Autism Spectrum Disorder

GAGAN JOSHI, MD Associate Professor of Psychiatry Director, Autism Spectrum Disorder Program The Bressler Clinical & Research Program for Autism Spectrum Disorder Massachusetts General Hospital, Harvard Medical School

www.mghcme.org Disclosures

My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose: PLEASE CONFIRM THAT DISCLOSURES MATCH WITH Research Support: SUBMITTED DISCLOSURES PI for Investigator-Initiated Studies: -National Institute of Mental Health (NIMH) grant Award #K23MH100450 -Demarest Lloyd, Jr. Foundation -Pfizer pharmaceuticals Site PI for Multi-Site Studies: -Simons Center for the Social Brain -F. Hoffmann-La Roche Ltd. Honoraria: -Governor’s Council for Medical Research and Treatment of Autism in New Jersey -American Academy of Child and Adolescent Psychiatry -Canadian Academy of Child and Adolescent Psychiatry -The Israeli Society for ADHD

www.mghcme.org Features of AUTISM CORE Features Impaired Social-Emotional Competence Restricted/Repetitive Behaviors (RRBs) I. Non-verbal communication (NVC) VIII. Cognitive/Behavioral Rigidity - Eye contact (joint-attention) - Routines (routine-bound) - Receptive and Expressive emotional NVC - Rituals (verbal & motor) (facial expression, verbal tone, touch) - Resistance to change (transitional difficulties) II. Verbal communication - Rigid pattern of thinking (rule-bound/highly opinionated) - Level of verbal communication - Lack spontaneity/tolerance for unstructured time - Atypical style of speech (pedantic, professorial) - Social inflexibility III. Emotional processing IX. Repetitive patterns - Emotional awareness, recognition - Speech (delayed echolalia, scripting, idiosyncratic phrases) - Emotional expression (verbal & non-verbal) - Motor mannerisms (flapping, clapping, rocking, swaying) - Empathy (Theory of mind) - Interests (non-progressive, non-social) IV. Social (inter-personal) processing X. Atypical Salience - Social motivation & awareness - Interests (odd/idiosyncratic) - Sharing (activities, affect, back & forth conversations) - Social-emotional stimuli - Contextual understanding (social adaptability) - Atypical fears V. Abstracting ability XI. Sensory Dysregulation - Black & white/concrete/literal thinking - Atypical sensory perceptions/responses - Tolerance for ambiguity VI. Introspective/Introceptive ability ASSOCIATED Features (self awareness of cognition, emotions, & physiological state) • Intellectual disability - Psychological mindedness • Novelty averse behaviors VII. Executive Control (moderation of emotions, motivations, interests) • Poor motor co-ordination - All or none approach (lack moderation) - Abnormal intensity of interests DSM Criteria for Autism

Schizophrenic reaction Schizophrenia - Childhood Type - Childhood Type Pervasive Developmental Disorders

Infantile Autism Psychotic Reaction in Autistic, Atypical, & Children with Autism Withdrawn Behavior Childhood Atypical Onset PDD PDD

DSM-I DSM-II DSM-III (1952) (1968) (1980)

Pervasive Developmental Disorders Pervasive Developmental Disorders Autism Spectrum Disorder

Autistic Autistic Disorder Disorder Autism Spectrum Asperger's PDD-NOS Disorder PDD-NOS Disorder

DSM-III-R DSM-IV/R DSM-5 (1987) (1994/2000) (2013)

www.mghcme.org

DSM-5 DIAGNOSTIC CRITERIA FOR AUTISM SPECTRUM DISORDER (299.00)

A Persistent deficits in social interaction and communication as manifested by lifetime history of all three of the following: I Deficits in social-emotional reciprocity - Inability to initiate or respond to social interactions - Inability to share affect, emotions, or interests - Difficulty in initiating or in sustaining a conversation II Deficits in nonverbal communicative behaviors used for social interaction - Abnormal to total lack of understanding and use of eye contact, affect, body language, and gestures - Poorly integrated verbal and nonverbal communication III Deficits in developing, maintaining, and understanding relationships - Difficulty in adjusting behavior to social contexts - Difficulty in making friends - Lack of interest in peers

B Restricted, repetitive, and stereotyped patterns of behavior, interests, or activities as manifested by lifetime history of at least two of the following: I Stereotyped or repetitive speech, motor movements, or use of objects - Motor stereotypies or mannerisms (lining up toys) - Echolalia, stereotyped, or idiosyncratic speech II Excessive adherence to sameness, routines, or ritualized patterns of verbal or nonverbal behavior - Transitional difficulties - Greeting rituals - Rigid patterns of thinking III Highly restricted, fixated interests that are abnormal in intensity or focus - Preoccupation with excessively circumscribed or perseverative interests DSM-5 Diagnostic Criteria for Autism IV Hyper- or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment - Sensory integration issues DSM-5 DIAGNOSTIC CRITERIA FOR AUTISM SPECTRUM DISORDER (299.00) - Apparent indifference to pain/temperature AUTISM SPECTRUM DISORDER- Excessive smelling(299.00), touching, or visual fascination with lights or movements A Persistent deficits in social interaction and communication C Symptoms must be present in the early developmental period as manifested by lifetime history of ______all three of the following: Symptoms may not fully manifest until social demands exceed limited I Deficits in social-emotional reciprocity capacities, or may be masked by learned strategies in later life. - Inability to initiate or respond to social interactions - Inability to share affect, emotions, or interests D Symptoms cause clinically significant impairment in functioning - Difficulty in initiating or in sustaining a conversation E These disturbances are not better explained by intellectual disability II Deficits in nonverbal communicative behaviors used for social interaction To make comorbid diagnoses of ASD & ID, social communication should be below - Abnormal to total lack of understanding and use of eye contact, affect, body language, and gestures that expected for general developmental level. - Poorly integrated verbal and nonverbal communication Specify if: III Deficits in developing, maintaining, and understanding relationships With or without accompanying intellectual impairment - Difficulty in adjusting behavior to social contexts With or without accompanying language impairment - Difficulty in making friends - Lack of interest in peers Associated with a known medical or genetic condition or environmental factor Associated with another neurodevelopmental, mental, or behavioral disorder B Restricted, repetitive, and stereotyped patterns of behavior, interests, or activities With catatonia as manifested by lifetime history of______at least two of the following:

I Stereotyped or repetitive speech, motor movements, or use of objects - Motor stereotypies or mannerisms (lining up toys) - Echolalia, stereotyped, or idiosyncratic speech II Excessive adherence to sameness, routines, or ritualized patterns of verbal or nonverbal behavior - Transitional difficulties - Greeting rituals - Rigid patterns of thinking III Highly restricted, fixated interests that are abnormal in intensity or focus - Preoccupation with excessively circumscribed or perseverative interests IV Hyper- or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment - Sensory integration issues - Apparent indifference to pain/temperature - Excessive smelling, touching, or visual fascination with lights or movements C Symptoms must be present in the early developmental period Symptoms may not fully manifest until social demands exceed limited www.mghcme.org capacities, or may be masked by learned strategies in later life. D Symptoms cause clinically significant impairment in functioning E These disturbances are not better explained by intellectual disability To make comorbid diagnoses of ASD & ID, social communication should be below that expected for general developmental level. Specify if: With or without accompanying intellectual impairment With or without accompanying language impairment Associated with a known medical or genetic condition or environmental factor Associated with another neurodevelopmental, mental, or behavioral disorder With catatonia

Prevalence of ASD

20 18 17/1000 16 14 12 10 7/1000 8 6 4 2 0 2000 2002 2004 2006 2008 2010 2012 2014 2016 Substantial rise in the prevalence of AUTISM in intellectually capable populations

Centers for Disease Control & Prevention (CDC) Surveys: ADDM Network Surveys 2000, 2002, 2004, 2006, 2008, 2010, 2012, 2014, 2016 www.mghcme.org Age at Diagnosis of ASD

By DSM-IV Diagnosis By Age Range (In Children 8 years Old) ✝80% more likely to have psychiatric 8 40 comorbidity compared 36% to cases identified at 7 35 earlier ages (<9 years) 6.25 ✝ 6 30 27% 5 4.5 25 4 20% 4 20 17% 3 15

2 (%) Diagnosis at Age 10

Mean Age at Diagnosis (years) at Diagnosis Age Mean 1 5

0 0 Autistic Disorder PDD-NOS Asperger's Disorder <3 years 3 - 5 years 6 - 8 years ≥9 years

Delayed Diagnosis of Broader Phenotype of Autism

www.mghcme.org SOCIAL RESPONSIVENESS SCALE© SRS-2: Results

Parent Form Aw Cog Com Mot RBR TOTAL ≥90

Score

- T 50

AWARNESS COMMUNICATION ≤30 COGNITION MOTIVATION RRB TOTAL

Raw Score 17 26 44 20 40 147

T-score 86 87 86 79 90 90

www.mghcme.org Autistic Traits in Psychiatrically Referred Youth

Attending Psychiatry Outpatient Clinic

Total N: 303 Age Range: 4-18 years IQ: Predominantly Intact

+ Significant ASD Traits SRS Screen for ASD: 34% (N=110) (Raw score: ♂>70; ♀>65) (34%)

One-third of youth screened positive for ASD

www.mghcme.org Recognition of Autism in Psychiatrically Referred Youth

ASD Under-recognized in Psychiatric Populations

www.mghcme.org CBCL – ASD Profile Level of Dysfunction on Child Behavior Checklist in Psychiatrically Referred Youth Non-ASD Psychiatric Controls (N=62) ASD (N=65) 75 ASD Youth Age range: 6-18 years *** 70 *** *** IQ ** *** Mean IQ: 99 ±14

** IQ>70: 100%

score - 65 ASD Subtypes Autistic Disorder = 52% CBCL T CBCL Asperger’s Disorder = 25% 60 PDD-NOS = 23%

Statistical Significance: *p≤0.05, **p≤0.01, ***p≤0.001 55 Anxious/ Somatic Withdrawn Social Thought Attention Delinquent Aggressive depressed complaints ______behavior ______problems problems______problems behavior behavior

CBCL-ASD Subscales (Withdrawn behavior, Social, & Thought Problems) aggregate cutoff T-score of ≥195 is suggestive of ASD

www.mghcme.org 3/4/2021 13 CBCL: Results

Syndrome Scale, Externalizing, Internalizing & Total Problems Scores Competence Scale Scores

100 100 95 95 90 85 90 80 75 85 70

65 e

e 80 60

r r

o o c

c 55

S S -

- 75 50

T T 45 70 40 35 65 30 25 60 20 15 55 10 5 50 0

Rule- Attention Anxious/ Aggressive Somatic Withdrawn/ Thought Social Breaking External Internal Total Problem Activities Social School Total Problems Depressed Behavior Complaints Depressed Problems Problems Behavior R-Score 19 19 27 7 6 20 17 7 34 32 133 R-Score 11 3.5 2 16.5

T-Score 96 86 86 70 70 87 88 70 76 78 82 T-Score 47 29 27 30

Borderline: 65-69 Borderline: 60-63 Borderline: 31-35 Threshold Threshold Clinical: ≥ 70 Clinical: ≥ 63 Clinical: ≥ 36

www.mghcme.org MGH AUTISM SPECTRUM DISORDER DSM-5 DIAGNOSTIC SYMPTOM CHECKLIST©

Concurrent Validity Diagnostic Correspondence with: - SRS: 95% - ADOS: 86% Neuropsychological Correlates of HF-ASD

Processing Speed Cognitive Flexibility Wechsler Adult Intelligence Scale Delis Kaplan Executive Function System (WAIS-III) (D-KEFS) 120 15 109 103 *** 105 AB 12 89 11 11 90 10 10 10 10 *** *** 75 *** AB AB HC [N=52] AB 8 8 60 ADHD [N=52] 7

ASD [N=26] Mean Score Mean 45 Score Mean 5 30 15 0 0 Processing Speed Number-Letter Inhibition Switching Index Switching Colour -Word Colour-Word Trail Making Subtest Interference Subtest Interference Subtest

HC=Healthy Controls; A=Versus HC, B=Versus ADHD; Statistical Significance: *p≤0.05, **p≤0.01, ***p≤0.001

www.mghcme.org Autism Diagnostic Interview-Revised (ADI-R) Autism Diagnostic Observation Schedule (ADOS)

• Semi-structured assessment • Requires trained raters (training is expensive, time consuming, and not readily available) • Assessment is expensive, time-consuming, with limited accessibility • ? sensitivity to detect ASD in high-functioning and in adult populations • ? validity in populations with emotional and behavioral difficulties

www.mghcme.org Prevalence of ASD in Psychiatrically Referred Youth

Non-ASD Total N: 2323 Total Duration: 15 years (1991-2006) Male: 87%

ASD Age (yrs): 9.7 ±3.6 (3-17) 9.3% Intellectual Ability Clinically not [N=217] & Language Skills: impaired in majority of the referred youth

Autism Prevalence >5-fold Higher than General Population

Joshi et al., 2010 www.mghcme.org Burden of Psychopathology in ASD

Lifetime Psychiatric Comorbidities Youth Adults 8 8 *** 6.5 ±2.5 *** 6 ±3.4 6 6 5 ±3

4 4 3.5 ±2.7

2 2 Mean # of Psychiatric Disorders Psychiatric of # Mean

0 0 Non-ASD ASD Non-ASD ASD

Statistical Significance: ***p≤0.001 Greater Burden of Psychopathology

www.mghcme.org Psychopathology Associated with ASD Lifetime Psychiatric Comorbidity Attention-deficit/Hyperactivity Disorder Oppositional Defiant Disorder Conduct Disorder Multiple (≥2) Anxiety Disorders *** Major Depressive Disorder Bipolar I Disorder Psychosis Substance Use Disorders *** Percentage 0 10 20 30 40 50 60 70 80 90 Anxiety Disorders Repetitive Behavior Disorders Multiple Anxiety Disorders *** Separation Anxiety Disorder OCD Specific Phobia *** Generalized Anxiety Disorder Tic Disorder Agoraphobia *** Social Phobia Panic Disorder Tourette's Disorder Post Traumatic Stress Disorder Percentage 0 10 20 30 40 50 60 70 Percentage 0 5 10 15 20 25 ASD NON-ASD Statistical Significance: ***p≤0.001

Joshi et al., 2010 www.mghcme.org 3/4/2021 20 Risk for Psychiatric Disorders in ASD

A***B** A*** A***B***

A***

A***B***

A***

A***B**

A***

*p<0.05, **p<0.005, ***p<0.001; A Versus Controls. B Versus ADHD-AT

Joshi et al., 2019 www.mghcme.org 3/4/2021 21 Gender Profile of Autistic Traits

Social Responsiveness Scale (SRS-2)

Male Female 120 106 101 100

Score - 60

2 Mean R Mean 2 36 - 40 35

SRS 19.5 20 20 16 18 19 20 12.5 13

0 Composite Social Social Social Social Autistic Score Awareness Motivation Communication Cognition Mannerisms

www.mghcme.org 3/4/2021 22 Gender Profile of Psychopathology

Child Behavior Checklist (CBCL)

100

** 80 73.5 69 * 70 69 70 69.5 68 65.5 67 66 66 66 67 66.5 66 67 62.5 65 * Score 59 61 60.560.5 - 60

40 CBCL Mean T 20

0 Total Externalizing Delinquent Aggressive Internalizing Anxious/ Withdrawn/ Somatic Attention Social Thought Problems Problems Behaviors Behaviors Problems Depressed Depressed Complaints Problems Problems Problems

Male Female

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

www.mghcme.org 3/4/2021 23 Gender Profile of Psychiatric Disorders

90 80 77 75

59 60 51 44 45 40

30 Percentage (%) Percentage 18 19 15

0 ADHD Major Depressive Disorder Bipolar Multiple (≤2) Disorder Anxiety Disorders Male Female

www.mghcme.org Emotional Dysregulation in ASD

Child Behavior Checklist Prevalence of ED in Psychiatrically -Emotional Dysregulation Profile (CBCL- Referred ED) ASD Youth

A*** B*** CBCL-ED profile based on the composite 90 83% T-scores of CBCL subscales: 75 - Attention - Aggression 60 54% - Anxious/Depressed 45

Level of ED of Prevalence 30 CBCL-AAA Subscales Emotional Composite T-Score Dysregulation (ED) 15 2% <180 Low/No ED 0 ≥180 Presence of ED HC ADHD ASD

Statistical Significance: *p≤0.05, **p≤0.01, ***p≤0.001 A = vs. HC; B = vs. ADHD

www.mghcme.org 3/4/2021 25 Prescribing Patterns: Clinical Profile

Total N 54 Age (yrs) 13 ±3 (7-19) Male 76% Autistic Disorder 61% Asperger’s Disorder/PDD-NOS 39% Associated Psychopathology

Mood Disorders 94%

ADHD 83%

Anxiety Disorder 67%

ADHD+Anxiety Disorder+Mood Disorder 57%

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

www.mghcme.org 3/4/2021 26 Prescribing Patterns: Treatment Profile 100

80 Mean # of Psychotropic Medications 3 ±1.5 74% Psychopharmacological Treatment 70 -Monotherapy 18% 60 -Combination Therapy 80% 50

40 33% 30 26% 24% 22%

Percentage of Subjects20 (N=54) 15% 15% 9% 10 7%

0 1 2 Second Typical Stimulants Non-stimulants SSRIs Conventional Benzodiazepines CAM Others Generation Anti-Psychotic Mood Stabilizers 1 [N=8] [N=2] [N=1] Anti-Psychotic Melatonin , Inositol , Omega-3 FA 2 Naltrexone[N=4], Buspirone[N=3], Metformin[N=3], Anti-Psychotics (83%) Anti-ADHD (46%) 1 Benzotropine[N=2], Buproprion[N=2], Duloxetine[N=2], 1 Nortriptyline[N=1], Propranolol[N=1] 93% of ASD youth were prescribed NON-FDA approved medication

www.mghcme.org U.S. Food and Drug Administration (FDA)

Risperidone* and Aripiprazole** FDA approved for the treatment of irritability including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods in children and adolescents with autistic disorder

(ages: 6-17* / 5-16** years)

www.mghcme.org Agents for Treatment of Irritability/Aggression in Youth with Autistic Disorder

Risperidone & Aripiprazole • Typically expected short- & long- term treatment response • Rapid (< 1 week) and robust anti-irritability/aggression response • Additionally effective in managing hyperactivity & repetitive behaviors • Short-term treatment associated with weight gain as expected (risperidone > Aripiprazole)

Lurasidone: Efficacy NOT superior to placebo

www.mghcme.org Risperidone + Parent Training* (*ABA based therapy for ASD & noncompliance) 24-week RCT in Youth with ASD ASD + Sign. Irritability: N=124 [RISP+PT=75] [ABC-Irritability score ≥18 + CGI-S ≥4]X Male: 85% Mean Age [Range]: 7.5 [4–13] years Efficacy IQ>70 : 66% PT+RISP superior to RISP • Mean Dose [mg/day]: Tolerability PT+RISP[2mg/day] < RISP[2.25mg/day] [p=0.04] Common AEs • Noncompliance Improvement (% ⇊ HSQ): Rhinitis 80% PT+RISP[71%] > RISP[60%] [p=0.006; ES=0.34] Inc. appetite 75% Weight gain 75% • Behavioral Improvement (⇊ ABC-subscales): [p=0.01; ES=0.48] Fatigue 75% - ABC-Irritability Sialorrhoea 42% [p=0.04; ES=0.55] - ABC-Hyperactivity Enuresis 39% - ABC-Stereotypy[p=0.04; ES=0.23]

www.mghcme.org BPD

BPD+ASD 16% Total N =155 SGN Monotherapy Response of ASD Youth with BPD

Rate of Anti-manic Response Adverse Effects

80 ( p = 0.8 ) Sedation 69 Cold Symptoms 70 65 Increased Appetite GI Complaints 60 ( p = 0.7 ) Headache Agitation 47 50 44 Aches/Pains Dry Ears Nose Throat 40 Urinary Neurological Tics

Response Rate (%) Rate Response 30 Insomnia 20 Respiratory Cardiovascular… 10 Slurred Speech p=0.02 Teary Eyes p=0.02 BPD+ASD BPD 0 Anxiety YMRS (≥30%) YMRS (≥50%) Percent 0 10 20 30 40 50 BPD BPD+ASD

www.mghcme.org 12-Week Controlled Pharmaco-Imaging Trial of Memantine Hydrochloride (Namenda) in Youth with High-Functioning Autism Spectrum Disorder Clinical Trials Registration @ ClinicalTrials.gov Registration Number: NCT01972074 URL: https://clinicaltrials.gov/ct2/show/NCT01972074?term=namenda+and+autism&rank=6

Study Approved by: Partners Human Research Committee Institutional Review Board

Study Funded by: National Institute of Mental Health Award #MH100450 MRS Glutamate Activity in P r e g e n u a l Anterior Cingulate Cortex Proton Spectroscopy in Youth with HF-ASD TE - Stepped (J-PRESS) Spectrum

NAA Cho Cr Baseline Glutamate Levels in PgACC

(P=.001) 95.5 ± 14.6 Glutamate peak 76.6 ± 17.7 Voxel Placement at Pregenual ACC ACC MTL

[N=16] [N=37]

www.mghcme.org 3/4/2021 34 Prevalence of HIGH-Glu Activity in HF-ASD

61% 0%

39%

HIGH-Glu LOW-Glu NORMAL-Glu

www.mghcme.org A n t i - Glutamate Agent: Memantine Hydrochloride

• Memantine hydrochloride is a: - moderate-affinity - non-competitive - NMDA receptor antagonist • Memantine is approved by the U.S. Food and Drug Administration for the treatment of moderate to severe Alzheimer’s disease.

• Memantine improves or delays the decline in cognition (attention, language, visuo-spatial ability), as well as functioning in adults with dementia

www.mghcme.org 3/4/2021 36 Tolerability

STUDY MEDICATION MEM[N=21] PBO[N=21] p-value [t-statistic] [Range] [15-20] [10-20] [t =0.94] Dose (mg/day) 19.7 ±1 19 ±3 0.35 38 @ Maximum Study Dose 18 (86) 19 (95) (20mg/day)

Adverse Events (Mild-Moderate Severity)

Headache

Insomnia

Increased Appetite MEMANTINE [N=21] PLACEBO [N=21] Anxiety

Fatigue

Percentage 0 5 10 15 20

www.mghcme.org 3/4/2021 Memantine Response Based on B a s e l i n e PgACC Glu Activity

UnSelected Sample Glutamate Activity Based Sample

100 (P=.007) 90 [OR=16] 80% 80

70 (P=.03) [OR=4.82] 60 56%

Percent (%) 40 (P=.49) 30 25% 21% 20% 20

10 0% 0 Unselected Sample HIGH-Glutamate Sample NORMAL-Glutamate Sample Placebo Memantine Treatment Responders (Response criteria: ≥25%⇊SRS+ASD-CGI-I≤2)

www.mghcme.org In Summary

• Higher than expected prevalence of ASD in psychiatrically referred youth • Under-recognition of ASD in psychiatrically referred populations • Youth with ASD suffer from greater burden of psychopathologies • Symptom profile of psychopathologies in ASD is typical of the disorder • Paucity of controlled trials for the treatment of psychopathology in ASD • Subtype of ASD identified based on glutamate dysregulation in PgACC • Promising role of glutamate modulators for the treatment of ASD • Emerging role neuro-imaging guided pharmacotherapy in ASD

www.mghcme.org Acknowledgments

The Alan and Lorraine B r e s s l e r Clinical and Research Program for Autism Spectrum Disorder Massachusetts General Hospital Boston MA

Joseph Biederman, MD Sheeba A. Anteraper, PhD Yvonne Woodworth, BA Janet Wozniak, MD Kaustubh R. Patil, PhD Daniel Kaufman, BS Atilla Ceranoglu, MD Stephen Faraone, PhD Nina Dallenbach, BS Lynn Grush, MD Ronna Fried, EdD Allison Green, BA Amy Yule, MD Karmen Koester EdM, MA Philia Henderson, BA Carrie Vaudreuil, MD Maura Fitzgerald, MA Ellesse Cooper Robert Doyle, MD Maribel Galdo, LCSW Melissa De Leon

Phone: 617-726-7899 Email: [email protected] Facebook: Facebook.com/BresslerMGH