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
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).
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 BiomarkersGenetic 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.
Eligibility
Minimum age: 25 Years.
Maximum age: 79 Years.
Gender(s): Both.
Criteria:
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. Garza AA, Ha TG, Garcia C, Chen MJ, Russo-Neustadt AA. Exercise, antidepressant treatment, and BDNF mRNA expression in the aging brain. Pharmacol Biochem Behav. 2004 Feb;77(2):209-20. 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, Steenland K, Karnes C, Seals R, Carnevale C, Hermida A, Levey A. Late-life depression as a risk factor for mild cognitive impairment or Alzheimer's disease in 30 US Alzheimer's disease centers. J Alzheimers Dis. 2012;31(2):265-75. doi: 10.3233/JAD-2012-111922. 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. Pampallona S, Bollini P, Tibaldi G, Kupelnick B, Munizza C. Patient adherence in the treatment of depression. Br J Psychiatry. 2002 Feb;180:104-9. Review.
Starting date: March 2015
Last updated: April 3, 2015
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