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Chapter 1 Depression and Diabetes

Mary de Groot, PhD

Assessment and Diagnosis of Depression

Depression refers to a spectrum of disorders and cluster of symptoms that involve sad or blue mood or anhedonia, neurovegetative symptoms (e.g., changes in appetite, sleep), and cognitive impairments occurring during a discrete period of time. Major depressive disorder (MDD) is defined as a cluster of five or more of the following symptoms occurring two weeks or longer: depressed or sad mood, loss of pleasure or interest in routine activities, changes in weight or appetite, hyper- or hyposomnia, fatigue, psychomotor agitation or retardation, worthlessness or excessive guilt, decreases in concentration, and/or suicidal ideation or attempt (American Psychiatric Association [APA] 2000). Episodes may be recurrent or single events.

Subsyndromal depression or minor depressive disorders include dysthymia (low-grade depression lasting more than half of the time during a two-year period), adjustment disorder with depressed mood (a period of depression lasting no more than 6 months in response to an identifiable psychosocial stressor such as a major life event or medical event), and depressive disorder not otherwise specified (a period of depressive symptoms resulting in impairment in social or occupational functioning that does not meet criteria for other diagnostic categories) (APA 2000).

Diabetes-related distress is distinguished from depression spectrum disorders in that concerns are directly related to diabetes management and/or social support (e.g., interactions with relatives pertaining to self-care behaviors) (Fisher 2007). Distress is specifically associated with the experience of living and managing diabetes. Diabetes-related distress may coincide with or exist separately from depressive symptoms or episodes (Fisher 2007). Although diabetes-related distress is an appropriate target for psychosocial interventions, it is not currently designated as a psychiatric diagnosis.

Analyses of several national surveys have identified demographic and psychosocial correlates of MDD or depressive symptoms in individuals with diabetes that include: female sex, younger age, BMI >30 kg/m2, high school education, poverty, smoking, treatment with insulin, higher A1C, single marital status, poor health status perception, and increased number of complications (Egede 2003, Jones 2004, Katon 2004b, Nichols 2007). The onset of symptoms may be gradual or correspond closely to an external event that is readily identifiable by the patient.

Differential Diagnoses

The diagnosis of MDD is excluded in the presence of primary psychotic disorders (e.g., schizophrenia, schizoaffective disorder, delusional disorders) or the presence of manic or hypomanic periods resulting in the diagnosis of bipolar disorder I or II, respectively (APA 2000). Anxiety spectrum disorders (e.g., panic disorder, agoraphobia, specific phobia, social phobia, obsessive compulsive disorder, generalized anxiety disorder) may co-occur with the diagnosis of a depression spectrum disorder (APA 2000) (Table 1.1).

Table 1.1. DSM-IV Criteria for a Major Depressive Episode

A. Five or more of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either 1) depressed mood or 2) loss of interest or pleasure

1. depressed mood most of the day, nearly every day, as indicated by either subjective reports or observation made by others

2. markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others)

3. significant weight losses when not dieting or weight gain, or decrease or increase in appetite nearly every day

4. insomnia or hypersomnia nearly every day

5. psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)

6. fatigue or loss of energy nearly every day

7. feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sad)

8. diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others)

9. recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

B. The symptoms do not meet criteria for a Mixed Episode

C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning

D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism)

E. The symptoms are not better accounted for by bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.

Measurement of Depression

Depressive symptoms may be adequately measured using self-report symptom inventories such as the Beck Depression Inventory-II (BDI-II) (Beck 1996), the nine-item depression scale of the Patient Health Questionnaire (PHQ-9) (Kroenke 2001), or the Center for Epidemiologic Studies Depression Scale (CES-D) (Radloff 1977). These measures vary in the number and content of items and may be used selectively for a variety of purposes (e.g., clinical screening, research). All have been developed for the general population (i.e., they are not diabetes specific) and have demonstrated acceptable levels of validity and reliability. For each measure, clinical cutoff scores that correspond to clinically significant and diagnosable depression have been developed and validated in psychiatric samples (Radloff 1977, Beck 1996, Kroenke 2001). The BDI has been specifically validated for use in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) (Lustman 1997a). It should be noted that the BDI-II and PHQ-9 gather specific information about suicidal ideation and/or intent and plan. These measures should be used in a setting where patient responses can be evaluated by providers immediately following completion and where follow-up evaluation of risk of self-harm and referral are available.

Psychiatric interview protocols available for the assessment of depression range from semi-structured interviews such as the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) and Structured Clinical Interview for the DSM-IV-TR (SCID) (Spitzer 1992, Williams 1992) to structured interviews such as the Composite International Diagnostic Interview (CIDI) (Robins 1988) and the Diagnostic Interview Schedule (DIS) (Helzer 1988) that can be administered and scored through computer interface (Erdman 1992). The DIS has been validated for use in patients with T1D and T2D (Lustman 1986). These interview protocols require expert training in psychopathology and interview assessment. A clinician version of the SCID (Spitzer 1992, Williams 1992) is available; however, these interviews are more commonly used in the context of clinical research protocols.

Two measures have been created to measure diabetes-related distress: the Problem Areas in Diabetes (PAID) and Diabetes Distress Scale (DDS) (Welch 1997, Polonsky 2005, Fisher 2007). These measures show some shared variance with self-report depression questionnaires (Fisher 2007) as well as unique variance (Welch 1997, Hermanns 2006).

Prevalence of Comorbid Depression and Diabetes

The majority of studies have examined cross-sectional rates of MDD and/or depressive symptoms in samples diagnosed with T1D and T2D. Meta-analyses of the literature of prevalence rates of depression or depressive symptoms in patients with T1D have shown increased rates of depression in diabetes samples compared with nondiabetic control subjects (21.6 T1D vs. 11.4% nondiabetic) (Anderson 2001, Barnard 2006, Shaban 2006). Similarly, meta-analyses conducted on studies of depression in people with T2D have found increased rates of depression compared with nondiabetic control subjects (27 vs. 17.6%) (Anderson 2001, Ali 2006). Depression assessment methods and thresholds vary considerably in this literature as do rates of MDD and depressive symptoms (e.g., psychiatric interview protocols yield an average rate of depression of 11% compared with 31% in those using self-report questionnaires) (Anderson 2001). Psychiatric interviews provide greater diagnostic precision, and therefore lower prevalence rates, by permitting interviewers to determine the timing, origins, and alternative diagnostic explanations for individual depressive symptoms that may be endorsed by the patient (e.g., expectable bereavement vs. major depressive disorder). These distinctions are not made in self-report measures, so depressive symptoms attributable to any cause may be reported by respondents.

Overall, rates of depression among patients with T1D and T2D are ~2 times greater than those in the general population (Anderson 2001) (see one exception: Pouwer 2003). Women with diabetes are 1.6 times more likely to report depressive symptoms than their male counterparts with diabetes, with one study finding a stronger association among younger women (<40 years) (Anderson 2001, Zhao 2006). Rates of depression among men with T1D have been shown to exceed those in nondiabetic comparison samples (Barnard 2006, Shaban 2006). The majority of studies have been conducted with white, middle-class samples; however, rates of depressive symptoms do not appear to vary considerably across diverse racial, ethnic, or international samples (Gary 2000, Grandinetti 2000, Fisher 2001, Roy 2001, de Groot 2006, Wagner 2006, Asghar 2007, de Groot 2007). Few studies have used well-controlled prospective designs.

Well-controlled prospective longitudinal studies of the psychological characteristics of children and adolescents with T1D have shown mixed findings with regard to elevated rates of comorbid depression. Some studies have observed elevated rates (Kokkonen 1995, Kovacs 1997, Grey 2002), whereas others observed no differences in rates of depression compared to healthy control subjects (Jacobson 1997b). In one study, women with diabetes showed greater risk for depression recurrence than males with diabetes or psychiatric counterparts (Kovacs 1997). In a sample of youth (ages 10–21 years), men with T2D showed greater risk of self-reported depressive symptoms compared with men with T1D (Lawrence 2006). Depressive symptoms appear to increase the risk for worsened glycemic control, earlier-onset diabetic retinopathy, and increased adolescent hospitalizations and emergency department visits (Kovacs 1995, Stewart 2005, Lawrence 2006).

Few studies have examined the naturalistic course of depression in adults with T1D and T2D. Depressive symptoms and affective disorders have been found to be highly persistent (e.g., 73–79% remain depressed) in prospective longitudinal investigations over 1–5 years follow-up (Lustman 1988, Peyrot 1999) with or without treatment. For example, a 5-year follow-up of patients enrolled in an 8-week antidepressant treatment trial found that 92% of patients experienced persistent or recurrent MDD, with 58% experiencing recurrence within 12 months of treatment (Lustman 1997c).

Impact of Depression on Diabetes and Psychosocial Outcomes

Depression has been found to be associated with worsened glycemic control and diabetes complications in diagnosed T1D and T2D samples. In a meta-analysis of 25 cross-sectional studies, small-to-medium effect sizes in the relationship between hyperglycemia and depressive symptoms were observed (Lustman 2000a). Recent cross-sectional studies have mirrored this finding among Hispanic adults (Gross 2004), children with T1D (Stewart 2005), and postmenopausal women with a lifetime history of MDD (Wagner 2007b). Prospective studies of changes in depressive symptoms have not shown depression to predict changes in glycemic control among ethnically diverse middle-age and older adults (Gary 2005, Trief 2006). Adherence to self-care behaviors does not appear to be a mediator between depressive symptoms and glycemic control among adults with T1D and T2D (Lustman 2005). A meta-analysis of 27 studies found medium effect sizes in the association between depression and worsened long-term diabetes complications (e.g., macrovascular disease, neuropathy, nephropathy, retinopathy, microvascular disease) in both T1D and T2D samples (de Groot 2001, Clouse 2003). Recent work examining the relationship of depression and diabetic neuropathy is consistent with these findings (Vileikyte 2005).

There is accumulating evidence for negative outcomes associated with comorbid depression including: decreased adherence to diabetes self-care behaviors, such as dietary recommendations, exercise behaviors, and oral hypoglycemic regimens (Ciechanowski 2000, Vickers 2006); decreased quality of life (Jacobson 1997a, Gaynes 2002); decreased social support (Sacco 2006); increased functional disability compared to nondiabetic patients with MDD (Egede 2004, Bruce 2005) as well as significant unemployment and work disability (Von Korff 2005); increased hospitalizations in children with T1D (Stewart 2005); and earlier mortality after adjusting for covariates (e.g., age, diabetes complications) (Katon 2005, Zhang 2005, Ismail 2007). Minor depression may also be associated with lower self-reported health status, cognitive limitations (e.g., confusion, memory loss, difficulty making decisions), and diabetes symptoms (Egede 2002b, Katon 2007, McCollum 2007), although additional evidence is needed to further elucidate this relationship.

Analyses of the economic impact of comorbid depression and diabetes have indicated that individuals with both disorders have higher ambulatory care use, greater prescription expenditures, and higher overall health care expenditures than patients with diabetes alone (Ciechanowski 2000, Egede 2002b, Finkelstein 2003, Jones 2004, Nichols 2007).

Depression as a Predictor of Diabetes

A bidirectional association has been observed for depression and diabetes in which depression has been found to increase the risk of the development of T2D in prospective longitudinal cohorts (Eaton 1996, Knol 2006, Engum 2007) and the presence of diabetes increases the risk of developing depression postdiagnosis (Anderson 2001, Ali 2006, Barnard 2006, Shaban 2006). Some studies have reported as much as a two-fold risk of subsequent T2D in the presence of MDD or moderate depressive symptoms (Eaton 1996, Engum 2007), whereas others report modest or nonsignificant risk estimates over similar periods after adjusting for covariates such as BMI and education (Carnethon 2003, Saydah 2003, Arroyo 2004, Golden 2004, Carnethon 2007). A meta-analysis of nine studies found a 37% increase in risk for T2D with a lifetime history of depressive symptoms (Knol 2006). Evidence from the Third National Health and Nutrition Examination Survey (NHANES III) suggests that a lifetime history of MDD among women under the age of 40 years increased the risk of metabolic syndrome, although additional studies are needed to confirm this finding (Kinder 2004).

Treatment Methods and Providers

Depression can be effectively treated in diabetes patients using traditional treatment modalities such as antidepressant medications, individual cognitive behavioral therapy (CBT), and problem-solving therapy (PST). Randomized placebo-controlled trials of tricyclic (e.g., nortriptyline) (Lustman 1997b) and selective serotonin reuptake inhibitor (SSRI) antidepressant medications (e.g., fluoxetine [Lustman 2000b], sertraline [Goodnick 1997], paroxetine [Paile-Hyvarinen 2003]) have been shown to be efficacious in treating depression. An uncontrolled randomized trial comparing fluoxetine and paroxetine showed comparable improvement in depression in a sample of patients with T2D and MDD (Gulseren 2005). Nortriptyline (25–50 mg q.d.) has been found to have a hyperglycemic effect on blood glucose control following treatment. Fluoxetine (40 mg q.d. maximum dose), sertraline (50 mg q.d. maximum dose), paroxetine (20 mg q.d.), and bupropion extended release (150–450 mg q.d.) (Lustman 2007) have been found to be associated with overall improvement in glycemic control and for BMI when bupropion was tested (Lustman 2007). Maintenance treatment using sertraline has been shown to be effective in extending depression remission compared to placebo (Lustman 2006), with sustained hypoglycemic effects observed for one year following depression remission in both placebo and sertraline treatment groups. In this study, younger adults (age <55 years) showed longer periods of symptom remission in the sertraline group compared with placebo and older adults (Williams 2007).

CBT has also been shown to effectively treat depression in patients with T2D in a randomized controlled trial compared to a diabetes education intervention (Lustman 1998). Improvements in A1C in the CBT group were observed at the 6-month follow-up evaluation and exceeded those of the control group.

Recent studies have demonstrated the efficacy of a collaborative care approach utilizing PST (Katon 2004c). In the Pathways study, T1D and T2D participants meeting criteria for MDD or dysthymia (persistent low-grade depressive mood lasting 2 or more years) from nine primary care health settings were randomized to either a case management intervention embedded within a primary care setting or usual care (UC). Patients receiving the case management intervention received a stepped-care approach utilizing education and support for antidepressant medication and/or PST delivered by trained clinical specialist nursing staff (Katon 2004c). Patients receiving the intervention showed greater improvements in adequate dosing of antidepressant medications, less severe depression, higher patient ratings of global improvement, and higher satisfaction with care over a 12-month follow-up period (Katon 2004c). Patients with two or more diabetes complications receiving the intervention showed greater improvements in depression outcomes at follow-up compared with the UC group. Patients with fewer than two diabetes complications showed comparable depression outcomes to the UC group (Kinder 2006). Patient attachment style was shown to be associated with depression treatment success using PST compared to UC (Ciechanowski 2006). Overall, no improvements in glycemic control or adherence to diabetes self-care behaviors were observed from baseline to 6- or 12-month follow-up evaluation (Katon 2004c, Lin 2006). A small decrease in BMI was observed and nonadherence to oral hypoglycemic agents increased over time in the intervention group (Lin 2006). Participants did not receive diabetes-specific education or adherence support for diabetes self-management that might have contributed to improvement in glycemic outcomes. This treatment approach has been shown to be a cost-effective means of providing treatment for co-occurring depression, with limited additional cost associated with the intervention and significant cost savings associated with non–mental health expenditures over time (Katon 2006, Simon 2007).

A variety of barriers to adequate treatment of depression in patients with diabetes have been identified. These include stigma associated with mental illness and patient perceptions of depressive symptoms as a form of weakness or an inevitable consequence of chronic illness (Egede 2002a); perceived discrimination in medical and mental health care resulting in racial and ethnic disparities in the use of depression treatment (Egede 2002a, de Groot 2006, Wagner 2007a); lack of screening and adequate diagnosis by primary care physicians (Katon 2004a); lack of dose adjustment of antidepressant medications by primary care providers (Katon 2004a); and lack of referrals to psychotherapy services in addition to antidepressant medication treatment (Katon 2004a). Patient satisfaction with the use of antidepressant medications and mental health providers has been shown to be favorable among those who have received depression treatment (Katon 2004c, de Groot 2006).

Recommendations for Future Research

Based on the available literature, a number of areas merit additional research attention to further define the etiology, course, outcomes, and treatment of comorbid depression and diabetes.

1. Little is known about the physiologic factors responsible for apparent increased rates of depression in T1D and T2D. Further research is needed to evaluate the neurochemical, hormonal, immune/inflammatory, and neurological contributors to depression in diabetes.

2. Although there is mounting evidence for increased prevalence of depression in T1D and T2D, the majority of studies have been cross-sectional and uncontrolled in design. Prospective, controlled studies are needed to better characterize the course and impact of clinical depression in diabetes as well as the unique contribution of depression on the development of metabolic syndrome and T2D. Clinical definitions and thresholds should be used to distinguish depression syndromes from short-term emotional states (e.g., adjustment to the diagnosis of diabetes or the development of a complication) and diabetes-related distress.

3. There is currently a paucity of literature addressing rates and correlates of depression among children with T2D and women with gestational diabetes.

4. Although there is strong evidence for the efficacy of one tricyclic antidepressant medication and four SSRI medications, more research is needed to characterize the efficacy of short- and long-term use and relationship to glycemic control of the full spectrum of SSRI and SNRI (serotonin and norepinephrine reuptake inhibitor) antidepressant medications in both adults and children with diabetes.

5. Additional research is needed to evaluate exercise as an efficacious and effective treatment modality for the treatment of depression in patients with T1D and T2D.

6. Additional research is needed to investigate effective means of depression prevention in patients with diabetes.

7. Additional research is needed to establish the cost-effectiveness of all modes of depression treatment in patients with T1D and T2D.

Recommendations for Screening and Care

Depression is a frequent comorbid condition in patients with T1D and T2D. The following recommendations for clinical care are based on the literature and expert opinion (Evans 2005):

1. Depression screening is recommended at every visit for diabetes patients, accompanied by procedures to review patient responses and address clinically significant levels of symptoms. Increased concern is indicated for patients presenting with elevated blood glucose and with worsening diabetes complications and those who report a lifetime history of depression and may therefore be at increased risk for future depressive episodes. Providers may use a variety of brief screening tools to detect depressive symptoms in diabetes patients.

2. Providers are recommended to maintain a low threshold for depression treatment and promote rigorous, ongoing treatment of depression, once identified. Adequate adjustment of dosing for antidepressant medications, well-monitored maintenance therapy, and referrals to mental health services should be routinely provided by health care providers. Coordination of depression and diabetes care across providers is also recommended to ensure adequate depression treatment and follow-up care in light of the persistence and recurrence of depression in diabetes patients and the association with poor medical management.

3. Evidence supports the use of a stepped-care approach (medication and therapy) and monitored maintenance therapy to achieve symptom remission and improvements in glycemic control.

4. Use of a collaborative care approach that integrates therapy and antidepressant medication within primary care settings is suggested. This intervention paradigm has demonstrated the capacity to reduce some barriers, such as social stigma, to the effective treatment of depression in diabetes patients and has been shown to be cost-effective to health care organizations.

5. Incorporation of depression curricula into diabetes education and routine communication with patients about the role of depression in diabetes outcomes is recommended to reduce patient perceptions of stigma associated with mental illness and improve patient awareness of treatment options.

6. Incorporation of depression screening measures into clinical care outcomes within health care organizations is recommended.

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Mary de Groot, PhD, is an Associate Professor of Medicine at the Indiana University School of Medicine in Indianapolis, IN.