Depression and Diabetes: A Potentially Lethal Combination

Wayne Katon, MD1, Ming-Yu Fan, PhD1, Jrgen Untzer, MD, MPH1, Jennifer Taylor, PhD2,Harold Pincus, MD3,4, and Michael Schoenbaum, PhD5

1Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA; 2Green Ribbon Health,LLC, Tampa, FL, USA; 3Department of Psychiatry and Irving Institute for Clinical and Translational Research, Columbia University, New York, NY,USA; 4Rand Corporation, Pittsburgh, PA, USA; 5Division of Services and Intervention Research, National Institutes of Mental Health,Epidemiology and Economics, Bethesda, MD, USA.

OBJECTIVE: To assess whether Medicare fee-for-service beneficiaries with depression and diabetes hada higher mortality rate over a 2-year period comparedwith beneficiaries with diabetes alone.

DESIGN: Evidence of depression was based on a physi-cian diagnosis or self-reported prescription of an antide-pressant in the year prior to screening, or a score of3 onthe Patient HealthQuestionnaire two-item questionnaire.Mortality was assessed bi-monthly by checking Medicareclaims and eligibility files or from information fromtelephone contact with the participants family. Coxproportional hazard regression models were used tocalculate adjusted hazard ratios of death in depressedversus nondepressed beneficiaries with diabetes.

PARTICIPANTS: A total of 10,704 beneficiaries withdiabetes enrolled in a disease management programwere surveyed with a health assessment questionnaireand followed over a two-year period.

MAIN RESULTS: Comorbid depression in Medicare ben-eficiaries with diabetes participating in a disease manage-ment program was associated with an increased risk forall-causemortality over a two-year period of approximately36% to 38%, depending on the definition of depression thatwas used. No significant increase in rates of cause-specificmortality from macrovascular disease were found indepressed versus nondepressed beneficiaries.

CONCLUSION: Among a large Medicare cohort of fee-for-service beneficiaries with diabetes, comorbid de-pression was associated with an increase in all-causemortality over a two-year period. Future research will berequired to determine whether the increase in mortalityassociated with depression is due to potential behav-ioral mediators (i.e., smoking, poor adherence to diet) orphysiologic abnormalities (i.e., hypothalamic-pituitaryaxis dysregulation) associated with depression.

KEY WORDS: depression; diabetes; mortality.

J Gen Intern Med 23(10):15715

DOI: 10.1007/s11606-008-0731-9

Society of General Internal Medicine 2008

INTRODUCTION

Depression may adversely impact outcomes of chronic illnesses,such as diabetes, in several ways.1 Depression has been shown inpatients with diabetes to be associated with poor adherence toself-care regimens, such as glucose monitoring, diet, exerciseregimens and taking medications as prescribed.2 Depression hasbeen linked to having a higher number of Framingham riskfactors (i.e., smoking, obesity, sedentary lifestyle) for cardiacdisease in patients with diabetes.3 Depression is also associatedwith physiologic dysregulation of the hypothalamic-pituitary axis(HPA)4 and sympathetic nervous system5,6 as well as an increasein inflammatory markers,7,8 which may also adversely affect thecourse of diabetes. Given the adverse effect on self-care andphysiologic dysregulation, it is not surprising that longitudinalstudies have also shown that depression is linked with anincreased risk of microvascular and macrovascular complica-tions.9 Recent data has also suggested that comorbid depressionis not only linked to a higher risk for diabetic complications, butalso a higher risk for mortality.913

Since 2005, five studies (from four data sets) have examinedthe association of depression in patients with diabetes withmortality.913 At least half of the patients with diabetes in thesesamples were in pre-Medicare age groups (

GRH multi-disciplinary care coordination model is telephonicinterface by a personal nurse (PN), who educates and supportsparticipants in managing their own health and following theirproviders prescribed plan of care. For complex cases that requiremore intensive intervention, caremanagers (CMs) can engage thesupport of a field care manager (FCM). The FCM team includessocial workers and registered nurses, who interact with partici-pants, caregivers and families in person. As a third element ofGRHs program, trained community health workers (CHWs)moderate workshops to promote self management skills; CHWsalso compile relevant community resources and maintain GRHscommunity resource directory.

All participants receive a health assessment at baseline andat least every 612 months, using the Medicare DomainAssessment Tool (MDAT) developed for GRH. Depressionscreening is a core requirement of GRHs program and isadministered at set intervals as part of the MDAT, whichincludes a two-item depression screener, the Patient HealthQuestionnaire-2 (PHQ-2)15, and when needed a depressionassessment by the PN or FCM (collectively referred to as caremanagement). Participants screening positive for depressionon the PHQ-2 are further evaluated using the PHQ-9 and canthen be referred to their primary care provider or specialist forassessment, diagnosis and treatment recommendations. CMsmonitor depressive symptoms and response to treatment, andprovide information to participants to help them manage theirsymptoms and connect to appropriate resources. CMs alsopromote self-care and help participants communicate directlywith their physician(s); for participants whose depression isnot improving, CMs interface with the provider for review andadjustment of the treatment plan.

Sample

GRH's population was selected to include beneficiaries who: a)met the criteria for threshold conditions of diabetes, congestiveheart failure or both based on institutional (DRG) or physiciancodes (ICD-9) and had a hierarchical condition category (HCC)risk score16 of 1.35 or above as indicated from the initial claimsdata pull, which included services provided and discharges incalendar year 2004, and b) were eligible per the eligibilitydatabase dated May 11, 2005 (pulled on May 10, 2005).

This study reports results for 10,704 of the beneficiariesassigned to GRH with diabetes or both congestive heart failure(CHF) and diabetes. We excluded beneficiaries with CHF alone,because these patients are likely to have different clinical char-acteristics andmortality rates compared to thosewith diabetes.Weexcluded beneficiaries who were determined by GRH to beineligible for the program in practice, based on the eligibilitycriteria described above; those who declined to enroll in theprogram or could not be contacted during the enrollment process;those who did not complete an initial Medicare Domain Assess-ment Tool, whichwe designate asMDAT1; or thosewithCHF alone.

Data and Measures

Data on GRHs beneficiaries come from three main sources:MDATs administeredbyGRH; data onbeneficiary-reporteduse ofprescription drugs, assessed via periodic interviews conductedby GRHs CMs (typically in conjunction with MDATs); andMedicare eligibility and claims data provided to GRH by CMS.

Demographics

Limited demographic information was available via Medicareclaims, including beneficiaries age, sex, and race/ethnicity.Other sociodemographic measures, particularly education,literacy, employment status, and occupation, were availableon fewer than 5% of the analysis sample.

Clinical Variables

Based on ICD-9 codes, participants' level of medical illnessseverity was determined using the Charlson comorbidity index(CCI).17 Evidence of cerebrovascular accident (CVA), cardio-vascular event (CVD), cardiovascular procedures (coronaryartery bypass surgery, angioplasty, stent placement), andend-state renal disease (ESRD) was derived from ICD-9 andCPT procedure codes. Amputations were estimated fromoutpatient medical claims (ICD-9 and procedure codes) fromdata in the one-year period prior to beneficiary screening(MDAT) and in the one-year period after screening.

Information on depression status came from three sources:ICD-9 depression codes from Medicare claims data (296.2,296.3, 298.0, 300.4, 309.0, 309.1, 309.28, 311) in the year priorto program enrollment; the PHQ-2 screens administered as partof the MDAT (a score of 3 out of a possible 6 has been identifiedas the optimal cutoff on the PHQ-2 for the diagnosis of majordepression);15 and participant reports of using any antidepres-sant medication in the prior year based on the GRHMDAT initialinterview (i.e., any medication with an FDA indication fordepression). The participants identified as depressed by theICD-9 codes were included in our main survival analysis; thosewith possible depression, which was defined as lack of an ICD-9code of depression but reporting use of an antidepressantmedication in the prior year or scoring a 3 on the PHQ-2, wereadded to the ICD-9 subgroup in a sensitivity analysis.

Mortality over the 1-year period was assessed in two ways: 1)checking Medicare claims and eligibility files twice a month; and2) information from telephone contact with the participantsfamily collected by GRH for the purpose of running the program.

Statistics

The descriptive statistics (e.g., mean, standard deviation, per-centage) of the baseline characteristics were provided andcompared between participants with and without depressiondiagnoses (based on ICD-9 codes in the one-year prior to MDAT)using two-sample t-tests or chi-square tests. We also comparedthe prevalence of previous amputation and cerebrovascularaccident/cardiovascular disease between the depressed andnon-depressed groups using chi-square tests. We performed thesurvival analyses to compare the risk of death between partici-pants with and without depression using Cox proportionalhazards models.18 Mortality was assessed for up to two yearsafter MDAT1 (mean in censured participants was 656 days andmean in the those who died was 412 days). Participants enteredthe risk set on their MDAT1 screening date and their time-to-event variable was defined as the difference between MDAT1 andthe date of death. Baseline characteristics (age, gender, race, andCharlson comorbidity index), prior amputation, and prior CVA/CVD were also added to the model for adjustment. All analyseswere performed using SAS 9.1 (SAS Institute Inc., Cary, NC).

1572 Katon et al.: Depression, Diabetes and Mortality JGIM

RESULTS

As shown in Table 1, a total of 1657 (15.5%) of 10,704participants with diabetes had an ICD-9 diagnosis of depres-sion in the 12 months prior to screening. Participants with anICD-9 diagnosis of depression were significantly younger, morelikely to be female, less likely to be African-American, morelikely to be Hispanic, and had a higher severity of medicalillness based on the Charlson. Participants with depressionwere significantly more likely to have experienced prior toscreening with MDAT1 a previous cerebrovascular accident(CVA), but were less likely to have had a recent cardiovasculardisease procedure.

A total of 12.1% of participants with comorbid depressionversus 10.4% of nondepressed participants died during theapproximately 2-year post-screening period (p

In a second sensitively analysis, we compared risk of mortalityin beneficiaries treated with an antidepressant in the yearprior to screening compared to beneficiaries with no indicationof depression (i.e., no treatment with an antidepressantmedication or ICD-9 depression diagnosis and PHQ-2 nega-tive). Being treated with one or more antidepressant medica-tions in the year prior to screening was associated with a 24%increased risk of mortality in the subsequent 2-year period(HR=1.24, 95% CI 1.01, 1.53). No difference in combinedcerebrovascular and cardiovascular events was found betweenthose treated with antidepressants versus controls without adepression indicator in the subsequent 2-year period (HR=1.04, 95% CI 0.94, 1.15).

DISCUSSION

The data from this large, high-risk subset of Medicare beneficia-ries with diabetes show that comorbid depression increased therisk for mortality over a two-year follow-up period by approxi-mately 36% to 38%, depending on the definition of depressionthat was used. The mortality data are consistent with resultsfrom four of the other five studies of mixed-age patients withdiabetes.913 Our data suggest that depression is a significantrisk factor for mortality in older participants with diabetes, evenin the near term (i.e., two-year period). The mean age in thecurrent study was 75.6 years of age, which was approximately adecade higher than previous studies.

There were no differences found between depressed andnondepressed participants with diabetes in risk for a combinedcerebrovascular or cardiovascular event in the 2 years afterscreening. These data differ from the study by Black andcolleagues9, which showed in a longitudinal sample of agingHispanic patients that comorbid depression in patients withdiabetes significantly increased the risk for incident macro-vascular and microvascular complications compared topatients with diabetes alone. The study by Black and collea-gues differed because their respondents mean age wassignificantly younger (approximately two-thirds were less than65 years of age), there was a much longer follow-up period (7-year period) and the patients were from one ethnic/racialgroup.9 Rates of mortality from vascular disease may also bedecreasing in recent years in patients with diabetes due to themore aggressive treatment of blood pressure, cholesterol andglucose levels as well as widespread use of prophylacticmedications such as aspirin and beta blockers.19

Several prior studies have suggested that treatment withantidepressant medications may be associated with reducedmortality (or repeat myocardial infarction) after myocardialinfarction20 or cerebrovascular accident21. Our data showedthat treatment with an antidepressant was associated with24% higher mortality risk compared to nondepressed benefi-ciaries, but no increased risk of a combined cerebrovascular orcardiovascular event. Treatment in naturalistic care with anantidepressant is often associated with severity and persis-tence of depressive symptoms and few patients receive guide-line level antidepressant care.22 Therefore this increased riskof mortality associated with treatment is not surprising.

Limitations of this study include: lack of generalizabilitygiven that these participants with diabetes were from onegeographic region of the United States, and were older than thepopulations with diabetes reported in the past mortalitystudies.913 The two-year follow-up period was relatively short.The study depended, in part, on physician diagnosis (ICD-9codes) and physician treatment (use of antidepressants),which usually selects for participants with greater severity ofillness. There were baseline socioeconomic variables such aseducation and income that we were not able to adjust for.Finally, potential mediators of depressions adverse effect onclinical outcomes such as smoking, obesity, sedentary lifestyleand taking medications as prescribed were not available.

CONCLUSION

This study adds to the emerging evidence in young and middle-aged patients with diabetes that depression is also a risk factorfor mortality in older fee-for-service Medicare beneficiaries withdiabetes who have high levels of diabetes complications andmedical comorbidity.

Acknowledgements: This research has been supported by NIMHgrants MH 0751590 (Untzer, Principal Investigator), and K24 MH069741 (Katon, Principal Investigator)

Conflict of Interest: The authors do not have a conflict of interestwith the information contained in this article.

Corresponding Author: Wayne Katon, MD; Department of Psychi-atry and Behavioral Sciences, University of Washington School ofMedicine, 1959 NE Pacific Street, P.O. Box 356560, Seattle, WA98195, USA (e-mail: wkaton@u.washington.edu).

Table 3. Survival Analysis Comparing Risk of CVD/CVAby Depression Status (ICD9 Versus No Depression)

Independentvariables

Hazardratio

95% CI Chi-sqstatistics

P-value

Depression 0.96 [0.89, 1.04] 0.94 0.33History amputation 1.25 [0.98, 1.59] 3.36 0.07CVD, CVA or CVDprocedure

2.92 [2.72, 3.12] 933.27 0.000

Age 1.01 [1.00, 1.01] 17.77 0.001Male 1.04 [0.98, 1.10] 1.81 0.18African American 0.76 [0.67, 0.87] 17.11 0.000Hispanic 0.87 [0.71, 1.07] 1.79 0.18Other race 0.68 [0.48, 0.96] 4.84 0.03Charlson comorbidityindex

1.05 [1.04, 1.06] 77.82 0.001

Table 4. Survival Analysis Comparing Risk of Death by DepressionStatus (ICD9/MDAT1/RX Versus No Depression)

Independentvariables

Hazardratio

95% CI Chi-sqstatistics

P-value

Depression 1.38 [1.22, 1.57] 24.28 0.001History amputation 1.61 [1.07, 2.42] 5.29 0.02CVD, CVA or CVDprocedure

1.08 [0.95, 1.21] 1.44 0.23

Age 1.05 [1.05, 1.06] 194.91 0.001Male 1.25 [1.11, 1.40] 14.14 0.001African American 0.90 [0.69, 1.17] 0.66 0.42Hispanic 0.72 [0.46, 1.14] 1.94 0.16Other race 0.74 [0.35, 1.55] 0.65 0.42Charlson comorbidityindex

1.15 [1.13, 1.18] 197.49 0.001

1574 Katon et al.: Depression, Diabetes and Mortality JGIM

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Depression and Diabetes: A Potentially Lethal CombinationAbstractAbstractAbstractAbstractAbstractINTRODUCTIONMETHODSSampleData and MeasuresDemographicsClinical VariablesStatistics

RESULTSDISCUSSIONCONCLUSIONReferences

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