An Open-Label Clinical Trial Evaluating Sensitivity to Change in Cognition Using the THINC-it Following Treatment With Vortioxetine in Major Depressive Disorder
Phase: PHASE2
Conditions: Major Depressive Disorder, Cognitive Change
Sponsor: Brain and Cognition Discovery Foundation

 
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THINC-it Sensitivity to Change  
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An Open-Label Clinical Trial Evaluating Sensitivity to Change in Cognition using the 
THINC-it following Treatment with Vortioxetine in Major Depressive Disorder  
  
  
 
 
 
 
 
 
 
Investigator Initiated Trial 
  
Dr. Roger S. McIntyre 
Executive Director, 
Brain and Cognition Discovery Foundation (BCDF) 
1100 Dundas St W Unit #6 
Mississauga, ON 
L5C 4E7 
rogermcintyre28@gmail.com 
 
 

 
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Table of Contents 
BACKGROUND .......................................................................................................................................................3-5 
HYPOTHESIS ............................................................................................................................................................. 5 
STUDY DESIGN  ........................................................................................................................................................ 6 
STUDY POPULATION .............................................................................................................................................. 6 
ELIGIBILITY CRITERIA .....................................................................................................................................6-7 
INCLUSION CRITERIA FOR MDD ............................................................................................................. 7 
EXCLUSION CRITERIA FOR MDD .........................................................................................................7-8 
INCLUSION CRITERIA FOR HC ................................................................................................................. 8 
EXCLUSION CRITERIA FOR HC .............................................................................................................8-9 
ASSESSMENTS .......................................................................................................................................................... 9 
PRIMARY ASSESSMENTS .................................................................................................................................... 9 
SECONDARY ASSESSMENTS .........................................................................................................................9-10 
RATIONALE FOR SECONDARY ASSESSMENTS ............................................................................................ 10 
PROCEDURES FOR MDD ................................................................................................................................. 11-15 
PROCEDURES FOR HC .................................................................................................................................... 16-18 
OBEJECTIVES ......................................................................................................................................................... 19 
STUDY MEDICATION: VORTIOXETINE .......................................................................................................... 19 
SIDE EFFECTS ................................................................................................................................................. 19-20 
CONTRAINDICATIONS ....................................................................................................................................... 20 
STORAGE .............................................................................................................................................................. 21 
RATIONALE FOR VORTIOXETINE ................................................................................................................... 21 
TRANSITION TO ENROLMMENT  ..................................................................................................................... 21 
TRANSITION TO STANDARD OF CARE .......................................................................................................... 21 
CONDITIONS FOR WITHDRAWAL FROM THE STUDY ............................................................................... 21 
RECRUITMENT ....................................................................................................................................................... 22 
STATISTICAL PLAN ......................................................................................................................................... 23-24 
DATA HANDLING ................................................................................................................................................... 25 
PERSONAL DATA PROTECTION ...................................................................................................................... 25 
DATA RETENTION ................................................................................................................................................. 25 
PARTICIPANT PROTECTION .............................................................................................................................. 25 
PARTICIPANT COMPENSATION ........................................................................................................................ 26 
ADVERSE EVENT ................................................................................................................................................... 26 
SERIOUS ADVERSE EVENT .......................................................................................................................... 26-27 
RECORDING OF ADVERSE EVENTS ........................................................................................................... 27-28 

 
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REPORTING OF ADVERSE AND SERIOUS ADVERSE EVENTS .................................................................. 28 
REFERENCES ..................................................................................................................................................... 30-31 
                                                                                          
BACKGROUND 
 
Major depressive disorder (MDD) is a serious public health concern worldwide with ample 
documentation demonstrating that MDD is one of the leading contributors to the global burden 
of disease and is currently the leading cause of disability worldwide [1–3]. Moreover, the 
economic burden of MDD is estimated to total $210.5 billion with approximately 50% of the 
cost being attributable to impairment in role function (e.g., workplace performance: 
presenteeism, absenteeism, and short-/long-term disability) [4,5]. Accumulating evidence 
suggests that the treatment and resolution of mood symptoms among individuals with MDD is 
insufficient in facilitating full functional recovery among individuals affected by MDD wherein a 
highly reproduced observation is that impairments in cognitive function remain persistent, 
pervasive, and progressive during the “remitted” state [6–8]. The foregoing portrait of MDD as a 
multidimensional syndrome associated with cognitive impairment and differential functional 
implications, provides the impetus for evaluating the disparate domains commonly affected in 
this clinical population using valid and reliable measures/assessments capable of providing 
actionable information in the treatment and management of patients. 
 
Hitherto, clinical awareness surrounding the pertinence of cognitive impairment in MDD and its 
impact on functional recovery has been limited with no “gold standard tool(s)” to detect 
cognitive impairments in adults with MDD. Moreover, although several screening/measurement 
instruments are currently available that have demonstrated sensitivity to cognitive impairments 
in select cognitive domains, only one tool, to the authors’ knowledge, has been developed 
primarily to evaluate the four principal cognitive domains affected in adults (18-65) with MDD 
(i.e., executive function, learning and memory, processing speed, as well as 
attention/concentration) using a composite score. 
 
The recently validated digitalized metric for assessing/screening cognitive deficits among adults 

 
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(18-65) with MDD - the THINC-integrated tool (THINC-it) - developed by the Global THINC 
Task Force, effectively demonstrated its ability to detect and measure cognitive performance. 
This tool is able to significantly differentiate between  clinical (i.e., MDD) and healthy control 
populations based on measures of both objective and subjective cognition (McIntyre et al., 
2017). The THINC-it is accessible via computers/tablets (downloadable, free of charge from the 
THINC-it website: http://thinc.progress.im/en/form/download-thinc-it-tool) and is comprised of 
the paradigms drawn from four objective measures of cognition: the Choice Reaction Time 
(CRT) (i.e., THINC-it: Spotter); the 0 N-BACK Working Memory Task (i.e., THINC-it: Symbol 
Check); the Digit Symbol Substitution Test (DSST) (i.e., THINC-it: Codebreaker); and the Trail 
Making Test- Part B (TMT-B) (i.e., THINC-it: Trails); in addition to the Perceived Deficits 
Questionnaire for Depression – 5 Item (PDQ-5-D) which assesses subjects’ subjective 
experience of cognitive deficits.  
 
The THINC-it was designed for patient self-administration in a clinical setting with no 
requirement for the tool to be delivered and/or scored by a psychometrist/psychologist. Patient 
results are made immediately available, taking approximately 30 minutes to complete. 
Instructions are conveyed in a manner that is commensurate with a grade 6 education and are not 
culture-bound. It is anticipated that the THINC-it tool will be available in the primary care and 
specialty setting in a digital format, providing actionable information for the treatment and 
management of patients with MDD. 
 
The ideal gold standard tool for screening/assessing the presence of cognitive impairment in 
adults with MDD in the clinical ecosystem should include, but not be limited to, conceptual 
coverage of the cognitive domains affected in MDD (i.e., executive function, learning and 
memory, processing speed, and attention/concentration), validity and reliability, and minimal 
cultural/practice effects. The tool would also need to be brief and allow for easy administration 
and interpretation. Additionally, in order to make effective use of the information provided by 
the screening/assessment tool, it would also need to demonstrate sensitivity to change in 
cognitive function/performance following treatment. In keeping with this view, the objective 
herein is to establish sensitivity to change using THINC-it, as there is a need for an instrument 

 
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capable of tracking the progress of individuals receiving treatment for cognition dysfunction in 
MDD. 
 
An 8-week, open-label, sensitivity to change study assessing alterations in cognitive 
function/performance, as measured by the THINC-it, in adults (18-65) with Diagnostic and 
Statistical Manual, Fifth Edition (DSM-5)-defined MDD treated with vortioxetine (10-20 mg 
flexibly dosed) is proposed. This study will be performed by the Brain and Cognition Discovery 
Foundation (BCDF). The BCDF is an organization based in Toronto, Ontario, Canada led by Dr. 
Roger S. McIntyre. Membership of the BCDF has developed and validated rating scales and 
metrics for adults with mood disorders for over 10 years. A member of the BCDF provides 
diagnoses and treatment for adults (age 18-65) with mood disorders and provides clinical care to 
the largest catchment area in Canada. The BCDF conducts clinical research according to the 
International Conference on Harmonization, Declaration of Helsinki, and Good Clinical Practice 
(GCP) guidelines. The study will be approved by the community Research Ethics Board. 
HYPOTHESIS 
 
The primary aim of this study is to establish sensitivity to change in cognitive 
function/performance using THINC-it tool in adults (18-65) with MDD treated with vortioxetine 
(10-20 mg flexibly dosed for 8 weeks). Secondary aims of the study include, but are not limited 
to: (1) determining whether early changes (i.e., Day 14; Week 2) in cognitive 
function/performance predict symptomatic improvements in mood (defined as a reduction of 
50% or more on total mood score [as measured by the Montgomery Åsberg Depression Rating 
Scale [MADRS], at endpoint; and (2) determining whether early changes (i.e., Day 14; Week 2) 
in cognitive function/performance are capable of detecting the effect of vortioxetine treatment on 
secondary outcome measures assessing functional outcomes [e.g., Sheehan Disability Scale 
(SDS), Endicott Work Productivity Scale (EWPS), and the 5-Item World Health Organization 
Wellbeing Index (WHO-5)] at endpoint.  
 

 
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STUDY DESIGN 
 
This is an 8-week, open-label, sensitivity to change study assessing alterations in cognitive 
function/performance, as measured by the THINC-it, in adults (18-65) with Diagnostic and 
Statistical Manual, Fifth Edition (DSM-5)-defined MDD treated with vortioxetine (10-20 mg 
flexibly dosed) (N=100) and (N=50) age, and sex-matched, Healthy Controls. 
 
STUDY POPULATION 
 
All patients will be enrolled at a single site, located in Toronto, Ontario, Canada.  
The total planned number of participants is:  
❏    100 individuals with DSM-5-defined MDD (18-65 years of age) 
❏    50 Healthy Controls (18-65 years of age) matched on sex, and age 
 
ELIGIBILITY CRITERIA 
 
The eligibility criteria provided below do not unnecessarily filter and/or restrict select patients. 
The overarching aim of enrollment is to include representative patients to enhance the ecological 
validity of our results with careful consideration surrounding those patients likely to evince 
impairments/deficits in the dimension/domain of cognition. The rationale for the selection of 
those individuals with at least one prior major depressive episode (MDE), is based on extant 
literature indicating that individuals with recurrent MDD are at greater risk of inter-episodic 
“non-mood” symptoms including, but not limited to, cognitive impairments (e.g., indecision, 
difficulties with memory, and inability to concentrate) [8–11].  
 
Similarly, the ideal participants would be antidepressant naïve and not receiving any 
psychotropic medication. However, the majority of patients with MDD seeking healthcare and/or 
utilizing healthcare systems have been prescribed and are taking at least one psychotropic 
medication including, but certainly not limited to, an antidepressant. Indeed, the possibility of 

 
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introducing potential confounds moderated by medication (i.e., iatrogenic artifacts) are raised 
when including patients taking antidepressants and/or other psychotropic/general medications; 
nonetheless, excluding patients currently receiving pharmacological treatment would 
significantly reduce the feasibility of a timely enrollment and would be liable to criticisms of 
non-representativeness. Therefore, participants would be evaluated by a study clinician on a 
case-by-case basis to determine the potential of pharmacodynamic interactions between the study 
intervention and the participant’s current medication regimen as well as evaluating the likelihood 
of impacting study results. 
Participants are advised to NOT use the THINC-it tool outside of the study, as to not affect study 
results during your participation. 
 
Inclusion Criteria for Participants with MDD: 
1.    The participant is able and willing to provide informed consent. 
2.    The participant is male or female 18-65 years of age. 
3.    The participant has received a current diagnosis of a major depressive episode (MDE) as 
part of MDD as per DSM-5 criteria. 
4.    The participant’s current MDE is confirmed by the Mini International Neuropsychiatric 
Interview (M.I.N.I 5.0.). 
5.    The participant is an outpatient of a psychiatric setting. 
6.    The participant has a MADRS score ≥ 20 at screening and baseline. 
7. At least one prior MDE formally diagnosed by a healthcare provider or validated by previous 
treatment (e.g., guideline-informed pharmacotherapy and/or manual-based psychotherapy). 
 
Exclusion Criteria for Participants with MDD:  
1.  Current alcohol and/or substance use disorder as confirmed by the M.I.N.I 5.0. 
2.  Presence of comorbid psychiatric disorder other than MDD that is a focus of clinical 
concern as confirmed by the M.I.N.I 5.0. 
3.  Medications approved and/or employed off-label for cognitive dysfunction                      

 
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 (e.g., psychostimulants). 
4.  Any medication for a general medical disorder that, in the opinion of the investigator, may 
affect cognitive function. 
5.  Use of benzodiazepines within 12 hours of cognitive assessments. 
6.  Consumption of alcohol within 8 hours of cognitive assessments.7   
. Inconsistent use or 
abuse of marijuana.  
8.  Physical, cognitive, or language impairments sufficient to adversely affect data derived from 
cognitive assessments. 
9.  Diagnosed  reading disability or dyslexia. 
10. Clinically significant learning disorder by history. 
11. Electroconvulsive therapy (ECT) in the last 6 months. 
12. History of moderate or severe head trauma (e.g., loss of consciousness for >1 hour), other 
neurological disorders, or unstable systemic medical diseases that in the opinion of the 
investigator are likely to affect the central nervous system. 
13.  Pregnant and/or breastfeeding. 
14.  Received investigational agents as part of a separate study within 30 days of the screening 
visit. 
15. Actively suicidal/presence of suicidal ideation or evaluated as being a suicide risk (as per 
clinical judgment using the Columbia-Suicide Severity Rating Scale). 
16. Currently receiving treatment with Monoamine Oxidase Inhibitors (MAOIs) anti-
depressants, antibiotics such as linezolid, or intravenous methylene blue. 
17.  Previous hypersensitivity reaction to vortioxetine or any components of the formulation. 
Angioedema has been reported in patients treated with vortioxetine.  
18.  Clinical worsening symptoms of depression and suicide risk – in both adult and pediatric age 
groups. 
19. Serotonin syndrome  
20. Abnormal bleeding 

 
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21. Previous history of mania/hypomania  
22. Angle closure glaucoma 
23. Hyponatremia 
24. Moderate hepatic impairment 
25. History of seizures and epilepsy  
 
Inclusion Criteria for Healthy Controls:  
1.    No current or past history of mental disorder as evidenced by the M.I.N.I. 5.0 for DSM-IV.  
2.    No first-degree relative with an established diagnosis by a healthcare provider of a mood or 
psychiatric disorder.  
3.    No unstable medical disorders.  
 
Exclusion Criteria for Healthy Controls:  
1.    Use of any medication for a general medical disorder and/or condition that, in the opinion of 
the investigator, may affect cognitive function (e.g., corticosteroids, beta-blockers). 
2.    Pregnant and/or breastfeeding.  
3.    Consumption of alcohol within 8 hours of THINC-it tool administration.  
4.    Inconsistent use or abuse of marijuana. 
 
Transition to Enrollment 
 
Patient will discontinue only antidepressants. Patients’ existing antidepressant dosage will be 
decreased gradually over a course 10-14 days. At the same time, participants will be started on 
10mg of Vortioxetine. It takes about 10-14 days for Vortioxetine to achieve steady states. For 
patients who are already taking antidepressants at the start of study, if they are abruptly 
discontinued, they are at risk for discontinuation syndrome. Therefore, both drugs will be co-
prescribed for about 10-14 days and then the index antidepressant will be discontinued. 

 
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Serotonin syndrome or other additive side effects is very unlikely to be a concern. Should the 
patient’s physician determine another optimal schedule, this will be followed instead. All MDD 
participants will be supervised by Dr. Roger McIntyre, prior to enrollment of the study. All 
partients will be monitored by a psychiatrist during the study. Furthermore, patients will have 
access to a 24-hour study number where they can contact research staff anytime, should they 
experience any adverse events. Therefore, there will always be an open line of communication 
between patients and the research staff.  
The above mentioned procedures will only be carried out once participants have consented to 
take part in the research and signed the informed consent form.  
Patients will be seen by a clinician on a biweekly basis for the antidepressant washout period. 
Clinician will be assessing the patient on adverse side effects, as well as mood.  
 
ASSESSMENTS  
 
Primary Assessment Instrument  
❏    The THINC-it comprised of: Spotter, Symbol Check, Codebreaker, Trails, and PDQ-5-D 
❏    The National Adult Reading Test (NART)  
Secondary Assessment Instruments 
❏    Montgomery Åsberg Depression Rating Scale (MADRS) 
❏    Clinical Global Impression - Severity and Improvement (CGI-S/CGI-I) 
❏    Columbia Suicide Severity Rating Scale (C-SSRS) 
❏    Pen and paper Version of Digit Symbol Substitution Test (DSST) 
❏    Pen and paper Version of the Trail Making Test B (TMT-B) 
❏    Pen and paper Version of the Perceived Deficits Questionnaire for Depression (PDQ-5-D) 

 
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❏    Endicott Workplace Productivity Scale (EWPS) 
❏    Sheehan Disability Scale (SDS) 
❏    WHO-5 Well-Being Index (WHO-5) 
❏    Snaith-Hamilton Pleasure Scale Questionnaire (SHAPS) 
❏    International Physical Activity Questionnaire (IPAQ) 
❏    Generalized Anxiety Disorder Assessment (GAD-7) 
❏    THINC-it Satisfaction Questionnaire 
❏    36-Item Short Form Survey Instrument (SF-36) 
❏    Insomnia Severity Index (ISI) 
❏    Pittsburgh Sleep Quality Index (PSQI) 
❏    Epworth Sleepiness Scale (ESS) 
❏  Effort Expenditure for Rewards Task (EEfRT) – optional  
❏  Changes in blood biomarkers (e.g. BDNF, cytokines, insulin etc.) 
 
Data will be collected using paper based scales that will be administered by the rater or self-
reported by the participant. 

 
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RATIONALE FOR SECONDARY ASSESSMENTS INSTRUMENTS 
 
A critical question for addressing cognitive impairments in adults with MDD is not whether it 
exists, but rather determining whether these observed impairments in cognitive 
function/performance influence patient-reported, clinician-measured, and/or societally defined 
health outcomes. The answer to which additional testable hypotheses can be generated is to 
further investigate to what extent cognitive impairments affect these health outcomes and what 
methods of treatment are available to mitigate these cognitive symptoms. The pen and paper 
version of the DSST and PDQ-5-D will be administered as an additional measure of validity. 
Additionally, most individuals achieving remission continue to report/exhibit ongoing functional 
difficulties as well as significant reductions in quality of life, providing impetus for their 
measurement [14,15]. Consequently, the WHO-5 will be administered to assess overall quality of 
life and wellbeing.  
 
Moreover, these deficiencies correlate with greater illness burden measures and costs, 
particularly in the workplace [16]. Likewise, it is recognized that cognitive function in adults 
with MDD represents a principal determinant of broad-based psychosocial function [15,17,18]. 
Taken together, the SDS and EWPS will be administered to allow for secondary evaluation of 
the relationship between global functional impairment/disability and health-related work 
productivity with cognitive function in adults with MDD, respectively. It has been amply 
documented that impairments in cognitive function are correlated with, but dissociable from, 
depressive symptom severity [18]. Hence, the relationship between measures of cognitive 
impairment and depressive symptoms severity will include the following secondary measures: 
the MADRS, the CGI-S/CGI-I, and the CSSRS. 
 
PROCEDURES FOR PARTICIPANTS WITH MAJOR DEPRESSIVE DISORDER  
 
Visit 1 (Screening)  
The initial visit entails the provision of detailed study information to participant and obtainment 

 
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of informed written consent. A member of the research team will assess participants’ eligibility 
based on inclusion/exclusion criteria and confirm a diagnosis of MDD with the M.I.N.I  5.0 and 
the Structured Clinical Interview for DSM-5 (SCID) to assess for mixed features symptomology. 
Demographics including date of birth, sex, and race will be recorded. Years of education will be 
recorded as well. Lifestyle factors (i.e. caffeine, exercise, alcohol, nicotine and marijuana ) will 
also be recorded. Psychiatric and medical history, number of psychotropic medications received 
according to participant self-report/clinical chart review, as well as anthropometrics (including 
height, weight and waist circumference) will be measured. Resting heart rate and blood pressure 
will also be measured. Participants will be evaluated with the MADRS by a member of the 
research team trained in MADRS scoring to assure the severity threshold is indicative of non-
remission (MADRS ≥ 20). The Columbia Suicide Severity Rating Scale (CSSRS) will also be 
used as part of participant assessment. In addition, participants will be asked to report any 
experience of adverse event(s) prior to study enrollment. Participants will be asked to complete 
the NART to estimate premorbid intelligence quotient (IQ). Upon confirmation of study 
eligibility, the participant will be scheduled for future appointments. 
 
Visit 2 (Day 0: Week 0; Baseline) 
Participant will be asked to report any adverse event(s) or any changes to medications. The 
Clinical Global Impression – Severity (CGI-S), MADRS, as well as the CSSRS scales will be 
used as part of participant assessment. Anthropometrics (including weight and waist 
circumference), resting heart rate and blood pressure will be measured. History of caffeine, 
alcohol, nicotine, exercise and marijuana use will be recorded as well. Participants will be 
provided with an opportunity to work through the modified THINC-it to minimize potential 
practice effects with a research team member. This will allow the participant with an opportunity 
to ask any outstanding questions. The THINC-it tool will be administered via tablet to evaluate 
objective and subjective measures of cognitive function. THINC-it tests will be consistently 
delivered in the following order: Spotter, Symbol Check, Codebreaker, Trails, and PDQ-5-D to 
all participants with a member of the research team instructing participants to read the tutorial 

 
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instructions preceding each of the THINC-it tasks. Participants will complete the pen-and-paper 
version of the Digit Symbol Substitution Test (DSST) and the Trail Making Test B (TMT-B).  
Participants will also complete all secondary self-report assessments using paper-based 
scales/questionnaires and consist of the following scales: Endicott Workplace Productivity Scale 
(EWPS), Sheehan Disability Scale (SDS), Wellbeing Index (WHO-5), Snaith-Hamilton Pleasure 
Scale (SHAPS), Generalized Anxiety Disorder (GAD-7), Perceived Deficits Questionnaire for 
Depression (PDQ-5-D), International Physical Activity Questionnaire (IPAQ), 36-Item Short 
Form Survey Instrument (SF-36), Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index 
(PSQI), Epworth Sleepiness Scale (ESS) and THINC-it satisfaction questionnaire. All self 
reports will be administered by a member. All study procedures will take place in a quiet setting. 
Fasting (12-hours) clinical and research bloodwork will also be collected. 
 
Participants will receive vortioxetine 10-20 mg (flexibly dosed) over the course of 8 weeks and 
to be taken once daily with the option to increase to vortioxetine 20 mg/day following visit 3 of 
the treatment based on clinical discretion (e.g. efficacy and tolerability). This dose was chosen 
based on extant evidence demonstrating improvements in cognitive function (i.e., executive 
function, attention/speed of processing, and memory), independent of improvement in depressive 
symptoms, over an 8-week period [19, 20]. Participants will be asked to store the medication at 
room temperature (i.e., 15-30 °C).  
 
All participants will be fully informed of safety and tolerability concerns related to the treatment 
and will be instructed to report any treatment emergent adverse events (TEAEs) of concern to a 
member of the research team. Moreover, members of the research team will specifically probe 
and monitor all participants regarding side-effects at each visit. Participants will also be provided 
with a cell phone number accessible 24 hours a day, seven days a week. The cell phone will be 
carried on a rotating basis by individual members of the research team.  
Visit 3 (Day 14; Week 2) 
Participant will be asked to report any adverse event(s) or any changes to medications. The 
Clinical Global Impression – Severity (CGI-S), Clinical Global Impression – Improvement 

 
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(CGI-I), MADRS, as well as the CSSRS scales will be used as part of participant assessment. 
History of caffeine, alcohol, nicotine, and marijuana use will be recorded. Anthropometrics 
(including weight and waist circumference), resting heart rate and blood pressure data will be 
measured as well. THINC-it tool will be administered via tablet to evaluate objective and 
subjective measures of cognitive function. THINC-it tests will be consistently delivered in the 
following order: Spotter, Symbol Check, Codebreaker, Trails, and PDQ-5-D to all participants 
with a member of the research team instructing participants to read the tutorial instructions 
preceding each of the THINC-it tasks. Participants will complete the pen-and-paper version of 
the Digit Symbol Substitution Test (DSST) and the Trail Making Test B (TMT-B). 
 
Participants will also complete all secondary self-report assessments using paper-based 
scales/questionnaires and consist of the following scales: Endicott Workplace Productivity Scale 
(EWPS), Sheehan Disability Scale (SDS), Wellbeing Index (WHO-5), Snaith-Hamilton Pleasure 
Scale (SHAPS), Generalized Anxiety Disorder (GAD-7), Perceived Deficits Questionnaire for 
Depression (PDQ-5-D), 36-Item Short Form Survey Instrument (SF-36), Insomnia Severity 
Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and 
THINC-it satisfaction questionnaire. All self reports will be administered by a member. All study 
procedures will take place in a quiet setting. 
 
Participants will receive vortioxetine 10-20 mg (flexibly dosed) over the next 2 weeks to be 
taken once daily with the option to increase to vortioxetine 20 mg/day based on clinical 
discretion (e.g. efficacy and tolerability). This dose was chosen based on extant evidence 
demonstrating improvements in cognitive function (i.e., executive function, attention/speed of 
processing, and memory), independent of improvement in depressive symptoms, over an 8-week 
period [19, 20]. Participants will be asked to store the medication at room temperature (i.e., 15-
30 °C). 
 
All participants will be fully informed of safety and tolerability concerns related to the treatment 
and will be instructed to report any treatment emergent adverse events (TEAEs) of concern to a 
member of the research team. Moreover, members of the research team will specifically probe 

 
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and monitor all participants regarding side-effects at each visit. Participants will be advised to 
contact a research member’s 24hr study line in case of side effects. In the event of an emergency, 
participants are advised to contact their physician or visit the nearest emergency hospital. 
 
Visit 4 (Day 28; Week 4) 
A member of the research team will complete the MADRS, CGI-I, CGI-S, IPAQ and CSSRS 
with the participant as well as ask about any side-effects or changes to their medications. History 
of caffeine, alcohol, nicotine, and marijuana use will be recorded. Anthropometrics (including 
weight and waist circumference), resting heart rate and blood pressure data will be measured as 
well. Participants will receive additional vortioxetine for the following 4 weeks. 
 
Visit 5 (Day 56; Week 8) 
Participant will be asked to report any adverse event(s) or any changes to medications. Anthropometrics 
(including weight and waist circumference), resting heart rate and blood pressure will be measured as 
well. History of caffeine, alcohol, nicotine, and marijuana use will be recorded. The CGI-I scale, CGI- S 
scale, MADRS as well as the CSSRS will also be completed. Participants will be asked to complete the 
THINC-it to evaluate objective and subjective measures of cognitive function. Participants will complete 
the pen-and-paper version of the Digit Symbol Substitution Test (DSST) and the Trail Making Test B 
(TMT-B). 
 
Participants will also complete all secondary self-report assessments using paper-based 
scales/questionnaires and consist of the following scales: Endicott Workplace Productivity Scale 
(EWPS), Sheehan Disability Scale (SDS), Wellbeing Index (WHO-5), Snaith-Hamilton Pleasure 
Scale (SHAPS), International Physical Activity Questionnaire (IPAQ), Generalized Anxiety 

 
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Disorder (GAD-7), Perceived Deficits Questionnaire for Depression (PDQ-5-D), 36-Item Short 
Form Survey Instrument (SF-36), Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index 
(PSQI), Epworth Sleepiness Scale (ESS) and THINC-it satisfaction questionnaire. Clinical and 
research bloodwork will also be collected. All self reports will be administered by a member. All 
study procedures will take place in a quiet setting. Participants will be required to return 
completed medication packets.  
Effort Expenditure for Reward Task (MDD and HC) 
Optional: Participants will be asked if they are interested in completing a 20-minute computer 
based behavioral task to explore effort-based decision-making, called “Effort Expenditure for 
Reward Task”. This task has been added to objectively measure reward motivation among 
patients with MDD and HCs. Participants have to select between an Easy and a Hard task. Both 
tasks involve pressing the Spacebar for a predetermined amount of time. The Hard task offers 
more money (variable amounts: $1.24-$4.30) but is harder and takes twice as long. Participants 
make their selection knowingly under different win probabilities (i.e. they might not win money 
even if they are successful if the win probabilities are low). 
Participants will be given the option to complete this task at endpoint (Week 8). This task is only 
done once. Participants will be awarded the monetary value of the amount they win from doing 
this task. This is a necessary component of the task, as a tangible incentive is required. 30 MDD 
and 30 HC participants will completed this task only.  
 
Post Visits – Transition to Standard of Care 
 
Upon completion of the study, patient will be seen by research team clinician to determine 
whether medication will be discontinued. If medication discontinuation is required, the patient 
will receive medication reduction by clinician for a period of one week, followed by a period of 
1 week with no medication. Patient will be seen by physician 2 weeks post week 8, to monitor 
well being, including mood, adverse events and any suicide risks. This is a clinical visit with the 
psychiatrist and will undergo a full clinical psychiatric assessment to assure patient has a smooth 

 
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transition to standard of care with their main responsible physician. Should the patient need to 
see physician sooner, they are advised to contact the 24/7 study line to schedule an appointment. 
MDD participants will be followed up by physician but will not undergo ongoing provision of 
care after the study by the research physician.  
 
MDD PATIENT SUMMARY CHART 

 
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Visit 
 Screening  
(Visit 1) 
Week 0  
( 
(Baseline, 
Visit 2) 
 Week 2 
(Visit 3)  
 
 Week 
4(Visit 4) 
Week 8 
(Endpoint, Visit 
5) 
 Post-Study two 
weeks clinical 
visit for drug 
discontinuation. 
Additional 
visits will be 
scheduled as 
needed.  
Consent 
X 
 
Physician visit 
 
X 
X 
X 
X 
X 
Bloodwork 
 
X 
 
 
X 
 
Demographics 
X 
 
Inclusion/ exclusion 
X 
 
Adverse events 
X 
X 
X 
X 
X 
 
Current Medications  
X 
 
 
 
 
 
Medication Changes 
 
X 
X 
X 
X 
 
M.I.N.I  5.0 
X 
 
SCID 
X 
 
 
 
 
 
Psychiatric/Medical 
History 
X 
 
Anthropometrics 
X 
X 
X 
X 
X 
 
Lifestyle Factors 
X 
X 
X 
X 
X 
 
Montgomery Åsberg 
Depression Rating 
Scale (MADRS) > 20 
X 
X 
X 
X 
X 
 
THINC-it Practice 
X 
 
THINC-it Cognitive 
test 
X 
X 
X 
 
CSSRS 
X 
X 
X 
X 
X 
 
DSST (pen/paper)  
X 
X 
X 
 
TMT-B (pen/paper) 
 
X 
X 
 
X 
 
NART 
X 
 
CGI-I/CGI-S 
X 
X 
X 
X 
 
International Physical 
Activity 
Questionnaire (IPAQ) 
X 
X 
X 
 
Vortioxetine 
Treatment 
X 
X 
X 
 
Dispensing 
medication 
X 
X 
X 
 
Effort Expenditure for 
Rewards Task 
(EEfRT) – optional  
 
 
 
 
X 

 
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PROCEDURES FOR HEALTH CONTROL PARTICIPANTS 
 
 Phone Screen 
A member of the research team will assess participants’ eligibility based on inclusion/exclusion 
criteria. Demographics including date of birth, sex, years of education and race will be recorded. 
Medical history, psychiatric history and lifestyle factors (i.e. alcohol use, nicotine history, 
caffeine and marijuana use) will also be taken during the phone screen. Participants will also be 
asked about any current medications that they are currently taking. The CSSRS will also be used 
Endicott Workplace 
Productivity Scale 
(EWPS) 
X 
X 
X 
 
Sheehan Disability 
Scale (SDS) 
X 
X 
X 
 
Wellbeing Index 
(WHO-5) 
 
X 
X 
 
X 
 
Snaith-Hamilton 
Pleasure Scale 
Questionnaire 
(SHAPS) 
 
X 
X 
 
X 
 
Generalized Anxiety 
Disorder (GAD-7) 
X 
X 
X 
 
Perceived Deficits 
Questionnaire for 
Depression (PDQ-5-
D) 
 
X 
X 
 
X 
 
36-Item Short Form 
Survey Instrument 
(SF-36) 
 
X 
X 
 
X 
 
Insomnia Severity 
Index (ISI) 
 
X 
X 
 
X 
 
Pittsburgh Sleep 
Quality Index (PSQI) 
 
X 
X 
 
X 
 
Epworth Sleepiness 
Scale (ESS) 
 
X 
X 
 
X 
 
THINC-it satisfaction 
questionnaire 
X 
 
 
 
 

 
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as part of participant assessment. In addition, participants will be asked to report any experience 
of adverse event(s) prior to study enrollment. Upon confirmation of study eligibility, the 
participant will be asked to scheduled for future appointment visits. 
Visit 1 (Day 0: Week 1; Baseline) 
The initial visit entails the provision of detailed study information to participant and obtainment 
of informed written consent. Participants will also be asked to report any experience of adverse 
event(s) in addition to lifestyle factors. Anthropometrics (consisting of height, weight and waist 
circumference), resting heart rate and blood pressure will be measured. The MADRS will be 
completed by a member of the research team trained in MADRS scoring to ensure the participant 
does not exhibit depressive symptoms (i.e., MADRS total score ≤ 6). Healthy control 
participants will be evaluated by the M.I.N.I 5.0 to confirm no diagnosis of mental disorder 
(including MDD). Participants will also be asked to complete the NART to estimate premorbid 
IQ. 
Participants will be provided with a tutorial to work through the THINC-it. The THINC-it tool 
will be then administered to evaluate objective and subjective measures of cognitive function. 
The THINC-it will be consistently delivered in the following order: Spotter, Symbol Check, 
Codebreaker, Trails, and PDQ-5-D to all participants with a member of the research team 
instructing participants to read the tutorial instructions preceding each of the THINC-it tasks. 
Participants will complete the pen-and-paper version of the Digit Symbol Substitution Test 
(DSST) and the Trail Making Test B (TMT-B). 
Participants will also complete all secondary self-report assessments using paper-based 
scales/questionnaires and consist of the following scales: Endicott Workplace Productivity Scale 
(EWPS), Sheehan Disability Scale (SDS), Wellbeing Index (WHO-5), Snaith-Hamilton Pleasure 
Scale (SHAPS), Generalized Anxiety Disorder (GAD-7), International Physical Activity 
Questionnaire (IPAQ), Perceived Deficits Questionnaire for Depression (PDQ-5-D), 36-Item 
Short Form Survey Instrument (SF-36), Insomnia Severity Index (ISI), Pittsburgh Sleep Quality 
Index (PSQI), Epworth Sleepiness Scale (ESS) and THINC-it satisfaction questionnaire. All self 
reports will be administered by a member. All study procedures will take place in a quiet setting.  

 
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Participants will also be provided with a cell phone number accessible 24 hours a day, seven 
days a week. The cell phone will be carried on a rotating basis by individual members of the 
research team. 
Visit 2 (Day 14; Week 2) 
Participants will also be assessed with the MADRS. Lifestyle factors, medication updates and 
adverse events will be recorded. Anthropometrics will be measured (consisting of height, weight 
and waist circumferenceheight), resting heart rate and blood pressure will be measured. 
Participants will be asked to complete the THINC-it to evaluate objective and subjective 
measures of cognitive function, in addition to the DSST and TMT-B pen-and-paper cognitive 
tests.  
Participants will also complete all secondary self-report assessments using paper-based 
scales/questionnaires and consist of the following scales: Endicott Workplace Productivity Scale 
(EWPS), Sheehan Disability Scale (SDS), Wellbeing Index (WHO-5), Snaith-Hamilton Pleasure 
Scale (SHAPS), Generalized Anxiety Disorder (GAD-7), Perceived Deficits Questionnaire for 
Depression (PDQ-5-D), 36-Item Short Form Survey Instrument (SF-36), Insomnia Severity 
Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and 
THINC-it satisfaction questionnaire. All self reports will be administered by a member. 
Visit 3 (Day 14; Week 4) 
Participants will be assessed with the MADRS .  Lifestyle factors, medication updates and 
adverse events will also be recorded. Anthropometrics will be measured (consisting of height, 
weight and waist circumferenceheight), resting heart rate and blood pressure will be 
measured.The International Physical Activity Questionnaire (IPAQ) will be administered as well. 
 
Visit 4 (Day 56; Week 8) 

 
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Anthropometrics (including weight and waist circumference), resting heart rate and blood 
pressure will be measured.  Lifestyle factors will be measured. Participants will be assessed 
using the MADRS and be asked about any adverse events. Participants will be asked to complete 
the THINC-it to evaluate objective and subjective measures of cognitive function. Participants 
will complete the pen-and-paper version of the Digit Symbol Substitution Test (DSST) and the 
Trail Making Test B (TMT-B). 
 
Participants will also complete all secondary self-report assessments using paper-based 
scales/questionnaires and consist of the following scales: Endicott Workplace Productivity Scale 
(EWPS), Sheehan Disability Scale (SDS), Wellbeing Index (WHO-5), Snaith-Hamilton Pleasure 
Scale (SHAPS), Generalized Anxiety Disorder (GAD-7), International Physical Activity 
Questionnaire (IPAQ), Perceived Deficits Questionnaire for Depression (PDQ-5-D), 36-Item 
Short Form Survey Instrument (SF-36), Insomnia Severity Index (ISI), Pittsburgh Sleep Quality 
Index (PSQI), Epworth Sleepiness Scale (ESS) and THINC-it satisfaction questionnaire. All self 
reports will be administered by a member.  
 
HEALTH CONTROL SUMMARY CHART  
Visit 
Phone Screening Visit 1 
(Baseline, Week 
0) 
Visit 2  
(Week 2) 
Visit 3  
(Week 4) 
 Visit 4 
(Week 8) 
Consent 
X 
 
Demographics 
X 
 
Inclusion/exclusion 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
M.I.N.I  5.0 
X 
 
Psychiatric/Medical History 
X 
 
Current Medications 
X 
 
 
 
 
Changes in Medications 
 
X 
X 
X 
X 
Anthropometrics 
X 
X 
X 
X 
Montgomery Åsberg Depression Rating 
Scale (MADRS) 6> 
X 
X 
X 
X 
NART  
X 
 

 
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Lifestyle Factors 
X 
X 
X 
X 
X 
DSST (Pen/Paper) 
 
X 
X 
 
X 
TMT-B (Pen/Paper) 
 
X 
X 
 
X 
THINC-it Practice 
X 
 
THINC-it Cognitive test 
X 
X 
X 
Effort Expenditure for Rewards Task 
(EEfRT) – optional 
 
 
 
 
X 
International Physical Activity 
Questionnaire (IPAQ) 
 
X 
 
X 
X 
CSSRS 
X 
 
 
 
 
SELF REPORTS 
Endicott Workplace Productivity Scale 
(EWPS) 
X 
X 
X 
Sheehan Disability Scale (SDS) 
X 
X 
X 
Wellbeing Index (WHO-5) 
 
X 
X 
 
X 
Perceived Deficits Questionnaire for 
Depression (PDQ-5-D) 
 
X 
X 
 
X 
Snaith-Hamilton Pleasure Scale 
Questionnaire (SHAPS) 
X 
X 
X 
Generalized Anxiety Disorder (GAD-7) 
X 
X 
X 
36-Item Short Form Survey Instrument 
(SF-36) 
 
X 
X 
 
X 
Insomnia Severity Index (ISI) 
 
X 
X 
 
X 
Pittsburgh Sleep Quality Index (PSQI) 
 
X 
X 
 
X 
Epworth Sleepiness Scale (ESS) 
 
X 
X 
 
X 
THINC-it satisfaction questionnaire 
X 
 
 
OBJECTIVES 
 
Primary Objective:  
❏    To determine the sensitivity of the THINC-it to alterations in cognitive 
function/performance following intervention with vortioxetine over 8 weeks in adults aged 18-65 
with MDD. 
 

 
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THINC-it Sensitivity to Change  
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Secondary Objectives: 
❏    To determine whether early changes (i.e., Day 14; Week 2) in cognitive 
function/performance, as measured by the THINC-it, predict symptomatic improvements in 
mood, defined as a reduction of 50% or more on total mood score (as measured by the MADRS), 
at endpoint. 
❏    To determine whether early changes (i.e., Day 14, Week 2) in cognitive 
function/performance, as measured by the THINC-it, are capable of detecting the effect of 
vortioxetine treatment on secondary outcome measures of function (e.g., SDS, EWPS, WHO-5) 
at endpoint. 
 
STUDY MEDICATION: VORTIOXETINE 
 
Participants receiving vortioxetine will be provided 10 mg/day on days 1–14 of the treatment 
period, with the option to increase to vortioxetine 20 mg/day at the end of Week 2 based on 
investigator judgment. For the remaining 6 weeks, the dose of vortioxetine will be flexible at 10 
or 20 mg/day as adjudicated by a research clinician.  
 
Side effects 
Most Common: 
-     Gastrointestinal adverse events; including nausea, vomiting, constipation/diarrhea. 
Highest incidence occurs during the first week of treatment. 21-32% 
-       Sexual dysfunction 14-34% 
Less Common: 1-10% 
-       Dry mouth 
-       Dyspepsia (discomfort of the abdomen) 
-       Dizziness 
-       Somnolence/sedation 
-       Fatigue 
-       Insomnia 
-       Abnormal dreams 
-       Hyperhidrosis (increase sweating) 
-       Arthralgia (joint pain) 
-       Decreased appetite 

 
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Rare: %10> 
-       Nervous system disorders 
-       Skin and subcutaneous tissue disorders 
-       Psychiatric disorders 
 
• Serotonin Syndrome has been reported with serotonergic anti-depressants (SSRIs, SNRIs, 
and others), including with Vortioxetine both when taken alone, but especially when 
coadministered with other serotonergic agents (including triptans, tricyclic antidepressants, 
fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort). 
 
• Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase the 
risk of abnormal bleeding. Patients should be cautioned about the increased risk of bleeding 
when Vortioxetine is coadministered with nonsteroidal anti-inflammatory drugs (NSAIDs), 
aspirin, or other drugs that affect coagulation.  
 
• Activation of Mania/Hypomania can occur with antidepressant treatment. 
 
• Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated 
anatomically narrow angles treated with antidepressants. 
 
• Hyponatremia can occur in association with the syndrome of inappropriate antidiuretic 
hormone secretion (SIADH). 
 
Please see product monograph for full details.  
 
 
Contraindications 
 
Hypersensitivity to vortioxetine or any components of the formulation. Angioedema has 
been reported in patients treated with vortioxetine. The use of monoamine oxidase inhibitors 
(MAOI) intended to treat psychiatric disorders with vortioxetine or within 21 days of stopping 
treatment with vortioxetine is contraindicated because of an increased risk of serotonin 
syndrome. The use of vortioxetine within 14 days of stopping an MAOI intended to treat 
psychiatric disorders is also contraindicated.  
Starting vortioxetine in a patient who is being treated with MAOIs such as linezolid or 
intravenous methylene blue is also contraindicated because of an increased risk of serotonin 

 
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syndrome. 
 
Storage 
 
Medication will be stored at room temperature and locked at a medical health care facility. 
Rationale for Vortioxetine 
 
It has been amply documented that vortioxetine has a beneficial effect on cognitive domains 
commonly reported to be negatively affected in MDD (i.e., executive function, attention/speed of 
processing, and memory) at a dose of 10-20 mg per day [10,19–21]. Moreover, vortioxetine is 
the only psychopharmacological agent currently available that has a regulatory label in the EU 
and many other countries in the world describing its benefit on cognitive dysfunction in patients 
with MDD [22]. 
 
Transition to Standard of Care 
 
Patients will be informed of the transition to standard of care procedures (outlined here) post 
study prior to providing consent to participate in the study. These procedures will also be 
outlined in writing in the patient consent form itself.  
 
Upon completing the 8-week course of vortioxetine, if patients benefit from this drug, they will 
be encouraged to continue the treatment with their most responsible physician (MRP). Patients 
will be notified prior to study consent that not all drug plans will cover the cost of vortioxetine. 
Should patients wish to continue to use this drug post-study when they do not have coverage, 
they will be personally responsible for the costs. There will be a gradual discontinuation of the 
medication for two weeks after the end of the study. However, participants will not have further 
access to this drug from the research team after study completion. If patients do experience side 
effects during the study, a physician will make a recommendation regarding the discontinuation 
or dose reduction of the medication for the remainder of the study. If patients do not experience 

 
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any improvement upon study completion in mood or cognition, the medication will be gradually 
discontinued over a two-week period upon study completion (week 8).  
 
Vortioxetine discontinuation process 
 
At visit 8, patients will be seen by a clinician and provided with half of current vortioxetine 
dosage for a period of 1 week. This down titration will assure there are no adverse side effects 
with discontinuation of vortioxetine. During the second week, patients will not be on medication 
and will be seen by the clinician at the end of two weeks, to ensure that there are no risks or 
adverse events during this time period. The visits with the clinician are post-study, and not part 
of the study visits. Patients are encouraged to contact the 24/7 study phone line in the event that 
they would like to be scheduled with the physician earlier. MDD patients will be seen by 
research clinician to ensure a safe transition into standard of care by their main responsible 
physician.  
 
CONDITIONS FOR WITHDRAWAL FROM THE STUDY 
 
Participants may discontinue from the study treatment and assessments at any time. Specific 
reasons for discontinuing a participant from this study are: 
 
1.   Voluntary discontinuation by the participant at any time without prejudice to further      
treatment. 
2.   Non-compliance to the protocol as judged by the investigator. 
3.   Participant becomes pregnant. 
4.   Increased risk of suicide ideation. 
5.   Any adverse event that, in the opinion of an investigator, puts the subject at risk. 
 

 
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RECRUITMENT 
 
Membership of the BCDF provide consultation to approximately 20 new adult MDD patients per 
week. It is expected that approximately 10 participants per month will be eligible for the study 
herein. This estimate is based on previous experience in which a high proportion of persons 
referred to the THINC-it validation study met inclusion criteria. The clinical research experience 
of BCDF members demonstrates that it is possible (as evinced by publications) to recruit a 
minimum of two subjects per week for most studies conducted. Recruitment of all eligible 
subjects will be via media announcements in the general community. It is anticipated that the 
attrition rate will be 20%. Healthy controls will be consecutively recruited via media 
announcements and will be age-, sex- and education-matched in a 2-to-1 ratio. 
 
The loss to follow-up rate in our program has been relatively low, based on previous experience. 
The estimated dropout rate in our experience has been approximately 20% for open-label studies. 
With this in mind, however, the present study has been sufficiently powered to achieve the 
primary aims and objectives. 

 
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STATISTICAL PLAN                                                                                                                
Extant literature indicates that the effect size for cognitive deficits in first- and multiple-episode 
MDD patients is approximately 0.3-0.7 (Cohen’s d). Notwithstanding the range of reported 
effect sizes, a modal estimate of 0.4 is instantiated by meta-analyses across disparate domains 
[23]. Based on an effect size of 0.4, it is estimated that a sample size of 110 evaluable subjects 
would be required (with a power level of 0.8 and a probability level of 0.05). Similarly, results 
from our recently completed validation study of the THINC-it demonstrated- temporal reliability 
of 0.7-0.8, suggesting that repeat-measure performance on the THINC-it between visits would be 
consistent in the study being proposed herein. Taken together, performance on all the THINC-it 
tool metrics will be collected in the healthy control group (N=50) for comparison with 
performance of patients with MDD treated with vortioxetine over an 8-week period, flexibly 
dosed 10-20 mg/day as adjudicated by a research clinician, to assess detectable differences 
between groups. 
 
Participants with complete data from the 8 weeks of treatment will be included in analyses, 
which will be carried out using the Statistical Package for the Social Sciences (SPSS) software. 
The data will be preliminarily examined in exploratory analyses to obtain their distributional 
properties, examine any outlying data points, and explore bivariate relations between individual 
variables. Specific data analyses are subject to change based on the foregoing analyses, but in 
general we will set α = 0.05, two-tailed, and β = 0.20. 
 
Validation assessments will be employed based on previous psychometric validations of 
cognitive assessment, as reported by Harrison et al. (2007) wherein validation was informed by 
guidance regarding objective psychometric assessment by Ferris et al. (1997) stressing the 
importance of characterizing the reliability, validity, and sensitivity of cognitive measures; in 
addition, results from a recently completed validation study of the THINC-it completed by the 
BCDF will be used to determine the appropriate statistical measures required to perform the 
study herein.  
 
An important consideration when determining issues such as temporal (or ‘test-retest’) reliability 

 
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THINC-it Sensitivity to Change  
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is a reasonable expectation that the performance will not be impacted by disease or medication 
variables. Hence, it is necessary to conduct these analyses in a group of healthy controls (N=50) 
as compared to an intervention group (N=100) assessing sensitivity to change during vortioxetine 
treatment flexibly dosed 10-20 mg/day over an 8-week period.  
 
Evidence to date indicates that average performance on cognitive tasks in patients with MDD fall 
approximately 0.5-1.0 standard deviations (SD) below healthy control normative data that is age, 
sex and education matched [17]. In this study, a comparison of performance in the healthy 
control group versus the treatment group with vortioxetine over an 8-week period, flexibly dosed 
10-20 mg/day, will demonstrate both the deficit of magnitude as well as margin of improvement 
following 8 weeks of vortioxetine treatment in the latter group. Data from both groups will allow 
a comparison of overall THINC-it performance as well as improvement following vortioxetine 
treatment (sensitivity and specificity) on each test comprising the THINC-it tool. 
 
Interim analysis will be conducted both at primary and secondary measures. 
 
Test Sesitivity 
 
Performance on the primary metric for each THINC-it tool test will be calculated to determine 
test sensitivity. Descriptive statistics for performance of i) the Healthy Control group and ii) that 
of the patients with MDD treated with vortioxetine over 8 weeks will be examined to determine: 
•    Mean difference in performance on each test 
•    Variance in performance for each test 
•    Additional measure of central tendency and variability  
•    Other descriptions of the data, including skewness and kurtosis  
•    Mean difference in group performance, characterised as a standardised effect size 
 
Inferential statistical analysis will be conducted to determine significant difference in 

 
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performance within and between the two groups. An analysis of the sensitivity (true positive 
rate) and specificity (the true negative rate) of each test to the presence and subsequent 
improvement of cognitive impairment in patients with MDD will be conducted. Cut-off models 
designed to maximize sensitivity and specificity will be evaluated. The model will be optimized 
to obtain a pragmatic cut-off that maximizes the model with respect to levels of both sensitivity 
and specificity. In the event that no overlap is apparent, a threshold for determining impairment 
will be established. Secondary objectives will be addressed with correlative analysis between the 
total THINC-it tool and/or its components and the disparate secondary measures. 
 
DATA HANDLING 
 
Personal Data Protection 
 
All data collection material will be de-identified. Participant records will be distinguished using 
participant identification (PID) numbers. 
 
DATA RETENTION 
 
Records and documents pertaining to the conduct of the study as well as all data collected as part 
of the study will be retained in a secure place for 25 years in accordance with Health Canada 
regulations. All data collected throughout the study will be kept with membership of the BCDF 
for 25 years. 
 
PARTICIPANT PROTECTION 
 
Participants will not be placed at any risk as a result of the study. Information obtained will be 
maintained in a secure and confidential fashion. No participant will be coerced and/or placed 
under duress to complete study procedures. 

 
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PARTICIPANT COMPENSATION 
 
All participants (i.e., patients with DSM-5-defined MDD and healthy controls) will be provided 
with reasonable compensation (i.e., $150 CAD, plus modest out-of-pocket expenses for 
parking/public transit and food per visit maximum $30 CAD per visit) following successful 
completion of the clinical trial in its entirety. A cheque will be provided as reimbursement for 
every visit up to $30. Healthy participants will be reimbursed $100 CAD, plus up to $30 CAD 
for travel and food.  
 
ADVERSE EVENTS 
 
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, 
electrocardiogram). In clinical studies, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if no study treatment has been 
administered. 
 
Serious adverse events 
 
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), and at any procedure, that fulfills one or more of the following criteria: 
❏    Results in death 
❏    Is immediately life-threatening 
❏    Requires inpatient hospitalization or prolongation of existing hospitalization 

 
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THINC-it Sensitivity to Change  
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❏    Results in persistent or significant disability or incapability 
❏    Is a congenital abnormality or birth defect 
❏    Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above 
 
The causality of SAEs (i.e., their relationship to study treatment) will be assessed by the 
investigator(s). Note that SAEs that could be associated with any study procedure should also be 
reported. For such events the causal relationship is implied as “yes”. 
 
Recordings of Adverse Events 
 
Adverse events will be collected from baseline to endpoint. At each visit, subjects will be asked 
if they have experienced any health problems or side effects since the previous visit. All AEs 
will be recorded appropriately, whether or not considered related to the investigational product. 
This will include AEs spontaneously reported by the patient and/or observed by members of the 
research team as well as AEs reported in response to a direct question (e.g., “Have you 
experienced any health problems of side-effects since your last visit?”).  
 
For each AE, the following parameters will be described: 
❏    Start and Stop date 
❏    Action taken with regards to investigational product 
❏    Outcome 
❏    If the AE caused the patient to discontinue the investigational product 
❏    A statement if the AE fulfills the criteria for a SAE or not 
❏    The investigator’s assessment of the causal relationship between the event and the 
investigational product 
❏    Intensity of the AE 
    o   Mild (awareness of sign or symptom, but easily tolerated) 

 
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THINC-it Sensitivity to Change  
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    o   Moderate (discomfort sufficient to cause interference with normal activities) 
    o   Severe (incapacitating, with inability to perform normal activities) 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity. 
An AE of severe intensity need not necessarily be considered serious. For example, nausea that 
persists for several hours may be considered severe nausea, but not an SAE. On the other hand, a 
stroke that results in only a limited degree of disability may be considered a mild stroke but 
would be an SAE. Symptoms associated with overdose will be reported as AEs. Pregnancy in 
itself is not regarded as an AE. Follow-up of adverse events will be based upon the clinical 
judgment of the investigator. 
 
Reporting of Adverse and Serious Adverse Events 
 
The sponsor-investigator will comply with any and all national rules and regulations concerning 
safety reporting (adverse drug reactions or SAEs as required). All SAEs (according to the 
definition in ICH GCP) will be will be done by the investigator in accordance with local 
regulations and reported to the appropriate regulatory bodies.  
 
 
 
 
 
 
 

 
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[2] Alonso J, Vilagut G, Chatterji S, Heeringa S, Schoenbaum M, Bedirhan Üstün T, et al. 
Including information about co-morbidity in estimates of disease burden: results from the 
World Health Organization World Mental Health Surveys. Psychol Med 2011;41:873–86. 
[3] World Health Organization. SpringerReference, Berlin/Heidelberg: Springer-Verlag; 2011. 
[4] Greenberg PE, Fournier A-A, Sisitsky T, Pike CT, Kessler RC. The economic burden of 
adults with major depressive disorder in the United States (2005 and 2010). J Clin 
Psychiatry 2015;76:155–62. 
[5] Woo YS, Rosenblat JD, Kakar R, Bahk W-M, McIntyre RS. Cognitive Deficits as a 
Mediator of Poor Occupational Function in Remitted Major Depressive Disorder Patients. 
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[6] Jaeger J, Berns S, Uzelac S, Davis-Conway S. Neurocognitive deficits and disability in 
major depressive disorder. Psychiatry Res 2006;145:39–48. 
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