Psychological and pharmacological interventions for depression in patients with coronary artery disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the effects of psychological and pharmacological interventions for depression in CAD patients with comorbid depressive disorder. Effectiveness will be evaluated regarding different types of outcomes. Primary outcomes are remission of depression or reduction of depressive symptoms following the intervention, all‐cause and CAD‐related mortality as well as non‐fatal cardiac events or surgery (coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA)). Secondary outcomes are effects on cardiac parameters (e.g. heart rate variability, platelet activation), modifiable cardiac risk factors (blood pressure, serum cholesterol levels and smoking), health economics and health‐related quality of life.
Background
Coronary artery disease (CAD) is the single leading cause of death for both men and women in developed countries (Budde 2005). Similar to other chronic diseases (Baumeister 2007, Härter 2007b), a strong association between CAD and comorbid depression has been consistently reported. Results from the World Mental Health Survey (Ormel 2007) indicate a twofold increased risk of depression for patients with heart disease compared to patients without heart disease. Rudisch and Nemeroff (Rudisch 2003) reported prevalence rates for depression in CAD ranging from 17% to 27%. Depending on the assessment method the prevalence rates for depression in myocardial infarction vary between 15.5% and 31.1% (Thombs 2006). Four months after discharge most patients still suffer from depressive symptoms (Thombs 2006).
The increased prevalence rates raise the issue of the impact of comorbid depression on the patients´ life and the health care system. Recent original studies and systematic reviews document a significant prognostic association between comorbid depression and increased mortality, morbidity and health care costs as well as diminished quality of life and adherence to treatment regimen ( Barth 2004, Baumeister 2005, Frasure‐Smith 2000, Frasure‐Smith 2003, Herrmann‐Lingen 2006, Ziegelstein 2000).
Description of the condition
Coronary artery disease (CAD) is one of the most common forms of heart disease. One of the main underlying problems in cardiovascular disease is atherosclerosis, a process that plugs blood vessels with deposits of fat, cholesterol and other substances (WHO 1992). It is most serious when it restricts the blood supply to the heart (myocardial ischemia). Clinical manifestations of CAD are acute coronary syndrome comprising myocardial infarction (MI) and unstable angina (Antman 2004) as well as stable angina pectoris (Fox 2006). Stable angina pectoris is a clinical condition characterized by symptoms of discomfort in the chest, jaw, shoulder, back or arms mainly due to myocardial ischemia. Duration of the discomfort is brief and may be caused by periods of exertion or emotional stress (Fox 2006). MI refers to what is commonly known as a "heart attack". It occurs when prolonged myocardial ischemia leads to myocardial cell death (necrosis) (Alpert 2000).
Depression is an emotional state characterised by strong feelings of sadness, worthlessness and guilt, withdrawal from others, sleeplessness and loss of appetite, sexual desire and interest in usual activities (Davison 2003). Depressive disorders can be reliably diagnosed through structured clinical interviews. The severity of depressive symptoms is usually assessed by patient‐ or clinician‐administered validated rating scales. Cut‐off scores have been validated for these scales which correspond to the likelihood of an indication of depression (Sadock 2005). Recommendations for the assessment of depression in patients with cardiovascular disease are available (Davidson 2006).
Description of the intervention
Psychological interventions comprise cognitive behavioural therapy, psychodynamic psychotherapy, interpersonal psychotherapy, other approaches such as non‐directive or supportive therapy and counselling as well as single techniques of these interventions (Davison 2003). The mode of delivery comprises individual, group or family (including couple) therapy carried out by a health care professional.
Antidepressant drugs are commonly used treatments in depressed patients. In general, the available medications do not differ in their overall efficacy and effectiveness, but differ substantially regarding short‐ and long‐term side effects (Sadock 2005). Antidepressant treatment selection depends on the type of depressive disorder and the presence of comorbid somatic or mental disorders. Among many different drugs, main pharmacological classes of antidepressant medications are selective serotonin re‐uptake inhibitors (SSRIs), serotonin‐norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). For CAD patients with moderate, severe or recurrent depression, SSRIs are safe and effective pharmacological agents (Lichtman 2008). TCAs and MAOIs however are contraindicated in these patients because of their cardiac side effects (Lichtman 2008).
How the intervention might work
Many biological and behavioural mechanisms linking CAD and depression are proposed in the existing literature (Härter 2007a, Joynt 2003, Musselman 1998, Skala 2006), comprising pathophysiological pathways such as decreased heart rate variability, platelet activation and endothelial dysfunction (Antman 2004) in depressed CAD patients. Furthermore, an accumulation of behavioural risk factors (smoking, physical inactivity and imbalanced diet) and comorbid medical disorders (hypertension, diabetes and obesity) in depressed patients might affect the development and course of CAD (Joynt 2003). Psychosocial stress constitutes a risk factor for both CAD and depression (Joynt 2003).
Pharmacological treatments have been studied in systematic reviews of randomized controlled trials (RCTs) which have shown antidepressants to be effective in the depressed elderly (Mottram 2006) and in patients with dysthymia (Silva de Lima 2005). However, the differences between antidepressants and active placebos are small (Moncrieff 2004). A recent review concludes that pharmacological interventions for depression might influence physiological pathways linking depression and CAD (Skala 2006). Effective treatments in CAD patients with comorbid depressive disorder may not only improve depressive symptoms, but also might have a positive impact on physiological processes such as heart rate variability and platelet activation (Pollock 2000, Serebruany 2003, Yeragani 2002).
Psychological treatments may also affect physiological processes, but the interrelations between behavioural and physiological mechanisms remain unclear (Skala 2006). Psychological interventions could not only improve depression outcomes in CAD patients with comorbid depressive disorder (Berkman 2003, Lesperance 2007), but may also improve medical outcome parameters by encouraging behaviour changes towards a healthier lifestyle in these patients (Rees 2004).
A moderator of depression treatment outcomes in CAD might be onset of depression. In a study comparing MI‐patients with first‐ever versus ongoing and recurrent depression episodes, only incident post‐MI depression was associated with MI severity (Spijkerman 2005). New‐onset depression after myocardial infarction proved to be a significant predictor of cardiac mortality in another study, whereas pre‐existing depression did not (Dickens 2008).
Why it is important to do this review
With regard to the high prevalence rates and the impact of comorbid depression on both medical and psychosocial outcomes, there is a need for effective depression treatments in CAD. In various systematic reviews, psychological and psychopharmacological interventions have proven to be effective interventions for the treatment of depression in general (Sadock 2005). However, as yet, there has been no systematic review of psychological and pharmacological interventions on the effects of depression treatment in CAD patients with comorbid depressive disorders.
A Cochrane review examined the effects of non‐specific psychological interventions in CAD patients in general (Rees 2004), indicating small reductions in depression and anxiety symptoms, but no significant effects of psychological interventions on all‐cause or cardiac mortality. However, the review did not study the effects of depression‐specific treatment in the population of CAD patients with comorbid depressive disorder. Furthermore, the review included non‐specific psychological interventions (mainly stress management), whereas the focus of our review is on depression‐specific psychological or pharmacological interventions explicitly used for treating depression. Some RCTs may be included in both reviews, but the research questions remain different owing to the focus of our review on the effects of depression treatments in depressed CAD patients.
The review will allow conclusions on the effects of depression treatment concerning comorbid depressive disorders in CAD patients. Depending on the amount of primary studies, conclusions may be drawn concerning differential effects of type of intervention on the level of depression and mortality or non‐fatal cardiac events, as well as on patients’ quality of life and risk factors, thus providing a basis for treatment recommendations. Furthermore, follow‐up data may be examined concerning the economic impact of the various interventions. Sources of heterogeneity in the results of the primary studies can be explored and could help to provide suggestions for the design of future studies.
Objectives
To determine the effects of psychological and pharmacological interventions for depression in CAD patients with comorbid depressive disorder. Effectiveness will be evaluated regarding different types of outcomes. Primary outcomes are remission of depression or reduction of depressive symptoms following the intervention, all‐cause and CAD‐related mortality as well as non‐fatal cardiac events or surgery (coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA)). Secondary outcomes are effects on cardiac parameters (e.g. heart rate variability, platelet activation), modifiable cardiac risk factors (blood pressure, serum cholesterol levels and smoking), health economics and health‐related quality of life.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs)
Types of participants
Adults (18 years or older) with CAD (ICD‐10: I20‐I25 (WHO 1992)) and comorbid depressive disorder (ICD‐10: F32/33/34.1 (WHO 1992); DSM‐IV: 296.xx; 300.4 (APA 1994); including subthreshold conditions) assessed by standardized interviews, self‐reports, medical records or physicians´ diagnosis. Inclusion of primary studies will not be further limited to specific clinical subgroups in order to increase the generalisability of the results of the review.
With regard to comorbid depression, studies comprising mixed study samples (e.g. the ENRICHD‐trial which comprises both depressed CAD patients and CAD patients with low social support (Berkman 2003)) will be included in the review. The impact of mixed study samples on overall results will then be investigated through a subgroup analysis (see Subgroup analysis and investigation of heterogeneity).
Types of interventions
Psychological interventions comprise cognitive behavioural therapy, psychodynamic psychotherapy, interpersonal psychotherapy, other approaches such as non‐directive or supportive therapy and counselling (Davison 2003). Studies not explicitly labelling their intervention will be included if the techniques used can be assigned to one of the categories mentioned. The mode of delivery is defined as individual, group or family (including couple) therapy carried out by a health care professional. The comparison group will be 'no intervention' or 'usual care'. With regard to differential or incremental effects of different treatment approaches, trials with a control group receiving pharmacological treatment or another psychological treatment will be considered.
Pharmacological interventions include all antidepressant medications and other drug therapies used explicitly for treating depressive disorders (Sadock 2005). The control group will be placebo. Pharmacological treatments need to be compared to other pharmacological medications or psychological interventions if the differential or incremental effects are of interest.
Types of outcome measures
Primary outcomes
Primary outcomes include depression (measured either dimensionally or categorically) following the intervention assessed by validated self‐report questionnaires or standardized interviews, all‐cause and CAD‐related mortality as well as non‐fatal cardiac events or surgery (MI, CABG, PTCA).
Secondary outcomes
Secondary outcomes include the effects of depression treatment on cardiac parameters (e.g. heart rate variability, platelet activation) and modifiable cardiac risk factors (blood pressure, serum cholesterol levels and smoking). Furthermore economic evaluations of health care costs or resource utilization and health‐related quality of life will be studied.
Search methods for identification of studies
Electronic searches
The following databases will be searched for RCTs of treatment of depressive disorders in CAD patients: the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, the International Standard Randomized Controlled Trial Number registry (ISRCTN; http://isrctn.org/) and Cardiosource Registry of Randomized Cardiovascular Clinical Trials (http://www.cardiosource.com). A highly sensitive RCT filter will be used with the MEDLINE search (Higgins 2008). No language restrictions will be applied. See Appendix 1 for details of the MEDLINE search strategy. This will be adapted for searching the other databases.
Searching other resources
In addition, reference lists of all retrieved articles will be examined to identify other potentially relevant studies. Authors of included studies will be contacted and asked about their knowledge of other RCTs, published or unpublished, which might be relevant to the review.
Data collection and analysis
Selection of studies
Two reviewers will independently select relevant studies for inclusion. A list of titles and abstracts will be examined. If title and abstract contain sufficient information to determine exclusion, the article will be rejected. The full papers of all remaining articles will be retrieved and then reviewed by two authors independently. In addition, all other potentially relevant articles identified by checking the reference lists or personal communications will also be reviewed. A record of all rejected papers and the reasons for rejection will be documented. All foreign‐language papers (i.e. not English or German) will be translated into English. If the two reviewers disagree about the inclusion of an article, a third reviewer will be asked to review the article. Disagreements will then be solved by consensus discussion.
Data extraction and management
Data from full copies of primary studies will be independently extracted by two reviewers using a data extraction form. Information about participants (sample size at baseline and follow‐up, type of CAD, gender, age), type of depression (major depression, minor depression or dysthymic disorder), assessment method (standardized diagnostic interview, self‐report questionnaire, medical record or physician’s diagnosis), cut‐off used to indicate depression on self‐report questionnaire, mean and standard deviation of depression scores, type of intervention (type of psychological treatment versus type of pharmacological treatment), comparison group (no intervention, usual care, another psychological treatment or pharmacological treatment), length of follow‐up, descriptive statistics of primary and secondary outcomes, statistical methods, effect sizes and confidence intervals will be extracted.
Assessment of risk of bias in included studies
Two reviewers will independently assess the risk of bias in included studies using the Cochrane Collaboration's tool for assessing risk of bias (Higgins 2008). Sequence generation, allocation concealment, selective outcome reporting and other sources of bias will be described. With regard to psychological interventions, blinding of health care providers or patients concerning the treatment is not feasible, but an evaluation of outcomes can be performed by researchers that are unaware of the treatment allocation of patients. Trials of psychological interventions will therefore be evaluated regarding the blinding of the outcome assessors. In pharmacological trials blinding is possible for patients, personnel and outcome assessor and will be evaluated accordingly. The impact of possible bias in altering the results will then be evaluated and conclusions concerning an overall risk of bias for primary and secondary outcomes will be drawn.
Measures of treatment effect
Standardized mean differences for continuous variables, hazard ratios for survival data and odds ratios for dichotomous variables will be calculated with a 95% confidence interval.
Unit of analysis issues
The unit of analysis in the primary studies is the patient, which is randomized to either the treatment or the control group. Thus, the number of observations matches the number of units that are randomized. Cluster‐randomized will be evaluated if the performed analyses in the RCTs properly account for the clustering in the data (e.g. multilevel models, variance components analysis or generalized estimating equations). Cross‐over trials are not expected regarding the research question. Multiple observations in primary studies as well as heterogeneity concerning follow‐up length between studies will be analysed using different time frames, which might be defined to reflect short‐term, medium‐term and long‐term follow‐up.
Dealing with missing data
Missing data from published RCTs will be requested from the authors. Authors of unpublished studies, which were published as an abstract, presented at a congress or in a poster presentation, will be asked to provide missing data.
Assessment of heterogeneity
Heterogeneity will be tested for statistical significance by using the Q‐statistics with a 95% confidence interval. To examine the extent of heterogeneity, I2 will be computed.
Assessment of reporting biases
The existence of publication bias will be examined graphically by the use of a funnel plot (Higgins 2008) and statistically by testing for funnel plot asymmetry. Furthermore, fail‐safe N (Higgins 2008) will be calculated. Multiple publication bias will be addressed through contacting the authors of included trials. To examine outcome reporting bias, published protocols will be compared to the trial results publication regarding discrepancies in reported outcomes. Where no protocol is available, attempts to contact the authors will be made.
Data synthesis
A random effects model will be performed to compute an overall estimate of treatment outcomes. The overall effect sizes of the primary studies will be presented in a forest plot.
Subgroup analysis and investigation of heterogeneity
If heterogeneity is detected the extracted data will be checked for possible oversights. Sub‐group analyses will be performed to determine the impact of different treatment approaches (psychological vs. pharmacological interventions) and study samples (depressed CAD patients vs. mixed study samples) on results. Other possible factors leading to heterogeneity will be explored descriptively in order to generate new hypotheses.
Sensitivity analysis
Sensitivity analyses will be carried out to examine the impact of gender (men versus women), CAD subtype, assessment of depression diagnosis (self‐report questionnaires versus standardized diagnostic interviews), time of onset of depression (pre‐existing versus new‐onset depression), CAD severity and risk of bias of included studies on results.
