THINC-it Vortioxetine - Sensitivity to Change

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the sensitivity of the THINC-it tool, in measuring change in cognitive deficits in individuals with MDD after receiving vortioxetine.

Detailed Description
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Vortioxetine is used in this study as an antidepressant to improve mood, cognition and quality of life. Cognition refers to intellectual functions such as thinking, understanding, learning and remembering. Vortioxetine is approved by Health Canada for the treatment of MDD. In addition, vortioxetine has been reported to have a beneficial effect on cognitive areas such as executive function, attention/speed of processing, and memory, that are commonly affected negatively by MDD. Vortioxetine is recognized by Health Authorities in the EU and many other countries as having a benefit on cognitive dysfunction (loss of intellectual functions) in patients with MDD.Cognitive dysfunction is a highly persistent, pervasive and progressive abnormality in young adults (i.e., 18-65 years) with MDD. It has also been shown that among adults with MDD who are gainfully employed, measures of cognition are a greater determinant of overall workplace performance than is total depression symptom severity. Several lines of evidence indicate that cognitive deficits that persist between episodes of depression are critical determinants of functional recovery in the workplace. The functional implications associated with cognitive impairment provide the impetus for systematic evaluation, measurement and assessment of the domains of cognition expected to be impaired in this patient population. To date, no measurement tool has been sufficiently validated and/or determined to be sensitive to the cognitive deficits in younger adults with MDD. Major limitations of available comprehensive psychometric tools include relative lack of availability, cost, lack of access to most healthcare providers, and above all else, the lengthy time to administer. Moreover, the need for a psychometrist to interpret the results adds to the complexity and the costliness of such an endeavor. It is imperative that any tool recommended for clinical utility be aligned with the busy nature of a high-volume clinical practice. The ideal gold standard tool for assessing the presence of cognitive dysfunction in MDD in the clinical environment should include, but not be limited to, features such as good conceptual coverage of cognitive domains affected in MDD, good sensitivity and reliability, and it should be relatively uninfluenced by culture effects and practice effects. The tool would also need to be brief, easy to administer and interpret, and complement busy clinical practice. It is anticipated that the THINC-it tool will be free of charge and downloadable from the THINC-it website for use in the primary care and specialty setting. The THINC-it tool will be accessible via computers/tablets, will take 20 minutes to self-administer in a clinical setting, and the performance results will be immediately available.

Official Title
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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

Conditions
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Major Depressive Disorder, Cognitive Change

Intervention / Treatment
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* Drug: Vortioxetine
* Other: THINC-it Tool


Participation Criteria
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Eligibility Criteria
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MDD Population Inclusion Criteria: The participant is able and willing to provide informed consent. The participant is male or female 18-65 years of age. The participant has received a current diagnosis of a major depressive episode (MDE) as part of MDD as per DSM-5 criteria. The participant's current MDE is confirmed by the Mini International Neuropsychiatric Interview (M.I.N.I 5.0.). The participant is an outpatient of a psychiatric setting. The participant has a MADRS score ≥ 26 at screening and baseline. The participant's reported duration of the current MDE is at least 3 months. At least one prior major depressive episode validated by previous treatment (e.g., guideline-informed pharmacotherapy and/or manual-based psychotherapy). All participants will be screened for cognitive impairment based on DSST performance (pen-and-paper version) with a maximum baseline score of 70 correct symbols entered to avoid ceiling effects. Exclusion Criteria: Current alcohol and/or substance use disorder. 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. Medications approved and/or employed off-label for cognitive dysfunction (e.g., psychostimulants). Any medication for a general medical disorder that, in the opinion of the investigator, may affect cognitive function (e.g., corticosteroids, beta-blockers). Use of benzodiazepines within 12 hours of cognitive assessments. Consumption of alcohol within 8 hours of cognitive assessments. Recent use of marijuana as determined by a toxicology screen. Physical, cognitive, or language impairments sufficient to adversely affect data derived from cognitive assessments. Diagnosis 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 or evaluated as being a suicide risk (a score of > 4 on the MADRS and/or per clinical judgment using the Columbia-Suicide Severity Rating Scale). Currently receiving treatment with Monoamine Oxidase Inhibitors (MAOIs) anti-depressants, antibiotics such as linezolid, or intravenous methylene blue. Healthy Control Population Inclusion Criteria: No current or past history of mental disorder as evidenced by the M.I.N.I. 5.0 for DSM-IV. No first-degree relative with an established diagnosis by a healthcare provider of a mood or psychiatric disorder. No unstable medical disorders. Exclusion Criteria: 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). Pregnant and/or breastfeeding. Consumption of alcohol within 8 hours of THINC-it tool administration. Recent use of marijuana as determined by a toxicology screen.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Determining the effectiveness of a new tool used to detect changes in cognition among individuals with MDD.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Major Depressive Disorder Population<br>100 Individuals with DSM-5-defined MDD, aged 18-65 All participants receiving vortioxetine for a total of 8 weeks. Participants will receive10 mg/day on days 1-14 of the study treatment period, with the option to increase to vortioxetine 20 mg/day at the end of Week 2 based on physician's judgment. For the remaining 6 weeks, the dose of vortioxetine will be flexible at 10 or 20 mg/day as decided by a research doctor. Patients will receive the THINC-it over 3 time frame periods. The THINC-it comprised of: Spotter, Symbol Check, Codebreaker, Trails, and PDQ-5-D. | Drug: Vortioxetine<br>* Observing change in cognition using THINC-it tool in patients with MDD.<br>Other: THINC-it Tool<br>* Digitalized cognitive test application administering the following cognitive test components: Digit Symbol Substitution Test (DSST) Choice Reaction Time (CRT) One-back working memory tool Trail Making Test B (TMT-B) Perceived Deficits Questionnaire-5 Depression (PDQ-5-D)<br>|
| Other: Healthy Control Population<br>50 Healthy Controls (18-65 years of age) matched on sex, age, and years of education | Other: THINC-it Tool<br>* Digitalized cognitive test application administering the following cognitive test components: Digit Symbol Substitution Test (DSST) Choice Reaction Time (CRT) One-back working memory tool Trail Making Test B (TMT-B) Perceived Deficits Questionnaire-5 Depression (PDQ-5-D)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognition Measured Using the THINC-it Tool | Change in cognition as measured by the objective assessments of cognition within the THINC-it tool. THINC-it is the name of the cognition tool and is not an acronym. The objective measurements that comprise the THINC-it tool include the Spotter task (Choice Reaction Time), Symbol Check task(1-back test),Trails task(Trails Making Test B), and Codebreaker task (Digit Symbol Substitution Test). The composite score from all four tests were converted to standard z-score. Higher z-scores indicate better cognition. A z-score of zero indicates population mean. | Baseline and 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Mood as Measured by the Montgomery Åsberg Depression Rating Scale (MADRS) | Changes in mood assessed by the Montgomery Åsberg Depression Rating Scale [MADRS]. The overall score ranges from 0 to 60, where greater scores indicate worse depression. | Baseline and 8 weeks | 
| Changes in Cognitive Function Assessed by the Digit Symbol Substitution Task (DSST) | Changes in cognition assessed by the Digit Symbol Substitution Task (DSST). The outcome measure is the number of correct symbols copied by the participants. Higher scores indicate better performance (minimum score is 0 and maximum is 133). | Baseline and 8 weeks | 
| Changes in Cognitive Function Assessed by the Trail Making Test - Part B (TMT-B) | Changes in cognition assessed by the TMT-B. The outcome measure is time in seconds, where greater time indicates worse performance. | Baseline and 8 weeks | 
| Changes in Global Functional Impairment Using the Sheehan Disability Scale Total Score | Sheehan Disability Scale rates the extent to which his or her 1) work, 2) social life or leisure activities, and 3) home life or family responsibilities are impaired by his or her symptoms on a 10-point visual analog scale. The numerical ratings of 0-10 can be translated into a percentage if desired. The three items may be summed into a single dimensional measure of global functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired). | Baseline and 8 weeks | 
| Changes in the World Health Organization Wellbeing Index (5-Item) | The WHO-5 is a short questionnaire consisting of 5 simple and non-invasive questions, which tap into the subjective well-being of the respondents. The WHO-5 only contains positively phrased items. The respondent is asked to rate how well each of the 5 statements applies to him or her when considering the last 14 days. Each of the 5 items is scored from 5 (all of the time) to 0 (none of the time). The raw score therefore theoretically ranges from 0 (absence of well-being) to 25 (maximal well-being). A percent score out of 25 is reported. | Baseline and 8 weeks | 
| Changes in Changes in Anhedonia From Baseline to Week 8 | To establish sensitivity to change in anhedonia using the Snaith-Hamilton Pleasure Scale (SHAPS) total score in adults (18-65) with MDD treated with vortioxetine (10-20 mg flexibly dosed for 8 weeks). Higher score indicates more pleasure, with maximum of 56 points on the scale. | Baseline and 8 weeks |