Identifying Decision Making Parameters in Healthy Volunteers (HV) and Anxiety Patients (AD)
Phase: NA
Conditions: Anxiety, Healthy Volunteers
Sponsor: National Institute of Mental Health (NIMH)

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Abbreviated Title: Decision making in anxiety  
NIH IRB #: 000378 
Version Date: 05/01/2023 
Title: Identifying decision making parameters in healthy volunteers (HV) and anxiety patients 
(AD). 
 
 
 
Maryland Pao, MD: National Institute of Mental Health/OCD 
Building 10, Rm 6-5340 
Bethesda, MD 20892 
Phone: 301-435-5770 
E-mail: paom@mail.nih.gov 
 
 
 
Investigational Agents (if applicable): 
Drug Name: 
n/a 
IND Number: 
n/a 
Sponsor: 
n/a 
Manufacturer: 
n/a 
 
 
 

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TABLE OF CONTENTS  
TABLE OF CONTENTS ................................................................................................................ 2 
STATEMENT OF COMPLIANCE ................................................................................................ 6 
1 
PROTOCOL SUMMARY ...................................................................................................... 7 
1.1 
Synopsis ........................................................................................................................... 7 
1.2 
Schema ............................................................................................................................. 9 
1.3 
Schedule of Activities (SOA) ......................................................................................... 10 
2 
INTRODUCTION ................................................................................................................ 11 
2.1 
Study Rationale .............................................................................................................. 11 
2.2 
Background .................................................................................................................... 11 
2.3 
Risk/Benefit Assessment ................................................................................................ 13 
2.3.1 
Known Potential Risks ............................................................................................ 13 
2.3.2 
Known Potential Benefits ....................................................................................... 14 
2.3.3 
Assessment of Potential Risks and Benefits ........................................................... 14 
3 
OBJECTIVES AND ENDPOINTS ...................................................................................... 14 
4 
STUDY DESIGN.................................................................................................................. 15 
4.1 
Overall Design................................................................................................................ 15 
4.2 
Scientific Rationale for Study Design ............................................................................ 17 
4.3 
Justification for Dose ..................................................................................................... 18 
5 
STUDY POPULATION ....................................................................................................... 18 
5.1 
Inclusion Criteria ............................................................................................................ 18 
5.2 
Exclusion Criteria ........................................................................................................... 18 
5.3 
Inclusion of Vulnerable Participants .............................................................................. 18 
5.3.1 
Participation of NIH Staff or family members of study team members ................. 18 
5.4 
Inclusion of Pregnant Women, fetuses or neonates ....................................................... 19 
5.5 
Lifestyle Considerations ................................................................................................. 19 
5.6 
Screen Failures ............................................................................................................... 19 
5.7 
Strategies for Recruitment and Retention ...................................................................... 19 
5.7.1 
Costs ........................................................................................................................ 19 
5.7.2 
Compensation ......................................................................................................... 21 
6 
STUDY INTERVENTION ................................................................................................... 22 
6.1 
Study Interventions(s) Administration ........................................................................... 22 

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6.1.1 
Study Intervention Description ............................................................................... 22 
6.1.2 
Dosing and Administration ..................................................................................... 23 
6.2 
Preparation/Handling/Storage/Accountability ............................................................... 23 
6.2.1 
Acquisition and Accountability .............................................................................. 23 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .............................................. 23 
6.2.3 
Product Storage and Stability.................................................................................. 23 
6.2.4 
Preparation .............................................................................................................. 24 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................... 24 
6.4 
Study Intervention Compliance ...................................................................................... 24 
6.5 
Concomitant Therapy ..................................................................................................... 24 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..................................................................................... 24 
7.1 
Discontinuation of Study Intervention ........................................................................... 24 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................... 25 
7.3 
Lost to Follow-up ........................................................................................................... 25 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 25 
8.1 
Screening Procedures ..................................................................................................... 25 
8.1.1 
Screening activities performed prior to obtaining informed consent ...................... 25 
8.1.2 
Screening activities performed after a consent for screening has been signed ....... 25 
8.2 
Efficacy Assessments ..................................................................................................... 26 
8.2.1 
Clinical Evaluations ................................................................................................ 27 
8.2.2 
Biospecimen Evaluations ........................................................................................ 27 
8.2.3 
Correlative Studies for Research/Pharmacokinetic Studies .................................... 27 
8.2.4 
Samples for Genetic/Genomic Analysis ................................................................. 27 
8.3 
Safety and Other Assessments ....................................................................................... 27 
8.4 
Adverse Events and Serious Adverse Events ................................................................. 27 
8.4.1 
Definition of Adverse Event ................................................................................... 27 
8.4.2 
Definition of Serious Adverse Events (SAE) ......................................................... 27 
8.4.3 
Classification of an Adverse Event ......................................................................... 27 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 29 
8.4.5 
Adverse Event Reporting ........................................................................................ 29 
8.4.6 
Serious Adverse Event Reporting ........................................................................... 29 

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8.4.7 
Events of Special Interest........................................................................................ 29 
8.4.8 
Reporting of Pregnancy .......................................................................................... 29 
8.5 
Unanticipated Problems ................................................................................................. 29 
8.5.1 
Definition of Unanticipated Problems (UP) ........................................................... 29 
8.5.2 
Unanticipated Problem Reporting........................................................................... 30 
8.5.3 
NIH Intramural IRB Reporting of IND Safety Reports .......................................... 30 
9 
STATISTICAL CONSIDERATIONS.................................................................................. 30 
9.1 
Statistical Hypothesis ..................................................................................................... 30 
9.2 
Sample Size Determination ............................................................................................ 30 
9.3 
Populations for Analyses ................................................................................................ 31 
9.3.1 
Evaluable for toxicity .............................................................................................. 31 
9.3.2 
Evaluable for objective response ............................................................................ 31 
9.3.3 
Evaluable Non-Target Disease Response ............................................................... 31 
9.4 
Statistical Analyses ........................................................................................................ 31 
9.4.1 
General Approach ................................................................................................... 31 
9.4.2 
Analysis of the Primary Endpoints ......................................................................... 32 
9.4.3 
Analysis of the Secondary Endpoint(s)................................................................... 32 
9.4.4 
Safety Analyses ....................................................................................................... 32 
9.4.5 
Baseline Descriptive Statistics ................................................................................ 32 
9.4.6 
Planned Interim Analyses ....................................................................................... 32 
9.4.7 
Sub-Group Analyses ............................................................................................... 33 
9.4.8 
Tabulation of individual Participant Data ............................................................... 33 
9.4.9 
Exploratory Analyses .............................................................................................. 33 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................... 33 
10.1 
Informed Consent Process .......................................................................................... 33 
10.1.1 Consent/Assent Procedures and Documentation .................................................... 33 
10.1.2 Consent for minors when they reach the age of majority ....................................... 34 
10.1.3 Considerations for Consent of NIH staff, or family members of study team 
members ................................................................................................................................ 34 
10.1.4 Consent of Subjects who are, or become, decisionally impaired ........................... 34 
10.2 
Study Discontinuation and Closure ............................................................................ 34 
10.3 
Confidentiality and Privacy ........................................................................................ 35 

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10.4 
Future use of Stored Specimens and Data .................................................................. 35 
10.5 
Safety Oversight ......................................................................................................... 35 
10.6 
Clinical Monitoring .................................................................................................... 36 
10.7 
Quality Assurance and Quality Control ...................................................................... 36 
10.8 
Data Handling and Record Keeping ........................................................................... 37 
10.8.1 Data Collection and Management Responsibilities ................................................ 37 
10.8.2 Study Records Retention......................................................................................... 37 
10.9 
Protocol Deviations and Non-Compliance ................................................................. 37 
10.9.1 NIH Definition of Protocol Deviation .................................................................... 37 
10.10 
Publication and Data Sharing Policy .......................................................................... 38 
10.10.1 Human Data Sharing Plan ....................................................................................... 38 
10.10.2 Genomic Data Sharing Plan .................................................................................... 38 
10.11 
Collaborative Agreements .......................................................................................... 38 
10.11.1 Agreement Type...................................................................................................... 38 
10.12 
Conflict of Interest Policy........................................................................................... 38 
11 ABBREVIATIONS .............................................................................................................. 39 
12 REFERENCES ..................................................................................................................... 40 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
Identifying decision making parameters in healthy volunteers (HV) 
and anxiety patients (AD). 
Study Description: 
This study’s goal is to identify parameters of interest in decision making in 
the context of anxiety disorders, using theoretical models in healthy 
volunteers (HV) and anxiety patients (AD). Participants are asked to 
complete a decision-making task, namely the Multi-armed Bandit Task. 
The study will be conducted in the clinic. 
  
Participants (HV and AD) are asked to fill out questionnaires and complete 
the Multi-armed Bandit Task. An electric shock is used as the aversive 
stimulus. Monetary reward is used as the reward stimulus. Additionally, 
physiological signals (Heart rate, skin conductance activity, startle) are 
collected during the course of the task.  
 
In addition, in a pilot study, participants startle responses for varying shock 
parameters are recorded and analyzed.  
 
Objectives: 
 
The primary objective of this study is to use theoretical models in healthy 
volunteers (HV) and patients with an anxiety disorder (AD) to better 
understand how changes in anxiety are associated with changes in decision 
making.  In addition, this study will ascertain whether decision making 
parameters correlate with certain behavioral measures such as trait and state 
anxiety using (i) questionnaires, (ii) physiological measures. 
 
 
 
Endpoints: 
The primary endpoint of this study is a significant difference in model 
derived parameters between experimental manipulations (conditions) 
and/or population groups. The parameters of interest include: 1) Learning 
Rate, 2) Exploration parameter, 3) Discount rate, 4) Loss aversion, 5) 
Inverse Temperature. 
 
The secondary endpoints are a significant correlation between functions of 
model derived parameters and behavioral and/or physiological measures of 
anxiety including: 
1) Questionnaire scores 
2) Startle 
3) Skin conductance 
 
Study Population: 
 
 
 
 
 
Participants will be males and females, 18 years and older. They must be 
English-speaking. The study population will include patient and volunteer 
participants.  Number of participants: 
1)  
Multi-arm Bandit task: 80 (40 HV, 40 AD)  
Pilot: 20 HV 

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TOTAL ACCRUAL CEILING: 100 volunteers 
Description of 
Sites/Facilities 
Enrolling Participants: 
Single-site study at National Institutes of Health  
 
Description of Study 
Intervention: 
 
Multi-arm Bandit task. 
 
Electric shocks: Electric shocks are used as aversive stimuli. Electric 
shocks are one of the most efficient ways to induce anxiety in the 
laboratory. The shocks will be delivered through two disk electrodes 
located on the forearm or on two fingers  
 
Auditory startle: The startle reflex will be elicited with a 102 dB white 
noise (40-ms duration) delivered binaurally via headphones. 
 
 
Study Duration: 
12 months 
 
Participant Duration: 
One outpatient visit  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.2 
SCHEMA 
 
Figure 1: Schematic of Clinic Study Visit  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Recruitment 
Assessment 
Intervention 
Subjects will be screened under 01-M-
0254 and if eligible may be invited to 
participate in this study 
Study Visit: 
Sign consent form 
Fill out questionnaires 
Clinic: 
Task 
End of Study 

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1.3 
 SCHEDULE OF ACTIVITIES (SOA) 
  
Procedures 
Study Visit  
Informed consent 
X 
Concomitant 
medication review 
X 
Vital signs 
X 
Pregnancy test**  
X 
Adverse event review 
and evaluations 
X 
Questionnaires # 
X 
Multi-arm Bandit Task 
X 
Electric shocks 
X 
Auditory startle 
X 
Complete Case Report 
Forms (CRFs) 
X 
 
 
  *Screening to be conducted under 01-M-0254 screening protocol and consent. Screening may 
also happen under 17-M-0181. 
**Pregnancy test in females only. 
***Study visits are single visit outpatient studies 
# A complete list of the questionnaires used is included in section  3.1.4

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 INTRODUCTION 
1.4 
STUDY RATIONALE 
Anxiety disorders are characterized by aberrations in the processing of and response to threat, 
such as (1) Exaggerated threat appraisal, (2) Over generalization, (3) Persistent avoidance. These 
aberrations result in impaired decision making. In the recent past, a few studies have started to 
ask questions regarding the influence of anxiety on decision making using theoretical models. 
However, there is a number of avenues that can be taken to extend these efforts. Firstly, previous 
studies do not consider specific decision-making parameters due to limitation in their task 
design.  Secondly, the validity of these parameters needs to be confirmed using different study 
designs and larger sample sizes. Finally, the links between anxiety symptoms and specific 
parameters need to be examined and established. The present study will ascertain and open new 
avenues for understanding decision-making perturbations in the anxiety and provide basis for the 
optimization and development of novel treatment strategies.  
 
1.5 
BACKGROUND  
Fear and anxiety are normal adaptive responses to threat. Anxiety is considered pathological 
when it is either excessive or inappropriate to the context. The influence of anxiety goes beyond 
the subjective feelings and autonomic reactivity. Indeed, anxiety powerfully affects motivated 
behavior.  The majority of experimental tasks, used to probe behavior in anxiogenic 
environments or in response to aversive cues, usually focus on only one aspect of behavior. For 
example, previous studies by our group have targeted cognitive constructs like working memory 
(Balderston et al., 2016; Balderston et al., 2017), response inhibition (Grillon et al., 2017), or 
attention. Each of these cognitive processes contributes to decision making, the backbone of 
motivated behavior. 
In this study, we propose a holistic approach that evaluates many decision-making facets. 
Decision theory is a framework that permits to quantitatively understand optimal (maximizes 
rewards and minimizes punishments) and sub-optimal behavior in various environments ((Dayan 
& Daw, 2008)). This framework employs ideas from reinforcement learning (Sutton & Barto, 
1998), in which agents learn to adapt their behavior in function of rewards and punishments and 
optimize goal-directed behavior. 
One aim of decision theory is to develop mathematical models that approximate human behavior. 
These models have parameters which are optimized to fit behavior. The values of the fit 
parameters could help evaluate individual and group differences in decision making strategies 
that are not tractable otherwise. Recent papers have used decision making models to extract 
parameters of interest in the context of anxiety. For example, Charpentier et al. (Charpentier, 
Aylward, Roiser, & Robinson, 2017) considered parameters that contribute to loss aversion and 
risk aversion in decision making. Browning et al. (Browning, Behrens, Jocham, O'reilly, & 
Bishop, 2015) probed the rate of learning in volatile vs. stable scenarios. A number of decision- 
making models could not study parameters separately, which prevent the possibility to isolate the 
influence of individual parameters, and thus limit their usefulness. The issue lies in the fact that 
while the parameters themselves are distinct and separable, their estimation is not (Daw, 2011). 
For example, the estimation of two such parameters ‘softmax temperature’ and ‘learning rate’ 
may be correlated since they have similar effects on the observed data. Experiments that probe 
the distinct influences of individual parameters of decision making in anxiety could be of vital 

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importance in furthering our knowledge of the etiology of anxiety and related disorders. Our 
approach is to study induced anxiety in both healthy volunteers and anxiety patients. We will 
examine an array of parameters such as learning rate, exploration vs exploitation parameter, 
inverse temperature and loss aversion/gain seeking. 
 
1.5.1 Exploration vs exploitation: Multi-arm bandit Task 
Everyday decision-making requires individuals to choose among a set of actions and decide on 
the ‘best action’. This process involves learning the consequences of a particular action (either 
rewarding or punishing) and building an internal representation (value) associated with a 
particular choice. In a reinforcement learning framework, rewards and punishments are used to 
update the value associated with an action (Dayan & Daw, 2008). The learned value is then used 
to frame a policy for future actions. The optimal policy would result in the most favorable future 
outcomes. For example, a policy can be centered on the role of exploration in making decisions. 
Depending on whether the scenario is volatile on stable, different policies would be optimal. (A 
stable scenario is one in which the action-outcome relationship has few or no changes). In a 
stable scenario, the optimal policy would be to explore among the choices only when there is a 
mismatch in the perceived outcome. Similarly, in a volatile scenario, random sampling among 
the actions would result in better outcomes in the long run.  Previous work has shown that 
anxious individual have difficulty in learning whether action-outcome associations are volatile or 
stable (Browning et al., 2015). Such similar differences could also arise in the exploration-
exploitation trade-off: Should an individual increase their exploration and get a better 
understanding of the action-outcome contingencies or should the individual minimize 
exploration in order to exploit the contingencies already learnt? The optimal policy would thus 
be elucidated by the exploration parameter.  
1.5.2 Pilot studies 
Rewards and punishments form the basis for decision making. For the purposes of this study 
money is used as the reward and electric shocks are used as the punishments.  The rewards or 
punishments received have underlying dimensions. These include the magnitude, duration, 
frequency and probability of the rewards or punishments. Startle responses, which are an 
indication of physiological fear and/or anxiety would change depending on the parameters of the 
electric shock. Previous work has assessed some of these dimensions. For example, one study 
used predictable and unpredictable timing and varied the intensity of shock (Shankman, 
Robison-Andrew, Nelson, Altman, & Campbell, 2011). Another study examined the role of cue 
and temporal unpredictability (Davies & Craske, 2015). The difference between occurrence 
uncertainty and temporal uncertainty was the focus of yet another study (Bennett, Dickmann, & 
Larson, 2018). However, a comprehensive study that examines each of these parameters in a 
single study has not been conducted. [Note: The upper and lower bounds of these parameters will 
be assessed using the procedure mentioned in Auxiliary methods 4.1.3)] 
 

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1.6 
RISK/BENEFIT ASSESSMENT 
1.6.1 Known Potential Risks 
Questionnaires: There is minimal medical risk in completing the questionnaires. Some of the 
questions may make the participants feel uncomfortable or anxious. Participants may refuse to 
answer any question or to stop a test at any time and for any reason. 
Psychophysiological recording: The psychophysiological measures that will be obtained are non-
invasive, requiring the administration of no needles, drugs, or dyes. Little discomfort is expected. 
During electrode placement, the possibility of skin irritation from contact with the saline electrode 
paste exists. However, this is unlikely as the salt concentration of the paste is similar to that of 
human sweat. The risk is equivalent to that of an EEG recording. 
Electric shock: The shocks will be delivered through two disk electrodes located on the subject’s 
left wrist. The PI has extensive experience with shocks. The shock is generally described by 
subjects as anxiogenic and uncomfortable. The mean rating of aversiveness on a scale of 1 (not 
painful at all) to 10 (extremely painful) is about 5. Over 95% of subjects who experienced the 
shock chose to participate in the experiment.  
In very rare occasions, subjects have experienced symptoms that may be related to the shock. A 
participant with a condition called “cubital tunnel syndrome,” a repetitive motion injury similar to 
carpal tunnel syndrome, indicated worsening of his syndrome over the months subsequent to his 
participation. Another participant reported pain in her arms for several hours after testing. The pain 
was no longer present the next day. It is unclear whether these symptoms were due to the shocks. 
Nevertheless, subjects with neurological symptoms of the wrist and arms will be excluded from 
the study.  
Auditory startle stimulus: The auditory stimuli that will be used in the startle studies are 40-ms 
duration 102 dB white noise. Auditory startling sounds of much higher intensities are frequently 
used in startle studies. Sounds of higher intensities and longer duration are also widely used in 
aversive conditioning in human subjects, where they serve as unconditioned stimuli. The short 
duration (40 ms) of these sounds makes them safe (i.e., there is no danger of hearing impairment). 
In addition, a white noise is safer than a pure tone. The PI has been involved in similar studies and 
collaborations involving over 1000 of subjects with no adverse reactions. The auditory stimulus 
may trigger a migraine. 
 
Procedures to Minimize Risks 
 
Electric Shock: Shock will be delivered at a level that is judged by the subject as uncomfortable 
but tolerable. Study shock levels will be determined before the test begins. The subject may stop 
the experiment at any time if they find the discomfort to be too great. 
 
 
Confidentiality: We will actively protect confidentiality of the subjects and the data in each step. 
Information will be stored using a confidential case number, and no identifiers (name, address, 
etc.) will be used that could allow direct linking of database information to individual subjects. 
Data will be kept in password-protected computers. Only study investigators will have access to 
the data. 
 

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1.6.2 Known Potential Benefits 
There is no direct benefit to the participants but is likely to yield generalizable knowledge about 
the underlying brain mechanism of fear and anxiety.  
1.6.3 Assessment of Potential Risks and Benefits 
This is a minimal risk protocol enrolling adult volunteers. The risks are reasonable in relation to 
anticipated benefit.  
2 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
The primary objective of this 
study is to examine whether 
there are changes in decision 
making (such as choice learning, 
exploration) associated with 
increased or decreased anxiety, 
by employing theoretical models 
in healthy volunteers and anxiety 
patients.  
 
 
The primary endpoint of this study is 
a significant difference in model 
derived parameters between 
experimental manipulations 
(conditions) and/or population 
groups. 
The parameters of interest include: 
1) Learning Rate 
2) Exploration parameter 
3) Discount rate  
4) Loss aversion 
5) Inverse Temperature 
 
 
 
Computational models 
allow for the testing of 
different decision-
making theories in a 
quantitative fashion. 
(Daw et al. 2009) and 
allow for interpretation 
of trial by trial 
observations 
(O’Doherty et al., 2003; 
Bayer and Glimcher, 
2005). 
Secondary 
 
 
In addition, this study will 
ascertain whether decision 
making parameters correlate 
with certain behavioral measures 
such as trait and state anxiety 
using (i) questionnaires, (ii) 
physiological measures. 
 
 
 
The secondary endpoints are a 
significant correlation between 
functions of model derived 
parameters and behavioral and/or 
physiological measures of anxiety 
including: 
1) Questionnaire scores 
2) Startle 
3) Skin conductance 
Models estimate 
parameters involved in 
the decision-making 
process which are 
otherwise subjective in 
nature (Platt and 
Glimcher, 1999; Sugrue 
et al., 2004). The 
validation of these 
computational 
constructs with other 
physiological and/or 
behavioral measures 
are vital for their 
interpretation. This 
might help to uncover 
what is the implication 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
influencing specific 
parameters of decision 
making. 
Tertiary/Exploratory  
 
 
 
In addition, this protocol will 
pilot studies that measure the 
effects of changing stimulus 
parameters (such as amplitude, 
duration, frequency, probability) 
on physiological responses and 
decision making 
 
The endpoints of this this pilot study 
are changes in physiological 
responses as a function of changing 
stimulus parameters 
Understanding the 
relationship between 
stimulus parameters 
and physiological 
responses such as 
startle, will allow for 
better measures of 
anxiety 
 
3 
STUDY DESIGN 
3.1 
OVERALL DESIGN 
The purpose of the clinic experiments is to identify robust differences in model derived 
parameters.  
The study includes one visit that is expected to last 3-4 hours and is designed to have 2 
conditions/ scenarios in order to better delineate the model parameters. An additional telehealth 
consenting visit may occur prior to the study visit.  The tasks and related auxiliary procedures are 
described in the sub-sections below: 
3.1.1 Multi-arm Bandit task 
As mentioned in the objective section, the primary purpose of the study is to quantitatively assess 
decision making strategies in aversive and rewarding scenarios and probe their relevance to fear 
and anxiety. To this end, participants perform a choice making task, where they strive to 
maximize rewards (if present) and minimize punishments (if present). On each trial, participants 
are presented with a set of different choices or scenarios. The participant then takes an action OR 
a set of actions. After a variable time period the participant receives a reward/punishment 
probabilistically associated with that action. Thus, by repeated sampling among the options, the 
participant should employ a policy that maximizes reward (monetary) AND/OR minimizes 
punishment (shocks). After a set of these trials the probabilities associated with the options are 
changed, such that the participant needs to resample among the options to once again determine 
the optimal action.  
In addition to performing the optimal action, participants may be asked to indicate the 
probability of reward/ punishment they feel is associated with their action. This way, the 
participants reveal their expectation of reward AND/OR punishment for the taken action. After a 
short time interval, the actual probability of reward AND/OR punishment is revealed to the 
participant. 

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The two conditions are designed to affect the nature of the optimal strategy, such that in one 
condition, the highest cumulative outcome depends on purely value-driven exploration; whereas, 
in the other condition, the best strategy involves adequate random exploration. 
3.1.2 Pilot studies 
The pilot studies are used to vary the parameters of the shock stimulus in the clinic study, so as 
to determine the efficacy of the aversive stimuli. Startle responses (see Auxiliary study 
procedures) which are an indication of physiological fear and/or anxiety are expected to change 
depending on the parameters of the electric shock. The shock parameters of interest are the 
amplitude (3 levels), probability (4 levels), resulting in a total of 12 levels.  [Note: The upper and 
lower bounds of these parameters will be assessed using the procedure mentioned in Auxiliary 
methods 4.1.3)] 
 
3.1.3 Auxiliary study procedures 
A subset of the procedures described below will be employed to deliver aversive stimuli and 
record physiological metrics. 
Questionnaires: 
Participants will be asked to complete a subset of the following questionnaires: 
• 
State-Trait Anxiety Inventory (Spielberger, Gorsuch, Lushene, Vagg, & Jacobs, 1983): 
40-item scale assessing state anxiety (20 items) and trait anxiety (20 items). 
• 
Anxiety Sensitivity Index (ASI;Reiss et al., 1986): 16-item scale assessing anxiety 
sensitivity in terms of the dispositional tendency to fear the somatic and cognitive symptoms of 
anxiety due to a belief that these symptoms may be dangerous or harmful. 
• 
Penn State Worry Questionnaire (PSWQ; Meyer, Miller, Metzger, & Borkovec, 1990): 
16 items assessing chronic, excessive, and uncontrollable worry. 
• 
Intolerance of Uncertainty Scale short form (IUS-12; Carleton, Norton, & Asmundson, 
2007): 12-item scale assessing reactions to impending uncertainty, ambiguous situations, and the 
future. It consists of two factors: prospective anxiety (7 items) and inhibitory anxiety (5 items). 
• 
BIS/BAS scale (Carver et al., 1992):24 items assessing individual differences in the 
sensitivity of two motivational systems, the behavioral approach system (BAS) and a behavioral 
avoidance (or inhibition) system (BIS). 
• 
DOSPERT Risk-taking behaviors scale (RTBS; Weber, Blais, & Betz, 2002): 14-item 
scale assessing people’s willingness to engage in risky decision-making across different risk-
taking domains including health/safety, recreation, ethics, social interaction, gambling.  
• 
Positive Affect/Negative Affect Scale (PANAS; Watson, Clark, & Tellegen, 1988): 20-
item scale assessing positive (10 items) and negative (10 items) affects. 
• 
Barratt Impulsiveness Scale (BIS-11; Patton et al., 1995): 11-item scale assessing 
personality/behavioral construct of impulsiveness. 
• 
Sensation Seeking Scale (SSS) Form V (Zuckerman et al., 1978): 40-item scale assessing 
sensation seeking behaviors according to four dimensions associated with sensation seeking that 
are thrill and adventure seeking, experience seeking, disinhibition and boredom susceptibility. 
Curiosity and Exploration Inventory (CEI-II) (Kashdan, T.B., et al.;2009): 10-item scale 
assessing individual differences in the recognition, pursuit, and integration of novel and 
challenging experiences and information. 
 

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Startle response  
The startle reflex will be elicited with a 102 dB white noise (40-ms duration) delivered 
binaurally via headphones. The eyeblink component of the startle reflex will be recorded 
binaurally with two electrodes placed under each eye. Eyeblink responses will be scored in the 
20-100 ms window following the onset of the startle stimulus. 
 
Autonomic measures 
Heart rate, skin conductance activity (event-related responses and spontaneous fluctuations)  to 
evaluate changes in autonomic arousal. The heart rate will be monitored with two disposable 
electrodes, one on each wrist. A computer algorithm will detect the R-wave in each cardiac cycle 
and calculate the number of whole and fractional heart beats for 500 ms periods in each 
condition. The skin conductance will be measured using two Ag-AgCl electrodes filled with a 
.05M NaCl electrolyte. Electrodes will be placed on the distal phalanges of the index and second 
fingers of the left hand.   
 
Electric shock: forearm or fingers 
Electric shocks are one of the most efficient ways to induce anxiety in the laboratory. The shocks 
will be delivered through two disk electrodes located on the forearm or on two fingers.   
Test shocks 
At the beginning of the study a shock workup procedure is conducted to determine the setting for 
the overall procedure for each subject. The level of shock is initially set at 3.5 μAmp (the low 
range).  A shock is administered and the subject is asked to rate it on a scale from 1 (not at all 
unpleasant) to 10 (extremely unpleasant but not painful). We then increase the level of shock 
slightly until the subject identifies the sensation at a rating level of 10.  The level is selected 
based on the subjective ratings provided by the participant. Once the level 10 is ascertained, 
participants will receive shocks corresponding to that magnitude or lower for the remainder of 
the study visit. In addition, subjects are reminded that they have the opportunity to withdraw 
from the study at any time if they wish.  
Participant rating of the experience:  
At the end of the study subjects are asked to retrospectively rate their experience of the shock on 
a scale from 1 (not at all unpleasant) to 10 (extremely unpleasant but not painful). This provides 
us with an assessment of the overall unpleasantness of the experience during the entire shock 
experiment.  
 
3.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The rationale for the study design stems from the primary and secondary objectives, namely, to 
estimate and probe the role of various decision-making parameters in anxiety. To that end, a 
multi-arm bandit task is utilized which involves specific parameters of interest. The task is to be 
performed by healthy volunteers and anxiety patients in order to test whether these parameters 
differ across groups. The clinic study allows the use of electric shocks (which serve as an 
aversive stimulus and negative reinforcer). Additionally, startle and other physiological signals 
can be probed in the clinic version of the task.  
 

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3.3 
JUSTIFICATION FOR DOSE 
N/A 
 
4 
STUDY POPULATION 
4.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Provision of signed and dated informed consent form 
2. Male or female, aged 18-50, inclusive 
3. Patients only: Primary DSM5 diagnoses of an anxiety disorder (GAD, SAD, panic 
disorder)                
4.2 
EXCLUSION CRITERIA  
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Non-English speaking individual 
2. Pregnancy or positive pregnancy test 
3. Any significant medical or neurological problems as determined by investigators (e.g. 
cardiovascular illness, respiratory illness, neurological illness, seizure, etc.) 
4. Current or past serious mental disorders (e.g., bipolar or psychotic disorders) (except for 
anxiety and depressive disorders in patients) 
5. Current alcohol or substance use disorder 
6. History of moderate or severe alcohol or substance use disorder within one year prior to 
screening 
7. Current or past significant organic central nervous system disorders as determined by 
investigators, including but not limited to seizure disorder or neurological symptoms of 
the wrist and arm (e.g., carpal tunnel syndrome) for shocks to be delivered on affected 
arm. 
8. Positive urine toxicology screen at screening visit under 01-M-0254 
9. Employees of NIMH or an immediate family member of a NIMH employee. 
10.  Healthy volunteers only: Current DSM-5 disorders. 
4.3 
INCLUSION OF VULNERABLE PARTICIPANTS 
4.3.1 Participation of NIH Staff or family members of study team members 
NIH staff and family members of study team members may be enrolled in this study as this 
population meets the study entry criteria.  Neither participation nor refusal to participate as a 
subject in the research will have an effect, either beneficial or adverse, on the participant’s 
employment or position at NIH. 
Every effort will be made to protect participant information, but such information may be 
available in medical records and may be available to authorized users outside of the study team 
in both an identifiable an unidentifiable manner. 
The NIH Frequently Asked Questions (FAQs) for Staff Who are Considering Participation in 
NIH Research will be made available.  Please see section 9.1.3 for consent of NIH Staff. 

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4.3.2 Justification for exclusion of non-English speaking subjects: 
We exclude non-English speakers since not all the instruments and test we use are validated in 
other languages. 
4.3.3. Justification for exclusion of subjects over 50 years of age: 
As people get older, their startle response decreases64. The upper age limit will be 50 years old to 
minimize the confounding effects of age.  
4.3.4. Justification for exclusion of pregnant women: 
We will exclude pregnant as the effects of shock are unknown on a developing fetus.  
4.3.5. Justification for exclusion of children: 
In order to elicit anxiety responses similar to those occurring in anxiety disorders it is important 
that out stressor is highly unpleasant. We thus chose to use electric shock as the stressor. Though 
shock stressors are well tolerated by adults (and used frequently in the literature to assess stress 
reactions in healthy and disordered individuals), such methods may be inappropriate for children. 
We will not enter children under age 18 because of ethical concerns about exposing them to 
threat of shock. Moreover, concerns regarding the legal inability to provide informed consent 
before age 18 (and the consequent dependence on parental decision) preclude inclusion of 
subjects under age 18. 
4.3.6. Justification for exclusion of decisionally impaired adults: 
All subjects must be able to provide their own consent. We do not want to enroll participants 
who do not understand the risk/benefit ratio of the study, particularly when there is no benefit to 
the participants. 
4.4 
INCLUSION OF PREGNANT WOMEN, FETUSES OR NEONATES 
N/A 
4.5 
LIFESTYLE CONSIDERATIONS 
N/A 
4.6 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
personal reason, use of exclusionary PRN medication, or due to a transient medical condition 
may be rescreened. 
 
4.7 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Recruiting 
Recruitment will be done by NIMH IRP, Clinical Center Office of Patient Recruitment, and 
Branch staff. All advertising methods will comply with the most current regulations (NIH and 

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OHSRP SOPs and guidelines, as well as FDA guidelines for FDA-regulated research) and the 
NIMH policy on recruitment materials.  
 
Participants will be recruited under the screening protocol 01-M-0254: “The Evaluation of 
Patients with Mood and Anxiety Disorders and Healthy Volunteers.”  All recruitment materials 
(paper or web ads, flyers and listserv announcements) will be IRB approved under this protocol 
prior to use. Under this protocol recruitment will be done via print media and through advertising 
on the internet and websites.  NIH employees/staff will not be directly recruited by or through 
their supervisors to participate in this study. NIMH employees/staff and their immediate family 
members cannot participate in this protocol. We will use the following recruitment methods: 
 
A. Advertisements  
i. 
Print advertisements 
ii. 
Flyer advertisements 
iii. 
Online advertisements 
i. Web ads will direct readers to the study specific link on the NIMH Join a 
Study website. 
iv. 
Text advertisements  
v. 
Notecard advertisements 
vi. 
Postcard advertisements  
vii. 
Animated storyboard video 
B. Advertising venues  
i. 
Internal NIH media (e.g. flyering boards, newsletters) 
ii. 
NIH Internet (e.g. http://nimh.nih.gov/JoinAStudy) 
iii. 
Listservs 
• IRB approved ads will be posted on listservs with the permission of the moderator 
and IRB required statement on how the receiver was identified.  Listservs may 
include provided by OPR or local groups. We will not post/send directly to the 
listserv. Rather, an email with information about our study information will be 
sent to the administrator of the listserv, which will include the following 
disclaimer: 
“You are receiving this message because your email address is included in the 
above listserv. The purpose of this message is to inform you of our NIMH 
research studies. The moderator of the listserv has permitted its use for this 
distribution.” 
iv. 
Print publications (e.g. local or university newspapers, magazines, health care 
organizations, etc) 
v. 
Online paid advertising (e.g. university online newspapers, local websites, 
Facebook, Instagram, Twitter) or unpaid (e.g. NIH Twitter and Facebook 
accounts such as the NIH record) 
vi. 
Craigslist (posted under the “Volunteer” category)  
vii. 
Notecards and/or flyers may be posted on bulletin boards at local establishments 
including grocery stores, coffee shops, community centers, college campuses, and 
NIH Clinical Center with approval of the venue or in accord with their policy. 
They may be made available at outreach exhibits, speaking engagements, and 
professional meetings with approval of the venue or in accordance with their 

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policy. Clinicians who are contacted will be provided with information to 
disseminate to patients as they see fit.  We will explain to them that individuals 
interested in participating in our studies will need to initiate contact with our 
group and that we will not make this initial contact. Notecards and/or flyers may 
be given directly to those requesting study information.  
viii. 
Office of Patient Recruitment list of volunteers. 
ix. 
Research Match database 
x. 
Participants screened through NIMH protocol #17-M-0181 titled “Recruitment 
and Characterization of Research Volunteers for NIMH Intramural Studies” and 
referred to our study. Data and study procedures done under #17-M-0181 may be 
used toward eligibility determination. 
C. Prescreening Database 
i. 
We may also use the Survey tool in REDCap (Research Electronic Data Capture) to 
assist with recruitment, pre-screen potential participants, and evaluate our recruitment 
strategies. REDCap is a secure web application for building and managing online 
surveys and databases. REDCap Survey will not contain PHI and contains workflows 
that support the collection of de-identified data. Interested persons may be directed to 
REDCap from a link in our IRB approved advertisements. In our secure confirmation 
email to potential healthy participants, we may include the link to offer to allow 
participants to pass along as a WOM recruitment strategy with the disclaimer that 
they should not forward the confirmation email. Potential participants will be given 
an automated survey when they click on the link. The survey would ask the potential 
participant our non-PII prescreening questions that we currently ask via a phone 
prescreen. The subject will be provided with a numeric code automatically by the 
database and will also be provided the phone number for our study staff and will be 
asked to call our research team to continue screening. The potential participant will be 
instructed to provide their unique numeric code during this phone screen. The unique 
code will allow the staff to connect the person to the non-PII information that has 
already been entered by the potential subject.  This allows us to speed up the 
prescreening process as we will have access to their answers. We will be the only 
ones with access to the responses. We will also use REDCap to develop an 
anonymous survey to evaluate our screening efforts. 
4.7.1 Costs 
There is no cost to participate. 
4.7.2 Compensation 
Volunteers will be compensated for time and research-related inconveniences. Participants in the 
clinic study will be given $120 for their participation in the single outpatient visitThese tasks use 
monetary incentives to assess motivation. Participants may win up to an additional $25 in the 
study task. Subjects may also be compensated an additional $20 if they complete an extra visit 
for Telehealth consent.  
Travel is not compensated.  If subjects do not complete the study they will be paid half of the 
compensation. NIH employees or staff who participate during work hours must have permission 
from their supervisor. NIH employees or staff must either participate outside of work hours or 
take leave in order to receive compensation.  We will use the NIH payment system to provide 

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compensation. Participants with direct deposits set up will receive it via direct deposit within 6 to 
8 weeks.  
 
 
5 
STUDY INTERVENTION 
5.1 
STUDY INTERVENTIONS(S) ADMINISTRATION 
5.1.1 Study Intervention Description 
There will be no IND obtained for the use of any of the commercial agents used in this study.  
 
The devices used in the study are not used to diagnose, treat, prevent, cure, or mitigate any 
disease or condition. The devices are not being studied in this protocol and are not part of the 
research question. The devices are used as study procedures in the task to provide a threat (shock 
or startle device) without the purpose of diagnosis. There is no known increase of risk using 
these devices.  
 
The devices used on the study include the following:  
IDE  
Manufacturer/mnodel 
Device 
Size 
Description 
of 
Components 
Settings/applications 
Approved 
for 
indications 
Shock 
device 
Digitimer  DS7A  
225 x 
100 x 
255mm 
(w x h 
x d) 
Input: 
electrical via 
BNC socket 
on rear 
panel 
Output:rear 
panel BNC, 
positive 
TTL pulse 1 
ms wide 
Settings: initially set at 3.5 mA and 
individually determined by subjects 
during shock workup based on 
subject rating of aversiveness. 
Maximum possible current setting of 
the device is 99.9.mA. 
Duration: 100 ms 
Frequency: NA. Single pulse of 100 
ms given 12 times per session 
Yes* 
Startle 
device 
N/A 
100mm 
x 
60mm 
x 
25mm 
 
Teensyboard 
3.2, Audio 
adaptor 
board for 
Teensy 3.0 – 
3.6 
 
Settings: 103 dB output 
Duration: 40ms 
Frequency: 
Yes* 
 
 
 
 
 
 
*Shock device, and startle deviceare FDA approved devices and are not attempting to serve as a 
new indication nor an increased risk from their indication. It is not being used for treatment in 
this study but used in a research setting as aversive stimulus (shock and startle) in healthy and 
anxiety volunteers. The shock device and auditory startle have been used in our 01-M-0185, 02-
M-0321, and 03-M-0093 protocols for almost two decades without significant adverse events.  
This study meets the criteria for exemption for an IND as this investigation is not intended to 
support a new indication for use or any other significant change to the labeling; the drugs are 
already approved and marketed and the investigation is not intended to support a significant 
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administration or dosage level or use in a patient population or other factor that significantly 
increases the risks (or decreases the acceptability of the risks) associated with the use of the drug 
product. The route of administration and dosage used in this study is identical to those used in 
patient populations. The study intervention is commercially available but is not being used in 
accordance with approved labeling, specifically the population/disease as this protocol uses it on 
healthy volunteers. 
 
Acoustic startle and shock device used in this protocol are considered non-significant risk (NSR) 
devices and will only be used within published guidelines.  
Auditory startle and shock device do not meet criteria for a Significant Risk device as outlined 
Under 21 CFR 812.3(m), as an investigational device that:  
1. Is intended as an implant and presents a potential for serious risk to the health, safety, or 
welfare of a subject  
Response: Auditory startle and shock device are not implantable devices. 
2. Is purported or represented to be for a use in supporting or sustaining human life and presents 
a potential for serious risk to the health, safety, or welfare of a subject  
Response: Auditory startle and the shock device are not for use in supporting or sustaining 
human life. They do not present a potential for serious risk to the health, safety, or welfare of 
participants when used as described in this protocol.  
3. Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or 
otherwise preventing impairment of human health and presents a potential for serious risk to the 
health, safety, or welfare of a subject  
Response: Auditory startle and shock device, as used under this protocol is not of substantial 
importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing 
impairment of human health and does not present a potential for serious risk to the health, safety 
or welfare of a subject.  
4. Otherwise presents a potential for serious risk to the health, safety or welfare of a subject  
Response: Auditory startle and shock device have been in use numerous for decades and have 
been cleared by the FDA. Safety guidelines have been developed and updated allowing its 
dissemination to a wide range of clinical and non-clinical settings. The FDA has generally 
waived pre-IDE inquiries for auditory startle and  shock device studies on a NSR device basis. 
Hence, the NIH IRB, like most US IRBs, has accepted NSR designation for auditory startle and 
shock device within these limitations.  
5.1.2 Dosing and Administration 
Not applicable. 
5.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
Not applicable. 
5.2.1 Acquisition and Accountability 
Not applicable. 
5.2.2 Formulation, Appearance, Packaging, and Labeling 
Not applicable. 

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5.2.3 Product Storage and Stability 
Not applicable. 
5.2.4 Preparation 
Not applicable. 
5.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable. 
5.4 
STUDY INTERVENTION COMPLIANCE 
It is anticipated that participants in this study will occasionally miss or fail to complete an 
assessment or procedure, such as a completion of a rating scale or fail to complete a procedure 
within protocol-specified time frames due to equipment malfunction. Omissions such as these 
will be considered expected events and not protocol deviations provided they are infrequent and 
do not include data needed to assess safety or the primary study outcome.  Cumulative 
proportions of these missed events will be monitored by the Investigators.  If an individual 
misses more than 15% of the required assessments/procedures or if more than 15% of the 
participants miss completion of the same assessment or procedure, it will be considered a 
deviation. If they do not complete the computer task then the participant will be considered a 
withdrawal and we will not use their data. The source documents of the questionnaire, computer 
task data will be used to calculate study intervention compliance. 
5.5 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. Medications to be reported in the Case Report Form 
(CRF) are concomitant prescription medications, over-the-counter medications and supplements. 
Current use of medications that pass the blood brain barrier and act on histamine (i.e. 
diphenhydramine), dopamine (methylphenidate), norepinephrine (buproprion), serotonin 
(sertraline), or acetylcholine (amitryptiline) receptors will be exclusionary. Subjects will be 
excluded if they take these medications on a chronic basis. Subjects will be included if they have 
not taken the medication for five half-lives prior to a study visit. 
 
6 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL  
6.1 
DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from the task will mean discontinuation from the study, and remaining study 
procedures will be stopped.  Only clinical evaluations of AEs and follow up calls may occur 
following discontinuation. Any new clinically relevant finding will be reported as an adverse 
event (AE). 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
• Completion of study intervention 

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• If any significant worsening of symptoms or active suicidal ideation, clinical adverse 
event (AE), laboratory abnormality, or other medical condition or situation occurs such 
that continued participation in the study would not be in the best interest of the 
participant 
• Concomitant medication use  
• Investigator discretion 
• Positive pregnancy test 
 
6.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request.  
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
• Significant study intervention non-compliance  
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• Subject has completed the study  
• Death 
• Screen Failure 
• The reason for participant discontinuation or withdrawal from the study will be recorded 
in CRIS.  
6.3 
LOST TO FOLLOW-UP 
7 
STUDY ASSESSMENTS AND PROCEDURES 
7.1 
SCREENING PROCEDURES 
7.1.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
• Email, written, in person or telephone communications with prospective subjects.  
• Review of existing medical records to include H&P, laboratory studies, etc.   
• Review of existing MRI, x-ray, or CT images. 
• Review of existing photographs or videos. 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes. 
7.1.2 Screening activities performed after a consent for screening has been signed 
 
Clinic: 
Prior to consenting to the study, subjects will have undergone a screening under protocol 01-M-
0254, “The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers” or 
17-M-0181 “Recruitment and Characterization of Research Volunteers for NIMH Intramural 
Studies” within 365 days of their enrollment in this study. Psychiatric history will be assessed 
using the SCID-I/NP (see First et al., 2001) using DSM-IV or DSM-5 diagnostic criteria. 

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Diagnostic eligibility (i.e., absence of current or past history of any DSM-IV or DSM-5 Axis I 
disorder) will have been determined prior to entry to the initial study according to DSM-IV or 
DSM-5 criteria and confirmed by the SCID-I/NP.  We will require that all subjects have an 
updated physical examination and the following tests: physical exam, urine pregnancy test (for 
premenopausal women), and toxicology screening.  A pregnancy test will be done in women of 
childbearing age who are not surgically sterile (i.e. bilateral oophorectomy, complete 
hysterectomy). Results of these tests will identify patients who should be excluded because of 
active medical problems or substance abuse that might affect clinical phenomenology or make 
participation in the protocol unsafe.  Subjects are expected to meet all other inclusion and 
exclusion criteria to be eligible for study participation. Information obtained under the 01-M-
0254 screening protocol or 17-M-0181 recruitment protocol may be used for research data in this 
protocol.  
 
All screening tests and procedures must be performed within one year prior to enrollment, unless 
a time period is specifically mentioned. 
 
7.2 
EFFICACY ASSESSMENTS 
7.2.1 Clinical Evaluations 
Questionnaires: 
State-Trait Anxiety Inventory (Spielberger, Gorsuch, Lushene, Vagg, & Jacobs, 1983): 40-item 
scale assessing state anxiety (20 items) and trait anxiety (20 items). 
• 
Anxiety Sensitivity Index (ASI;Reiss et al., 1986): 16-item scale assessing anxiety 
sensitivity in terms of the dispositional tendency to fear the somatic and cognitive symptoms of 
anxiety due to a belief that these symptoms may be dangerous or harmful. 
• 
Penn State Worry Questionnaire (PSWQ; Meyer, Miller, Metzger, & Borkovec, 1990): 
16 items assessing chronic, excessive, and uncontrollable worry. 
• 
Intolerance of Uncertainty Scale short form (IUS-12; Carleton, Norton, & Asmundson, 
2007): 12-item scale assessing reactions to impending uncertainty, ambiguous situations, and the 
future. It consists of two factors: prospective anxiety (7 items) and inhibitory anxiety (5 items). 
• 
BIS/BAS scale (Carver et al., 1992):24 items assessing individual differences in the 
sensitivity of two motivational systems, the behavioral approach system (BAS) and a behavioral 
avoidance (or inhibition) system (BIS). 
• 
Risk-taking behaviors scale (RTBS; Weber, Blais, & Betz, 2002): 14-item scale assessing 
people’s willingness to engage in risky decision-making across different risk-taking domains 
including health/safety, recreation, ethics, social interaction, gambling. 
• 
Positive Affect/Negative Affect Scale (PANAS; Watson, Clark, & Tellegen, 1988): 20-
item scale assessing positive (10 items) and negative (10 items) affects. 
• 
Barratt Impulsiveness Scale (BIS-11; Patton et al., 1995): 11-item scale assessing 
personality/behavioral construct of impulsiveness. 
• 
Sensation Seeking Scale (SSS) Form V (Zuckerman et al., 1978): 40-item scale assessing 
sensation seeking behaviors according to four dimensions associated with sensation seeking that 
are thrill and adventure seeking, experience seeking, disinhibition and boredom susceptibility. 

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Curiosity and Exploration Inventory (CEI-II) (Kashdan, T.B., et al.;2009): 10-item scale 
assessing individual differences in the recognition, pursuit, and integration of novel and 
challenging experiences and information. 
 
7.2.2 Clinical Evaluations 
Not applicable. 
7.2.3 Biospecimen Evaluations 
Not applicable.  
7.2.4 Correlative Studies for Research/Pharmacokinetic Studies 
Not applicable.  
7.2.5 Samples for Genetic/Genomic Analysis 
Not applicable. 
7.3 
SAFETY AND OTHER ASSESSMENTS 
Not applicable.  
7.4 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
7.4.1 Definition of Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
7.4.2 Definition of Serious Adverse Events (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
7.4.3 Classification of an Adverse Event 
7.4.3.1 Severity of Event 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity.  
• Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 

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• Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.] 
 
7.4.3.2 Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
investigator who examines and evaluates the participant based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect.  
 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study intervention, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
• Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician.] 
 
7.4.3.3 Expectedness  
The LIP or Medical Associate Investigator will be responsible for determining whether an 
adverse event (AE) is expected or unexpected.  An AE will be considered unexpected if the 
nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the study intervention. 

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7.4.4 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
The Principle Investigator will record all reportable events with start dates occurring any time 
after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the 
last day of study participation.  At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information 
until resolution or stabilization. 
7.4.5 Adverse Event Reporting  
Reportable events for this protocol will be tracked and reported in compliance with Policy 801. 
7.4.6 Serious Adverse Event Reporting  
Reportable events for this protocol will be tracked and reported in compliance with Policy 801. 
7.4.7 Events of Special Interest  
Not applicable.  
7.4.8 Reporting of Pregnancy  
Not applicable. 
7.5 
UNANTICIPATED PROBLEMS 
7.5.1 Definition of Unanticipated Problems (UP) 
Any incident, experience, or outcome that meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; and 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
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• Suggests that the research places participants or others (which many include research 
staff, family members or other individuals not directly participating in the research) at a 
greater risk of harm (including physical, psychological, economic, or social harm) than 
was previously known or expected. 
7.5.2  Unanticipated Problem Reporting  
The investigator will report unanticipated problems (UPs) to the NIH Institutional Review Board 
(IRB) as per Policy 801. 
7.5.3 NIH Intramural IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NIH Intramural IRB. 
 
8 
STATISTICAL CONSIDERATIONS 
8.1 
STATISTICAL HYPOTHESIS 
Multi-arm bandit: The two conditions in the multi-arm bandit are designed, in such a way that in one 
condition, purely value-driven exploration would result in the highest cumulative outcomes; whereas in 
the other condition, random exploration would be the optimal strategy. The primary null hypothesis for 
would be: There is no significant scenario (1 vs. 2) x population (HV vs. AD) interaction Additionally, the 
secondary null hypothesis would be: There is no significant correlation between the difference of the 
exploration specific parameter and anxiety scores. 
 
8.2 
SAMPLE SIZE DETERMINATION 
 
Multi-arm bandit study 
• Outcome measure used for calculations (almost always the primary variable): For the 
first behavioral experiment, the two conditions are designed to affect the nature of the 
optimal strategy, such that in one condition, the highest cumulative outcome depends on 
purely value-driven exploration; whereas, in the other condition, the best strategy 
involves adequate random exploration. From our pilot study, we know that there is a 
significant difference between scenarios in HV. Paired t-test p = 0.0014, tstat=3.5139, 
df=31, sd=13.4323. 
• Test statistic: The model derived parameters will be analyzed using a 2-way repeated 
measures ANOVA, with the scenarios (experimental manipulation) and population 
(healthy volunteers, anxiety patients) being the 2 factors. 
• Null hypotheses: There is no significant difference in model derived parameters between 
the 2 conditions and/or populations. 
• Type I error rate (alpha): 0.05 
• Power level: 80% 
• Statistical method used to calculate the sample size, with a reference for it and for any 
software utilized: Repeated measure anova power analysis using R function wp.rmanova 
• Anticipated impact of dropout rates, withdrawal: 10-15% 
• Accrual rate and duration of study: The expected accrual rate is 2 participants a week. 
Thus, the total duration of each of our experiments is expected to be around 9 months.  

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Power analysis:  
To run the power analysis, we use the R function wp.rmanova, with number of groups 
(Ng)=2, number of measurments (nm) = 2, Nonsphericity correction coefficient (Nscor)=1, 
Alpha = 0.05, power=0.8, Effect size (f) [Table below lists the sample size determined for 
different effect sizes.] We chose an effect size of f=0.35 and thus require a sample size of 66 
subjects (33 HV and 33 AD). Given that we expect 15-20% of subjects to have bad EMG 
recordings, unanalyzable or small startle responses, or random choice probabilities, we will 
recruit a total of 80 subjects (40 HV, 40 AD) 
 
N 
F 
Ng 
nm 
Nscor 
Alpha 
Power 
198 
0.2 
2 
2 
1 
0.05 
0.8 
89 
0.3 
2 
2 
1 
0.05 
0.8 
66 
0.35 
2 
2 
1 
0.05 
0.8 
51 
0.4 
2 
2 
1 
0.05 
0.8 
33 
0.5 
2 
2 
1 
0.05 
0.8 
 
 
8.3 
POPULATIONS FOR ANALYSES 
Multi-arm bandit study 
• The subjects will be healthy adult male and female volunteers, ages 18-50. For each 
experiment there will be 2 groups, healthy controls, and anxiety patients  
• The target number of completers for the clinic study will be N=40 per group for a total of 
80 completers. Subjects who drop out will be replaced. The total accrual number for the 
clinic study will be 80 (see power analysis). 
 
 
Pilot study 
Pilot studies designed to test out additional stimulus parameters and factors underlying decision 
making will require additional participants. We plan to recruit up to 20 HV. 
8.3.1 Evaluable for toxicity  
Not applicable. 
8.3.2 Evaluable for objective response  
Not applicable. 
8.3.3 Evaluable Non-Target Disease Response 
Not applicable. 
8.4 
STATISTICAL ANALYSES 
8.4.1 General Approach 
• The main expected outcome measures are changes in the model derived parameters such 
as learning rate, exploration across conditions. 

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• Startle and performance data will be analyzed with ANOVAs, paired t-tests and other 
statistical tests as appropriate with significance levels set at 0.05 
• For all parametric tests the appropriate checks on the distribution of the data will be 
performed prior to analysis. 
 
8.4.2 Analysis of the Primary Endpoints 
Clinic study: 
• For the clinic experiment, the two conditions are designed to affect the nature of the 
optimal strategy. In one condition, the highest cumulative outcomes depend on purely 
value-driven exploration; whereas, in the other condition, the best strategy depends on 
random exploration. The model derived parameter (exploration inverse temperature) is 
one parameter that reflects the strategy used by the participant. In addition, another 
parameter of interest is the learning rate, which reflects the speed of learning based on 
prior trials.  
• The model derived parameters follow an interval scale there is one data point per 
participant per condition. 
• The difference in parameter estimates between the 2 conditions will be tested for 
significance using a paired t-test. 
• The assumptions for the validity of a paired t-test: (1) The dependent variable must be 
continuous (interval/ratio). (2) The observations are independent of one another. (3) The 
dependent variable should be approximately normally distributed. (4) The dependent 
variable should not contain any outliers. 
• Once we have a full sample (healthy volunteers and anxiety patients) the model derived 
parameters will be analyzed using a 2-way ANOVA, with the condition (experimental 
manipulation) and population (healthy volunteers, anxiety patients) being the 2 factors. 
 
8.4.3 Analysis of the Secondary Endpoint(s) 
• We expect this change in parameter estimates to be influenced by anxiety, that will be 
measured using potentiated startle and anxiety questionnaires. 
• We expect this change in parameter estimates to be further influenced by the individual’s 
reinforcement learning tendency, curiosity, exploration, sensation seeking, measured 
using self-reported questionnaires. 
• The correlation coefficient between the difference in model derived parameters (between 
conditions) and the total scores and/or the total scores of the sub-scales of self-reported 
questionnaires will be computed. 
8.4.4 Safety Analyses 
Not applicable. 
8.4.5 Baseline Descriptive Statistics 
Not applicable. 

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8.4.6 Planned Interim Analyses 
Not applicable. 
8.4.7 Sub-Group Analyses 
Not currently planned. 
8.4.8 Tabulation of individual Participant Data 
Not applicable.  
8.4.9 Exploratory Analyses 
Not applicable.  
9 
REGULATORY AND OPERATIONAL CONSIDERATIONS 
9.1 
INFORMED CONSENT PROCESS 
9.1.1 Consent/Assent Procedures and Documentation 
Study investigators designated as able to obtain consent are outlined in the KSP form.  All study 
investigators obtaining informed consent have completed the NIMH HSPU ‘Elements of 
Successful Informed Consent’ training. 
All participants will receive a verbal explanation in terms suited to their comprehension of the 
purposes, procedures and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review the written consent form and ask 
questions regarding this study prior to signing.  Consent forms will be signed in the presence of a 
witness. Consent may be obtained in-person or using NIH-approved telehealth platforms. 
 
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee as applicable for review prior to consenting. A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomfort and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to any research 
activities taking place. 
 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s). Whether in person or remote, the privacy of 
the subject will be maintained. Consenting investigators (and participant when in person) will be 
located in a private area (e.g., clinic consult room). When consent is conducted remotely, the 
participant will be informed of the private nature of the discussion and will be encouraged to 
relocate to a more private setting if needed. If the consent process is occurring remotely, 
participants and investigators will view individual copies of the approved consent document on 
screens at their respective locations; the same screen may be used when both the investigator and 
the participant are co-located but this is not required.  
 

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Note: When required, the witness signature will be obtained similarly as described for the 
investigator and participant below. 
 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to the participant) or on the electronic document. The 
process for documenting signatures on an electronic document is described below. 
 
When a hand signature on an electronic document is used for the documentation of consent, this 
study will use the following electronic platform to obtain the required signatures: 
• iMedConsent platform (which is 21 CFR Part 11 compliant) 
 
Both the investigator and the participant will sign the electronic document using a finger, stylus 
or mouse. Electronic signatures (i.e., the “signature” and a timestamp are digitally generated) 
will not be used. 
 
9.1.2 Consent for minors when they reach the age of majority  
Not applicable.  
9.1.3 Considerations for Consent of NIH staff, or family members of study team members 
Consent for NIH staff will be obtained as detailed above with following additional protections: 
Consent from staff members will be obtained by an individual independent of the staff member’s 
team whenever possible.  Otherwise, the consent procedure will be independently monitored by 
the CC Department of Bioethics Consultation Service in order to minimize the risk of undue 
pressure on the staff member. 
9.1.4 Consent of Subjects who are, or become, decisionally impaired 
Consent is obtained the day of the study visit. Participants who are decisionally impaired are 
excluded and subjects would not become decisionally impaired during the time frame of the 
single, outpatient study visit.  
 
9.2 
STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants and the Institutional Review Board (IRB) and will 
provide the reason(s) for the termination or suspension.   
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
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Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the IRB. 
9.3 
CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the study or 
the data will be released to any unauthorized third party without prior written approval of the 
sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements. 
Study participant research data (including demographics information and clinical rating scales), 
which is for purposes of statistical analysis and scientific reporting, will be transmitted in a 
HIPAA compliant manner and securely stored in the Clinical Trials Data Base (CTDB) 
sponsored by NICHD. Individual participants whether they have been in a NIH study before or 
not, and their research data will be identified by a unique study identification (ID) number. The 
study data entry and study management systems used by CTDB will be secured and password 
protected. All study investigators will have access to data in CTDB with different level of access, 
e.g. data entry, reporting. Electronic data (including imaging data) and electronic personally-
identifiable health information (ePHI) will be stored on secure servers within the NIH firewall 
with access for study personnel only. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants. 
9.4 
FUTURE USE OF STORED SPECIMENS AND DATA 
No specimens are collected.  Data will be de-identified and stored at the clinical site for an 
indeterminate period of time so that they could be used in future studies and shared for 
collaboration with other researchers. Data from structured diagnostic interviews and symptom 
ratings are kept in secure research files and electronically on the Branch server space or within 
the CTDB database. Clinical data will be entered into CRIS and therefore will go into BTRIS. 
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may be submitted to open-access repositories for secondary research. A code, which will be kept 
by the study team on a password and firewalled server and/or in a locked file cabinet, will link 
de-identified data and samples to clinical and demographic information.  Participants will 
provide informed consent for this use. 
  
9.5 
SAFETY OVERSIGHT 
Safety oversight will be under the direction of the PI and research team and the NIMH Office of 
Regulatory Oversight (ORO).  
9.6 
CLINICAL MONITORING 
As per ICH-GCP 5.18 clinical protocols are required to be adequately monitored. Monitoring for 
the NIH site will be conducted according to the “NIMH Intramural Program Guidelines for 
Monitoring of Clinical Trials”. Monitors under contract to the NIMH OCD ORO will visit the 
NIH site to monitor aspects of the study in accordance with the appropriate regulations, policies 
and the approved protocol. The objectives of a monitoring visit will be: 1) to verify the existence 
of signed informed consent documents and documentation of the ICF process for each monitored 
subject; 2) to verify the prompt and accurate recording of all monitored data points, and prompt 
reporting of all SAEs; 3) to compare abstracted information from clinical databases (e.g. CTDB) 
with individual subjects’ records and source documents (subjects’ charts, laboratory analyses and 
test results, physicians’ progress notes, nurses’ notes, and any other relevant original subject 
information); and 4) to help ensure investigators are in compliance with the protocol. The 
monitors also will inspect the clinical site study files to ensure that regulatory requirements 
(Office for Human Research Protections-OHRP), NIH, and applicable guidelines (ICH-GCP) are 
being followed. During the monitoring visits, the investigator (and/or designee) and other study 
personnel will be available to discuss the study progress and monitoring visit. 
 
The investigator (and/or designee) will make study documents (e.g., consent forms, clinical 
database records and pertinent hospital/sources or clinical records readily available for inspection 
by the local IRB, OHRP, the site monitors, as applicable and the NIMH staff for confirmation of 
the study data. 
 
A specific protocol monitoring plan will be discussed with the Principal Investigator and study 
staff. The plan will outline the frequency of monitoring visits based on such factors as study 
enrollment, data collection status and applicable regulatory obligations. 
9.7 
QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
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on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 
 
9.8 
DATA HANDLING AND RECORD KEEPING 
 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.   
Hardcopies of the study visit worksheets will be provided for use as source document worksheets 
for recording data for each participant enrolled in the study.  Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents.  
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into Clinical Research Information 
System (CRIS), a 21 CFR Part 11-compliant data capture system provided by the Clinical 
Center. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents. 
9.8.1 Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Conference on Harmonisation (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the study 
intervention, and as per the NIH Intramural Records Retention Schedule. No records will be 
destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
sponsor to inform the investigator when these documents no longer need to be retained. 
 
9.9 
PROTOCOL DEVIATIONS AND NON-COMPLIANCE 
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations and/or non-compliance to the NIH Institutional Review Board as per Policy 801.  All 
deviations must be addressed in study source documents, reported to National Institute of Mental 
Health Clinical Director.  The investigator is responsible for knowing and adhering to the 
reviewing IRB requirements. 
9.9.1 NIH Definition of Protocol Deviation 
A protocol deviation is any changed, divergence, or departure from the IRB-approved research 
protocol.  

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• Major deviations: Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact the rights, welfare or safety of the subject, or to 
substantially negatively impact the scientific integrity or validity of the study. 
• Minor deviations: Deviations that do not have the potential to negatively impact the 
rights, safety or welfare of subjects or others, or the scientific integrity or validity of the 
study. 
9.10 PUBLICATION AND DATA SHARING POLICY 
9.10.1 Human Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of 
NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals.  Data from this study may be 
requested from other researchers two years after the completion of the primary endpoint by 
contacting Dr. Christian Grillon. 
9.10.2 Genomic Data Sharing Plan 
This protocol is not subject to the Genomic Data Sharing (GDS) Policy.  
9.11 COLLABORATIVE AGREEMENTS  
Not applicable. 
9.11.1 Agreement Type 
Not applicable. 
9.12 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the National Institute 
of Mental Health has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported 
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10 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be 
customized for each protocol (i.e., abbreviations not used should be removed and new 
abbreviations used should be added to this list). 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 

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PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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