A Three-arm, Parallel Group, Multicentre, Double-blind, Randomized Controlled Trial Evaluating the Impact of GeneSight Psychotropic and Enhanced-GeneSight Psychotropic, on Response to Psychotropic Treatment in Outpatients Suffering From a Major Depressive Disorder (MDD) and Having Had - Within the Current Episode - an Inadequate Response to at Least One Psychotropic Medication Included in GeneSight Psychotropic
Phase: PHASE4
Conditions: Depressive Disorder, Major, Depression, Depressive Disorder
Sponsor: Assurex Health Inc.

                                                                                                                        
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A three-arm, parallel group, multicentre, double-blind, randomized controlled trial 
evaluating the impact of GeneSight Psychotropic and Enhanced-GeneSight 
Psychotropic, on response to psychotropic treatment in outpatients suffering from a 
major depressive disorder (MDD) and having had – within the current episode - an 
inadequate response to at least one psychotropic medication included in GeneSight 
Psychotropic 
 
 
 
 
 
 
 
 
 
Short Title:  Pharmacogenomic Decision Support with GeneSight Psychotropic to Guide 
the Treatment of Major Depressive Disorder 
 
 
 
 
Protocol Version 1.5 
 2 May 2017 
 
 
ClinicalTrials.gov Identifier: NCT02466477 
 
Sponsor: Assurex Health, Ltd. 
250 College St., Room R38 
Toronto, Canada M5T 1R8 
 
 
 
 
 
 
 
 
 
 
 
 

                                                                                                                        
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Key Study Contacts 
 
Sponsor: 
Assurex Health Ltd. 
 
Sponsor contact: 
Ana Gugila 
250 College St. R-38, 
Toronto, ON 
M5T 1R8 
Office: 416-813-2741 
Protocol Contributors: 
Centre for Addiction and Mental Health (CAMH) 
(250 College Street, Toronto, ON M5T 1R8) 
 
Daniel J. Mueller, MD, PhD 
Head, Pharmacogenetics Research Clinic, CAMH 
Associate Professor, Department of Psychiatry, 
University of Toronto 
E-mail: Daniel.Mueller@camh.ca 
 
James L. Kennedy, MD 
Director, Neuroscience Research Department and 
Head, Psychiatric Neurogenetics Section, CAMH 
Professor, Department of Psychiatry and Institute of 
Medical Science, University of Toronto 
E-mail: Jim.Kennedy@camh.ca 
 
Programs for Assessment of Technology in 
Health (PATH)  
(43 Charlton Avenue East, 2nd Floor, Hamilton, ON 
L8N 1Y3) 
 
James M. Bowen, MSc 
Assistant Professor (Part-Time) & Research 
Associate, Department of Clinical Epidemiology and 
Biostatistics, McMaster University 
Program Manager, PATH, St. Joseph’s Healthcare 
Hamilton 
E-mail: bowenj@mcmaster.ca 
 
Robert Hopkins, PhD 
Assistant Professor (Part-Time), Department of 

                                                                                                                        
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Clinical Epidemiology and Biostatistics, McMaster 
University 
Biostatistician, PATH, St. Joseph’s Healthcare 
Hamilton 
E-mail: hopkinr@mcmaster.ca 
 
Jean-Eric Tarride, PhD 
Associate Professor, Department of Clinical 
Epidemiology and Biostatistics, McMaster University 
Faculty member, PATH, St. Joseph’s Healthcare 
Hamilton 
E-mail: tarride@mcmaster.ca 
 
AssureRx Canada Ltd. (ARxC) 
(250 College Street, Toronto, ON M5T 1R8) 
 
Alexa Gilbert, MSc 
Clinical Development Manager 
E-mail: agilbert@assurerxcanada.ca 
 
Assurex Health, Inc. 
(6030 S. Mason-Montgomery Road, Mason, Ohio 
45040, USA) 
 
C. Anthony Altar, PhD 
E-mail: tonyaltar@gmail.com 
 
Bryan Dechairo, PhD 
Senior Vice President, Medical & Clinical Development  
E-mail: bdechairo@assurerxhealth.com 
 
Authors’ Contributions  
JB, BD, AG, and BY wrote the initial protocol and 
contributed to the study design. CAA, JK, DM, and JET 
helped with study design and provided input into the 
protocol, RH provided statistical expertise in clinical 
trial design. All authors contributed to refinement of the 
initial study protocol. 

                                                                                                                        
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Methodology/Coordinating 
Centre(s): 
Topstone Research 
1 Eva Road, Suite 1009 
Toronto, ON 
M9C 4Z5 
 
Programs for Assessment of Technology in Health 
(PATH)  
43 Charlton Avenue East, 2nd Floor, 
Hamilton, ON  
L8N 1Y3 
Medical Monitor: 
Deepen Patel, MD 
1 Eva Road, Suite 100 
Toronto, ON 
M9C 4Z5 
Office: 416-620-2201 ext. 4401 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                                                                                                                        
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TABLE OF CONTENTS 
 
1.0 
SYNOPSIS .................................................................................................................................................... 10 
1.1 
Study Title ...................................................................................................................................................... 10 
1.2 
Objectives ...................................................................................................................................................... 10 
1.3 
Interventions and Duration ........................................................................................................................... 10 
1.4 
Design and Outcomes .................................................................................................................................... 11 
1.5 
Sample Size and Population .......................................................................................................................... 11 
2.0 
ADMINISTRATIVE INFORMATION ............................................................................................................... 11 
2.1 
Title ................................................................................................................................................................ 11 
2.2 
Trial Registration ........................................................................................................................................... 12 
2.3 
Protocol Version ............................................................................................................................................ 12 
2.4 
Organizational Structure ............................................................................................................................... 12 
 
MaRS EXCITE ........................................................................................................................................ 12 
 
Methodology Centre ............................................................................................................................ 12 
 
Trial Monitoring Committee ................................................................................................................ 13 
3.0 
BACKGROUND AND RATIONALE ................................................................................................................. 13 
3.1 
Major Depressive Disorder (MDD) ................................................................................................................. 13 
3.2 
GeneSight Psychotropic (GEN) ....................................................................................................................... 14 
3.3 
Enhanced-GeneSight Psychotropic (E-GEN)................................................................................................... 15 
3.4 
Study Rationale ............................................................................................................................................. 15 
3.5 
Choice of Comparators .................................................................................................................................. 16 
4.0 
OBJECTIVES ................................................................................................................................................. 16 
4.1 
Hypothesis ..................................................................................................................................................... 16 
4.2 
Primary Objectives ......................................................................................................................................... 16 
4.3 
Secondary Objectives ..................................................................................................................................... 16 
5.0 
TRIAL DESIGN ............................................................................................................................................. 17 
6.0 
METHODS: PARTICIPANTS, INTERVENTIONS, AND OUTCOMES .................................................................. 17 
6.1 
Study Setting ................................................................................................................................................. 17 
6.2 
Eligibility Criteria ........................................................................................................................................... 17 
 
Inclusion Criteria .................................................................................................................................. 18 
 
Exclusion Criteria ................................................................................................................................. 18 
7.0 
INTERVENTIONS ......................................................................................................................................... 19 
7.1 
Interventions ................................................................................................................................................. 19 

                                                                                                                        
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GeneSight Psychotropic (GEN) ............................................................................................................. 19 
 
Enhanced GeneSight Psychotropic (E-GEN) ......................................................................................... 20 
 
Treatment as Usual (TAU) .................................................................................................................... 20 
7.2 
Modifications ................................................................................................................................................. 21 
7.3 
Concomitant Care .......................................................................................................................................... 21 
8.0 
OUTCOMES ................................................................................................................................................. 21 
8.1 
Primary Outcome Measure ........................................................................................................................... 21 
 
17-Item Hamilton Depression Scale (HAM-D17) ................................................................................... 21 
8.2 
Secondary Outcome Measures ...................................................................................................................... 21 
 
Clinical Outcome Measures of MDD Symptoms and Medication Side Effects .................................... 21 
 
Clinical Outcome Measures of Health Related Quality of Life ............................................................. 23 
 
Economic Outcome Measures ............................................................................................................. 24 
 
Other Outcome Measures ................................................................................................................... 25 
9.0 
STUDY TIME SCHEDULE ............................................................................................................................... 25 
9.1 
Screening Visit (Visit 1) .................................................................................................................................. 28 
9.2 
Enrollment and Randomization ..................................................................................................................... 31 
9.3 
Baseline Visit (Visit 2) .................................................................................................................................... 31 
9.4 
Week 4 Visit (Visit 3) ...................................................................................................................................... 32 
9.5 
Week 8 Visit (Visit 4) ...................................................................................................................................... 33 
9.6 
Week 12 Visit (Visit 5) .................................................................................................................................... 33 
9.7 
Long-Term Follow-Up - Months 6, 9 and 12 Visits (Visits 6, 7 and 8) ............................................................ 33 
9.8 
Early Termination (ET) Visit ........................................................................................................................... 35 
9.9 
Unscheduled Visits ......................................................................................................................................... 35 
10.0 
SAMPLE SIZE .......................................................................................................................................... 35 
11.0 
RECRUITMENT ........................................................................................................................................ 35 
12.0 
METHODS: ASSIGNMENT OF INTERVENTIONS........................................................................................ 36 
12.1 
Allocation .................................................................................................................................................. 36 
 
Sequence Generation ...................................................................................................................... 36 
13.0 
BLINDING ............................................................................................................................................... 36 
14.0 
METHODS: DATA COLLECTION, MANAGEMENT, AND ANALYSIS ............................................................ 37 
14.1 
Data Collection Methods .......................................................................................................................... 37 
 
Participant Retention ...................................................................................................................... 37 
 
Participant Withdrawal ................................................................................................................... 38 
 
Discontinuation of Study ................................................................................................................. 38 
15.0 
DATA MANAGEMENT ............................................................................................................................. 39 
15.1 
Inspection of Records ................................................................................................................................ 39 

                                                                                                                        
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15.2 
Retention of Records ................................................................................................................................. 39 
16.0 
STATISTICAL METHODS .......................................................................................................................... 40 
16.1 
Clinical Analysis ........................................................................................................................................ 40 
 
Descriptive Statistics ....................................................................................................................... 40 
 
Diagnostics ...................................................................................................................................... 40 
 
Continuous Outcomes..................................................................................................................... 41 
 
Categorical Outcomes ..................................................................................................................... 42 
 
Within-Group and Between-Group Composite Phenotype Analyses ............................................. 42 
 
Decision Rule ................................................................................................................................... 43 
16.2 
Economic Analysis..................................................................................................................................... 43 
17.0 
METHODS: MONITORING ....................................................................................................................... 43 
17.1 
Data Monitoring ....................................................................................................................................... 43 
17.2 
Harms ....................................................................................................................................................... 44 
 
Definitions ....................................................................................................................................... 44 
 
Evaluating, Recording and Reporting of Adverse Events ................................................................ 44 
18.0 
AUDITING ............................................................................................................................................... 46 
19.0 
ETHICS AND DISSEMINATION ................................................................................................................. 47 
20.0 
RESEARCH ETHICS APPROVAL ................................................................................................................ 47 
21.0 
CONSENT OR ASSENT ............................................................................................................................. 48 
22.0 
CONFIDENTIALITY .................................................................................................................................. 48 
23.0 
DECLARATION OF INTERESTS ................................................................................................................. 48 
23.1 
Financial Disclosure .................................................................................................................................. 48 
24.0 
DISSEMINATION POLICY ......................................................................................................................... 49 
25.0 
REFERENCES ........................................................................................................................................... 51 
26.0 
APPENDICES ........................................................................................................................................... 53 
APPENDIX I: List of Psychotropic Medications Included in the Canadian version of GeneSight Psychotropic (GEN) 
and Enhanced GeneSight Psychotropic (E-GEN) ..................................................................................................... 53 
APPENDIX II: 17-Item Hamilton Depression Rating Scale (HAM-D17) ...................................................................... 54 
APPENDIX III: 16-Item Self-Report Quick Inventory of Depression Symptomology (QIDS-SR16) .............................. 57 
APPENDIX IV: 9-Item Patient Health Questionnaire (PHQ-9) .................................................................................. 59 
APPENDIX V: Generalized Anxiety Disorder 7-Item (GAD-7) Scale .......................................................................... 60 
APPENDIX VI: Clinical Global Impression (CGI) ........................................................................................................ 61 
APPENDIX VII: Udvalg for Kliniske Undersogeler (UKU) Side Effect Rating Scale .................................................... 63 
APPENDIX VIII: Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER) ................................................ 65 

                                                                                                                        
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APPENDIX IX: EuroQol (EQ-5D-5L) .......................................................................................................................... 66 
APPENDIX X: Short Form (36) Health Survey (SF-36) .............................................................................................. 68 
APPENDIX XI: Pharmacogenetics in Psychiatry Follow-Up Questionnaire (PIP-FQ) ................................................ 71 
APPENDIX XII: Mini International Neuropsychiatric Interview (MINI) for Axis 1 ..................................................... 74 
APPENDIX XIII: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) 
criteria for MDD ...................................................................................................................................................... 75 
APPENDIX XIV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) 
criteria for Current Substance Use Disorder ............................................................................................................ 76 
APPENDIX XV: 16-Item Clinician Quick Inventory of Depression Symptomology (QIDS-C16) ................................... 77 
APPENDIX XVI: Biological Specimens ...................................................................................................................... 80 
 

                                                                                                                        
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PRINCIPAL SITE INVESTIGATOR SIGNATURE 
PAGE 
 
 
 
 
 
 
 
Investigator name: 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
Date: 
 
 
 
 
Institution Name: 
 
 
By my signature, I agree to personally supervise the conduct of this study at my study site 
and to ensure its conduct is in compliance with the protocol, informed consent, Research 
Ethics Board (REB) procedures, instructions from Assurex Health representatives, the 
Declaration of Helsinki, International Conference on Harmonization (ICH) Good Clinical 
Practices Guidelines, and national/local regulations governing the conduct of clinical 
studies. 
 
The signature also confirms that the Investigator agrees that the results of this study may 
be used for submission to national and/or international registration and supervising 
authorities. The authorities will be notified of the Investigator’s name, address, 
qualifications and extent of involvement. 
 
 
 
 
 
 

                                                                                                                        
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1.0 SYNOPSIS 
1.1 Study Title 
A three-arm, parallel group, multicentre, double-blind, randomized controlled trial 
evaluating the impact of GeneSight Psychotropic (GEN) and Enhanced-GeneSight 
Psychotropic (E-GEN), on response to psychotropic treatment in outpatients suffering 
from a major depressive disorder (MDD) and having had – within the current episode - an 
inadequate response to at least one psychotropic medication included in GEN. 
1.2 Objectives 
The first primary objective of this study is to compare the efficacy of GEN to treatment as 
usual (TAU) in improving response to psychotropic treatment in outpatients suffering from 
a major depressive disorder (MDD) and having had – within the current episode - an 
inadequate response to at least one psychotropic medication included in GEN. 
The second primary objective for this study is to validate the clinical utility of the new 
Centre for Addiction and Mental Health (CAMH) markers and demonstrate the superior 
predictive capabilities of E-GEN as compared to GEN. 
1.3 Interventions and Duration 
Patient DNA will be collected for all participants and measured for variations in drug target 
genes and in drug metabolizing genes. Subsequently, recommendations for optimal 
choices and dose adjustments for the 33 most commonly prescribed antidepressant and 
antipsychotic medications will be provided to participants randomized to the GEN arm. 
This pharmacogenomics-based interpretive report will be provided to treating clinicians 
of patients in the GEN arm of the study, allowing clinicians to use the report to support 
their treatment decisions. 
The E-GEN test incorporates into the existing GEN product new markers patented by 
CAMH and licensed by Assurex that are predictive of side effect of antipsychotic-induced 
weight gain (AIWG).  The pharmacogenomics-based interpretive report from E-GEN will 
also be provided to treating clinicians of patients in the E-GEN arm of the study, allowing 
clinicians to use the report to support their treatment decisions. 
Participants randomized to the TAU arm will also require collection of patient DNA. A 
pharmacogenomics-based interpretive report will again be generated from GEN, 
however, this report is not provided to the treating clinician until up to 28 days prior to the 
completion at 12 months of the study at which point the report will be provided to the 
participant. Therefore, patients in this arm will receive clinical treatment as usual, without 
the use or knowledge of pharmacogenetics results by their treating clinicians.  

                                                                                                                        
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Research evaluation visits for all three arms will be completed at baseline, 4, 8 and 12 
weeks.  To capture long-term information, including comparison between GEN and E-
GEN, and each test with TAU, follow-up will also be conducted at 6, 9, and 12 months.  
The information collected at months 6 and 9 will be by telephone interviews while 
participants will return for a physician visit at month 12.  
1.4 Design and Outcomes 
A multicentre, double-blind, randomized controlled trial examining three different 
treatment pathways.  Participants will be stratified by outpatient treatment site.  The 
primary outcome measure will be change in HAM-D17 score between baseline and 8 
weeks.  Secondary outcomes will be measured by the 16-item Self-Report Quick 
Inventory of Depressive Symptomatology (QIDS-SR16), 9-item Patient Health 
Questionnaire (PHQ-9), Generalized Anxiety Disorder 7-Item (GAD-7) Scale, Clinical 
Global Impression of Severity (CGI-S), Clinical Global Impression of Improvement (CGI-
I), Clinical Global Impression Efficacy Index (CGI-EI), changes to initial prescribing based 
on availability of pharmacogenomic data, response rates to psychotropic medication, 
remission rates, time to response/remission, Udvalg for Kliniske Undersogelser (UKU) 
side effect rating scale, Frequency, Intensity, and Burden of Side Effects Ratings 
(FIBSER), weight gain, EuroQol (EQ-5D) and Short Form (36) health survey (SF-36) for 
quality of life, Pharmacogenetics in Psychiatry Follow-Up Questionnaire (PIP-FQ) for 
physician’s attitude and experience to pharmacogenomic testing, healthcare resource 
utilization and productivity losses, healthcare costs and cost-effectiveness of GEN, E-
GEN and TAU.  Evaluation of early and long-term effects on primary and secondary 
outcomes will be completed. 
1.5 Sample Size and Population 
This study will enroll 570 participants who present with moderate to severe MDD as 
measured by a total score of ≥11 on the QIDS-C16 and 16-item Self Report Quick 
Inventory of Depressive Symptomatology (QIDS-SR16), and an inadequate response 
within the current episode to at least one psychotropic treatment included in the GEN. 
2.0   ADMINISTRATIVE INFORMATION 
2.1 Title 
A three-arm, parallel group, multicentre, double-blind, randomized controlled trial 
evaluating 
the 
impact 
of 
GeneSight 
Psychotropic 
and 
Enhanced-GeneSight 
Psychotropic, on response to psychotropic treatment in outpatients suffering from a major 
depressive disorder (MDD) and having had – within the current episode - an inadequate 
response to at least one psychotropic medication included in GeneSight Psychotropic. 

                                                                                                                        
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2.2 Trial Registration 
ClinicalTrials.gov Identifier: NCT02466477 
WHO Trial Registration Data Set:  
http://apps.who.int/trialsearch/Trial2.aspx?TrialID=NCT02466477 
2.3 Protocol Version 
Issue date: 2 May 2017 
Version: 1.5 
2.4 Organizational Structure 
 MaRS EXCITE 
This evaluation is being facilitated through the MaRS Excellence in Clinical Innovation 
and Technology Evaluation (“EXCITE”) program. The EXCITE program connects health 
technology innovators with experienced, award-winning researchers to get the right 
evidence and data needed to show the value of the technology and to facilitate 
discussions with relevant health system stakeholders to determine what it takes to get 
the technology adopted successfully.  The goal of the program is to support the 
evaluation of new health technologies to develop a robust evidence package that can 
be used for both regulatory or licensing approval and reimbursement reviews and to 
connect the innovators with the health system concerning conditions needed for 
successful adoption of the technology. 
 
 Methodology Centre 
Methodology Centres are responsible for overseeing the design and execution of 
EXCITE studies. 
 
Topstone Research is a specialty contract research organization located in Toronto, 
Ontario Canada selected at the Methodology Centre for this study. Topstone provides 
supportive research infrastructure for academic institutions and primary care physicians. 
 

                                                                                                                        
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The Programs for Assessment of Technology in Health (PATH), based at St. Joseph’s 
Healthcare Hamilton, will be responsible for the economic evaluation associated with 
the study, as a part of the MaRS EXCITE program. 
 Trial Monitoring Committee 
The Trial Monitoring Committee membership will be comprised of 5 experts (clinicians, 
scientists, and statisticians) that have relevant expertise and experience in clinical trials, 
statistics and treatment of MDD but are completely independent of the conduct of the 
trial, the PIs, the Trial Sponsor and/or the Trial Funders.  The PIs may be asked to 
attend open sessions of the Trial Monitoring Committee meeting. 
 
The Trial Monitoring Committee is the only group involved in the trial that will have 
access to unblinded data and its role is to review accumulating trial data (focusing on 
ethical, safety and efficacy endpoints), quality of trial conduct, trial progress, and 
compliance. It is also responsible for taking into consideration data emerging from other 
related studies, and in turn making appropriate recommendations. The Trial Monitoring 
Committee will agree on a Charter of Operations and the frequency of meetings as 
appropriate. 
 
3.0 BACKGROUND AND RATIONALE 
3.1 Major Depressive Disorder (MDD) 
Major depressive disorder (MDD) is a highly prevalent(1) mental disorder and a leading 
source of disease burden worldwide(2). Epidemiological studies estimate 12-month and 
lifetime prevalence of MDD in Canada to be 4% and 10.8% respectively(3). MDD is 
expected to be the second greatest cause of disability by 2020 and has been shown to 
cause significant morbidity, affecting people’s ability to work, function in relationships, and 
engage in social activities. Moreover, MDD increases the risk of suicidal ideation, 
attempted suicide, and death by completed suicide.  
Prospective longitudinal studies of patient samples show that MDD is a chronic illness, 
characterized by remitting and recurrent depressive episodes (4, 5). A major depressive 
episode is characterized by a low mood or an inability to experience pleasure 

                                                                                                                        
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(anhedonia), or both, for more than 2 weeks, combined with several cognitive and 
vegetative symptoms and the occurrence of distress or impairment(6). 
Drugs currently available to treat depression can mostly be categorized having their main 
effect of increasing synaptic levels of the monoaminergic neurotransmitters.  These 
include drugs that elevate norepinephrine (NE) (the tricyclic or tetracyclic antidepressants 
[TCAs]), those that increase serotonin (5-HT) (the selective serotonin reuptake inhibitors 
[SSRIs]), and those that increase both NE and 5-HT (the monoamine oxidase inhibitors 
[MAOIs], and the norepinephrine and serotonin reuptake inhibitors [SNRIs](7, 8). While 
all antidepressants achieve similar levels of efficacy, treatment failures are relatively high 
ranging from 30 to 60%(9).  Additionally, many of these compounds are associated with 
significant adverse events (AEs). 
3.2 GeneSight Psychotropic (GEN) 
The GeneSight Psychotropic (GEN) product is a pharmacogenomic decision support tool 
that helps clinicians to make informed, evidence-based decisions about proper drug 
selection. More specifically, patients are tested for clinically important genetic variants of 
multiple pharmacokinetic and pharmacodynamic genes that affect a patient’s ability to 
metabolize, tolerate or respond to medications.  
GEN individualizes psychotherapeutic selection and improves response to psychotropic 
medications by measuring nucleotide variations in eight genes: CYP1A2, CYP3A4, 
CYP2B6, CYP2C9, CYP2C19, CYP2D6; SLC6A4, and HTR2A. Results are analyzed 
using proprietary algorithms to recommend the selection and dosing of the 33 most 
commonly prescribed Health Canada approved antidepressant and antipsychotic 
medications (see Appendix I) including a full representation of the SSRI and SNRI drug 
classes.  Tricyclic antidepressants, an MAOI, and typical and atypical antipsychotics are 
also represented. The test generates a report for each patient that stratifies 
antidepressant and antipsychotic medications into one of three “bins”: “Green bin” 
medications – use as directed, “Yellow bin” medications – use with caution, and “Red bin” 
medications – use with increased caution and more frequent monitoring. Clinicians 
receive the easy to implement report within three days of sample collection, which is 
among the fastest responses in the personalized medicine industry. 
The clinical utility of GEN has been evaluated in three previous prospective trials.  Hall-
Flavin et al.(10) reported the results of an open-label pilot study (n = 44) comparing GEN 
to treatment as usual (TAU) without the benefit of pharmacogenomic testing.  The GEN 
guided arm demonstrated a 30.8% improvement in the 17-item Hamilton Depression 
Rating Scale (HAM-D17) score by the end of the 8 week treatment period, compared to 
an 18.2% improvement in the TAU arm (p = 0.04).  Results of the larger (n = 165) open-
label trial(11) mirrored these findings, demonstrating a 46.9% improvement in HAM-D17 

                                                                                                                        
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score in the GEN arm, compared to a 29.9% improvement in the TAU arm (p < 0.0001).  
The third trial used a randomized, double-blind trial design (n = 51)(12).  Due to the small 
sample size, the trial was underpowered to detect a significant difference in improvement 
between the two arms (TAU and GEN).  However, effect sizes of improvement reflected 
those seen in previous trials.  The GEN group experienced a 30.8% improvement in HAM-
D17, compared to 20.7% in TAU.  Odds ratios for response were calculated, showing that 
GEN-guided participants had a 2.14 times greater likelihood of response compared to 
TAU participants, which was similar to the 4.67 (smaller trial) and 2.06 (larger trial) odds 
ratios calculated for the other two earlier studies. 
The GEN test can also predict those patients with greater healthcare utilizations, disability 
days, and other events who were prescribed psychotropic medications whose metabolism 
and brain responses are not optimally matched with the individual’s genetic profile(13). 
3.3 Enhanced-GeneSight Psychotropic (E-GEN) 
The current GEN test lacks predictive genes for a major complication of antipsychotic 
drug use: antipsychotic-induced weight gain (AIWG).  
An enhanced version of the GEN test, E-GEN, was developed by incorporating 6 new 
genes (represented by 7 SNPs) patented by CAMH and licensed by Assurex that are 
predictive for AIWG, to those used in the GEN algorithm (Table 1). An increasing risk 
level associated with AIWG is estimated by an increasing number of risk genotypes that 
a given patient possesses among the 7 SNPs. 
 
Table 1. Antipsychotic-Induced Weight Gain Markers.  MC4R, melanocortin 4 
receptor; CNR1, cannabinoid receptor 1; NPY, neuropeptide Y; GCG, glucagon-like 
peptide 1 gene; HCRTR2, orexin/hypocretin receptor 2; NDUFS1, NADH dehydrogenase 
(ubiquinone) Fe-S protein 1. 
 
 
 
 
 
Gene 
Polymorphism 
 
 
 
MC4R 
Rs489693 
 
 
 
CNR1 
Rs806378 
 
 
 
NPY 
Rs16147 
 
 
 
GCG 
Rs13429709 
 
 
 
HCRTR2 
Rs3134701 
Rs4142972 
 
 
 
NDUFS1 
Rs6435326 
 
 
 
3.4 Study Rationale 
Previous studies utilizing an open-label design have shown significant improvement in 
patient outcomes following use of the GEN test(11).  However, although effect sizes were 

                                                                                                                        
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similar to those seen in the open-label studies, a small (n = 51) blinded, randomized 
controlled trial(12) (RCT) did not detect a statistically significant outcome.  Therefore, the 
first rationale for this trial is to utilize a double-blinded RCT design to replicate previous 
findings of improvement in clinical outcomes in participants treated with the benefit of 
GEN testing.  Another rationale for this study is to determine the added benefit of using 
E-GEN testing, as compared to GEN testing, to guide treatment selection based on 
pharmacogenomic information. Furthermore, this trial also intends to develop an 
evidence-based case for the value of GEN and E-GEN to Canadian healthcare payers. 
It is expected that results from this trial will be used to inform guidelines for the use of 
pharmacogenomic testing in the treatment of MDD.  Results may also be shared with 
regulatory bodies in Canada and abroad. 
3.5 Choice of Comparators 
The comparator chosen for this study is treatment as usual (TAU) which provides a “real 
world” comparison of standard of care with patients who receive GEN or E-GEN test 
results. 
4.0 OBJECTIVES 
4.1 Hypothesis 
GEN and E-GEN reduces MDD symptoms and is more cost-effective than TAU for 
patients suffering from MDD and having had – within the current episode – an inadequate 
response to at least one psychotropic medication included in GEN.  Furthermore, E-GEN 
improves predictions of patients’ clinical responses and provides greater clinical utility as 
compared to GEN. 
4.2 Primary Objectives 
The first primary objective of this study is to compare the efficacy of GEN to TAU in 
improving response to psychotropic treatment in outpatients suffering from a major 
depressive disorder (MDD) and having had – within the current episode - an inadequate 
response to at least one psychotropic medication included in GEN. 
The second primary objective for this study is to validate the utility of the new CAMH 
markers and demonstrate the superior predictive capabilities and greater clinical utility of 
E-GEN as compared to GEN. 
4.3 Secondary Objectives 
To compare the three intervention alternatives (GEN, E-GEN, and TAU) with respect to: 

                                                                                                                        
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 MDD symptoms;  
 Changes to initial prescribing based on availability of pharmacogenomics data; 
 Response rates to psychotropic medication;  
 Remission rates;  
 Time to response/remission; 
 Medication side effects, including weight gain;  
 Health-related quality of life;  
 Physician’s attitude and experience to DNA testing;  
 Healthcare resource utilization and productivity losses;  
 Total estimated healthcare costs associated with the treatment and management 
of patients;  
 Cost-effectiveness of the GEN and E-GEN technology relative to TAU 
5.0 TRIAL DESIGN 
This study is designed as a three-arm multi-centre, double-blind (participants and raters), 
randomized controlled trial to compare the clinical and economic outcomes of GEN, E-
GEN and TAU for patients suffering from a MDD and having had – within the current 
episode - an inadequate response to at least one psychotropic medication included in 
GEN.  Participants will be randomized in a 1:1:1 ratio to each of the three treatment arms. 
6.0 METHODS: PARTICIPANTS, INTERVENTIONS, AND OUTCOMES 
6.1 Study Setting 
This study will be conducted in an outpatient setting.  Participants will be recruited from 
academic and community hospital outpatient clinics, family health teams and primary 
health care clinics in Ontario. 
6.2 Eligibility Criteria  
Patients meeting the following criteria will be approached for study enrollment: 

                                                                                                                        
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 Inclusion Criteria 
1. 18 years of age or older; 
2. Suffer from a Major Depressive Episode meeting Diagnostic and Statistical Manual 
of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria; 
3. Have had an inadequate response within the current episode to at least one 
psychotropic treatment (listed in Appendix I). Inadequate response is defined as 
inadequate efficacy after 6 weeks of a psychotropic treatment or discontinuation of 
a psychotropic treatment due to adverse events (AEs) or intolerability; 
4. Have each a screening and baseline score on the 16-item Clinician Quick Inventory 
of Depressive Symptomatology (QIDS-C16) and 16-item Self-Report Quick 
Inventory of Depressive Symptomatology (QIDS-SR16) rating scales ≥ 11; 
5. Be able to understand the requirements of the study and provide written informed 
consent to participate in this study; 
6. Agree to abide by the study protocol and its restrictions and be able to complete 
all aspects of the study, including all visits and tests.  
 Exclusion Criteria 
Any of the following conditions are cause for exclusion from the study: 
1. Patients posing a serious suicidal risk and/or in need of immediate hospitalization 
as judged by the Investigator; 
2. Patients with a diagnosis of Bipolar I or II disorder;  
3. Patients with a current Axis I diagnosis of:  
 Delirium 
 Dementia 
 Amnestic and/or other cognitive disorder  
 Schizophrenia or other psychotic disorder; 
4. Patients having experienced hallucinations, delusions, or any psychotic 
symptomatology within the current depressive episode or during prior depressive 
episodes; 
5. Patient is currently in an inpatient facility; 
6. Patients with a history of hypothyroidism unless taking a stable dose of thyroid 
medication and asymptomatic or euthyroid for at least 6 months; 

                                                                                                                        
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7. Patients who meet DSM-IV-TR criteria for any significant current substance use 
disorder; 
8. Patients with:  
 hepatic insufficiency (three times the upper limit of normal (ULN) for 
aspartate aminotransferase (AST) and/or alanine aminotransferase 
(ALT)); liver transplant recipient; cirrhosis of the liver;  
 malignancy (except basal cell carcinoma) and/or chemotherapy within 1 
year prior to screening; malignancy more than 1 year prior to screening 
must have been local and without metastasis and/or recurrence, and if 
treated with chemotherapy, without nervous system complications; 
 significant unstable medical condition or life threatening disease with 
anticipated survival of less than 6 months;  
 need for therapies that may obscure the results of treatment and/or of the 
study; 
9. Participation in another clinical trial within 30 days of the screening visit; 
10. Anticipated inability to attend scheduled study visits;  
11. Patients who in the judgment of the Investigator may be unreliable or 
uncooperative with the evaluation procedure outlined in this protocol; 
12. Patients with a history of prior pharmacogenomic testing; 
13. Any change in psychotropic medication (including change in dosage) between 
screening and baseline; 
14. Patients currently receiving electroconvulsive therapy (ECT), deep brain 
stimulation (DBS) or transcranial magnetic stimulation (TMS) treatments, or 
currently scheduled to receive maintenance treatments of ECT, DBS, or TMS 
during the course of the study; 
15. Patients who self-report to be pregnant or lactating; 
16. Patients with a history of gastric bypass surgery 
7.0 INTERVENTIONS 
7.1 Interventions 
 GeneSight Psychotropic (GEN) 
Patients randomized to the GEN group will have buccal swabs of their cheeks taken by 
the clinician and mailed to the Assurex Health Ltd. (ARx) pharmacogenomics lab in a 

                                                                                                                        
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secure envelope labeled with a unique identifier to ensure accuracy and validity.  Once 
received, the pharmacogenomic laboratory will analyze the sample and determine the 
patient’s genotypes and corresponding phenotypes for each of the genes tested on the 
GEN panel.  These phenotypes will provide a clear picture of how functional each gene 
is with respect to drug metabolism (for CYP450 genes) and/or drug response (for 
neurotransmitter transporter and receptor genes).   
After laboratory testing is complete and phenotypes are assigned, GEN technology 
categorizes the green, yellow, or red status of each drug and which footnote(s) will 
accompany each drug.  This is accomplished by integrating the genetic data with the 
pharmacology for each medication on the GEN panel (see Appendix I), and incorporating 
data gleaned from Health Canada-approved labels and published literature.  
Within three days of sample receipt at the laboratory, results are returned via the 
GeneSight clinician portal to the treating clinicians in the form of an interpretive report that 
categorizes medications into three independent bins titled “Use as Directed”, the Green 
Bin, “Use With Caution”, the Yellow Bin, and “Use with Increased Caution And With More 
Frequent Monitoring”, the Red Bin.  Medications in the Green Bin are least likely to be 
affected by genetic polymorphisms identified in the tested individual.  Medications in the 
Yellow Bin are at risk for gene-drug interactions that may necessitate alternative dosing 
or medication selection.  Medications in the Red Bin are at higher risk for a gene-drug 
interaction that may necessitate alternative dosing or medication selection.  Guided by 
these results, the treating physician may decide to modify a participant’s psychotropic 
medication selection, dose, dose regimen and/or number of medications. 
 Enhanced GeneSight Psychotropic (E-GEN) 
All procedures for patients randomized to the E-GEN arm will be the same as for patients 
randomized to the GEN arm except that for E-GEN, the pharmacogenomic laboratory will 
also analyze each patient’s genotypes and corresponding phenotypes for the 7 CAMH 
markers for AIWG.  The treating clinicians will receive an interpretive report that reflects 
all of the E-GEN genes.   
Guided by the results from E-GEN, the treating physician may decide to modify a 
participant’s psychotropic medication, in terms of type of medication, dose, dose regimen 
and/or number of medications. 
 Treatment as Usual (TAU) 
Patients randomized to the TAU arm will also have their DNA collected and a 
pharmacogenomics-based interpretive report will be generated using GEN testing.  
However, this report will not be shared with the treating clinicians until up to 28 days prior 
to the completion at 12 months of the study at which point the report will be provided to 

                                                                                                                        
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the participant by the treating clinician.  Therefore, patients in this arm will receive clinical 
treatment as usual, without the use or knowledge of genotyping results by their treating 
clinicians. 
7.2 Modifications 
At any time point, clinicians can modify a participant’s medication based on their clinical 
judgment.  Any switch or change in medications will be recorded on the CRF accordingly. 
Women of childbearing age are advised to use a method of birth control during the course 
of the study. If they intend to get pregnant during the course of the study, then they should 
advise their primary care physician and/or psychiatrist to ensure that the 
pharmacotherapy being prescribed can be assessed for safety in pregnancy. 
7.3 Concomitant Care 
During the study, patients will be allowed to use concomitant medications at the 
Investigators’ discretion. The dose and dose regimen of concomitant medications will be 
recorded on the CRFs. 
8.0 OUTCOMES  
8.1 Primary Outcome Measure 
 17-Item Hamilton Depression Scale (HAM-D17) 
The primary outcome will be the mean change in the HAM-D17 score between baseline 
and 8 weeks.  The HAM-D17 assesses mood, feelings of guilt, insomnia, agitation or 
retardation, anxiety, weight loss and somatic symptoms(14-16) (see Appendix II).  
8.2 Secondary Outcome Measures 
 Clinical Outcome Measures of MDD Symptoms and Medication Side Effects 
i. 
16-Item Self-Report Quick Inventory of Depressive Symptomatology (QIDS-SR16) 
The QIDS-SR16 is a patient reported measure designed to assess the severity of 
depressive symptoms(17, 18).  The scale assesses the nine DSM-IV criteria 
symptom domains for major depression: sad mood, concentration, self-outlook, 
suicidal ideation, involvement, energy/fatigability, sleep disturbance (4 items: 
initial, 
middle, 
late 
insomnia, 
and 
hypersomnia), 
appetite/weight 
increase/decrease (4 items), and psychomotor agitation/retardation (2 items) (see 
Appendix III). 
ii. 
9-Item Patient Health Questionnaire (PHQ-9) 

                                                                                                                        
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The PHQ-9 consists of nine questions, rated 0–3 according to the increased 
frequency of difficulty experienced in each area covered. Scores are self-rated by 
patients, with a possible range of 0–27, are summed and can then be interpreted 
as follows: no depression (0), minimal (1–5), mild (6–9), moderate (10–14), 
moderately severe (15–19), or severe (>20) depression (see Appendix IV). 
iii. 
Generalized Anxiety Disorder 7-Item (GAD-7) Scale 
The GAD-7 is a brief measure of symptoms of anxiety, based on diagnostic criteria 
described in DSM-IV(19). It consists of seven questions and is calculated by 
assigning scores of 0, 1, 2, and 3, to the response categories of “not at all”, “several 
days”, “more than half the days,” and “nearly every day,” respectively (see 
Appendix V). 
iv. 
Clinical Global Impression (CGI) 
The Clinical Global Impression Scale (CGI) is a brief clinician-rated instrument that 
consists of three different global measures (see Appendix VI):  
 Severity of illness: overall assessment of the current severity of the patient's 
symptoms (CGI-S);  
 Global improvement: overall comparison of the patient's baseline condition with 
his current state (CGI-I);  
 Efficacy index: overall comparison of the patient's baseline condition to a ratio 
of current therapeutic benefit and severity of side effects (CGI-EI). 
v. 
Changes to initial prescribing based on availability of pharmacogenomic data 
The influence of pharmacogenomic data on a physician’s initial prescription for 
both GEN and E-GEN will be evaluated by documenting the psychotropic 
medication prescribed before the availability of the pharmacogenomics data.  This 
will be compared to changes (if any) to the physician’s prescription when 
pharmacogenomics data becomes available.   
vi. 
Response Rates to Psychotropic Medication 
A responder is defined as a participant who satisfies the following criteria: 
 HAM-D17: a 50% change from baseline in total scale score; 
vii. 
Remission Rates 
A remitter is defined as a participant who satisfies the following criteria: 
 HAM-D17 ≤ 7; 
viii. 
Time to response or remission 

                                                                                                                        
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Time to response or remission of depressive symptoms over 8 weeks and 12 
weeks, and maintenance of response/remission up to 12 months as measured by 
the HAM-D17. 
ix. 
Udvalg for Kliniske Undersogeler (UKU) Side Effect Rating Scale 
The UKU side effect rating scale, which is available as a patient self-rated 
assessment, is a comprehensive scale designed to assess the side effects in 
patients treated with psychotropic medications (see Appendix VII). 
x. 
Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER) 
The FIBSER is a reliable and valid self-rated global measure of these three 
domains of side effects (frequency, intensity, and burden) in a population receiving 
treatment for depression (see Appendix VIII). 
xi. 
Weight Gain 
The side effect of AIWG will be evaluated by measuring study patients’ weight and 
waist-to-hip ratio at baseline and at every visit. 
xii. 
Medication Compliance 
Medication compliance or adherence will be evaluated using two validated 
questionnaires, the Morisky 8-item medication adherence scale and the Brief 
Adherence Rating Scale (BARS), as well as prescription filling frequency between 
study visits to evaluate persistence and to validate costs of medication use(20-24).   
 Clinical Outcome Measures of Health Related Quality of Life 
i. 
EuroQol (EQ-5D-5L) 
The EQ-5D is designed for self-completion and assesses health across five 
domains: 
mobility, 
self-care, 
usual 
activities, 
pain/discomfort, 
and 
anxiety/depression. In the 5-level versions of EQ-5D (EQ-5D-5L), each domain 
has five levels of severity; health ‘today’ is assessed (See Appendix IX). The EQ 
Visual Analogue scale (EQ VAS) is a single 20 cm vertical visual analogue scale, 
with a range of 0 to 100, where 0 is the worst and 100 is the best imaginable health. 
ii. 
Short Form (36) Health Survey (SF-36)  
The SF-36 is a generic health status profile measure, consisting of eight 
dimensions: physical functioning, role-physical, bodily pain, general health, vitality, 
social functioning, role-emotional and mental health(25).  These eight dimensions 
produced separate scores by taking a simple summation of individual item 
responses, and applying a linear transformation, in order to place them onto a 0 to 
100 scale (see Appendix X).  

                                                                                                                        
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 Economic Outcome Measures 
i. 
Healthcare Resource Utilization and Productivity Losses 
Resource utilization and productivity losses incurred by GEN, E-GEN and TAU 
patients will be captured throughout the study.  Information to be collected 
includes: physician visits (general practitioners, psychiatric, and other specialties), 
hospital utilization (psychiatric and non-psychiatric), emergency department visits 
(psychiatric and non-psychiatric institutions), medication use (antidepressants, 
antipsychotics, and other medications), and laboratory tests.  For patients 
employed at the beginning of the study, productivity losses will be captured.  This 
includes absenteeism (the number of days out of work) and number of disability 
claims (both short and long term) filed.  
Participants will complete an economic questionnaire to capture healthcare 
resource utilization and productivity losses. Since participants may differ in terms 
of their baseline resource utilization, the questionnaire will be administered at 
baseline to document historical resource utilization, over the 3 months preceding, 
the intervention. Appropriate unit costs for Ontario will then be assigned to the data 
collected in order to provide an indication of the relative costs associated with 
receiving GEN, E-GEN and TAU.   
Data on patient health care resource utilization will also be collected by the Institute 
for Clinical Evaluative Sciences (ICES). ICES is a research institute in Ontario that 
is a secure and confidential repository for publicly-funded administrative health 
data. Data on physician visits, hospitalizations, emergency department visits, and 
drug costs covered by the Ontario Drug Benefits (ODB) program are available for 
all Ontario residents and costs are accessible at the individual level through use of 
an encrypted health card number. Primary data collected from the study will also 
be linked via health card number, encrypted at ICES, to the ICES administrative 
databases for patients who had consented to data linkage. As before, costs 
associated with health services utilization will be based on utilization described 
above, with standard unit costs for Ontario as a multiplier.  
The costs information captured (from economic questionnaire and ICES) will be 
used to conduct the economic evaluation of introducing GEN and E-GEN as 
compared to TAU.  A trial-based economic evaluation will be conducted by 
comparing 1-year costs and outcomes associated with the different treatment 
arms. Since various treatments are compared in this analysis, an efficiency frontier 
will be created by ranking all options by costs and effectiveness.  Any treatments 
dominated by other treatments having lower costs and higher efficacy will be 
eliminated from the analyses. In addition, any strategy dominated through the 

                                                                                                                        
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principle of extended dominance will also be eliminated. Extended dominance 
rules out any intervention that is dominated by a linear combination of other 
strategies which produce greater benefit at a lower cost.  The remaining options 
will form the efficiency frontier and incremental cost-effectiveness ratios will be 
calculated by comparing each option to the next one. Sampling uncertainty will be 
dealt by bootstrapping costs and effects. The short term results of the trials will be 
extrapolated to a longer time horizon (e.g. 5 years) by developing a decision 
analytic model (e.g. Markov model).  A probabilistic analysis will be conducted to 
account for the uncertainty in the model parameters and modeling assumptions 
will be tested using sensitivity analyses.  For both the trial-based and modeling-
based economic evaluations, a cost-effectiveness plane will be used to present 
the results and show the efficiency frontier. Multiple cost-effectiveness 
acceptability curves will be used for presenting the results of the trial- and model-
based economic evaluations. 
 Other Outcome Measures 
i. 
Pharmacogenetics in Psychiatry Follow-Up Questionnaire (PIP-FQ) 
The PIPFQ is a questionnaire (developed by CAMH) to evaluate physicians’ 
attitude and experience to pharmacogenetics testing (see Appendix XI).  
Information is solicited from the physician on the processing of the physician’s last 
referral, and for the entire study at 12 months. 
9.0 STUDY TIME SCHEDULE 
Study evaluation measures will be obtained over a 1-year period and will consist of seven 
scheduled assessments, not including screening and enrollment (Figure 1).  Assessment 
visits will occur at baseline, 4 weeks, 8 weeks, 12 weeks, 6 months, 9 months and 12 
months following randomization.  The short-term follow-up visits will occur up to and 
including 12 weeks with the assessment of the primary outcome at 8 weeks, followed by 
long-term study visits at 6, 9 and 12 months.  The following outlines the evaluations to be 
completed at each of the visits. 

                                                                                                                        
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Figure 1. Study Time Schedule 
 
 
 
 
Screening/  
Randomization
Baseline
Time Point
- t1             
(Visit 1)
t0           
(Visit 2)
Week 4 
(Visit 3)
Week 8 
(Visit 4)
Week 12 
(Visit 5)
Month 6 
(Visit 6)
Month 9 
(Visit 7)
Month 12 
(Visit 8)
ENROLLMENT
Informed consent
x
Eligibility screening
x
Randomization
x
Eligibility baseline
x
INTERVENTIONS
GeneSight Psychotropic (GEN)
Enhanced GeneSight Psychotropic (E-GEN)
Treatment as usual (TAU)
ASSESSMENTS
Buccal swab for genotyping
x
Vital signs
x
Mini International Neuropsychiatric Interview (MINI) for Axis 1
x
Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition, Text Revision (DSM-IV-TR) criteria for MDD
x
DSM-IV-TR criteria for current substance use disorder
x
Phlebotomy for laboratory panel
x
Biobank sample
x
Urine sample for drug screen and laboratory panel
x
16-item Clinician Quick Inventory of Depressive 
Symptomatology (QIDS-C16) 
x
16-item Self Report Quick Inventory of Depressive 
Symptomatology (QIDS-SR16) 
x
x
x
x
x
x
x
Changes to initial prescribing based on availability of 
pharmacogenomic data
x
x
Medical history and psychiatric history
x
x
Psychotropic medication history (current and past) and 
response
x
x
Past (within one month) concomitant non-psychotropic 
medications
x
x
Current concomitant non-psychotropic medications
x
x
x
x
x
x
x
x
x
Demographics, Employment, Insurance
x
Smoking status and amounts
x
x
x
x
x
x
Height
x
Weight and waist-to-hip ratio
x
x
x
x
x
x
Adverse events (AEs)
x
x
x
x
x
x
Pharmacogenetics in Psychiatry Follow-Up Questionnaire 
(PIPFQ)
x
x
17-item Hamilton Depression Rating Scale (HAM-D17)
x
x
x
x
x
x
x
x
9-item Patient Health Questionnaire (PHQ-9)
x
x
x
x
x
x
Generalized Anxiety Disorder 7-Item (GAD-7) Scale
x
x
x
x
x
x
Clinical Global Impression of Severity (CGI-S)
x
x
x
x
Clinical Global Impression of Improvement (CGI-I)
x
x
x
Clinical Global Impression Efficacy Index (CGI-EI)
x
x
x
Udvalg for Kliniske Undersogeler (UKU) side effect rating 
scale
x
x
x
x
x
x
Frequency, Intensity, and Burden of Side Effects Ratings 
(FIBSER)
x
x
x
x
x
x
EuroQol (EQ-5D-5L)
x
x
x
x
x
x
Short Form (36) Health Survey (SF-36)
x
x
x
x
x
Healthcare resource utilization and productivity losses
x
x
x
x
x
x
x
x
Current psychotropic medication and psychotropic 
medication trials since last visit
x
x
x
x
x
x
x
x
Medication adjustments (including dose changes, switching, 
augmentation and discontinuation)
x
x
x
x
x
x
Medication compliance: Morisky 8-item and BARS
x
x
x
x
x
x
x
STUDY PERIOD
Short-term visits
Long-term follow-up
Early 
Termination 
Visit (ET)

                                                                                                                        
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9.1 Screening Visit (Visit 1) 
Following informed consent, all consecutive patients at the recruiting centres will be 
screened against the inclusion/exclusion criteria outlined previously.  A screening log will 
be maintained at each of the centres.   
Potential patients will be provided with a study information sheet describing the purpose 
and design of the study as well as the nature of the interventions and time commitment. 
Written informed consent will be obtained prior to performing any study procedures. In 
addition, the Investigator or designee must explain to each patient, before enrollment into 
the study, that for evaluation of study results, the patient’s protected health information 
obtained during the study may be shared with the study Sponsor, regulatory agencies, 
and the Research Ethics Board (REB)/Independent Ethics Committee (IEC). It is the 
Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per applicable regulations. 
The following will be performed at the screening visit: 
 Administer informed consent; 
 Perform buccal swabs for GEN and E-GEN tests; 
 Buccal swabs will be obtained and sent to AssureRx laboratory.  A buccal swab 
sample will be analyzed for the pharmacogenomic testing immediately upon 
receipt at AssureRx.  The unanalyzed buccal swabs and associated isolated DNA 
will be stored at AssureRx laboratory (see Appendix XVI, Part a). The sample will 
be de-identified, but matched to clinical data with the unique patient identification 
number. 
 Record patient age; 
 Review and record medical and psychiatric history; 
 Review and record past and current psychotropic medications including response; 
 Review and record past (within three months) and current concomitant non-
psychotropic medications; 
 Obtain vital signs; 
o Vital signs, including temperature, heart rate, sitting systolic and diastolic 
arterial blood pressure and radial artery pulse rate. Vital signs should be 
measured with the patient seated and rested at least 5 minutes. 
 Perform psychiatric assessments including:  
o Mini International Neuropsychiatric Interview (MINI) for Axis 1 
The MINI was developed as a short and efficient diagnostic interview to be used 
in clinical as well as research settings(26) (see Appendix XII).  It follows DSM-
IV and the ICD-10 criteria for psychiatric disorders, screening for 17 Axis I 
disorders, with brief suicidality and antisocial personality modules. The Axis I 
disorders included in the MINI were selected based upon the 12-month 

                                                                                                                        
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prevalence reported in the Epidemiologic Catchment Area Study(27) and the 
National Comorbidity Survey(28). The MINI has been validated in the U.S. and 
Europe and administration time ranges from approximately 15-20 minutes for 
individuals with few positively endorsed symptoms to 20-30 minutes for 
individuals who meet criteria for current diagnoses. 
o DSM-IV-TR criteria for MDD 
The diagnostic criteria for MDD, single or recurrent are shown in Appendix XIII. 
o DSM-IV-TR criteria for current substance use disorder 
The diagnostic criteria for current substance use disorder are shown in 
Appendix XIV. 
o 16-Item Clinician Quick Inventory of Depressive Symptomatology (QIDS-C16) 
The QIDS-C16 has been extensively evaluated in patients with MDD(17, 
18).Similar to the QIDS-SR16, the scale assesses the nine DSM-IV criteria 
symptom domains for major depression: sad mood, concentration, self-outlook, 
suicidal ideation, involvement, energy/fatigability, sleep disturbance (4 items: 
initial, 
middle, 
late 
insomnia, 
and 
hypersomnia), 
appetite/weight 
increase/decrease (4 items), and psychomotor agitation/retardation (2 items) 
(see Appendix XV).  
o QIDS-SR16 
 Collect blood for safety laboratories (hematology, and serum biochemistry).  
Blood samples will be collected for the following clinical laboratory tests: 
o Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) and platelet count. 
o Serum chemistry: sodium, chloride, potassium, bicarbonate, glucose, total 
bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
creatinine, triglycerides, cholesterol, HDL, and LDL. 
o Any abnormal laboratory value must be assessed, with written notation, by the 
Investigator. If an abnormal laboratory value is clinically significant, the 
Investigator must immediately contact the medical monitor to discuss the 
patient’s continued eligibility in the trial.  
 Collect blood for de-identified DNA and RNA pharmacogenomic research biobank; 
o An additional aliquot of blood will be collected and stored for future 
pharmacogenomic research at the CAMH laboratories (see Appendix XVI, Part 
b). The sample will be de-identified, but matched to clinical data with the unique 
patient identification number. 
 Collect urine sample for drug screen; 
o Urine samples will be collected for drug screening (barbiturates, cannabinoids, 
cocaine, and opiates). 

                                                                                                                        
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o Any abnormal blood laboratory value must be assessed, with written notation, 
by the Investigator. If an abnormal laboratory value is clinically significant, the 
Investigator must immediately contact the medical monitor to discuss the 
patient’s continued eligibility in the trial.  
 Collect information on physician’s prescription (including any changes) to patient’s 
psychotropic medication based on information available at this visit; 
 Collect information on history of prior pharmacogenomics testing; 
 Collect information on current or recent (30 days) enrollment in other studies; 
 Evaluate patient against the inclusion/exclusion criteria. 
After signing an informed consent form (ICF), the patient has 2 weeks to be evaluated for 
enrollment in the study.  Although the Screening Visit window is 2 weeks prior to 
enrollment, it is preferable that the participant be assessed at least 3 days prior to 
enrollment since the genotype results and GeneSight report typically take 2 or 3 days to 
be issued after receipt of buccal swabs. 
 
The Investigator should contact the medical monitor, as clinically necessary, if the 
rescheduled visit will extend the screening beyond 2 weeks. 
 
Patients’ psychotropic medication should not be modified (in terms of type and dosage) 
during the screening period (i.e. between the Screening and Baseline visits), except for 
treatment with benzodiazepines.  
 
Each patient will be assigned a unique patient identifier (UPI). At the Screening Visit, each 
patient will be assigned a screening number upon signing the ICF. All screening numbers 
will be assigned by the site in strict numerical sequence and no numbers will be skipped 
or omitted (e.g., each patient will be assigned to the lowest screening number available). 
The UPI will be on all case report form (CRF) pages.  
 
If at the end of the screening period the participant is found to be ineligible as per the 
inclusion/exclusion criteria, then the participant will become a Screen Failure and is exited 
from the study. The UPI will not be reused. If the participant is eligible at the end of the 
screening period, then the participant will be enrolled and randomized. If the participant 
is found to be ineligible as per the inclusion/exclusion criteria at baseline, then the subject 
will become a Randomization Failure. 

                                                                                                                        
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9.2 Enrollment and Randomization  
Patients who meet all the inclusion/exclusion criteria will be enrolled in the study with a 
1:1:1 randomization allocation to one of three groups: GEN, E-GEN, or TAU.  
Investigators will be then given the results of the GEN test for the participants randomized 
to GEN, and of the E-GEN test for the participants randomized to E-GEN.  Investigators 
will use the report to support their treatment decision based on this information.  However, 
raters and participants will be blinded.   
9.3 Baseline Visit (Visit 2) 
Within 14 days of Screening Visit, the baseline assessment visit for the study will be 
completed.   
Prior to any change or adjustment in antidepressant medication, the following will be 
evaluated and recorded: 
 Psychiatric or quality of life evaluations: 
o QIDS-SR16  
o HAM-D17 (Central rater) 
o CGI-S (Treating clinician) 
o PHQ-9 
o GAD-7 
o EQ-5D-5L 
o SF-36 
 Patient demographics;   
Patients’ date of birth, age, gender, ethnicity, height (without shoes), annual income, 
highest education, and health insurance coverage will be recorded. 
 Medical and psychiatric history; 
 The complete medical history will be conducted with a review of all body systems and 
the patient's past and concurrent illnesses, drug use (including urine drug test), alcohol 
use, drug allergies, and family medical history.   Particular attention will be paid to past 
psychiatric history, in particular age at first depressive episode, frequency of relapses, 
response to previous treatments, and other concomitant psychiatric disorders and 
their treatment. 

                                                                                                                        
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 Past 
and 
current 
psychotropic 
medications 
including 
response; 
The generic name of the psychotropic medication, the doses used, start and end date, 
as well as response to treatment (efficacy and AEs) will be recorded. 
 Past (within three months) and current concomitant non-psychotropic medications 
(including 
nicotine 
replacement 
and 
smoking 
cessation 
medications); 
The generic name of the medication, the doses used, start and end date will be 
recorded. 
 Smoking status and amounts 
 Weight (without shoes, with clothes) and waist-to-hip ratio 
 Changes (if any) to physician’s prescription of psychotropic medication based on 
availability of pharmacogenomics data in GEN and E-GEN 
 PIP-FQ 
 UKU side effect rating scale 
 FIBSER 
 AEs  
 Medication adjustments (including dose changes, switching, augmentation and 
discontinuation) 
 Health resource utilization and productivity losses 
9.4 Week 4 Visit (Visit 3) 
Participants will return to the study centre at the end of Week 4 ± 4 days (Visit 3) of the 
study.  The following will be evaluated and recorded: 
 Psychiatric or quality of life evaluations: 
o QIDS-SR16 
o HAM-D17 (Central rater) 
o PHQ-9 
o GAD-7 
o Morisky scale (med compliance) 
o BARS scale (med compliance) 
 Smoking status and amounts 
 Weight and waist-to-hip ratio 

                                                                                                                        
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 Current psychotropic medication and psychotropic medication trials since last visit 
 Current concomitant non-psychotropic medications (including nicotine replacement 
and smoking cessation medications) 
 UKU side effect rating scale 
 FIBSER 
 AEs 
 Medication adjustments (including dose changes, switching, augmentation and 
discontinuation) 
 Health resource utilization and productivity losses 
9.5 Week 8 Visit (Visit 4) 
Participants will return to the study center at the end of Week 8 ± 4 days (Visit 4) of the 
study.  The evaluation at this visit will be the same as that completed at Week 4 (Visit 3). 
9.6 Week 12 Visit (Visit 5) 
Participants will return to the study center at the end of Week 12 ± 4 days (Visit 5) of the 
study.  In addition to the evaluations conducted at Week 8, the following will also be 
assessed: 
 Psychiatric or quality of life evaluations: 
o CGI-S (Treating clinician) 
o CGI-I (Treating clinician) 
o CGI-EI (Treating clinician) 
o EQ-5D-5L  
o SF-36 
o Morisky scale (med compliance) 
o BARS scale (med compliance) 
9.7 Long-Term Follow-Up - Months 6, 9 and 12 Visits (Visits 6, 7 and 8) 
The long-term follow-up visits at the end of months 6 and 9 ± 14 days (Visits 6 and 7) will 
be completed by telephone.  The following will be evaluated at these visits: 
 Psychiatric or quality of life evaluations: 
o HAM-D17  

                                                                                                                        
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o EQ-5D-5L 
o SF-36 (only at month 6) 
o Morisky scale (med compliance) 
o BARS scale (med compliance) 
 Current psychotropic medication and psychotropic medication trials since last visit 
 Current concomitant non-psychotropic medications (including nicotine replacement 
and smoking cessation medications) 
 Health resource utilization and productivity losses 
 Documentation of disclosure of GEN report to participant at month 12 visit 
 Participants will return to the study center at the end of month 12 (Visit 8) ± 21 days 
of the study.  The following will be evaluated at this visit: 
 Psychiatric or quality of life evaluations: 
o QIDS-SR16  
o HAM-D17 (Central rater) 
o CGI-S (Treating clinician) 
o CGI-I (Treating clinician) 
o CGI-EI (Treating clinician) 
o PHQ-9 
o GAD-7 
o EQ-5D-5L 
o SF-36 
 Smoking status and amounts 
 Weight and waist-to-hip ratio 
 Current psychotropic medication and psychotropic medication trials since last visit 
 Current concomitant non-psychotropic medications (including nicotine replacement 
and smoking cessation medications) 
 UKU side effect rating scale 
 FIBSER 
 AEs 

                                                                                                                        
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 Medication adjustments (including dose changes, switching, augmentation and 
discontinuation) 
 Medication compliance 
 Health resource utilization and productivity losses 
9.8 Early Termination (ET) Visit 
If ET occurs, the participant should attend an in-clinic visit as soon as possible to complete 
ET procedures that will consist of all procedures scheduled for Week 12 (refer to section 
on Week 12 Visit (Visit 5)). 
9.9 Unscheduled Visits 
Investigators may see participants for clinical management of their depression at any 
time.  There is no “Unscheduled Visit” in this study but the visit should be recorded in the 
patient chart as per standard clinical practice. 
10.0 SAMPLE SIZE 
The study will recruit participants from approximately 8-12 sites stratified into 2 clusters.  
CAMH will constitute one study site and a single stratified cluster. The remaining sites will 
constitute the second cluster. The sample size required for this study was calculated 
using effect size estimates drawn from a previous study conducted by Hall-Flavin et 
al.(11)  Assuming an effect size of 0.30 in HAM-D17 score favoring the treatment group, 
intra class coefficient between clusters of 20%, statistical power of 90%, an alpha level of 
0.05, and an expected 16.7% rate of premature discontinuation (based on ongoing 
studies and experience with the intervention) by Week 8 (primary endpoint), a total of 570 
participants (i.e., 190 per treatment arm) are required to detect the same effect in this 
study.  Sample size calculations were determined using SAS (SAS Institute, Inc., Version 
9.3, Cary, NC). 
11.0 RECRUITMENT 
Approximately 8-12 study centres will participate in this study in order to enroll the number 
of participants outlined above.  It is estimated that this study will take approximately 36 
months to complete.  This timeline is based on a 24-month participant recruitment 
timeframe and also assuming the collection of 8-week and 1-year follow-up data to 
examine the consequences of the GEN and E-GEN on patient outcomes, healthcare 
resource utilization and productivity losses.  Changes to these assumptions will require 

                                                                                                                        
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an adjustment of stated timelines.  Participant recruitment plan details can be found in the 
study Project Management Plan. 
12.0 METHODS: ASSIGNMENT OF INTERVENTIONS 
12.1 Allocation 
 Sequence Generation 
Participants will be randomly assigned to one of the three treatments arms with a 1:1:1 
allocation as per a computer generated randomization schedule stratified by site using 
permuted blocks of random sizes.  The block sizes will not be disclosed, to ensure 
concealment. 
13.0 BLINDING 
This study will be conducted under double-blind conditions so that neither the patient nor 
study staff members involved in patient assessments will know whether the patient is 
receiving GEN, E-GEN, or TAU.  Only the treating clinician at the study site and AssureRx 
will have knowledge of the intervention arm assigned to the patient.   
All assessments will be administered by the site, with the exception of the primary 
outcome measure (HAM-D17), which will be conducted by 1-2 trained central rater(s) not 
involved in the clinical care of the individual and blinded to the treatment allocation.  The 
rater will be trained and inter-rater reliability will be determined through rater scoring of 
the HAM-D17 while viewing a DVD-recording of a standardized patient interview.  
At randomization, the treating clinician will receive the results of the GEN test for patients 
allocated to GEN and the results of the E-GEN test for patients allocated to the E-GEN, 
and may decide to change the participant’s treatment based on the results of the test. 
The treating clinician will therefore not be blinded to treatment allocation.  AssureRx will 
also not be blinded to treatment allocation in order to release the appropriate report (either 
GEN, E-GEN or no report (TAU)) to the treating clinician and to provide follow-up support 
to the treating clinician on report interpretation.  However, both treating clinician and 
AssureRx will be blinded to trial data. 

                                                                                                                        
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14.0 METHODS: DATA COLLECTION, MANAGEMENT, AND ANALYSIS 
14.1 Data Collection Methods 
Data will be collected using a validated electronic data capture (EDC) solution. Electronic 
case report forms (eCRFs) will be utilized for recording data from each subject meeting 
the eligibility criteria and being randomized into the study. Electronic access to the CRF 
will be available to all Investigator sites. All study staff responsible for entering data into 
the eCRF system will be trained prior to the start-up of the study. A personal log-in will be 
provided for all responsible personnel to allow for an audit trail relating to the study data 
to be maintained. 
All evaluations performed shall be entered in a timely manner into the eCRF by a member 
of the site staff delegated responsibility for this specific task by the Principal Investigator 
of the clinical site. It is the responsibility of the Investigator to ensure that the eCRFs are 
properly completed. The data in the eCRFs should be consistent with the relevant source 
documents. The Investigator will sign the designated signature fields of the eCRF to 
confirm that the information on each screen is accurate and complete. All data must be 
stored in an unidentifiable form treated with strict confidentiality in accordance with 
applicable data-protection regulations. 
Captured data will be monitored electronically and source data verification (SDV) will take 
place at the site where all information will be verified against the individual patient records. 
Any inconsistencies will be presented as queries; either as automatically generated 
queries if raised by the logical data checks of the eCRF system, or by manually generated 
queries if raised by the data validation checks or the SDV performed by the data manager 
(DM) or the CRA respectively. Queries shall be resolved in a timely manner by a trained 
member of the site staff. 
 Participant Retention 
Once a patient is enrolled, the study site will make every reasonable effort to follow the 
patient for the entire study period. If a patient fails to return for scheduled visits, a 
documented effort must be made to determine the reason.  If the patient cannot be 
reached by telephone after two attempts, a certified letter should be sent to the patient 
requesting contact with the Investigator. This information should be recorded in the study 
records. 

                                                                                                                        
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 Participant Withdrawal 
Early Withdrawal Criteria 
Participants will only be withdrawn from the study for the following scenarios:  
1. Participant withdraws consent for participation for any reason; 
2. Participant is deemed lost to follow-up after all exhaustive measures have been 
taken to contact and locate the participant or the subject moves away; 
3. A protocol violation occurs, whereby the respective Ethics Board or Sponsor 
requires that a participant is withdrawn from the study; 
4. Participant dies; 
5. A serious or life-threatening Reportable Event occurred or adverse event that 
prevents further participation; 
6. Investigator judges that for any reason continuation of the study is inappropriate 
for the patient, this includes non-compliance with study procedures. 
7. Participant permanently loses capacity to consent to research during participation 
in the study. 
The reason for early withdrawal from the study will be documented, and all relevant CRFs 
will be completed. The Sponsor must be notified of all patient withdrawals as soon as 
possible. 
If participant is withdrawn early, all efforts should be made to bring the patient in for an 
Early Termination (ET) visit as soon as possible (see section on Early Termination (ET) 
Visit). 
If permission to use protected health information is withdrawn, it is the Investigator’s 
responsibility to obtain a written request, to ensure that no further data will be collected 
from the patient and the patient will be removed from the study. 
  Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for any reason at any time and 
to discontinue participation by an individual Investigator or site for poor enrollment or 
noncompliance. 

                                                                                                                        
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15.0 DATA MANAGEMENT 
Data Management will be conducted by the sponsor appointed CRO.  
Data will be transmitted electronically into the web based EDC system. Data will be coded 
according to pre-specified dictionaries and in accordance with the CRO Standard 
Operating Procedures (SOP). The handling of data, including data quality control, will 
comply with all applicable regulatory guidelines. 
A detailed description of the analyses to be performed will be provided in the statistical 
analysis plan (SAP). 
15.1 Inspection of Records 
Monitors, auditors, and other authorized representatives of the Sponsor, the REB/IEC 
approving this study, Health Canada, other domestic government agencies, and other 
foreign regulatory agencies will be granted direct access to the study patient’s original 
medical and study records for verification of the data and/or clinical trial procedures. 
Access to this information will be permitted to representatives of the aforementioned 
organizations to the extent permitted by law. The investigator(s) will be expected to 
cooperate with such a visit and to provide assistance and documentation (including all 
study documentation, and patient source data) as requested. Wherever possible de-
identified data will be provided to protect participant privacy. 
15.2 Retention of Records 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. These 
records include, but are not limited to, the identity of all participating patients, all original 
signed informed consent documents, copies of all CRFs, safety reporting forms, source 
documents, and detailed records of treatment disposition, and adequate documentation 
of relevant correspondence.  
The Investigator shall retain study records for a period of 25 years or according to the 
institutional policy following the date a marketing application is approved for GEN or E-
GEN for the indication for which it is being investigated; or, if no application is to be filed, 
or if the application is not approved for such indication, for a period of 25 years or 
according to the institutional policy after all investigations with the test are discontinued 
and Health Canada is notified.  

                                                                                                                        
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If the Investigator moves, withdraws from an investigation, or retires, the responsibility for 
maintaining the records may be transferred to another person (e.g., Sponsor, other 
investigator) who will accept the responsibility. Notice of this transfer, must be made to 
the Sponsor. 
16.0 STATISTICAL METHODS 
16.1 Clinical Analysis 
Hall-Flavin et al.(11) experienced significant participant attrition during the course of their 
investigation.  Post hoc analyses using intention-to-treat (ITT) analyses, however, 
revealed little differences between the observed data and inputed data (e.g., last 
observation carried forward (LOCF) and estimation/maximization (EM) algorithm 
imputation). Two analyses will be completed with the study data: under the principle of 
intention-to-treat  all randomized individuals will be analysed, i.e., the  Full Analysis Set 
(FES),  and a per protocol (PP) analysis for randomized participants where adherence to 
the protocol and visits was followed. Therefore, to account for participant attrition in the 
current study, ITT with multiple imputation with LOCF and EM algorithm imputation will 
be employed to account for missing data, assuming the data are missing completely at 
random. To assess the potential impact that the multiple imputation has on the final 
estimates, an EM algorithm imputation (interative mean imputation) will be used as 
exploratory sensitivity analysis.  
 Descriptive Statistics    
Continuous variables will be summarized with standard descriptive statistics including 
means, standard deviations, medians, and ranges. Categorical variables will be 
summarized with frequencies and percentages. Ninety-five percent confidence intervals 
will be provided for descriptive statistics, as warranted. 
 Diagnostics 
Prior to formal statistical analyses, diagnostics will be conducted to determine appropriate 
statistical models. The independence assumption of ANOVA will be tested by examining 
the correlation between error terms for each dependent variable across levels of the 
indicator variable. To this end, the Durbin-Watson test statistic will be used to determine 
if the independence assumption was upheld. Values approaching 2.0 from the left or right 
were considered to be an indication of independence. The normality assumption will be 
tested by plotting residuals against the normal probability plot and by deriving the Shapiro-
Wilk (S-W) test statistic. The dependent variable will formally be considered to be non-

                                                                                                                        
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normally distributed if the p-value for the S-W test was < 0.05. Homogeneity of variance 
will be tested by employing the statistic derived by Brown and Forsythe. If the associated 
p-value for the test statistic is < 0.05, then the dependent variable will be assumed to 
exhibit non-constant variance. If a given dependent variable did not meet the above 
mentioned assumptions (e.g., clustering due to study site), generalized estimating 
equations (GEEs) will be employed to account for the lack of independence between 
outcomes using an autoregressive correlation structure and identity link function. 
 Continuous Outcomes    
If the HAM-D17 scores from baseline to end of Week 8 of the study meet the assumptions 
of ANOVA modeling, repeated-measure (i.e., mixed) ANOVA models will be used to 
model the outcome scores over time. This model accounts for a between-group and 
within-individual effect, which allows for the examination of average differences between 
groups while also accounting for the correlation between participant scores between each 
measurement. If the HAM-D17 scores do not meet standard ANOVA assumptions, GEEs 
will be used to model repeated measurements of outcome scores over time, as these 
models are more robust to departures from the standard assumptions and also allow the 
investigator to specify the correlation structure of the repeated measurements. Mean 
symptom improvement for all continuous measures (i.e., depression scales) will be 
calculated using the standard formula ( 
𝑦2−𝑦1
𝑦1 )*-100, where y1 is the baseline score for 
each participant for each rating scale and y2 is the 8 week score for each participant for 
each rating scale.  
Two hypotheses related to the primary objectives will be tested, where μ1 is the mean 
HAM-D17 % symptom improvement in the GEN group, μ2 is the mean HAM-D17 % 
symptom improvement in the E-GEN group and μ3 is the mean HAM-D17 % symptom 
improvement in the TAU group.  
Primary objective (1): 
H0: 
μ1 = μ2 = μ3 
Ha: 
μ1 = μ2 > μ3 
Primary objective (2): 
H0: 
μ1 = μ2 = μ3 
Ha: 
μ1 < μ2 > μ3 

                                                                                                                        
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For all continuous measures, a responder will be defined as a participant with 50% 
change from baseline in total scale score. Remitters at week 8 and at week 12 will be 
defined as HAM-D17 ≤7 in each treatment group. Differential time to response/remission 
of depressive symptoms over 8 and 12 weeks will be plotted using Kaplan-Meier curves 
and Cox proportional hazard models will test the null hypothesis of no difference in time 
to response/remission between groups. 
 Categorical Outcomes    
Categorical outcomes (i.e., remission, response) will be analyzed with 2x2 contingency 
tables, logistic regression, or loglinear models, where appropriate. Relative risk of 
response and remission will be determined between each treatment arm (i.e., GEN and 
E-GEN) using the TAU group as the referent group and the standard formula  
𝑎/(𝑎+𝑏)
𝑐/(𝑐+𝑑), 
where a is the number of responders/remitters in each GEN or E-GEN group, b is the 
number of non-responders/non-remitters in the GEN or E-GEN group, c is the number of 
responders/remitters in the TAU group, and d is the number of non-responders/non-
remitters in the TAU group. Standard chi-square tests will be used to determine if the 
relative risk of response/remission is statistically significant between groups. If expected 
frequencies are too small for asymptotic assumptions, Fisher’s exact tests will be 
employed to test for differences in categorical outcomes between groups. Ninety-five 
percent confidence intervals will be calculated and provided for the relative risk of 
response/remission between groups.  
 Within-Group and Between-Group Composite Phenotype Analyses    
A three-level indicator variable (eg., green, yellow, and red categories) will be created 
using a proprietary algorithm which combines the phenotypes ascribed to each gene for 
each participant and drug metabolism information for each of the GeneSight panel drugs.  
This is done to reduce the dimensionality inherent to such data by generating a single 
composite phenotype for each participant. The final indicator variable will be labeled 
‘composite_phenotype,’ with the first level scored as ‘green,’ (e.g., use medication(s) as 
directed) the second level scored as ‘yellow,’ (e.g., use medication(s) with caution) and 
the third level scored as ‘red’ (e.g., use medication(s) with caution and frequent 
monitoring).  If parametric assumptions are upheld, 1-way independent ANOVA models 
will employed to test the independent ability of the composite phenotype variable to 
predict each respective continuous outcome (i.e., percent improvement from baseline for 
HAMD-17) between study groups. If parametric (i.e., standard) assumptions are not met, 
GEEs will be employed test the independent ability of the composite phenotype variable 
to predict each respective continuous outcome. Three tests will be conducted for each 

                                                                                                                        
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continuous outcome: an overall ANOVA test and two planned contrasts involving the 
comparison of the first level (i.e., green category) to that of the third (i.e., red category), 
and the first two levels (i.e., green and yellow categories) of the composite phenotype 
variable to that of the third level. To account for multiple testing, the Sidak correction will 
be employed using the formula 1 – (1-α)1/n where n is the number of independent tests 
and α is the nominal level (i.e., 05) of statistical significance 
 Decision Rule    
An overall alpha-level of 0.05 will be used to determine statistical significance and all 
statistical tests will be two-sided. All data will be analyzed using SAS (SAS Institute, Inc., 
Version 9.3, Cary, NC). 
16.2 Economic Analysis 
The economic analysis will include a detailed micro costing evaluation.  Using the data 
collected from the trial and ICES as the foundation, this will be based upon both a ‘within 
trial’ analysis, as well as modeling and decision analytic techniques to estimate the long-
term cost-effectiveness comparing the use of GEN, E-GEN and TAU.  Analyses will be 
carried out from the perspective of the Canadian healthcare payer, but a societal 
perspective will also be considered (e.g. productivity costs due to absenteeism and 
disability). 
17.0 METHODS: MONITORING 
17.1 Data Monitoring 
Monitoring visits will be conducted during the study at regular intervals. The monitoring 
visits will be conducted to ensure protocol adherence, quality of data, accuracy of entries 
in the eCRF, compliance with regulatory requirements and continued adequacy of the 
investigational site and its facilities.  
Incorrect or missing entries in the CRFs will be queried and will be corrected 
appropriately.  
All clinical data will undergo quality control checks prior to clinical database lock. Edit 
checks will then be performed for appropriate databases as a validation routine using 
SAS ® to check for missing data, data inconsistencies, data ranges, etc. Each eCRF is 
reviewed and signed by the principal investigator (PI). 

                                                                                                                        
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17.2 Harms 
The GEN and E-GEN is not a drug intervention, and this study is an evaluation of the 
impact of the results report on a patient’s major depression.   
Contact information for questions regarding GEN and E-GEN for this study is as follows: 
Medical Information 
Office Phone: 855-891-9415 
Fax: 513-492-7946 
Email: MedInfo@assurexhealth.com 
 Definitions 
Adverse event (AE) means any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug related. An AE can therefore be any 
unfavorable and unintended sign (including a clinically significant abnormal laboratory 
finding), symptom or disease temporally associated with the use of an investigational 
product, whether or not considered related to the investigational product.  Any worsening 
of a preexisting condition (i.e., any clinically significant adverse change in frequency 
and/or intensity) which is temporally associated with the use of the investigational product 
is also an AE. 
 Evaluating, Recording and Reporting of Adverse Events 
At each visit all AEs that are observed, elicited by the Investigator, or reported by the 
participant, will be recorded in the appropriate section of the AE CRF and evaluated by 
the Investigator. 
Minimum information required for each AE includes type of event, duration (start and end 
dates), severity, seriousness, causality to study drug, action taken, and outcome. 
Severity of AEs will be graded by the Investigator using the following criteria as guidelines: 
1. Mild: Nuisance, barely noticeable. 
2. Moderate: Uncomfortable, troublesome symptoms not significantly interfering with 
daily activities or sleep. 
3. Severe: Symptoms significantly interfere with daily activities or sleep. 

                                                                                                                        
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The relationship of the AE to the study drug should be specified by the Investigator, using 
the following definitions: 
1. Not Related: Concomitant illness, accident or event with no reasonable association 
with study drug. 
2. Unlikely Related: The event has little or no temporal sequence from administration 
of the study drug, and/or a more likely alternative etiology exists. 
3. Possibly Related: The event follows a reasonable temporal sequence from 
administration of study drug but which could also be explained by concurrent 
disease or other factors or medications 
4. Probably Related: The event follows a reasonable temporal sequence from 
administration of study drug, unlikely to be attributed to concurrent disease or other 
factors or medications. A clinically reasonable response may be observed if the 
study drug is withdrawn or dose reduced. 
5. Definitely Related: The event follows a reasonable temporal sequence from 
administration of study drug and is definitive pharmacologically; cannot to be 
attributed to concurrent disease or other factors or medications. A clinically 
reasonable response should be observed if the study drug is withdrawn or dose 
reduced. 
If discernible at the time of completing an AE CRF, a specific disease or syndrome rather 
than individual associated signs and symptoms should be recorded on the AE CRF.  
However, if an observed or reported sign, symptom, or clinically significant laboratory 
anomaly is not considered by the Investigator to be a component of a specific disease or 
syndrome, then it should be recorded as a separate AE on the AE CRF (clinically 
significant laboratory abnormalities are those that are identified as such by the 
Investigator and/or those that require intervention). 
Investigators should follow the Health Canada process for reporting untoward events of 
marketed medications by submitting a Canada Vigilance Adverse Reaction Reporting 
Form to MedEffect for a Serious Adverse Event (SAE): 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose 
(including overdose) that meets one or more of the following criteria: 
 Is fatal, as a direct outcome of the AE 

                                                                                                                        
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 Is life threatening 
This serious criterion applies if the participant, in the view of the Investigator, is at 
substantial risk of dying from the AE as it occurs.  It does not apply if an AE 
hypothetically might have caused death if it were more severe. 
 Requires or prolongs inpatient hospitalization 
This serious criterion applies if the reported AE necessitates an inpatient admission 
(in Canada) or a minimum 24-hour inpatient hospitalization (outside Canada) or, if in 
the opinion of the Investigator, prolongs an existing hospitalization.  A hospitalization 
for an elective procedure, a routinely scheduled treatment or a social admission is not 
an SAE. 
 Results in permanent or significant disability/incapacity 
This serious criterion applies if the “disability” caused by the reported AE results in a 
substantial disruption of the participant’s ability to carry out normal life functions. 
 Results in a congenital anomaly/birth defect 
This serious criterion applies if a participant exposed to the investigational product 
gives birth to a child with congenital anomaly or birth defect. 
 Requires intervention to prevent damage/permanent impairment 
This serious criterion applies if the reported AE necessitates a medical or surgical 
intervention to preclude permanent impairment of a body function, or prevent 
permanent damage to a body structure.  An elective procedure is not an SAE. 
Important medical events that do not meet any of the criteria above may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
18.0 AUDITING 
Audits and inspections may be carried out by the Sponsor’s quality assurance department 
or designee, Health Canada, or other regulatory authorities to whom information on this 
study has been submitted. All documents pertinent to the study must be made available 
for such inspection. Informed consent of patients participating in this study must include 
the authorization to access these source documents. 

                                                                                                                        
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19.0 ETHICS AND DISSEMINATION 
The study will be conducted in compliance with the Canadian Tri-Council Policy 
Statement: Ethical Conduct for Research Involving Humans (TCPS2), Health Canada 
(HC) Food and Drug Regulations, and the International Conference on Harmonization 
(ICH) Guidelines (E6) for Good Clinical Practice and Personal Health Information 
Protection Act privacy legislation and all applicable Canadian laws and regulations, as 
well as any local laws and regulations and all applicable guidelines. 
20.0 RESEARCH ETHICS APPROVAL 
Investigators will agree that the study will be conducted according to the principles of the 
ICH E6 Guideline on GCP and the ethical principles that have their origins in the World 
Medical Association Declaration of Helsinki. The Investigator will conduct all aspects of 
this study in accordance with all national, state, and local laws or regulations.  
This trial was designed and organised taking all ethical considerations into account. The 
protocol and the Informed Consent Form will be approved by the relevant competent 
authorities (CA) and Research Ethics Boards and possibly other public bodies according 
to local requirements before commencement.  
If a protocol amendment is necessary, this will be prepared and submitted to the central 
or local REB. If the amendment is considered to be substantial, it will be submitted to the 
CA, REB and possibly other public bodies according to local requirements for review and 
approval. The protocol amendment will not be implemented before approvals are 
obtained, if required. Minor amendments which do not affect the safety or physical or 
mental integrity of the clinical trial participants or the scientific value of the trial (i.e. non-
substantial amendments) do not need to be submitted to CA. 
Written Informed Consent 
The informed consent process must take place before any study-specific procedures are 
initiated. Signed and dated written informed consent must be obtained from each patient 
prior to screening.  All ICFs must be approved for use by the Sponsor and receive 
approval/favorable opinion from an REB prior to their use. If the consent form requires 
revision (e.g., due to a protocol amendment or significant new safety information), it is the 
Investigator’s responsibility to ensure that the amended informed consent is reviewed and 
approved by the Sponsor or designee prior to submission to the governing REB and that 
it is read, signed and dated by all patients subsequently enrolled in the study as well as 
those currently enrolled in the study if directed by the REB. 

                                                                                                                        
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21.0 CONSENT OR ASSENT 
Site study coordinators will introduce the trial to potential participants identified as meeting 
the study criteria.  The potential participants will be given written and verbal information 
about the trial (including potential risks and benefits) and will be able to have an informed 
discussion with the site study coordinator.  They are then encouraged to discuss potential 
participation with others, as they deem appropriate and given at least 24 hours to consider 
whether or not to provide informed consent.  All participants will be told that they are free 
to withdraw from the trial at any time, without giving a reason and without any effect on 
their current or future healthcare. 
22.0 CONFIDENTIALITY 
All records identifying the patient will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.  Patient names 
and other patient-level data will be collected and stored in locked file cabinets in areas 
with limited access at the study site.  All reports, data collection, process and 
administrative forms will contain a patient unique identifier number in order to maintain 
patient confidentiality.  All records that contain names or other personal identifiers, such 
as locator forms and informed consent forms, will be stored separately from study records 
identified by patient unique identifier number.  Study findings stored on a computer will 
be protected in accordance with local data protection laws. 
Monitors, auditors, and other authorized representatives of the Sponsor, the REB/IEC 
approving this study, Health Canada, other domestic government agencies, and other 
foreign regulatory agencies will be granted direct access to the study patient's original 
medical and study records for verification of the data and/or clinical trial procedures. 
Access to this information will be permitted to representatives of the aforementioned 
organizations to the extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the GEN or E-GEN may ultimately be marketed, but 
the patients' identities will not be disclosed in these documents. 
23.0 DECLARATION OF INTERESTS 
23.1 Financial Disclosure 
Sites will ensure that prior to their participation in the study, the Site Investigators and any 
sub-investigators complete and return to the Sponsor the Financial Disclosure Statement 

                                                                                                                        
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form provided by the Sponsor. The Site Investigator and any sub-investigators will 
promptly notify the site and Sponsor of any required revision to their Financial Disclosure 
Statement during the term of this Agreement and for 1 year following completion of the 
study. Upon Sponsor's written request following completion of the study, the Site 
Investigator and any sub-investigators will provide an updated Financial Disclosure 
Statement form to the Sponsor. 
24.0 DISSEMINATION POLICY 
The objectives, the content and the results of the present clinical study as well as all 
further information must be handled as strictly confidential. All data and results are the 
exclusive property of Sponsor and CAMH.  
After completion of the study or when the study data are adequate (in the Sponsor's and 
CAMH’s reasonable judgment), the Investigator(s) may prepare the data derived from the 
Study for publication or presentation at a medical-scientific meeting. Such data will be 
submitted to the Sponsor, CAMH and MaRS EXCITE for review and comment prior to 
publication. In order to ensure that the Sponsor, CAMH, and MaRS EXCITE will be able 
to make comments and suggestions where pertinent, material for public dissemination 
will be submitted to the Sponsor, CAMH and MaRS EXCITE for review at least 60 days 
prior to submission for publication, public dissemination, or review by a publication 
committee. In the event that Sponsor and CAMH coordinate a multi-centre publication, 
the participation of the Investigator(s) or other representative of the Investigator(s)s as a 
named author shall be determined in accordance with Sponsor and CAMH publication 
policy and International Committee of Medical Journal Editors (ICMJE) standards for 
authorship. 
The Investigator agrees that all reasonable comments made by the Sponsor, CAMH, 
MaRS EXCITE in relation to a proposed publication by the Investigator will be 
incorporated by the Investigator into the manuscript.  
During the period for review of a proposed publication, the Sponsor and CAMH shall be 
entitled to delay publication in order to protect proprietary information. No publication of 
any material related to the study may be published without the prior written consent of the 
Sponsor and CAMH. 
Except as requested by law the Sponsor, CAMH, MaRS EXCITE or the Investigator will 
not reveal the results of the study to a third party without a mutual agreement about the 
analysis and interpretation of the data. 

                                                                                                                        
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25.0 REFERENCES 
1. 
Hasin DS, Goodwin RD, Stinson FS, Grant BF. Epidemiology of major depressive 
disorder: results from the National Epidemiologic Survey on Alcoholism and Related 
Conditions. Arch Gen Psychiatry. 2005;62(10):1097-106. 
2. 
Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional 
burden of disease and risk factors, 2001: systematic analysis of population health 
data. Lancet. 2006;367(9524):1747-57. 
3. 
Patten SB, Kennedy SH, Lam RW, O'Donovan C, Filteau MJ, Parikh SV, et al. 
Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines 
for the management of major depressive disorder in adults. I. Classification, burden 
and principles of management. J Affect Disord. 2009;117 Suppl 1:S5-14. 
4. 
Mueller TI, Leon AC, Keller MB, Solomon DA, Endicott J, Coryell W, et al. 
Recurrence after recovery from major depressive disorder during 15 years of 
observational follow-up. Am J Psychiatry. 1999;156(7):1000-6. 
5. 
Solomon DA, Keller MB, Leon AC, Mueller TI, Shea MT, Warshaw M, et al. 
Recovery from major depression. A 10-year prospective follow-up across multiple 
episodes. Arch Gen Psychiatry. 1997;54(11):1001-6. 
6. 
aan het RM, Mathew SJ, Charney DS. Neurobiological mechanisms in major 
depressive disorder. CMAJ. 2009;180(3):305-13. 
7. 
Connolly KR, Thase ME. Emerging drugs for major depressive disorder. Expert Opin 
Emerg Drugs. 2012;17(1):105-26. 
8. 
Kennedy SH, Rizvi SJ. Emerging drugs for major depressive disorder. Expert Opin 
Emerg Drugs. 2009;14(3):439-53. 
9. 
Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D Project 
results: a comprehensive review of findings. Curr Psychiatry Rep. 2007;9(6):449-
59. 
10. Hall-Flavin DK, Winner JG, Allen JD, Jordan JJ, Nesheim RS, Snyder KA, et al. 
Using a pharmacogenomic algorithm to guide the treatment of depression. Transl 
Psychiatry. 2012;2:e172. 
11. Hall-Flavin DK, Winner JG, Allen JD, Carhart JM, Proctor B, Snyder KA, et al. Utility 
of integrated pharmacogenomic testing to support the treatment of major depressive 
disorder in a psychiatric 
outpatient 
setting. Pharmacogenet Genomics. 
2013;23(10):535-48. 
12. Winner JG, Carhart JM, Altar CA, Allen JD, Dechairo BM. A prospective, 
randomized, double-blind study assessing the clinical impact of integrated 
pharmacogenomic 
testing 
for 
major 
depressive 
disorder. 
Discov 
Med. 
2013;16(89):219-27. 
13. Winner J, Allen JD, Altar CA, Spahic-Mihajlovic A. Psychiatric pharmacogenomics 
predicts health resource utilization of outpatients with anxiety and depression. 
Transl Psychiatry. 2013;3:e242. 
14. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 
1960;23:56-62. 

                                                                                                                        
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15. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc 
Clin Psychol. 1967;6(4):278-96. 
16. Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. 
Arch Gen Psychiatry. 1988;45(8):742-7. 
17. Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, et al. The 16-
Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-
C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic 
major depression. Biol Psychiatry. 2003;54(5):573-83. 
18. Trivedi MH, Rush AJ, Ibrahim HM, Carmody TJ, Biggs MM, Suppes T, et al. The 
Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) and Self-Report 
(IDS-SR), and the Quick Inventory of Depressive Symptomatology, Clinician Rating 
(QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders: 
a psychometric evaluation. Psychol Med. 2004;34(1):73-82. 
19. Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing 
generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092-7. 
20. Cramer JA, Roy A, Burrell A, Fairchild CJ, Fuldeore MJ, Ollendorf DA, et al. 
Medication compliance and persistence: terminology and definitions. Value Health. 
2008;11(1):44-7. 
21. Byerly MJ, Nakonezny PA, Rush AJ. The Brief Adherence Rating Scale (BARS) 
validated against electronic monitoring in assessing the antipsychotic medication 
adherence of outpatients with schizophrenia and schizoaffective disorder. Schizophr 
Res. 2008;100(1-3):60-9. 
22. Muntner P, Joyce C, Holt E, He J, Morisky D, Webber LS, et al. Defining the minimal 
detectable change in scores on the eight-item Morisky Medication Adherence Scale. 
Ann Pharmacother. 2011;45(5):569-75. 
23. Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-
reported measure of medication adherence. Med Care. 1986;24(1):67-74. 
24. Morisky DE, Ang A, Krousel-Wood M, Ward HJ. Predictive validity of a medication 
adherence measure in an outpatient setting. J Clin Hypertens (Greenwich). 
2008;10(5):348-54. 
25. Ware JE, Snow KK, Kolinski M, Gandeck B. SF-36 health survey manual and 
interpretation guide. 1993 1993. 
26. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The 
Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and 
validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J 
Clin Psychiatry. 1998;59 Suppl 20:22-33. 
27. Regier DA, Myers JK, Kramer M, Robins LN, Blazer DG, Hough RL, et al. The NIMH 
Epidemiologic Catchment Area program. Historical context, major objectives, and 
study population characteristics. Arch Gen Psychiatry. 1984;41(10):934-41. 
28. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al. 
Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United 
States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 
1994;51(1):8-19. 

                                                                                                                        
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26.0 APPENDICES 
APPENDIX I: List of Psychotropic Medications Included in the Canadian version of 
GeneSight Psychotropic (GEN) and Enhanced GeneSight Psychotropic (E-GEN) 
Antidepressants 
Amitriptyline 
Bupropion 
Citalopram 
Clomipramine 
Desipramine 
Desvenlafaxine 
Doxepin 
Duloxetine 
Escitalopram 
Fluoxetine 
Fluvoxamine 
Imipramine 
Mirtazapine 
Nortriptyline 
Paroxetine 
Selegiline 
Sertraline 
Trazodone 
Venlafaxine 
 
Antipsychotics 
Aripiprazole 
Asenapine 
Chlorpromazine 
Clozapine 
Fluphenazine 
Haloperidol 
Lurasidone 
Olanzapine 
Paliperidone 
Perphenazine 
Quetiapine 
Risperidone 
Thiothixene 
Ziprasidone 
 
 
 

                                                                                                                        
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APPENDIX II: 17-Item Hamilton Depression Rating Scale (HAM-D17) 
1. 
DEPRESSED MOOD (Sadness, hopeless, helpless, worthless) 
0 
Absent 
1 
These feeling states indicated only on questioning 
2 
These feeling states spontaneously reported verbally 
3 
Communicates feeling states nonverbally—i.e., through facial expression, posture, 
voice, and tendency to weep 
4 
Patient reports VIRTUALLY ONLY these feeling states in his/her spontaneous verbal 
and non-verbal communication 
 
2.  
FEELINGS OF GUILT 
0 
Absent 
1 
Self-reproach, feels he/she has let people down 
2 
Ideas of guilt or rumination over past errors or sinful deeds 
3 
Present illness is a punishment; delusions of guilt 
4 
Hears accusatory or denunciatory voices and/or experiences threatening visual 
hallucinations 
 
3. 
SUICIDE 
0 
Absent 
1 
Feels life is not worth living 
2 
Wishes he/she were dead or any thoughts of possible death to self 
3 
Suicidal ideas or gestures 
4 
Attempts at suicide (any serious attempt rates 4) 
 
4. 
INSOMNIA, EARLY 
0 
No difficulty falling asleep 
1 
Complains of occasional difficulty falling asleep—i.e., more than ½ hour 
2 
Complains of nightly difficulty falling asleep  
 
5. 
INSOMNIA, MIDDLE 
0 
No difficulty 
1 
Patient complains of being restless and disturbed during the night 
2 
Waking during the night—any getting out of bed rates 2 (except for purposes of 
voiding) 
 
6. 
INSOMNIA, LATE 
0 
No difficulty 
1 
Waking in early hours of the morning but goes back to sleep 
2 
Unable to fall asleep again if he/she gets out of bed 
 
7. 
WORK AND ACTIVITIES 
0 
No difficulty 

                                                                                                                        
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1 
Thoughts and feelings of incapacity, fatigue or weakness related to activities, work, 
or hobbies 
2 
Loss of interest in activity, hobbies, or work—either directly reported by patient, or 
indirect in listlessness, indecision, and vacillation (feels he/she has to push self to 
work or activities) 
3 
Decrease in actual time spent in activities or decrease in productivity. In hospital, 
rate 3 if patient does not spend at least three hours a day in activities (hospital job or 
hobbies) exclusive of ward chores 
4 
Stopped working because of present illness. In hospital, rate 4 if patient engages in 
no activities except ward chores or if patient fails to perform ward chores unassisted 
 
8. 
RETARDATION (Slowness of thought and speech, impaired ability to concentrate, 
decreased motor activity) 
0 
Normal speech and thought 
1 
Slight retardation at interview 
2 
Obvious retardation at interview 
3 
Interview difficult 
4 
Complete stupor 
 
9. 
AGITATION 
0 
None 
1 
Fidgetiness 
2 
Playing with hands, hair, etc. 
3 
Moving about, can't sit still 
4 
Hand-wringing, nail biting, hair-pulling, biting of lips 
 
10. ANXIETY PSYCHIC 
0 
No difficulty 
1 
Participantive tension and irritability 
2 
Worrying about minor matters 
3 
Apprehensive attitude apparent in face or speech 
4 
Fears expressed without questioning 
 
11. ANXIETY (SOMATIC) 
Physiological concomitants of anxiety such as: Gastrointestinal—dry mouth, wind, 
indigestion, diarrhea, cramps, belching; Cardiovascular—palpitations, headaches; 
Respiratory—hyperventilation, sighing; Urinary frequency; Sweating 
0 
Absent 
1 
Mild 
2 
Moderate  
3 
Severe 
4 
Incapacitating 
 
12. SOMATIC SYMPTOMS, GASTROINTESTINAL 
0 
None 

                                                                                                                        
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1 
Loss of appetite but eating without staff encouragement; heavy feelings in abdomen 
2 
Difficulty eating without staff urging; requests or requires laxatives or medication for 
bowels or medication for GI symptoms 
13. SOMATIC SYMPTOMS, GENERAL 
0 
None 
1 
Heaviness in limbs, back, or head; backaches, headache, muscle aches; loss of 
energy and fatigability 
2 
Any clear-cut symptom rates 2 
 
14. GENITAL SYMPTOMS 
Symptoms such as: loss of libido, menstrual disturbances 
0 
Absent 
1 
Mild 
2 
Severe 
 
15. HYPOCHONDRIASIS 
0 
Not present 
1 
Self-absorption (bodily) 
2 
Preoccupation with health 
3 
Frequent complaints, requests for help, etc. 
4 
Hypochondrial delusions 
 
16. LOSS OF WEIGHT 
0 
No weight loss  
1 
Probable weight loss associated with present illness 
2 
Definite (according to patient) weight loss 
3 
Not assessed 
 
17. INSIGHT 
0 
Acknowledges being depressed and ill 
1 
Acknowledges illness but attributes cause to bad food, climate, overwork, virus, need 
for rest, etc. 
2 
Denies being ill at all 
 
 

                                                                                                                        
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APPENDIX III: 16-Item Self-Report Quick Inventory of Depression Symptomology 
(QIDS-SR16) 
 
 

                                                                                                                        
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APPENDIX IV: 9-Item Patient Health Questionnaire (PHQ-9) 
Over the last 2 weeks, how often have you been bothered by any of the following 
problems? 
(circle one number on each line) 
 
 
Not at all 
Several 
days 
More 
than 
half 
the 
days 
Nearly 
everyday 
 
 
 
 
 
1. Little interest or pleasure in 
doing things 
0 
1 
2 
3 
 
 
 
 
 
2. Feeling down, depressed, or 
hopeless 
0 
1 
2 
3 
 
 
 
 
 
3. Trouble falling or staying 
asleep, or sleeping too much 
0 
1 
2 
3 
 
 
 
 
 
4. Feeling tired or having little 
energy 
0 
1 
2 
3 
 
 
 
 
 
5. Poor appetite or overeating 
0 
1 
2 
3 
 
 
 
 
 
6. Feeling bad about yourself, or 
that you are a failure, or have 
let yourself or your family 
down 
0 
1 
2 
3 
 
 
 
 
 
7. Trouble concentrating on 
things, such as reading the 
newspaper or watching 
television 
0 
1 
2 
3 
 
 
 
 
 
8. Moving or speaking so slowly 
that other people could have 
noticed. Or the opposite – 
being so fidgety or restless 
that you have been moving 
around a lot more than usual 
0 
1 
2 
3 
 
 
 
 
 

                                                                                                                        
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9. Thoughts that you would be 
better off dead, or of hurting 
yourself in some way 
0 
1 
2 
3 
APPENDIX V: Generalized Anxiety Disorder 7-Item (GAD-7) Scale 
 
 

                                                                                                                        
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APPENDIX VI: Clinical Global Impression (CGI) 
 
 
1. SEVERITY OF ILLNESS (CGI-S) 
 
Considering your total clinical experience with this particular population, how ill is the 
patient at this time? 
 
0 = Not assessed 
1 = Normal, not at all ill 
2 = Borderline mentally ill 
3 = Mildly ill 
 
4 = Moderately ill 
5 = Markedly ill 
6 = Severely ill 
7 = Among the most extremely ill 
patients 
 
 
2. GLOBAL IMPROVEMENT (CGI-I) 
 
Rate total improvement compared to baseline, whether or not, in your judgment, it is due 
entirely to drug treatment. 
 
0 = Not assessed 
1 = Very much improved  
2 = Much improved 
3 = Minimally Improved   
 
4 = No change 
5 = Minimally worse 
6 = Much worse 
7 = Very much worse 
 
3. EFFICACY INDEX (CGI-EI) 
 
Rate this item on the basis of DRUG EFFECT ONLY Select the terms which best describe 
the degrees of therapeutic effect and side effects and record the number in the box where 
the two items intersect. 
 
EXAMPLE: Therapeutic effect is rated as "Moderate" and side effects are judged "Do not 
significantly interfere with patient's functioning."  Record 06 
 
THERAPEUTIC EFFECT 
SIDE EFFECTS 
None 
Does not 
significant
ly 
interfere 
with 
patient's 
Significan
tly 
interfere 
with 
patient's 
functionin
g 
Outweigh 
therapeuti
c effect 

                                                                                                                        
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functionin
g 
MARKED 
– 
Vast 
improvement. 
Complete 
or 
nearly 
complete 
remission of all symptoms 
01 
02 
03 
04 
MODERATE – Decided 
improvement. 
Partial 
remission of symptoms 
05 
06 
07 
08 
MINIMAL 
– 
Slight 
improvement 
which 
doesn't alter status of care 
of patient 
09 
10 
11 
12 
UNCHANGED 
OR 
WORSE 
13 
14 
15 
16 
 
 
 
 

                                                                                                                        
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APPENDIX VII: Udvalg for Kliniske Undersogeler (UKU) Side Effect Rating Scale 
 

                                                                                                                        
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APPENDIX VIII: Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER) 
 
 

                                                                                                                        
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APPENDIX IX: EuroQol (EQ-5D-5L) 
 

                                                                                                                        
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APPENDIX X: Short Form (36) Health Survey (SF-36) 

                                                                                                                        
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APPENDIX XI: Pharmacogenetics in Psychiatry Follow-Up Questionnaire (PIP-FQ) 
 
Pharmacogenetics in Psychiatry Follow-up Questionnaire v2.0 
“Genetics of antipsychotic drug metabolism, response and side effects” 
 
Participant ID 
 
Prescription Change Questionnaire:  To be completed at baseline & every 
prescription change 
 
Regarding the GeneSight or Enhanced Genesight provided to you for this 
participant related to your treatment decision today. 
 
1) Was the information provided to you been easy to understand as you made this 
treatment decision? 
 
Understood Very Well 
□ 
Mostly Understood  
□ 
Satisfactory Understanding□ 
Mostly Did Not Understand □ 
Did Not Understand At All □ 
 
2) How satisfied were you with the information provided to you for this treatment 
decision? 
 
Very Satisfied 
 
□ 
Satisfied 
 
 
□ 
Neutral 
 
 
□ 
Unsatisfied  
 
□ 
Very Unsatisfied 
 
□ 
 
3) Was the information given to you, helpful in this treatment decisions? 
 
Very Helpful  
 
□ 
Helpful 
 
 
□ 
Neutral 
 
 
□ 
Not Helpful  
 
□ 
Very Unhelpful 
 
□ 
 

                                                                                                                        
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Pharmacogenetics in Psychiatry Follow-up Questionnaire v2.0 
“Genetics of antipsychotic drug metabolism, response and side effects” 
 
Participant ID 
 
Long-term follow-up questionnaire: To be completed at 12 months or early 
termination 
 
 
Regarding the GeneSight or Enhanced Genesight provided to you for this 
participant 
 
1) Was the information provided to you easy to understand since the participant 
enrolled in the study? 
 
Understood Very Well 
□ 
Mostly Understood  
□ 
Satisfactory Understanding□ 
Mostly Did Not Understand □ 
Did Not Understand At All □ 
 
2) How satisfied were you with the information provided to you since the participant 
enrolled in the study 
 
Very Satisfied 
 
□ 
Satisfied 
 
 
□ 
Neutral 
 
 
□ 
Unsatisfied  
 
□ 
Very Unsatisfied 
 
□ 
 
3) Was the information given to you, helpful in this treatment decisions since the 
participant enrolled in the study? 
 
Very Helpful  
 
□ 
Helpful 
 
 
□ 
Neutral 
 
 
□ 
Not Helpful  
 
□ 
Very Unhelpful 
 
□ 
 
 
 
 
 

                                                                                                                        
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If the participant was cared for without the availability of the pharmacogenetic 
information (treatment as usual), for this participant 
 
1) Would the pharmacogenetic information provided by GeneSight have been helpful 
for treatment decisions since the participant enrolled in the study? 
 
Very Helpful  
 
□ 
Helpful 
 
 
□ 
Neutral 
 
 
□ 
Not Helpful  
 
□ 
Very Unhelpful 
 
□ 

                                                                                                                        
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APPENDIX XII: Mini International Neuropsychiatric Interview (MINI) for Axis 1 

                                                                                                                        
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APPENDIX XIII: Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition, Text Revision (DSM-IV-TR) criteria for MDD 
 
 
DIAGNOSTIC CRITERIA FOR 296.2X OR 296.3X 
MAJOR DEPRESSIVE DISORDER, SINGLE OR RECURRENT 
 
A. 
The presence of one or more major depressive episodes. 
 
B. 
The major depressive episodes are not better accounted for by Schizo-
affective 
Disorder 
and 
are not 
superimposed on 
Schizophrenia, 
Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not 
Otherwise Specified (NOS). 
 
C. 
There has never been a Manic Episode, a Mixed Episode, or a Hypomanic 
Episode (Note:  This exclusion does not apply if any of the manic-like, mixed-
like, or hypomanic-like episodes are substance- or treatment-induced or are 
due to the direct physiological effects of a general medical condition). 
 
 
 

                                                                                                                        
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APPENDIX XIV: Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition, Text Revision (DSM-IV-TR) criteria for Current Substance Use Disorder 
 
Criteria for Substance Use Disorder: 
 
A pattern of substance use leading to significant impairment or distress, as manifested 
by one or more of the following:  
1. Failure to fulfill major role obligations at work, school, home such as repeated 
absences or poor work performance related to substance use; substance-
related absences, suspensions, or expulsions from school; neglect of children 
or household  
2. Frequent use of substances in situation in which it is physically hazardous (e.g., 
driving an automobile or operating a machine when impaired by substance use)  
3. Frequent legal problems (e.g. arrests, disorderly conduct) for substance abuse  
4. Continued use despite having persistent or recurrent social or interpersonal 
problems (e.g., arguments with spouse about consequences of intoxication, 
physical fights) 

                                                                                                                        
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APPENDIX XV: 16-Item Clinician Quick Inventory of Depression Symptomology 
(QIDS-C16) 
1. 
Sleep Onset Insomnia 
0 
Never takes longer than 30 minutes to fall asleep. 
1 
Takes at least 30 minutes to fall asleep, less than half the time. 
2 
Takes at least 30 minutes to fall asleep, more than half the time. 
3 
Takes more than 60 minutes to fall asleep, more than half the time. 
 
 
2. 
Mid-Nocturnal Insomnia 
0 
Does not wake up at night. 
1 
Restless, light sleep with few awakenings. 
2 
Wakes up at least once a night, but goes back to sleep easily. 
3 
Awakens more than once a night and stays awake for 20 minutes or more, more 
than half the time. 
 
 
3. 
Early Morning Insomnia 
0 
Less than half the time, awakens no more than 30 minutes before necessary. 
1 
More than half the time, awakens more than 30 minutes before need be. 
2 
Awakens at least one hour before need be, more than half the time. 
3 
Awakens at least two hours before need be, more than half the time. 
 
 
4. 
Hypersomnia 
0 
Sleeps no longer than 7-8 hours/night, without naps. 
1 
Sleeps no longer than 10 hours in a 24 hour period (include naps). 
2 
Sleeps no longer than 12 hours in a 24 hour period (include naps). 
3 
Sleeps longer than 12 hours in a 24 hour period (include naps). 
 
Enter the highest score on any 1 of the 4 sleep items (1-4 above) _____ 
 
 
5. 
Mood (Sad) 
0 
Does not feel sad. 
1 
Feels sad less than half the time. 
2 
Feels sad more than half the time. 
3 
Feels intensely sad virtually all the time. 
 
 
6. 
Appetite (Decreased) 
0 
No change from usual appetite. 
1 
Eats somewhat less often and/or lesser amounts than usual. 
2 
Eats much less than usual and only with personal effort. 
3 
Eats rarely within a 24-hour period, and only with extreme personal effort or with 
persuasion by others. 
 
 
7. 
Appetite (Increased) 

                                                                                                                        
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0 
No change from usual appetite. 
1 
More frequently feels a need to eat than usual. 
2 
Regularly eats more often and/or greater amounts than usual. 
3 
Feels driven to overeat at and between meals. 
 
 
8. 
Weight (Decrease) Within The Last Two Weeks 
0 
Has experienced no weight change. 
1 
Feels as if some slight weight loss occurred. 
2 
Has lost 2 pounds or more. 
3 
Has lost 5 pounds or more. 
 
 
9. 
Weight (Increase) Within The Last Two Weeks 
0 
Has experienced no weight change. 
1 
Feels as if some slight weight gain has occurred. 
2 
Has gained 2 pounds or more. 
3 
Has gained 5 pounds or more. 
 
 
Enter the highest score on any 1 of the 4 appetite/weight change items (6-9 above) 
_____ 
 
 
10. Concentration/Decision Making 
0 
No change in usual capacity to concentrate and decide.  
1 
Occasionally feels indecisive or notes that attention often wanders. 
2 
Most of the time struggles to focus attention or make decisions. 
3 
Cannot concentrate well enough to read or cannot make even minor decisions. 
 
 
11. Outlook (Self) 
0 
Sees self as equally worthwhile and deserving as others.  
1 
Is more self-blaming than usual. 
2 
Largely believes that he/she causes problems for others. 
3 
Ruminates over major and minor defects in self. 
 
 
12. Suicidal Ideation 
0 
Does not think of suicide or death.  
1 
Feels life is empty or is not worth living. 
2 
Thinks of suicide/death several times a week for several minutes. 
3 
Thinks of suicide/death several times a day in depth, or has made specific plans, 
or attempted suicide. 
 
 
13. Involvement 
0 
No change from usual level of interest in other people and activities.  
1 
Notices a reduction in former interests/activities. 
2 
Finds only one or two former interests remain. 
3 
Has virtually no interest in formerly pursued activities. 
 
 

                                                                                                                        
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14. Energy/Fatiguability 
0 
No change in usual level of energy.  
1 
Tires more easily than usual. 
2 
Makes significant personal effort to initiate or maintain usual daily activities. 
3 
Unable to carry out most of usual daily activities due to lack of energy. 
 
 
15. Psychomotor Slowing 
0 
Normal speed of thinking, gesturing, and speaking.  
1 
Patient notes slowed thinking, and voice modulation is reduced. 
2 
Takes several seconds to respond to most questions; reports slowed thinking. 
3 
Is largely unresponsive to most questions without strong encouragement. 
 
 
16. Psychomotor Agitation 
0 
No increased speed or disorganization in thinking or gesturing.  
1 
Fidgets, wrings hands and shifts positions often. 
2 
Describes impulse to move about and displays motor restlessness. 
3 
Unable to stay seated. Paces about with or without permission. 
 
 
Enter the highest score on either of the 2 psychomotor items (15 or 16 above) _____ 
 
 
TOTAL SCORE: _____ (RANGE 0-27) 

                                                                                                                        
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APPENDIX XVI: Biological Specimens  
a) Unanalyzed Buccal Swabs and Associated Isolated DNA 
The unanalyzed buccal swabs and associated isolated DNA will be stored at Assurex 
Health Ltd., 250 College Street, R-38, Toronto, ON. The test results (the GeneSight 
report) will be retained indefinitely. The buccal swabs will be stored for three years after 
the completion of the study. 
 If a request is made to destroy the samples on an individual basis, they will be destroyed 
by incineration. 
The laboratory director of Assurex Health Ltd. will have access to the unanalyzed buccal 
swabs and associated isolated DNA. These samples will not be shared with other outside 
organizations or laboratories, and will not be used for research purposes beyond internal 
GeneSight assay development or improvement.  There will also be no cross-border 
transfer of these samples. 
b) Blood for DNA and RNA Extraction 
Blood Collection and Transport 
Blood will be collected into tubes containing appropriate anticoagulants so that DNA and 
RNA can be isolated respectively.   
The blood-containing tubes will be transported to the Neurogenetics Lab at CAMH located 
at 250 College Street, R-50, Toronto, ON.  The transport of these tubes will be contracted 
to a commercial lab services (e.g. LifeLabs Medical Laboratory Services) and will be 
carried 
out 
according 
to 
Transportation 
of 
Dangerous 
Goods 
requirement 
(http://www.tc.gc.ca/eng/tdg/moc-infectious-type1b-471.html). 
Processing Methods 
Upon arrival, the DNA and RNA will be isolated and frozen down (at -80°C or in liquid 
nitrogen) for long term storage and future testing. 
All samples will be logged in and bar coded with a unique storage ID.   
The samples will retained for 25 years at the Neurogenetics Lab at CAMH located at 250 
College Street, R-50, Toronto, ON. Samples will be destroyed at the end of 25 years by 
incineration.  If a request is made to destroy the samples on an individual basis, they will 
also be destroyed by incineration. 
The scientists who will carry out analyses on these materials will not have access to 
personal identifiers and will not be able to link the results of these tests to personal 

                                                                                                                        
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identifier information.  No individual results will be presented in publications, reports or 
presentations. 
Participants will not be informed on an individual basis of any results from these studies. 
 
The authorized study personnel of the Neurogenetics Lab at CAMH will have access to 
the DNA and RNA biobank samples. The DNA and RNA samples collected in this study 
will be used for future research studies at CAMH.  CAMH may collaborate with other 
research organizations, including commercial companies who may want to use the 
samples and already collected medical information for studying genetic material and 
substances related to research on psychiatric disorders. Any study data that is sent 
outside of the hospital will have a number code and will not contain any identifying 
information about the study participant.  There will be no cross-border transfer of these 
samples.