Embed Size (px)
Citation preview
www.mghcme.org
GAGAN JOSHI, MD Assistant Professor of Psychiatry Director, Autism Spectrum Disorder Program Clinical & Research Program in Pediatric Psychopharmacology Massachusetts General Hospital, Harvard Medical School
Pharmacologic Treatment of Social Cognition in
Autism
www.mghcme.org
My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose: Research Support: PI for Investigator-Initiated Studies: -National Institute of Mental Health (NIMH) grant Award #K23MH100450 -Pfizer pharmaceuticals Site PI for Multi-Site Studies: -Simons Center for the Social Brain -Duke University -Forest Research Laboratories -Sunovion pharmaceuticals Co-Investrigator for Clinical Trials: -U.S. Department of Defense -Merck Schering Plough Corporation -Pamlab LLC. Honoraria: -Governor’s Council for Medical Research and Treatment of Autism in New Jersey -American Academy of Child and Adolescent Psychiatry -Medical Society of Delaware -Simons Foundation
Disclosures
P h a r m a c o t h e r a p y f o r C o r e F e a t u r e s o f A u t i s m
Controlled Trials Total Autism Target Core Features of Autism
Agent Study Age [N] Subtype HF Features Measure ASD SI SC RRB SSRIs Fluoxetine Hollander et al., 2005 Youth 39 AuD, ApD - Autism CY-BOCS, CGI-ASD - - - ±*
Hollander et al., 2012 Adults 34 ASD + Autism Y-BOCS - NA NA + Fluvoxamine McDougle et al., 1996 Adults 30 AuD - Autism RFRRS, Y-BOCS + - +** +
McDougle et al., 2000 Youth 34 ASD - Autism CY-BOCS - - - - Citalopram King et al., 2009 Youth 149 ASD - RRB ABC, CY-BOCS - - - - TCAs Clomipramine Remington et al., 2001 Youth 36 AuD NA Autism CARS, ABC - - - - Atypical Antipsychotics Risperidone RUPP, 2002
McDougle et al., 2005 Youth 101
63 AuD ± Irritability ABC, CY-BOCS NA - - +
Aripiprazole Owen et al., 2009 Marcus et al., 2009
Youth 98 218
AuD NA Irritability ABC, CY-BOCS + - + +
Anticonvulsants Mood Stabilizers Valproic Acid Hollander et al. 2006 Youth 13 ASD - Autism CY-BOCS NA NA NA ±*
Hollander et al. 2010 Youth 27 AuD ± Irritability ABC, CY-BOCS, VABS
NA - - -
SI=Social Interaction; SC=Social Communication; RRB=Restricted Repetitive Behaviors; NA=Not Assessed; AuD=Autistic Disorder; ApD=Asperger’s Disorder; CY-BOCS=Children’s Yale-Brown Obsessive Compulsive Scale; CGI-ASD=Clinical Global Impression-ASD; Y-BOCS=Yale-Brown Obsessive Compulsive Scale; RFRRS=Ritvo-Freeman Real-Life Rating Scale; ABC=Aberrant Behavior Checklist; CARS=Childhood Autism Rating Scale; ADOS=Autism Diagnostic Observation Schedule; VABS=Vineland Adaptive Behavior Scale; SSRIs=Selective Serotonin Reuptake Inhibitors; TCAs=Tricyclic Antidepressants; *Statistically but not clinically significant; **Repetitive language use only
Promising efficacy for treating RRBs in youth with ASD
Promising efficacy for treating RRBs in adults with ASD Lack of efficacy for treating RRBs in youth with ASD
Atypical antipsychotics::
SSRIs::
www.mghcme.org
AuD+ Sign. Irritability: [ABCIrritability ≥18+CGI-S ≥4]X
N = 101 [RISP=49]
Mean Age [Range]: 9 ±3 [5–17]
Pre-pubertal [≤12 yrs.]: 87%
Male: 81%
IQ ≥70: 17%
Mean Dose: [Range]:
1.8 ±0.7 mg/day [0.5–3.5]
RISP Flexible Dose Titration Schedule AM PM Daily Dose
Initial Dose <20 Kg - 0.25 mg ≥20 Kg - 0.5 mg Maximum Dose ≤45 Kg 1 mg 1.5 mg 2.5 mg/day >45 Kg 1.5 mg 2 mg 3.5 mg/day
69%
12%
0
20
40
60
80
100
Risperidone Placebo
Pe
rce
nt
Re
sp
on
din
g (34/49)
(6/52)
p < 0.001
Response criteria: ≥25% ↓ ABCIrritability score + CGI-I ≤2
Efficacy - Irritability
Efficacy – Other Features
•Sign. improvement in: - Repetitive behaviors(CY-BOCS &
ABC)
- Hyperactivity(ABC)
•No change in other core features of ASD
8-week RCT in Autistic Disorder Youth with Irritability
Risper idone
www.mghcme.org
Autistic Disorder + Sign. Irritability:
[ABC-Irritability score ≥18 + CGI-S ≥4]X
N = 98 [ARIP=47]
Mean Age [Range]: 9 years [6–17]
Pre-pubertal [Children]: 85%
Male: 88%
Mean Dose [Range]: 8.5 [2–15] mg/day
ARIP Flexible Dose Titration Schedule
Duration Daily Dose N [%] Week-I 2 mg/day 02 [05] Week-II-VI 5 mg/day 13 [33] Week-II-VI 10 mg/day 16 [41] Week-II-VI 15 mg/day 08 [21]
Ar ip ip razo le
8-week RCT in Autistic Disorder Youth with Irritability
www.mghcme.org
52%
14%
0
20
40
60
80
100
Aripiprazole Placebo
Perc
en
t R
esp
on
din
g
Response criteria: ≥25% ￬ ABC-I + CGI-I ≤ 2
p < 0.001
Sign. improvement on ABC-I & CGI-I from week-1 onwards
Parent-Rated ABC - Irritability Subscale
Efficacy - Irritability
Efficacy – Other Features
p<0.001
(-5)
(-13)
Significant improvement in: - Hyperactivity(ABC-H)
- Repetitive behaviors(ABC-Stereotypy & CY-BOCS)
- Communication(ABC-Inappropriate speech)
Ar ip ip razo le
www.mghcme.org
Ar ip ip razo le
Tolerability • 77% of the participants completed the trial • Adverse Events: - ARIP[92%] vs. PBO[72%]
- Severity: Mild-moderate - Serious AEs: None - Tx-Limiting AEs: ARIP(N=5)* vs. PBO(N=3) - Common AEs: - Fatigue(21%)
- Somnolence(17%)
• EPS: ARIP(17% [N=8]) > PBO(8% [N=4])
• Weight gain: - Mean: ARIP > PBO (2kg vs. 0.8kg; p<0.005)
- Clinically sign: ARIP > PBO (29% vs. 6%; p<0.01) (≥7% inc. from baseline)
• Metabolic Parameters & EKG: - No clinically significant change with treatment
*N=1 x Fatigue, Vomiting, Wt gain, SIB, Aggression
8-week Crossover RCT in Youth with ASD1
• 39 ASD youth between 5-16 years • Liquid Fluoxetine dosing: - Starting dose: 2.5 mg/day - Mean dose [Range]: 10 ±4 [2.5-20] mg/day or 0.4 mg/kg/day
Tolerability • Common AEs: Agitation, Sedation, & Anorexia
• Dose-limiting AEs [Agitation]: FXT[6/19] vs. PBO[2/20]
CY-
BO
CS
ES = 0.76 p=0.004
Statistically but not
Clinically significant
improvement
Efficacy: Repetitive Behaviors
12-week RCT in Adults with HF-ASD2
CGI-I ≤2: - Global: FXT[35%] > PBO[0%]
- RRB: FXT[50%] > PBO[8%]
Y-B
OC
S Sc
ore
p=0.005
• 34 medication-free adults with HF-ASD • Mean Age [Range]: 34 ±14 years [18-60] • Liquid FXT dosing: - Starting dose: 10 mg/day - Mean dose [Range]: 65 ±29 [20-80] mg/d
Efficacy: Repetitive Behaviors
Tolerability • TEAE Severity: Mild-moderate • Serious AEs: None • D/Os d/t AEs: Fluoxetine(N=1) vs. PBO(N=0)
• Common AEs: - Sleep disturbance(N=3) - Headaches(N=3)
www.mghcme.org
Fluoxe t ine
Youth: L imi ted to lerabi l i ty and e f f icacy a t best Adul ts : Wel l to lera ted w i th promis ing e f f icacy
www.mghcme.org
Fluvoxamine
• Total N = 30 • Mean dose: 275 mg/day
Efficacy • Superior to PBO: - Repetitive thoughts & behaviors(Y-BOCS)
- Aggression
- Global ASD Severity(CGI-I)
Tolerability • Mild AEs: - Sedation - Nausea
12-week RCT in Adults
with Autistic Disorder1 • Total N = 52 (OLT=18; RCT=34) • Mean dose: 67 ±32mg/day2(low-dose)
Efficacy • No improvement in:2 - Repetitive behaviors(CY-BOCS)
- Anxiety(SCARED)
- Global ASD Severity(CGI-I)
Tolerability • Sign. AEs: - Anxiety - Insomnia - Agitation
OLT2 & RCT3 in
Youth with ASD
Youth: Poorly tolerated with limited efficacy at best
Adults: Well tolerated with promising efficacy
www.mghcme.org www.mghcme.org
• 149 ASD youth with moderate to severe repetitive behaviors • Liquid Citalopram mean dose: 16.5 ± 6.5 mg / day
Efficacy • No improvement in: - Repetitive behaviors (CY-BOCS-PDD: -2 vs. -2; p=0.81)
- Other core domains of ASD (Social interaction (ABC-SW) & Communication (ABC-IS))
- ASD severity (CGI-I≤2: 33% vs. 34%; p>0.99) - Hyperactivity (ABC-H)
• Improvement in: - Irritability (ABC-I: -3.2 vs. -0.9; p=0.03)
Tolerability • ≥ 1 AE: Citalopram > Placebo (97% vs. 87%; p=0.03)
• Common AEs: Inc. Energy(38%), Impulsiveness(19%), Hyperactivity(12%), Dec. Concentration(12%), Stereotypy(11%), Diarrhea(26%), Insomnia(18%)
• Tx. Limiting AEs: Citalopram[9/73] > Placebo[7/76]
• Serious AEs: Seizure on Citalopram[N=1]
12-week RCT in ASD Youth with Repetitive Behaviors
Ci ta lopram
www.mghcme.org
• Fluoxetine & Fluvoxamine in Adults (but not youth)
with ASD
• Bumetanide in children with ASD
• Risperidone & Aripiprazole as alternative agents
• Citalopram lack response in Youth with ASD
• Divalproex Sodium lack response in Youth with ASD
Agents for Tx of Repetitive Behaviors in ASD
Ag e n ts f o r Tx o f R e p e t i t i ve Be h a v i o r s i n A S D
www.mghcme.org
Controlled Trials
Ph a rm a c o the ra py f o r C o re Fe a tu re s o f Au t i s m
Total Autism Target Core Features of Autism
Agent Action Study Age [N] Subtype HF Features Measure ASD SI SC RRB
GABAergic Agents Bumetanide Lemmonier et al.,
2012 Youth 60 ASD - Autism CARS,
ADOS +
[CARS+CGI]
- - + [ADOS]
Cholinergic Agents
Donepezil Acetylcholinesterase inhibitor
Chez et al., 2003 Youth 43 ASD - Autism CARS, EOWPVT-R, ROWPVT
+?? NA - NA
Galantamine Acetylcholinesterase inhibitor & Nicotinic receptor modulator
Niederhofer et al., 2002
Youth 20 AuD - Autism ABC - +* +* -
Mecamylamine (Inversine)
Nicotinic receptor antagonist [Non-competitive]
Arnold et al., 2012 Youth 20 ASD - Autism ABC, SRS, RBS
- - - -
SI=Social Interaction; SC=Social Communication; RRB=Restricted Repetitive Behaviors; NA=Not Assessed; AuD=Autistic Disorder CARS=Childhood Autism Rating Scale; EOWPVT-R=Expressive One-Word Picture; Vocabulary Test-Revised; ROWPVT=Receptive One-Word Picture Vocabulary Test; ABC=Aberrant Behavior Checklist;
CPRS=Conner’s Parent Rating Scale; SRS=Social Responsiveness Scale; RBS=Repetitive Behavior Scale
*Statistically but not clinically significant
Promising efficacy for treating RRBs in ASD
Lack efficacy for treating core features of ASD
GABAergic agent (bumetanide):
Cholinergic agents:
www.mghcme.org
Controlled Trials
Ph a rma co the ra py f o r C o re Fe a tu re s o f Au t i s m
Role of Oxytocin for improving social deficits in ASD under study
Oxytocin Total Autism Target Core Features of Autism
Administration Study Age [N] Subtype HF Features Measure SI SC RRB Single Dose Intravenous Hollander et al., 2003 Adults 15 AuD, ApD + ASD Investigator-
developed NA NA +
Intravenous Hollander et al., 2007 Adults 15 AuD, ApD + ASD Affective speech comprehension task
+ NA NA
Intranasal Guastella et al., 2010 Youth 16 ASD NA Emotion recognition
RMET NA + NA
Chronic Dose Intranasal (24 IU BID)
Anagnostou et al., 2012
Adults 19 ASD + ASD SRS, Y-BOCS, RBS-R, RMET
- + +
Intranasal (12-24 IU QAM)
Dadds et al., 2013 Youth 38 ASD + ASD FOS-ASD, SRS, SSRS - - -
Intranasal (18/24 IU BID)
Guastella et al., 2014 Youth 26 ASD ±
ASD SRS, CGI -
-
-
SI=Social Interaction; SC=Social Communication; RRB=Restricted Repetitive Behaviors; NA=Not Assessed; AuD=Autistic Disorder; ApD=Asperger’s Disorder; RMET=Reading the Mind in the Eyes Test; SRS=Social Responsiveness Scale; Y-BOCS=Yale-Brown Obsessive Compulsive Scale; RBS-R= Repetitive Behavior Scale-Revised; FOS-ASD=Family Observation Schedule-ASD; SSRS=Social Skills Rating Scale
www.mghcme.org
Stimulants: Methylphenidate
Antidepressants: TCA (nortriptyline) SSRIs (Sertraline, Citalopram, Fluoxetine) MAOIs
Anticonvulsants: Lithium, Valproate, Lamotrigine, Topiramate
Antipsychotics: Risperidone, Clozapine
Antibiotics: Riluzole, Ampicillin, Minocycline, Ceftriaxone
Antivirals: Amantadine
Anti-tuberculosis: D-cycloserine
Mucolytic: N-Acetylcysteine
Others: Memantine
Ketamine
ECT
TMS
Glu tamate Modu la t ing Agents
www.mghcme.org
P h a r m a c o t h e r a p y f o r C o r e F e a t u r e s o f A u t i s m
No controlled-trials in intellectually capable populations of youth with ASD
Glutamate Modulat ing Agents Control led-Tr ia ls
Age Total Dose Autism Target Core Features of Autism
Agent Action Study [Range] [N] [Range] Subtype HF Features Measure SI SC RRB
Lamotrigine Glu release inhibitor Belsito et al., 2001 (12-week RCT)
Children [3-11]
28 5 mg/kg/d AuD - ASD ABC - - -
Amantadine NMDA Glu receptor antagonist (low affinity)
King et al., 2001 (4-week RCT)
Youth [5-15]
39 168 mg/d [90-200]
AuD - Irritability & Hyperactivity
ABC - - -
D-cycloserine
NMDA Glu receptor agonist/antagonist
Urbano et al., 2014 Urbano et al., 2015 (8-week RCT)
Young Adults [14-25]
20 50 mg/d ASD + ASD ABC, SRS, - - -
N-Acetylcysteine Glu release inhibitor Hardan et al., 2012 (12-week RCT)
Children 29 2700 mg/d AuD - Irritability ABC, SRS, RBS-R
- - + [SRS+ RBS-R]
Wink et al., 2016 (12-week RCT)
Children 31 56* [34-64]* *mg/kg/d
ASD - ASD CGI-ASD - - -
Dean et al., 2016 (6-month RCT)
Children 98 500 mg/d AuD - ASD SRS, RBS, CCC, DBC
- - -
SI=Social Interaction; SC=Social Communication; RRB=Restricted Repetitive Behaviors; NA=Not Assessed; Glu=Glutamate; AuD=Autistic Disorder; ABC=Aberrant Behavior Checklist; VABS=Vineland Adaptive Behavior Scale; PL-ADOS=Pre-Linguistic Autism Diagnostic Observation Schedule; CARS=Childhood Autism Rating Scale; SRS=Social Responsiveness Scale; CY-BOCS=Children’s Yale-Brown Obsessive Compulsive Scale; RBS-R=Repetitive Behavior Scale-Revised; CCC-2=Children’s Communication Checklist–Second Edition; DBC-P= Developmental Behaviour Checklist–Primary Carer Version
www.mghcme.org
16 1/17/20
17
Efficacy
PBO NAC
• Trial Completion 12/15 13/14
• Treatment-limiting AEs
None ↑irritability[N=1]
Common AEs PBO NAC p=value GI AEs 47% 79% NS - Nausea/vomiting
20% 43% NS
- Diarrhea 7% 21% NS - Constipation 13% 21% NS
Tolerability
p<0.001
ABC - Irritability Subscale
• Sign. improvement in: - RRBs(RBS-R/SRS) • No change in other core features of ASD
Autistic Disorder + Irritability: [CGI-S for Irritability ≥4]X
N = 29 [NAC=14]
Male: 94%
Mean Age [Range]: 7 ±2 [3–11]
Concomitant psychotropic Tx: 48%
12-week RCT in Children with Autistic Disorder
NAC Flexible Titration Schedule
Duration NAC Dosing (mg/day)
Week I-4 900 mg QDay Week 5-8 900 mg BID Week 9-12 900 mg TID
N-Ace ty lcys te ine
www.mghcme.org
• 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
A n t i - G l u t a m a t e r g i c A g e n t : M e m a n t i n e H y d r o c h l o r i d e
www.mghcme.org
www.mghcme.org
12-week OLT of Memantine Hydrochloride
for the Treatment of Social Deficits in
Young Adults with HF-ASD
Demographic Character is t ics
Participants
Total participants 18
Gender (male) 14 (78%)
Ethnicity (Caucasian) 18 (100%)
Full Scale IQ
Mean 106 ±15
Range 75 - 125
Age (years)
Mean 28 ±9.6 Range 18-47
Study Medication
Flexible Dose Titration Schedule
Duration (Weeks)
Maximum Dose
0-1 5 mg/day
1-2 10 mg/day
2-3 15 mg/day
4-12 20 mg/day
• Memantine hydrochloride: 5 mg & 10 mg tablets
• Taken in divided dosage (AM & Afternoon)
Study Medication (Memantine)
Mean dose [Range]
19.7 ±1.2 [15-20] mg/day
At dose 20 mg/day 17 (94%)
At dose 15 mg/day 01 (6%)
www.mghcme.org
www.mghcme.org
0
10
20
30
40
50
60
70
80
90
100
0 6 12
Mea
n S
core
Weeks
SRS-A MGH-ASD-RS BRIEF-GEC BPRS-ASD
A S D F e a t u res : Tr e a tm en t R e s p on s e
Self-, Informant-, & Clinician-Rated Measures
Statistical Significance: *p≤0.05, **p≤0.01, ***p≤0.001
**
***
***
***
*
***
**
**
www.mghcme.org
Reading Non-Verbal Emotional Cues: DANVA2 Performance
Errors in Reading Non-verbal Emotions
Statistical Significance: *p≤0.05, **p≤0.01, ***p≤0.001
8.5
7
8.5
** 5
0
2
4
6
8
10
Tone of Voice Facial Expressions
Tota
l Err
ors
Mea
n S
core
Baseline Endpoint
Non-verbal Communication: Treatment Response
www.mghcme.org
Statistical Significance: *p≤0.05, **p≤0.01, ***p≤0.001
2.5
4.5
1.5
* 3
0
1
2
3
4
5
High Intensity Low Intensity
Err
ors
Mea
n S
core
Baseline Endpoint
Non-verbal Communication: Treatment Response
Reading Non-Verbal Emotional Cues: DANVA2 Performance
Errors in Reading Facial Expressions
www.mghcme.org
14 ±9
8.5 ±5.5
7 ±4.5 8 ±6.5 8 ±5.5
*** 8 ±6
** 5.5 ±4 *
4 ±4
** 4.5 ±4.5
6 ±8.5
0
5
10
15
20
ADHD-SCL BAI HAM-A BDI HAM-D
Mea
n S
core
Baseline Endpoint
(ES=0.8) (ES=0.6) (ES=0.65) (ES=0.65) (ES=0.35)
Statistical Significance: *p≤0.05, **p≤0.01, ***p≤0.001
ADHD-SCL=ADHD Symptom Checklist; BAI=Beck Anxiety Inventory; HAM=A=Hamilton Anxiety Scale;
BDI=Beck Depression Inventory; HAM-D=Hamilton Depression Scale
Associated Psychopathology: Treatment Response
www.mghcme.org
Adverse Even ts
Reported > I visit
Experienced any AEs:
6 (33.3%)
Serious AEs: None
Treatment Limiting AEs: N=1 Decreased energy, emotional numbness, feeling dissociated, feeling on edge (resolved on d/c)
0% 2% 4% 6% 8% 10% 12%
Musculoskeletal
Decreased energy
Insomnia
Cold/Infection/Allergy
Headache
Subjects (%)
www.mghcme.org
T h e A l a n a n d L o r r a i n e B r e s s l e r
C l i n i c a l a n d R e s e a r c h P r o g r a m
for Aut ism Spect rum Disorder
Massachusetts General Hospi ta l
Boston MA
Joseph Biederman, MD
Janet Wozniak, MD
Atilla Ceranoglu, MD
Lynn Grush, MD
Amy Yule, MD
Carrie Vaudreuil, MD
Robert Doyle, MD
A c k n o w l e d g m e n t s
Yvonne Woodworth, BA
Daniel Kaufman, BS
Ryan Kilcullen, BA
Abigail Belser, BA
Philia Henderson, BA
Stefani Callinan, BS
Melissa De Leon
Sheeba A. Anteraper, PhD
Kaustubh R. Patil, PhD
Stephen Faraone, PhD
Ronna Fried, EdD
Maribel Galdo, LCSW
Maura Fitzgerald, MA
Phone: (617) 726-7899 Email: [email protected] Facebook:
Facebook.com/BresslerMGH
Web Link: http://www.massgeneral.org/psychiatry/services/autism_conditions.aspx
