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A Multi-level Life-span Characterization of Adult-depression and Effects of Medication and Exercise (MEDEX)

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ClinicalTrials.gov Identifier: NCT02407704
Recruitment Status : Completed
First Posted : April 3, 2015
Results First Posted : May 23, 2018
Last Update Posted : May 23, 2018
Sponsor:
Information provided by (Responsible Party):
Kirk Erickson, PhD, University of Pittsburgh

Brief Summary:
This pilot study aims to test a model that predicts that enhanced neurotransmitter gamma-aminobutyric acid (GABA) function in reward and affect-regulation central nervous system (CNS) circuits mediates the antidepressant effects of exercise. State-of-the-art magnetic resonance (MR) imaging, cognitive assessment, accelerometry, genetic, and inflammatory biomarkers will be acquired through the coordination of efforts from several established research programs at Western Psychiatric Institute and Clinic. This pilot study will be used as a platform for testing a causal/mediating role of GABA interneurons in reward processing and affect regulation in humans. This pilot study is not powered for testing a full causal model, but rather is intended to test overall feasibility of the intervention and acquisition of measures (see specific aim 1 below). This is a necessary prerequisite for designing a larger more definitive study of the model, which will be a component of a future grant application. Additionally, the data from this study will be used to test the clinical efficacy of exercise as an adjunctive treatment for late life depression (LLD; Specific Aim 2), as well as imaging, cognitive, and sleep aims (Specific Aims 3 and 4).

Condition or disease Intervention/treatment Phase
Depression Depressive Disorder, Major Depressive Disorder Unipolar Depression Major Depressive Disorder Drug: Venlafaxine XR Other: Aerobic Exercise Drug: Lorazepam Phase 4

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 31 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multi-level Life-span Characterization of Adult-depression and Effects of Medication and Exercise
Study Start Date : March 2015
Actual Primary Completion Date : November 2016
Actual Study Completion Date : December 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Aerobic Exercise + Venlafaxine XR

Venlafaxine (Effexor) Extended-Release (XR) comes in capsule form and is taken by mouth. Target dose will be 150mg/d, with a maximum dose of 300mg/d (response dependent) for a minimum of 12 weeks.

Exercise will include walking on a treadmill 1 hour 3 times/week for 12 weeks. Heart rate will be closely monitored during sessions. The intensity of the exercise will start at 50% of the age-based maximum for the first week and then increase and be maintained at 60-70% of the age-based maximum for the remainder of the intervention.

Lorazepam may be used in the study for patients who either are already on this drug or who need it for sleep and/or anxiety. This will be administered in pill form (2mg or less per 24 hours).

Drug: Venlafaxine XR
Other Name: Effexor XR

Other: Aerobic Exercise
Other Names:
  • Physical Activity
  • Cardiovascular Exercise

Drug: Lorazepam
Lorazepam may be used in the study for patients who either are already on this drug or who need it for sleep and/or anxiety. Patients taking another benzodiazepine will be asked to convert from their current benzodiazepine to an equivalent dose of Lorazepam (2mg or less in 24 hours). This will be administered in pill form.
Other Name: Ativan

Active Comparator: Venlafaxine XR Only

Venlafaxine (Effexor) XR comes in capsule form and is taken by mouth. Target dose will be 150mg/d, with a maximum dose of 300mg/d (response dependent) for a minimum of 12 weeks.

Lorazepam may be used in the study for patients who either are already on this drug or who need it for sleep and/or anxiety. This will be administered in pill form (2mg or less per 24 hours).

Drug: Venlafaxine XR
Other Name: Effexor XR

Drug: Lorazepam
Lorazepam may be used in the study for patients who either are already on this drug or who need it for sleep and/or anxiety. Patients taking another benzodiazepine will be asked to convert from their current benzodiazepine to an equivalent dose of Lorazepam (2mg or less in 24 hours). This will be administered in pill form.
Other Name: Ativan




Primary Outcome Measures :
  1. Number of Participants Experiencing Remission [ Time Frame: Baseline, weekly for weeks 1 and 2, then biweekly for weeks 4-12 ]
    Study completers will be classified as remitters vs. non-remitters. Remission will be defined as a MADRS score of 10 or less for at least two consecutive assessments. The MADRS will also be used to assess clinical response throughout the trial and to determine final medication dosage. At the end of week 6, those with a MADRS score greater than 10 will have the venlafaxine XR increased from 150 mg/d to a maximum of 300 mg/d.


Secondary Outcome Measures :
  1. Inflammatory Biomarkers [ Time Frame: Baseline and 12 weeks ]
    Blood samples were collected to assess biomarkers, but funding is not yet available to perform analyses.

  2. Genetic Biomarkers [ Time Frame: Baseline and 12 weeks ]
    Blood samples were collected to assess biomarkers, but funding is not yet available to perform analyses.

  3. Physical Activity (SenseWear Physical Activity-monitoring Armband) [ Time Frame: Baseline and 12 weeks ]
    This will be used to acquire objective information about physical activity. This armband is worn around the upper arm (left triceps) for 1 week and collects information about skin temperature, galvanic skin response, heat flux, and motion via a 3-axis accelerometer. This information is used in an algorithm to determine energy expenditure (EE). The device has a resolution of 1-minute indicating that we can acquire the above information on a minute-by-minute basis, which will allow us to determine both duration and intensity of activity during a normal week. Higher values indicate higher levels of activity.

  4. Cardiovascular Fitness (Submaximal VO2) [ Time Frame: Baseline and 12 weeks ]
    Cardiorespiratory fitness was measured via submaximal VO2 on a motorized treadmill while measuring oxygen utilization via Parvo Medics True one metabolic cart. The submaximal test followed a modified Balke protocol in which speed remained constant with the intensity being increased every two minutes via a raise of 2.0% of the incline. The speed was an agreed upon speed between participant and staff (between 2.0 and 4.0 mph). The submaximal VO2 was stopped when participant reached 85% of age predicted maximal heart rate (220 - age), rating of perceived exertion (RPE) equal to or greater than 15 for those who have blunted heart rate response due to beta block medication, or volitional termination by participant. Vital signs were monitored throughout the test and cool down period. Peak VO2 values for this cohort ranged from 14.04 to 36.48 ml/kg/min, with higher values correlated to higher fitness level.

  5. Functional Magnetic Resonance Imaging (fMRI) [ Time Frame: Baseline and 12 weeks ]
    Brain imaging conducted with a 7 Tesla scanner. Of particular interest were changes in hippocampal volume, GABA, and glutamate. The changes regarding hippocampal volumes are reported below. This measurement is reported in mm^3, with higher numbers indicating higher levels of gray matter in the hippocampal region. Volume is combined between right and left hemispheres. GABA and glutamate are not reported. The method used to obtain the data was being piloted for this study, and due to methodological challenges, the data is not considered to be accurate and therefore cannot be analyzed/shared.

  6. Neurocognitive Function (Neuropsychological Battery) [ Time Frame: Baseline and 12 weeks ]
    The battery evaluates several cognitive domains. The Wechsler Adult Intelligence Scale, 4th ed. Digit Span subtest assesses attention and working memory. The Repeatable Battery of Neuropsychological Status (RBANS) measures Immediate and Delayed Memory, Attention, Language Abilities, and Visuospatial Functioning. Total index scores range from 40-155. The California Verbal Learning Test, 2nd Ed. (CVLT) assesses non-contextual verbal learning and memory. Z-scores are calculated for each of the constructs assessed by the CVLT. Subtests from the Deli-Kaplan Executive Function System (D-KEFS) assess aspects of executive functioning, including set-shifting (Trail Making Test Conditions 4 and 5: scaled score ranging from 0-19) and inhibition (Color-Word Interference Test Condition 3: weighted scaled score ranging from 1-19). Given that standardized scores are calculated for each of the neuropsychological measures, higher scores always indicate better cognitive functioning.



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Ages Eligible for Study:   60 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Ages 20-39 (recruitment complete) and 60-79 years old (open to recruitment)
  2. Major depressive disorder (MDD), single or recurrent, as diagnosed by the PRIME-MD
  3. MADRS ≥ 15
  4. In-town and available to commute to Oakland for a 12-week period
  5. Study nurse practitioner approval to participate in a 12-week moderate intense exercise intervention
  6. Eligible to undergo MRI

Exclusion Criteria:

  1. Inability to provide informed consent.
  2. Modified Mini-Mental Score (3MS) less than 84 or dementia based upon Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria including poor performance on the clinical neuropsychological battery, IQCODE, and all available clinical information.
  3. Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms.
  4. Abuse of or dependence on alcohol or other substances within the past three months
  5. High risk for suicide [e.g., active suicidal ideation (SI) and/or current/recent intent or plan] AND unable to be managed safely in the clinical trial (e.g., unwilling to be hospitalized). Urgent psychiatric referral will be made in these cases.
  6. Contraindication to venlafaxine XR as determined by study physician including history of intolerance of venlafaxine XR in the study target dosage range (venlafaxine XR at up to 300 mg/day).
  7. Inability to communicate in English (i.e., interview cannot be conducted without an interpreter; subject largely unable to understand questions and cannot respond in English).
  8. Non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview)
  9. Unstable/uncontrolled medical illness, including delirium, hypertension, hyperlipidemia, or cerebrovascular or cardiovascular risk factors that are not under medical management.
  10. Subjects taking psychotropic medications that cannot be safely tapered or discontinued prior to study initiation
  11. If a patient failed a trial of venlafaxine (12 weeks of treatment with venlafaxine including at least 6 weeks on 300mg/day), he/she would not be eligible.
  12. Other drugs that may affect the GABA system will be excluded (e.g., Kava, Valerian, Theanine, and GABA supplements).
  13. The drug Linezolid (Zyvox) should be discontinued prior to study enrollment and should not be used during the study.
  14. Exclusion criteria for MR scans include: cardiac pacemaker, aneurysm clip, cochlear implant, pregnancy, intrauterine device, shrapnel, history of metal fragments in the eye, neurostimulators, weight >250 lbs., tinnitus, or claustrophobia.
  15. Current medical condition or treatment for a medical condition that could affect balance, gait, or contraindicate participation in moderate intensity physical activity.
  16. Observed gait condition or use of walking assisted device that would contraindicate use of treadmill for exercise testing and intervention.
  17. Current congestive heart failure, angina, uncontrolled arrhythmia, or other symptoms indicative of an increased acute risk for a cardiovascular event; within the previous 12 months having a myocardial infarction, coronary artery bypass grafting, or angioplasty; conditions requiring chronic anticoagulation (i.e. recent or recurrent DVT).
  18. Eating disorders that would contraindicate physical activity.
  19. Report exercise on more than three days per week for greater than 20 minutes per day over the past three months.
  20. Report plans to relocate to a location not accessible to the study site or having employment, personal, or travel commitments that prohibit attendance to at least 80 percent of the scheduled intervention sessions and all of the scheduled assessments.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02407704


Locations
United States, Pennsylvania
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
Kirk Erickson, PhD
Investigators
Principal Investigator: Kirk Erickson, PhD University of Pittsburgh

Additional Information:
Publications:
Organization WH: Depression: A global public health concern, WHO Department of Mental Health and Substance Abuse,
Wilkinson, GS, Robertson, GJ. WRAT4 Wide Range Achievement Test professional manual (4th ed.). Lutz, FL: Psychological Assessment Resources, 2006.
Borkowski JG, Benton, AL, & Spreen O. Word Fluency and brain damage. Neuropsychologia 5:135-140, 1967.
Wechsler, D. WAIS-IV administration and scoring manual. San Antonio, TX: Psychological Corporation, 2008.
Delis DC, Kramer JH, Kaplan E, & Ober, BA. The California verbal learning test manual (2nd ed.). San Antonio, TX: The Psychological Corporation, 2000.

Responsible Party: Kirk Erickson, PhD, Associate Professor/Principal Investigator, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT02407704     History of Changes
Other Study ID Numbers: MH090333-04
PRO13110090 ( Other Identifier: University of Pittsburgh Institutional Review Board )
MH090333 ( Other Grant/Funding Number: NIH )
First Posted: April 3, 2015    Key Record Dates
Results First Posted: May 23, 2018
Last Update Posted: May 23, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Kirk Erickson, PhD, University of Pittsburgh:
Exercise
Physical activity
GABA
Venlafaxine
fMRI
Spectroscopy
Reward system
BDNF
Sleep
Cognitive function
Biomarkers
Aerobic exercise

Additional relevant MeSH terms:
Depressive Disorder, Major
Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Disease
Depression
Depressive Disorder
Pathologic Processes
Behavioral Symptoms
Mood Disorders
Mental Disorders
Venlafaxine Hydrochloride
Lorazepam
Serotonin and Noradrenaline Reuptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Anticonvulsants
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Hypnotics and Sedatives
Central Nervous System Depressants
Anti-Anxiety Agents
Tranquilizing Agents
GABA Modulators
GABA Agents