Aerobic Exercise After Traumatic Brain Injury

Study Overview
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Brief Summary
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The purpose of this study is to examine the effects of individualized aerobic exercise regimen on recovery after traumatic brain injury (TBI).Investigators will determine if exercise facilitates recovery by facilitating neuroplasticity and decreasing neuroinflammation.

Detailed Description
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Exercise-based therapies can promote recovery of function and are easily implemented in the clinical rehabilitation setting. This study will determine if exercise facilitates recovery by improving markers of neuroplasticity and decreasing neuroinflammatory responses. The investigators will also determine if variations in genes involved in neuroplasticity, and inflammation influence the responsiveness to exercise and rehabilitation. Recovery will be determined by assessing cognitive function, life quality and balance.

Official Title
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Effects of Aerobic Exercise and Rehabilitation After Traumatic Brain Injury

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Other: Aerobic Exercise (AER)
* Other: Rehabilitation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All participants will provide informed consent and have to comply with the procedures of the study. Age will range from 18 to 60 years. Except for the non-injured control group, subjects will be required to have experienced TBI. All participants should be fluent in English or Spanish. All participants should have the ability to comply with the research protocol. Capable of exercising in aerobic exercise equipment (with or without trunk support). Able to walk independently with or without a device Exclusion Criteria: Current diagnosis of degenerative neurological disease. A history of cerebral vascular accidents. A history of major psychosis as defined by DSM-IV. Subjects receiving physical therapy in a location that is not CNS. Pregnancy. A history of previous TBI requiring hospitalization. Inability to cooperate Orthopedic impairment that compromises exercise performance Any cardiovascular or respiratory condition that jeopardizes patient health during exercise.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Intervention will consist of aerobic exercise sessions at predetermined heart rate range.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Aerobic Exercise (AER)<br>Consented participants will be randomly assigned to aerobic exercise regimen (AER) + Standard Rehabilitation(R+AER) or Standard Rehabilitation only (R) group. In order to determine the necessary time window for AER exercise treatment, TBI subjects will partake in supervised AER sessions for a period of 12 weeks. After a baseline evaluations follow-ups will take place at take place at weeks 4, 8 and 12. Thus each participants will be evaluated 4 times. | Other: Aerobic Exercise (AER)<br>* Aerobic exercise will be performed by utilizing aerobic exercise equipment 3 times per week.<br>|
| Active Comparator: Rehabilitation (R)<br>Participants with traumatic brain injury that are enrolled in a comprehensive rehabilitation program. These participants will receive standard rehabilitation. Given that the duration of the rehabilitative program is variable the duration of participation will be no less than 4 weeks and will not exceed 12 weeks. Activity levels will be monitored. | Other: Rehabilitation<br>* Rehabilitative program is focused on completion of activities of daily living, initiation, appropriate behavior and community integration for five days per week at the Centre for Neuro Skills.<br>|
| No Intervention: Control (C)<br>Healthy volunteers' responsiveness to exercise will be compared to TBI responsiveness. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aerobic Exercise Induced Changes in Cardio Pulmonary Exercise (CPET) at baseline | CPET will allow us to determine oxygen consumption (VO2). Results will be reported as change in VO2 levels. | Baseline | 
| Aerobic Exercise Induced Changes in Cardio Pulmonary Exercise (CPET) at Week 4 | CPET will allow us to determine oxygen consumption (VO2). Results will be reported as change in VO2 levels. | Week 4 | 
| Aerobic Exercise Induced Changes in Cardio Pulmonary Exercise (CPET) at Week 8 | CPET will allow us to determine oxygen consumption (VO2). Results will be reported as change in VO2 levels. | Week 8 | 
| Aerobic Exercise Induced Changes in Cardio Pulmonary (CPET) at Week 12 | CPET will allow us to determine oxygen consumption (VO2). Results will be reported as change in VO2 levels. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aerobic Exercise Induced Changes in Cognitive Function at baseline | Attention, processing speed, reaction times, memory and nonverbal reasoning are evaluated by CNS Vital Signs. All scores are aggregated to one reported value (Neurocognitive Index). Scoring is by a computer based auto-scored multivariate scoring system developed by the manufacturers. | Baseline | 
| Aerobic Exercise Induced Changes in Cognitive Function at Week 4 | Attention, processing speed, reaction times, memory and nonverbal reasoning are evaluated by CNS Vital Signs. All scores are aggregated to one reported value (Neurocognitive Index). Scoring is by a computer based auto-scored multivariate scoring system developed by the manufacturers. | Week 4 | 
| Aerobic Exercise Induced Changes in Cognitive Function at Week 8 | Attention, processing speed, reaction times, memory and nonverbal reasoning are evaluated by CNS Vital Signs. All scores are aggregated to one reported value (Neurocognitive Index). Scoring is by a computer based auto-scored multivariate scoring system developed by the manufacturers. | Week 8 | 
| Aerobic Exercise Induced Changes in Cognitive Function at Week 12 | Attention, processing speed, reaction times, memory and nonverbal reasoning are evaluated by CNS Vital Signs. All scores are aggregated to one reported value (Neurocognitive Index). Scoring is by a computer based auto-scored multivariate scoring system developed by the manufacturers. | Week 12 | 
| Verbal Memory Assessed by the California Verbal Learning Test (CVLT II) at baseline | The California Verbal Learning Test (CVLT II) is a verbal memory cognitive assessment. It assesses repetition learning, serial position effects, semantic organization, intrusions, and proactive interference. CVLT II scores have a mean of 0 and a SD of 1. The range of scores is +5 to -5 reported in increments of .5. | Baseline | 
| Verbal Memory Assessed by the California Verbal Learning Test (CVLT II) at Week 4 | The California Verbal Learning Test (CVLT II) is a verbal memory cognitive assessment. It assesses repetition learning, serial position effects, semantic organization, intrusions, and proactive interference. CVLT II scores have a mean of 0 and a SD of 1. The range of scores is +5 to -5 reported in increments of .5. | Week 4 | 
| Verbal Memory Assessed by the California Verbal Learning Test (CVLT II) at Week 8 | The California Verbal Learning Test (CVLT II) is a verbal memory cognitive assessment. It assesses repetition learning, serial position effects, semantic organization, intrusions, and proactive interference. CVLT II scores have a mean of 0 and a SD of 1. The range of scores is +5 to -5 reported in increments of .5. | Week 8 | 
| Verbal Memory Assessed by the California Verbal Learning Test (CVLT II) at Week 12 | The California Verbal Learning Test (CVLT II) is a verbal memory cognitive assessment. It assesses repetition learning, serial position effects, semantic organization, intrusions, and proactive interference. CVLT II scores have a mean of 0 and a SD of 1. The range of scores is +5 to -5 reported in increments of .5. | Week 12 | 
| Quality of Life Measured by the NeuroQOL at baseline | The NeuroQOL assesses quality of life in the domains of Physical Domain, Mental Domain, Cognitive Domain, and Social Domain. Items are scored on a 5-point scale that uses different language depending on assessment. The questions range from least (1) to most (5) based on frequency of behavior, amount of difficulty, or degree of agreement. T-score are used, mean of 50 and SD of 10 | Baseline | 
| Quality of Life Measured by the NeuroQOL at Week 4 | The NeuroQOL assesses quality of life in the domains of Physical Domain, Mental Domain, Cognitive Domain, and Social Domain. Items are scored on a 5-point scale that uses different language depending on assessment. The questions range from least (1) to most (5) based on frequency of behavior, amount of difficulty, or degree of agreement. T-score are used, mean of 50 and SD of 10 | Week 4 | 
| Quality of Life Measured by the NeuroQOL at Week 8 | The NeuroQOL assesses quality of life in the domains of Physical Domain, Mental Domain, Cognitive Domain, and Social Domain. Items are scored on a 5-point scale that uses different language depending on assessment. The questions range from least (1) to most (5) based on frequency of behavior, amount of difficulty, or degree of agreement. T-score are used, mean of 50 and SD of 10 | Week 8 | 
| Quality of Life Measured by the NeuroQOL at Week 12 | The NeuroQOL assesses quality of life in the domains of Physical Domain, Mental Domain, Cognitive Domain, and Social Domain. Items are scored on a 5-point scale that uses different language depending on assessment. The questions range from least (1) to most (5) based on frequency of behavior, amount of difficulty, or degree of agreement. T-score are used, mean of 50 and SD of 10 | Week 12 | 
| Depression measured by the Beck Depression Inventory-II at baseline | The Beck Depression Inventory- II (BDI-II) assesses depressive symptom severity. The BDI-II is comprised of 21 individual items reflecting specific cognitive, affective, and physical symptoms of depression. Each item includes four statements that vary in the description of symptom of severity. Scores range from 0 to 3, with a score of 3 indicating a severe symptoms and a score of 0 indicating an absence of concern with that particular aspect of depressive symptomology. The total score is the sum of all endorsed statements. The maximum total score is 63. The BDI-II Manual designates the following raw score classifications depression severity: ≤13 = minimal; 14-19 = mild; 20-28 = moderate; ≥ 29 = severe. | Baseline | 
| Depression measured by the Beck Depression Inventory-II at Week 4 | The Beck Depression Inventory- II (BDI-II) assesses depressive symptom severity. The BDI-II is comprised of 21 individual items reflecting specific cognitive, affective, and physical symptoms of depression. Each item includes four statements that vary in the description of symptom of severity. Scores range from 0 to 3, with a score of 3 indicating a severe symptoms and a score of 0 indicating an absence of concern with that particular aspect of depressive symptomology. The total score is the sum of all endorsed statements. The maximum total score is 63. The BDI-II Manual designates the following raw score classifications depression severity: ≤13 = minimal; 14-19 = mild; 20-28 = moderate; ≥ 29 = severe. | Week 4 | 
| Depression measured by the Beck Depression Inventory-II at Week 8 | The Beck Depression Inventory- II (BDI-II) assesses depressive symptom severity. The BDI-II is comprised of 21 individual items reflecting specific cognitive, affective, and physical symptoms of depression. Each item includes four statements that vary in the description of symptom of severity. Scores range from 0 to 3, with a score of 3 indicating a severe symptoms and a score of 0 indicating an absence of concern with that particular aspect of depressive symptomology. The total score is the sum of all endorsed statements. The maximum total score is 63. The BDI-II Manual designates the following raw score classifications depression severity: ≤13 = minimal; 14-19 = mild; 20-28 = moderate; ≥ 29 = severe. | Week 8 | 
| Depression measured by the Beck Depression Inventory-II at Week 12 | The Beck Depression Inventory- II (BDI-II) assesses depressive symptom severity. The BDI-II is comprised of 21 individual items reflecting specific cognitive, affective, and physical symptoms of depression. Each item includes four statements that vary in the description of symptom of severity. Scores range from 0 to 3, with a score of 3 indicating a severe symptoms and a score of 0 indicating an absence of concern with that particular aspect of depressive symptomology. The total score is the sum of all endorsed statements. The maximum total score is 63. The BDI-II Manual designates the following raw score classifications depression severity: ≤13 = minimal; 14-19 = mild; 20-28 = moderate; ≥ 29 = severe. | Week 12 | 
| Visual Search/ Processing Speed measured by Trail Making Test (TMT) at baseline | The Trail Making Test (TMT) provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. The TMT consists of two parts. TMT-A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. Task requirements are similar for TMT-B except the person must alternate between numbers and letters (e.g., 1, A, 2, B, 3, C, etc.). The score on each part represents the amount of time required to complete the task. | Baseline | 
| Visual Search/ Processing Speed measured by Trail Making Test (TMT) at Week 4 | The Trail Making Test (TMT) provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. The TMT consists of two parts. TMT-A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. Task requirements are similar for TMT-B except the person must alternate between numbers and letters (e.g., 1, A, 2, B, 3, C, etc.). The score on each part represents the amount of time required to complete the task. | Week 4 | 
| Visual Search/ Processing Speed measured by Trail Making Test (TMT) at Week 8 | The Trail Making Test (TMT) provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. The TMT consists of two parts. TMT-A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. Task requirements are similar for TMT-B except the person must alternate between numbers and letters (e.g., 1, A, 2, B, 3, C, etc.). The score on each part represents the amount of time required to complete the task. | Week 8 | 
| Visual Search/ Processing Speed measured by Trail Making Test (TMT) at Week 12 | The Trail Making Test (TMT) provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. The TMT consists of two parts. TMT-A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. Task requirements are similar for TMT-B except the person must alternate between numbers and letters (e.g., 1, A, 2, B, 3, C, etc.). The score on each part represents the amount of time required to complete the task. | Week 12 | 
| Sleepiness will be measured by the Epworth Sleepiness Scale at baseline | The Epworth Sleepiness Scale is used to measure a patient's sleepiness. The test is a list of eight situations in which the patient rates their tendency to become sleepy on a scale of 0, no chance of dozing, to 3, high chance of dozing. Total score is based on a scale of 0 to 24. The scale estimates whether you are experiencing excessive sleepiness. | Baseline | 
| Sleepiness will be measured by the Epworth Sleepiness Scale at Week 4 | The Epworth Sleepiness Scale is used to measure a patient's sleepiness. The test is a list of eight situations in which the patient rates their tendency to become sleepy on a scale of 0, no chance of dozing, to 3, high chance of dozing. Total score is based on a scale of 0 to 24. The scale estimates whether you are experiencing excessive sleepiness. | Week 4 | 
| Sleepiness will be measured by the Epworth Sleepiness Scale at Week 8 | The Epworth Sleepiness Scale is used to measure a patient's sleepiness. The test is a list of eight situations in which the patient rates their tendency to become sleepy on a scale of 0, no chance of dozing, to 3, high chance of dozing. Total score is based on a scale of 0 to 24. The scale estimates whether you are experiencing excessive sleepiness. | Week 8 | 
| Sleepiness will be measured by the Epworth Sleepiness Scale at Week 12 | The Epworth Sleepiness Scale is used to measure a patient's sleepiness. The test is a list of eight situations in which the patient rates their tendency to become sleepy on a scale of 0, no chance of dozing, to 3, high chance of dozing. Total score is based on a scale of 0 to 24. The scale estimates whether you are experiencing excessive sleepiness. | Week 12 | 
| Vestibular function will be measured by the Berg Balance Test at baseline | The Berg Balance Scale is used to determine vestibular function through a series of predetermined tasks. It is a 14 item list with each item consisting of a five-point ordinal scale ranging from 0 to 4, with 0 indicating the lowest level of function and 4 the highest level of function. | Baseline | 
| Vestibular function will be measured by the Berg Balance Test at Week 4 | The Berg Balance Scale is used to determine vestibular function through a series of predetermined tasks. It is a 14 item list with each item consisting of a five-point ordinal scale ranging from 0 to 4, with 0 indicating the lowest level of function and 4 the highest level of function. | Week 4 | 
| Vestibular function will be measured by the Berg Balance Test at Week 8 | The Berg Balance Scale is used to determine vestibular function through a series of predetermined tasks. It is a 14 item list with each item consisting of a five-point ordinal scale ranging from 0 to 4, with 0 indicating the lowest level of function and 4 the highest level of function. | Week 8 | 
| Vestibular function will be measured by the Berg Balance Test at Week 12 | The Berg Balance Scale is used to determine vestibular function through a series of predetermined tasks. It is a 14 item list with each item consisting of a five-point ordinal scale ranging from 0 to 4, with 0 indicating the lowest level of function and 4 the highest level of function. | Week 12 | 
| Aerobic capacity and endurance will be measured with the 6 Minute Walk Test at baseline | The 6 Minute Walk Test (6MWT) is a exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. The goal is for the individual to walk as far as possible in six minutes. The individual is allowed to self-pace and rest as needed as they traverse back and forth along a marked walkway. A lower score (reflecting less distance covered in 6 minutes) indicates worse function. An increase in the distance walked indicates improvement in basic mobility. | Baseline | 
| Aerobic capacity and endurance will be measured with the 6 Minute Walk Test at Week 4 | The 6 Minute Walk Test (6MWT) is a exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. The goal is for the individual to walk as far as possible in six minutes. The individual is allowed to self-pace and rest as needed as they traverse back and forth along a marked walkway. A lower score (reflecting less distance covered in 6 minutes) indicates worse function. An increase in the distance walked indicates improvement in basic mobility. | Week 4 | 
| Aerobic capacity and endurance will be measured with the 6 Minute Walk Test at Week 8 | The 6 Minute Walk Test (6MWT) is a exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. The goal is for the individual to walk as far as possible in six minutes. The individual is allowed to self-pace and rest as needed as they traverse back and forth along a marked walkway. A lower score (reflecting less distance covered in 6 minutes) indicates worse function. An increase in the distance walked indicates improvement in basic mobility. | Week 8 | 
| Aerobic capacity and endurance will be measured with the 6 Minute Walk Test at Week 12 | The 6 Minute Walk Test (6MWT) is a exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. The goal is for the individual to walk as far as possible in six minutes. The individual is allowed to self-pace and rest as needed as they traverse back and forth along a marked walkway. A lower score (reflecting less distance covered in 6 minutes) indicates worse function. An increase in the distance walked indicates improvement in basic mobility. | Week 12 | 
| Evaluation of Inflammatory Biomarkers at Baseline | Biomarkers IL10, IL12, IL-1β, IL-4 , IL-5, IL-6, IL-7, IL-8, TNFα, will be measured in blood serum before and after a 30 minute aerobic activity. Results will be reported as change in levels. | Baseline | 
| Evaluation of Inflammatory Biomarkers at Week 4 | Biomarkers IL10, IL12, IL-1β, IL-4 , IL-5, IL-6, IL-7, IL-8, TNFα, will be measured in blood serum before and after a 30 minute aerobic activity. Results will be reported as change in levels. | Week 4 | 
| Evaluation of Inflammatory Biomarkers at Week 8 | Biomarkers IL10, IL12, IL-1β, IL-4 , IL-5, IL-6, IL-7, IL-8, TNFα, will be measured in blood serum before and after a 30 minute aerobic activity. Results will be reported as change in levels. | Week 8 | 
| Evaluation of Inflammatory Biomarkers at Week 12 | Biomarkers IL10, IL12, IL-1β, IL-4 , IL-5, IL-6, IL-7, IL-8, TNFα, will be measured in blood serum before and after a 30 minute aerobic activity. Results will be reported as change in levels. | Week 12 | 
| Evaluation of Neuroplasticity, Stress Biomarkers at Baseline | Biomarkers BDNF, GH, ACTH, Cortisol, Melatonin, VEGF will be measured in blood serum before and after a 30 minute aerobic activity. Results will be reported as change in levels. | Baseline | 
| Evaluation of Neuroplasticity, Stress Biomarkers at Week 4 | Biomarkers BDNF, GH, ACTH, Cortisol, Melatonin, VEGF will be measured in blood serum before and after a 30 minute aerobic activity. Results will be reported as change in levels. | Week 4 | 
| Evaluation of Neuroplasticity, Stress Biomarkers at Week 8 | Biomarkers BDNF, GH, ACTH, Cortisol, Melatonin, VEGF will be measured in blood serum before and after a 30 minute aerobic activity. Results will be reported as change in levels. | Week 8 | 
| Evaluation of Neuroplasticity, Stress Biomarkers at Week 12 | Biomarkers BDNF, GH, ACTH, Cortisol, Melatonin, VEGF will be measured in blood serum before and after a 30 minute aerobic activity. Results will be reported as change in levels. | Week 12 | 
| Evaluation of Neurodegeneration Biomarkers at Baseline | Biomarkers sCAM1, vCAM-1, sFAS will be measured in blood serum before and after a 30 minute aerobic activity. Results will be reported as change in levels. | Baseline | 
| Evaluation of Neurodegeneration Biomarkers at Week 4 | Biomarkers sCAM1, vCAM-1, sFAS will be measured in blood serum before and after a 30 minute aerobic activity. Results will be reported as change in levels. | Week 4 | 
| Evaluation of Neurodegeneration Biomarkers at Week 8 | Biomarkers sCAM1, vCAM-1, sFAS will be measured in blood serum before and after a 30 minute aerobic activity. Results will be reported as change in levels. | Week 8 | 
| Evaluation of Neurodegeneration Biomarkers at Week 12 | Biomarkers sCAM1, vCAM-1, sFAS will be measured in blood serum before and after a 30 minute aerobic activity. Results will be reported as change in levels. | Week 12 | 
| BDNF / Val66Met at baseline | Evaluation of genetic material BDNF / Val66Met will be measured in a saliva sample. Results will be reported as% difference from the general population. | Baseline | 
| BDNF / Val66Met at Week 4 | Evaluation of genetic material BDNF / Val66Met will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 4 | 
| BDNF / Val66Met at Week 8 | Evaluation of genetic material BDNF / Val66Met will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 8 | 
| BDNF / Val66Met at Week 12 | Evaluation of genetic material BDNF / Val66Met will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 12 | 
| IL-1β / rs16944 at baseline | Evaluation of genetic material IL-1β / rs16944 will be measured in a saliva sample. Results will be reported as% difference from the general population. | Baseline | 
| IL-1β / rs16944 at Week 4 | Evaluation of genetic material IL-1β / rs16944 will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 4 | 
| IL-1β / rs16944 at Week 8 | Evaluation of genetic material IL-1β / rs16944 will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 8 | 
| IL-1β / rs16944 at Week 12 | Evaluation of genetic material IL-1β / rs16944 will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 12 | 
| TrkB at baseline | Evaluation of genetic material TrkB will be measured in a saliva sample. Results will be reported as% difference from the general population. | Baseline | 
| TrkB at Week 4 | Evaluation of genetic material TrkB will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 4 | 
| TrkB at Week 8 | Evaluation of genetic material TrkB will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 8 | 
| TrkB at Week 12 | Evaluation of genetic material TrkB will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 12 | 
| COMT / VAll58Met at baseline | Evaluation of genetic material COMT / VAll58Met will be measured in a saliva sample. Results will be reported as% difference from the general population. | Baseline | 
| COMT / VAll58Met at Week 4 | Evaluation of genetic material COMT / VAll58Met will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 4 | 
| COMT / VAll58Met at Week 8 | Evaluation of genetic material COMT / VAll58Met will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 8 | 
| COMT / VAll58Met at Week 12 | Evaluation of genetic material COMT / VAll58Met ewill be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 12 | 
| DRD2 / A to T & A to G at baseline | Evaluation of genetic material DRD2 / A to T & A to G will be measured in a saliva sample. Results will be reported as% difference from the general population. | Baseline | 
| DRD2 / A to T & A to G at Week 4 | Evaluation of genetic material DRD2 / A to T & A to G will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 4 | 
| DRD2 / A to T & A to G at Week 8 | Evaluation of genetic material DRD2 / A to T & A to G will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 8 | 
| DRD2 / A to T & A to G at Week 12 | Evaluation of genetic material DRD2 / A to T & A to G will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 12 | 
| ANKKI / TAQIA at baseline | Evaluation of genetic material ANKKI / TAQIA will be measured in a saliva sample. Results will be reported as% difference from the general population. | Baseline | 
| ANKKI / TAQIA at Week 4 | Evaluation of genetic material ANKKI / TAQIA will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 4 | 
| ANKKI / TAQIA at Week 8 | Evaluation of genetic material ANKKI / TAQIA will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 8 | 
| ANKKI / TAQIA at Week 12 | Evaluation of genetic material ANKKI / TAQIA will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 12 | 
| PPPIRIB / C to T at baseline | Evaluation of genetic material PPPIRIB / C to T will be measured in a saliva sample. Results will be reported as% difference from the general population. | Baseline | 
| PPPIRIB / C to T at Week 4 | Evaluation of genetic material PPPIRIB / C to T will be measured in a saliva sample. Results will be reported as% difference from the general population. | week 4 | 
| PPPIRIB / C to T at Week 8 | Evaluation of genetic material PPPIRIB / C to T will be measured in a saliva sample. Results will be reported as% difference from the general population. | week 8 | 
| PPPIRIB / C to T at Week 12 | Evaluation of genetic material PPPIRIB / C to T will be measured in a saliva sample. Results will be reported as% difference from the general population. | week 12 | 
| MAO-A /MAOA-H & MAOA-L at baseline | Evaluation of genetic material MAO-A /MAOA-H & MAOA-L will be measured in a saliva sample. Results will be reported as% difference from the general population. | Baseline | 
| MAO-A /MAOA-H & MAOA-L at Week 4 | Evaluation of genetic material MAO-A /MAOA-H & MAOA-L will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 4 | 
| MAO-A /MAOA-H & MAOA-L at Week 8 | Evaluation of genetic material MAO-A /MAOA-H & MAOA-Lwill be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 8 | 
| MAO-A /MAOA-H & MAOA-L at Week 12 | Evaluation of genetic material MAO-A /MAOA-H & MAOA-L will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 12 | 
| 5-HTR2A / AI438G at baseline | Evaluation of genetic material 5-HTR2A / AI438G will be measured in a saliva sample. Results will be reported as % difference from the general population. | Baseline | 
| 5-HTR2A / AI438G at Week 4 | Evaluation of genetic material 5-HTR2A / AI438G will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 4 | 
| 5-HTR2A / AI438G at Week 8 | Evaluation of genetic material 5-HTR2A / AI438G will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 8 | 
| 5-HTR2A / AI438G at Week 12 | Evaluation of genetic material 5-HTR2A / AI438G will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 12 | 
| 5-HT1A / C1019G at baseline | Evaluation of genetic material 5-HT1A / C1019G will be measured in a saliva sample. Results will be reported as% difference from the general population. | Baseline | 
| 5-HT1A / C1019G at Week 4 | Evaluation of genetic material 5-HT1A / C1019G will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 4 | 
| 5-HT1A / C1019G at Week 8 | Evaluation of genetic material 5-HT1A / C1019G will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 8 | 
| 5-HT1A / C1019G at Week 12 | Evaluation of genetic material 5-HT1A / C1019G will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 12 | 
| 5-HTR2B / HTR2B Q20 at baseline | Evaluation of genetic material 5-HTR2B / HTR2B Q20 will be measured in a saliva sample. Results will be reported as% difference from the general population. | Baseline | 
| 5-HTR2B / HTR2B Q20 at Week 4 | Evaluation of genetic material 5-HTR2B / HTR2B Q20 will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 4 | 
| 5-HTR2B / HTR2B Q20 at Week 8 | Evaluation of genetic material 5-HTR2B / HTR2B Q20 will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 8 | 
| 5-HTR2B / HTR2B Q20 at Week 12 | Evaluation of genetic material 5-HTR2B / HTR2B Q20 will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 12 | 
| TPH / A218C & A779C at baseline | Evaluation of genetic material TPH / A218C & A779C will be measured in a saliva sample. Results will be reported as% difference from the general population. | Baseline | 
| TPH / A218C & A779C at Week 4 | Evaluation of genetic material TPH / A218C & A779C will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 4 | 
| TPH / A218C & A779C at Week 8 | Evaluation of genetic material TPH / A218C & A779C will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 8 | 
| TPH / A218C & A779C at Week 12 | Evaluation of genetic material TPH / A218C & A779C will be measured in a saliva sample. Results will be reported as% difference from the general population. | Week 12 |