The Relationship Among Changes in Brain Network Activation in Adult Outpatients With Major Depressive Disorder

Study Overview
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Brief Summary
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The purpose of this study is to explore patterns of Brain Network Activation (BNA) changes from baseline to endpoint on 1) efficacy of core symptoms of Major Depressive Disorder (MDD) and 2) improvement of cognitive dysfunction with acute treatment with flexible dose vortioxetine in adult outpatients with MDD and subjective complaints of cognitive dysfunction.

Detailed Description
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Vortioxetine is a novel antidepressant with hypothetical multimodal mechanism of action. It is thought to work through a combination of multiple pharmacological modes of action: 5-HT (hydroxytryptamine, or serotonin) reuptake inhibition, 5-HT3 (hydroxytryptamine, or serotonin) and 5-HT7 (hydroxytryptamine, or serotonin) receptor antagonism, 5-HT1A (hydroxytryptamine, or serotonin) receptor agonism, and 5-HT1B (hydroxytryptamine, or serotonin) receptor partial agonism. In vivo nonclinical studies have demonstrated that vortioxetine enhances levels of the neurotransmitters 5-HT (hydroxytryptamine, or serotonin), norepinephrine (NE), dopamine (DA), acetylcholine and histamine in specific areas of the brain. These affinities are all considered to be of clinical relevance and involved in the mechanism of action at therapeutic doses. Vortioxetine has been shown to improve core depressive symptoms and improve cognitive function in adult outpatients with MDD and subjective complaints of cognitive function. This pilot study is intended to evaluate the extent to which BNA technology can provide clinically valuable information and provide information toward designing a subsequent confirmatory study that will further elucidate the effect of vortioxetine on MDD and cognitive function in this population. This exploratory study will ascertain the acute changes in core depression symptoms, cognitive function, tolerability, and safety using flexible-dose vortioxetine in adult outpatients with MDD with subjective complaints of cognitive functioning, as measured by BNA changes and standard outcome measures for depression and cognition. The study consists of 8 weeks of open-label treatment for MDD with response to treatment measured by standard research depression scales and BNA electroencephalogram (EEG) readings taken at certain points during the trial. An important aim in this study is to explore what correlations may exist between changes in measured brainwave patterns and reported change in depressive symptoms

Official Title
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Relationship Among Changes in Brain Network Activation, Changes in Core Depressive and Cognitive Symptoms and Safety and Tolerability in Adults With Major Depressive Disorder Treated With Open-Label, Flexible-Dose Vortioxetine

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: vortioxetine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject has single episode or recurrent MDD (acute onset of recurrence of recurrent MDD with poor inter-episode recovery) (inter-episode periods cannot meet full MDD criteria) as the primary diagnosis according to DSM-IV-TR criteria. The current major depressive episode (MDE) will be confirmed using the Mini International Neuropsychiatric Interview (MINI V6.0.0). The subject has a MADRS total score ≥26. Subject reports subjective cognitive dysfunction (such as difficulty concentrating, slow thinking, and difficulty in learning new things or remembering things). The reported duration of the current MDE is at least 3 months and no longer than 24 months. The subject is a man or woman between 18 and 65 years old, inclusive. Right-handed, normal (corrected) vision, and normal hearing. Exclusion Criteria: The subject has a score of ≥70 on the Digit Symbol Substitution Test (DSST) at the Baseline Visit. Failure to respond to or inability to tolerate an adequate trial of vortioxetine in the past. Exposure to an investigational compound 30 days prior to enrollment Exposure to any psychoactive or otherwise excluded medication within five half-lives of the baseline visit or during the study. Excluded medications include: antidepressants, anxiolytics, anticonvulsants, barbiturates, chloral hydrate, lithium, antipsychotics, benzodiazepines, hypnotics, monoamine oxidase inhibitors (MAOIs), muscle relaxers, triptans, centrally-acting antihistamines, central alpha-2 agonists, decongestants, psychostimulants, dopamine agonists, opioid pain medications, oral corticosteroids, L-methylfolate, S-adenosyl methionine (SAMe), 5-HTP (hydroxytryptophan), St. John's Wort, The subject has 1 or more of the following: Primary psychiatric disorder other than MDD as defined in the Diagnostic and Statistical Manual of Mental Disorders 4 Text Revision (DSM-IV-TR) (as assessed by the MINI, Version 6.0.0). Current or history of attention deficit hyperactivity disorder (ADHD), pervasive developmental disorder, manic or hypomanic episode, schizophrenia, or any other psychotic disorder, including major depression with psychotic features, mental retardation, organic mental disorders, or mental disorders due to a general medical condition as defined in the DSM-IV-TR. Current diagnosis of alcohol or other substance abuse or dependence (excluding nicotine or caffeine) as defined in the DSM-IV-TR that has not been in sustained full remission for at least 6 months (for abuse) and 12 months (for dependence) prior to Screening. Positive urine drug screen prior to Baseline. Presence or history of a clinically significant neurological disorder (including epilepsy). Neurodegenerative disorder (Alzheimer Disease, Parkinson Disease, multiple sclerosis, Huntington Disease, etc). Any unstable medical condition as determined by the principal investigator (PI). Any DSM-IV Axis II disorder that might compromise the study as determined by the PI. The subject has any other disorder for which the treatment takes priority over treatment of MDD or is likely to interfere with study treatment or impair treatment compliance. The subject has physical, cognitive, or language impairment of such severity as to adversely affect the validity of the data derived from the neuropsychological tests. The subject has a significant risk of suicide according to the PI's clinical judgment. The subject, in the opinion of the PI, poses a risk of harm to others. The subject has initiated formal cognitive or behavioral therapy, systemic psychotherapy within less than 6 months of study screening, or has plans to initiate such therapy during the study. The subject has received electroconvulsive therapy, vagus nerve stimulation, or repetitive transcranial magnetic stimulation within 12 months prior to Screening. The current MDE is considered by the PI to have been resistant to 2 adequate antidepressant treatments of at least 6 weeks duration each at the recommended dose. The subject is pregnant or breastfeeding, or is intending to become pregnant before, during, or within 30 days after participating in this study.

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Other - vortioxetine<br>Open-label vortioxetine | Drug: vortioxetine<br>* Open-label vortioxetine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Montgomery and Asberg Depression Rating Scale (MADRS) | The MADRS is a 10-item rating scale designed to assess the severity of symptoms of depression. Range is 0-60. Higher score means more severe. | from baseline to endpoint (up to 8 weeks) | 
| Change From Baseline to Endpoint in Digital Symbol Substitution Test. | Change in cognitive function defined as change from baseline to endpoint. The Digital Symbol Substitution Test (DSST) is a cognitive test designed to assess psychomotor speed of performance requiring visual perception, spatial decision-making and motor skills. The DSST consists of 133 digits and requires the subject to substitute each digit with a simple symbol in a 90-second period. The number of correct symbols within the allowed time (eg, 90 sec) is measured. It takes approximately 5 minutes to complete and score the DSST. | Baseline to endpoint (week 8) | 
| BNA Scores Amplitudes | Brain Network Analytics (BNA) is a tool intended for the post-hoc statistical analysis of the human EEG, utilizing both resting-state EEG and event-related potentials (ERP) waveforms. The BNA algorithm compares a patient's ERP amplitudes and latencies to those of a large group of healthy, age-matched subjects in order to visualize and quantify changes in specific brain functions. The BNA algorithm was used to detect subjects' P200 and P300 ERP components from EEG data recorded during the AOB and VGNG tasks. BNA scores represent these ERP components in terms of amplitude (in microvolts) and latency (in milliseconds). | Baseline to Endpoint (8 weeks) | 
| BNA Scores Latencies | Brain Network Analytics (BNA) is a tool intended for the post-hoc statistical analysis of the human EEG, utilizing both resting-state EEG and event-related potentials (ERP) waveforms. The BNA algorithm compares a patient's ERP amplitudes and latencies to those of a large group of healthy, age-matched subjects in order to visualize and quantify changes in specific brain functions. The BNA algorithm was used to detect subjects' P200 and P300 ERP components from EEG data recorded during the AOB and VGNG tasks. BNA scores represent these ERP components in terms of amplitude (in microvolts) and latency (in milliseconds). | Baseline to Endpoint (8 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Hamilton Depression Rating Scale (HDRS) 17 From Baseline to 8 Week Endpoint | The HDRS is a clinician-rated used to rate the patient's depressive state. The 17 question version of the scale rates depressive state based on feelings of depression, guilt, suicidality, anxiety, agitation, somatic symptoms, level of insight, patterns of insomnia, loss of interest in work and other activities, weight loss, and hypochondriasis. Additionally, the 28 question version rates depersonalization, paranoia, obsessions/compulsions, hypersomnia, appetite increase, and psychomotor slowing. The total score is obtained by summing the score of each item, 0-4 (symptom is absent, mild, moderate, or severe) or 0-2 (absent, slight or trivial, clearly present). Scores can range from 0 to 54 for the 17 question version and 0 to 83 for the 28 question version. Scores between 0 and 6 do not indicate the presence of depression, scores between 7 and 17 indicate mild depression, scores between 18 and 24 indicate moderate depression, and scores over 24 indicate severe depression. | Baseline to endpoint (week 8) | 
| Changes in Hamilton Depression Rating Scale (HDRS) 28 From Baseline to 8 Week Endpoint | The HDRS is a clinician-rated used to rate the patient's depressive state. The 17 question version of the scale rates depressive state based on feelings of depression, guilt, suicidality, anxiety, agitation, somatic symptoms, level of insight, patterns of insomnia, loss of interest in work and other activities, weight loss, and hypochondriasis. Additionally, the 28 question version rates depersonalization, paranoia, obsessions/compulsions, hypersomnia, appetite increase, and psychomotor slowing. The total score is obtained by summing the score of each item, 0-4 (symptom is absent, mild, moderate, or severe) or 0-2 (absent, slight or trivial, clearly present). Scores can range from 0 to 54 for the 17 question version and 0 to 83 for the 28 question version. Scores between 0 and 6 do not indicate the presence of depression, scores between 7 and 17 indicate mild depression, scores between 18 and 24 indicate moderate depression, and scores over 24 indicate severe depression. | Baseline to endpoint (week 8) | 
| Changes in Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-16-SR) From Baseline to 8 Week Endpoint | The QIDS-16-SR is a 16-item self-rated assessment of the severity of depressive symptoms. The assessments can be used to screen for depression, although they have been used predominantly as measures of symptom severity. The nine domains comprise 1) sad mood; 2) concentration; 3) self-criticism; 4) suicidal ideation; 5) interest; 6) energy/fatigue; 7) sleep disturbance (initial, middle, and late insomnia or hypersomnia); 8) decrease or increase in appetite or weight; and 9) psychomotor agitation or retardation. The total score ranges from 0 to 27 with higher scores equating to more severe symptomatology. The seven day period prior to assessment is the usual time frame for assessing symptom severity. | Baseline to endpoint (week 8) | 
| Changes in Clinical Global Impression Scale (CGI-S) From Baseline to 8 Week Endpoint | The CGI-S assesses the clinician's impression of the subject's current mental illness state (considering their total clinical experience with this particular population) via 7 point scale (ranging from 1-7) with higher scores equating to more symptoms. For example, a score of 1 = normal, not at all ill and a score of 7 = severely ill. | Baseline to endpoint (week 8) | 
| Correlations Between BNA Amplitude Scores and Clinical, Cognitive, and Functionality Assessments Using Baseline Scores | Pearson correlation was used to examine the associations between baseline BNA amplitude scores and outcomes including measures of MDD symptoms, cognitive function and functionality. | Baseline to Endpoint (8 weeks) | 
| Correlations Between BNA Latency Scores and Clinical, Cognitive, and Functionality Assessments Using Baseline Scores | Pearson correlation was used to examine the associations between baseline BNA latency scores and outcomes including measures of MDD symptoms, cognitive function and functionality. | Baseline to Endpoint (8 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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depression, brain network activation, vortioxetine