Inclusion criteria.

Patients with AHF (as defined by New York Heart Association Classes II-IV) selected from patients admitted to the inpatient hospital at Cedars-Sinai Medical Center as well as from heart failure patients presenting to the outpatient programs of the Cedars-Sinai Smidt Heart Institute; with a life expectancy of greater than 6 months at enrollment; as well as depression as evidenced by a score of ten or greater on the nine item Patient Health Questionnaire (PHQ-9) [40] and confirmed by a diagnosis of Major Depressive Disorder, Persistent Depressive Disorder (Dysthymia), and Depressive Disorder Unspecified, as defined by the Mini International Neuropsychiatric Interview (MINI) 7.02 [41].

Exclusion criteria.

Imminent danger to oneself or to others, cognitive impairments as evidenced by a Montreal Cognitive Assessment (MOCA) score of less than 23 [42], bipolar, psychotic, and substance induced disorders as evidenced by the MINI 7.02, and patients in active treatment of depression who are already receiving antidepressants, psychotherapy, or both, as well as an inability to communicate in English.

Behavioral Activation psychotherapy (BA).

For patients assigned to the BA arm of the study, we will adapt the Brief Behavioral Activation Treatment for Depression (BATD), Revised Treatment Manual (BATD-R) [43]. This evidence-based, manualized treatment for depression is based on the theory that people with depression tend to stop engaging in enjoyable or meaningful activity, thus leading to a vicious downward spiral of reduced activity and worsening depressed mood. The strategy behind the treatment is to help depressed patients restore pleasurable and meaningful activity into their lives even while they are still suffering from depression. In so doing, patients can reverse the vicious cycle of anhedonia and depressed mood, enabling them to experience reductions in depressive symptoms and improvements in mood.

The original BATD-R manual was designed to be delivered over the course of ten weekly sessions. We will expand the treatment to include 12 weekly sessions, as well as three monthly follow-up sessions over three consecutive months. Ten psychotherapists will provide the BA treatment to patients. Eight of the therapists are licensed clinical social workers. Two therapists have Master of Social Work degrees but are not yet licensed. Patients will be told that the treatment will be provided remotely and that they can speak with their therapists by telephone or via a HIPAA compliant, secured video-conferencing platform (i.e., Webex). When patients have to be hospitalized due to acute health problems, their therapists will provide bedside treatment to patients in the hospital when feasible.

Therapists will be monitored and supervised by a licensed clinical psychologist and co-investigator of the study. The psychologist will provide all therapists with an initial two-hour training in the BATD-R manual as well as weekly supervision during which therapists can discuss their individual cases. Weekly supervision is intended to ensure consistent and reliable delivery of the BA treatment and to prevent therapist drift. With patient consent, the psychologist will listen in on at least one BA session provided by each therapist as a further check on fidelity to the manual. BA Therapists use the following tools to document between session goal assignment and completion as well as patient engagement in BA psychotherapy: (1) BA Patient Tracking Log where BA therapists document patients’ assigned activities from week to week, including the following week, and document the completed goals; (2) BA Survey where BA therapists keep track of patients’ engagement by having the therapists answer questions about number of sessions completed, whether the patient appears to understand, actually use and apply the treatment concepts in his/her life, and actually engage in the planned activities including new activities beyond their usual, in addition to questions about potential challenges and obstacles to engaging in BA therapy.

Therapists will introduce themselves to their patients by phone or Webex, or in person when patients are hospitalized. Patients will be provided with a booklet of worksheets and told they will use these worksheets as part of the treatment. Therapists will try contacting their patients on a weekly basis and delivering as many of the 12 sessions of the BA treatment as possible over the 12-week intervention period. The length of sessions vary depending on the individual patient, and therapists never allow sessions to exceed 50 minutes. Patients will be informed that engaging in weekly assignments between sessions is a critical component of the treatment and essential to its overall success in helping patients overcome depression.

Session 1 of the treatment provides patients with psychoeducation about depression and the rationale for why BA could potentially help them counteract depression. Patients are given the assignment of writing down how they spend their time each day on a Daily Monitoring Form and rating the enjoyment and importance of each activity on a 0–10 rating scale.

In session 2, therapists review the Daily Monitoring Forms and discuss any problems or obstacles the patients face in completing this task. Therapists use troubleshooting strategies if patients have trouble completing the forms. Therapists then introduce and discuss the Life Areas, Values and Activities Form to patients. Patients are asked to identify and explore five areas of their lives: (1) relationships, (2) education/career/volunteering, (3) recreation and interests, (4) mind/body/spirituality, and (5) daily responsibilities. Through interactive dialogue, therapists help patients articulate their values in each of the five life areas (for example, “being a loving parent” in the relationship area, or “being creative” in the recreation/interest life area). From their identified values, patients are asked to identify specific activities that represent expressions of their values in each of these areas. Patients will continue to track their current activities for the coming week on the Daily Monitoring Forms.

In sessions 3 and 4, therapists continue to help patients define and refine their values and the specific activities linked to their values which they would find enjoyable and important. Therapists help patients develop a list of 15 activities from which to choose and schedule for the coming weeks. Patients are encouraged to include activities in all five life areas, on the theory that the more activities they plan in different life areas, the more likely the odds of reducing depression. Patients are encouraged to select activities that are observable and measurable, and to break activities down into their smallest parts. Patients rank their proposed 15 activities from the least to the most difficult on the Activities Selection and Ranking Form. Patients then use the Daily Monitoring Form to plan the activities they are to engage in during the coming weeks. As each week passes, patients are encouraged to engage in their scheduled activities and to rate their level of enjoyment and importance for each activity.

Sessions 5 and 6 introduce patients to the concept that patients do not have to pursue all activities alone. They could enlist other people in their social support system to help them engage in valued activities. Patients are shown the Contracts Form and encouraged to name people who could help them engage in activities. Patients continue to report what activities they engaged in during the previous week, what obstacles and problems they faced pursuing their activities, and what activities they planned for the coming week.

In sessions 7 through 9, therapists continue to review with patients the previous week’s activities, their ratings of enjoyment and importance for each activity, and their planned activities for the coming week. In addition, therapists review each of the concepts and principles from the earlier sessions, including the concept of the five life domains, their values in each area, and the activities linked to their values. Therapists review the idea of selecting and ranking different activities, using them to plan and schedule activities for the coming week, and soliciting the help of other people to engage in valued and enjoyable activities.

In sessions 10 through 12, patients continue to report on the previous week’s scheduled activities, their enjoyment and importance, any obstacles getting in the way, and their planned activities for the coming week. With session 12 being the last weekly session, therapists explain that their next contact with the patient is going to be three consecutive monthly sessions. Patients are encouraged to continue scheduling and engaging in enjoyable and meaningful activities on their own. At each of the three follow-up sessions, patients report their activities and any problems they encounter. At the third and last follow-up session, patients are encouraged to continue engaging in activities on their own. Patients are also told that they are welcome to contact their therapist on an as-needed basis if they run into obstacles and feel that they need additional coaching to continue engaging in valued and enjoyable activities.

Antidepressant Medication Management (MEDS).

The MEDS intervention is delivered remotely using the evidence-based collaborative care model for depressed adults [33], using a care manager (a social worker or registered nurse) whose role is to 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 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 guidelines [33] and study protocol antidepressant medication guidelines detailed in Table 1.

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Table 1. Recommendations for antidepressant medications for patients with HF.

https://doi.org/10.1371/journal.pone.0244453.t001

The care manager then contacts the patient via weekly telephone calls for 12 weeks, and then monthly for three months. The MEDS intervention is designed to be delivered by telephone because patients with heart failure have a significant burden of illness that prevents them from making regular clinic visits for antidepressant supervision. During each telephone call, the care manager will encourage patients to adhere to the antidepressant medication treatment, will track the patient’s progress or lack thereof, and will inform the treating physician and the psychiatrist regarding the patient’s condition. The psychiatrist will be available for direct consultation for patients who are not progressing, or who are experiencing adverse effects. Antidepressant medications from any class may 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 the MEDS intervention. After six months, patients are invited to call the care manager as needed.

The treatment content for each intervention over time is shown below (Fig 3).

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Fig 3. Treatment content over time.

Abbreviations: PHQ-9: Nine-Item Patient Health Questionnaire, MINI: Mini International Neuropsychiatric Interview, MOCA: Montreal Cognitive Assessment, SF-12: 12-item Short Form Medical Outcomes Study, KCCQ: Kansas City Cardiomyopathy Questionnaire, CBQ-HF: Caregiver Burden Questionnaire for Heart Failure).

https://doi.org/10.1371/journal.pone.0244453.g003

Assessment of primary outcome.

The primary outcome, change in depressive symptom severity, will be assessed by the 9-item patient-reported Patient Health Questionnaire (PHQ-9) at 6 months from baseline.

Assessment of secondary outcomes.

The secondary outcome of physical and mental HRQoL will be assessed by the 12-item Short Form Medical Outcomes Study SF-12v2. Heart-Failure-Specific HRQoL will be measured by the 23-item patient-reported Kansas City Cardiomyopathy Questionnaire (KCCQ), which is the most sensitive, specific, and responsive HRQoL for heart failure [46]. Caregiver burden will be assessed by the Caregiver Burden Questionnaire for Heart Failure (CBQ-HF), 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 [47]. Furthermore, we will assess morbidity by the number of ED visits, hospital readmissions, and total days in the hospital; and mortality. Hospital use will be obtained from the California Office of Statewide Health Planning and Development, and mortality data from the National Death Index, following the end of the study. Secondary outcomes will be assessed at 3, 6 and 12-months after starting treatment.

Additional outcomes.

Adherence to assigned treatment, other treatments received for depression, and dose of anti-depressant medication will be collected by self-report. The brief medication questionnaire [48] will be used to assess antidepressant medication adherence in the MEDS arm patients after 3, 6, and 12 months of starting treatment by the research nurse. Information about the dosage of the BA intervention delivered 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 be reported as percentage of completed BA sessions. For adverse events, deaths from all causes and self-harm will be recorded and will be reported to the IRB as detailed in the Ethical Issues/Human Research section.

Variables collected.

The PHQ-9, SF-12, KCCQ, and CBQ-HF scores will be considered in analyses as quantitative continuous variables; morbidity, hospital readmissions, and total days in the hospital will be considered as quantitative discrete variables; and mortality will be considered as a qualitative nominal variable. The covariates that will be considered are age, sex, race, ethnicity, marital status, employment, educational level, insurance, recruitment site (Inpatient or Outpatient), ejection fraction, NYHA Class, and medical history. We also plan to account for the presence of a caregiver as a covariate when comparing PHQ-9 and other outcomes between MEDS and BA. Furthermore, we will consider medications, specifically those classified as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-Blockers, Loop Diuretics, Aldosterone antagonists, Opiates, and Antidepressants.

Analytic plan.

The primary analysis will focus on PHQ-9, such that the same approach will be applied to other quality of life questionnaires. Furthermore, secondary analyses will be outlined for number of readmissions and ED visits, time to death and length of stay. All tests of hypotheses will be two-sided with a significance level of 5%. R version 3.2.5 will be used for calculations [45]. Summary statistics will be presented as percentages for categorical variables and as means ± standard deviations, medians with interquartile ranges for 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) [49] 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. The primary and secondary endpoints have their distribution support limited to positive integers. Therefore, we will compare continuous distributions in R+ starting from one-parameter distribution such as the Exponential, and we will increase the level of model complexity as needed based on residual plots up to four-parameter distributions such as the Box-Cox power exponential. While we do not expect to need to model shape and scale as functions of covariates, we will explore modeling them as functions of time. Such strategy will allow us to choose the most parsimonious distribution while obtaining an acceptable model fit.Time will be modeled as a continuous variable with random coefficients using penalized cubic splines [50] to avoid overfitting. Random effects will also be added to address the correlation among patients at the same site. In addition, covariables described above will be considered in the regression models [51]. Model diagnostics will be performed based on analysis of residual plots and worm-plots [52]. Analyses of recurring readmissions and ED visits times will be modeled with mortality using Joint Frailty Models [53] 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 from GAMLSS with random effects describing repeated measures.

Heterogeneity (HTE) analysis.

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 [54]. If the interaction is statistically significant, then the main analysis will be repeated for each group separately. Multiplicity will be addressed with Holm correction. As an exploratory analysis, we will consider non-parametric random effects such that patients will be clustered based on a finite mixture with their latent cluster indicators estimated using the EM algorithm. The selection of the total number of components will be pragmatic based on GAIC and diagnostic plots.

Per-protocol analysis.

In the non-naïve per-protocol analysis, propensity scores for adherence will be estimated as a function of percentage of completed BA sessions (BA arm) and the brief medication questionnaire score (MEDS arm) at each time point and incorporated in the final models as inverse-probability weights [55].

Missing data.

Missing data patterns for the variables with missing values will be examined using the method proposed by Little [56]. Maximum effort will be made to minimize the loss of information. If the data is found to be not missing at completely random, missing values will be imputed with values drawn from a fully conditional specification using the multivariate imputation by chained equations (MICE) algorithm [57, 58], with the number of imputed datasets chosen such that the maximum loss of efficiency of 5%. Imputed values will be checked if they are plausible as diagnostics. The outlined statistical analysis will be performed for each imputed dataset and results will be pooled according to a previously established protocol [59]. In addition, a sensitivity analysis under the assumption of missing not at random (MNAR) will be performed using pattern mixture models assuming various scenarios to assess the robustness of the results.