Diabetes Care
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Diabetes Care 30:459-466, 2007
DOI: 10.2337/dc06-1769
© 2007 by the American Diabetes Association
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lustman, P. J.
Right arrow Articles by Clouse, R. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lustman, P. J.
Right arrow Articles by Clouse, R. E.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Clinical Care/Education/Nutrition
Original Article

Factors Influencing Glycemic Control in Type 2 Diabetes During Acute- and Maintenance-Phase Treatment of Major Depressive Disorder With Bupropion

Patrick J. Lustman, PHD1,2, Monique M. Williams, MD1,3, Gregory S. Sayuk, MD3, Billy D. Nix1 and Ray E. Clouse, MD1,3

1 Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
2 Department of Veterans Affairs Medical Center, St. Louis, Missouri
3 Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri

Address correspondence and reprint requests to Patrick J. Lustman, PhD, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8134, St. Louis, MO 63110. E-mail: lustmanp{at}wustl.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
OBJECTIVE—Depression management in both short- and longer-term treatment studies has been associated with improvement in glycemic control. We used bupropion hydrochloride (Wellbutrin XL) to determine whether this improvement could be attributed to changes in anthropometrics or diabetes self-care.

RESEARCH DESIGN AND METHODS—Ninety-three patients with type 2 diabetes and major depressive disorder (MDD) received bupropion hydrochloride in a two-phase, open-label treatment trial. Those who completed the acute phase (10 weeks; n = 75) and whose depression remitted (n = 63) continued bupropion at the remission dose and were followed in the maintenance phase (24 weeks) until attrition (n = 8) or relapse of MDD (n = 0). Self-report scales were used to measure depression symptom severity and diabetes self-care behaviors. Body composition and glycemic control were determined using dual-energy X-ray absorptiometry and serial determinations of A1C.

RESULTS—BMI, total fat mass, and A1C decreased and composite diabetes self-care improved over the acute phase (–0.5 kg/m2, –0.7 kg, –0.5%, and +0.4, respectively, P < 0.01 for each), effects that persisted through the maintenance phase for BMI, A1C, and self-care (P ≤ 0.01 for each). Reductions in BMI (B = 0.30, P = 0.01) and depression severity (B = 0.04, P = 0.046) independently predicted lower A1C after acute-phase treatment, whereas only reduction in depression severity (B = 0.08, P = 0.001) predicted A1C over the maintenance interval.

CONCLUSIONS—In the short term, improvement in glycemic control during bupropion treatment is predicted independently by improvements in mood and body composition. Longer-term improvements in glycemic control are predicted primarily by sustained improvement in mood via mechanisms independent of anthropometric and self-care modifications.

Abbreviations: BDI, Beck Depression Inventory • DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. • HDRS, Hamilton Depression Rating Scale • MDD, major depressive disorder • PHQ-9, Patient Health Questionnaire • SDSCA, Summary of Diabetes Self-Care Activities


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
Findings from prospective population studies in the U.S. (1–3), Japan (4), Canada (5), and the Netherlands (6) indicate that depression is an independent risk factor for the development of type 2 diabetes. In patients with established diabetes, depression portends a more severe illness course, increasing the risks of micro- and macrovascular disease complications (7). The psychiatric disorder appears to make a causal contribution, at least in some instances. For example, in a 10-year prospective study of women participating in a university hospital–based diabetes registry, Clouse et al. (8) found that major depressive disorder (MDD) identified at the index evaluation predicted the development of clinically evident coronary heart disease, with the effect being independent of traditional risk factors such as smoking, hypertension, and hyperlipidemia.

Depression-associated glucose dysregulation probably contributes to some of these observations. Linkage of depression with hyperglycemia and insulin resistance has been reported in cross-sectional (9–11) and prospective studies (12) and corroborated in meta-analysis (13). In controlled clinical trials, cognitive behavior therapy and conventional pharmacotherapy have proven effective for acute- and maintenance-phase management of MDD in diabetic patients (14–17). Improvement in mood also produced improvement in glycemic control and insulin sensitivity in most (14–18), but not all (19), studies. The effects of antidepressant medication on glycemic control (measured as A1C levels) have been less uniform, with some agents appearing to have direct hyperglycemic effects (e.g., nortriptyline) (15) and others having hypoglycemic effects (e.g., fluoxetine) (16). In other studies, improvements in A1C and/or insulin sensitivity were observed without mechanistic exploration (20). Depression increases the risk of being overweight or obese (21), and antidepressants may independently affect weight and visceral adiposity (5,21). Currently it is not known whether antidepressant treatment–related improvements in A1C are mediated predominantly by weight change, especially during longer-term therapy or through weight-independent effects on factors influencing glucose regulation (e.g., catecholamines, cortisol, and cytokines).

The antidepressant properties of bupropion have been demonstrated in controlled and open-label studies of psychiatric patient samples (22–25), and it has gained favor for having efficacy comparable to that of other antidepressants yet with fewer side effects (22,26,27). Bupropion does not interfere with sexual functioning and has been associated with significantly greater weight loss compared with placebo in randomized, double-blind, placebo-controlled studies of overweight and obese individuals with (28) and without (29) depression. Jain et al. (28) studied 422 obese patients with depressive symptoms who received randomized treatment with bupropion or placebo and were followed for 26 weeks while receiving a 500 kcal/day-deficit diet. The group receiving bupropion lost more weight (4.4 vs. 1.7 kg, P < 0.001) and had a higher percentage of patients who lost at least 5% of their baseline weight (40 vs. 16%, P < 0.05) than the placebo group. On the basis of these collective observations, we designed a study to see 1) whether A1C improved during acute- and maintenance-phase treatment with bupropion and 2) whether changes in A1C were related to changes in mood, diabetes self-care, or anthropometrics. Because we expected to see weight reductions with bupropion, the study might provide strong evidence of weight-independent effects of depression improvement on glycemic control, if they exist.


   RESEARCH DESIGN AND METHODS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
RESULTS--
 CONCLUSIONS--
 References
 
The study was a two-phase depression treatment trial. In phase one (acute), patients with MDD received up to 10 weeks of open-label treatment with bupropion. In phase two (maintenance), those who achieved remission of MDD continued to receive bupropion at the remission dose and were followed for up to 24 weeks or until MDD returned. The primary outcome measure was glycemic control, measured with serial determinations of A1C over the 34-week study interval. As the study involved open-label treatment of MDD with bupropion, depression outcomes were considered secondary. Thus, the duration of the acute phase (10 weeks) was constructed to allow sufficient time for an adequate trial of bupropion without compromising the patient’s ability to get other treatment in the face of suboptimal improvement. Measures of depression symptom severity, diabetes self-care, BMI (weight in kilograms divided by the square of height in meters), body composition (total body fat and percent body fat), and diabetes self-care behaviors were taken during the acute- and maintenance-treatment phases. We hypothesized that all measures would reflect significant improvement during treatment and that improvement of depression would predict the A1C level after acute-phase treatment and over the depression-free interval of maintenance independent of the effects of other measured factors.

Patients were recruited from January 2004 through November 2005 via advertisements in public media or by referral from university-based diabetes educators and physicians. Study treatment was completed by March 2006. To enroll, patients were required to be 18–80 years of age, have type 2 diabetes, and meet the criteria for MDD as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) (30). Patients were excluded from participation for having active suicidal ideation, a history of attempted suicide, received electroconvulsive therapy within the 3 months before study entry, a history of psychotic disorder, organic mental disorder, current alcohol or other substance abuse disorder, or a contraindication to bupropion or being unwilling to discontinue other psychoactive medications. Patients with advanced hepatic or renal disease, those with a history of treatment with monamine oxidase inhibitors, or those who had been taking benzodiazepines, terfenadine, astemizole, or digoxin within 3 months of study entry were also excluded, as were those with a history of seizure disorder and women who were pregnant or were lactating. Patients taking an antidepressant at the time of study enrollment were tapered off the medication over an interval ≤2 weeks while bupropion was introduced. Informed consent to participate was obtained from all patients before undergoing medical and psychiatric evaluations. The study was reviewed and approved by the Washington University Medical Center Human Studies Committee. One hundred and five individuals underwent telephone screening and subsequent in-office evaluations. Of these individuals, 93 (90.2%) satisfied all eligibility requirements and were enrolled in the study (Fig. 1).


Figure 1
View larger version (35K):
[in this window]
[in a new window]

  		Figure 1— Subject participation in relation to phases of the study design.

 
Bupropion therapy and monitoring
Enrolled subjects began open treatment with 150 mg/day bupropion hydrochloride extended release (Wellbutrin XL) administered in the morning. The dose was adjusted biweekly by increments of 150 mg/day during the acute phase to a maximum of 450 mg/day, depending on side effects and clinical response. The final dose used to achieve recovery during the acute phase was continued during the maintenance phase without adjustment. At each study office visit, the patient was seen by the physician assistant and the psychiatric technician. Psychometric assessments were performed by the technician independent of the physician assistant’s assessment. The physician assistant evaluated the clinical response and provided clinical management with the structure of the interaction guided by the manual used in the National Institutes of Mental Health Treatment of Depression Collaborative Research Program (31). Initial treatment sessions lasted 45–60 min, and subsequent sessions lasted 15–30 min. Visit frequency was every 2 weeks during the acute phase and every 8 weeks during maintenance; the latter was designed to resemble a primary care monitoring schedule.

A partial remission was required to continue to the maintenance phase and was defined as the absence of MDD per DSM-IV criteria and a Beck Depression Inventory (BDI) score ≤9 at the 10-week assessment. During maintenance-phase observation, a BDI score ≥14 was considered cause for psychiatric diagnostic reevaluation to determine whether MDD had returned. In depression screening studies of diabetic patients, a BDI total score ≥14 has had positive predictive values of 0.57 and 0.65 for MDD when the base rate of depression is 15 and 20%, respectively (32).

Measures
Demographic and diabetes characteristics.
Demographic information including age, sex, race, marital status, education, and type of diabetes was gathered during the eligibility determinations. Other features of depression and diabetes (age of onset of diabetes, method of diabetes treatment, family history of diabetes, family history of depression, number of previous depression episodes, and history of depression treatment) and the presence of diabetes complications (neuropathy, retinopathy, nephropathy, and coronary heart disease) were determined from a composite assessment of current symptoms, physical examination, objective test results obtained by review of clinical records, and patient report of prior diagnoses. Changes in diabetes management regimens were recorded at each visit.

Assessment of depression.
The presence of MDD was assessed using the Diagnostic Interview Schedule–Version IV (30), a highly structured psychiatric interview that allows assignment of diagnoses in accordance with the criteria set forth in DSM-IV (33). The severity of current depression symptoms was measured using two self-report measures, the BDI (34) and the Patient Health Questionnaire-9 (PHQ-9) (35), and one clinician-based assessment, the Structured Interview Guide for the Hamilton Depression Rating Scale (HDRS) (36). The BDI has been the measure most frequently used in depression treatment trials in diabetic populations (14–16) and was identified before data collection as the primary measure of depression severity.

Assessment of glycemic control and diabetes self-care behaviors.
A1C levels were measured before and after the acute phase and bimonthly during maintenance. A1C is an aggregate measure of glycemic control over the 120-day period before testing (37). Because of the time interval incorporated in a single A1C measurement, the short interval between depression assessments, and the fact that follow-up was scheduled up to the point of relapse or recurrence, all values obtained during the maintenance phase were considered reflective of the depression-free interval after remission (17,38). A1C level was determined using a Bayer DCA2000 glucometer, a model certified for its comparability to the reference methods established by the Diabetes Control and Complication Trial (39).

The Summary of Diabetes Self-Care Activities (SDSCA) (40) scale is a 12-item self-report questionnaire that measures levels of self-care behavior and the degree of adherence with medical provider–recommended activities. Toobert et al. (41) provided a psychometric review attesting to the reliability and validity of the SDSCA scale. In the present study we used the SDSCA questions that assess diet amount, exercise, and adherence to glucose monitoring, domains with potential relevance to depression. Raw score averages were calculated for each of these subscales. These indexes provided a meaningful way of characterizing changes in self-care that occurred during the trial. Higher scores indicate greater attention to self-care. Raw scores for each were converted to z scores and also were averaged to form an aggregated z score for the SDSCA.

Anthropometrics and body composition analyses.
At each study visit, height was measured to the nearest 0.5 cm with the patient in bare feet, and weight was measured on a balance scale to the nearest 0.5 kg. BMI was calculated by dividing body weight (in kilograms) by the square of height (in meters). Total body fat mass and percent body fat were determined by using whole-body dual-energy X-ray absorptiometry (QDR-1000/W; Hologic, Waltham, MA) according to a previously described validated method (42). Body composition was measured at baseline, after acute-phase treatment, and at the final maintenance visit.

Statistical analysis
Measures of central tendency were reported as means ± SD for continuous variables unless otherwise noted. Mean A1C values before and after acute-phase treatment were compared using a paired Student’s t test. An average of the A1C levels beyond the acute phase was calculated for each subject over the depression-free interval of maintenance. Values for the BDI, BMI, total body fat mass, percent body fat, and SDSCA scales were computed and compared in the same fashion with the exception that total body fat mass and percent body fat were measured only at the primary observation points: pretreatment, after acute-phase treatment, and at the conclusion of maintenance. All changes were calculated by subtracting the baseline value from the follow-up value for reporting summary changes and for use in subsequent regression models. Changes in diabetes management regimens were coded linearly (decrease, no change, or augmentation) for each study phase. Linear regression on A1C was performed to identify predictors of A1C 1) after acute-phase treatment and 2) during the depression-free interval of maintenance. Independent variables included in the two regression analyses were changes in BMI, BDI, diabetes management, and SDSCA scale scores from the baseline values. Baseline A1C was also included in the models. Body composition measures were highly correlated with each other and with BMI. Thus, BMI was included in the regression model, whereas body composition variables were used only in exploratory analyses of BMI-A1C relationships. Results are presented as standardized (ß) and unstandardized (B) regression coefficients with 95% CIs. P < 0.05 was used as the determinant of statistical significance for all analyses.


   RESULTS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
CONCLUSIONS--
 References
 
Selected demographic, depression, and diabetes characteristics of the sample are presented in Table 1 for all subjects who entered the trial and for whom bupropion treatment was initiated (n = 93) and according to whether they did (n = 75) or did not (n = 18) complete the acute phase of treatment. Those who failed to complete this phase were significantly more likely to be African American (P = 0.007) and older at the first onset of major depression (P = 0.05); the groups were otherwise similar statistically on the measured clinical characteristics shown in the table. Six patients (6.5%) withdrew from the study during the acute phase because of medication side effects (Fig. 1). Increased anxiety was the most frequent side effect and occurred in three of the six patients. The next most common side effects were nausea, dizziness, and skin irritation, each occurring in two patients. No serious adverse events were reported. Augmentation of diabetes management occurred in 12 patients during the acute phase and in 2 patients during the maintenance phase. The management regimen was decreased in one patient during the acute phase and in four patients during the maintenance phase.


View this table:
[in this window]
[in a new window]

  		Table 1— Clinical characteristics of the type 2 diabetic sample

 
Effects on mood and diabetes self-care behavior
Of the 75 patients who completed the acute phase, 63 (84%) satisfied the criteria for remission after 10 weeks of treatment. The mean daily dose in those who completed the acute phase was 334 mg/day (median 300 mg/day, range 150–450 mg/day). The average daily dose of bupropion was higher in the subset whose depression failed to remit, as expected, given the protocol increases in bupropion in the case of insufficient response (400 vs. 321.4 mg/day, P = 0.02). Severity of depression declined significantly on all measures during the acute phase in the subset whose depression remitted (BDI –18.1 ± 7.1, P < 0.01; PHQ-9 –6.8 ± 5.4, P < 0.01; HDRS –14.9 ± 5.8, P < 0.01). However, in the subset whose depression did not remit, significant improvement was seen on some, but not all, measures (BDI –7.9 ± 10.2, P = 0.02; PHQ-9 –5.9 ± 6.4, P = 0.01; HDRS –2.67 ± 5.9, P = 0.14).

Of the 63 patients whose depression remitted and whose treatment continued beyond the acute phase, 55 (87.3%) completed the subsequent 24 weeks of maintenance and 8 (12.7%) discontinued participation prematurely. These groups did not differ significantly in terms of age, race, sex, or severity of depression symptoms at baseline. All 55 (100%) of those who completed the maintenance phase remained free of MDD throughout this phase. The BDI total score remained ≤9 throughout maintenance in 41 (74.5%) of the 55; this subset thus qualified sequentially for full remission and then recovery from the index episode of MDD (30).

Raw scores on the SDSCA subscales measuring adherence to diet and exercise improved significantly during acute-phase treatment (+0.3 ± 0.8 and +0.7 ± 1.8, respectively, P = 0.002 for each comparing baseline to 10-week values) and remained significantly improved during the depression-free interval of maintenance compared with the baseline values (+0.3 ± 0.8 and +0.4 ± 1.5, P = 0.002 and 0.02, respectively). Adherence to glucose testing did not change significantly over the course of the study (acute phase +0.3 ± 1.7, P = 0.23; maintenance phase –0.1 ± 1.5, P = 0.71). The summary scale score improved significantly over the acute phase (+0.4 ± 1.0, P = 0.001) and remained improved but not significantly so during the depression-free interval of maintenance (+0.2 ± 1.0, P = 0.06).

Effects on body composition
Changes in anthropometrics during the acute and maintenance phases relative to pretreatment baseline values are shown in Table 2. Anthropometric measures except percent fat declined significantly during the acute phase in the 75 patients who completed this phase of treatment. Similar changes were observed within the subsets of patients whose MDD remitted or did not remit during the acute phase. In the 55 patients who completed the maintenance phase, changes from baseline over the maintenance interval were significant for weight and BMI; total body fat mass showed a trend toward significance, and, in this instance, the reduction in percent body fat was also significant.


View this table:
[in this window]
[in a new window]

  		Table 2— Changes in anthropometrics during acute and maintenance phases relative to pretreatment baseline values

 
Effects on glycemic control
A1C levels at baseline, at the end of the acute-phase treatment, and during the depression-free interval of maintenance are shown in Fig. 2 for all subjects who completed the study. A1C decreased in the overall subject group during the acute phase (–0.5 ±1.0%, P < 0.001). The effect was completely attributable to changes in the subset showing remission (–0.6 ± 1.1%, P < 0.001), as the change in those who did not show a remission was minimal and insignificant (–0.1 ± 0.7%, P = 0.7). A1C levels remained significantly lower than baseline during the depression-free interval of maintenance (–0.7 ± 1.3%, P < 0.001).


Figure 2
View larger version (29K):
[in this window]
[in a new window]

  		Figure 2— A1C values at baseline, after 10 weeks of (acute-phase) treatment, and during the subsequent 24 weeks of maintenance treatment. Acute-phase treatment with bupropion was associated with a significant decrease in A1C (n = 75) that persisted over the maintenance interval (n = 63). *P < 0.001 compared with baseline.

 
Predictors of A1C at the conclusion of the acute phase and during the depression-free interval of maintenance were identified in separate multiple regression analyses that controlled for A1C at baseline (Table 3). Changes in BMI, BDI, and subscales of the SDSCA over the acute phase and over the depression-free interval of maintenance were included in the first and second models, respectively. The multiple R, R2, and F associated with the models were 0.88, 0.78, and 25.3 (model 1) and 0.85, 0.71, and 18.2 (model 2), respectively. Significant predictors in the first analysis (acute phase) were baseline A1C as well as improvement (reduction) in the BDI and BMI. Only baseline A1C and improvement in depression were retained as significant predictors in the second analysis (maintenance phase), with reduction in BMI trending toward significance. The pattern of findings was similar when total body fat mass was substituted for BMI in the regressions, with reduction in total body fat mass predicting A1C for the acute phase (B = 0.26, P = 0.001) but not for the maintenance phase (B = 0.13, P = 0.16). Percent body fat was not a significant predictor at either point when substituted for BMI (acute-phase B = 0.02, P = 0.81; maintenance-phase B = 0.12, P = 0.18).


View this table:
[in this window]
[in a new window]

  		Table 3— Predictors of A1C after acute-phase and during maintenance-phase bupropion treatment of MDD

 

   CONCLUSIONS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
References
 
Our study was designed to evaluate the plausibility of some mechanisms that accompany treatment of MDD in patients with diabetes, which were postulated in previous research to account for improvements in A1C (14–16,43). We selected bupropion because it is capable of reducing depression and weight simultaneously and hypothesized that these effects would be accompanied by improved glycemic control in diabetic patients with MDD. This was neither an efficacy nor effectiveness trial but rather an experiment in which bupropion was used to perturb depression and anthropometrics. The relationships of these perturbations to changes in A1C, when examined within the context of alterations in diabetes self-care that can accompany mood improvement, were then studied over time intervals corresponding to milestones in depression management (i.e., acute- and maintenance-phase treatment). This study had the potential to demonstrate that depression improvement has a favorable effect on glycemic control that is weight independent and unrelated to improved diabetes self-care, a finding that would support the presence of other mediators of the depression-hyperglycemia relationship (13,38).

As we had anticipated, bupropion treatment of our diabetic subjects was accompanied by significant reductions in depression. Depression remitted in 68% of those who started bupropion treatment and in 84% of those who completed the acute phase. Of those whose depression remitted and who continued to receive bupropion, 87% completed the subsequent 6-month study interval, and none of these had a recurrence. Improvements in depression were accompanied by improvements in anthropometrics, some diabetes self-care behaviors, and glycemic control. Reductions in depression severity and BMI each independently predicted lower A1C after the acute phase. Reduction in depression severity was the only independent predictor of A1C over the maintenance interval. The pattern of findings was similar when weight or total body fat was used in place of BMI in the regression model. Whereas SDSCA scale–derived measures of adherence to diet and exercise improved significantly during the acute phase and remained improved during the maintenance phase, these improvements were not independently predictive of improvements in glycemic control over the same intervals.

The findings from the current study replicate those of our previous studies showing that antidepressant pharmacotherapy provides effective relief from depression in diabetic patients and that euthymic effects of depression treatment have euglycemic effects as well (14–17). In the present study, significant improvement in A1C was confined to the subset of patients achieving MDD remission during the acute phase. The unstandardized coefficient for the relationship of depression and A1C was 0.04 for the acute phase and 0.08 for the maintenance phase (Table 3), indicating that for every drop of 1 point in the BDI there were corresponding reductions in A1C of 0.04 and 0.08%, respectively, controlling for other measured factors. Reductions in the BDI in the range of those observed in this study (18.1) could translate to improvements in A1C in the range of 0.6 to 1.2% over intervals corresponding to the acute and maintenance phases. Glycemic control sufficient to avoid complications is difficult to achieve even with intensive diabetes care and monitoring (44). Thus, depression management qualifies as ancillary treatment supporting the end goal of improved diabetes control. Furthermore, to our knowledge, this is the first demonstration of broad improvement in diabetes self-care during depression treatment. In prior studies by Lin et al. (45) and Williams et al. (46), successful depression treatment led to increases in physical activity (46) but had no effect on other aspects of diabetes self-care (e.g., adherence to medical advice regarding diet and glucose testing) (46). The difference may relate to greater improvement in depression symptoms achieved in the present study or the failure of earlier studies to look at an effect of depression improvement independent of treatment.

Finally, we found that depression improvement–related reductions in A1C occurred in the presence and independently of favorable effects on anthropometrics and diabetes self-care. Although weight loss and improved self-care may occur with depression relief, they did not adequately explain the normoglycemic effect of depression improvement. With regard to diabetes self-care, the findings can be compared with those reported in a recent study of patients with type 1 diabetes (38). In that study, depression was associated significantly with higher A1C after controlling for weight and insulin dose, and addition of the SDSCA scale into the mediational analysis had no effect on the parameter estimate, indicating that poor self-care did not mediate the effect.

Although statistically significant, the reductions in weight observed in the subset showing remission over the acute (1.5 kg) and maintenance (2.1 kg) phases were modest. This finding is perhaps disappointing, given the substantial improvement that occurred in mood and the conspicuous linkage of depression with obesity. Simon et al. (21) recently demonstrated that nearly one-quarter of the cases of obesity occurring in the population are attributable to the association of obesity and depression. On the other hand, small durable improvements in BMI are genuine accomplishments and can have significant beneficial effects on health (47). It is encouraging that clinically important improvements in A1C can occur in the absence of large changes in anthropometrics. The findings suggest the possibility of weight-independent physiological mechanisms such as those we postulated previously (38,48). These may include changes to the hypothalamic- and limbic-hypothalamic pituitary-adrenal axes, hippocampal glucocorticoid receptors, the autonomic nervous system, and immunoinflammatory processes (49–56).

Although this study was not a randomized, controlled trial, we were impressed with the high rate of depression remission (87%) and the absence of depression recurrence in those who completed the acute and maintenance phases, respectively. A number of factors may have contributed to these robust benefits in this sample, including open-label administration of treatment, weight loss, the absence of study discontinuation referable to sexual side effects and an overall improvement in sexual functioning in our sample (57), and the more frequent monitoring and greater attention (compared with the general practice setting) that is given to participants in a clinical trial. Given the bidirectional interaction of mood with glucose regulation (48), it is also possible that observed reductions in weight and A1C (and probably insulin sensitivity as well) served to reinforce the antidepressant effects of bupropion or had euthymic effects independent of bupropion. The antidepressant potential of insulin-sensitizing maneuvers, be they behavioral or pharmacotherapeutic, is a matter worthy of future research.

Although this study advances our understanding of the mechanisms involved in the interaction of depression and glucose regulation, it has several important limitations. The fact that bupropion was administered in a research setting and without a comparator treatment limit, respectively, the external and internal validity of the depression treatment findings. The measure of diabetes self-care is not a precise measure of behaviors and may have underestimated the effect. The study was possibly underpowered to detect BMI/total body fat mass effects in the maintenance phase; on the other hand, a larger sample probably would not have diminished the effect of BDI change. The design does not precisely establish the temporal sequences among the variables; thus, directional statements are meant to be interpreted cautiously. We cannot, for example, rule out the possibility that glycemic improvement preceded and facilitated depression improvement, although the rapid reduction in depression and the aggregate nature of the A1C measure argue against this. With the lack of a placebo-control condition, it is also possible that the improvements in A1C were a direct effect of bupropion, a possibility that merits further study. Despite these evident limitations, our study affirms the importance of depression management in diabetic patients in its potential to improve glycemic control, even though the mechanisms involved are not fully understood. This advantage could lead to better outcomes, measured not only in quality of life but also in reduced or delayed onset of complications.


   Acknowledgments
 
This work was supported in part by grants from the National Institutes of Health (DK63202), the Sidney R. Baer, Jr., Foundation, and GlaxoSmithKline, Inc., the manufacturer of Wellbutrin XL.


   Footnotes
 
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication August 21, 2006. Accepted for publication November 28, 2006.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 

  1. Golden SH, Williams JE, Ford DE, Yeh HC, Sanford CP, Nieto FJ, Brancati FL: Depressive symptoms and the risk of type 2 diabetes: the Atherosclerosis Risk in Communities study. Diabetes Care 27:429–435, 2004[Abstract/Free Full Text]
  2. Arroyo C, Hu FB, Ryan LM, Kawachi I, Colditz GA, Speizer FE, Manson J: Depressive symptoms and risk of type 2 diabetes in women. Diabetes Care 27:129–133, 2004[Abstract/Free Full Text]
  3. Carnethon MR, Kinder LS, Fair JM, Stafford RS, Fortmann SP: Symptoms of depression as a risk factor for incident diabetes: findings from the National Health and Nutrition Examination Epidemiologic Follow-Up Study, 1971–1992. Am J Epidemiol 158:416–423, 2003[Abstract/Free Full Text]
  4. Kawakami N, Takatsuka N, Shimizu H, Ishibashi H: Depressive symptoms and occurrence of type 2 diabetes among Japanese men. Diabetes Care 22:1071–1076, 1999[Abstract/Free Full Text]
  5. Brown LC, Majumdar SR, Newman SC, Johnson JA: History of depression increases risk of type 2 diabetes in younger adults. Diabetes Care 28:1063–1067, 2005[Abstract/Free Full Text]
  6. Knol MJ, Twisk JW, Beekman AT, Heine RJ, Snoek FJ, Pouwer F: Depression as a risk factor for the onset of type 2 diabetes mellitus: a meta-analysis. Diabetologia 49:837–845, 2006[Medline]
  7. de Groot M, Anderson RJ, Freedland KE, Clouse RE, Lustman PJ: Association of depression and diabetes complications: a meta-analysis. Psychosom Med 63:619–630, 2001[Abstract/Free Full Text]
  8. Clouse RE, Lustman PJ, Freedland KE, Griffith LS, McGill JB, Carney RM: Depression and coronary heart disease in women with diabetes. Psychosom Med 65:376–383, 2003[Abstract/Free Full Text]
  9. Ciechanowski PS, Katon WJ, Russo JE, Hirsch IB: The relationship of depressive symptoms to symptom reporting, self-care and glucose control in diabetes. Gen Hosp Psychiatry 25:246–252, 2003[Medline]
  10. Van der Does FE, De Neeling JN, Snoek FJ, Kostense PJ, Grootenhuis PA, Bouter LM, Heine RJ: Symptoms and well-being in relation to glycemic control in type II diabetes. Diabetes Care 19:204–210, 1996[Abstract]
  11. Lustman PJ, Carney RM, Clouse RE: Depression and the reporting of diabetes symptoms. Int J Psychiatry Med 18:295–303, 1988[Medline]
  12. Kovacs M, Mukerji P, Iyengar S, Drash A: Psychiatric disorder and metabolic control among youths with IDDM: a longitudinal study. Diabetes Care 19:318–323, 1996[Abstract]
  13. Lustman PJ, Anderson RJ, Freedland KE, de Groot M, Carney RM: Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care 23:434–442, 2000[Medline]
  14. Lustman PJ, Griffith LS, Freedland KE, Kissel SS, Clouse RE: Cognitive behavior therapy for depression in type 2 diabetes: a randomized controlled trial. Ann Intern Med 129:613–621, 1998[Abstract/Free Full Text]
  15. Lustman PJ, Griffith LS, Clouse RE, Freedland KE, Eisen SA, Rubin EH, Carney RM, McGill JB: Effects of nortriptyline on depression and glycemic control in diabetes: results of a double-blind, placebo-controlled trial. Psychosom Med 59:241–250, 1997[Abstract/Free Full Text]
  16. Lustman PJ, Freedland KE, Griffith LS, Clouse RE: Fluoxetine for depression in diabetes: a randomized, double-blind, placebo-controlled trial. Diabetes Care 23:618–623, 2000[Abstract/Free Full Text]
  17. Lustman PJ, Clouse RE, Nix BD, Freedland KE, Rubin EH, McGill JB, Williams MM, Gelenberg AJ, Ciechanowski PS, Hirsch IB: Sertraline for prevention of depression recurrence in diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 63:521–529, 2006[Abstract/Free Full Text]
  18. Okamura F, Tashiro A, Utumi A, Imai T, Suchi T, Tamura D, Sato Y, Suzuki S, Hongo M: Insulin resistance in patients with depression and its changes during the clinical course of depression: minimal model analysis. Metabolism 49:1255–1260, 2000[Medline]
  19. Katon WJ, Von Korff M, Lin EH, Simon G, Ludman E, Russo J, Ciechanowski P, Walker E, Bush T: The Pathways Study: a randomized trial of collaborative care in patients with diabetes and depression. Arch Gen Psychiatry 61:1042–1049, 2004[Abstract/Free Full Text]
  20. Goodnick PJ: Use of antidepressants in treatment of comorbid diabetes mellitus and depression as well as in diabetic neuropathy. Ann Clin Psychiatry 13:31–41, 2001[Medline]
  21. Simon GE, Von Korff M, Saunders K, Miglioretti DL, Crane PK, van Belle G, Kessler RC: Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry 63:824–830, 2006[Abstract/Free Full Text]
  22. Coleman CC, Cunningham LA, Foster VJ, Batey SR, Donahue RM, Houser TL, Ascher JA: Sexual dysfunction associated with the treatment of depression: a placebo-controlled comparison of bupropion sustained release and sertraline treatment. Ann Clin Psychiatry 11:205–215, 1999[Medline]
  23. Weisler RH, Johnston JA, Lineberry CG, Samara B, Branconnier RJ, Billow AA: Comparison of bupropion and trazodone for the treatment of major depression. J Clin Psychopharmacol 14:170–179, 1994[Medline]
  24. Pitts WM, Fann WE, Halaris AE, Dressler DM, Sajadi C, Snyder S, Ilaria RL: Bupropion in depression: a tri-center placebo-controlled study. J Clin Psychiatry 44:95–100, 1983[Medline]
  25. Feighner JP, Meredith CH, Stern WC, Hendrickson G, Miller LL: A double-blind study of bupropion and placebo in depression. Am J Psychiatry 141:525–529, 1984[Abstract/Free Full Text]
  26. Masand PS, Ashton AK, Gupta S, Frank B: Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. Am J Psychiatry 158:805–807, 2001[Abstract/Free Full Text]
  27. Gardner EA, Johnston JA: Bupropion—an antidepressant without sexual pathophysiological action. J Clin Psychopharmacol 5:24–29, 1985[Medline]
  28. Jain AK, Kaplan RA, Gadde KM, Wadden TA, Allison DB, Brewer ER, Leadbetter RA, Richard N, Haight B, Jamerson BD, Buaron KS, Metz A: Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. Obes Res 10:1049–1056, 2002[Medline]
  29. Anderson JW, Greenway FL, Fujioka K, Gadde KM, McKenney J, O’Neil PM: Bupropion SR enhances weight loss: a 48-week double-blind, placebo-controlled trial. Obes Res 10:633–641, 2002[Medline]
  30. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 1994
  31. Fawcett J, Epstein P, Fiester SJ, Elkin I, Autry JH: Clinical management-imipramine/placebo administration manual: NIMH Treatment of Depression Collaborative Research Program. Psychopharmacol Bull 23:309–324, 1987[Medline]
  32. Lustman PJ, Clouse RE, Griffith LS, Carney RM, Freedland KE: Screening for depression in diabetics using the Beck Depression Inventory. Psychosom Med 59:24–31, 1997[Abstract/Free Full Text]
  33. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Washington, DC, American Psychiatric Association, 1987
  34. Beck AT, Beamesderfer A: Assessment of depression: the Depression Inventory. Mod Probl Pharmacopsychiatry 7:151–169, 1974[Medline]
  35. Spitzer RL, Kroenke K, Williams JB: Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders: Patient Health Questionnaire. JAMA 282:1737–1744, 1999[Abstract/Free Full Text]
  36. Williams JB, Link MJ, Rosenthall NE: Structured Interview Guide for the Hamilton Depression Rating Scale–Seasonal Affective Disorder Version (SIGH-SAD). New York, New York State Psychiatric Institute, 1992
  37. Tests of glycemia in diabetes. Diabetes Care 27:91S–93S, 2004[Medline]
  38. Lustman PJ, Clouse RE, Ciechanowski PS, Hirsch IB, Freedland KE: Depression-related hyperglycemia in type 1 diabetes: a mediational approach. Psychosom Med 67:195–199, 2005[Abstract/Free Full Text]
  39. DCCT: The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–985, 1993[Abstract/Free Full Text]
  40. Wysocki T: Impact of blood glucose monitoring on diabetic control: obstacles and interventions. J Behav Med 12:183–205, 1989[Medline]
  41. Toobert DJ, Hampson SE, Glasgow RE: The Summary of Diabetes Self-Care Activities measure: results from 7 studies and a revised scale. Diabetes Care 23:943–950, 2000[Abstract]
  42. Salamone LM, Fuerst T, Visser M, Kern M, Lang T, Dockrell M, Cauley JA, Nevitt M, Tylavsky F, Lohman TG: Measurement of fat mass using DEXA: a validation study in elderly adults. J Appl Physiol 89:345–352, 2000[Abstract/Free Full Text]
  43. Lustman PJ, Griffith LS, Clouse RE, Freedland KE, Eisen SA, Rubin EH, Carney RM, McGill JB: Effects of alprazolam on glucose regulation in adult diabetic patients: results of a double-blind, placebo-controlled trial. Diabetes Care 18:1133–1139, 1995[Abstract]
  44. Harris MI: Medical care for patients with diabetes: epidemiologic aspects. Ann Intern Med 124:117–122, 1996[Abstract/Free Full Text]
  45. Lin EH, Katon W, Rutter C, Simon GE, Ludman EJ, Von Korff M, Young B, Oliver M, Ciechanowski PC, Kinder L, Walker E: Effects of enhanced depression treatment on diabetes self-care. Ann Fam Med 4:46–53, 2006[Abstract/Free Full Text]
  46. Williams JW Jr, Katon W, Lin EH, Noel PH, Worchel J, Cornell J, Harpole L, Fultz BA, Hunkeler E, Mika VS, Unutzer J: The effectiveness of depression care management on diabetes-related outcomes in older patients. Ann Intern Med 140:1015–1024, 2004[Abstract/Free Full Text]
  47. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403, 2002[Abstract/Free Full Text]
  48. Lustman PJ, Clouse RE: Treatment of depression in diabetes: impact on mood and medical outcome. J Psychosom Res 53:917–924, 2002[Medline]
  49. Musselman DL, Betan E, Larsen H, Phillips LS: Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment. Biol Psychiatry 54:317–329, 2003[Medline]
  50. Ramasubbu R: Insulin resistance: a metabolic link between depressive disorder and atherosclerotic vascular diseases. Med Hypotheses 59:537–551, 2002[Medline]
  51. Boden G, Hoeldtke RD: Nerves, fat, and insulin resistance. N Engl J Med 349:1966–1967, 2003[Free Full Text]
  52. De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M: Brain corticosteroid receptor balance in health and disease. Endocr Rev 19:269–301, 1998[Abstract/Free Full Text]
  53. Gold PW, Goodwin FK, Chrousos GP: Clinical and biochemical manifestations of depression: relation to the neurobiology of stress (2). N Engl J Med 319:413–420, 1988[Abstract]
  54. Kathol RG: Etiologic implications of corticosteroid changes in affective disorder. Psychiatr Med 3:135–162, 1985[Medline]
  55. Lopez JF, Chalmers DT, Little KY, Watson SJ: A.E. Bennett Research Award: Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry 43:547–573, 1998[Medline]
  56. Nemeroff CB: The neurobiology of depression. Sci Am 278:42–49, 1998[Medline]
  57. Sayuk GS, Clouse RE, Nix BD, Williams MM: Improvement in sexual functioning in depressed diabetic patients treated with Wellbutrin XL®. In Proceedings of the Annual Meeting of the American Psychosomatic Society, Denver, CO, 2006. McLean, VA, American Psychosomatic Society, 2006, Abstract 1085

Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 J Am Board Fam MedHome page
N. Mier, A. Bocanegra-Alonso, D. Zhan, S. Wang, S. M. Stoltz, R. I. Acosta-Gonzalez, and M. A. Zuniga
Clinical Depressive Symptoms and Diabetes in a Binational Border Population
J Am Board Fam Med, May 1, 2008; 21(3): 223 - 233.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
J. S. Gonzalez, S. A. Safren, E. Cagliero, D. J. Wexler, L. Delahanty, E. Wittenberg, M. A. Blais, J. B. Meigs, and R. W. Grant
Depression, Self-Care, and Medication Adherence in Type 2 Diabetes: Relationships across the full range of symptom severity
Diabetes Care, September 1, 2007; 30(9): 2222 - 2227.
[Abstract] [Full Text] [PDF]

Home page
 Psychosom. Med.Home page
P. J. Lustman and R. E. Clouse
Depression in Diabetes: The Chicken or the Egg?
Psychosom Med, May 1, 2007; 69(4): 297 - 299.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lustman, P. J.
Right arrow Articles by Clouse, R. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lustman, P. J.
Right arrow Articles by Clouse, R. E.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum