Recent meta-analyses of cross-sectional studies provide evidence

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1 Depression-Related Hyperglycemia in Type 1 Diabetes: A Mediational Approach PATRICK J. LUSTMAN, PHD, RAY E. CLOUSE, MD, PAUL S. CIECHANOWSKI, MD, IRL B. HIRSCH, MD, AND KENNETH E. FREEDLAND, PHD Objective: Depression is linked with hyperglycemia and with an increased risk for diabetes complications, but the mechanisms underlying these relationships have not been established. In this study, we applied mediational analysis methods to determine whether the hyperglycemic effect of depression could be mediated by poor diabetes self-care. Methods: Depression symptoms and diabetes self-care activity were assessed in a primary care sample of 188 patients with type 1 diabetes by using the Hopkins Symptom Checklist-90 (SCL-90) and the Summary of Diabetes Self-Care Activities (SDSCA). A composite score of self-care activity was formed from SDSCA ratings for diet amount, exercise, and glucose testing. Degree of hyperglycemia (level of glycosylated hemoglobin [HbA 1c ]), weight, insulin dose, and other clinical characteristics were obtained from electronic medical records. Ordinary least-squares regression was used to determine the effect of depression on HbA 1c level controlling for weight and insulin dose. The SDSCA score was then added to the regression model to determine whether it attenuated the effect of depression symptoms on HbA 1c level, thus providing suggestive evidence of mediation from these cross-sectional data. Results: Depression symptoms, poor diabetes self-care, and hyperglycemia were correlated with one another in univariate analyses (p.05). Depression symptoms were associated with higher HbA 1c after controlling for weight and insulin dose (parameter estimate for depression 0.53, t 3.6, p.001). Inclusion of SDSCA in the model minimally attenuated the effect of depression symptoms (adjusted parameter estimate for depression 0.50, t 3.3, p.001). Conclusions: These findings do not support mediation of the depression hyperglycemia relationship by diabetes self-care behavior. Other pathways, including psychophysiological mechanisms, should be investigated. Key words: depression, diabetes mellitus, insulin resistance. SCL-90 Hopkins Symptom Checklist-90; SDSCA Summary of Diabetes Self-Care Activities; HbA 1c glycosylated hemoglobin; CHD coronary heart disease; BMI body mass index; AN- COVA analysis of covariance; SEM standard error of mean. INTRODUCTION Recent meta-analyses of cross-sectional studies provide evidence that depression in persons with type 1 or type 2 diabetes is linked both with hyperglycemia and with increased risk for diabetes complications such as coronary heart disease (CHD), the principal cause of morbidity and mortality in this population (1 4). Prospective evidence that depression may causally contribute to the development of CHD in diabetic patients also is beginning to appear (3,4). In a 10-year follow-up study of women undergoing scheduled annual diabetes evaluations while participating in a diabetes registry, Clouse et al. (3) found that depression at index evaluation predicted accelerated onset (p.01) and increased risk for incident CHD, the effect remaining significant after controlling for other risk factors, including age, smoking, and body mass index (age-adjusted hazard ratio 5.2, 95% confidence interval , p.01). The mechanisms by which depression worsens the course of established diabetes are unclear, but its relationship with hyperglycemia is a likely contender. Depression adversely From the Departments of Psychiatry (P.J.L., R.E.C., K.E.F.) and Medicine (R.E.C.), Washington University School of Medicine, St. Louis, MO; the Department of Veterans Affairs Medical Center (P.J.L.), St. Louis, MO; and the Departments of Psychiatry and Behavioral Sciences (P.S.C.) and Medicine (I.B.H.), University of Washington, Seattle, WA. This work was supported in part by grants DK36452, DK53060, and DK59364 from the National Institutes of Health. Address correspondence and reprint requests to Patrick J. Lustman, PhD, Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8134, St. Louis, MO lustmanp@wustl.edu Received for publication July 14, 2004; revision received September 7, DOI: /01.psy ad affects a number of behaviors that could interfere with diabetes self-care such as dietary management, physical activity, and adherence to medical treatment (3). Consequently, poor adherence to diabetes self-care is thought to be a primary explanation for depression-related hyperglycemia and previously has been shown to mediate the effects of stress on metabolic control in type 1 diabetes (5). However, the relationship between depression and hyperglycemia, a relationship sustained over long periods of time (6), may be independent of fluctuations in stress; other physiological processes may be in play. Nevertheless, diabetes self-care behavior remains one of the most plausible mediators of depression s effects on diabetes. Clarifying the role of self-care in the chain of events that link depression with hyperglycemia and poor diabetes outcomes may help guide the design of interventions. The purpose of the present study was to use mediational analysis methods to investigate the role of diabetes self-care behaviors in depression-associated hyperglycemia. Diabetes self-care was measured using the validated Summary of Diabetes Self-Care Activities (7,8). Patients with type 1 diabetes were chosen so that we could more precisely evaluate glycemic level in relationship to weight and diabetes treatment (insulin dose) while limiting the effect of intrinsic insulin availability, a prominent variable in type 2 diabetic populations. Because the data were cross-sectional, positive findings would necessarily be exploratory, and longitudinal studies would be required in which the temporal precedence among the variables would be defined and a true mediation analysis could be performed (9). METHODS Participants Depression symptoms and diabetes self-management activities were measured in a cross-sectional survey of 276 type 1 diabetic patients treated at the University of Washington Diabetes Care Center (DCC) during both 1998 and Patients were paid $3 for the time and effort spent completing and returning the study questionnaires. The study was reviewed and approved by /05/ Copyright 2005 by the American Psychosomatic Society 195

2 P. J. LUSTMAN et al. the University of Washington Institutional Review Board, and the principal findings, which describe the importance of attachment style to diabetes self-management and glycemic control, have been reported by Ciechanowski et al. (10). The subjects of the present study represented a convenience sample (n 188, 68%) of the initial type 1 patients who were still being followed at the DCC as of September Psychometric testing of these subjects occurred in the interval extending from July 1 to December 31, Measures Symptoms of depression were measured with the revised version of the Hopkins Symptom Checklist-90 (SCL-90) (11). This self-report instrument was designed to measure psychologic symptom patterns in psychiatric and medical patients and has been validated in both populations. Each item is rated on a five-point distress scale (0 4) ranging from not at all at one pole to extremely at the other. The SCL-90 is scored and interpreted in terms of its nine primary dimensions or subscales, one of which assesses depression. The 20 items that comprise this subscale were used to assess the severity of depression symptoms (10,12). Specific components of diabetes self-care were assessed with the Summary of Diabetes Self-Care Activities (SDSCA) (13). The SDSCA is a 12-item self-report questionnaire that measures levels of self-care behavior and the degree of adherence with physician-recommended activities. Data attesting to the reliability and validity of the SDSCA recently were summarized by Toobert and Glasgow (7,8). The present study used the SDSCA questions that assess diet amount, exercise, and adherence to glucose monitoring, domains with potential relevance to depression. Raw scores for each were converted to z scores and averaged to form a composite z score for the SDSCA. A higher score indicates greater attention to self-care. The SDSCA and the SCL-90, the independent variables in the mediational analysis, were obtained simultaneously. Demographic and clinical data were determined from questionnaire responses, electronic medical records, and medical charts. The degree of hyperglycemia was assessed by using the HbA 1 value linked to the office visit during which insulin dose data were recorded. HbA 1c measurement was performed with a Bayer DCA2000 glucometer, a model that is certified by the National Glycohemoglobin Standardization Program for its comparability to the reference methods established by the Diabetes Control and Complication Trial (14). Insulin dose (total number of units per day) for the office visit closest to the date of psychometric testing was recorded from the patient s medical chart. The majority of visits occurred within 3 months of psychometric testing; no interval exceeded 6 months. Statistical Analysis Ordinary least-squares multiple regression analysis was used to determine the effect of depression scale score on HbA 1c level, adjusting for weight and insulin dose. To further investigate the relationship between depression symptoms and HbA 1c levels, subjects were subdivided into depressed and nondepressed subsets using the SCL-90 depression score. The base rate of major depression in patients with type 1 diabetes is approximately 10% (15); accordingly, the score representing the 90th percentile for the current sample was used as the threshold for establishing depression cases. Depressed subjects were further stratified by severity using the SCL-90 depression subscale scores to segregate the upper and lower quartile as having severe and mild depression symptoms, respectively, compared with the remainder (moderate symptoms). Analyses of covariance (ANCOVAs) were performed comparing A1C levels in depressed and nondepressed subjects and across severity subsets (within the depressed subject group) while controlling for between group differences in weight and insulin dose. Mediational analysis was performed using the principles and procedures described by Baron and Kenny (16), as well as Kraemer (9) and Babyak (17), recognizing that the lack of temporal precedence information about the independent variables renders preliminary any inferences about causal mediation. Pearson s r was used to evaluate univariate relationships among continuous variables. Correlation of the independent variables with each other and with the dependent variable was a prerequisite for proceeding with mediational analysis. The SDSCA score was then added to the original regression analysis to test the hypothesis that diabetes self-care behavior mediates the effect of depression symptoms on HbA 1c level. Attenuation of the effect of depression symptoms by the addition of the SDSCA score would provide evidence that self-care behavior partially mediates this effect; elimination of depression from the model would provide evidence that the effect is completely mediated by self-care behavior. RESULTS Selected demographic, depression, and diabetes characteristics of the sample of 188 patients with type 1 diabetes are presented in Table 1. None of these was significantly different from the findings in the larger group of 276 patients. Raw scores on SDSCA subscale items are presented in Table 2. The ordinary least-squares regression demonstrated a significant effect of depression symptoms as a continuous variable on HbA 1c level after controlling for the effects of weight and insulin dose (t 3.6, p.001). The parameter estimate of this effect was When the subjects were stratified by depression caseness as defined, HbA 1c levels were significantly higher in the depressed than in the nondepressed group (covariate-adjusted means standard error of mean [SEM] 8.8% 0.3% vs. 7.6% 0.1%, F 10.1, p.0001) (Fig. 1). Scores on the SCL-90 depression subscale were in the depressed group compared with in the nondepressed group. HbA 1c levels also varied in relation to severity of depression symptoms within the depressed group (p.02 across subgroups). These findings corroborate previous observations demonstrating the association of depression with hyperglycemia (1). Depression symptoms, SDSCA composite score, and HbA 1c level were significantly correlated with one another (Table 3). When the SDSCA score was added to the ordinary least-squares regression analysis, the parameter estimate for the depression effect on HbA 1c level was altered minimally (parameter estimate 0.50, t 3.3, p.001) and the SDSCA score had no significant effect within the model (p.40). Thus, no evidence was obtained that diabetes self-care behavior as measured by the SDSCA mediates the relationship between depression symptom scores and HbA 1c levels. TABLE 1. Clinical Characteristics of the Sample Characteristic Subjects* (N 188) Age (yrs) White, n (%) 181 (96) Female, n (%) 94 (50) Married, n (%) 129 (69) Education beyond high school, n (%) 172 (92) Use of insulin pump, n (%) 55 (29) Age of diabetes onset (yrs) Weight (lbs) Total daily insulin dose (units) HbA 1c (%) SCL-90 depression subscale score *Grouped values reported as mean SD. HbA 1c glycosylated hemoglobin level; SCL-90 Hopkins Symptoms Checklist

3 MEDIATION OF DEPRESSION-RELATED HYPERGLYCEMIA TABLE 2. Raw Scores on Subscales of the Summary of Diabetes Self-Care Activities (SDSCA) Measure Subscale Item Mean (SD) Median (Range) Diet amount Followed recommended diet* 3.7 (0.9) 4.0 ( ) Limited calories as recommended 3.4 (1.1) 4.0 ( ) Exercise Performed 20 min of physical activity* 4.1 (2.1) 4.0 ( ) Followed recommended exercise plan 3.2 (1.5) 3.0 ( ) Participated in specific exercise session* 2.8 (2.4) 2.0 ( ) Glucose testing Tested glucose level* 6.9 (0.6) 7.0 ( ) Followed recommended glucose testing plan 4.5 (0.8) 5.0 ( ) Scored as *number of adherent days out of the past seven, or the relative adherence to the recommended advice on a scale from 1, not at all to 5, completely. SD standard deviation. Figure 1. Mean glycosylated hemoglobin (HbA 1c ) level in relation to depression status after adjusting for weight and total daily insulin dose. HbA 1c levels were significantly higher in depressed compared with nondepressed subjects and showed a stepwise increase in relation to depression severity within the depressed subject group. Error bars represent standard error of mean. DISCUSSION Morbidity from diabetes is a significant public health issue, accounting for more than one of every $10 spent for health care in the United States (18). Hyperglycemia is the most robust predictor of diabetes complications (14,19 22). Treatments that directly lower glucose reduce the risk of complications and comprise the cornerstone of diabetes management (14,20 22). Diabetes care also targets other risk factors for complications (eg, hypertension, hyperlipidemia) and factors that may oppose efforts to achieve glycemic control. Depression is considered one such factor and is included among the components of comprehensive care outlined in the American Diabetes Association s clinical practice recommendation entitled Standards for Medical Care in Diabetes (23). Clinically significant depression is present in approximately one in four patients with diabetes (type 1 or type 2) and is associated with hyperglycemia and with increased risk for diabetes complications (1,2,15,24). The mechanisms responsible for these effects presently are unclear. The most common explanation is that depression reduces adherence to medical care recommendations (25), a hypothesis supported by crosssectional observations in diabetes and other medical illnesses (12,24,26 30). Adherence is recognized as an important contributor to diabetes control, particularly in type 1 diabetes, and also was correlated with lower HbA 1c levels in our patient sample (31 33). In the present study, we used a preliminary application of mediational analysis to help determine the role of diabetes self-care behaviors in depression-associated hyperglycemia. Consistent with this approach, we established that depression symptoms and diabetes self-care (the independent variables) correlated with each other and with HbA 1c (the dependent variable). Using regression analysis, we found that depression symptoms predicted HbA 1c level, an effect independent of weight and insulin dose. Adding diabetes self-care to the regression model, however, did not significantly alter the significant effect of depression. The findings were identical in post hoc analyses of the subset of subjects (n 123) in whom body mass index information was available. We conclude that, although adherence to diabetes self-care may importantly influence metabolic control, diabetes self-care behavior did not mediate the additional hyperglycemia associated with depression. Alternative theories are emerging that could explain the depression hyperglycemia relationship, one being that depression induces insulin resistance (24). Insulin resistance is a hallmark feature of type 2 diabetes preceding overt hyperglycemia by a number of years, and factors that increase insulin resistance exacerbate hyperglycemia in any form of diabetes (34 36). A limited amount of information supports the association of depression with insulin resistance in nondiabetic individuals (37 42); some of these investigations were methodologically flawed by not controlling for confounding factors. Other potential mediators of the relationship involve the hypothalamic pituitary adrenal axis, the autonomic nervous system, and immunoinflammatory processes (43 45). Because of its broad association with inflammatory markers, depression may influence cellular modulation of the stress response, including effects on the transcriptional factor nu- 197

4 TABLE 3. Intercorrelation of Measures of Depression, Diabetes Self-Care, and Glycemic Control P. J. LUSTMAN et al. Diabetes Self-Care Behavior Depression Severity Glycemic Control Measure SDSCA SCL-90-D HbA 1c SDSCA r 1.0 r 0.26, p.0001 r 0.15, p.04 SCL-90-D r 0.26, p.0001 r 1.0 r 0.23, p.002 HbA 1c r 0.15, p.04 r 0.23, p.002 r 1.0 SDSCA Summary of Diabetes Self-Care Activity; SCL-90-D depression subscale of the Hopkins Symptom Checklist-90, HbA 1c glycosylated hemoglobin level. clear factor- that regulates proinflammatory cytokines, adhesion molecules, and chemokines (46). There also is some evidence that insulin resistance decreases with depression treatment (41), but a shared precursor event leading to both depression and insulin resistance remains plausible. For example, Chiba et al. (47) found that specific tyrosine hydroxylase gene microsatellite polymorphisms were shared between nondepressed subjects with insulin resistance and depressed subjects. Such processes might make depression-associated hyperglycemia less responsive to depression treatment alone (25,48). Our study has a number of strengths and some important limitations. Strengths include the facts that the sample of type 1 patients was relatively large (n 188), constrained some factors that affect glycemic control (weight, insulin availability), and enabled precise measurement of other potentially confounding factors (diabetes treatment assessed by insulin dose). The study satisfied certain prerequisites for mediational analysis: 1) measures of the independent variables, depression symptoms, and diabetes self-care, correlated significantly with one another and with the dependent variable (HbA 1c ); 2) assessment of these variables was objective and blinded to assure independence of their errors of measurement; and 3) the independent variable had a significant effect on the dependent variable. The cross-sectional design of the study did not allow us to determine precisely the temporal relationships among the variables, a factor that would have been of greater relevance had the results suggested mediation, and no available measure perfectly reflects the spectrum of behaviors involved in diabetes self-care. In fact, adherence to the insulin regimen is measured only by proxy with the SDSCA yet is a key factor in glycemic control. Prospective or controlled treatment trials that incorporate behavioral monitoring (eg, activity diaries, insulin use) are needed to establish fully the causal pathways linking depression with poor metabolic control. Additionally, although the SCL-90 has been validated in medically ill populations, the measure is not as widely used as other self-report measures (eg, Beck Depression Inventory). Depression has been associated with increases in HbA 1c levels typically in the range of 0.5% to 1.0% (1). Although seemingly small, sustained elevations of this magnitude are clinically significant and accelerate the appearance of diabetes complications (14). Adherence to self-care recommendations is an essential aspect of the diabetes management plan, but additional targets for improving glycemic control appear relevant in depressed patients. Whether depression-associated hyperglycemia can be reversed with conventional depression treatment remains uncertain, the outcomes in part being confounded by direct hyperglycemic effects of some antidepressant medications (49). Likewise, until the mechanisms and directionality underlying the relationship between depression and hyperglycemia are fully understood, treatment remains empiric and targeted at reducing depression symptoms as if they impose hyperglycemic risk (23,50). Novel treatment approaches that have the capacity to improve both depression and glycemic control need exploration for optimizing outcomes in depressed diabetic patients. 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