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The Effect of a Primary Care Practice–Based Depression Intervention on Mortality in Older Adults: A Randomized Trial

Joseph J. Gallo, MD, MPH; Hillary R. Bogner, MD, MSCE; Knashawn H. Morales, ScD; Edward P. Post, MD, PhD; Julia Y. Lin, PhD; and Martha L. Bruce, PhD, MPH
[+] Article, Author, and Disclosure Information

From the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Weill Medical College of Cornell University, White Plains, New York.

Grant Support: The mortality follow-up of PROSPECT participants was funded by the National Institute of Mental Health (principal investigator, Joseph J. Gallo, MD, MPH [R01 MH065539]). The PROSPECT was a collaborative research study funded by the National Institute of Mental Health. The 3 groups included in the funded study were the Advanced Centers for Intervention and Services Research of Cornell University (coordinating center; principal investigator, George S. Alexopoulos, MD, and co-principal investigators, Martha L. Bruce, PhD, MPH, and Herbert C. Schulberg, PhD [R01 MH59366, P30 MH68638]), University of Pennsylvania (principal investigator, Ira Katz, MD, PhD, and co-principal investigators, Thomas Ten Have, PhD, and Gregory K. Brown, PhD [R01 MH59380, P30 MH52129]), and University of Pittsburgh (principal investigator, Charles F. Reynolds III, MD, and co-principal investigator, Benoit H. Mulsant, MD [R01 MH59381, P30 MH52247]). Additional small grants came from Forest Laboratories and the John D. Hartford Foundation. Participation of Drs. Gallo, Bogner, Post, and Bruce was also supported by National Institute of Mental Health awards (K24 MH070407, K23 MH67671, K23 MH01879, and K02 MH01634). Dr. Bogner is a Robert Wood Johnson Foundation Generalist Physician Faculty Scholar (2004 to 2008).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Joseph J. Gallo MD, MPH, Department of Family Medicine and Community Health, School of Medicine, University of Pennsylvania, 3400 Spruce Street, 2 Gates Building, Philadelphia, PA 19104; e-mail, galloj@uphs.upenn.edu.

Current Author Addresses: Drs. Gallo and Bogner: Department of Family Medicine and Community Health, School of Medicine, University of Pennsylvania, 3400 Spruce Street, 2 Gates Building, Philadelphia, PA 19104.

Dr. Morales: Center for Clinical Epidemiology and Biostatistics, School of Medicine, University of Pennsylvania, 423 Guardian Drive, 626 Blockley Hall, Philadelphia, PA 19104.

Dr. Post: University of Michigan and Ann Arbor Veterans Affairs Healthcare System, Health Services Research & Development (11H), 2215 Fuller Road, Ann Arbor, MI 48105.

Dr. Lin: Cambridge Health Alliance, 120 Beacon Street, Somerville, MA 02143.

Dr. Bruce: Cornell University, 21 Bloomingdale Road, White Plains, NY 10605.

Author Contributions: Conception and design: J.J. Gallo, H.R. Bogner, M.L. Bruce.

Analysis and interpretation of the data: J.J. Gallo, H.R. Bogner, K.H. Morales, J.Y. Lin, M.L. Bruce.

Drafting of the article: J.J. Gallo, H.R. Bogner, K.H. Morales, M.L. Bruce.

Critical revision of the article for important intellectual content: J.J. Gallo, H.R. Bogner, K.H. Morales, E.P. Post, M.L. Bruce.

Final approval of the article: J.J. Gallo, H.R. Bogner, K.H. Morales, E.P. Post, M.L. Bruce.

Statistical expertise: K.H. Morales, E.P. Post.

Obtaining of funding: J.J. Gallo, E.P. Post, M.L. Bruce.

Administrative, technical, or logistic support: E.P. Post.

Collection and assembly of data: J.J. Gallo, E.P. Post, M.L. Bruce.

Ann Intern Med. 2007;146(10):689-698. doi:10.7326/0003-4819-146-10-200705150-00002
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Depression has been linked to increased deaths, approximately doubling the risk for death in community samples across a wide range of depression assessment strategies (15). In our study, compared with older adults receiving usual care, older adults with depression in practices randomly assigned to an intervention consisting of a depression care manager working with primary care physicians to provide algorithm-based care were less likely to die. We found a statistically significant interaction between depression status and practice intervention assignment. Specifically, older adults in the intervention group who met standard criteria for major depression were less likely to die over the 5-year follow-up than were older adults who met criteria for major depression in the usual care group.

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Figure 1.
Study flow diagram.

CES-D = Centers for Epidemiologic Studies Depression scale; NDI = National Death Index.

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Figure 2.
Survival curves and 95% CIs for patients with major depression (top), minor depression (middle), or no depression (bottom) in practices randomly assigned to the intervention or usual care group.(14)

Data from Prevention of Suicide in Primary Care Elderly: Collaborative Trial (1999 to 2004) .

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The Effect of a Primary Care Practice-Based Depression Intervention on Mortality in Older Adults: Re
Posted on June 1, 2007
Brett D. Thombs
McGill University
Conflict of Interest: None Declared

Recently, Gallo et al. (1) reported that a depression care management intervention significantly reduced risk of 5-year mortality among older primary care patients with major depression compared to patients with usual care. There were no deaths from suicide among patients with major depression in either group. The results from this study are of potentially great importance. Despite many studies that report prospective relationships between depression and important outcomes like mortality, there is generally little evidence that depression treatment reduces overall mortality rates.

The statistical methods used by Gallo et al. for covariate adjustment, however, are known to result in model overfitting, which raises the question of whether these findings would generalize to other similar patient samples. On an unadjusted basis, patients in the intervention practices with major depression were not at lower risk of mortality. They were at significantly greater risk only after adjusting for 10 "influential covariates" that Gallo et al. identified based on significant univariate associations with time to death. Methods like this, however, that prescreen variables for subsequent entry into multivariate regression analyses are indirect versions of automated variable selection procedures (e.g., stepwise regression) (2). The Statistical Guidelines published online by the Annals of Internal Medicine counsel against prescreening variables and state, "Authors should avoid stepwise methods of model building, except for the narrow application of hypothesis generation for subsequent studies." It has been amply demonstrated that prescreening and other automated variable selection methods capitalize on variability unique to a given sample, radically underestimate the degrees of freedom used to determine estimates in regression models, often generate substantially inflated Type I error rates and artifactually small p values, and don't consistently produce replicable findings (3).

In the study by Gallo et al., the combined effect of adding the group of 10 preselected "influential covariates" was to substantially elevate, and possibly exaggerate, the hazard ratio associated with the intervention for patients with major depression. It also produced the surprising and unexpected finding that these results were largely due to a reduction in deaths related to cancer (15 in usual care practices versus 8 in treatment practices). Gallo et al. concluded that further investigation is needed to clarify the mechanisms behind the relationship between the depression intervention and decreased mortality risk from cancer. Given the limitations of their analytical methods, however, investigation of causal mechanisms is not warranted until the basic findings of the study are reproduced.

Conflict of Interest:

None declared

Response to Thombs and Ziegelstein
Posted on July 3, 2007
Joseph J. Gallo
University of Pennsylvania
Conflict of Interest: None Declared

We appreciate Dr. Thombs' and Dr. Ziegelstein's observation that our study was of great importance in reporting the beneficial effect of a depression intervention on mortality. Thombs and Ziegelstein were concerned about "pre-screening" of covariates, leading to over-fitting and ignoring the issue of confounding, resulting from post hoc selection of covariates for inclusion only if they were associated with the outcome. We had a pre-specified approach to identifying and including potential confounders because we knew that imbalances would be likely and adjustment with patient-level variables would be necessary given the practice- randomized design. Our pre-specified approach did address the concern about confounding by identifying potential confounders for inclusion in the model by their association (p < 0.10) with the interaction variables of interest, randomization assignment and baseline depression status, as well as the dependent variable, time to death. Using this approach, only age, level of educational attainment, baseline smoking status, history of myocardial infarction reported at baseline, and baseline suicidal ideation were identified as potential confounders. The intent-to-treat hazard ratio and corresponding 95% confidence interval for patients with major depression was consistent with the reported result (adjusted hazard ratio was 0.62 with 95% confidence interval [0.42, 0.92]). Additional variables for which we adjusted the point estimates reported in Table 4 were requested by reviewers. We want to emphasize the pre-specified nature of our statistical approach and the care with which we selected variables for inclusion in models. The "surprising and unexpected finding" related to a reduction in cancer deaths was unadjusted and therefore was not influenced by the selection of covariates in multivariate models. We stated "any evidence of a potential association of practice intervention assignment and specific causes of death must be viewed as an opportunity for generation of hypotheses to be tested in future intervention research." We did not call for research on mechanisms related to the decreased mortality risk from cancer. On the other hand, we would not want to be dismissive of the findings with regard to cancer deaths. We did suggest that mediators of the effect of a depression intervention on mortality do deserve further study to increase our understanding of how depression leads to increased mortality. We believe this is the first publication of a randomized clinical trial to report decreased mortality in association with treatment of depression; replication would be welcome.

Conflict of Interest:

None declared

Submit a Comment/Letter

Summary for Patients

Depression Care Management and Death among Older Persons with Depression

The summary below is from the full report titled “The Effect of a Primary Care Practice–Based Depression Intervention on Mortality in Older Adults. A Randomized Trial.” It is in the 15 May 2007 issue of Annals of Internal Medicine (volume 146, pages 689-698). The authors are J.J. Gallo, H.R. Bogner, K.H. Morales, E.P. Post, J.Y. Lin, and M.L. Bruce.


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