Depression and Advanced Complications of Diabetes

RESEARCH DESIGN AND METHODS

Group Health is a mixed-model prepaid health plan serving approximately half a million members in Washington state. Most Group Health members receive medical services within the integrated group practice, which includes 30 primary care clinics in western Washington. The Group Health enrollment is demographically similar to the area population. All study procedures were approved by institutional review boards at Group Health and the University of Washington. This research was supported by grants from the National Institutes of Health (MH 073686).

The cohort for this longitudinal prospective study, the Pathways Epidemiologic Follow-Up Study, was initially sampled between 2000 and 2002 from adults in the Group Health diabetes registry who received care at any of nine primary care clinics in the Seattle/Puget Sound area selected because of the socioeconomic, racial, and ethnic diversity of the patients they serve (15). The Group Health diabetes registry includes all Group Health members meeting any of the following eligibility criteria in the preceding 12 months: filled prescription for insulin or an oral hypoglycemic agent, two fasting plasma glucose levels ≥126 mg/dl, two random plasma glucose levels ≥200 mg/dl, two outpatient diagnoses of diabetes, or any inpatient diagnosis of diabetes (15).

Surveys were mailed to 9,063 potentially eligible patients, but 1,222 patients were later found to be ineligible due to reasons such as death, disenrollment, erroneous diagnosis of diabetes, or cognitive impairment. Among 7,841 eligible patients, 4,839 subjects (61.7% of eligible patients) returned the baseline questionnaire. Patients with type 1 diabetes (n = 216) were excluded, and 4,623 patients with type 2 diabetes participated in the study and comprised the original Pathways Epidemiologic Study cohort (16).

Pathways Epidemiologic Follow-Up Study

Approximately 5 years after enrollment, surviving members of the original cohort of patients with type 2 diabetes were recontacted by mailed letter and follow-up telephone call during 2005–2007. Consenting patients completed a 20-min telephone interview and were asked for permission to review their electronic and paper medical records for information on medical conditions. Waiver of consent to review electronic and paper medical records was approved by the human subjects review committee for patients who had died since enrollment in the cohort.

Assessment of clinical adverse outcomes of diabetes

Using medical record review, ICD-9 diagnostic and procedure code data, and Washington state death certificate data, we identified physician-diagnosed and objectively documented macrovascular and microvascular complications of diabetes, before baseline and during follow-up. Microvascular complications included end-stage renal disease (ESRD), low vision or blindness, proliferative retinopathy or photocoagulation procedures for diabetes, foot ulcers, and amputations. Macrovascular complications included myocardial infarction, stroke, congestive heart failure (CHF), cardiovascular procedures (percutaneous coronary artery intervention, coronary artery bypass grafting, and abdominal aortic aneurysm repair), and revascularization of the lower extremity. Deaths due to coronary, cerebrovascular, or peripheral arterial disease were include as adverse macrovascular events, and deaths due to ESRD were included as adverse microvascular events (3). The specific codes and definitions for some of these adverse diabetes outcomes were adopted from the Women's Health Initiative Study (17). Please see the online appendix (available at http://care.diabetesjournals.org/cgi/content/full/dc09-1068/DC1) for codes and definitions used to identify these advanced microvascular and macrovascular complications.

Assessment of depression

The Patient Health Questionnaire-9 (PHQ-9) (18) was used to ascertain probable major and minor depression at baseline and follow-up. The PHQ-9 is a self-report measure of depression symptoms based on the American Psychiatric Association's DSM-IV criteria for diagnosis of depressive episode and has been found to have an adequate sensitivity and high specificity in relation to a diagnosis of major depression based on structured interviews (14,18). Following a standardized method, each item was scored as positive if endorsed as “more than half the time” or “nearly all the time,” and a diagnosis of probable major depression required a positive response to one of the two core symptoms (depressed mood or loss of interest) and a total of five positive symptoms for at least the last 2 weeks. Criteria for probable minor depression required at least one core symptom (depressed mood or loss of interest) and a total of two to four positive symptoms for at least the last 2 weeks.

Covariates: demographic, clinical, and self-care characteristics

Potential confounders and mediators for the association of depression and adverse diabetes outcomes were selected a priori, as covariates. We use the term “mediator” to refer to variables that maybe on the causal pathway in the relationship between depression and adverse events, even though these mediators were assessed at the same time as depression. The mailed survey included sociodemographic characteristics (age, sex, race, educational attainment, and marital status), diabetes duration, diabetes treatment (none or diet, oral hypoglycemic only, or any insulin), height, weight, and health habits from the Summary of Diabetes Self-Care Questionnaire (smoking, physical activity, diet, and blood glucose monitoring) (19). Review of paper and electronic medical records provided data on hypertension and glycemic control (A1C). Medical comorbidity was adjusted using RxRISK, an empirically derived comorbidity measure based on medications patients take to manage chronic diseases (20). This pharmacy-based comorbidity adjustor has been found to yield good prediction of hospitalization and mortality risks, in addition to total health care costs. For this study, antidepressant and hypoglycemic medications were not included in the calculation of the RxRisk score. Thus, the modified RxRisk score should be considered a measure of overall medical comorbidity other than depression or diabetes.

Statistical analyses

We estimated the association between depression and adverse outcomes using a proportional hazards model (21). Because the length of follow-back (i.e., years of observation prior to baseline survey) varied across individuals, analyses were stratified by years of follow-back to account for variations in the amount of prior data available. These models adjusted for evidence of a prior history of adverse outcomes. We also explored whether prior adverse outcome history modified the effect of depression by including the interaction between depression and prior adverse outcomes. Sensitivity analyses examined the effect of depression among individuals with no indication of a prior adverse outcome.

Proportional hazards models censor individuals at the time of disenrollment, death from other causes (i.e., attributed to neither macrovascular nor microvascular events), or the end of follow-up, whichever comes first. We fit four proportional hazards models to each adverse outcome, with each sequential model adding covariates. The first model included only baseline depression (major, minor, or none) and an indicator of prior adverse outcomes within the same class (microvascular or macrovascular). The second model added demographic characteristics (age, sex, race, education, and marital status). The third model added clinical characteristics at baseline (diabetes duration, treatment type, RxRisk score, and hypertension diagnosis). The fourth model added baseline clinical characteristics and health habits or self-care behaviors that may be affected by depression (A1C, BMI, smoking, and limited physical activity) (10,16).