A Multi-level Life-span Characterization of Adult-depression and Effects of Medication and Exercise
NCT ID: NCT02407704
Last Updated: 2018-05-23
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE4
31 participants
INTERVENTIONAL
2015-03-31
2016-12-31
Brief Summary
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Detailed Description
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Aim 1: Establish the infrastructure, protocol, and procedures for recruiting, screening, enrolling, and maintaining a sample of 30 adults (both younger adults and older adults) with major depression in a 12-week exercise intervention. The primary aim is to establish both feasibility and proof-of-concept on a wide range of biologically and clinically relevant outcomes.
Aim 2: Examine whether the 12-week physical activity + pharmacotherapy intervention reduces depressive symptoms in both younger and older adults above and beyond that of treatment as usual (TAU). Hypothesis 1: In both younger and older adults the antidepressant properties of pharmacotherapy will be augmented when combined with aerobic exercise such that the combined intervention will have higher rates of response and remission compared to only pharmacotherapy treatment.
Aim 3: Examine whether the 12-week combined physical activity and pharmacotherapy intervention changes the structural morphology in specific subfields of the hippocampus. Hypothesis 1: The medication intervention will increase hippocampal volume in the dentate gyrus and carbonic anhydrase I (CA1), but combining aerobic exercise with pharmacotherapy will magnify the effects of exercise. Hypothesis 2: The effect on hippocampal volume will be larger for older versus younger adults Aim 4: Explore how the combination of pharmacotherapy and exercise (compared with pharmacotherapy and TAU) influences a range of brain and behavioral outcomes, including resting state brain dynamics, MR spectroscopic measures of GABA, sleep efficiency, and cognitive performance. Hypothesis 1: Antidepressant pharmacotherapy will alter resting state networks, increase GABA levels, and improve sleep efficiency and cognitive performance - but these effects will be greater when combined with an aerobic exercise intervention. Hypothesis 2: These effects will be moderated by age such that the effects will be greater in older adults, supporting a dissociation between depression in younger and adults, and providing justification for fully powered study to explore these models and treatment-predictive biomarkers.
Depression is a significant global public health concern; it is the second leading cause of disability worldwide and is currently estimated to affect 350 million people. Antidepressant medications have shown to be more effective than placebo in treating depression. However, for 20-40% of individuals suffering from depression the pharmacotherapy has a slow or inadequate response. Thus, identifying alternative treatments for depression is a public health priority.
Background:
Physical activity is emerging as one of the most promising non-pharmaceutical treatments for depression. Greater amounts of self-reported physical activity are associated with fewer depressive symptoms in epidemiological studies and randomized interventions find that participation in physical activity enhances mood in depressed populations. A Cochrane review of 32 randomized interventions concluded that participation in physical activity is effective for reducing depressive symptoms compared to either no treatment or to a control condition. Importantly, antidepressants and physical activity may work through similar biological pathways to influence both mood and cognitive function. In fact, both antidepressants and physical activity increase levels of Brain-derived neurotrophic factor (BDNF) in serum and hippocampus, may mitigate or reverse hippocampal atrophy, influence expression and kinetics of serotonin and GABA pathways, regulate brain network connectivity, alter inflammatory pathways, and improve sleep efficiency. Our proposal aims to characterize these effects from the genetic to the behavioral and cognitive level, and isolate the effects of physical activity from those of medication.
Significance:
If effective, physical activity could become a first line of treatment for depression, which might also help reduce cognitive deficits, job productivity, and risk of other psychiatric conditions. Furthermore, although physical exercise has shown promise in reducing depressive symptoms, researchers still do not understand the biological pathways by which it works. One of the leading hypotheses of depression is that disruptions in GABA systems underlies the deficits. In contrast, improvements in GABA signaling is one of the ways in which exercise may improve brain function and reduce depressive symptoms. Along this line, investigators hope to determine the type of exercise (aerobic versus stretching and toning) that can be promoted in the future to improve brain function and reduce depressive symptoms. Demonstrating these links could be an important first step for developing more effective treatment plans for those suffering from depression.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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).
Venlafaxine XR
Aerobic Exercise
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.
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).
Venlafaxine XR
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.
Interventions
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Venlafaxine XR
Aerobic Exercise
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
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.
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.
60 Years
79 Years
ALL
No
Sponsors
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Kirk Erickson, PhD
OTHER
Responsible Party
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Kirk Erickson, PhD
Associate Professor/Principal Investigator
Principal Investigators
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Kirk Erickson, PhD
Role: PRINCIPAL_INVESTIGATOR
University of Pittsburgh
Locations
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University of Pittsburgh
Pittsburgh, Pennsylvania, United States
Countries
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References
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Butters MA, Young JB, Lopez O, Aizenstein HJ, Mulsant BH, Reynolds CF 3rd, DeKosky ST, Becker JT. Pathways linking late-life depression to persistent cognitive impairment and dementia. Dialogues Clin Neurosci. 2008;10(3):345-57. doi: 10.31887/DCNS.2008.10.3/mabutters.
Kohler S, Thomas AJ, Barnett NA, O'Brien JT. The pattern and course of cognitive impairment in late-life depression. Psychol Med. 2010 Apr;40(4):591-602. doi: 10.1017/S0033291709990833. Epub 2009 Aug 6.
Tedeschini E, Levkovitz Y, Iovieno N, Ameral VE, Nelson JC, Papakostas GI. Efficacy of antidepressants for late-life depression: a meta-analysis and meta-regression of placebo-controlled randomized trials. J Clin Psychiatry. 2011 Dec;72(12):1660-8. doi: 10.4088/JCP.10r06531.
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Blumenthal JA, Babyak MA, Doraiswamy PM, Watkins L, Hoffman BM, Barbour KA, Herman S, Craighead WE, Brosse AL, Waugh R, Hinderliter A, Sherwood A. Exercise and pharmacotherapy in the treatment of major depressive disorder. Psychosom Med. 2007 Sep-Oct;69(7):587-96. doi: 10.1097/PSY.0b013e318148c19a. Epub 2007 Sep 10.
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Blumenthal JA, Babyak MA, Moore KA, Craighead WE, Herman S, Khatri P, Waugh R, Napolitano MA, Forman LM, Appelbaum M, Doraiswamy PM, Krishnan KR. Effects of exercise training on older patients with major depression. Arch Intern Med. 1999 Oct 25;159(19):2349-56. doi: 10.1001/archinte.159.19.2349.
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Other Identifiers
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PRO13110090
Identifier Type: OTHER
Identifier Source: secondary_id
MH090333
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
MH090333-04
Identifier Type: -
Identifier Source: org_study_id
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