Conditions: Depression Heart Failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 494
Healthy volunteers: no

Brief summary:
We are doing this study to help patients, caregivers, and providers make decisions about how best to manage depressive symptoms in advanced heart failure. There are two evidence-based treatment approaches to treating depression in patients with advanced heart failure, behavioral action psychotherapy and treatment with anti-depressant medications. In this study we want to compare the effectiveness of these two treatment options to learn which treatment works better.

Detailed description:
Aim 1: To compare the effectiveness of BA vs. MEDS, for depressed AHF patients. Hypothesis 1: Compared to depressed AHF patients who receive MEDS, patients receiving BA will have significantly greater improvements in the primary outcome of depressive symptom severity as measured with the PHQ-9 at 6-month follow-up. Significantly greater improvements will also be detected in the secondary outcomes of general physical and mental HRQoL (SF-12v2), heart failure-specific HRQoL (KCCQ), and caregiver burden (CBQ-HF) at 3, 6, and 12 months.

Aim 2: To compare the impact of BA vs. MEDS on disadvantageous outcomes of Morbidity (as evidenced by ED visits, hospital readmissions, total days in the hospital), and Mortality among depressed AHF patients.

Hypothesis 2: Compared to depressed AHF patients who receive MEDS, those receiving BA will have significantly less Morbidity (as evidenced by less frequent ED visits, lower readmission rates, fewer total days in the hospital), and reduced Mortality at the data collection points of 3, 6, and 12 months.

Arms:
arm 1: The medication management group will meet with the patient in a one 50 minute in person introductory antidepressant medication treatment session to educate the patient about depression and medication options. Patients will get prescribed a standard of care anti-depressant medication by treating physician, followed by 12 weekly follow up telephone visits, then on a monthly basis for 3 months, and then as needed thereafter. arm 2: BA is an evidence-based psychotherapy with more than 25 randomized trials showing effectiveness in depression. The therapy group will consist of an introductory in person 50-minute treatment session, followed by 12 weekly telephone 50-minute outpatient treatment sessions, then 3 monthly telephone 50-minute outpatient maintenance sessions. A typical BA session will last 50 minutes and include a review of the previous session and completed daily monitoring record forms, an in-depth discussion of life areas and value, and verbal reinforcement of activity engagement. arm 3: Caregivers of patients receiving the the above described Medication Management (MEDS) intervention were monitored for caregiver burden at 3, 6, and 12 months. arm 4: Caregivers of patients receiving the the above described Behavioral Activation Psychotherapy (BA) intervention were monitored for caregiver burden at 3, 6, and 12 months.

Interventions: intervention 1: Behavioral Activation Therapy intervention 2: Medication Management
Intervention descriptions: intervention 1: The therapy group will consist of an introductory in person 50-minute treatment session, followed by 12 weekly telephone 50-minute outpatient treatment sessions, then 3 monthly telephone 50-minute outpatient maintenance sessions. A typical BA session will last 50 minutes and include a review of the previous session and completed daily monitoring record forms, an in-depth discussion of life areas and value, and verbal reinforcement of activity engagement. intervention 2: Collaborative care model will be used. The medication management group will meet with the patient in a one 50 minute in person introductory antidepressant medication treatment session to educate the patient about depression and medication options. Patients will get prescribed a standard of care anti-depressant medication by treating physician, followed by 12 weekly follow up telephone visits, then on a monthly basis for 3 months, and then as needed thereafter.

Protocol document:
Prot_SAP_000.pdf: 
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Section 1.0 
 
General Information  
 
Title: Personalized Treatments for Depressive Symptoms in Patients with Advanced Heart Failure 
Collaborator/Sponsor: Patient-Centered Outcomes Research Institute (PCORI) 
Principal Investigator: Waguih William IsHak, MD, FAPA  
Co-Investigators and Key Personnel: Michelle Hamilton, MD (Co-I); Asher Kimchi, MD, FACC, 
FAHA, FIACS(Co-I); Itai Danovitch, MD, MBA (Co-I); Brennan Spiegel, MD (Co-I); Harriet Aronow, 
PhD (Co-I); Jeanne Black, PhD, MBA (Co-I); Rebecca Hedrick, MD (Co-I/Psychiatrist); Robert 
Chernoff, PhD (Psychologist); Marcio Diniz, PhD (Co-I/Biostatistician); James Mirocha, MS 
(Statistician; Gabriel Edwards, MD, MPH (Post-doc Fellow); Samuel Korouri, BA (Research 
Coordinator); Mia Mazer, CCRP (research coordinator); Research Nurses Stacy Collier, RN/MSN, 
Jori Ottenhoff, RN/BSN, and Mia Pasini, RN/MSN. 
 
Section 2.0 
 
Background information 
 
Heart Failure (HF) is a chronic syndrome affecting over 5.7 million in the US and 26 million adults 
worldwide. Depression is a leading cause of disability and premature mortality, affecting roughly 
350 million people worldwide. Depressive symptoms in heart failure patients are common as 
shown by a number of studies including a Cochrane review that concluded that depressive 
symptoms are detected in up to 85% of HF patients. Systematic reviews place the prevalence at 
a range from 10-60%. Robust studies show a prevalence of 48%. Due to the heightened 
prevalence of depression in cardiovascular patients, the American Heart Association (AHA) 
recommends screening for depression among cardiovascular patients using the PHQ-2 and the 
PHQ-9.  
 
Impact of HF on Individuals and Populations: Depressive symptoms are associated with poor 
outcomes in HF. Depression and HF have bidirectional effects through both biological and 
psychosocial mechanisms.  
 
Impact on Functioning: In general, functioning impairments are closely correlated to depression 
severity. HF symptoms greatly restrict patients’ daily physical activities. Among cardiac patients, 
those with HF reported more depression and significant mood disruption compared to patients 
with other cardiac illnesses. Among chronic illnesses, HF patients reported the poorest physical 
and social functioning.  
 
Impact on HRQoL: HRQoL is markedly decreased among HF patients compared to the general 
population. Furthermore, a poorly rated HRQoL is more common among depressed HF 
compared to non-depressed HF patients and spouses. Surprisingly, the severity of heart failure is 
a weak predictor of HRQoL. The largest predictor of poor HRQoL was the severity of depression.  
 
Impact on Overall Physical and Mental Health: Depressed HF patients experience worsening of 
cardiac functioning and perform worse on physical exams, such as the 6-minute walk test. 
Studies report that HF patients with more severe physical symptoms experience greater 
depression severity. Depressed HF patients report lower mental and physical health scores, after 
adjusting for relevant variables.  
 


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Impact on Caregivers: Studies have found that caregivers report feeling unprepared for the 
caregiving role and inadequately supported by the healthcare team, negatively impacting their 
psychosocial and physical health. Spouses of HF patients also report a significantly reduced well-
being and feel burdened in the caregiving role. In 2004, Dracup et al., found that the spouses 
were at greater risk for low levels of emotional well-being and tend to feel less in control over 
the health outcomes of their loved one. There is also a correlation between caregiver burden 
and caregiver depression.  Hooley et al. found that depressed caregivers (BDI-II ≥10) had much 
higher burden scores. 
  
Impact on Morbidity (ED Visits, hospital readmissions, and total days in the hospital): Studies 
have consistently shown that ED visits are increased in depressed HF patients. Moreover, 
Depressed HF patients have a 4.1 times higher risk of hospitalization than non-depressed 
patients on antidepressants (95% Cl: 1.2-13.9 p = 0.022). A history of depression in HF patients 
may be a predictor of prolonged hospital length of stay. A UK study found that among 54,000 
males with HF diagnosis, there were 986,000 bed-days. Among 59,000 women, there were 1.37 
million bed-days.  
 
Impact on Mortality: Increased severity of depressive symptoms increases risk for functional 
decline or death at six months among heart failure patients. A study of 1,017 outpatient heart 
failure patients, depression was found to be an independent risk factor for mortality after 
adjusting for confounders. 
 
Gaps in Knowledge about the Treatment of Depressive Symptoms in Heart Failure: 
 
Overview of the state of current research literature and trials: BA is a patient-centered and 
personalized psychotherapy treatment that is evidence-based as shown in more than 25 
randomized clinical trials. BA is a well-established and effective treatment for depression with 
effects comparable to CBT and antidepressant medication. Specific to cardiac patients, BA 
therapy was feasible and effective, with positive impact on cardiac caregivers. Antidepressants 
are well established in treating depression in patients with advanced medical illness. When 
depressed patients are treated using the Collaborative Care model, research has shown that 
patients respond better to antidepressants as evidenced by lower depression severity, less 
functional impairment and greater HRQoL at 3, 6 and 12-months follow-up. The Collaborative 
Care model has been successfully implemented among depressed inpatients with cardiac 
disease. Although the AHA recommends screening for depression there are no official guidelines 
on depressive symptom management in AHF and there is a lack of consensus on how to best 
manage them. There are no trials comparing BA to antidepressants or to their combination for 
depressed AHF patients. 
 
The gaps in evidence and the potential for the study to fill the evidence gaps:  
- 
There are few trials of head-to-head comparisons between pharmacological and 
psychotherapeutic interventions in depressive symptom treatment in cardiovascular 
disease and none included comparing the above interventions in advanced heart failure. 
The proposed study aims at comparing the effectiveness of the two interventions. 
- 
The optimal management of heart failure includes self-care and management of AHF 
symptoms, including depression. Self-activation or self-care have been shown to 
improve patient outcomes, disease management and are associated with better patient-


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reported outcomes. However, psychotherapy in heart failure has been limited to CBT. 
The proposed study involves the utilization of BA, which has been shown to be as 
effective as CBT but is much more feasible yet understudied in this population. 
- 
Existing antidepressant trials did not measure long-term effects and stopped at 12-week 
follow-up. Larger and more robust RCTs are needed to evaluate the longitudinal effects 
interventions on depressed HF patients. The proposed study extends the follow-up to 
one year. 
- 
Even though there is compelling evidence that antidepressants work, many patients do 
not receive antidepressants, largely due to the absence of a model for medication 
management, rather than the knowledge of which specific antidepressant is best. The 
proposed study implements the evidence-based Collaborative Care Model in order to 
test the effectiveness of antidepressant medication management in AHF. 
- 
The impact of treating depressed AHF patients (using psychotherapy or 
pharmacotherapy) on general physical and mental HRQoL, heart failure-specific HRQoL, 
caregiver burden, Morbidity (as evidenced by frequency of ED visits, readmissions, total 
days in the hospital), and Mortality, is largely unknown. The proposed study aims at 
examining and comparing this impact on the above outcomes at 3, 6, and 12 months. 
 
Potential for the study to improve the quality of the evidence available to help patients and 
relevant stakeholders make informed health decisions and improve health care and outcomes 
- Potential for the study findings to be adopted into clinical practice and improve delivery of 
care  
Improving the Quality of the Evidence: Depression is an important health concern; yet, it is 
largely undiagnosed and untreated in this population. Only about 50% of those who are 
diagnosed will receive therapy or antidepressant medication. Most antidepressant trials have 
focused on short-term outcomes, while the long-term effects of the patient’s mood and 
functional outcomes have been ignored. Given the prevalence and impact of depressive 
symptoms in AHF, there is a need for evidence on the comparative effectiveness of 
psychotherapy vs. pharmacotherapy. This study will improve the quality of evidence by offering 
clinicians specific, actionable information on how the widely used effective interventions of BA 
or MEDS, perform in AHF where depressive symptoms are exceedingly common. 
Adoption into Clinical Practice: In order for any study findings to be adopted into clinical practice 
and improve delivery of care, it would need to meet the following conditions: perceived 
advantage, consistency with current practices where adoption is to occur, complexity of 
innovation (the simpler the better), time-frame for implementation (gradual is better) and 
visibility once adopted (the more the better).  
• 
The proposed study will likely be adopted if one of the two treatments (we hypothesized 
that it is BA) is shown to have advantage over the other in terms of the primary outcome of 
reduction of depressive symptom severity as well as the secondary equally important quality 
of life outcomes, caregiver burden, morbidity, and mortality.  
• 
We designed our study by emulating the real-world as much as possible in order to enable 
its consistency with current practice, i.e., Antidepressant Medication Management using the 
Collaborative Care Model with a Care Manager linking the patient case with the primary 
care physician and a consultation psychiatrist and using technology to deliver psychotherapy 
to save time, effort, overcome access barriers to treatment, and improve compliance. This 
plan could be facilitated in future years through outsourcing to new Collaborative Care 
Model online health services e.g., Concert Health, which provides remote-access using 


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psychiatric consultants who are specialty-trained and licensed experts as a liaison and 
resource in providing medication consultations to PCPs. 
• 
The innovative aspects of the proposed study are simple and user friendly, especially with 
the use of every day technology to receive psychotherapy and collect patient-reported 
outcomes. Furthermore, if BA is effective in depressed AHF patients (consistent with its 
effectiveness among patients with other advanced diseases) it will facilitate its use by 
enabling a broad range of providers to deliver the intervention39. We hypothesize that BA 
may be more efficacious than MEDS, and if this is hypothesis is confirmed by findings, then 
it would open the door for a feasible psychotherapeutic option which is necessary in AHF if 
contraindications and drug-drug effects to existing medication can be avoided.  
• 
The implementation of our study findings will be optimal if it is done gradually in a wide 
variety of hospitals, primary care, and cardiology practices. Starting with depression 
screening, passing by identifying patient in most need of treatment, and ending with 
implementing the study findings using the evidence-based treatments, will likely have 
significant positive impact on depressed AHF patients and their caregivers.  
• 
The proposed study contains interventions that are straightforward to explain and easy to 
understand making it ideal to communicate widely, thus increasing their visibility once 
implemented. The results of this study will also enhance awareness and lay the groundwork 
for an official guideline on treating depressed AHF patients. 
How the research is focused on questions that affect outcomes of interest - Patient-
Centeredness? 
• 
In January 2017, we created a Health and Wellness Partnership (HWP) that meets monthly 
and consists of patients, caregivers, program founders such as Life Restyle Retreat, Painted 
Brain, Life Adjustment Team, and Clearview Treatment Programs as well as leaders from 
NAMI. The purpose of HWP is to actively participate in shaping research and clinical 
initiatives by providing patient-centered input. Two heart failure patients, who are familiar 
with depression struggles, joined in providing input to the proposal as it evolved from an LOI 
to a full application.  
• 
Our patients and caregivers have expressed the need to focus not only on depressive 
symptoms but also on quality of life outcomes, which prompted us to include measures of 
HRQoL.  They also urged us to “encourage depressed patients to get out there, and engage 
in fun activities, anything that may be cool, fun or different to them”, which shaped our 
choice of the kind of evidence-based psychotherapy we chose for this study. The 
intervention in this study is patient-centered because BA is a personalized therapy that can 
be integrated into daily life, to facilitate and promote activities that are desirable and 
pleasurable to the individual.  
• 
Our patients and caregivers highlighted the importance of “long-term engagement 
treatment plan with depressed patients”, prompting us to design the study for 1-year 
maintenance and follow-up. Through ongoing engagement, dialogue, and debates, our 
patients, caregivers, and stakeholders, have identified a set of advantageous and a set of 
disadvantageous outcomes in depressed AHF patients for our research effort. Therefore, the 
proposed study aims to answer the following questions: 1. Which is the best treatment 
option to positively impact the most important and advantageous outcomes of improving 
depressive symptoms, improving general physical and mental HRQoL, improving heart 
failure-specific HRQoL, and reducing caregiver burden? 2. Which treatment option is most 
likely to reduce the disadvantageous outcomes of Morbidity (ER visits, hospital 
readmissions, total days in the hospital) and Mortality?  


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Section 3.0 
 
Trial objectives and purpose 
 
Overview: Depressive symptoms are detected in nearly half of patients with heart failure and 
constitute a risk factor for functional decline and death. The goal of the proposed research is to 
generate scientific evidence to help patients, caregivers, and providers, make decisions about 
how best to manage depressive symptoms in advanced heart failure. This real-world 
randomized pragmatic trial will compare the effectiveness of two evidence-based treatment 
approaches for enhancing patient care plans: (1) Behavioral Activation (BA), a patient-centered 
psychotherapy which emphasizes engagement in enjoyable and valued personalized activities as 
selected by the patient; (2) Antidepressant Medication Management (MEDS). The proposed 
research will examine the impact of these treatment enhancements on the following outcomes 
that patients and caregivers have identified as most important or advantageous: depressive 
symptom reduction, general physical and mental health-related quality of life (HRQoL), heart 
failure-specific HRQoL, and caregiver burden. We will also examine the following outcomes that 
patients and caregivers have identified as disadvantageous: Morbidity (as evidenced by frequent 
emergency department (ED) visits, hospital readmissions, longer hospital stays), and Mortality.  
 
All patient/caregiver-centered outcomes will be longitudinally collected in order to assess the 
short, intermediate, and long-term impact on patients’ lives. Cedars-Sinai Medical Center 
(CSMC), a non-profit 958-bed multi-specialty academic general acute care hospital in Los 
Angeles, is an ideal place to perform this research as it is home to one of the largest heart 
programs in the US (ranked 4th in the nation) and includes the largest heart transplant center in 
the world; a life-saving/promoting treatment for heart failure in non-depressed patients. The 
Consultation-Liaison (C/L) psychiatry program is a fully staffed service with psychiatrists, 
psychologists, psychiatric social workers, and psychiatric nurses, where one of every ten medical 
inpatients is seen by C/L.   
 
The research team has extensive experience in depression and heart failure research and its 
close partnership with patients, caregivers, and providers led to the development and evolution 
of this proposal. 
 
Definitions:  
Advanced heart failure (AHF) will be defined as New York Heart Association (NYHA) Class II, III, 
and IV in which patients experience shortness of breath with palpitations and physical activity 
limitations, characterized as moderate, severe, and at rest, respectively1.  
 
Depressive Symptoms will be defined as a score of 10 or above on the patient-reported 9-item 
Patient Health Questionnaire (PHQ) and confirmed by the MINI International Neuropsychiatric 
Interview for the DSM-5 (MINI 7.02) brief structured interview to meet DSM-5 criteria for 
current Major Depressive Disorder, Persistent Depressive Disorder (Dysthymia), and Depressive 
Disorder Unspecified, and not meet DSM-5 criteria for Bipolar, Psychotic, or Substance-induced 
Disorders.  
 
 


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AIMS: Our partnership of investigators, patients, caregivers, & stakeholders, developed the 
following aims: 
 
Aim 1: To compare the effectiveness of BA vs. MEDS, for depressed AHF patients.  
Hypothesis 1: Compared to depressed AHF patients who receive MEDS, patients receiving BA 
will have significantly greater improvements in the primary outcome of depressive symptom 
severity as measured with the PHQ-9 at 6-month follow-up. Significantly greater improvements 
will also be detected in the secondary outcomes of general physical and mental HRQoL (SF-
12v2), heart failure-specific HRQoL (KCCQ), and caregiver burden (CBQ-HF) at 3, 6, and 12 
months. 
Aim 2: To compare the impact of BA vs. MEDS on disadvantageous outcomes of Morbidity (as 
evidenced by ED visits, hospital readmissions, total days in the hospital), and Mortality among 
depressed AHF patients.  
Hypothesis 2: Compared to depressed AHF patients who receive MEDS, those receiving BA will 
have significantly less Morbidity (as evidenced by less frequent ED visits, lower readmission 
rates, fewer total days in the hospital), and reduced Mortality at the data collection points of 3, 
6, and 12 months. 
 
 
Figure 1. Conceptual Framework 
 
Section 4.0 
 
Trial Design 
 


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D.7.a. Overview: The design is an individual randomized pragmatic trial comparing three active 
treatments (BA vs. MEDS; total 300 subjects, i.e., 150 patients in each arm) in inpatients and 
outpatients with advanced heart failure who screen positive for depression on the patient-
reported PHQ-9 (score of 10 or above) and are confirmed to be depressed using MINI 
International Neuropsychiatric Interview for the DSM-5 (MINI 7.02) brief structured interview to 
diagnose Major Depressive Disorder (MDD), Persistent Depressive Disorder (Dysthymia), and 
Depressive Disorder Unspecified, and to rule out Bipolar, Psychotic, and Substance-induced 
Disorders . The study will be initiated during an inpatient admission or an outpatient visit at 
Cedars-Sinai Medical Center inpatient hospital or outpatient program of the Smidt Heart 
Institute at Cedars-Sinai Medical Center. The study will compare the two interventions using the 
following patient-reported outcomes depressive symptom severity (primary outcome), general 
physical and mental HRQoL, heart failure-specific HRQoL, and caregiver burden at 3, 6, and 12-
months after starting BA or MEDS. The study will also assess outcomes identified by 
patients/caregivers as disadvantageous including Morbidity (as evidenced by ED visits, 
readmissions, total days in the hospital), and Mortality at 3, 6, and 12 months. This Intent-to-
Treat design preserves the notion of “As randomized, so analyzed”. As a secondary analysis, per-
protocol effects will be estimated adjusting by post-randomization confounding. 
 
D.7.b. Study Timeline: This 3-year study has the final goal of randomizing a full sample size of 
300 subjects (150 in each group). Patient recruitment and follow-up will begin in a rolling 
fashion after a 2-month initiation phase and will last for 20 months with an expected 
recruitment rate of 20-21 patients per month (10-11 patients for each group) to reach a target 
of 416 patients from which 28% are expected to dropout leaving 300 to analyze. The following 
12 months will be spent on collecting follow-up data until reaching the last batch of patients, 
followed by 2 months of data analysis/manuscript preparation. 
 
Randomization, identification and stratification of subgroups, and Data/Variables  
1. Randomization: Randomization will be performed through the REDCap (Research Electronic 
Data Capture) system66. REDCap will incorporate allocation tables generated in R82. Study 
participants will be randomized 1:1 to the two treatment arms of the study.  
 
2. Allocation concealment and Blinding: We will use central allocation to prevent participants, 
investigators, and treating clinicians from foreseeing assignment. The study design does not 
permit blinding of subjects to the treatment received. Lack of blinding creates a possibility of a 
placebo effect, particularly for depression. For this reason, secondary analyses will include 
measures that are less likely to be subject to a placebo effect, such as hospital readmission.  
 
3. Data Collection Procedures: The surveys as detailed in the Outcome section. The variables will 
be extracted from the electronic medical record.  
 
1. Key outcomes  
a. Primary outcome: Depressive symptom severity as measured by the PHQ at 6 
months. 
b. Secondary outcomes: at 3, 6, and 12 months 
                                                        i.        General physical and mental quality of life as measured by 
the SF-12v2 


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                                                        ii.       Heart failure-specific quality of life as measured by the 
KCCQ 
                                                        iii.      Caregiver burden as measured by the CBQ-HF 
                                                        iv.      Morbidity as measured by ED visits, readmissions, and total 
days in the hospital 
 
 
v.     Mortality. Mortality Data will be confirmed via the National 
Death Index.  
 
2. Co-variates: 
a. Demographics (age, sex, race, ethnicity, marital status, employment, 
educational level, insurance) 
b. Location of recruitment: Inpatient, Outpatient 
c. NYHA Stage: II, III, or IV 
d. Ejection fraction 
e. Baseline: PHQ-9, SF-12v2, KCCQ, CBQ-HF 
f. Medical History as detailed in the attached tables 
g. Medications as detailed in the attached tables 
                                                             i.      Angiotensin-converting enzyme inhibitor or angiotensin 
receptor blocker 
                                                             ii.      β-Blocker 
                                                             iii.     Digoxin 
                                                             iv.     Loop Diuretic and Thiazide 
                                                             v.      Aldosterone antagonist 
                                                             vi.     Opiate 
                                                             vii.     Antidepressant 
 
 
   viii.    Calcium Channel Blockers 
 
 
   Ix.      Cannabinoid 
 
 
   X.       Steroids 
 
 
   XI. Angiotensin receptor neprilysin inhibitor (ARNI) 
 
 
   XII. Mineralocorticoid receptor antagonists 
 
 
   XIII. Hydralazine and Nitrates 
 
 
   XIV. Sodium-glucose co-transporter 2 (SGLT2) inhibitors 
 
 
   XV. Ivabradine 
 
 
   XVI. Statin 
 
 
   XVII. Antiaggregants 
 
 
   XVIII. Anticoagulants 
 
 
   XIX. Antiarhythmics 
 
3. Intervention-related variables: 
a. BA administration: Smart Phone/Table or Telephone 
b. Antidepressant medications name, dose, frequency, duration 
c.  Adapted Brief Medication Questionnaire (for adherence to antidepressant 
medications) 
d. Percentage of completed BA sessions (for adherence to BA treatment) 
e. Antidepressant medication related side-effects (e.g. sexual dysfunction with 
SSRIs)  
f. Antidepressant use in the BA arm 


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g. Psychotherapy use in the MEDS arm 
 
4. Additional Variables 
a. Caregiver information 
b. Providers information: PMD, Cardiologist 
c. Principal Diagnosis at enrollment 
d. PHQ scores 
e. Past treatment for depression 
f. Past antidepressants  
g. Suicide history 
h. History of psychosis, anxiety, or PTSD  
i. 
Heart failure treatment history 
j. 
Time since HF diagnosis (years) 
k. BMI 
l. 
History of Smoking, Alcohol, or Substance use disorder  
m. Allergies (Medications and Non-medications)  
n. Medical co-morbidities  
i. Hypertension  
ii. Diabetes With/Without chronic complications 
iii. Obstructive sleep apnea  
iv. Atrial fibrillation or atrial flutter  
v. Myocardial infarction  
vi. Chronic obstructive pulmonary disease 
vii. Percutaneous coronary intervention 
viii. Coronary artery bypass graft  
ix. Stroke or transient ischemic attack 
x. Implantable cardiac defibrillator  
xi. Valvular disease 
xii. Peripheral vascular disease 
xiii. Hypothyroidism 
xiv. Renal failure 
xv. Liver disease 
xvi. Rheumatoid arthritis or collagen vascular disease 
xvii. Obesity 
xviii. Anemia 
 
4. Assuring completeness of outcome data and Missing data plan: To maximize retention of 
study subjects throughout the follow-up period, we will do the following; First, at recruitment, 
we will ask patients to provide names, addresses, telephone numbers, and email addresses for 2 
close relatives and/or friends, in case the patient cannot be reached. Second, we will send 
subjects text reminders using the IPad/Tablet (or by mail if they do not have access). Third, 
when we cannot reach subjects or their close contacts, we will search for address, obituaries, or 
US Social Security Death Index at https://www.familysearch.org/search/collection/1202535. We 
are implementing the Standards in the Prevention and Handling of Missing Data in 


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Observational and Experimental PCOR (Li et al., 2012). The study staff will make every effort to 
ensure that data collection is complete on all the measures and variables. Having dedicated a 
Research Nurse assigned to each patient and collecting the data primarily using computerized 
method (REDCap) in addition to the study Research Coordinator as supervised by the PI will 
ensure completion. The primary anticipated source of missing data is patients discontinuing the 
study due to dropping out, illness, hospitalization, or death. If a subject discontinues 
participation, the study will document the following information which will be also discussed 
with the DSMB: (1) the reason for discontinuation; (2) who decided the discontinuation; (3) 
whether the discontinuation involves some or all types of participation; (4) information on key 
outcomes will be collected using LOCF. Statistical methods to deal with missing data is detailed 
below in the analytic plan. 
 
5. Identifying and Assessing Participant Subgroups: We explored a number of subgroups based 
on our knowledge from the literature and clinical experience. Antidepressant medication and BA 
psychotherapy may have different impact on depression in AHF patients, given that depressive 
symptom severity as measured by the PHQ-9 is an influential factor in the outcome (Bhatt et al., 
2016). Depressed AHF patients with reduced ejection fraction seemed to benefit significantly 
more from depression interventions compared to usual care (Bekelman et al., 2018). The 
severity of heart failure as measured by the NYHA objective classes could have a differential 
benefit from antidepressants or psychotherapy in depressed patients with heart disease 
(Lesperance et al., 2007). Therefore, we identified three subgroups for which analyses will be 
performed: (a) Baseline PHQ categorized as Moderate (10-14), Moderately Severe (15-19) and 
Severe (20-27) with the exploratory hypothesis that BA will be superior to MEDS in the 
Moderate and  Moderately Severe groups, but not for the Severe group; (b) Heart Failure Type 
defined as reduced ejection fraction ≤40% and >40% with the confirmatory hypothesis that BA is 
superior to MEDS in both groups, and (c) Heart Failure symptom severity using NYHA Objective 
Classes (Class II, III and IV) with the exploratory hypothesis that BA is superior to MEDS in class III 
and IV, but not for class II.  
 
Overview of Study Protocol/Procedures 
1. The study will recruit from heart failure patients admitted to the inpatient hospital at Cedars-
Sinai Medical Center as well as from heart failure patients presenting to the outpatient program 
of the Smidt Heart Institute at Cedars-Sinai Medical Center. At both sites, when a patient is 
identified to have the diagnosis of Heart Failure, the inpatient or outpatient nurse will screen 
the patient for depressive symptoms using the PHQ-2. If the patient is answers positively to one 
of the two questions, PHQ-9 will be administered. If the score is ≥10, the nurse will notify the 
treating physician. The treating physician will ask the patient if they have any interest in taking 
part in the proposed study and/or would like to learn more about it. If the patient agrees, a Co-
Investigator (Co-I) will be assigned to the patient to educate the patient and the caregiver about 
depression and treatment options including alternatives, risks, and potential benefits. The 
patient and the caregiver will be informed about the study and will be given a blank copy of the 
informed consent with the patient to read and consult with loved ones if necessary. A blank 
caregiver informed consent form for the data collection about the caregiver burden will be also 
given.  
2. The PI or Co-I/designee will meet with the patient for informed consent. If the patient 
consents to the study, the patient will be given a copy of the signed consent. Data on the 
caregiver burden will be collected only after the caregiver signs their informed consent form to 


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participate. If the patient does not agree to the study, they would continue treatment without 
undue influence of their decision on their medical care. The meeting will be held either in-
person or via an approved e-consenting procedure. 
 
3. Co-I/designee will administer the MINI International Neuropsychiatric Interview for the DSM-
5 (MINI 7.02) brief structured interview to diagnose Major Depressive Disorder, Persistent 
Depressive Disorder (Dysthymia), and Depressive Disorder Unspecified, and to rule out Bipolar, 
Psychotic, and Substance-induced Disorders.  
4. Co-I/designee will check whether the patient meets the inclusion and exclusion criteria 
detailed in section D.10.a. This will include using the Montreal Cognitive Assessment (MoCA)64, 
to exclude depressed AHF patients with significant cognitive impairments if the MOCA score is < 
2365 as well as confirming with the treating physician that the patient’s condition is not terminal, 
i.e., life expectancy is > 6months. 
5. If the patient meets criteria, the patient will be enrolled in the study and assigned a Research 
Nurse. 
6. The Research Nurse will collect all the variables from the patient, caregiver, and the medical 
record including information on baseline co-morbidities. 
7. The Research Nurse or Designee will then randomize the patient into BA or MEDS. 
8. The Research Nurse will train the patient and the caregiver on the use of their own Smart 
Phone/iPad/Tablet to collect outcome measures. The patient will take the study Patient-
Reported Measures (PHQ-9, SF-12v2, and KCCQ) at baseline on their own Smart 
Phone/iPad/Tablet using the REDCap interface66. If the patient does not have access to or is 
unable to use a Smart Phone/iPad/Tablet, paper and pencil forms will be used. The Research 
Nurse will authorize an incentive payment of $100 for Baseline Measures and $25 for the 
caregiver burden measure.  
9. If the patient is randomized to the BA arm, the Research Nurse or designee will be assign the 
patient a BA Therapist who will provide BA following the BA guidelines described below, starting 
with an introductory treatment session, preferably in the presence of the patient’s caregiver, 
delivered using their own Smart Phone/iPad/Tablet in order to work through any future user 
problems, followed by 12-weekly 50-minute sessions using their own Smart Phone/iPad/Tablet. 
A visit is considered missed, if it doesn’t occur once a week (anytime within that week is 
acceptable as it is based off the patient’s schedule). If the patient does not have access to or is 
unable to use a Smart Phone/iPad/Tablet, a telephone will be used. After 3 months, BA sessions 
will change to monthly sessions for three months. Contact thereafter will be on as needed basis.  
10. If the patient is randomized to the MEDS arm, the Research Nurse or designee will be assign 
the patient a Care Manager who in collaboration with the treating team, and taking into 
account the patient/caregiver input, will coordinate starting the patient on antidepressant 
medication following the Collaborative Care Model46 (CCM) guidelines described below. The role 
of the Care Manager is to oversee the antidepressant medication management care that the 
patient will receive, and to liaison between the patient, the treating physician, and the 
psychiatrist involved in the patient’s care. Antidepressant medications will be maintained 
throughout the course of the study. The Care Manager will maintain contact with the 
patient/caregiver on a weekly basis in the first 12 weeks, then on a monthly basis for 3 months, 
and then on as needed basis thereafter. For the 12 weekly visits, A visit is considered missed, if it 
doesn’t occur once a week (anytime within that week is acceptable as it is based off the 
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11. After starting treatment, the integrity of the delivery of BA or MEDS according to the 
research protocol guidelines will be supervised and monitored by study Co-I who will on a 
quarterly basis: (1) review each patients’ medical records and contact the BA Therapists and 
Care Managers, to ensure the integrity and adherence to the research protocol guidelines. 
12. At the Patient-reported outcome measurement points of 3, 6, and 12 months from starting 
treatment, the Research Nurse will contact the patient to take the Patient-Reported Follow-up 
Measures on their own Smart Phone/iPad/Tablet or by Mail and authorize incentive payment of 
$50 each time for Follow-up Measures and $10 each time for the caregiver burden measure.  
13. At the Morbidity and Mortality outcome measurement points of 3, 6, and 12 months from 
starting treatment, the Co-I/Designee will collect the data on Morbidity (ED visits, readmissions, 
total days in the hospital), and Mortality.  
14. All medications (dose, frequency, and duration), medication side effects, medication-
interactions will be collected and recorded by the Research Nurse. 
15. All treatment discontinuations and protocol deviations will be recorded in detail by the study 
Research Coordinator. Whereas participant drop-out and added interventions are important in 
any community-based RCT, in a pragmatic study these factors are extremely salient to the 
understanding of the comparison between effective interventions.  Adherence to the assigned 
intervention will be measured directly by tracking missed “visits” and monitoring 
“missed/inaccurate medication use”.  Furthermore, we will report information about the 
number of BA patients who are subsequently prescribed antidepressant medications and MEDS 
patients who actively enroll in psychotherapy.   
 
Summary of the Timeline, Sample Size, and Recruitment Plan: The study will run for three 
years and aims at analyzing data on 300 subjects (150 in each group). Given a 28% dropout rate, 
the study will recruit 416 patients (208 patients per arm). After 2 months of initiation phase 
including staff training, the study will recruit patients in a rolling fashion for 20 months. The 
expected recruitment rate is 20-21 patients per month (10-11 patients for each group). The 
study will collect follow-up data after 12 months, then 2 months will be spent on data analysis 
and manuscript preparation. 
 
 
Section 5.0. 
 
Selection and Withdrawal of Subjects 
 
The study population will be selected from all patients at Cedars-Sinai Medical Center who are 
admitted with heart failure and all patients presenting to the outpatient program of the Smidt 
Heart Institute at Cedars-Sinai Medical Center. The study population will consist of AHF patients 
(as evidenced by NYHA class II, III, or IV), with life expectancy > 6months (as evidenced by 
confirmation with the treating physician), who are depressed (as evidenced by a PHQ-9 score of 
≥10, with a confirmed DSM-5 Depressive Disorder diagnosis (as evidenced by the MINI 7.02), 
with no imminent danger to self or others (as evidenced by , not experiencing cognitive 
impairments (as evidenced by a MOCA score of ≥23) or Bipolar/Psychotic/Substance-induced 
Disorders (as evidenced by the MINI 7.02), and are not being actively treated for depression (as 
evidenced by not receiving antidepressants, psychotherapy, or both). The inclusion and 
exclusion criteria are detailed in Table 1. 
Table.                          Inclusion Criteria 
Exclusion Criteria 


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1. HF New York Heart Association classes: II-IV. 
2. Life expectancy of more than 6 months. 
3. PHQ-9 score ≥10. 
4. Diagnosis of Major Depressive Disorder, 
Persistent Depressive Disorder (Dysthymia), 
and Depressive Disorder Unspecified, as 
confirmed by the MINI 7.02. 
1. Imminent danger to self or others. 
2. Cognitive impairments with a MOCA score of 
< 23. 
3. Bipolar, Psychotic, and Substance-induced 
Disorders. 
4. Patients in active treatment of depression 
who 
are 
already 
on 
antidepressants, 
psychotherapy, or both. 
 
Recruitment and Enrollment: We will recruit patients who present to the inpatient and 
outpatient heart failure programs at Cedars-Sinai Medical Center (CSMC) who have a diagnosis 
of heart failure (Class II-IV) and screen positive for depression using a score ≥10 on the Patient 
Health Questionnaire (PHQ) for depression. We intend to use an additional inpatient IRB 
approved and HIPAA compliant recruitment tool called the ‘Deep 6 Cohort Builder’ a software 
application designed to efficiently and effectively, identify and recruit eligible patients for 
clinical trials. Additionally, patients will be recruited from psychiatry consults ordered on AHF 
patients with depression. The study will be promoted via printed flyers, which will be posted on 
CSMC campus and physician newsletters. Co-Is will be responsible for informational sessions 
about the study protocol with cardiologists and internists on medical staff at Cedars-Sinai as well 
as those in the community as they have done before during the $10 million BEAT-HF study at 
CSMC. 
 
 
 
Table. Recruitment 
Patients 
Caregivers 
Estimated number of potentially eligible study participants: The Cedar-Sinai inpatient 
heart failure program treats 1,750 patients per year (latest figure from 2017) yielding 
3,062 potentially eligible study participants in the course of 21 months of enrollment. 
Additionally, the outpatient program treats 2,500 patients per year, yielding another 
4,375 potentially eligible study participants in the course of 21 months of enrollment. 
7,437 
7,437 
Total number of study participants expected to be screened: 15% of participants will be 
excluded from screening due to critical medical status (Thoma, 2010). 
6,321 
6,321 
Total number of study participants expected to be eligible of those screened: 48% (3,034) 
are expected to screen positive for depression8.  
3,034 
3,034 
Target sample size: We plan to enroll 416 study participants (15% of patients approached) 
with an estimated maximum dropout rate of 28%, in order to have 300 study participants 
(150 in each arm) for final data analysis. 
416 
416 
If applicable, total number of practices or centers that will enroll participants: 
2 
Projected month first participant enrolled (month after project initiation): 
11/2018 
Projected month last participant enrolled (month after project initiation): 
6/2020 
Projected rate of enrollment (anticipated number enrolled per month of enrollment 
period): 
20-21/month  
Estimated percentage of participant dropout: 
28% 
 


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Retention: We focused on improving our retention plan, and estimate a dropout rate of 28% 
using the following interventions especially the ones that our research team that conducted the 
BEAT-HF study had mastered: 
1. If the patient meets inclusion criteria, the patient will be enrolled in the study and assigned a 
Clinical Research Nurse (CR-RN) who will perform their role according to the model described 
above. Retention in this study is largely connected to relationship building with the CR-RN who 
is expected to be available, reachable, resourceful, and will maintain frequent contact with all 
patients according to the study procedures described above.  
2. We will adopt a risk identification system with pre-planned retention strategies as detailed by 
Zweben, Fucito, and O’Malley in 2009, and summarized in the table below (Zweben, 2009).  
3. We will consider the implementation of evidence-based models such as AASAP (anticipate, 
acknowledge, standardize, accept, plan), to improve retention of patients (Fisher, 2012). 
4. We will take more of an engagement approach toward consenting patients rather than mere 
retention, as described in the engagement efforts by the Clinical Trials Transformation 
Initiative’s (CTTI) (Patrick-Lake, 2018). 
 
This study does not propose any exclusion criteria based upon gender or minority status. 
Subjects from both genders and in all ethnic and racial categories will be actively recruited. The 
ethnic/racial distribution in the Cedars-Sinai Medical Center demographic catchment area is 
approximately 10% African-American, 10% Asian, 40% White/non-Hispanic, and 40% Hispanic. 
We expect a recruitment pool in roughly the same percentages. All of our recruitment efforts 
will clearly state that we encourage women, minorities and those from disadvantaged 
backgrounds to contact the research team for more information about participating in research. 
Although depression is more common among females, we intend to split enrollment equally 
between the genders. Balancing gender (50% / 50%) in the sample size maximizes the chance of 
detecting a gender difference if one is present, with the smallest number of cases. 
 
Inclusion of Children: Because some medical inpatients are children ages 18-21, we may enroll 
them in our study. By definition (CFR46.102), “children are persons who have not attained the 
legal age for consent to treatments or procedures involved in the research, under the applicable 
law of the jurisdiction in which the research will be conducted.” However, both the State of 
California and our local IRB allow subjects over 18 years of age to provide legal 
consent to participate in research. Individuals under the age of 18 are being excluded from this 
research because the purpose of the project is to validate a measure of depressive symptoms 
designed for an adult population, developed on individuals aged 18 years or older. 
 
Estimated Final Racial/Ethnic and Gender Enrollment Table: We plan on enrolling 416 patients 
(dropout rate of 28%) in order to achieve a sample size of 300 patients for data analysis. 


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Section   6.0 
 
Treatment of Subjects 
 
There is currently no standard of care for treating depression in patients with heart failure. 
Behavioral Activation Psychotherapy (BA):  
Evidence of Effectiveness and Widespread Use: BA is an evidence-based psychotherapy with 
more than 25 randomized clinical trials showing effectiveness in depression. Past meta-analyses 
and reviews established BA as an effective treatment and viable alternative to other 
psychotherapies. BA effects are comparable to CBT and antidepressant medication. BA was 
shown to be both feasible and effective in cardiac patients (Busch, 2017). Moreover, BA had a 
positive impact on cardiac caregivers, and it may be a non-pharmaceutical treatment of choice 
in cardiac patients.  
Intervention: The patient is introduced to BA using a one 50-minute Introductory BA Treatment 
Session, followed by 12 weekly 50-minute Outpatient Treatment Sessions, then 3 monthly 50-
minute Outpatient Maintenance Sessions, preferably attended by the patient’s identified 
caregiver. Contact thereafter will be on as needed basis. A typical BA session will last 50 minutes 
and include a review of the previous session and completed daily monitoring record forms, an 
in-depth discussion of life areas and value, and verbal reinforcement of activity engagement. 
The patient assignment will be to chart progress of activity engagement by duration, frequency, 
self-reported level of mastery, review of engagement in 3-5 activities considered rewarding and 
important and will provide support and encouragement. Based on input from our 
patient/caregiver group, the BA therapist will provide encouragement to participate in an in-
person or online “Meetup” /similar group for the activity of the patient’s choice. All sessions will 
be delivered via Telemedicine (Smart Phone/iPad/Tablet), or telephone calls in case of lack of 
access or inability to use the equipment. The therapist will be a licensed mental health 
practitioner of any level except doctoral level to enable implementation and dissemination in a 
variety of settings. The BA sessions will be in accordance of the revised treatment manual for 
depression69. The therapists will receive a 2-hour training on the BA application study protocol, 
 
Ethnicity 
 
Total (N) 
Race 
Not Hispanic or Latino 
Hispanic or Latino 
 
Male (N) 
Female (N) 
Male (N) 
Female (N) 
American Indian/Alaska Native 
3 
2 
 
 
5 
Asian 
20 
21 
 
 
41 
Hawaiian/Pacific Islander 
3 
3 
 
 
6 
Black or African American 
16 
15 
3 
3 
37 
White 
124 
124 
25 
25 
298 
More than one race 
14 
15 
 
 
29 
Total (N) 
180 
180 
28 
28 
416 


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as well as BA theory, technique, and evidence and will also receive weekly 1.5-hour supervision 
to ensure adherence to study protocol (all by BA expert). 
Antidepressant Medication Management (MEDS):  
Evidence of Effectiveness and Widespread Use: Evidence has been well established for the 
effectiveness of antidepressants in patients with advanced medical illness43. MEDS delivered 
using the Collaborative Care Model (CCM) has been shown to lead to lower depression severity, 
less functional impairment and greater HRQoL at 3, 6 and 12-months follow-up. CCM is a real-
world, flexible, and personalized treatment approach that involves active engagement of the 
patient, treating physician, and psychiatrist, highly coordinated by a non-physician Care 
Manager. MEDS using CCM has been successfully implemented among depressed inpatients 
with cardiac disease and has been shown to enhance patient care after discharge from inpatient 
to outpatient settings, which commonly incorporates telemedicine, with high effectiveness.  
Intervention: The MEDS intervention will be delivered using the evidence-based Collaborative 
Care Model (CCM) for depressed adults using a Care Manager. A Care Manager can be a nurse, 
nurse practitioner, physician’s assistant, or social worker. After randomization to MEDS, the 
Care Manager will meet with the patient in a one 50-minute Introductory Antidepressant 
Medication Treatment Session, to educate the patient about depression and medication options 
and collect information on the patient/caregiver preferences/input. The meeting will be either 
conducted in person or through approved online meeting The Care Manager will then 
coordinate the collaboration and communication between the psychiatrist and the treating 
physician, resulting in starting the patient on antidepressant medication by the treating 
physician according the CCM rules and study protocol MEDS guidelines. The Care Manager will 
maintain contact with the patient/caregiver on a weekly basis in the first 12 weeks, then on a 
monthly basis for 3 months, and then on as needed basis thereafter. The Care Manager will 
communicate questions, problems, medication changes between the patient, the treating 
physician and the psychiatrist. The Care Manager will encourage patients to adhere to 
antidepressant medication treatment, will inform the treating physician and the psychiatrist of 
the patient’s progress or lack of thereof, and will maintain contact with the psychiatrist to 
review progress of the patient’s treatment plan and the psychiatrist will be available for direct 
consultations for patients who are not progressing. For the purpose of this study, MEDS will be 
initiated or continued according to the following requirements: Antidepressant medications 
from any class could be selected as long as the patient is maintained on the therapeutic dose 
according to the APA guidelines, and patient/caregiver input is always taken into account, in 
order to personalize MEDS. Handouts/ and brochures will be provided to the patient and the 
patient’s primary care provider including guidelines for choosing antidepressants in depressed 
AHF patients. These guidelines include drug-drug interactions with heart-related and other 
medications that the patient may be prescribed. The Care Managers will receive a 2-hour 
training on the MEDS application study protocol, as well as CCM technique, and evidence and 
will also receive weekly 1.5-hour supervision to ensure adherence to study protocol by Co-I. 
 
 
Section 7.0  
 
Assessment of Efficacy 
 
This is a comparative effectiveness pragmatic trial, i.e., it is not a trial to establish efficacy of 
an intervention, but to determine which intervention is more effective in the real world. 
 


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Overview: Patient-reported outcomes will be collected at pre-determined timepoints using 
questionnaires that will be administered online using the REDCap interface through the use of a 
smart phone/tablet, or by pencil and paper by mail or collected by the Research Nurse. The 
primary outcome measure will be patient self-reported depressive symptom severity using PHQ-
9 at 6 months from the start of treatment. The secondary outcomes will be self-reported 
general physical and mental HRQoL (SF-12v2), heart failure-specific HRQoL (KCCQ), caregiver 
burden measure, in addition to Morbidity (as evidenced by ED visits, readmissions, and total 
days in the hospital), and Mortality rate, at baseline and after 3, 6, and 12-months from the start 
of treatment. The following outcome measures will be analyzed in all study participants:  
Depressive Symptom Severity: The 9-item patient-reported Patient Health Questionnaire (PHQ-
9).  
Physical and Mental HRQoL: The 12-item Short Form Medical Outcomes Study SF-12v2 for 
assessment of Physical and Mental HRQoL. 
Heart Failure-Specific HRQoL: The 23-item patient-reported Kansas City Cardiomyopathy 
Questionnaire (KCCQ) which is the most sensitive, specific and responsive to HRQoL for heart 
failure.  
Caregiver Burden: The Caregiver Burden Questionnaire for Heart failure (CBQ-HF) is a 26-item 
self-reported scale that measures caregiver burden on a Likert severity scale of 4 domains of 
physical, emotional/psychological, social and lifestyle burdens within a 4-week recall period.  
Patient/caregiver disadvantageous outcomes of Morbidity (as evidenced by ED visits, hospital 
readmissions, total days in the hospital), and Mortality each interval of 3, 6, and 12-months after 
starting treatment.  
Additional outcomes:  Adapted Brief Medication Questionnaire will be used to assess adherence 
to the intervention in patients after 3, 6, and 12 months of starting treatment by the Research 
Nurse. Information about adherence to BA in the BA arm patients will be collected by the 
Research Nurse from the BA therapists after 3, 6 and 12 months of starting BA treatment and 
will reported as percentage of completed BA sessions. For adverse events, all deaths from all 
causes and self-harm will be recorded and will be reported to the IRB as detailed in the Human 
Protection section. 
 
 
Section 8.0   
 
Assessment of Safety 
 
Protection of Human Subjects 
This Human Subjects Research meets the criteria for Section 5, titled “Human Subjects Research 
Policy, from the “Supplemental Grant Application Instructions for All Competing Applications 
and Progress Reports.” (a component of the PCORI funding application) 
 
 
Risks to the Subjects 
1. Risks to Human Subjects Involvement, Characteristic and Design: The study is a randomized 
controlled trial (RCT) that will enroll 300 patients with heart failure who screened positive for 
depression using the PHQ-9 score of 10 or above. The study aims to compare the effectiveness 
of Behavioral Activation (BA) vs. antidepressant medication management (MEDS). We will 
randomize patients using the MS Excel random number generator to ensure that there is an 
equal distribution of participants in the study groups. We will measure changes in self-reported 
depressive symptom severity, general physical and mental HRQoL, heart-failure-specific HRQoL, 


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and caregiver burden. We will also measure Morbidity (as evidenced by ER visits, readmissions, 
and total days in spent in the hospital) as well as Mortality. Research material will be collected 
specifically for this research project and will include interview data, patient-rated and clinician 
scales, and physical and laboratory examinations. All subjects will be assigned a unique code 
number to protect personal privacy. All data and samples will be stored according to code 
number and the only personal identifiers that will be associated with a sample are sex, age, and 
ethnicity. The code (with linkages) and any identifying data will be kept in a password-protected 
file located in a room separate from the other study files. The hard copy data files 
(documentation obtained from interviews, diagnostic procedures and testing) will be stored in 
the CSMC Psychiatry Research Offices. Digital files will be maintained by the onsite data 
manager on a secured computer. Computer entries of data will be identified by code only. 
 
Data Management: Data will be collected and recorded into a database system. Each record will 
include the subject’s unique identifying number, demographic information, visit type, visit date, 
total scores and individual item scores on each of the measures. The Data Management 
Coordinator (study Research Coordinator) will review data integrity in terms of accuracy (using 
error alerts) and completion of all items on a daily basis. A record of the data will be printed for 
each visit and will be kept under double lock and key at the research data storage bop in the 
Psychiatric Research Division. An electronic backup copy of the data will be saved on the secure 
server upon data entry, in addition to weekly CD disks. A separate data copy on CD will be 
stored on a weekly basis offsite under double lock and key to enable data retrieval in the event 
of a catastrophe preventing access to the facility or the data. A backup CD will be created on a 
quarterly basis. The PI will oversee compliance with the procedures set forth. The database will 
be designed and managed by the Cedars-Sinai Biostatistics and Bioinformatics Research Center 
(BBRC)– a group that provides support for clinical trials throughout CSMC. Reports generated 
from the database will provide a basis for ongoing monitoring of subject accrual and retention, 
as well as completeness of data. These will be used to identify and resolve problems that may 
arise. Back-up copies of the database will be created daily per CSMC EIS standard protocol for all 
hospital-wide data servers. Access to data will be restricted to the study team but the code 
linking subject identification # to patient health information (PHI) will be restricted to only the PI 
and the study Research Coordinator. Data will only be released to a third party in an emergency 
medical situation or when required by law. 
 
2. Risk due to Study Procedures: Minimal psychological or emotional discomfort may arise due to 
the screening procedure and interviews /questionnaires conducted at each study visit. The 
instruments administered during the course of the study pose no specific risks or discomforts 
beyond those of a standard clinical interview situation such as feeling upset at a review of the 
psychiatric status or experiencing boredom or fatigue. There are questions that will be asked 
that may cause some subjects to feel uncomfortable. However, it will always be emphasized 
that all questions are optional, and participation is voluntary. Each subject will be screened for 
suicidal ideation and intent prior to study entry and any subject who is actively suicidal will be 
excluded from study participation and referred for appropriate care. The subject will be 
reminded that he/she may always decline to participate in this study and he/she may 
discontinue at any time. 
 
3. Potential Risks: Behavioral activation will have minimal risk to the patients as study 
participation consists of education, learning, and completing a number of self-administered 


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questionnaires and extracting data from a patient’s medical chart. Patients using antidepressant 
may experience side effects from the medication, including bleeding risk, bradycardia, 
hypertension, electrocardiogram (EKG) changes, reduced cardiac conduction and output, 
arrhythmias, and sudden death. If patients experience these symptoms, they will be asked to 
stop using the antidepressant. To minimize the side effects, we will start with a low dose and 
work our way to the therapeutic dose with closed-monitoring for adverse effects mentioned 
above. 
 
4. Adequacy of Protection against Risks: All patients meeting the eligibility criteria will be 
enrolled in the trial. The patient will receive an Informed Consent detailing the protocol, 
including research procedures and requirements for follow-up, as well as the risks and benefits 
of the study participation. The PI, Research Coordinator, and the research support team contact 
information will appear on the Informed Consent. Subjects will be informed that study 
participation is completely voluntary and that they can withdraw at any time. Once all data 
collection is complete, patient names will be replaced with a randomly-assigned study 
identification number for the purposes of de-identification. All identifiable data will be kept on a 
password protected file on a stationary desktop computer and kept separate from the patient 
medical record and other study data. The computer contains firewall and real-time anti-virus 
and anti-spyware protection that is kept up-to-date. 
 
B. Vulnerable Populations: The study does not involve pregnant women, human 
fetuses/neonates, or prisoners.  
 
C. Data and Safety Monitoring Plan (DSMB): Given randomization and according to PCORI 
standards, a DSMB will be enacted to ensure safety monitoring of patients. The DSMB will be 
independent from the research team at CSMC.  As specified by PCORI, the DSMB will have an 
appropriate Chair and staff to monitor study safety, minimize research-associated risk, review 
and report adverse events to the IRB. DSMB will be composed of senior investigators with 
experience with intervention studies in the community as well as studies of depression. The 
primary goals of the DSMB are as follows: 1) To monitor and advise on scientific and ethical 
issues related to the study implementation for the protection of human subjects, 2) To review 
and approve the protocol and subsequently conduct annual reviews to determine whether 
participant safety has been adequately safeguarded, 3) To review procedures and decisions 
regarding the adequate protection of specific participants when investigators break protocol 
because of adverse events or clinical deterioration, 4) To review progress to see that enrollment 
goals have been met, 5) To monitor and advise on ethical issues related to adverse events, 6) To 
oversee the confidentiality of data, and quality of data collection, management, and analysis, 7) 
To recommend, if necessary, discontinuation, modification, or termination of the study based 
upon emerging data (in the study and literature) and evaluation of risk/benefit ratio, and 8) 
When possible, to serve as the final arbiters of whether individuals should be removed from the 
study. Although our treating clinicians are empowered to take whatever immediate action is 
necessary to safeguard the welfare of individuals, the DSMB will be called upon whenever 
possible to render judgments in the advent of serious suicidal intent or clinical deterioration. 
The DSMB will meet once per year, as well as needed. In advent of emergencies, the DSMB will 
meet via teleconference. For each meeting, the DSMB will first meet in an open session 
attended by the PI. The group will first review the research protocol and plans for data and 
safety monitoring. This group will be used to review any problems in implementing the safety 


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plan and for suggesting any necessary modifications to the safety plan. The DSMB will then meet 
in a closed session for the purpose of reviewing emerging trial data. Confidentiality will be 
maintained by providing data without any identifying information to the committee. At the 
conclusion of the meeting, the DSMB will make recommendations to the PI and the Internal 
Review Board (IRB). The DSMB will make recommendations concerning the continuation or 
conclusion of the study. The DSMB will monitor both safety and outcome data as part of the 
yearly review. Outcome evaluations will include review of data quality and timeliness, 
participant recruitment, accrual and retention, and review of interim "masked" outcome results 
on primary and secondary measures. Safety evaluations will include review of adverse events 
and symptom measures for each participant. The DSMB will further consider external factors 
such as scientific and therapeutic developments that may impact the safety or the ethics of the 
study. All serious adverse events will be reported to the members of the DSMB and the IRB 
according to CSMC IRB policies and procedures guidelines. A report of all non-serious adverse 
events will be provided to the DSMB yearly. PCORI will be informed of all actions taken by the 
IRB as part of the continuing review (see appendix D). 
 
D. Emergency Procedures: Safety checks and suicide risk assessment will be performed at each 
point of contact and enrolled patients in both groups will be given an emergency phone number 
to contact the study staff in case of a psychiatric or medical emergency (given the FDA warning 
of suicide risk following starting depression treatment). An on-site psychiatrist will provide 
emergency care for patients with increased suicide risk and suicidal behaviors. In-between visits; 
24-hour emergency coverage is provided by a psychiatrist on-call for research subjects. All 
subjects are provided with the PI emergency contact number. Emergency care will be provided 
on-site for injuries arising due to the protocol only. If further treatment for a research-related 
injury is needed, it will be provided at no cost. 
 
Section 9.0. 
   
Statistics 
 
Sample Size and Power:  
Aim 1: To compare the effectiveness of BA vs. MEDS, for depressed AHF patients.   
Power Considerations: The main hypothesis to be tested is whether there is a difference in the 
change of PHQ-9 from baseline to 6 months between two groups (BA and MEDS).  
The standard deviation for the two groups was estimated equal to 5.42 based on previous 
literature (Ekers, 2014) using the 95% confidence interval width asymptotic formulae for the 
difference between two change score 
means at 6 months, assuming the standard 
deviations were equal between groups. We 
assume a minimal detectable standardized 
mean difference (mean difference/pooled 
standard deviation) for PHQ-9 between 
arms (BA and MEDS) equal to 0.42 (Ekers, 
2014) that corresponds to a minimal 
detectable mean difference of 2.27 in PHQ-
9 score units if we use the estimated 
standard 
deviation. 
Under 
these 
assumptions, the required sample size for 
each group is 90 (Total = 180) patients using 5% significance, 80% power, and two-sided two 
Table 1. Minimum detectable difference for 
secondary endpoints in Aim 1 with 80% power at 
5% significance level 
Endpoint 
Standard 
Deviation 
Minimum 
Detectable 
Difference 
SF-12v2 (Physical) 
3.28 
1.4 
SF-12v2 (Mental) 
4.86 
2 
KCCQ (Quality of Life) 
18.08 
7.6 
CBQ-HF 
(Emotional Well-being) 
17.90 
7.5 


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sample equal-variance t-test. We argue that 2.27 PHQ-9 score units is a clinical meaningful 
difference because Richards (2016) uses 1.9 in PHQ-9 score units as equivalence margin for their 
non-inferiority trial between CBT and BA. 
Table 1 presents the minimum detectable difference assuming a sample size of 90 patients for 
each group for the secondary endpoints SF-12v2, KCCQ and CBQ-HF with standard deviations 
estimated based on previous literature (Seerija, 2015 and Trivedi, 2016). For SF-12v2 and CBQ-
HF, correlation between pre- and post- measures were assumed equal zero as a conservative 
estimate. For KCCQ, the largest 95% confidence interval width at 6 months was used similarly to 
PHQ-9. 
Statistical Considerations: Descriptive measures followed by spaghetti plots will be presented.  
Multivariable Generalized Additive Model for Location, Scale and Shape (GAMLSS) (Rigby et al., 
2005) will be fitted considering baseline response, time, treatment, and interaction between 
time and treatment as covariables with random effects describing repeated measures at 3, 6, 
and 12 months after treatment. In addition, admitting diagnosis, medical comorbidities, and 
other demographic, clinical, or utilization variables will be considered as control covariables. 
Time will be modeled as continuous variable using penalized cubic splines (Eilers et al., 1996) to 
avoid overfitting. Model diagnostics will be performed based on analysis of and Worm-plots (van 
Buuren et al., 2001).  All tests of hypotheses will be two-sided with a significance level of 5%. 
Calculations will be performed using R, version 3.2.5 (R Core Team, 2016). 
 
Aim 2: To compare the impact of BA vs. MEDS on Morbidity (as evidenced by ED visits, hospital 
readmissions, total days in the hospital), and Mortality among depressed AHF patients. 
 Power Considerations: The main hypothesis to be tested is whether there is difference for 
number of readmissions and ED visits. Baseline 
response rate and mean of exposure time are 
assumed equal to 1. Table 2 presents the minimum 
detectable response rate ratio (RR) using Poisson 
regression as function of R2 for regression of group 
variable on control variables with 80% of power at 5% 
significance (Freedland et al, 2016; Moraska et al., 2013). 
Statistical Considerations: Recurring readmissions and ED visits times will be modeled with 
Mortality using Jointly Frailty Models (Rondeau et al., 2007) as a function of treatment. Smooth 
parameters will be estimated based on Shared Frailty models. The Length of Stay will be 
modeled as function of treatment using GAMLSS. Covariables as in Aim 1 will also be considered.  
All tests of hypotheses will be two-sided with a significance level of 5%. Calculations will be 
performed using R, version 3.2.5 (R Core Team, 2016). 
Since we expanded our recruitment to the outpatient program, we would like to expand the 
sample size beyond the power calculation to 150 for each group (Total = 300 patients) to bring 
the study size close to equivalent heart failure studies and enable subgroup analyses. We 
estimate a dropout rate of 28%. Therefore, we plan on enrolling 416 patients (15% of to be 
approached eligible patients) in order to achieve a sample size of 300 patients for data analysis.  
 
Table 
2. 
Minimum 
detectable 
response RR for Aim 2 
R2 
0.2 
0.4 
0.6 
0.8 
Response 
RR 
1.57 
1.68 
1.88 
2.43 


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Analytic Plan  
The primary outcome is Depressive symptom severity as measured by the PHQ-9 score 
(quantitative continuous variable) at 6 months.  The secondary outcomes measured at 3, 6 and 
12 months are: General physical and mental quality of life as measured by the SF-12v2 score 
(quantitative continuous variable), Heart failure-specific quality of life as measured by the KCCQ 
score (quantitative continuous variable), Caregiver burden as measured by the CBQ-HF score 
(quantitative continuous variable), Morbidity as measured by number of ED visits (quantitative 
discrete variable), readmissions (quantitative discrete variable), and total days in the hospital 
(quantitative discrete variable), and Mortality (qualitative nominal variable). 
 


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The covariables that will be considered are: Age, sex, race, ethnicity, marital status, 
employment, educational level, insurance, recruitment site (Inpatient or Outpatient), Ejection 
Fraction, NYHA Class, Medical History as detailed in the attached tables, Medications especially 
Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, β-Blocker, Loop 
Diuretic, Aldosterone antagonist, Opiate, and Antidepressant. 
 
Aim 1: Summary statistics will be presented as percentages in the case of categorical variables 
and as means with standard deviations, medians with interquartile ranges in the case of 
continuous variables. Analysis of PHQ-9 as well as other outcomes questionnaires will be 
performed using multivariable Generalized Additive Model for Location, Scale and Shape 
(GAMLSS)83 considering baseline response, time, treatment, and interaction between time and 
treatment as covariables with random effects describing repeated measures at 3, 6, 12 months 
after treatment. Time will be modeled as continuous variable using penalized cubic splines84 to 
avoid overfitting.  Random effects will also be added to address the correlation among patients 
at the same site. 
Missing data will be treated as missing at random (MAR) using multivariate imputation by 
chained equations (van Buuren, 2007). The dataset will be imputed with values drawn from a 
distribution specifically modeled for each covariable, such that between 5 to 10 different 
imputed datasets will be created. Imputed values will be checked if are plausible as diagnostics. 
The outlined statistical analysis will be performed for each imputed dataset and results will be 
pooled according to Rubin (1987). In addition, a sensitivity analysis under the assumption of 
missing not at random (MNAR) will be performed using mixture models assuming various 
scenarios to assess the robustness of the results. In addition, covariables described above will be 
considered in the regression models. Model diagnostics will be performed based on analysis of 
residual plots and Worm-plots. 
 
Aim 2: Analyses of recurring readmissions and ED visits times will be modeled with Mortality 
using Jointly Frailty Models as a function of treatment to model non-ignorable missing data 
generated by death. Time until death will be defined as the time between index time and the 
event. Time between recurring events such as ED visits and readmissions will be defined as the 
time between the last event and the next event. Individuals who are lost to follow-up are 
censored at the time of the last known contact. Smooth parameters will be estimated based on 
Shared Frailty models. The total days in the hospital will be modeled as function of treatment 
using Poisson regression and variations available in GAMLSS with random effects describing 
repeated measures.  
In the HTE analysis, the presence of interaction between treatment and subgroup factor 
(Baseline PHQ, Heart Failure Type using Ejection Fraction, Heart Failure symptom severity using 
NYHA Classes) will be tested in the regression model (Wang et al., 2007).  If the interaction is 
statistically significant, then the main analysis will be repeated for each group separately. 
Multiplicity will be addressed with Holm correction.    
In the per-protocol analysis, propensity scores for adherence will be estimated as function of 
Percentage of completed BA sessions (BA arm) and Adapted Brief Medication Questionnaire 
(MEDS  arm) at each time point and incorporated in the final models as inverse-probability 
weights. 
All tests of hypotheses will be two-sided with a significance level of 5%. R version 3.2.5 will be 
used for calculations. 
 


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Section 10.0   
 
 
Ethical considerations relating to the trial 
 
Risk due to Study Procedures:  Minimal psychological or emotional discomfort may arise due to 
the screening procedure and interviews /questionnaires conducted at each study visit. The 
instruments administered during the course of the study pose no specific risks or discomforts 
beyond those of a standard clinical interview situation such as feeling upset at a review of the 
psychiatric status or experiencing boredom or fatigue. There are questions that will be asked 
that may cause some subjects to feel uncomfortable. However, it will always be emphasized 
that all questions are optional, and participation is voluntary. Each subject will be screened for 
suicidal ideation and intent prior to study entry and any subject who is actively suicidal will be 
excluded from study participation and referred for appropriate care. The subject will be 
reminded that he/she may always decline to participate in this study and he/she may 
discontinue at any time. 
 
Potential Risks: Behavioral activation will have minimal risk to the patients as study participation 
consists of education, learning, and completing a number of self-administered questionnaires 
and extracting data from a patient’s medical chart. Patients using antidepressant may 
experience side effects from the medication, including bleeding risk, bradycardia, hypertension, 
electrocardiogram (EKG) changes, reduced cardiac conduction and output, arrhythmias, and 
sudden death. If patients experience these symptoms, they will be asked to stop using the 
antidepressant. To minimize the side effects, we will start with a low dose and work our way to 
the therapeutic dose with closed-monitoring for adverse effects mentioned above. 
Adequacy of Protection against Risks: All patients meeting the eligibility criteria will be enrolled 
in the trial. The patient will receive an Informed Consent detailing the protocol, including 
research procedures and requirements for follow-up, as well as the risks and benefits of the 
study participation. The PI, Research Coordinator, and the research support team contact 
information will appear on the Informed Consent. Subjects will be informed that study 
participation is completely voluntary and that they can withdraw at any time. Once all data 
collection is complete, patient names will be replaced with a randomly-assigned study 
identification number for the purposes of de-identification. All identifiable data will be kept on a 
password protected file on a stationary desktop computer and kept separate from the patient 
medical record and other study data. The computer contains firewall and real-time anti-virus 
and anti-spyware protection that is kept up-to-date. 
 
 
Section 11.0. 
 
Data Handling, Recordkeeping, and Quality Control and Assurance 
 
Data and samples will be collected primarily using a computerized method (REDCap) in addition 
to the study Research Coordinator as supervised by the PI. All data and samples will be stored 
according to an assigned code number and the only personal identifiers associated with a 
sample include sex, age, and ethnicity. The code (with linkages) and any identifying data will be 
kept in a password-protected file located in a room separate from the other study files. The hard 
copy data files (documentation obtained from interviews, diagnostic procedures and testing) 
will be stored in the CSMC Psychiatry Research Offices. Digital files will be maintained by the 


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onsite data manager on a secured computer. Computer entries of data will be identified by code 
only. Additionally, a copy of the informed consent form and HIPPA consent form will be placed 
in the patient’s medical chart and another copy will be given to the research coordinator. 
Informed consent forms will be stored in the Department of Psychiatry research office under 
lock and key. Data and samples will be collected primarily using a computerized method 
(REDCap) in addition to the study Research Coordinator as supervised by the PI. All data and 
samples will be stored according to an assigned code number and the only personal identifiers 
associated with a sample include sex, age, and ethnicity. The code (with linkages) and any 
identifying data will be kept in a password-protected file located in a room separate from the 
other study files. The hard copy data files (documentation obtained from interviews, diagnostic 
procedures and testing) will be stored in the CSMC Psychiatry Research Offices. Digital files will 
be maintained by the onsite data manager on a secured computer. Computer entries of data will 
be identified by code only. Data will be collected and recorded into a database system. Each 
record will include the subject’s unique identifying number, demographic information, visit type, 
visit date, total scores and individual item scores on each of the measures. The Data 
Management Coordinator (study Research Coordinator) will review data integrity in terms of 
accuracy (using error alerts) and completion of all items on a daily basis. A record of the data will 
be printed for each visit and will be kept under double lock and key at the research data storage 
cabinet in the Psychiatric Research Division. An electronic backup copy of the data will be saved 
on the secure server upon data entry, in addition to weekly CD disks. A separate data copy on 
CD will be stored on a weekly basis offsite under double lock and key to enable data retrieval in 
the event of a catastrophe preventing access to the facility or the data. A backup CD will be 
created on a quarterly basis. The PI will oversee compliance with the procedures set forth. The 
database will be designed and managed by the Cedars-Sinai Biostatistics and Bioinformatics 
Research Center (BBRC)– a group that provides support for clinical trials throughout CSMC. 
Reports generated from the database will provide a basis for ongoing monitoring of subject 
accrual and retention, as well as completeness of data. These will be used to identify and 
resolve problems that may arise. Back-up copies of the database will be created daily per CSMC 
EIS standard protocol for all hospital-wide data servers. Access to data will be restricted to the 
study team but the code linking subject identification # to patient health information (PHI) will 
be restricted to only the PI and the study Research Coordinator. Data will only be released to a 
third party in an emergency medical situation or when required by law. 
 
Section 12.0. 
 
 
Financing and Insurance 
 
This study will be funded principally by PCORI. No costs to the participants. 
 
Section 13.0. 
 
 
Publication Policy 
 
Dissemination and Implementation Plan 
The stakeholders and the investigator team will be facilitating the dissemination and 
implementation of the study results and their incorporation into practice. We will be enlisting 
the help of the leadership of diverse professional organizations from the HWA, patient partners, 
CSMC investigator team within the stakeholder team to help us disseminate the results of this 
study within their respective fields and to professional/provider audiences. Joint presentations 
will be conducted by our researchers and stakeholders in order to disseminate study results to 
patients, communities, and scientific conferences. Our patient partners will collaborate on 


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patient-centered materials including a website that details the results of the study. We will work 
with the HWP organizations (NAMI, The Life Adjustment, LifeREstyle, Painted Brain, and 
Clearview Treatment Team, Community Partnered-Participatory Research) and other Clinician 
Partners. Furthermore, the PI and co-investigators will be present the study findings at national 
professional cardiology and psychiatry conferences. Additionally, the study results will be made 
publicly available and accessible through the online portal of Barbra Streisand Women’s Heart 
Center, in a sub-site on the Cedars-Sinai Center for Outcomes Research, which will explain 
characteristics, methodology and results of the study. Announcements of the study’s progress 
will be distributed in lay language throughout the following CSMC newsletters geared towards 
patients and providers, including The Bridge, Cedars Science, and Cedars-Sinai Discoveries 
Magazine. In an effort to extend the dissemination of our findings to outside health care 
institutions, they will be shared with the NIH-funded Clinical Translational Science Institutes 
(CTSI) at UCLA and the American Heart Association. We will collaborate closely with the Cedars-
Sinai communication team to communicate our study results and communicate 
implementation/educational efforts to other health systems. For example, the communications 
team operates Facebook, Instagram and Twitter accounts in an effort to enhance reader-
friendliness. Along the duration of the study, participants will be emailed a satisfaction survey, 
and will be provided with sharing their comments, suggestions, and on way to improve the 
study. The results from the comparison arms may be documented into the Dissemination & 
Implementation Repository by PCORI to answer the following questions: Psychotherapy or Meds 
for Heart Failure Depression? Gaining control of your depressive symptoms during Heart Failure: 
Which depression treatment will work best for you? We will continue to collaborate with our 
stakeholders for identifying and addressing barriers to dissemination and implementation of the 
study results throughout the three years of the study. For example, the perspectives of the 
stakeholders are likely to differ widely, and at times will conflict. Conflicts will be resolved by 
consensus. With regard to dissemination, all stakeholders will be provided with data and 
information that are both meaningful and accessible and will be relevant to a given participant 
or stakeholder. After completion of the study, the results will be presented at weekly seminars 
hosted by the CSMC Heart Institute, open to the public, patients and their caregivers and NAMI 
general public weekly seminars.  
Possible barriers to disseminating and implementing the results of this research  
We designed our study to be generalizable to the community health setting (e.g., use of BA, low 
cost and burden to patient). The use of depression screening is common among outpatient and 
general practitioner settings. However, its use is limited in large hospitals and inpatient settings. 
Therefore, the identification of depressed HF patients at other inpatient settings may be a 
barrier of our protocol implementation. We will encourage the implementation of depression 
screening in outpatient and inpatient heart failure programs in order to improve detection and 
treatment initiation. Barriers to dissemination and implementation include: availability of 
providers to deliver therapy, comfort of primary care physicians or cardiologists in prescribing 
antidepressant medications, stigma around depression, difficulty for debilitated patients in 
attending additional appointments, complexity of patients and perceived importance of 
depression relative to other comorbidities. An additional barrier may be the generalizability of 
our setting-situated in a dense urban location albeit consisting of diverse ethnic and 
socioeconomic groups. The use of BA and its ease of remote delivery mode and low-cost 
personnel would address providers’ availability to deliver this therapy. The study’s 
antidepressant management guidelines and Care Manager role would enhance PMD and 
cardiologist comfort with administering MEDs. This study’s dissemination and implementation 


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efforts include enhancing awareness of depressive symptoms in HF and enhancing the 
communication process between the provider and the patient’s depressive symptoms, which 
could help address the stigma and deliver patient-centered interventions. 
 


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APPENDIX A:  
FLOWCHART OF 
PROCEDURES 
Procedures 
Baseline 
Visit 
Visit #2 
(Introductory 
Session) 
3 months 
follow-up visit 
  
6 months 
follow-up visit 
12 months 
follow-up visit 
 
Informed Consent 
X 
 
 
 
 
MINI to confirm 
Diagnosis 
X 
 
 
 
 
MOCA to ruled out 
cognitive disorder 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Primary outcome 
measure:  PHQ-9 
X 
 
X 
X 
X 
Secondary outcome 
measures: SF-12v2, 
KCCQ, CBQ-HF 
X 
 
X 
X 
X 
Morbidity measures: 
ED visits, 
readmissions, total 
hospital days 
 
 
X 
X 
X 
Mortality rate 
 
 
X 
X 
X 
 Adapted Brief 
Medication 
Questionnaire 
 
 
 
X 
 
X 
 
X 
Percentage of 
completed BA 
sessions  
 
 
X 
X 
X 
Behavioral Activation 
 
X 
Completed 12 
weekly 
sessions with 
BA Therapist 
Completed 3 
monthly 
sessions with 
BA Therapist 
Completed as 
needed contact 
MEDS 
 
X 
Completed 12 
weekly 
contacts with 
Care Manager 
Completed 3 
monthly 
contacts with 
Care Manager 
Completed as 
needed contact 


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Appendix B: Recommendations for Antidepressant Medications for HF Patients 
Order 
Medications 
Side effects  
 
(rare/overdose 
cases) * 
Interacting 
Agents 
common to HF 
Clinical Effect 
& Monitoring 
Recommended 
Medication and 
dose 
1st 
line 
SSRIs 
(sertraline, 
paroxetine, 
fluoxetine) 
Sexual 
dysfunction, GI: 
decreased 
appetite, nausea, 
diarrhea, 
constipation, dry 
mouth. CNS: 
insomnia, 
sedation, 
agitation, 
tremors, 
headache, 
dizziness. 
NSAIDS, oral 
anticoagulants, 
antiplatelets 
 
Diuretics 
 
Clonidine 
 
Increased risk 
for bleeding 
 
  
Hyponatremia 
 
Hypothermia, 
sedation 
Sertraline 
(50mg/day) 
2 
Dopaminergic 
and 
norepinephrine 
agents 
(bupropion) 
Dry mouth, GI: 
constipation, 
nausea CNS: 
insomnia, 
dizziness, 
headache, 
agitation, 
anxiety. Weight 
loss, anorexia, 
myalgia, tremor, 
sweating, rash , 
hypertension 
Clonidine 
 
 
Warfarin 
 
Hypothermia, 
sedation 
 
Increased 
international 
normalized 
ratio 
Recommended 
in HF patients 
with high BMI 
 
OR 
hypotension 
2 
Noradrenergic 
and 
serotonergic 
agents 
(mirtazapine)  
Flulike 
symptoms, 
changes in 
urinary 
symptoms, 
weight gain, GI: 
decreased 
appetite, nausea, 
diarrhea, 
constipation, dry 
mouth, CNS: 
sedation, 
confusion. 
Hypotension* 
Clonidine 
 
 
Warfarin 
 
Hypothermia, 
sedation 
 
Increased 
international 
normalized 
ratio 
Recommended 
in HF patients 
with low BMI 
 
OR 
Hypertension 
OR if patient is 
unresponsive 
to SSRIs or 
DNRIs 
3 
SNRI 
Sexual 
NSAIDS, oral 
Increased risk 
Use if patient 


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(venlafaxine, 
duloxetine) 
dysfunction, GI: 
decreased 
appetite, nausea, 
diarrhea, 
constipation, dry 
mouth. CNS: 
insomnia, 
sedation, 
headache. 
hyponatremia, 
hypertension  
anticoagulants, 
antiplatelets 
 
for bleeding 
 
was 
unresponsive 
to SSRI, DNRI or 
mirtazapine 
X 
TCAs 
Orthostatic 
hypotension, 
tachycardia, QT 
prolongation, 
weight gain 
 
 
Not 
recommended 
for HF patients 
X 
MAOIs 
Orthostatic 
hypotension, 
hypertension 
bradycardia, 
weight gain 
 
 
Not 
recommended 
for HF patients 
 
1. Start medication according to guideline and conversation between primary care 
provider, patient and caregiver (12 weeks). 
 
2. If side effects occur:  
Consider drug-drug interactions: 
a. serotonin syndrome: antidepressants, opioids, stimulants, 5-HT1 agonists, herbs, 
mood stabilizers, antipsychotics, antiemetics (ondansetron, metoclopramide), antibiotics 
(linezolid) 
b. QTc Prolongation: SSRIs, antipsychotics, opioids, macrolides, fluoroquinolones, 
antiarrhythmics 
 
3. Stop medication if side effects persist (10-14 days) after starting use, except sexual 
dysfunction 
 
4. Refer to PI/Co-I in the event of: 
a. refractory mood symptoms 
b. development of psychotic and or manic symptoms 
c. suicidal ideation 
*following will be reported to the Data & Safety Monitoring Board (DSMB) 
* PI/Co-I will be available after hours and patients will be given a 24-hour number to on-
call Psychiatrist 
 


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Appendix C: Patient/Caregiver-Reported and Clinician-Administered Instruments  
Name of 
instruments 
How 
Administered? 
Description 
Patient Health 
Questionnaire 
(PHQ-9) 
Self-administered 
The PHQ-993 was developed as a self-report instrument that corresponded with the 
validated Primary Care Evaluation of Mental Disorders PRIME-MD clinician-
administered instrument. Using data from nearly 4000 primary care outpatients, 
aged 18 or older, the PHQ-9 measures all nine dimensions of depression assessed in 
the DSM criteria for MDD on a 0-3 scale. Compared to a mental health professional’s 
assessment, the PHQ-9 demonstrates a high degree of specificity and sensitivity (88% 
each). The PHQ has been extensively validated in outpatient medical patients, 
including primary care patients, and patients in specialty clinics with a variety of 
disorders 
12-item short 
form (SF-12v2) 
Self-administered 
The SF-12v2 is a 12-item questionnaire used to assess generic health outcomes from 
the patient’s perspective. Generic patient-reported outcome (PRO) measures like the 
SF-12v2 assess general physical and mental health-related quality of life (HRQoL), 
including the impact of any and all illnesses on a broad range of functional domains. 
Kansas City 
Cardiomyopathy 
Questionnaire 
(KCCQ) 
Self-administered 
The KCCQ is a 23-item, self-administered instrument that quantifies physical 
function, symptoms (frequency, severity and recent change), social function, self-
efficacy and knowledge, and HRQoL. In the KCCQ, an overall summary score can be 
derived from the physical function, symptom (frequency and severity), social 
function and HRQoL domains. For each domain, the validity, reproducibility, 
responsiveness and interpretability have been independently established. Scores are 
transformed to a range of 0-100, in which higher scores reflect better health status.  
Caregiver 
Burden 
Questionnaire 
(CBQ-HF) 
Self-administered 
The Caregiver Burden Questionnaire - Heart Failure Version 3.0 (CBQ-HF) is a 
quantitative survey of 26 questions covering the past four weeks of the caregiver’s 
experience is evaluated as caregiver burden. The questionnaire is based on 
interviews of HF caregivers and uses a 5-point Likert severity scale assessing 4 
domains of physical, emotional/psychological, social and lifestyle burdens81. 
MINI 
International 
Neuropsychiatric 
Interview for the 
DSM-5 (MINI 
7.02) 
Clinician-
administered 
The MINI International Neuropsychiatric Interview for the DSM-5 (MINI 7.02) is a 
brief structured interview to check if the patient meets DSM-5 criteria for current 
Major Depressive Disorder, Persistent Depressive Disorder (Dysthymia), and 
Depressive Disorder Unspecified, and to rule out DSM-5 criteria for Bipolar, 
Psychotic, or Substance-induced Disorders. 
The Montreal 
Cognitive 
Assessment 
(MoCA) 
Clinician-
administered 
The Montreal Cognitive Assessment (MoCA).64 The MoCA is a one-page test 
available online and is administered in approximately 10 minutes with maximum 
score of 30. It assesses short-term memory recall, visuospatial abilities, executive 
functions, attention, concentration, and working memory, language, and 
orientation to time and place. 
 Adapted Brief 
Medication 
Questionnaire  
Clinician-
administered 
The  Adapted Brief Medication Questionnaire will be used to assess antidepressant 
medication adherence in the MEDS arm patients after 3, 6, and 12 months of 
treatment. The scale is used to rank the degree of adherence instead of defining an 
absolute cutoff for adherence.  
 
 


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Appendix D: Reportable Adverse Events 
 
Serious side effects associated with anti-depressants 
• 
Common side effects associated with taking anti-depressants will not be reported (see 
appendix B). General common side effects include sedation and, decreased sexual 
desire, in addition to specific ones listed in Appendix B. 
• 
Only serious side effects not anticipated in the typical adverse effect profiles of these 
medications will be reported.  These side effects include serotonin syndrome and new 
onset suicidal ideations after starting antidepressant medications.  
Severe suicidal ideation resulting in Suicidal attempts. 
All reportable protocol deviations will be reported per Cedars Sinai Medical Center (CSMC) IRB 
policies and procedures. 
All protocol deviations, Adverse Events, and Serious Adverse Events will be reported per Cedars 
Sinai Medical Center (CSMC) IRB policies and procedures. Additionally, only deaths specifically 
attributable to the study intervention will be reported to the IRB. For some context, the 
mortality rate for individuals with heart failure are as high as 25% at one year, with hospital 
readmission as high as 25%-50% within 6 months after discharge (Joynt, 2004). Therefore, a 
significant morbidity and mortality rate is expected for this population secondary to their 
medical illness irrespective to the effect of the study intervention and should not be considered 
a Serious Adverse Event for the purpose of IRB reporting. Patients with advanced heart failure 
are commonly admitted to the hospital for medical reasons, therefore for the purpose of 
reporting study-interventions-related events, any hospitalizations directly related to depressive 
symptoms, side effects of antidepressant medications or behavioral activation psychotherapy 
will be reported.  
 
Appendix B: Recommendations for Antidepressant Medications for HF Patients 
Order 
Medications 
Side effects  
 
(rare/overdose 
cases) * 
Interacting 
Agents 
common to HF 
Clinical Effect 
& Monitoring 
Recommended 
Medication and 
dose 
1st 
line 
SSRIs 
(sertraline, 
paroxetine, 
fluoxetine) 
Sexual 
dysfunction, GI: 
decreased 
appetite, nausea, 
diarrhea, 
constipation, dry 
mouth. CNS: 
insomnia, 
sedation, 
agitation, 
tremors, 
headache, 
dizziness. 
NSAIDS, oral 
anticoagulants, 
antiplatelets 
 
Diuretics 
 
Clonidine 
 
Increased risk 
for bleeding 
 
  
Hyponatremia 
 
Hypothermia, 
sedation 
Sertraline 
(50mg/day) 


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2 
Dopaminergic 
and 
norepinephrine 
agents 
(bupropion) 
Dry mouth, GI: 
constipation, 
nausea CNS: 
insomnia, 
dizziness, 
headache, 
agitation, 
anxiety. Weight 
loss, anorexia, 
myalgia, tremor, 
sweating, rash , 
hypertension 
Clonidine 
 
 
Warfarin 
 
Hypothermia, 
sedation 
 
Increased 
international 
normalized 
ratio 
Recommended 
in HF patients 
with high BMI 
 
OR 
hypotension 
2 
Noradrenergic 
and 
serotonergic 
agents 
(mirtazapine)  
Flulike 
symptoms, 
changes in 
urinary 
symptoms, 
weight gain, GI: 
decreased 
appetite, nausea, 
diarrhea, 
constipation, dry 
mouth, CNS: 
sedation, 
confusion. 
Hypotension* 
Clonidine 
 
 
Warfarin 
 
Hypothermia, 
sedation 
 
Increased 
international 
normalized 
ratio 
Recommended 
in HF patients 
with low BMI 
 
OR 
Hypertension 
OR if patient is 
unresponsive 
to SSRIs or 
DNRIs 
3 
SNRI 
(venlafaxine, 
duloxetine) 
Sexual 
dysfunction, GI: 
decreased 
appetite, nausea, 
diarrhea, 
constipation, dry 
mouth. CNS: 
insomnia, 
sedation, 
headache. 
hyponatremia, 
hypertension  
NSAIDS, oral 
anticoagulants, 
antiplatelets 
 
Increased risk 
for bleeding 
 
Use if patient 
was 
unresponsive 
to SSRI, DNRI or 
mirtazapine 
X 
TCAs 
Orthostatic 
hypotension, 
tachycardia, QT 
prolongation, 
weight gain 
 
 
Not 
recommended 
for HF patients 
X 
MAOIs 
Orthostatic 
hypotension, 
hypertension 
bradycardia, 
 
 
Not 
recommended 
for HF patients 


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weight gain 
 
1. Start medication according to guideline and conversation between primary care 
provider, patient and caregiver (12 weeks). 
 
2. If side effects occur:  
Consider drug-drug interactions: 
a. serotonin syndrome: antidepressants, opioids, stimulants, 5-HT1 agonists, herbs, 
mood stabilizers, antipsychotics, antiemetics (ondansetron, metoclopramide), antibiotics 
(linezolid) 
b. QTc Prolongation: SSRIs, antipsychotics, opioids, macrolides, fluoroquinolones, 
antiarrhythmics 
 
3. Stop medication if side effects persist (10-14 days) after starting use, except sexual 
dysfunction 
 
4. Refer to PI/Co-I in the event of: 
a. refractory mood symptoms 
b. development of psychotic and or manic symptoms 
c. suicidal ideation 
*following will be reported to the Data & Safety Monitoring Board (DSMB) 
* PI/Co-I will be available after hours and patients will be given a 24-hour number to on-
call Psychiatrist 
 
 
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