Originally published as JCO Early Release 10.1200/JCO.2005.95.037 on August 8 2005

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Depression and Survival After Hematopoietic Stem Cell Transplantation: Where Do We Go From Here?

Department of Behavioral Science, University of Kentucky College of Medicine, Lexington, KY

In this issue of the Journal of Clinical Oncology, Prieto et al¹ report the results of a prospective study of the relationship between depression and mortality following hematopoietic stem cell transplantion (HSCT) for a malignant disease. They found that a diagnosis of major depression during the first 3 to 4 weeks of hospitalization for HSCT was associated with poorer survival at 1 and 3 years post-HSCT. This elevated mortality risk for depressed HSCT recipients, compared with nondepressed HSCT recipients, was evident even after they adjusted for a variety of demographic and clinical variables potentially linked to prognosis after HSCT.

Superficially, these results are neither surprising nor innovative. As the authors note, depression as an independent risk factor for early mortality has been the focus of quite a bit of prior research using a variety of community and clinic populations.² While the relationship between depression and mortality has been studied most extensively in the context of cardiovascular disease, this relationship has undergone scrutiny in the oncology setting in general, as well as the HSCT setting in particular. As the authors also note, results in the oncology setting have been mixed, with the majority of published studies supporting the hypothesized link between depression and poorer survival.³ The present study is thus largely consistent with prior research in the oncology setting, including research linking depression to poorer survival after HSCT.^4,5

However, the present study by Prieto et al is noteworthy for its relatively superior methodology. This superiority is evidenced in several significant aspects of the research design and data analyses, including (1) remarkably high rates of study accrual and retention; (2) the use of formal DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) diagnostic criteria for indexing the presence or absence of major depression; (3) serial assessment of depressive disorder at specific points in time ranging across the first 3 to 4 weeks of HSCT hospitalization; and (4) control in the data analyses for multiple demographic, clinical, and behavioral variables that might also be associated with post-HSCT survival, thus enabling more precise examination of the potential independent link between depressive disorder and post-HSCT survival.

Despite its methodological strengths, however, the conclusions drawn by the present study are not quite definitive. To their credit, the authors acknowledge a number of limitations of their study, some of them quite serious. For example, the failure to account for concurrent or subsequent treatment for depression in those diagnosed with depressive disorders and the focus on depressive disorders present only during the first 3 to 4 weeks of HSCT hospitalization represent significant obstacles to a reliable and comprehensive explication of the depression-survival relationship in HSCT recipients. Other limitations are less well acknowledged. For example, one can question the adequacy of the procedures used to classify HSCT recipients with regard to the primary study variable: the presence or absence of depressive disorder. Specifically, the appropriateness of the use of modified DSM-IV criteria for diagnosing depressive disorder⁶ and the procedures for considering inconsistent diagnoses across serial assessments in determining whether a depressive disorder was present or absent could be debated by reasonable individuals. Finally, the relatively small sample size (n = 199) and low prevalence of major depression (9%) make interpretation of null results problematic. In particular, although the authors attempted to identify variables that might interact with a diagnosis of major depression in predicting post-HSCT survival, none of the interaction terms were statistically significant. Unfortunately, the study was likely underpowered to detect any but the largest of "true" interaction effects. Concluding that there is a main effect for depressive disorder on post-HSCT survival when, in fact, this effect is limited to a particular type of transplantation, sex, age group, or prognostic risk category would be quite misleading.

Where do we go from here? Quite clear clinical and research paths are apparent. In light of previous research also indicating a link between depression and poorer post-HSCT mortality^4,5 and morbidity⁷ outcomes, the time has come to consider depression more seriously in the HSCT setting. As the authors suggest, greater attention should be devoted to identifying and treating depression over the course of HSCT, with depression typically underdiagnosed and undertreated in the oncology setting.^8-10 Indeed, although not the focus of study, some of the information reported here suggested little correlation between the diagnosis of depression in the study sample and receipt of appropriate psychiatric or pharmacologic treatment for depression. Fortunately, identification and treatment of depression in the oncology setting could be improved with specialized training in depression recognition and management^11,12 or general communication skills,¹³ coupled with a willingness to make this a clinical priority.

From a research standpoint, there is a clear need to move beyond relatively simple and atheoretical demonstrations of a main effect relationship between depression and survival. Although the considerable amount of work represented in the Prieto et al study reported here should not be discounted, additional relatively simple epidemiologic studies of this nature should not be a research priority at this time. Rather, research should move in at least several new directions. First, future epidemiologic investigations should be sufficiently powered to identify potential interaction effects, enabling more precise specification of the conditions under which depression is linked to survival. Second, research to identify the biologic and/or behavioral mechanisms that account for the observed depression-survival relationship would be of enormous theoretical interest. Identification of specific mechanisms underlying the observed depression-survival relationship would enhance confidence in the validity of this relationship and potentially suggest additional specific avenues for clinical management. Several plausible biobehavioral mechanisms are suggested in the Prieto et al report and these would constitute a good starting point for future study. Finally, research evaluating approaches to enhance the identification and management of depression in the HSCT setting should be implemented. This research should be designed to assess the impact on both short- and long-term psychological, behavioral, and clinical end points, including survival, and should be designed to elucidate the biobehavioral mechanisms through which the intervention might affect outcomes. Ideally, this research should include some assessment of costs associated with intervention so that some determination of the cost effectiveness of the intervention can be made. Enthusiasm for enhanced efforts to attend to psychological problems in the oncology setting is often tempered by the assumption that such efforts are not cost effective. Certainly an enhanced focus on depression identification and management in the HSCT setting could be dismissed on this basis in the absence of evidence to the contrary. Consequently, information on associated costs and benefits will be critical to the maintenance and dissemination of any successful intervention.

In conclusion, the study by Prieto et al suggests strongly that depression early in the course of HSCT is an independent risk factor for a poorer prognosis. In doing so, the results of this reasonably well-designed study are consistent with a growing body of research linking depression to poorer survival outcomes in both the HSCT and general oncology settings. Although some will automatically dismiss the possibility that psychological states can affect clinical outcomes, this tendency is countered by others who uncritically embrace this possibility. Clearly, there is potential harm in both extremes. In this case, however, the clinical implications of the depression-mortality link are quite clear: at the least, greater attention should be paid to the identification and management of depression in the HSCT setting. Furthermore, the consequences of mistakenly accepting and acting on this link would appear to be small. Certainly, it is appropriate to be wary of directly or indirectly "blaming" patients for a poor clinical outcome, in this case implying that their depression caused their deaths. However, if one assumes that the depression-survival link is real, the potential benefits of accepting this link and acting on it would appear to outweigh any costs associated with acceptance of this link. Even if later determined that depression was not an independent risk factor for a poor prognosis or later determined that interventions to enhance the identification and treatment of depression did not result in improved survival outcomes, better management of depression in the HSCT and oncology settings would still be the likely result. Few would dispute that this alone would be a desirable outcome strictly from a quality-of-life perspective.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

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