Exploring the association, as well as diagnostic and treatment challenges

Disclosure: Dr. Diane McIntosh and Dr. Kevin Kjernisted both receive honoraria, are on advisory boards or are doing research with Eli Lilly, Astra Zeneca, Wyeth, Janssen-Ortho, Sanofi-Aventis, Servier, Brain Cells International, Novo Nordisc, Lundbeck and Biovail.

Diabetes mellitus and major depressive disorder are both chronic, debilitating illnesses that may progress for years before a diagnosis. In a large survey carried out in the United States from 1999 to 2002, approximately one-quarter of diabetes cases were undiagnosed. The diagnosis rate for depression is no better: Studies in primary-care settings indicate one-half to two-thirds of individuals with depression are undiagnosed.

Most of the psychiatric care in Canada is provided by family physicians who are required (in a very short space of time) to diagnose, assess severity and treat what is often a hidden, stigma-laden diagnosis. Most depressed or anxious patients report somatic rather than psychiatric symptoms when presenting to their family doctor.

Identifying depression: barriers and tools
A sense of personal failure, potential stigmatization, humiliation and fear may create barriers to seeking help for patients suffering from depression. Additionally, patients with chronic diseases, such as diabetes, COPD or heart disease, may assume that low mood is an expected result of living with a serious illness. Likewise, there is a great deal of overlap between symptoms of a chronic illness and depression, particularly neuro-vegetative symptoms such as fatigue, changes in appetite and weight, and sleep disturbance, which might obscure the diagnosis of depression. Ideally, all patients with chronic illnesses should be screened for depression.

To diagnose depression, the DSM-IV requires the presence of depressed mood or anhedonia (loss of interest/ pleasure), as well five or more symptoms, including weight loss or appetite change, insomnia or hypersomnia, psychomotor retardation or agitation, fatigue or loss of energy, feelings of worthlessness or inappropriate guilt, cognitive decline and suicidal ideation. Sometimes depressed patients are not able to identify feelings of sadness but may say they feel indifference, numbness or nothing. Anhedonia might be an even more sensitive indicator of the presence of depression. There is a great deal of overlap between depression and anxiety symptoms: Significant anxiety is inherent in 60% to 90% of depressive episodes. The presence of anxiety makes the depression feel much worse. Psychic agitation and panic attacks in particular increase the risk of suicide. Screening for the presence of anxiety is imperative, especially when assessing suicide risk.

Physicians often do not think they have time to administer psychiatric screening tools, especially if they must take part in the process. However, without the use of a screening questionnaire, physician diagnosis of major depressive disorder is poor (sensitivity, 40%; specificity, 87%). A patient-administered (self-report) tool that is easy and quick to complete tends to be more valuable in clinical practice. Several two- and three-question screening tests for depression have been developed for primary care, but these tests have inadequate sensitivity (80%). The Patient Health Questionnaire (PHQ-9) is comprised of nine questions that directly evaluate the presence of DSM-IV criteria of major depression. Its validity and reliability have been demonstrated in large samples of primary-care patients. In addition, the PHQ includes a question about functional impairment that is required to make a psychiatric diagnosis.

Using the PHQ-9, a diagnosis of major depression is probable if five or more of the PHQ-9 items have been present “more than half of the days” over the past two weeks and if one of the symptoms is depressed mood or anhedonia. A total PHQ-9 score of less than 10 probably rules out major depression, while a score of 15 or more is strong evidence of major depression. Scores of 10 to 14 are in a grey zone and should be followed up with a clinical interview. As always when diagnosing major depression, the clinician must rule out physical causes of depression (e.g., hypothyroidism), use of drugs or medication that may cause depression, normal bereavement and history of a hypo-manic or manic episode. The sum of the nine items’ scores has also been validated as a continuous measure of depression severity that can be used to monitor clinical response to therapy.

The diabetes-depression association
Approximately 8% of American adults living with diabetes were experiencing a major depressive episode when they were interviewed as part of a 2006 telephone survey (n=18,814) conducted by researchers from the division of adult and community health at the National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control, in Atlanta. Depression was much more prevalent in patients with type 2 diabetes who used insulin (13.3%) than in those who did not use insulin (8.3%) or in patients with type 1 diabetes (6.3%). This might be associated with the length of time a patient has lived with diabetes, since insulin is often reserved until late in the course of type 2 care. Gender, race/ethnicity, geographic location and age all significantly affected the probability that a person with diabetes had co-morbid depression. Women are about twice as likely to experience major depression as men, and the same is true for diabetic patients. Adults between the ages of 30 and 59 were at the highest risk of depression (10% to 13.7%); depression rates were significantly lower among 18- to 29-year-olds (3.2%) and those older than 59 (2.0% to 5.5%).

In order to determine whether an association exists between diabetes and depression, the prevalence of depression must be compared between people with and without diabetes. One often cited meta-analysis from researchers in the department of psychiatry at Washington University school of medicine in St. Louis, Mo., estimated the prevalence of depression in people with diabetes is double that in people without diabetes. However, not all of the studies reviewed in this meta-analysis included a non-diabetic comparison group, and the analysis did not distinguish between type 1 and type 2 diabetes. More studies have since been published that suggest the association between diabetes and depression is less robust and more complicated.

In type 1 diabetes, the current evidence suggests that if an association exists with depression, the strength of this association is not clear and may be overshadowed by other variables, such as gender. The diagnosis of type 2 diabetes has not been shown to increase the risk of a subsequent diagnosis of depression. On the other hand, a depression diagnosis increases the risk of a subsequent diagnosis with type 2 diabetes. This suggests that depression may lead to insulin resistance via behavioural and/or metabolic pathways (e.g., increased cortisol and pro-inflammatory cytokines). However, the expected positive correlation between depression and insulin resistance among non-diabetic and pre-diabetic patients has not been consistently established. Three recent studies have found such a correlation, but four others have not. The large number of covariates influencing both diabetes and depression hinder studies to investigate a causal relationship between the two conditions. Thus, it will take carefully designed studies to better understand this complicated relationship.

Effect of co-morbid depression on diabetes
A large meta-analysis published in 2000 by researchers from the department of psychiatry at Washington University school of medicine and the department of Veterans Affairs Medical Center, both in St. Louis, Mo., concluded there is a significant association between depression and glycemic control in both type 1 and type 2 diabetes. However, this result is controversial because numerous studies have found no such relationship, and it is possible that depression adversely affects glycemic control in type 1 diabetes but not in type 2. Another large meta-analysis found a consistent association between depression and the many complications of diabetes, including retinopathy, nephropathy, neuropathy, macrovascular complications and sexual dysfunction. More recently, several other studies reported significant associations between depression and disease burden in diabetes. Depression may contribute to the progression of diabetes directly via shared underlying pathophysiologies recently implicated in the etiologies of both depression and diabetes.

The adherence rate for depression treatment is dismal. This is associated with several factors, including treatment side-effects (e.g., weight gain, sexual side-effects), poor motivation, perceived stigma, “I’m feeling better so thought I’d stop,” cost of treatment or ineffectiveness. It stands to reason that depressed diabetic patients also are poorly compliant with their depression and diabetic treatments. A study of 4,463 patients with type 2 diabetes revealed those who were depressed were less likely to meet treatment guidelines for physical activity, food intake and medication adherence. Another study found the rate of attrition from weight control programs for patients with type 2 diabetes was much higher in depressed patients than non-depressed patients. Depressed patients often feel like they are failures, and poor glycemic control and weight gain might provide further “evidence” of their personal weakness and failure.

Treatment options
Patients with major depression and diabetes may benefit from treatment with both antidepressants and cognitive behavioural therapy. When selecting an antidepressant for a diabetic patient, it is important to consider its metabolic and bariatric side-effects. There is significant preclinical and clinical evidence that selective serotonin reuptake inhibitors (SSRIs) reduce hyperglycemia, normalize glucose homeostasis and increase insulin sensitivity without causing significant weight gain for most patients. Dual-mechanism serotonin norepinephrine reuptake inhibitors (SNRIs) do not appear to affect glucose homeostasis, do not usually cause significant weight gain and may also help manage diabetic neuropathic pain. The SNRI duloxetine (Cymbalta) has recently received Health Canada approval as an antidepressant as well as an indication for diabetic peripheral neuropathic pain. Several tricyclic antidepressants also provide relief of neuropathic pain, but these are potentially associated with hyperglycemia, increased appetite and weight gain, and pose a greater risk for overdose than most of the more recently available antidepressants.

Monoamine oxidase inhibitors are associated with hypoglycemia and weight gain. Mirtazapine, a noradrenergic and specific serotonergic antidepressant, is also associated with weight gain but does not appear to influence glucose homeostasis. Buproprion, a noradrenergic and dopaminergic antidepressant, does not affect serotonin levels and may improve glucose homeostasis, promote weight loss and assist with smoking cessation. The efficacy of bupropion in treating neuropathic pain has been evaluated in only one trial, but the results were promising: Neuropathic pain relief was improved or much improved in 73% of patients.

Cognitive-behavioural therapy (CBT) may be effective for patients with major depression as well as for those who, while not clinically depressed, suffer from diabetes-related distress. Many of the concepts that are important in depression are also important in managing diabetes —for example, self-efficacy, exercise and medication adherence. The impact of new learning (the expected outcome of CBT) on brain remodelling or neuroplasticity might be an important factor in the effect of CBT on recovery from depression. Whether CBT leads to neurogenesis has not been empirically established.

Integrating depression and diabetes concepts into one CBT program may be beneficial for both disorders. A study published in 1998 assessed patients with co-morbid depression and type 2 diabetes who participated in a diabetes education program. In this study where patients were assigned to either 10 weeks of individual CBT or no specific antidepressant treatment, 85% in the CBT group achieved remission from their depression compared with 27% of patients in the control group, supporting the effectiveness of CBT. HbA1c levels were similar in the two groups immediately following treatment, but were significantly better in the CBT group six months post-treatment: 9.5% vs 10.9% for controls. This led to the appealing hypothesis that effective treatment of depression may have the additional benefit of improving glycemic control in patients with diabetes. However, the results of two more recent studies do not support this hypothesis. One study included patients with type 1 and type 2 diabetes and found that CBT was highly effective in reducing depressive symptoms for patients with subclinical or clinical depression, but that both HbA1c and fasting blood glucose remained unchanged from baseline to every endpoint in the 12-month followup.

A second study was a randomized controlled trial of a case management program designed to improve the quality of treatment of depression in patients with diabetes. The individualized case management program included stepped care for non-responders, collaborative care and followup support, and resulted in significantly better depression outcomes than did usual care. However, no differences in HbA1c outcomes were observed. Therefore, when treating patients with co-morbid depression and diabetes, it is insufficient to treat one disease and hope it will generalize to the other. Rather, the best treatment integrates both depression and diabetes-associated targets.

Numerous studies reinforce the need for full symptom remission in depression treatment, which significantly reduces relapse rates and improves psychosocial functioning. However, there are a number of potential patient- and physician-related obstacles to achieving remission. Patients might be resistant to dose increases, they might feel they’re “well enough” because they feel better despite residual symptoms or, for a variety of reasons, they might simply fail to return for followup. Physicians might be concerned about using higher doses of antidepressants or feel they do not have the expertise to combine or augment an antidepressant to optimize treatment. If this is the case, a psychiatric consult should be considered.

The saying “the dose that got you well keeps you well” is important to remember, since many patients wish to decrease their antidepressant dose soon after they start to feel better.

Conclusion
Depression appears to be more prevalent among patients with type 2 diabetes than the general population. Depression is universally under-diagnosed and failure to recognize it might be more common in patients with diabetes and other medical illnesses because of the assumption that low mood is an inevitable result of a chronic disease as well as the overlap of somatic symptoms between depression and the medical illness. We recommend screening all patients with the PHQ-9. SSRIs and SNRIs are appropriate first-line treatments for co-morbid depression, as is buproprion, because they do not pose risk of hyper- or hypoglycemia or significant weight gain. Cognitive behavioural therapy that integrates depression and diabetes is also supported by the literature. Patients who have had two or more severe depressive episodes are at high risk of relapse or recurrence; therefore, maintenance therapy with antidepressants and/or cognitive be-havioural therapy is recommended.

Dr. Diane McIntosh is a clinical assistant professor, University of British Columbia; private practice psychiatrist, Vancouver.

Dr. Kevin Kjernisted is a clinical associate professor, University of British Columbia; consultant psychiatrist, Anxiety Disorders Clinic, UBC; private practice psychiatrist, Vancouver.

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