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

Information source: University of Pittsburgh
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Depression; Depressive Disorder, Major; Depressive Disorder; Unipolar Depression; Major Depressive Disorder

Intervention: Venlafaxine XR (Drug); Aerobic Exercise (Other); Lorazepam (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: University of Pittsburgh

Official(s) and/or principal investigator(s):
Kirk Erickson, PhD, Principal Investigator, Affiliation: University of Pittsburgh

Overall contact:
Swathi Gujral, BS, Phone: 412-624-4524, Email: swh24@pitt.edu


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).

Clinical Details

Official title: A Multi-level Life-span Characterization of Adult-depression and Effects of Medication and Exercise

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Change in Montgomery-Asberg Depression Rating Scale (MADRS) from baseline to end of 12 week Venlafaxine XR treatment trial

Secondary outcome:

Inflammatory Biomarkers

Genetic Biomarkers

Physical Activity/Sleep Efficiency (SenseWear physical activity-monitoring armband)

Cardiovascular Fitness (submaximal VO2)

Functional Magnetic Resonance Imaging (fMRI)

Neurocognitive function (neuropsychological battery)

Detailed description: Specific Aims: 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.


Minimum age: 25 Years. Maximum age: 79 Years. Gender(s): Both.


Inclusion Criteria: 1. Ages 25-39 and 65-79 years old 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 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 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, IUD, 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. 21. Current Type I or II Diabetes

Locations and Contacts

Swathi Gujral, BS, Phone: 412-624-4524, Email: swh24@pitt.edu

University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States; Recruiting
Swathi Gujral, BS, Phone: 412-624-4524, Email: swh24@pitt.edu
Sarah Walker, MA, Phone: 412-246-5685, Email: walkerse2@upmc.edu
Kirk Erickson, PhD, Principal Investigator
Howard J Aizenstein, MD, PhD, Sub-Investigator
Charles F Reynolds III, MD, Sub-Investigator
Meryl A Butters, PhD, Sub-Investigator
Francis Lotrich, MD, PhD, Sub-Investigator
Jordan F Karp, MD, Sub-Investigator
Mark D Miller, MD, Sub-Investigator
Ariel G Gildengers, MD, Sub-Investigator
Jacqueline Stack, RN, MSN, CNS, Sub-Investigator
George Grove Jr., MS, Sub-Investigator
Michelle Zmuda, BS, Sub-Investigator
Isaac Delozier, BS, Sub-Investigator
Gregory Parsh, BS, Sub-Investigator
Cary Zik, BA, Sub-Investigator
Additional Information

Brain Aging & Cognitive Health Lab, University of Pittsburgh

Related publications:

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. Review.

Köhler 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.

Galper DI, Trivedi MH, Barlow CE, Dunn AL, Kampert JB. Inverse association between physical inactivity and mental health in men and women. Med Sci Sports Exerc. 2006 Jan;38(1):173-8.

Hassmén P, Koivula N, Uutela A. Physical exercise and psychological well-being: a population study in Finland. Prev Med. 2000 Jan;30(1):17-25.

Barbour KA, Edenfield TM, Blumenthal JA. Exercise as a treatment for depression and other psychiatric disorders: a review. J Cardiopulm Rehabil Prev. 2007 Nov-Dec;27(6):359-67. doi: 10.1097/01.HCR.0000300262.69645.95. Review.

Rimer J, Dwan K, Lawlor DA, Greig CA, McMurdo M, Morley W, Mead GE. Exercise for depression. Cochrane Database Syst Rev. 2012 Jul 11;7:CD004366. doi: 10.1002/14651858.CD004366.pub5. Review. Update in: Cochrane Database Syst Rev. 2013;9:CD004366.

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. Epub 2007 Sep 10.

Erickson KI, Miller DL, Roecklein KA. The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist. 2012 Feb;18(1):82-97. doi: 10.1177/1073858410397054. Epub 2011 Apr 29. Review.

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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.

Mather AS, Rodriguez C, Guthrie MF, McHarg AM, Reid IC, McMurdo ME. Effects of exercise on depressive symptoms in older adults with poorly responsive depressive disorder: randomised controlled trial. Br J Psychiatry. 2002 May;180:411-5.

Organization WH: Depression: A global public health concern, WHO Department of Mental Health and Substance Abuse,

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Reynolds SL, Haley WE, Kozlenko N. The impact of depressive symptoms and chronic diseases on active life expectancy in older Americans. Am J Geriatr Psychiatry. 2008 May;16(5):425-32. doi: 10.1097/JGP.0b013e31816ff32e.

Bridle C, Spanjers K, Patel S, Atherton NM, Lamb SE. Effect of exercise on depression severity in older people: systematic review and meta-analysis of randomised controlled trials. Br J Psychiatry. 2012 Sep;201(3):180-5. doi: 10.1192/bjp.bp.111.095174. Review.

Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci. 2004 Nov;20(10):2580-90.

Lebowitz BD, Pearson JL, Schneider LS, Reynolds CF 3rd, Alexopoulos GS, Bruce ML, Conwell Y, Katz IR, Meyers BS, Morrison MF, Mossey J, Niederehe G, Parmelee P. Diagnosis and treatment of depression in late life. Consensus statement update. JAMA. 1997 Oct 8;278(14):1186-90. Review.

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Starting date: March 2015
Last updated: April 3, 2015

Page last updated: August 23, 2015

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