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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 Disorder
PDD-NOS
PDD-NOS Disorder
DSM-III-R DSM-IV/R DSM-5
(1987) (1994/2000) (2013)
www.mghcme.org
- Transitional difficulties
- Greeting rituals
- Rigid patterns of thinking
DSM-5 Diagnostic Criteria for Autism 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
- Sensory integration issues
- Apparent indifference to pain/temperature
DSM-5 DIAGNOSTIC CRITERIAUTISM
FOR AUTISM SPECTRUM
PECTRUM A
DISORDER (299.00)
ISORDER S D (299.00)
- Excessive smelling, 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
- Difficulty in making friends
With or without accompanying language impairment
- 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.orgPrevalence 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.orgAge at Diagnosis of ASD
By DSM-IV Diagnosis By Age Range
✝80% more likely to
(In Children 8 years Old) have psychiatric
8 40 comorbidity compared
36% to cases identified at
7 35 earlier ages (SOCIAL RESPONSIVENESS SCALE©
SRS-2: Results
Parent Form
Aw Cog Com Mot RBR TOTAL
≥90
80
70
T-Score
60
50
40
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.orgA u t i s t i c Tr a i t s i n
P s y c h i a t r i c a l l y R e f e r r e d Yo u t h
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.orgRecognition of Autism in
P s y c h i a t r i c a l l y R e f e r r e d Yo u t h
ASD Under-recognized in Psychiatric Populations
www.mghcme.orgCBCL – 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
CBCL T-score
** IQ>70: 100%
65 ASD Subtypes
Autistic Disorder = 52%
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.org3/4/2021 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
80 60
T-Score
T-Score
55
75 50
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: ≥ 36
Clinical: ≥ 70 Clinical: ≥ 63
www.mghcme.orgMGH 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
Mean Score
Mean Score
HC [N=52] AB 8 8
60 ADHD [N=52] 7
45 ASD [N=26]
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.orgAutism 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.orgPrevalence of ASD in
P s y c h i a t r i c a l l y R e f e r r e d Yo u t h
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.orgBurden of Psychopathology in ASD
Lifetime Psychiatric Comorbidities
Youth Adults
8 8
***
6.5 ±2.5 ***
Mean # of Psychiatric Disorders
6 ±3.4
6 6
5 ±3
4 4 3.5 ±2.7
2 2
0 0
Non-ASD ASD Non-ASD ASD
Statistical Significance: ***p≤0.001
Greater Burden of Psychopathology
www.mghcme.orgPsychopathology 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.org3/4/2021 20
Risk for Psychiatric Disorders in ASD
A***B**
A***
A***B***
A***
A***B***
A***
A***B**
A***
*p3/4/2021 21
G e n d e r P ro f i l e o f A u t i st i c Tra i t s
Social Responsiveness Scale (SRS-2)
Male Female
120
106
101
100
80
SRS-2 Mean R-Score
60
40 35 36
18 19 19.5 20 20
20 13 16
12.5
0
Composite Social Social Social Social Autistic
Score Awareness Motivation Communication Cognition Mannerisms
www.mghcme.org3/4/2021 22
Gender Profile of Psychopathology
Child Behavior Checklist (CBCL)
100
80 **
73.5
70 70 69.5
CBCL Mean T-Score
68 69 *
65.5 67 66 66 66 67 66.5 66 67 69
62.5 65 *
59 61 60.560.5
60
40
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.org3/4/2021 23
Gender Profile of Psychiatric Disorders
90
80
77
75
59
60
51
Percentage (%)
44
45 40
30
18 19
15
0
ADHD Major Depressive Disorder Bipolar Multiple (≤2)
Disorder Anxiety Disorders
Male Female
www.mghcme.orgEmotional 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
Prevalence of ED
- Aggression 60 54%
- Anxious/Depressed
45
Level of 30
CBCL-AAA Subscales Emotional
Composite T-Score Dysregulation (ED) 15
2%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.org3/4/2021 26
Prescribing Patterns: Treatment
Profile
100
90
80
Mean # of Psychotropic Medications 3 ±1.5
74%
Psychopharmacological Treatment
Percentage of Subjects (N=54)
70
-Monotherapy 18%
60 -Combination Therapy 80%
50
40
33%
30 26%
24%
22%
20 15% 15%
9%
10 7%
0 1 2
Second Typical Stimulants Non-stimulants SSRIs Conventional Benzodiazepines CAM Others
Generation Anti-Psychotic Mood Stabilizers 1 Melatonin[N=8], Inositol[N=2],
Anti-Psychotic Omega-3 FA[N=1]
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.orgU.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.orgAgents 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.orgR i s p e r i d o n e + P a r e n t Tr a i n i n g *
(*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
IQ>70 : 66%
Efficacy
PT+RISP superior to RISP
• Mean Dose [mg/day]:
PT+RISP[2mg/day] < RISP[2.25mg/day] [p=0.04]
Tolerability
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):
Fatigue 75%
- ABC-Irritability[p=0.01; ES=0.48] Sialorrhoea 42%
- ABC-Hyperactivity[p=0.04; ES=0.55] Enuresis 39%
- ABC-Stereotypy[p=0.04; ES=0.23]
www.mghcme.orgBPD
BPD+ASD
16%
Total N =155SGN Monotherapy Response of
A S D Yo u t h w i t h B P D
Rate of Anti-manic Response Adverse Effects
80 ( p = 0.8 ) Sedation
69 Cold Symptoms
70 65 Increased Appetite
GI Complaints
60
Response Rate (%)
( p = 0.7 ) Headache
Agitation
50 47
44 Aches/Pains
Dry Ears Nose Throat
40 Urinary
Neurological
30 Tics
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.org12-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
Pregenual Anterior Cingulate Cortex
P ro to n S p e c t ro s co p y i n Yo u t h w i t h H F - A S D
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.org3/4/2021 34
Prevalence of HIGH-Glu Activity in HF-ASD
61%
0%
39%
HIGH-Glu LOW-Glu NORMAL-Glu
www.mghcme.orgAnti-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.org3/4/2021 36
To l e r a b i l i t y
STUDY MEDICATION MEM[N=21] PBO[N=21] p-value [t-statistic]
Dose[Range] (mg/day) 19.7 ±1 [15-20] 19 ±3 [10-20] 0.35 [t38=0.94]
@ 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.org3/4/2021
Memantine Response Based on
Baseline PgACC Glu Activity
UnSelected Sample G l u t a m a t e Ac t i v i t y B a s e d S a m p l e
100
(P=.007)
90 [OR=16]
80%
80
70 (P=.03)
[OR=4.82]
60 56%
Percent (%)
50
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.orgIn 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.orgAcknowledgments
The Alan and Lorraine Bressler
Clinical and Research Program
for Autism Spectrum Disorder
M a s s a ch us etts G en er a l H o s p it al
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: MGHASDprogram@Partners.org
Facebook: Facebook.com/BresslerMGH
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