Target Engagement for Oxytocin: Response to 8 Doses
Phase: NA
Conditions: Schizophrenia Spectrum
Sponsor: University of California, Los Angeles

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Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to Clinical Effects 
 
 
 
PI:  Stephen R Marder, MD 
 
NCT02498236 
 
Original posting date 6/9/2016 
 
Reposting date 10/4/2018 
 

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PROTOCOL 
 
 
Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to Clinical Effects 
 
 
Intranasal oxytocin (OT) has shown promise as an agent that can effective ly improve social 
processing in disorders that are characterized by impairments in social behaviors, in cluding 
schizophrenia. However, important gaps in our understanding of OT’s effects on the brain have  
greatly limited its development as a  therapeutic agent and made it difficult to interpret mixed   
research findings. One very important therapeutic function of OT may be its ability to enhance  
learning of social information. The proposed research will evaluate, in sequential steps, OT’s effects 
on learning social cognitive skills in psychotic patients within a manualized training program that we 
have developed. The initial step (R21) is to demonstrate target  engagement (i.e., that OT is getting   
to the brain and influencing social processes) and to establish optimal dosing of OT. Promising 
neurophysiological measures of target engagement for OT include EEG mu suppression while 
observing biological motion, and pupillary dilation during an emotion recognition task. 
 
The R21 phase will determine the dose-response curve to OT for proposed measures of target 
engagement (i.e., mu suppression and pupillary dilation). The proposed study will use a single 
administration, within-subjects, crossover design to model the dose-response to OT across a large 
range of doses. Subjects with schizophrenia will be randomized to either: 8, 12,  24, 36, 48, 60, 72,    
or 84 IU OT (6 subjects to each dose). Each subject will receive OT and placebo in a dministrations 
separated by one  week in randomized order. 30 minutes following OT administration, mu   
suppression and pupillary response will be assessed. We will also collect data on two measures of 
social salience (operationally defined here as behavioral tasks of social preference) to examine their 
correlations with measure of target engagement. 
 
 
Specific Aims 
 
R21 Specific Aims: This phase will determine the dose-response  curve  to  OT for  proposed 
measures of  target engagement (i.e., mu suppression and pupillary dilation). The proposed study    
will use a single administration, within-subjects, crossover design to model the dose-response to OT 
across a large range of doses. Subjects with schizophrenia will be randomized to either: 8, 12, 24,    
36, 48, 60, 72, or 84 IU OT (6 subjects to each dose). Each subject will receive OT and placebo in 
administrations separated by one week in randomized order.  30  minutes  following  OT 
administration, mu suppression and pupillary response will be assessed. We will also collect data on 
two measures of social salience (operationally defined here  as  behavioral  tasks  of  social 
preference) to examine their correlations with measure of target engagement. 
 
Aim 1. To determine the dose-response relationship OT versus placebo for measures of target 
engagement. 
H1: At the optimal level of OT we will observe significant effects on 
-suppression. 
H2: At the optimal level of OT we will observe significant effects on pulillary dilation. 
 
A Go/No GO decision will be based on Specific Aim 1. If either hypothesis is sup ported we will   
decide to go to the R33. Specific Aim 2 is exploratory and the results of the analysis will not be used 
for a Go/No Go decision. 

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Aim 2. To evaluate the relationship between target engagement and measures of social salience. 
 
 
Background 
 
A.1 Social  Cognition as an Intervention Target Serious mental illnesses such as schizophrenia are 
associated  with impairments in the ability to process social information ,  referred to as  social cognition. 
These impairments involve skills in detecting basic social cues, such as identifying emotions expressed in 
faces, as well as higher  level skills involved in mentalizing, such as understanding the thoughts and feelings  
of others[1]. These impairments present an attractive target for intervention since they  are associated with 
poor community functioning, including the ability to work, succeed in educational activities, and to sustain 
social relationships[2, 3]. In fact, social cognition is more closely related to daily function than non -social 
cognition  in schizophrenia  [2].  It is likely that improving social cognition with  psychosocial or 
pharmacological approaches will have clinically important effects on the serious  social disabilities that limit  
the potential of these individuals. Although research from a number of groups [4, 5] – including our own [6] 
– has had promising results with training interventions for social cognition, these approaches have limited 
efficacy. This has convinced us to develop a research program that focuses on strategies for improving the 
potency of  social cognition  training.   As noted below (section C.2.1), our initial results with intranasal 
oxytocin (OT) showed promise [7] for enhancing the effects of social cognition training. 
A.2 Limitations of Social  Cognition Training Social cognition comprises a group of  processes that can 
be applied to understanding and responding to social information [2]. A recent consensus process [8]  
identified four core domains: emotion processing, social perception, theory of mind/mental state attribution, 
and attributional style/bias. Studies of training interventions for social cognition in schizophrenia (reviewed in [9]) 
found that the such approaches are effective for improving social cue detection, such as facial emotion identification 
skills[6, 10]. However, these approaches were relatively ineffective for inferential processes such as mentalizing and 
theory of mind. Given the severe impairments in processing social information in schizophrenia and their impact on 
social functioning it is plausible that a medication that can improve the training of mentalizing would result in 
substantially better social functioning. As described below in C.2.1, we hypothesized that these higher order 
processes would be aided by a pharmacological agent that helped patients to allocate more neural resources to 
social information. In our pilot study [7], we administered intranasal OT or placebo thirty minutes prior to a social 
cognition skills training (SCST). The findings from that trial were mixed in that patients in both the OT and placebo 
groups improved in their abilities in social cue detection.  This was not surprising since we previously found that 
these abilities responded well to our training intervention[6]. We did find an effect of OT on our measure of empathic 
accuracy (described in section C.2.2d ) but not on a measure of theory of mind (The Awareness of Social Inference 
Test /TASIT). Since the abbreviated form of training we used in that trial included training in empathy, but not theory 
of mind, we interpreted our findings as indicating that OT’s effects were on the learning of mentalizing skills. Since 
the abbreviated form of the intervention we used in that trial included training in empathy, but not theory of mind, we 
interpret our findings as indicating that OT’s effects were on the learning of mentalizing skills. This encourages us to 
systematically explore ways that we can pharmacologically improve the training of patients with impaired social 
cognition. 
We emphasize that our approach focuses on the facilitation of learning that occurs during training sessions. There is 
already some evidence that intranasal OT in single doses [11] or with chronic dosing [12] can result in improved 
social cognition. However, here we chose a substantially different, and potentially valuable, approach.  Specifically, 
we posit that OT can enhance learning and the resulting improvements will be sustained even when the subject is 
drug-free. In our pilot study we evaluated social cognition domains one week and one month after the last 
administration of OT. The advantages of OT on empathic accuracy were seen at both times supporting our 
interpretation that OT was improving learning. 
A.3 Oxytocin  effects on brain Oxytocin is a peptide hormone that plays an important role in regulating 
mammalian social behaviors [13]. In animals, OT has been shown to support the formation of attachment 
bonds [14]. These effects are paralleled in healthy humans for whom OT can have prosocial effects that 

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include improving trust and cooperation [15].  These prosocial effects have encouraged a number of groups  
to explore exogenous OT as a therapeutic agent for psychiatric disorders that are associated with  
impairments in social behaviors, including autism and schizophrenia. 
OT has very poor passage through the blood brain barrier.  As  a  result,  oral  and  intravenous 
administrations are not effective for increasing brain levels. Evidence from rodent studies supports a direct 
pathway through which intranasally administered OT diffuses directly to the brain  [16].  It is also plausible   
that OT affects behavior through an indirect route by causing central release through a peripheral    
mechanism [17]. Although the exact path from nose to brain is not clear, there is compelling evidence that 
intranasal OT has effects on areas of the brain that have been linked to social behaviors. For example,  
studies using functional MRI have shown that the administration of OT can have effects on socially -relevant 
brain areas including the amygdala [18] and the ventral tegmental area [19]. 
The inability to use peripheral blood to estimate brain levels of OT has been an important imp ediment for 
clinical research with OT. As a result, important decisions for clinical trials, including dose and duration of  
drug action, have been based on very limited information. This is a substantial problem since studies in 
animals indicate that the dose-response of OT differs for different behavioral effects with some showing 
inverted-U shaped dose responses[20]. In addition, it has been difficult to explain why some individuals 
respond to OT and others do not. The R21 phase of this proposal will evaluate promising indicators of OT’s 
effects on the brain, specifically examining the dose-response relationship for our proposed 
psychophysiological target measures of neural engagement. If these responses are reliable and valid 
indicators of OT’s brain activity, they have the potential for facilitating treatment development by providing 
information for dosage selection, duration of  drug effects, and identification of  non-responders.   This 
proposal will not be able to link OT to a particular receptor  – such an approach to target engagement will   
only be feasible when a PET ligand for the OT receptor is identified. How ever, our proposed approach can 
indicate that intranasally administered OT has entered the brain and engaged a social processing network. 
A.4 Oxytocin and Social Salience  The R21 and R33 phases are designed to improve our understanding  
of the neurobiology underlying one of OT’s properties; that is, OT’s ability to increase the salience of social 
information [19]. For the purposes of this proposal we define social salience as the bias of the individual 
toward allocating cognitive resources toward social information. If both social and non-social stimuli are 
present, greater social salience would lead the individual to demonstrate what appears to be a greater 
preference for social over non-social information. The evidence that OT increases social salience comes  
from a number of sources. In sheep, OT promotes the selective olfactory recognition of offspring [21]. In 
humans, administered OT increases gaze toward eye regions [22] which are probably the most socially 
communicative part of faces. Moreover, studies with fMRI [23] found that this tendency toward increasing 
gaze to the eye is associated with an increased coupling of amygdala and superior colliculi activity. This 
supports the view that OT biases an individual toward social visual information. OT also improves the 
encoding of positive social memories [24], and improves empathic accuracy [25]. The measures of target 
engagement in this proposal  – EEG mu suppression during biological versus non-biological motion and  
pupil dilation while detecting social information – both reflect allocation of neural resources to social 
information. This proposed study also includes measures of social preference as indicators of social  
salience.   By evaluating the relationship between OT target engagement and social preference, this  
research program may contribute to our understanding of how OT affects human social behavior. 
B. Innovation – R21 and R33 
B.1 Novel methods for studying OT’s target engagement 
The selected measures of target engagement – EEG 
mu suppression while observing biological motion and pupil dilation during an emotion recognition task – are 
plausibly related to how the brain focuses attention on social information. These methods are supported by our pilot 
data (which is summarized below, C1.e-f) and, if validated in the R21, will represent a methodological advance for 
OT clinical research. 
B.2 Approach to Dose-Response of OT Decisions about the dose of OT have been largely based on trial and 
error. The measures of target engagement provide a unique and innovative approach for modeling the dose- 

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response of OT. Moreover, our use of multiple doses of OT in the R21 maximizes the information available for 
understanding dose-response. 
B.3 Focus on OT’s effects on learning Our innovative approach to studying OT is focused on how it can affect 
learning. First, we are focused on an acute effect of OT and not administering drug chronically. This addresses a 
concern from preclinical studies which indicate that the increases in social behaviors following acute administration of 
OT are lost with chronic administration [26]. 
Second, subjects in our study will only receive OT prior to training 
sessions and social cognition measures will only be assessed days after OT administration when the drug has 
washed out of the system. As a result, observed improvements will be attributable to OT’s effects on learning rather 
than to direct drug effects on social cognition. 
B.4 OT and social salience The design of the R33 has the potential to link OT’s effects on social cognition training 
to our measures of target engagement in brain and to our proposed measures of social salience. This has the 
potential to advance OT as a therapeutic agent for impaired social cognition. In particular, it would indicate that 
patients with impairments in a brain system related to the attribution of social salience may benefit from OT. 
B.5 Social salience as a mediator of improvement in social cognition  An exploratory component of this project 
is the inclusion of social preference paradigms as indicators of social salience. Although somewhat speculative, we 
will be able to test the intriguing possibility that improvements in social cognition in people with psychosis come about 
because of changes in the salience of social information in their environment. This possibility, if supported, would 
focus rehabilitation efforts on enhancing the engagement value of social stimuli for individuals with social processing 
deficits. 
C. Approach 
C.1. R21 Approach 
C.1.a Measures of Target Engagement For the purposes of this study, we selected measures that were 
suitable for clinical trials. That is, their administration is relatively inexpensive and results in modest subject 
burden.   We considered an fMRI measure of target engagement of OT, but conclude d – because of cost   
and subject burden – that it would not be feasible to include this in the R33 phase of the program. The 
proposed measures, pupil dilation during an emotion recognition task and mu suppression while observing 
biological motion, measure brain responses that are plausibly related to  OT’s  effect  on  how subjects 
process social  information.  That  is,  pupil dilation appears to measure the allocation of  resources to 
detecting social information and EEG mu suppression appears to measure the acti vation of the mirror   
neuron system which is important for processing social information. 
Pupil dilation during an emotion recognition task Pupillary responses have been used for decades to 
examine cognitive and social processing. The muscles responsible for constricting or dilating the pupil  
receive input from the parasympathetic and sympathetic nervous systems,  respectively.  Pupil  dilation 
occurs in response to increased sympathetic activity as well as in response to decreased parasympathetic 
activity [27]. Phasic increases in pupil dilation can be stimulus- or task-driven, with larger pupil diameter 
reflecting greater processing demands [28]. Pupil diameter also increases in response to emotional arousal 
that is not valence-specific, reflecting sensitivity to processing of emotionally-laden stimuli [29]. Two recent 
studies have examined the effects of OT on pupillary responses to emotionally-laden stimuli. In the first, 
Leknes et al. [30] found that the administration of a single intranasal dose of OT to healthy volunteers  
resulted in greater pupil dilation than placebo when subjects were engaged in a task that required the 
recognition of emotional expressions. In the second, Prehn et al. [31] examined pupillary responses  in 
healthy men when viewing faces depicting various emotions, and found that OT improved performance 
compared to placebo during a dynamic facial recognition task. Moreover,  larger  pupil  dilation  was 
correlated with better task performance. Both groups interpreted their findings as indicating that the pupil 
response indicated greater allocation of resources to social information. 
EEG mu suppression while observing biological motion The mirror neuron system (MNS) is 
hypothesized to reflect the brain’s ability to map visual representations of others’ actions onto the motor 
representations in the observer of the same actions, an important mechanism underlying the capacity to 
understand and imitate social actions [32]. The MNS can be assessed in humans through EEG 

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measurements of neural oscillations in the mu range (8-13 Hz). While mu rhythms overlap in frequency with 
the more commonly known alpha rhythms (most apparent when the brain is “at rest”), they can be 
distinguished from alpha based on where on the scalp they are seen. Mu rhythms are typically seen over 
central scalp sites, overlaying sensorimotor cortex, whereas alpha rhythms are typically seen over occipital 
scalp sites.  Mu rhythm amplitudes are largest when a person is at rest and  decreases in amplitude when   
that person moves, observes movement, or even simply imagines moving  [33]. This decrease in amplitude   
is called mu suppression and reflects engagement of the MNS. Mu suppression has been seen in response   
to a variety of stimuli, including point-light walkers depicting biological motion [32, 34]. Given that OT has  
been shown to increase responding to social stimuli, Perry et al.  [35] examined its effects on mu    
suppression in healthy students when viewing stimuli depicting biological motion. The results of this st udy 
found greater mu suppression within a narrower frequency band (8-10 Hz) when subjects viewed point light 
biological motion than when they viewed non-biological motion (consisting of  moving  dots  depicting  a 
circle). Perry et al. also found that single doses of OT led to greater suppression of mu oscillations than 
placebo while subjects observed a point light display of a human walking. 
C.1.b Social Processing in Psychiatric Disorders Impairments in social cognition cross diagnostic 
boundaries. For this research program we elected to limit the sample to diagnostic groups that had been 
studied using social cognition training programs that were similar to the system we plan to employ. Such 
studies have focused mostly on schizophrenia and schizoaffective disorders. Previous work from our group 
[36] found that many patients with bipolar illness had relatively preserved social cognition. As a result, we 
restricted the sample to include only non-affective psychotic disorders. 
 
C.1.c Study Subjects: Subjects will be 48 outpatient men and women 18 to 55 years old with non-affective 
psychotic disorders (schizophrenia, schizoaffective disorder, and delusional disorder) who are in a stable 
condition on antipsychotic and other medications. Stability criteria will include no recent hospitalizations within 
the six months prior to study entry and no changes in psychiatric medication or dosage changes greater than 
10% within the past three months. Inclusion criteria will also include ability to provide informed consent, 
without serious medical conditions, and without recent substance use disorder. Exclusion criteria will include a 
positive pregnancy test, unstable medical conditions, history of serious head injury, and hyponatremia. 
Women will be excluded who are sexually active and not using an effective form of contraception. We will 
recruit subjects from a number of sources including the UCLA Psychosis Clinic which is led by the PI, the West 
Los Angeles VA Healthcare Center, and community board and care facilities where we are able to distribute 
flyers describing the study. The VA site manages more than 2000 patients with schizophrenia and the UCLA 
Psychosis Clinic has approximately 120 patients. Including subjects with other non-affective psychotic 
disorders will increase the recruitment pool. 
 
We hope to have 48 subjects complete the study with valid and useable data. In order to reach that number 
while allowing for screen failures and subject attrion, we may enroll as many as 100 subjects. Subjects may 
participate in one or both locations (the VA and UCLA), so we cannot estimate how many subjects will 
participate in one location versus the other. 
 
Duration of Research: 
The R21 is a two year study that could be extended for three more years as an R33 based on the results of the 
first two years of the study. That would involve a new IRB submission for the R33. We estimate the R21 will 
take approximately 2.5 – 3 years. 
 
Recruitment of Subjects: 

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To meet our recruitment goals, patients with schizophrenia will be recruited from five sources: previous 
participants who have asked to be contacted for future studies by initialing this preference in a consent form 
from another study, participants of the MIRECC Treatment and Clinical Neuroscience Repository (Marder 
#0042), outpatient mental health clinics within the VA Greater Los Angeles Healthcare System (VAGLAHS), 
the UCLA Psychosis Clinic; and local board and care facilities. Patients will include persons who meet DSM-5 
criteria for schizophrenia. We have well-established connections to several VA clinics and local board and care 
facilities. These relationships have been built on a demonstrated respect of their policies. We only recruit at 
locations where the staff members have been fully informed about the type of research we perform, the 
associated risks and benefits, and have approved our recruiter’s presence. The main recruitment locations we 
might visit for this study are the following within the VA: DDTP, 206 Mental Health Clinic, MHICM, Day Tx, the 
Domiciliary, Exodus Lodge, and the following board and care facilities: The Manor, Golden Manor, Ocean View 
Manor, Brentwood Manor, Beverlywood Manor, the Graduate House, and Step Up on 2nd. 
 
Any patient with schizophrenia who is not already part of the Repository will be asked to review and sign the 
MIRECC Treatment and Clinical Neuroscience Repository (Marder, #0042) consent form and HIPAA 
authorization for initial screening purposes prior to consenting for this study. Patients who agree will be asked 
to respond to a brief screening interview which includes questions about their mental health, medical and 
educational history, residence, past hospitalizations (if any), past or current drug use (if any), and current 
medications (if any). We will also ask for permission to review medical records and contact their primary care 
provider (PCP) or other responsible clinician to help determine mental health diagnosis or other general 
eligibility questions. If, after joining the repository, the patient continues to appear eligible for this study, the 
participant will be asked to review and sign the consent and HIPAA form for this study. The information from 
the repository combined with details provided in the diagnostic interview and rating scales will be reviewed 
during the weekly lab case review and the final determination of eligibility will occur at that time. 
No 
telephone screening will be performed for this study. All screening procedures will occur in person with our 
recruiter or Drs. Marder, Dunn, or Yang. 
 
Patients who are not willing to join the repository will be asked to review and sign the consent and HIPAA form 
for this study only and proceed to the diagnostic interview to determine study eligibility. 
 
Study Locations 
We have lab space in two places that we will use for this study: offices at the VA Greater Los Angeles 
Healthcare System MIRECC in Building 210 and the UCLA Translational Research Center for Neuropsychiatry 
(TRCN), which is located at the UCLA Semel Institute. Subjects' participation in this study may occur at one or 
both locations (meaning all activities will be conducted in both locations, and individual subjects may 
participate in one or both places). 
All subjects will be asked to sign the VA consent form and HIPAA 
authorization since all data will be stored in our VA lab space, and if they are a UCLA patient, then they will 
also be asked to sign the UCLA HIPAA authorization. 
 
We acknowledge that the use of multiple testing sites always requires some additional consideration. In this 
case, we are fortunate in that we are involved in setting up performance-based and EEG labs in the new space 
on the 2nd floor of Semel. The rooms will be dedicated testing rooms, and very similar (in size and 
arrangement of furniture) as our lab space at the VA. In addition, the testing conditions will be similar, with, 
most importantly, the same EEG system used at both sites. For personnel, we will be using the same staff at 
both locations for all aspects of the study, and the lab staff who will administer the EEG and pupillometry tasks 
have all been trained by Dr. Wynn on the Biosemi system. The testing parameters between the two sites will 
also be similar (same size monitors, distances from screen, room lighting, etc.). All staff have current VA 
appointments and are up-to-date on trainings. 

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C.1.d Study procedures: Following an initial screening, subjects will be scheduled for a first visit during 
which informed consent will be obtained. Other assessments will include the Structured Clinical Interview for 
DSM-4 (SCID) modified for DSM-5 diagnostic criteria; a medical history; and a physical examination with 
laboratory tests including venipuncture (CBC and basic metabolic panel), urine specimen for urinalysis, and 
urine pregnancy tests for women. In addition, basic demographic information and a psychiatric history will be 
collected. One week later subjects will be randomly assigned to one of 8 dosing groups: 8, 12, 24, 36, 48, 60, 
72, and 84 IU of oxytocin. (See Table 1) 
 
Table1: Study Events 
Screening 
Visit 1 (1 wk post 
screening) 
Visit 2 (2 wk post 
screening) 
Screening, SCID, demographics, 
consent 
X 
OT Challenge 
X 
X 
 
OT challenge Each subject will participate 
in 2 OT challenges: one at the assigned 
dose and the other on placebo. The 
challenges will be separated by one week 
and will occur in randomized order. A single 
formulation of OT will be used and dose will 
be adjusted by the number of nasal sprays 
of OT or placebo. On the day of the 
challenge the study staff will observe the 
subject as he or she applies the assigned 
number of sprays of OT or placebo. We do 
not believe that subjects will be able to 
    Table 2: Timeline of Oxytocin Challenge Procedures  
Time (minutes) 
Procedure 
0 
Drug administration, setting 
up of EEG electrodes 
30 
Biological Motion Mu 
Suppression 
45 
Pupillometry Task 
65 
Gaze-cuing task 
95 
One-armed bandit task 
discriminate OT from placebo. In a prior study [11] subjects were unable to distinguish OT from placebo. The 
pupillometry, EEG, and social preference measures will be administered 30 minutes following OT or placebo 
administration in a standardized order (see Table 2). 
 
C.1.e. EEG Mu Suppression Task To assess mu suppression, we will use a biological motion task in which 
subjects will be asked to identify either the gender, the emotion (happy or sad), or intention (moving towards or 
away) of a point-light walker. This paradigm has been validated in a previous study to show greater mu 
suppression when viewing biological versus non-biological motion, and greater mu suppression when subjects 
were administered OT [37]. Stimuli consist of 5 s video clips. Each video clip contains all three dimensions, e.g. 
a clip can show a sad woman walking 
toward the observer, a happy man 
walking away, etc. Additionally, a non- 
biological motion clip will be used as a 
control stimulus, and consists of dots 
moving in a circle either to the left or 
right of the screen. Clips will be 
presented on a monitor approximately 
70 cm from the participant. E-Prime will 
be used for stimulus presentation and 
for syncing of triggers with the EEG 
equipment. 
 
Stimuli will be presented in four 
separate randomized blocks, with each 

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block consisting of a separate task, requiring the subject to identify only one dimension (e.g., identify only 
gender, only emotion, only intention, direction of circle). A total of 23-26 clips per block will be administered. 
Twenty of the clips will be of one level of the dimension (e.g., male walkers) while 3-6 clips will be of the other 
level (e.g., female walkers). The participants are instructed to silently count the number of occurrences of the 
rare event and report this at the end of the block to ensure that they are attending to the task. This task will 
take approximately 15 minutes to complete. 
 
EEG data will be initially filtered with a 0.5 Hz high-pass filter and re-referenced to the mastoids. Eyeblinks will 
be corrected using standard algorithms [38]. Artifacts exceeding +/- 100 V in amplitude at any electrode site 
will be rejected. As in prior studies the first 10 s of each block will not be analyzed to remove potential 
confounds of attentional shifts due to initiation of the stimuli [37, 39]. The first 2 s of each remaining 5 s clip will 
be analyzed [37]. A fast Fourier transform (FFT) using a Hanning window will be performed in 0.5 Hz intervals. 
Integrated power between 8-10, 10-12, and 15-25 Hz range will be assessed. Mu suppression will be 
calculated as the log10 ratio of the power during the biological motion clips relative to the moving circle clips. 
This ratio is intended to account for individual differences in EEG power as well as normalize ratio data that are 
not typically normally distributed. A negative number indicates mu suppression. Six electrode sites will be 
examined: C3, Cz, C4 (where mu suppression is expected), and O1, Oz, and O2 (where typical alpha 
modulation is seen). 
EEG activity will be collected continuously throughout the session and amplified using a 64-channel BioSemi 
ActiveTwo amplifier (BioSemi, Germany). Data will be sampled at 1,024 Hz with filter settings of DC to 100 Hz. 
Sixty-four cap-mounted Ag-AgCl electrodes will be positioned using a modified international 10-20 system 
placement scheme. Additionally, four electrodes will be used to measure horizontal electrooculogram (EOG; 
placed on the outer canthus of the left and right eye) and vertical EOG (placed above and below the left eye). 
All electrodes will be referenced using common mode rejection during EEG recording and rereferenced offline 
to linked-mastoids. Data will be processed using Brain Vision Analyzer 2. 
Pilot Data: We collected pilot data in 11 stable schizophrenia patients who were receiving an antipsychotic 
medication. After we obtained informed consent, subjects were administered 40 IU of OT or placebo in 
randomized order on 2 occasions separated by one week. The mu suppression paradigm was administered 
approximately 30 minutes following the nasal spray. As can be seen in Figure 1, mu suppression was greater 
than placebo in all three tasks, with an average effect size of d = 0.24. 
 
C.1.f Pupillometry Task To assess pupil dilation to 
social stimuli, we will administer a facial affect 
identification task. This paradigm has been modified 
and adapted from previously published studies in 
healthy controls [40]. Stimuli will consist of male and 
female faces depicting happy, afraid, or neutral 
expressions, drawn from the Japanese and 
Caucasian Facial Expressions of Emotion and 
Neutral Faces dataset [41]. Additionally, the same 
stimuli have been scrambled to use as control 
stimuli. A dark grey background will be used 
throughout the experiment. Stimuli will be presented 
on a monitor approximately 70 cm from the 
participant. E-Prime will be used for stimulus 
presentation and for syncing with the pupillometry 
system. 
 
Sixteen of each stimulus type will be shown in a randomized order. Each trial begins with a 3 s fixation cross 
followed by the presentation of the stimulus for 5 s. After stimulus offset, a screen will be shown with written 
options for type of stimulus. Participants will be instructed to not blink during the presentation of the fixation 
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cross and stimulus. Once the choice screen appears they are instructed to identify which stimulus type was 
shown and they can blink freely. They can then initiate the next trial when they feel they will not need to blink. 
This task will take approximately 20 minutes to complete. 
 
Pupillary responses from the right eye will be continuously recorded using a ViewPoint EyeTracker USB-220 
(Arrington Research, AZ), using an infrared light source and infrared camera. The recording system will be 
connected to the presentation computer to synchronize trigger signals that indicate the beginning of a trial. 
Pupillometry data will be continuously recorded at 220 Hz and stored for offline data analysis. Pupillometry 
data will be analyzed with custom-written scripts in Matlab. Cleaning of data (e.g., removal of blinks) and data 
reduction will be accomplished following standard procedures [40, 42-44]. Briefly, data will be smoothed using 
a 20-point moving average filter. Eyeblinks, defined as changes in pupil size that are too large and rapid to 
represent actual pupil dilation or constriction, will be replaced by linear interpolation. Pupil diameter, measured 
as the average dilation over the 0.2 s preceding the onset of the stimulus, will be subtracted from pupil 
diameter after stimulus onset to produce a pupil dilation difference score: positive scores indicate dilation while 
negative scores indicate constriction. Stimulus-locked pupillary response will be averaged for each stimulus 
type. Data will be analyzed as the mean change in pupil size occurring between 0.8-2.5 s after stimulus 
presentation. 
 
Pilot Data: Pilot data are available for 8 stable schizophrenia patients on antipsychotic medication who 
received double-blind 40 IU of intranasal OT or placebo administered a week apart. We assessed the effects 
of OT on pupillary responses using the paradigm described above. First, we found that greater pupil dilation 
was seen to faces, compared to a scrambled face (data not shown), consistent with prior studies. Second, as 
can be seen in Figure 2, OT reduced pupillary dilation to fearful faces in comparison to placebo (d=.81), 
consistent with OT down-regulating amygdala activation to fearful faces [18, 45] and consistent with the one 
previously published paper showing less dilation on OT to fearful faces [31]. While the sample size is small, 
these pilot data demonstrate the expected pupillary response to faces and the feasibility of OT to influence 
pupil size. 
C.1.g. Social Salience measures: For the purposes of the R21 and the R33 we will use behavioral measures 
of social preference to assess social salience. The two tasks, a gaze-cuing task and a one-armed bandit task, 
assess social orienting and social reward, respectively, and both are considered indices of social salience. As 
noted below, recent work in our laboratory indicates that individuals with schizophrenia are less likely than 
controls to show a preference for social cues. 
Gaze-cuing task: To assess social 
orienting, we will use a gaze-cuing task in 
which subjects will be asked to indicate the 
location of a target (the letter X in one of 
two peripheral boxes) following an 
uninformative central cue (either social or 
nonsocial) [46, 47]. The social cue will be 
a drawing of eyes gazing left or right; the 
nonsocial cue will be an arrow pointing left 
or right. On each trial a fixation cross will 
be presented for 700 ms along with two 
peripheral boxes (left and right), followed 
by the cue at the center of the screen for 
150 ms. After cue offset, the target will 
appear and remain on the screen until a 
response is made. Subjects will be asked 
to detect the location of the target as 
quickly and accurately as possible; both 
accuracy and reaction time will be 
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recorded. We will use 4 stimulus onset asynchronies (SOAs) between the cue and the target (i.e., SOA of 150, 
250, 350, and 700 ms) to examine the time course of social orienting across SZ patients and controls as a 
function of the SOA. There will be 100 trials for each SOA per type of cue (social or nonsocial); there will also 
be 40 catch trials with a nondirectional cue to detect and exclude invalid performance. Both social and 
nonsocial cues are uninformative, meaning that the direction of the cue will be consistent with the target 
location on half of the trials (congruent condition) and inconsistent on the other half (incongruent condition). 
The two types of cues will be randomly presented throughout the task. The difference between congruent and 
incongruent conditions is the cuing effect. The dependent measure typically used is the ratio of social and 
nonsocial cuing effects: a ratio greater than 1.0 shows preferential orienting towards social cues. This task will 
take 30 minutes to complete. 
Pilot data: We adapted an existing task [46, 47] and collected pilot data with 3 controls and 3 schizophrenia 
patients who were stable on antipsychotic medication. As expected, controls showed a ratio greater than 1.0, 
indicating a preferential orienting for social cues. In contrast, patients showed a preference towards nonsocial 
stimuli (ratio <1.0) (Figure 3). 
 
One-armed bandit task: To measure reactivity to social vs. nonsocial rewards, we will employ a one-armed 
bandit task [48, 49]. This task has two blocks with identical trial structures except for the type of reward (i.e., 
social or nonsocial). The order of the blocks will be counterbalanced across subjects. For the social reward 
block, we will use color photographs of unfamiliar faces from the NimStim collection [50], showing happy 
(positive outcome), angry (negative outcome) or neutral (neutral outcome) emotional expressions. For 
nonsocial reward, we will use: an image of a dollar bill (positive outcome), an image of a dollar bill crossed out 
(negative outcome), or an image of an empty rectangle (neutral outcome). 
For each trial, after a fixation point (500 ms), two slot machines will appear: a “neutral” machine paired either 
with a “good” slot machine or a “bad” slot machine. A good slot machine has an 80% probability of a positive 
outcome and a 20% probability of neutral outcome; a bad slot machine has an 80% probability of negative 
outcome and a 20% probability of neutral outcome; and a neutral machine is always associated with neutral 
outcome. Subjects will have up to 2.5 seconds to choose the slot machine that will give them the optimal 
outcome. Then, the reward outcome will be presented for 
1.5 s. The main dependent measure will be the total number 
of trials the subject chooses the machine with the optimal 
outcome (i.e., a good over a neutral machine; a neutral over 
a bad machine). Subjects will not be told the reward 
probabilities of each slot machine and need to learn them 
over the course of the task. All subjects will receive the 
same compensation regardless of their performance. This 
task takes 30 minutes to complete. 
Pilot Data: We adapted an existing one-armed bandit task 
[48, 51] and piloted it with 4 controls and 7 stable 
schizophrenia patients on antipsychotic medication (Figure 
4). For the social reward condition, the patients chose the 
optimal outcome much less frequently than the controls did; 
but the two groups did not differ on the nonsocial reward 
condition. 
Risks and Safety: 
Oxytocin is a hormone that is secreted by the pituitary gland. The safety of raising OT by a nasal spray has 
been supported by numerous trials. The doses of OT that will be used in the R21 phase do not exceed the 
doses that have been used in a number of trials. This study will use a maximum dose of 84 IU administered 
once whereas studies have administered as much as 320 IU in a single day [1]. David Feifel (personal 
communication) has administered 84 IU twice daily and did not find adverse effects. We do not anticipate side 
effects at this dose although nasal irritation and headache are possible. 

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Since hyponatremia is a possible effect of OT we will exclude subjects with hyponatremia. Trials of chronic OT 
in schizophrenia indicate that it may improve symptoms of psychosis. The most serious side effects would 
occur in pregnant women since OT can increase tone in the pregnant uterus. It can also promote lactation. We 
will avoid these effects by screening women with pregnancy tests and excluding those who are pregnant. 
 
Other Possible Oxytocin (intranasal) Risks: Stinging in the nose, runny nose, or tearing of the eyes. There is 
also a very small chance (1 report in the scientific literature each) of the development of psychotic thinking. 
Other possible risks may include: increased heart rate, increased or decreased blood pressure, abnormal heart 
rate, flushing, headache, allergic reaction that can be severe, and seizure for patients with a history of 
epilepsy. One of the study psychiatrists will briefly assess each subject before they leave after a study visit to 
make certain they are not experiencing any ongoing side effects that might require treatment. 
 
Psychiatric interviews: It is possible that some of the questions may lead participants to think of upsetting 
experiences. They may refuse to answer any question they wish, and this will not affect participation. 
 
Social Cognitive Testing: These tests may be challenging for participants and may lead to feelings of 
frustration at times. If a participant tires, they can receive additional rest periods or testing can be continued on 
another day. 
 
EEG tasks: Preparation for application of EEG electrodes involves cleansing the skin with a mild abrasive for 
the purpose of obtaining a clean, low impedance signal. Participants are informed during preparation that if 
they feel any discomfort to let the tester know and they will reduce or cease cleansing. Slight flushing where 
the electrodes were applied to the skin may occur in a very few cases which disappears after a couple of days 
(similar to receiving a professional facial cleansing). 
 
Blood draws: As with any blood draw, there are limited risks of infection, excessive bleeding, nerve injury, 
blood clots, allergic reaction, nausea, vomiting, dizziness, fainting, or need for blood transfusion. 
 
Urine Tox Screens: If a participant tests positive for any illegal drugs, there is a remote possibility that 
someone outside this research lab may learn of this result, however, the researcher staff will not release this 
information to anyone and the researchers will obtain a Certificate of Confidentiality, which protects subjects' 
privacy. Both the urine sample and the results will be identified only by a code number, and the urine sample 
will be destroyed immediately after the results are obtained. 
 
Although this protocol does not contain procedures that would be expected to increase suicidal ideation or 
suicide risk, it is not uncommon for patients with schizophrenia to have periods of suicidal ideation. Some of 
the measurement procedures may identify such suicidal ideation. If suicidal ideation or other evidence of 
suicide risk is identified during the course of this protocol, one of the clinically trained staff members of this 
study (i.e., Stephen Marder, M.D., Walter Dunn, M.D., Ph.D., Yvonne Yang, M.D., Ph.D., Amy Jimenez, Ph.D., 
or Lena Reddy, Ph.D.) will gather additional information to evaluate lethality and any imminent danger to self 
and to guide appropriate intervention. Information such as the specific thoughts regarding suicide, any plans to 
harm oneself, accessibility of means, relevant psychiatric history, use of medications and illicit substances, and 
availability of support systems will be considered. For lower levels of suicidal ideation, interventions will include 
notification of the participant’s key support persons, such as their treating psychiatrist, psychotherapist, and/or 

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family members. For imminent suicide risk, hospitalization will be arranged. The limitations on confidentiality 
regarding disclosures that a participant is having suicidal thoughts are also described in the relevant consent 
forms. 
 
Potential Benefits: 
The R21 may result in a better understanding of the relationship between OT dose and the response of a brain 
network associated with social information processing. This could result in a more scientific approach to 
making decisions about the dose of intranasal OT. 
 
Risk / Benefit Ratio: 
As discussed previously, there is a great need to develop treatments for social cognitive deficits in patients with 
psychosis, given their important role in functional recovery. Due to the nature of the study, patients who agree 
to participate will not derive a lasting benefit from the experimental treatment after the study is complete. 
However, the knowledge gained from the study will contribute to research which may lead to future improved 
treatments. Due to the minimal safety risks of the study treatment and procedures, the risks are deemed small 
and justifiable in relation to the benefits. 
 
Informed Consent Process and Comprehension: 
The consent process will take place one-on-one in a private room at the research project offices at the VA. 
The study coordinator will explain the purpose of the study and all interviewing and testing procedures in detail 
and then one of the study psychiatrists (Drs. Marder, Yang or Dunn) will meet with the subject to review the 
procedures, risks, and benefits more thoroughly, answer questions, and sign the consent form. We have 
several procedures in place to ensure that prospective participants fully understand the procedures, risks, and 
protections of the study. First, the consent form is written in easy to understand language. Second, the 
researcher reads the form to and with the potential subject, and invites questions after each section of the 
form. Third, the researcher asks the subject a series of questions about the study, such as what they are to do 
if they no longer want to participate, or what they would do if they experience any stress during the protocol. 
All subjects in this study will have the capacity to give informed consent. Comprehension of information 
specific to the study (i.e. purpose, procedures, risks, protections) will be assessed by the researcher during the 
informed consent process using the form “Evaluation of Capacity to Sign Consent.” Subjects who do not have 
the capacity to give informed consent (those who cannot successfully understand the consent form and 
respond to the questions in the Evaluation of Capacity to Sign Consent will not be included. We may include 
subjects who are under conservatorship who can demonstrate clear understanding of the consent form and 
research procedures as evidenced by their response to the Evaluation of Capacity to Sign Consent. Subjects 
will be informed that participation in research is voluntary and refusal to participate will not jeopardize their care 
at their institution. There are no waivers or modifications of treatment for research purposes. 
 
C.1.h. Data Analysis: The primary goal of the R21 phase is to determine the dose response curve to RT for 
mu suppression and pupillary response. Prior to modeling the form of the curves we will obtain descriptive 
statistics and graphical summaries for the measures of target engagement on placebo, at each of the active 
doses. We will also plot the within subject change scores and the overall dose-response curve. To formally 
determine whether there is target engagement we will fit a logistic dose response curve to the data for each of 
the outcome measures. We assume that the OT dose response curve can be adequately modeled using a 4- 
parameter model with a lower asymptote, slope, E50 (point of half of maximum response), and upper 
asymptote as the parameters. However, we will also fit a 5 parameter model that allows for an asymmetry in 
the acceleration and deceleration of the change slope to determine whether the additional parameter is 
necessary to represent the empirical dose response curve. Independent of which of the models for the dose 

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response curve we finally choose we will determine whether there is target engagement by testing whether the 
upper asymptote is significantly different from zero using a z-test based on the parameter estimate and its 
standard error. Specifically this test allows us to determine whether there is a measurable change in the 
outcome variable of interest at the optimum dose of OT (where the upper asymptote is reached) while 
borrowing strength across all the measurement points. For the secondary aim, examining the relationship 
between target engagement and social salience we will use multiple linear regression models with the social 
salience measures as the outcomes and change in pupillary response and mu suppression in response (OT vs 
placebo) as the predictors, adjusted for OT dose. 
Power: Calculations for the R21 Phase are based on the primary goal of detecting target engagement based 
on the OT dose response curves for mu suppression and pupillary response using a sample of size n=48. To 
estimate power we simulated 10000 replicate data sets following our study design (8 different doses of OT, 
with 6 observations at each dose) using the effect sizes from our pilot data on pupillary dilation and mu 
suppression, as well as the results reported in Prehn [31] for 47 normal participants on pupillary dilation, and 
the results reported in Perry [35] for mu suppression in 24 normal participants.. Specifically, the simulations 
conservatively assumed that the observed effect sizes represented the upper asymptote (i.e., that the optimal 
dose had been reached and observations at higher dosage levels than those employed in the respective 
studies would not show a stronger response). In addition, we assumed that the variances observed at 24, 36, 
48, and 60 IU (the middle of the dose range where maximum change in the targets would be expected to 
occur) were as large as the variances reported in the studies, while the variances at the extreme ends of the 
range (8,12, 74 and 84 IU) were half of that. This is based on the patterns of variance heterogeneity common 
observed for dose response curves. 
Under these assumptions the power for detecting a significant upper asymptote is 84% for pupillary response 
data that show an effect size of d = .81 at the optimal dose, equivalent to the results from our pilot data, and 
92% using an effect size of d = 1.22, the average effect size reported in Prehn [31]. For mu suppression, the 
power is 89% for an effect size of d = 1.03 at the optimal dose, equivalent to the results in Perry (2010) and 
45% for an effect of d = .24, the average effect seen across task conditions in our pilot data. These are 
extremely conservative estimates as we expect that these studies were not conducted at the optimal dose, and 
the estimate of measurement error is most likely inflated as it is based on observations in the steepest part of 
the dose response curve, where the response is least stable. The wide range of doses that is covered by our 
design ensures that we will be able to find a stable estimate for the optimal dose of OT. 
 
C.1.i. Go/No Go decision: After all 48 subjects have completed the OT challenge, we will evaluate 
whether the dose response curves for pupillary response or EEG mu suppression show significant target 
engagement on OT relative to placebo. If there is a significant departure from placebo on either measure of 
target engagement, the R33 will be initiated. 
 
D. Milestones and Timeline:   As noted in the timeline, we anticipate that the start-up for the R21   will 
be accomplished in 3 months. We view this as feasible since all of the assessments  – including the 
target engagement measures – have already been administered in our group. The 2 month start  up of 
the R33 is also feasible since our group therapists are experienced in social cognition training. The 
rates of subject recruitment required for the R21 and the R33 are similar to recent studies completed 
by our group. 
 
Table 4 
Year 
1, July 2015 
2, July 2016 
3, July 2017 
4, July 2018 
5, July 2019 
R21 start up, IRB, 
training 
R21 collection 
N = 48 
R21 lock & analysis 
Go/No Go decision 
R33 start up 

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R33 collection 
N = 120 
R33 lock & analysis 
 
 
 
E. Resource Sharing Plan The proposed study has a data sharing plan consistent with NIH policy. 
Final data that have not yet been published will be shared after acceptance of publication of the 
relevant paper. Data will be de-identified before sharing on a need to know basis, and on the 
agreement that once the data analysis is complete, the data will be returned or destroyed. 
 
As part of the conditions of the grant from NIMH which funds this study, we have been informed that 
we are required to submit de-identified subject data to the National Institute of Mental Health Data 
Archive (NDA). The types of data we will submit include the following: demographic data, data from 
diagnostic and symptom assessments, and social salience / social cognition performance data, and 
EEG task data 

 
RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Participant Name:  
Date:    
 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
INTRODUCTION 
You are being invited to take part in a research study at the VA Greater Los Angeles 
Healthcare System and UCLA under the direction of Stephen R. Marder, M.D. and his 
research team because you are 18 to 55 years of age and have no history of serious head 
injury or significant medical diseases, understand spoken English, and you are diagnosed with 
schizophrenia, schizoaffective disorder, or delusional disorder. Before you decide to take part, 
it is important for you to know why the research is being done and what it will involve. This 
includes any potential risks to you, as well as any potential benefits to you and/or to the future 
population of individuals you represent. 
 
Read the information below closely, and discuss it with family and friends if you wish. Ask one 
of the study staff if there is anything that is not clear or if you would like more details. Take 
your time to decide. If you do decide to take part, your signature on this consent form will 
show that you received all of the information below, and that you were able to discuss any 
questions and concerns you had with a member of the study team. 
 
Your participation in this study is voluntary. If you don’t take part, you can still receive all usual 
care that is available to you. Your decision not to take part will not affect the relationship you 
have with your doctor or other staff, and it will not affect the usual care that you receive as a 
patient. If you decide to take part, you may still withdraw at any time. If you do not wish to be 
in this study or leave the study early, you will not lose any benefits to which you are entitled. 
 
BACKGROUND AND PURPOSE 
People with psychosis often experience difficulties in the areas of living independently, 
working, and social relationships. These difficulties seem to be associated with problems in 
thinking (referred to as cognition) such as difficulties in memory or attention. They also include 
problems in perceiving how others are feeling. There are no approved medication treatments 
available for these problems and other types of treatments are very limited in their availability. 
With this research, we hope to learn whether administration of a medication, oxytocin, which is 
also a hormone and neurotransmitter in your body, will improve different aspects of your ability 
to perceive and respond to people. 
 
 
 
 
 
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Version Date: 6/9/2016 
Page 2 of 13 
 
 
 
RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
This experimental medication (oxytocin) is being tested while you are taking your usual 
psychiatric medication. Thus, this study is researching a treatment that is different from your 
usual standard of care. 
 
Because this is a research study, the study drug will only be given to you during this study and 
not after the study is over. 
 
INVESTIGATOR DISCLOSURE 
This study is being funded by the National Institute of Mental Health (NIMH). NIMH is 
providing financial support for this study. 
 
DURATION OF THE RESEARCH: 
This is a two year study that could be extended for three more years based on the results of 
the first two years of the study. This study will involve three visits.  The first visit will include 
the screening and interview procedures and will last about 2 hours. If, based on the results of 
that visit, you are eligible to participate in the study, then there will be two more visits spaced 
one week apart. Both of these visits will last about 3 hours and include receiving the study 
medication, or placebo, before assessments (on one week you will receive either oxytocin or 
placebo, and for the following week, you will receive the one you did not receive the first time). 
 
This study is designed to enroll 48 participants. In order to allow for people who drop out of 
the study or are determined to be ineligible after the screening visit, we plan on enrolling up to 
100 subjects. 
 
STUDY PROCEDURES 
We have lab space in two places that we will use for this study: offices at the VA Greater Los 
Angeles Healthcare System MIRECC in Building 210 and the Translational Research Center 
for Neuropsychiatry (TRCN), which is located at the UCLA Semel Institute. Your participation 
in this study may occur in one or both locations. All participants will be asked to sign the VA 
consent form and HIPAA authorization since all study data will be stored in our lab space at 
the VA, and if you are a UCLA patient, then you will also be asked to sign the UCLA HIPAA 
authorization. As part of this HIPAA authorization, you will be asked to provide your 
permission to allow our research staff to review your medical records and contact your primary 
mental health care provider as part of this study. We sometimes need to review your medical 
records and contact your provider to help determine your eligibility and suitability for 
participating in the study. 
 
If you decide to take part in this study, this is what will happen: 

Version Date: 6/9/2016 
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RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
Screening Visit: 
As part of this study, you will be interviewed about your personal life experiences and 
emotional well-being by a specially-trained interviewer. The interview will include a Psychiatric 
and Social History Schedule, which is a brief interview that includes questions about your 
occupational and educational history, your residence, past hospitalizations (if any), and current 
medications (if any). It will also include a verification of psychiatric diagnoses with the 
Structured Clinical Interview for DSM-V (SCID I). You may at any time refuse to answer any 
questions. The psychiatric interview you will receive is not, and does not take the place of, a 
full psychiatric evaluation. 
 
You will also receive a brief medical exam, and have blood drawn for basic lab assessments 
(CBC and metabolic panel) and a urine samples for urinalysis. If you are female, you will be 
asked to provide a urine sample for a pregnancy test to ensure that you are not pregnant. 
These samples will all be coded and destroyed after analysis. 
 
If you are already a participant in the MIRECC Treatment and Clinical Neuroscience 
Repository (Marder, 0042), we will be using some of the information about you stored in this 
repository in addition to these interviews to determine if you are eligible for this study. 
 
If you are not eligible for this study based on the information provided in your clinical 
interviews, medical records (if applicable), and primary care provider (if applicable), your 
participation will end at this time. 
 
Oxytocin or Placebo (Visit 1 and Visit 2): 
You will be assigned by chance (like flipping a coin) to receive either nasal spray containing 
oxytocin or nasal spray without oxytocin for your first visit. You will be randomly assigned to 
one of 8 dosing groups: 8, 12, 24, 36, 48, 60, 72, and 84 IU of oxytocin. One half of 
participants will receive oxytocin nasal spray for the first visit and one half will receive nasal 
spray without oxytocin. For your second visit, you will receive the spray that you did not receive 
the first time (either oxytocin or placebo). So, for one visit you will receive the oxytocin nasal 
spray and the other you will receive the placebo spray.  The clinical interviewers and testers 
will not know whether you are receiving oxytocin or the placebo but the primary investigator, 
Dr. Marder, will know. 
 
Thirty minutes before each of the two assessment visits, you will be given a nasal spray 
containing either oxytocin or placebo. 

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RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
Assessments (Visit 1 and Visit 2): 
a) Prior to participating in study assessments, you will be asked to provide a specimen of urine 
to test for the presence of drugs (legal and illegal), which may affect the results of this study. 
The drugs classes that will be screened for include: benzodiazepines (drugs typically given as 
a sedative or to reduce anxiety), barbiturates (drugs which cause reduced activity in the brain, 
ranging from mild to heavy sedation), amphetamines (drugs which act as stimulants), opiates 
(drugs which are used to treat pain), PCP (phencyclidine, a drug which induces hallucinatory 
effects), cocaine, and THC (tetrahydrocannabinol, the psychoactive chemical in marijuana). If 
the urine screen is positive for substance use, you will not be able to participate in the study 
that day. You will not be disqualified from the study, but instead you will be asked to come 
back on a different day. However, if you test positive for drugs on multiple occasions (i.e., more 
than 4 times), you may be disqualified from the study. If you test positive for intoxicants, you 
will be offered referrals to treatment facilities (community or VA-based as appropriate). If you 
are noticeably intoxicated during assessment, you will be offered transportation back to your 
residence for your safety and that of others. 
 
b) After receiving the nasal spray containing either oxytocin or placebo, you will be asked to 
receive standard measures of brain activity (EEG) while looking at briefly presented people 
and objects as well as a series of moving dots resembling human movements on a computer 
screen. EEG is a technique that detects and records electrical activity generated by the brain. 
Electrical activity is measured by placing small recording electrodes on the surface or your 
scalp, forehead, and ear lobes. Electrodes are small silver discs (about the size of an eraser 
on a pencil) that detect very low levels of electrical activity. Small recording electrodes will 
also be placed near your eyelids to record eye movement. The electrodes will be filled with a 
gel containing salt. The EEG recording will take approximately 1 hour. 
 
c) You will also be asked to have measurements of your pupil and eye movements recorded 
while looking at pictures of faces and a series of moving dots resembling human movements 
on a computer screen. The method of recording your pupil and eye movements is called 
pupillography and is a safe, non-invasive measure. You will rest your chin and forehead in a 
chin rest device so as to limit your head movements. A small camera is placed about 12 inches 
away from your eye to record only your pupil and eye movements; your face will not be 
recorded at any time. A small infrared light, that is harmless and invisible to the human eye, 
will be directed at your eye in order for the camera to detect your pupil. This task will take 
approximately 45 minutes to complete. 
 
d) You will be asked to take two tests that measure your interest in social versus non-social 
cues and rewards. For the first task, you will be asked to indicate the location of a target (the 

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RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
letter X in one of two peripheral boxes) following a central cue that contains either social 
information (such as a pair of eyes gazing left or right), or nonsocial information (an arrow 
pointing left or right). After cue offset, the target will appear and remain on the screen until a 
response is made. You will be asked to detect the location of the target as quickly and 
accurately as possible. The second task, a motivation task, involves several scenarios in 
which two slot machines will appear: a “neutral” machine paired either with a “good” slot 
machine or a “bad” slot machine. You will have a few seconds to choose the slot machine that 
will give the optimal outcome. Then, the reward outcome will be presented for a few seconds. 
The type of reward presented will be social or nonsocial. Examples of social rewards include 
color photographs of faces showing happy (positive outcome), angry (negative outcome) or 
neutral (neutral outcome) emotional expressions. Examples of nonsocial rewards include an 
image of a dollar bill (positive outcome), an image of a dollar bill crossed out (negative 
outcome), or an image of an empty rectangle (neutral outcome). Together, these tasks will 
take about 1 hour to complete. 
 
e) You will be examined briefly by a study doctor before you leave after each of these two 
visits to make sure that you are not experiencing any side effects from the oxytocin or placebo 
that might require treatment. 
 
Your involvement in this research project will in no way affect any other treatment you are 
currently receiving. 
 
Responsibilities and expectations of you as a participant in the study include: 
 
o Take the study medication as instructed at study visits. 
o Keep your study appointments. If it is necessary to miss an appointment, please 
contact the investigator or research study staff to reschedule as soon as you 
know you will miss the appointment. 
o Complete the testing to the best of your ability. 
o Ask questions as you think of them. 
o Tell the investigator or research staff if you change your mind about staying in 
the study. 
 
POSSIBLE RISKS OR DISCOMFORTS 
Any procedure has possible risks and discomforts. The procedures in this study may cause 
all, some or none of the risks or side effects listed. Rare, unknown, or unforeseeable 
(unexpected) risks also may occur. 

Version Date: 6/9/2016 
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RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
Risks of study drug 
 
Oxytocin is  a  hormone  which  has  effects  on  reproductive  and  social  behavior.  In 
women, naturally secreted oxytocin leads to contraction of the womb (uterus) during childbirth 
and the production of milk for breastfeeding. Manufactured oxytocin is sometimes given to 
induce labor if it has not started naturally or it can be used to strengthen contractions to aid 
childbirth. In addition, manufactured oxytocin is often given to speed up delivery of the 
placenta and reduce the risk of heavy bleeding by contracting the uterus. Therefore, female 
participants who are pregnant, planning to become pregnant or are breastfeeding cannot 
participate in this study. 
 
Possible Oxytocin (intranasal) Risks: Stinging in your nose, runny nose, or tearing of your 
eyes. There is also a very small chance (1 report in the scientific literature each) of the 
development of psychotic thinking. Other possible risks may include: increased heart rate, 
increased or decreased blood pressure, abnormal heart rate, flushing, headache, allergic 
reaction that can be severe, and seizure for patients with a history of epilepsy. 
 
Psychiatric interviews and questionnaires: it is possible that some of the questions may lead 
you to think of upsetting experiences. You are free to not answer any question you wish, and 
this will not affect your participation. 
 
Testing for use of legal and illegal drugs: If you test positive for any illegal drugs, there is a 
remote possibility that someone outside this research lab may learn of this result, however, the 
researcher staff will not release this information to anyone and the researchers have obtained 
a Certificate of Confidentiality, which protects your privacy. Both your urine sample and the 
results will be identified only by a code number, and the urine sample will be destroyed 
immediately after the results are obtained. 
 
Measures of social cognition: These tests may be challenging for you and may make you feel 
frustrated at times. You can stop the taking the test at any time by telling the staff that you 
want to stop. It is also possible that you may find some tests boring. If you get tired taking the 
tests, you can ask for more breaks or take the tests on another day. During the measures of 
your pupil and eye movements, you might become slightly restless having to hold your head 
still. 
 
Measures of brain activity (EEG) while looking at briefly presented objects on a computer 
screen: when the recording disks are applied to your eyelids and scalp, your skin will first be 
cleaned with rubbing alcohol which might cause some slight skin irritation. 

Version Date: 6/9/2016 
Page 7 of 13 
 
 
 
RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
Blood draws: As with any blood draw, there are limited risks of infection, excessive bleeding, 
nerve injury, blood clots, allergic reaction, nausea, vomiting, dizziness, fainting, or need for 
blood transfusion. 
 
As in any research study, it is possible that personal information about you could become 
known to other people. The investigators will take precautions to prevent this from happening. 
Your name will not appear on any questionnaires or test that you complete during the study. 
Instead, all questionnaires and tests you complete will be coded with a study ID. 
 
Risks of the usual care you receive are not risks of the research. Those risks are not included 
in this consent form. You should talk with your health care providers if you have any questions 
about the risks of usual care. 
 
POTENTIAL BENEFITS 
There is no certain direct benefit to you from your participation in the study, although you may 
briefly experience an improvement in social perception and understanding after receiving the 
oxytocin nasal spray. However, the information we get from this study may help us treat 
future patients. 
 
ALTERNATIVES TO PARTICIPATING IN THIS RESEARCH 
You may choose not to participate in this study. Refusal to participate will involve no penalty or 
loss of benefits to which you are otherwise entitled. You may discuss these options with your 
doctor. 
There are no currently available FDA-approved medications for the treatment of cognitive 
problems in schizophrenia. The alternative to participation is to continue with the care you are 
already receiving. You can also ask your psychiatrist if there are any cognitive training 
programs (non medication-based treatment) available for you to participate in. 
 
CONFIDENTIALITY 
Taking part in this study will involve collecting private data about you. This data will be 
protected in the following ways: 
 
Your research data in this study will be identified only by an assigned study number. All hard 
copy data collected (interviews, assessments) will be coded where possible, and original 
documents with sensitive information will be stored separately from coded data. All hard copy 
data will be stored in locked drawers in locked offices. Electronic data with identifiers will be 
password protected, encrypted and stored on the secure VA network, and no data with 

Version Date: 6/9/2016 
Page 8 of 13 
 
 
 
RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
identifiers collected at the VA will leave the VA lab space. The blood and urine samples and 
results of the lab tests will be coded, and the samples destroyed immediately after results are 
obtained. Data collected at the UCLA TRCN, if applicable, will be securely transmitted to the 
VA, and hard copy source documents will be securely transported back to our VA lab space for 
storage. 
 
We will not share your records or identify you unless we have to. There are times when we 
may have to show your records to other people. For example, someone from State or Federal 
Regulatory Agencies, UCLA Office of the Human Research Protection Program, the Office of 
Human Research Protection (OHRP), the Government Accountability Office (GAO), the VA 
Office of Research Oversight (ORO), the Institutional Review Board – VAGLAHS and any of its 
delegated subcommittees, our local Research and Development Committee, the Research 
Compliance Officer and other study monitors may look at portions of records that identify you. 
The information collected in this study will be processed to meet the purpose of the clinical 
study. It may also be used in reports of the study, scientific presentations, and/or publications, 
but your identity will not be disclosed. 
 
This research is covered by a Certificate of Confidentiality issued by the Department of Health 
and Human Services (DHHS). This Certificate will protect the investigators from being forced 
to release any research data in which you are identified, even under a court order or 
subpoena. Disclosure will be necessary, however, upon request of DHHS for audit or program 
evaluation purposes. 
 
This protection, however, is not absolute. A Confidentiality Certificate does not prevent you or 
a member of your family from voluntarily releasing information about yourself or your 
involvement in this research. Note however, that if an insurer or employer, learns about your 
participation, and obtains your consent to receive research information, then the investigator 
may not use the Certificate of Confidentiality to withhold this information. This means that you 
and your family must also actively protect your own privacy. 
 
The Certificate of Confidentiality does not prevent the researchers from disclosing voluntarily, 
without your consent, information that would identify you as a participant in a research project 
under the following circumstances. The Certificate of Confidentiality will not be used to prevent 
disclosure to local authorities of child abuse and neglect, or harm to self or others. 
 
As just mentioned above, we may not be able to keep confidential any disclosure or 
endorsement of thoughts to harm yourself. In the event that you tell the research staff that you 
are thinking about killing yourself or you answer yes to a question about having thoughts about 

Version Date: 6/9/2016 
Page 9 of 13 
 
 
 
RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
suicide, the research staff will ask you more questions about the thoughts. Depending on how 
intense your thoughts are or how much you feel like hurting yourself, your treating psychiatrist, 
case manager, family and/or friends will be notified of your thoughts and will be asked to work 
with you on a plan to keep you safe. If your thoughts of harming yourself are very strong, the 
research staff will help get you to a hospital for safety. 
 
Data from this study may be submitted to the National Institute of Mental Health Data Archive 
(NDA). NDA is a data repository run by the National Institute of Mental Health (NIMH) that 
allows researchers studying mental illness to collect and share deidentified information with 
each other. A data repository is a large database where information from many studies is 
stored and managed. Deidentified information means that all personal information about 
research participants such as name, address, and phone number is removed and replaced 
with a code number. With an easier way to share, researchers hope to learn new and 
important things about mental illnesses more quickly than before. 
 
During and after the study, the researchers will send deidentified information about your health 
and behavior and in some cases, your genetic information, to NDA. Other researchers 
nationwide can then file an application with the NIMH to obtain access to your deidentified 
study data for research purposes. Experts at the NIMH who know how to protect health and 
science information will look at every request carefully to minimize risks to your privacy. 
 
You may not benefit directly from allowing your information to be shared with NDA. The 
information provided to NDA may help researchers around the world treat future children and 
adults with mental illnesses so that they have better outcomes. NIMH will also report to 
Congress and on its web site about the different studies that researchers are conducting using 
NDA data. However, you will not be contacted directly about the data you contributed to NDA. 
 
You may decide now or later that you do not want to share your information using NDA. If so, 
contact the researchers who conducted this study, and they will tell NDA, which can stop 
sharing the research information. However, NDA cannot take back information that was 
shared before you changed your mind. If you would like more information about NDA, this is 
available on-line at http://data-archive.nimh.gov. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by 
U.S. Law. This website will not include information that can identify you. At most, the website 
will include a summary of the results. You can search this website at any time. 

Version Date: 6/9/2016 
Page 10 of 13 
 
 
 
RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
COSTS TO PARTICIPANTS AND PAYMENT 
 
Costs to Participants: 
You will not be charged for any treatments or procedures that are part of this research study. 
If you usually pay co-payments for VA care and medications, you will still pay these co- 
payments for VA care and medications that are not part of this study. 
 
PAYMENT OFFERED FOR PARTICIPATION 
You will be paid $50 for each of the study visits. You will also be reimbursed for any study 
related travel expenses. You will receive payment in cash at the end of each day of 
participation. 
 
MEDICAL TREATMENT AND COMPENSATION FOR INJURY 
Every reasonable safety measure will be used to protect your well-being. Since you may 
participate in more than one location for this study, if you are injured as a result of taking part 
in this study, the institution where you are injured, UCLA or the VA, will provide necessary 
medical treatment at no cost to you. 
 
If you should have a medical concern or get hurt or sick as a result of taking part in this study, 
call: 
 
DURING THE DAY: 
 
Dr. Marder at 310-268-3647 or Dr. Yvonne Yang at 203-887-7674 or Dr. Walter Dunn at 310- 
478-3711 49234. 
AFTER HOURS: 
 
You can also call the UCLA Page Operator at (310) 825-6301 to reach Dr. Marder, or one of 
the study psychiatrists Dr. Yvonne Yang, or Dr. Walter Dunn 24 hours a day, 7 days week. 
 
Emergency and ongoing medical treatment will be provided as needed at the VA for a study- 
related injury. If you are injured as a result of being in this study at UCLA, the University will 
provide all necessary emergency medical treatment and any additional necessary care to the 
extent of your insurance coverage. UCLA and the VA do not normally provide any other form 
of compensation for injury. 
 
You do not give up any of your legal rights and you do not release the VA from any liability by 
signing this form. 

Version Date: 6/9/2016 
Page 11 of 13 
 
 
 
RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
YOUR RIGHT TO TERMINATE PARTICIPATION 
It is up to you to decide whether or not to take part in this study. If you decide to take part you 
may still withdraw at any time. If you do not wish to be in this study or leave the study early, 
you will not lose any benefits to which you are otherwise entitled. If you don’t take part, you 
can still receive all usual care that is available to you. Your decision not to take part will not 
affect the relationship you have with your doctor or other staff and it will not affect the usual 
care that you receive as a patient. 
 
RIGHT OF INVESTIGATOR TO TERMINATE YOUR PARTICIPATION 
The study doctor has the right to end your participation in this study for any of the following 
reasons: if it would be dangerous for you to continue; you do not follow study procedures as 
directed by the study doctors; or if you become ill during the research. The investigator, Dr. 
Marder, will make this decision. If your participation is discontinued, it will not affect your 
relationship with the VA or the care you may receive here. In addition, your study doctor may 
end your participation without regard to your consent. 
 
PERSONS TO CONTACT ABOUT THIS STUDY 
If you have questions about your rights as a study participant, or you want to make sure this is 
a valid VA study, you may contact the VA Greater Los Angeles Institutional Review Board 
(IRB). This is the Board that is responsible for overseeing the safety of human participants in 
this study. You may call the VA Greater Los Angeles IRB at 1-310-268-4437 if you have 
questions, complaints or concerns about the study, or if you would like to obtain information or 
offer input. 
 
SIGNIFICANT NEW FINDINGS 
Sometimes during the course of a research study, new information becomes available about 
the study drug that is being studied that might change a person’s decision to stay in the study. 
If this happens, your research doctor will tell you about it and discuss with you whether you 
want to continue in the study. If you decide to withdraw from the study, your research doctor 
will arranges for your medical care to continue. If you decide to continue in the study, you 
might be asked to sign an updated informed consent form. Your research doctor could also 
decide it to be in your best interests to withdraw you from the study. If so, he or she will 
explain the reasons and arrange for your usual medical care to continue. 
 
AGREEMENT TO PARTICIPATE IN THE RESEARCH STUDY 
Dr. Marder or an approved member of his research team has explained the research study to 
you. You have been told of the risks or discomforts and possible benefits of the study. You 

Version Date: 6/9/2016 
Page 12 of 13 
 
 
 
RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
have been told of other choices of treatment available to you. You have been given the 
chance to ask questions and obtain answers. 
 
You voluntarily consent to participate in this study. You also confirm that you have read this 
consent, or it has been read to you. You will receive a copy of this consent after you sign it. A 
copy of this signed consent will also be put in your medical record if applicable. 
 
I agree to participate in this research study as has been explained in this document. 
 
Participant’s Name 
 
Participant’s Signature 
 
Date 
 
 
Name of person obtaining 
consent 
 
Signature of person obtaining 
consent 
 
Date 
 
It is likely that there will be related studies in the future that may interest you. Please initial the 
section below indicating whether you agree to allow us to contact you with information about 
future related studies. Your decision will not affect your medical care or your participation in 
the current study. 
 
  
 I agree to allow the investigators to contact me about future studies. 
 
  
 I DO NOT agree to allow the investigators to contact me about future studies. 

Version Date: 6/9/2016 
Page 13 of 13 
 
 
 
RESEARCH CONSENT FORM 
VA Greater Los Angeles 
Study Title: Enhancing Social Cognitive Training with Oxytocin: Linking Target Engagement to 
Clinical Effects 
Principal Investigator:  Stephen R. Marder, M.D. 
Phone: 310-268-3647 
 
RIGHTS OF HUMAN SUBJECTS IN MEDICAL EXPERIMENTS 
 
Any person who is requested to consent to participate as a subject in a research study 
involving a medical experiment or who is requested to consent on behalf of another has the 
right to: 
 
1. Be informed of the nature and purpose of the experiment. 
 
2. Be given an explanation of the procedures to be followed in the medical experiment, and 
any drug or device to be utilized. 
 
3. Be given a description of any attendant discomforts and risks reasonably to be expected 
from the experiment. 
 
4. Be given an explanation of any benefits to the subject reasonably to be expected from the 
experiment, if applicable. 
 
5. Be given a disclosure of any appropriate alternative procedures, drugs or devices that might 
be advantageous to the subject, and their relative risks and benefits. 
 
6. Be informed of the avenues of medical treatment, if any, available to the subject after the 
experiment if complications should arise. 
 
7. Be given an opportunity to ask any questions concerning the experiment or the procedure 
involved. 
 
8. Be instructed that consent to participate in the medical experiment may be withdrawn at any 
time and the subject may discontinue participation in the medical experiment without prejudice. 
 
9. Be given a copy of any signed and dated written consent form used in relation to the 
experiment. 
 
10. Be given an opportunity to decide to consent or not to consent to a medical experiment 
without the intervention of any element of force, fraud, deceit, duress, coercion, or undue 
influence on the subject's decision.