Pharmacologic Treatment of Social Cognition in Autism

Transcription

1 Pharmacologic Treatment of Social Cognition in Autism GAGAN JOSHI, MD Assistant Professor of Psychiatry Director, Autism Spectrum Disorder Program Clinical & Research Program in Pediatric Psychopharmacology Massachusetts General Hospital, Harvard Medical School

2 Disclosures 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 #K23MH 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

3 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 Youth Youth AuD ± Irritability ABC, CY-BOCS NA McDougle et al., 2005 Aripiprazole Owen et al., 2009 AuD NA Irritability ABC, CY-BOCS Marcus et al., 2009 Anticonvulsants Mood Stabilizers Valproic Acid Hollander et al Youth 13 ASD - Autism CY-BOCS NA NA NA ±* Hollander et al 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 Atypical antipsychotics:: SSRIs:: 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

4 Percent Responding Risperidone 8-week RCT in Autistic Disorder Youth with Irritability AuD+ Sign. Irritability: [ABC Irritability 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 [ ] RISP Flexible Dose Titration Schedule AM PM Daily Dose Initial Dose <20 Kg mg 20 Kg 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 Efficacy - Irritability (34/49) 69% Risperidone p < (6/52) 12% Placebo Response criteria: 25% ABC Irritability score + CGI-I 2 Efficacy Other Features Sign. improvement in: - Repetitive behaviors (CY-BOCS & ABC) - Hyperactivity (ABC) No change in other core features of ASD

5 Aripiprazole 8-week RCT in Autistic Disorder Youth with Irritability 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]

6 Percent Responding A r i piprazole Efficacy - Irritability 100 p<0.001 (-13) (-5) % p < % Parent-Rated ABC - Irritability Subscale 0 Aripiprazole Placebo Response criteria: 25% ABC-I + CGI-I 2 Sign. improvement on ABC-I & CGI-I from week-1 onwards Efficacy Other Features Significant improvement in: - Hyperactivity (ABC-H) - Repetitive behaviors (ABC-Stereotypy & CY-BOCS) - Communication (ABC-Inappropriate speech)

7 Aripiprazole 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: - Clinically sign: ARIP > PBO (29% vs. 6%; p<0.01) ( 7% inc. from baseline) Metabolic Parameters & EKG: - No clinically significant change with treatment ARIP > PBO (2kg vs. 0.8kg; p<0.005) *N=1 x Fatigue, Vomiting, Wt gain, SIB, Aggression

8 CY-BOCS Y-BOCS Score Fluoxetine 8-week Crossover RCT in Youth with ASD 1 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 12-week RCT in Adults with HF-ASD 2 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 Efficacy: Repetitive Behaviors p=0.004 ES = 0.76 Statistically but not Clinically significant improvement p=0.005 CGI-I 2: - Global: FXT [35%] > PBO [0%] - RRB: FXT [50%] > PBO [8%] Tolerability Common AEs: Agitation, Sedation, & Anorexia Dose-limiting AEs [Agitation]: FXT [6/19] vs. PBO [2/20] 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) Youth: Limited tolerability a nd efficacy a t best Ad u l t s : We l l tolerated w i t h p r o m i s i n g e f f i c a c y

9 Fluvoxamine 12-week RCT in Adults with Autistic Disorder 1 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 OLT 2 & RCT 3 in Youth with ASD Total N = 52 (OLT=18; RCT=34) Mean dose: 67 ±32mg/day 2 (low-dose) Efficacy No improvement in: 2 - Repetitive behaviors (CY-BOCS) - Anxiety (SCARED) - Global ASD Severity (CGI-I) Tolerability Sign. AEs: - Anxiety - Insomnia - Agitation Youth: Poorly tolerated with limited efficacy at best Adults: Well tolerated with promising efficacy

10 Citalopram 12-week RCT in ASD Youth with Repetitive Behaviors 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]

11 A g e n t s f o r Tx of R e p e t i t i v e B e h a v i o r s i n ASD Agents for Tx of Repetitive Behaviors in ASD 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

12 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 Action Study Age [N] Subtype HF Features Measure ASD SI SC RRB GABAergic Agents Bumetanide Cholinergic Agents Donepezil Acetylcholinesterase inhibitor Galantamine Mecamylamin e (Inversine) Acetylcholinesterase inhibitor & Nicotinic receptor modulator Nicotinic receptor antagonist [Non-competitive] Lemmonier et al., 2012 Youth 60 ASD - Autism CARS, ADOS + [CARS+CGI] [ADOS] Chez et al., 2003 Youth 43 ASD - Autism CARS, EOWPVT-R, ROWPVT +?? NA - NA Niederhofer et al., Youth 20 AuD - Autism ABC - +* +* 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 GABAergic agent (bumetanide): Cholinergic agents: Promising efficacy for treating RRBs in ASD Lack efficacy for treating core features of ASD

13 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 Oxytocin Controlled Trials 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 Investigatordeveloped Role of Oxytocin for improving social deficits in ASD under study 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 RMET NA + NA recognition 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) Intranasal (18/24 IU BID) Dadds et al., 2013 Youth 38 ASD + ASD FOS-ASD, SRS, SSRS 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

14 G l utamate Modulating A g e n t s 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

15 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 Glutamate Modulating Agents Controlled-Trials 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) Amantadine D-cycloserine NMDA Glu receptor antagonist (low affinity) NMDA Glu receptor agonist/antagonist King et al., 2001 (4-week RCT) Urbano et al., 2014 Urbano et al., 2015 (8-week RCT) N-Acetylcysteine Glu release inhibitor Hardan et al., 2012 (12-week RCT) Wink et al., 2016 (12-week RCT) Dean et al., 2016 (6-month RCT) Children [3-11] Youth [5-15] Young Adults [14-25] 28 5 mg/kg/d AuD - ASD ABC mg/d [90-200] AuD - Irritability & Hyperactivity ABC mg/d ASD + ASD ABC, SRS, Children mg/d AuD - Irritability ABC, SRS, RBS-R Children 31 56* [34-64]* *mg/kg/d [SRS+ RBS-R] ASD - ASD CGI-ASD Children 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 No controlled-trials in intellectually capable populations of youth with ASD

16 1/17/20 17 N - A c e t y l c ysteine 12-week RCT in Children with Autistic Disorder 16 Autistic Disorder + Irritability: N = 29 [CGI-S for Irritability 4]X [NAC=14] Male: 94% Mean Age [Range]: 7 ±2 [3 11] Concomitant psychotropic Tx: 48% Efficacy ABC - Irritability Subscale p<0.001 Sign. improvement in: - RRBs (RBS-R/SRS) No change in other core features of ASD Tolerability NAC Flexible Titration Schedule Duration NAC Dosing (mg/day) Week I mg QDay Week mg BID Week mg TID PBO NAC Trial Completion 12/15 13/14 Treatment-limiting None irritability [N =1] AEs Common AEs PBO NAC p=value GI AEs 47% 79% NS - 20% 43% NS Nausea/vomiting - Diarrhea 7% 21% NS - Constipation 13% 21% NS

17 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 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

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19 12-week OLT of Memantine Hydrochloride for the Treatment of Social Deficits in Young Adults with HF-ASD Demographic Characteristics Participants Total participants 18 Gender (male) 14 (78%) Ethnicity (Caucasian) 18 (100%) Age (years) Mean 28 ±9.6 Range Full Scale IQ Mean 106 ±15 Range Study Medication Memantine hydrochloride: 5 mg & 10 mg tablets Taken in divided dosage (AM & Afternoon) Duration (Weeks) Flexible Dose Titration Schedule Maximum Dose mg/day mg/day mg/day mg/day Study Medication (Memantine) 19.7 ±1.2 [15-20] Mean dose [Range] mg/day At dose 20 mg/day 17 (94%) At dose 15 mg/day 01 (6%)

20 Mean Score A S D F e a t u r e s : Tr e a t m e n t R e s p o n s e Self-, Informant-, & Clinician-Rated Measures SRS-A MGH-ASD-RS BRIEF-GEC BPRS-ASD * * ** * ** * * Weeks Statistical Significance: *p 0.05, **p 0.01, ***p ** * * ** * *

21 Total Errors Mean Score Non-verbal Communication: Treatment Response Reading Non-Verbal Emotional Cues: DANVA2 Performance Errors in Reading Non-verbal Emotions ** Tone of Voice Baseline Facial Expressions Endpoint Statistical Significance: *p 0.05, **p 0.01, ***p 0.001

22 Errors Mean Score Non-verbal Communication: Treatment Response Reading Non-Verbal Emotional Cues: DANVA2 Performance Errors in Reading Facial Expressions * High Intensity Baseline Endpoint Low Intensity Statistical Significance: *p 0.05, **p 0.01, ***p 0.001

23 Mean Score Associated Psychopathology: Treatment Response 20 (ES=0.8) (ES=0.6) (ES=0.65) (ES=0.65) (ES=0.35) ± *** 8 ±6 8.5 ±5.5 ** 7 ± ±4 * 4 ±4 8 ±6.5 8 ±5.5 ** 4.5 ±4.5 6 ±8.5 0 ADHD-SCL BAI HAM-A BDI HAM-D Baseline Endpoint Statistical Significance: *p 0.05, **p 0.01, ***p ADHD-SCL=ADHD Symptom Checklist; BAI=Beck Anxiety Inventory; HAM=A=Hamilton Anxiety Scale; BDI=Beck Depression Inventory; HAM-D=Hamilton Depression Scale

24 A d v erse Events Headache Reported > I visit Cold/Infection/Aller gy Insomnia Decreased energy Musculoskeletal 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% Subjects (%)

25 A c k n o w l e d g m e n t s 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 f or Autism Spectrum Disorder Massachusetts General Hospital Boston MA Joseph Biederman, MD Janet Wozniak, MD Atilla Ceranoglu, MD Lynn Grush, MD Amy Yule, MD Carrie Vaudreuil, MD Robert Doyle, MD Sheeba A. Anteraper, PhD Kaustubh R. Patil, PhD Stephen Faraone, PhD Ronna Fried, EdD Maribel Galdo, LCSW Maura Fitzgerald, MA Yvonne Woodworth, BA Daniel Kaufman, BS Ryan Kilcullen, BA Abigail Belser, BA Philia Henderson, BA Stefani Callinan, BS Melissa De Leon Phone: (617) MGHASDprogram@Partners.org Facebook: Facebook.com/BresslerMGH Web Link: