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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02407704

Acronym

MEDEX

Enrollment

Registered

2015-04-03

Start date

2015-03-31

Completion date

2016-12-31

Last updated

2018-05-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Depression, Depressive Disorder, Depressive Disorder, Major, Major Depressive Disorder, Unipolar Depression

Keywords

Exercise, Physical activity, GABA, Venlafaxine, fMRI, Spectroscopy, Reward system, BDNF, Sleep, Cognitive function, Biomarkers, Aerobic exercise

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).

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.

Interventions

DRUGVenlafaxine XR

OTHERAerobic Exercise

DRUGLorazepam

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

60 Years to 79 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants Experiencing Remission	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

Measure	Time frame	Description
Genetic Biomarkers	Baseline and 12 weeks	Blood samples were collected to assess biomarkers, but funding is not yet available to perform analyses.
Physical Activity (SenseWear Physical Activity-monitoring Armband)	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.
Inflammatory Biomarkers	Baseline and 12 weeks	Blood samples were collected to assess biomarkers, but funding is not yet available to perform analyses.
Functional Magnetic Resonance Imaging (fMRI)	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.
Neurocognitive Function (Neuropsychological Battery)	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.
Cardiovascular Fitness (Submaximal VO2)	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.

Countries

United States

Participant flow

Pre-assignment details

Participants were diagnosed using the SCID, and were excluded from participation if they did not meet criteria for Major Depressive Disorder. Participants were also excluded for presence of bipolar or psychotic disorders, alcohol/substance dependence within the past 3 months, or if they could not complete MRI.

Participants by arm

Arm	Count
Aerobic Exercise + Venlafaxine XR (60-79 Years of Age) 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. 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).	2
Venlafaxine XR Only (60-79 Years of Age) 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). 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.	3
Aerobic Exercise + Venlafaxine XR (20-39 Years of Age) 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. 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).	5
Venlafaxine XR Only (20-39 Years of Age) 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). 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.	5
Total	15

Withdrawals & dropouts

Period	Reason	FG002	FG003
Overall Study	Lost to Follow-up	0	2
Overall Study	Protocol Violation	0	1
Overall Study	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Aerobic Exercise + Venlafaxine XR (60-79 Years of Age)	Total	Venlafaxine XR Only (20-39 Years of Age)	Aerobic Exercise + Venlafaxine XR (20-39 Years of Age)	Venlafaxine XR Only (60-79 Years of Age)
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	1 Participants	3 Participants	0 Participants	0 Participants	2 Participants
Age, Categorical Between 18 and 65 years	1 Participants	12 Participants	5 Participants	5 Participants	1 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	2 Participants	14 Participants	5 Participants	4 Participants	3 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Montgomery Asberg Depression Rating Scale	27.00 units on a scale STANDARD_DEVIATION 0.71	23.73 units on a scale STANDARD_DEVIATION 4.23	25.60 units on a scale STANDARD_DEVIATION 4.55	21.80 units on a scale STANDARD_DEVIATION 5.81	24.33 units on a scale STANDARD_DEVIATION 3.51
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	1 Participants	3 Participants	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	1 Participants	11 Participants	4 Participants	3 Participants	3 Participants
Region of Enrollment United States	2 Participants	15 Participants	5 Participants	5 Participants	3 Participants
Sex: Female, Male Female	1 Participants	10 Participants	3 Participants	3 Participants	3 Participants
Sex: Female, Male Male	1 Participants	5 Participants	2 Participants	2 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 2	0 / 3	0 / 4	0 / 3
other Total, other adverse events	1 / 2	3 / 3	4 / 4	4 / 4
serious Total, serious adverse events	0 / 2	0 / 3	0 / 4	0 / 4

Outcome results

Primary

Number of Participants Experiencing Remission

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.

Time frame: Baseline, weekly for weeks 1 and 2, then biweekly for weeks 4-12

Population: 1 participant in the Venlafaxine XR Only (20-39 Years of Age) group was excluded from analyses as he/she discontinued the medication after week 8.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Aerobic Exercise + Venlafaxine XR (60-79 Years of Age)	Number of Participants Experiencing Remission	0 Participants
Venlafaxine XR Only (60-79 Years of Age)	Number of Participants Experiencing Remission	2 Participants
Aerobic Exercise + Venlafaxine XR (20-39 Years of Age)	Number of Participants Experiencing Remission	4 Participants
Venlafaxine XR Only (20-39 Years of Age)	Number of Participants Experiencing Remission	2 Participants

Secondary

Cardiovascular Fitness (Submaximal VO2)

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.