A Stepwise Psychotherapy Intervention for Reducing Risk in Coronary Artery Disease (SPIRR-CAD) — Rationale and design of a multicenter, randomized trial in depressed patients with CAD

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Abstract

Objective

Depressive symptoms are highly relevant for the quality of life, health behavior, and prognosis in patients with coronary artery disease (CAD). However, previous psychotherapy trials in depressed CAD patients produced small to moderate effects on depression, and null effects on cardiac events. In this multicentre psychotherapy trial, symptoms of depression are treated together with the Type D pattern (negative affectivity and social inhibition) in a stepwise approach.

Methods

Men and women (N=569, age 18–75 years) with any manifestation of CAD and depression scores ≥ 8 on the Hospital Anxiety and Depression Scale (HADS), will be randomized (allocation ratio 1:1) into the intervention or control group. Patients with severe heart failure, acutely life-threatening conditions, chronic inflammatory disease, severe depressive episodes or other severe mental illness are excluded. Both groups receive usual medical care. Patients in the intervention group receive three initial sessions of supportive individual psychotherapy. After re-evaluation of depression (weeks 4–8), patients with persisting symptoms receive an additional 25 sessions of combined psychodynamic and cognitive–behavioral group therapy. The control group receives one psychosocial counseling session. Primary efficacy variable is the change of depressive symptoms (HADS) from baseline to 18 months. Secondary endpoints include cardiac events, remission of depressive disorder (SCID) and Type D pattern, health-related quality of life, cardiovascular risk profile, neuroendocrine and immunological activation, heart rate variability, and health care utilization, up to 24 months of follow-up (ISRCTN: 76240576; NCT00705965). Funded by the German Research Foundation.

Introduction

Patients with coronary artery disease (CAD) suffer from high rates of psychological distress, especially depressive symptoms (15 to 30%) [1], [2], [3]. Recent meta-analyses have shown that depressive symptoms are associated with increased risk for cardiac events in patients with established CAD [4], [5], [6], [7]. Hazard ratios range between 1.6 and 2.2, depending on the original cardiac diagnosis, length of follow-up, definition of prognosis, measure of depression, and covariates adjusted for Ref. [8]. Increased risk is most probably mediated by poor health behavior and by the pathophysiological correlates of depressive symptoms, e.g. neuroendocrine and inflammatory activation, coagulation, and autonomic cardiovascular control [8], [9]. Current guidelines recommend treatment for comorbid depression in patients with CAD, although a significant effect on cardiac events has not been shown [10], [11].

A recent systematic review and one meta-analysis conclude that depression treatment with medication or cognitive behavioral therapy (CBT) in patients with CAD is associated with modest improvement in depressive symptoms but no improvement in cardiac outcomes [12], [13]. A Cochrane review [14] on various psychosocial interventions for depressive symptoms in patients with CAD found antidepressant effects comparable to those seen in the adult population in general as documented in two recent meta-analyses [15], [16], when publication bias and quality of studies are accounted for. Another meta-analysis on various psychosocial interventions found small effects on depression in men with CAD, but not in women [17].

Results from single RCTs, however, provide a more detailed insight into the efficacy of antidepressant treatment. For example, according to a secondary analysis of the SADHART trial, significant effects of sertraline on depressive symptoms in patients after myocardial infarction (MI) may occur only in patients with severe and recurrent depression [18]. The MIND-IT trial, investigating mirtazapine plus open-label citalopram in case of treatment failure in post MI patients with depression, revealed only short time effects on depression [19], and no effect on cardiac outcomes [20]. The CREATE trial [21] in patients with chronic CAD has shown a significant main effect of citalopram on depression, but the study was underpowered to detect differences in cardiac events. In post hoc analyses a benefit could only be observed in patients with recurrent depression.

With respect to psychotherapeutic interventions, the ENRICHD trial, designed to prove the effect of CBT, plus sertraline if needed, on clinical events in patients after MI with depression and/or low perceived social support, revealed small though significant effects on depressive symptoms, but no impact on clinical events [22]. The already mentioned CREATE trial also assessed the effect of interpersonal psychotherapy (IPT) compared to enhanced clinical management (ECM), resulting in (borderline) negative effects of IPT vs. ECM [21]. Another RCT on short-time individual CBT in a cardiac rehabilitation setting (PROTeCD) has shown no effect on depressive symptoms [23]. A recent RCT by Davidson at al., the COPES trial [24], assigned patients with persistent depressive symptoms post MI to a stepped-care approach, comprising either “problem-solving therapy” and/or pharmacotherapy, or usual care. After 6 months, patients in the intervention group described greater satisfaction with their depression care, fewer depressive symptoms, and fewer major adverse cardiac events [24].

Another three RCTs have been performed in patients after coronary artery bypass grafting (CABG): A home-based, nurse-delivered “informational and psychological support intervention” (two 1-h home visits) revealed small effects on depression in a subgroup of initially severely depressed patients [25]. A study on “telephone-delivered collaborative care”, including nurse contacts plus antidepressant medication and referral to mental health professionals, if necessary, showed significant but small effects on depression, particularly in men [26]. The most recent RCT designed to compare the effects of CBT, supportive stress management (SSM) and usual care on depression after CABG, revealed significantly higher remission rates with moderate to large effect sizes for CBT compared to usual care, but the study was underpowered to detect time-stable differences between CBT and SSM [27].

Frasure-Smith and Lesperance conclude in a recent editorial that “… the few treatment studies that have been done have not resulted in large enough changes in depression to make it reasonable to think that current depression treatments would have a clinically important impact on cardiac events” [8]. Thus, there is need to elaborate alternative concepts, and to investigate their efficacy with respect to depressive symptoms, cardiac outcomes, and possible mediators of these effects.

With respect to alternative psychotherapeutic approaches, until now, no RCT has addressed the efficacy of short-term psychodynamic psychotherapy (STPP) in depressed CAD patients. However, STPP is frequently used in routine treatment of depression in many countries and has shown to be effective in depressed patients without heart disease in recent meta-analyses (e.g. Ref. [28]).

Our interest in studying STPP was also stimulated by the evidence linking the “Type D personality” pattern with adverse cardiac events [29]. Type D has been conceptualized as a personality trait comprising negative affectivity in a broader sense (depressiveness, anxiousness, and irritability), and social inhibition. It seems to constitute a general propensity to experience psychological distress, often co-occurs with depression in patients with CAD, and may inhibit remission of depressive symptoms [29]. Although potential methodological pitfalls of the Type D construct have been under discussion [30], [31], a treatment approach tailored to focus not only on depressive emotions and cognitions but also on the Type D profile could be promising in terms of greater and/or more enduring effects of psychotherapy.

Until now, only one intervention study has evaluated the effects of a psychosocial intervention on the Type D pattern in patients with CAD (as confirmed by a Pubmed search last performed on 10/12/29 using search terms “Type D” AND personality AND (coronary OR myocardial)). Karlsson et al. [32] randomized 224 CAD patients to either “expanded cardiac rehabilitation” (stress management, increased physical training, smoking cessation and diet counseling, stay at a “patient hotel” after discharge), or routine rehabilitation. At one-year follow-up, the subgroup of patients with initially elevated total “Type D scores” had significant decrements in Type D-score, depression and anxiety and an increment in quality of life scores, while conventional rehabilitation had no impact on Type D scores, anxiety or depression. However, these results are difficult to interpret, since Type D was assessed by a poorly reported algorithm of unknown validity and it is also unclear, which element of the multimodal intervention accounted for the improvement.

From a clinical and theoretical point of view, enduring depressive symptoms and the Type-D pattern may particularly be accessible to psychodynamic group psychotherapy, because the aim of the psychodynamic technique is to systematically deal with individual maladaptive cycles of interaction as well as to elaborate alternative ways of action by newly gained understanding of own emotional experiences in the context of the group process itself. In addition, we assume that integrating established group-based CBT approaches, focusing on negative emotions and interactions in general, i.e. anger, hostile or defensive interactions, may further enhance the efficacy of the group psychotherapy. This rationale is supported by a secondary analysis of the already mentioned ENRICHD study [33]. In that study, the authors discuss a lack of transition from individual to group therapy as possible reason for the low efficacy of the intervention in more chronic forms of depression. This hypothesis was confirmed in a non-randomized secondary analysis, where a beneficial effect on survival could be observed in patients receiving individual and group therapy, but not in after individual therapy alone [33]. However, with respect to feasibility and economic reasons, it seems appropriate to prefer a stepwise psychotherapy approach, starting with few sessions of individual psychotherapy, reassess depression, and then offer group therapy in case of persistent depression only.

The aim of the SPIRR-CAD trial is to answer the research question whether a stepwise psychotherapy intervention combining individual and group psychotherapy based on psychodynamic principles and incorporating cognitive–behavioral elements can improve symptoms of depression in patients with CAD better than treatment as usual (TAU). In addition, we will investigate whether successful treatment translates into reduced physiological and behavioral coronary risk factors, physiological risk markers and improved quality of life. Furthermore, we will investigate whether the intervention is associated with reduced health care costs, and whether personality, gender and genetic polymorphisms predict treatment outcome.

Section snippets

Study organization

The study is conducted in accordance with Good Clinical Practice (GCP). Patients are recruited and treated at ten different study sites located at tertiary care hospitals with ten local principal investigators (see Appendix A). Several scientific co-workers contributing to the multidisciplinary approach of the study are responsible for special research questions, e.g. cardiovascular assessment, health economy, biostatistics, and data management and monitoring (see Appendix A). Leading

Discussion

This ongoing RCT is designed to evaluate the effects of a stepwise, combined short-term psychodynamic and cognitive–behavioral psychotherapy intervention on symptoms of depression in patients with CAD, compared to TAU plus one psychosocial counseling session. In addition to treatment effects observed directly after the intervention, a follow-up period of 6–12 months after termination of the psychotherapy will be performed in order to assess the maintenance of the effects.

Contrasting to previous

Acknowledgments

This study is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; DFG) (HE 3115/10-1; AL 559/3-1). The Clinical Trials Center Cologne (CTC Cologne) is supported by the German Federal Ministry of Research and Education (BMBF grant 01KN0706). Kits for the laboratory marker NT-proBNP will be provided by Roche Diagnostics.

The authors declare no conflicts of interest. Christoph Herrmann-Lingen receives royalties from Hans Huber Publishers (Berne, Switzerland) for the German

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