Journal of Diabetes and Its Complications 19 (2005) 113 122

Depression in diabetic patients The relationship between mood and glycemic control
Patrick J. Lustman a,c,*, Ray E. Clouse a,b
a b

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA c Department of Veterans Affairs Medical Center, St. Louis, MO, USA

Received 24 October 2003; received in revised form 20 January 2004; accepted 21 January 2004

Abstract Problem: Evidence from prospective and cross-sectional studies demonstrates that the presence of diabetes doubles the risk of comorbid depression. This commonly overlooked comorbidity affects more than one quarter of the diabetic population, making its recognition and treatment in diabetic patients clinically relevant. Methods: PubMed, PsycINFO, and MEDLINE databases were searched (search words: diabetes, depression, metabolic control, hyperglycemia, hypoglycemia) for articles that evaluated outcomes, relationships, and/or management of comorbid depression and diabetes published between 1980 and 2002. This review represents a synthesis of the findings including treatment recommendations. Results: Concurrent depression is associated with a decrease in metabolic control, poor adherence to medication and diet regimens, a reduction in quality of life, and an increase in health care expenditures. In turn, poor metabolic control may exacerbate depression and diminish response to antidepressant regimens. Psychotherapy and pharmacotherapy are effective in the presence of diabetes; both cognitive behavior therapy and selective serotonin reuptake inhibitors are weight neutral and have been associated with glycemic improvement in some studies. Conclusion: Depression is common in both type 1 and type 2 diabetes and has significant effects on the course and outcome of this medical illness. Conventional antidepressant management strategies are effective and the regimen should be tailored to the individual patient. Enhanced efforts toward good glycemic control may also contribute to improvements in mood and perceptions of well-being. D 2005 Elsevier Inc. All rights reserved.
Keywords: Antidepressant therapy; Depression; Diabetes; Glycemic control

1. Introduction Diabetes mellitus is a chronic disease resulting from defects in insulin secretion, insulin action, or both. It currently affects approximately 17 million people, or 6.2% of the population of the United States; this figure is expected to rise to 9% by 2025 (American Diabetes Association, 2003). Long-term macrovascular, neurological, and microvascular complications, such as retinopathy, nephropathy, and neuropathy, are significant causes of morbidity and mortality in patients with diabetes. More recently, major depression also has been shown to be a common comorbidity, affecting more
* Corresponding author. Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8134, St. Louis, MO 63110, USA. Tel.: +1-314-362-2621; fax: +1-314-747-4044. E-mail address: lustmanp@msnotes.wustl.edu (P.J. Lustman). 1056-8727/05/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jdiacomp.2004.01.002

than one quarter of the diabetic population (Anderson, Freedland, Clouse, & Lustman, 2001; Egede, Zheng, & Simpson, 2002; Gavard, Lustman, & Clouse, 1993; Goodnick, Henry, & Buki, 1995). Growing evidence from clinical studies indicates that diabetic patients with major depression demonstrate poor adherence to antidiabetic regimens, have poor glycemic control, and are at increased risk for retinopathy (Kovacs, Mukerji, Drash, & Iyengar, 1995) and macrovascular complications (Lloyd, Matthews, Wing, & Orchard, 1992). This article reviews diabetes-associated depression and its relationship to glycemic control. It describes approaches for the detection and management of depression, including the use of antidepressant therapies and their effects on glycemic control. Also reviewed are data showing the positive effects that good metabolic control has on psychological well-being and outcomes of the treatment of depression in diabetic patients.

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2. Depression in diabetes The prevalence of symptomatic major depression in the general adult population is 3% to 4%, a figure that is on the rise (Gavard et al., 1993). Diabetes has been reported to at least double the risk of comorbid depression, with the point prevalence approximating 11% in the diabetic population (Anderson et al., 2001; Egede et al., 2002; Goodnick et al., 1995). A recent meta-analysis suggests that the prevalence increases to 28.5% when diabetic patients with previous histories of depression are included in the figure, regardless of whether type 1 or type 2 disease is present (Anderson et al., 2001). Likewise, nearly a third of diabetic patients report an increase in depression symptoms when mood is measured using symptom inventories (Anderson et al., 2001). Depression in diabetes contributes to poor metabolic control, decreased quality of life, and increased medical morbidity and mortality (Ciechanowski, Katon, & Russo, 2000; Gary, Crum, Cooper-Patrick, Ford, & Brancati, 2000; Hanninen, Takala, & Keinnanen-Kiukaanniemi, 1999). Evidence from prospective and cross-sectional studies has indicated that depression is associated with factors related to glucose dysregulation, including obesity and nonadherence to treatment, which increase the risk of diabetic complications (Lustman, Griffith, & Clouse, 1988). A recent review of the literature found a consistent and statistically significant correlation between the symptoms of depression and the severity or number of diabetic complications, such as retinopathy, nephropathy, neuropathy, sexual dysfunction, and macrovascular disease (de Groot, Anderson, Freedland, Clouse, & Lustman, 2001). The risk of retinopathy in children with type 1 diabetes has also been demonstrated to be associated with major depression, as well as with the duration of the diabetes and poor glycemic control (Kovacs et al., 1995). Diabetes is associated with high medical costs. The economic burden of diabetes approached $132 billion in 2002 (American Diabetes Association, 2003a). Concurrent depression in patients with diabetes further increases health care use and expenditures, even after adjustments for differences in age, gender, race/ethnicity, health insurance coverage, and comorbidity (Ciechanowski et al., 2000; Egede et al., 2002). In 1996, mean health care expenditures for diabetic patients with depression were $247 million, as compared with $55 million for those without depression ( P < .0001) (Egede et al., 2002). The existence of a temporal relationship between depression and onset of both types of diabetes or diabetesassociated comorbidity has been hypothesized to exist. For depression in type 2 diabetes, the initial onset of major depressive disorder (MDD) has been suggested by the literature to occur independently and precede the diagnosis of type 2 diabetes by many years (Lustman et al., 1988). Studies have also suggested a causative temporal association between the existence of depressive symptomatology or

MDD and the development of type 2 diabetes (Eaton, Armenian, Gallo, Pratt, & Ford, 1996; Kawakami, Takatsuka, Shimizu, & Ishibashi, 1999). Depression is believed to contribute to the development or progression of diabetic complications through its behavioral and metabolic effects (de Groot et al., 2001). According to a national 21-year follow-up study, symptoms of depression were found to predict diabetes independently and through established risk factors for diabetes in patients, primarily in those of low socioeconomic status with high numbers of depressive symptoms (Carnethon, Kinder, Fair, Stafford, & Fortmann, 2003). On the other hand, psychosocial factors associated with the hardships imposed by chronic illnesses such as diabetes may themselves be responsible for concurrent depression in some patients. This mechanism appears to be particularly operational in type 1 diabetes, wherein the onset of diabetes antedates the first presentation of depression by many years (Talbot & Nouwen, 2000). 2.1. Depression and poor metabolic control Although depression is a relatively common condition in patients with diabetes, its association with glycemic control has only recently been reviewed (Lustman, Anderson, et al., 2000). A meta-analysis of 24 studies demonstrated that depression in patients with diabetes was significantly associated with hyperglycemia in both type 1 and type 2 disease ( P < .0001) (Lustman, Anderson, et al., 2000). Our working hypothesis has been that depression interferes with good glycemic control, and several types of observation support this hypothesis. For example, cortisol abnormalities associated with depression would have hyperglycemic effects as would weight gain, physical inactivity, and poor adherence to medication regimens. Recent information suggests that insulin resistance accompanies depression, independent of a relationship with weight, yet it improves with depression treatment (McCarty, 1994; Mueller, Heninger, & McDonald, 1969; Nathan, Sachar, Asnis, Halbreich, & Halpern, 1981; Okamura et al., 2000; Wright, Jacisin, Radin, & Bell, 1978). Likewise, we have shown that the remission of depression is associated with a reduction in glucosylated hemoglobin (A1C) levels in diabetic patients (Lustman, Griffith, Freedland, Kissel, & Clouse, 1998). The issue may be more complicated, however, in that poor glycemic control may adversely affect mood and thereby reinforce the relationship between diabetes and depression (Fig. 1). Early investigations using a hyperglycemic clamp demonstrated that hyperglycemia can provoke symptoms of anxiety in type 1 diabetic patients (Lustman, Carney, & Amado, 1981). In a study that prospectively examined the relationship between blood glucose levels and self-reported mood in adults with type 1 diabetes, negative mood states, including anger and sadness, were related to high blood glucose levels in the majority of patients (Gonder-Frederick, Cox, Bobbitt, & Pennebaker, 1989). Although directionality was not assessed, these findings also suggest that blood

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Favorable effects on depression and

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DEPRESSION
Changes in weight, physical

ANTIDEPRESSANT THERAPY
Adverse effects on glycemic control through biochemical and behavioral effects

activity, medication adherence, other health behaviors; CNS regulatory changes including Negative feedback with exacerbation of

HYPERGLYCEMIA
Provocation of T2DM or worsening course of T2DM or T1DM

Fig. 1. Diagram illustrating one hypothesis that depression can induce hyperglycemia through many mechanisms, particularly in the patient with existent diabetes. This hypothesis is consistent with recent findings that both depressive symptomatology and diagnosed MDD precedes and may increase the risk for the development of type 2 diabetes (Eaton et al., 1996; Kawakami et al., 1999). In turn, hyperglycemia may promote dysphoria. Although antidepressant interventions can improve both mood and hyperglycemia, their potential for direct hyperglycemic effects through behavioral (worsened medication adherence, dietary indiscretions) and collateral biochemical actions must be evaluated for each intervention.

glucose fluctuations in diabetic patients may have affective consequences (Gonder-Frederick et al., 1989). Moods found to be most frequently associated with low blood glucose levels included nervousness, fright, worry, and frustration (Gonder-Frederick et al., 1989). Mood changes associated with hypoglycemia may be caused by sympathetic arousal and other physiological and psychological mechanisms, such as cortical dysfunction resulting from inadequate quantities of glucose in the brain (GonderFrederick et al., 1989). Well-being and perceived health status are significantly correlated with A1C levels, lower levels being associated with global well-being (Van der Does et al., 1996). However, the effect of diabetes management on mood can only be established by treatment trials designed specifically to explore this question. To date, no such studies have been reported. Suggestive data can be found in two randomized, controlled clinical trials assessing the efficacy of two different diabetes interventions. In these studies, metabolic control and depression were correlated: As metabolic control improved, so did depression (Mazze, Lucido, & Shamoon, 1984; Testa & Simonson, 1998). Higher A1C levels have also been found to predict diminished responsiveness to antidepressant interventions and a worse course of depression over 5 years of observation (Lustman, Griffith, Clouse, et al., 1997; Lustman, Griffith, Freedland, & Clouse, 1997; Lustman, Griffith, et al., 1998). Therefore, just as hyperglycemia is responsible for the development of microvascular and macrovascular complications in diabetic patients, poor glycemic control may be a factor in the development, management, and course of depression in this population (Lustman, Anderson, et al., 2000).

2.2. The course of depression in diabetes Depression is an ongoing disease state in patients with diabetes. Twenty-five patients with diabetes who participated in an 8-week, placebo-controlled evaluation of the antidepressant effects of nortriptyline were followed for an additional 5 years (mean, 58.1F13.3 months) (Lustman, Griffith, Freedland, et al., 1997). At the time of follow-up, 16 (64%) were diagnosed with major depression. As previously observed in cross-sectional studies, glycemic control was significantly worse in the patients with depression than in those without (Fig. 2) (Lustman, Griffith, Freedland, et al., 1997). In the majority of the diabetic patients, evaluated, depression was a recurrent illness. These patients had an average of 4.8F4.1 episodes during the follow-up period (or one episode per year) (Lustman, Griffith, Freedland, et al., 1997). Even if mood was shown to have improved during the first clinical trial, reversion to symptomatic major depression during the follow-up was rapid: Nearly 60% of patients were depressed within the first year. The severity of the depressive episode during the follow-up was related to the incomplete remission of depression during the clinical trial. These findings are not dissimilar from those in the general population, wherein cessation of antidepressant therapy results in a reversion to symptomatic major depression in 25% to 50% of patients within 6 months and in another 20% within 18 months (Belsher & Costello, 1988; Lustman, Griffith, Freedland, et al., 1997; Prien & Kupfer, 1986; Shea et al., 1992; Thase, 1990). In the general population, the continuation of antidepressant medication beyond remission of depression reduces the risk of both

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Major depression at evaluation point Not depressed at evaluation point

HbA(1c)

11 9

7 5 Index Follow-up Evaluation point

Fig. 2. A1C levels in depressed diabetic patients at index evaluation and 5 years later. Patients who were depressed at the follow-up evaluation had significantly higher A1C levels than did those who were in remission (*P = .03 comparing the two groups at follow-up). Levels represent meansFS.E.M. Adapted with permission from Lustman, Griffith, Freedland, et al. (1997).

relapse and recurrence by up to 50% (Prien & Kupfer, 1986; Kupfer, 1991). Therefore, it seems appropriate that each episode of depression in patients with diabetes should be managed aggressively to complete resolution (Lustman, Griffith, Freedland, et al., 1997). Preliminary information from our own research group suggests that maintenance antidepressant therapy is effective in reducing recurrence rates, an approach that may be particularly useful in patients with relapsing depression.

3. Major depressive disorder as a risk factor for type 2 diabetes Major depressive disorder is a multidimensional phenomenon involving the interaction of biological and psychosocial factors that may increase the probability of developing type 2 diabetes (Talbot & Nouwen, 2000). Longitudinal studies have confirmed that MDD poses this risk (Talbot & Nouwen, 2000). Although depression typically follows the diagnosis of type 1 diabetes, the depressionrelated mechanisms contributing to the development of type 2 diabetes may be equally detrimental in type 1 diabetes once depression appears. In a prospective, population-based study of adults followed for 13 years, 89 new cases of diabetes were reported in 1715 individuals, representing a cumulative incidence of 5.2% (Eaton et al., 1996). The likelihood of developing diabetes was greater in the subset with depression (odds ratio: 2.2) (Eaton et al., 1996). Similarly, in an 8-year, prospective study of 2764 Japanese men, those with MDD or depressive symptoms had a higher risk of developing type 2 diabetes (Kawakami et al., 1999). These findings were independent of the diabetes risk factors of obesity, smoking, drinking, lack of leisure-time physical activity,

chronic medical conditions at baseline, and a family history of diabetes (Kawakami et al., 1999). These observations should motivate treating physicians to pay particular attention to metabolic changes in patients with depressive symptoms or MDD. Such attention may prove beneficial in the prevention and earlier detection of type 2 diabetes (Kawakami et al., 1999). MDD may be associated with the development of type 2 diabetes because of hyperglycemic effects of antidepressant medications, changes in diet and weight, and physical inactivity associated with chronic depression (Eaton et al., 1996). However, other depression-related biochemical changes may also be operative. Depressive disorders are accompanied by increased activity of the sympathoadrenal system via noradrenaline, dopamine, and adrenaline in the cerebrospinal fluid, plasma, or urine (Kawakami et al., 1999; Lake et al., 1982; Maes, Minner, Suy, Vandervorst, & Raus, 1991; Maes, Vandewoude, Schotte, Martin, & Blockx, 1990; Roy, Pickar, De Jong, Karoum, & Linnoila, 1988). These global effects are associated with an increase in blood glucose and an impairment of glucose tolerance (Surwit, Schneider, & Feinglos, 1992). Through a greater release of counterregulatory hormones, depression may impair the disposition of carbohydrate loads, thus increasing the risk of development of type 2 diabetes. In turn, hyperglycemia may induce arousal of the nervous system, making the patient more susceptible to environmental stress and possibly resulting in an increased frequency of depression (Lustman, Skor, Carney, Santiago, & Cryer, 1983). Furthermore, functional deficiencies in the activity of central neurotransmitters, such as norepinephrine and serotonin, are evident in animal models of diabetes, and may predispose patients to the development of depression (MacKenzie & Trulson, 1978; Trulson & Himmel, 1985). 3.1. Screening and monitoring for depression It is important that the primary care physician be able to identify depression in patients with diabetes. Several tools are available that screen for and monitor depression; however, some symptoms of depression and medical illness overlap (i.e., fatigue and changes in weight, appetite, and libido), and the tools must be used with appropriate caution (Lustman, Clouse, Griffith, Carney, & Freedland, 1997). Ten such tools are described below and summarized in Table 1 (Eaton et al., 1996; Lustman, Clouse, et al., 1997; Hamilton, 1960; Kroenke, Spitzer, & Williams, 2001; Lustman & Clouse, 1997; Zauszniewski, Chung, Krafcik, & Sousa, 2001). Perhaps the best known is the Beck Depression Inventory (BDI), an instrument that has been used in clinical and research settings for more than 35 years (Lustman, Clouse, et al., 1997). The BDI is a self-reported examination containing 21 items that measure the presence and severity of cognitive and somatic symptoms of depression on a scale from 0 (not present/mild) to 3 (present/severe); higher scores

P.J. Lustman, R.E. Clouse / Journal of Diabetes and Its Complications 19 (2005) 113122 Table 1 Screening/monitoring tools for depression Tool Beck Depression Inventory (Lustman, Clouse, et al., 1997) Method of administration Selfadministered Specific for depression? Yes Validated in diabetes?a Yes
b

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Advantages Used for more than 35 years 5 to 10 min to complete Easily scored by summing the ratings of each of 21 items Grades depression severity using DSM-based items Very rapidly completed test Useful for rating depression severity Does not include somatic symptoms Short test (8 items) Reliable and valid Brief interview Large database facilitates comparisons across studies Highly structured Includes temporal dimension Reliable and valid Semistructured Gold standard for making Axis I diagnosis May be adapted for use in studies involving one particular disorder (i.e., depression) Used to screen for MDD and depressive mood Useful in detecting early depression May be used to track patient progress over time Measures current depressive symptomatology (i.e., depressive affect) and criteria for major depressive disorder 20-item questionnaire, easy to administer Modifiable to Include only primary measures of depression CIDI-SF, short form of CIDI available May be conducted by trained interviewer

9-Item Patient Health Questionnaire (Kroenke et al., 2001) Depressive Cognition Scale (Zauszniewski et al., 2001)

Selfadministered Selfadministered

Yes

No

Yes

Yes

Hamilton Rating Scale for Depression (Hamilton, 1960) Diagnostic Interview Schedule (Eaton et al., 1996) Structured Clinical InterviewDSM IV (SCID) (Spitzer, Williams, Gibbon, & First, 1992) Zungs Screen for Depression (Colon de Marti, Guzman Yunge, & Guevera-Kamos, 1997) CES-D Screen for Depression (Fisher, Chesla, Mullan, Skatf, & Kanter, 2001) CIDI and CIDI-SF Screens for Depression (Kessler et al., 1994)

Interview

Yes

No

Interview

Interview

No (can be used for other DSM-IV diagnoses) Yes

Yes

Yes

Selfadministered

Yes

Yes

Selfadministered

Yes

Yes

Interview

Yes

Yes

DSM = Diagnostic and Statistical Manual of Mental Disorders. a A yes response indicates that the psychometric properties of the screening/monitoring tool are upheld when it is employed in diabetic samples. b Scores z16 reflect at least moderate depression symptom severity and have a 70% predictive value for major depression. Scores V9 indicate few depression symptoms or depression remission. Serial determinations may be useful for subjects with scores intermediate to these thresholds to clarify depression status (Lustman & Clouse, 1997).

indicate greater depression (Beck, Ward, Mendelson, Mock, & Erbaugh, 1961). It has been validated in patients with diabetes, effectively screens for major depression in this population and is readily accessible for clinical use (Beck et al., 1961; Lustman, Clouse, et al., 1997). The 9-item Patient Health Questionnaire (PHQ-9) also is a brief, selfadministered test that assesses the severity of symptoms of major depression (Kroenke et al., 2001). The PHQ-9 has not yet been validated in patients with diabetes. Additional tools for assessing depression include the Depressive Cognition Scale, the Hamilton Rating Scale for Depression, the National Institute of Mental Health Diagnostic Interview Schedule, the Structured Clinical Interview for DSM-IV (SCID), the Zung Self-Rating Depressive Scale (SDS), the Centers for Epidemiologic Studies Depression (CES-D) questionnaire, the Composite International Diagnostic Interview (CIDI) and short form of the interview

(CIDI-SF). The Depressive Cognition Scale is a 6-point scale that is graded from 0 (strongly agree) to 5 (strongly disagree) to assess eight depressive cognitions: worthlessness, powerlessness, hopelessness, helplessness, purposelessness, loneliness, emptiness, and meaninglessness. The test is self-administered (Zauszniewski, 1995; Zauszniewski et al., 2001). Strong disagreement with a specific item indicates the presence of a specific cognition, and higher composite scores indicate a greater number of depressive (negative) cognitions that may accompany or precede clinical depression (Zauszniewski, 1995). This tool has demonstrated validity in patients with diabetes and is useful in the early identification of patients at risk for developing depression. The Hamilton Rating Scale for Depression is another widely used depression measurement tool but is not selfadministered and thus is generally used in research settings

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(Hamilton, 1960). The National Institute of Mental Health Diagnostic Interview Schedule is a reliable tool for diagnosing major depression in many populations including patients with diabetes (Eaton et al., 1996; Lustman, Harper, Griffith, & Clouse, 1986; Popkin, Callies, Lentz, Colon, & Sutherland, 1988). This tool requires an interview by a trained technician, and thus it is less useful in clinical practice. Once depression has been diagnosed, monitoring of the clinical response to treatment is critical. Selfadministered rating scales (e.g., BDI, PHQ-9) or a focused abbreviated interview are suitable for this purpose (Kroenke et al., 2001). The SCID utilizes the Diagnostic Statistical Manual IV (DSMIV) and is considered by some authorities as the gold standard for a making the Axis I diagnosis of major depression (Spitzer, Williams, Gibbon, & First, 1992). This semistructured interview is administered by a clinician and consists of an introductory overview and a modular construction that allows adaptability for use in studies involving a particular diagnosis (i.e., depression). The SCID has demonstrated validity in diagnosing depression and other psychiatric disorders with high prevalence in patients with diabetes (Petrak et al., 2003). The SDS is a tool that has demonstrated usefulness in the early detection of depression during an initial evaluation by a primary care clinician (Colon de Marti, Guzman Yunque, & Guevara-Ramos, 1997) and has been utilized in studies examining the relationship between depressive symptoms and the incidence of type 2 diabetes (Kawakami et al., 1999). The CES-D questionnaire, like the BDI, is another popular self-administered tool for measuring primarily depressive affect and other current depressive symptomatology. The CES-D has been validated in patients with type 2 diabetes (Fisher, Chesla, Mullan, Skaff, & Kanter, 2001). The CIDI and short form of the interview (CIDISF) are structured diagnostic interviews that are designed to be administered by a trained interviewer and may be modified to include only primary measures of depression (Kessler et al., 1994); they are valid instruments for identifying MDD in diabetic patients.

Effective relief from depression usually requires specific intervention (Lustman, Clouse, & Freedland, 1998). Major depression may be managed with antidepressant pharmacotherapy and/or by a nonpharmacological approach utilizing cognitive behavioral therapy (CBT). For frequently recurring episodes, long-term or even lifelong antidepressant therapy may be required. In addition to the fact that depression may result in a measurable impact on glucose homeostasis, this disorder is debilitating and can impair all aspects of the patients functioning and quality of life (Lustman et al., 1992). Unfortunately, about two thirds of diabetic patients with depression do not receive treatment for depression (Kovacs, Obrosky, Goldston, & Drash, 1997; Lustman & Harper, 1987). Several approaches, however, are effective and available. 4.1. Cognitive behavioral therapy CBT, a psychotherapeutic approach aimed at correcting maladaptive thought patterns, is widely used to manage disorders involving anxiety and depression and problems with social functioning (Elkin et al., 1989; Frank et al., 1990). The approach generally requires weekly 1-h counseling sessions over a 4- to 6-month interval. Meta-analysis of four randomized studies conducted in nondiabetic adults who were severely depressed compared the outcomes of antidepressant medication or CBT (Derubeis, Gelfand, Tang, & Simons, 1999). CBT was found to be equally as effective as medication in improving the depression scores on the Hamilton and Beck scales (Derubeis et al., 1999). Additionally, CBT has been shown to be an effective nonpharmacological option in type 2 diabetes patients with major depression, producing moderate improvements in glycemic control (Lustman, Griffith, et al., 1998). 4.2. Antidepressant pharmacotherapy In the pharmacological management of depression in patients with diabetes, it is essential to avoid antidepressants with potential for adverse effects and drug interactions. The monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) are rarely used to treat depression in diabetic patients for this reason. The selective serotonin reuptake inhibitors (SSRIs) appear to be preferred antidepressant agents in patients with concurrent diabetes (Goodnick, 2001). The SSRIs have effective antidepressant potential and possess a favorable pharmacological profile. In contrast to the MAOIs and TCAs, the SSRIs are not associated with hyperglycemia in short-term use and may improve metabolic control through their positive effect on weight loss, thereby improving insulin resistance (Goodnick et al., 1995; Van Tilburg et al., 2001). An 8-week, randomized, placebo-controlled, double-blind study evaluated the efficacy of the SSRI fluoxetine for depression in 60 patients with type 1 or type 2 diabetes and MDD (Lustman, Freedland, Griffith, & Clouse, 2000). This agent significantly

4. Management of concomitant depression in diabetes Concomitant depression occurring in diabetic patients follows a chronic and severe course compared with depressed individuals without diabetes (Lustman, Griffith, Gavard, & Clouse, 1992). An episode of depression typically lasts for 6 to 9 months but may last for up to 2 years. Most patients experience recovery (Keller, Shapiro, Lavori, & Wolfe, 1982a) or enter remission from an initial episode of major depression (Mueller & Leon, 1996). Unfortunately, patients that recover from an initial episode of major depression have a high risk for relapse, experiencing additional episodes during the course of the patients life (Keller, Shapiro, Lavori, & Wolfe, 1982b).

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reduced depressive symptoms relative to placebo ( P V .03) (Lustman, Freedland, et al., 2000). A trend toward better glycemic control (measured as improvement in mean A1C) with fluoxetine was not attributable to changes in weight, which was unaffected by SSRI treatment in this study (Lustman, Freedland, et al., 2000). Because the improvement in A1C was associated with treatment more than with depression remission, direct insulin-sensitizing effects of at least some SSRIs are plausible. 4.3. Antidiabetic therapy A significant association has been demonstrated in studies designed to assess the effect of glycemic control on mood. Whether glycemic control is achieved through diet, oral hypoglycemics, insulin, or combinations of oral agents with insulin therapy, the evidence suggests that patients with adequate glycemic control will have an improved sense of well-being (Lustman, Griffith, Clouse, et al., 1997; Testa & Simonson, 1998; Van der Does et al., 1996). The effects of insulin on mood were assessed in a recent, controlled, unblinded study that examined 40 elderly patients with type 2 diabetes who were not achieving glycemic goals on oral hypoglycemic therapy (Reza, Taylor, Towse, Ward, Hendra, 2002). Of these 40 patients, 30 were started on insulin therapy, while 10 remained on oral therapy and served as the control group. Insulin therapy consisted of twice-daily isophane or premixed soluble/isophane insulin.

The control and insulin groups achieved significant reductions in A1C as compared with baseline after 4 and 12 weeks, respectively ( P < .05). However, only the insulin group experienced significant improvement in mood (as measured by the Geriatric Depression Scale) at both 4 and 12 weeks ( P < .05). None of the patients treated with insulin during the study elected to return to oral therapy after study completion (Reza et al., 2002). Thus, improved treatment satisfaction and mood may be an advantage to insulin therapy in some patients with type 2 diabetes independent of a conspicuous advantage in metabolic control over oral hypoglycemic therapy. Whether one form of insulin therapy over another is superior in its effects on mood has not been established but also merits consideration. A 28-week, randomized, controlled, open-label study recently compared the effects of insulin glargine and NPH insulin on treatment satisfaction and psychological well-being in 474 patients with type 1 diabetes (Bradley, Witthaus, & Stewart, 1999; Witthaus, Stewart, & Bradley, 2001). Although all patients reported improvement in treatment satisfaction, those who received insulin glargine had more pronounced improvement at all time points. Outcomes also were better with insulin glargine for perceived frequency of both hyperglycemia and hypoglycemia. However, no differences in psychological wellbeing between the treatment groups were observed in this study. At present, the available data suggest that improved metabolic control can improve mood and that insulin

Initial intervention

Evaluate for depression as a contributor to the development of type 2 diabetes

Determine diabetes status Goal: FPG <110130 mg/dL; SMBG <100120 mg/dL; A1C <6.57.0%

If glucose control goals are being met, follow up every 3 to 6 months

If glucose control goals are not being met, institute initial antidiabetic therapya

Treat clinically significant depression episodes with psychotherapy or antidepressantsd

If glucose control goals are being met, follow up every 3 to 6 months

If glucose control goals are not being met, institute intermediate antidiabetic therapyb

Evaluate for depression as a contributor to poor metabolic control in any type of diabetes

Consider maintenance psychotherapy or antidepressants for relapsing depression

If glucose control goals are being met, follow up every 3 to 6 months

If glucose control goals are not being met, institute advanced antidiabetic therapy c

Fig. 3. This diagram illustrates a combined treatment algorithm for managing concomitant depression and type 2 diabetes. Depression may participate in the development and/or progression of diabetes at any point in its course. Patients not meeting appropriate glucose control targets should have their diabetes treatment adjusted in stepwise progression following conventional recommendations, such as those provided in this example (Texas Diabetes Council, 2003). Clinically significant depression should be managed simultaneously, maintenance therapy being offered for patients with relapsing depression. The diabetes management component of this algorithm was adapted with permission from the Texas Diabetes Council (2003).

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regimens may have further, favorable effects on treatment satisfaction and mood (Bradley et al., 1999; Mazze et al., 1984; Reza et al., 2002; Testa & Simonson, 1998). Additional studies may show whether there is an advantage in improvement of mood, at least in selected instances, of insulin regimens that improve metabolic control in refractory patients, for example, insulin glargine. The mechanisms for such effects also require further study, as mood improvements may well occur secondary to decreased glucose variability, reduced postprandial hyperglycemia, or other improvements in glucose dynamics that may occur independent of changes in A1C.

5. Treatment algorithm for comorbid depression and type 2 diabetes Because of the particular importance of depression to the onset and course of type 2 diabetes, an algorithm incorporating the management of both seems relevant but was not discovered in the literature review. Based on available information regarding the bidirectional interaction of these disorders, a prototypical management strategy is presented in Fig. 3. This combined management approach includes one commonly utilized algorithm for treating type 2 diabetes (Texas Diabetes Council, 2003) together with a recommendation to screen for, identify, and treat depressive symptoms as contributors to poor metabolic control or MDD as a contributor to the development of type 2 diabetes. At the time of diagnosis of diabetes, patients without a prior diagnosis of depression should be screened for depression symptoms. Additional evaluation using full diagnostic interviews and standard diagnostic criteria for the diagnosis of a depressive disorder may then be indicated (Coyne, Palmer, & Sullivan, 2003; Das, Gross, & Weissman, 2003; Whooley & Simon, 2000). Likewise, patients with depression who do not have diabetes should be monitored over time for the development of glucose intolerance. Diabetic patients with a clinical diagnosis of depression should be treated. The treatment choice depends on patient preference, accessibility, and tolerance. The treatment regimen should be individualized and simplified as much as possible to allow patients to adhere to both the diabetes and depression treatment regimens, since depression itself can interfere with adherence (Lustman, Clouse, et al., 1998; McGill, Lustman, Griffith, & Freedland, 1992; Van Tilburg et al., 2001).

burden, functional impairment, quality of life, and selfmanagement of the primary disease. Among patients with diabetes, more than one quarter has depression at a clinically significant level. Despite this, depression is recognized and treated in only about one third of these cases. The hyperglycemia of diabetes produces significant morbidity and mortality. Depression also increases the risk of diabetic complications. The two processes, diabetes and depression, negatively interact in that depression leads to poor metabolic control and hyperglycemia exacerbates depression. A contemporary treatment approach advocates an aggressive stance toward both diabetes and depression management to optimize global outcome. Further investigation is needed to determine the best strategies for long-term management of patients with these chronic comorbid conditions.

Acknowledgments This work was supported in part by grants DK36452, DK53060, and DK59364 from the National Institutes of Health.

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