RCT on Co-management of Obesity, Depression, and Elevated CVD Risk in Primary Care-- Engaging Self-regulation Targets to Understand the Mechanisms of Behavior Change and Improve Mood and Weight Outcomes
Phase: NA
Conditions: Depression, Obesity
Sponsor: Palo Alto Medical Foundation

Research Aimed at Improving Both Mood and Weight 
(RAINBOW) in Primary Care: A Type 1 hybrid design randomized 
controlled trial
Jun Ma, MD, PhD1,2, Veronica Yank, MD2, Nan Lv, PhD1, Jeremy D. Goldhaber-Fiebert, 
PhD3, Megan A. Lewis, PhD4, M. Kaye Kramer, DrPH5, Mark B. Snowden, MD, MPH6, Lisa
G. Rosas, MPH, PhD1,2, Lan Xiao, PhD1, and Andrea C. Blonstein, MBA, RD1
1Palo Alto Medical Foundation Research Institute, Ames Building, 795 El Camino Real, Palo Alto, 
CA 94301, USA
2Department of Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA
3Stanford Health Policy, Centers for Health Policy and Primary Care and Outcomes Research, 
117 Encina Commons, Stanford, CA 94305, USA
4RTI International, 3040 Cornwallis Road, Research Triangle Park, NC, 27709, USA
5Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, 3512 
Fifth Avenue, Pittsburgh, PA 15213, USA
6Department of Psychiatry and Behavioral Sciences, University of Washington School of 
Medicine, 325 Ninth Avenue, Seattle, WA 98104, USA
Abstract
Effective interventions targeting comorbid obesity and depression are critical given the increasing 
prevalence and worsened outcomes for patients with both conditions. RAINBOW is a type 1 
hybrid design randomized controlled trial. The objective is to evaluate the clinical and cost 
effectiveness and implementation potential of an integrated, technology-enhanced, collaborative 
care model for treating comorbid obesity and depression in primary care. Obese and depressed 
adults (n=404) will be randomized to usual care enhanced with the provision of a pedometer and 
information about the health system’s services for mood or weight management (control) or with 
the Integrated Coaching for Better Mood and Weight (I-CARE) program (intervention). The 12-
month I-CARE program synergistically integrates two proven behavioral interventions: problem-
Corresponding author: Jun Ma, MD, PhD, Palo Alto Medical Foundation Research Institute, 795 El Camino Real, Ames Building, 
Palo Alto, CA, Telephone: (650) 853-4809, Fax: (650) 329-9114, maj@pamfri.org. 
Trial registration: ClinicalTrials.gov #NCT02246413
Authors’ Contribution
JM conceived the study, obtained funding, has the overall responsibility for its design and conduct, and drafted the manuscript. VY, 
JGF, MAL, MKK, and MBS participated in the design of the study. LX contributed to planning the statistical analyses. NL 
contributed to drafting the manuscript. All authors participated in critical revisions for important intellectual content.
Competing Interests
The authors declare that they have no financial, research, organizational, or other interests to disclose that are relevant to the execution 
of this research or this publication.
These materials were adapted with permission from Dr. Wayne Katon, Principal Investigator for the TEAMcare trial (http://
www.teamcarehealth.org).
HHS Public Access
Author manuscript
Contemp Clin Trials. Author manuscript; available in PMC 2016 July 01.
Published in final edited form as:
Contemp Clin Trials. 2015 July ; 43: 260–278. doi:10.1016/j.cct.2015.06.010.
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solving therapy with as-needed intensification of pharmacotherapy for depression (PEARLS) and 
standardized behavioral treatment for obesity (Group Lifestyle Balance™). It utilizes traditional 
(e.g., office visits and phone consults) and emerging care delivery modalities (e.g., patient web 
portal and mobile applications). Follow-up assessments will occur at 6, 12, 18, and 24 months. We 
hypothesize that compared with controls, I-CARE participants will have greater improvements in 
weight and depression severity measured by the 20-item Depression Symptom Checklist at 12 
months, which will be sustained at 24 months. We will also assess I-CARE’s cost-effectiveness 
and use mixed methods to examine its potential for reach, adoption, implementation, and 
maintenance. This study offers the potential to change how obese and depressed adults are treated
—through a new model of accessible and integrative lifestyle medicine and mental health 
expertise—in primary care.
Keywords
Depression; obesity; randomized controlled trial; problem solving therapy; standard behavioral 
treatment; lifestyle change
1. Introduction
Effective interventions targeting comorbid obesity and depression are critical given the 
increasing prevalence and worsened outcomes for patients with both conditions.1 Obesity 
affects 36% of women and men in the United States (US)2 and is an independent risk factor 
for major chronic diseases such as type 2 diabetes mellitus and cardiovascular disease.3,4
Similarly, depression is associated with increased risks of these chronic diseases5 and is a 
leading cause of disability worldwide.6,7 Lifetime risk of major depressive disorder (MDD) 
is 20% in US women and 13% in men, and the 12-month prevalence is 8.6% and 4.9%, 
respectively.8,9 Moreover, over their lifetime, 4% of the US general adult population meets 
the criteria for a chronic depressive disorder.10 Mounting epidemiologic evidence1,11 has 
shown a bidirectional relationship between obesity and depression, especially in women. 
Prospective studies also reveal that the obesity-depression relationship is temporally 
reciprocal, i.e., baseline obesity predicting later depression and vice versa.12–14 Not only are 
obesity and depression associated with the same health complications (e.g., type 2 diabetes 
mellitus and cardiovascular disease), but their coexistence exerts synergistic adverse effects 
on treatment adherence and response for both conditions.15–17
Thus, adults who are both obese and depressed are a growing population of great public 
health concern and should be a prime target for clinical interventions to prevent type 2 
diabetes mellitus and cardiovascular disease. Some studies suggested the potential benefits 
of behavioral interventions in obese and depressed adults.18–21 Although proven treatments 
exist for obesity and depression separately, there is currently a limited evidence base about 
how to treat them in concert in ways that are effective and practical in primary care settings, 
where most people seek and receive care.
The RAINBOW (Research Aimed at Improving Both Mood and Weight) trial was designed 
to evaluate the clinical and cost effectiveness and implementation potential of an integrated, 
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technology-enhanced, collaborative care model for treating obese and depressed adults in 
primary care. This paper describes the study design and methodology.
2. Methods
2.1. Study Design
RAINBOW is a 2-arm randomized controlled trial in which patients ≥18 years of age with 
comorbid depression and obesity will be randomized to receive usual care alone or 
combined with an integrated treatment for the two coexisting disorders, the “Integrated 
coaching for better mood and weight (I-CARE)” intervention. All study procedures and 
materials have been approved by the Institutional Review Board for the Palo Alto Medical 
Foundation (PAMF). The study uses an effectiveness-and-preliminary-implementation 
(Type 1 hybrid) design, aimed at testing intervention effectiveness while gathering 
information on its potential for implementation in real-world settings.22 Framed within the 
Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) model, the 
specific aims focus on outcome and process evaluations.
Aim 1. Determine the clinical and cost effectiveness of I-CARE vs. usual care
—Hypothesis 1. Compared with controls, I-CARE participants will achieve greater mean 
reductions in body mass index (BMI) and Depression Symptom Checklist-20 (SCL-20) 
score at 12 months, which are the study’s co-primary endpoints.
Hypothesis 2. Mean BMI and SCL-20 scores will remain significantly lower (improved) at 
24 months (i.e., 12 months post-treatment) in I-CARE participants compared to controls.
Hypothesis 3. The I-CARE intervention will be cost-effective within 2 years and over a 
projected longer term compared to usual care, based on the ratio of incremental direct 
medical and nonmedical costs (estimated from health system and societal perspectives) to 
incremental benefits (measured by quality-adjusted life years gained).
Aim 2. Examine I-CARE’s potential for reach, adoption, implementation, and 
maintenance—A mixed methods approach utilizing detailed process data will be used to 
examine RE-AIM attributes other than effectiveness: reach (e.g., patient participation rate 
and reasons for refusal), adoption (e.g., characteristics of participating clinics and 
providers), implementation (e.g., fidelity of a multi-faceted strategy to support intervention 
delivery within the trial: standard coach training, co-located psychiatric-medical supervision, 
structured audit and feedback, and external and internal expert facilitation), and maintenance 
(e.g., expected setting-level sustainability based on post-trial surveys and interviews with 
stakeholders).
2.2. Eligibility Criteria
Participants will be recruited from multiple medical centers of PAMF, which is a large 
community-based multispecialty group practice in Northern California. Patients ≥18 years of 
age who are obese and depressed will be eligible to participate (Table 1). Those with 
significant medical (e.g., type 2 diabetes mellitus or cardiovascular disease) or psychiatric 
comorbidities (e.g., psychotic or bipolar disorders) or special lifestyle circumstances (e.g., 
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pregnancy or planned relocation) will be excluded. Women and men of any racial or ethnic 
background who speak English, meet the inclusion criteria, and have no exclusion criteria 
will be enrolled.
2.3. Recruitment and Screening
The target sample size of 404 eligible and consenting participants will be enrolled over a 2-
year period. Recruitment and screening will proceed in 5 steps (Table 1). First, PAMF 
patient electronic health records (EHRs) will be pre-screened to identify potential 
participants meeting basic eligibility criteria (e.g., age, BMI, time with PAMF, and absence 
of exclusionary medical or psychiatric comorbidities). Second, primary care providers 
(PCPs) will review lists of potentially eligible patients, exclude those they deem 
inappropriate for the study because of medical reasons, and authorize study contact for the 
rest. Third, patients will be mailed or emailed study invitations that contain a web link for 
the study screening form that patients can complete on their own or with research staff over 
the phone. Research staff will begin calling patients 2 weeks after the invitations are sent. 
Fourth, patients who screen eligible must complete the baseline assessment consisting of a 
self-administered online questionnaire and an in-person examination visit. Finally, a study 
physician will review patients’ EHRs to confirm final eligibility before randomization. 
Based on the demographics of obese and depressed patients seen in primary care at PAMF, 
the gender and minority racial/ethnic composition of the target enrollment population is 
estimated to be 64% female, 10% non-Hispanic black, 18% Hispanic/Latino, and 44% 
Asian.
2.4. Randomization and Blinding
A staff person not involved in outcome assessments or data analysis will perform 
randomization using a web-based system23 that we developed and have used successfully in 
several trials.24,25 Participants will be randomly assigned in a 1:1 ratio to the usual care 
control group or the I-CARE intervention group. The web-based randomization program 
uses Pocock’s minimization, a covariate-adaptive method,26,27 to achieve better than chance 
marginal balance between study arms across multiple baseline characteristics: clinic, gender, 
age, race/ethnicity, education, BMI, SCL-20 score, therapeutic class of antidepressant 
medication taken, and number of hospitalization. The system’s computational algorithm 
automatically adjusts the randomization probability based on the characteristics of all the 
previously randomized participants, thus minimizing the total covariate imbalance between 
arms after each new patient is randomized. Efron’s biased-coin method28 is applied to 
protect allocation concealment with the use of non-extreme randomization probabilities 
(2/3:1/3). Specifically, for each patient about to be randomized, the system automatically 
calculates an imbalance score for each of the above-mentioned baseline covariates, and then 
a total imbalance score, S, by summing across the covariates. If S = 0, the randomization 
probability for receiving the intervention for that patient will be set to ½, and if S < 0 (S > 
0), the randomization probability will be set to 2/3 (1/3).
By design, treatment assignments are identifiable to participants and the lifestyle coach, but 
the investigators, data and safety monitoring board members, outcome assessors, and data 
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analyst will be blinded throughout the trial. Further, the lifestyle coach will be masked to all 
outcome measures obtained by outcome assessors during blind assessments.
2.5. Continuation of Usual Care
We will recruit from patients who have used PAMF for routine care for at least 1 year and 
thus have a higher likelihood of an established relationship with their PCP. During informed 
consent, patients will be clearly instructed that they should continue to receive any medical 
care (e.g., depression and weight control care) as usual. For patient safety and 
generalizability, no standard care will be withheld at any time from participants once 
enrolled, regardless of treatment assignment. They will be advised to consult with their PCP 
about their conditions. PCPs will be free to prescribe medications or refer patients for mental 
health and/or obesity consultation, and patients will be free to seek care in the community. 
All participants will receive information on PAMF health and wellness classes and programs 
relating to mood and weight, as well as a Fitbit ZIP™ wireless activity tracker.
To retain the integrity of usual care, PCPs will not be told which of their patients are 
enrolled in the study and in which treatment group if enrolled. They will only identify which 
of their patients are in the I-CARE intervention if and when they are contacted by the study 
care team to make antidepressant medication changes. We anticipate the number of I-CARE 
participants per PCP to be small considering we will be recruiting at multiple large PAMF 
primary care clinics.
Based on our prior primary care-based trials, we anticipate low rates of changes in 
concomitant therapy for depression or obesity in usual care within the 12-month intervention 
period. In the TEAMcare study,29 the number of antidepressant medication initiations and/or 
adjustments in the TEAMcare intervention (3.37; 95% CI, 2.92–3.89) was 6.2 times (P <.
001) that of usual care (0.53; 0.34–0.82) over 12 months. In the 15-month E-LITE trial,24 no 
one had drug or surgical treatment for obesity; 15 of the 81 (19%) usual care controls used a 
nonstudy weight-loss program (13 in a commercial program and 2 in a routine class at the 
clinic), compared to 5 of the 79 (6%) coach-led and 3 of the 81 (4%) self-directed 
participants (all used a commercial program) (P = 0.003).
As we have done in those trials, from the EHR we will determine PCP orders and referrals 
throughout the trial period for intervention and control participants. We will also survey 
participants about any programs or products that they may have used on their own to treat 
depression or obesity during the trial. We will conduct secondary analyses using data on out-
of-study treatments to elucidate their potential confounding effects on the primary intention-
to-treat findings.
2.6. Intervention
Participants in the control group will receive no intervention from the study. Participants in 
the I-CARE group will complete a 12-month integrated intervention for comorbid obesity 
and depression.
2.6.1. Integrated collaborative care—The I-CARE intervention integrates the essential 
components of the Diabetes Prevention Program-based Group Lifestyle Balance™ (GLB) 
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program for weight loss and cardiometabolic risk reduction24,30,31 with the PEARLS 
program32,33 for collaborative stepped depression care, which uses Problem Solving 
Therapy (PST) combined with behavioral activation as first-line, intensified with stepwise 
increases in doses and number of antidepressant medications as needed. Both programs are 
nationally recognized and provide standard coach training and support.34,35 We have shown 
the effectiveness of both programs separately in our previous trials.24,31–33,36–38 In this 
study, we innovatively integrate them for the treatment of adults with comorbid obesity and 
depression in primary care.
2.6.2. Synergistic conceptual models for behavior change—The GLB program is 
based on Social Cognitive Theory,39 which emphasizes a triadic, reciprocally deterministic 
relationship between the individual, environment, and behavior. Social Cognitive Theory 
recognizes that behavior change is a dynamic process that moves at variable speed through 
stages of readiness to change. Positive outcome expectancies through realistic goal setting 
and guided action planning are associated with initiation of behavior change, and self-
efficacy developed for specific behaviors (e.g., self-weighing, dietary change and physical 
activity) predict establishment and maintenance of behavior change. Social Cognitive 
Theory suggests that self-efficacy is enhanced through social support and gradual mastery of 
self-regulation skills (e.g., self-monitoring, action planning, and problem solving).39
The PST for depression has important overlap with the GLB as follows: both (1) are based 
on cognitive and behavioral models of behavioral change; (2) involve goal setting and action 
planning; (3) require monitoring of specific targets from week to week; (4) assign home 
activities to be done between sessions; (5) incorporate problem solving and relapse 
prevention; (6) are interactive treatment methods that actively engage participants; and (7) 
recognize the value of engaging with support from a lifestyle coach to accomplish these 
goals. Because both interventions share common cognitive and behavioral principles, it is 
expected that patients can focus on applying familiar skills to behavior change for both 
improved depression and weight loss simultaneously. Thus, participants are likely to 
transition between the PST and GLB programs smoothly. The sequential, overlapping 
combination of PST and GLB programs is also expected to be synergistic in that patients 
who have gained new behavior change skills using PST will probably be more likely to 
benefit from the GLB program and vice versa, thereby reinforcing improved outcomes for 
both disorders.
2.6.3. Intervention format, structure and content—The 12-month I-CARE 
intervention has an intensive phase and a maintenance phase.
2.6.3.1. Format: Delivered by a trained lifestyle coach, I-CARE begins with a 6-month 
intensive phase including 9 one-on-one clinic visits of 60 minutes each, and 11 home-
viewed 20–30 minute GLB videos and self-study activities, followed by phone calls at least 
once a month for 15–30 minutes during the 6-month maintenance phase (Table 2). The I-
CARE trained lifestyle coach will conduct the visits and phone calls, and additionally can 
communicate with patients via the secure EHR patient portal throughout the intervention. 
Throughout the intervention, participants will be asked to wear a study-provided Fitbit 
pedometer, log their weight on Fitbit website or mobile application (“app”), and log minutes 
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of physical activity and dietary intake using MyFitnessPal website or app. Each participant 
will set up an online user account for Fitbit and one for MyFitnessPal, and share them with 
the lifestyle coach as a “friend.” Fitbit pedometers interface with the personal computer or 
Fitbit app on a mobile device to automatically and wirelessly upload a participant’s daily 
steps into the person’s Fitbit account. Participants will manually enter their weights, minutes 
of physical activity, and foods consumed into their accounts on a computer or through the 
mobile apps. Once friended the lifestyle coach will be able to view participant’s self-tracked 
data, monitor their progress, and use it to facilitate individualized coaching.
2.6.3.2. Structure, content, and curriculum: The PEARLS intervention for depression 
begins with PST at the first one-on-one visit and the GLB program is introduced in the fifth 
visit during week 6 (Table 2). PST teaches participants problem-solving skills using a 
structured 7-step method and workbook-style paper materials. Within the first 3–4 sessions, 
participants are typically able to begin utilizing the method by themselves to form action 
plans for behavior change. Over the remaining sessions, problem-solving skills are 
augmented and reinforced but no new content is delivered. During the first 5 visits, the 
lifestyle coach will also instruct participants on, and help troubleshoot issues with, the use of 
secure email via the EHR-integrated patient portal, MyFitnessPal, and Fitbit, all of which 
are accessible online or via Android- and iPhone-compatible apps.
During the fifth I-CARE visit (week 6), participants will receive the in-home GLB core 
program materials, including self-directed videos and a workbook. The lifestyle coach will 
review the content from 11 out of the 12 core GLB video sessions (excluding the problem 
solving session due to overlap with PST) during visits 6 through 9. During the maintenance 
phase, post-core GLB print materials (which are included in the workbook) will be 
discussed during each phone encounter.
Throughout the 12-month intervention, the coach will practice problem solving skills with 
participants and provide between-session support via EHR-embedded secure email. The 
coach will provide lifestyle counseling following the GLB program on weight management, 
healthy eating, and physical activity after GLB is introduced. The coach and participant will 
develop a maintenance plan once targeted depression and weight loss goals (or a personal 
maximum achievable level of improvement) are reached for at least 1 month, and a relapse 
prevention plan when the participant is nearing the end of the 12-month intervention. Coach 
contact will cease after 12 months, although participants will be followed through 24 months 
in order to assess intervention durability and cost-effectiveness.
2.6.4. Psychiatric and medical supervision of lifestyle coach and medication 
management support for PCPs—Rather than a separate care manager providing care 
for each illness in primary care systems, which may be prohibitively expensive, a lifestyle 
coach who is cross-trained using the standardized GLB34 and PEARLS35 training protocols 
will provide integrated coaching for comorbid obesity and depression, under the supervision 
of a study psychiatrist and a study physician who are identified from among local PAMF 
providers. After each one-on-one visit, the coach will document patient progress on key 
intervention tracking parameters (e.g., date and content; most current Patient Health 
Questionnaire-9 [PHQ-9] score; pedometer steps; self-reported weight and minutes of 
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physical activity) in the EHR—viewable by all providers on the patient’s care team to 
facilitate care coordination. Working together as a study care team, the coach will meet for 2 
hours each week with the study psychiatrist, study physician, and intervention manager. 
They use an online tracking database to view each participant’s progress for ongoing case 
management. The form will include a flag for cases not meeting pre-defined progress 
milestones for depression (e.g., compared to visit 1, PHQ-9 score <25% decrease by week 4; 
another <25% decrease by week 8; or PHQ-9 score >5 or <50% decrease by week 12), 
weight loss (e.g., <3% decrease by week 12; <5% decrease by week 20), and for physical 
activity (e.g., <150 minutes/week of moderate-intensity physical activity or <8000 steps per 
day by week 12). Each week the coach and supervisors will discuss new and flagged cases 
(5–10 minutes of discussion per case). The study psychiatrist and physician will provide 
psychiatric and medical advice to the coach during case review meetings, but they will not 
directly interact with intervention participants. Consistent with stepped care strategies, for 
patients with unremitting depression symptoms the supervising psychiatrist will recommend 
antidepressant medication changes, according to the study medication protocol (Appendix 
A), taking into account potential medical or substance abuse etiologies. The psychiatrist 
communicates her recommendations via secure EHR staff messaging to PCPs who, as 
treating physicians, will be responsible for prescribing the recommended antidepressant 
medications. PCPs may consult the study psychiatrist if they have questions about any 
recommended medication changes. The coach will monitor condition status, coordinate 
communication between the supervising psychiatrist and the patient’s PCP regarding 
medication changes, and help problem solve barriers to medication adherence during 
scheduled visits.
2.7. Participant Safety
Participants will be carefully screened using a multistep enrollment process, and individuals 
for whom the intervention is deemed medically inappropriate or unsafe will be excluded. 
The study physician will review medical charts of all the participants after baseline 
assessments and before randomization. During screening women who are pregnant, 
lactating, or planning to become pregnant during the study period will be excluded. If a 
participant becomes pregnant during the study, she will be excluded from further 
participation in all study activities, and her PCP will be notified. Participants who are 
diagnosed with any other exclusionary condition (e.g., coronary heart disease, stroke, 
diabetes, and cancer) following randomization may continue in the trial with approval of the 
study physician. Established alert levels (e.g., for high blood pressure) and alert conditions 
(e.g., suicidality, angina, and peripheral vascular disease) will help ensure that participants 
are referred for further evaluation and therapy when clinically indicated. The PHQ-9 and the 
SCL-20 will be used to assess suicidal risk. Study staff will follow the self-harm protection 
protocol (Appendix B) if a participant responds “2” (“more than half the days”) or “3” 
(“nearly every day”) to item 9 of the PHQ-9 or responds “3” (‘quite a bit”) or “4” 
(“extremely”) to item 2 of the SCL-20.
To ensure unbiased ascertainment between the intervention and control group, outcome 
assessors will systematically screen all participants for adverse events during in-person 
assessments at baseline, 6, 12, 18, and 24 months using a standard interview and reporting 
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form as done in our previous trials.25,30,40 Positive response will be recorded and then 
reviewed by the study safety officer for seriousness, study relatedness, and expectedness. An 
adverse event is defined as any untoward medical or psychological event experienced by a 
patient during or as a result of his/her participation in the study that represents a new 
symptom or an exacerbation of an existing condition, whether or not considered study 
related based on appropriate medical judgment. Documentation in EHR will be used to 
verify patient self-reports. Adverse events discovered outside these planned evaluations 
(e.g., during intervention encounters) will be duly noted and followed up with, as needed, to 
assure participant safety. We will report adverse events according to the data and safety 
monitoring plan (Appendix C).
2.8. Retention
As we have done in our previous trials,24,25,30,40 we will implement a series of strategies to 
minimize loss to follow-up: (1) careful staff selection and standardized training in trial-
specific protocols, rapport building, motivational interviewing, and problem solving as 
appropriate to their study roles; (2) legally adequate, effective informed consent; (3) 
education of participants about the importance of follow-up assessments regardless of 
treatment adherence; (4) prudent participant incentives (e.g., pedometer, cash incentives of 
$20) and flexible scheduling (outside of work hours, multiple locations); (5) promotion of 
study “brand” identity with a logo and a website; (6) ongoing monitoring of recruitment and 
retention; (7) up-to-date participant contact information and two emergency contacts; (8) 
diligent efforts to re-engage inactive participants; and (9) alternative means of obtaining 
measurements.
2.9. Study measures and data collection schedule (Table 3)
2.9.1. Primary outcomes—The co-primary outcomes are changes in BMI and SCL-20 
score at 12 months. BMI will be calculated based on height and weight measured per 
standard protocols.41 The SCL-20 is a valid, reliable measure of depression severity.42,43 It 
has been used in numerous depression treatment trials in primary care and community 
settings,32,33,37,38 making it particularly useful for cross-study comparisons and data 
synthesis in meta-analyses.
2.9.2. Secondary outcomes—BMI and SCL-20 score at 24 months will be secondary 
outcomes. Additional secondary outcome measures will include depression treatment 
response (>50% decline in SCL-20 score from baseline) and remission (SCL-20 score <0.5), 
waist circumference and resting blood pressure according to standardized protocols,41 and 
the following measures at 12 and 24 months:
Obesity-specific problems: The Obesity-Related Problem Scale specifically measures the 
impact of obesity on psychosocial functioning. The 8-item scale has high internal reliability 
and sound test–retest reliability, correlates strongly with a wide range of theoretically related 
constructs, and is responsive to weight loss intervention.44
Anxiety: Anxiety will be measured with the Generalized Anxiety Disorder Scale (GAD-7) 
and the Panic Disorder module of the Mini-International Neuropsychiatric Interview 
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(MINI). GAD-7 is a valid and reliable 7-question scale for screening generalized anxiety 
disorder and strongly associated with multiple domains of functional impairment.45 The 
MINI has high validity and reliability scores;46 and in the present study we will specifically 
use module E to screen for panic disorder.
Disability: The Sheehan Disability Scale is a validated questionnaire that measures 
functional disability and is sensitive to treatment effects in clinical trials.47 Patients rate the 
extent to which they symptoms impair work/school, social, and family life on a visual 
analog scale from 0 to 10 and answer the number of days when their symptoms cause them 
to miss work/school and be unproductive at work/school.
Quality of life: Quality of life will be measured with the Short Form-8 Health Survey 
(SF-8) and Euro-QoL 5D. The SF-8 is an 8-item version of the SF-36 that measures overall 
health-related quality of life.48 Euro-QoL 5D (EQ-5D-5L) include 5 domains (mobility, self-
care, usual activities, pain and discomfort, and depression and anxiety) scored on 5 levels 
(no, slight, moderate, severe, or extreme problems) and current health rated on a visual 
analogue scale from 0 to 100. It has been shown to be a valid and reliable tool to measure 
utility based quality of life.49 Values from the EQ-5D-5L instrument will be used to 
calculate quality-adjusted life years that are used to inform incremental benefits of the I-
CARE intervention relative to control.
Costs: These include direct medical costs and direct nonmedical costs. Direct medical costs 
will include the costs of identifying eligible patients, providing the intervention, addressing 
side effects, and health care utilization. Direct nonmedical costs will include intervention-
related “out-of-pocket” costs (e.g., value of participant time spent on intervention activities). 
We will obtain authorization from patients for extraction of EHR data on health care 
utilization (e.g., office visits, in-patient stays, procedures, medications, laboratory tests). We 
will also interview participants about their medication use (with the aid of containers of 
regularly-taken medication brought by participants to the visits), general wellness service 
use, and out of network health care utilization. Also, we will survey the coach and patients 
using adapted resource utilization and cost capture instruments based on the Diabetes 
Prevention Program and Diabetes Prevention Program translation trials.50,51
2.9.3. Potential effect modifiers and mediators—To complement the primary and 
secondary findings, we will explore for whom and under what condition (effect modifiers) 
and how (mediators) treatment effects occur. Data will be collected on measures of potential 
moderators (e.g., gender, age, race/ethnicity, education, posttraumatic stress disorder) and 
mediators (e.g. dietary intake, physical activity, problem solving, and sleep quality) 
responses to the intervention. Posttraumatic stress disorder (PTSD) will be measured with 
the 17-item PTSD checklist – Civilian Version that has high reliability and validity.52
Participants’ dietary intake will be assessed by multiple-pass 24-hour diet recalls,53 the 
gold-standard dietary assessment method. Physical activity will be measured using Stanford 
7-day Physical Activity Recall, which is a reliable measure that is sensitive to change in 
physical activity.54 Participants’ problem solving skills will be assessed using the reliable 
and valid Social Problem-Solving Inventory-Revised: Short Form that contains 25 items in 
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the following five scales: positive problem orientation, rational problem solving, negative 
problem orientation, impulsive/careless style, and avoidance style.55 Sleep quality will be 
measured with the 8-item PROMIS sleep disturbance and sleep impairment scales short 
forms.56
2.9.4. Process measures—As in an effectiveness-and-preliminary-implementation 
(Type 1 hybrid) design, we will use mixed methods to collect process measures that will 
provide a nuanced understanding of why the intervention is (or is not) more effective than 
usual care, whether high intervention fidelity is achieved, what barriers and enablers there 
are, how these may translate into real-world implementation, and what modifications can be 
made to maximize implementation success.22 We will frame the process evaluation around 
the RE-AIM framework (Table 4). In addition to focusing on effectiveness, RE-AIM 
examines the reach, adoption, implementation, and maintenance of the program, and any 
barriers or enablers in each of these domains.57,58 We will conduct survey and interview 
different stakeholders, including participants, recruitment staff, study care team, internal 
experts (study physician advisors), PCPs, and medical and administrative leaders at 
participating clinics, at multiple time points throughout the trial period.
In addition to qualitative evaluation through surveys and interviews, we will also collect 
data on the screening process, e.g., the proportion and representativeness of the patients who 
are eligible at initial and subsequent screenings, reasons for exclusion, and demographics of 
patients who screen ineligible or decline participation. We also will assess the proportion 
and representativeness of physicians willing to approve screening of their potentially eligible 
patients, patient retention rates, and the representatives of patients who complete follow-up 
assessments and reasons for dropout.
Intervention exposure and adherence measures will include attendance at one-on-one visits, 
reasons for missed visits, frequency of self-monitoring records and secure emails, self-
reported completion of in-home videos, and number of completed counselling phone calls. 
Self-monitoring data obtained during intervention program will be used for adherence 
monitoring and for the coach to use in tailoring feedback for individual participants.
2.10. Statistical Analysis
2.10.1. Analytic plan—Repeated-measures mixed-effects linear (for continuous 
outcomes) or logistic models (for categorical outcomes) using intention-to-treat tests of 
group by time interactions will evaluate between-group differences in primary (Aim 1, 
Hypotheses 1 and 2) and secondary outcomes. The fixed effects of each model will include 
the baseline value of the outcome of interest, randomization balancing factors, group, time 
point, and group-by-time interaction indicators. The models will account for the non-
independence of repeated measures using a covariance structure within participants to be 
determined by the least Bayesian Information Criterion and clustering of patients within 
primary care providers. Maximum likelihood estimation in mixed modeling will be used for 
missing data. We will document the extent and pattern of missing data and the reasons, and 
will conduct sensitivity analyses of the impact of missing data (e.g., with multiple 
imputation,59–61 on stability of the primary results). Models will be adjusted for nonlinearity 
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and/or unequal variances based on residuals from a model using residual plots. Polynomial 
terms may be included if indicated. Appropriate transformation of the outcome variable 
(e.g., logarithmic) will be considered as a remedy for unequal variances. Also, the model 
could be altered to a heterogeneous variance model if participants in different intervention 
arms are found to have different variances. We will verify that mixed model-based results 
are not sensitive to violations of model assumptions with permutation and bootstrap 
resampling tests.62,63
Mediation analyses will explore changes in potential putative mediators (e.g. problem 
solving, antidepressant medication change, physical activity, dietary intake, sleep quality) 
and their effects on treatment response. Using MacKinnon’s product of coefficients test 
(řŚ)64 we will examine longitudinal and contemporaneous mediation separately. 
Longitudinal mediation refers to changes in mediators from baseline to 6 months followed 
by change in BMI and/or SCL-20. Contemporaneous mediation refers to changes in 
mediators and change in BMI and/or SCL-20 from baseline to 12 months. Asymmetric 
confidence limits will be constructed based on the distribution of the product with the 
PRODCLIN program. Because multicollinearity may be present in a multiple mediator 
model, we first will test each mediator separately in a single-mediator model. Next, 
multiple-mediator models will be used to test for independent and suppression effects when 
all variables found to be at least marginally significant in the single-mediator models are 
entered simultaneously. To determine the extent of mediated effect, the percentage of total 
effect mediated will be calculated for each significant mediator as řŚ/(řŚ+ ś), where ś is 
the direct intervention effect on outcome.
Moderation analyses will explore differences in intervention effect by potential subgroups 
(e.g., according to gender, age, race/ethnicity, and education). These analyses will follow the 
same general analytic approach as described above for primary and secondary outcomes, 
with the inclusion of appropriate moderator main effects and moderator-by-group interaction 
terms.
Cost-effectiveness analyses (Aim 1, Hypothesis 3) will extend and combine existing models 
for obesity and depression that we and others have developed.65–70 We will compare 
incremental costs, estimated from the perspectives of health systems (direct medical costs 
only) and society (direct medical and non-medical costs), to incremental benefits, expressed 
as quality-adjusted life years gained. We will also consider the number needed to treat as an 
important and clinically-relevant outcome and estimate the intervention cost per number 
needed to treat. The use of quality-adjusted life years allows for comparisons of both 
changes in morbidity and health status as well as mortality effects based on change in the 
risk of death and, among survivors, reduction in quality of life due to nonfatal events, given 
the probabilities of disease progression in the target population.68,71 We will convert 
Cohen’s d effect sizes to estimates of the number needed to treat to have one more patient 
with better outcomes in the intervention arm vs. usual care.72 We will exclude from all 
analyses research-related costs, such as costs of recruitment, screening, and outcome 
surveillance that are beyond those recommended for routine clinical practice. Intervention 
start-up costs, fixed costs of sustaining the intervention, and marginal costs of adding 
additional participants to the intervention will be differentiated because they are relevant for 
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different decisions: whether to implement the intervention in the first place and whether to 
sustain or expand it over time. We will use simulation models, similar to those in Diabetes 
Prevention Program and Sequenced Treatment Alternatives to Relieve Depression,68,73,74 to 
analyze incremental cost-effectiveness ratios during the trial and projected into 5-, 10-, 20-, 
30-year, and lifetime horizons. Cost-utility estimates with different time horizons will be 
useful for stakeholders deciding on program implementation. Sensitivity analyses will be 
performed and results will be interpreted according to standard guidelines.75–77
We will analyze quantitative process data using standard tests, e.g., Student’s t-tests and ů2
tests for continuous and categorical variables, respectively (Aim 2). We will use NVivo to 
analyze all qualitative data.78 Two independent and trained researchers will code all 
qualitative data separately by stakeholder group (e.g., participants, recruitment staff, study 
care team, internal experts, PCPs, and medical and administrative leaders) using principles 
of content analysis.79 Codes will be developed based on the RE-AIM domains assessed. 
Quantitative process data and qualitative data will be combined to draw conclusions about 
reach, adoption, implementation, and maintenance of the intervention.80
2.10.2. Sample size and data interpretation—The trial with 202 participants per arm 
has 90% power to detect a standardized mean difference of 0.35 (Cohen’s d) in the primary 
endpoints of BMI and SCL-20 scores at 12 months between the intervention and usual care 
group at ř=5% (2-sided), assuming at least 85% retention at 12 months based on prior trial 
experiences.32,33,38,81,82 We used a t-test with simplified assumptions to estimate power, 
whereas actual power likely will be greater due to increased efficiency associated with 
repeated-measures mixed models with baseline and covariate adjustments.83 Because 
treatment success will be judged on both (not either) primary outcomes, multiplicity 
adjustment is unnecessary.84 No multiplicity adjustment will be made for secondary 
analyses, which are intended to complement the primary findings and to inform future 
research. They will be interpreted within that context, considering the totality of evidence 
available.84,85
We chose a d of 0.35 as the minimum important between-group difference based on our 
prior studies and other available literature. Previously, we observed a standardized mean 
difference of 0.46 between usual care and the GLB weight loss intervention being tested in 
the current trial. This corresponded to a mean of 5.0% vs. 2.6% weight loss over 15 
months.24 Weight loss of ≥5% is widely regarded clinically significant,86 while a weight 
change of <3% defines weight maintenance.87 Hence, the net BMI lowering effect of the 
intervention relates to the minimal clinically important difference in weight reduction. A 
meta-analysis of behavioral weight-loss studies reported effect sizes of 0.61–0.67 for 
improvements in depression and self-esteem.88 The d effect sizes in the PEARLS trials 
ranged from 0.35–0.74.32,33 Further, the National Institute for Clinical Excellence in the 
U.K. defines a threshold of clinical significance for depression treatment as a standardized 
effect size of 0.50.89
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2.11. Quality Control
2.11.1. Data management—Study data will be entered into computerized databases 
including the following: (1) Microsoft Access for recruitment and intervention tracking data; 
(2) REDCap90 hosted at the PAMF Research Institute for self- and interviewer-administered 
questionnaire data and physical measurements; and (3) the Nutrition Data System for 
Research (NDS-R) (Minneapolis, MN) licensed for data collection and nutrient analysis 
based on multiple-pass 24-hour diet recalls.91,92 These databases employ automatic, real-
time range, logic, and missing value checks, as applicable. Also, the outcome assessors are 
trained on data collection protocols (e.g., multiple-pass 24-hour diet recall using NDS-R and 
7-day physical activity recall), and their performance is continuously monitored. All datasets 
will be cleaned, verified and archived, and then read into SAS (version 9.2; SAS Institute 
Inc, Cary, NC) datasets, which also will be archived. One official copy of all study data and 
a master data dictionary will be maintained and updated regularly. All analytic and tracking 
databases will be stored in a password-protected, encrypted network drive with continuous 
backups. For the protection of participant confidentiality, unique anonymous study IDs will 
be used for data storing, tracking and reporting. Protected health information will be stored 
separately from all other study data, and will be used and disclosed in accordance with the 
Health Insurance Portability and Accountability Act regulations. Regular reports will be 
produced on (1) patient accrual and follow-up completion/retention in relation to goals and 
timeline; (2) the randomization process and group comparability on the balancing variables; 
(3) key baseline characteristics of the sample, by (blinded) group, related to the primary and 
secondary outcome variables and proposed effect modifiers and mediators; (4) intervention 
exposure and adherence; and (5) protocol violations. Any observed delays in these processes 
or data irregularities will be followed up and resolved in a timely manner.
2.11.2. Intervention fidelity—Following recommendations for behavioral intervention 
studies,93 we will standardize intervention materials and provide rigorous coach training and 
oversight to ensure intervention fidelity. All one-on-one sessions and phone calls will be 
audiotaped, and a random sample of at least 10% will be reviewed and rated for protocol 
adherence using a structured rating scale. The lifestyle coach will follow a structured 
framework for composing secure emails, which will be sampled for periodic review as part 
of routine quality control efforts. The coach will complete a checklist of critical intervention 
behaviors and materials delivered during one-on-one sessions, and document the frequency, 
duration, and purpose of phone and email communications. These records will be subject to 
periodic reviews using standardized evaluation forms. If a coach scores below an a priori 
performance standard, she will receive more frequent audit and feedback and “booster” 
training if necessary.
To monitor and support participants’ receipt of and adherence to the intervention, the coach 
will review and give feedback on homework and self-monitoring records and document 
participants’ mastery of protocol-specific, achievement-based objectives. The coach will 
routinely inquire about barriers to treatment receipt and adherence, recommend problem-
solving strategies, and provide ongoing support using motivational interviewing 
techniques.94
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3. Discussion
Research on integrated therapy in comorbid obesity and depression is lacking. One 
randomized controlled trial by Linde and Simon et al. tested the efficacy of an intensive 
intervention with 203 obese and depressed women in a primary care setting that combined 
behavioral weight-loss and cognitive-behavioral depression treatments into 26 group visits 
over 1 year, compared with behavioral weight-loss treatment alone for the same number of 
sessions.20 There were no significant differences between groups at 12 months for weight or 
depression symptoms measured by SCL-20.20 Pagoto et al. completed an efficacy trial in 
161 obese women with major depressive disorder who were treated sequentially with 
behavioral activation therapy for depression followed by behavioral weight-loss treatment, 
or received behavioral weight-loss treatment only. Both study arms involved 26 weekly 
individual and group sessions during a 6-month intensive phase, and 6 group and 10 phone 
sessions during 18 months of maintenance.95 At 12 months (primary endpoint), the two 
groups did not differ in weight loss, but sequential treatment led to greater improvement in 
Beck Depression Inventory-II scores.21 Participants with better depression treatment 
response and remission lost greater weight regardless of random assignment. Simon’s and 
Pagoto’s efficacy trials tested high-intensity behavioral interventions (≥26 in-person visits in 
1 year), included women only, and neither used team-based multicondition collaborative 
care involving as-needed stepped treatment intensification with antidepressant 
medications.38,96,97 The findings of these trials reinforce a critical need for alternative 
comorbidity treatment models that can be integrated within primary care and better engage 
obese and depressed patients, thereby enhancing effectiveness and generalizability.
The current study uniquely adapts and integrates the GLB video program for weight loss 
with the PEARLS program for collaborative stepped depression care. The intervention 
incorporates conventional clinic- and home-based modes of care delivery (e.g., office visits 
plus phone consults and in-home video), and leverages low-cost, wide-reach health 
information technologies (e.g., web, secure email, and mobile apps). Using an effectiveness-
and-preliminary-implementation (Type 1 hybrid) design,22 this is the first study to test the 
clinical and cost effectiveness and implementation potential of combining these two proven, 
nationally recognized programs to treat obese and depressed adults in primary care. The in-
depth process evaluation data collected from different stakeholders will not only strengthen 
the interpretation of primary findings, but also provide important contextual and experiential 
information to inform researchers, policy makers, health system administrators, clinicians, 
and patients about the potential for future dissemination and implementation. Furthermore, 
our study psychiatrist and physician are practicing clinicians in the health system where this 
study is being conducted. Although a lifestyle coach is to be hired and paid by the study to 
conduct the intervention, we will purposely select candidates in health professions that are 
typical in the primary care workforce (e.g., health educators and registered dietitians). Coach 
training for the study can be readily scaled in future dissemination and implementation of 
the intervention if warranted by findings from this study. Both GLB and PEARLS programs 
are nationally recognized and provide standard coach training and support.
This study leverages two proven behavioral interventions in ways that are practical and 
likely to have a synergistic therapeutic effect on two prevalent and commonly coexisting 
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chronic conditions, obesity and depression. In turn, this could help prevent long-term 
complications of these conditions, such as type 2 diabetes mellitus, cardiovascular disease, 
and dementia.3,15,17,98 If successful, this study will offer the potential to change how obese 
and depressed adults are treated using an integrated multicondition collaborative care model 
in primary care.
Acknowledgments
The project described is supported by Award Number R01HL119453 from the National Heart, Lung and Blood 
Institute and internal funding from the Palo Alto Medical Foundation Research Institute. JGF is supported in part by 
NIH/NIA K01AG037593-01A1. VY is supported in part by NIDDK K23DK097308. The content is solely the 
responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung and 
Blood Institute or the National Institutes of Health. No sponsor or funding source has a role in the design or conduct 
of the study; collection, management, analysis or interpretation of the data; or preparation, review or approval of the 
manuscript.
The authors dedicate this work to the deceased Wayne Katon, MD, who contributed significantly to the conception 
and design of the RAINBOW study. The authors extend special thanks to RAINBOW participants and their 
families who make this study possible. The authors also thank the study physician advisors (Meg Durbin, MD, Ed 
Yu, MD, and Bahar Aghighi, MD), the study Data and Safety Monitoring Board members (William Haskell, PhD, 
Mickey Trockel, MD, Sandra Tsai, MD, and Manisha Desai, PhD), and the study team members who have made 
substantial contributions to the conduct of the study (Veronica Luna, BS, Andrea Blonstein, MBA, RD, Elizabeth 
Jameiro, MD, Nancy Wittels, MS, Elizabeth Ward, MD, and Lenard Lesser, MD, MSHS).
Investigators at Palo Alto Medical Foundation Research Institute, the University of Washington, and the University 
of Pittsburgh collaborated to create the RAINBOW I-CARE intervention, which integrates adaptations of the 
Program to Encourage Active, Rewarding Lives for Seniors and the Group Lifestyle Balance™ Program. The 
University of Washington and the University of Pittsburgh provided training and support for RAINBOW study staff 
at Palo Alto Medical Foundation Research Institute.
Appendix A. Study Medication Protocol
I-CARE Treatment of Depression with Medications
A. Initiating Antidepressants
When starting patients on antidepressants, they need to understand that side effects can 
occur before the medication’s therapeutic effects help them to feel better. It is helpful to 
draw the figure below for patients, illustrating that side effects peak in the first 1–2 weeks 
and then subside, whereas therapeutic effects often peak at 3–4 weeks. This figure can 
prevent patients from getting discouraged prematurely and discontinuing medications.
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B. Antidepressant Side Effects
Short-Term Side Effects—These occur within the first several weeks and include 
jitteriness, insomnia, headache, and nausea, and other side effects that may be idiosyncratic 
to the individual patient. These symptoms are usually lessened by starting antidepressants at 
a low dose and increasing the dose weekly. Short-term side effects usually disappear within 
2–3 weeks.
Long-Term Side Effects
ߖ
Diarrhea is particularly common with sertraline (Zoloft), but can occur with 
other SSRIs or with bupropion (Wellbutrin). Changing to a low dosage of 
paroxetine (Paxil) at 5–10 mg and titrating upward by 5–10 mg every 7–10 days 
to a dosage of 20–50 mg may help because paroxetine (Paxil) has slight 
anticholinergic effects.
ߖ
Sexual dysfunction can occur in up to one third of patients receiving selective 
serotonin reuptake inhibitors (SSRIs), such as fluoxetine. It is important to ask 
about sexual function, since many patients with diabetes already have 
problematic sexual functioning. The most common sexual side effect is delayed 
orgasm or inability to experience orgasm. Patients can be switched or cross-
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tapered to bupropion SR if they experience this side effect on an SSRI. The 
addition of bupropion SR 100 mg twice a day or buspirone 15 mg twice a day to 
an SSRI regimen also often alleviates sexual dysfunction.
ߖ
Sleep problems continue to occur in approximately 25–33% of patients despite 
effective SSRI treatment. For people bothered by insomnia, trazodone could be 
prescribed, starting at 25 mg at bedtime and increasing the dose by 25 mg 
increments every 5 days until insomnia is successfully treated.
ߖ
Weight gain, a significant problem for many people with type 2 diabetes, is 
worsened for 5–10% of SSRI-treated patients. Paroxetine is the SSRI that has 
the most weight gain associated with it. Because bupropion and fluoxetine are 
not associated with weight gain, these antidepressants are good first choices for 
overweight people.
C. Choice of Antidepressant
For patients already taking an anti-depressant at a sub-therapeutic dose, the first 
treatment action step is to titrate up the antidepressant dosage. All titrations should be done 
slowly, on a weekly basis, until PHQ-9 score goals are achieved: either < 5 or a decrease of 
half the baseline total score.
For patients who have never taken antidepressants, fluoxetine or bupropion SR are good 
first-line antidepressant choices due to lack of weight gain with these medications. Initiation 
and titration are shown in the schematic below.
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Patients who have tried one SSRI unsuccessfully in the past can be switched to either a 
second SSRI, bupropion SR, or venlafaxine XR.
Patients with coexisting anxiety can usually be effectively treated by starting on citalopram 
or sertraline.
Patients with moderate to severe neuropathy may be treated with either venlafaxine XR, 
duloxetine, or bupropion SR. These medications have been shown in randomized controlled 
trials in non-depressed individuals to reduce neuropathic pain.
Patients with pre-existing sexual dysfunction can usually be successfully treated with 
bupropion SR. While other antidepressants are likely to worsen problems with sexual 
response, initiating treatment with bupropion SR may improve function. Adding an 
antidepressant such as bupropion SR or an anti-anxiety agent such as buspirone to an SSRI 
can also help sexual function in patients with diabetes and may be viewed very positively. 
The TCM should work with the consulting psychiatrist when carrying out antidepressant 
augmentation strategies.
D. Strategies for Overcoming Common Issues with Taking Antidepressants
A variety of strategies may help patients take antidepressants, including:
ߖ
Provide rationale for use.
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ߖ
Pay vigorous attention to side-effects.
ߖ
Counter demoralization, fear of dependence, and loss of control.
ߖ
Enlist family/spousal support.
ߖ
Elicit resistance and relationship to prior experience with medication.
ߖ
Identify relevant illness aspects (phobic, paranoid).
ߖ
Increase contact with brief phone check-ins.
ߖ
Give specific instructions (take regardless of symptom change, don’t stop on 
own).
ߖ
Use symptom scale PHQ-9 to chart progress.
Depression Goal: PHQ-9 < 5 OR at least 50% decrease from baseline in PHQ-9
•
TCM to encourage patient to fill out PHQ-9 weekly until reaches a “steady state”, 
then prn.
•
TCM to discuss behavioral activation methods, medication adherence strategies, 
rationale for initial and long-term maintenance therapy with antidepressants (e.g., 
don’t decrease dose or stop without checking with TCM or PCP; take regardless of 
symptoms), and side effects (most disappear at 2 weeks).
•
TCM to contact PCP and team psychiatrist if patient has: acute suicidal symptoms, 
psychotic symptoms, manic symptoms, severe lack of appetite with insufficient 
oral intake or weight loss, suspected alcohol or drug misuse, or severe medication 
side effects.
•
Create My Better Health Plan initially and update at each visit.
ANTIDEPRESSANT MEDICATION
_____ Fluoxetine 10 mg/day × 1 week; then 20mg/day × 1 week. If PHQ-9 hasn’t 
decreased by 50% or more, increase to 30mg/day. At week 4, if PHQ-9 hasn’t 
decreased by 50% or more, increase to 40mg/day. Can increase fluoxetine up to a 
maximum of 60 mg/day as needed/tolerated.
_____ If two or more negative SSRI trials or for those patients with preexisting 
diabetes-related sexual dysfunction, start Bupropion SR 100mg/day for 1 week; then 
100mg 2×/day for a week; then 200mg in am & 100mg in pm. If PHQ-9 at 4 weeks 
isn’t decreased by 50%, increase dose to 200mg BID.
_____ If patient doesn’t fit above criteria, or has significant medical or psychiatric 
symptoms, antidepressant medications to be suggested by CAREteam consulting 
psychiatrist or PCP.
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Antidepressant Medications
Drug
Starting dose
Usual Dose
Indications
Side Effects
Starting antidepressants: improvement often seen in first two weeks. If not seen by 8 weeks, likely needs new agent 
or second agent. Check in at least weekly when starting antidepressants. 3/3 of people with depression will improve 
with antidepressants.
Stopping antidepressants: Recurrence of depression is common. 64% of patients with depression had a recurrence 10 
years after stopping their antidepressants. If patients do decide to stop their antidepressants, encourage them to talk with 
their PCP prior to stopping and help them understand that there are fewer problems when antidepressant dosages are 
tapered over a two week period.
Selective serotonin reuptake inhibitors (SSRIs)
Citalopram (Celexa)
10
20–40
Max FDA daily 
recommended
dose for patients 
>60 yrs old is 20 
mg
Jitteriness, restlessness, 
agitation, GI distress, 
nausea, diarrhea, 
insomnia usually 
improve in 2 weeks.
Weight gain for some 
patients.
Fluoxetine (Prozac)
10
20–60
First line (weight 
gain less likely)
Fluvoxamine (Luvox)
50
50–300
Paroxetine (Paxil)
20
20–60
Worst for sexual 
dysfunction,
weight gain, 
sedation; mild 
anticholinergic
effects (helps 
diarrhea)
Same as above.
Paroxetine CR (Paxil CR)
25
25–75
Same as above.
Sertraline (Zoloft)
50
50–200
Same as above.
Dopamine-norepinephrine reuptake inhibitors
Bupropion SR (Wellbutrin SR)
**When dose > 100 mg give 
bid.
100
300–400
Weight gain rare. 
May improve 
sexual
functioning.
Useful for 
lethargic patients.
Contraindicated in 
patients with seizure 
history or eating 
disorders.
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
Venlafaxine XR (Effexor XR)
—
**When dose > 75 mg, give 
bid.
37.5, 75 & 100
75–300
Effective for diabetic 
neuropathy,
fibromyalgia, chronic 
pain.
Duloxetine (Cymbalta)—
30
60–120
Effective for diabetic 
neuropathy,
fibromyalgia, chronic 
pain.
Serotonin modulators
Trazodone (Desyrel)
25–50
50–300
Useful for 
insomnia
associated with 
depression/
anxiety.
Doses > 50 mg can cause 
orthostatic hypotension 
or (rarely) priapism.
Tricyclics and tetracyclics
Amitriptyline (Elavil)
25–50
100–300
Anticholinergic side 
effects and weight gain.
Elders particularly 
susceptible to memory 
change, confusion, 
hallucinations, sedation 
Amoxapine (Asendin)
50
100–400
Clomipramine (Anafranil)
25
100–250
Maprotiline (Ludiomil)
50
100–225
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Antidepressant Medications
Drug
Starting dose
Usual Dose
Indications
Side Effects
Doxepin (Adapin, Sinequan)
and orthostatic 
hypotension.
Contraindicated in 
patients with recent 
MI, cardiac conduction 
problems
25–50
100–300
Imipramine (Tofranil)
25–50
100–300
Desipramine (Norpramin)
50
100–300
Nortriptyline (Pamelor)
25
50–200
Protriptyline (Vivactil)
10
15–60
Noradrenergic and specific serotonergic antidepressant
Mirtazapine (Remeron)
15
15–45
Causes weight gain in 
50% of patients. Helpful 
for anxious patients with 
insomnia and no 
appetite.
Appendix B. RAINBOW Self-harm Protection Protocol
Rationale
1.
The Patient Health Questionnaire-9 (PHQ-9) has a question regarding self-harm 
risk. If a participant reports frequently contemplating suicidal ideation (“more than 
half the days” or “nearly every day” over the last 2 weeks), a clinical response is 
indicated. The Symptom Checklist (SCL-20) questionnaire also has a question 
regarding self-harm risk. If a participant reports frequently contemplating suicidal 
ideation (“quite a bit” or “extremely” over the past 2 weeks), a clinical response is 
indicated.
2.
This protocol includes two self-harm protection procedures: one for participants 
self-screening online and the other for research staff conducting the telephone (e.g., 
during phone screening or intervention phone consult) or in-person (e.g., during a 
baseline or follow-up assessment or intervention visit) interviews.
3.
The research staff conducting the telephone or in-person interviews are non-
clinicians.
4.
Current suicidal ideation is the only interview finding that clearly requires further 
clinical assessment and possible intervention.
5.
This protocol refers to self-harm risk responded to an online self-screening (PHQ-9 
only), telephone or in-person interview (PHQ-9 or SCL-20) as follows:
-
Responding “2” (“more than half the days”) or “3” (“nearly every day”) 
to the PHQ-9 question – “Over the last 2 weeks, how often have you been 
bothered by thoughts that you would be better off dead or thoughts of 
hurting yourself in some way?”
-
Responding “3” (‘quite a bit”) or “4” (“extremely”) to the (SCL-20) 
question – “Overall in the past 2 weeks how much were you distressed by 
thoughts of ending your life?”
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6.
Either question can be endorsed at several different time points. The PHQ-9 is 
administered during online self-screening or phone screening by a research 
associate, and during every in-person or phone intervention sessions. The SCL-20 
is completed at the clinic during baseline and follow-up assessments (6, 12, 18, and 
24 months).
Procedures
A. For participants self-screening online
1.
During the online self-screening, if a participant responds “2” (“more than half the 
days”) or “3” (“nearly every day”) to the PHQ-9 question “Over the last 2 weeks, 
how often have you been bothered by thoughts that you would be better off dead or 
thoughts of hurting yourself in some way?” the participant will be shown the 
following instructions:
“Please note: we do not monitor this screener in real time; if this is an emergency 
call 911.
For more immediate attention, because you have been bothered by thoughts that 
you would be better off dead or of hurting yourself in some way in the last 2 
weeks, you should call your physician or other healthcare professional right 
away, or go to the emergency room.
You may also call the National Suicide Hotline at 800-SUICIDE/800-784-2433 
or the National Suicide Prevention Lifeline at 800-273-TALK/800-273-8255. 
The helplines are available 24 hours every day.
We will have a study clinician contact you within 1–2 days. In the meantime, do 
not delay seeking medical attention.”
2.
The research staff will generate daily reports (except for weekends and holidays) 
on any positive suicidality responses from the newly completed PHQ-9s since the 
last report. The research staff will follow the following procedural steps based on 
the participant’s answers to screening questions and should not attempt to perform 
any independent assessment of self-harm risk.
3.
If positive suicidality responses are identified, the research staff will contact the 
study psychiatrist via a high priority staff message in EPIC. The study psychiatrist 
is licensed and has clinical privileges at PAMF. The study psychiatrist will notify 
the research staff of receipt of message within 24 hours; otherwise staff will call to 
confirm receipt. The assessment request and study psychiatrist’s follow-up attempts 
and actions will be documented in the study Safety Monitoring Database.
4.
If the study psychiatrist is not available, the research staff will send a high priority 
staff message in EPIC to the participant’s PCP or covering physician (using the dot 
phrase *) requesting that he/she contact the patient and enter an urgent mental 
health referral into EPIC as deemed appropriate. The PCP or covering physician 
may in addition schedule a follow up appointment with the patient as deemed 
appropriate.
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5.
The study psychiatrist will attempt to contact the participant as soon as possible 
(within 1–2 days) to conduct a PHONE assessment of current suicidal ideation for 
level of lethality and need for further referral. This assessment will be based on 
characteristics of suicidal patients (low-, moderate-, or high-risk) and clinical 
strategies for managing suicidal patients at these different thresholds. These 
strategies could include prompt emergency intervention by a licensed mental health 
professional when the immediate suicide risk is high and the participant has refused 
other interventions.
6.
If there is an IMMINENT/HIGH risk of harm, including but not limited to: an 
active plan to harm oneself or another person, grave disability impacting the 
participant’s ability to care for him/herself or severely impairing participant’s 
judgment and/or without reasonable supportive resources, then the study 
psychiatrist will ask for participant’s location and advise the participant that she is 
obligated to take immediate action to get help for the participant. The study 
psychiatrist will call 911, giving participant’s name, date of birth, location, medical 
conditions and current risk factors and notify any immediate family member or 
emergency contact if relevant.
The study psychiatrist will check study database to see whether patient is an I-
CARE participant.
A.
For enrolled I-CARE participants, the study psychiatrist will contact the 
study health coach via phone or confidential email, who will contact the 
participant weekly thereafter (unless currently hospitalized) to complete the 
PHQ-9 (until patient’s PHQ-9 score <5, or score decreases by 50%), assess 
progress, and coordinate patient’s follow up care with the study psychiatrist. 
The study psychiatrist will also send a staff message to inform patient’s PCP 
of this action (dot phrase **).
B.
For patients excluded from enrollment, or enrolled control participants, the 
study psychiatrist will send a high priority staff message in Epic (dot 
phrase**) to inform participant’s PCP or covering physician of the action of 
calling 911 and give potential resources for follow up following 
hospitalization. The PCP may in addition choose to call or schedule a follow 
up appointment with the patient as deemed appropriate.
7.
If there is MODERATE RISK of harm, with the participant having significant 
symptoms, but able to tend to basic needs, expressing willingness to get help, 
possibly having suicidal thoughts but denying an active suicidal plan:
A.
For enrolled I-CARE participants, the study psychiatrist will contact the 
study health coach, via phone or confidential email, who will contact the 
participant weekly thereafter by phone to complete the PHQ-9 (until 
patient’s PHQ-9 score <5, or score decreases by 50%), assess progress, and 
assist participant with follow-up. The study psychiatrist will send a staff 
message to inform patient’s PCP of this action. The study psychiatrist will 
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be available as needed to consult with the health coach and the participant’s 
PCP.
B.
For patients excluded from enrollment, or enrolled control participants, The 
study psychiatrist will send a high priority staff message in Epic (using the 
dot phrase ***) to inform participant’s PCP or covering physician of follow 
up plan.
8.
If there is LOW RISK of harm, with participant denying suicidal or homicidal 
thoughts, able to carry out basic activities of daily living, with reasonable social 
supports and agreeable to getting help:
A.
For enrolled I-CARE participants, the study psychiatrist will staff message 
the study health coach who will contact the participant weekly thereafter to 
complete the PHQ-9 (until patient’s PHQ-9 score <5, or score decreases by 
50%), assess progress, and coordinate the patient’s follow up care with the 
study psychiatrist. The study psychiatrist will send a staff message to inform 
patient’s PCP of this action.
B.
For patients excluded from enrollment, or enrolled control participants, the 
study psychiatrist will send a staff message in Epic (using the dot phrase 
****) to inform participant’s PCP of follow up plan.
9.
The study psychiatrist in scenarios 6–8 above will complete a study Self-Harm 
Risk Clinician Assessment Form that is part of the study Safety Monitoring 
Database.
B. PROCEDURES for telephone or in-person interviews with research staff
During telephone or in-person interviews with research staff, if a participant’s response 
suggests suicidal ideation on PHQ-9 or SCL-20 per definition in Rationale #5, the 
interviewer will ask “Do you have a plan for how you would commit suicide?”
1.
If yes, the interviewer stop the interview, get the participant’s location (if phone 
interview), let the participant know that you are concerned for his/her safety and 
therefore need to call for help, and call 911 immediately. You do NOT need 
participant’s consent to call 911 if you feel there is a possibility of immediate risk 
of harm to self or others.
2.
If no, the interviewer will tell the participant that the study psychiatrist will contact 
him/her within 24–48 hours and give the participant the Resource Contact 
Information Form or verbally give the participant the resource contact phone 
numbers if interviewing participant by phone. The interviewer will then offer to 
continue with the interview. Before moving on, it may be helpful to acknowledge 
to the patient that we will continue to monitor suicidal thoughts throughout the 
study, as they are a fairly common symptom of depression, and part of the 
depressive illness itself. Also helpful to instill hope: “We will work together to get 
you feeling better.”
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Dot Phrases for use in EPIC
RESEARCH STAFF high priority dot phrases to alert PCP or covering 
physician via Epic if the study psychiatrist is unavailable—*This message is to 
inform you that your patient recently endorsed suicidal thoughts on the PHQ-9 and/or 
SCL-20 while participating in the RAINBOW study.
As the study psychiatrist is not immediately available, we urge you to contact your patient 
and initiate an Urgent Mental Health referral in Epic if deemed appropriate.
In addition, you may choose to schedule a follow up appointment with the patient at your 
discretion.
-For enrolled I-CARE participants: Our health coach will contact your patient within one 
week and weekly thereafter to complete PHQ-9 and assess progress, consulting with the 
study psychiatrist as needed.
Study psychiatrist dot phrases to alert PCPs via Epic
For HIGH RISK PATIENTS: **This message is to inform you that your patient was 
recently assessed by the RAINBOW study psychiatrist to be at high risk for self harm based 
on responses to PHQ-9 and/or SCL-20. As a result, 911 has already been contacted and 
patient is en route to being evaluated in an emergency room setting for possible psychiatric 
and/or medical admission to the hospital. Appropriate family member/emergency contact 
has already been contacted.
-For enrolled I-CARE participants, our health coach will contact your patient within one 
week and weekly thereafter to complete PHQ-9 and assess progress, consulting with the 
study psychiatrist as needed.
For MODERATE RISK PATIENTS: ***This message is to inform you that your patient 
recently endorsed having suicidal thoughts over the past two weeks on the PHQ-9 and/or 
SCL-20 and has been contacted and assessed by the RAINBOW study psychiatrist by 
phone.
We urge you to contact your patient and initiate an Urgent or Routine Mental Health referral 
in Epic as deemed appropriate.
In addition, you may choose to schedule a follow up appointment with the patient at your 
discretion.
-For enrolled I-CARE participants: Our health coach will contact your patient within one 
week and weekly thereafter to complete PHQ-9 and assess progress, consulting with the 
study psychiatrist as needed.
For LOW RISK PATIENTS: ****This message is to inform you that your patient recently 
endorsed having significant depressive and/or anxiety symptoms over the past two weeks on 
the PHQ-9 and/or SCL-20.
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A.
For enrolled I-CARE participants, our study health coach will contact the 
participant within one week and weekly thereafter to complete the PHQ-9 and 
assess progress, consulting with the study psychiatrist as needed.
For patients excluded from enrollment, or enrolled control participants, we recommend you 
advise your participant who is in network to contact PA (650-853-4726) or Fremont 
(510-498-2942) Behavioral Health intake referral line to schedule a routine appointment 
with a mental health provider. If participant is out of network, we recommend that you 
advise he/she to contact their insurance provider for an in-network mental health provider. If 
neither of the above options are available, the patient should be advised to schedule an 
appointment with their PCP or covering physician within the next 1–2 weeks to discuss 
treatment options.
Appendix C. RAINBOW Data and Safety Monitoring Plan
The following procedures will be followed to ensure the safety of study participants and the 
validity and integrity of data in compliance with NIH requirements.
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Functions of the Data and Safety Monitoring Board (DSMB)
We will empanel a DSMB prior to enrollment of the first study participant. A DSMB in the 
context of this investigator-initiated randomized controlled trial exists for the purpose of 
providing the investigators, the cognizant IRB(s) and the sponsor with objective, scientific 
monitoring of the conduct of the study from the standpoint of ensuring (1) the protection and 
safety of human subjects and (2) the validity and integrity of the trial. The DSMB will be an 
independent, advisory body to the investigators and funding agency. To fulfill its functions, 
the DSMB will review the original protocol and any subsequent amendments, perform 
expedited monitoring of serious adverse events (SAEs) that are unexpected and at least 
possibly related to the study, perform ongoing monitoring of drop-outs and non-SAEs, 
determine whether study procedures should be changed or the study should be halted 
because of serious safety concerns and/or major problems with the study conduct, and 
perform periodic review of the completeness and validity of data to be used for analysis of 
effectiveness and safety. The DSMB will also monitor implementation of procedures to 
ensure research participant privacy and data confidentiality.
As in any clinical trial, it is not possible to anticipate all possible adverse events (AEs). We 
will conduct extensive training with our staff in ascertaining, monitoring, and documenting 
AEs—serious or not. The study investigators have extensive experience in clinical trial 
organization and management, including data and safety monitoring for single site and 
multi-site trials. We have established procedures for rendering first aid and life threatening 
emergencies. Study physicians will oversee these procedures.
Membership of the DSMB
The DSMB will consist of 3–5 outside members (not part of the investigative team) with 
expertise in a variety of disciplines including mental health, biobehavioral medicine, 
preventive medicine, nutrition, physical activity, biostatistics, clinical trial designs, and 
bioethics of research conduct. In the event of an award, we will work with NIH-designated 
Project Official to appoint an appropriate DSMB. The expertise of the members will include 
the disciplines and skills needed to initially review the protocol and then to monitor trial 
progress, data quality, and participant safety. The voting members must have no personal 
stake in the scientific outcomes of the study. They will not be included as authors of 
publications from the study, but will be acknowledged for their contribution. The PI and 
Reporting Investigator (Ma) will be responsible for overseeing the preparation of AEs and 
SAEs and all statistical reports to the DSMB.
Functional Organization of the DSMB
One individual will serve as Chairperson of the DSMB and will communicate by e-mail and 
telephone conference with the other members on an as-needed basis. Communication 
pertaining to expedited review of unexpected and possibly study-related SAEs will occur 
within a week of receiving the report of such events from Dr. Ma. Reporting and 
communication about routine trial monitoring will occur during DSMB meetings throughout 
the study.
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DSMB Meetings and Recommendations
The DSMB will convene every 4–6 months, in person or by conference call, with the 
investigators to review summaries of patient accrual, data collection, the timeliness of data 
transfer to analysis files, group balance and data concerning the execution of the 
randomization process, analysis plans and results, and the numbers and characteristics of 
any SAEs, and the numbers and rates of non-SAEs. At the end of each meeting, DSMB 
members will make a recommendation regarding the continuation of the trial and the time 
interval and format of the next meeting. In addition, there will be an evaluative statement 
regarding SAEs, protocol exceptions, and other matters of data quality, integrity of the trial, 
and timeliness. The DSMB’s findings and recommendations will be documented in the 
meeting minutes and transmitted to the investigators and sponsor for their information and 
action. A draft of the meeting minutes will be made available to the DSMB Chair for 
approval prior to distribution of a final version to other DSMB members, the funding 
agency, and the investigators.
Monitoring of Safety Data by the DSMB
Blinded Reporting
Safety information for this study will be reported to the DSMB by group but with the true 
identity of the treatment groups masked. This will maintain proper blinding of the 
investigators, outcome assessors, and the DSMB. However, if there are extraordinary 
concerns regarding patient safety, the DSMB may request unblinded data, e.g., on 
unexpected SAEs or unanticipated problems, in order to determine the nature and extent of 
toxicity of the intervention under study or the integrity of the trial conduct. When this 
occurs, the unblinded results will not be released to the investigators unless warranted for 
safety protection of the research participants.
No formal interim analyses are proposed of study outcomes by study group before primary 
data analyses. Follow-up data will be reported for all participants, irrespective of random 
assignment, during the course of the study. For purposes of study monitoring, including 
review of planned primary outcome analyses, the DSMB may wish to review results with 
permuted group assignments to test the analysis programs.
SAEs
For ongoing monitoring of this study, all SAEs will be reported to the DSMB during its 
regularly scheduled meetings, regardless of any judgment of their expectedness or 
relatedness to the study. Expedited reviews will occur for all unexpected and possibly study-
related events meeting the NIH definition of SAEs, i.e., any fatal event, immediately life-
threatening event, permanently or substantially disabling event, event requiring or 
prolonging inpatient hospitalization, or any congenital anomaly. Dr. Ma will concurrently 
notify the DSMB and the IRB by email within 72 business hours of the detection of an SAE 
requiring expedited review and will submit all relevant information about the event and a 
proposed corrective and preventive action plan (CAPA). The relevant information may 
include, but is not limited to, that about the event and its outcome, dosing history of a 
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suspect medication/treatment, concomitant medications, the subject’s medical history and 
current conditions, and all relevant laboratory data. Within one week of receiving the 
notification, the DSMB will render their determination of the event and recommendations 
about the CAPA in a letter signed by the chair and transmitted by email to Dr. Ma and the 
IRB.
Non-SAEs
At periodic intervals, the DSMB will be provided with summaries of the numbers and rates 
of all AEs by blinded treatment group. “Blinded treatment group” means an arbitrary 
labeling (e.g., 1 and 2) that does not reveal the true identity of the groups. These reports will 
include types of events, affected body system(s), severity, expectedness, study relatedness, 
and treatment phase. Data on individual non-SAEs is not expected to be needed for this 
review. At the discretion of the DSMB, however, the Chair may request unblinded and/or 
individual-level results to determine the nature and extent of adverse consequences.
Other Safety-Related Reports
It is considered necessary for the purpose of monitoring the safety of the study that the 
DSMB review not only AEs and SAEs, but other data that may reflect differences in safety 
between treatment groups. For example, these may include treatment retention rates and 
reasons for drop-outs. In addition, mean (SD) changes in SCL-20 score, weight, BMI, and 
cardiovascular risk factors from baseline to follow-up will be reported for all participants, 
irrespective of random assignment, because as noted above, interim outcome analyses by 
group are not planned in this trial.
Study Stopping Rules
Formal stopping rules for safety, efficacy, and futility are not proposed as part of this 
application but may be established per recommendations of the DSMB following the 
funding of the grant. If at any time during the course of the study, the DSMB judges that risk 
to participants may significantly outweighs the potential benefit, the DSMB shall have the 
discretion and responsibility to request all necessary information for detailed analyses, and if 
warranted, recommend that the study be terminated. Stopping rules for the trial could 
include stopping because of a significant number of injuries or illnesses that can reasonably 
be attributed to participation in the study, inability to recruit and measure the required 
number of participants to conduct the primary outcome analyses, poor intervention quality 
and delivery, serious deviation from study protocols, or other circumstances that would 
render the study unlikely to produce scientifically valid findings. The DSMB will carefully 
weigh the risk of completing the trial as planned against the risk of prematurely stopping the 
trial for safety or futility.
Monitoring of Data Quality by the DSMB
For each DSMB meeting, Dr. Ma will submit a detailed report on data quality and 
completeness. At a minimum, this will include the following: (1) patient accrual and follow-
up completion/retention in relation to goals and timeline; (2) the randomization process and 
group comparability on the balancing variables; (3) key baseline characteristics of the 
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sample, by blinded group, related to the primary and secondary outcome variables and 
proposed effect modifiers and mediators; (4) indices of intervention adherence; and (5) 
protocol violations.
Annual Report to the sponsor
As part of each annual progress report to the NIH, Dr. Ma will include a summary of 
findings regarding safety and quality based on data received to that point in the study and 
any new DSMB recommendations about patient safety, protocol adherence, and data quality.
Protection against Depression-related Risks
Protection against risks of worsening depression and self-harm
Some of the questions about depression, thoughts of death and other psychiatric symptoms 
and conditions as a part of the screening may be distressing to some patients. However, in 
general the questions will not be particularly intrusive or distressing, and stress will likely be 
transient. In addition, participants are free to choose not to any questions. It is widely 
accepted that asking questions about thoughts of death or suicide does not lead to increased 
risk of suicide. Nevertheless, in the event that a patient is identified as being suicidal in the 
screening or follow-up phase of the study (not because of being asked questions), we have a 
self-harm protection protocol (below) in place that will alert the study supervising 
psychiatrist to assess the patient’s suicidal thoughts by telephone, followed by notification of 
the patient’s primary care provider and appropriate clinical action if necessary.
Protection against risk of worsening anxiety
The Generalized Anxiety Disorder 7-Item (GAD-7) Scale is a screening tool that has been 
developed to screen for 4 anxiety disorders: Post Traumatic Stress Disorder, Panic Disorder, 
Generalized Anxiety Disorder, and Social Phobia. A score of ≥10 indicates a high 
probability of 1 or more of these disorders. Patients with coexisting anxiety who meet all 
inclusion and exclusion criteria will be eligible to participate. They can usually be 
effectively treated by starting on citalopram or sertraline. Patients carrying a diagnosis of 
bipolar or psychotic disorder will not be eligible to participate. However, patients with 
undiagnosed anxiety disorders or panic attacks can have an exacerbation of anxiety 
symptoms if an antidepressant is started at therapeutic dose or if an antidepressant like 
buproprion is used. Patients screening positive on the GAD-7 will be asked follow-up 
questions to screen for panic disorder. Patients with suspected panic disorder should be 
discussed with a psychiatrist before starting or increasing the dosage of a patient’s planned 
antidepressant. SSRIs are effective treatments for both panic disorder and depression, but 
patients with comorbid panic should be started on lower dosages initially.
Protection against adverse reactions to antidepressant medications (ADMs)
Consistent with the stepped depression care strategies, the study supervising psychiatrist will 
contact PCPs of intervention participants with unremitting symptoms (e.g., PHQ-9 score 
remains >50% of baseline by week 10 of PST) to recommend initiating or adjusting ADMs. 
Health coaches will support and educate intervention participants regarding ADM 
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management in preparation for potential recommendations by the study psychiatrist and 
action by their PCP.
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Table 1
Inclusion and exclusion criteria
Pre-
screening
(Electronic
health record 
data)
PCP Clearance
Screening
(Patient
reports by 
phone or 
online)
Baseline
Visit
(In-person
interview,
physical
exam and, if 
clinically
indicated,
study
physician
clearance)
Inclusion Criteria: (patients will be included if meeting all of the 
following)
Ethnicity: All ethnic groups
√
Gender: Both men and women
√
Age: ≥18 years
√
Body mass index ≥30.0 kg/m2 (non-Asians) or ≥27.0 kg/m2 (Asians)
√
√
Clinically significant depression PHQ-9 ≥10
√
PAMF patient for ≥1 year and seen in primary care at least once in the 
preceding 24 months
√
Able and willing to enroll and provide written, informed consent, i.e., 
to: meet the time and data collection requirements of the study; be 
randomized to one of two intervention arms; participate in follow-up 
for 24 months; and allow extraction of relevant information from their 
medical records.
√
Exclusion Criteria: (patients will be excluded if meeting any of the 
following)
Active suicidal ideation per PHQ-9 interview that includes active plan 
and/or intent (item #9 ≥2)
√
√
Any Axis I disorder other than Minor or Major Depressive Disorder 
and/or Dysthymia, with the exception of any comorbid Anxiety 
Disorder
√
√
Active Bulimia Nervosa within the past 3 months (however Binge 
Eating Disorder without purging is not an exclusionary condition)
√
√
Active alcohol or substance use disorder (including prescription drugs)
√
√
√
Ongoing psychiatric care with a provider outside of PAMF
√
Had bariatric surgery within the past 12 months or plan to undergo 
bariatric surgery during the study period
√
√
√
Pre-existing diabetes (other than during pregnancy)
√
√
√
√
Pre-existing cardiovascular disease: e.g., coronary heart disease 
(myocardial infarction, angina pectoris, percutaneous coronary 
intervention, and coronary artery bypass graft surgery), 
cerebrovascular disease (stroke, transient ischemic attack), peripheral 
vascular disease, heart failure, or aortic aneurysm.
√
√
√
√
Diagnosis of cancer (other than non-melanoma skin cancer) that is/was 
active or treated with radiation or chemotherapy within the past year
√
√
√
Severe medical comorbidities that require aggressive treatment, e.g., 
stage 4 or greater renal disease, liver failure
√
√
√
Diagnosis of a terminal illness and/or residence in a long-term care 
facility
√
√
Cognitive impairment based on the Callahan 6-item screener
√
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Pre-
screening
(Electronic
health record 
data)
PCP Clearance
Screening
(Patient
reports by 
phone or 
online)
Baseline
Visit
(In-person
interview,
physical
exam and, if 
clinically
indicated,
study
physician
clearance)
Inability to speak, read or understand English
√
√
√
√
Having no reliable telephone service, or no regular Internet access via 
a computer and/or mobile device (e.g., smartphone)*
√
Plan to move out of the area or transfer care outside PAMF during the 
study period
√
Currently pregnant, lactating, or planning to become pregnant during 
the study period
√
√
√
√
Already enrolled, or planning to enroll, in a research study that would 
limit full participation in the study or confound the observation and 
interpretation of the study’s findings
√
Family/household member of another participant or of a staff member
√
√
Investigator discretion for clinical safety or protocol adherence reasons
√
*We do not employ a behavioral run-in for technology use (typical in efficacy trials) as an inclusion criterion because of the importance of 
balancing scientific rigor and generalizability in this type 1 hybrid design RCT. It is an integral part of the intervention curriculum that the coach 
instructs on, and helps troubleshoot issues with, technologies (e.g., MyFitnessPal and Fitbit websites and mobile applications) used in the 
intervention, as would be expected if the intervention were delivered in routine practice.
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Table 2
Intervention Outlinea,b
Week
Visitc
Minutes
Content
1
1
60
•
Introduction to I-CARE Mood and I-CARE Lifestyled sequenced integration (5 min)
•
Technology: Fitbit, MyFitnessPal – using, linking, friend requests to coach; My Health Online.e
Encouragement to wear Fitbit and check uploads (10 min)
•
Physical activity safety guidelines handout (GLB Session 4, pages 3,4)
•
Evaluation of bathroom scale ownership
•
I-CARE Mood Session 1 (45 min)
2
2
60
•
I-CARE Mood Session 2 (60 min)
•
Provision of bathroom scale to participants requiring one
3
3
60
•
I-CARE Mood Session 3 (60 min)
4
4
60
•
I-CARE Mood Session 4 (50 min)
•
Technology: MyFitnessPal – explanation of logging physical activity minutes and weight; 
introduction to logging diet; importance of self-monitoring (10 min)
6
5
60
•
I-CARE Mood Session 5 (45 min)
•
I-CARE Lifestyle introduction and self-study guidelines (5 min)
•
Technology: MyFitnessPal – review of logging physical activity and weight; explanation of logging 
diet; importance of self-monitoring (10 min)
8
6
60
•
I-CARE Lifestyle Progress Check (5 min)
•
I-CARE Mood Session 6 (30 min)
•
Technology: MyFitnessPal, Fitbit, My Health Online check in (5 min)
•
Goals confirmation: weight, physical activity, steps (5 min)
•
Optional tools to reduce calorie intake: meal plans, packaged meals (5 min)
•
I-CARE Lifestyle Session (GLB Sessions #1,2) (10 min)
12
7
60
•
I-CARE Lifestyle Progress Check (10 min)
•
I-CARE Mood Session 7 (35 min)
•
I-CARE Lifestyle Session (GLB Sessions #3,4,5,6) (15 min)
16
8
60
•
I-CARE Lifestyle Progress Check (10 min)
•
I-CARE Mood Session 8 (35 min)
•
I-CARE Lifestyle Session (GLB Sessions #8,9,10) (15 min)
20
9
60
•
I-CARE Lifestyle Progress Check (10 min)
•
I-CARE Mood Session 9 (35 min)
•
I-CARE Lifestyle Session (GLB Sessions #11,12) (10 min)
•
Overview of weeks 21–52 (5 min)
21–52
Phone
15–30
•
I-CARE Lifestyle Progress Check (5–10 min)
•
I-CARE Mood Session (5–10 min)
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Week
Visitc
Minutes
Content
•
I-CARE Lifestyle Session (5–10 min)
•
Discussion of maintenance plan when program goals met
aIn-between session support as needed via EHR secure email, between weeks 1–52.
bCo-located psychiatric and medical supervision during weekly intervention management team meeting, between weeks 1–52.
cThe 9 one-on-one I-CARE sessions will occur primarily in the clinic, but video conferences (as the second option) or phone sessions (as the last 
option and for visits 1–5, phone session is only an option upon PI and intervention manager approval) throughout the intensive phase will be an 
option for participants with considerable constraints.
dI-CARE Mood is the PEARLS program; I-CARE Lifestyle is the GLB program.
eParticipants receive Fitbit, MyFitnessPal, and My Health Online instructions via mail or e-mail prior to first session.
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Table 3
List of measures and data collection schedule.
Study Measures
Instrument
Collection Method
Month
Screening
0
6
12
18
24
Eligibility Screening
Depression severity
Patient Health Questionnaire-9 (PHQ-9 and Dysthymia questions)
Self-report
x
Suicidal ideation
PHQ-9 (item #9 ≥2)
Self-report
x
Bulimia nervosa
PHQ eating disorder module
Self-report
x
Alcohol/substance abuse
CAGE Adapted to Include Drugs (CAGE-AID)
Self-report
x
Cognitive Impairment
6-item Screener
Interview
x
Primary/Secondary Outcomes
BMI (height)
Height
Biophysical
x
BMI (weight)
Weight
Biophysical
x
x
x
x
x
Depression severity treatment response, and 
remission
Depression symptom Checklist-20 (SCL-20)
Self-report
x
x
x
x
x
Cardiovascular risk factors
Blood pressure, waist circumference
Biophysical
x
x
x
x
x
Obesity-specific health related questions
Obesity-related Problem Scale
Self-report
x
x
x
x
x
Anxiety
Generalized Anxiety Disorder Scale (GAD-7); Panic Disorder module of the 
Mini-International Neuropsychiatric Interview (MINI)
Self-report
x
x
x
x
x
Disability
Sheehan Disability Scale
Self-report
x
x
x
x
x
Generic health related quality of life
SF-8 Health Survey
Self-report
x
x
x
x
x
Utility based quality of life
EuroQOL-5D-5L
Self-report
x
x
x
x
x
Direct medical costs, direct nonmedical 
costs
Health care utilization: from electronic health record (EHR); intervention cost: 
coach time, survey lifestyle coach for Intervention process accounting, 
intervention-related patient “out-of-pocket” costs.
EHR; process documentation; 
self-report
x
x
x
x
x
Absenteeism-Presenteeism questionnaire
Self-report
x
x
x
x
x
Participant Expense Survey
Self-report
x
x
x
x
x
Medication use, general wellness services, and out of network health care 
utilization questionnaire
Interview
x
x
x
x
x
Potential effect modifiers
Sociodemographics
Age, gender, education, race/ethnicity
Self-report
x
Posttraumatic stress disorder (PTSD)
17-item PTSD checklist – Civilian Version (PCL-C)
Self-report
x
Potential effect mediators
Dietary intake
24-hr diet recalls
Interview
x
x
x
x
x
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Study Measures
Instrument
Collection Method
Month
Screening
0
6
12
18
24
Physical activity
7-day Physical Activity Recall
Interview
x
x
x
x
x
Problem solving
Social Problem-Solving Inventory-Revised: Short Form
Self-report
x
x
x
x
x
Sleep habits and quality
PROMIS Sleep Disturbance and Sleep Impairment Scales
Self-report
x
x
x
x
x
Safety
Activity
Rose Angina and Peripheral Vascular Disease Questionnaires
Self-report
x
x
x
x
x
Severe high or low blood pressure
Blood pressure
Biophysical
x
x
x
x
x
Adverse Events (AE)
AE form
Interview
x
x
x
x
x
Self-harm risk
SCL-20 suicidality item
Self-report
x
x
x
x
x
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Table 4
Summary of Quantitative and Qualitative Measures for the Process Evaluation
RE-AIM Domains
Example Questions, Data Sources, and Methods
Quantitative
Qualitative
Reach
Using patient survey and recruitment 
tracking data we will assess the percentage 
and characteristics of participants 
compared to non-participants, e.g., by 
soliciting demographic information from 
potential participants and reasons for 
screening refusal or ineligibility.
We will ask study staff at the beginning, mid-point, and 
end of the 2-year recruitment period: What were the 
barriers to and enablers of recruiting participants? Was 
there variability in these factors related to demographics 
or other characteristics? How were the barriers 
addressed? Were the solutions successful? What could be 
changed to maximize reach?
Adoption
Using administrative data we will describe 
the characteristics of participating clinics, 
and the percentage and characteristics of 
PCPs approached that participated (e.g., 
PCPs referring patients for screening or 
making recommended antidepressant 
medication changes).
Via interviews with internal experts, PCPs, and medical 
and administrative leaders we will ask: What were the 
barriers to and enablers of clinic and PCP participation? 
Why did the barriers exist? What recommendations do 
they have for addressing barriers and maximizing 
adoption?
Implementation (staff perspective)
Using intervention tracking data we will 
assess time and resources required for 
coach training, intervention delivery, 
coach supervision, and fidelity assurance.
Via interviews with study care team, internal experts, 
PCPs, and medical and administrative leaders we will 
ask: What were the barriers to and enablers of delivering 
the intervention, and were they different across 
participating clinics? How might these factors translate or 
not to real-world implementation? Were certain 
components more challenging to deliver than others? 
What modifications could be made to maximize real-
world implementation?
Implementation (patient perspective)
Using intervention tracking data we will 
assess participants’ receipt of and 
adherence to the intervention, e.g., by 
monitoring the number of in-person 
sessions, phone calls and DVD sessions 
completed, reasons for missed sessions, 
secure email and self-monitoring 
frequency, and consistency of adherence 
across participant subgroups.
Via interviews with a 10% random sample of 
intervention participants we will ask: How relevant and 
acceptable were the knowledge and skills gained? How 
often did they practice the intervention strategies? What 
were the perceived benefits? What problems did they 
encounter? How satisfied were they with program format, 
materials, and coach performance?
Maintenance
Using follow-up data through 24 months 
we will assess attrition rates and adverse 
events by participant characteristics and 
treatment condition; the durability of 
intervention effects on depression, obesity, 
and health-related quality of life; and 
simulation model-based projections of 
cost-effectiveness within trial and long 
term.
Via interviews with study care team, internal experts, 
PCPs, and medical and administrative leaders we will 
ask: How could the intervention be integrated into regular 
care and sustained after the study ended? What resources, 
policies, and care process redesigns would be needed to 
maximize sustainability?
Contemp Clin Trials. Author manuscript; available in PMC 2016 July 01.