Conditions: ANXIETY DISORDERS (or Anxiety and Phobic Neuroses)
Keywords: Anhedonia Mood and Anxiety Spectrum Disorders CERC-501 (investigational product) Kappa Opioid Receptor (KOR)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 163
Healthy volunteers: no

Brief summary:
The available treatment for patients with mood and anxiety disorders have significant limitations (Rush, 2007; Denys and de Geus, 2005). There is a need to develop new treatments for people with these disorders. Many research studies carried out in animals and a few preliminary studies carried out in humans suggest that medications which block kappa opioid receptors (KOR) have potential for being effective new treatments for patients with mood and anxiety spectrum disorders. These medications have shown particular promise for improving one important type of difficulty experienced by many patients who suffer from mood and anxiety spectrum disorders referred to as anhedonia, which is an impairment in reward-related function. In this study we will test the hypothesis that KOR antagonism is a promising means of improving anhedonia in patients with mood and anxiety spectrum disorders. We will do so by evaluating whether we can establish Proof of Concept (POC) that a relatively selective KOR antagonist, CERC-501 (formerly known as LY2456302), engages neural circuits involved in mediating reward-related function in patients with mood and anxiety spectrum disorders with anhedonia. We are attempting to establish POC in this study in order to determine whether there is a sufficient basis for pursuing future work evaluating whether KOR antagonism has therapeutic effects on clinical and behavioral measures of reward-related functioning.

Detailed description:
FAST-MAS addresses an important problem and critical barrier to progress in Mood and Anxiety Spectrum Disorders and if the aims of the project are achieved, FAST-MAS could shift scientific knowledge, technical capacity, and clinical practice in a positive direction.

The Mood and Anxiety Spectrum disorders are both extremely common and associated with significant morbidity and mortality and, as such, represent an important public health problem in the United States.

The mood disorders include the following diagnostic entities: major depressive disorder (MDD), bipolar disorder (including subtypes of mania, mixed state, and depressed, as well as types I and II), and dysthymic disorder. Available epidemiologic data suggest that the prevalence of these mood disorders is extremely high among adults in the United States, approaching 10%. Among the mood disorders, MDD has high lifetime prevalence, with recent estimates up to 16%. According to the World Health Organization (WHO), MDD is currently the leading cause of disability with the greatest burden of illness in developed countries and the third most common cause of disability worldwide. MDD is life shortening due to both suicide and its association with increased mortality from other medical conditions. It is also a highly recurrent condition with between 50% and 75% of persons diagnosed with MDD experiencing more than one episode. Bipolar Disorder is also a highly recurrent condition. The lifetime prevalence of bipolar disorder has been estimated to be approximately 3.4% in the World Health Survey Initiative. Approximately 60% of affected individuals experience severe or very severe role impairment based on the Sheehan Disability Scale and, like MDD, bipolar disorder is associated with significant suicide risk.

The anxiety disorders are also very common and associated with significant adverse impact on affected individuals and society. These disorders include the following diagnostic entities: generalized anxiety disorder (GAD), panic disorder, obsessive-compulsive disorder, social phobia, specific phobias, and post-traumatic stress disorder (PTSD). As a group, these conditions affect approximately 18% of adults in a given year and they are associated with significant co-morbidities and adverse consequences. Of the anxiety disorders, GAD appears to be associated with the greatest per patient cost and disability with a degree of disability comparable to that of MDD and comparable to chronic medical conditions such as arthritis, diabetes, and peptic ulcer disease. It affects approximately 6.8 million adults in the U.S. and is a highly chronic condition. Panic disorder affects about 6 million American adults and is twice as common in women as men. Panic disorder is also highly disabling and often chronic and even mild forms of this disorder are linked to significantly increased impairment in function and quality of life as well as a number of comorbidities. Approximately 2.2 million adults in the U.S. are affected by obsessive-compulsive disorder and this disorder is often accompanied by psychiatric comorbidities. Roughly half of individuals with this condition have a chronic unremitting course which is associated with significant disability and morbidity. Social phobia, also known as social anxiety disorder, is seen in roughly 15 million adults in the U.S. and is often associated with MDD or other anxiety disorders. It is generally a chronic condition that leads to a great degree of disability due to substantial impairment in social, educational, and occupational function. Approximately 8 million adults in the U.S. experience PTSD and approximately 12% of the population have PTSD at some point in their lives and affected individuals frequently experience associated MDD, other anxiety disorders and substance use problems. The level of disability associated with this condition tends to be quite high and includes impairment in social and occupational function and quality of life. There are also substantial financial and social costs associated with PTSD due to increased hospitalization rates, suicidality, and substance use problem.

Mood disorders and anxiety disorders are highly prevalent conditions, many of which are chronic, nearly all of which are associated with substantial comorbidities, disability and impairment and some are associated with an increased risk for mortality. Despite the availability of many pharmacologic, psychotherapeutic, brain stimulation, and combination treatment options available to clinicians, many patients with Mood and Anxiety Spectrum Disorders respond poorly to treatment. In light of the impairments, costs, and risks of these disorders, the limitations of the available treatments represents an enormous burden to public health and speak strongly to the need for new treatments for these conditions as well as novel methodologies of treatment development that are not only faster than existing methodologies but which also promote new ways of thinking about these disorders and their treatment and capitalize on recent and ongoing developments in basic science.

This study will be a six-site randomized, double-blind, PBO (placebo) -controlled, parallel-group mono-therapy study to assess the effects of CERC-501 (formerly known as LY2456302) compared to PBO in adults age 21-65 years with mood and anxiety spectrum disorders. We will recruit a total of 90 subjects, of which 45 will be randomized to CERC-501 and 45 to placebo for 8 weeks of treatment

Arms:
arm 1: Oral dosing of 10 mg CERC-501 (formerly known as LY2456302) administered daily for 8 weeks arm 2: Oral daily administration of 10 mg placebo for 8 weeks

Interventions: intervention 1: CERC-501 intervention 2: placebo
Intervention descriptions: intervention 1: Oral dosing of 10 mg CERC-501 daily for 8 weeks intervention 2: oral dosing of 10 mg placebo daily for 8 weeks

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
Study Title: 
A Phase 2a Study to Evaluate the Kappa Opioid Receptor As a Target for the Treatment of Mood and 
Anxiety Spectrum Disorders by Evaluation of Whether CERC-501 Engages Key Neural Circuitry Related to 
the Hedonic Response 
 
Version Date: 
October 06, 2016 
 
NCT02218736 


FAST-MAS KOR Phase 2a Study Protocol 
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Page 1 of 75 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
A Phase 2a Study to Evaluate the Kappa Opioid Receptor As a 
Target for the Treatment of Mood and Anxiety Spectrum 
Disorders by Evaluation of Whether CERC-501 Engages Key 
Neural Circuitry Related to the Hedonic Response 
 
Abbreviated Title: 
FAST-MAS KOR Phase 2a 
 
Protocol Version: 
6.0 
Version Date: 
 October 06, 2016 
 
Contract Title: 
New Experimental Medicine Studies: Fast-Fail Trials in Mood and 
Anxiety Spectrum Disorders (FAST-MAS) 
Contract #: 
HHSN271201200006I 
Contractor: 
Duke University 
 
Contract PI: 
Andrew D. Krystal, M.D., M.S. 
Professor, Department of Psychiatry and Behavioral Sciences 
Duke University Medical Center 
Box 3309 
Durham, NC 27710 
 
 
Task Order #: 
HHSN27100004 
Overall Study PI: 
Andrew D. Krystal, M.D., M.S. 
 
 
Supported by:  
National Institute of Mental Health (NIMH) 
 
 
 
 
 
 
 
 
Confidential: This document and its contents are the property of the Duke Clinical 
Research Institute. The information contained herein is confidential and is to be used only 
in connection with matters authorized by Duke Clinical Research Institute. No portion of 
this document is to be disclosed to others without prior written permission of Duke 
Clinical Research Institute. 
 
 


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Abbreviated Study Title: FAST-MAS KOR Phase 2a 
 
Contract #: HHSN271201200006I 
Task Order #: HHSN27100004 
 
Coordinating Center [CC]: Duke Clinical Research Institute (DCRI) 
Data center [DCC]: Duke Clinical Research Institute (DCRI) 
 
Phase of Study:  
Phase 2a 
Target enrollment: 
90 Patients 
 
FDA Approval(s) 
IND 
 No  Yes 
 
Drug: CERC-501 
IND #: 121225 held by Dr. Andrew Krystal 
Drug supplied by: Cerecor 
IRB Approvals: 
Multi-Institutional Project 
 No Yes 
NIMH Data and Safety Monitoring Board 
 No  Yes 
 
Third Party Agreement(s): 
Technology Transfer Agreement 
 No  Yes 
Agreement type and number: Clinical Trial Research Support Agreement 
Effective Date: 10/1/13 
Expiration Date: End of study 
 
Samples are being stored 
 No  Yes 
 
 
 
 


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STATEMENT OF COMPLIANCE 
 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonisation (ICH) guideline E6: Good Clinical Practice: Consolidated Guideline and 
the applicable regulatory requirements from Title 45 of the Code of Federal Regulations 
(CFR) Part 46 and 21 CFR parts 50 (informed consent) and 56 (institutional review board 
(IRB)  and 312 (Investigational New Drug Application IND). 
 
All individuals responsible for the design and conduct of this study have completed 
Human Participants Protection Training and are qualified to be conducting this research 
prior to the enrollment of any participants.  
 
 
INVESTIGATOR STATEMENT 
 
I have read the protocol and agree to conduct the study as outlined and in accordance 
with all applicable local, state, and federal regulation. 
 
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
 
-------------------------------------------- 
---------- 
Signature of Principal Investigator 
Date 
 
 
------------------------------------------------------------ 
Name of Principal Investigator (printed or typed) 
 
 


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PRÉCIS (Protocol Synopsis) 
Protocol Title 
“A Phase 2a Study to Evaluate the Kappa Opioid Receptor as a Target for the 
Treatment of Mood and Anxiety Spectrum Disorders by Evaluation of Whether 
CERC-501 Engages Key Neural Circuitry Related to the Hedonic Response” 
Trial 
Product 
CERC-501, previous research name LY2456302 
Objectives 
Primary 
 
Evaluate the impact of CERC-501 10 mg relative to PBO on reward-
related neural circuitry in terms of ventral striatal fMRI activation during 
anticipation of reward during the Monetary Incentive Delay (MID) Task. 
Secondary 
 
Clinical Anhedonia Measure: To determine if 10 mg of CERC-501 is 
superior to PBO in improving a clinical self-report measure of anhedonia 
the Snaith Hamilton Pleasure Scale (SHAPS) 
 
Behavioral Anhedonia Measure: To evaluate the impact of CERC-501 
relative to PBO on a behavioral measure of anhedonia the Probabilistic 
Reward Task (PRT) 
Exploratory 
Objectives 
To assess the effects of CERC-501 relative to placebo on: 
 
Ventral striatal fMRI activation during anticipation of loss during the 
MID Task 
 
Resting state delta EEG current density in the rostral anterior cingulate.  
 
Resting state fMRI connectivity 
 
Self-rated affective responses to cues and feedback during the MID Task 
 
The Effort-Expenditure for Rewards Task (EEfRT) 
 
The Visual Analogue Scale for Anhedonia (VAS) 
 
The Temporal Experience of Pleasure Scale (TEPS) 
 
The Hamilton Depression Rating Scale (HAM-D) 
 
The Hamilton Anxiety Scale (HAM-A) 
 
The Cognitive and Physical Functioning Questionnaire (CPFQ) 
To assess the safety and tolerability of CERC-501 on systematically collected 
and spontaneously reported adverse events. 
Study Design 
Double-Blind, Placebo-Controlled Multi-Site Trial 
Study 
Population 
Patients with mood and anxiety disorders and anhedonia; age 21 – 65 years 
inclusive 
Number of 
Participants 
90 
Duration of 
Participant 
Participation 
A total of up to 16 weeks 
Up to 30 days for screening, 8 weeks of treatment and 4 weeks for a follow-up 
visit 
Dose Schedule 
10 mg CERC-501 daily for 8 weeks 
Estimated Start 
May, 2015 
Estimated End 
April 2017 
 
 


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Table of Contents 
PRÉCIS (Protocol Synopsis) ............................................................................................ 4 
LIST OF ABBREVIATIONS .......................................................................................... 8 
1. BACKGROUND AND SIGNIFICANCE ................................................................... 9 
1.1. Overview ............................................................................................................................. 9 
1.2. Background ....................................................................................................................... 10 
1.2.1. KOR Antagonism Promising Target for Treating Mood and Anxiety Disorders ....... 10 
1.2.2. Rationale for Studying Effects of KOR Antagonist on Anhedonia ............................ 12 
1.2.3. Properties of CERC-501 ............................................................................................. 12 
1.2.4. Rationale for Studying 10 mg Dosage of CERC-501 ................................................. 18 
1.3. Public Health Significance ............................................................................................... 19 
2. STUDY OBJECTIVES ............................................................................................... 19 
3. SUBJECTS .................................................................................................................. 20 
3.1. Description of Study Populations ................................................................................... 20 
3.2. Inclusion Criteria ............................................................................................................. 21 
3.3. Exclusion Criteria ............................................................................................................ 21 
4. STUDY DESIGN AND METHODS.......................................................................... 22 
4.1. Study Overview ................................................................................................................ 22 
4.2. Recruitment ...................................................................................................................... 25 
4.3. Screening ........................................................................................................................... 26 
4.4. Study Procedures ............................................................................................................. 27 
4.5. End of Participation / Early Termination ...................................................................... 30 
5. STORAGE OF DATA AND SAMPLES................................................................... 31 
6. RISKS AND DISCOMFORTS .................................................................................. 31 
6.1. Risks of Discontinuing Medications for Study Participation ....................................... 32 
6.2. Risks of Being Without Therapy During the Study ...................................................... 32 
6.3. Risks to Confidentiality ................................................................................................... 32 
6.4. Risks Associated with Treatment ................................................................................... 33 
6.5. Risks of Venipuncture ..................................................................................................... 34 
6.6. Risks Associated with fMRI Scanning ........................................................................... 34 
6.7. Risks associated with EEG and ECG studies ................................................................ 35 
6.8. Risks to Those of Reproductive Potential ...................................................................... 35 
6.8.1. Females ....................................................................................................................... 35 
6.8.2. Males........................................................................................................................... 35 
6.8.3. Pregnancy ................................................................................................................... 36 
7. SUBJECT SAFETY MONITORING ....................................................................... 36 
7.1. Parameters to be Monitored ........................................................................................... 36 
7.2. Criteria for Stopping Procedures in an Individual ....................................................... 37 
8. OUTCOME MEASURES .......................................................................................... 37 
8.1. Primary Outcome Measures ........................................................................................... 37 
8.2. Secondary Outcome Measures ........................................................................................ 37 
8.3. Exploratory Outcome Measures ..................................................................................... 38 
8.4. Description of Outcome Measures .................................................................................. 38 
8.4.1. Monetary Incentive Delay Task-related fMRI ............................................................ 38 
8.4.2. The Snaith-Hamilton Pleasure Scale (SHAPS) .......................................................... 40 
8.4.3. Probabilistic Reward Task .......................................................................................... 41 
8.4.4. Other Efficacy Assessments ....................................................................................... 43 


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9. STATISTICAL ANALYSIS ...................................................................................... 47 
9.1. Analysis of Data/Study Outcomes ................................................................................... 47 
9.1.1. Analysis of data/ study outcomes ............................................................................... 47 
9.1.2. Planned analyses and statistical methodology to be used ........................................... 48 
9.2. Power Analysis ................................................................................................................. 50 
10. HUMAN SUBJECTS PROTECTION .................................................................... 51 
10.1. Subject Selection ............................................................................................................ 51 
10.1.1. Statement of equitability ........................................................................................... 51 
10.1.2. Justification for exclusion of children ...................................................................... 51 
10.1.3. Justification for exclusion of other vulnerable subjects ............................................ 51 
10.1.4. Safeguards for vulnerable populations ..................................................................... 51 
10.1.5. Qualifications of Investigators .................................................................................. 52 
11. ANTICIPATED BENEFIT ...................................................................................... 52 
12. CLASSIFICATION OF RISK (for the study as a whole) ...................................... 53 
12.1. Risk Classification .......................................................................................................... 53 
12.2. Overall Risk and Benefit Consideration ...................................................................... 53 
13. CONSENT DOCUMENTS AND PROCESS ......................................................... 53 
13.1. Consent Procedures ....................................................................................................... 53 
14. DATA AND SAFETY MONITORING .................................................................. 53 
14.1. Data and Safety Monitor ............................................................................................... 53 
14.2. Data and Safety Monitoring Plan ................................................................................. 53 
15. QUALITY ASSURANCE ........................................................................................ 54 
15.1. Program Management Committee ............................................................................... 54 
15.2. Quality Assurance Plan ................................................................................................. 55 
15.2.1. Monitoring and Managing Study Timelines ............................................................. 55 
15.2.2. Monitoring for Protocol Deviations .......................................................................... 55 
15.2.3. Site Training ............................................................................................................. 55 
15.2.4. Site Electronic Data Capture (EDC) System Training.............................................. 56 
15.2.5. Research Ethics Training .......................................................................................... 56 
15.2.6. Ongoing Site Management/Monitoring .................................................................... 56 
16. ADVERSE EVENT AND UNANTICIPATED PROBLEM REPORTING ........ 56 
16.1. Plan for Assessment for Adverse Events ...................................................................... 56 
16.1.1. Adverse Events ......................................................................................................... 57 
16.1.2. Serious Adverse Events (SAE) ................................................................................. 57 
16.1.3. Assessment of Adverse Event Severity .................................................................... 58 
16.1.4. Assessment of Causal Relationship to Study Drug ................................................... 58 
16.1.5. Expectedness of Adverse Event ................................................................................ 58 
16.2. Documentation of Adverse Events ................................................................................ 58 
16.3. Reporting of Adverse Events ......................................................................................... 59 
17. ALTERNATIVES TO PARTICIPATION ............................................................. 60 
18. CONFLICT OF INTEREST .................................................................................... 60 
18.1. Distribution of NIH Guidelines ..................................................................................... 60 
18.2. Conflict of Interest ......................................................................................................... 60 
18.3. Role of a Commercial Company or Sponsor ............................................................... 60 
19. TECHNOLOGY TRANSFER ................................................................................. 60 
20. RESEARCH AND TRAVEL COMPENSATION ................................................. 60 


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21. REFERENCES .......................................................................................................... 61 
APPENDICES ................................................................................................................. 69 
Appendix 1. Eligibility Checklist ........................................................................................... 70 
Appendix 2. List of Prohibited Medications ......................................................................... 72 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CPFQ 
The Cognitive and Physical Functioning Questionnaire 
CSSRS 
Columbia Suicide Severity Rating Scale 
DCRI 
Duke Clinical Research Institute 
DSMB 
Data Safety Monitoring Board 
EDC 
Electronic Data Capture 
EEfRT 
Effort Expenditure for Rewards Task 
EEG 
Electroencephalogram 
FDA 
United States Food and Drug Administration 
fMRI 
Functional Magnetic Resonance Imaging 
HAM-A 
Hamilton Rating Scale for Anxiety 
HAM-D 
Hamilton Rating Scale for Depression 
HIPPA 
Health Insurance Portability and Accountability Act 
HSP 
Human Subjects Protection 
KOR 
Kappa Opioid Receptor 
CERC-501 
Investigational Kappa Opioid Receptor Antagonist 
MID 
Monetary Incentive Delay Task 
MINI 
Mini International Neuropsychiatric Interview (Mental State Examination) 
MRI 
Magnetic Resonance Imaging 
NIMH 
National Institute of Mental Health 
PBO 
Placebo 
PHI 
Protected Health Information 
PK 
Pharmacokinetic 
POC 
Proof of Concept 
PRISE 
Patient Reported Inventory of Side-Effects 
PRT 
Probabilistic Reward Task 
RDoC 
Research Domain Criteria Project 
SAE 
Serious Adverse Event 
SHAPS 
Snaith-Hamilton Pleasure Scale 
TEPS 
Temporal Experience of Pleasure Scale 
VAS 
Visual Analogue Scale 
 
 
 


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1. BACKGROUND AND SIGNIFICANCE 
 
1.1. Overview 
 
This Phase 2A study is a double-blind, placebo-controlled, randomized, parallel-group, 6-
site, trial of 8 weeks of daily dosing with 10 mg of CERC-501 (LY2456302) that is 
intended to test whether we can establish Proof of Concept (POC) that kappa opioid 
receptor (KOR) antagonists engage neural circuits involved in mediating the reward 
response. This will be specifically determined by testing whether CERC-501, a relatively 
selective KOR antagonist, increases ventral striatal activation in response to reward-
predicting cues. We are attempting to establish POC in this study in order to determine 
whether there is a sufficient basis for pursuing future work evaluating whether KOR 
antagonism has therapeutic effects on clinical and behavioral measures of reward-related 
functioning, a domain of function that is impaired in many patients with Mood and 
Anxiety Spectrum Disorders. 
 
The primary outcome measure which is being used to establish POC is neural activation 
within the ventral striatum during the Monetary Incentive Delay (MID) Task, as assessed 
with fMRI (Wacker et al., 2009; Pizzagalli et al., 2004, 2008a, 2009; Treadway et al., 
2012; Stoy et al., 2012; Ossewaarde et al., 2011; Knutson et al., 2008). This study also 
includes a number of secondary and exploratory measures to assess various domains of 
reward-related function including: the Snaith-Hamilton Pleasure Scale (SHAPS), a self-
report assessment of global reward function (Gilbert et al., 2002; Snaith et al., 1995); the 
Probabilistic Reward Task (PRT), an objective behavioral assessment of the capacity to 
learn from rewards (Barr et al., 2008; Bogdan and Pizzagalli, 2006, 2009; Pizzagalli et 
al., 2005, 2007, 2008a; Vrieze et al., 2013); the Effort-Expenditure for Rewards Task 
(EERT), a behavioral measure of the extent to which an individual is motivated by 
reward (Treadway et al., 2009, 2012a,b); the Temporal Experience of Pleasure Scale 
(TEPS), a self-report measure that assesses anticipatory pleasure (‘wanting’) and 
consummatory pleasure (‘liking’) (Gard et al., 2006; Stanford et al., 2011); a visual 
analogue scale (VAS) rating of hedonic respone; an additional measure of the 
engagement of neural circuits mediating the hedonic response, resting qEEG current 
density measures of delta power (Wacker et al., 2009; Pizzagalli et al., 2004); and self-
ratings of the reward response to stimuli in terms of ratings of affective responses to cues 
and feedback during the Monetary Incentive Delay Task (Pizzagalli et al., 2009). All of 
these are exploratory measures except the SHAPS and the PRT, which have previously 
been shown to be modulated by dopamine, affected by stress, associated with striatal 
function, predictive of clinical outcome and anhedonic symptoms, and improved with 
antidepressant therapy (Bogdan et al., 2011; Pizzagalli et al., 2005, 2008a,b, 2009; 
Santesso et al., 2008; Vrieze et al., 2013a,b; Di Giannantonio and Martinotti, 2012; 
Martinotti et al., 2011; Wacker et al., 2009). Other measures included in this study are: 
assessment for adverse effects, the Cognitive and Physical Functioning Questionnaire 
(CPFQ), and traditional anxiety (Hamilton Rating Scale for Anxiety [HAM-A]) and 
depression (Hamilton Rating Scale for Depression [HAM-D] measures, which are being 
evaluated in exploratory analyses to provide information regarding changes in depression 
and anxiety severity with treatment (Hamilton 1960, 1967; Fava et al., 2009). 
 
 


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1.2. Background 
 
The available treatments for patients with mood and anxiety disorders have significant 
limitations (Rush, 2007; Denys and de Geus, 2005). There is a need to develop new 
treatments for people with these disorders. Many research studies carried out in animals 
and a few preliminary studies carried out in humans suggest that medications which 
block kappa opioid receptors (KOR) have potential for being effective new treatments for 
patients with mood and anxiety spectrum disorders (see below). These medications have 
shown particular promise for improving one important type of difficulty experienced by 
many patients who suffer from mood and anxiety spectrum disorders referred to as 
anhedonia, which is an impairment in reward-related function. In this study we will test 
the hypothesis that KOR antagonism is a promising means of improving anhedonia in 
patients with mood and anxiety spectrum disorders. We will do so by evaluating whether 
we can establish Proof of Concept (POC) that a relatively selective KOR antagonist, 
CERC-501 (LY2456302; see Investigator Brochure), engages neural circuits involved in 
mediating reward-related function in patients with mood and anxiety spectrum disorders 
with anhedonia. We are attempting to establish POC in this study in order to determine 
whether there is a sufficient basis for pursuing future work evaluating whether KOR 
antagonism has therapeutic effects on clinical and behavioral measures of reward-related 
functioning. 
 
In addition to being a relatively selective KOR antagonist, CERC-501 is also well-suited 
for this study based on its pharmacologic and safety profiles (see Investigator Brochure). 
The 10 mg dosage of CERC-501 was chosen for evaluation because of preclinical 
studies, single and multiple ascending dose studies in humans, a single-dose PET study of 
KOR occupancy (Zheng et al., 2013), and pupillometry data obtained following 
administration of the mu agonist fentanyl (see Investigator Brochure). The following 
sections include details of the rationale for this study. 
 
1.2.1. KOR Antagonism Promising Target for Treating Mood and Anxiety 
Disorders 
There is an extensive set of pre-clinical studies suggesting that KOR antagonists are 
likely to have therapeutic effects in those with mood and anxiety spectrum disorders. This 
includes studies indicating a role of the kappa opiate system in mediating both anxiety 
and depression symptoms and studies suggesting that KOR antagonists have effects on 
animal models of both major depression and anxiety. 
 
A number of studies indicate that the kappa opiate system is critical for mediating the 
adverse effects of stress. An important aspect of stress-related pharmacology is the 
dynorphins, a group of opioid peptides that exert their effects primarily through binding 
to KOR (Bruchas et al., 2009). Evidence suggests that stress leads to anxiety by CRF1 
receptor activation of dynorphins in the basolateral amygdala which then bind to KOR 
(Bruchas et al., 2009). Place aversion and social avoidance occurring with repeated stress 
is mediated via dynorphin activation in ventral striatum, an effect which can be mimicked 
by KOR agonists and blocked by KOR antagonists (Land et al., 2009; Schindler et al., 
2012). KOR antagonists also block stress-related impairment in elevated plus maze 
spontaneous exploration (Peters et al., 2011). 
 


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Non-stress anxiety paradigms also suggest that KOR antagonists are likely to have 
anxiolytic effects. Prodynorphin knockouts (prodynorphin is the precursor protein for 
dynorphins) and KOR antagonists have been found to have anxiolytic-like effects in the 
novelty-induced hypophagia test, the defensive burying tests, the elevated plus maze test, 
fear-potentiated startle test, open-field test, and light-dark test (Carr and Lucki, 2010; 
Knoll et al., 2011; Wittmann et al., 2009). 
 
A larger literature suggests that KOR antagonists are likely to have anti-depressant 
effects and may prevent the depression-like consequences of stress. Dynorphin mediates 
the dysphoric aspects of stress via binding to KOR and this effect is prevented by 
knocking out dynorphin or administering a KOR antagonist (Land et al., 2008). The 
depression-like behaviors caused by chronic stress, uncontrollable stress, and social-
defeat stress are mediated by kappa opiate receptors and can be mimicked by KOR 
agonists (McLaughlin et al., 2006; Knoll and Carlezon, 2010). KOR antagonist treated 
mice and KOR knockout mice show a reduction of stress-induced depression-like 
behavior (McLaughlin et al., 2006; Knoll and Carlezon, 2010). Stress has also been found 
to trigger KOR activation of dorsal raphe neurons which project to nucleus accumbens 
and decrease dopamine release thereby diminishing reward and increasing drug seeking 
(Lemos et al., 2012). 
 
More generally, rodent studies show that administering KOR antagonists or knocking out 
the prodynorphin gene leads to antidepressant-like effects as assessed by reduced 
immobility in the forced swim test and reduced learned helplessness (via nucleus 
accumbens and hippocampal mediated mechanisms), whereas KOR agonists have 
depressogenic effects in conjunction with decreasing nucleus accumbens dopamine 
release (Reindl et al., 2008; Shirayama et al., 2004; Carlezon et al., 2006; McLaughlin et 
al., 2003; Mague et al., 2003; Todtenkopf et al., 2004; Chartoff et al., 2012; Chartoff et 
al., 2009). 
 
Perhaps the best recognized effect of KOR antagonists in animal models is to prevent the 
development of anhedonic-like states. The literature suggesting that KOR antagonists 
have such effects speaks to the potential of these agents to have therapeutic effects on 
anhedonia in humans, which is a core symptom of mood and anxiety disorders that cuts 
across diagnostic boundaries. In this regard, there is evidence that KOR stimulation 
inhibits dopamine release in the striatum (nucleus accumbens and caudate) and induces a 
negative mood state (Bruijnzeel, 2009). Consistent with this model, a series of studies 
indicate that KOR agonists decrease phasic dopamine release in the nucleus accumbens 
and increase intracranial self-stimulation (a model of anhedonia), whereas KOR 
antagonists have the opposite effect, increasing nucleus accumbens dopamine release and 
decreasing self-stimulation (Ebner et al., 2010; Muschamp et al., 2011; Carlezon et al., 
2006; Maisonneuve et al., 1994). Further, KOR agonists block cocaine’s anti-anhedonic 
effect on intracranial self-stimulation (Tomasiewicz et al., 2008) and block the 
reinforcing/rewarding effects on drugs of abuse (Wee and Koob, 2010), whereas, giving a 
KOR antagonist prior to cocaine withdrawal prevented anhedonic-like intracranial self-
stimulation responses (Chartoff et al., 2012). 
 
Although data in humans on the effects of selective KOR antagonists are lacking, 
preliminary data from humans are consistent with the animal data in suggesting that this 


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target is likely to have therapeutic effects in mood and anxiety spectrum disorders. In an 
open-label study, 6 patients who had failed antidepressant medications and ECT were 
found to improve with buprenorphine (a KOR antagonist and partial mu agonist) 
treatment (Nyhuis et al., 2008). Findings of a double-blind, placebo-controlled, pilot 
study in 32 patients with treatment-resistant depression treated with the combination of 
buprenorphine and a mu receptor antagonist (simulated kappa opiate receptor antagonist) 
indicate that this combination had a significant antidepressant effect (Ehrich, 2012). 
 
Together, the available data provide a compelling indication that KOR antagonists are 
likely to have therapeutic effects in patients with mood and anxiety spectrum disorders. 
These data point to the adverse effects of stress and particularly anhedonia as therapeutic 
targets of interest with these agents. 
 
1.2.2. Rationale for Studying Effects of KOR Antagonist on Anhedonia 
We chose to focus on anhedonia as an endpoint for this study because: 1) the available 
data suggest that anhedonia is the dimension of mood and anxiety spectrum disorders that 
is most likely to be improved by KOR antagonists (see above); 2) anhedonia is associated 
with measurable neurobiological mechanisms which can be studied with available 
methodologies that could be used to establish POC in terms of engagement of relevant 
neural circuitry (Wacker et al., 2009; Pizzagalli et al., 2004, 2009; Treadway et al., 2012; 
Stoy et al., 2012; Ossewaarde et al., 2011); and 3) anhedonia allows us to accomplish our 
goal of studying an important aspect of dysfunction that cuts across mood and anxiety 
spectrum disorders, consistent with the NIMH’s RDoC framework. 
 
The data indicating that KOR antagonists are likely to improve anhedonia are strong 
relative to the data indicating that there will be other therapeutic effects of KOR 
antagonists. As a result, it seems likely that, if there are any therapeutic effects of these 
agents in those with mood and anxiety spectrum disorders, a therapeutic effect on 
anhedonia would be evident. As a result, anhedonia is an appropriate primary endpoint 
for a POC study with a KOR antagonist the treatment of patients with mood and anxiety 
spectrum disorders. Failure to demonstrate a therapeutic effect of a KOR antagonist on 
the neural circuitry related to anhedonia using a dosage that had been demonstrated to 
have acceptable kappa opiate receptor occupancy would be a reasonable indication to fail 
KOR antagonism as a treatment for mood and anxiety disorders. 
 
1.2.3. Properties of CERC-501 
This study will evaluate CERC-501 (LY2456302), a high-affinity, selective kappa opioid 
receptor antagonist. Its favorable pharmacologic and adverse effects profiles support its 
use in this study. 
 
1.2.3.1. Clinical Pharmacology 
CERC-501 (LY2456302) is a structurally unique kappa-selective opioid receptor 
antagonist, as highlighted in Tables 1 and 2. CERC-501 selectively occupies kappa 
opioid receptors in vivo, as shown in Figure 1. 
 
 
 


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Table 1 – Receptor Binding Affinity, hKi (nM) 
Compound 
Mu 
Kappa 
Delta 
FP3FBZ 
35.8 
0.57 
211 
CERC-501 
24.0 
0.81 
155 
norBNI 
34.7 
0.13 
9.49 
JDTic 
11.5 
0.06 
188 
Naltrexone 
0.58 
1.81 
12.4 
All data represent the mean of n=3 exp on separate occasions. 
 
Table 2 – Antagonist Potency, hKb (nM) 
Compound 
Mu 
Kappa 
Delta 
FP3FBZ 
21.3 
1.57 
293 
CERC-501 
17.4 
0.81 
110 
norBNI 
32.9 
0.80 
14.1 
JDTic 
6.58 
0.10 
168 
Naltrexone 
0.47 
2.26 
11.3 
All data represent the mean of n=3 exp on separate occasions. 
 
 
 


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Figure 1 – Occupancy of kappa opioid receptors in rats in vivo 
 
 
 
N = 3 male SD rats per dose group; Mu: naltrexone administered at 10 mg/kg IV; Kappa: GR103545 
administered at 1.5 mg/kg IV; Delta: naltriben administered at 10 mg/kg IV. 
 
1.2.3.2. Pharmacokinetic Studies and Drug-Drug Interactions 
Exposures increased approximately proportionally with dose and steady state was 
reached within 7 to 8 days of once per day (QD) dosing. Moderate accumulation of 
CERC-501 (LY2456302) - average accumulation ratio (AUC) across dose groups was 
calculated to be 1.8 (range: 1.8 to 1.9). Degree of accumulation after multiple dosing was 
consistent with the half-life observed after single dose (see Figure 2). Excretion is mostly 
through the urine. 
 
There is no definitive drug-drug interaction study yet. However, the risk of drug-drug 
interactions is currently perceived as relatively low. There was no irreversible inhibition 
of CYP2C8; however, competitive reversible inhibition was observed with inhibitory 
constant (Ki) = 3.7 uM. Given a projected maximum drug concentration at steady state 
(Cmax,ss) = 143 ng/mL (0.34 uM) following multiple dosing at 35 mg, the highest dose 
to be tested in Study LAFB, a value of Cmax,ss/Ki = 0.1 indicates the possibility of an 
interaction with CYP2C8 substrates. For this reason, medications that are primarily 
metabolized by cytochrome P450 2C8 (CYP2C8) (cerivastatin, paclitaxel, repaglinide, 
sorafenib, and torsemide) will be exclusionary for all studies with CERC-501 until 
definitive drug-drug interaction studies are carried out. 
 
 


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Figure 2 – Mean (+/- SD) of CERC-501 Plasma Concentration 
 
 
1.2.3.3. Selectivity for the Kappa-Opioid Receptor 
While CERC-501 (LY2456302) is a selective kappa opioid receptor antagonist in the 
efficacy dose range, in vivo rat receptor occupancy studies have shown that CERC-501 
exhibits mu opioid receptor antagonist activity at higher doses. Therefore, the potential 
mu antagonist activity of CERC-501 was assessed using an intravenous (IV) agonist 
challenge with the mu agonist fentanyl, which is known to induce miosis. These agonist-
induced effects can then be blocked by mu opioid antagonists. CERC-501 reversal of 
fentanyl-induced miosis was assessed over a dose range determined from the safety and 
PK data of CERC-501 in Part 1 of the study. CERC-501 was tested up to 60 mg PO and 
the effect on fentanyl-induced miosis was linear. CERC-501 blocked fentanyl-induced 
miosis at 60 mg to modest degree, indicating kappa selectivity at < 10 mg. The dose that 
produces 50% of Emax (ED50) estimate was 21.9 mg, suggesting the doses of 25 mg and 
60 mg have some moderate effect. Naltrexone at the 50 mg dose completely reversed 
fentanyl-induced miosis (Lilly Study GCAQ; steady state). 
 
1.2.3.4. Kappa-Opioid Receptor Occupancy in the Human Brain 
KOR Occupancy in the human brain is based on a Positron Emission Tomography (PET) 
Study (See Figure 3). The novel PET tracer [11C]PKAB (LY2879788) was validated as a 
specific kappa antagonist PET tracer in non-human primate studies and human clinical 
trials in collaboration with the Yale PET Center. The clinical trial I2Z-MC-LAFC 
assessed brain kappa OR occupancy after single oral doses of 0.5-25 mg CERC-501, 
measured by PET with the radioligand LY2879788 after single oral doses of CERC-501 
of 0.5, 2, 4,10, 25 mg in 13 healthy subjects. Kappa-opioid receptor occupancy (RO) was 
measured in high uptake regions (amygdala, anterior cingulate, frontal cortex, and insula) 
with the specific kappa-opioid antagonist PET tracer LY2829788 at two time-points post-
dose, at around Tmax (approximately 2.5 hours post-dose; “peak scan”) and on day 2 at 
around 22.5 hours post-dose (“trough scan”). As shown in Figure 3, 10 mg is associated 
with mean peak RO of 94% (range: 93-94%) at 2 hours post-dose, and a mean trough RO 
of 72% (range 68-75%) at 24 hours post-dose. 
 
Time (h)
0
6
12
18
24
Mean (+/-SD) LY2456302 Plasma Concentration (ng/mL)
0
10
20
30
40
50
60
Day 1
Day 13


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Figure 3 – Kappa receptor occupancy in humans after a singe oral dose of CERC-
501 
 
Brain kappa opioid RO after a single oral dose of CERC-501 (LY2456302) as measured by PET and [11]C-
PKAB in healthy subjects. 
 
1.2.3.5. Nonclinical Safety Pharmacology 
The toxicity profile of CERC-501 (LY2456302) has been characterized in rat, mouse, 
dog, and rabbit through a package of in vitro, repeat-dose (up to 6 months in dogs and 
rats and up to 2 weeks in mice), reproductive and genotoxicity studies and through safety 
pharmacology studies. No adverse effects were observed in dogs at a high dose of 2000 
mg/kg/day. In the 6-month rat study, the only adverse findings were dose-related 
histopathologic changes in the stomach, primarily decreased parietal cells and 
inflammation at all dose levels. Although a NOAEL was not observed, the gastric 
findings were minimal to moderate in severity, not life threatening, and partially 
reversible over a 1-month recovery period. Dose levels of 2000 mg/kg/day in mice, ≥800 
mg/kg/day in rats, or ≥200 mg/kg/day in rabbits exceeded the maximum tolerated dose 
(MTD) resulting in adverse clinical signs, decreased food consumption and body weight, 
and mortality/euthanasia. Convulsions were also noted after 1 or 2 doses of CERC-501 at 
2000 mg/kg (mice), 1500 mg/kg (rats), or 1000 mg/kg (rabbits). CERC-501 was not 
genotoxic in a standard battery of genotoxicity tests. These nonclinical toxicology results 
demonstrate an acceptable safety profile for the proposed clinical study of CERC-501. 
Following 6 months of treatment, the margin of safety (MOS) based on the area under 
curve (AUC) is 196-fold for the dog and 59-fold for the rat, for all effects, excluding the 
stomach findings in rats (Table 5.3 of the Investigator’s Brochure). A NOAEL for the 
stomach changes in the rat was not established. The MOS for convulsions is 38-fold 
based on Cmax, in the most sensitive species (rabbit), and is ≥38-fold based on both 
Cmax and AUC for convulsions in a mouse ethanol withdrawal model. In nonclinical 
safety pharmacology studies with CERC-501, there were no effects on the central or 
peripheral nervous systems or respiratory function in rats given doses up to 800 mg/kg. In 
dogs, there was an apparent trend for increased QT and QTc intervals following a single 


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dose of 1000 mg/kg compared to vehicle, although the increases were not statistically 
significant. 
 
1.2.3.6. Clinical Safety Data 
In total, 73 healthy subjects have been exposed to single or multiple doses of CERC-501 
(LY2456302) in 3 completed clinical pharmacological studies (Studies LAFA, LAFB, 
and LAFC). No significant safety concerns were encountered in Study LAFA after 
single-dose administration of CERC-501 up to 60 mg, in Study LAFB after multiple-dose 
administration of CERC-501 up to 35 mg, and in Study LAFC after single-dose 
administration of CERC-501 up to 25 mg. In these studies, there were no serious adverse 
events (SAEs). 
 
In Study LAFA, 1 subject, a 47-year-old white male participating in Part 1, was 
discontinued from the study due to a treatment-related adverse event (AE) of mild 
ventricular tachycardia. This subject experienced a mild 5-beat ventricular tachycardia 
approximately 8 hours after receiving a single 25-mg dose of CERC-501 in Part 2. The 
subject was asymptomatic during the AE. Follow-up telemetry monitoring for 24 hours 
did not reveal any clinically significant findings; overall, there was no clear dose 
dependency observed, as no ventricular tachycardia was observed after administration of 
a higher (60 mg) dose of CERC-501. 
 
No subjects were discontinued from Study LAFB or Study LAFC. In Study LAFA, 126 
AEs were reported by 20 of 32 subjects. Of these 126 AEs, 23 were considered by the 
investigator to be related to CERC-501 with the most common (occurring >1 incidence) 
in CERC-501-treated subjects being: headache (6 events), diarrhea (4 events), nausea (3 
events), and anxiety (2 events). Most of the 126 AEs were of mild-to-moderate severity; 
only 2 events (vomiting and flushing), not related to CERC-501 administration, as 
determined by the investigator, were severe. 
 
In Study LAFB, 52 AEs were reported by 19 of 37 subjects. Of these 52 AEs, 22 were 
considered by the investigator to be related to CERC-501, with the most common 
(occurring >1 incidence) in CERC-501-treated subjects being dyspepsia (5 events), 
pruritus generalized (3 events), headache (2 events), diarrhea (2 events), and abdominal 
pain (2). Of note, 2 subjects receiving 10 mg CERC-501 and 1 subject receiving 35 mg 
CERC-501 experienced a total of 24 AEs or more than half of all reported. All AEs were 
of mild severity, with the exception of 1 moderate AE of hemorrhoids, not related to 
CERC-501, as determined by the investigator, which occurred after administration of 10 
mg CERC-501. 
 
In Study LAFC, 21 AEs of mild-to-moderate severity were reported by 11 of 13 subjects; 
none of the AEs were considered by the investigator to be related to CERC-501. Most 
events were related to the study procedure. 
 
There have been no clinically significant values, changes, or trends in clinical laboratory 
data, with the following exception: 1 subject in Study LAFA experienced mildly elevated 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (>2 times 
the upper limit of normal), which were not considered by the investigator to be related to 
study drug, after receiving a single dose of 4 mg CERC-501 in Part 2 of Study LAFA. 


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Given the results of the 6-month rat study, where there were adverse dose-responsive 
findings in the glandular stomach included parietal cell loss, inflammation and mucus cell 
hyperplasia, FDA expressed safety concerns for the stomach lesions. Minimal to slight 
effects were observed at the low dose. There was no NOAEL. No other adverse effects in 
the rat and no adverse effects in dogs at a dose of 2000 mg/kg. These findings are of low 
risk (nonclinical) and may be species-specific (rat only). Both the FDA Division of 
Psychiatry Products (DPP) and Division of Anesthesia, Analgesia, and Addiction 
Products (DAAAP) agreed that studies in a third species would provide considerable 
weight-of evidence to support the conclusion that the effect was species specific; 
however, there was still concern that CERC-501 may exacerbate alcohol-induced 
gastrointestinal pathology. The FDA agreed that a negative second non-rodent species 
chronic toxicology study would provide a weight-of-evidence argument that GI findings 
in 6-month rat study are species-specific. This study may obviate the need to conduct 
routine endoscopies with biopsy in future clinical studies. The FDA concluded that since 
GI findings were only seen in rats (but not dogs), after 6 months of dosing (but not after 1 
month of dosing) and were essentially reversible, the NOAEL/LOAEL provided an 
adequate safety margin for the proposed dose of 10 mg and duration of an 8-week study 
with CERC-501. The FDA has agreed that an 8-wk POC study in MDD patients can be 
conducted without routine endoscopies and biopsies.  
 
1.2.4. Rationale for Studying 10 mg Dosage of CERC-501 
In the single-ascending dose study, dose escalation was halted at 60 mg based on PK 
analysis of this dose level. This analysis indicated that the Cmax for CERC-501 
(LY2456302) was close to the 180-ng/mL limit required to maintain a 30-fold MOS to 
the NOAEL for convulsions observed in rabbits. Data from the completed multiple-dose 
study showed that the mean C (CV%) after multiple (14) QD doses of 35 mg was 81 
ng/mL (23%). This is well below the maximum desired concentration of 180 ng/mL. The 
PET study carried out with the Kappa Opiate Receptor tracer LY2879788 demonstrated 
that single, oral doses of 0.5 mg up to 25 mg CERC-501 penetrated the blood-brain 
barrier, led to specific target engagement, and blocked significantly and in a dose-related 
manner, kappa opioid receptors in the brain (Zheng et al., 2013) (See Figure 3). 
Approximately 2.5 hours postdose (“peak scan”), brain kappa opioid receptors were 
almost saturated at doses of 10 mg or more (96.7% receptor occupancy), whereas at 
trough the receptor occupancy was >60%. Sustained and substantial target engagement 
was observed for at least 22.5 hours. 
 
An additional consideration motivating the choice of 10 mg of CERC-501 are potential 
effects on mu opioid receptors (MOR) which may be depressogenic. CERC-501 is a 
potent, high-affinity KOR antagonist with no appreciable affinity at several non-opioid 
cell surface receptor targets, including monoaminergic, muscarinic, cholinergic, and 
adrenergic receptors, as well as the central benzodiazepine binding site, ion channels, or 
transporters. However, in vitro binding and functional assays suggest that this agent does 
have some MOR antagonist effects, though the affinity for KOR is over 6 times greater. 
In vivo receptor occupancy and pharmacology assays indicate that oral administration of 
CERC-501 exhibits at least a 30-fold functional kappa selectivity over mu and delta 
opioid receptors (See Figure 1). The potential that CERC-501 might have some mu 
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patients with depression because of several lines of evidence suggesting that mu 
antagonists might be depressogenic (Berrocoso et al., 2009; Escriba et al., 2004; Kennedy 
et al., 2006). As a result, pupillometry was carried out following administration of the mu 
agonist fentanyl to determine the degree to which various dosages of CERC-501 would 
block the mu agonist effects of fentanyl as indicated by pupil diameter (See 1.2.3.3 
above). This test was carried out in a human multiple-ascending dose study. Moderate mu 
antagonist effects of CERC-501 were seen with the 60 mg dosage but were felt to be 
“minimal” at dosages below 60 mg (See Investigator Brochure). Based on these data, the 
10 mg dose was felt to represent the best tradeoff between kappa and mu effects. It 
provides sufficient KOR antagonism while at the same time having relatively minimal 
MOR blockade based on pupillometry. 
 
A further consideration supporting the choice of the 10 mg dosage of CERC-501 is that 
this is also the highest dosage where completed toxicity studies support carrying out a 
trial as long as 8 weeks of daily dosing in humans. On these bases, the 10 mg dose was 
chosen for evaluation in this Phase 2a study. 
 
1.3. Public Health Significance 
The available treatments for patients with mood and anxiety spectrum disorders have 
significant limitations (Rush, 2007; Denys and de Geus, 2005). This study will contribute 
significantly to public health by taking steps to address these limitations by: 1) 
expeditiously testing a promising new treatment for mood and anxiety spectrum 
disorders; 2) evaluating a potential target in the brain which could serve as the basis for 
development of additional new candidate compounds for the treatment of patients with 
mood and anxiety spectrum disorders; 3) establishing more expeditious methods for 
evaluating potential new therapies for patients with mood and anxiety spectrum 
disorders; and 4) specifically establishing methods for the development of new therapies 
targeting anhedonia, an important RDoC endpoint. 
 
2. STUDY OBJECTIVES 
 
The Primary Objectives of this study are: 
 Specific Aim 1:  
Establish POC for KOR antagonism by evaluating the impact of CERC-501 10 
mg relative to Placebo (PBO) on reward-related neural circuitry in terms of 
ventral striatal fMRI activation during anticipation of reward during the Monetary 
Incentive Delay (MID) Task. 
 
The Secondary Objectives of this study are: 
 Secondary Aim 1:  
Clinical Anhedonia Measure: To determine if 10 mg of CERC-501 is superior to 
PBO in improving a clinical self-report measure of anhedonia, the Snaith 
Hamilton Pleasure Scale (SHAPS). 
 Secondary Aim 2:  
Behavioral Anhedonia Measure: To evaluate the impact of CERC-501 relative to 
PBO on a behavioral measure of anhedonia, the Probabilistic Reward Task (PRT). 
The Exploratory Objectives of this study are; 


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 To assess the effects of CERC-501 relative to placebo on: 
o Ventral striatal fMRI activation during anticipation of loss during the MID 
Task 
o Resting state delta EEG current density in the rostral anterior cingulate 
o Resting state fMRI connectivity 
o Self-rated affective responses to cues and feedback during the MID Task 
o The Effort-Expenditure for Rewards Task (EEfRT) 
o The Visual Analogue Scale for Anhedonia (VAS) 
o The Temporal Experience of Pleasure Scale (TEPS) 
o The Hamilton Depression Rating Scale (HAM-D) 
o The Hamilton Anxiety Scale (HAM-A) 
o The Cognitive and Physical Functioning Questionnaire (CPFQ) 
o Clinical Global Impression Severity and Improvement (CGI-S and CGI-I) 
Ratings 
 To assess the safety and tolerability of CERC-501 on systematically collected and 
spontaneously reported adverse events 
 
 
3. SUBJECTS 
 
3.1. Description of Study Populations 
 
We will enroll 90 subjects in this trial. The inclusion and exclusion criteria are listed 
below. We will stratify enrollment to ensure that there is ample cross-diagnostic 
representation so that the therapeutic effects of CERC-501 on anhedonia may be assessed 
independently of its effect on any particular mood and anxiety spectrum disorder. This 
will be accomplished by attempting to randomize subjects who meet the anhedonia entry 
criteria and have an anxiety disorder but do not currently meet major depressive disorder 
(MDD) criteria based on the MINI (subjects with a past history of MDD but who do not 
currently meet diagnostic criteria could be included).  Anhedonia is a core symptom of 
MDD, and one of its diagnostic criteria, but this is not the case for anxiety disorders. As a 
result, we are including a requirement for inclusion of patients with anxiety disorders 
because without such a criterion, we run the risk of only including subjects with 
anhedonia occurring in the setting of MDD, which would result in our being unable to 
distinguish an antidepressant effect which included a beneficial effect on anhedonia from 
an anhedonia-specific effect.  However, because there has been no prior work 
establishing the prevalence of the target subgroup (those who meet our anhedonia entry 
criterion and have an anxiety disorder but do not currently meet MDD criteria) it is 
unclear how difficult it will be to randomize these individuals.   As a result, we will not 
stratify enrollment to ensure a fixed number of subjects of this type as this could 
jeopardize the ability of the study to randomize the total target number of subjects (90) 
and, thereby, impede accomplishing the primary aims.  Instead, we will seek to 
include approximately 33% of the total number randomized (30 subjects) of this type but 
will prioritize meeting the primary aims of the study (randomizing 90 total subjects) over 
this goal. 
See Appendix 1 for an Eligibility Checklist. 
 


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3.2. Inclusion Criteria 
1. Age between 21 and 65 years of age (inclusive) 
2. Must meet DSM-IV TR diagnostic criteria for: Major Depressive Disorder, 
Bipolar I or II Depressed, Generalized Anxiety Disorder, Social Phobia, Panic 
Disorder, or Post Traumatic Stress Disorder 
3. Snaith-Hamilton Pleasure Scale (SHAPS) score ≥ 20 
4. Reliable and willing to be available for the duration of the study 
5. Willing and able to give written informed consent to participate 
6. Able to understand and comply with instructions 
7. If female of childbearing potential, must agree to use dual methods of 
contraception and be willing and able to continue contraception for 6 weeks after 
the last dose of study drug. Females using oral contraception must have started 
using it at least 2 months prior to the Baseline Visit 
8. If male of childbearing potential, must have undergone surgical sterilization (such 
as a vasectomy) or agree to use a condom used with a spermicide during 
participation in the study and for 1 month after the last dose of study drug 
 
3.3. Exclusion Criteria 
1. Expected to require any hospitalization during the course of the study 
2. Current/history of a psychotic disorder, current manic or mixed episode, autism 
spectrum disorders, mental retardation 
3. Met DSMIV-TR criteria for substance abuse within the last 3 months or substance 
dependence within the last 6 months, excluding caffeine and/or nicotine 
4. History of unstable or untreated serious medical condition based on physician 
evaluation, medical history, and screening laboratory testing 
5. Active suicidal intent or plan, or history of attempt within the past 3 months based 
on physician evaluation and Columbia Suicide Severity Rating Scale (C-SSRS) 
6. Use of any antidepressant, antipsychotic, anxiolytic, anticonvulsant, mood 
stabilizing, muscle relaxant, centrally acting antihistaminergic, stimulant or 
insomnia medications (See Appendix 2) within 5 half-lives of baseline or at any 
time during after baseline 
7. Use of any medication that is primarily metabolized by Cytochrome P450 2C8 
within 14 days of baseline or at any time during the study. This includes: 
Cerivastatin, Paclitaxel, Repaglinide, Sorafenib, Rosiglitazone, Trimethoprim, 
Amodiaquine, Morphine, Amiodarone, Cabazitaxel, Carbemazepine, 
Chloroquine, Ibuprofen, Teprostinil, Torsemide. 
8. Any contraindications to the magnetic resonance imaging procedures 
9. Positive urine drug screen at Screening Visit  
10. Use of any investigational medication within 3 months prior to the start of this 
study or scheduled to receive an investigational drug other than the study drug 
during the course of this study 
11. Known hypersensitivity to CERC-501 
12. History of severe allergies or multiple adverse drug reactions 
13. History of gastric disease (including peptic ulcer disease, gastritis, upper GI 
bleeding, or any GI precancerous condition), current clinically evident 
gastrointestinal complaints.  
14. Current use of a proton pump inhibitor or histamine 2 blocker, or a history of 


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chronic NSAID use 
15. History of use of Salvia divinorum or use of Salvia divinorum at any time during 
the study 
16. Any other condition that in the opinion of the investigator would preclude 
participation in the study 
17. Any smoking of cigarettes or use of other nicotine containing products within the 
last month or at any time during the study 
18. Pregnant or lactating 
 
 
4. STUDY DESIGN AND METHODS 
 
4.1. Study Overview 
 
This study will be a six-site randomized, double-blind, PBO-controlled, parallel-group 
mono-therapy study to assess the effects of CERC-501 compared to PBO in adults age 
21-65 years with mood and anxiety spectrum disorders. We will recruit a total of 90 
subjects, of which 45 will be randomized to CERC-501 and 45 to placebo for 8 weeks of 
treatment. 
 
Following phone screening subjects will come to the research unit/clinic for a face-to-
face screening visit. Subjects who sign informed consent will undergo rigorous screening 
including: a medical, psychiatric, medication, and treatment history, vital signs, physical 
examination, urine drug screen, MINI, clinical diagnostic interview for psychiatric 
disorders, beta-HCG serum pregnancy test (women), ECG, Snaith-Hamilton Pleasure 
Scale (SHAPS), Visual Analog Scale for Anhedonia, Temporal Experience of Pleasure 
Scale (TEPS), CSSRS, CGI-S, CGI-I and a battery of clinical laboratory tests (See Table 
3 for Schedule of Assessments). All study events, their corresponding dates, and results 
of these examinations will be reported on the corresponding case report forms (CRFs). 
All subjects will be off of all antidepressant, antipsychotic, anxiolytic, anticonvulsant, 
mood stabilizing, muscle relaxant, centrally acting antihistaminergic, stimulant or 
insomnia medications (See Appendix 2) within 5 half-lives of baseline or at any time 
during after baseline and will have to remain off of all such medications other than study 
medication during the trial. 
 
Subjects who require tapering off of medications will discuss a medication tapering plan 
with a study physician. The study physician will develop a plan for safely decreasing and 
stopping medications that is tailored to each subject to minimize risks and discomfort and 
will be conducted in consultation with the subject’s treating physician when applicable. 
This plan will be communicated to the subject including a detailed indication of the times 
at which medications are to be decreased, the possible side-effects that they may 
experience with decreases in medication dosage, the possible worsening of symptoms 
they may experience as medication dosage is lowered, and a plan for how to proceed if 
they develop side-effects or symptoms worsen. A study physician will be responsible for 
monitoring subjects during the washout including scheduling assessment visits if needed 
and addressing any side effects or worsening of symptoms that occur. Subjects who 
develop clinically significant adverse effects or worsening will receive appropriate 
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evaluation/treatment. This plan will be designed so that subjects are free of all excluded 
medications at least 5 half-lives prior to the baseline visit (see Exclusion Criteria above). 
Subjects will also undergo a mock MRI scanning session at this visit. 
 
Subjects will return to the research unit/clinic for a baseline assessment visit up to 30 
days after the screening visit. At this visit subjects will undergo interval history, physical 
examination, ECG, vital signs, battery of laboratory tests, MRI, EEG, SHAPS, TEPS, 
VAS, CSSRS, PRT, EEfRT, HAM-D, HAM-A, CPFQ, CGI-I and CGI-S and will have 
the option of having blood collected to be sent to Rutgers for potential genetic analysis or 
other future analysis. Blood will also be collected for tests for assessment for gastric 
adverse events including gastrin and pepsinogen I/II levelsAt the end of this visit, 
subjects who continue to qualify will be randomized to CERC-501 10 mg or placebo in a 
1:1 ratio using IVRS randomization within the EDC. 
 
IVRS Randomization will be carried out using the Simple Internal Randomization Engine 
(SIRE), which is a tool developed by the DCRI to randomize study patients. SIRE is fully 
integrated with the EDC database. A randomization list in hardcopy will also be kept 
under lock and key by the statistician as a back-up should the computer system be down. 
In case of system failure, the statistician will provide the individual dispensing the 
medication at a site with the medication allocation over the phone. It will also allow study 
physicians to obtain the randomization information from the statistician and procedures 
to break the blinding in cases of emergencies. All individuals having interactions with the 
subjects will remain blind to treatment group assignment other than in cases of 
emergencies. 
 
Subjects will then return for treatment visits at weeks 2, 4, 6 and 8 following 
randomization during which the following study assessments will take place: Interval 
history, battery of lab tests, Vital signs, physical examination, ECG, SHAPS, TEPS, 
VAS, CCRS, CGI-I, and CGI-S, Adverse Effects Assessment with Patient Reported 
Inventory of Side-Effects (PRISE), and blood will be collected for determination of 
CERC-501 levels. At the week 4 and week 8 visits blood will also be collected for tests 
for assessment for gastric adverse events including gastrin and pepsinogen I/II levels. 
 
In addition at the 8 week post-randomization visit subjects will also undergo MRI, EEG, 
PRT, EEfRT, HAM-D, HAM-A, and CPFQ and will have the option of having blood 
collected to be sent to Rutgers for potential genetic analysis or other future analysis. 
Following this visit study drug will be discontinued and subjects will be instructed to 
return in 4 weeks for a final visit. 
 
At the final visit, subjects will undergo: vital signs, interval history, SHAPS, TEPS, VAS, 
CSSRS, CGI-I, CGI-S and a clinical interview for adverse effects. At the conclusion of 
this visit subject participation in the study will end. 
 
 


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Table 3. Schedule of Assessments, Outcome Measures, Labs, and Procedures 
 
Screen Baseline 
 
Follow 
Up 
Double-Blind 
Treatment Period 
Follow 
Up 
Visit 
Screen 
A0 
 
Phone  
A1
† 
A2
† 
A3† 
A4† 
1 
Month† 
Weeks from Baseline 
Up to -
4 
0 
1 
2  
4 
6 
8 
12 
Informed Consent 
X 
 
 
 
 
 
 
 
Physical Exam / Medical History / 
Demographics 
X 
X 
 
X 
X 
X 
X 
 
Treatment History 
X 
X 
 
X 
X 
X 
X 
X 
Mini-International Neuropsychiatric Interview 
(MINI) 
X 
 
 
 
 
 
 
 
Clinical Interview/Interval History  
X 
X 
 
X 
X 
X 
X 
 
Electrocardiogram (ECG) 
X 
X 
 
X 
X 
X 
X 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
HCG (serum) 
X 
 
 
 
 
 
 
 
Labs* 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medication Adherence 
 
 
 
X 
X 
X 
X 
 
fMRI with Monetary Incentive Delay Task, 
Resting State Connectivity 
 
X 
 
 
 
 
X** 
 
Snaith-Hamilton Pleasure Scale (SHAPS) 
X 
X 
 
X 
X 
X 
X 
X 
Probabilistic Reward Task (PRT) 
 
X 
 
 
 
 
X 
 
Effort Expenditure for Rewards Task (EEfRT) 
 
X 
 
 
 
 
X 
 
Quantitative EEG (QEEG) 
 
X 
 
 
 
 
X 
 
Temporal Experience of Pleasure Scale 
X 
X 
 
X 
X 
X 
X 
X 
Visual Analogue Scale for Anhedonia 
X 
X 
 
X 
X 
X 
X 
X 
HAM-D 
 
X 
 
 
 
 
X 
 
HAM-A 
 
X 
 
 
 
 
X 
 
Cognitive and Physical Functioning 
Questionnaire (CPFQ) 
 
X 
 
 
 
 
X 
 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
Columbia Suicide Severity Rating Scale 
(CSSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Collection for Rutgers 
 
X 
 
 
 
 
X 
 
Blood Collection for Gastric Adverse Events** 
 
X 
 
 
X 
 
X 
 
Blood Sample for Drug Blood Level Testing 
 
 
 
X 
X 
X 
X 
 
Adverse Effects Assessment with Patient 
Reported Inventory of Side-Effects (PRISE) 
 
X 
 
X 
X 
X 
X 
X 
X 
Clinical Global Impression–Severity (CGI-S) 
X 
X 
 
X 
X 
X 
X 
X 
Clinical Global Impression – Improvement 
(CGI-I) 
 
X 
 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
Mock MRI Scanning Session 
X 
 
 
 
 
 
 
 
*Complete blood count with differential, Electrolytes, Metabolic Panel, Thyroid Function Tests, 
Urinalysis. **Tests for assessment of gastric adverse events include: gastrin, and pepsinogen I/II 
levels. 
** Not performed if subject terminates from drug prior to week 8. 
† ±4 days 


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4.2. Recruitment 
 
Subjects will be recruited at each study site. The information collected at that time is used 
simply to rule out any obvious exclusion criteria, such as age and substance 
abuse/medical history, as well as to collect some simple demographic information. If a 
participant is deemed ineligible or decides not to participate in the study, their 
information is destroyed, i.e., shredded. If an individual appears to meet enrollment 
criteria and is interested in participating, a face-to-face interview is conducted by one of 
the project investigators. A release of information is obtained for review of any available 
historical and clinical data. The nature of the project, procedures, relative risks and 
benefits, and alternatives to participation in the project are discussed with the individual. 
Following this discussion, the individual is given a copy of the consent form to review, 
and any questions are answered. The process of informed consent will be obtained in 
accordance with 21CFR50 and local IRB standards by study personnel who have 
participated in institutionally approved training in human subject protection. Upon 
obtaining voluntary, written, informed consent, medical and psychiatric screening 
procedures will be used to confirm study eligibility. Documentation regarding the 
informed consent process and the subject’s study participation will be made in the 
subject’s medical record and/or study source documents.  
 
In order to ensure a high rate of enrollment in the proposed study a number of procedures 
will be implemented under the direction of the Contract PI Dr. Krystal and implemented 
via the weekly Coordinating Committee (CC) meetings that include all of the Site PIs, the 
DCRI Project Leader, and the Leader of the Assessment/Signal Detection Core for the 
study, Richard Keefe, Ph.D. As part of this effort, each site will submit a site recruitment 
plan which will be reviewed by the CC prior to the commencement of the trial. The 
Committee will discuss each plan and make suggestions for ways to facilitate recruitment 
at each site. Throughout the trial it will be the responsibility of Dr. Krystal or his 
designee, to track recruitment closely at each site and to present these data at the regular 
CC meetings for review. This review will include discussing the recruitment at each site 
in the context of the recruitment strategies they are employing in order to make ongoing 
modifications of the recruitment strategies of slower recruiting sites. This will also 
provide a forum for PIs of sites that are more successful in recruiting to share the 
strategies that have been most effective with the PIs of slower recruiting sites. In general, 
we will attempt to optimize recruitment and retention by promoting practices that are 
associated with effective recruitment across the sites and minimize practices which are 
unsuccessful through careful planning, establishing input and PI and site staff buy-in, 
adaptive recruitment strategies to address site idiosyncrasies, and adopting 
comprehensive and active community outreach. Assessment of recruitment will be based 
on the rate of enrollment needed to meet our enrollment target. This target requires us to 
enroll 90 subjects in 9 months with 6 sites. As a result, each site will have to enroll 1.7 
subjects per month for us to successfully meet our recruitment goal. Because it is 
understood that sites will vary in startup speed it is assumed that some sites will have to 
enroll more rapidly than 1.7 subjects per month for us to meet our recruitment target. As 
a result, we will assess sites against a benchmark of enrolling 2 subjects per month. All 
sites who do not meet this benchmark for more than 1 month and all sites that fall below 
1.0 subject per month in any month will be the focus of a recruitment evaluation which 


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will result in the formation of a recruitment plan for that site which will be followed up 
with ongoing close monitoring. In the case where a site falls below a recruitment rate of 
one subject per month for 3 months a thorough evaluation of the site and the factors that 
might be responsible for the under-recruiting of subjects will be carried out. Such sites 
will be discussed with the NIMH Contracting Officer’s Representative (COR) and 
considered for being dropped from the study. In this case the DCRI, in coordination with 
the NIMH COR, will need to determine what steps should be taken including assessing 
the wisdom of closing a low enrolling site and initiate a new one. Likewise, we will 
discuss with NIMH COR the need to add additional sites, if that proves necessary. 
 
It is anticipated that we will enroll twice as many women as men mirroring the gender 
distribution of mood and anxiety spectrum disorders. Because we have geographically 
diverse sites, we anticipate that the study population will have the ethnic distribution of 
the general U.S. population. A strong effort will be made to achieve these racial/ethnicity 
distribution enrollment targets. Each site has experience recruiting minorities through a 
concentrated effort in communities that have high representation of ethnic and racial 
minorities and through advertisements in newspapers and radio stations whose 
readers/listeners are predominantly of specific racial or ethnic minorities. The CC will 
monitor the gender and racial/ethnic composition of the subjects enrolled throughout the 
study to assess whether the planned targets are being met. If not, the CC will work 
together to formulate a plan to address identified problems. 
 
4.3. Screening 
 
Screening Visit: Day -30 to Day -1 (4 - 6 hours) 
Once a subject has signed an inform consent for this study subjects will undergo a set of 
screening tests to determine if they meet the inclusion/exclusion criteria for the study. 
These screening tests will include: 
 Medical, psychiatric, and medication history 
 Vital signs (temperature, blood pressure, and pulse) 
 Physical examination 
 Pregnancy Test (beta-HCG serum pregnancy test – females only) 
 Electrocardiogram (ECG) 
 Urine drug screen 
 Mini-International Neuropsychiatric Interview (MINI) 
 Snaith-Hamilton Pleasure Scale (SHAPS) 
 Temporal Experience of Pleasure Scale (TEPS) 
 Visual Analogue Scale for Anhedonia (VAS) 
 Columbia Suicide Severity Rating Scale (CSSRS) 
 Clinical Global Impression – Severity (CGI-S) 
 Battery of clinical laboratory tests including: Complete blood count with 
differential, Electrolytes, Metabolic Panel, Thyroid Function Tests, Urinalysis 
 Mock MRI scanning session 
 
Those who qualify to continue with the study based on the screening assessment will be 
asked to return 1-30 days later for additional evaluations. Subjects who require 
medication tapering will discuss a medication tapering plan with a study physician during 


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this visit (for details see Section 4.1. Study Overview). This plan will be designed so that 
subjects are free of all excluded medications at least 5 half-lives prior to the baseline visit 
(see Section 3.3. Exclusion Criteria).  Qualifying subjects will be instructed about not 
using any prohibited medications during the study including substances of abuse.  They 
will be specifically instructed about not using Salvia divinorum, which has kappa opioid 
agonist effects and is not an illegal substance.   
 
A potential subject who previously screen failed due to a positive breath test ONLY may 
be brought back for re-screening.  Subject should sign a new informed consent and all 
screening procedures must be repeated. 
 
4.4. Study Procedures 
 
Baseline: Day 0 Visit (6 – 8 hours): 
Following rigorous screening, subjects will return to the clinic/research unit up to 30 days 
later and undergo the following assessments and procedures: 
 Structural MRI, fMRI during Monetary Incentive Delay Task, Resting State 
Connectivity fMRI 
 Interval history 
 Battery of clinical laboratory tests including: Complete blood count with 
differential, Electrolytes, Metabolic Panel, Thyroid Function Tests, Urinalysis. 
 EEG 
 Vital signs (temperature, blood pressure, and pulse) 
 Physical examination 
 Electrocardiogram (ECG) 
 Snaith-Hamilton Pleasure Scale (SHAPS) 
 Temporal Experience of Pleasure Scale (TEPS) 
 Visual Analogue Scale for Anhedonia (VAS) 
 Columbia Suicide Severity Rating Scale (CSSRS) 
 Probabilistic Rewards Task (PRT) 
 Effort Expenditure for Rewards Task (EEfRT) 
 Hamilton Depression Rating Scale (HAM-D) 
 Hamilton Anxiety Rating Scale (HAM-A) 
 The Cognitive and Physical Functioning Questionnaire (CPFQ) 
 Clinical Global Impression – Severity (CGI-S) 
 Clinical Global Impression – Improvement (CGI-I) 
 
Adverse events assessment with the Patient Reported Inventory of Side-Effects 
(PRISE) 
 Blood sample collection for tests for assessment for gastric adverse events 
including gastrin, and pepsinogen I/II levels.    
 Blood sample collection to be sent to Rutgers for potential genetic analysis or 
other future analysis (optional) 
 
At the end of this visit subjects will be randomized to CERC-501 10 mg or placebo, will 
be provided with enough study medication for a 2-week period and will be instructed to 
take the medication every morning. Subjects will also be instructed to bring all of their 
study drug packaging and unused study drug with them to each visit.  


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Week 1 – Telephone Follow Up: 
Subjects will be called after one week to assess for any safety concerns. Any safety issues 
identified will be addressed as appropriate.  
 
Week 2 Visits (4 – 6 hours per visit): +/- 4 days 
At this visit subjects will undergo the following assessments and procedures: 
 Interval history 
 Battery of clinical laboratory tests including: Complete blood count with 
differential, Electrolytes, Metabolic Panel, Thyroid Function Tests, Urinalysis 
 Vital signs (temperature, blood pressure, and pulse) 
 Physical examination 
 Electrocardiogram (ECG) 
 Snaith-Hamilton Pleasure Scale (SHAPS) 
 Temporal Experience of Pleasure Scale (TEPS) 
 Visual Analogue Scale for Anhedonia (VAS) 
 Columbia Suicide Severity Rating Scale (CSSRS) 
 Clinical Global Impression – Severity (CGI-S) 
 Clinical Global Impression – Improvement (CGI-I) 
 Adverse events assessment with the Patient Reported Inventory of Side-Effects 
(PRISE) 
 Inspection of medication blister packs to assess medication adherence 
 Blood sample for drug blood level testing 
 
At the end of this visit subjects will receive enough study medication for another 2 week 
period, and will be instructed to take the medication each morning, to bring all study drug 
packing and unused study drug to the next visit, and to return to the clinic/research unit in 
2 weeks. 
 
Week 4 Visit (4 – 6 Hours): +/- 4 days 
At this visit subjects will undergo the following assessments and procedures: 
 Interval history  
 Battery of clinical laboratory tests including: Complete blood count with 
differential, Electrolytes, Metabolic Panel, Thyroid Function Tests, Urinalysis. 
 Vital signs (temperature, blood pressure, and pulse) 
 Physical examination 
 Electrocardiogram (ECG)  
 Snaith-Hamilton Pleasure Scale (SHAPS)  
 Temporal Experience of Pleasure Scale (TEPS)  
 Visual Analogue Scale for Anhedonia (VAS)  
 Columbia Suicide Severity Rating Scale (CSSRS) 
 Inspection of medication blister packs to assess medication adherence 
 Blood sample for drug blood level testing 
 Clinical Global Impression – Severity (CGI-S) 
 Clinical Global Impression – Improvement (CGI-I) 


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 Adverse events assessment with the Patient Reported Inventory of Side-Effects 
(PRISE) 
 Blood sample for tests for assessment for gastric adverse events including gastrin, 
and pepsinogen I/II levels.   
 
At the end of this visit subjects will receive enough study medication for another 2 week 
period, and will be instructed to take the medication each morning, to bring all study drug 
packing and unused study drug to the next visit, and to return to the clinic/research unit in 
2 weeks.  
 
Week 6 Visit (4 – 6 Hours): +/- 4 days 
At this visit subjects will undergo the following assessments and procedures: 
 Interval history  
 Battery of clinical laboratory tests including: Complete blood count with 
differential, Electrolytes, Metabolic Panel, Thyroid Function Tests, Urinalysis. 
 Vital signs (temperature, blood pressure, and pulse) 
 Physical examination 
 Electrocardiogram (ECG)  
 Snaith-Hamilton Pleasure Scale (SHAPS)  
 Temporal Experience of Pleasure Scale (TEPS)  
 Visual Analogue Scale for Anhedonia (VAS)  
 Columbia Suicide Severity Rating Scale (CSSRS) 
 Inspection of medication blister packs to assess medication adherence 
 Blood sample for drug blood level testing 
 Clinical Global Impression – Severity (CGI-S) 
 Clinical Global Impression – Improvement (CGI-I) 
 Adverse events assessment with the Patient Reported Inventory of Side-Effects 
(PRISE) 
 
At the end of this visit subjects will receive enough study medication for another 2 week 
period, and will be instructed to take the medication each morning, to bring all study drug 
packing and unused study drug to the next visit, and to return to the clinic/research unit in 
2 weeks.  
 
Week 8 Visit (6 – 8 Hours): +/-4 days 
At this visit subjects will undergo the following assessments and procedures: 
 Structural MRI, fMRI during Monetary Incentive Delay Task, Resting State 
Connectivity fMRI 
 Interval history  
 Battery of clinical laboratory tests including: Complete blood count with 
differential, Electrolytes, Metabolic Panel, Thyroid Function Tests, Urinalysis 
 Electroencephalogram (EEG) 
 Vital signs (temperature, blood pressure, and pulse) 
 Physical examination 
 Electrocardiogram (ECG) 
 Snaith-Hamilton Pleasure Scale (SHAPS) 


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 Temporal Experience of Pleasure Scale (TEPS) 
 Visual Analogue Scale for Anhedonia (VAS) 
 Columbia Suicide Severity Rating Scale (CSSRS) 
 Probabilistic Rewards Task (PRT) 
 Effort Expenditure for Rewards Task (EEfRT) 
 Hamilton Depression Rating Scale (HAM-D) 
 Hamilton Anxiety Rating Scale (HAM-A) 
 The Cognitive and Physical Functioning Questionnaire (CPFQ) 
 Blood sample collection to be sent to Rutgers for potential genetic analysis or 
other future analysis (optional) 
 Clinical Global Impression – Severity (CGI-S) 
 Clinical Global Impression – Improvement (CGI-I) 
 Blood sample for tests for assessment for gastric adverse events including gastrin 
and pepsinogen I/II levels.   
 Adverse events assessment with the Patient Reported Inventory of Side-Effects 
(PRISE) 
 Inspection of medication blister packs to assess medication adherence 
 Blood sample for drug blood level testing 
 
At the end of this visit study drug will be discontinued and subjects will be instructed to 
return to the clinic/research unit in 4 weeks. 
 
Week 12 Visit: Post Medication Follow-up (2 - 4 hours) +/- 4 days 
At this visit subjects will undergo the following assessments: 
 Vital signs 
 Interval history 
 Snaith-Hamilton Pleasure Scale (SHAPS) 
 Temporal Experience of Pleasure Scale (TEPS) 
 Visual Analogue Scale for Anhedonia (VAS) 
 Columbia Suicide Severity Rating Scale (CSSRS) 
 Adverse events assessment with the Patient Reported Inventory of Side-Effects 
(PRISE) 
 Clinical Global Impression – Severity (CGI-S) 
 Clinical Global Impression – Improvement (CGI-I) 
 
At the conclusion of this visit subject participation in the study will end. 
 
4.5. End of Participation / Early Termination 
 
At the end of the week 12 visit, participation in the study will end. The results of all of 
the laboratory assessments and EEGs, ECGs, and physical examinations that could affect 
the subject’s health care will be shared with them and their health care provider if they 
would like this to occur. Subjects will meet with the study physician and options for 
treatment will be reviewed. Participants will not be informed as to their treatment 
assignment at this meeting. 
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personnel to contact the subject and determine the reason for withdrawal. The measures 
taken to follow up must be documented. 
Subjects have the right to withdraw from the study at any time for any reason. If a subject 
withdraws from the study before Week 8, the subject should have a complete evaluation 
performed at the time of withdrawal that includes all Week 8 procedures EXCEPT fMRI 
(see Table 3 Schedule of Assessments). Subjects will be followed through Week 12 
follow up unless they specifically withdraw their consent for further contact or for 
medical records review. When a subject withdraws before completing the study, the 
reason for withdrawal is to be documented on the eCRF and in the source document. 
Subjects who withdraw will not be replaced. 
 
5. STORAGE OF DATA AND SAMPLES 
 
After the database is closed, data will be stored in the secure server located at North 
Pavilion Datacenter, 2400 Pratt Street, Durham NC. The server is named GNEISS. The 
data will stored in \\gneiss\ct. All data will be stored as SAS version 9 datasets. The 
software is maintained and managed by the Duke Clinical Research Institute (DCRI) 
Information Technology (IT) group.  The Director of Statistical Operations is responsible 
for granting access to the database as per our Standard Operating Procedures (SOPs). 
Once a year, the Director of Statistical Operations or Associate Director of Statistics 
reviews all trial access permissions and remove any trial access that is no longer 
appropriate. The data will be stored in gneiss for a maximum of 6 years. After six years, 
it will be archived. The Director of Statistical Operations, the Associate Director, 
Statistical Group for Manuscript Analysis (SIGMA) & Faculty and Fellows Affairs, and 
the Lead Biostatistician for the study or designee will approve the archival of the files 
from the DCRI network. The final datasets will be stripped of identifiers prior to release 
for sharing. 
 
Blood samples for mailing to Rutgers for storage for potential genetic or other future 
analyses will be collected at baseline and after 8 weeks of treatment with study drug. 
These samples will be handled, processed, and mailed in accordance with applicable 
state, federal, and international regulations.  
 
All samples will be logged into protected computer databases with all coded identifiers 
received from the FAST-MAS sites. A unique in-house RU ID # will be assigned as 
samples are logged into the RUCDRLIMS. This RU ID # for each specimen will be used 
to track the sample throughout processing, transformation and DNA and Plasma 
extraction. This new ID # that is unrelated to sample origin provides an additional level 
of security for maintaining sample anonymity. The FAST-MAS ID # and RU ID # will be 
cross-referenced in the computer database. The Alternate ID # will not be entered into the 
clinical or genetic databases. It will be used solely by the RUCDR as a secondary ID to 
help resolve labeling discrepancies that may occur during sample collection and 
submission. 
 
 
6. RISKS AND DISCOMFORTS 
 


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The main potential risks (and burdens) to the subjects can be categorized as follows: 
 
6.1. Risks of Discontinuing Medications for Study Participation 
 
In order to participate in this study all subjects must be free of all antidepressant, 
antipsychotic, anxiolytic, anticonvulsant, mood stabilizing, muscle relaxant, centrally 
acting antihistaminergic, stimulant or insomnia medications (See Appendix 2) within 5 
half-lives of baseline or at any time during after baseline and will have to remain off of 
all such medications other than study medication during the trial. There are risks 
associated with discontinuing medications which depend on the type of medication 
stopped, and the dosage and duration of use. Adverse effects requiring medical attention 
could also occur including seizures. 
 
6.2. Risks of Being Without Therapy During the Study 
 
During participation in this study subjects will go through periods of time without 
receiving treatment for their mood and anxiety spectrum disorder. This will occur 
because subjects will need to be off of all antidepressant and anxiolytic medications for 5 
half-lives prior to starting the trial and during the trial, they may receive placebo during 
the study, the study medication may lack therapeutic effects for their condition, and all 
subjects will be off of study medications during weeks 8-12 of the study and will not be 
allowed to take other medications during this period. Risks of going without therapy 
include significant worsening of the symptoms of their mood and anxiety spectrum 
disorder. 
 
6.3. Risks to Confidentiality 
 
Patients will grant the experimenters access to protected health information. They will 
also reveal sensitive information about themselves, which will include their psychiatric 
status and any history of substance abuse. Subjects may feel uncomfortable revealing this 
information, and there is a risk of losing confidentiality. Subjects will also be informed in 
the consent document that confidentiality will be limited in cases where the subject 
reveals intentions to harm themselves or others, and the investigator feels that the proper 
authorities may need to be notified in order to prevent the occurrence of harm to the 
subject, or others. 
 
Subject confidentiality is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their agents. The study protocol, documentation, data, and 
all other information generated will be held in strict confidence. All files will be kept 
secure and only authorized research personnel will have access. Only staff members who 
have a need to know personal identifying information will have access to this 
information.  
 
All subject data will be kept strictly confidential, and no subject-identifying information 
will be released to anyone outside the project. Confidentiality will be through several 
mechanisms. First, each subject will be assigned a unique subject number which will then 
be used on all study forms, including the electronic data capture system (EDC). Secondly, 
any study forms, blood samples, or paper records that contain subject information will be 


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kept at the clinical sites in secured areas, and identified by the unique subject number. 
Once blood is collected, there will be no subject identifiers placed on blood samples, only 
the unique subject number and the date of sample collection. Third, access to all subject 
data and information, including laboratory specimens, will be restricted to authorized 
personnel. In the case of computerized data, this restricted access will be assured through 
user logon IDs and password protection. This protects forms from unauthorized view and 
modifications as well as inadvertent loss or damage.  
 
Any data, forms, reports, and other records that leave the site will not contain the 
subject’s name or any other direct identifier.  The subject will be identified by a unique 
identifier to maintain subject confidentiality. Information will not be released without 
written permission of the participant, except as necessary for monitoring by the 
Institutional Review Board (IRB), the NIMH DSMB, the FDA, the government Office of 
Human Research Protections (OHRP) and/or any other government officials, safety 
monitors/committees that may need the information to make sure that the study is done in 
a safe and proper manner, learn more about side effects, and/or analyze the results of the 
study. 
 
All subject data will be kept strictly confidential, and no subject-identifying information 
will be released to anyone outside the project. Confidentiality will be through several 
mechanisms. First, each subject will be assigned an anonymous study unique subject 
number which will then be used on all study forms, including the electronic data capture 
system (EDC). Secondly, any study forms, blood samples, or paper records that contain 
subject information will be kept at the clinical sites in secured, locked areas, and 
identified by the coded by unique subject number. Once blood is collected, there will be 
no subject identifiers placed on blood samples, only the unique subject number and the 
date of sample collection. Third, access to all subject data and information, including 
laboratory specimens, will be restricted to authorized personnel. In the case of 
computerized data, this restricted access will be assured through user logon IDs and 
password protection. This protects forms from unauthorized view and modifications as 
well as inadvertent loss or damage.  
 
 
 
 
6.4. Risks Associated with Treatment 
 
The most important risk identified in studies carried out to date is a potential risk of 
worsening of peptic ulcer disease in patients with gastric infection with Helicobacter 
pylori. This is based on findings of decreased parietal cells and inflammation in the 
stomach of rats. 
 
In addition, subjects with a history of peptic ulcer disease or gastritis will also be 
excluded from participating in the study. 
 
Other risks associated with the study drug include: headache, diarrhea, nausea, vomiting, 
flushing, anxiety, upset stomach, itchiness, and ventricular tachycardia (rapid heartbeat 
that requires immediate medical attention which was observed in 1 subject in the prior 


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studies). There is also the possibility that CERC-501 might lead to symptoms of 
depression based on the fact that this agent might have some mu opioid antagonist effects 
which several lines of evidence suggest might be depressogenic (Berrocoso et al., 2009; 
Escriba et al., 2004; Kennedy et al., 2006). 
 
In addition to these risks there may be other risks of the study medication which are 
currently unknown as the number of individuals treated with this medication so far is 
limited. 
 
To protect subjects from such unknown risks we will not allow subjects to participate in 
the study if they have: 1) any clinically significant abnormality on the screening tests; 2) 
any clinically significant medical, psychiatric, or substance use-related disorder other 
than a mood and anxiety spectrum disorder. ; 3) excessive alcohol intake or unwillingness 
to stop alcohol consumption for the duration of the study; 4) taken a prescribed 
medication within 30 days of the first study day, or nonprescription medication except 
vitamins and acetaminophen (up to 4 g/day) within 15 days of starting study drug, or 
need to continue any medication during the study; 5) taken an investigational medication 
within 3 months prior to the start of this study; 6) smoked cigarettes within the last month 
or at any time during the study; or 7) a history of severe allergies or multiple adverse 
drug reactions. 
 
We will further protect subjects from unanticipated risks by monitoring for adverse 
effects at every visit during treatment by carefully checking for any adverse reactions and 
by assessing suicidality with the Columbia Suicide Severity Rating Scale (CSSRS) and 
the CGI-S. If subjects experience an adverse reaction, appropriate medical care will be 
provided. This may include referral to an appropriate practitioner outside of the study, 
transfer to an Emergency Room, or hospital admission. Subjects will be monitored 
regularly until the adverse reaction is resolved. Unexpected adverse reactions occurring 
during the period of participation in the study or that are relevant to subjects after their 
participation in the study will be communicated to them. All adverse reactions will be 
reviewed by the NIMH Data and Safety Monitoring Board. They will make ongoing 
evaluations of the risks of study participation and can recommend that the study be 
terminated in cases where the risks are deemed to be excessive. 
 
6.5. Risks of Venipuncture 
 
Subjects will undergo venipuncture 6 times during the study. Complications of drawing 
blood from a vein occur approximately 2% of the time and include discomfort at the site 
of puncture; possible bruising and swelling around the puncture site; rarely an infection; 
and, uncommonly, faintness from the procedure. 
 
In order to minimize the risks of drawing blood from a vein, sterile technique will always 
be used and these procedures will be carried out by individuals with sufficient training. 
 
6.6. Risks Associated with fMRI Scanning 
 
The risks associated with fMRI scanning include the development of anxiety inside the 
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object in the scanner room. In order to reduce the risk of developing fear during MRI 
procedures, subjects will have a practice MRI scanning session before having any MRI 
scans to help them get used to being inside the MRI scanner. Rarely people develop 
anxiety inside the scanner and decide not to continue in the study. This session will 
provide subjects with an opportunity to make sure they are comfortable with proceeding 
with MRI scanning. 
 
Risks of injury during MRI will be reduced by evaluating subjects for risk factors 
including having implanted metal devices. If such risk factors are identified subjects 
would not be allowed to participate in the study. In addition, the area around the MRI 
scanner is kept free of objects that could pose a risk to subjects. 
 
6.7. Risks associated with EEG and ECG studies 
 
Risks associated with EEG and ECG studies: The risks associated with undergoing EEG 
and ECG studies include skin irritation at the sites electrodes are applied/removed and the 
general inconvenience of having to set aside time to undergo such monitoring. The risk of 
skin irritation will be minimized by having highly experienced individuals attach the 
electrodes and using methods that decrease the likelihood of irritation. 
 
6.8. Risks to Those of Reproductive Potential 
 
6.8.1. Females 
Being a part of this study while pregnant may expose the unborn child to significant risks, 
some of which may be currently unforeseeable. In order to protect subjects from this risk, 
pregnant women will be excluded from the study. For all women of childbearing 
potential, a blood pregnancy test will be done and it must be negative before subjects can 
continue in this study. If sexually active, subjects must agree to use appropriate 
contraceptive measures for the duration of the study and for 1 month afterwards. 
Medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal 
ligation or hysterectomy), (2) approved hormonal contraceptives (such as birth control 
pills, patches, implants or injections), (3) barrier methods (such as a condom or 
diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). Contraceptive 
measures such as Plan B (TM), sold for emergency use after unprotected sex, are not 
acceptable methods for routine use. If subjects do become pregnant during this study or if 
they have unprotected sex, they will be instructed to inform the study physician 
immediately. 
 
6.8.2. Males 
Participation in this research has the potential to damage sperm, which could cause harm 
to a child that a subject might father while on this study. Such harm may be currently 
unforeseeable. As a result, in order to protect subjects, sexually active male subjects will 
have to agree to use a medically acceptable form of birth control during and 1 month after 
this study in order to participate. Medically acceptable contraceptives include: (1) 
surgical sterilization (such as a vasectomy), or (2) a condom used with a spermicide. 
Contraceptive measures such as Plan B (TM), sold for emergency use after unprotected 
sex, are not acceptable methods for routine use. Subjects will be instructed to inform their 


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partners of the potential for harm to an unborn child and that they should immediately 
inform the study doctor if pregnancy occurs. 
 
6.8.3. Pregnancy 
This protocol does not allow for currently pregnant women to be included in the study, 
due to the unknown risk to the fetus with this medication. At study entry, all women must 
have a negative pregnancy test to be allowed to enroll into the study, and must practice an 
acceptable method of birth control while in the study. ßHCG serum pregnancy tests will 
be performed for all women, unless surgically sterile, at the screening visit and if 
clinically indicated at any time during the study. All women of childbearing potential will 
be instructed to notify the Investigator if they become pregnant at any time during the 
study or within 30 days of last study evaluation. The pregnancy will be followed until 
delivery. If any subject is found to be pregnant during the study, study drug will be 
immediately discontinued. The subject will remain in the study for continued follow up 
of the pregnancy. If the pregnancy occurs in a female subject or the partner of a male 
subject during the study or within 30 days of the end of the study the investigator will 
inform the subject of their right to receive treatment information. If the female subject or 
partner agrees to the primary care physician being informed, the investigator will notify 
the primary care physician that the subject or her partner was participating in a clinical 
study at the time she became pregnant and provide details of treatment the subject 
received. All reported pregnancies will be followed up to final outcome. The outcome, 
including any premature termination, will be reported on the appropriate CRF page.  
 
7. SUBJECT SAFETY MONITORING 
 
 
 
The Principal Investigator or a Co-Investigator at each of the sites will monitor all 
subjects for adverse effects throughout their participation in the study. 
 
 
7.1. Parameters to be Monitored 
 
The Site Principal Investigator (PI) or a Co-Investigator (Co-I) at each site will monitor 
all subjects for adverse effects throughout their participation in the study. This will 
include carrying out a clinical interview for adverse events at each visit which will 
consist of asking the subject whether they experienced any new symptoms or changes 
since the last visit. In addition, a series of safety assessments will be carried out and the 
findings reviewed by the site PI or a Co-I. These safety assessments will include: the 
Columbia Suicide Severity Rating Scale (CSSRS) (Posner, 2011), vital signs (height, 
weight, blood pressure, and pulse), physical examination, Beta-HCG serum pregnancy 
test, urine drug screen, complete blood count with differential, electrolytes, 
comprehensive metabolic panel including liver function tests, thyroid function tests, 
urinalysis, CGI-I, and ECG. 
 


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These data will be used to assess for adverse event type, severity, expectedness, and 
causal relationship to study drug as defined in Section 16 below. The plan for 
documentation and reporting of Adverse Events is also included in Section 16 below. 
 
In terms of monitoring for suicidality, subjects will be assessed at every visit with the 
Columbia Suicide Severity Rating Scale (CSSRS). Subjects who answer "yes" to item 5 
of the CSSR-S ("Active suicidal ideation with specific plan and intent) and are 
considered by clinical interview to be at risk are immediately removed from the study and 
appropriate intervention is implemented. In case of ambiguity regarding suicidal plans, 
the patient is removed from the study and provided appropriate treatment. Any subject 
with an increase in suicidality will undergo thorough assessment by the study psychiatrist 
who will determine the appropriate course of action including whether acute intervention 
is needed and whether it is in the best interests of the subject to continue in the study. If 
necessary, the study psychiatrist will seek consultation from the study PI or medical 
monitor. Subjects for whom continued participation is deemed not to be in their best 
interest will be discontinued from the study. 
 
The site PI will follow all Adverse Events until resolution or they no longer believe that it 
is clinically significant. AEs ongoing at the time of the last dose of study drug will be 
followed up for as long as necessary to adequately evaluate the participant’s safety, until 
they are resolved, or until it is determined by the site PI or designated Co-Investigator not 
to be clinically significant.  
 
7.2. Criteria for Stopping Procedures in an Individual 
 
If a participant experiences a severe adverse event (see Section 16 below), study 
procedures, including taking study medication, will be stopped for that individual. This 
will also occur if: 
 A subject is assessed with a CGI-I score greater than 5 
 In the opinion of the site PI or Co-I that it is in the participant’s best interest to 
discontinue study procedures. 
 
8. OUTCOME MEASURES 
 
8.1. Primary Outcome Measures 
 
 Reward-Related Circuit Engagement POC Outcome for the study will be task-
related fMRI ventral striatal (e.g., nucleus accumbens) activation occurring with 
reward and anticipation during the Monetary Incentive Delay (MID) Task 
 
8.2. Secondary Outcome Measures 
 
 Clinical Anhedonia Outcome for this study will be the total score Snaith-
Hamilton Pleasure Scale (SHAPS) 
 
 Behavioral Anhedonia Outcome for this study will be Response Bias and 
Reward Learning Scores on the Probabilistic Reward Task (PRT) 


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8.3. Exploratory Outcome Measures 
 
 Ventral striatal fMRI activation during anticipation of loss during the MID Task 
 Resting state delta EEG current density in the rostral anterior cingulate 
 Resting state fMRI connectivity 
 Self-rated affective responses to cues and feedback during the MID Task 
 The Effort-Expenditure for Rewards Task (EEfRT) 
 The Visual Analogue Scale for Anhedonia (VAS) 
 The Temporal Experience of Pleasure Scale (TEPS) 
 The Hamilton Depression Rating Scale (HAM-D) 
 The Hamilton Anxiety Scale (HAM-A) 
 The Cognitive and Physical Functioning Questionnaire (CPFQ) 
 Clinical Global Impression – Severity (CGI-S) 
 Clinical Global Impression – Improvement (CGI-I) 
 Safety and tolerability of CERC-501 on systematically collected and 
spontaneously reported adverse events 
 
8.4. Description of Outcome Measures 
 
8.4.1. Monetary Incentive Delay Task-related fMRI 
 
fMRI during the Monetary Incentive Delay (MID) Task will yield the primary outcome 
measure for this study with which we will evaluate whether we can establish POC for 
KOR antagonists by assessing whether CERC-501 engages the neural circuitry that 
mediates reward-related function (Wacker et al., 2009; Pizzagalli et al., 2004, 2009; 
Knutson et al., 2008). We will specifically assess whether CERC-501 leads to greater 
ventral striatal activation than placebo during anticipation of rewards with MID Task-
related fMRI. 
 
Evidence supporting the use of the MID Task-related fMRI for this purpose is that 
depressed patients were found to have decreased ventral striatal activation to anticipated 
reward with this task (Stoy et al., 2012) and that this measure has been demonstrated to 
be sensitive to changes occurring with antidepressant/anxiolytic therapies (SSRI and 
SNRI) in small open-label studies including those with major depression and healthy 
controls and a double-blind placebo-controlled study in healthy controls (Stoy et al., 
2012; Ossewaarde et al., 2011). 
 
The MID fMRI will be obtained on Day 0 (baseline) and after 8 weeks of daily treatment 
with study drug (Visit A4). The test will be carried out as previously described (Knutson 
et al., 2008). The MID task was designed to elicit neural responses to monetary incentive 
anticipation and outcomes. To test the specificity of the findings, both reward and 
penalties will be included. It will be administered in two task runs each of which will 
consist of 90 6-second trials. For each trial, subjects will be presented with one of nine 
possible cue shapes for 250 msec while their gaze is fixed on a crosshair on a computer 
screen. The period of waiting for the cue shape will vary from 2000-2500 msec. These 
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(n=72, denoted by circles), potential for monetary losses (n=72; denoted by squares), or 
that no response is required (n=36; denoted by triangles). Gain cues will signal the 
possibility of winning $0.00 (n=18; no lines), $0.20 (n=18; one horizontal line), $1.00 
(n=18; two horizontal lines), or $5.00 (n=18; three horizontal lines). Similarly, loss cues 
will signal the possibility of losing $0.00 (n=18; no lines), $0.20 (n=18; one horizontal 
line), $1.00 (n=18; two horizontal lines), or $5.00 (n=18; three horizontal lines). “No 
response” trials (n=36; a triangle) will indicate that the subject should not respond during 
that trial, and instead should wait until the cue signaling the next trial appeared. Trial 
types will be pseudo-randomly ordered within each run, and runs will be counterbalanced 
across subjects. 
 
When subjects are presented with the cue shape they will be instructed to respond by 
pressing a button when they are presented with a white target for a period of 160-360 
msec. They will also be instructed that on incentive trials, subjects could either gain or 
avoid losing money by pressing the button during target presentation. 1650 msec after the 
white target disappears, subjects will be notified as to how much money they had gained 
or lost on that trial and their total winnings (or losses). 
 
Subjects will undergo at least 10 minutes of training and practice prior to testing. They 
will also see the money that they could potentially win prior to fMRI testing. Task 
difficulty will be based on reaction times collected during practice sessions and will aim 
to allow subjects to successfully press the button during target presentation on incentive 
trials on 66% of the trials. 
 
Scan Acquisition: All scans will be conducted on research dedicated 3.0 Tesla MRI 
scanners running the latest software version using an advanced 32-channel RF coil. MR 
compatible video projection system with vision correction lenses, high quality 
headphones and a button box will be used for fMRI task presentation and response 
recording. Physiological monitoring is performed and digitally recorded during all scans. 
 
Resting state connectivity will also be assessed with fMRI for exploratory analysis. 
 
MRI acquisition sequences (use 32-channel headcoil): 
 
(1) Localizer (Time: ~ 15 s); 
(2) EPI-Monetary Incentive Delay Task (Time: 4 min 32 s): Gradient-echo echo-planar 
(EPI) fMRI scans with physiological monitoring, axial, TR/TE: 2000/30 ms, flip 
angle: 70 deg, FOV: 25.6 cm, matrix: 64x64, 32 axial slices, acceleration factor = 2, 
voxel size: 4x4x4 mm, 137 fMRI time points + 4 dummy scans at the beginning 
(total 141 points/TRs), total scan time 4 min 42 seconds (141 x 2 s) for each run. 
This duration is same as that of the E-prime stimulus file. Repeat the same fMRI run 
(corresponding to individual E-prime stimulus files), totaling five fMRI runs. 
(3) EPI-resting state connectivity fMRI: Same as 2, except no task will be used, and 
only one run is needed. Subjects are instructed to keep eyes closed, and try to think 
nothing in particular. 
(4) DTI: Spin-echo EPI acquisition at128x128 matrix, acceleration factor =2, voxel size: 
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~80 ms), TR = 8 s (or shortest possible to accommodate all slices within), 64 slices, 
total scan time 4 min 24 seconds. 
(5) High resolution T1-weighted volume (Time: <5min) for registration and 
morphometric characterization (3D MP-RAGE or IP-SPGR), 128 axial slices to 
cover whole brain, voxel size: 1x1x1 mm; 
(6) Axial PD/T2 TSE, to rule out incidental findings (Time: <5 min): 64 axial slices 
from apex, voxel size: 1x1x2mm. 
 
Note: brain volume must be kept the same for all series (series 2-6) 
 
 
8.4.2. The Snaith-Hamilton Pleasure Scale (SHAPS) 
 
The Snaith-Hamilton Pleasure Scale (SHAPS) (Snaith et al., 1995) is a well-validated 14-
item questionnaire used to assess anhedonia. It asks participants to agree or disagree with 
statements of hedonic response in pleasurable situations (e.g., “I would enjoy my favorite 
television or radio program”). Four responses are possible: Strongly disagree, Disagree, 
Agree, or Strongly agree. Each item on the SHAPS is worded so that higher scores 
indicate greater pleasure capacity. A total score can be derived by summing the responses 
to each item. Items answered with “strongly agree” are coded as “1”, while a “strongly 
disagree” response was assigned a score of “4.” Therefore, scores on the SHAPS can 
range from 14 to 56, with higher scores corresponding to higher levels of anhedonia. 
 
The SHAPS covers four domains of hedonic experience: interest/pastimes, social 
interaction, sensory experience, and food/drink (Snaith et al., 1995). Participants 
completing the SHAPS are instructed to respond based on their ability to experience 
pleasure “in the last few days.” This scale has shown adequate overall psychometric 
properties in clinical and student samples (Gilbert el al., 2002; Snaith et al., 1995). The 
SHAPS convergent validity has been supported by its correlations with MADRS Hedonic 
Tone item, the Mood and Anxiety Symptom Questionnaire Anhedonic Depression 
subscale, and Positive and Negative Affect Schedule-Positive Affect subscale (Gilbert et 
al., 2002; Snaith et al., 1995). Its discriminant validity has been supported by its lack of 
association with MADRS Depressed Mood and Anxiety items (Snaith et al., 1995). The 
SHAPS has satisfactory test-retest validity in healthy participants over an interval of three 
weeks (intraclass correlation coefficient between test and retest: r = .70, p < .001; 
Franken et al., 2007). Besides being well-validated, the SHAPS is of utility for our study 
because there is an established cutoff for clinical significance. Although this is also true 
for the Anhedonic Depression subscale of the Mood and Anxiety Symptoms 
Questionnaire (MASQ), we wanted a scale that assessed anhedonia and was not 
depression specific or specific to any other disorder given the goal of using it across 
diagnostic boundaries. ROC using the MADRS anhedonia item score (cutoff was 
clinically significant level) as a discriminator suggests that a SHAPS score of ≥ 20 
corresponds to clinically significant anhedonia (Snaith et al., 1995). This was validated in 
30 volunteers from the general population. It should be noted that the original ROC 
analysis was done with dichotomous ratings rather than the current 4 option rating 
system. The original finding was that 3 or more negative answers indicated clinical 
significance which corresponds to a score of at least 20 with the current rating system. 
 


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Another important consideration that supports the use of the SHAPS in this study is that 
it is the only anhedonia measure that we are aware of that has been found to significantly 
improve with the administration of a treatment in at least one clinical trial (Di 
Giannantonio and Martinotti, 2012; Martinotti et al., 2011). In a study of alcohol 
dependent individuals, treatment with acetyl-l-carnitine led to statistically significantly 
greater improvement in the SHAPS than placebo by 10 days after initiating treatment 
(Martinotti et al., 2011). In an 8-week trial comparing the effects of venlafaxine XR and 
agomelatine treatment in depressed patients, significant improvement from baseline on 
the SHAPS was observed in both groups with significantly greater improvement being 
found for the agomelatine treated patients (Di Giannantonio and Martinotti, 2012). 
Finally, SHAPS scores among healthy participants have been related to reward-related 
activation within frontostriatal pathways (see e.g., Wacker et al., 2009), providing an 
additional reason for its inclusion in the current study. 
 
The SHAPS will be collected at all study visits. It will be used to screen subjects for 
having anhedonia as part of inclusion/exclusion assessment. It will also be compared in 
subjects receiving CERC-501 and PBO in secondary analysis to assess the effects on a 
clinical self-rated measure of anhedonia. 
 
8.4.3. Probabilistic Reward Task 
 
The Probabilistic Reward Task (PRT) (adapted from Tripp & Alsop (1999)) was 
designed to objectively assess participants’ propensity to modulate behavior as a function 
of reinforcement history. This task has been validated in multiple independent samples 
(e.g., Barr et al., 2008; Bogdan and Pizzagalli, 2006, 2009; Pizzagalli et al., 2005, 2007, 
2008a,b; Vrieze et al., 2013a,b). Participants will complete two blocks of 100 trials, in 
which they will be asked to determine whether a briefly presented mouth on a cartoon 
face was ‘long’ or ‘short’, and report their decision by pressing one of two corresponding 
keys on a computer keyboard (‘z’ or ‘/’). Importantly, the brief presentation time (100 
ms) and the minimal difference in length between the two target stimuli (11.5 vs. 13 mm) 
make it difficult for participants to perceptually distinguish which stimulus is presented. 
Moreover, an asymmetrical reinforcement ratio is implemented across the two blocks so 
that one of the two stimuli (the ‘rich’ stimulus) is consistently rewarded (“Correct!! You 
Won 20 Cents”) three times more frequently than the ‘lean’ stimulus (30 vs. 10 times per 
block). Reinforcement allocation and key assignments will be counterbalanced across 
participants. Participants are instructed to respond as quickly and accurately as possible 
to maximize monetary rewards, and that not all correct responses will be followed by 
rewards. In healthy participants, such asymmetric reinforcement schedule has been found 
to induce a systematic preference (response bias) for choosing the stimulus paired with 
more frequent reward (Macmillan and Creelman, 1996). Healthy controls are able to 
successfully modulate their behavior based on their experience, resulting in a significant 
response bias for the more frequently rewarded stimulus. In contrast, individuals with 
elevated depressive symptoms (Pizzagalli et al., 2005) or MDD (Pizzagalli et al., 2008b) 
– specifically MDD subjects with anhedonia (Vrieze et al., 2003) – show a blunted 
response bias, and overall reduced reward learning. Of note, reward learning negatively 
correlated with anhedonic symptoms and predicted them one month later (Bogdan and 
Pizzagalli, 2006; Pizzagalli et al., 2005) and predicted the persistence of a MDD 
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trial probability analyses revealed that MDD subjects were impaired at integrating 
reinforcements over time and expressing a response bias in the absence of immediate 
reward. This impairment correlated with anhedonic symptoms, even after considering 
anxiety and distress symptoms (Pizzagalli et al, 2008b). 
 
Data reduction and analyses: After removing trials with outlier reaction times (see 
Pizzagalli et al., 2005 for detail), response bias (log b) will be computed according to the 
following formula: 
 
 
To avoid issues related to having a zero in one cell of the formula, 0.5 will be added to 
every cell of the detection matrix (Hautus and Collins, 2003). As evident from the 
formula, response bias reflects the participants’ preference for the stimulus paired with 
more frequent rewards. Reward learning will be operationalized as the change in 
response bias from Block 1 to Block 2 (RB = Response Bias [Block 2] – Response Bias 
[Block 1]). 
 
The results of a number of studies provide the rationale for using the PRT in this study. 
This includes a study identifying that PRT score predicts clinical outcome to naturalistic 
antidepressant treatment. In this study, 69 inpatients and 63 healthy controls performed 
the PRT at baseline (i.e., at intake for patients), and patients were administered the task 
again after 8 weeks of antidepressant treatment (Vrieze et al., 2013a). Relative to 
controls, MDD patients showed reduced reward learning (F[2,280]=3.53, p=0.03). 
Critically, this blunting was found only in patients with high anhedonia (p=0.007). Of 
note, Hamilton Depression Rating Scale (HDRS) scores were not related to reward 
learning. Also SHAPS scores uniquely predicted reward learning even when controlling 
for depression severity (HRSD scores) and anxiety comorbidity (β=0.33, t=3.08, 
p=0.003). Further, reward learning did not correlate with overall depressive symptoms 
(adjusted Beck Depression Inventory [BDI] score computed without anhedonic items) 
(p>.71) (Pizzagalli et al., 2005). Critically, the link between anhedonia and blunted 
reward learning was confirmed when entering the adjusted BDI scores as a covariate in a 
partial correlation (r=-.38, p=0.008). 
 
Additional findings of interest are that, in healthy controls, reward learning is reduced (1) 
under acute stress (Bogdan and Pizzagalli, 2006; Bogdan et al., 2011) and during 
naturalistic stressors (Nikolova et al., 2012); and (2) by a pharmacological challenge 
(single low dose of the D2/D3 agonist pramipexole) affecting DA (Pizzagalli et al., 
2008a). Notably, the deleterious effects of stress on reward learning were largest in 
subjects reporting anhedonic symptoms in daily life (Bogdan and Pizzagalli, 2006) and 
carrying genetic markers previously associated with depression risk (Bogdan et al., 2010, 
2011; Nikolova et al., 2012). Blunted reward learning in subjects receiving pramipexole 
was assumed to result from activation of presynaptic DA autoreceptors, leading to 
decreased phasic DA bursts in response to unpredictable rewards. Conversely, reward 
learning was increased by a nicotine patch (Barr et al., 2008), a manipulation assumed to 
activate mesocorticolimbic DA neurons (Kenny and Markou, 2006). The heritability of 
reward learning is substantial, 48% (Bogdan and Pizzagalli, 2009), and reward learning is 
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associated with reward-related ACC and striatal activation and DA release (Santesso et 
al., 2008; Vrieze et al., 2013b). 
 
The PRT will be carried out at baseline and after 8 weeks of double-blind treatment. The 
change from baseline in CERC-501 and PBO groups will be compared in secondary 
analysis to assess the effects on a behavioral outcome measure that assessed reward-
related function. 
 
8.4.4. Other Efficacy Assessments 
 
Other efficacy assessments carried out in this study to be employed in exploratory 
analyses include resting state delta EEG current density in the rostral anterior cingulate, 
the Visual Analogue Scale for Anhedonia (VAS), The Effort Expenditure for Rewards 
Task (EEfRT), the Temporal Experience of Pleasure Scale (TEPS), The Hamilton Rating 
Scale for Depression (HAM-D), The Hamilton Rating Scale for Anxiety (HAM-A), and 
the Cognitive and Physical Functioning Questionnaire (CPFQ). The VAS-Anhedonia, 
TEPS, and CPFQ are self-report instruments. The EEfRT is a behavioral task. The HAM-
D and HAM-A are clinician administered assessements which will be administered by 
appropriately trained and monitored raters. The training, assessment, and maintenance of 
inter-rater reliability will be managed by the Duke Signal Detection Team. Clinical raters, 
neuropsychological technicians, and all staff involved in collection and analysis of 
clinical measures will be blinded to treatment assignment and to clinical status. They will 
have no interactions with subjects other than the administration of the specific tests they 
are assigned to administer. Raters and patients will complete best-guess forms so that the 
adequacy of the blind can be assessed. Best-guess forms will be used to formally assess 
the adequacy of the blind for patients and raters. 
 
8.4.4.1. Resting state delta EEG current density in the rostral anterior cingulate 
 
We will obtain resting state, eyes-closed quantitative EEG (QEEG) in order to provide an 
additional, secondary circuit-based measure of hedonic function. We will obtain resting 
state current density using Low Resolution Electromagnetic Magnetic Tomography 
(LORETA) based on evidence that using this method, greater resting EEG delta (1.5- 6 
Hz) current density (i.e., lower brain activity) in the rostral anterior cingulate is correlated 
with higher anhedonia scores with the MASQ anhedonic depression subscale (Wacker et 
al., 2009; Pizzagalli et al., 2004). 
 
The recordings will consist of at least 32 channels of EEG data with electrodes located 
according to the Modified International 10-20 System. Right infra-orbital and left outer 
canthus electrodes will be used to monitor eye movements. Recordings will be obtained 
with a referential montage employing a linked-ear reference. EEG files will be named 
according to a standardized convention and processed in order to ensure that there are no 
subject identifiers included with the recorded data. The data digitization rate will be at 
least 256 Hz. Electrode impedances will be maintained at below 5 kOhm during the 
recordings. Standard square-wave and bio-calibrations will be performed at the beginning 
of each study. The EEG data will be recorded with subjects in a semi recumbent position, 
with eyes closed in a maximally alert state in a sound-attenuated room with subdued 
lighting. Data collection will occur for 20 minutes (10 minutes with eyes closed and 10 


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minutes with eyes opened) following calibration with filter settings of 0.5 and 70 Hz. 
Analysis will be carried out using Low Resolution Electromagnetic Magnetic 
Tomography (LORETA) (see Statistical Analysis Section) to produce estimates of resting 
state EEG delta current density in the rostral anterior cingulate which has previously been 
reported to correlate with a self-rated anhedonia measure (Wacker et al., 2009; Pizzagalli 
et al., 2004). 
 
The Duke QEEG Core will receive the data collected at each of the sites, and it will 
undergo analysis blinded to subject and study time point and entered manually. The 
studies will first undergo epoch-by-epoch visual artifacting with confirmation by a 
second rater. In cases of discrepancies, a third rater will be employed for resolution. 
QEEG analysis will only be carried out if a minimum of 30 seconds of waking, artifact-
free data are available. The data will undergo Laplacian transformation to produce 
current density estimates (Wacker et al., 2009; Pizzagalli et al., 2004). The current 
density data will undergo spectral analysis via Fast Fourier Transformation (FFT) with 
boxcar windowing to generate power estimates in the following frequency bands: delta 
(1.5–6.0 Hz), theta (6.5–8.0 Hz), alpha1 (8.5–10.0 Hz), alpha2 (10.5–12.0 Hz), beta1 
(12.5–18.0 Hz), beta2 (18.5–21.0 Hz), beta3 (21.5–30.0 Hz), and gamma (36.5–44.0 Hz). 
This will be carried out with the LORETA software, at each voxel (n = 2394; voxel 
resolution = 7 mm3), current density will be computed as the squared magnitude of the 
intracerebral current density within each of the eight frequency bands (unit: amperes per 
square meter, A/m2). Current density estimates will be intensity-normalized to unity and 
log-transformed before statistical analyses. This will be carried out in 2-second segments 
and averaged over the available artifact-free, waking data. These data will be used to 
estimate resting state EEG current density. The primary QEEG outcome will be EEG 
delta current density in the rostral anterior cingulate which has found to correlate with 
self-rated anhedonia (Wacker et al., 2009; Pizzagalli et al., 2004). Resting state EEG 
current density power estimates in other frequency bands will be analyzed to evaluate the 
specificity of possible findings. Exploratory analysis for patterns of EEG activity that are 
predictors and correlates of outcome will be carried out using EEG power in all bands 
derived from all of the electrodes, employing principal components analysis (Krystal et 
al., 1995). 
 
8.4.4.2. Exploratory Anhedonia Measures 
 
To complement the SHAPS we include 3 secondary anhedonia measures: the Effort-
Expenditure for Rewards Task (EEfRT), the Visual Analogue Scale for Anhedonia 
(VAS-Anhedonia) and the Temporal Experience of Pleasure Scale (TEPS). These will be 
compared in subjects receiving CERC-501 and PBO in exploratory analysis.  
 
The Effort-Expenditure for Rewards Task (EEfRT; Treadway et al., 2009) is intended 
to assess the motivation to pursue rewards, one important dimension of reward-related 
function. It has been validated in a study of 60 individuals who were screened to have 
anhedonia with the SHAPS (Treadway et al., 2009). The EEfRT was found to be 
correlated with the Beck Depression Inventory (BDI) anhedonia scale and the Chapman 
anhedonia scale. The EEfRT task is a multi-trial game in which participants are given an 
opportunity on each trial to choose between two different task difficulty levels in order to 
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within a short period of time. Each button press raises the level of a virtual “bar” viewed 
onscreen by the participant. Participants are eligible to win the money allotted for each 
trial if they raise the bar to the “top” within the prescribed time period. Each trial presents 
the subject with a choice between two levels of task difficulty, a ‘hard task’ and an ‘easy 
task.’ Successful completion of hard-task trials requires the subject to make 100 button 
presses, using the non-dominant little finger within 21 seconds, while successful 
completion of easy-task trials requires the subject to make 30 button presses, using the 
dominant index finger within 7 seconds. For easy-task trials, subjects are eligible to win 
the same amount, $1.00, on each trial if they successfully complete the task. For hard-
task choices, subjects are eligible to win higher amounts that vary per trial within a range 
of $1.24 – $4.30 (“reward magnitude”). Subjects are not guaranteed to win the reward if 
they complete the task; some trials are “win” trials, in which the subject receive the stated 
reward amount, while others are “no win” trials, in which the subject receives no money 
for that trial. To help subjects determine which trials are more likely to be win trials, 
subjects are provided with accurate probability cues at the beginning of each trial. Trials 
have three levels of probability: “high” 88% probability of being a win trial, “medium” 
50% and “low” 12%. Probability levels always apply to both the hard task and easy task, 
and there are equal proportions of each probability level across the experiment. Each 
level of probability appears once in conjunction with each level of reward value for the 
hard task. All subjects receive trials presented in randomized order. 
 
All trials begin with a 1-second fixation cross, following a 5-second choice period in 
which subjects are presented with information regarding the probability of receiving 
reward and the reward magnitude of the hard task. Subjects are told that if they did not 
make a choice within 5 seconds, they will be randomly assigned to either the easy or the 
hard task for that trial. After making a choice, subjects are then shown a 1-second 
“Ready” screen and then they complete the task. Following task completion, subjects are 
shown a 2 second feedback screen informing them that the task was successfully or 
unsuccessfully completed. If subjects successfully complete the task, then a second 
feedback screen appears for 2 seconds in which subjects are told whether they had won 
money for that trial (reward feedback). In total, easy-task trials take approximately 15 
seconds, whereas hard-task trials take approximately 30 seconds. 
 
Subjects are told that they will receive a base-rate of compensation for their participation. 
In addition, they are told that two of their win trials will be randomly selected at the end 
of the experiment as “incentive trials,” for which they will receive the actual amount won 
on those trials. Subjects are informed that they have twenty minutes to play as many trials 
as they can. Since hard-task trials take approximately twice as much time to complete as 
easy-task trials, the number of trials that the subject is able to play depends in part on the 
choices that he or she makes. This means that making more hard-task trials toward the 
beginning of the experiment could reduce the total number of trials, which could in turn 
mean that the subject does not get a chance to play high-value, high-probability trials that 
might appear towards the end of the playing time. This trade-off is explained clearly to 
the subject. Importantly, subjects are not provided with any information regarding the 
distribution of trial types. The goal of this trade-off is to ensure that neither a strategy of 
always choosing the easy or the hard option could lead to an ‘optimal’ performance on 
the task. Moreover, the complexity of variables (with varying monetary reward levels, 
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of an optimal response selection, and subjects are required to make decisions within a 
brief amount of time. This is done to help ensure that subject decisions reflected 
individual differences in the willingness to expend effort for a given level of expected 
reward value. 
 
The VAS-Anhedonia is a standard VAS assessment of anhedonia severity which is 
included because it provides a global anhedonia indicator which takes very little time to 
obtain and which was found to be sensitive to change with treatment in a prior placebo-
controlled trial in alcohol dependent subjects (Martinotti et al., 2011). The test consists of 
making a rating on a 100 mm scale in response to the directive: "Make a mark on the line 
below that indicates how much pleasure you experience from food, sexual behavior, and 
meeting friends". At the left end of the scale is the anchor "No Pleasure" and at the right 
end of the scale is the anchor "Extreme Pleasure." 
 
We also include the Temporal Experience of Pleasure Scale (TEPS) because it 
provides different information about reward-related function than the SHAPS and has 
been found to be correlated with activation in the key circuits of interest (nucleus 
accumbens and putamen) in Monetary Incentive Delay Task-related fMRI (Stanford et 
al., 2011). The TEPS is an 18-item self-report measurement of anticipatory (10 items) 
and consummatory (eight items) components of anhedonia which consists of a series of 
statements that must be rated according to how accurate they are for the individual (Gard 
et al., 2006). The scale differentiates the role of anticipatory pleasure (‘wanting’) from 
consummatory pleasure (‘liking’). Both components are currently believed to be relevant 
to measuring anhedonia. 
 
8.4.4.3. Other Exploratory Measures 
 
The Hamilton Rating Scale for Depression (HAM-D) 17-item version (Hamilton, 
1967) will be included in exploratory analysis to provide confirmatory support for 
changes in depression severity with treatment. This interviewer-administered semi-
structured interview is one of the most widely used instruments in depression treatment 
studies. 
 
The Hamilton Rating Scale for Anxiety (HAM-A) is a rating scale designed to measure 
the severity of anxiety symptoms (Hamilton, 1959). It is widely used in both clinical and 
research settings. The scale consists of 14 items, each defined by a series of symptoms, 
and measures both psychic anxiety (mental agitation and psychological distress) and 
somatic anxiety (physical complaints related to anxiety). It has been demonstrated to 
acceptable reliability, validity and sensitivity to change (Maier, 1988). Each item is 
scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0–56, where 
<17 indicates mild severity, 18–24 mild to moderate severity and 25–30 moderate to 
severe. This instrument will be included in secondary analysis to provide confirmatory 
support for changes in anxiety severity with treatment. 
 
The Cognitive and Physical Functioning Questionnaire (CPFQ) is a 7-item self-report 
instrument was intended to be a brief scale for measuring cognitive and executive 
dysfunction in patients with mood and anxiety disorders (Fava et al., 2009). This scale 


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has been demonstrated to have strong internal consistency, good temporal stability and 
sensitivity to change with treatment (Fava et al., 2009). 
 
The Clinical Global Impression - Severity (CGI-S) is a widely administered clinician 
rated global measure of subject overall illness severity.  Subjects are rated on a 1-7 scale 
where 1 corresponds to “Normal, Not at All Ill”, 2 is “Borderline Mentally Ill”, the 
anchor for 3 is “Mildly Ill”, the anchor for 4 is “Moderately Ill”, 5 is “Markedly Ill”, 6 is 
“Severely Ill”, and 7 is “Among the Most Extremely Ill Patients”.  It will be administered 
at all subject visits.   
 
The Clinical Global Impression - Improvement (CGI-I) is a widely administered 
clinician rated global measure of the degree of improvement from the initial assessment 
in subject overall illness severity.  Subjects are rated on a 1-7 scale where 1 corresponds 
to “Very Much Improved”, 2 is “Much Improved”, the anchor for 3 is “Minimally 
Improved”, the anchor for 4 is “No Change”, 5 is “Minimally Worse”, 6 is “Much 
Worse”, and 7 is “Very Much Worse”.  It will be administered at all subject visits.   
 During the course of the trial subjects for whom the CGI-I is greater than 5 
will be removed from the study and appropriate care given, for safety 
purposes.  
 
9. STATISTICAL ANALYSIS 
 
9.1. Analysis of Data/Study Outcomes 
 
9.1.1. Analysis of data/ study outcomes 
 
9.1.1.1. Data Management 
All data management activities, including establishing a trial electronic case report form 
and procedures for randomization will be done within the framework of the Duke 
Clinical Research Institute (DCRI) and will conform to FDA GCP requirements. 
 
Electronic data validation checks with data entry discrepancy flags will utilized. The 
flags will be triggered by missing values, logically inconsistent values, and values beyond 
limits. Data checks will be automated and occur daily and lead to the generation of 
queries in the EDC system which are communicated to the sites. The sites will then 
review the queries and make appropriate clarifications and corrections. The EDC system 
will also track queries and produce reports of outstanding queries. 
 
As the sites are entering data, on-screen edit checks run real-time to catch missing values, 
out of range values, and logical inconsistencies. These will be specified by the DCRI 
Clinical Data Specialist (CDS) working in conjunction with the statistician. The sites will 
be trained on reliably entering data. A final database audit on a representative sample of 
the data will also be carried out. 
 
9.1.1.2. Interim Analysis. 
There will be no interim analysis carried out. 
 
9.1.1.3. Primary Outcome Measures 


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 Reward-Related Circuit Engagement POC Outcome for the study will be task-
related fMRI ventral striatal (e.g., nucleus accumbens) activation occurring with 
reward and anticipation during the Monetary Incentive Delay (MID) Task 
 
9.1.1.4. Secondary Outcome Measures 
 Clinical Anhedonia Outcome for this study will be the total score Snaith-
Hamilton Pleasure Scale (SHAPS) 
 
 Behavioral Anhedonia Outcome for this study will be Response Bias and 
Reward Learning Scores on the Probabilistic Reward Task (PRT) 
 
9.1.1.5. Exploratory Outcome Measures 
 Ventral striatal fMRI activation during anticipation of loss during the MID Task 
 Resting state delta EEG current density in the rostral anterior cingulate 
 Resting state fMRI connectivity 
 Self-rated affective responses to cues and feedback during the MID Task 
 The Effort-Expenditure for Rewards Task (EEfRT) 
 The Visual Analogue Scale for Anhedonia (VAS) 
 The Temporal Experience of Pleasure Scale (TEPS) 
 The Hamilton Depression Rating Scale (HAM-D) 
 The Hamilton Anxiety Scale (HAM-A) 
 The Cognitive and Physical Functioning Questionnaire (CPFQ) 
 Clinical Global Impression - Severity (CGI-S) 
 Clinical Global Impression – Improvement (CGI-I) 
 Safety and tolerability of CERC-501 on systematically collected and 
spontaneously reported adverse events 
 
9.1.2. Planned analyses and statistical methodology to be used 
We will employ “Intention-to-Treat” (ITT) principles. Statistical tests will be performed 
based on a two-sided test at the 5% level of significance. Supporting analyses will also be 
performed. A “per protocol” analysis will restrict the analysis to participants who receive 
minimal exposure to the intervention, have a minimal number of longitudinal evaluations, 
and/or are free of major protocol violations. A “completer” analysis will only include 
participants who completed acute treatment without exiting or prematurely terminating 
from their assigned treatment. Because participants may be removed differentially across 
the treatment arms in these analyses, both approaches are vulnerable to differential 
selection bias and will be interpreted cautiously. 
 
Most of the study outcomes are observed repeatedly at well-defined time-points post-
randomization, so that statistical methods for repeated measures data will be applied. This 
includes the linear model with structured covariance matrices and the mixed effects 
models as implemented in PROC MIXED in SAS. Site will also be included as an 
independent variable in order to account for variability among the study sites. 
 
Covariates in Regression Models: The baseline value of the outcome, centered about its 
sample mean, will be included in each analysis. Otherwise, only age and sex will be 
entered as covariates. 


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Missing Values: We will proactively monitor the amount of missing data, and ensure that 
we respond quickly to emerging problems. Statistically, missing data will be addressed 
through the use of mixed models analysis which will be carried out with PROC MIXED 
in SAS. We will carry out an assessment of the degree to which the structured covariance 
matrix in mixed effects models fits the data.  
 
Other Confounders Arising Post-Randomization: Logistic regression analysis will be 
carried out to investigate: (a) adherence to the assigned study intervention (this will 
include serum levels of study drug and blister pack check data), (b) co-administration of 
psychotropic medications, and (c) discontinuation from the study intervention. First, we 
will determine whether these effects occur differentially across the treatment arms 
suggesting that a differential selection bias may have influenced the results. Then, we 
will investigate whether baseline characteristics are predictive of any behavior. This will 
include demographic characteristics, initial severity as measured by the baseline values of 
the outcome variables, and clinical characteristics such as diagnoses and medications 
taken at baseline. 
 
Magnitude of the Clinical Effect: To evaluate the clinical significance of the impact of 
treatment on outcome, effect sizes (Hedge’s g) will be calculated as (ME – MC) / SD 
pooled, where ME represents the adjusted mean of experimental treatment, MC 
represents the adjusted mean of the comparison treatment, and SD pooled represents 
pooling of the standard deviations from within both groups. We will also assess how the 
estimated magnitude of treatment effect and the estimated standard deviation deviate 
from those postulated in sample size planning. 
 
fMRI Analysis: The monetary incentive delay task entails three key task phases: 
anticipating making a response, anticipating an outcome, and receiving that outcome. 
Functional brain responses to these three task phases will be identified using a General 
Linear Model based statistical analyses (GLM). Here, a statistical test is carried out 
between the actual data (fMRI time series) and a predicted model (event timings and 
parametric modulations by behavior). If the fit between the predicted and actual data is 
good, then a relationship is concluded to exist between the actual data (voxel intensity 
values) and task-related factors (anticipation, response, receipt). Having tested the fit at 
the single subject level for each experimental session, the data will be combined into a 
second-level, random-effects, repeated-measures analysis of variance. Statistical 
inferences about task effects will be made after appropriate correction for multiple 
comparisons. Regions of interest or ROIs will be defined with reference to a standard 
brain atlas (that of Talaraich and Tournoux). The fMRI primary analysis (see below) will 
focus on the ventral striatum. However, exploratory analyses will be carried out with 
other ROIs. Cluster-wise parameter estimates for each condition (anticipation, response, 
receipt) will be extracted for the ventral striatum (and from the other predefined ROIs for 
exploratory analysis) and correlated with receptor occupancies. In this manner our 
regression analyses will be robust to non-independence error. 
 
9.1.2.1. Primary Analysis 
Point estimate and the corresponding confidence interval for the primary study outcome 
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the adjusted predicted score will be obtained. A mixed effects model analysis will be 
carried out for the primary outcome of the study, task-related fMRI activation in the 
ventral striatum during anticipation of reward occurring during the Monetary Incentive 
Delay Task. This analysis will test the hypothesis that CERC-501 will lead to a greater 
increase in ventral striatal activation during anticipation of reward than placebo. 
 
9.1.2.2. Secondary Analysis 
A mixed effects model analysis will also be carried out for the secondary outcomes of the 
study, SHAPS score and PRT-derived Reward Learning and Response Bias. These 
analyses will test the hypothesis that CERC-501 will: 1) decrease SHAPS score to a 
greater degree than PBO; and 2) increase PRT-derived reward learning and response bias 
to a greater degree than PBO. 
 
9.1.2.3. Exploratory Analysis 
Exploratory mixed effects model analyses will also be carried out with the exploratory 
outcomes of the study. This includes: ventral striatal fMRI activation during anticipation 
of loss during the MID Task; resting state delta EEG current density in the rostral anterior 
cingulate; resting state fMRI connectivity; self-rated affective responses to cues and 
feedback during the MID Task; EEfRT total reward; VAS score; TEPS anticipatory and 
consummatory pleasure scores; HAM-D score; HAM-A score; CGI-S, CGI-I, and CPFQ 
score. 
 
9.2. Power Analysis 
 
A total of 90 subjects will be randomized: 45 subjects randomized to CERC-501 and 45 
to placebo and included in the primary efficacy analysis. We conservatively anticipate 
that we will have incomplete data on up to 20% of subjects due to subject drop out or loss 
of data due to factors such as poor scan quality. As a result, we estimate that we will have 
complete data on as few as 72 subjects and as many as 90 subjects. In the section above, 
we outline how we will address the issue of missing data including carrying out analyses 
on the intent-to-treat (ITT) population and employing mixed effect models. If we assume 
the worst case scenario of 72 subjects, for a one tailed t-test at an alpha value of 0.05, 
power is 80% to identify an effect size of 0.58. For a one tailed t-test at an alpha value of 
0.10 power is 80% to identify an effect size of 0.50. In Figure 4, it is indicated the effect 
that could be detected with 80% power at the alpha=0.05 level as a function of number of 
subjects. 
 
Our capacity to estimate the expected effect size on our primary outcome measure is 
limited by the studies that have been carried out with this measure to date. The most 
relevant study was carried out by Stoy and co-workers (2011) who evaluated 15 patients 
with major depression and 15 controls and administered open-label escitalopram to both 
groups for 6 weeks and assessed outcome with fMRI activation of the ventral striatum 
during the MID. However, it must be kept in mind that estimates of power based on this 
study are likely overly optimistic because this was an open-label treatment study and only 
included 15 depressed subjects. We can estimate the expected effect size for our study 
from the ventral striatal activation to reward anticipation subject group by time 
interaction observed in this study. The effect size for a greater increase in those with 
depression compared with controls is 0.88. We can also estimate effect size from the pre-


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to-post treatment difference in ventral striatal activation during reward anticipation and 
reward during the MID with fMRI within the depressed group which are 1.1 and 1.0 
respectively. These effect sizes suggest that we are likely to have more than sufficient 
power to detect a significant effect with our primary outcome measure in the proposed 
study at the alpha=0.05 level with 80% power. 
 
Figure 4 – Effect size 
 
 
 
10. HUMAN SUBJECTS PROTECTION 
 
10.1. Subject Selection 
 
10.1.1. Statement of equitability 
 
Subjects in this study will all be recruited within the vicinity of each of the sites by the 
site teams. We expect that the racial and sexual distributions of patients enrolled in this 
study will reflect those of the general population in each region. All of the sites have 
experience recruiting minorities through a concentrated effort in communities that have 
high representation of ethnic and racial minorities and through advertisements in 
newspapers and radio stations whose readers/listeners are predominantly of specific racial 
or ethnic minorities. 
 
10.1.2. Justification for exclusion of children 
 
Children (those under age 21) will not be included in this study because insufficient data 
are available with CERC-501 in adults to judge potential risk in children. 
 
10.1.3. Justification for exclusion of other vulnerable subjects 
 
Because the aims of this study can be achieved with individuals who are not members of 
vulnerable groups (those who lack capacity for consent, prisoners, pregnant women etc.), 
we will not have to include any vulnerable subjects. 
 
10.1.4. Safeguards for vulnerable populations 
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In order to protect vulnerable populations, they will be excluded from participation in this 
study. This includes pregnant women. In order to identify women who are pregnant, all 
women of childbearing potential will undergo a blood pregnancy test and it must be 
negative before subjects can continue in this study. If sexually active, female subjects 
must agree to use appropriate contraceptive measures for the duration of the study and for 
1 month afterwards. Medically acceptable contraceptives include: (1) surgical 
sterilization (such as a tubal ligation or hysterectomy), (2) approved hormonal 
contraceptives (such as birth control pills, patches, implants or injections), (3) barrier 
methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine 
device (IUD). Contraceptive measures such as Plan B (TM), sold for emergency use after 
unprotected sex, are not acceptable methods for routine use. If subjects do become 
pregnant during this study or if they have unprotected sex, they will be instructed to 
inform the study physician immediately. 
 
Participation of sexually active men has the potential to damage sperm, which could 
cause harm to a child that a subject might father while on this study. As a result, in order 
to protect subjects, sexually active male subjects will have to agree to use a medically 
acceptable form of birth control during and 1 month after this study in order to 
participate. Medically acceptable contraceptives include: (1) surgical sterilization (such 
as a vasectomy), or (2) a condom used with a spermicide. Contraceptive measures such as 
Plan B (TM), sold for emergency use after unprotected sex, are not acceptable methods 
for routine use. Subjects will be instructed to inform their partners of the potential for 
harm to an unborn child and that they should immediately inform the study doctor if 
pregnancy occurs. 
 
10.1.5. Qualifications of Investigators 
The overall principal investigator for this study is Dr. Andrew D. Krystal, MD, MS. He is 
highly experienced in serving as the principal investigator for single-site and multi-site 
clinical trials with patients with mood and anxiety spectrum disorders. This includes 
those employing fMRI scanning as will be carried out in the current study. Each one of 
the site PIs was selected because they too are highly experienced in serving as PIs for 
studies of patients with mood and anxiety spectrum disorders and they themselves or 
those at their site also have experience and expertise in carrying out the assessments that 
will be carried out in this study. 
 
11. ANTICIPATED BENEFIT 
 
Subjects may not receive any direct benefit from participating in this study. There is a 
small possibility that we may detect an unrelated medical condition during the procedures 
conducted in this study which could have health benefits for some individuals. Some 
individuals may experience improvement in their symptoms through participation in the 
study, though some are likely to remain the same or get worse. However, the drug will 
not be available to subjects after the study concludes. The information that we get from 
this study may help us to better treat future patients with mood and anxiety disorders. 
 
The available treatments for patients with mood and anxiety spectrum disorders have 
significant limitations. This study has the potential to take steps to address these 


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limitations by: 1) testing a promising new treatment for mood and anxiety spectrum 
disorders; 2) evaluating a potential target in the brain which could serve as the basis for 
development of additional new candidate compounds for the treatment of patients with 
mood and anxiety spectrum disorders; 3) establishing more expeditious methods for 
evaluating potential new therapies for patients with mood and anxiety spectrum 
disorders; and 4) specifically establishing methods for the development of new therapies 
targeting anhedonia, an important endpoint. 
 
 
12. CLASSIFICATION OF RISK (for the study as a whole) 
 
12.1. Risk Classification 
 
This study is associated with more than minimal risk 
 
12.2. Overall Risk and Benefit Consideration 
 
The risks of the study are reasonable in relation to the anticipated benefit described in 
Section 11. 
 
13. CONSENT DOCUMENTS AND PROCESS 
 
13.1. Consent Procedures 
 
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. 
 
14. DATA AND SAFETY MONITORING 
 
14.1. Data and Safety Monitor 
 
Data and safety will be monitored by the NIMH Data and Safety Monitoring Board 
(DSMB). The NIMH DSMB functions include, among many, the assessment of interim 
data to determine whether the treatment interventions show a clear risk when compared 
with placebo. The main purpose of the NIMH DSMB is to assess safety of the 
interventions by determining whether an increased number of adverse events occur 
among study participants receiving the intervention compared to the participants 
receiving placebo treatment. Data will be reviewed every 4 months after the NIMH 
DSMB approval of the protocol and consent form. 
 
14.2. Data and Safety Monitoring Plan 
 
As described above, an independent DSMB will be established by NIMH that will meet 
regularly to review trial data in order to protect subject safety and data integrity. The 


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DSMB will meet prior to the start of the study to review the protocol and consent form. 
After the study commences, the DSMB will meet at least every 4 months. 
 
Prior to each DSMB meeting that takes place after the study commences, the Principal 
Investigator will generate and circulate a full report to the NIMH DSMB members and 
the study biostatistician, summarizing recruitment, patient status and safety data for the 
study to be reviewed at that DSMB meeting including SAE reports. These reports will be 
prepared illustrating patient status and safety data. Patient status reports will summarize 
the number of subjects screened, eligible, randomized, treated, and completing the study -
- by month and overall to-date. Detailed tables will be provided on reasons for 
ineligibility, and reasons for early termination of enrolled subjects. Safety reports will 
include summary data on all subjects experiencing the emergence or worsening of any 
adverse event (including abnormal laboratory values) during the course of a study, and 
during each study phase (screening, treatment, follow-up) -- each relative to the number 
of subjects in that phase. More detailed reports will provide information on the specific 
types of adverse events experienced, and the number that constituted Serious Adverse 
Events (SAEs) or led to termination from the study. Details of all SAEs occurring during 
a study will be provided to the DSMB for review of the nature and outcome of each SAE, 
as well as that all appropriate follow-up and required reporting was done in a timely 
manner. Tabulation and descriptions for protocol deviations will also be included in the 
report. 
 
In addition to reviewing these data, the DSMB will also review procedures for ensuring 
that data are collected and analyzed per protocol privacy and that subject confidentiality 
is being maintained. 
 
The DSMB will also carry out an overall assessment of the risk-benefit ratio of the study 
based on the available data. If there is a concern that the risks might outweigh the 
benefits, then enrollment will be suspended pending a more detailed review. However, if 
it is clear that the risks outweigh the benefits, then they will recommend permanently 
stopping the study. 
 
15. QUALITY ASSURANCE 
 
15.1. Program Management Committee 
 
The Program Management Committee (PMC) will have primary responsibility for 
Quality Assurance Monitoring for this study. This committee will be chaired by the 
DCRI Project Leader and Co-Chaired by the FAST-MAS PI, Andrew Krystal, MD, MS. 
This committee will also include several teams: 1) Site Management – this includes a 
Clinical Research Associate (CRA), who, along with the Project Lead will have primary 
site management responsibility; 2) Data Management – this includes the Lead 
Biostatistician, and the Program Manager of electronic data system (EDC) and data 
management group; 3) Assessment/Signal Detection – Richard Keefe, Ph.D. will lead 
oversight of assessments and quality of data collection; 4) Magnetic Resonance Imaging 
(MRI) – Allen Song, Ph.D. will lead oversight for ensuring the quality of MRI methods, 
MRI data collection, and MRI data analysis. 
 


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15.2. Quality Assurance Plan 
 
The PMC will meet regularly via teleconference (weekly from the beginning of study 
start up until the end of the study) to provide operational leadership to ensure that the 
study is implemented and managed efficiently and effectively and to oversee Quality 
Assurance. In this effort, they will work collaboratively with the NIMH Program Team. 
The Quality Assurance Plan includes the PMC carrying out the following key activities. 
 
15.2.1. Monitoring and Managing Study Timelines 
One of the most important responsibilities of the PMC will be to monitor study timelines 
by assessing whether key timeline milestones are being met by each of the sites. The 
PMC will be responsible for collecting ongoing data on whether milestones are being 
met. Dr. Krystal will then lead forming a strategy to address problems in meeting 
recruiting or other milestones and will work directly with the site PI in the 
implementation of that strategy. 
 
15.2.2. Monitoring for Protocol Deviations 
Another important function of the PMC will be to monitor for protocol deviations. These 
will be identified via review of electronic case report by the Site Management and Data 
Management teams. In addition each site will report all protocol deviations to the Site 
Management team. The PMC will monitor the protocol deviations and institute plans for 
addressing ongoing problems/deficiencies where needed. 
  
15.2.3. Site Training 
Site Training will take place in a number of steps. This will include training from the Site 
Management team on many study procedures, training from Dr. Keefe on completing 
subject assessments, training from Dr. Song on MRI procedures, and EDC training (see 
following section). The procedures to be carried out at the sites will be reviewed. This 
will also be the case for requirements for training of staff and documentation that those 
carrying out tasks for this study have the appropriate training documented. 
 
Dr. Keefe will implement processes that he and his group have developed for rater 
training and data quality review to promote the collection of high quality data. These 
processes will be employed in this FAST-MAS study and are outlined below: 
 
a. Develop a protocol-specific guide for the MINI, HAM-D, HAM-A and C-SSRS. 
b. Provide all testing materials to the sites. 
c. Pre-screen 2 raters per site, including assessing the sites for their rater 
training/credentials, extent of rater experience, and experience with clinical 
populations, and experience with the specific instruments used in this study. 
d. Implement training procedures, including preparations for training, sending 
protocol-specific procedures, and providing access to clinical rating training 
videos for raters to review prior to the investigator’s meetings. 
e. Individual certification of at least one rater per site. 
f. Review of testing procedures by Dr. Keefe via a presentation to the site 
investigators. 
g. Either in-person or phone training and certification for all raters. 
 


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15.2.4. Site Electronic Data Capture (EDC) System Training 
The Data Management team will conduct a web-based training on the EDC systems for 
site personnel. The site teams will enter data in the training environment during the 
training session, ask questions, and receive feedback on their work. In addition to the 
training session, the Data Management team will be available on a continuing basis to 
assist site personnel over the phone with questions related to remote data entry. 
Throughout the trial, for new study coordinators training will be delivered via a web-
based program and telephone. 
 
15.2.5. Research Ethics Training 
The CC will ensure that all faculty, clinical staff having direct patient contact, and all 
personnel involved in site and data management involved in this study will meet human 
subjects training requirements.  
 
15.2.6. Ongoing Site Management/Monitoring 
Ongoing Management/Monitoring of each site will be carried out by the DCRI Site 
Management team which consists of the DCRI Project Leader, and a Clinical Research 
Associate (CRA). Site Management will include both on-site and in-house monitoring, 
routine communication with the site personnel, and collection of site-related data and 
documents. A particular focus will be to work with the site on effective recruiting 
strategies. The CRA will also provide ongoing monitoring of the recruitment at the site 
and report this to the FAST-MAS PI along with suggestions for improving enrollment. 
The CRA will carry out the same type of monitoring and trouble-shooting with protocol 
implementation and quality of adherence to study procedures. Dr. Keefe and the Signal 
Detection team will also play an important role in ongoing monitoring in order to 
maintain high quality in study assessments. Their activities will include: 
 
a. Monitoring frequency of assessments carried out by raters. 
b. Raters not administering assessments for 4 months will be required to complete 
refresher training. 
c. Carrying out a phone certification process for replacement raters when there is 
site rater turnover. 
d. Participate in biweekly conference calls to prepare for training meetings, review 
data collection processes, and address all study-related assessment issues as they 
arise over the course of the study. 
 
16. ADVERSE EVENT AND UNANTICIPATED PROBLEM 
REPORTING 
 
All adverse events serious and non-serious, expected and unexpected, related and 
unrelated to study drug will be documented and reported to the sponsor. 
 
16.1. Plan for Assessment for Adverse Events 
 


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The Principal Investigator or a Co-Investigator at each site will monitor all subjects for 
adverse effects from the time of signature on the informed consent throughout their 
participation in the study. This will include carrying out a clinical interview for adverse 
events at each visit and administering the Patient Reported Inventory of Side Effects 
(PRISE) . In addition, a series of safety assessments will be carried out and the findings 
reviewed by the site PI or Co-I. These safety assessments will include: the Columbia 
Suicide Severity Rating Scale (CSSRS) (Posner, 2011), vital signs (height, weight, blood 
pressure, and pulse), physical examination, Beta-HCG serum pregnancy test, urine drug 
screen, complete blood count with differential, electrolytes, comprehensive metabolic 
panel including liver function tests, thyroid function tests, urinalysis, the Clinical Global 
Impression – Improvement (CGI-I), the Clinical Global Impression – Severity (CGI-
S)and ECG and EEG ( obtained at baseline, at the end of 8 weeks of daily treatment with 
study drug).  In addition, because gastritis was noted in some of the rats administered 
CERC-501 and some gastric-related side-effects were observed in the Phase 1 human 
studies, specific assessment for gastric adverse events will be carried out in this study.  
This will consist of collecting blood at baseline, 4 weeks, and 8 weeks of double-blind 
treatment from which gastrin and pepsinogen I/II levels will be determined.    
 
These data will be used to assess for adverse event type, severity, expectedness, and 
causal relationship to study drug as defined below. 
 
16.1.1. Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with 
the use of the study drug in a subject whether or not considered drug related. An AE can 
therefore be any unfavorable and unintended sign, symptom or disease temporally 
associated with the use of the drug. Any change in clinical status, ECGs, laboratory tests, 
physical examinations, etc., that is considered clinically significant by the site 
investigators. 
 
16.1.2. Serious Adverse Events (SAE) 
An SAE is any adverse event where any of the following is the case: 
 Is associated with death. 
 Is life-threatening: Places the subject at immediate risk of death at the time of the 
event as it occurred. This includes suicide attempts. It does not include an AE 
that, had it occurred in a more severe form, might have caused death. 
 Causes persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
 Is associated with inpatient hospitalization or prolongation of hospitalization. 
 Is associated with a congenital anomaly or birth defect. 
 Important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered a serious adverse event when, based 
upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition above. This determination is based on the opinion of either the 
investigator or sponsor (e.g., if either believes it is serious, it must be considered 
serious). 
 


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16.1.3. Assessment of Adverse Event Severity 
The determination of adverse event severity will be made by the site PI or site Co-I. The 
severity of AEs will be graded using the following definitions:  
 Mild: Participant is aware of symptoms or has minor findings, but tolerates them 
well and no or minimal intervention is required 
 Moderate: Participant experiences enough symptoms or findings to require 
intervention 
 Severe: Participant experiences symptoms or findings that require significant 
intervention or is life threatening (participant is at immediate risk of death from 
symptoms or findings that require aggressive medical management) 
 
16.1.4. Assessment of Causal Relationship to Study Drug 
The site PI or Co-Investigator will rate the causal relationship of any adverse event to the 
study drug using the following: 
 Not related: There is not a reasonable causal relationship to the investigational 
product and the adverse event 
 Unlikely related: An AE that has some possibility of being related to the study 
drug but this possibility is remote.  
 Possibly related: An AE that has little or no relationship to the study drug and 
there exists a more likely alternative cause 
 Probably related: An AE that is likely to be related to the administration of the 
study drug and an alternative cause less likely when compared to the study drug 
 Definitely Related: An AE that has a strong temporal relationship to the study 
drug. AE will recur with continued or repeated use of the study drug, and 
another cause is unlikely or less likely 
 
16.1.5. Expectedness of Adverse Event 
Any adverse event, the specificity, nature, or severity of which is not consistent with the 
investigator brochure will be considered an unexpected AE. AEs that are expected based 
on the investigator brochure consist of peptic ulcer disease, gastritis, headache, diarrhea, 
nausea, vomiting, flushing, anxiety, upset stomach, and itchiness. 
 
16.2. Documentation of Adverse Events 
All events determined to be an AE, based on physical examination, laboratory findings, 
or other means, will be recorded. Each AE will be entered into the electronic data capture 
(EDC) system by the site PI or qualified designee. The investigator will provide date of 
onset and resolution, assessment of severity, intensity, and frequency, action(s) taken, 
changes in study drug dosing, relationship to study drug, and outcome. When additional 
relevant information related to an AE becomes available, the site PI or Co-I will record 
follow-up information according to the same process used for reporting the initial event 
as described above. They will follow all Adverse Events until resolution or they no 
longer believe that it is clinically significant. AEs ongoing at the time of the last dose of 
study drug will be followed up for as long as necessary to adequately evaluate the 
participant’s safety, until they are resolved, or until it is determined by the investigator 
not to be clinically significant. All women of childbearing potential will be instructed to 
notify the Investigator if they become pregnant at any time during the study or within 30 
days of last study evaluation. The pregnancy will be followed until delivery. Any 


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associated AEs or SAEs that occur to the mother or fetus/child will be recorded in the 
EDC system. 
 
16.3. Reporting of Adverse Events 
Any SAE entered into the EDC system will generate automatic notification to the DCRI 
Safety Surveillance Team. The DCRI Safety Surveillance Team will review all SAEs at 
the time they are reported and immediately report them to the Principal Investigator Dr. 
Krystal. Dr. Krystal or his designee will be responsible for notifying the NIMH Contract 
Officer’s Representative (COR), NIMH DSMB and Cerecor within 1 – 2 business days of 
receipt of all site reported SAEs. Dr. Krystal or his designee will be responsible for 
forwarding written IND Safety reports (for those events identified as serious, related and 
unexpected) to the NIMH COR, NIMH DSMB, Cerecor, the site PIs, and the Duke IRB 
within 7 days (fatal/life threatening) and/or 15 days (for all other event determined to 
meet expedited reporting criteria). 
 The individual site principal investigators will be responsible for reporting SAEs 
occurring in subjects at their respective sites to their local Institutional Review Boards 
(IRB) per local IRB reporting requirements.  
 
Dr. Krystal or his designee will be responsible for notifying the FDA in a written IND 
safety report of  all SAEs determined to meet expedited reporting criteria within 7 days 
(for fatal/life threatening events) and/or 15 days (for all other event determined to meet 
expedited reporting criteria) per 21 CRF 312. 32.  Sites will be responsible for submitting 
IND Safety Reports to their respective IRBs per their local requirements.  Documentation 
will be retained by each investigative site.   
 
Pregnancy occurring during a clinical investigation, although not considered a serious 
adverse event, must be reported to the DCRI within the same timelines as a serious 
adverse event.  The pregnancy will be recorded on the appropriate pregnancy form and 
will be followed until final outcome. Any associated AEs or SAEs that occur to the 
mother or fetus/child will be recorded on the appropriate AE or SAE eCRF form and 
processed accordingly.  The DCRI Safety Group will notify the NIMH COR, NIMH 
DSMB, and Cerecor of any pregnancy occurring during the study within the same 
timelines as a serious adverse event.  The site principal investigators will be responsible 
for notifying the respective IRB of any pregnancies occurring at their sites. 
 
In addition, Dr. Krystal or designee will promptly report to the NIMH COR, NIMH 
DSMB and the site principal investigators any unanticipated problems that are not 
adverse events within 1–2 business days of becoming aware of an unanticipated and life 
threatening problem or within 15 days of  becoming aware of all other unanticipated 
problems. Unanticipated problems are any event that is: unexpected in nature, frequency 
or severity; related or possibly related to participation in the research; or suggest that the 
risk of harm to subjects is increased.  
 
Expected or non-serious adverse events will be reported to the NIMH COR, NIMH 
DSMB prior to each Board meeting. 
 
 
 


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17. ALTERNATIVES TO PARTICIPATION 
 
Subjects will be informed that they do not have to participate in this study to receive 
treatment for their condition. Instead of taking part in this study, subjects could receive an 
FDA approved treatment available by prescription to treat their mood or anxiety disorder. 
 
 Alternative treatments and procedures. In some, cases patients will have failed 
or partially responded to conventional treatment. Their main alternative to 
participation will be treatment with another traditional treatment which includes 
antidepressant or anxiolytic medication, and/or psychotherapy, a newer form of 
treatment such as repetitive transcranial magnetic stimulation (rTMS), or a more 
intensive form a treatment like ECT. The risks and benefits of the alternatives are 
those of the possible treatments. 
 
18. CONFLICT OF INTEREST 
 
18.1. Distribution of NIH Guidelines 
 
NIH guidelines on conflict of interest have been distributed to all investigators. 
 
18.2. Conflict of Interest 
 
All investigators will abide by the conflict-of-interest policies of their own institution. 
 
18.3. Role of a Commercial Company or Sponsor 
 
Cerecor will be providing study medication for this study. No personal identifiers of 
participants will be shared with Cerecor. 
 
 
19. TECHNOLOGY TRANSFER 
 
A Clinical Trial Support Agreement exists between Cerecor, who is providing study 
medication (CERC-501) for this study, and who owns the intellectual property for 
CERC-501, and Duke University. This Agreement includes a confidentiality provision – 
participant personal identifiers will not be shared with Cerecor. 
 
 
20. RESEARCH AND TRAVEL COMPENSATION 
 
All subjects will be compensated for time and research-related inconveniences. The 
amount of compensation will be prorated for parts of the study completed if subjects do 
not complete the study. Local site and institutional policy will be used to determine the 
amount of compensation.  
 
 


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APPENDICES 
 
Appendix 1. Eligibility Checklist 
Appendix 2. List of Prohibited Medications 
 
 
 


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Appendix 1. Eligibility Checklist 
 
□ Age 21 through 65 years of age 
□ Meets DSM-IV TR diagnostic criteria for: Major Depressive Disorder, Bipolar I 
or II Depressed, Generalized Anxiety Disorder, Social Phobia, Panic Disorder, or 
Post Traumatic Stress Disorder 
□ Snaith-Hamilton Pleasure Scale (SHAPS) score ≥ 20 
□ Reliable and willing to be available for the duration of the study 
□ Willing and able to give written informed consent to participate 
□ Able to understand and comply with instructions 
□ If female of childbearing potential, must agree to use dual methods of 
contraception and be willing and able to continue contraception for 6 weeks after 
the last dose of study drug. Females using oral contraception must have started 
using it at least 2 months prior to the Baseline Visit 
□ If male of childbearing potential, must have undergone surgical sterilization (such 
as a vasectomy) or agree to use a condom used with a spermicide during 
participation in the study and for 1 month afterward 
□ Not expected to require hospitalization during the course of the study 
□ No current/history of a psychotic disorder, current manic or mixed episode, 
autism spectrum disorders, mental retardation 
□ Did not meet DSMIV-TR criteria for substance abuse within the last 3 months or 
substance dependence within the last 6 months, excluding caffeine and/or nicotine 
□ No history of unstable or untreated serious medical condition based on physician 
evaluation, medical history, and screening laboratory testing.  
□ No active suicidal intent or plan, or history of attempt within the past 3 months 
based on physician evaluation and Columbia Suicide Severity Rating Scale (C-
SSRS) 
□ No use of any antidepressant, antipsychotic, anxiolytic, anticonvulsant, mood 
stabilizing, muscle relaxant, centrally acting antihistaminergic, stimulant or 
insomnia medications within 5 half-lives of baseline or at any time during after 
baseline 
□ No use of any medication that is primarily metabolized by Cytochrome P450 2C8 
within 14 days of baseline or at any time during the study. This includes: 
Cerivastatin, Paclitaxel, Repaglinide, Sorafenib, Rosiglitazone, Trimethoprim, 
Amodiaquine, Morphine, Amiodarone, Cabazitaxel, Carbemazepine, 
Chloroquine, Ibuprofen, Teprostinil, and Torsemide 
□ Without magnetic resonance imaging contraindications 
□ No positive urine drug screen at any time during the study 
□ No use of any investigational medication within 3 months prior to the start of this 
study or scheduled to receive an investigational drug other than CERC-501 during 
the course of this study 
□ No known hypersensitivity to CERC-501 
□ No history of severe allergies or multiple adverse drug reactions 
□ History of gastric disease including peptic ulcer disease or gastritis, upper GI 
bleeding, or any GI precancerous condition, clinically evident gastrointestinal 
complaints. 
□ Current  use of a proton pump inhibitor or histamine 2 blocker or a history of 
chronic NSAID use.  


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□ History of use of Salvia divinorum or use of Salvia divinorum at any time during 
the study. 
□ Without any other condition that in the opinion of the investigator would preclude 
participation in the study 
□ No smoking of cigarettes or use of any nicotine containing products within the 
last month or at any time during the study 
□ Not pregnant or lactating 
 
 
 
 


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Appendix 2. List of Prohibited Medications 
 
 
 
Generic 
Trade Name 
Benzodiazepines and Non-Benzodiazepine hypnotics 
Alprazolam 
Xanax 
 
 
 
 
Brotizolam 
 
 
 
 
 
Chlordiazepoxide HCl 
Librium 
 
 
 
 
Clonazepam 
Klonopin 
Paxam 
Rivotril 
 
 
Clorazepate dipotassium 
Apo-
Clorazepate 
Gen-Xene 
Novo-Clopate 
Tranxene(-SD) 
 
Estazolam 
ProSom 
 
 
 
 
Flunitrazepam 
Rohypnol 
 
 
 
 
Flurazepam 
Dalmane 
 
 
 
 
Diazepam 
Valium 
Diastat 
Diazemuls 
Antenex 
Ducene 
Novo-Dipam 
Vivol 
Dizac 
 
 
Loprazolam 
 
 
 
 
 
Lorazepam 
Apo-
Lorazepam 
Ativan 
Novo-Lorazem 
Nu-Loraz 
 
Lormetazepam 
 
 
 
 
 
Midazolam 
Aldurazyme 
Versed 
 
 
 
Nitrazepam 
Mogadon 
 
 
 
 
Oxazepam 
Novoxapam 
Serax 
 
 
 
Quazepam 
Doral 
 
 
 
 
Temazepam 
Restoril 
 
 
 
 
Triazolam 
Halcion 
 
 
 
 
Zaleplon 
Sonata 
 
 
 
 
Zolpidem 
Ambien 
 
 
 
 
Antidepressants 
Bupropion 
Wellbutrin 
(SR) 
Zyban 
 
 
 
Citalopram 
Celexa 
Seropram 
Cipramil 
 
 
Clomipramine 
Anafranil (SR) 
Placil 
 
 
 
Duloxetine 
Cymbalta 
 
 
 
 
Doxepine 
Sinequan 
 
 
 
 
Escitalopram 
Cipralex 
Lexapro 
 
 
 
Desipramine 
Norpramin 
Pertofran(e) 
 
 
 
Fluoxetine 
Prozac 
Lovan 
Erocap 
Sarafem 
Zactin 
Fluvoxamine 
Fevarin 
Luvox 
 
 
 
Imipramine 
Apo-
Imipramine 
Impril 
Janimine 
Norfranil 
Novopramine 
Tipramine 
Tofranil 
Tofranil-PM 
 
 
Mianserine 
Tolvon 
 
 
 
 
Mirtazapine 
Remeron 
 
 
 
 
Nefazodone 
Dutonin 
Serzone 
 
 
 
Paroxetine 
Paxil (CR) 
Aropax 
Seroxat 
Deroxat 
 
Sertraline 
Zoloft 
Lustral 
 
 
 
Trazodone 
Desyrel 
Dividose 
Molipaxin 
Trazon 
Trialodine 
Protriptyline 
Triptil 
Concordin 
Vivactil 
 
 
Reboxetine 
Edronax 
 
 
 
 
Venlafaxine 
Effexor (TR) 
 
 
 
 
 
 


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Generic 
Trade Name 
Centrally active sedating antihistamines 
Azelastine HCl 
Astelin 
Optivar 
 
 
 
Dimenhydrinate 
Dramamine 
 
 
 
 
Diphenhydramine 
Benadryl 
Sominex 
Nytol 
Tylenol 
 
Hydroxyzine HCl 
Atarax 
Vistaril 
 
 
 
Levocabastine 
Livostin 
 
 
 
 
Methdilazine 
 
 
 
 
 
Promethazine 
Phenergan 
Anergan 
Pentazine 
Phenazine 
 
Phencen 
Phenerzine 
Phenoject 
Pro-50 
 
Promacot 
Pro-Med 50 
Promet 
Prorex 
 
Prothazine 
Shogan 
V-Gan-50 
 
 
Trimeprazine 
 
 
 
 
 
Antipsychotics 
Aripiprazole 
Abilify 
 
 
 
 
Chlorpromazine  
Chlorpromanyl 
Largactil 
Novo-
Chlorpromazine 
Thorazine 
 
Clozapine 
Clozaril 
 
 
 
 
Fluphenazine decanoate 
Modecate 
Prolixin 
Decanoate 
 
 
 
Fluphenazine enanthate 
Moditen 
Enanthate 
Prolixin 
Enanthate 
 
 
Fluphenazine HCl 
Anatensol 
 
 
 
 
Haloperidol 
Haldol 
Dozic 
Peridol 
Serenace 
 
Lurasidone 
Latuda 
 
 
 
 
Loxapine 
Loxapac 
 
 
 
 
Mesoridazine Besylate 
Serentil 
 
 
 
 
Molindone 
Moban 
 
 
 
 
Olanzapine 
Zyprexa 
 
 
 
 
Prochloperazine 
Compazine 
 
 
 
 
Quetiapine Fumarate 
Seroquel 
 
 
 
 
Risperidone 
Risperdal 
 
 
 
 
Thioridazine HCl 
Phenothiazines 
Serentil 
Prolixin 
Thorazine 
 
Mellaril 
Trilaton 
Vesprin 
 
 
Thiothixene 
Navane 
 
 
 
 
Ziprasidone 
Geodon 
 
 
 
 
Psychotropics miscellaneous 
Lithium 
Camcolit 
Carbolith 
Duralith 
Eskalith 
 
Lituane 
Lithicarb 
Lithizine 
Lithobid 
 
Lithonate 
Lithotabs 
Priadel 
Cibalith-S 
 
Melatonin 
 
 
 
 
 
Modafinil 
Provigil 
 
 
 
 
Phenelzine sulfate 
Nardil 
 
 
 
 
St. John’s Wort 
 
 
 
 
 
Sodium oxybate 
Xyrem 
 
 
 
 
Tranyleypromine sulfate 
Parnate 
 
 
 
 
Stimulants 
Dextroamphetamine 
Dexedrine 
 
 
 
 
Laevoamphetamine 
(amphetamine sulfate) 
Alderall 
Benzedrine 
 
 
 
Methamphetamine 
Methedrone 
Desoxyn 
Gradumet 
 
 
Methylphenidate 
Ritalin 
Metadate 
Methylin 
Concerta 
 
Modafinil 
Provigil 
 
 
 
 
R-Modafinil 
Nuvigil 
 
 
 
 
 


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Generic 
Trade Name 
Medications Primarily Metabolized by Cytochrome P450 2C8 
Cerivastatin  
 
 
 
 
 
Paclitaxel 
 
 
 
 
 
Repaglinide 
 
 
 
 
 
Sorafenib 
 
 
 
 
 
Rosigilatazone 
 
 
 
 
 
Trimethoprim 
 
 
 
 
 
Amodiaquine 
 
 
 
 
 
Morphine 
 
 
 
 
 
Cabazitaxel 
 
 
 
 
 
Amiodarone 
 
 
 
 
 
Carbemazepine 
 
 
 
 
 
Chloroquine 
 
 
 
 
 
Ibuprofen 
 
 
 
 
 
Teprostinil 
 
 
 
 
 
Torsemide 
 
 
 
 
 
Alpha-1 andAlpha-2-agonists / antagonists 
Clonidine 
Aruclonin 
Atensina 
Barclyd 
Catapres 
Catanidin 
Prazosin 
Minipress 
 
 
 
 
Methyldopa 
Aldoclor 
Aldomet 
 
 
 
Decongestants 
Ephedrine 
Amesec 
Aminomal con 
Antiasmatico 
Adalixin 
Argyrophedrine 
Apracur 
Phenylephrine  
Accuhist 
Aclophen 
Aerohist Plus 
AH-chew 
Ak-Dilate 
Pseudoephedrine 
4 cold & 
cough-30 MG-
Capsule 
Acamol 
Accuhist DM 
Acetaminophe 
and 
Pseudoephedrine 
Actagen 
Phenylpropanolamine 
(PPA) 
Acutrim 
Alamine 
Alcinal 
Aler-Releaf 
Alka-Seltzer 
plus cold 
Xylometazoline 
Aforinol 
Amidrin 
Imidin 
Nasan 
Nasben 
Respiratory Stimulants 
Levodopa 
Sinemet 
 
 
 
 
Pramipexole 
Mirapex 
 
 
 
 
Ropinorole 
Requip 
 
 
 
 
Rotigotine 
Neupro 
 
 
 
 
Anti-Seizure Medications 
Gabapentin 
Neurontin 
 
 
 
 
Valproic Acid 
Depakote 
 
 
 
 
Carbemazepine 
Tegretol 
 
 
 
 
Lamotrigine 
Lamictal 
 
 
 
 
Pregabalin 
Lyrica 
 
 
 
 
Opioids 
Buprenorphine 
Suboxone 
 
 
 
 
Dihydrocodeinone 
Vicodin 
 
 
 
 
Methadone 
Methadone 
 
 
 
 
Morphine 
Morphine 
 
 
 
 
Oxycodone 
Oxycontin 
 
 
 
 
Tramadol 
Ultram 
 
 
 
 
(Dextro)propoxyphene 
Darvon 
 
 
 
 
Meperidine 
Demerol 
 
 
 
 
 
 
 


FAST-MAS KOR Phase 2a Study Protocol 
Version 6.0 
Task Order #: HHSN27100004 
Version Date 10/06/16 
Contract #: HHSN271201200006I 
 
Page 75 of 75 
Generic 
Trade Name 
Sympathicomimetics 
(bronchodilators: e.g., albuterol, salmeterol, terbutaline; xanthines: e.g., theophylline) 
Tertbutaline 
 
 
 
 
 
Salmeterol 
Serevent 
 
 
 
 
Clenbuterol 
Spiropent 
 
 
 
 
Ephedrine 
Bronkaid 
 
 
 
 
Levosalbutamol  
Xopenex 
 
 
 
 
Salbutamol/albuterol 
Proventil 
Ventolin 
 
 
 
Theophylline 
Elixophyllin 
Norphyl 
Theo-Dur 
Uniphyl 
 
Aminophylline 
Phyllocontin 
Truphylline 
Minomal R 
 
 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
Study Title: 
A Phase 2a Study to Evaluate the Kappa Opioid Receptor As a Target for the Treatment of Mood and 
Anxiety Spectrum Disorders by Evaluation of Whether CERC-501 Engages Key Neural Circuitry Related to 
the Hedonic Response 
 
Version Date: 
October 06, 2016 
 
NCT02218736 


 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
Fast-Fail Trials in Mood and Anxiety Spectrum Disorders (FAST-MAS) 
Kappa Opioid Receptor Phase 2a (KOR2) 
 
Version Date: December 18, 2017 
 
 
 


1 
 
TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS .................................................................................................................................................... 3 
STUDY FLOW CHART ...................................................................................................................................................... 5 
1. 
HYPOTHESES AND AIMS ....................................................................................................................................... 6 
1.1 
PRIMARY AIM .......................................................................................................................................................... 6 
1.2 
SECONDARY AIMS .................................................................................................................................................... 6 
1.3 
EXPLORATORY AIMS ................................................................................................................................................. 7 
2. 
BACKGROUND AND RATIONALE ........................................................................................................................... 7 
3. 
STUDY DESIGN .................................................................................................................................................... 10 
3.1 
OVERVIEW ............................................................................................................................................................ 10 
3.2 
PROCEDURES ......................................................................................................................................................... 10 
4. 
STUDY POPULATION ........................................................................................................................................... 14 
4.1 
OVERVIEW OF STUDY POPULATION ............................................................................................................................ 14 
4.2 
INCLUSION CRITERIA ............................................................................................................................................... 15 
4.3 
EXCLUSION CRITERIA ............................................................................................................................................... 15 
5. 
RANDOMIZATION ............................................................................................................................................... 16 
6. 
DURATION OF TREATMENT AND STUDY PARTICIPATION .................................................................................. 16 
7. 
STATISTICAL ANALYSIS ........................................................................................................................................ 16 
7.1 
SAMPLE SIZE ......................................................................................................................................................... 16 
7.2 
STATISTICAL METHODS ........................................................................................................................................... 17 
7.3 
PRIMARY AND SECONDARY EFFICACY ASSESSMENTS ..................................................................................................... 19 
7.4 
OTHER EFFICACY ASSESSMENTS ................................................................................................................................ 23 
7.5 
EXPLORATORY ASSESSMENTS ................................................................................................................................... 23 
7.6 
PSYCHIATRIC DIAGNOSTIC ASSESSMENT ..................................................................................................................... 25 
7.7 
SAFETY/ADVERSE EFFECTS ASSESSMENTS ................................................................................................................... 25 
7.8 
Vital Signs/Laboratory Assessments ............................................................................................................... 25 
8. 
REFERENCES ........................................................................................................................................................ 28 
APPENDIX A. GENERAL MILESTONES OF STUDY .......................................................................................................... 26 
APPENDIX B. SCHEDULE OF ASSESSMENTS, OUTCOME MEASURES, LABS AND PROCEDURES ................................... 27 
APPENDIX C. TABLE SHELLS ......................................................................................................................................... 34 
TABLE 1A.     DEMOGRAPHICS – INTENT TO TREAT ......................................................................................................................... 34 
TABLE 1B  
DEMOGRAPHICS - PER PROTOCOL ............................................................................................................................. 35 
TABLE  1C.     DEMOGRAPHICS – STUDY COMPLETERS ..................................................................................................................... 36 
TABLE  1D.     DEMOGRAPHICS – STUDY COMPLETERS ..................................................................................................................... 37 
 
TABLE 2.    PRE- TO POST-TREATMENT CHANGES IN FMRI ACTIVATION DURING ANTICIPATION OF REWARD ........................................ 38 
TABLE 3.    PRE- TO POST-TREATMENT CHANGES IN SHAPS ......................................................................................................... 39 
TABLE 4.   
 PRE- TO POST-TREATMENT CHANGES IN SHAPS ........................................................................................................ 40 
TABLE 5.    PRE- TO POST-TREATMENT CHANGES IN FMRI ACTIVATION DURING ANTICIPATION OF LOSS ............................................. 41 
TABLE 6.    PRE- TO POST-TREATMENT CHANGES IN RESTING STATE DELTA EEG CURRENT DENSITY IN THE ROSTRAL ANERIOR CINGULATE42 
TABLE 7.    PRE- TO POST-TREATMENT CHANGES IN RESTING STATE FMRI CONNECTIVITY ................................................................. 43 
TABLLE 8.      PRE- TO POST-TREATMENT CHANGES IN MONETARY REWARD TASK ............................................................................... 44 


2 
 
TABLE 9.         PRE- TO POST TREATMENT CHANGES IN THE EEFRT .................................................................................................... 45 
TABLE 10.      PRE- TO POST-TREATMENT CHANGES IN VAS ............................................................................................................ 46 
TABLE 11.      PRE- TO POST-TREATMENT CHANGES IN TEPS ........................................................................................................... 47 
TABLE12.      PRE- TO POST-TREATMENT CHANGES IN HAM-A ........................................................................................................ 48 
TABLE 13.     PRE- TO POST-TREATMENT CHANGES IN HAM-D ....................................................................................................... 49 
TABLE 14.     PRE- TO POST-TREATMENT CHANGES IN CGI-I ............................................................................................................ 50 
TABLE 15.     PRE- TO POST-TREATMENT CHANGES IN CGI-S ........................................................................................................... 51 
TABLE 16.     PRE- TO POST-TREATMENT CHANGES IN CPFQ .......................................................................................................... 52 
TABLE 17.     DESCRIPTIVE STATISTICS FOR ALL OUTCOMES AND ASSESSMENTS IN FINAL ANALYSIS ......................................................... 53 
 
 
APPENDIX D. FIGURES ................................................................................................................................................. 61 
 
 
 
 
 
 


3 
 
STUDY SYNOPSIS 
 
Title: 
A Phase 2A Study to Evaluate the Kappa Opioid Receptor as a Target for the Treatment of 
Mood and Anxiety Spectrum Disorders by Evaluation of Whether LY2456302 Engages Key 
Neural Circuitry Related to the Hedonic Response 
Indication: 
Mood and Anxiety Spectrum Disorders 
 
Location: 
1. Baylor College of Medicine 
2. Case Western Reserve University 
3. Duke University 
4. Indiana University 
5. Mount Sinai School of Medicine 
6. Yale University 
Rationale: 
We chose to focus on anhedonia as an endpoint for this study because: 1) the available data 
suggest that anhedonia is the dimension of mood and anxiety spectrum disorders that is 
most likely to be improved by KOR antagonists; 2) anhedonia is associated with measurable 
neurobiological mechanisms which can be studied with available methodologies that could 
be used to establish POC in terms of engagement of relevant neural circuitry; and 3) 
anhedonia allows us to accomplish our goal of studying an important aspect of dysfunction 
that cuts across mood and anxiety spectrum disorders, consistent with the NIMH’s RDoC 
framework. 
Objectives: 
To assess the effects of LY2456302 compared to PBO in adults age 21-65 years with mood 
and anxiety spectrum disorders 
 
Study 
Design: 
This study will be a six-site randomized, double-blind, PBO-controlled, parallel-group mono-
therapy study to assess the effects of LY2456302 compared to PBO in adults age 21-65 years 
with mood and anxiety spectrum disorders.  We will recruit a total of 90 subjects, of which 
45 will be randomized to LY2456302 and 45 to placebo for 8 weeks of treatment. 
 
Primary 
Objectives: 
Primary Specific Aim: To establish POC for KOR antagonism by evaluating the impact of 
LY2456302 10 mg relative to Placebo (PBO) on reward-related neural circuitry in terms of 
ventral striatal fMRI activation during anticipation of reward during the Monetary Incentive 
Delay (MID) Task 
 
Secondary 
Objectives: 
Secondary Specific Aim 1 (Clinical Anhedonia Measure):  To determine if 10 mg of 
LY2456302 is superior to PBO in improving a clinical, self-report measure of anhedonia, the 
Snaith Hamilton Pleasure Scale (SHAPS), in patients with mood and anxiety spectrum 
disorders. 
 
Secondary Specific Aim 2 (Behavioral Anhedonia Measure): To evaluate the impact of 
LY2456302 relative to PBO on a behavioral measure of anhedonia, the Probabilistic Reward 
Task (PRT), in patients with Mood and Anxiety Spectrum Disorders.  
 
 
Exploratory 
Objectives: 
To assess the effects of LY2456302 relative to placebo on:  
 
 Ventral striatal fMRI activation during anticipation of loss during the MID Task  


4 
 
 
 Resting state delta EEG current density in the rostral anterior cingulate.  
 
 Resting state fMRI connectivity  
 
 Self-rated affective responses to cues and feedback during the MID Task  
 
The Effort-Expenditure for Rewards Task (EefRT)  
 
The Visual Analogue Scale for Anhedonia (VAS)  
 
The Temporal Experience of Pleasure Scale (TEPS)  
 
The Hamilton Depression Rating Scale (HAM-D)  
 
The Hamilton Anxiety Scale (HAM-A)  
 
Clinical Global Impression – Improvement (CGI-I) 
 
Clinical Global Impression – Severity (CGI-S) 
 
The Cognitive and Physical Functioning Questionnaire (CPFQ)  
 
To assess the safety and tolerability of LY2456302 on systematically collected and 
spontaneously reported adverse events.  
 
 


5 
 
                                                            STUDY FLOW CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects who sign informed consent will undergo rigorous screening including: a medical, 
psychiatric, medication, and treatment history, vital signs, physical examination,  pregnancy test, 
ECG, urine drug screen, MINII, Snaith-Hamilton Pleasure Scale (SHAPS), Temporal Experience of 
Pleasure Scale (TEPS), Visual Analog ue Scale for Anhedonia (VAS), Columbia Suicide Severity Rating 
Scale (CSSRS), and a battery of clinical laboratory tests, Urea Breathe Test, Mock MRI scanning session   
SCREENING: Day -30 to Day -1 
Subjects who qualify will be randomly assigned to receive LY2456302 or PBO in a 1:1 ratio using 
IVRS randomization within the EDC 
Baseline visit (day 0, prior treatment initiation)  
The Baseline Assessment Visit will occur within 30 days of screening.  During this visit, all primary 
and secondary outcome measures will be assessed. Vital signs (pulse rate, blood pressure, height, 
weight) will be collected at Baseline.  Blood samples will be collected, and fMRI and QEEG imaging 
sessions will be scheduled at Baseline. 
RANDOMIZATION: Day 0 
 2, 4, 6, 8 week treatment visits (+ 1 week) 
During these visits, all primary and secondary outcome measures will be assessed. Vital signs 
(pulse rate, blood pressure, height, weight) will be collected. Adverse events will be assessed.   
Blood samples will be collected, and  fMRI and QEEG imaging sessions will be scheduled at 8 
weeks (endpoint) after treatment initiation. 
Double-Blind Treatment Period: Week 2,4,6,8 
During this visit, vital signs (pulse rate, blood pressure, height, weight) will be collected.  
Interval history will be assessed.  Snaith-Hamilton Pleasure Scale (SHAPS), Temporal 
Experience of Pleasure Scale (TEPS), Visual Analogue Scale for Anhedonia (VAS), Columbia 
Suicide Severity Rating Scale (CSSRS) will be assessed.  Adverse events will be collected 
using the Patient Reported Inventory of Side-Effects (PRISE). Clinical Global Impression – 
Severity Scales (CGI-S) and Clinical Global Impression – Improvement (CGI-I) will be 
assessed  At the conclusion of this visit, subject participation in the study will END. 
Post Medication Follow-up: Week 12 


6 
 
2. HYPOTHESES AND AIMS 
 
2.8 
Primary Aim  
 
 We will conduct a multicenter, randomized, parallel-group, placebo-controlled, Phase 2A trial of 10 mg 
of LY2456302 in 90 adults with mood and anxiety spectrum disorders in order to achieve the following 
aims.  
 
Primary Specific Aim (Proof of Concept/Engagement of Neural Circuitry Related to Anhedonia):  to 
establish POC for KOR antagonism by evaluating the impact of LY2456302 10 mg relative to Placebo 
(PBO) on reward-related neural circuitry in terms of ventral striatal fMRI activation during 
anticipation of reward during the Monetary Incentive Delay (MID) Task.   
 
This will be achieved by comparing pre- to post-treatment changes in LY2456302 and PBO groups on 
ventral striatal fMRI activation during anticipation of reward during the monetary incentive delay 
task (MID). 
 
We hypothesize that compared with PBO, LY2456302 will increase monetary incentive delay task-
associated fMRI activation in the ventral striatum.  This will be the primary outcome measure for the 
proposed study  
  
 
1.2  
Secondary Aims  
 
Secondary Specific Aim 1 (Clinical Anhedonia Measure):   To determine if 10 mg of LY2456302 is 
superior to PBO in improving a clinical self-report measure of anhedonia, the Snaith Hamilton Pleasure 
Scale (SHAPS) across 8 weeks of treatment. 
 
We hypothesize that LY2456302 will result in improvement in anhedonia relative to PBO, as 
determined by a pre- to post-treatment decrease in the score on the Snaith-Hamilton Pleasure 
Scale (SHAPS) across 8 weeks of treatment.  
 
Secondary Specific Aim 2 (Behavioral Anhedonia Measure): To evaluate the impact of LY2456302 
relative to PBO on a behavioral measure of anhedonia, the Probabilistic Reward Task (PRT). 
 
 
We hypothesize that LY2456302 will result in statistically significant improvement in anhedonia 
relative to PBO, as reflected in a pre- to post-treatment increase in Reward Responsiveness (i.e., 
the ability to modulate behavior as a function of reinforcement history) as assessed by the 
Probabilistic Reward Task (PRT), which has been found to be related to the proposed primary 
outcome measure, over 8 weeks of treatment in adults with mood and anxiety spectrum 
disorders. 
 
 


7 
 
1.3  
Exploratory Aims 
 
The Exploratory Aims of this study are: 
 
To assess the effects of LY2456302 relative to placebo on:  
 
 
Ventral striatal fMRI activation during anticipation of loss during the MID Task  
 
Resting state delta EEG current density in the rostral anterior cingulate  
 
Resting state fMRI connectivity  
 
Self-rated affective responses to cues and feedback during the MID Task  
 
The Effort-Expenditure for Rewards Task (EefRT)  
 
The Visual Analogue Scale for Anhedonia (VAS)  
 
The Temporal Experience of Pleasure Scale (TEPS)  
 
The Hamilton Depression Rating Scale (HAM-D)  
 
The Hamilton Anxiety Scale (HAM-A)  
 
The Cognitive and Physical Functioning Questionnaire (CPFQ)  
 
Clinical Global Impression Severity and Improvement (CGI-S and CGI-I) Ratings  
 
To assess the safety and tolerability of LY2456302 on systematically collected and spontaneously 
reported adverse events  
 
 
2. BACKGROUND AND RATIONALE  
 
 The available treatments for patients with mood and anxiety disorders have significant limitations 
(Rush, 2007; Denys and de Geus, 2005). There is a need to develop new treatments for people with 
these disorders. Many research studies carried out in animals and a few preliminary studies carried out 
in humans suggest that medications which block kappa opioid receptors (KOR) have potential for being 
effective new treatments for patients with mood and anxiety spectrum disorders (see below). These 
medications have shown particular promise for improving one important type of difficulty experienced 
by many patients who suffer from mood and anxiety spectrum disorders referred to as anhedonia, 
which is an impairment in reward-related function. In this study we will test the hypothesis that KOR 
antagonism is a promising means of improving anhedonia in patients with mood and anxiety spectrum 
disorders. We will do so by evaluating whether we can establish Proof of Concept (POC) that a relatively 
selective KOR antagonist, LY2456302 (see Investigator Brochure), engages neural circuits involved in 
mediating reward-related function in patients with mood and anxiety spectrum disorders with 
anhedonia. We are attempting to establish POC in this study in order to determine whether there is a 
sufficient basis for pursuing future work evaluating whether KOR antagonism has therapeutic effects on 
clinical and behavioral measures of reward-related functioning.  
 
In addition to being a relatively selective KOR antagonist, LY2456302 is also well-suited for this study 
based on its pharmacologic and safety profiles (see Investigator Brochure). The 10 mg dosage of 
LY2456302 was chosen for evaluation because of preclinical studies, single and multiple ascending dose 
studies in humans, a single-dose PET study of KOR occupancy (Zheng et al., 2013), and pupillometry data 
obtained following administration of the mu agonist fentanyl (see Invesigator Brochure). The following 
sections include details of the rationale for this study. 
 


8 
 
2.1. KOR Antagonism Promising Target for Treating Mood and Anxiety Disorders  
 
There is an extensive set of pre-clinical studies suggesting that KOR antagonists are likely to have 
therapeutic effects in those with mood and anxiety spectrum disorders. This includes studies indicating a 
role of the kappa opiate system in mediating both anxiety and depression symptoms and studies 
suggesting that KOR antagonists have effects on animal models of both major depression and anxiety.  
 
A number of studies indicate that the kappa opiate system is critical for mediating the adverse effects of 
stress. An important aspect of stress-related pharmacology is the dynorphins, a group of opioid peptides 
that exert their effects primarily through binding to KOR (Bruchas et al., 2009). Evidence suggests that 
stress leads to anxiety by CRF1 receptor activation of dynorphins in the basolateral amygdala which then 
bind to KOR (Bruchas et al., 2009). Place aversion and social avoidance occurring with repeated stress is 
mediated via dynorphin activation in ventral striatum, an effect which can be mimicked by KOR agonists 
and blocked by KOR antagonists (Land et al., 2009; Schindler et al., 2012). KOR antagonists also block 
stress-related impairment in elevated plus maze spontaneous exploration (Peters et al., 2011). 
 
Non-stress anxiety paradigms also suggest that KOR antagonists are likely to have anxiolytic effects. 
Prodynorphin knockouts (prodynorphin is the precursor protein for dynorphins) and KOR antagonists 
have been found to have anxiolytic-like effects in the novelty-induced hypophagia test, the defensive 
burying tests, the elevated plus maze test, fear-potentiated startle test, open-field test, and light-dark 
test (Carr and Lucki, 2010; Knoll et al., 2011; Wittmann et al., 2009).  
A larger literature suggests that KOR antagonists are likely to have anti-depressant effects and may 
prevent the depression-like consequences of stress. Dynorphin mediates the dysphoric aspects of stress 
via binding to KOR and this effect is prevented by knocking out dynorphin or administering a KOR 
antagonist (Land et al., 2008). The depression-like behaviors caused by chronic stress, uncontrollable 
stress, and social-defeat stress are mediated by kappa opiate receptors and can be mimicked by KOR 
agonists (McLaughlin et al., 2006; Knoll and Carlezon, 2010). KOR antagonist treated mice and KOR 
knockout mice show a reduction of stress-induced depression-like behavior (McLaughlin et al., 2006; 
Knoll and Carlezon, 2010). Stress has also been found to trigger KOR activation of dorsal raphe neurons 
which project to nucleus accumbens and decrease dopamine release thereby diminishing reward and 
increasing drug seeking (Lemos et al., 2012).  
 
More generally, rodent studies show that administering KOR antagonists or knocking out the 
prodynorphin gene leads to antidepressant-like effects as assessed by reduced immobility in the forced 
swim test and reduced learned helplessness (via nucleus accumbens and hippocampal mediated 
mechanisms), whereas KOR agonists have depressogenic effects in conjunction with decreasing nucleus 
accumbens dopamine release (Reindl et al., 2008; Shirayama et al., 2004; Carlezon et al., 2006; 
McLaughlin et al., 2003; Mague et al., 2003; Todtenkopf et al., 2004; Chartoff et al., 2012; Chartoff et al., 
2009).  
 
Perhaps the best recognized effect of KOR antagonists in animal models is to prevent the development 
of anhedonic-like states. The literature suggesting that KOR antagonists have such effects speaks to the 
potential of these agents to have therapeutic effects on anhedonia in humans, which is a core symptom 
of mood and anxiety disorders that cuts across diagnostic boundaries. In this regard, there is evidence 
that KOR stimulation inhibits dopamine release in the striatum (nucleus accumbens and caudate) and 
induces a negative mood state (Bruijnzeel, 2009). Consistent with this model, a series of studies indicate 
that KOR agonists decrease phasic dopamine release in the nucleus accumbens and increase intracranial 
self-stimulation (a model of anhedonia), whereas KOR antagonists have the opposite effect, increasing 


9 
 
nucleus accumbens dopamine release and decreasing self-stimulation (Ebner et al., 2010; Muschamp et 
al., 2011; Carlezon et al., 2006; Maisonneuve et al., 1994). Further, KOR agonists block cocaine’s anti-
anhedonic effect on intracranial self-stimulation (Tomasiewicz et al., 2008) and block the 
reinforcing/rewarding effects on drugs of abuse (Wee and Koob, 2010), whereas, giving a KOR 
antagonist prior to cocaine withdrawal prevented anhedonic-like intracranial self-stimulation responses 
(Chartoff et al., 2012).  
 
Although data in humans on the effects of selective KOR antagonists are lacking, preliminary data from 
humans are consistent with the animal data in suggesting that this target is likely to have therapeutic 
effects in mood and anxiety spectrum disorders. In an open-label study, 6 patients who had failed 
antidepressant medications and ECT were found to improve with buprenorphine (a KOR antagonist and 
partial mu agonist) treatment (Nyhuis et al., 2008). Findings of a double-blind, placebo-controlled, pilot 
study in 32 patients with treatment-resistant depression treated with the combination of 
buprenorphine and a mu receptor antagonist (simulated kappa opiate receptor antagonist) indicate that 
this combination had a significant antidepressant effect (Ehrich, 2012). 
 
Together, the available data provide a compelling indication that KOR antagonists are likely to have 
therapeutic effects in patients with mood and anxiety spectrum disorders. These data point to the 
adverse effects of stress and particularly anhedonia as therapeutic targets of interest with these agents. 
 
2.2. Rationale for Studying Effects of KOR Antagonist on Anhedonia 
    
  
We chose to focus on anhedonia as an endpoint for this study because: 1) the available data suggest 
that anhedonia is the dimension of mood and anxiety spectrum disorders that is most likely to be 
improved by KOR antagonists (see above); 2) anhedonia is associated with measurable neurobiological 
mechanisms which can be studied with available methodologies that could be used to establish POC in 
terms of engagement of relevant neural circuitry (Wacker et al., 2009; Pizzagalli et al., 2004, 2009; 
Treadway et al., 2012; Stoy et al., 2012; Ossewaarde et al., 2011); and 3) anhedonia allows us to 
accomplish our goal of studying an important aspect of dysfunction that cuts across mood and anxiety 
spectrum disorders, consistent with the NIMH’s RdoC framework.  
 
The data indicating that KOR antagonists are likely to improve anhedonia are strong relative to the data 
indicating that there will be other therapeutic effects of KOR antagonists. As a result, it seems likely that, 
if there are any therapeutic effects of these agents in those with mood and anxiety spectrum disorders, 
a therapeutic effect on anhedonia would be evident. As a result, anhedonia is an appropriate primary 
endpoint for a POC study with a KOR antagonist the treatment of patients with mood and anxiety 
spectrum disorders. Failure to demonstrate a therapeutic effect of a KOR antagonist on the neural 
circuitry related to anhedonia using a dosage that had been demonstrated to have acceptable kappa 
opiate receptor occupancy would be a reasonable indication to fail KOR antagonism as a treatment for 
mood and anxiety disorders. 
  
 
 
 
 
 


10 
 
3. STUDY DESIGN  
 
3.1 Overview  
 
This study will be a six-site randomized, double-blind, PBO-controlled, parallel-group mono-therapy 
study to assess the effects of LY2456302 compared to PBO in adults age 21-65 years with mood and 
anxiety spectrum disorders. We will recruit a total of 90 subjects, of which 45 will be randomized to 
LY2456302 and 45 to placebo for 8 weeks of treatment. 
 
3.2 Procedures 
Screening Visit: Day -30 to Day -1 (4 – 6 hours): 
  
Subjects will undergo a set of screening tests to determine if they meet the inclusion/exclusion criteria 
for the study. These screening tests will include:  
 
 Medical, psychiatric, and medication history  
 
 Vital signs (temperature, blood pressure, and pulse)  
 
 Physical examination  
 
 Pregnancy Test (beta-HCG serum pregnancy test – females only)  
 
 Electrocardiogram (ECG)  
 
 Urine drug screen  
 
 Mini-International Neuropsychiatric Interview (MINI)  
 
 Snaith-Hamilton Pleasure Scale (SHAPS)  
 
 Temporal Experience of Pleasure Scale (TEPS)  
 
 Visual Analogue Scale for Anhedonia (VAS)  
 
 Columbia Suicide Severity Rating Scale (CSSRS)  
 
 Clinical Global Impression – Severity (CGI-S)  
 
 Battery of clinical laboratory tests including: Complete blood count with differential, 
Electrolytes, Metabolic Panel, Thyroid Function Tests, Urinalysis  
 
 Urea Breathe Test to test for the presence of Heliobacter pylori,  
 
 Mock MRI scanning session  
 
Those who qualify to continue with the study based on the screening assessment will be asked to return 
1-30 days later for additional evaluations. Subjects who require medication tapering will discuss a 
medication tapering plan with a study physician during this visit (for details see Section 4.1. Study 
Overview). This plan will be designed so that subjects are free of all excluded medications at least 5 half-
lives prior to the baseline visit (see Section 3.3. Exclusion Criteria). Qualifying subjects will be instructed 
about not using any prohibited medications during the study including substances of abuse. They will be 
specifically instructed about not using Salvia divinorum, which has kappa opioid agonist effects and is 
not an illegal substance. 
 
Baseline: Day 0 (A0) Visit (6 – 8 hours): 
Following rigorous screening, subjects will return to the clinic/research unit up to 30 days later and 
undergo the following assessments and procedures:  
 
Structural MRI, fMRI during Monetary Incentive Delay Task, Resting State Connectivity fMRI  


11 
 
 
Interval history  
 
Battery of clinical laboratory tests including: Complete blood count with differential, 
Electrolytes, Metabolic Panel, Thyroid Function Tests, Urinalysis.  
 
EEG  
 
Vital signs (temperature, blood pressure, and pulse)  
 
Physical examination  
 
Electrocardiogram (ECG)  
 
Snaith-Hamilton Pleasure Scale (SHAPS)  
 
Temporal Experience of Pleasure Scale (TEPS)  
 
Visual Analogue Scale for Anhedonia (VAS)  
 
Columbia Suicide Severity Rating Scale (CSSRS)  
 
Probabilistic Rewards Task (PRT)  
 
Effort Expenditure for Rewards Task (EefRT)  
 
Hamilton Depression Rating Scale (HAM-D)  
 
Hamilton Anxiety Rating Scale (HAM-A)  
 
The Cognitive and Physical Functioning Questionnaire (CPFQ)  
 
Clinical Global Impression – Severity (CGI-S)  
 
Clinical Global Impression – Improvement (CGI-I)  
 
Adverse events assessment with the Patient Reported Inventory of Side-Effects (PRISE)  
 
Blood sample collection for tests for assessment for gastric adverse events including gastrin, and 
pepsinogen I/II levels.  
 
Blood sample collection to be sent to Rutgers for potential genetic analysis or other future 
analysis (optional)  
 
At the end of this visit subjects will be randomized to LY2456302 10 mg or placebo, will be provided with 
enough study medication for a 2-week period and will be instructed to take the medication every 
morning. Subjects will also be instructed to bring all of their study drug packaging and unused study 
drug with them to each visit. 
Week 2 Visits (4 – 6 hours per visit):  
 
At this visit subjects will undergo the following assessments and procedures:  
 
Interval history  
 
Battery of clinical laboratory tests including: Complete blood count with differential, 
Electrolytes, Metabolic Panel, Thyroid Function Tests, Urinalysis  
 
Vital signs (temperature, blood pressure, and pulse)  
 
Physical examination  
 
Electrocardiogram (ECG)  
 
Snaith-Hamilton Pleasure Scale (SHAPS)  
 
Temporal Experience of Pleasure Scale (TEPS)  
 
Visual Analogue Scale for Anhedonia (VAS)  
 
Columbia Suicide Severity Rating Scale (CSSRS)  
 
Clinical Global Impression – Severity (CGI-S)  
 
Clinical Global Impression – Improvement (CGI-I)  
 
Adverse events assessment with the Patient Reported Inventory of Side-Effects (PRISE)  
 
Inspection of medication blister packs to assess medication adherence  


12 
 
 
Blood sample for drug blood level testing  
 
At the end of this visit subjects will receive enough study medication for another 2 week period, and will 
be instructed to take the medication each morning, to bring all study drug packing and unused study 
drug to the next visit, and to return to the clinic/research unit in 2 weeks. 
 
Week 4 Visit (4 – 6 Hours):  
 
At this visit subjects will undergo the following assessments and procedures:  
 
Interval history  
 
Battery of clinical laboratory tests including: Complete blood count with differential, 
Electrolytes, Metabolic Panel, Thyroid Function Tests, Urinalysis.  
 
Vital signs (temperature, blood pressure, and pulse)  
 
Physical examination  
 
Electrocardiogram (ECG)  
 
Snaith-Hamilton Pleasure Scale (SHAPS)  
 
Temporal Experience of Pleasure Scale (TEPS)  
 
Visual Analogue Scale for Anhedonia (VAS)  
 
Columbia Suicide Severity Rating Scale (CSSRS)  
 
Inspection of medication blister packs to assess medication adherence  
 
Blood sample for drug blood level testing  
 
Clinical Global Impression – Severity (CGI-S)  
 
Clinical Global Impression – Improvement (CGI-I)  
 
Adverse events assessment with the Patient Reported Inventory of Side-Effects (PRISE)  
 
Blood sample for tests for assessment for gastric adverse events including gastrin, and 
pepsinogen I/II levels.  
 
At the end of this visit subjects will receive enough study medication for another 2 week period, and 
will be instructed to take the medication each morning, to bring all study drug packing and unused 
study drug to the next visit, and to return to the clinic/research unit in 2 weeks. 
 
Week 6 Visit (4 – 6 Hours):  
 
At this visit subjects will undergo the following assessments and procedures:  
 
Interval history  
 
Battery of clinical laboratory tests including: Complete blood count with differential, 
Electrolytes, Metabolic Panel, Thyroid Function Tests, Urinalysis.  
 
Vital signs (temperature, blood pressure, and pulse)  
 
Physical examination  
 
Electrocardiogram (ECG)  
 
Snaith-Hamilton Pleasure Scale (SHAPS)  
 
Temporal Experience of Pleasure Scale (TEPS)  
 
Visual Analogue Scale for Anhedonia (VAS)  
 
Columbia Suicide Severity Rating Scale (CSSRS)  
 
Inspection of medication blister packs to assess medication adherence  
 
Blood sample for drug blood level testing  


13 
 
 
Clinical Global Impression – Severity (CGI-S)  
 
Clinical Global Impression – Improvement (CGI-I)  
 
Adverse events assessment with the Patient Reported Inventory of Side-Effects (PRISE)  
 
At the end of this visit subjects will receive enough study medication for another 2 week period, and will 
be instructed to take the medication each morning, to bring all study drug packing and unused study 
drug to the next visit, and to return to the clinic/research unit in 2 weeks.  
 
Week 8 Visit (6 – 8 Hours):  
 
At this visit subjects will undergo the following assessments and procedures:  
 
Structural MRI, fMRI during Monetary Incentive Delay Task, Resting State Connectivity fMRI  
 
 Interval history  
 
Battery of clinical laboratory tests including: Complete blood count with differential, 
Electrolytes, Metabolic Panel, Thyroid Function Tests, Urinalysis  
 
Electroencephalogram (EEG)  
 
Vital signs (temperature, blood pressure, and pulse)  
 
Physical examination  
 
Electrocardiogram (ECG)  
 
Snaith-Hamilton Pleasure Scale (SHAPS)  
 
Temporal Experience of Pleasure Scale (TEPS)  
 
Visual Analogue Scale for Anhedonia (VAS)  
 
Columbia Suicide Severity Rating Scale (CSSRS)  
 
Probabilistic Rewards Task (PRT)  
 
Effort Expenditure for Rewards Task (EefRT)  
 
Hamilton Depression Rating Scale (HAM-D)  
 
Hamilton Anxiety Rating Scale (HAM-A)  
 
The Cognitive and Physical Functioning Questionnaire (CPFQ)  
 
Blood sample collection to be sent to Rutgers for potential genetic analysis or other future 
analysis (optional)  
 
Clinical Global Impression – Severity (CGI-S)  
 
Clinical Global Impression – Improvement (CGI-I)  
 
Blood sample for tests for assessment for gastric adverse events including gastrin and 
pepsinogen I/II levels.  
 
Adverse events assessment with the Patient Reported Inventory of Side-Effects (PRISE)  
 
Inspection of medication blister packs to assess medication adherence  
 
Blood sample for drug blood level testing  
 
At the end of this visit study drug will be discontinued and subjects will be instructed to return to 
the clinic/research unit in 4 weeks. 
Week 12 Visit: Post Medication Follow-up (2 – 4 hours)  
 
At this visit subjects will undergo the following assessments:  
 
Vital signs  
 
 Interval history  


14 
 
 
 Snaith-Hamilton Pleasure Scale (SHAPS)  
 
Temporal Experience of Pleasure Scale (TEPS)  
 
Visual Analogue Scale for Anhedonia (VAS)  
 
Columbia Suicide Severity Rating Scale (CSSRS)  
 
Adverse events assessment with the Patient Reported Inventory of Side-Effects (PRISE)  
 
Clinical Global Impression – Severity (CGI-S)  
 
Clinical Global Impression – Improvement (CGI-I)  
 
At the conclusion of this visit subject participation in the study will end. 
 
End of Participation 
 
At the end of the week 12 visit, participation in the study will end. The results of all of the laboratory 
assessments and EEGs, ECGs, and physical examinations that could affect the subject’s health care will 
be shared with them and their health care provider if they would like this to occur. Subjects will meet 
with the study physician and options for treatment will be reviewed. Participants will not be informed as 
to their treatment assignment at this meeting.  
In case a subject is lost-to-follow-up, every possible effort must be made by the study site personnel to 
contact the subject and determine the reason for withdrawal. The measures taken to follow up must be 
documented.  
 
Subjects have the right to withdraw from the study at any time for any reason. If a subject withdraws 
from the study before Week 8, the subject should have a complete evaluation performed at the time of 
withdrawal that includes all Week 8 procedures EXCEPT fMRI (see Table 3 Schedule of Assessments). 
Subjects will be followed through Week 12 follow up unless they specifically withdraw their consent for 
further contact or for medical records review. When a subject withdraws before completing the study, 
the reason for withdrawal is to be documented on the eCRF and in the source document. Subjects who 
withdraw will not be replaced. 
 
4. STUDY POPULATION 
 
4.1 Overview of Study Population  
 
We will enroll 90 subjects in this trial. The inclusion and exclusion criteria are listed below. We will 
stratify enrollment to ensure that there is ample cross-diagnostic representation so that the therapeutic 
effects of LY2456302 on anhedonia may be assessed independently of its effect on any particular mood 
and anxiety spectrum disorder. This will be accomplished by requiring that at least 33% of the subjects 
randomized meet the anhedonia entry criteria and have an anxiety disorder but do not currently meet 
major depressive disorder (MDD) criteria based on the MINI (subjects with a past history of MDD but 
who do not currently meet diagnostic criteria could be included). Anhedonia is a core symptom of MDD 
and one of its diagnostic criteria but this is not the case for anxiety disorders. As a result, we are 
including a requirement for inclusion of patients with anxiety disorders because without such a criterion, 
we run the risk of only including subjects with anhedonia occurring in the setting of MDD, which would 
result in our being unable to distinguish an antidepressant effect which included a beneficial effect on 
anhedonia from an anhedonia-specific effect. 
 


15 
 
 
 
 
4.2 Inclusion Criteria  
 
1. Age between 21 and 65 years of age 
2. Must meet DSM-IV TR diagnostic criteria for: Major Depressive Disorder, Bipolar I or II 
Depressed, Generalized Anxiety Disorder, Social Phobia, Panic Disorder, or Post Traumatic Stress 
Disorder 
3. Snaith-Hamilton Pleasure Scale (SHAPS) score ≥ 20 
4. Reliable and willing to be available for the duration of the study 
5. Willing and able to give written informed consent to participate 
6. Able to understand and comply with instructions 
7. If female of childbearing potential, must agree to use dual methods of contraception and be 
willing and able to continue contraception for 6 weeks after the last dose of study drug. Females 
using oral contraception must have started using it at least 2 months prior to the Baseline Visit 
8. If male of childbearing potential, must have undergone surgical sterilization (such as a 
vasectomy) or agree to use a condom used with a spermicide during participation in the study 
and for 1 month afterward 
 
4.3 Exclusion Criteria 
  
1. Expected to require hospitalization during the course of the study 
2. Current/history of a psychotic disorder, current manic or mixed episode, autism spectrum 
disorders, mental retardation 
3. Met DSMIV-TR criteria for substance abuse within the last 3 months or substance dependence 
within the last 6 months, excluding caffeine and/or nicotine 
4. History of unstable or untreated serious medical condition based on physician evaluation, 
medical history, and screening laboratory testing 
5. Active suicidal intent or plan, or history of attempt within the past 3 months based on physician 
evaluation and Columbia Suicide Severity Rating Scale (C-SSRS) 
6. Use of any antidepressant, antipsychotic, anxiolytic, anticonvulsant, mood stabilizing, muscle 
relaxant, centrally acting antihistaminergic, stimulant or insomnia medications (See Appendix 2) 
within 5 half-lives of baseline or at any time during after baseline 
7. Use of any medication that is primarily metabolized by Cytochrome P450 2C8 within 14 days of 
baseline or at any time during the study. This includes: Cerivastatin, Paclitaxel, Repaglinide, 
Sorafenib, Rosiglitazone, Trimethoprim, Amodiaquine, Morphine, Amiodarone, Cabazitaxel, 
Carbemazepine, Chloroquine, Ibuprofen, Teprostinil, Torsemide. 
8. Any contraindications to the magnetic resonance imaging procedures 
9. Positive urine drug screen at any time during the study 
10. Use of any investigational medication within 3 months prior to the start of this study or 
scheduled to receive an investigational drug other than the study drug during the course of this 
study 
11. Known hypersensitivity to LY2456302 
12. History of severe allergies or multiple adverse drug reactions 
13. History of gastric disease (including peptic ulcer disease,  gastritis, upper GI bleeding, or any GI 
precancerous condition), current clinically evident gastrointestinal complaints, or positive urea 


16 
 
breath test 
14. Current use of a proton pump inhibitor or histamine 2 blocker, or a history of chronic NSAID use.  
15. History of use of Salvia divinorum or use of Salvia divinorum at any time during the study.  
16. Any other condition that in the opinion of the investigator would preclude participation in the 
study 
17. Any smoking of cigarettes or use of other nicotine containing products within the last month or 
at any time during the study 
18. Pregnant or lactating 
 
 
5. RANDOMIZATION 
 
IVRS Randomization will be carried out using the Simple Internal Randomization Engine (SIRE), 
which is a tool developed by the DCRI to randomize study patients. SIRE is fully integrated with the 
EDC database. A randomization list in hardcopy will also be kept under lock and key by the 
statistician as a back-up should the computer system be down. In case of system failure, the 
statistician will provide the individual dispensing the medication at a site with the medication 
allocation over the phone. It will also allow study physicians to obtain the randomization 
information from the statistician and procedures to break the blinding in cases of emergencies. All 
individuals having interactions with the subjects will remain blinded to treatment group assignment 
other than in cases of emergencies. 
 
 
2. 
DURATION OF TREATMENT AND STUDY PARTICIPATION 
 
Expected duration of study participation is up to 120 days, including up to 30 days of screening and 
Baseline, an 60-day treatment period, and a 30-day follow-up visit.  Please see Table 1 (Milestones of 
Study) for additional information. 
 
 
 
 
2. 
STATISTICAL ANALYSIS 
 
7.1 Sample Size 
 
A total of 90 subjects will be randomized: 45 subjects randomized to LY2456302 and 45 to placebo are 
included in the primary efficacy analysis.  We conservatively anticipate that we will have incomplete 
data on up to 20% of subjects due to subject drop out or loss of data due to factors such as poor scan 
quality.   As a result, we estimate that we could have complete data on as few as 72 subjects and as 
many as 90 subjects.    In the Statistical Analysis section below, we outline how we will address the issue 
of missing data including carrying out analyses on the intent-to-treat (ITT) population and employing 
mixed effect models.  If we assume the worst case scenario of 72 subjects, for a one tailed t-test at an 


17 
 
alpha value of 0.05, power is 80% to identify an effect size of 0.58.  For a one tailed t-test at an alpha 
value of 0.10 power is 80% to identify an effect size of 0.50.   
Our capacity to estimate the expected effect size on our primary outcome measure is limited by the 
studies that have been carried out with this measure to date.  The most relevant study was carried out 
by Stoy and co-workers (2011) who evaluated 15 patients with major depression and 15 controls and 
administered open-label escitalopram to both groups for 6 weeks. However, it must be kept in mind that 
estimates of power based on this study are likely overly optimistic because this was an open-label 
treatment study and only included 15 depressed subjects.  We can estimate the expected effect size for 
our study from the ventral striatal activation to reward anticipation subject group by time interaction 
observed in this study.   The effect size for a greater increase in those with depression compared with 
controls is 0.88.   We can also estimate effect size from the pre-to-post treatment difference in ventral 
striatal activation during reward anticipation and reward during the MID with fMRI within the depressed 
group which are 1.1 and 1.0 respectively.  These effect sizes suggest that are likely to have more than 
sufficient power to detect a significant effect with our primary outcome measure in the proposed study 
at the alpha=0.05 level with 80% power.   
 
 
 
 
7.2 Statistical Methods 
Data Management: All data management activities, including establishing a trial eCRF, procedures for 
randomization and biomarker acquisition and tracking, will be done within the framework of DCRI and 
will conform to FDA GCP requirements.  
Interim Analysis:  As specified in the protocol, there will be no interim analysis carried out. 
0
20
40
60
80
100
120
140
160
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Number of Subjects Per Group
Effect Size Detectable at alpha=0.05 with 80% Power 


18 
 
Primary Efficacy Analysis:  We will employ “Intention-to-Treat” (ITT) principles. Statistical tests will be 
performed based on a one-sided test at the 5% level of significance. Supporting analyses will also be 
performed. An “as treated” analysis will be done per the actual treatment patients received.  A “per 
protocol” analysis will restrict the analysis to participants who receive minimal exposure to the 
intervention, have a minimal number of longitudinal evaluations, and/or are free of major protocol 
violations. A “completer” analysis will only include participants who completed acute treatment without 
exiting or prematurely terminating from their assigned treatment. Because participants may be removed 
differentially across the treatment arms in these analyses, both approaches are vulnerable to 
differential selection bias and will be interpreted cautiously.  
 
Point estimate and the corresponding confidence interval for the primary study outcome (fMRI 
ventral striatal activation during reward anticipation of reward during the MID) of the adjusted 
predicted score will be obtained. A mixed effects model analysis will be carried out for the primary 
outcome of the study, task-related fMRI activation in the ventral striatum during anticipation of 
reward occurring during the Monetary Incentive Delay Task. This analysis will test the hypothesis 
that LY2456302 will lead to a greater increase in ventral striatal activation during anticipation of 
reward than placebo. 
 
Most of the study outcomes are observed repeatedly at well-defined time-points post-randomization, so 
that statistical methods for repeated measures data will be applied. This includes the linear model with 
structured covariance matrices and the mixed effects models as implemented in PROC MIXED in SAS. 
Site will also be included as an independent variable in order to account for variability among the study 
sites. 
Secondary  Efficacy Analysis : A mixed effects model analysis will also be carried out for the secondary 
outcomes of the study, SHAPS score and PRT-derived Reward Learning and Response Bias. These 
analyses will test the hypothesis that LY2456302 will: 1) decrease SHAPS score to a greater degree than 
PBO; and 2) increase PRT-derived reward learning and response bias to a greater degree than PBO.  
 
Exploratory Analysis: Exploratory mixed effects model analyses will also be carried out with the 
exploratory outcomes of the study. This includes: ventral striatal fMRI activation during anticipation of 
loss during the MID Task; resting state delta EEG current density in the rostral anterior cingulate; resting 
state fMRI connectivity; self-rated affective responses to cues and feedback during the MID Task; EefRT 
total reward; VAS score; TEPS anticipatory and consummatory pleasure scores; HAM-D score; HAM-A 
score; CGI-S, CGI-I, and CPFQ score. 
 
Covariates in Regression Models:  The baseline value of the outcome, centered about its sample 
mean, will be included in each analysis. Otherwise, only age and sex will be entered as covariates. 
Missing Values in Longitudinal Data:  We will proactively monitor the amount of missing data, and 
ensure that we respond quickly to emerging problems. Statistically, missing data will be addressed 
through the use of mixed models analysis which will be carried out with PROC MIXED in SAS. We will 
carry out an assessment of the degree to which the structured covariance matrix in mixed effects 
models fits the data. 


19 
 
Other Confounders Arising Post-Randomization: Logistic regression analysis will be carried out to 
investigate: (a) adherence to the assigned study intervention, (b) co-administration of psychotropic 
medications, and (c) discontinuation from the study intervention, and we will apply logistic regression 
analysis to investigate these factors. First, we will determine whether these effects occur differentially 
across the treatment arms suggesting that a differential selection bias may have influenced the results. 
Then, we will investigate whether baseline characteristics are predictive of any behavior. This will 
include demographic characteristics, initial severity as measured by the baseline values of the outcome 
variables, and clinical characteristics such as diagnoses and medications taken at baseline.  
Magnitude of the Clinical Effect: To evaluate the clinical significance of the impact of treatment on 
outcome, effect sizes (Hedge’s g) will be calculated as (ME – MC) / SD pooled, where ME represents the 
adjusted mean of experimental treatment, MC represents the adjusted mean of the comparison 
treatment, and SD pooled represents pooling of the standard deviations from within both groups.  For 
dichotomous outcomes, the number needed to treat (NNT) or harm (NNH)–defined as the number of 
subjects who need to be treated in order to bring about one additional good outcome (NNT) or harm 
(NNH)—will be calculated (± 95% CI) according to methods outlined by Sackett and colleague 
 
7.3 Primary and Secondary Efficacy Assessments 
 
The capacity of LY2456302 for engaging reward circuitry in those with mood and anxiety spectrum 
disorders will be assessed as follows 
 
 
The Primary Outcome for this study will be task-related fMRI ventral striatal (e.g., nucleus 
accumbens) activation occurring with reward and anticipation during the Monetary Incentive 
Delay (MID) Task  
 
 The Secondary Outcomes will be: 
 
o An objective behavioral measure of anhedonia, the Probabilistic Reward Task (PRT). 
o A clinical self-report measure of anhedonia, the Snaith-Hamilton Pleasure Scale 
(SHAPS)  
 
 
Monetary Incentive Delay Task-related fMRI  
fMRI during the Monetary Incentive Delay (MID) Task will be obtained as the primary outcome in the 
proposed study in order to establish Proof of Concept in terms of a change in a neurobiological target.  
This neurobiological target will be the neural circuitry of the hedonic response, alterations of which we 
hypothesize underlie core clinical symptoms in patients with Mood and Anxiety Spectrum Disorders.   
Engagement of this neurobiological target will be evaluated with task-related fMRI assessments 
consisting of obtaining fMRI during the Monetary Incentive Delay Task (Wacker et al., 2009; Pizzagalli et 


20 
 
al., 2004, 2009; Knutson et al., 2008).  This measure was chosen because it provides functional neural 
circuit-based indices of the hedonic response to stimuli.  This is manifested in terms of the degree of 
activation of the ventral striatum.   Evidence supporting the use of the Monetary Incentive Delay Task-
related fMRI for this purpose is that depressed patients were found to have decreased ventral striatal 
activation to anticipated reward with this task (Knutson et al., 2008) and that this measure has been 
demonstrated to be sensitive to changes occurring with antidepressant/anxiolytic therapies (SSRI and 
SNRI) in a small open-label studies including those with major depression and healthy controls and a 
double-blind placebo-controlled study in healthy controls (Stoy et al., 2012; Ossewaarde et al., 2011).   
 
This test will be obtained at baseline and at the end of double-blind treatment and will be carried out as 
previously described (Knutson et al., 2008).  
 
 
Probabilistic reward task 
 
The Probabilistic Reward Task (PRT) (adapted from Tripp & Alsop (1999)), was designed to objectively 
assess participants’ propensity to modulate behavior as a function of reinforcement history.  This task 
has been validated in multiple independent samples (e.g., Barr et al. 2008; Bogdan and Pizzagalli, 2006, 
2009; Pizzagalli et al. 2005, 2007, 2008; Vrieze et al., 2012). Participants will complete two blocks of 100 
trials, in which they will be asked to determine whether a briefly presented mouth on a cartoon face  
was ‘long’ or ‘short’, and report their decision by pressing one of two corresponding keys on a computer 
keyboard (‘z’ or ‘/’). Importantly, the brief presentation time (100 ms) and the minimal difference in 
length between the two target stimuli (11.5 vs. 13 mm) make it difficult for participants to perceptually 
distinguish which stimulus is presented. Moreover, an asymmetrical reinforcement ratio is implemented 
across the two blocks so that one of the two stimuli (the ‘rich’ stimulus) is consistently rewarded 
(“Correct!! You Won 5 Cents”) three times more frequently than the ‘lean’ stimulus (30 vs. 10 times per 
block).   Reinforcement allocation and key assignments will be counterbalanced across participants. 
Participants are instructed to respond as quickly and accurately as possible to maximize monetary 
rewards, and that not all correct responses will be followed by rewards.  In healthy participants, such 
asymmetric reinforcement schedule has been found to induce a systematic preference (response bias) 
for choosing the stimulus paired with more frequent reward (Macmillan & Creelman, 2005).  
 
Healthy controls are able to successfully modulate their behavior based on their experience, resulting in 
a significant response bias for the more frequently rewarded stimulus. In contrast, individuals with 
elevated depressive symptoms (Pizzagalli et al 2005) or MDD (Pizzagalli et al 2008c) show a blunted 
response bias, and overall reduced reward learning. Of note, reward learning negatively correlated with 
anhedonic symptoms and predicted them one month later (Bogdan and Pizzagalli 2006; Pizzagalli et al 
2005). Moreover, trial-by-trial probability analyses revealed that MDD subjects were impaired at 
integrating reinforcements over time and expressing a response bias in the absence of immediate 
reward. This impairment correlated with anhedonic symptoms, even after considering anxiety and 
distress symptoms (Pizzagalli et al 2008c). 
 


21 
 
Data reduction and analyses. After removing trials with outlier reaction times (see Pizzagalli et al. 2005 
for detail), response bias (log b) will be computed according to the following formula: 
 







co
incorre
inc
correct
Le
Rich
Lea
Rich
b
*
*
log
2
1
log
 
 
 
   
  
 
To avoid issues related to having a zero in one cell of the formula, 0.5 will be added to every cell of the 
detection matrix (Hautus, 1995).  As evident from the formula, response bias reflects the participants’ 
preference for the stimulus paired with more frequent rewards. Reward learning will be operationalized 
as the change in response bias from Block 1 to Block 2. 
 
We will collect data at two timepoints which will each consist of two blocks of data for which our intent 
is to compute the change in response bias (RB) between these two blocks: RB = Response Bias (Block 2) 
– Response Bias (Block 1).  Response Bias will be computed for each block (formula written above). We 
will collect the following 16 numbers: 
 
   Baseline:  
   i) Rich correct block 1; ii) Lean incorrect block 1; iii) Rich incorrect block 1; iv) Lean correct block 1;   
  v) Rich correct block 2; vi) Lean incorrect block 2; vii) Rich incorrect block 2; viii) Lean correct block 2;   
  
    
 
   End of Double-Blind Treatment:  
 
   i) Rich correct block 1; ii) Lean incorrect block 1; iii) Rich incorrect block 1; iv) Lean correct block 1;   
  v) Rich correct block 2; vi) Lean incorrect block 2; vii) Rich incorrect block 2; viii) Lean correct block 2;   
  
The results of number of studies provide the rationale for using the PRT in this study and considering 
using the PRT to select subjects for entry into the trial. This includes a study identifying that PRT score 
predicts clinical outcome to naturalistic antidepressant treatment.  In this study, 69 inpatients and 63 
healthy controls performed the PRT at baseline (i.e., at intake for patients), and patients were 
administered the task again after 8 weeks of antidepressant treatment (Vrieze, Pizzagalli et al, in press).  
Relative to controls, MDD patients showed reduced reward learning (F(2,280)=3.53, p=0.03). Critically, 
this blunting was found only in patients with high anhedonia (p=0.007). Second, MDD subgroup (low vs. 
high anhedonia, as defined by the Snaith Hamilton Pleasure Scale (SHAPS) cutoff of 7) predicted reward 
learning when controlling for overall depression severity (R2=0.13, p=0.001). Of note, HDRS scores were 
not related to reward learning. Also SHAPS score uniquely predicted reward learning even when 
controlling for depression severity (HRSD scores) and anxiety comorbidity (β=0.33, t=3.08, p=0.003). 
Third, reduced reward learning at study entry increased the odds of a persisting diagnosis of MDD after 
8 weeks of treatment (OR: 7.84, CI: 1.17-52.42, p=0.03).         
 
 


22 
 
The Snaith-Hamilton Pleasure Scale (SHAPS) 
 
The Snaith-Hamilton Pleasure Scale (SHAPS) (Snaith et al., 1995) is a well-validated 14-item 
questionnaire used to assess anhedonia. It asks participants to agree or disagree with statements of 
hedonic response in pleasurable situations (e.g., “I would enjoy my favorite television or radio 
program”). Four responses are possible: Strongly disagree, Disagree, Agree, or Strongly agree. Each item 
on the SHAPS is worded so that higher scores indicate greater pleasure capacity. A total score can be 
derived by summing the responses to each item. Items answered with “strongly agree” are coded as “1”, 
while a “strongly disagree” response was assigned a score of “4.” Therefore, scores on the SHAPS can 
range from 14 to 56, with higher scores corresponding to higher levels of anhedonia.  The SHAPS covers 
four domains of hedonic experience: interest/pastimes, social interaction, sensory experience, and 
food/drink (Snaith et al., 1995). Participants completing the SHAPS are instructed to respond based on 
their ability to experience pleasure “in the last few days.” This scale has shown adequate overall 
psychometric properties in clinical and student samples (Gilbert, Allan, Brough, Melley, & Miles, 2002; 
Snaith et al., 1995). The SHAPS convergent validity has been supported by its correlations with MADRS 
Hedonic Tone item, the Mood and Anxiety Symptom Questionnaire Anhedonic Depression subscale, and 
Positive and Negative Affect Schedule-Positive Affect subscale (Gilbert et al., 2002; Snaith et al., 1995). 
Its discriminant validity has been supported by its lack of association with MADRS Depressed Mood and 
Anxiety items (Snaith et al., 1995).  The SHAPS has satisfactory test-retest validity in healthy participants 
over an interval of three weeks (intraclass correlation coefficient between test and retest: r = .70, p < 
.001; Franken, Rassin & Murris, 2007). Besides being well-validated, the SHAPS is of utility for our study 
because there is an established cutoff for clinical significance.  Although this is also true for the 
Anhedonic Depression subscale of the Mood and Anxiety Symptoms Questionnaire (MASQ), we wanted 
a scale that assessed anhedonia and was not depression specific or specific to any other disorder given 
the goal of using it across diagnostic boundaries.  ROC using MADRS anhedonia item score (cutoff was 
clinically significant level) as discriminator suggests that a SHAPS score of ≥ 20 is clinically significant 
anhedonia (Snaith et al., 1995). This was validated in 30 volunteers from the general population.  It 
should be noted that the original ROC analysis was done with dichotomous ratings rather than the 
current 4 option rating system.   The original finding was that 3 or more negative answers indicated 
clinical significance which corresponds to a score of at least 20 with the current rating system.   One 
other important consideration that supports the use of the SHAPS in this study is that it is the only 
anhedonia measure that we are aware of that has been found to significantly improve with the 
administration of a treatment in at least one clinical trial (Di Giannantonio and Martinotti, 2012; 
Martinotti et al., 2011).  In a study of alcohol dependent individuals, treatment with acetyl-l-carnitine 
led to statistically significantly greater improvement in the SHAPS than placebo by 10 days after 
initiating treatment (Martinotti et al., 2011).   In an 8-week trial comparing the effects of venlfafaxine XR 
and agomelatine treatment in depressed patients, significant improvement from baseline on the SHAPS 
was observed in both groups with significantly greater improvement being found for the agomelatine 
treated patients (Di Giannantonio and Martinotti, 2012).  


23 
 
Finally, SHAPS scores among healthy participants have been related to reward-related activation within 
frontostriatal pathways (see e.g., Wacker et al., 2009), providing an additional reason for its inclusion in 
the current study.  
 
The SHAPS will be collected at all study visits. It will be used to screen subjects for having anhedonia as 
part of inclusion/exclusion assessment. It will also be compared in subjects receiving LY2456302 and 
PBO in secondary analysis to assess the effects on a clinical self-rated measure of anhedonia. 
 
7.4. Other Efficacy Assessments   
 
Other efficacy assessments carried out in this study to be employed in exploratory analyses include  
ventral striatal fMRI activation during anticipation of loss during the MID Task; resting state delta 
EEG current density in the rostral anterior cingulate; resting state fMRI connectivity; self-rated 
affective responses to cues and feedback during the MID Task; EefRT total reward; VAS score; TEPS 
anticipatory and consummatory pleasure scores; HAM-D score; HAM-A score; CGI-S, CGI-I, and 
CPFQ score. 
 
The VAS-Anhedonia, TEPS, and CPFQ are self-report instruments.  The EefRT is a behavioral task and this 
task and the HAM-D, and HAM-A will be administered by appropriately trained and monitored raters.  
The training, assessment and maintenance of inter-rater reliability will be managed by the Duke Signal 
Detection Team. Clinical raters, neuropsychological technicians, and all staff involved in collection and 
analysis of clinical measures will be blinded to treatment assignment and to clinical status. They will 
have no interactions with subjects other than the administration of the specific tests they are assigned 
to administer. Raters and patients will complete best-guess forms so that the adequacy of the blind can 
be assessed.  Best-guess forms will be used to formally assess the adequacy of the blind for patients and 
raters. 
7.5. Exploratory Assessments  
 
Exploratory Anhedonia Measures: To complement the SHAPS we include 3 secondary anhedonia 
measures: the Effort-Expenditure for Rewards Task (EefRT), the Visual Analogue Scale for Anhedonia 
(VAS-Anhedonia) and the Temporal Experience of Pleasure Scale (TEPS). These will be compared in 
subjects receiving LY2456302 and PBO in exploratory analysis.  
 
The Effort-Expenditure for Rewards Task (EefRT; Treadway et al., 2009) is intended to assess the 
motivation to pursue rewards, one important dimension of reward-related function. It has been 
validated in a study of 60 individuals who were screened to have anhedonia with the SHAPS (Treadway 
et al., 2009). The EefRT was found to be correlated with the Beck Depression Inventory (BDI) anhedonia 
scale and the Chapman anhedonia scale. The EefRT task is a multi-trial game in which participants are 
given an opportunity on each trial to choose between two different task difficulty levels in order to 
obtain monetary rewards.  
 
The VAS-Anhedonia is a standard VAS assessment of anhedonia severity which is included because it 
provides a global anhedonia indicator which takes very little time to obtain and which was found to be 


24 
 
sensitive to change with treatment in a prior placebo-controlled trial in alcohol dependent subjects 
(Martinotti et al., 2011). The test consists of making a rating on a 100 mm scale in response to the 
directive: “Make a mark on the line below that indicates how much pleasure you experience from food, 
sexual behavior, and meeting friends”. At the left end of the scale is the anchor “No Pleasure” and at the 
right end of the scale is the anchor “Extreme Pleasure.”  
 
We also include the Temporal Experience of Pleasure Scale (TEPS) because it provides different 
information about reward-related function than the SHAPS and has been found to be correlated with 
activation in the key circuits of interest (nucleus accumbens and putamen) in Monetary Incentive Delay 
Task-related fMRI (Stanford et al., 2011). The TEPS is an 18-item self-report measurement of 
anticipatory (10 items) and consummatory (eight items) components of anhedonia which consists of a 
series of statements that must be rated according to how accurate they are for the individual (Gard et 
al., 2006). The scale differentiates the role of anticipatory pleasure (‘wanting’) from consummatory 
pleasure (‘liking’). Both components are currently believed to be relevant to measuring anhedonia.  
 
Other Exploratory Measures  
 
The Hamilton Rating Scale for Depression (HAM-D) 17-item version (Hamilton, 1967) will be included in 
exploratory analysis to provide confirmatory support for changes in depression severity with treatment. 
This interviewer-administered semi-structured interview is one of the most widely used instruments in 
depression treatment studies.  
 
The Hamilton Rating Scale for Anxiety (HAM-A) is a rating scale designed to measure the severity of 
anxiety symptoms (Hamilton, 1959). It is widely used in both clinical and research settings. The scale 
consists of 14 items, each defined by a series of symptoms, and measures both psychic anxiety (mental 
agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). It has 
been demonstrated to acceptable reliability, validity and sensitivity to change (Maier, 1988). Each item 
is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0–56, where <17 indicates 
mild severity, 18–24 mild to moderate severity and 25–30 moderate to severe. This instrument will be 
included in secondary analysis to provide confirmatory support for changes in anxiety severity with 
treatment. 
 
The Cognitive and Physical Functioning Questionnaire (CPFQ) is a 7-item self-report instrument was 
intended to be a brief scale for measuring cognitive and executive dysfunction in patients with mood 
and anxiety disorders (Fava et al., 2009). This scale has been demonstrated to have strong internal 
consistency, good temporal stability and sensitivity to change with treatment (Fava et al., 2009). 
Intended to be a brief scale for measuring cognitive and executive dysfunction in patients with mood 
and anxiety disorders (Fava et al., 2009). This scale has been demonstrated to have strong internal 
consistency, good temporal stability and sensitivity to change with treatment (Fava et al., 2009). 
 
The Clinical Global Impression – Severity (CGI-S) is a widely administered clinician rated global measure 
of subject overall illness severity. Subjects are rated on a 1-7 scale where 1 corresponds to “Normal, Not 
at All Ill”, 2 is “Borderline Mentally Ill”, the anchor for 3 is “Mildly Ill”, the anchor for 4 is “Moderately 
Ill”, 5 is “Markedly Ill”, 6 is “Severely Ill”, and 7 is “Among the Most Extremely Ill Patients”. It will be 
administered at all subject visits.  
 
The Clinical Global Impression – Improvement (CGI-I) is a widely administered clinician rated global 
measure of the degree of improvement from the initial assessment in subject overall illness severity. 


25 
 
Subjects are rated on a 1-7 scale where 1 corresponds to “Very Much Improved”, 2 is “Much Improved”, 
the anchor for 3 is “Minimally Improved”, the anchor for 4 is “No Change”, 5 is “Minimally Worse”, 6 is 
“Much Worse”, and 7 is “Very Much Worse”. It will be administered at all subject visits.  
 
During the course of the trial subjects for whom the CGI-I is greater than 5 will be removed from the 
study and appropriate care given, for safety purposes.  
 
 
7.6. Psychiatric Diagnostic Assessment 
 
The psychiatric diagnostic assessment will consist of a clinical interview and administration of the Mini-
International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998).  The MINI is a brief, structured 
psychiatric interview administered to determine the presence of any neuropsychiatric disorders). It is a 
reliable and valid psychiatric diagnostic instrument.  It will be used in place of other lengthier diagnostic 
tools (i.e., SCID-I) in order to decrease subject burden.   
 
7.7. Safety/Adverse Effects Assessments 
 
Safety assessments will be collected as secondary outcome measures for this Phase 2A study and will be 
conducted throughout the study at the protocol specified treatment visits.  Specific safety assessments 
will include: Spontaneously reported adverse events (Aes) and the Columbia Suicide Severity Rating 
Scale (C-SSRS) (Posner, 2011).  The C-SSRS will be administered at screening, baseline, and all 
assessment visits (See Table 2 Schedule of Assessments).  Aes will be rated by the identifying 
investigator for relationship to study drug and severity.  Unexpected Aes and all those rated as serious 
Aes will be reported to the relevant IRBs and the FAST-MAS PI, Dr. Krystal, who will communicate these 
to the study Data and Safety Monitoring Board (DSMB) and the FAST-MAS NIMH Program Officers.   All 
Aes will be tabulated and provided to the DSMB on a regular basis for their review.  Appropriate medical 
care will be provided to all those experiencing Aes.  This may include referral to an appropriate 
practitioner outside of the study, transfer to an Emergency Room, or hospital admission.  All subjects 
with Aes will be monitored regularly for the status of their AE until the AE is resolved.  
 
7.8. Vital Signs/Laboratory Assessments 
  
These assessments will include vital signs (height, weight, blood pressure, and pulse), beta-HCG test, 
urine drug screen, laboratory assessments (Complete blood count with differential, Electrolytes, 
Metabolic Panel [including liver function tests], Thyroid Function Tests, Urinalysis), and ECG.   Tests for 
assessment of gastric adverse events include: gastrin, pepsinogen I/II, intrinsic factor, antiparietal 
antibodies, and vitamin B12 levels.  Height will be assessed at baseline only.  Otherwise vital signs will be 
obtained at all treatment visits.   Beta-HCG, urine drug screen, and height will be obtained only at 
baseline.   The laboratory assessments will occur at baseline and all assessment visits.  ECG testing will 
occur 1,2,3 minutes after initial dosing and then at all assessment visits (See Schedule of Assessments).  
These tests will be reviewed within 24 hours by the site PI or Co-investigator.  Where clinically significant 
findings are noted, appropriate medical intervention will be recommended as indicated. 


26 
 
 
 
Appendix A. General Milestones of 
Study 
Study Months 
Contract Execution and Study Startup 
4.0 
First Subject Enrolled 
12 
Last Subject Enrolled 
Last Subject Completes  
Treatment and F/u 
3.0* 
Database Lock and Sites Closed 
1.0 
Statistical Analysis Complete 
2.0 
Manuscript (or Final Clinical Study 
Report) Complete 
2.0 
*First patient first visit to last patient last visit = 15 months 
 


27 
 
Appendix B. Schedule of 
Assessments, Outcome 
Measures, Labs, and Procedures 
Screening 
Baseline 
Follow 
up 
Double-Blind 
Treatment Period 
Follow 
Up 
Visit 
Screening 
A0 
Phone 
A1 
A2 
A3 
A4 1 Month 
Weeks from Baseline 
Up to -4 
0 
1 
2  
4 
6 
8 
12 
Informed Consent 
X 
 
 
 
 
 
 
 
Physical Exam / Medical History / 
Demographics 
X 
X 
 
X 
X 
X 
X 
 
Treatment History 
X 
X 
 
X 
X 
X 
X 
X 
Mini-International 
Neuropsychiatric Interview (MINI) 
X 
 
 
 
 
 
X 
 
Clinical Interview/Interval History  
X 
X 
 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
X 
X 
X 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
HCG 
X 
 
 
 
 
 
 
 
Labs* 
X 
X 
 
X 
X 
X 
X 
 
Urea Breath Test for H. Pylori 
X 
 
 
 
 
 
 
 
Medication Adherence 
 
 
 
X 
X 
X 
X 
 
fMRI with Monetary Incentive 
Delay Task, Resting State 
Connectivity 
 
X 
 
 
 
 
X 
 
Snaith-Hamilton Pleasure Scale 
(SHAPS) 
X 
X 
 
X 
X 
X 
X 
X 
Probabilistic Reward Task (PRT) 
 
X 
 
 
 
 
X 
 
Effort Expenditure for Rewards 
Task (EefRT) 
 
X 
 
 
 
 
X 
 
Quantitative EEG (QEEG) 
 
X 
 
 
 
 
X 
 
Temporal Experience of Pleasure 
Scale 
X 
X 
 
X 
X 
X 
X 
X 
Visual Analogue Scale for 
Anhedonia 
X 
X 
 
X 
X 
X 
X 
X 
HAM-D 
 
X 
 
 
 
 
X 
 
HAM-A 
 
X 
 
 
 
 
X 
 
Cognitive and Physical Functioning 
Questionnaire (CPFQ) 
 
X 
 
 
 
 
X 
 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
Columbia Suicide Severity Rating 
Scale (CSSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Collection for Rutgers 
 
X 
 
 
 
 
X 
 
Blood Collection for Gastric 
Adverse Events** 
 
X 
 
 
X 
 
X 
 
Blood Sample for Drug Blood Level 
Testing 
 
 
 
X 
X 
X 
X 
 
Adverse Effects Assessment with 
Patient Reported Inventory of 
Side-Effects (PRISE) 
 
X 
 
X 
X 
X 
X 
X 


28 
 
Clinical Global Impression-Severity 
(CGI-S) 
 
X 
 
X 
X 
X 
X 
X 
Clinical Global Impression-
Improvement (CGI-S) 
 
X 
 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
Mock MRI Scanning Session 
X 
 
 
 
 
 
 
 
 
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Appendix C. TABLE SHELLS 
Table 1a. Demographics  
Intent-to-Treat 
 
 
Placebo 
LY 
Total 
Age 
 
 
 
 
21-35 
 
 
 
 
36-50 
 
 
 
        51-65 
 
 
 
 
 
 
 
Gender 
 
 
 
        Male          
 
 
 
        Female 
 
 
 
 
 
 
 
Race/Ethnicity 
 
 
 
        Caucasian 
 
 
 
        African American 
 
 
 
        Asian      
 
 
 
        American 
Indian/Alaskan 
Native 
 
 
 
        Native Hawaiian Or Other 
Pacific 
        Islander 
 
 
 
        Hispanic Origin  
 
 
 
        Non-Hispanic Origin 
 
 
 
More than one race 
 
 
 
Unknown or not reported 
 
 
 


35 
 
Table 1b. Demographics  
As Treated 
 
 
Placebo 
LY 
Total 
Age 
 
 
 
 
21-35 
 
 
 
 
36-50 
 
 
 
        51-65 
 
 
 
 
 
 
 
Gender 
 
 
 
        Male          
 
 
 
        Female 
 
 
 
 
 
 
 
Race/Ethnicity 
 
 
 
        Caucasian 
 
 
 
        African American 
 
 
 
        Asian      
 
 
 
        American 
Indian/Alaskan 
Native 
 
 
 
        Native Hawaiian Or Other 
Pacific 
        Islander 
 
 
 
        Hispanic Origin  
 
 
 
        Non-Hispanic Origin 
 
 
 
More than one race 
 
 
 
Unknown or not reported 
 
 
 
 


36 
 
Table 1c. Demographics  
 
Per Protocol 
 
 
Placebo 
LY 
Total 
Age 
 
 
 
 
21-35 
 
 
 
 
36-50 
 
 
 
        51-65 
 
 
 
 
 
 
 
Gender 
 
 
 
        Male          
 
 
 
        Female 
 
 
 
 
 
 
 
Race/Ethnicity 
 
 
 
        Caucasian 
 
 
 
        African American 
 
 
 
        Asian      
 
 
 
        American 
Indian/Alaskan 
Native 
 
 
 
        Native Hawaiian Or Other 
Pacific 
        Islander 
 
 
 
        Hispanic Origin  
 
 
 
        Non-Hispanic Origin 
 
 
 
More than one race 
 
 
 
Unknown or not reported 
 
 
 


37 
 
Table 1d. Demographics  
 
Study Completers 
 
 
Placebo 
LY 
Total 
Age 
 
 
 
 
21-35 
 
 
 
 
36-50 
 
 
 
        51-65 
 
 
 
 
 
 
 
Gender 
 
 
 
        Male          
 
 
 
        Female 
 
 
 
 
 
 
 
Race/Ethnicity 
 
 
 
        Caucasian 
 
 
 
        African American 
 
 
 
        Asian      
 
 
 
        American 
Indian/Alaskan 
Native 
 
 
 
        Native Hawaiian Or Other 
Pacific 
        Islander 
 
 
 
        Hispanic Origin  
 
 
 
        Non-Hispanic Origin 
 
 
 
More than one race 
 
 
 
Unknown or not reported 
 
 
 


38 
 
Table 2. Pre- to Post-Treatment Changes in fMRI Activation during Anticipation of Reward 
Primary Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
 
fMRI Activation  
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 
 


39 
 
Table 3. Pre- to Post-Treatment Changes in SHAPS 
Secondary Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
Snaith Hamilton Pleasure Scale  
(Clinical Anhedonia Measure) 
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 
 
 


40 
 
Table 4. Pre- to Post-Treatment Changes in PRT 
Secondary Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
Probabilistic Reward Task  
(Behavioral Anhedonia Measure) 
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 


41 
 
Table 5. Pre- to Post-Treatment Changes in fMRI Activation During Anticipation of Loss 
For Exploratory Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
Ventral Striatal fMRI Activation 
During Anticipation of Loss 
During the MID Task  
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 
 


42 
 
Table 6. Pre- to Post-Treatment Changes in Resting State Delta EEG Current Density in the Rostral Anterior 
Cingulate 
For Exploratory Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
Resting State Delta EEG Current 
Density in the Rostral Anterior 
Cingulate  
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 
 
 


43 
 
Table 7. Pre- to Post-Treatment Changes in Resting State fMRI Connectivity 
For Exploratory Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
Resting State fMRI Connectivity 
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 
 
 


44 
 
Table 8. Pre- to Post-Treatment Changes in Self-rated Affective Responses to Cues and Feedback During the MID 
Task 
For Exploratory Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
Self-rated Affective Responses to 
Cues and Feedback During the 
MID Task 
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 


45 
 
Table 9. Pre- to Post-Treatment Changes in The EEfRT 
For Exploratory Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
The Effort-Expenditure for 
Rewards Task (EEfRT) 
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 


46 
 
Table 10. Pre- to Post-Treatment Changes in VAS 
For Exploratory Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
The Visual Analogue Scale for 
Anhedonia 
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 


47 
 
Table 11. Pre- to Post-Treatment Changes in TEPS 
For Exploratory Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
The Temporal Experience of 
Pleasure Scale 
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 


48 
 
Table 12. Pre- to Post-Treatment Changes in HAM-A 
For Exploratory Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
The Hamilton Anxiety Rating 
Scale (HAM-A) 
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 


49 
 
Table 13. Pre- to Post-Treatment Changes in HAM-D 
For Exploratory Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
The Hamilton Depression Rating 
Scale (HAM-D) 
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 


50 
 
Table 14. Pre- to Post-Treatment Changes in CGI-I 
For Exploratory Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
Clinical Global Impression - 
Improvement (CGI-I) 
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 


51 
 
Table 15. Pre- to Post-Treatment Changes in CGI-S 
For Exploratory Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
Clinical Global Impression -  
Severity (CGI-S) 
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 


52 
 
Table 16. Pre- to Post-Treatment Changes in CPFQ 
For Exploratory Outcome 
 
 
Outcome 
Cases 
Fixed Effect 
Estimate 
Standard 
Error 
DF 
95 Confidence 
Interval 
(Lower, 
Higher) 
P-Value 
The Cognitive and Physical 
Functioning Questionnaire 
(CPFQ) 
ITT 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
As Treated 
 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
Per Protocol  
 
Timept 
 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
Completers 
Timept 
Treatment 
Timept* 
Treatment 
 
 
 
 
 
 
 
 
 


53 
 
 
 
Table 17a. Descriptive Statistics for All Outcomes and Assessments in the Final Analysis 
 
Intent-to-Treat 
 
Variable 
Mean 
SD 
Range 
fMRI Activation During Anticipation of Reward (Primary Outcome) 
                       Baseline 
                       Week 8 
 
 
 
Snaith-Hamilton Pleasure Scale (SHAPS-Secondary Outcome) 
                       Baseline 
                       Week 2 
                       Week 4 
                       Week 6 
                       Week 8 
                       Month 1 
                       LOCF 
 
  
 
 
Probabilistic Reward Task (PRT-Secondary Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
fMRI Activation During Anticipation of Loss (Exploratory Outcome ) 
                        Format the same with fMRI (see the first row) 
 
 
 
Resting State Delta EEG Current Density in the Rostral Anterior Cingulate 
(Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
Monetary Reward Task (Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
Effort Expenditure for Rewards Task (EEfRT-Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
Visual Analogue Scale for Anhedonia (VAS-Exploratory Outcome) 
                        Format the same with SHAPS (see the second row) 
 
 
 
Temporal Experience of Pleasure Scale (TEPS) 
                        Format the same with SHAPS (see the second row) 
 
 
 
HAM-A (Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 


54 
 
HAM-D (Exploratory Outcome) 
                         Format the same with fMRI (see the first row) 
 
 
 
Clinical Global Impression-Improvement (CGI-I-Exploratory Outcome) 
                         Format the same with SHAPS (see the second row) 
 
 
 
Clinical Global Impression-Severity (CGI-S-Exploratory Outcome) 
                           Format the same with SHAPS (see the second row) 
 
 
 
Cognitive and Physical Functioning Questionnaire (CPFQ-Exploratory Outcome) 
                           Format the same with fMRI (see the first row) 
 
 
 
 
 


55 
 
Table 17b. Descriptive Statistics for All Outcomes and Assessments in the Final Analysis 
 
As Treated 
 
Variable 
Mean 
SD 
Range 
fMRI Activation During Anticipation of Reward (Primary Outcome) 
                       Baseline 
                       Week 8 
 
 
 
Snaith-Hamilton Pleasure Scale (SHAPS-Secondary Outcome) 
                       Baseline 
                       Week 2 
                       Week 4 
                       Week 6 
                       Week 8 
                       Month 1 
                       LOCF 
 
  
 
 
Probabilistic Reward Task (PRT-Secondary Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
fMRI Activation During Anticipation of Loss (Exploratory Outcome ) 
                        Format the same with fMRI (see the first row) 
 
 
 
Resting State Delta EEG Current Density in the Rostral Anterior Cingulate 
(Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
Monetary Reward Task (Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
Effort Expenditure for Rewards Task (EEfRT-Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
Visual Analogue Scale for Anhedonia (VAS-Exploratory Outcome) 
                        Format the same with SHAPS (see the second row) 
 
 
 
Temporal Experience of Pleasure Scale (TEPS) 
                        Format the same with SHAPS (see the second row) 
 
 
 
HAM-A (Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
 
 
 


56 
 
HAM-D (Exploratory Outcome) 
                         Format the same with fMRI (see the first row) 
 
 
 
Clinical Global Impression-Improvement (CGI-I-Exploratory Outcome) 
                         Format the same with SHAPS (see the second row) 
 
 
 
Clinical Global Impression-Severity (CGI-S-Exploratory Outcome) 
                           Format the same with SHAPS (see the second row) 
 
 
 
Cognitive and Physical Functioning Questionnaire (CPFQ-Exploratory Outcome) 
                           Format the same with fMRI (see the first row) 
 
 
 
 
 
 


57 
 
Table 17c. Descriptive Statistics for All Outcomes and Assessments in the Final Analysis 
 
Per Protocol 
 
Variable 
Mean 
SD 
Range 
fMRI Activation During Anticipation of Reward (Primary Outcome) 
                       Baseline 
                       Week 8 
 
 
 
Snaith-Hamilton Pleasure Scale (SHAPS-Secondary Outcome) 
                       Baseline 
                       Week 2 
                       Week 4 
                       Week 6 
                       Week 8 
                       Month 1 
                       LOCF 
 
  
 
 
Probabilistic Reward Task (PRT-Secondary Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
fMRI Activation During Anticipation of Loss (Exploratory Outcome ) 
                        Format the same with fMRI (see the first row) 
 
 
 
Resting State Delta EEG Current Density in the Rostral Anterior Cingulate 
(Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
Monetary Reward Task (Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
Effort Expenditure for Rewards Task (EEfRT-Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
Visual Analogue Scale for Anhedonia (VAS-Exploratory Outcome) 
                        Format the same with SHAPS (see the second row) 
 
 
 
Temporal Experience of Pleasure Scale (TEPS) 
                        Format the same with SHAPS (see the second row) 
 
 
 
HAM-A (Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
 
 
 


58 
 
HAM-D (Exploratory Outcome) 
                         Format the same with fMRI (see the first row) 
 
 
 
Clinical Global Impression-Improvement (CGI-I-Exploratory Outcome) 
                         Format the same with SHAPS (see the second row) 
 
 
 
Clinical Global Impression-Severity (CGI-S-Exploratory Outcome) 
                           Format the same with SHAPS (see the second row) 
 
 
 
Cognitive and Physical Functioning Questionnaire (CPFQ-Exploratory Outcome) 
                           Format the same with fMRI (see the first row) 
 
 
 
 
 
 
 
 
 


59 
 
Table 17d. Descriptive Statistics for All Outcomes and Assessments in the Final Analysis 
 
Completers 
 
Variable 
Mean 
SD 
Range 
fMRI Activation During Anticipation of Reward (Primary Outcome) 
                       Baseline 
                       Week 8 
 
 
 
Snaith-Hamilton Pleasure Scale (SHAPS-Secondary Outcome) 
                       Baseline 
                       Week 2 
                       Week 4 
                       Week 6 
                       Week 8 
                       Month 1 
                       LOCF 
 
  
 
 
Probabilistic Reward Task (PRT-Secondary Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
fMRI Activation During Anticipation of Loss (Exploratory Outcome ) 
                        Format the same with fMRI (see the first row) 
 
 
 
Resting State Delta EEG Current Density in the Rostral Anterior Cingulate 
(Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
Monetary Reward Task (Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
Effort Expenditure for Rewards Task (EEfRT-Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
Visual Analogue Scale for Anhedonia (VAS-Exploratory Outcome) 
                        Format the same with SHAPS (see the second row) 
 
 
 
Temporal Experience of Pleasure Scale (TEPS) 
                        Format the same with SHAPS (see the second row) 
 
 
 
HAM-A (Exploratory Outcome) 
                        Format the same with fMRI (see the first row) 
 
 
 
 
 
 


60 
 
HAM-D (Exploratory Outcome) 
                         Format the same with fMRI (see the first row) 
 
 
 
Clinical Global Impression-Improvement (CGI-I-Exploratory Outcome) 
                         Format the same with SHAPS (see the second row) 
 
 
 
Clinical Global Impression-Severity (CGI-S-Exploratory Outcome) 
                           Format the same with SHAPS (see the second row) 
 
 
 
Cognitive and Physical Functioning Questionnaire (CPFQ-Exploratory Outcome) 
                           Format the same with fMRI (see the first row) 
 
 
 
 
 


61 
 
Appendix D. FIGURES 
Attached below is an example for Figures (Template from Another Trial).  The two curves will represent two treatments instead of the 
populations for this trial. 
Note: for MINI, fMRI, PRT, EEfRT, QEEG, HAM-D and HAM-A and CPFQ, we will use bar graphs to compare the mean predicted probabilities 
pre to post treatment. 
 


62 
 
 
 
 
CGI-I: Mean Predicted Probability
    0.00
    0.05
    0.10
    0.15
    0.20
    0.25
    0.30
    0.35
    0.40
    0.45
    0.50
    0.55
    0.60
    0.65
    0.70
    0.75
    0.80
    0.85
    0.90
    0.95
    1.00
Time Point
Week 2
 Week 4
Week 8
Month 2
Month 3
Month 6
Figure 6G. CGI-I predicted Scores by Time Periods
Evaluable
MITT


63 
 
Figure 1a.  Pre- to Post-Treatment Changes in fMRI Activation During Anticipation of Reward – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: fMRI: Mean Predicted Probability 
Figure 1b.  Pre- to Post-Treatment Changes in fMRI Activation During Anticipation of Reward – As Treated 
X Axis Label: Time Points 
Y Axis Label: fMRI: Mean Predicted Probability  
Figure 1c.  Pre- to Post-Treatment Changes in fMRI Activation During Anticipation of Reward – Per Protocol 
X Axis Label: Time Points 
Y Axis Label: fMRI: Mean Predicted Probability  
Figure 1d.  Pre- to Post-Treatment Changes in fMRI Activation During Anticipation of Reward – Study Completers 
X Axis Label: Time Points 
Y Axis Label: fMRI: Mean Predicted Probability  
 
Figure 2a.  Changes in Snaith-Hamilton Pleasure Scale (SHAPS) – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: SHAPS: Mean Predicted Probability 
Figure 2b. Changes in Snaith-Hamilton Pleasure Scale (SHAPS) – As Treated 
X Axis Label: Time Points 


64 
 
Y Axis Label: SHAPS: Mean Predicted Probability  
Figure 2c.  Changes in Snaith-Hamilton Pleasure Scale (SHAPS) – Per Protocol 
X Axis Label: Time Points 
Y Axis Label: SHAPS: Mean Predicted Probability  
Figure 2d.  Changes in Snaith-Hamilton Pleasure Scale (SHAPS) – Study Completers 
X Axis Label: Time Points 
Y Axis Label: SHAPS: Mean Predicted Probability  
 
Figure 3a.  Changes in Reward Learning and Response Bias (PRT) – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: PRT: Mean Predicted Probability 
Figure 3b. Changes in Reward Learning and Response Bias (PRT)  – As Treated 
X Axis Label: Time Points 
Y Axis Label: PRT: Mean Predicted Probability  
Figure 3c. Changes in Reward Learning and Response Bias (PRT)  – Per Protocol 
X Axis Label: Time Points 
Y Axis Label: PRT: Mean Predicted Probability  
 


65 
 
Figure 3d. Changes in Reward Learning and Response Bias (PRT)  – Study Completers 
X Axis Label: Time Points 
Y Axis Label: PRT: Mean Predicted Probability  
 
Figure 4a.  Pre- to Post-Treatment Changes in fMRI Activation During Anticipation of Loss – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: fMRI: Mean Predicted Probability 
Figure 4b.  Pre- to Post-Treatment Changes in fMRI Activation During Anticipation of Loss – As Treated 
X Axis Label: Time Points 
Y Axis Label: fMRI: Mean Predicted Probability  
Figure 4c.  Pre- to Post-Treatment Changes in fMRI Activation During Anticipation of Loss – Per Protocol 
X Axis Label: Time Points 
Y Axis Label: fMRI: Mean Predicted Probability  
Figure 4d.  Pre- to Post-Treatment Changes in fMRI Activation During Anticipation of Loss – Study Completers 
X Axis Label: Time Points 
Y Axis Label: fMRI: Mean Predicted Probability  
 
 


66 
 
Figure 5a.  Pre- to Post-Treatment Changes in Resting State Delta EEG Current Density – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: EEG: Mean Predicted Probability 
Figure 5b.  Pre- to Post-Treatment Changes in Resting State Delta EEG Current Density – As Treated 
X Axis Label: Time Points 
Y Axis Label: EEG: Mean Predicted Probability  
Figure 5c.  Pre- to Post-Treatment Changes in Resting State Delta EEG Current Density – Per Protocol 
X Axis Label: Time Points 
Y Axis Label: EEG: Mean Predicted Probability  
Figure 5d.  Pre- to Post-Treatment Changes in Resting State Delta EEG Current Density – Study Completers 
X Axis Label: Time Points 
Y Axis Label: EEG: Mean Predicted Probability  
 
Figure 6a.  Pre- to Post-Treatment Changes in Resting State fMRI Connectivity – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: fMRI: Mean Predicted Probability 
 
 


67 
 
Figure 6b.  Pre- to Post-Treatment Changes in Resting State fMRI Connectivity – As Treated 
X Axis Label: Time Points 
Y Axis Label: fMRI: Mean Predicted Probability  
Figure 6c.  Pre- to Post-Treatment Changes in Resting State fMRI Connectivity – Per Protocol 
X Axis Label: Time Points 
Y Axis Label: fMRI: Mean Predicted Probability  
Figure 6d.  Pre- to Post-Treatment Changes in Resting State fMRI Connectivity – Study Completers 
X Axis Label: Time Points 
Y Axis Label: fMRI: Mean Predicted Probability  
 
Figure 7a. Changes in Self-rated Affective Responses to Cues and Feedback During the MID Task – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: MRT: Mean Predicted Probability 
Figure 7b.  Changes in Self-rated Affective Responses to Cues and Feedback During the MID Task – As Treated 
X Axis Label: Time Points 
Y Axis Label: MRT: Mean Predicted Probability  
Figure 7c.  Changes in Self-rated Affective Responses to Cues and Feedback During the MID Task – Per Protocol 
X Axis Label: Time Points 


68 
 
Y Axis Label: MRT: Mean Predicted Probability  
Figure 7d.  Changes in Self-rated Affective Responses to Cues and Feedback During the MID Task – Study Completers 
X Axis Label: Time Points 
Y Axis Label: MRT: Mean Predicted Probability  
 
Figure 8a.  Pre- to Post-Treatment Changes in EEfRT – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: EEfRT: Mean Predicted Probability 
Figure 8b.  Pre- to Post-Treatment Changes in EEfRT – As Treated 
X Axis Label: Time Points 
Y Axis Label: EEfRT: Mean Predicted Probability  
Figure 8c.  Pre- to Post-Treatment Changes in EEfRT – Per Protocol 
X Axis Label: Time Points 
Y Axis Label: EEfRT: Mean Predicted Probability 
Figure 8d.  Pre- to Post-Treatment Changes in EEfRT – Study Completers 
X Axis Label: Time Points 
Y Axis Label: EEfRT: Mean Predicted Probability 
 


69 
 
Figure 9a.  Changes in Visual Analogue Scale for Anhedonia (VAS) – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: VAS: Mean Predicted Probability 
Figure 9b.  Changes in Visual Analogue Scale for Anhedonia (VAS) – As Treated 
X Axis Label: Time Points 
Y Axis Label: VAS: Mean Predicted Probability  
Figure 9c.  Changes in Visual Analogue Scale for Anhedonia (VAS) – Per Protocol 
X Axis Label: Time Points 
Y Axis Label: VAS: Mean Predicted Probability  
Figure 9d.  Changes in Visual Analogue Scale for Anhedonia (VAS) – Study Completers 
X Axis Label: Time Points 
Y Axis Label: VAS: Mean Predicted Probability  
Figure 10a.  Changes in Temporal Experience of Pleasure Scale (TEPS) – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: TEPS: Mean Predicted Probability 
Figure 10b.  Changes in Temporal Experience of Pleasure Scale (TEPS) – As Treated 
X Axis Label: Time Points 
Y Axis Label: TEPS: Mean Predicted Probability  


70 
 
Figure 10c.  Changes in Temporal Experience of Pleasure Scale (TEPS) – Per Protocol 
X Axis Label: Time Points 
Y Axis Label: TEPS: Mean Predicted Probability  
Figure 10d.  Changes in Temporal Experience of Pleasure Scale (TEPS) – Study Completers 
X Axis Label: Time Points 
Y Axis Label: TEPS: Mean Predicted Probability  
Figure 11a.  Pre- to Post-Treatment Changes in Hamilton Rating Scale for Anxiety (HAM-A) – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: HAM-A: Mean Predicted Probability 
Figure 11b.  Pre- to Post-Treatment Changes in Hamilton Rating Scale for Anxiety (HAM-A) – As Treated 
X Axis Label: Time Points 
Y Axis Label: HAM-A: Mean Predicted Probability  
Figure 11c.  Pre- to Post-Treatment Changes in Hamilton Rating Scale for Anxiety (HAM-A) – Per Protocol 
X Axis Label: Time Points 
Y Axis Label: HAM-A: Mean Predicted Probability 
 Figure 11d.  Pre- to Post-Treatment Changes in Hamilton Rating Scale for Anxiety (HAM-A) – Study Completers 
X Axis Label: Time Points 
Y Axis Label: HAM-A: Mean Predicted Probability 


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Figure 12a.  Pre- to Post-Treatment Changes in Hamilton Rating Scale for Depression (HAM-D) – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: HAM-D: Mean Predicted Probability 
Figure 12b.  Pre- to Post-Treatment Changes in Hamilton Rating Scale for Depression (HAM-D) – As Treated 
X Axis Label: Time Points 
Y Axis Label: HAM-D: Mean Predicted Probability  
Figure 12c.  Pre- to Post-Treatment Changes in Hamilton Rating Scale for Depression (HAM-D) – Per Protocol 
X Axis Label: Time Points 
Y Axis Label: HAM-D: Mean Predicted Probability  
Figure 12d.  Pre- to Post-Treatment Changes in Hamilton Rating Scale for Depression (HAM-D) – Study Completers 
X Axis Label: Time Points 
Y Axis Label: HAM-D: Mean Predicted Probability  
Figure 13a.  Changes in Clinical Global Impression – Improvement (CGI-I) – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: CGI-I: Mean Predicted Probability 
Figure 13b.  Changes in Clinical Global Impression – Improvement (CGI-I)–As Treated 
X Axis Label: Time Points 


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Y Axis Label: CGI-I: Mean Predicted Probability  
Figure 13c.  Changes in Clinical Global Impression – Improvement (CGI-I)–Per Protocol 
X Axis Label: Time Points 
Y Axis Label: CGI-I: Mean Predicted Probability  
Figure 13d.  Changes in Clinical Global Impression – Improvement (CGI-I)– Study Completers 
X Axis Label: Time Points 
Y Axis Label: CGI-I: Mean Predicted Probability  
 
Figure 14a.  Changes in Clinical Global Impression – Severity (CGI-S) – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: CGI-S: Mean Predicted Probability 
Figure 14b.  Changes in Clinical Global Impression –Severity (CGI-S)–As Treated 
X Axis Label: Time Points 
Y Axis Label: CGI-S: Mean Predicted Probability  
Figure 14c.  Changes in Clinical Global Impression – Severity (CGI-S)–Per Protocol 
X Axis Label: Time Points 
Y Axis Label: CGI-S: Mean Predicted Probability  
 


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Figure 14d.  Changes in Clinical Global Impression – Severity (CGI-S)– Study Completers 
X Axis Label: Time Points 
Y Axis Label: CGI-S: Mean Predicted Probability  
 
Figure 15a.  Pre- to Post-Treatment Changes in Cognitive and Physical Functioning Questionnaire (CPFQ) – Intent-to-Treat Population 
X Axis Label: Time Points 
Y Axis Label: CPFQ: Mean Predicted Probability 
Figure 15b.  Pre- to Post-Treatment Changes in Cognitive and Physical Functioning Questionnaire (CPFQ) – As Treated 
X Axis Label: Time Points 
Y Axis Label: CPFQ: Mean Predicted Probability  
Figure 15c.  Pre- to Post-Treatment Changes in Cognitive and Physical Functioning Questionnaire (CPFQ) – Per Protocol 
X Axis Label: Time Points 
Y Axis Label: CPFQ: Mean Predicted Probability 
Figure 15d.  Pre- to Post-Treatment Changes in Cognitive and Physical Functioning Questionnaire (CPFQ) – Study Completers 
X Axis Label: Time Points 
Y Axis Label: CPFQ: Mean Predicted Probability