Wayne J. Katon, MD

Major depression and type 2 diabetes mellitus are common chronic illnesses within the general US population, with prevalence rates of approximately 5% to 10% and 11%, respectively.

 Moreover, depression and type 2 diabetes mellitus, individually, can be among the most disabling chronic disorders one can acquire, and when they occur comorbidly, they are even more detrimental. Together they exhibit a bidirectional relationship, with each disease an independent risk factor for development of the other.

In the presence of diabetes, the prevalence of depression increases to 15% to 30% depending on depression definition, population sample, and study type.

 In depressed cohorts, the risk of developing diabetes has been shown to be twice that of nondepressed persons.

 The bidirectional relationship between depression and diabetes is not limited to its effects on prevalence; instead, studies show that when these diseases are comorbid, they significantly amplify the cost, morbidity, and mortality expected from either one alone.

In the case of depression, changes in blood sugar levels have been linked directly to moods such as anger, anxiety, sadness, frustration, and even general well-being-common themes in depressed patients.

 Clinically, more than 70% of patients with diabetes have depressive episodes that last longer than 2 years.

 Dysthymia and double depression may also be more common in patients with diabetes. This was demonstrated in a large cohort of diabetic, primary care patients, well over half of whom had dysthymia.

 MDD is highly recurrent in diabetic patients-nearly 80% of depressed persons with diabetes experienced a relapse of symptoms, with an average relapse rate of nearly 1 episode every year.

Patient disability experienced in the home, workplace, or otherwise is exacerbated by the relationship between comorbid diabetes and depression. Studies that examined disability have shown not only that depression itself is one of the most disabling chronic conditions but also that the functional impairment it causes is substantially worse when it occurs in the context of another chronic disease, such as diabetes.

The course of diabetes becomes profoundly worse in depressed patients. 

 has been associated with decreased self-care, including decreased adherence to exercise, medications, smoking cessation, and eating a healthy diet.

 Depression contributes to the pathophysiology of diabetes by leading to greater body mass index, higher hemoglobin A

) levels, and increased medical comorbidity.

 It has also been associated with a myriad of adverse outcomes, including microvascular complications such as retinopathy, nephropathy, neuropathy, and sexual dysfunction, as well as the macrovascular complications of coronary artery and cerebrovascular disease.

Depression in diabetic patients is also a 

, hospitalization, and even death. In the case of dementia, diabetes and depression are independent risk factors for vascular and Alzheimer-type dementias, and comorbid they impart substantially more risk than either one alone. Effective treatment of depression and diabetes may be one of the most powerful interventions available for decreasing the prevalence of dementia. Treating depression in patients with diabetes and dementia may help slow the rate of functional and cognitive decline over time.

Not surprisingly, depression also contributes to decreased quality of life and increased costs of diabetes care. In one study of Medicare beneficiaries, the costs of the care for depressed versus nondepressed patients with diabetes was 4.5-fold higher.

 A second study of mixed-age patients with diabetes found that comorbid depression severity influenced costs as well; costs for severely depressed patients were 86% higher than those for patients with less severe depressive symptoms.

diagnosis of depression in the context of diabetes

 and other chronic medical conditions can be challenging. Many of the symptoms of depression can overlap with a chronic disorder such as diabetes, and depression itself is associated with an increased likelihood of the patient experiencing diabetic symptoms. Examples of overlapping symptoms include fatigue or decreased energy, change in appetite or weight, difficulty in concentration, and sleep disturbances.

Some general concepts can be helpful when thinking about depression in diabetes. Dividing the symptoms of depression into somatic (energy, sleep, appetite/weight, concentration) and psychological (mood, interest, suicidal thoughts, guilt, worthlessness) is important. The psychological symptoms of depression have little overlap with the signs or symptoms of diabetes, which make them particularly specific to depression in this context.

This is supported by studies that used the Beck Depression Inventory (BDI) to identify which symptoms successfully differentiated between the depressed and nondepressed, medically ill patients. Study findings included 6 symptoms that were discriminatory: a sense of failure, loss of social interest, feelings of being punished, suicidal ideation, dissatisfaction, and indecisiveness.

The somatic symptoms of depression are less specific to depression in patients with diabetes; however, that does not mean that they are without value. While the mere presence or absence of somatic symptoms is less helpful, there are many characteristics of these symptoms, such as severity, timing, etiology, and proportion, that can be useful. The more severe the somatic symptom, the more specific it is to depression.

These symptoms are also more specific when they develop in conjunction with at least 1 of the 2 cardinal symptoms of depression, so understanding the timing or onset of somatic symptoms is informative. Considering the etiology of the symptom, or whether the somatic symptom could be caused by diabetes can be helpful because symptoms unrelated to medical illness are more likely due to depression. And finally, if the somatic symptom is out of proportion to the illness, medication, or another relevant factor, it may be more likely due to depression.

Despite challenges associated with diagnosing depression in the medically ill, studies performed in ambulatory diabetic cohorts have been encouraging. In general, they have shown that common depression screening scales, including the BDI and Patient Health Questionnaire-9 (PHQ-9), retain both their sensitivity and specificity in identifying depression when administered in outpatient settings.

Clinical tips and implications for treating depression in patients with diabetes

Many studies have examined the effectiveness of treatment for depression in diabetic patients. This has included the examination of evidence-based psychotherapy; psychopharmacology; mixed-treatment modalities; and systems-based approaches, such as those using collaborative depression care models to treat depression in primary care (

). Cognitive-behavioral therapy (CBT) with added emphasis on diabetes self-management can be effective at treating depression and may also help reduce HbA

Psychopharmacological approaches have proved effective for treating acute depressive episodes, for maintenance therapy for MDD, and for successfully preventing relapse of depressive episodes. Moreover, there is observational evidence that antidepressant use may increase the risk of type 2 diabetes mellitus.

Collaborative depression care programs have successfully improved depression outcomes. However, only multicondition collaborative care programs, such as TEAM-care, have demonstrated the ability to improve depression as well as diabetes-related measures such as blood pressure and HbA

 and low-density lipoprotein cholesterol levels.

Choice of psychopharmacological agents in the treatment of depression in diabetic patients deserves special attention because depression in these patients is complicated not only by the adverse effects of medication but also by the effects of diabetes. For instance, some SSRIs may cause weight gain, which will exacerbate insulin resistance and may contribute to sexual dysfunction, worsening a common, long-term complication of diabetes. SSRIs may also cause drug-drug interactions via their effects on the cytochrome P-450 (CYP) isoenzymes by interfering with the metabolism of diabetes medications. For example, fluoxetine, fluvoxamine, and sertraline may inhibit the CYP2C9 isoenzyme and affect the metabolism of the sulfonylureas tolbutamide and glimepiride.

TCAs, while effective for treating depression in diabetes, have unique properties that limit their usefulness. First, TCAs may cause elevations in fasting blood glucose levels and they are more likely to cause weight gain than other, newer antidepressants. Second, many adverse effects associated with TCAs, such as orthostasis and arrhythmia, are particularly problematic when diabetes itself targets the nervous and cardiovascular systems.

Bupropion, in particular, possesses many qualities attractive for treatment of the diabetic patient, and it has been found to be efficacious for depression in this population.

 This drug is weight-neutral (or may even help diabetic patients lose weight); it is associated with less sexual dysfunction; it can be effective for smoking cessation (a common and costly comorbidity in depressed diabetic patients); and it has shown efficacy in treating neuropathic pain.

 However, bupropion is ineffective for treating co-occurring anxiety disorders. Venlafaxine and duloxetine, which have shown efficacy in treating depression and neuropathic pain, may also be useful in diabetic patients with depression.

Mr M, a 54-year-old with diabetes and hypertension, was referred for evaluation by his primary care physician. During the interview, Mr M rated his mood as “fair,” but he is experiencing decreased interest in leisurely activities, such as hiking and cigar smoking, as well as decreased motivation for self-care, including eating a healthy diet and taking regular blood sugar readings. He describes frequent nighttime waking, with no more than 3 hours of uninterrupted sleep; normal appetite, with a recent 5-lb weight gain; normal concentration; and decreased energy. He denies hopelessness but endorses feelings of guilt and describes himself as a bad partner to his wife because he’s currently unable to work and no longer engages in physical activity with her. When asked if he ever has thoughts of hurting himself or others, he replies, “Yeah, sometime I think I’m no good and people might be better off without me.”

Mr M is clearly depressed; he has decreased interest, guilty thoughts, feelings of being ineffective, and intermittent suicidal ideation. He’s not sleeping well (possibly because of polydipsia) and has decreased energy as well as a recent 5-lb weight gain. Additional history about the duration of both his depression and diabetes may be helpful, as would specific symptoms that the patient attributes to his diabetes, including the severity of these symptoms. Knowing the time of onset of his decreased interest and somatic symptoms may be useful. Direct inquiry into whether the patient suffers from anxiety, sexual dysfunction, or neuropathy may also help guide treatment.

 and Montreal Cognitive Assessment during the initial patient evaluation. These examinations should be repeated regularly over time to track the patient’s progress and response to treatment. Additional history can be obtained from the patient’s primary care physician. Pending further history, CBT with an emphasis on diabetes self-care should be discussed as a possible option, as should treatment with bupropion, an SSRI, or a dual-acting agent.

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Diabetes mellitus and depression symptoms are associated with with decreased self-care and less adherence to exercise, medications, smoking cessation, and eating a healthy diet.

Treatment Implications for Comorbid Diabetes Mellitus and Depression

Family caregivers provide unpaid assistance to care recipients who have difficulty with daily functioning because of physical, cognitive, or emotional impairment. Although caregiving varies with a recipient's problems, it usually involves helping with maintenance and/or higher-level activities. Caregivers of persons with dementia and Parkinson disease (PD) absorb a great deal of the indirect costs (eg, lost wages, in-home support) of these diseases. In 1991, the total US direct medical cost of Alzheimer disease (AD) was $20 billion ($12,700 per patient per year plus $1454 for diagnoses in the first year).

 Unfortunately, the costs to caregivers are not only economic but also psychosocial and physical.

We focus here on the stressors and reactions of caregivers of persons with dementia and related disorders. We also consider caregivers who are at high risk for problems and how psychiatrists can help them and their care recipients.

Many caregivers face 3 to 15 years of continuous exposure to physical and psychosocial demands. As AD progresses, caregivers must continually monitor the care recipient, cope with difficult behaviors, and witness the deterioration of the recipient.

 Caregiving may be a dress rehearsal for bereavement because it can involve prolonged grief, and bereavement is associated with several negative sequelae, including higher mortality rates.

Caregiver burden can include physical, psychological, social, and financial problems4; embarrassment; overload; and resentment.

 Across all stages of dementia, feelings of lost control and/or communication on the part of the caregiver are the best predictors of perceived burden.

 Caregiver responses vary with their relationship to the recipient. Spouses are at risk because of their own physical frailties and loss of support.

 Alternatively, caring for a spouse may be viewed as a marriage commitment, but caring for a parent may produce conflicts with a spouse and/or children.

A meta-analysis of 84 articles found that caregivers had higher levels of depression, perceived stress, and lower levels of self-efficacy than noncaregivers.

 Differences were related to study quality, relationship of caregiver to recipient, and caregiver demographics. Psychiatric morbidity in caregivers varies with sample type. Neundorfer

 found that 25% of the caregivers who were randomly selected from an AD registry had clinical depression.

 found that 36% of caregivers who were not seeking help had clinical depression, compared with 68% of self-referred caregivers. Russo and associates

 found that a diagnosis of current major depression disorder had been made within the past month for 7% of caregivers versus 1% of demographically similar noncaregivers. Depression varied from 11% to 37%

 in caregivers of stroke victims and from 2% to 4% in community dwelling older adults.

Recent research has continued to elucidate connections between chronic stress and the immune system. A metaanalysis of 23 studies of 1594 caregivers of persons with dementia and 1478 demographically similar noncaregivers found that caregivers had a 15% lower level of antibody responses (poorer IgG responses to vaccines, high levels of herpes simplex virus antibodies in absence of a challenge) and a 23% higher level of stress hormones (eg, cortisol) than noncaregivers.

Because antibody responses to vaccination are lower in older adults, older caregivers may be at higher risk for influenza; and chronically elevated epinephrine and cortisol levels may lead to increased risk of hypertension and diabetes. Caregivers who experience chronic stress may be at risk for cognitive problems as well.

 Such problems may have a negative impact on self-care, their ability to be caregivers, the information they provide about care recipients, and their responses to cognitive therapies.

There have been 3 prospective studies that used case-control comparisons of noncaregivers with caregivers. In one study, caregivers providing the most assistance had the greatest risk for at least one negative health outcome relative to other caregivers and noncaregivers over 1 to 6 years.

 In another study, caregivers reporting distress had a 63% higher death rate than noncaregivers over 4 years.

 Yet another study found that the higher incidence of coronary disease in caregivers than in noncaregivers was explained by the anger, distress, health habits, and metabolic syndrome levels of the caregivers.

 Unfortunately, these studies could not assess whether persons who become caregivers are at greater risk for negative outcomes prior to and independent of caregiving.

 found that 73% of caregivers with a history of diagnosed depression had recurrent depression while caregiving, but only 30% of noncaregivers with such a history had a recurrence during a similar time. Caregivers with recurrent depression are at added risk for medical illnesses, because depression increases the risk for heart disease

 Medical illnesses may interact with caregiving and exacerbate physiologic risk.

A history of cancer may predispose one to immunologic risk.

 Caregivers with cancer histories have lower natural killer cell activity (NKA) than noncaregivers with cancer histories, but NKA does not differ in individuals free of cancer histories.

 This is important because a major function of NKA is to attack tumors.

Normotensive caregivers and noncaregivers do not differ in systolic blood pressure reactivity to a laboratory stressor, but hypertensive caregivers show greater reactivity than hypertensive noncaregivers.

 Reactivity may exacerbate the effects of hypertension.

 Caregivers with coronary disease show higher levels of the metabolic syndrome than noncaregivers with coronary disease. However, no difference exists for individuals free of such disease.

Caregivers with diabetes and/or coronary disease may be at higher risk for complications from these diseases than are noncaregivers with these diseases. This may be especially true of caregivers with heart disease or diabetes and depression. Depression is a risk factor for mortality among patients with post–myocardial infarction and patients with type 2 diabetes.

 End-organ damage secondary to ischemic heart disease or diabetes may make depressed caregivers more vulnerable to mortality.

Studies have shown that interventions to support caregivers have proved beneficial to health outcomes. Interventions with active treatments reduced burden (ie, perceived psychological problems),

 and pleasant event therapies (ie, interventions that teach caregivers to identify and pursue experiences that give them pleasure on a regular basis) decreased depression.

 Among persons with coronary disease, higher levels of the metabolic syndrome in caregivers than noncaregivers are explained, in part, by the fact that caregivers also have lower levels of pleasant experiences than noncaregivers. Pleasant experiences are also correlated with higher NKA in caregivers with cancer histories.

Dietary and physical activity interventions show 1-year improvements in health behaviors, depression, and sleep problems.

 In a meta-analysis, Brodaty and associates

 examined 34 interventions and found benefits in caregiver distress/knowledge that were reflected in improved care-recipient mood and delayed nursing home admission. They noted that programs may be more successful if they involve care recipients and caregivers, are more intensive, and are modified to caregivers' needs. Other investigators have found that interventions should be tailored to caregiver ethnicity,

 because ethnic groups respond differently to caregiving.

Psychiatrists who treat patients with PD or AD should also monitor and help treat the caregivers of these patients, especially if the caregivers have preexisting medical conditions. Caregiver decline may be associated with decline in the patient receiving care. Reciprocal relationships between caregiver dispositions and care recipient health/functioning should be monitored and when negative feedback is observed it should be mitigated through psychiatric treatment.

 For instance, depression in a caregiver may result in poorer adherence to medical regimens in the patient, such as taking prescription medication at regular intervals. Screening and treatment of caregivers for depression may help improve their energy and concentration as well as their ability to keep the patient on medical regimens, preventing the patient's health decline.

Older caregivers with major depression or dysthymia secondary to caregiving are vulnerable to poor outcomes because they may not seek mental health treatment.

 Those that do are less likely than younger depressed individuals to receive specialty mental health services,

 and the services they do receive are usually in primary care rather than mental health specialty care.

Such inadequacies have fostered interventions that deliver evidencebased depression care within a primary care setting.

 These programs integrate allied health/mental health professionals into primary care to provide:  

More time to educate patients (in this case, the caregivers) about depression. 

 More frequent patient (ie, caregiver) contacts by telephone or in person. 

 Tracking of depression symptoms with a standard scale such as the Patient Health Questionnaire (PHQ-9). 

 Better adherence to antidepressant therapy and/or provision of shortterm psychotherapy. 

 More return visits to primary care physicians or mental health specialists for caregivers who are not improving. 

 Guidance for the primary care physician on the use of antidepressant medications.

Collaborative care for depressed older adults (who had a mean of 3 comorbid medical illnesses) improved quality of care and physical functioning and lowered depression compared with usual care.

 Collaborative care for patients with diabetes and depression saves medical costs, thus balancing out the mental health costs needed to improve depression.

 Because the stress associated with caregiving may exacerbate medical conditions and health risks, collaborative care models are essential for treating physical and psychiatric conditions in caregivers.

Such models should be adapted to caregivers' needs, including home visits, help with management of difficult behaviors, greater use of telephone contacts, and management of mental and physical illnesses.

Drs Vitaliano and Katon are professors in the department of psychiatry and behavioral sciences at the University of Washington in Seattle. They report that they have no conflicts of interest concerning the subject matter of this article.

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Caregivers may face years of continuous exposure to physical and psychosocial demands with burdens that can include physical, psychological, social, and financial problems; embarrassment; overload; and resentment.

Author | Wayne J. Katon, MD

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