US Pharm. 2016;41(11):26-29.

ABSTRACT: Research suggests a bidirectional relationship between depression and diabetes wherein the incidence of depression is increased in patients with diabetes and the incidence of diabetes—specifically, type 2 diabetes mellitus—is increased in patients with depression. The successful management of patients with comorbid depression and diabetes may be challenging because of the complex interplay between these disease states. Healthcare providers should be aware of common theories regarding the association between depression and diabetes in order to identify opportunities to decrease incident depression and diabetes and tailor treatment options based on patient-specific factors.

Depression and diabetes are chronic disease states with the potential to impact many aspects of life. In 2014, an estimated 6.7% (15.7 million) of adults in the United States had at least one major depressive episode in the past year.1 Among mental and behavior disorders, major depression causes the most disability. Diabetes, which affects approximately 9.3% (29.1 million) of the U.S. population, can cause serious disability as well.2 Depression and diabetes are among the top five diseases or disorders leading to disability in the U.S.3 These diseases are extremely costly, with estimated direct and indirect costs of $245 billion and $210.5 billion, respectively; this further increases the societal affect associated with these disease states.2,4

Patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) may become burdened with the self-care challenges associated with a diabetes diagnosis, and this psychological stress may precipitate depression.5 Conversely, depression is often associated with poor behavioral choices (e.g., physical inactivity, unhealthy dietary habits) that may result in T2DM.6 The English physician Thomas Willis observed in the late 1600s that diabetes sometimes occurred in patients after significant life stress or sorrow.6,7 Many studies have accordingly investigated the potential link between depression and diabetes. Research suggests a bidirectional relationship between these two disease states wherein the incidence of depression is increased in patients with diabetes and the incidence of diabetes (specifically T2DM) is increased in patients with depression.8,9 This relationship is of concern owing to the increased mortality, morbidity, and medical costs that may result from concomitant diabetes and depression.6 Moreover, the American Diabetes Association (ADA) guidelines report a twofold increased risk for new-onset infarction in individuals with comorbid diabetes and major depressive disorder (MDD).10 To optimize patient outcomes, it is important for healthcare providers to be knowledgeable about the proposed pathogenesis of comorbid diabetes, as well as treatment options.

Possible Pathogenesis

A number of hypotheses have been made regarding the comorbidity of diabetes and depression. Most theories focus on the physiological burden of diabetes and on behavioral and biological factors. Additional hypotheses stress the role of environmental factors (e.g., childhood adversity, socioeconomic status), intrauterine environment (e.g., low birthweight, fetal undernutrition), or pharmacologic treatment (e.g., antidiabetic and antidepressant agents) in incident diabetes and depression; however, additional studies are needed to provide robust data in support of these theories.7,11

Physiological Burden of Diabetes Diagnosis: A diagnosis of diabetes may require substantial life changes to normalize glucose and prevent diabetic complications. As a result, patients may exhibit depressive symptoms stemming from their perception of how diabetes may adversely affect their life.12 A meta-analysis found an increased risk of depression in patients who were diagnosed with diabetes compared with patients who had diabetes but were unaware of their diagnosis.13 This finding indicates that stress, along with knowledge of the challenges and potential complications associated with diabetes, may lead to depression.12 The physiological burden associated with the diabetes diagnosis may lead to emotional distress, loss of interest and energy, and poor concentration, resulting in a depressive state.14

Behavioral Factors: Lifestyle factors play an essential role in the etiology of both depression and T2DM. Patients with depressive symptoms (e.g., reduced interest and pleasure in activities, fatigue, sleep and appetite abnormalities) may be less likely to exercise and eat properly, which may lead to obesity.12,15 Obesity is prevalent in patients with depression and is a risk factor for metabolic syndrome, which may lead to T2DM. In a cross-sectional study, compared with patients without depressive symptoms, those with depressive symptoms exhibited worse adherence to dietary and exercise regimens.16 A meta-analysis concluded that depression was related to nonadherence to diabetes treatment recommendations (e.g., diet, medication use, glucose monitoring).12,17 Furthermore, depression is linked to poor self-care and metabolic control, which may result in T2DM.7 Consequently, patients may be caught in a vicious cycle, with worsening diabetes and depression resulting from poor behavioral choices.12

Biological Factors: Depression and diabetes are associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction.12 Stimulation of the HPA axis increases the production of cortisol, a stress hormone, by the adrenal cortex.5,15 Excess cortisol leads to increased glucose and insulin resistance; chronic elevation of cortisol increases the risk of metabolic syndrome, which elevates the risk of T2DM.15 Stress can activate the sympathetic nervous system, increasing cortisol. Furthermore, the inflammatory system is activated as a result of this cascade and produces proinflammatory cytokines, which are postulated to lead to insulin resistance.5 Cortisol and cytokines induce negative changes in the monoamine system and hippocampus, worsening depressive symptoms.5,18,19

Diabetes and Incident Depression

Most research on diabetes and incident depression has involved T2DM; however, it is unclear whether the incidence of depression varies based on the type of diabetes. Results from several studies suggest that there are no significant differences and that risks are present in both T1DM and T2DM.7,9 The incidence of depression in T2DM is increased in patients using insulin compared with those using other treatment options.12,20,21 This increased risk may be due to the fact that insulin is often associated with more severe disease, potentially resulting in greater challenges and psychological burdens. Most studies have demonstrated higher rates of depression in women with diabetes compared with men, which parallels the rates observed in men and women in the general population.9

Several studies support the increased probability of depression in patients with diabetes.5,22,23 In meta-analyses by Mezuk et al and Nouwen et al, there was an increased incidence of depression of 15% and 24%, respectively, in patients with diabetes compared with patients without diabetes.6,22,23 Conversely, a meta-analysis conducted by Anderson et al suggests that diabetes virtually doubles the prevalence of depression.24 In the literature, the risk of depression in patients with diabetes varies based on the use of self-report questionnaires versus formal diagnostic criteria and/or interviews to qualify a patient with depression.6,12,24 As a result, differences in study findings may be attributed to heterogeneity across studies.12 Despite variations in study results, available evidence supports the link between diabetes and incident depression, although the evidence that depression leads to incident diabetes is stronger.

Depression and Incident Diabetes

Depression is associated with physiological abnormalities, largely because of poor lifestyle habits. Patients with depression tend to be unengaged and nonadherent to physical and dietary recommendations, which can lead to established risk factors for T2DM, such as obesity, hyperglycemia, and metabolic syndrome.6,9,22 As may be expected given the pathology of T1DM, there is no evidence that depression leads to an increased risk of T1DM.9

The relationship between depression and incident T2DM is supported by several meta-analyses.8,22,25 Mezuk et al found that depression is associated with a 60% increase in T2DM.22 Other robust meta-analyses evaluated the bidirectional relationship between depression and diabetes.9,15 As discussed earlier, study results differ according to the parameters investigators use to define depression. In a 5-year longitudinal study, clinically significant depression—including MDD and less severe forms of depression identified through a standardized interview—was associated with a 65% increased risk of diabetes.6,25 Researchers found that nonsevere depression, persistent depression, and untreated depression may contribute to diabetes, especially in older persons.25 In one study, the association between depression and incident T2DM persisted after BMI and lifestyle factors were controlled for, highlighting a potential ability of depression to cause diabetes beyond major risk factors presented above.26

Clinical Management

The ADA guidelines recommend that patients with diabetes be routinely screened for psychosocial problems (e.g., depression) with the Patient Health Questionnaire (PHQ)-2, PHQ-9 (as follow-up if the PHQ-2 is positive), or another validated screening tool.10 If a patient is diagnosed with depression and diabetes, appropriate treatment is essential to lessen the risk of complications. Increased adherence and completion of appropriate self-care behaviors are expected to occur with treatment.15 Additionally, studies suggest that treatment of depression may be associated with normalization of blood glucose.24 Treatment options include pharmacotherapy, psychotherapy (most commonly cognitive-behavioral therapy [CBT]), or a combination of the two. A comparison of PHQ-9 scores throughout the treatment process may be used to evaluate the success of depression intervention in patients with diabetes.12

CBT is effective in alleviating depressive symptoms. Furthermore, beneficial effects on glycemic control occur when CBT includes diabetes self-management education.11 CBT is the treatment of choice in individuals unable to initiate or tolerate pharmacotherapy.27 Pharmacotherapy and CBT may be used concurrently in severe cases. Additional studies are needed to establish the cost benefit of CBT in patients with comorbid diabetes and depression.

With sufficient dosing, antidepressants can ameliorate depressive symptoms in diabetes patients at a level comparable to that seen in the general population.11,12 The potential of antidepressants to increase the risk of diabetes is a source of controversy.6,12 Some studies suggest that antidepressants may affect glucose homeostasis; however, results are inconsistent.6,26,28 Variability exists in antidepressants’ ability to cause hyperglycemic (i.e., tricyclic antidepressants), euglycemic, or hypoglycemic effects (i.e., selective serotonin reuptake inhibitors [SSRIs] and serotonin-noradrenaline reuptake inhibitors).12,29 Additional research is needed to fully elucidate the effectiveness of specific antidepressants, effects on glycemic control, and the potential to improve or worsen diabetes outcomes.12 Accordingly, an antidepressant should be selected based on side effects, patient preference, and response. As is the case with general depression, SSRIs tend to be the treatment of choice for most patients with diabetes because of their side-effect profile and efficacy.

Collaborative-care interventions have demonstrated effectiveness in comorbid depression and diabetes, resulting in increased self-care, improved quality of life, treatment satisfaction, and better glycemic control.11,27 Accordingly, ADA guidelines recommend a stepwise collaborative-care approach for the management of depression in patients with diabetes.10 The pharmacist is a key member of the multidisciplinary team and can provide recommendations to potentially reduce the risk of incident diabetes or depression. The pharmacist can also provide education and medication management, empower patients to develop appropriate coping skills, and serve as a consistent monitoring source between physician visits. Collaborative care should be combined with treatment interventions, education, and support to optimize health outcomes in patients.12,29


It is crucial to identify opportunities to minimize the impact of comorbid depression and diabetes because this bidirectional relationship has major implications for patients and for the U.S. Although the management of diabetes and depression can be challenging given the complex interplay between them, CBT, pharmacotherapy, and collaborative care may lead to cost savings and improve patient self-care and functionality.


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