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Oxytocin and its effect on Social Cognition and Repetitive Behavior Domains in Autism Evdokia Anagnostou, MD Assistant professor University of Toronto, Bloorview Kids Rehab

Financial disclosures Consultation fees from IntegraGen Eric Hollander has a patent in oxytocin and related disorders in autism –IN oxytocin pilot study has been approved by the Mount Sinai School of Medicine Conflict of Interest committee: conflict of interest management plan DSMB Statistical oversight from an outside institution

Social Impairment Repetitive Behaviors & Compulsivity Speech/ Communication Deficits Social Phobia Schizoid/Schizotypal Personality Disorders Asperger’s syndrome Obsessive Compulsive Disorder AUTISM Impulsivity/ Aggression Expressive/Receptive Language Disorders EEG Abnormalities ADHD Symptoms

Social Deficits in autism DSM-IV-TR deficits in –Non verbal behaviors, e.g. eye contact –developmentally appropriate peer relationships –Sharing enjoyment –Social and emotional reciprocity Parents: prefer to stay isolated, do not seem to recognize other people, miss social cues Social cognition: –deficits in social recognition (Benton) (Szatmari et al 1990, Davies et al, 1994, Barton 2003) and recognition of facial expressions, age and sex (Hobson, 1987, Tantam et al, 1989) –Deficits in face processing

Repetitive behaviors Restrictive interests Rigid routines / Ritualistic behaviors Stereotypy Preoccupation with parts of objects

Oxytocin 9 aminoacid neuropeptide Synthesized in PVN and SON ( for systemic release) –Separate neuronal groups synthesize OT for central release, PVN, amygdala, BnST (Vries & Buijs, 1983) Peripheral release is important for delivery, and lactation Central release important for social cognition (recognition and memory), bonding, trust, and implicated in models of anxiety and social phobia

Oxytocin social deficits and repetitive behaviors Animal Studies –Social recognition and memory Popik et al 1992, Benelli et al 1995, Benelli et al 1995, Engelmann et al 1998, Ferguson et al 2000, Ferguson 2001, Choleris et al 2003, –Social bonding: Pedersen et al 1982, Insel, 1992, Insel and Young 2001, Bales & Carter, 2003, 2004 –Repetitive Behaviors Drago et al, 1986, Insel and Winslow, 1991, Meisenberg & Simmons, 1983, Nelsom & Alberts, 1997

Oxytocin and social deficits Animal Studies –Social recognition and processing Central administration of oxytocin facilitates social memory (Popik et al 1992, Benelli et al 1995) in small doses OTR antagonists cause amnesia of social recognition in female rats (Benelli et al 1995, Engelmann et al 1998) Transgenic male mice that lack Oxytocin gene are unable to recognize familial conspecific (Ferguson et al 2000), not due to olfaction, learning and memory deficits In the oxytocin knockout, ICV oxytocin prior to exposure to conspecific rescues social recognition (Ferguson 2001) Effects seen in males and females (Choleris et al 2003) Oxytocin KO mouse, after 90 sec of social encounter, absent Fos induction in medial amygdala, BdST and medial preoptic area but not in the olfactory bulb vs.. wild type (Ferguson et al, 2001) Social recognition in oxytocin knock out also rescued by bilateral microinjections of oxytocin into medial amygdala prior to exposure to conspecific (Ferguson et al 2001) Oxytocin important in social memory (Crawley, 2007) –Oxytocin acts in medial amygdala during social encounter for normal processing of social information.

Oxytocin and social deficits Social bonding: ICV OXT administration in virgin rats will induce maternal behaviors (Pedersen et al 1982), ICV OT antagonist administration inhibits onset of maternal behaviors (Insel, 1992) Oxytocin – maternal/psychosexual behaviors –Prairie Vole: Social, monogamous –Montane Vole: non-monogamus, not social –Medow Vole: solitary, non monogamous –Difference : Distribution of OTR and V1aR Prairie vole: ICV oxytocin administration, pair bonding without mating ( Insel and Young 2001) in females, AVP same effect in males Peripheral administered Oxytocin during development leads to long lasting consequences in social behavior into adult hood ( Bales et Carter, 2003, 2004)

Oxytocin and social deficits Human studies –Domes et al (2007), mind reading –Kirsch et al (2005), fMRI of amygdala activation –Kosfeld et al (2005), trust game –Guastella et al (2008) eye gaze

Oxytocin Improves “Mind-Reading” in Humans, Domes et al healthy controls, yoa 24 IU of oxytocin vs. placebo 1 week apart No Axis I disorders No meds or substance abuse Testing started 45 min after administration

Emotion matching task illustrates fMRI activation of the amygdala, Kirsh et al participants, ages No axis I No meds, or substance abuse 27 IU of oxytocin vs. placebo 1 week apart Administration of OT was 30 min before the start of the fMRI scan. Participants were asked to select, from the two faces on the bottom, the one that expressed the same emotion as the face on the top.

Dramatic reduction in amygdala activity when shown frightful faces after administration of nasal oxytocin Suggests that oxytocin mediates social fear and trust via the amygdala and related circuitry. Source: NIMH Genes, Cognition and Psychosis Program

Significant decrease in the coupling of amygdala to the midbrain under oxytocin Kirsch et al., The Journal of Neuroscience, 2005

Oxytocin increases Gaze to the Eye region (Guastella et al 2008) 52 healthy controls, years Placebo controlled challenge, dose: 24 IU Measure: –24 human female and male faces –eyetracker

Oxytocin and autism Decrease blood levels oxytocin in autism and Absence of normal developmental increase in oxytocin blood levels with age in autism Altemus et al 1994, Modahl et al 1998, Green et al 2001, Kosfeld et al, 2005, Kirsch et al, 2005 Genetic associations –Wu et al (2005), 195 Chinese Han family trios: Transmissive disequilibrium for two nucleotide polymorphisms in OTR gene. –Jacob et al (2007), + association of OXTR and autism in a Caucasian sample –Ylisaukko-oja et al (2006), AGRE + Finish cohort –Kim et al (2002), disequilibrium between 1 SNP in AVPR1a and autism –Other AVPR1a + findings: Wassink et al, 2004, Yirmiya et al, 2006 (social skills) –Allelic associations between PRL, PRLP and OXTR and affiliative behaviors: Yrigollen et al, 2008

Oxytocin vs. Placebo Infusions in Autism Repetitive behaviors Social cognition

IV Oxytocin, social cognition and repetitive behaviors in autism 15 adults with HFA or Asperger syndrome Double blind cross over challenge Outcome measure for repetitive behaviors: composite of items such as need to know, repeating, need to tell, need to touch Outcome measure for social cognition: Comprehension of affective speech

Oxytocin vs. Placebo on Social Cognition in Autism: Subject Entry Criteria DSM-IV diagnosis of Autistic disorder or Asperger disorder Autism Diagnostic Interview - Revised (ADI-R) Medically healthy Medication free for at least 2 weeks prior to and throughout the study

Subject Demographics Fifteen adult subjects 14 male, 1 female Mean age: 32.9 years; range: 19.4 – 55.6 Diagnosis: Autistic disorder (N=6), Asperger disorder (N=9)

Subject Information ADI-R Descriptive Statistics ADI-R Symptom DomainsMin./Max. Possible ScoreMeanStd. Dev. Qualitative Impairments in Reciprocal Social Interaction Communication (Verbal) Repetitive Behaviors and Stereotyped Patterns

Methods Challenge Procedures  All 15 subjects completed both oxytocin and placebo challenges on separate days  Each subject served as their own control  Continuous infusion oxytocin/placebo over 4 hours  Order of infusions was counterbalanced  Oxytocin infusion: 10 u/ml in 1L NS; initial rate 10 ml/h to minimize potential side effects, gradually titrated up to 700ml/hr during 4th hour

Effects of oxytocin vs. placebo infusions on repetitive behaviors over time Hollander et al, Neuropsychopharmacology, 2003 F=3.3, df=4,48, p=0.024

Oxytocin and Repetitive Behaviors Individual Cases: Baseline to Endpoint

Oxytocin vs. Placebo: Comprehension of Affective Speech Hollander et al, Biol Psych, 2006 Oxytocin Placebo Drug x Time x Order Effect (z=-2.134, p=.03, d=0.66): Mixed Model Analysis: Dichotomized Scores 4 hour Infusion Delay = ± days 4 hour Infusion

IV oxytocin challenge – fMRI study In progress Normalization of ventral cingulate activation in response to emotional go-nogo

Oxytocin vs. placebo in adult autism: A pilot study Intranasal oxytocin imported from Switzerland with FDA IND-waiver 6-week randomized placebo controlled trial –Sample : 20 adults with ASD Ages Diagnosis confirmed with ADI / ADOS BID dosing of 24 IU / dose

Oxytocin vs. placebo in autism Pilot study Outcome measures Social Cognition: DANVA2, Diagnostic Analysis of Nonverbal accuracy 2 (Baum & Nowicki) –Stimuli (faces, paralanguage, and adult postures) in 4 emotions: happy, sad, angry, fearful and in two intensities: low and high –Good internal consistency, construct validity, test retest reliability, and convergent and discriminant validity

Oxytocin vs. placebo in autism Pilot study Child faces: 12 F, 12 M, equal numbers of emotions and high vs. low intensity Instructions: I AM GOING TO SHOW YOU SOME PEOPLES’ FACES AND I WANT YOU TO TELL ME HOW THEY FEEL. I WANT YOU TO TELL ME IF THEY ARE HAPPY, SAD, ANGRY, OR FEARFUL (SCARED).

Oxytocin vs. placebo in autism Pilot study Child paralanguage test –32 trials, 16F, 16 M, and equal number of high vs. low intensity emotions –Instructions: I AM GOING TO PLAY AN AUDIO TAPE IN WHICH YOU WILL HEAR SOMEONE SAY THE SENTENCE: “I’M GOING OUT OF THE ROOM NOW, BUT I’LL BE BACK LATER.” I WANT YOU TO LISTEN TO THE SENTENCE AND TELL ME IF THE PERSON SAYING THE SENTENCE IS HAPPY, SAD, ANGRY, OR FEARFUL (SCARED).

Oxytocin vs. placebo in autism Pilot study RBS-R (Bodfish et al) –Stereotyped Behavior Subscale –Self Injurious Behavior Subscale –Compulsive behavior subscale –Ritualistic behavior subscale –Sameness Behavior subscale –Restrictive Behavior subscale YBOCS High order repetitive behaviors Low order repetitive behaviors

Oxytocin vs. placebo in autism Pilot study Baseline Characteristics Data attachment because not yet published presented at the meeting was removed from this attachment because it is not yet published –No significant differences between groups in age, non verbal IQ and gender)

Oxytocin vs. placebo in autism Pilot study –Data presented at the meeting was removed from this attachment because it is not yet published –In summary improvements were noted in both social cognition ( DANVA paralanguage test) and Repetitive behaviors (YBOCS and RBS-R) as well as in irritability and global functioning

Oxytocin vs. placebo in autism P ilot study Safety Profile (Data presented at the meeting was removed from this attachment because it is not yet published) –Well tolerated with some increase in irritability in 2 subjects on placebo

Future directions Larger scale clinical trials with IN Oxytocin Identify appropriate mode of administration Refine peripheral sampling procedures Develop oxytocin ligands Pharmacokinetics and pharmacodynamics of IN and IV oxytocin Small molecule oxytocin analogs Investigate appropriate measures sensitive to change for pro-social behaviors

Seaver and NY Autism Center of Excellence Team Latha Soorya, PhD Eric Hollander, MD Jennifer Bartz, PhD Danielle Halpern, PhD Ting Wang, PhD Research assistants: Jessica Cuellar, Lauren Pepa