2. CANDIDATE’S BACKGROUND
My goal in seeking a Mentored Research Scientist Development Award is to receive the additional
training and experience necessary to achieve my long-term career objective of becoming an independent
investigator of the effects of physical activity on mental health. I am proposing a career development plan, to
which I will commit at least 75% FTE over the term of the award, that includes focused coursework, mentorship
from a multi-disciplinary group of established researchers, and a pilot study examining the feasibility of
conducting an RCT to examine the efficacy of an exercise intervention in the prevention of depression in
Hepatitis C (HPC) patients receiving IFN-α treatment. The experience and knowledge obtained from the
completion of this plan will allow me to obtain R01 funding to conduct an RCT of sufficient size to examine the
efficacy of exercise in the prevention of IFN-α induced depression in HPC patients.
I completed my doctoral training in the Department of Kinesiology at Arizona State University. An
interdisciplinary mix of coursework in kinesiology and psychology provided me with the unique knowledge base
necessary to conduct research examining the relationship between physical activity and mental health. During
my graduate training, I completed two meta-analyses examining the antidepressant effects of exercise and
anxiolytic effects of exercise.1,2 This afforded me the opportunity to familiarize myself with past research
examining the effects of exercise on mental health, while also identifying important areas for further research.
Based on these efforts, I focused my dissertation on the identification of individual differences in depression
and responses to exercise treatment. This work resulted in two first-author publications. The first is a crosssectional examination of the moderating effect of physical activity on the relationship between serotonin
transporter genotype (5-HTTLPR) and depressive symptoms.3 The second manuscript examines the efficacy
of a 5-week exercise intervention in alleviating depressive symptoms across 5-HTTLPR genotypes.4
Following the completion of my PhD, I began an NRSA T32-fellowship in the Department of Psychiatry
at the University of Rochester Medical Center (URMC) in September 2008. The environment at URMC allowed
me to advance my research interests in physical activity and mental health, under the supervision and support
of my mentors, Jeffrey Lyness, MD and Jan Moynihan, PhD. The fellowship also provided numerous
educational opportunities to further enhance my research knowledge and skills. I attended several
weekly/biweekly meetings designed to foster research skills through interdisciplinary and collaborative learning
and took coursework in a variety of topics, including research ethics, grant writing, biostatistics and
epidemiology. Finally, I attended the NIMH-sponsored Summer Research Institute in Geriatric Psychiatry at the
University of Michigan in July 2009. My research activities at URMC focused on the examination of the
relationships between physical activity, depressive symptoms and inflammation through the analysis of an
existing data set, resulting in a paper examining the moderating effect of physical activity on the relationship
between depressive symptoms and interleukin-6.5
In March 2010, I accepted a faculty position in the Department of Psychiatry at the University of Texas
Southwestern Medical Center at Dallas. My move to UT-Southwestern allows me the opportunity to work with
and be mentored by Dr. Madhukar Trivedi. Dr. Trivedi has extensive experience in the design and conduct of
multi-site trials. Relevant to my research interests, Dr. Trivedi is the principal investigator of two controlled trials
examining the use of exercise in mental health and substance use, Treatment with Exercise Augmentation for
Depression (TREAD; 5-R01-MH067692-05)6,7 and Stimulant Reduction Intervention using Dosed Exercise
(STRIDE; U10-DA-0200).8,9 Among my current responsibilities is serving as the National Intervention Director
for STRIDE. In this role, I am responsible for the training and supervision of intervention facilitators and for
monitoring participant adherence and implementing behavioral strategies to maximize participant adherence.
My involvement in STRIDE has provided an introduction to the implementation and conduct of clinical trials and
the specific challenges associated with multi-site RCTs.
I have continued to build my publication record at UT-Southwestern. I am first-author of two papers
reporting the results of secondary analysis of the TREAD study. The first paper, in press in Psychological
Medicine, examines the effects of exercise on sleep quality in patients with non-remitted Major Depressive
Disorder (MDD).10 The second paper examines the role of inflammatory cytokines in the antidepressant
response to exercise and is in press in Molecular Psychiatry.11 I am also co-author on a secondary analysis
from TREAD examining the moderating role of BDNF on antidepressant response to exercise12 and on papers
describing the STRIDE trial design,9 and the selection of the endpoint used in STRIDE.8 Additionally, Dr.
Trivedi and I have contributed book chapters for upcoming editions of Lifestyle Medicine13 and Encyclopedia of
Exercise Medicine in Health and Disease.14 Finally, since joining the faculty at UT-Southwestern, I have sought
additional training opportunities to further my research skills and knowledge. I attend two training workshops:
the New Investigator Workshop at the 2011 NCDEU meeting and 2011 OBSSR/NHLBI Summer Institute on
Design and Conduct of Randomized Controlled Trials Involving Behavioral Intervention.
3. CAREER GOALS AND OBJECTIVES:
My long-term career goal is to become an independent investigator and leader in the study of the effects of
physical activity on mental health. This line of research will examine the role of physical activity in the treatment
and prevention of mental illness and the physiological mechanisms potentially underlying the effects of
exercise on mental health. However, progress toward my career goal requires additional training. To continue
toward this goal, I am proposing a career development plan that includes focused coursework, mentorship
from a multi-disciplinary group of established researchers and practical research experience that addresses my
training needs. The proposed training plan focuses on three training objectives: (1) training in the design and
conduct of RCTs in clinical population, (2) training in psychopathology diagnosis and assessment, and (3)
advanced training in biostatistical methods. The knowledge, skills and experience I will acquire through
the proposed training plan will be necessary to compete successfully for an R01 and achieve my goal
of becoming an independent investigator.
11. RESEARCH STRATEGY
11.1 Significance
Depressive disorders affect approximately 10% of the population in the United States annually with a
lifetime prevalence of 10% in men and 15% in women. Along with the high prevalence, the costs associated
with depressive disorders have also grown. The annual economic burden of depressive disorders is estimated
at $83 billion35 and depressive disorders are predicted to be the greatest contributor to global health burden by
the year 2030.36 Even among individuals who do not meet diagnostic criteria for Major Depressive Disorder
(MDD), depressive symptoms have negative influences on health. Elevated depressive symptoms are
associated with an increased risk of MDD,37 functional impairment,38-40 higher rates of disability,41 and
increased social dysfunction.39,42 Further increasing the burden of depressive disorders is the limited
accessibility and effectiveness of treatments. Only 55% of people afflicted with a depressive disorder are
receiving treatment, while alleviation of depressive symptoms is seen in only 32% of those receiving
treatment.43 Even with optimal access and treatment, data indicate only 34% of disability associated with
depression would be averted.44 These data highlight the public health burden of depressive disorders
and the need for implementation of strategies to prevent depressive disorders.
The Institute of Medicine and the National Institute of Mental Health have each produced reports calling
for major efforts to develop, evaluate, and implement prevention interventions focused on mental, emotional,
and behavioral disorders.45,46 The IOM paradigm for preventive interventions includes “selective” interventions,
which target at-risk individuals that are not yet symptomatic. It has been argued that the use of selective
interventions to prevent depression in medical illness should be prioritized.47 Selective prevention interventions
targeting medically ill populations, such as post-stroke48 and macular degeneration patients49 have been
efficacious in preventing the incidence of depression. The proposed research involves a selective
intervention aimed at preventing depression among Hepatitis C (HPC) patients receiving Interferon-α
(IFN-α) treatment.
IFN-α is an efficacious treatment for HPC; however, IFN-α treatment results in a significant increase in
depressive symptoms, with between 30-50% of patients developing MDD.50-53 In one of the largest prospective
studies of HPC patients receiving IFN-α treatment, 39% of patients experienced moderate to severe levels of
depression.54 This increased depressive symptomatology in HPC patients is associated with significantly
impaired quality of life,55,56 reduced IFN-α treatment adherence57 and poorer IFN-α treatment outcomes.58 This
is in addition to the burdens typically associated with elevated depressive symptoms, such as functional
impairment,38,39,59 higher rates of disability,41 and increased social dysfunction.39,60 Given the high risk of
increased depressive symptoms during IFN-α treatment and the effects this increase in depressive
symptomatology has on treatment adherence, treatment outcomes and patient quality of life, it is
important to identify effective strategies for preventing the development of depressive symptoms in
this population.
To date, research has focused on the prophylactic use of selective serotonin reuptake inhibitors
(SSRIs) in the prevention of IFN-α induced depression in HPC patients. Open label trials61-63 suggest that the
administration of SSRIs may reduce the incidence of depression during IFN-α treatment. However, out of four
randomized controlled trials (RCTs), only one trial has shown a significantly lower rate of MDD in patients
receiving SSRIs compared to those receiving placebo.64-67 Furthermore, SSRI treatment did not result in
improved adherence to IFN-α treatment compared to placebo. In addition to these results, it has been
postulated that non-depressed patients might be resistant to taking SSRIs, therefore non-pharmacological
interventions may be more suitable for prevention.68 Taken as a whole, this indicates the need for
alternative strategies for the prevention of IFN-α-induced depression.
Within the HPC population, the successful completion of this project offers several potential benefits.
First, the prevention of IFN-α induced depression will eliminate the physical, psychosocial and economic
burdens often associated with depression. Additionally, the successful implementation of an exercise
intervention during IFN-α therapy may have the potential to improve treatment adherence and outcomes.
Considering the reduced treatment adherence associated with depression, prevention of depression is likely to
improve adherence to IFN-α therapy, thus improving treatment outcomes. Furthermore, it has been postulated
that weight loss and increased of insulin sensitivity associated with exercise may be especially beneficial for
patients with HPC.69
Perhaps more importantly, the examination of exercise in the prevention of interferon-induced MDD has
implications beyond the HPC population. MDD is a heterogeneous disease and it has been postulated that the
biological underpinnings of MDD are equally varied. As a result, there are likely multiple biological targets for
the prevention and treatment of MDD and therefore, multiple treatment options are likely necessary to
effectively treat and prevent MDD. Inflammation has been implicated in the development MDD and
inflammatory responses to SSRI treatment may provide insights into inadequacy of current MDD treatments.
Patients with a history of non-response to SSRIs have elevated levels of IL-6.70 Similarly, elevated baseline
inflammation is predictive of non-response to a variety of depressive treatments.71-73 The model of IFN-α
induced depression provides strong evidence for the role of inflammation in the development of MDD.74
Completion of the proposed project will provide further insight into the role of inflammation in the etiology of
MDD, while also exploring the role of exercise as a treatment option for MDD patients with elevated systemic
inflammation. Furthermore, several medical illnesses are associated with an increased risk of depression.75
This increased co-morbidity may be at least partially explained by elevated inflammation associated with these
medical illnesses.76 If exercise proves to be efficacious in preventing depression in HPC patients, the results
may be generalizable to other medically ill groups.
11.2 Innovation
The proposed project presents a novel strategy for preventing the incidence of depression in HPC
patients receiving IFN-α therapy. The potential of an exercise intervention to prevent depression during IFN-α
treatment is supported by longitudinal data demonstrating that physical activity reduces future risk of
depression.77,78 Furthermore, exercise is efficacious as a stand-alone and/or adjunctive treatment for
depression.2,7,79 The potential for exercise to prevent the increase of depressive symptoms in HPC patients
receiving IFN-α treatment is also biologically plausible. Examination of the mechanisms responsible for the
development of IFN-α induced depression provides insight into potential prevention strategies. IFN-α treatment
increases peripheral levels of several proinflammatory cytokines, including increases interleukin-6 (IL-6),
interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α);80 and several studies have reported associations between
increases in these cytokines and increases in depressive symptoms.74,81-84 Prather et al.85 examined the
temporal relationships between IFN-α treatment, IL-6, sleep disturbances and depressive symptoms in a
cohort of non-depressed HPC patients receiving IFN-α treatment. They report increases in IL-6 predicted
higher depressive symptoms the following month and higher depressive symptoms predicted with higher levels
of IL-6 the following month.74 This suggests a positive feedback system resulting in increases in IL-6 and
depressive symptoms following IFN-α treatment. Furthermore, the relationship between IL-6 and depression
was mediated by changes in sleep quality, with increases of IL-6 predicting a worsening of sleep quality and
the worsening of sleep quality predicting an increase in depressive symptoms (see Figure 1).
Figure'1.'IFN,induced'depression'
model'proposed'by'Prather et al.:'
Sleep%
In(lammation%
Depression%
This model of IFN-α-induced depression suggests that an
intervention that decreases inflammation and/or improves
sleep quality may be effective in preventing IFN-α-induced
depression. Higher levels of physical activity and physical fitness
are associated with lower levels of IL-6,5,86 while exercise
interventions have been shown to reduce inflammatory
cytokines.87,88 Similarly, exercise improves various aspects of sleep
quality in individuals with sleep complaints89,90 and in individuals
with depression.91,92 Therefore, it is plausible that exercise may
prevent an increase in inflammation and worsening of sleep quality
during IFN-α treatment and ultimatley lead to the prevention of IFNα-induced depression.
My previous work further supports exercise as a potential strategy to prevent IFN-α induced
depression. First, in a cross-sectional analysis of primary care patients, we report physical activity moderates
the relationship between inflammation and depressive symptoms.5 In this sample, elevated levels of IL-6 were
associated with elevated depressive symptoms among individuals who did not engage in regular physical
activity, however there was no relationship between IL-6 and depressive symptoms among active individuals.
This would suggest that physical activity may “protect” against the development of depressive
symptoms in the presence of inflammation. Next, we examined pro-inflammatory cytokines as predictors of
antidepressant response to exercise in patients with non-remitted MDD.11 We found higher baseline levels of
TNF-α were associated with greater decreases in depressive symptoms following an exercise intervention.
This is in contrast to studies that report lower inflammation predicts treatment response to SSRIs.71,93 This
would support the use of exercise in the current study, given the elevated inflamation resulting from from IFN-α
and the apparent inefficacy of SSRIs to prevent the development of MDD in HPC patients receiving INF-α
therapy. Finally, in the same sample, we found improvements in self-reported sleep quality following the
exercise intervention.10 Again, this is in contrast to previous reports of residual sleep disturbances following
SSRI treatment.94-96 Taken as whole, this line of research would suggest that the mechanisms
responsible for the antidepressant effects of exercise likely differ from the mechanisms of SSRIs and
suggest that exercise may be efficacious in the prevention of IFN-α induced MDD.
The proposed project is a novel application of an exercise intervention and therefore, no research in
humans is available on the effects of exercise on the development of depression during IFN-α treatment.
However, animal models provide further support of the hypothesis. In a study of rats, concurrent treadmill
running protected against the development of neurocognitive deficits during IFN-α administration.97 In
summary, this previous research supports the plausibility of exercise in the prevention of IFN-α
induced depression.
11.3 Approach
Previous Work
The proposed research is a logical extension of my previous work examining the effects of exercise on
mental health. In addition to the work cited above, I have completed two meta-analyses examining the
antidepressant and anxiolytic effects of exercise.1,2 The results of these analyses indicate that exercise
interventions are efficacious in reducing depressive and anxious symptoms. The completion of these analyses
also provided the opportunity to familiarize myself with past research examining the effects of exercise on
mental health, while also identifying important areas for further research. Based on these efforts, I next focused
on the identification of individual differences in depression and responses to exercise treatment. I conducted a
randomized controlled trial of healthy college students to examine the moderating effect of the 5-HTTLPR
genotype on changes in depressive symptoms following exercise. This work resulted in two publications, the
first is a cross-sectional examination of the moderating effect of physical activity on the relationship between
serotonin transporter genotype (5-HTTLPR) and depressive symptoms3 and the second manuscript examines
the efficacy of a 5-week exercise intervention in alleviating depressive symptoms and the moderating effect of
5-HTTLPR genotype.4 I have also co-authored a paper from the Treatment with Exercise Augmentation for
Depression (TREAD) study on the effects of brain derived neurotrophic factor (BDNF) on exercise
augmentation of MDD.12
The gaps in my research experience are complemented by the expertise of my proposed mentors and
consultants. Dr. Madhukar Trivedi will serve as my primary mentor during the training period. Dr. Trivedi has
extensive experience in the design and conduct of multi-site trials in depression. He served as the Co-Director
of the National Coordinating Center in the multi-site trial of treatment-resistant depression, Sequenced
Treatment Alternatives to Relieve Depression (STAR*D).16-19 Additionally, Dr. Trivedi has been a principal
investigator in multiple clinical trials funded through NIMH, including the currently funded Establishing
Moderators/Biomarkers of Antidepressant Response (EMBARC; 1U01MH092221). Of particular relevance to
the proposed project, Dr. Trivedi is the principal investigator of two controlled trials examining the use of
exercise in mental health and substance use, Treatment with Exercise Augmentation for Depression (TREAD)7
and Stimulant Reduction Intervention using Dosed Exercise (STRIDE).9
Dr. Steve Blair, Professor of Exercise Science and Epidemiology at the University of South Carolina will
provide additional mentorship in the implementation of exercise interventions in clinical populations. Dr. Blair
has extensive experience in conducting RCTs using exercise interventions in clinical populations, including the
Dose-Response to Exercise in Women (DREW; HL66262, Blair PI).20-22 DREW was an RCT designed to
examine the effect of three doses of aerobic exercise on cardiorespiratory fitness and blood pressure in
overweight or obese post-menopausal women with elevated blood pressure. Results of DREW identified a
dose-response relationship between exercise dose and improvements in cardiorespiratory fitness. Dr. Blair
also has been the PI on four other NIH-funded RCTs. His RCTs have included >1200 adult women and men
aged 20-89 years and of numerous racial/ethnic groups. Dr. Blair served as an investigator for TREAD and is
currently a consultant for STRIDE.
Dr. William Lee will serve as a consultant for the proposed project. Dr. Lee is the Director of the Clinical
Center for Liver Diseases at UT-Southwestern, and leads large clinical trials of the treatment of Hepatitis B and
C27-29 and was the founding Principal Investigator for the Acute Liver Failure Study Group (5U01DK058369).30
Dr. Lee will provide expertise in conducting clinical research in the HPC population and will also help facilitate
recruitment of participants from the UT-Southwestern Clinical Center for Liver Diseases.
Dr. Ryan Huebinger will serve as a consultant for the proposed project. Dr. Huebinger is an instructor in
the Department of Surgery at UT-Southwestern. Dr. Huebinger’s work is focused on the examination of
biomarkers and genetic variants as they relate to clinical outcomes.31,32 Dr. Huebinger will to offer advice on
the proper methods for sample collection and oversee the analysis of samples for inflammatory makers. Dr.
Huebinger conducted analyses of BDNF and inflammatory cytokines on blood samples collected during
TREAD.11,12
Participants
Individuals who have been diagnosed with HPC and prescribed IFN-α will be recruited from the UTSW Clinical
Center for Liver Diseases. Adults, ages 18-65, will be included. Participants will provide written informed
consent before any protocol-specified procedures are carried out. Participants must receive medical clearance
to exercise with protocol-defined stress testing (in accordance with American College of Sports Medicine
(ACSM) guidelines) from protocol approved medical personnel. Individuals will be excluded from participation if
they: 1) have a medical condition contraindicating exercise participation, 2) are currently physically active –
defined as moderate intensity physical activity on 3 or more days per week for the last month, 3) have been
diagnosed with current MDD or are currently receiving antidepressant medication treatment (including SSRIs
and SNRIs) 4) suicidality, 5) current psychotic disorder.
Screening
Mini International Neuropsychiatric Interview (MINI). The MINI98 is a structured diagnostic interview
designed to screen for Axis I psychiatric disorders in the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV, 4th ed) and International Classification of Diseases (ICD-10, 10th ed).99 In comparison to the
Structured Clinical Interview for DSM-IV Disorders (SCID-P), kappa values are good (only one diagnosis <
.50), specificities and negative predictive values are .85 or higher across diagnoses, and in general, sensitivity
is .70 or higher.99 The MINI is being used to ensure standardized psychiatric diagnoses. The MINI will be
administered at the screening visit and will be used to identify Axis I psychiatric diagnoses.
Prior and Concomitant Medications. The Prior and Concomitant Medications form assesses prescribed
medications taken by the participant. The Prior and Concomitant Medications form will be administered at the
screening visit and then monthly thereafter, if the participant endorses a change in medication status.
Physical Activity Readiness Questionnaire-Revised (PAR-Q). The PAR-Q100 asks 7 health-related
questions to determine whether a person needs to consult with their physician prior to engaging in an exercise
program. The PAR-Q will be administered at the screening visit.
Physical Exam/ Medical History. A physical exam will be conducted for all participants to provide
clearance for exercise. The medical personnel conducting the exam will review the participant’s medical
history. The medical personnel will also evaluate results from the medical exam, maximal testing and lab
results, and will determine whether the participant is medically cleared to exercise.
Maximal Exercise Testing. Maximal exercise testing will be conducted during the screening process to
examine cardiorespiratory responses in order to rule out ischemic response to exercise (with its implications of
cardiovascular disease), to identify participants for whom exercise might be hazardous, and to provide data for
the exercise prescription. A trained technician will process the test data and a report will be generated that
contains the following information: 1) participant’s symptoms before, during and after testing, 2) maximal heart
rate achieved and percent of predicted maximal heart rate achieved, 3) time on treadmill and estimated
maximal metabolic equivalent (METS) achieved, and 4) ECG interpretation. Identification of symptoms or
conditions that require the test be stopped (based on ACSM’s Guidelines for Exercise Testing and
Prescription) will result in discontinuation of the test, as well as ineligibility for participation in the study. The
test may be rescheduled and/or repeated in the event of equipment difficulty or failure, the failure of the
participant to achieve their age-predicted maximal heart rate, or other situations determined by the testing
and/or medical personnel to warrant a rescheduling of the test.
Measures/Assessments
Quick Inventory of Depressive Symptomatology - Clinician Rated (QIDS-C16). The QIDS-C16 101-103 is a
16-item version of the 30-item Inventory of Depressive Symptomatology (IDS) designed to assess severity of
depression-specific symptoms. Scores range from 0 to 27 with higher scores representing greater severity of
depressive symptoms. The QIDS has been used in a number of major trials such as STAR*D. The QIDS-C16
has high reliability (Cronbach’s alpha of 0.90), good concurrent validity (correlations between the QIDS-C16 and
the 17-item Hamilton Rating Scale for Depression ranging between .86 and .93), and good inter-rater reliability
(kappa of .85)101. The QIDS-C16 will be administered at baseline, every 2 weeks for the first 6 weeks and every
4 weeks thereafter by a blinded rater.
Pittsburgh Sleep Quality Index (PSQI). The PSQI104 is a 19-item scale designed to assess sleep quality
and disturbances. Scores range from 0 to 21 with higher scores representing worse sleep quality. The PSQI
has demonstrated reliability (Cronbach’s alpha of 0.80) in the assessment of self-reported sleep quality and
validity when compared to sleep diaries and polysomnography.105 The PSQI will be administered at baseline,
every 2 weeks for the first 6 weeks and every 4 weeks thereafter by a blinded rater.
Inflammatory markers. Blood samples will be obtained at baseline, Week 3 and subsequently every
four weeks. Samples will be frozen at −80 °C until the time of analysis. Samples will be analyzed using a
multiplexed ELISA method (Meso Scale Discovery) for IL-1beta, IL-6, IL-10 and TNF-alpha.
Accelerometers. Participants in both interventions will wear Actigraph GT3X+ accelerometers for 7
days in Weeks 1, 7, 15, and 23. Accelerometer data will be used to monitor physical activity outside of the
intervention and to provide an objective measure of sleep quality. Accelerometers provide valid and reliable
data on both physical activity106 and sleep quality.107
Intervention
50 participants will be randomly assigned to either: 1) exercise intervention or 2) health education control group
for 26 weeks. Randomization will occur 2 weeks prior to initiation of IFN-α treatment.
Exercise (EX). Participants randomized to the EX condition will complete an exercise dose of 12
kilocalories per kilogram of bodyweight per week (KKW). The 12 KKW dose will result in approximately 120
minutes of exercise per week. All exercise sessions will be conducted in the Exercise Lab located in the UTSouthwestern Mood Disorders Research Program and Clinic and will be supervised by a trained exercise
facilitator. The weekly exercise dose will be divided between at least 3 sessions, with additional sessions (up to
two) completed as needed to achieve the target exercise dose and to allow for participants to develop
autonomy in completing sessions. The exercise dose that was selected (12 KKW) is similar to doses shown to
be efficacious in the treatment of major depressive disorder. In order to improve tolerability, the dose will be
ramped so that participants achieve 6 KKW the fist week, 9 KKW the second week, and 12 KKW in the third
and subsequent weeks. Exercise intensity will be fixed to a range consistent with moderately high to high
intensity, but will also be ramped up gradually in order to increase tolerability for participants; 50-60% maximal
heart rate (HRmax) during the first week 60-70% maximal heart rate (HRmax) during the second week and 7085% HRmax for the third week and beyond. The ramping procedure proposed has successfully been
implemented in the STRIDE study.108 Quantification of this range will be based on each participant’s maximal
heart rate as determined during maximal exercise testing at screening. Participants will wear a heart rate
monitor throughout the exercise session and the exercise facilitator will monitor heart rate. The participants will
warm up for 5 minutes (0 grade and 50-70% of speed) prior to initiation of the exercise prescription. Blood
pressure will be assessed after 5 minutes of exercise. The exercise session will be halted if an extreme
elevation in blood pressure is observed. The speed and/or grade can be adjusted to maintain the heart rate at
a safe exercising level within the desired range. After completion of the exercise prescription, the participant
will cool down (0 grade and 50-70% of speed) until their heart rate returns to within 15% of their resting heart
rate. Following cool down, the participant will be led through 5-10 minutes of stretching.
Health Education (HE). Participants randomized to the HE condition will attend 3 sessions per week
during which educational items such readings, websites, and audio and video materials will be viewed by
participants and facilitators will instruct participants to log the materials reviewed. Instructional topics include
areas such as healthy eating habits, recipes for healthy eating, preventive health care and recommended
health screenings (e.g., cancer prevention, cardiovascular disease prevention), accessing health care
resources, and other health related topics that are relevant to adults. Participants will be encouraged to
suggest topics of interest to help maintain their involvement and engagement in the sessions throughout the
duration of the study. The HE program is similar to a health education intervention currently used as an
attentional control group in STRIDE, which was modeled after similar programs developed by Marcus et al
(1999) and Rejeski et al (2005) that have been used successfully as control groups in clinical trials examining
exercise as an intervention (Marcus et al, 1999; LIFE Study Investigators, 2006).
Study Flow and Timeline
Screening
(2-4 days)
Randomization/
Intevention
Begins
(Week 1)
Initiation of IFNα treatment
(Week 3)
Postintervention
assessments
(Week 27)
Recruitment of participants will begin in July 2013, with a recruitment goal of 2 participants per month. At this
rate, recruitment will end in June 2015 and the last intervention sessions and assessment visits will occur in
December 2015.
Analysis
Based on recommendations of Leon et al.,109 Aims 1 and 2 of the proposed pilot study examine the feasibility
of conducting an exercise intervention in patients undergoing IFN-α treatment. The feasibility of the study will
be assessed by the following criteria:
1) Screening - the number of participants screened per month
2) Recruitment - the percentage of screened participants that are ultimately randomized
3) Intervention Adherence – defined as percentage of weekly exercise dose completed by participants
randomized to the exercise condition.
4) Retention – defined as percentage of assessments completed
The data collected related to these criteria will be used as the basis for a subsequent R01 application
proposing an RCT sufficiently powered to examine the efficacy of an exercise intervention in the prevention of
IFN-α-induced depression. Outcomes related to screening and randomization will inform the proposed timeline
and provide estimates for the number of clinical sites required to complete an adequately powered trial. Data
related to exercise adherence and participant retention will inform alterations made to study procedures to
address any difficulties encountered related to adherence and retention.
Consistent with Aim 3, we will conduct a data analysis examining the efficacy of the exercise
intervention in preventing the increase of depressive symptoms during IFN-α treatment. A mixed-effects
repeated measures model will be used to analyze the primary outcome measure, QIDS-C total score. The
independent variables in the model will be time (weeks 3, 5, 7, 11, 15, 19, 23, 27)(within-subjects factor),
treatment group (EX, HE)(between-subjects factor), and treatment group by time interaction. The model will
allow for random slopes and intercepts while all other factors will be fixed effects. The baseline value of the
dependent variable (QIDS-C) will be included as a covariate as will the other potential covariates if needed
[age, race, gender, history of depression]. The need for higher order time terms or the transformation log
(time+1) to obtain a better fitting model will be considered. The goodness of fit of the final model will be
investigated. The analysis will use all available data from all randomized patients with at least one postbaseline visit (i.e., modified “intent to treat” sample) and all tests will be two-sided with alpha of .05 used for
significance. The hypothesis will be tested by the significance of the treatment group by time interaction effect
and treatment group main effect. The analysis will be done using SAS Proc Mixed. Similar analyses will be
conducted to examine preliminary effects of an exercise intervention on inflammatory cytokines and sleep
quality (Aim 4).
Missing data will be created due to the study design because data will not be collected for enrolled
participants with a QIDS-C greater than 16 who will be withdrawn from the study to receive treatment for MDD.
However, this missing data will not be a source of bias because the proposed mixed-effects models are not
biased by data that are missing at random.110 Data are missing at random if the probability of the data being
missing is determined by variables measured in the study. Because the criterion for removal from the study is
the observed value of the QIDS-C, we can conclude that missing observations are missing at random and will
not bias the mixed-effects analysis.
As a secondary analysis, Kaplan-Meier survival curves stratified by treatment group will be computed
for time to initiation of depression treatment. The groups will be compared by log-rank test. A Cox Proportional
Hazards analysis will also be done to allow for a covariate-adjusted analysis.
The sample size was based on an analysis conducted to determine the sample size needed to detect an
adherence rate of 70% with a Confidence Interval (CI) of ± 12.5 with a probability of 0.80 (similar to using a
power of 0.80 in a power analysis). We assumed a standard deviation of 40 as this was greater the standard
deviation for adherence in the TREAD trial (SD = 35), and therefore a more conservative estimate.7 The table
below shows the sample size required to obtain a CI’s of ± 10.0, ± 12.5, ± 15 at standard deviations of 30, 35,
and 40 (assuming a mean of 70% and probability of 0.80). Based on this analysis, we chose a sample size of
50.
Total Sample Size needed to obtain CI of stated width with probability of 0.80:
Assumed
Standard 95% CI Width:
95% CI Width:
95% CI Width:
Deviation
70% ± 10
70% ± 12.5
70% ± 15
30
44
30
22
35 (TREAD)
57
39
28
40
73
49
36
Design Rationale and Alternative Strategies
In making design decisions, we considered the aims of the proposed study and the stage of the research
question. The proposed intervention is novel in that exercise interventions have not been used previously in
selective prevention trials of depression. Based on recommendations of Leon et al.,109 the proposed pilot study
reflects the design of a subsequent large RCT aimed to determine the efficacy of an exercise intervention to
prevent the development of depression in patients receiving IFN-α treatment. This design includes two
intervention arms: 1) a dosed exercise intervention and 2) a health education control group. The rationale for
the selection of these two treatment arms was based on previous research, current clinical practices and
recommendations of experts in clinical trial design.
Exercise dose and intensity. The 12 KKW dose of exercise was selected because it is comparable to
exercise doses found to be efficacious in reducing depressive symptoms in patients with MDD.111 Furthermore,
this dose of exercise is consistent with current public health recommendations for physical activity.112 Similarly,
the selected intensity of exercise, 70-85% of maximal HR, has been used in trials demonstrating reduction of
depressive symptoms in patients with MDD.2
Intervention duration. The duration of the intervention and assessment of primary endpoint was chosen
to match the typical duration of IFN-α treatment. We considered an intervention that preceded the initiation of
the IFN-α treatment based on data suggesting that baseline levels of depression, sleep and inflammation are
related to the development of depression during IFN-α treatment. Our study begins the exercise program 2
weeks prior to initiation of IFN-α treatment. This 2 week timeframe matches the typical clinical course of time
between the decision to treat with IFN-α and the initiation of IFN-α treatment. We also considered ending the
exercise intervention after 4 months since the development of depression in patients undergoing IFN-α
treatment typically occurs within the first 4 months of treatment. However, if our proposed mechanistic model is
correct, discontinuation of exercise during IFN-α treatment may result in subsequent development of
depression in some patients. We do recognize that exercise “pre-treatment” or shorter intervention durations
may be efficacious in reducing IFN-α-induced depression and will consider examining these possibilities in
future trials.
Selection of control group. The strengths and weakness of using a HE control group were carefully
considered prior to selection. The primary benefit of the HE control group is that it ensures comparable
interpersonal contact across the two interventions. As a result, a significant effect observed in the exercise
condition cannot be attributed to differences in attention or participation outcome expectations. A potential
concern with an attentional control group is a threat to internal validity due to lack of equipoise in treatment
fidelity procedures and interventionist allegiance.113 To reduce these concerns, the HE intervention will be
manualized (based on the HE intervention used in STRIDE) and intervention fidelity procedures will be the
same across the two interventions. Finally, the study will be described to staff and participants as a comparison
of two health-related interventions to eliminate potential expectancy bias.
We also considered a study design to with a comparison group receiving SSRIs. However, because
this is a novel intervention we felt it was first necessary to design a trial that would result in the ability to identify
the largest possible treatment effect and reduce the likelihood of a Type II error. If our future trial is successful
in demonstrating this effect, a future trial comparing exercise to antidepressant medications would be
appropriate.
Assessments. The assessments conducted in the current pilot study also match the assessments that
will be proposed in a subsequent R01 application to conduct a large RCT the efficacy of an exercise
intervention to prevent the development of depression in patients receiving IFN-α treatment. Assessments will
be completed by blinded raters to reduce the potential for bias. The subsequent RCT will allow for additional
analyses of proposed mediators of IFN-α-induced depression (sleep and inflammation). While the sample size
of the pilot study does not allow for a properly powered analysis of these mediators, the inclusion of these
assessments is critical to the pilot study to accurately assess the feasibility in collecting this data.
Potential Problems
One of the most common potential problems in exercise interventions is assuring adherence to the exercise
prescription. We will implement several strategies to help ensure adequate exercise adherence. First, the
design of the exercise intervention includes flexibility allowing the participants to schedule sessions around
other obligations. Furthermore, while the prescribed dose is intended to be completed in 3 sessions, additional
sessions (up to two) may be completed to allow for additionally flexibility in completing the prescribed exercise
dose. For the majority of the study, participants will be asked to exercise within a heart rate range of 70-85% of
maxHR. This will ensure that participants are exercising at a consistent intensity, but this range will allow for
some flexibility in the range to allow participants to exercise at a level that is most comfortable for them. We will
also gradually increase the dose and intensity of the exercise over the first 3 weeks of the intervention to allow
participants to become comfortable with the exercise program. Additionally, we chose to supervise all exercise
sessions to ensure fidelity to the exercise prescription. The DREW study also used supervised sessions and
had excellent adherence to the exercise prescription, with 92% of participants completing the 6 month
evaluation and these individuals achieved 97% of their target 6 month caloric expenditure in exercise
sessions.21 Finally, a behavioral adherence plan that has been used by Dr. Trivedi in previous exercise trials6,9
will be implemented to help retain participants in the interventions and optimize participant adherence. This
multi-component behavioral adherence plan incorporates empirically validated behavioral strategies to
reinforce participation in the interventions and reduce salient participant- and disease-related barriers to
intervention adoption and maintenance. These strategies include: 1) multidisciplinary psychoeducation about
adherence; 2) the use of behavioral and monetary reinforcers for attendance/adherence to the intervention; 2)
written reference materials; 3) skills training (e.g., instruction in appropriate exercise form, intensity); 4) weekly
exercise prescription; 5) self-monitoring of adherence and performance (e.g., heart rate, caloric expenditure);
6) adherence feedback from exercise facilitators; and 7) weekly intervention planning (individually-tailored
plan).
Every research study has potential risks to the participants. Several strategies will be implemented to
maximize participant safety. All participants will undergo a physical exam and maximal exercise test to be
cleared to engage in the exercise intervention. Additionally, participants in the EX condition will have their heart
rate and blood pressure monitored prior to, during and after each exercise session. Study staff supervising
exercise sessions will be CPR certified and trained to use the available automatic defibrillator. Warm-ups prior
to exercise and cool-downs/stretching following exercise will be implemented to reduce the risk of injury
associated with exercise. These same procedures have been used successfully in the STRIDE trial. Finally,
development of MDD will be monitored in all participants using the QIDS-C. Participants scoring >16
(indicating severe depression) will be referred to a psychiatrist for evaluation. Additionally, participants scoring
between 11-15 (indicating moderate depression) will be assessed two weeks later. Two consecutive scores of
>11 will result in referral. The QIDS-C will also be used to monitor suicidality. Any participant scoring >2 on
item 12 of the QIDS-C will meet with a clinician prior to the participant leaving the clinic.
10. SPECIFIC AIMS
The public health burden of depression33 combined with the limited accessibility and effectiveness of
current treatments34 highlight the need for implementation of strategies to prevent depression. Prior
selective prevention interventions in depression have targeted medically ill populations, such as post-stroke35
and macular degeneration patients.36 The proposed research involves a selective preventive intervention
aimed at reducing depression among Hepatitis C (HPC) patients receiving Interferon-α (IFN-α) treatment.
IFN-α treatment is an efficacious treatment for HPC; however, IFN-α treatment results in a significant
increase in depressive symptoms.37-39 This increased depressive symptomatology is associated with
significantly impaired quality of life,40,41 reduced IFN-α treatment adherence42 and poorer IFN-α treatment
outcomes.43 The increase in depressive symptoms and the associated effects highlight the need for
effective strategies aimed at the prevention of IFN-α induced depression. Research examining the
prophylactic use of SSRIs to prevent IFN-α induced depression has failed to demonstrate a preventative
effect44-46 and highlights the need for alternative strategies for the prevention of IFN-α-induced depression.
One potential prevention strategy is exercise. Exercise is efficacious as a stand-alone or augmentative
treatment for major depressive disorder (MDD)2,7,47 and epidemiological evidence suggests physical activity is
protective against the future incidence of MDD.48,49 The mechanisms for development of IFN-α induced MDD
further support the potential for prevention using exercise. IFN-α treatment increases peripheral levels of
interleukin-6 (IL-6)50,51 and decreases in sleep quality.52 These changes have been shown to mediate the
increase in depressive symptoms during IFN-α treatment.53 Conversely, higher levels of physical activity and
physical fitness are associated with lower levels of IL-6,5,54 while exercise interventions have been shown to
reduce IL-6.55,56 Similarly, exercise improves various aspects of sleep quality in individuals with sleep
complaints57,58 and in individuals with MDD.59,60 Taken as a whole, previous research supports the
plausibility of exercise in the prevention of IFN-α-induced MDD.
The purpose of the proposed project is to conduct a pilot study of an exercise intervention to prevent
IFN-α induced MDD in HPC patients. Participants will be recruited from the UT Southwestern Clinical Center
for Liver Disease and randomized to 26 weeks of either aerobic exercise (EX) or a health education (HE)
group. Based on the recommendation of Leon et al.61, the primary aims of the pilot study will be to determine
the feasibility of conducting an RCT examining the efficacy of an exercise intervention to prevent depression in
HPC patients receiving IFN-α treatment. Secondary aims will be to assess the effects of the exercise
intervention on depressive symptoms and proposed mediators (inflammatory cytokines and sleep quality).
Specific Aims
Specific Aim 1. Examine the feasibility of recruitment and randomization of eligible HPC patients into a
RCT examining the efficacy of exercise in the prevention of IFN-α induced depression.
Aim 1A. Assess the number of participants screened for participation per month.
Aim 1B. Assess the percentage of screened eligible participants that are randomized.
Specific Aim 2. Examine the feasibility of maintaining participant engagement throughout the trial.
Aim 2A. Assess intervention adherence – defined as percentage of weekly intervention sessions attended.
Aim 2B. Assess participant retention – defined as percentage of assessments completed
Specific Aim 3. Conduct an analysis of the efficacy of an exercise intervention in preventing increases
in depressive symptoms in HPC patients receiving IFN-α treatment.
Hypothesis: Participants in the exercise intervention will have lower depressive symptoms compared to the HE
group at the end of the 26-week study.
Specific Aim 4. Conduct an analysis of the effects of an exercise intervention on mediators of IFN-α
induced depression in HPC patients receiving IFN-α treatment.
Hypothesis: Participants in the EX group will have lower levels of inflammatory cytokines (IL-1beta, IL-6, IL-10
and TNF-alpha) compared to the HE group at the end of the 26-week study.
Hypothesis: Participants in the EX group will have higher sleep quality compared to the HE group at the end of
the 26-week study.
The successful completion of the proposed research and training plan will provide the knowledge and
experience necessary to progress toward becoming an independent investigator examining the role of physical
activity in the treatment and prevention of mental illness. Specifically, the data from the proposed study will
serve as the basis for an R01 application to be submitted during the final year of the K01 award. The R01 will
propose an RCT sufficiently powered to examine the efficacy of an exercise intervention in the prevention of
IFN-α-induced depression.
4. CAREER DEVELOPMENT/TRAINING ACTIVITIES:
4.1 Training in the Design and Conduct of RCTs in Clinical Populations
The primary aim of my application is to acquire training to conduct clinical research. To date, the majority of my
scholarly productivity has been the result of secondary data analyses5,10-12 and meta-analyses.1,2 My
experience in leading RCTs is limited to a trial conducted in healthy college students3,4. As a co-investigator for
STRIDE, I gained exposure to conducting clinical trials, however, I was not involved in the design of the trial
and my role during the trial did not encompass all of the duties that would be required of a Principal
Investigator. Therefore, I have prepared a comprehensive training plan that includes mentorship, coursework
and practical experience. The proposed coursework will provide training broadly in conducting clinical
research, while the mentorship and practical experience will be tailored to provide the skills and knowledge
necessary to conduct research in mood disorders and to conduct exercise interventions in clinical populations.
Mentorship: My primary mentor is Dr. Madhukar Trivedi. Dr. Trivedi has extensive experience in the design
and conduct of multi-site trials in mood disorders. He served as the Co-Director of the National Coordinating
Center in the multi-site trial of treatment-resistant depression, Sequenced Treatment Alternatives to Relieve
Depression (STAR*D)15-19 and has been a principal investigator in multiple clinical trials funded through NIMH,
the Texas Department of Mental Health, the pharmaceutical industry, and several foundations. Of particular
relevance to my research interest, Dr. Trivedi has conducted research in the area of exercise and mental
health. He was the principal investigator on the recently completed project TREAD7 and is the principal
investigator on the multi-site project STRIDE.9 I will meet weekly with Dr. Trivedi throughout the duration of the
award.
Dr. Steve Blair, Professor of Exercise Science and Epidemiology/Biostatistics at the University of South
Carolina will provide additional mentorship. Dr. Blair has extensive experience in conducting RCTs using
exercise interventions in clinical populations, including the Dose-Response to Exercise in Women (DREW;
HL66262, Blair PI).20-22 Dr. Blair also has been the PI on four other NIH-funded RCTs. These studies have
included women and men 20-89 years of age and sizable percentages have been from numerous racial/ethnic
groups. All of these studies had excellent adherence to the exercise program.23-26 Dr. Blair also serves as a
consultant for STRIDE. As a result, I have had the opportunity to communicate and meet with Dr. Blair to
discuss issues related to conducting exercise interventions. Dr. Blair and I will have monthly phone calls and
will meet in-person once per year during the award, during which we will discuss the progress of the pilot
study. More broadly, we will discuss the challenges associated with conducting exercise interventions in
clinical populations and the skills and knowledge necessary to address these difficulties. Dr. Blair is also a
faculty member for the Physical Activity and Public Health course that I propose to attend during Year 1 of the
training plan.
Dr. William Lee will serve as a consultant for the proposed project. Dr. Lee is the Director of the Clinical
Center for Liver Diseases at UT-Southwestern, and leads large clinical trials of the treatment of Hepatitis B and
C27-29 and was the founding Principal Investigator for the Acute Liver Failure Study Group and was the
founding Principal Investigator for the Acute Liver Failure Study Group (5U01DK058369).30 Dr. Lee and I will
meet monthly during the preparation and implementation of the proposed pilot study. Dr. Lee will provide
expertise in conducting clinical research in the HPC population and will also help to facilitate recruitment of
participants from the UT-Southwestern Clinical Center for Liver Diseases.
Dr. Ryan Huebinger will serve as a consultant for the proposed project. Dr. Huebinger is an instructor in the
Department of Surgery at UT-Southwestern. Dr. Huebinger’s work is focused on the examination of biomarkers
and genetic variants as they relate to clinical outcomes.31,32 Dr. Huebinger will offer advice on the proper
methods for sample collection and oversee the analysis of samples for inflammatory makers. Dr. Huebinger
conducted analyses of BDNF and inflammatory cytokines on blood samples collected during TREAD.11,12
Coursework: In addition to the individual mentorship, I will take advantage of the training opportunities offered
through the CTSA-supported Department of Clinical Sciences at UT Southwestern. The Department offers
courses covering various aspects of clinical research that will provide the knowledge and skills necessary to
become an independent investigator.
Clinical Research Questions & Methods (DCS 5103, Summer 2013) – This course teaches students to identify
the type of research questions that lead to career-building and development and enhances their ability to
critically evaluate research questions and methods.
Clinical Research: From Proposal to Implementation (DCS 5115, Fall 2013) - The overall objective of this
course is to acquire a working knowledge of how to implement a clinical research proposal.
Clinical Research Management & Leadership (DCS 5108, Spring 2014) - This course is a structured review
and discussion of the basics of management and leadership theory and practice. Topics include project
management and budgeting, information systems, leadership style, effective interviewing and hiring
techniques, conflict resolution, and the basics of organizational culture.
Physical Activity and Public Health Course (PAPH; September 2013): The PAPH is an 8-day course
sponsored by the Center for Disease Control and Prevention and the University of South Carolina Prevention
Research Center. The course is designed to develop research competencies related to physical activity and
public health. Topics include grantsmanship skills; research funding opportunities; measurement of physical
activity; design of epidemiologic studies; dose-response issues; individual, community, and policy
interventions; critical research needs on physical activity in women, minorities, youth, and the elderly; and
numerous special topics.
Practical Experience: The mentorship and coursework related to the conduct of RCTs in clinical populations
will be complemented by practical experience in RCT conduct through the proposed research project, which
will provide me with the opportunity to design and manage my own research trial. This experience will be
critical to successfully compete for a future R01.
4.2 Training in Psychopathology Diagnosis and Assessment
My previous training and experience has provided me knowledge in several aspects necessary to achieve my
career objective of becoming an independent investigator of the effects of physical activity on mental health.
However, I have thus far had limited formal training related to psychiatric disorders. Therefore, a second aim of
my proposed training is to gain knowledge and experience related to psychopathology diagnosis and
assessment through a combination of mentorship and coursework.
Mentorship: Weekly meetings with Dr. Trivedi will include didactic discussions regarding psychopathology,
with an emphasis on Major Depressive Disorder (MDD). Topics of discussion will include diagnosis and
assessment of MDD, treatment options, disease course, and medical comorbidities.
Dr. David Morris will serve as a consultant for the proposed project. Dr. Morris is an Assistant Professor in
the Department of Psychiatry at UT-Southwestern. Dr. Morris has extensive expertise in the development and
implementation of clinical assessment procedures, and training and certification of clinical raters, having
performed in this capacity for many of the largest federally funded multi-center psychiatric treatment trials to
date. He was the clinical outcomes manager for the STAR*D and CO-MED trials, as such was responsible for
all aspects of data collection including rater training and certification. Dr. Morris also trained and certified all
raters for the NIMH funded REVAMP study and B-SNIP study, and is currently performing this duty for the
EMBARC study and the CTN STRIDE trial. Dr. Morris will train and certify me on all clinical assessments. Dr.
Morris will also provide ongoing supervision, as well as quarterly recertification and training for all clinical
measures.
Coursework: The mentorship of Dr. Trivedi and Dr. Morris will be complemented with coursework offered
through the Department of Clinical Psychology at UT-Southwestern.
Advanced Abnormal Psychology (PSY 5356, Fall 2013) - This course includes intensive consideration of
psychopathology, emphasizing description, etiology, prognosis, treatment modes and clinical research
findings.
Practical Experience: Dr. Morris will oversee my training in the diagnostic and assessment tools used in the
pilot study, including the Mini International Neuropsychiatric Interview (MINI) and the Quick Inventory of
Depressive Symptomatology - Clinician Rated (QIDS-C16), which will be used in the proposed research trial.
4.3 Advanced Training in Biostatistical Methods
Mentorship: During the data analysis stage of the proposed project, I will meet weekly with Dr. Thomas
Carmody, Associate Professor in the Department of Psychiatry at UTSW. Dr. Carmody has over 20 years
experience as a biostatistician and is an expert in study design and longitudinal analysis of projects in the area
of mental health. Dr. Carmody participated in the design of the TREAD study and was responsible for analysis
of the main outcomes of this study7 and a secondary analysis of the TREAD data.6 He has worked with Dr.
Trivedi on several major projects including TMAP33 and IMPACTS.34
Coursework: The coursework proposed, offered through the School of Public Health, will complement the
mentorship provided by Dr. Carmody and provide the necessary knowledge and skills to complete the data
analysis of the proposed pilot study.
Intermediate Biostatistics (PH 1700, Fall 2014) – This course focuses on the application of data analysis on
research problems of public health and the biological sciences. PH1700 is a prerequisite for other statistical
courses.
Applied Statistical Analysis I (PH 1820, Fall 2015) – The course emphasizes the design, implementation,
analysis, and reporting of research investigations. Topics include two-sample inference using t-distributions,
robustness and resistance, alternatives to the t-test based analyses, comparisons among several samples,
linear combinations and multiple comparisons, simple and multiple linear regression methods, regression
diagnostics, variable selection, and related methods.
Applied Statistical Analysis II (PH 1821, Spring 2016) – This course is a continuation of PH 1820. Topics
include the analysis of variance for two-way classifications, factorial arrangements and blocking designs,
analysis of repeated measures and other multivariate responses, exploratory tools for summarizing multivariate
responses, logistic methods for binary response variables and binomial counts, and log-linear regression for
Poisson counts.
Statistical Methodology in Clinical Trials (PH 1835, Fall 2016) – This course covers the use of current statistical
methodology in the design, execution, and analysis of clinical trials. Some of the topics include study design,
randomization, sample size issues, data analysis issues, and interim monitoring.
Practical Experience: During the analysis phase, I will be responsible for the analysis of preliminary efficacy
for the proposed pilot study. During our weekly meetings, I will work with Dr. Carmody to accurately analyze
and interpret the data from the pilot study.
Timeline
Activity
Courses:
Mentoring:
Weekly meeting w/ Dr. Trivedi
Monthly phone call w/ Dr. Blair
Monthly meeting w/ Dr. Lee
Montlhy meeting w/ Dr. Carmody
Monthly meeting w/ Dr. Morris
Practical Experience:
Pilot Study
Psychopathology Assessment
Publications
Grant Submission
Year 1 (April 2013-March 2014) Year 2 (April 2014-March 2015) Year 3 (April 2015-March 2016) Year 4 (April 2016-March 2017)
Summer: DCS 5103 (1 hour)
Fall: PH 1700 (4 hours)
Fall: PH 1820 (3 hours)
Fall: PH 1835 (3 hours)
September: PAPH
Spring: PH 1821 (3 hours)
Fall: DCS 5115 (1 hour)
PSY 5356 (3 hours)
Spring: DCS 5108 (2 hours)
Preparation/Implementation
STRIDE Baseline Manuscripts
Analysis and Manuscript Preparation
STRIDE Results Manuscripts
STRIDE Results Manuscripts
Publication of Pilot Study
Preparation & Submission of R01
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RESUME AND SUMMARY OF DISCUSSION: This is a resubmitted application for a Mentored
Research Scientist Development Award from a candidate interested in the effects of physical activity on
mental health. The research specifically proposed here would examine the utility of exercise to prevent
depression associated with interferon-α for treatment of hepatitis–C. The resubmission was generally
regarded as very responsive to the previous review and improved. The candidate, mentors and
environment were regarded as outstanding. The research proposed would address a significant
problem and also lay the groundwork for research on other chronic conditions where medication
adherence can be challenging due to side effects. The main question reviewers had was related to
some uncertainty that the candidate needed four years of additional training under this award given his
accomplishments to date;; however, some reassurance regarding this was provided by Dr. Tamminga’s letter. There was also some lack of clarity regarding the primary mentor’s availability. On balance, the
application as a whole was regarded as outstanding.
DESCRIPTION (provided by applicant): This proposal is for a K01 Mentored Research Scientist
Development Award for Dr.
, Assistant Professor in the Department of Psychiatry at
University of Texas Southwestern Medical Center. The K01 award will provide the
with the
additional training and experience necessary to become an independent investigator studying the
effects of physical activity on mental health. The proposed career development plan includes focused
coursework, mentorship from a multi-disciplinary group of established researchers and practical
research experience. The training plan focuses on two training objectives: (1) training in the design and
conduct of RCTs in clinical population, (2) training in psychopathology diagnosis and assessment and
(3) advanced training in biostatistical methods. Dr. Madhukar Trivedi will serve as the primary mentor
and will oversee the training plan. Dr. Trivedi has extensive experience in the design and conduct of
multisite trials in mood disorders. Dr. Steve Blair and Dr. Thomas Carmody will provide additional
mentorship. Dr. Blair has extensive experience in conducting RCTs using exercise interventions in
clinical populations. Dr. Carmody is an expert in study design and longitudinal analysis of projects in the
area of mental health. The research project is a pilot study of an exercise intervention to prevent
depression in Hepatitis C patients receiving Interferon-alpha (IFN- α) treatment. IFN- α is an efficacious
treatment for Hepatitis C (HPC); however, IFN- α treatment results in a significant increase in
depressive symptoms. The potential of an exercise intervention to prevent depression during IFN- α
treatment is supported by longitudinal data demonstrating that physical activity reduces future risk of
depression. Furthermore, exercise is efficacious as a stand-alone and/or adjunctive treatment for
depression. Participants will be recruited from the Clinical Center for Liver Diseases at UTSouthwestern and randomized to 26 weeks of either: aerobic exercise or a health education control
group. The aims of the pilot study are: 1) to examine the feasibility of recruitment and randomization of
eligible HCV patients into an RCT, 2) to examine the feasibility of maintaining participant engagement
throughout the duration of the trial, 3) to conduct an analysis of the preliminary efficacy of an exercise
intervention in preventing depression in Hepatitis C patients receiving IFN-¿ treatment, and 4) to
conduct an analysis of the preliminary effects of an exercise intervention on mediators of IFN- α
induced depression in HPC patients receiving IFN- α treatment. The successful completion of the
proposed research and training plan will provide the knowledge and experience necessary to progress
toward his career goal of becoming an independent investigator examining the role of
physical activity in the treatment and prevention of mental illness. Specifically, the data obtained from
the proposed pilot study will serve as the basis for an R01 application to be submitted during the final
year of the K01 award. The R01 will propose an RCT sufficiently powered to examine the efficacy of an
exercise intervention in the prevention of IFN- α -induced depression.
PUBLIC HEALTH RELEVANCE: IFN-¿ treatment results in a significant increase in depressive
symptoms, which can negatively impact treatment adherence and outcomes. The prevention of IFN-¿induced depression will eliminate the physical, psychosocial and economic burdens often associated
1 K01 MH097847-01A1
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with depression and can potentially improve treatment adherence and outcomes. If exercise proves to
be efficacious in preventing depression in HCV patients, the results may be generalizable to other
medically ill groups at risk for depression. Furthermore, the model of IFN- ¿ induced depression
provides strong evidence for the role on inflammation in the development of MDD. Completion of the
proposed project will provide further insight into the role of inflammation in the etiology of MDD, while
also exploring the role of exercise as a treatment option for MDD patients with elevated systemic
inflammation. !
CRITIQUE 1:
Candidate: 2
Career Development Plan/Career Goals /Plan to Provide Mentoring: 3
Research Plan: 2
Mentor(s), Co-Mentor(s), Consultant(s), Collaborator(s): 2
Environment and Commitment to the Candidate: 1
Overall Impact:
This is a very promising investigator who is diligently following a training trajectory in clinical research.
He has a relatively unique skill set for the type of research he is proposing (exercise interventions in
depression). He has chosen an excellent group of mentors, and has designed his study to be a useful
vehicle for acquiring the needed skills to lead clinical studies in depressed populations.
1. Candidate:
Strengths
The applicant appears to be a serious investigator who has narrowed his focus and maintained
it through his prior research and training. His prior training in kinesiology and counseling and
sport psychology and his publications of meta-analyses in this field and of biological
associations with exercise, position him well for this research. As he is interested in expanding
into clinical trials of exercise, the proposed training will be very beneficial. His letters of
reference are generally quite positive.
Weaknesses
None.
2. Career Development Plan/Career Goals & Objectives/Plan to Provide Mentoring 3:
Strengths
The mentors are all excellent and well suited to the goals of this application, assuming they are
able to provide sufficient time to mentoring.
The planned coursework is excellent and well thought out.
Weaknesses
The candidate might have been expected to have acquired more clinical research skills by this
time already in his research trajectory and clinical trial experiences, making another 4-year
training goal less necessary. However, his letter of recommendation from his Department Chair
makes it clear the she feels the current training grant is important for the applicant’s continued career development.
It is not clear that a full 4 additional years of mentored research support should be required to
meet his training needs
The mentoring time commitment by Dr. Trivedi is not clear (one place says” regularly,” another says “weekly.”)
3. Research Plan:
1 K01 MH097847-01A1
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Strengths
This is an important topic, and the applicant brings excellent background to the study. The
resources and support are all excellent.
Positive findings in this study could lead to investigating exercise in other depressive conditions
with inflammatory relationships.
Weaknesses
The design seems adequate for assessing feasibility for this approach in this patient population.
4. Mentor(s), Co-Mentor(s), Consultant(s), Collaborator(s):
Strengths
Mentors are all outstanding.
In addition to being a leading researcher with excellent experience in clinical trials, Dr. Trivedi
has additional expertise in studying exercise in depression, making him an ideal mentor, if he is
able to commit sufficient time (the Budget Justification states weekly meetings;; Dr. Trivedi’s letter states “regular meetings.”)
Dr. Blair is an excellent authority on exercise research, although the amount of contact (monthly
phone calls plus one in-person meeting a year) is quite little for strong mentorship.
Dr. Carmody will add valuable mentorship in statistical analyses.
Dr. Lee will contribute the needed expertise in hepatic disease and will facilitate access to the
subjects and will be able to help coordinate the exercise intervention into the interferon
treatment.
Dr. O’Hara will provide very useful consultation
Weaknesses
None, other than assurance that the mentoring team will provide sufficient in-person contact to
provide adequate mentoring.
5. Environment and Institutional Commitment to the Candidate:
Strengths
Excellent.
Weaknesses
None.
Protections for Human Subjects:
Acceptable Risks and Adequate Protections
Inclusion of Women, Minorities and Children:
G1A - Both Genders, Acceptable
M1A - Minority and Non-minority, Acceptable
C1U - Children and Adults, Unacceptable
The application did not acknowledge the notion that 18-21 yo are "children"
neurodevelopmentally.
Resubmission:
Applicant has been responsive to prior comments.
Training in the Responsible Conduct of Research:
Acceptable
CRITIQUE 2:
1 K01 MH097847-01A1
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Candidate: 2
Career Development Plan/Career Goals /Plan to Provide Mentoring: 2
Research Plan: 3
Mentor(s), Co-Mentor(s), Consultant(s), Collaborator(s): 1
Environment Commitment to the Candidate: 1
Overall Impact:
Candidate has a very solid background and commitment to his chosen field. His mentoring panel is
superb, and the academic environment at U of Texas Southwestern is outstanding with a distinguished
depression program, that has been a leader in evaluating the MH benefits of exercise interventions.
The work proposed, and career development plan are likely to lead the candidate to become an
independent scientist, with a strong program in selective preventive interventions in med/psych
populations. He has been responsive to the last review in making adjustments to both the career plan
(e.g. augmented experiences to learn more about MDD, and adjustment of the research plan such as
inclusion of the HE control group, clearer justification for the sample size, and articulation of a
mechanistic model of how exercise may exert its preventive effect in the hepatitis patient population
receiving interferon therapy. While overall very well-conceived and written there are some issues with
the application such as confusing referencing (e.g. in the background section), the issue of how the
remaining 1.5 years of the K award period will be spent-certainly part of this time will be taken up with
writing an R01 but this should only take 4-6 months.
1. Candidate:
Strengths
Strong commitment to the study of exercise as an intervention.
Recent data-based publications in press indicate momentum. Candidate has moved beyond
the critique of only having meta-analyses and reviews supporting his study plan.
Thirteen publications, only 4 years out from his PhD degree, NCDEU new investigator award
2011.
Weaknesses
Relative lack of clinical experience with depressed patients.
2. Career Development Plan/Career Goals & Objectives/Plan to Provide Mentoring:
Strengths
Well described. Good summary figure demonstrating well thought out sequence of events, e.g.
further training in assessment will take place in year 1 prior to the beginning the proposed trial.
Weaknesses
[None noted]
3. Research Plan:
Strengths
Addresses a major public health need, i.e. the need for preventive strategies for the depression
and other high prevalence psychiatric conditions. The rate of depression in HPC patients
receiving IFN therapy is 30-50%, and recent data suggest that SSRIs aren’t particularly effective as a preventive agent.
Appropriate screening/assessment procedures.
Well-conceived trial plan with justification for the 26 week time period.
Appropriate clinical measures with blind raters administering key ratings (e.g. QIDS)
Weaknesses
Trial underpowered, but will allow for assessment of feasibility, adherence to intervention
Two enrolled patients per month does not seem an especially high flow rate.
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4. Mentor(s), Co-Mentor(s), Consultant(s), Collaborator(s):
Strengths
Dr. Trivedi, the primary mentor, is an international leader in depression clinical trials. Dr. David
Morris has been brought on as a consultant to enhance the candidate’s learning in assessment of psychopathology. Dr. Blair (U of South Carolina) is an expert in exercise interventions in
clinical populations, and collaborator of Dr. Trivedi on other trials. Dr. Lee, as Director of the
Liver Center, will provide expertise, and access to hepatitis C patients. Dr. Huebinger will
perform cytokine/inflammatory marker assays. Dr. Carmody, a senior biostatistician at UT
Southwestern, will support the analysis of the proposed trial.
Weaknesses
None.
5. Environment and Institutional Commitment to the Candidate:
Strengths
Outstanding environment, with strong institutional commitment to the candidate’s career development (see Chair’s letter).
Weaknesses
[None noted]
Protections for Human Subjects:
Acceptable Risks and Adequate Protections
See below.
Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):
Unacceptable
Should have a DSMB panel to review study progress at least annually.
Inclusion of Women, Minorities and Children:
G1A - Both Genders, Acceptable
M1A - Minority and Non-minority, Acceptable
C1U - Children and Adults, Unacceptable
Candidate did not acknowledge the notion that 18-21 year old are "children" per NIH.
Resubmission:
Responsive to the initial review. Adjustments to research plan based on this, e.g. inclusion of
an HE comparison group to match the 2 study groups for amount of clinician attention/contact.
Training in the Responsible Conduct of Research:
Acceptable
Comments on Format (Required):
Ethics courses (ethics in clinical science I and II-to be done in year 1).
Comments on Subject Matter (Required):
Appropriate to the candidate's clinical trial focus.
Comments on Faculty Participation (Required; not applicable for mid- and senior-career
awards):
Weekly and monthly contact with mentors in addition to course exposure.
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Comments on Duration (Required):
As above.
Comments on Frequency (Required):
As above.
CRITIQUE 3:
Candidate: 2
Career Development Plan/Career Goals /Plan to Provide Mentoring: 3
Research Plan: 4
Mentor(s), Co-Mentor(s), Consultant(s), Collaborator(s): 1
Environment Commitment to the Candidate: 1
Overall Impact:
Adherence is a crucial factor in the outcome of treatment for Hepatitis C, but the main treatment
modality, interferon alpha, is associated with a wide range of side effects, including depressive
symptoms and depression. This project aims to address how depressive mood symptoms might be
improved by an exercise program. This project addresses a significant public health issue and the
results could have important implications for the treatment of other chronic conditions in which
adherence to treatment is important for good outcomes. However, there were concerns about the
research plan on the last review some of which have been responded to, but not all of them. There
was also concern about the appropriateness of the candidate for a K award, in the context of what is
proposed in this application, which has also not been completely resolved.
1. Candidate:
Strengths
Fairly strong candidate with demonstrated training, expertise, and record of publications in the
field of exercise.
Excellent mentors.
Strong reference letters.
Weaknesses
[None noted]
2. Career Development Plan/Career Goals & Objectives/Plan to Provide Mentoring:
Strengths
The career development plan has several good courses in year one.
Weekly meetings with Dr. Trivedi and monthly meetings/phone call with other mentors over all
four years will give the candidate access to a wealth of supervision and advice.
Weaknesses
As mentioned in the last review, the candidate already has worked closely with his primary
mentor. The reviewer had asked “it is not clear why this additional level of support is required”. The same reviewer asked why the candidate needed further training in clinical trials if he had
already been the “National Director” of a large multisite clinical trial. Unfortunately the
introduction does not adequately address these crucial questions. Thus, as was the case during
the last review, there is some question about the justification for 4 years of support under this K
award mechanism.
3. Research Plan:
Strengths
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Candidate has access to the population he plans to study, and strong support from a mentor
(Lee) who has access to the clinical population. However, as noted below, it is not clear that
there will be enough subjects.
His primary mentor (Trivedi) has vast experience in clinical trials and already works closely with
the candidate.
Weaknesses
In the review of the literature, which is used to justify the study design, the candidate shifts from
findings related to diagnosed major depression and depressive symptoms, implying that these
are more or less the same with regard to his hypotheses.
In aim 3 it states that the analysis will look for efficacy of the exercise intervention in “preventing the increase of depressive symptoms during INF alpha treatment” but it is not completely clear
how the QUIDS scores will be used for this purpose. Even less clear is how the analysis of
sleep data and cytokine data will be conducted.
As mentioned in the previous review, need for the work on cytokines is not crisply justified.
An SSRI control group or other intervention known to be efficacious in depression would have
been a better control group, since health education is not known to prevent or treat depression
or depressive symptoms. This is discussed but the justification that they want the largest
treatment effect, is puzzling.
Since aim 1 is feasibility of the proposed study, it is somewhat troubling that it is not known
whether there will be enough subjects to conduct the research. What happens for the rest of the
award (years 2-4) if the study is not feasible?
4. Mentor(s), Co-Mentor(s), Consultant(s), Collaborator(s):
Strengths
Primary mentor (Trivedi) is well known and experienced in conducting clinical trials in mood
disorders and has also investigated the use of exercise in treating depression. This excellent
mentor has already been working closely with the candidate.
Other mentors are also excellent and leaders in their respective fields.
Weaknesses
None.
5. Environment and Institutional Commitment to the Candidate:
Strengths
Environment is excellent.
Strong department support as evidenced by letters.
Weaknesses
None.
Protections for Human Subjects:
Acceptable Risks and Adequate Protections
There are in place adequate safeguards for foreseeable risks.
Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):
Acceptable
Acceptable data and safety monitoring plan is proposed.
Inclusion of Women, Minorities and Children:
G1A - Both Genders, Acceptable
M1A - Minority and Non-minority, Acceptable
C1A - Children and Adults, Acceptable
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Children 18-21 will be included and this is acceptable
Resubmission:
The candidate has responded to most of the comments made by reviewers of the previous
submission.
One important addition regarding training in clinical psychopathology has been very well
covered in this resubmission.
Training in the Responsible Conduct of Research:
Acceptable
Comments on Format (Required):
Has had previous training and has proposed further courses and discussions with mentors.
Comments on Subject Matter (Required):
The course chosen are suitable
Comments on Faculty Participation (Required; not applicable for mid- and senior-career
awards):
Faculty are qualified and committed to provide the necessary training
Comments on Duration (Required):
Duration is appropriate
Comments on Frequency (Required):
Frequency is appropriate
THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW
OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON
THE FOLLOWING ISSUES:
PROTECTION OF HUMAN SUBJECTS: ACCEPTABLE. Plans for the protection of human subjects
are well described.
INCLUSION OF WOMEN PLAN: ACCEPTABLE. Women will be well represented in the sample.
INCLUSION OF MINORITIES PLAN: ACCEPTABLE. Minorities will be well represented in the sample.
INCLUSION OF CHILDREN PLAN: ACCEPTABLE. Children age 18-20 are eligible for inclusion.
COMMITTEE BUDGET RECOMMENDATIONS: It is unclear that a full 4 years is required to achieve
the training goals. However, this is not unreasonable. It is also not clear that the applicant should
require this much additional training in clinical trials, given his prior experiences, although Dr.
Tamminga does attest to his need for this additional training. The application requests 100% (12 cal
mo.) salary support for
, but the Department Chair’s (Dr Tamminga) letter of
recommendation specifies only that at least 75% time will be protected from clinical and teaching
duties.
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NIH has modified its policy regarding the receipt of resubmissions (amended applications).
See Guide Notice NOT-OD-10-080 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD10-080.html.
The impact/priority score is calculated after discussion of an application by averaging the
overall scores (1-9) given by all voting reviewers on the committee and multiplying by 10. The
criterion scores are submitted prior to the meeting by the individual reviewers assigned to an
application, and are not discussed specifically at the review meeting or calculated into the
overall impact score. For details on the review process, see
http://grants.nih.gov/grants/peer_review_process.htm#scoring.