13.5 10.01–17.06 18.06 14.54–21.58 16.1 12.68–19.54 0.20 0.27 Social 13.60 10.08–17.12 9.8 7.26–12.27 12.06 8.71–15.41 8.6 6.10–11.02 0.41 0.13 withdrawal Stereotypy 8.53 6.41–10.66 3.6 2.03–5.26 9.31 7.31–11.32 5.9 4.37–7.49 0.02 0.41 Inappropriate 6.33 5.02–7.65 4.2 3.24–5.26 6.84 5.63–8.06 5.99 4.50–6.97 0.004 0.50 speech ADHD Rating ADHD Rating Scale - ADHD Rating Scale - Scale Inattention 20.53 19.17–21.90 14.7 12.55–16.78 20.41 18.75–22.06 19.5 17.52–21.56 0.0001 1.17 Hyperactivity 19.00 17.38–20.62 10.6 8.50–12.75 19.50 17.71–21.29 18.7Inattention 16.6–20.69 ,0.0001 1.72 Hyperactivity Total 39.53 37.33–41.73 25.2 21.44–29.03 39.91 37.50–42.32 38.0 34.4–41.63 ,0.0001 2.03 a At week 8, the least-squares mean values on the hyperactivity subscale were within30 1 standard deviation of the population mean; the least-squares mean values at 30 endpoint are adjusted for baseline. b Effect sizes were calculated by taking the difference in the least-squares means at endpoint and dividing by the pooled standard deviation at baseline. c Raw baseline scores on the Aberrant Behavior Checklist-hyperactivity subscale were nearly 2 standard deviations above the population mean for developmentally disabled children 6 to 10 years of age. 20 20 analyzed are presented in Table 3. There were no group or aggressive, and his speech was normal in tone and tempo. differences at baseline, and analysis of covariance models During the entireP=0.0001; episode, there wasES no 1.17 change in his sleep. P<0.0001; ES 1.72 (adjusted for IQ $70 and,70) showed no group differences The study medication was discontinued for this subject, but from baseline to endpoint on any subtests. The interactions assessments10 were continued. One other subject in the 10 between cognitive test scores at baseline and treatment were guanfacine group also stopped treatment with the study drug not significant. Examination on whether performance on any because of adverseBaseline events and remained in the studyEndpoint for Baseline Endpoint cognitive subtest predicted positive outcome in either assessment. As shown in Figure 1, two subjects in the treatment group was uninformative. guanfacine group droppedGuanfacine out of the study ER completely be-Placebo Guanfacine ER Placebo cause of multiple adverse events (drowsiness, fatigue, mid-sleep Medication Dose The modal daily dose at week 8 was 3 mg/day (range: 1 mg/day–4 mg/day) for the extended-release guanfacine FIGURE 2. Least-Squares Means on Aberrant Behavior Checklist- group and 3 mg/day (range: 2 mg/day–4 mg/day) for the Hyperactivity Subscale Scores for Extended-Release Guanfacine placebo group. and PlaceboABC During- theHyperactivity 8-Week Triala Subscale CGI-Improvement ≤2: 50 Safety Results Placebo [50%] [9.4%] The numbers and percentages of subjects with parent- Guanfacine Guanfacine ER >PBO reported mild, moderate, and severe adverse events are 40 shown in Table 4. The adverse event labels in this table were derived from a list of preferred terms established before Significant improvement in: 30 [⇊ 13%] launching the study. The items on the Adverse Event Review (ABC-Stereotypy) and verbatim complaints were matched to the preferred • Repetitive behaviors terms. There was one serious adverse event in the guanfacine p<0.001 (ES-1.7) 20 (ABC-Inappropriate speech) treatment group. Six days after the scheduled increase to 2 mg • Communication per day, the child (a 6 year-9-month-old boy) became verbally [⇊ 44%] and physically aggressive toward his mother. The police were 10 Response similar to Typicals

summoned, and the boy was taken to the emergency room. ABC Hyperactivity Least Square Means Upon evaluation, he was agitated and threatened hospital [50-55%] [25%] personnel, and his speech was pressured. The medication 0 (GXR > PBO )* 0 2 468 was discontinued, and he remained on the child psychiatric Week inpatient service for 3 days. Upon discharge, he was hyper- a Higher scores reflect greater hyperactivity. ABC= Aberrant Behavior active and impulsive (similar to baseline). He was not agitated Checklist.

6 ajp.psychiatryonline.org ajp in Advance Guanfacine ER – Efficacy

PBO GXR • Dose-limiting AEs 5/32 9/30 [d/t emotional lability/drowsiness] [16%] [30%]

• Treatment-limiting AEs None 2 - Agitation[N=1] - Drowsiness[N=1]

• Serious AEs None 1 (agitation @ 2mg/d)

Common AEs* PBO GXR p-value Drowsiness 9% 87% <0.001 Fatigue 9% 63% <0.001 Dec. appetite 6% 43% <0.001 Dry mouth 3% 40% <0.001 Emotional/tearful 9% 40% 0.01 Irritability 9% 37% 0.01 Anxiety 3% 30% 0.01 Mid-sleep awakening 6% 30% 0.02 *Reported in ≥5% & <0.05

Typically expected ADHD treatment response of GXR in children with ASD

43 Alpha-2 Adrenergic Agonist: Clonidine

Delivery Oral Clonidine Transdermal Clonidine (Jaselkis, et al. 1992) (Frankhauser, et al. 1992) 6-week double-blind, cross-over 4-week, double-blind, cross-over clonidine PO 4-10 mcg/kg/d clonidine TTD 3.5 mcg/kg/d Methods n=8 males, 5-13yo (8 ±3 yrs.) with ASD n=9 males (~13 yrs.) with ASD + + hyperactivity (prior hx. of poor hyperarousal symptoms (including response) hyperactivity) Parent-teacher ratings: Superior to PBO in reducing Hyperactivity No effect on ADHD symptoms per Efficacy No significant separation from PBO on parent ratings any of the clinician rated scales

Drowsiness Sedation Tolerability Hypotension Fatigue In Summary…..

ADHD Response in ASD Youth • Methylphenidate & Atomoxetine. - Response in patients HF-ASD is similar to observed with ADHD - Adverse effects more frequent than typically expected may point to missed comorbidities - Improves affect regulation & joint attention - Response rate & magnitude in patients with low IQ is less than expected

• Guanfacine ER. Response similar to observed in children with ADHD • Clonidine. Poorly tolerated

Consider using clinical scales for monitoring treatment effect ADHD checklists, ECG, labs, etc. The Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorders

Massachusetts General Hospital, Boston MA Yvonne Woodworth, BA Joseph Biederman, MD Sheeba A. Anteraper, PhD Daniel Kaufman, BS Janet Wozniak, MD Kaustubh R. Patil, PhD Alison Greene, BA Gagan Joshi, MD Stephen Faraone, PhD Nina Dallenbach, BA Lynn Grush, MD Ronna Fried, EdD Emmaline Cook, BA Amy Yule, MD Maribel Galdo, LCSW Cecilia Law, BA Carrie Vaudreuil, MD Maura Fitzgerald, MA Alissa Charles, BA Robert Doyle, MD [email protected]

(617) 726-7899 [email protected] Facebook.com/BresslerMGH http://www.massgeneral.org/psychiatry/services/autism_conditions.aspx