Modeling Mood Course to Detect Markers of Effective Adaptive Interventions
Phase: NA
Conditions: Bipolar Disorder
Sponsor: University of Wisconsin, Madison

Protocol for Aim 2 
Modeling Mood Course to Detect Markers for Effective Adaptive Interventions  
 
Date: 
11/2/17 
Clinicaltrials.gov ID: 
NCT03358238 
Version: 
2 
Principal Investigator: 
Melvin McInnis 
Contact:  
Heinz C. Prechter Bipolar Research Fund 
University of Michigan Depression Center 
Rachel Upjohn Building 
4250 Plymouth Road 
Ann Arbor, MI 48109-2700 
bpresearch@umich.edu 
1-877-864-3637 
Institute: 
University of Michigan 
 
 
 
 
 
 
 
 
 
 
 
 

Contents 
Introduction ........................................................................................................................................................ 3 
A. Type of Research ...................................................................................................................................... 3 
B. Purpose/Objective of the Study.................................................................................................................. 3 
C. Background of the Study ........................................................................................................................... 3 
Participant Selection .......................................................................................................................................... 4 
A. Inclusion and exclusion criteria .................................................................................................................. 4 
B. Gender ...................................................................................................................................................... 4 
C. Racial/Ethnic Origin ................................................................................................................................... 4 
D. Vulnerable Populations .............................................................................................................................. 4 
E. Age ............................................................................................................................................................ 5 
F. Total Number of Participants to be Enrolled ............................................................................................... 5 
Study Design / Method / Procedures ................................................................................................................. 5 
A. Summary of the Research Design ............................................................................................................. 5 
B. Analysis of Study Results .......................................................................................................................... 7 
C. Monitoring ................................................................................................................................................. 7 
D. Storage and Confidentiality of Data ........................................................................................................... 8 
Participant Recruitment and Informed Consent ................................................................................................. 8 
A. Recruiting .................................................................................................................................................. 8 
B. Informed Consent / Assent ........................................................................................................................ 8 
 
 
 
 

Introduction 
A. Type of Research 
The research to be conducted under this protocol falls under the general heading of a clinical trial with a 
behavioral intervention. It investigates how individuals with bipolar disorder interact with mobile and wearable 
technology, incorporating both qualitative and quantitative analyses.  
B. Purpose/Objective of the Study 
Our long-term objective is to develop a mobile health platform for the translation of a psychosocial 
intervention for bipolar disorder (BP) into an effective adaptive intervention. In this particular part of the study, 
we explore how to engage individuals with BP in long-term monitoring of their daily patterns of mood, 
stress, sleep, circadian rhythm, and medical adherence. To answer this question, we will study how 
individuals with BP interact with a smart-phone application and activity tracker.  Three hypotheses will be 
tested for how to engage individuals with BP:  individuals with BP prefer and better adhere to monitoring 
of their daily patterns when... 
          (H1) using activity trackers over self-reports;  
          (H2) they review weekly symptoms with another person; and    
          (H3) the collected data is synthesized into information perceived to offer new insight.   
 
C. Background of the Study 
Bipolar (BP) disorder is a chronic illness of profound shifts in mood ranging from mania to depression. BP 
is successfully treated by combining medication with psychosocial therapy, but care can prove inadequate in 
practice. With gaps in coverage and medication, along with imprecise guidelines on when, where, and how to 
intervene, promising psychosocial therapies require adaptive strategies to better address the specific needs of 
individuals in a timely manner (NIMH Strategy 2). To accomplish this, however, requires evidence-based 
practices for adapting a psychosocial therapy. This project aims to address this knowledge gap by establishing 
a mobile health platform for translating a psychosocial therapy in BP into an effective adaptive intervention. 
To adapt a psychosocial therapy to information in the moment, then symptoms should be monitored 
frequently over extended periods. Frequent observations (multiple times a day) are needed to capture the 
diurnal patterns (Wirz-Justice 2008) and rapid mood shifts (Kramlinger and Post 1996) associated with BP. 
Extended observation (weeks to years) captures full length episodes (Solomon, Leon et al. 2010) and certain 
medication effects (Goodwin, Jamison et al. 2007).     
Mood is commonly charted with self-reports, often on a one-dimensional scale such as the Mood 24/7 
scale (April C. Foreman 2011) and the NIMH Life Chart Method (Denicoff, Leverich et al. 2000). However, 
mood in BP may not be one-dimensional. NIMH’s RDoC, for example, defines both a negative valence and 
positive valence domain (Cuthbert and Insel 2013). Accuracy of self-reports may also depend on an 
individual’s mood (Born, Amann et al. 2014) and time of day (Wirz-Justice 2008). They also require individuals 
to actively record symptoms, a burden that leads to disengagement (Nahum-Shani, Smith et al. 2014). In sum, 
self-reports are subjective and time-intensive and lose information that limit its utility in charting BP.  
BP can also be charted passively through sensors on smart-phones and wearable devices (Depp, 
Mausbach et al. 2010). Smart-phone platforms MONARCA (MONitoring, treAtment and pRediCtion of bipolAr 
Disorder Episodes) and PRIORI (Predicting Individual Outcomes for Rapid Intervention; McInnis, PI, 
R34MH100404) aim to predict mood from patterns of speech and behavior from recorded calls, number of 
phone calls, and phone call duration.  However, smart-phones do not monitor circadian and sleep rhythms, a 
primary target of therapies such as sleep deprivation (Wu, Kelsoe et al. 2009) and interpersonal and social 
rhythm therapy (Frank, Kupfer et al. 2005). Disrupted circadian rhythms are thought to be central to BP 
etiology, with connections to risk genes, animal models, and pharmacological therapy (McClung 2013). 
Actigraphy is a promising alternative that can evaluate sleep and circadian rhythms. Pagani, Clair et al. 
(2015) have linked actigraphic variables to genetic differences between BP-I and non-BP-I individuals that 
include later wake times, longer sleep durations, and lower activity levels in BP-I subjects during euthymia. In a 
current study with the investigators, actigraphy data revealed that BP individuals wake up significantly later 
than non BP individuals, while reporting they are less rested, drink more caffeine, and use more sleep 
medication. Lower activity is also found to be significantly associated with an increase in depressive 

symptoms, whereas higher activity is associated with an increase in manic symptoms. A validated 
mathematical model of circadian rhythms were developed by Dr. Daniel Forger (Forger, Jewett et al. 1999). 
With these models and statistics, Dr. Forger, his student Olivia Walch, and a co-investigator of the current 
study, Amy Cochran, analyzed sleep habits from over 5000 users from over 100 countries collected with a 
smartphone app ENTRAIN (Walch, Cochran et al. 2016). This work has been published in Science Advances 
and featured in over 100 media outlets across the globe that include Huffington Post, BBC, Wired, and TIME. 
Participant Selection 
A. Inclusion and exclusion criteria 
We will recruit 54 individuals from the Prechter Longitudinal study of Bipolar Disorder who (i) have agreed to be 
contacted for future research, (ii) have a smart-phone, and (iii) have either a diagnosis of bipolar disorder or do 
not have a diagnosis of bipolar disorder.  Four individuals without a diagnosis of bipolar disorder will be used to 
test instruments for two-week study. Once instruments are tested, 50 individuals with a diagnosis of bipolar 
disorder will be recruited for a six-week study.   
B. Gender  
Participation is open to men and women. For the six-week study, we will recruit 25 women and 25 men to 
balance gender in the 50 individuals.  
C. Racial/Ethnic Origin 
Participation is open to all ethnic and racial groups. The research team’s capacity to enroll a study sample with 
adequate representation of minorities is enhanced by the diversity of Washtenaw and surrounding Counties, in 
which the majority of the clinic patients live. According to the U.S. Census’ American Fact Finder 2010 
Demographic Profile Data, the demographics of the population of Washtenaw County are estimated as follows: 
 
• 
72.1% White alone, not Hispanic or Latino 
• 
12.7% Black or African American 
• 
7.9% Asian 
• 
4.0% Latino or Hispanic 
• 
3.4% Two or more races 
• 
0.3% American Indian or Alaskan Native 
• 
0.0% Native Hawaiian or Other Pacific Islander 
 
Recruitment milestones have been submitted to the National Institute of Health (see table below). Actual 
recruitment will be reported to the NIH every four months.  
 
Total 
Racial Minority 
Hispanic 
August 1, 2017 
0 
0 
0 
December 1, 2017 10 
2 
1 
April 1, 2018 
22 
5 
2 
August 1, 2018 
35 
9 
3 
December 1, 2018 50 
13 
4 
 
D. Vulnerable Populations 
The study is limited to a subgroup of the population which does not specifically target pregnant women and/or 
fetuses; lactating women; women of child-bearing potential; prisoners; cognitively impaired adults; college 
students; economically or educationally disadvantaged persons; patients of the study team; employees, 
students or trainees of the study team; or family members of the study team.  

E. Age 
Participation is open to adults (18 years of age or older). For the six-week study, we will recruit 24 individuals 
under the age of 40 and 26 individuals 40 years of age or older, with equal numbers of women and men in 
each age group.  
F. Total Number of Participants to be Enrolled 
A total of 54 individuals will participate in either the two-week study or the six-week study.  
Study Design / Method / Procedures 
A. Summary of the Research Design 
Recruitment and Arms. Fifty individuals with BP will be recruited from the Prechter Longitudinal Study 
of Bipolar Disorder (PI: Melvin McInnis; HUM606) to participate in a six-week study. They have already 
completed a Diagnostic Interview for Genetic Studies (DIGS) about their health and mental illness history. We 
will access the diagnostic information and other data from the longitudinal study so not to repeat the interview 
process. Each subject in the six-week study. will also be randomly assigned to one of two arms (Arm NR=No 
Review or Arm R=Review), stratified by age and gender. Four individuals without BP will also be recruited from 
the Prechter study to pilot the instruments over two weeks; these four individuals will all be assigned to Arm 
R. The study is necessarily not blinded.  
Randomization.  Prior to the start of the study, a randomized list of assignment to one of the two arms 
will be generated for each of four groups: women < 40 years of age (N=12), women ≥ 40 years of age (N=13), 
men < 40 years of age (N=12), men ≥ 40 years of age (N=13). For the two groups of 12 participants, the 
randomized list will be comprised of two random blocks of size four and two random blocks of size two with 
blocks placed in random order. For the two groups of 13 participants, the randomized list will be comprised of 
two random blocks of size four, one random block of size three, and one random block of size two with random 
blocks in placed in random order. Together, there will be two random blocks of size three. Because the size is 
an odd number, these blocks will each be unbalanced, but together will ensure equal participants in each arm; 
which arm is over-represented in each group is chosen uniformly at random. Using logical statements and 
subject ids, randomization will be automatically embedded as a computed variable in REDCap.  
Entrance interview. A summary of participation in the study is given in the table below. First, we 
will mail each participant an activity tracker like a FitBit or an Apple Watch, along with a return box with 
postage paid.  Once they receive the activity tracker, we will schedule a time to talk to them over the phone to 
assess their mood and functioning and to explain how to set-up and use the study smartphone application and 
activity tracker, including how to report and review your information and set preferences for notifications.  
Activity tracker and smart-phone application. We will ask each participant to wear the activity 
tracker at all times, except to charge the tracker or to shower. Automatic messages will be sent to the 
participant to remind them to wear the tracker. The tracker will automatically collect information about physical 
activity and sleep. The smart-phone application will automatically prompt the user twice-a-day (once in the 
morning and once in the evening) on questions about their mood, stress, bed and wake times, and medication 
adherence.  These questions will be prompted automatically by the smart-phone app.  The smart-phone app 
will also allow the participant to review their information provided to the study team, including information 
collected from the activity tracker and processed offline by computational algorithms.   
Weekly interviews. We will also contact each participant weekly to complete questionnaires to assess 
the severity of depressive symptoms and manic symptoms.  In addition to these assessments, the participants 
in Arm R will also review with the study team what you reported over the week about your mood, stress, and 
medication adherence, and what the activity tracker reported about their sleep and physical activity.   
Exit interview. At the end of the study, we will interview each participant to assess functioning, mood, 
and engagement/preference with smart-phone application and activity tracker.  This assessment will take 
about one hour. The participant will then be asked to mail any study equipment (e.g., activity tracker) using the 
return box.  

Table 1. Summary of participation in study.  
Name 
Instruments 
Time per 
event 
(min) 
Event time 
Entrance 
Phone 
Interview 
Investigator 
provided 
data 
• 
Young Mania Rating Scale (YMRS) 
• 
Structured Interview Guide for the Hamilton Depression Rating 
Scale (SIGH-D) 
• 
36-Item Short Form Survey (SF-36) 
• 
Set-up 
o 
Subject ID 
o 
Prechter ID 
o 
Typical wake time and bed time 
o 
Weekly interview time 
o 
Medication type, time, and frequency 
60 
Day 0 
Reminder 
Automated 
• 
Message reminder to wear activity tracker  
0 
Days 1-42;  
Early morning 
Early morning = 2 
hours after 
subjects "typical" 
wake time 
Daily Self-
Report 
through 
App 
User 
provided 
data 
• 
Brief inventory of symptoms and medication adherence: 
o 
Shortened YMRS 
o 
Shortened SIGH-D 
o 
Stress 
o 
Bed and wake times (morning only) 
o 
Medication adherence (at most once daily; depends on 
medication routine) 
5 
Days 1-42; 
Morning and 
Evening 
Morning (Evening) 
= first (last) 
quarter of subjects 
"typical" wake 
period 
Activity 
Tracker 
Automated 
• 
Uploaded daily activity data  
 
0 
Days 1-42;  
Mid-Night 
Mid-Night = 
middle of subjects 
"typical" sleep 
period 
Daily 
Computed 
Variables 
Automated 
• 
Computed variables: 
o 
Circadian phase 
o 
Physical and sedentary behavior 
o 
Sleep duration 
o 
Longitudinal patterns of sleep, mood, and stress 
0 
Days 1-42;  
Mid-Night 
Weekly 
Phone 
Interview 
Investigator 
provided 
data 
• 
YMRS 
• 
SIGH-D 
• 
Review (Arm R only) of collected and computed 
variables through activity tracker 
Arm NR: 
20 
Arm R: 40 
Days 7, 14, 21, 
28, 35;  
Weekly meeting 
time 
Exit Phone 
Interview 
Investigator 
provided 
data 
• 
YMRS 
• 
SIGH-D 
• 
SF-36 
• 
Review (Arm R only) 
• 
Engagement with monitoring of symptoms: 
o 
Preference and burden: self-report 
o 
Preference and burden: activity tracker 
o 
Preference and burden: computed variables 
o 
Preference and burden: weekly interviews (+review) 
o 
Comparison: self-report vs. activity tracker 
o 
Comparison: computed vs. non-computed variables 
60 
Day 42;  
Weekly meeting 
time 
    
Study termination. The study team may decide to end participation of any person in the study if (i) the 
team believes it is not in the person’s best interest to stay in the study; (ii) the person becomes ineligible; (iii) 

the person’s condition changes or needs treatment that is not allowed while taking part in the study; (iv) the 
person does not follow instructions from the study team; or (v) the study has been suspended or cancelled.   
Suicidality. We will ask about questions about suicide (e.g., attempts, ideation) as part of the 
Structured Interview Guide for the Hamilton Rating Scale for Depression. The outpatient psychiatry department 
at the University of Michigan has standard procedures that are followed when there is a concern for patient 
safety and the University of Michigan psychiatric emergency room is available 24/7. In instances when the 
study team anticipates a threat of self-harm, or harm to others due to the individuals worsening psychiatric 
condition, we will take all clinically indicated appropriate actions to protect the individual, which may include 
hospitalization. We may need to breach confidentiality in these instances, but will limit the sharing of 
knowledge to the bare minimum required for safety. 
B. Analysis of Study Results 
Our primary outcomes evaluate three hypotheses about how to engage individuals with BP, which 
are that individuals with BP prefer and better adhere to monitoring of their daily patterns when... 
     (H1) using activity trackers over self-reports;  
     (H2) they review weekly symptoms with another person; and    
     (H3) the collected data is synthesized into information perceived to offer new insight.   
To evaluate these hypotheses, we measure adherence to activity trackers in each individual as the 
proportion of days with at least 16 hours of wearing the activity track and adherence to self-reports in each 
individual as the proportion of days with at least 2/3 of the daily self-report questions answered. Note that 16 
hours is 2/3 of a day and is chosen to correspond with the 2/3 of daily questions used to defined adherence to 
self-reports. Here, a day is considered to start and end at 12am. For (H1), we use two outcome measures: 
• 
Proportion of individuals with preference for activity trackers over self-reports to monitor their daily 
patterns, as reported at the end of the study, and 
• 
Average difference in adherence to activity trackers and adherence to self-reports.  
For (H2), we use three outcome measures: difference between Arm R and Arm NR in the 
• 
Average adherence to activity trackers, 
• 
Average adherence to self-reports, and 
• 
Proportion of individuals with a preference for monitoring their daily patterns over not monitoring, as 
reported at the end of the study.  
For (H3), we use two outcome measures: difference between individuals who report computed variables (e.g, 
circadian phase) did offer new insight into their daily patterns and those individuals who report that the 
computation variables did not offer new insight in the 
• 
Average adherence to activity tracker, and  
• 
Average adherence to self-report.  
Our secondary outcomes focus on understanding what factors impact the change from baseline to 6 weeks 
in SF-36, YMRS, and SIGHD scores. Secondary outcomes of particular interest are 
• 
Average difference in changes in SF-36, YMRS, and SIGHD scores between Arm R and Arm NR  
• 
Cross-correlation coefficients between  
o Average adherence to activity trackers and changes in SF-36, YMRS, and SIGHD scores 
o Average adherence to self-reports and changes in SF-36, YMRS, and SIGHD scores  
• 
Average difference in changes in SF-36, YMRS, and SIGHD scores between individuals that report at 
the end of the study a preference for monitoring daily symptoms over not monitoring symptoms  
To analyze these outcome measures, we will use a one-way ANOVA to measure differences in 
covariates between groups and cross-tabulation with a Pearson’s chi-squared test to measure differences in 
categorical variables between groups. Significance will be considered an alpha level of 0.05. 
C. Monitoring 
Monitoring safety of the study will be the responsibility of the research team and principal investigator. 
On a monthly basis, the candidate with a research assistant of the Prechter study will review any serious 
adverse events; drop-outs and non-serious adverse events; proposed amendments to the study protocol 

including those for reasons related to the safety of study subjects; completeness and validity of data to be used 
for analyses; progress towards Recruitment Milestone Report (RMR) for all subjects and for minority 
recruitment; and any violation/deviations in protocol including breach in subject privacy and confidentiality. 
Immediately upon review, reports will be relayed to the Prechter study team and Dr. Melvin McInnis and any 
adverse events including violation/deviations in protocol will be reported to the IRBs. Each adverse event will 
also be assessed according to its relatedness to the proposed study and expectedness as specified by the 
IRB, informed consent, and protocols.  As in any research study, it is not possible to anticipate all possible 
adverse events. The Prechter team has substantial experience in monitoring, interviewing, and treating 
individuals with bipolar disorder. They do extensive training with our staff on ascertaining, monitoring, and 
documenting adverse events. Established procedures are in place at the site for rendering first aid and life 
threatening emergencies. In the case of this study, all investigators and study staff will be trained in monitoring 
and documenting adverse events. 
D. Storage and Confidentiality of Data 
We will the secure, HIPAA-compliant web-based application known as REDCap, as well as fully 
automated encryption technology and secure websites (https) for data capture. Study records that contain 
patient names will have access limited to the Principal Investigator and the immediate study team that is 
collecting the data. Confidentiality will be preserved by coding all study data with a unique identifying research 
number, and referring to this number in all analyses. Data from REDCap will be downloaded through secure 
internet connections and stored in secure, restricted access servers which are behind a firewall, under 
intrusion monitoring; will be made accessible only to the members of the study team; and will have all 
personally-identifiable information (e.g., participants’ names, email addresses) removed and will be coded with 
a participant ID. Data will be backed up regularly on secure, restricted access servers that are administered by 
the University of Michigan School of Information’s highly trained information technology department. Coded 
data will be stored separately from the link between the participant’s personally-identifiable information and 
participant ID. In addition, the smart-phone application will use fully automated encryption technology and 
secure websites for data capture to minimize the risk of security breach to the files. 
Participant Recruitment and Informed Consent 
A. Recruiting 
Participants will be recruited through email or phone from the Prechter Longitudinal Study of Bipolar 
Disorder (HUM606) who have agreed to be contacted for future studies. 
B. Informed Consent / Assent 
The following steps will be taken to consent participants for the study:  
1) Participants will be emailed a pdf version of the consent form prior to the start of the study. The form 
will provide important information about the study, including the purpose of the study, and the risks and 
possible benefits of participating in the study.  
2) A member of the study team will phone each participant, provide a complete description of the study to 
the participants, answer any questions, and give them enough time to participate.  
3) At the end of the phone call, the participant will be emailed from REDCap an electronic version of the 
consent form that is designed as a REDCap survey.   
4) If the participant decides to participate, the electronic version can be completed and will be identical to 
the pdf version of the consent form in content and order. Each of the 12 sections of the consent form 
will be contained on separate pages of the electronic consent that the participant will click through. At 
the 12th section, the participant will be asked to provide an electronic version of their signature through 
the use of a mouse or touch-screen device and then submit the consent form.   
5) The study member receiving the consent form will print the signed consent form and then sign and date 
the form. Each participant will be emailed a copy of his or her signed informed consent form and the 
printed form will be placed in a secure filing location within a locked cabinet behind locked doors.