Cognitive-behavioral Treatment of Depression in Patients With Acute Coronary Syndrome
Phase: NA
Conditions: Depression
Sponsor: University of Bologna

 
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COGNITIVE-BEHAVIORAL TREATMENT OF DEPRESSION IN 
PATIENTS WITH ACUTE CORONARY SYNDROME  
(TREATED ACS Study) 
 
Date: October 19th, 2009 
 
 
 
 
 
NCT: 2008.1263 

 
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COMPAGNIA DI SAN PAOLO 
BANDO PROGRAMMA NEUROSCIENZE 
Multicentre research grant application form 
 
 
GENERAL INFORMATION 
 
1.  Coordinator 
Name 
Chiara Rafanelli 
Title & Position 
MD, PhD, Full Professor of Clinical Psychology 
Institution 
Department 
Laboratory 
University of Bologna 
Department of Psychology 
 
Address 
 
Viale Berti Pichat, 5 
40127 Bologna, Italy 
Phone 
Fax 
E-mail 
+39-051-2091847 
+39-051-243086 
chiara.rafanelli@unibo.it 
2. Project 
1.Title 
COGNITIVE-BEHAVIORAL TREATMENT OF 
DEPRESSION IN PATIENTS WITH ACUTE 
CORONARY SYNDROME 
2. Acronym 
TREATED ACS 
3. Duration (years) 
3 years 
4. Starting date 
October 2009 
5. Key words (max. 5) 
Myocardial infarction, unstable angina, 
psychotherapy, psychological well-being, depressive 
mood 
3. Partners and Centres involved in the study (Max. 5) 
1. Coordinator 
Chiara Rafanelli, MD, PhD, 
Department of Psychology, University of Bologna, 
Bologna, Italy 
2. Principal Investigator 
and affiliation 
Giovanni Abbate Daga, MD 
Eating Disorders Unit SCDU of Psychiatry CPR 
DCA, Department of Neuroscience, University of 
Torino, San Giovanni Battista Hospital 
Consortium Agreement 
YES X 
NO 

 
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4. Previous support by the Compagnia di San Paolo 
Previous Support by the 
Compagnia di San Paolo 
to the Coordinator and/or 
the Investigators? 
YES 
NO X 
If YES, provide details 
(Grant holder, project title 
and duration, amount 
funded) 
 
5. Abstract  
The abstract (Max. 250 words) should be organized in the following sections: (i) State 
of the art; (ii) Objective and rationale; (iii) Experimental Plan; (iv) Expected results 
and their relevance. 
State of the art: Depression in association with acute coronary syndromes (ACS) is an 
independent risk factor for subsequent cardiac events and mortality. However, the only 
randomised behavioral intervention trial attempting to reduce cardiac risk in depressed 
ACS patients showed that changes in depression did not translate into improved 
survival. Such intervention did not address issues such as lifestyle modification and 
improvement in psychological well-being, which were found to affect individual 
vulnerability to medical disease. Our research group has developed a well-being 
enhancing psychotherapeutic strategy, well-being therapy (WBT), which has been 
validated in a number of controlled clinical trials.  
Objective and rationale: To evaluate the efficacy of cognitive behavioral treatment 
(CBT) with WBT in improving depressive symptomatology and well-being, as well as 
reducing cardiac risk in depressed and/or demoralized ACS patients compared to 
clinical management (CM). The same protocol will be carried out in two centres 
(Bologna and Torino). 
Experimental plan: 100 patients after a first episode of ACS, meeting DSM-IV 
criteria for depressive disorders and DCPR criteria for demoralization will be 
randomized to one of two treatment groups: 1) CBT supplemented by WBT; 2) CM. In 
both groups, treatment will consist of twelve, 45-minute sessions once a week. A two-
year follow-up will be performed.  
Expected results and their relevance: It is expected that psychological treatment may 
significantly decrease psychological distress, cardiac morbidity and mortality at 
follow-up compared to clinical management. The findings may entail considerable 
preventive implications and possible large reductions in health costs. 
 
 
RESEARCH PLAN 
 
 
Background and rationale 
 
Cardiovascular diseases are the leading cause of death and disability in Europe. Acute 
coronary syndromes (ACS), such as myocardial infarction and unstable angina, are 
comorbid with major depressive disorder (APA, 2000) almost 20% of the time. 
Depression is more than transitory psychological distress: the period of sadness or lack 

 
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of interest is abnormally intense or abnormally long and interferes with a variety of 
personal, interpersonal and social activities. Most patients with depression during the 
initial ACS hospitalization continue to have depression 1 to 4 months later. Depression 
impairs health status more than heart disease itself and it is also associated with poor 
long-term psychosocial outcomes. Several studies suggest that major depressive 
disorder, and minor depression, that do not meet the criteria for a diagnosis of major 
depressive disorder, in addition to their effects on quality of life, are risk factors for 
recurrent events in patients with established cardiac disease (Barth et al, 2004; Rafanelli 
et al, 2006, 2007). Several prognostic studies have shown that depression is a predictor 
for survival after ACS (Frasure-Smith et al, 1995) independently of previous cardiac 
history, cardiac disease severity, or residual left ventricular function. The risk is directly 
related to the severity of mood symptoms: a 1- to 2-fold increase in ACS for minor 
depression and a 3- to 5-fold increase for major depression (Bunker et al, 2003; Carney 
et al, 2008).  
Recent studies remark that the classification into diagnostic subgroups of affective 
disorders is important for an improved clinical and pathophysiological understanding of 
the relationship with cardiovascular diseases. Dysthymia, a chronic feeling of 
depression, less intense than major depression, plays an important role regarding this 
relation. Moreover, dysthymia has shown a stronger association with ACS than unipolar 
major depression (Baune et al, 2006). In an article by Rafanelli et al (2010), the authors 
found a prevalence of 13.4% of dysthymia in CHD patients. Among the variables 
examined as potential risk factors for cardiac outcome events, only dysthymia diagnosis 
in the years preceding the first episode of CHD attained statistical significance in 
multivariate analysis (controlled for age, LVEF and absolute cardiac risk).  
Recent studies outlined the need to assess different aspects of depression in medically ill 
patients as well, such as demoralization. This concept has not been defined in current 
psychiatric nosography. In recent years, psychosomatic research has focused increasing 
attention on this issue. Psychosocial variables that were derived from psychosomatic 
research were translated into operational tools by a group of international researchers 
(Fava et al, 1995), such as Diagnostic Criteria for Psychosomatic Research (DCPR), 
whereby individual patients could be better diagnosed. Demoralization defined by the 
DCPR (Rafanelli et al, 2003) is a feeling state characterized by the patient's 
consciousness of having failed to meet his or her own expectations (or those of others) 
or being unable to cope with some pressing problems; the patient experiences feelings 
of helplessness, hopelessness or giving up. Using this definition, a recent study of ACS 
patients (Rafanelli et al, 2005) revealed that 20% of them were also demoralized. 
Among patients with major depression, 17% were not demoralized, and among 
demoralized patients, 7% did not meet the criteria for major depression. The treatment 
implications of the syndrome of demoralization as defined by the DCPR have not yet 
been established.  
The negative impact of depression on post-ACS prognosis underscores the need for 
interventions to address these problems. Although antidepressants are effective in 
reducing depression in ACS patients (Frasure-Smith et al, 2006), their use in cardiac 
patients remains controversial. Moreover, the SADHART study (Glassman et al, 2002) 
tested the SSRI sertraline against placebo but found no significant differences in 
outcome over the 24 weeks of the trial. On the other hand, cognitive behavioral therapy 
(CBT) is a brief well-established and effective treatment for depression. Over 75% of 
patients show significant improvements. In earlier clinical trials, CBT has been found to 

 
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be as effective as imipramine in the treatment of depression. In addition, this approach 
has been found superior to other approaches and has been shown to be an effective 
treatment for depression for older adults and for those with severe depression. As 
relatively brief goal-oriented, collaborative, and emotionally supportive forms of 
treatment, cognitive-behavioral is generally well accepted by cardiac patients. Even 
though the only randomized behavioral intervention trial attempting to reduce morbidity 
and mortality in depressed patients with existing coronary disease (ENRICHD study) 
showed that changes in depression did not translate into improved survival, there 
remains the need to further investigate if treating depression can reduce the risk of 
morbidity and mortality in ACS patients.  
In addition, an extensive body of evidence suggests the influence of psychological well-
being in altering individual vulnerability to disease or quality of life. Ryff and Singer 
(1996) remark that, historically, mental health research is dramatically weighted on the 
side of psychological dysfunction and health is equated with the absence of illness 
rather than the presence of wellness. In a naive conceptualization, yet the one implicitly 
endorsed by the traditional psychiatric nosography, well-being and distress may be seen 
as mutually exclusive (i.e. well-being is lack of distress). According to this model, well-
being should result from removal of distress. Yet, there is evidence both in psychiatric 
and psychosomatic research to call such views in question. Carol Ryff's 
multidimensional model of psychological well-being includes environmental mastery, 
personal growth, purpose in life, autonomy, self-acceptance and positive relations with 
others (Ryff, 1986). Ryff and Singer discussed the contours of positive human health, 
and how it is rooted in a biopsychosocial consideration of the patient. Since 
psychological well-being seemed to altering individual vulnerability to disease or 
quality of life, it has been found that therapy specifically addressed to the various 
aspects of well-being has yielded clinical benefits in improving quality of life in chronic 
and life-threatening illnesses. Well-being therapy, developed by GA Fava (1999), is a 
short-term, well-being-enhancing psychotherapeutic strategy based on Carol D. Ryff's 
model. It may be applied as an additional ingredient of cognitive behavioral packages. 
The first validation studies appeared to be promising (Fava et al, 2006). 
 
 
Specific aims and preliminary findings 
 
The specific aims of this project are to 1) assess, by reliable methods, the presence of 
DSM-IV mental depression (major and minor, chronic and acute) and DCPR 
demoralization in patients with a first episode of ACS; 2) evaluate the efficacy of CBT 
in combination with WBT and lifestyle modification versus standard CM in reducing 
psychological distress and improving well-being scores after treatment; 3) evaluate the 
efficacy of CBT in combination with WBT and lifestyle modification versus CM in 
reducing the risk of morbidity and mortality in depressed and/or demoralized patients 
after a first episode of acute myocardial infarction or unstable angina. A two-year 
follow-up of the patients’ population will be performed. 
The first validation studies on the application of sequential treatment of CBT with WBT 
and lifestyle modification in the residual phase of recurrent depression were carried on 
by the coordinator’s group of research (Fava et al, 1998a, 1998b). The results appeared 
to be promising. The sequential approach has in fact yielded significant advantages in 
terms of relapse rates and number of episodes of depression, and has resulted in 

 
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enduring remission during a drug free state in the majority of patients during a six-year 
follow-up. Patients who received such treatment reported a substantially lower rate of 
relapse (40%) during the 6-year follow-up than the patients assigned to clinical 
management (90%). Such difference was significant, both in terms of comparison of 
mean survival time and survival analysis (Fava et al.,2004). The findings have 
dramatically outlined the importance of psychotherapy and clinical psychology in the 
prevention of relapse in recurrent depression. The sequential approach has been 
subsequently applied with success also in the U.K. (Paykel et al.,1999; Teasdale et 
al.,2000), Canada (Ma & Teasdale, 2002) and Netherlands (Bockting et al.,2005). A 
multicentre randomized controlled trial employing the PI’s protocol is currently in 
progress in Germany. The findings of this sequential strategy have achieved further 
importance in view of the disappointing results of the U.S. mega-trial STAR*D, which 
has predominantly used sequenced pharmacological strategies (Rush et al., 2006). 
We assume that the combination of CBT and WBT, including lifestyle modification, 
may yield more profound and enduring effects on psychological distress, cardiac 
morbidity and mortality than CBT alone. 
 
Endpoints. As the primary end-point, the present research includes the improvement in 
depression as assessed by variations in overall CID score of at least 4.1 points, after 
CBT-WBT versus CM. The expected superiority of CBT-WBT versus CM is set to the 
80%, at, if the pre/post treatment difference of CID scores is at least 4.1 points (Fava et 
al, 1998b). As secondary end-points the study includes: 1) the improvement of 
psychological distress and well-being evaluated through the variations in the overall 
Symptom Questionnaire (SQ) and Psychological Well-Being scales (PWB) scores; 2) 
the decrease of stress biomarker after CBT-WBT versus CM; 3) the reduction of 
cardiovascular major adverse events (cardiac mortality, recurrent heart attack and new 
hospitalization for cardiovascular causes) after CBT-WBT versus CM. 
 
 
Study design and methods 
 
The same protocol will be carried out in the two participating centres (Maggiore 
Hospital in Bologna and Molinette Hospital in Torino, Italy). 
Participants will be patients recovering from a first episode of acute myocardial 
infarction or instable angina. Myocardial infarction will be documented by cardiac 
symptoms (presence of acute chest, epigastric, neck, jaw, or arm pain or discomfort or 
pressure without apparent non- cardiac source) and signs (acute congestive heart failure 
or cardiogenic shock in the absence of non-CHD causes) associated with ECG findings 
(characteristic evolutionary ST-T changes or new Q waves) and/or cardiac biomarkers 
(blood measures of myocardial necrosis, specifically CK, CK-MB, CK-MBm, or 
troponin, cTn). Instable angina will be documented by cardiac symptoms (chest pain 
lasting less than 20 minutes) with likely ECG findings (ST-segment depression and 
abnormal T-wave) in absence of myocardial necrosis biomarkers.  
Medically eligible patients involved in the study have to meet, when screened 30 days 
after their index event, the following criteria: 1) a current diagnosis of at least one of the 
following: major or minor depression, dysthymia according to DSM-IV criteria, and 
demoralization according to DCPR criteria 2) no history of bipolar disorder (DSM-IV 
criteria), 3) no major depression with psychotic features, 4) no history of substance 

 
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abuse or dependency during the previous 12 months 5) no serious suicide risk 6) no 
current use of antidepressants 7) no current treatment with any form of psychotherapy 
8) Mini-Mental State Examination score higher than 24; 9) written informed consent 
provided by the patient to participate. The patients’ diagnoses will be established by the 
consensus of a psychiatrist and a clinical psychologist independently using the 
Structured Clinical Interview for DSM-IV (First et al, 1994). Patients who will meet all 
of the study’s eligibility criteria will be administered, both at intake and at the end of the 
treatment, by the same clinical psychologist blind as to treatment assignment who had 
evaluated them on intake, both observer-rated (Paykel’s Clinical Interview for 
Depression, CID, 1985) and self-rating questionnaires (Kellner’s Symptom 
Questionnaire-SQ, 1987, and Ryff’s Psychological Well-being Scales-PWB, 1989). 
Medically eligible patients with a prior episode of major depression will be enrolled if 
meeting the symptom criteria for a major or minor depressive episode for at least 7 
rather than the usual 14 days. The DSM-IV duration criterion for dysthymia will not be 
changed.  
After the initial assessment, patients will be randomized with a computer-generated 
program to 1 of 2 treatment groups: 1) cognitive behavioral treatment (CBT) combined 
with well-being therapy (WBT) according to a standardized protocol 2) standard clinical 
management (CM). In both groups treatment will consist of twelve, 45-minute sessions 
once a week and will be provided by 3 clinical psychologists, who will administer both 
types of interventions in the two groups. The usual format of CBT is one weekly 
therapy session coupled with daily practice exercises designed to help the patient apply 
CBT skills in their home environment. This approach involves several essential 
features: identifying and correcting inaccurate thoughts associated with depressed 
feelings (cognitive restructuring), helping patients to engage more often in enjoyable 
activities (behavioral activation), and enhancing problem-solving skills. The first of 
these components, cognitive restructuring, involves collaboration between the patient 
and the therapist to identify and modify habitual errors in thinking that are associated 
with depression. Depressed patients often experience distorted thoughts about 
themselves, their environment and their future. Information from the patient's current 
experience, past history, and future prospects is used to counter these distorted thoughts. 
In addition to self-critical thoughts, patients with depression typically cut back on 
activities that have the potential to be enjoyable to them, because they anticipate that 
such activities will not be worth their effort. Unfortunately, this usually results in a 
vicious cycle, where in depressed mood leads to less activity, which in turn results in 
further depressed mood, etc. The second component of CBT, behavioral activation, 
seeks to remedy this downward spiral by negotiating gradual increases in potentially 
rewarding activities with the patient. The aim of the therapy is also to make the patient 
aware of chronic and often subtle life stresses that exert harmful consequences on the 
individual over a certain amount of time. Examples may be unawareness of the longer 
time that an increasing age requires for recovering from demanding days, inadequate 
rest, prolonged anxiety, inappropriate sleeping habits, and inability to protect oneself 
from requests that exceed the potential of the individual. When patients are depressed, 
problems in daily living often seem insurmountable. In the final process, the CB 
therapist provides instruction and guidance in specific strategies for solving problems 
(e.g. breaking problems down into small steps). The techniques included in WBT that 
may be used in overcoming impairments in environmental mastery, purpose in life, 
personal growth, autonomy, self-acceptance and positive relations with others may 

 
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include: (a) cognitive restructuring (modification of automatic or irrational thoughts); 
(b) scheduling of activities (mastery, pleasure, and graded task assignments); (c) 
assertiveness training; (d) problem solving. CM will consist of reviewing the patients’ 
clinical status, and providing the patient with support and advice if necessary. Specific 
interventions such as exposure strategies, diary work, and cognitive restructuring will 
not be allowed. The patient will be encouraged to share the main events that took place 
in the previous 2 weeks. Both CBT and CM intervention will be manualized. Treatment 
integrity will be checked by submitting 10 randomly selected sessions (5 involving CBT 
and 5 involving CM) to 2 independent assessors, who will have to rate the overall 
treatment integrity and identify all sessions. The treatment will be provided at Maggiore 
Hospital in Bologna, and at Molinette Hospital in Torino, in laboratory spaces expressly 
dedicated to the psychological interviews with the patients. The clinical psychologists 
involved in the study have to present substantial previous clinical experience with CBT 
and WBT, including treatment of depression also of patients with chronic disease or, 
more specifically, coronary disease.  
The cardiologists involved in the study will evaluate the patients at intake and once 
every 6 months to monitor changes in clinical course of cardiac disease. Data from 
electrocardiogram, echocardiogram, X ray, blood pressure, blood samples (cholesterol 
levels, 
creatinine, 
glycosylated 
haemoglobin, 
C-reactive 
protein, 
coagulation/fibrynolysis biomarkers) and waist/hip ratio will be provided at intake. 
TIMI RISK SCORE for STEMI (Morrow et al, 2000) and GRACE RISK SCORE for 
UA/NSTEMI (Bassand et al, 2007) will also detected at intake for mortality risk within 
1 month after patients’ cardiac index episode.  
Both before and after psychological treatment, among laboratory testing, the following 
biomarkers will be investigated: urinary cortisol excretion, blood DHEA-S level, blood 
glycosylated haemoglobin, coagulation/fibrinolysis markers, urinary norepinephrine, 
urinary epinephrine. The association of these biomarkers with stress increases health 
risk, regardless of the presence of psychiatric disorder (Lupien et al, 1998). Among 
blood laboratory testing, hyperhomocysteinemia levels will be also detected, since 
elevated homocysteine metabolism was established as an independent risk for vascular 
disease (the risk increase directly with total homocysteine level 6% to 7% for every 1 
μmol/liter increase in total homocysteine level) (Folstein et al, 2007). Heart rate 
variability (HRV) will be also investigated. Decreased HRV, in fact, a predictor of 
mortality, is reduced in patients with major depressive disorder after ACS (Glassman et 
al, 2007). Moreover, markers of pathophysiological mechanisms implicated in ACS will 
be investigated since they provide incremental value over existing ischemic biomarkers. 
Systemic markers of inflammation such as elevated C-reactive protein (CRP) levels 
(Morrow et al, 1998) will be studied for its prognostic value (Biasucci et al, 1996).  
Before and after psychological treatment, and then after 3, 6, 9, 12, 18 and 24 months 
the differences between the two groups in CID, SQ and PWB scores will be analyzed.  
 
 
STATISTICAL PLAN 
 
The sample size was calculated based on the results of previous studies carried out by 
the Coordinator of the present project. According to the statistical analyses performed in 
previous studies focusing on treatment efficacy (Fava et al, 1998), a sample size of 100 
patients (50 per treatment group) seems appropriate. In the present study, to obtain the 

 
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same difference between the mean CID scores with a power of 80%, at least 16 subjects 
per arm are required according to calculations performed with the piface software 
(Lenth, 2001, 2006-2009). Multivariate ANOVA will be used to examine differences in 
dimensional psychological variables (i.e. CID total score, SQ and PWB scales scores) 
between patients assigned to CBT-WBT and CM at pre-intervention. Mixed-model 
ANOVA (Repeated Measures) will be performed to test differences between groups 
(CBT-WBT or CM) on the CID total score, the PWB scales, and the SQ scale scores at 
different follow-up evaluations. For the comparison between the means of the two 
groups (CBT-WBT vs CM) in the scores of psychological measures (CID, SQ e PWB) 
and in the values of the biomarkers, analysis of the covariance will be used, considering 
baseline scores as covariates. The missing data will be analyzed with the Intention-To-
Treat procedure. Survival analysis will be used in order to evaluate the period of time 
occurred between baseline and new negative cardiac outcomes. The follow-up time 
considered for relapse will be 24 months after the end of the treatment. Survival 
analysis will be used for time until relapse into cardiac events. Among factors 
investigated as possible predictors of outcome, assignment to CBT in combination with 
WBT or to CM will be included. The Kaplan-Meier method will be used for estimating 
survival curves. When relapse is the event of interest, survival will be referred to 
relapse-free status. The log-rank test and Cox proportional hazards model will be 
included to compare any survival distributions for each of the factors considered. For all 
tests performed, the significance level will be set at 0.05, two-tailed.  
 
 
Time schedule of the project 
 
All the patients admitted to the Hospital starting from September 2009 for a first 
episode of myocardial infarction or unstable angina could be potentially involved in the 
study. The clinical picture will be evaluated by both means of ECG/echocardiogram 
charts and laboratory testing. At that time, cardiovascular risk factors, left ventricular 
ejection, HRV, TIMI and GRACE scores will be also provided. After one month of 
their admission, at their first control visit routinely scheduled by the cardiologists to 
check the clinical status of the patients, the clinical psychologists involved in the study 
will present to the patients the project to obtain informed consent. They will also 
administer interviews and questionnaires to select depressed patients. Among them, 
who were affected during the previous month by the presence of at least one of the 
following depressive emotional states such as DSM major or minor depression, 
dysthymia, DCPR demoralization, will be included in the study. The patients who will 
satisfy inclusion criteria will be randomized to one of the two treatments assignment. 
Both before and after the treatments, urinary and blood biomarkers of cardiac 
prognostic value will be detected. The duration of the study for each subject is expected 
to be 27-28 months. Included are 3-4 months of intervention and 24 months of follow-
up. The duration of the overall study is expected to be 3 years for each patient. Every 
three months for the first year and then every 6 months for the following time, the 
patients will be reassessed through the same questionnaires by the same clinical 
psychologists who had evaluated them at the first assessment. 
 
 

 
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