OBJECTIVE:The protective effects of female gender on the appearance and course of coronary heart disease (CHD) in nondiabetic subjects are diminished in the presence of diabetes. Depression predicts onset of and poor outcome from CHD in nondiabetic populations. We hypothesized that the doubled rates of depression in female diabetic patients could help explain the high prevalence of CHD in women with diabetes. METHOD:Seventy-six female type 1 and type 2 diabetic patients with (N=16) or without (N=60) active major depression (DSM-III) at index evaluation underwent systematic annual investigation of diabetes and its complications for up to 10 years. Occurrences of CHD and other macrovascular complications were examined in relation to depression status using survival analysis statistics. A multivariate model incorporating other CHD risk factors (age, duration of diabetes, body mass index, glycosylated hemoglobin, and presence of hypertension, hyperlipidemia, or tobacco use) was used to determine independent effects of depression on outcome. RESULTS:Development of CHD was significantly more rapid in the depressed subset (p<0.01 between 10-year curves), an effect that persisted after controlling for base-line differences in body mass index. Depression also was retained as an independent predictor of CHD in the multivariate model with an age-adjusted hazard ratio of 5.2 (95% CI: 1.4-18.9; p=.01). In contrast, depression did not predict the development of clinically apparent peripheral or cerebrovascular disease. CONCLUSIONS:In this sample of diabetic women, major depression was an independent risk factor that accelerated the development of CHD. Depression recognition and management may improve outcomes from diabetes in this gender subgroup.

OBJECTIVE:Depression is prevalent in patients with diabetes. It is associated with poor glycemic control and is linked to an increased risk for diabetic complications. In this study, we assessed the efficacy of fluoxetine for depression in patients with diabetes.RESEARCH DESIGN AND METHODS:Sixty patients with diabetes (type 1, n = 26; type 2, n = 34) and major depressive disorder entered an 8-week randomized placebo-controlled double-blind trial. Patients were given daily doses of fluoxetine (up to 40 mg/day). The Beck Depression Inventory (BDI) and Hamilton Rating Scale for Depression (HAMD) were used to measure the severity of depression and to determine the percentage of patients who achieved substantial improvement or complete remission. GHb levels were obtained to monitor glycemic control.RESULTS:Reduction in depression symptoms was significantly greater in patients treated with fluoxetine compared with those receiving placebo (BDI, -14.0 vs. -8.8, P = 0.03; HAMD, -10.7 vs. -5.2, P = 0.01). The percentage of patients achieving a significant improvement in depression per the BDI was also higher in the fluoxetine group (66.7 vs. 37.0%, P = 0.03). Additionally, trends toward a greater rate of depression remission (48.1 vs. 25.9%, P = 0.09 per the HAMD) and greater reduction in GHb (-0.40 vs. -0.07%, P = 0.13) were observed in the fluoxetine group.CONCLUSIONS:Fluoxetine effectively reduces the severity of depression in diabetic patients. Our study demonstrated that after only 8 weeks, this treatment also produced a trend toward better glycemic control.

Little is known about which factors may adversely affect response to psychotherapy in diabetic patients with major depression. We studied the relationship of various demographic, diabetes, and depression characteristics to change in depression in 42 patients with type 2 diabetes who completed a randomized clinical trial of cognitive behavior therapy (CBT). Depression remitted in a significantly greater percentage of the patients treated with CBT than with the control intervention (85.0% vs 27.3%, p < 0.001). In the sample as a whole, nonremission of depression was associated with lower compliance with blood glucose monitoring, higher glycated hemoglobin (GHb) levels, higher weight, and a history of previous treatment for depression. In the group treated with CBT, the presence of diabetes complications and lower compliance with blood glucose monitoring were significant independent predictors of diminished response. These findings show that factors related to the medical illness, such as the presence of diabetes complications, may negatively influence the prognosis for recovery from depression. Specific coverage of these issues during psychotherapy may optimize the likelihood of treatment success in patients with diabetes.

Data from controlled studies [1-8] suggest that depression is more prevalent in diabetic patients than in the general U.S. population and that it is associated with poor glycemic control and decreased compliance with therapy [3, 5, 9-16]. Depression has also been associated with an increased risk for complications of diabetes, particularly cardiovascular disease and retinopathy [17-20]. The mechanisms of these associations are not fully understood, but it is plausible that alleviation of depression improves glycemic control and thereby decreases the risk for complications. Pharmacotherapy for depression may be poorly tolerated or may be insufficient to produce full remission in as many as 50% of diabetic patients with major depression [21-23]. The usefulness of nonpharmacologic approaches to the management of depression, such as psychotherapy, has not been systematically studied. Approximately two thirds of patients who have both diabetes and major depression do not receive specific antidepressant treatment, in part because their physicians tend to attribute their depression to poorly controlled or advancing diabetes [24, 25]. Therapy for these patients still largely centers on medical management, which may include emotional support and diabetes education; this approach is probably suboptimal. Our study was designed to determine the antidepressant efficacy of cognitive behavior therapy (CBT) added to supportive diabetes education. A secondary aim was to determine whether remission of depression is associated with improved glycemic control. Methods Patients Our study was advertised to primary care physicians working within the Washington University School of Medicine and BJC Healthcare System, St. Louis, Missouri, and it was publicized in various mass media advertisements. The study protocol was reviewed and approved by the Human Studies Committee of Washington University School of Medicine. Patients with type 2 diabetes mellitus who were 21 to 70 years of age were eligible for participation if they were able to answer questions, fill out study forms, and give informed consent. The diagnosis of type 2 diabetes was made according to the criteria developed by the American Diabetes Association [26] and was confirmed by a statement from the patient's primary physician. Patients also had to meet the diagnostic criteria for major depression and had to have a score of at least 14 on the Beck Depression Inventory (BDI). Patients were excluded from participation if they had active suicidal ideation or a history of attempted suicide; had a history of panic disorder, bipolar depression, or any psychotic disorder; had a current substance abuse disorder; or were currently taking psychoactive medications. Assessment of Depression The presence of the major Axis I clinical syndromes was assessed by using the National Institute of Mental Health Diagnostic Interview Schedule (DIS) [27], and these syndromes were diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders [28]. The reliability and validity of the DIS in psychiatric and epidemiologic studies have been extensively reported [29]. Evidence also indicates that the DIS is sensitive and useful for patients with diabetes, in whom the somatic manifestations of the medical disease (such as fatigue, weakness, sleep disturbances, and sexual dysfunction) mimic the symptoms of a psychiatric disorder [30, 31]. Although the DIS is suitable for use by trained lay personnel, diagnostic evaluations in our study were done by a clinical social worker and a psychologist, both of whom had been trained in the use of the DIS by the instrument's developers and the staff of the St. Louis site of the National Institute of Mental Health Epidemiologic Catchment Area Study [27, 32]. The severity of current symptoms of depression was measured by using the BDI [33]. This measure asks patients to provide a self-rating from 0 to 3 on each of 21 items; these ratings are added together to produce a total score. The BDI has been studied extensively and has been shown to be a reliable and valid measure of the severity of depression [34]. Depression manifests similarly on this instrument in diabetic and psychiatric patients, particularly with regard to the cognitive symptoms of depression [31]. Assessment of Diabetes Glycosylated hemoglobin (GHb) levels were measured to assess average glycemic control in the 120-day period before testing [35-37]. Total GHb levels were measured with the Pierce Glyco-Test (Pierce Chemical, Rockford, Illinois), an affinity assay that removes confounding by hemoglobin variants, such as hemoglobin F. The range of GHb levels for normal, nondiabetic persons in the Barnes-Jewish Hospital outpatient laboratory is 4.4% to 6.3%. In this laboratory, the between-run coefficients of variation for values greater than 6.6% are all 5% or less, the recommended standard [38]. The presence of complications of diabetes (neuropathy, retinopathy, and nephropathy) was determined by a physician-investigator on the basis of review of each patient's medical history, current symptoms, physical examination results, and objective test results (which were obtained through review of clinical records). Assessment of Compliance Compliance with self-monitoring of blood glucose levels was determined by using electronic memory glucometers (LifeScan, Inc., Milpitas, California), which recorded the date, time, and result of blood glucose testing. Patients were instructed to test their blood glucose levels four times per day on two nonconsecutive days each week. Values for weekly compliance with blood glucose monitoring were computed by dividing the number of samples measured on the two test days by 8 (the number of tests requested) and multiplying the result by 100%. Study Design Patients were informed that depression in diabetes can be a cause or a consequence of poor glycemic control and that the study would determine whether focusing on the mental or the physical side of the problem was the most effective way to relieve depression. These concepts were familiar to most patients and were generally well accepted. No patients declined further evaluation because they were unwilling to accept random assignment. Patients who met the inclusion criteria and gave informed consent underwent a 1-week period of glucometer training and baseline assessment, after which they were randomly assigned to study groups. The randomization pattern was determined by a computer algorithm, and assignments were concealed in sealed envelopes. A secretary who was not otherwise involved with the study opened each patient's envelope after the patient had completed the baseline assessment. During the 10-week treatment period, all patients participated in a diabetes education program by meeting in 1-hour, biweekly, individual sessions with a certified diabetes educator. A variety of diabetes self-care topics were covered in these sessions, and diet and exercise regimens were systematically reviewed and modified as needed. Patients continued to see their diabetologists during the trial, and these physicians were given GHb and glucometer data from our study to facilitate management. The diabetes education program was designed to control for the nonspecific effects of supportive attention as well as the potential influence of enhanced self-care and glycemic control on mood and ideation. Patients were randomly assigned to receive CBT or to receive no specific antidepressant treatment other than the diabetes education program. Patients in the CBT group received 1 hour of treatment weekly for 10 weeks from a licensed psychologist who had been the principal cognitive therapist in an early empirical trial of CBT [39]. Cognitive behavior therapy treats depression by using 1) behavioral strategies to re-involve patients in pleasurable social and physical activities; 2) problem-solving procedures to resolve stressful circumstances; and 3) cognitive techniques to identify distorted or maladaptive thought patterns and replace them with more accurate, adaptive, and useful views. Study outcomes were measured immediately after the end of the 10-week treatment period and at a follow-up evaluation 6 months later. At each evaluation, assessments of diabetic control and depression were made and scored independently of one another. The study personnel who monitored patient progress were not involved in treatment, and assessors were blinded to treatment assignments. No additional study protocol treatment was provided after the end of the 10-week treatment period. Patients who remained depressed at that point (BDI score 10) were referred to their primary physician for antidepressant medication or to a psychotherapist. Glycemic control and severity of depression were measured again at the 6-month follow-up visit, and patients were restudied at that time with an abbreviated psychiatric interview. Self-monitoring of blood glucose levels was not measured after the end of the 10-week treatment period. Statistical Analysis Differences in the demographic and clinical characteristics of patients receiving CBT and controls were determined in the intention-to-treat and completer samples by using the Fisher exact test for categorical data and the Student t-test for continuous data. The results of an intention-to-treat analysis of the depression outcomes are provided for the purpose of comparison [40, 41]. The analyses of study outcomes focused on the completer sample. Analyses of covariance (ANCOVAs) were used to determine the effects of treatment on symptoms of depression and glycemic control after treatment and at 6-month follow-up with beginning levels of the dependent measures (BDI score and GHb level) as the covariates. The post-treatment and follow-up BDI data were not normally distributed. Consequently, the scores were categorized and Fisher exact tests were used to analyze the data. We used ANCOVA for a secondary analysis afte

OBJECTIVE:Depression is a prevalent and chronic condition in diabetes and is associated with poor glucose regulation and poor compliance with diabetes treatment. This investigation evaluated the effects of nortriptyline on depression and glycemic control to see whether depression in diabetes is treatable and whether restoring mental health contributes to improved medical outcome.METHOD:Sixty-eight diabetic patients with poor glycemic control, 28 of whom had active major depression (DSM-IIIR), completed a randomized, placebo-controlled, double-blind trial involving 8 weeks of treatment with nortriptyline targeted to therapeutic plasma levels (50-150 ng/ml). Depression improvement was determined with the Beck Depression Inventory; glucose control was measured by glycated hemoglobin levels. Compliance behavior was assessed using medication dispensing devices and glucometers equipped with electronic memory.RESULTS:The reduction in depression symptoms was significantly greater in depressed patients treated with nortriptyline compared with those receiving placebo (-10.2 vs -5.8, p = .03). Nortriptyline was not statistically superior to placebo in reducing glycated hemoglobin of the depressed subjects (p = .5). However, path analysis indicated that the direct effect of nortriptyline was to worsen glycemic control whereas depression improvement had an independent beneficial effect on glycated hemoglobin. These findings were not explained by the relationships of nortriptyline treatment to weight change (r = -0.21, p = .31) or depression improvement to compliance with the protocol for self-monitoring of blood glucose (r = 0.01, p = .97).CONCLUSIONS:Major depression in diabetic patients can be effectively treated with nortriptyline at the expense of a direct hyperglycemic effect. Path analysis demonstrated a treatment-independent effect of depression improvement on glycemic control, suggesting that a more ideal antidepressant agent may both restore mental health and improve medical outcome.

The course of depression in patients with comorbid medical illness is poorly understood. We report a 5-year follow-up study of 25 diabetic patients who had participated in an 8-week depression treatment trial. When a patient completed the trial, primary physicians were informed of patient outcomes and advised to monitor for relapse and treat those with ongoing depression. At the 5-year reevaluation, depression was assessed using DSM-III-R criteria, and a depression severity scale was formed that reflected the presence, severity, frequency, and duration of depression episodes as well as a global assessment of functioning. Recurrence or persistence of depression occurred in 23 (92%) of the patients with an average of 4.8 depression episodes over the 5-year follow-up period. The duration of the longest episode averaged 16 ± 4 months. Teversion to major depression occurred frequently and rapidly also in the subset that remitted during the treatment trial: 58.3% were depressed again within the first year. At the time of the follow-up interview, major depression was evident in 16 (64%) of the subjects, and glycemic control was significantly worse in this group compared with those without depression (gHb: 13.3% ± 2.6% vs 11.1% ± 1.9%, p = 0.03). Severity of depression over follow-up was related to the presence of neuropathy at entry and to incomplete remission during the initial treatment trial. Nineteen patients (82.6% of those who relapsed) received additional courses of antidepressant therapy, but none was treated continuously for depression prophylaxis. In this diabetic sample, depression was a recurrent condition in the vast majority of cases, and initial treatment response did not confer lasting euthymia. Whether maintenance antidepressant medication would be useful in preventing depression recurrence and promoting better glycemic control in diabetes remains to be studied.

Objective The purpose of this study was to determine the utility of the Beck Depression Inventory (BDI) as a screening tool for major depression in diabetes. Method One hundred seventy-two diabetic outpatients (insulin-dependent diabetes mellitus [IDDM] = 59, or non-insulin-dependent diabetes mellitus [NIDDM] = 113) being evaluated for a treatment trial were studied. BDI scores were calculated for the complete 21-item measure as well as for the cognitive (13 items) and somatic (eight items) symptom subgroups. The presence of depression was determined using the National Institute of Mental Health Diagnostic Interview Schedule in accordance with the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) criteria. Receiver operating characteristic (ROC) analyses were used to evaluate the performance of the screening test in relation to the diagnostic standard. Results Depressed subjects were effectively discriminated from nondepressed subjects by using the full 21-item BDI, the cognitive items alone, or the somatic items alone (p <.001 for each comparison), although the cognitive items were more effective than the somatic items (p <.0005). BDI total scores between 12 and 14 inclusive displayed the best balance between sensitivity (0.90-0.82) and specificity (0.84-0.89), but a cutoff score > or = to16 for the entire 21-item measure exhibited the best balance between sensitivity and positive predictive value when prediction values were extrapolated to a diabetic population with a depression prevalence rate of 20%. This cutoff score would capture >70% of the patients diagnosed with major depression yet provide >70% certainly that a person screening positive actually has the psychiatric disorder. Conclusion The BDI is an effective screening test for major depression in diabetic patients. Prospective studies are needed to confirm the test's precise performance characteristics in the general clinical setting.

OBJECTIVE:To determine the effects of alprazolam on glucose regulation in anxious and nonanxious patients with poor glycemic control and establish whether regulatory benefits are related to anxiolytic effects of the medication. RESEARCH DESIGN AND METHODS:Fifty-eight patients with poor glycemic control, 16 (27.6%) of whom had a symptomatic generalized anxiety disorder, were entered into a randomized, double-blind, placebo-controlled, 8-week trial using alprazolam (up to 2 mg/day) as the active agent. Generalized anxiety disorder was determined in accordance with Diagnostic and Statistical Manual of Mental Disorders criteria, and anxiety symptoms were measured using the Hopkins Symptom Checklist. Glycated hemoglobin levels were used to determine glucose regulation. Compliance behavior was assessed using glucometers and medication monitors equipped with electronic memory. RESULTS:A statistically significant reduction in glycated hemoglobin level was observed in patients treated with alprazolam compared with those receiving placebo (-1.1 vs. -0.3%, P = 0.04). This treatment effect was not a function of differences in compliance behaviors. Anxiety symptoms decreased in both alprazolam- and placebo-treated patients with generalized anxiety disorder, but reduction in glycated hemoglobin level was not dependent on alleviation of anxiety. CONCLUSIONS:A short course of alprazolam improved glucose regulation in patients with a history of poor diabetes control. This effect was not directly related to concomitant changes in anxiety. Alprazolam treatment of anxious patients with poorly controlled diabetes may result in decreased anxiety and improved glucose regulation through independent mechanisms.

Depression in diabetes is a prevalent and chronic condition. The etiology is unknown but is probably complex; and biological, genetic, and psychological factors remain as potential contributors. Several neuroendocrine and neurotransmitter abnormalities common to both depression and diabetes have been identified, adding to etiological speculations. Pharmacotherapy of depression may improve both mood and glucose regulation in diabetes, although controlled studies of the efficacy of psychotherapy and pharmacotherapy for depression in diabetes are not yet available. Depression has potential interactions with diabetes on multiple levels and remains an important clinical focus independent of the medical disease.

The interrelationship of life stress, social support, and glucose regulation was studied in eighty patients with diabetes mellitus (insulin-dependent = 40, non-insulin-dependent = 40). Glucose control was measured using glycosylated hemoglobin (HbA1); stress and social support were determined by the Social Readjustment Rating Scale and a Visual Analog Scale of social support. A two-way analysis of variance [social support (high/low) by life stress (high/low)] revealed that neither social support nor life stress was independently associated with HbA1. However, a significant interaction between these parameters was found. When reported stress was low, the HbA1 means were not statistically different for both high and low social support groups. As stress increased, variations in social support were associated with differences in glucose control. Under conditions of high stress, low social support subjects had significantly higher HbA1 than subjects with high social support (x̄ = 11.8% vs. x̄ = 9.9%, p = .04). These data suggest that during stressful times social support may insulate patients with diabetes from the adverse physiologic and behavioral consequences of stress and thereby foster better glucose control.

Little is known about the course of affective illnesses in patients with diabetes or in other physically ill patients. We report a follow-up study of 37 diabetic adults with major depression (according to DSM-III), 28 (76%) of whom were located and reinterviewed 5 yr after the index evaluations. At follow-up, 18 (64%) of the 28 depressed patients had experienced an episode of major depression within the previous 12 mo; 12 of these patients satisfied diagnostic criteria for depression at the time of reevaluation. The 18 patients with recurrent depression had a mean of 4.2 depressive episodes over the 5-yr period. An additional 4 patients met criteria for current dysthymic disorder, bringing the number to 22 (79%) of the total patients ill with affective disorder during the 5-yr follow-up period. In contrast, the likelihood of symptomatic affective disorder was only 10% over the same follow-up period in a comparison group of diabetic subjects without depression at the index evaluation (P < .001). Occurrence of depressive episodes appeared independent of diabetes complications because both the depressed and comparison groups had similar rates of neuropathy, retinopathy, and nephropathy. These data suggest that the natural course of depression in diabetes is malevolent, possibly more so than depression in the medically well.

The lifetime prevalence of psychiatric illness was determined in 114 patients with diabetes mellitus (types I and II) who were selected randomly from patients undergoing diabetes evaluations at a large medical center. The relationship of psychiatric illness to diabetic control was studied using glycosylated hemoglobin (HbAi) and self-report measures of metabolic symptoms. Seventy-one percent of the patients had a lifetime history of at least one criteria-defined psychiatric illness; affective and anxiety disorders were the most common diagnoses. A significant difference (p=.02) in mean glycosylated hemoglobin levels was observed comparing patients with a recent psychiatric illness (X=10.8%) to those never psychiatrically ill (X=9.6%). These psychiatrically ill patients also- reported more symptoms of poor metabolic control and more distress associated with these symptoms than did patients never psychiatrically ill (p<.0001 for both). The overall report of diabetes symptoms was unrelated to HbA1 (p=.25) and was influenced primarily by the recent presence of psychiatric disorder (p<.0001). We conclude that emotional illness is associated with both poorer metabolic control and the increased report of clinical symptoms of diabetes.