Randomized, Double-Blinded, Placebo-Controlled Study Evaluating Vortioxetine for Cognitive Deficits in Persons With Post-COVID-19 Condition
Phase: PHASE2
Conditions: Post-COVID-19 Condition, Post-COVID-19 Syndrome, Cognitive Impairment
Sponsor: Brain and Cognition Discovery Foundation

 
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Randomized, Double-Blinded, Placebo-Controlled Study 
Evaluating Vortioxetine for Cognitive Deficits in Persons 
with Post-COVID-19 Condition (Protocol Number: 
BCDF002) 
 
 
 
Principal Investigator:  
Dr. Roger S. McIntyre, M.D., FRCPC 
Chairman and Executive Director, 
Brain and Cognition Discovery Foundation (BCDF) 
77 Bloor Street West, Suite 600, Toronto, ON, M5S 1M2 
longcovid@bcdfoundation.ca 
 
Sub-Investigator (Study Physician): 
Dr. Pawel Drzadzewski, M.D.  
Family Physician, CRTCE/KJK HealthPlex 
1100 Dundas Street West, Unit #4, Mississauga, ON, L5C 4E7 
 
Additional Investigators: 
Dr. Simon J. Graham, Ph.D., P.Eng 
Department of Medical Biophysics, Sunnybrook Research Institute 
 
Dr. Bradley MacIntosh, Ph.D. 
Department of Medical Biophysics, Sunnybrook Research Institute 
 
Dr. Matthew J. Burke, M.D., FRCPC 
Cognitive Neurologist, Neuropsychiatry Program 
Associate Scientist, Hurvitz Brain Sciences Research Program 
Sunnybrook Health Sciences Centre 
 
 
 

 
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Tables of Contents 
 
Background 
3 
Hypotheses 
3 
Study Design 
4 
Study Population 
4 
Recruitment 
6 
Study Visits 
6 
Sample Size 
10 
Feasibility 
10 
Study Flow 
20 
Conditions for Withdrawal From the Study 
18 
Participant Compensation 
19 
Study Medication: Vortioxetine 
19 
Data Handling 
22 
Data Collection and Retention 
22 
Participant Protection 
22 
Statistical analysis plan 
27 
Publication Plan 
28 
Documentation 
28 
Contract Details 
28 
References 
29 
 
 
 
Background 
Since the World Health Organization (WHO) declaration of COVID-19 as a global pandemic in 
March 2020, it is estimated that over 375 million people have tested positive for the virus globally 

 
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1. Consensus exists that the true infection rate is considerably higher, with estimates of 
approximately 5-10 fold greater, suggesting 1.9 to 3.75 billion persons have been infected with 
COVID-19. A significant percentage of individuals who have recovered from acute COVID-19 
infection present with unabating, non-specific, distressing, and functionally impairing symptoms 
(i.e., post-COVID-19 condition) 1,23. Commonly reported symptoms include, but are not limited to, 
cognitive impairment (e.g., “brain fog”), fatigue, apathy, depression, anxiety, insomnia, anergia, 
and loss of appetite 4,5. Toward the aim of identifying a common nomenclature and case definition, 
the World Health Organization (WHO) has recently proposed the moniker ‘post COVID-19 
condition’ 6. It is estimated that approximately 10-30% of persons infected with COVID-19 
experience characteristic symptoms persisting for more than 12 weeks following documentation 
of positive COVID-19 diagnosis  2,6.  
 
Consensus exists that the phenomenology of post-COVID-19 condition is subserved by 
disturbance in immune-inflammatory systems 7. Currently, no treatment is identified as safe and 
effective for post-COVID-19 condition 7,8. A candidate treatment for post-COVID-19 condition 
should be capable of improving measures of cognitive function (i.e., objective and subjective), 
motivation and energy, as well as reducing fatigue 7–9. The rationale for prioritizing cognition as a 
primary therapeutic target is based on a concatenation of study results reporting that cognitive 
complaints/deficits and fatigue are some of the most common and debilitating features of post-
COVID-19 condition 10–12. The candidate treatment would be preferred to target biological systems 
subserving circadian rhythms, as well as reward and reinforcement brain mechanisms. The profile 
of the candidate treatment should also have preliminary evidence documenting favourable 
modulatory effects on circulating pro-inflammatory cytokines, as well as immune cellular systems 
(e.g., macrophages). Preliminary evidence suggests that some antidepressants (e.g., SSRIs) are 
capable of reducing respiratory complications secondary to COVID-19 13,14. Putative mechanisms 
implicated include sigma-1 agonism and acid sphingomyelinase 13. A limitation of SSRIs, 
however, for specifically targeting post-COVID-19 condition, is that they are not proven to be pro-
cognitive and/or beneficial for reward systems and are, instead, reported to have, in some cases, 
dyscognitive and reward blunting effects (e.g., emotional blunting) 13,15–17. 
 
Vortioxetine is established as pro-cognitive, as evidenced by significant improvement on both 
subjective and objective measures 1819,20. Vortioxetine is also documented to improve anticipatory 
and consummatory measures of reward function/anhedonia as evaluated by validated reward 
paradigms, as well as the Snaith Hamilton Pleasure Scale (SHAPS) 21,22. Vortioxetine also 
improves general functioning 
18. Furthermore, vortioxetine has demonstrated significant 
improvement on measures of motivation and energy 23,24. Moreover, vortioxetine is not associated 
with emotional blunting and has preliminary evidence of improving sleep behaviour and circadian 
rhythms 23,25. The candidacy of vortioxetine as an effective treatment for post-COVID-19 condition 
is also strengthened by evidence indicating that vortioxetine exerts modulatory effects on cellular 
and cytokine systems known to be activated in persons with post-COVID-19 condition 26,27. 
Hypotheses 
Herein, we hypothesize that vortioxetine (5-20 mg) will be more effective than placebo in the 
treatment of cognitive impairment in persons with post-COVID-19 condition.  

 
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Study Design 
Eight-week, randomized, double-blinded, placebo-controlled clinical trial  
● Eight-week intervention (i.e., weeks 0-8) 
● Two-week drug discontinuation and safety follow-up period (i.e., weeks 8-10) 
 
Primary Endpoint: Week 8 
Outcomes 
Primary Outcomes 
● Baseline-to-endpoint (i.e., Week 8) change in Digit Symbol Substitution Test (DSST) 
(Pen/Paper Version and Online CogState Version as part of the CogState Online 
Cognitive Battery). Remote participants will not complete the pen/paper version of the 
DSST.  
 
Secondary Outcomes 
● Baseline-to-endpoint change in: 
o CogState Online Cognitive Battery 
o Trails Making Test (TMT)-A/B 
o Rey's auditory verbal learning test (RAVLT) 
o Perceived Deficits Questionnaire, 20-item (PDQ-20) 
o Fatigue Severity Scale (FSS) 
○ Snaith Hamilton Pleasure Rating Scale (SHAPS) 
○ Generalized Anxiety Scale, 7-item (GAD-7) 
○ World Health Organization Wellbeing Scale, 5-item (WHO-5) 
○ EuroQol, 5-dimension, 5-level (EQ-5D-5L) 
○ Sheehan Disability Scale (SDS) 
○ Post-Covid Functional Scale (PCFS) 
○ fMRI and the Effort Expenditure for Rewards Task (EEfRT) 
○  
○ Behavioural Activation Scale (BAS) 
○ International Physical Activity Questionnaire (IPAQ) 
○ Quick Inventory of Depressive Symptomatology (16-Item) (Self-Report) (QIDS-
SR16) 
● Safety outcomes  
○ Spontaneously reported adverse events 
○ Laboratory (including but not limited to CBC, TSH, electrolytes) 
Study Population  
Inclusion Criteria 
● Age 18+ 
● Meets WHO-defined post-COVID-19 condition 
○ WHO definition: ‘Post COVID-19 condition occurs in individuals with a history of 
probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of 

 
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COVID-19 with symptoms that last for at least 2 months and cannot be explained 
by an alternative diagnosis. Common symptoms include fatigue, shortness of 
breath, cognitive dysfunction but also others and generally have an impact on 
everyday functioning. Symptoms may be new onset following initial recovery from 
an acute COVID-19 episode or persist from the initial illness. Symptoms may 
also fluctuate or relapse over time.’ 6 
○ To ensure the above criteria is met, participants will only be included in the study 
if they meet all eligibility criteria more than 12 weeks from their confirmed and 
documented positive polymerase chain reaction (PCR) SARS-CoV-2 test, rapid 
antigen, or antibody test. In lieu of a prior positive test, a signed confirmation of a 
presumptive prior COVID-19 case from a healthcare provider, including the study 
physician, is acceptable.  
● Documented history of SARS-CoV-2 infection with typical symptoms, and requiring 
positive SARS-CoV-2 test (PCR,antigen, or serology) at some point during the course of 
the acute course of illness. In lieu of a prior positive test, a confirmation of a presumptive 
prior COVID-19 case from a healthcare provider, including the study physician, is 
acceptable.  
● Subjective cognitive complaints as detected by the Perceived Deficits Questionnaire 
(PDQ)-5. 
● Ability to provide written informed consent. 
● Resident of Canada.  
Exclusion Criteria 
● Current symptoms are fully explained by major depressive disorder or bipolar disorder.  
● Pre-existing conditions that may cause cognitive impairment, or symptoms similar to 
those seen in post-COVID-19 condition (e.g., ADHD, major neurocognitive disorder, 
schizophrenia, chronic fatigue syndrome [CFS]/ encephalitis meningitis [EM]), as 
assessed by Mini International Neuropsychiatric Interview (MINI) 7.0.2. 
● Inability to follow study procedures.  
● Known intolerance to vortioxetine and/or prior trial of vortioxetine with demonstrated 
inefficacy.  
● If participants are currently taking other antidepressants, they will be asked to 
discontinue the antidepressant for 2-4 weeks in order to participate in the study.  
● Patients on other antidepressants are allowed to participate only if the antidepressant is 
prescribed at subtherapeutic doses for a primary indication other than mood disorders. 
Participants will be made aware in the consent form that the combination of the two 
antidepressants would be considered investigational and that the safety/efficacy profiles 
are unknown 28–30. 
● Current alcohol or substance use disorder.  
● Inability to provide consent.  
● Current alcohol and/or substance use disorder as confirmed by the M.I.N.I 7.0.2. 
● Presence of comorbid psychiatric disorder that is a primary focus of clinical concern as 
confirmed by the M.I.N.I. 7.0.2. 
● Medications approved and/or employed off-label for cognitive dysfunction                      
 (e.g., psychostimulants).  

 
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● Any medication for a general medical disorder that, in the opinion of the investigator, 
may affect cognitive function. 
● Use of benzodiazepines within 12 hours of cognitive assessments. 
● Consumption of alcohol within 8 hours of cognitive assessments. 
● Physical, cognitive, or language impairments sufficient to adversely affect data derived 
from cognitive assessments. 
● Diagnosed reading disability or dyslexia. 
● Clinically significant learning disorder by history. 
● Electroconvulsive therapy (ECT) in the last 6 months. 
● 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. 
● Pregnant and/or breastfeeding. 
● Received investigational agents as part of a separate study within 30 days of the 
screening visit. 
● Actively suicidal/presence of suicidal ideation or evaluated as being at suicide risk (as 
per clinical judgment). 
● Currently receiving treatment with Monoamine Oxidase Inhibitors (MAOIs) 
antidepressants, antibiotics such as linezolid, or intravenous methylene blue. 
● Previous hypersensitivity reaction to vortioxetine or any components of the formulation. 
Angioedema has been reported in patients treated with vortioxetine.  
● Serotonin syndrome.  
● Abnormal bleeding. 
● Previous history of mania/hypomania.  
● Angle closure glaucoma. 
● Hyponatremia. 
● Moderate hepatic impairment. 
● Active seizure disorder/epilepsy, not controlled by medication (per study physician 
assessment). 
● Presence of any unstable medical conditions. 
Recruitment 
Recruitment will take place via media announcements (e.g., print, social media, public 
broadcasting stations). Announcement of study recruitment will also be provided to primary 
health care providers in Canada. 
Study Visits  
Study visits may be conducted remotely (e.g. zoom), by telephone or in-person. Visits with the 
study physician will primarily occur via a secure online platform (e.g. OTN) or by telephone. If 
required/requested, in-person visits with the study physician may be scheduled.  
Participants may be emailed a secure, unique and anonymized RedCap link to complete self-
report questions at home within 24 hours of their scheduled visit (before or after visit). This is to 
reduce participant burden during the visit with research staff/study physicians. Participants will 

 
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be asked to complete self-report questionnaires at the same time block of the day during all 
study visits (i.e. all mornings, afternoons or evenings). 
Pre-Screen 
Participants will be pre-screened via telephone, email, or an online form to determine if they 
meet above noted inclusion and exclusion criteria.  
 
Screening Visit (Visit 0) 
Once participants provide written, informed consent, they will undergo a comprehensive 
assessment to determine eligibility during the screening visit. Details of assessments completed 
are included in Table 1.  
 
Baseline (Visit 1) 
Participants will undergo the various assessments listed in Table 1. In addition, participants will 
have their blood drawn and may be invited to participate in an optional fMRI scan (see details 
below). Participants will also be assessed by a study physician at one time point between the 
screening and baseline visits and be provided a prescription for vortioxetine. Research staff 
(i.e.research coordinators/research assistants) will dispense the medication to the participant 
based on the direction from the study physician/prescription from the study physician for the first 
two weeks of the study. For remote participants, research staff will mail medication for the first 
two weeks of the study with appropriate temperature monitoring.  
 
Laboratory Assessment: Participants will be asked to fast for 8 hours prior to their baseline (visit 
1) and week 8 (visit 4). Participants will have blood drawn for standard clinical parameters. 
These include glucose, insulin, electrolytes, liver and kidney function tests, lipids, CBC, 
inflammatory markers (e.g. CRP, ESR), albumin and protein. Participants may also have their 
blood drawn for various exploratory secondary analyses (e.g. cytokines). Approximately 20 mL 
of blood will be drawn in 4-5 blood tubes. Two of these tubes will include lavender tubes with 
EDTA for exploratory analyses. A urine or blood pregnancy test will be conducted for all female 
participants.  
 
Remote participants will be provided a blood requisition form via email or mail to have clinical 
blood drawn and analyzed at the participant’s local blood lab facility. Blood will not be collected 
for exploratory purposes from remote participants. Female participants may provide a blood or 
urine sample to the local blood lab to confirm non-pregnancy. Participants may also be mailed a 
home pregnancy test.  
 
Exploratory Blood Analyses: For participants seen in-person, they will be able to volunteer to 
provide a blood sample for exploratory analyses. The sample will be collected at a local blood 
lab (e.g. Mount Sinai Hospital), followed by processing and storage of the sample at the 
Biospecimen Repository and Processing Lab (Lunenfeld-Tanenbaum Research Institute, Sinai 
Health). Participants may also have blood drawn at the same time for clinical purposes at Mount 
Sinai Hospital. The clinical blood tubes will be delivered to another local lab (e.g.Dynacare, 
LifeLabs) for analyses. Alternatively, participants may also have blood drawn separately for 
clinical analyses at a local blood lab near them - this will result in two separate blood draws.   
 

 
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fMRI: A subset of participants may be offered the opportunity to have an fMRI scan completed 
at baseline and endpoint for secondary, exploratory purposes. This is optional and not the 
primary focus of the study. Participants may still participate in the study and decide not to 
participate in this component. During the imaging, participants will be asked to complete a 
cognitive task (e.g. Effort Expenditure for Rewards Task, Trails Making Test A/B). Participants 
will be awarded the amount of money they earn during this task, on top of the standard 
compensation to all participants. Please see “Participant Compensation” for more details.  
 
Week 2 (Visit 2): Participants will complete items listed in Table 1, Week 2 (Visit 2). The study 
physician will determine if the participant is eligible for a dose increase. Research staff 
(i.e.research coordinators/research assistants) will dispense medication to the participant based 
on the direction from the study physician/prescription from the study physician for the next six 
weeks of the study. For remote participants, medication for the remaining six weeks of the study 
will be mailed out as well as medication for discontinuation by research staff with appropriate 
temperature monitoring. 
Week 4 (Visit 3): Participants will complete items listed in Table 1, Week 4 (Visit 3).  
 
Week 8 (Visit 4): Participants will complete items listed in Week 8 (Visit 4). The study physician 
will also discuss transition of care (see below) and/or medication continuation. Participants will 
also have their blood drawn and may be asked to participate in the optional fMRI scan.  
 
Optional Post-Study (Week 10): Clinical visit with physician if the participant is discontinuing the 
study medication and/or as needed. If a participant chooses to continue with the study 
medication, he/she will be asked to follow up with his/her most responsible physician (MRP) for 
ongoing care and this post-study visit would not be needed. Participants will be informed prior to 
signing the consent form that research staff/research physician will not be able to tell them if 
they received drug or placebo when they finish the study at week 8 and they will have to wait 
until the entire study is complete to find out.  
 
Table 1. Study schedule with assessments 
Study Visit 
Screening 
(Visit 0) 
Baseline 
(Visit 1) 
Visit 2 
Visit 3 
End-of-study 
(Visit 4) 
Week 
(-1 to -21 
days from 
baseline) 
0 
 
2 
(+/- 2 days) 
4 
(+/- 2 days) 
8 
(+/- 2 days) 
Consent 
X 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Past COVID-19 Infection 
Information 
X 
 
 
 
 

 
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M.I.N.I 7.0.2 
X 
 
 
 
 
Psychiatric/Medical History 
X 
 
 
 
 
Lifestyle Factors 
X 
 
 
 
 
Current Medications 
X 
X 
X 
X 
X 
Medication Changes  
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
Anthropometrics 
 
X 
X 
 
X 
MoCA 
 
X 
 
 
 
SETS 
 
X 
 
 
 
DSST  
 
X 
X 
 
X 
TMT-A/B 
 
X 
X 
 
X 
RAVLT 
 
X 
X 
 
X 
CogState Online Cognitive 
Battery** 
 
X 
X 
 
X 
PDQ-20 
 
X 
X 
X 
X 
GAD-7 
 
X 
X 
X 
X 
SHAPS 
 
X 
X 
X 
X 
FSS 
 
X 
X 
X 
X 
WHO-5 
 
X 
X 
X 
X 
SDS 
 
X 
X 
X 
X 
BAS 
 
X 
X 
X 
X 
EQ-5D-5L 
 
X 
X 
X 
X 
QIDS-SR16 
 
X 
X 
X 
X 
IPAQ 
 
X 
 
X 
X 
PCFS 
X 
X 
X 
X 
X 
EEfRT 
 
X 
 
 
X 

 
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Physician Assessment* 
X 
 
X 
X 
X 
Laboratory assessments 
 
X 
 
 
X 
fMRI + Cognitive Test 
 
X 
 
 
X 
 
Abbreviations: a:  BAS: Behavioural Activation Scale; DSST: Digit Symbol Substitution Test; 
EQ-5D-5L: 5-Level EQ-5D version; fMRI: functional magnetic resonance imaging; FSS: Fatigue 
Severity Scale; GAD-7: Generalized Anxiety Disorder, 7-item; IPAQ: International Physical 
Activity Questionnaire; EEfRT: Effort Expenditure for Rewards Task ; M.I.N.I: Mini-International 
Neuropsychiatric Interview; MoCA: Montreal Cognitive Assessment; PCFS: Post-Covid 
Functional Scale; PDQ-20: Perceived Deficits Questionnaire, 20-item; Quick Inventory of 
Depressive Symptomatology (16-Item) (Self-Report) (QIDS-SR16); RAVLT: Rey's auditory 
verbal learning test; RPE: Borg Rating of Perceived Exertion Scale; SDS: Sheehan Disability 
Scale; SETS: Stanford Expectations of Treatment Scale; SHAPS: Snaith-Hamilton Pleasure 
Scale; TMT-A/B: Trails Making Test-A/B; WHO-5: World Health Organization Well-Being Index, 
5-item. 
*One physician assessment will be conducted between the baseline and screening visit.  
**May be conducted remotely.  
Sample Size 
● Total recruitment N=200 (i.e., 100 subjects allocated to vortioxetine [5-20 mg] and 
placebo each).  
● The target sample size is based on effect sizes reported by previous clinical trials that 
evaluated the efficacy of antidepressants vs placebo and nutraceuticals in individuals 
with chronic fatigue syndrome 6,23–25. 
● The effect size of vortioxetine on DSST-measured cognitive function is estimated at 
approximately 0.2-0.5 2627. Previous experience without patients enrolled in clinical trials 
(investigator-initiated trials) with vortioxetine as part of the THINC-it tool validation 
indicated that vortioxetine improves measures of processing speed (the prominent 
domain validated by the DSST) of significance with a sample size of 200.  
● It is then estimated that a sample size of 100 per treatment arm would detect clinically 
relevant change with vortioxetine treatment on DSST as the dependent measure 27,31. 
Feasibility 
● It is estimated, based on prior general population research conducted by the BCDF, that 
recruitment will take approximately 12 months. 
● Community research ethics board approval, 2-4 weeks (BCDF is an independent 
research center not requiring university- or hospital-based REB reviews). 
 
Description of Study Procedures 
 
Efficacy Assessments 

 
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Digit Symbol Substitution Test (DSST) 
The DSST is a neuropsychological test sensitive to brain damage, dementia, age and 
depression.32,33. The DSST consists of digit-symbol pairs followed by a list of digits. The 
participant will select the corresponding symbol as fast as possible. The number of correct 
symbols within 90 seconds will be recorded. The test is administered by trained personnel. The 
DSST will be administered at baseline (visit 1), and weeks 2 and 8 visits.  
 
Rey Auditory Verbal Learning Test (RAVLT) 
The RAVLT is a neuropsychological assessment designed to evaluate verbal memory in 
patients aged 16 years and older 34. It is presented as a list-learning paradigm wherein the 
participant is read a list of 15 nouns and is asked to recall as many words from the list as 
possible. After five repetitions of free-recall, a second “interference” list (List B) is presented in 
the same manner, and the participant is asked to recall as many words from List B as possible. 
After the interference trial, the participant is immediately asked to recall the words from List A, 
which they have heard five times previously. After a 20 min delay, the participant is asked to 
again recall the words from List A.  This assessment directly tests recognition memory, as 
opposed to free-recall. The test is administered by trained personnel. The RAVLT will be 
administered at baseline (visit 1), and weeks 2 and 8 visits.  
 
Trail Making Tests A/B (TMT-A/B) 
The TMT-A/B are well established tests sensitive to impairment in multiple cognitive domains, 
including attention, visual memory and processing speed, executive functioning, and overall 
cognitive functioning. The tests are administered by a trained personnel. Participants are asked 
to connect circles in numerical sequence as part of TMT-A and in alternating numerical and 
alphabetical sequence as part of TMT-B (e.g., 1-A-2-B). If a participant makes a mistake, the 
administrator points out the error, and the participant must return to the last correct circle and 
continue the task. The tests are timed and participants are given five minutes to complete each 
test; a shorter time denotes higher performance 35. The TMT- A/B will be administered at 
baseline (visit 1), and weeks 2 and 8 visits.  
 
CogState Online Cognitive Battery 
The CogState Online Cognitive Battery (https://www.cogstate.com/) employed in the present 
trial will consist of four tests: 
Domain: Executive Function  
1. Operation: Digit Symbol substitution test  
Cognitive Test: CogState DSST – Symbols - “In this test, subjects are 
presented with a legend that defines nine symbols, with each symbol 
corresponding to a digit from 1 to 9. The subject is then presented with a 
conveyor belt in the middle of the screen that displays a series of empty 
boxes labelled with a number. The subject must select the symbol that 
corresponds to the number of a given highlighted box from symbol 
options presented at the bottom of the screen. The subject must try to 
place as many correct symbols in the boxes as possible over the duration 
of the test.” 36 

 
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Time: 3 min  
Domain: Attention 
2. Operation: Choice Reaction Time  
Cognitive Test: CogState Detection Test - “The Detection test measures 
processing speed using a simple reaction time paradigm. The on-screen 
instructions ask: “Has the card turned over?”. A playing card is presented 
face down in the center of the screen. The card flips over so it is face up. 
As soon as the card flips over the participant must press “Yes”. The 
participant is encouraged to work as quickly as they can and be as 
accurate as possible.” 36 
 
 
 
Time: 3 min 
3. Operation: Choice Reaction Time 
Cognitive Test: CogState Identification Test - “The Identification test 
measures attention using a choice reaction time paradigm. The on-screen 
instructions ask: “Is the card red?”. A playing card is presented face down 
in the center of the screen. The card flips over so it is face up. As soon as 
it flips over the participant must decide whether the card is red or not. If it 
is red the participant should press “Yes”, and if it is not red the participant 
should press “No”. The participant is encouraged to work as quickly as 
they can and be as accurate as possible.” 36 
Time: 3 min  
Domain: Memory  
4. Operation: Visual Learning  
Cognitive Test: CogState One Card Learning Test - “The One Card 
Learning test measures visual memory using a pattern separation 
paradigm. The on-screen instructions ask: “Have you seen this card 
before in this test?”. A playing card is presented face up in the center of 
the screen and the participant must decide whether they have seen the 
card before in this test. The participant is encouraged to work as quickly 
as they can and be as accurate as possible.” 36 
Time: 6 min 
 
Each participant will be completing the battery twice on the same day to assess test reliability 
and as an objective measure of fatigue.The CogState Online Cognitive Battery will be 
administered at baseline (visit 1), and weeks 2 and 8 visits.  
 
Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR-16) 
The QIDS-SR-16 37 is a 16-item self-rated scale designed to assess the severity of depressive 
symptoms in the nine diagnostic symptom domains of a major depressive episode, exclusive of 
atypical or melancholic symptoms, over the past 7 days. The QIDS-SR-16 is sensitive to change 
with various treatments, demonstrating its utility in research settings. The total score ranges 
from 0 to 27 with 0 representing no depression and 27 representing severe depression. The 
total score is the sum of the 9 symptom domains. The QIDS-SR-16 will be administered at 
baseline, and weeks 2, 4, and 8 visits.  
 

 
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Patient Health Questionnaire, 9-item (PHQ-9) 
The PHQ-9 is a self-rated measure of depressive symptom severity in the past two weeks. Each 
of the nine items is rated on a Likert scale, ranging from 0 (not at all) to 3 (nearly every day), 
and summed for a total score between 0 (no symptoms) to 27 (most severe) 38. The 
standardized cut-off scores are ≥5, 10, 15, and 20 for mild, moderate, moderate-severe, and 
severe symptoms, respectively. The PHQ-9 will be administered at baseline, and weeks 2, 4, 
and 8 visits.  
 
Perceived Deficits Questionnaire, 20-item (PDQ-20) 
The PDQ-20 is a self-report measure originally developed for the assessment of cognitive 
impairment in the past two weeks for multiple sclerosis 39. It is a 20-item questionnaire that 
generates 4 subscale scores (attention/concentration, retrospective memory, prospective 
memory, and planning/organization), and a total score which is the sum of the scores for the 20 
items.  Each item is rated on a 5-point scale ranging from 0 (never) to 5 (almost always). The 
combined subscales yield a total score ranging from 0 to 80, with a higher score indicating 
greater perceived cognitive impairment. The PDQ-20 will be administered at baseline, and 
weeks 2, 4, and 8 visits.  
 
Snaith-Hamilton Pleasure Scale (SHAPS) 
The SHAPS is a self-report measure designed to assess the degree to which a person is able 
to experience pleasure or the anticipation of a pleasurable experience 40. It includes 14 items 
involving four domains of hedonic experience: interest/pastimes, social interaction, sensory 
experience, and food/drink. Each item has four possible responses: strongly disagree, disagree, 
agree, or strongly agree. For each item, a score of 2 or less constitutes a “normal” score, while 
an “abnormal” score is defined as 3 or more, and the final score ranges from 0 to 14 41. The 
SHAPS will be administered at baseline, and weeks 2, 4, and 8 visits.  
 
Generalized Anxiety Disorder Scale, 7-item (GAD-7) 
The GAD-7 is useful in primary care and mental health settings as a screening tool and 
symptom severity measure for the seven most common anxiety disorders 42. Participants 
choose one of 4 severity scores (i.e., 0: not at all, 1: several days, 2: more than half the days, 3: 
nearly every day) associated with problems related to the common anxiety disorders and then 
indicate the degree to which these problems caused functional and/or social difficulties over the 
past two weeks. Scores are determined by calculating the values for each column. The 
minimum score is 0 and the maximum score is 32, where higher scores indicate worse anxiety.  
The GAD-7 will be administered at baseline, and weeks 2, 4, and 8 visits.  
 
EQ-5D, 5-level (EQ-5D-5L) 
The EQ-5D is a standardized measure of health status for clinical and economic appraisal that 
was developed by the EuroQol Group. The 5-level version of the EQ-5D (i.e., EQ-5D-5L) 
consists of a descriptive system and a visual analogue scale and has been validated in 34 
countries, including Canada 43,44. The descriptive system comprises five dimensions: mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has five 

 
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response levels: no problems, slight problems, moderate problems, severe problems, unable 
to/extreme problems, and the participant is asked to rate their present health (i.e., “your health 
today”). Responses are coded as single-digit numbers expressing the severity level selected in 
each dimension, ranging from 1 (no problems) to 5 (extreme problems). A participant’s self-
rated health is recorded on a vertical visual analogue scale (range 100 to 0), where the 
endpoints are labelled ‘The best health you can imagine’ (100) and ‘The worst health you can 
imagine’ (0). EQ-5D-5L health states can be summarized to derive how good or bad a health 
state is according to the preferences of the general population of a country/region. The EQ-5D-
5L will be administered at baseline, and weeks 2, 4, and 8 visits.  
 
 
World Health Organization Well-Being Index, 5-item (WHO-5) 
The WHO-5 is a measure of overall well-being, rated on a scale of 0 to 25, with higher scores 
denoting higher quality of life in the past two weeks 45. There are five items, each rated on a 
five-point Likert scale (5-All the time to 0-At no time). A score below 13 denotes poor wellbeing. 
A ≥10% difference denotes a significant change. The WHO-5 will be administered at baseline, 
and weeks 2, 4, and 8 visits.  
 
Fatigue Severity Scale (FSS) 
The Fatigue Severity Scale (FSS) is a self-rated 9-item measure used to evaluate the impact of 
fatigue within the last week 46. Responses to the FSS are based on the past week and each 
statement may be rated from a scale of 1 to 7 where 1 represents “disagree” and 7 represents 
“agree”. The minimum score that can be achieved from this scale is 9, and the maximum is 63. 
A total score of 36 or more suggests the presence of fatigue.The FSS will be administered at 
baseline, and weeks 2, 4, and 8 visits.  
 
Behaviour Inhibition System/Behavioural Activation System (BIS/BAS) 
The behaviour inhibition system (BIS)/ behavioural activation system (BAS) is a 24-item self-
report questionnaire 47This questionnaire assesses aversion to threat as well as reward-seeking 
behaviour. Items are based on a 4-point Likert scale ranging from 1 (i.e, very true for me) to 4 
(very false for me). Items 1, 6, 10, 13, 15, 18 and 20 represent BIS (i.e., punishment sensitivity 
scale). Items 3, 5, 11, 14 and 19 represent the BAS Reward Responsiveness. Items 2, 7, 9 and 
17 represent BAS drive (i.e., motivation and pursuit to achieve goals). Items 4, 8, 12 and 16 
represent BAS Fun Seeking (i.e., to seek new reward as well as obtain it spontaneously). 
BIS/BAS scores may be calculated based on the sum of each subsection.The BIS/BAS will be 
administered at baseline, and weeks 2, 4, and 8 visits.  
 
International Physical Activity Questionnaire (IPAQ) 
The International Physical Activity Questionnaire (IPAQ) is a 7-item scale that measures various 
intensities of physical activity as well as sitting time based on the past 7 days 48. The minimum 
number of days is 0 and the maximum number of days is 7. The IPAQ is administered by 
research staff at baseline, week 4 and week8 visits.  
 

 
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Post-COVID-19 Functional Status Scale (PCFS) 
The Post-COVID-19 Functional Status (PCFS) scale assesses present functional ability (i.e., “in 
your current daily life”) as it relates to daily activities (including work and/or school) 49. The 
PCFS is based on a grading system wherein the lowest grade 0 indicates no 
limitations/symptoms and the highest grade 4 represents the most limitations. The PCFS  will be 
administered at baseline, and weeks 2, 4, and 8 visits.  
 
Effort-Expenditure for Rewards Task (EEfRT) 
The Effort-Expenditure for Rewards Task (EEfRT) is a multi-trial task that measures reward and 
motivation 50. Participants are given an opportunity to earn a monetary reward based on 
successful completion of a task under various reward probabilities. In each trial, participants 
may choose to complete either the “easy task” or “hard task”. To complete the “easy task”, the 
participant must use their dominant index finger and press the space bar 30 times within 7 
seconds. To complete the “hard task”, the participant must use their non-dominant little fingers 
and press the bar 100 times within 21 seconds. The value associated with the “easy task” is $1 
while the value associated with the “hard task” may vary from $1.24-$4.30. However, successful 
completion of the task does not guarantee delivery of the monetary reward. More specifically, a 
probability is applied to the each trial and the probability varies from trial to trial. . This 
probability and the monetary value associated with a particular trial’s “easy” and “hard” tasks is 
presented to the participant so they may make an informed decision as to which task they would 
like to complete. The EEfRT will be administered at baseline and week 8 visit. Participants are 
notified before they start the EEfRT task that they will be awarded the entire monetary value 
they earn from completing this task. 
 
fMRI 
Individuals who participate in the fMRI will complete a cognitive task (e.g., EEfRT, TMT A/B) to 
obtain various functional, physiological and anatomical measurements. This is a secondary 
measure in this study and the data will be used for various exploratory analyses. Analyses may 
include standard anatomical examination, magnetic resonance spectroscopy (MRS) to measure 
brain chemistry; diffusion tensor imaging (DTI) to measure the electrical connections between 
neurons and arterial spin labelling (ASL) to measure blood flow in the small vessels of the brain.  
 
Exploratory Blood Analyses 
Plasma samples will be collected and stored for exploratory analyses. Please see above 
“Baseline (Visit 1)” for further description of the procedure.   
   
Safety Assessments 
Clinical Laboratory Tests 
Blood samples will be obtained at baseline for routine laboratory test:  
●   Haematology: complete blood count (CBC) 
●   Biochemistry: hemoglobin A1c (HbA1C), Sodium, Potassium, Lipid Assessment 
(includes cholesterol, HDL-C, Triglycerides, calculated LDL-C & Chol/HDL-C ratio) 
●  Other tests: Chloride, Bicarbonate, C-reactive peptide (CRP), erythrocyte 
sedimentation rate (ESR), estimated glomerular filtration rate (EGFR) 

 
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● hCG pregnancy screen (as applicable)  
 
A urine pregnancy test will be administered if no hCG pregnancy screen has been conducted.  
  
In the event of an unexplained clinically significant abnormal laboratory test value, the test 
should be repeated and will be followed up until it has returned to the normal range and/or an 
adequate explanation of the abnormality is found. 
 
Adverse Events  
All AEs occurring after the participant signs the ICF and up to the last study event will be 
recorded. Any unresolved AEs that are ongoing at the end of the study will be followed until 
resolution or no longer considered clinically significant by the investigator. 
 
Other Assessment Instruments  
 
Mini International Neuropsychiatric Interview Version 7.0.2 (M.I.N.I. Version 7.0.2) 
The MINI was designed as a brief structured interview for the major Axis I psychiatric disorders 
in DSM-5 and International Classification of Diseases-10. Validation and reliability studies have 
been done comparing the MINI to the Structured Clinical Interview for DSM-5 Patient Edition 
and the Composite International Diagnostic Interview (a structured interview developed by the 
World Health Organization). Version 7.0.2 of the MINI will be used for this study. The results of 
these studies show that the MINI has similar reliability and validity properties, but can be 
administered in a much shorter period (mean 18.7 ± 11.6 min, median 15 min) than the above 
referenced instruments. It can be used by clinicians after a brief training session. At screening, 
participants will be assessed for MDD and BD, as documented by DSM-5 criteria, and the lack 
of other psychiatric diagnoses will be confirmed by use of the MINI.  
 
Montreal Cognitive Assessment (MoCA) 
The MoCA is a 10-minute cognitive screening tool designed to detect mild cognitive impairment 
51. The MoCA evaluates short-term memory recall, visuospatial abilities, executive functioning, 
attention, concentration, and working memory, language, and orientation to time and place. It is 
a one-page 30-point test. In clinical practice, patients screened and found to have a MoCA 
score over 26 would be extremely unlikely to meet clinical and neuropsychological criteria for 
MCI even after extensive evaluation. The MoCA demonstrates high test-retest reliability, and 
good internal consistency, and there is a close correlation between MoCA and MMSE scores. 
Version November 7, 2004 will be administered by clinicians who have completed the official 
MoCA training and certification (https://www.mocatest.org/training-certification/). At baseline in-
person visits, participants will be assessed for mild cognitive impairment (operationalized as a 
MoCA score <26). 
 
Stanford Expectations of Treatment Scale (SETS) 
The SETS is a self-report tool designed to measure patient outcome expectancy in clinical trials 
52. The six-item SETS contains two subscales: positive expectancy (α = 0.81–0.88) and 
negative expectancy (α = 0.81–0.86). Each of the six items includes 7 selection options: 
strongly disagree, moderately disagree, slightly disagree, neither agree nor disagree, slightly 

 
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agree, moderately agree, strongly agree. The positive and negative subscales demonstrate 
strong internal reliability and are able to predict post treatment response. Most participants are 
able to complete the SETS in approximately 1 min. The SETS  will be administered at baseline 
visits.  
Study Site 
The study will be conducted at the Brain and Cognition Foundation (BCDF) main site in Toronto 
(77 Bloor St. West, Toronto, ON, M5S 1M2). BCDF is a non-profit organization engaged in 
research and educational activities as it relates to brain health and disease, including but not 
limited to studies in persons with mood disorders, as well as persons who are at-risk for mood 
disorders. BCDF conducts both proof-of-mechanism, as well as phase 1-3 clinical trials and is 
one of the most active clinical research organizations in the world based on bibliometrics. Study 
medication and placebo will be stored in a secured/locked cabinet and office at BCDF and 
medication will be dispensed by research staff per instruction/prescription of the study 
physician.  
 
The study physician will be based out of the medical clinic at CRTCE/KJK HealthPlex in 
Mississauga. As part of participants' ongoing clinical monitoring and care, all participants will 
have a medical file opened for them at CRTCE/KJK HealthPlex. The study physician evaluating 
the participant will be documenting the visits in the participant’s medical chart at CRTCE/KJK 
HealthPlex. The majority of the study visits with the study physician will be conducted remotely. 
However, in-person visits with the study physician may be scheduled at CRTCE/KJK HealthPlex 
upon the request of the participant or the study physician.  
 
Participants will complete blood draws for clinical and exploratory blood analyses at a local 
laboratory near the BCDF office in Toronto. Exploratory blood samples will be stored at the 
Biospecimen Repository and Processing Lab (Lunenfeld-Tanenbaum Research Institute, Sinai 
Health). Please see “Baseline (Visit 1)” for more details.  
 
fMRI scans are completed at an external institution (e.g. Sunnybrook Health Sciences Centre, 
University of Toronto). The research staff will inform participants where these scans will be 
taking place. 
 
Remote Visits 
Due to the ongoing COVID-19 pandemic, participants may choose to participate in the study 
completely remotely. Study visits will be conducted over online (e.g. Zoom) and telephone 
platforms. Visits with the study physician may be done over the secure Ontario TeleNetwork 
(OTN) or telephone. Participants will be mailed the study medication. Anthropometrics (e.g. 
height and weight) will be self-reported by participants. Participants will be mailed or emailed a 
lab requisition form to complete standard clinical blood tests at their local blood lab. Female 
participants will be asked to provide a urine or blood sample to confirm non-pregnancy. Female 
participants may also be mailed a home pregnancy test. 
 
Study Flow 

 
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Conditions for Withdrawal From the Study 
Premature Discontinuation 
If participation in the study is terminated prematurely for any reason, the reason for such early 
termination should be documented. The reason for any early termination should be recorded, 
providing as much information as possible.  
The reason for early termination can be selected from as follows: 
● Screen Failure: Participant does not qualify to participate in the study. 
● Lack of efficacy (e.g., increased suicidality). 
● Adverse Event: Clinical or laboratory events occurred that, in the medical judgment of 
the investigator for the best interest of the participant, are grounds for discontinuation. 
This includes serious and non-serious AEs regardless of relation to study medication. 
● Death: The participant died.    
● Withdrawal of Consent: The participant desired to withdraw from further participation in 
the study in the absence of an investigator-determined medical need to withdraw. If the 
participant gave a reason for withdrawing, it should be recorded in the eCRF.   
● Protocol Violation: The participant’s findings or conduct failed to meet the protocol entry 
criteria or failed to adhere to the protocol requirements (e.g., drug non-compliance, 
failure to return for a defined number of visits, becoming pregnant during trial). The 
violation necessitated early discontinuation from the study.   
● Lost to Follow-Up: The participant stopped coming for visits and study personnel were 
unable to contact the participant.   

 
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● Non-compliance: The participant was non-compliant with study visits or procedures.   
● Other: The participant was discontinued for a reason other than those listed above. 
Withdrawal Procedures and Next Steps 
All data outlined in Table 1 will be collected for all participants up until and including the time of 
withdrawal from the study. Recruitment will occur for this study on an ongoing basis until 200 
participants are recruited and have completed the study. Participants withdrawn from the study 
will follow the outlined “Transition to Standard Care” and “Medication Discontinuation Process” 
outlined below.  
Participant Compensation 
Compensation for In-Person Participants 
Participants will receive $125 CAD at week 2 visits, $125 at week 4 visits and $250 at week 8 
visit. Participants may also choose to receive the full $500 at the end of the study (week 8). 
Participants who complete the EEfRT task will be awarded their earnings from this task in 
addition to the $500. The EEfRT may also be administered as a stand alone assessment (i.e., 
outside of fMRI) or as part of the fMRI assessment. Participants who complete the EEfRT will be 
compensated with what they earn from this task in addition to the $500. Participants that 
complete exploratory blood work will also be compensated $50.  
 
Compensation for Remote Participants 
Participants will receive $31.25 CAD at week 2 visits, $31.25 at week 4 visits and $62.50 CAD 
at week 8 visit. Participants may also choose to receive the full $250 at the end of the study 
(week 8).  
Study Medication: Vortioxetine 
AGE: 18-64 
Participants receiving vortioxetine will be provided 10 mg/day on days 1–14 of the treatment 
period, and will be titrated to 20 mg/day at the start of week 3 (day 15) based on study clinician 
judgment. For the remaining 6 weeks, the dose of vortioxetine will be 20 mg/day, unless 
adjudicated otherwise by a study clinician.  
AGE: >65 
Per product monograph, participants 65+ receiving vortioxetine will be provided 5 mg/day on 
days 1–14 of the treatment period, and will be titrated to 10 mg/day at the start of week 3 (day 
15) based on study clinician judgment. For the remaining 6 weeks, the dose of vortioxetine will 
be 10 mg/day, unless adjudicated otherwise by a study clinician. 
Age: 65 
Individuals aged 65 may start at 5mg or 10mg on days 1-14, and this dose may be titrated to 
10mg or 20mg, respectively, at the start of week 3 based on the recommendation of the study 
physician. 
Vortioxetine will be encapsulated in a capsule shell made of Capsugel® empty hard gelatin 
capsule (non-porcine / pure-bovine origin). Colorant: Swedish Orange OpC307. Size: AA. 

 
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Excipients: Gelatin, Red Iron Oxide, Titanium Dioxide. The filler used for both the active capsule 
with vortioxetine and the entire placebo capsule is Capsulac® 60 Lactose Monohydrate 
(Ph.Eur/USP-NF/JP). 
Individuals aged 65 may start at 5mg or 10mg on days 1-14, and this dose may be titrated to 
10mg or 20mg, respectively, at the start of week 3 based on the recommendation of the study 
physician. 
Side effects 
● Serotonin Syndrome has been reported with serotonergic antidepressants (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). 
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 
● Itchy skin 
● Nasopharyngitis 
 
 
Rare: Less than 1% 
● Nervous system disorders 
● Skin and subcutaneous tissue disorders 
● Psychiatric disorders 
● Abnormal bleeding  

 
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● Clinical worsening or suicide risk  
 
Post-Market Adverse Reactions 
The following adverse events have been identified during post-approval use of Vortioxetine. 
These events are reported voluntarily from a population of uncertain size, and it is not possible 
to reliably estimate their frequency or establish a causal relationship to drug exposure. 
● Hyperprolactinaemia 
● Acute pancreatitis 
● Anaphylactic reaction 
● Serotonin syndrome, headache 
● Agitation, aggression 
● Angioedema 
● Hemorrhage (including contusion, ecchymosis, epistaxis, gastrointestinal or vaginal 
hemorrhage) 
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 or antibiotics such as linezolid 
or 
intravenous methylene blue is also contraindicated because of an increased risk of serotonin 
syndrome. 
Storage 
Medication will be stored at room temperature in a locked cabinet and office space at BCDF (77 
Bloor Street West, Suite 600, Toronto, ON, M5S 1M2). 
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.  
If patients do experience side effects during the study, the study physician will make a 
recommendation regarding the discontinuation or dose reduction of the medication for the 

 
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remainder of the study. If participants do not experience any improvement upon study 
completion in mood or cognition, the medication will be gradually discontinued over a two-week 
period upon study completion (end of week 8). Participants will take half of their final dose of 
vortioxetine during the first week post-study and no medication during the second week of 
discontinuation. Participants will be provided with one week worth of medication for this 
discontinuation process but will not be provided any further supply thereafter.  
Vortioxetine discontinuation process 
At the end of week 8, patients will be seen by the study physician and provided with half of 
current vortioxetine dosage for a period of 1 week. This is in keeping with the product insert, 
although vortioxetine does not cause discontinuation syndrome. During the second week, 
patients will not be on medication and will be seen by the study physician at the end of two 
weeks, to ensure that there are no risks or adverse events during this time period. This visit with 
the clinician is post-study, and not part of the study visits. Patients are encouraged to contact 
the study team in the event that they would like to be scheduled with the physician earlier.  
Data Handling 
Personal Data Protection 
All data collection material will be de-identified. Participant records will be distinguished using 
participant identification (PID) numbers. 
Data Collection and Retention 
The majority of data will be collected electronically through the secure RedCap platform. 
Participants will also sign the consent form via the RedCap platform after a thorough discussion 
with research staff during the in-person screening visit. Participants will receive an electronic 
copy of their consent form via email. Participants may also receive a printed copy of the consent 
form if this is preferred. 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. Data collected as hard copies (e.g. paper format) 
may be digitized and stored electronically, after which the hard copies will be destroyed (even 
before the 25 years). 
Participants’ de-identified plasma samples (labelled with participant ID) will be stored in a -80 
degrees Celsius freezer for a maximum of 15 years from the time of collection. Participants may 
choose to withdraw their samples at any time. 
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. 
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 

 
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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. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. Follow-up of 
adverse events should be based upon the clinical judgement of the investigator. 
Assessment of Intensity 
Each AE will be classified according to the following criteria: 
●     Mild: The AE does not interfere in a significant manner with the participant’s normal 
level of functioning. 
●     Moderate: The AE produces some impairment of functioning, but is not hazardous to 
the participant’s health. 
●     Severe: The AE produces significant impairment of functioning or incapacitation and 
is a definite hazard to the participant’s health. 
 When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the experience should be noted. If the intensity category changes over several 
days, those changes should be recorded separately (with distinct onset dates). 
Severity versus Seriousness 
It is important to distinguish between serious and severe AEs.  Severity is used to describe the 
intensity of a specific event while the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This is not the same as "seriousness," which is based 
on participant/event outcome at the time of the event.  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 should be reported as AEs. For further information regarding 
overdose, see section.  
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 or side-effects since your last visit?”).  
 
For each AE, the following parameters will be described: 
● Discovery (i.e., spontaneous or solicited) 

 
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● Start date 
● Stop date or ongoing 
● 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) 
    o   Moderate (discomfort sufficient to cause interference with normal activities) 
    o   Severe (incapacitating, with inability to perform normal activities) 
● Resolution  
Assessment of Causality 
Each AE will be assessed as to its relationship to the IP, based on the following criteria. 
Although the attribution by the investigator will be collected for reported events, for analytic 
purposes a temporal association with the use of the IP will be assumed sufficient for at least 
plausible association. 
●     Not related: No causal relationship exists between the IP and the AE, but an obvious 
alternative cause exists, eg, the participant’s underlying medical condition or 
concomitant therapy. 
●     Possibly related: A connection with the administration of the IP appears unlikely, but 
cannot be ruled out with certainty. An AE may be considered possibly related if or 
when it meets 2 of the following criteria: (1) it follows a reasonable temporal 
sequence from administration of the IP; (2) it could not readily have been produced 
by the participant’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the participant; or (3) it follows a known pattern of response 
to the IP. 
●     Related: There is a reasonable/plausible possibility that the AE may have been 
caused by the IP. 
 When assessing the relationship to the IP, the following criteria will be considered: 
●     Known class effect 
●     Biological plausibility 
●     Lack of alternative explanation—concomitant drug or disease 
 
Action Taken Regarding Investigational Product 
Dose modifications of IP (ie, dose not changed, drug withdrawn, drug interrupted, or dose 
increased). 
●     Not Applicable: Participant died, study treatment had been completed prior to 
reaction/event, or reaction/event occurred prior to start of treatment. 
Other Action Taken for Event 

 
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●     1 = None (ie, no treatment was required) 
●     2 = Medication required (ie, prescription and/or OTC medication was required to treat 
the AE) 
●     3 = Hospitalisation or prolongation of hospitalisation required (ie, hospitalisation was 
required or prolonged because of the AE, whether medication was required) 
●     4 = Other 
Adverse Event Outcome 
●     1 = Recovered/Resolved (ie, the participant fully recovered from the AE with no 
residual effect observed) 
●     2 = Recovering/Resolving (ie, the AE improved but has not fully resolved) 
●     3 = Not Recovered/Not Resolved (ie, the AE itself is still present and observable) 
●     4 = Recovered/Resolved with Sequelae (ie, the residual effects of the AE are still 
present and observable, including sequelae/residual effects) 
●     5 = Fatal (ie, ‘fatal’ should be used when death is a direct outcome of the AE) 
●     6 = Unknown 
Clinical Laboratory Changes 
Any abnormality in a laboratory value that is new in onset or which has worsened in severity or 
frequency from the baseline condition and meets 1 of the following criteria will be recorded on 
the AE pages of the eCRF: 
●     Requires therapeutic intervention or diagnostic tests 
●     Leads to discontinuation of IP 
●     Has accompanying or inducing symptoms or signs 
●     Is judged by the investigator as clinically significant 
Combined elevations of aminotransferases and bilirubin, either serious or nonserious, and 
whether causally related, meeting the criteria of a potential Hy’s Law case (total bilirubin level ≥ 
2 × upper limit of normal [ULN] with simultaneous ALT or AST ≥ 3 × ULN) should always be 
reported to the sponsor as soon as possible following the procedures outlined in Section 10.2 
for SAE reporting, with the investigator’s assessment of seriousness, causality, and a detailed 
narrative. 
Overdose 
Any instance of overdose (suspected or confirmed) must be fully documented as an AE or SAE 
if it meets the SAE criteria. Details of any signs or symptoms and their management should be 
recorded including details of any antidote(s) administered. 
Adverse Event Follow-up 
All AEs will be followed until resolved or stable and the outcome documented on the eCRF. If 
the investigator detects an AE in a study participant after the last scheduled follow-up visit and 

 
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considers the event possibly related or related to prior study treatment, the investigator will 
document it. 
Serious Adverse Events (SAE)/Serious Adverse Drug 
Reaction (SADR) 
Definition: A serious adverse event (SAE)/Serious Adverse Drug Reaction (SADR) 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 
● 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 
Any serious, untoward event that may occur subsequent to the reporting period that the 
investigator assessed as related to IP should also be reported and managed as an SAE. The 
investigator should follow participants with AEs until the event has resolved or the condition has 
stabilized. In case of unresolved AEs, including significant abnormal clinical laboratory values at 
the end of study assessment, these events will be followed until resolution or until they become 
clinically not relevant. Disability/incapacitating: An AE is incapacitating or disabling if the 
experience results in a substantial and/or permanent disruption of the participant's ability to 
carry out normal life functions. 
The causality of SAEs/SADRs (i.e., their relationship to study treatment) will be assessed by the 
investigator(s). Note that SAEs/SADRs that could be associated with any study procedure 
should also be reported. For such events the causal relationship is implied as “yes”. 
Serious unexpected adverse drug reaction (SUADR) Definition: means a serious 
adverse drug reaction (SADR) that is not identified in nature, severity or frequency in the risk 
information set out in the investigator's brochure or on the label of the drug. 
Reporting of SAEs/SADRs/SUADRs 
All SAEs/SADRs/SUADRs should be reported to the sponsor immediately. The immediate 
reports should be followed promptly by detailed, written reports. The immediate and follow-up 
reports should identify subjects by unique code numbers assigned to the trial subjects rather 
than by the subjects' names, personal identification numbers, and/or addresses.  
The QI should comply with the applicable regulatory requirement(s) related to the reporting of 
serious unexpected adverse drug reactions to the regulatory authority(ies) and the REB. 
SAEs/SADRs: The sponsor-investigator will comply with any and all national rules and 
regulations concerning safety reporting (SADRs or SAEs as required). All SAEs/SADRs 
(according to the definition in ICH GCP) will be done by the investigator in accordance with local 
regulations and reported to the appropriate regulatory bodies.  

 
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27 
 
SUADRs: In accordance with section C.05.014 of the Regulations, it is the responsibility of a 
sponsor to inform Health Canada, in an expedited manner, of all SUADRs in respect of a drug 
during the course of a Phase I-III clinical trial, whether or not the event occurred inside or 
outside of Canada: 
a. this information must be submitted within 15 calendar days after becoming aware of 
the event if it is neither fatal nor life threatening 
b. if the event is fatal or life threatening, Health Canada must be advised of the event 
within 7 calendar days after the sponsor first became aware of it. 
In cases where the event is fatal or life threatening, the sponsor must submit a complete 
report to Health Canada within 8 calendar days after the first notification (initial report) to 
Health Canada of the event. Follow-up reports of fatal or life threatening reactions must include 
an assessment of the importance of the event and the implication of any findings, including 
relevant previous experience with the same or similar drugs. 
In addition, in keeping with ICH GCP, the sponsor should expedite reporting of all SUADRs to 
all concerned QI(s)/institution(s), the REB(s) where required (ICH E6, 5.17.1). 
Statistical analysis plan 
Data will be analyzed for a modified intent-to-treat set: the full analysis set (FAS) will comprise 
all patients who received at least one dose of study medication and had at least one valid post-
baseline assessment of the primary outcome.  
● The MMRM model will use study visit as a fixed factor and the interaction between 
treatment and visit to allow for estimation of treatment effect at specific time points. 
Additionally, the interaction term of visit and baseline to allow for time dependent 
adjustment of baseline. An unstructured covariance matrix will be used.  
 
To control for type I error, the following sequence of hierarchically ordered primary and key 
secondary end points will be used at a significance level of 0.05 1-sided for the primary 
outcome: 
● Primary endpoint: Change from baseline to week 8 between vortioxetine and placebo in 
DSST performance score 
● Secondary endpoint: Change from baseline to week 2 between vortioxetine and placebo 
in DSST performance score 
The change from baseline in DSST performance score after 8 weeks of treatment will be 
analyzed with a one-sided mixed model for repeated measures (MMRM) with treatment and 
study visits as fixed factors and baseline DSST performance as covariate. For secondary 
analyses, the change from baseline in DSST, CogState Online Cognitive Battery, PDQ-20, 
TMT-A/B, SHAPS, FSS, GAD-7, WHO-5, EQ-5D-5L, BAS, RPE, RAVLT, PCFS, EEfRT, SETS, 
QIDS-SR16, IPAQ and SDS will also be analyzed using a mixed model for repeated measures 
(MMRM) using all available data. Withdrawal rates will be compared between placebo- and 
vortioxetine-randomized participants at week 8. 
A power calculation was obtained via computer simulations on the primary outcome of 
difference in the change from baseline in DSST performance score between vortioxetine and 
placebo. Assuming an SD of 8.0 for the change from baseline in the DSST performance score 

 
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28 
 
at week 1 and a 15% dropout rate, based on previous randomized, placebo-controlled trials with 
vortioxetine, it was calculated that 100 subjects (modified per treatment group) are required to 
achieve 80% power to detect a difference of 3.1 in the change from baseline in DSST 
performance score between vortioxetine and placebo (i.e., Cohen’s d=0.38) by an MMRM with a 
1-sided significance level of p<0.05 26,53.  
The magnitude of fMRI-determined ventral striatal (including nucleus accumbens) activation 
during anticipation of gain versus no-incentive trials, as well as loss versus no-incentive trials, in 
the EEfRT task. Mean and maximum fMRI ventral striatal activation will be assessed.  
Publication Plan 
Manuscript will be prepared within two weeks of the last subject's last visit. Manuscript will be 
submitted to a high-impact peer-reviewed journal. Data from the study will also be presented at 
national and international meetings.  
Documentation 
We will be documenting the findings in the form of peer-reviewed manuscripts as well as 
posters at international meetings.  
Contract Details 
Brain and Cognition Discovery Foundation 
77 Bloor Street West, Suite 600, Toronto, ON, M5S 1M2 
 
 

 
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29 
 
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