Oxytocin as Adjunctive Treatment of Schizophrenia
Phase: PHASE2
Conditions: Schizophrenia
Sponsor: Emory University

12/07/13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OXYTOCIN AS ADJUNCTIVE TREATMENT OF SCHIZOPHRENIA 
 
IRB# 00052127 
 
Protocol Dated: 12/07/2013 
 
 
NCT01568528 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
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OXYTOCIN AS ADJUNCTIVE TREATMENT OF SCHIZOPHRENIA 
 
Principal Investigator: 
Erica Duncan, MD 
Associate Professor 
Department of Psychiatry and Behavioral Sciences 
Emory University School of Medicine 
Mental Health Service, Atlanta VAMC 
 
SPECIFIC AIMS 
 
 
The focus of the current project is to advance our understanding of the effects of oxytocin (OT) 
on components of social cognition in schizophrenia (SCZ). Despite the rapid increase in our 
understanding of the role of OT in rodent models of social behavior and an explosion of interest in the 
prosocial effects of OT in healthy controls, little work has been done to dissect the potential effects of 
OT on SCZ subjects with social deficits.  Social deficits are a crucial aspect of the functional 
impairments that limit the rehabilitation of patients with SCZ.  In particular, SCZ patients with enduring 
negative symptoms (deficit syndrome, Kirkpatrick et al. 1989) have prominent social deficits as a core 
feature of this subtype of the illness. Our currently available medications do very little to improve these 
social deficits.  Hence it is of utmost public health importance to address the knowledge gap regarding 
the potential of OT to improve social function in this illness.  Intact social function depends on the 
competent functioning of several cognitive domains that subserve perception of social cues and the 
generation of motivated social behavior. We propose to conduct a pharmacological challenge study of 
OT vs. placebo administration to study the effects of OT on specific components of social cognition in 
male deficit syndrome SCZ subjects. 
 
 
Primary Hypothesis: Intranasal OT will improve social cognition in subjects with deficit syndrome 
SCZ. 
 
Specific Aim 1: Administer OT intranasally vs. placebo in a parallel group double-blind design to 40 
deficit syndrome SCZ subjects.  Following OT or placebo (PBO) dosing, components of social 
cognition will be assessed as follows. 
 
a. Evaluate the salience of social cues by the measurement of visual scan paths during gaze at 
pictures of faces.  
 
b. Evaluate sensitivity to social reward by means of a computerized social reward ball-tossing 
task that assays social interactions in response to social reward. 
c. Evaluate social cognition by means of testing the ability to correctly identify emotion from 
pictures of faces (Facial Emotion Identification Test, FEIT). 
 
BACKGROUND 
 
Impaired social functioning is an important symptom in SCZ  
 
SCZ is a chronic severe psychotic illness that affects two to three million Americans, over 
100,000 of whom are veterans (Owen et al. 2004). There are several key symptom domains that 
characterize the illness. Positive symptoms (such as hallucinations and delusions) are at least 
somewhat responsive to antipsychotic medication in a majority of patients.  Negative symptoms such 
as poor motivation, anhedonia, poor social function, and poor occupational function are poorly 
responsive to medication or other currently available treatments.  The deficit syndrome has been 
defined as a complex of these negative symptoms that endure throughout the course of a 
schizophrenia patient's disease (Kirkpatrick et al. 1989). The social impairments seen in these patients 
are core deficits that have been linked to poor functional outcomes (Couture et al. 2006; Fett et al. 

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
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2011).  Furthermore, deficits in social cognition have been proposed to underlie and contribute 
significantly to impaired social functioning (Kern et al. 2008; Green et al. 2008). An underlying 
hypothesis of this work is that if social cognition could be effectively treated, these patients would 
improve their social and functional outcomes, potentially enabling them to achieve occupational 
competence, sustain stable independent living, and lead more fulfilling independent lives. Thus our 
understanding and treatment of the social impairments of SCZ is very important from a public health 
perspective. 
 
OT effects on social cognition and behavior 
Studies in rodents demonstrate a critical role for the neuropeptide OT in social bonding (Young 
et al. 2005).  A large and rapidly growing translational literature indicates that this neuropeptide may 
also play a prosocial role in human behavior. The prosocial effects of OT adminstration have already 
been extensively reviewed in the literature (Striepens N et al., 2011). In the area of trust and altruism, 
studies utilizing a variety of economic and cooperation paradigms indicate that OT enhances trusting 
and social cooperation (Baumgartner T et al., 2008; De Dreu CK et al., 2010; Declerck CH et al., 2010; 
Kosfeld M et al., 2005; Mikolajczak M et al., 2010; Zak PJ et al., 2007).  Feelings of empathy to others 
were enhanced with OT in three studies (Domes et al. 2007; Bartz et al. 2010; Hurlemann et al. 2010). 
Several studies indicate that OT increases the ability of healthy controls to identify emotion in faces (Di 
Simplicio et al. 2009; Fischer-Shofty et al. 2010, Marsh et al. 2010). There are reports using memory 
paradigms, in which OT administration induced enhanced recall of faces after OT (Savaskan et al. 
2008; Rimmele et al. 2009), although an earlier study found no improvement (Ferrier et al. 1980). OT 
administration also increased recall of social words (Unkelbach et al. 2008).  There is some indication 
that OT effects on recall are specific to emotional stimuli since several studies in healthy controls 
found that OT did not improve memory for nonsocial stimuli (Bruins J et al., 1992; Fehm-Wolfsdorf G 
et al., 1984; Geenen V et al., 1988; Kennett DJ et al., 1982). 
 
OT as potential treatment in SCZ 
 
Several lines of reasoning suggest that OT could be helpful as adjunct treatment of SCZ.  
(1) Patients with SCZ have altered OT levels compared to healthy controls (Linkowski et al. 1984; 
Beckmann et al. 1985; Legros et al. 1992; Goldman et al. 2008; Keri et al. 2009). 
(2) fMRI in concert with intranasal OT administration was associated with reduced blood-oxygen-level-
dependent (BOLD) activation in the amygdala during presentation of fearful/threatening faces and 
scenes (Kirsch et al. 2005). This study gives indirect support to the idea that OT may ameliorate 
paranoia in patients with SCZ.   
(3) The negative symptoms of SCZ include social isolation, autism, and amotivation for social 
engagement.  There is face validity to the notion that OT could help with these symptoms in virtue of 
its pro-social action.  
(4) To date there are three published placebo controlled trials of OT in SCZ. In the first study, OT was 
given in a placebo-controlled double-blind randomized crossover design (Feifel et al. 2010).  In this 
study of fifteen completers, the Positive and Negative Symptom Scale (PANSS) and the Clinical 
Global Impressions scale (CGI) were used as outcome measures.  OT added to antipsychotic 
treatment resulted in a significant improvement in positive symptoms, as measured by the PANSS 
total score, PANSS positive symptom subscale, PANSS negative symptom subscale, and the CGI.  
The effect size for these changes ranged from 0.40 for PANSS positive symptoms to 0.74 for the CGI. 
Furthermore, treatment with OT was well tolerated, with no significant differences between OT and 
placebo in rates of adverse effects nor in blood chemistry (Feifel et al. 2010).  This same group 
published a second paper indicating an improvement in verbal memory in SCZ subjects following three 
weeks of twice daily OT (Feifel et al. 2012). The third study reports that two weeks of OT reduced 
psychotic symptoms and improved performance in a Theory of Mind task (Pedersen et al. 2011).  
 
 

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
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Dissecting components of social impairment in SCZ 
 
Intact social competence depends on adequate function in several cognitive domains that 
subserve perception of social cues and motivated social behavior.  We propose to interrogate these 
composite domains after administration of OT vs. placebo in this project. 
 
i. 
Eye tracking. Relevant social cues must be of sufficient salience to command attention.  This 
aspect of social cognition has been investigated by means of visual scan path paradigms that 
quantify the amount of time a subjects spends looking at the eyes and mouth regions of pictures of 
faces presented while the position of the eyes is tracked. The amount of eye gaze is predictive of a 
subject's ability to correctly identify emotions and meaning in others (Haxby et al. 2002). A single 
dose of OT significantly increases the amount of eye gaze in healthy controls (Guastella et al. 
2008a) and in high functioning subjects with autism spectrum disorders (Andari et al. 2010). SCZ 
subjects have abnormalities in visual scan paths while viewing pictures of faces (Phillips and David 
1997; Loughland et al. 2002a). Thus we hypothesize that OT will increase gaze at the eyes in 
subjects with deficit syndrome SCZ (Specific Aim 2a). 
ii. Social Reward Ball-Tossing Task. Social stimuli must be sufficiently rewarding to motivate 
decision-making and behavior. This aspect of social function has been investigated with a 
computerized social interaction game that assays the effects of social reinforcement on decision-
making.  In a task developed by Andari et al. (2010) that was derived from an earlier task by 
Williams et al. (2000), subjects engage in a computerized version of a ball-toss game in which 
three fictional partners vary the proportion of times they throw the ball back to the subject. The 
outcome measure of interest was the choices made by the subject regarding to which fictional 
player they would throw the ball. In a study of high functioning autism spectrum subjects, OT 
administration selectively enhanced return of the ball to the most socially cooperative fictional 
partner (Andari et al. 2010).  This result was interpreted as evidence that OT enhances appropriate 
behavioral responses to the social reward of reciprocity. We hypothesize that OT administration 
will enhance socially reinforced behavior in subjects with deficit syndrome SCZ (Specific Aim 2b). 
iii. Facial Emotion Identification Task (FEIT). The socially competent person must be able to correctly 
identify the emotions in others in order to respond appropriately during social communication. The 
correct identification of emotions in others is a key aspect of social cognition that has been linked 
to functional outcomes in SCZ (Couture et al. 2006). This aspect of social cognition has been 
investigated in paradigms that query the subjects on identifying emotions displayed in pictures.  
Most studies in the literature report that patients with SCZ are deficient in the correct identification 
of emotions displayed in pictures of faces (Addington et al. 2006; Bigelow et al. 2006; van’t Wout et 
al. 2007; Averbeck et al. 2012 and see review in Couture et al. 2006), although not all studies have 
found such impairments (de Achaval et al. 2010).  The classic series of pictures of faces 
introduced by Eckman and Friesen (1976) have been used in many studies of affect recognition, 
but other series of pictures have also been utilized (Erwin et al. 1992; Kerr and Neale 1993).  OT 
administration has been shown in two studies to increase the correct identification of emotions in 
faces in subjects with SCZ (Goldman et al. 2011; Averbeck et al. 2012).  We hypothesize that 
deficit syndrome SCZ subjects will exhibit improvement in facial emotion recognition after 
administration of OT (Specific Aim 2c). 
 
 
METHODS 
 
1. Description of study population 
 
Subjects for the study will be forty male patients with a diagnosis of SCZ.  Diagnosis will be 
determined using the Structured Clinical Interview for DSM-IV Axis I Disorders/SCID-P (Spitzer et al. 
1992).  Subjects must be categorized as having a primary deficit syndrome on the Kirkpatrick 
Schedule for the Deficit Syndrome (Kirkpatrick et al. 1989).   
 

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
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Additional inclusion criteria: 
 
1. Subjects must be between 18 and 65 years old at the time of study screening. 
2. Subjects must demonstrate adequate decisional capacity, in the judgment of the consenting 
study staff member, to make a choice about participating in this research study. 
3. Subjects must have been psychiatrically and medically stable for 8 weeks prior to consent in 
the judgment of the Principal Investigator. 
4. Subjects must have been maintained on a stable treatment of antipsychotics and/or other 
concomitant psychotropic treatment for at least 6 weeks prior to consent. 
5. Subjects must have no more than a moderate severity rating on hallucinations and unusual 
thought content as shown by a score of ≤ 4 on the Positive and Negative Symptoms Scale 
(PANSS).  
6. Subjects must be able to validly complete the Measurement and Treatment Research to 
Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB), in the 
judgment of the consenting study staff person. 
7. Subjects must have the visual, auditory, and motor capacity to use the computer software in 
the judgment of the consenting study staff person. Visual acuity must be at least 20/30 
corrected. 
8. Subjects must have a minimal level of extrapyramidal symptoms as shown by a Simpson-
Angus Scale total score 6. 
9. Subjects must have a minimal level of depressive symptoms as shown by a Calgary 
Depression Scale (CDSS) total score 10. 
 
Exclusion criteria: 
 
1. Female sex 
2. History of bipolar disorder 
3. Active substance dependence within the prior 30 days (cigarette smoking is allowed) 
4. Has had a psychiatric hospitalization in the 8 weeks prior to consent. 
5. Suicidal or homicidal ideation in the previous six months 
6. Subjects who have answered ‘yes’ to Question 5 (Active Suicidal Ideation with Specific Plan 
and Intent) on the Columbia-Suicide Severity Rating Scale, C-SSRS, or who have answered 
‘yes’ to any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted 
attempt, preparatory act or behavior) on the C-SSRS “Suicidal Behavior” portion shall be 
excluded from the study if ideation or behavior occurred within one month of consent.  Subjects 
excluded for this reason will be referred for appropriate treatment.  
7. History of mental retardation or pervasive developmental disorder 
8. History of neurological disorder (e.g., traumatic brain injury, seizure disorder, Parkinson’s 
Disease, dementia), loss of consciousness for more than 10 minutes due to head trauma, 
known HIV infection, or AIDS 
9. Treatment with a benzodiazepine in the two weeks prior to consent. 
 
We will also be collecting data from up to twenty male participants, who have no psychiatric diagnosis 
and will be controls for this project. These controls will NOT receive oxytocin. They will only receive 
psychiatric screening interview, MCCB Consensus Cogntive Battery assessment, urine drug screen, 
vision testing, and the three social cognition tasks. For the control participants, the criteria is as 
follows: 
 
Inclusion criteria: 
• 
Male 
• 
Ages 18 - 65 

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
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Exclusion criteria: 
• 
Female 
• 
History of a psychotic disorder, or depression requiring medication 
• 
Active substance abuse or dependence within the prior 30 days 
• 
Medical admission within the past six months 
 
 
- Criteria to rule out subjects with medical problems likely to present a confound:  
• 
Known HIV infection or AIDS 
• 
History of TBI 
• 
Seizure disorder 
• 
Known Alzheimer’s Disease or other dementia 
• 
Minimal cognitive impairment (MCI) 
• 
Parkinson’s Disease 
• 
Unstable medical condition  
 
All subjects must provide informed consent as indicated by their signature on an Emory IRB-approved 
consent form and HIPAA authorization prior to participating in this study. 
 
2. Study design 
 
The study will be a double-blind placebo-controlled parallel group study of intranasal OT vs. 
intranasal placebo administered on a single test day. 
 
3. Baseline evaluation 
 
A diagnosis of schizophrenia will be confirmed by a structured diagnostic interview (SCID-
patient version). Current symptoms will be rated by means of the Positive and Negative Symptom 
Scale (PANSS; Kay et al. 1987).  The Kirkpatrick Schedule for the Deficit Syndrome will be used to 
confirm that subjects have a primary deficit syndrome (Kirkpatrick et al. 1989).  As per new FDA 
requirements governing management of suicidality in clinical trials, the Columbia-Suicide Severity 
Rating Scale (C-SSRS) will be administered on the Baseline day.  As a safety precaution, subjects will 
receive a medical history, measurement of vital signs, a blood draw for chemistry, and a urinalysis to 
screen for unstable medical conditions.  Subjects will also receive a urine toxicology screen to rule out 
active drug use at Baseline.  Eye chart screening will be used to insure adequate visual acuity. The 
Simpson-Angus Scale (Simpson and Angus 1970) will be used to assess the extrapyramidal 
symptoms since clinically significant Parkinsonian side effects to antipsychotic medications could be a 
confound in our outcome measures. The Calgary Depression Scale (CDSS; Addington et al. 1992) will 
be performed to assess depressive symptoms since significant  depressive symptoms could also be a 
confound in our outcome measures. 
 
Because the social cognition measures rely in part on cognitive domains such as verbal 
memory, visual memory, and attention, these domains at Baseline will be assessed by means of the 
MCCB. The development of the MCCB was supported by the National Institute of Mental Health, and 
has emerged as the most respected battery of tests for understanding the cognitive functioning of 
people with SCZ.  It is a standardized battery consisting of 10 individually administered tests that 
examine speed of processing, attention/vigilance, working memory, verbal learning, visual learning, 
reasoning and problem solving, and social cognition (Kern et al. 2008).   
 
4. Description of pharmacological challenge 
 
 
OT intervention will be administration of OT intranasally at a dose of three 4 IU puffs per nostril 
for a total dose of 24 IU.  This dose has been used in a number of other similarly designed challenge 

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
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studies examining the effects of a single dose of OT (Kirsch et al. 2005; Kosfeld et al. 2005; Guastella 
et al. 2008a; Guastella et al. 2008b; Rimmele et al. 2009; Andari et al. 2010). 
The PBO/control will consist of the OT vehicle only. Treatment assignment will be by random 
allocation in blocks of six.  Both experimenters and subjects will be blind to the treatment they are 
receiving.  
Thirty minutes after drug administration vital signs will be done. Testing of outcome measures 
for Specific Aims 1a - 1c will commence 45 minutes after administration of OT or placebo in the 
following order: Eye Tracking, Social Reward Ball-Tossing Task, and FEIT.   
 
5. Social cognition outcome measures 
a. Eye tracking. Methods will be similar to those used in Andari et al. (2010) and Guastella et al. 
(2008a).  In order to assess the processing of social stimuli, subjects will be presented with a series of 
human faces of mixed sex and race showing neutral emotions and instructed to visually scan each 
face.  There will be two face identification tasks used in the Eye Tracking session: (i) Sex Identification 
Task. After 2 seconds (sec) looking at each of 24 male and female faces from the NimStim set of facial 
expressions (Tottenheim et al. 2009), the subjects will indicate with a button press whether the face 
was male of female. (ii) Gaze DirectionTask. After 2 sec looking at each of 24 faces  from the Wicker B 
database (Wicker et al. 2008) with gaze either averted or gaze looking straight ahead, the subjects will 
indicate with a button press whether the face was looking directly at them or looking away.  
Presentation software (Neurobehavioral Systems, Inc., Albany CA) will be used to present the visual 
stimuli and record the subjects' responses.  
 
Subjects will be seated with their chin resting on a chin rest, their forehead resting against a 
bar, and head strap fastened to minimize head movements. The Applied Science Laboratories (ASL) 
Model 5000 Eye Tracking System will be used to track and quantify the eye movements of the 
subjects at a sampling rate of 50 Hz during the tasks.  Calibration of eye position will be performed 
according to standard recommended procedures by ASL. Gaze position time in milliseconds (ms) and 
frequency saccades will be recorded by the ASL system. 
 
Six regions of interest (ROIs) will be defined for each face stimulus: eyes, nose mouth, 
forehead, cheeks, and outside the contours of the face.  The data will be processed off line for each 
face stimulus as the total time of fixation inside each of the ROIs and the number of saccades elicited 
by the face. 
 
b. Reward Ball-Tossing Task. Methods will be adapted from Andari et al. (2010). In order to assess 
social reward sensitivity, subjects will perform a computerized Social Reward Ball-Tossing Task that 
consists of a modified version of Cyberball.  Subjects will play an animated ball-tossing game with two 
fictional partners (A and B) who will be represented by their photos.  Unbeknownst to subjects, the 
photos of the partners will be manipulated so that the photo of player A will display a smiling face 
(positive social reward) and the photo of player B will display an angry expression (negative social 
reward). These faces expressions will be presented on the screen in an animated fashion in order to 
enhance emotional responses in the subjects. The subject will commence playing a ball-tossing game 
in which the ball is tossed between the subject and his partners. The probability of ball-toss 
reciprocation will be randomly assigned between partners so that the subject has 50% of chance to 
receive the ball from A or B. These trials will be interleaved with neutral trials (neutral expressions) and 
non-social trials where subjects will play with random geometric shapes associated with positive and 
negative non-social rewards (green light versus red light).  
 
c. Facial Emotion Identification Test (FEIT). The methods to be used are based on studies using this 
test in SCZ (Mueser et al. 1996; Wolwer et al. 1996; Penn and Combs 2000; Addington et al. 2006).  
The stimuli are19 standard black and white pictures of faces showing one of six different emotions 
(happy, sad, angry, surprise, disgusted, ashamed) that were developed by Ekman and Friesen (1976).  
The pictures are shown for 15 sec, with 10 sec between each face. After the presentation of each face 

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
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the subject is asked to choose which of the six emotions was displayed.  The score on the test is the 
sum of correct responses. 
 
Specific Aim 1a: Evaluate the salience of social cues by the measurement of eye tracking (visual 
scanpaths) during gaze at pictures of faces. 
 
Hypothesis: Subjects receiving OT will exhibit more total gaze time within facial regions, and will have 
greater preference for gaze at the face area most salient for facial emotion decoding (eyes) than 
subjects receiving placebo.  We hypothesize that during the Gaze Direction Task the OT group will 
have reduced saccades than the PBO group. This was seen in the Andari et al. (2010) study and 
interpreted as resulting from the subjects exploring the faces with multiple brief fixations separated by 
saccades indicating greater anxiety during this task that required examination of the eyes in order to 
make the judgment about gaze direction of the face stimuli. 
   
Design and methods: 40 subjects with SCZ will randomized in a double-blind manner to receive a 
single dose of either OT or PBO, 45 minutes after which they will be tested on the Eye Tracking Tasks. 
 
 
Statistical approach: The data will be analyzed separately for the Sex identification Task and the Gaze 
Direction Task.  Within each of these tasks, the total fixation time in each of the ROIs and the total 
number of saccades will be computed for each face stimulus for each subject.  Descriptive statistics in 
the OT and PBO groups will be computed for each of the face categories (male vs. female in the Face 
Identification Task or direct vs. averted gaze for the Gaze Direction Task). Mixed model ANOVAs will 
be constructed with a between-subjects factor of group (OT vs. PBO) and repeated measures factors 
of face (male vs. female or direct vs. averted gaze) and ROI.  The initial analysis will use for the ROIs 
the areas within vs. outside the facial contours. Follow up ANOVAs will use all six ROIs (eyes, nose, 
mouth, forehead, cheeks, and outside the facial contours).  The number of saccades will be analyzed 
in a similar manner.  Should Baseline MATRICS total or subscale domain scores differ between the 
OT and PBO groups, those domain scores that differ significantly will be used as covariates in the 
ANOVAs.  Significant main effects will be followed up by appropriate post-hoc tests. 
 
Specific Aim 1b: Evaluate sensitivity to social reward by means of a computerized social reward ball-
tossing task that assays social interactions in response to social reward. 
 
Hypothesis: We predict that subjects in the PBO group will be insensitive to differences between the 
positive (socially rewarding) partner and the negative (socially non-rewarding) partner.  Based on the 
results of previous literature on the social deficits of patients with SCZ, we predict that those subjects 
in the OT group will send more balls to the positive partner and decrease the latency in tossing the ball 
to the positive partner compared to the negative partner than will the subjects in the PBO group. We 
predict that the OT effect is likely to be selective for social trials as opposed to non-social trials.  
   
Design and methods: 40 subjects randomized to receive a single dose of OT vs. placebo will perform 
the social reward ball-tossing task.  Performance on the task will be compared between the OT and 
PBO groups. 
 
Statistical approach: The number of balls sent to each of the partners, as well as the reaction time for 
each of the subjects' ball toss will be quantified to assess socially reinforced learning. An increase of 
number of balls sent to the positive player and a decrease in the reaction time to toss the ball to this 
player compared to the negative partner would indicate that social reward was affecting the subjects' 
behavior. The number of ball tosses to A and B within each block will be quantified. These data will 

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
9 
then be analyzed using a four-factor ANOVA (factors are OT vs. PBO; Player A vs. Player B; and 
block type [positive affect, negative affect, neutral affect, non-social reward]). 
 
Specific Aim 1c: Evaluate social cognition by means of testing the ability to correctly identify emotion 
from pictures of faces as assessed by the FEIT. 
 
Hypothesis: We hypothesize that the OT subjects will perform significantly better than the PBO on the 
FEIT. 
   
Design and methods: 40 subjects randomized to receive a single dose of OT vs. PBO will perform the 
FEIT.  Performance on the task will be compared between the OT and PBO groups. 
 
 
Statistical approach: Descriptive statistics in the OT and PBO groups will be computed.  The OT and 
PBO subjects' performance on the FEIT will be analyzed by means of a between-subjects ANOVA on 
the sum of correct responses.  If Baseline MATRICS total or subscale scores differ between the OT 
and PBO groups, those subscale scores that differ significantly will be used as covariates in the 
ANOVAs. 
 
6. Sample size determination 
 
Sample size calculations are based on effect sizes (Cohen's d) in published studies of the 
social cognition tasks to be used.  For all calculations alpha is set at 0.05. 
 
Specific Aim 1a, Eye Tracking. For the eye tracking task, several studies reported abnormalities in eye 
tracking in SCZ compared to healthy controls.  In two studies by Loughland et al. (2002a and 2002b), 
SCZ had reduced fixation on faces with an effect size of 0.74 and 0.73 respectively.  The study by 
Green et al. (2003) reported a larger effect size of 1.12 for the reduction in the number of fixations on 
angry faces in SCZ subjects compared to controls. There is one study of OT administration in healthy 
controls in which the effect size for increased gaze to the eye region of face pictures after OT vs. PBO 
administration was 1.20 (Guastella et al. 2008a).  If we conservatively assume that OT administration 
to our SCZ subjects will yield increased gaze to face stimuli with half the improvement reported in the 
Guastella et al. study, this would yield an effect size of approximately 1.0.  Taken together, basing our 
sample size calculation for eye tracking on a conservatively anticipated effect size of 0.74, a sample 
size of 20 subjects per group will be required to yield power of 0.80. 
 
Specific Aim 1b, Social Reward Ball-Tossing Task. There are no published studies of this task in SCZ, 
so sample size calculations are based on the use of a similar task in high functioning autism subjects 
after OT or PBO (Andari et al. 2010).  In that paper, the number of ball tosses to the "good" partner 
minus the ball tosses to the "bad" partner were significantly higher after OT than after PBO, with an 
effect size of 1.39.  Assuming we see an improvement in this outcome measure in our SCZ at a more 
modest effect size of 0.8, a sample size of 18 subjects per group will yield a power of 0.80 (one-
tailed).  
 
Specific Aim 1c, FEIT. The sample size determination for this task is based on several studies 
reporting reduced performance on this task in SCZ compared to healthy controls. In the Penn and 
Combs study (2000) a very large effect size of 2.2 was reported for this between-group difference.  
Addington et al. (2006) reported a between-group difference effect size of 0.82. An earlier study 
(Mueser et al. 1996) reported a between-group difference at an intermediate effect size of 1.79. We 
conservatively estimate that we will see the smallest of these three effect sizes, namely 0.82, for a 
difference between OT and PBO. This effects size will require a sample size of 19 subjects per group 
(1-tailed) to yield a power of 0.80. 

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
10 
 
Summary of sample size determination. Based on the above calculations, we will plan to complete 20 
subjects per group or a total of 40 subjects. This number will enable us to detect significant between-
group differences with power of 0.80 and alpha set at 0.05. 
 
7. How this project will promote the goals of the CTSN and promote obtaining NIH funding 
 
This project fits well within the area of interest of the CTSN since it represents a direct clinical 
translation of the preclinical neurobiology of OT.  This project will provide necessary pilot data for a 
larger more definitively powered clinical trial of OT in SCZ that will be submitted to NIH. In that grant 
submission, in addition to the clinical trial component with social cognition outcome measures, a 
Specific Aim will be added to examine fMRI correlates of processing of social stimuli in the OT and 
PBO treated groups. 
 
8. DSMB 
 
The study will be closely monitored by the Principal Investigator, Dr. Erica Duncan, who is an 
attending psychiatrist at the Atlanta VA and an Associate Professor of Psychiatry at Emory University. 
In addition, the study will be monitored by the DSMB of the Department of Psychiatry and Behavioral 
Sciences at Emory University. This board is composed of Larry Tune MD, Boadie Dunlop MD, Bobbi 
Woolwine, LCSW, Tanja Mletkzo, Ray Tiyamiyu and Emeka Madubuike. Any unexpected or serious 
adverse events will be reported to the Emory University IRB in accord with the reporting requirements 
of the IRB. 
 
9.  Risk-benefit ratio 
 
Subjects will receive a total of $100 to compensate for their time and effort to participate in the study. 
This is necessary in order to sustain motivation and engagement in the study and in order to 
compensate subjects for their time and travel expenses.  As per the rules of our Institutional Review 
Board at Emory University, subjects will be compensated on a prorated basis on each of the two days 
that they come for study visits. Patients with schizophrenia may potentially benefit from knowledge 
gained in this study about OT as an adjunctive treatment option. 
  
10.  Risks  
1. Phlebotomy: The risks are bleeding, infection at the blood draw site, and pain.  
2. Measurement of vital signs: There are no risks.  
Interviews for psychiatric history and symptom rating: The risk is that emotionally upsetting material 
may come up in the interviews.  
3. Cognitive testing: The risk is one of frustration or boredom.  
4. Loss of confidentiality: Collection of identifying information and information about psychiatric 
diagnosis and symptoms poses the risk of loss of confidentiality.  
5. Intranasal OT administration: OT (Syntocinon) may trigger labor in pregnant women and milk 
ejection in women who recently gave birth. Since we will only enroll men, these side effects are not of 
concern for this study. In rare cases, nausea, vomiting, irregularities of the pulse, skin rashes and 
allergic reactions in combination with shortage of breath, blood pressure decreases or circulatory 
collapse have been reported following the regular and repeated administration of Syntocinon. 
However, it is important to note that no adverse side effects have been reported following the 
administration of OT in schizophrenia subjects for three weeks in the Feifel et al. (2010) study at twice 
the daily dose we will use.    
 
11. Steps taken to minimize risks  
1. Phlebotomy: The risks will be minimized by the use of standard sterile technique.  
2. Measurement of vital signs: No steps necessary.  

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
11 
Interviews for psychiatric history and symptom rating: If emotionally upsetting material arises during 
interviews, the rater will redirect the interview into less emotionally laden areas and give the subject a 
chance to recover. Subjects will not be required to discuss material they are uncomfortable discussing.  
3. Cognitive testing: Subjects will be guided through the cognitive testing with sensitivity to difficulties 
they may be having. They will be given the opportunity to rest if needed.  
4. Loss of confidentiality: Study data and subject information will be stored in locked file cabinets in the 
research lab of Dr. Duncan, to which only research staff have keys and access. All electronic data 
containing HIPAA identifiers will be stored only on VA approved password approved computers 
located within the Duncan lab at the Atlanta VAMC, or backed up and password protected on VA 
research servers.  
5. Intranasal OT administration: Prior to randomization, subjects will be screened with measurement of 
vital signs, SMA-12 (basic chemistry), and urinalysis. Subjects will be excluded for clinically significant 
abnormalities in these measures.  
 
PLAN FOR DISCHARGE OF INVESTIGATOR/SPONSOR RESPONSIBILITIES TO THE FDA 
 
The following responsibilities to the FDA will be performed by the PI with the assistance of the study 
team. 
 
1.  Responsibilities as the IND Sponsor: 
a. Maintain an effective IND with respect to the investigations. 
b. Submit annual reports on the progress of the investigation to the FDA. 
c. Report essential information on the IND that is not within the scope of a protocol amendment, IND 
safety reports, or annual report, such as new toxicology, chemistry or technical information. 
d. Submitting a protocol amendment to describe any change(s) in the protocol. 
e. Selecting only qualified investigators by training and experience as appropriate experts to 
investigate the drug.    
f. Providing each participating investigator with all information required to conduct the study 
properly. 
g. Obtaining the following information from each participating investigator before permitting them 
to begin any activity on the investigation: 
i. 
Signed and completed investigator statement(s) – Form FDA 1572  
ii. 
Curriculum Vitae or other statements of qualification on file for all investigators  
iii. 
Clinical Protocol  
iv. 
Financial Disclosure Information (see next section)  
 
2.  Financial Disclosure: 
Maintain current, complete and accurate records documenting the financial interests of all participating 
clinical investigators, including sponsor payments, for the duration of their participation in any covered 
studies under the IND, plus 1 year following the completion of the study.  
 
3. Study Management: 
a. Notify the FDA in written IND safety reports, of adverse events related to the drug that is both 
serious and unexpected.  
b. Review and evaluate the evidence relating to the safety and effectiveness of the drug, and report 
serious and unexpected adverse events to FDA. 
c. If the PI determines that the investigational drug presents unreasonable and significant risk to 
subjects, discontinue those investigations and notify the FDA and IRB.  This notification would 
occur as soon as possible, and in no event later than 5 working days after making the 
determination.  
 

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
12 
4. Monitoring And Selection Of Study Monitors: 
a. Arrange for the monitoring of the progress of all clinical investigations being conducted under the 
IND, to ensure that the investigation is conducted in accordance with approved investigational 
plan and protocol covered by the IND and in compliance with the signed FDA form 1572.   
b. Select a monitor qualified by training and experience to monitor the progress of all clinical 
investigations conducted under its IND.  
 
5.  Receipt, Storage, Disposition, and Return of Investigational Drug: 
Maintain adequate records showing receipt, shipment, or other disposition of the investigational drug.  
These records must include the name of the investigator to whom the drug is shipped, and the date, 
quantity, and the batch or code mark of each such shipment.   
 
6.  Current Good Manufacturing Practices (CGMP): 
Ensure the minimum current good manufacturing practice for preparation of drug products for 
administration to humans in compliance with the requirements of § 501(a)(2)(B) of the FD&C Act.  
 
7.  Labeling and Representation of Investigational New Drug: 
a. Immediate packaging of the IND intended for human use bears a label with the statement, 
“Caution: New Drug – Limited by Federal (or United States) law to investigational use”.  
b. Insure that the IND drug label does not bear any statement that is false or misleading, and 
does not represent the IND as safe or effective for the purpose it is being investigated.  
c. Insure that the  investigator does not represent the IND as safe or effective for the purposes for 
which it is under investigation.  
 
8.  ClinicalTrials.gov: 
Insuring that the clinical trials is registered and results reported.  The trial will be registered at trial 
initiation, but not later than 21 days after enrollment of first participant and to report summary results 
information for interventional studies of drugs within 1 year of completing data collection for the pre-
specified primary outcome.   

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
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7. Budget 
 
 

E. Duncan, Oxytocin as adjunctive treatment of schizophrenia 
 
 
14 
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