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Triple Threat Complicates Treatment

Kurt Ullman

This is the second of a two-part series examining the interplay between diabetes and depression. Part one (DOC News, June 2007, page 1) looked at the factors that underlie the relationship. Part two explores the common involvement of cardiovascular disease.

It's a daunting combination to treat, but depression, diabetes, and cardiovascular disease present together in many patients, research suggests.

In one recent study, patients with major depression and type 1 or type 2 diabetes were 1.5–2 times more likely to have three or more cardiovascular disease (CVD) risk factors compared with those with diabetes but no depression.¹ In addition, an analysis of 13 years of psychiatric data from the Baltimore Epidemiologic Catchment Area revealed an association between a depression diagnosis and an increased odds ratio for type 2 diabetes (2.2), myocardial infarction (4.5), and stroke (2.7).² Other studies have shown depression to be an independent risk factor for both type 2 diabetes and heart disease.^3,4

"There is quite a bit of evidence of the relationship between these three disorders," says Sherita Golden, MD, assistant professor of medicine and epidemiology at Johns Hopkins University School of Medicine in Baltimore. "We know that depression is a risk factor for the development of type 2 diabetes and also for CVD."

THREE MAJOR PATHWAYS

Researchers are investigating two metabolic pathways for this overlap in diseases and a third, behavioral one—probably the best understood of the three.

The behavioral pathway involves health risks and noncompliance. "Depression has been associated with unhealthy lifestyles, including smoking, nonadherence to medications, and an unhealthy diet," says Michelle Riba, MD, professor and associate chair of the department of psychiatry at University of Michigan Medical School in Ann Arbor. "These are all risk markers for both CVD and diabetes and indicate one reason there may be a link."

One meta-analysis of 24 studies demonstrated an association between depression and higher glycated hemoglobin (A1C) levels.⁵ Other studies have found increased complications, including macrovascular disease and lower levels of adherence to both diabetic and CVD treatment regimens.

One metabolic pathway for the connection is increased hypothalamic-pituitary-adrenal (HPA) function.

"Many studies show depression causes activation of the HPA axis and sympathetic nervous system," says Golden. "This activation results in higher cortisol and catecholamine levels, which, in turn, leads to insulin resistance and the beginning of both diabetes and CVD concerns."

Another metabolic pathway to which major depression has been linked is dysregulation of pro- and anti-inflammatory cytokines, including increased serum levels of interleukin-1ß, interleukin-2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor (TNF), and the IL-2 and IL-6 receptors.⁶ These may influence development of type 2 diabetes and heart disease. However, since most of this research was done in those already diagnosed with depression, assigning cause-and-effect relationships is impossible.

"The hope is to eventually identify a common pathway, find markers, and then stratify the risks," Riba says. "While we can probably work on lessening the behavioral impacts starting now, we need to know the pathophysiology to develop new medications and treatments."

The pathophysiology will likely be multifactoral.

"I am not sure what their relative contributions will be, but I think all three pathways will be significant contributors," says Golden. "It is also probable that there will be interactions between the pathways."

TREATMENT CONSIDERATIONS

Meanwhile, as researchers continue exploring pathways and causes, primary care physicians (PCPs) face the challenge of treating this trio.

"The call to action for the primary care doctor is to recognize all of the risk factors for depression, CVD, and diabetes and treat them independently," says Martin Abrahamson, MD, medical director for Joslin Diabetes Center in Boston. Abrahamson and other experts suggest the following treatment strategies for PCPs:

• Routine screening of all patients for depression, diabetes, and cardiovascular problems. Recognize that these conditions often co-occur and suggest lifestyle modifications as needed for each condition.
  
• Vigilance in managing medications. Any one of these diseases can present a management challenge to the physician. All three together require juggling multiple medications, especially given the aggressive management of blood glucose, lipids, and blood pressure stemming from changes in guidelines for therapeutic targets, says Abrahamson. "Unfortunately in this group, polypharmacy will be the norm," he says. "The challenge will be getting the lipids, blood pressure, and blood glucose as close to normal as possible while still addressing the depression."
  
• Taking a multidisciplinary approach. Managing people with these coexisting conditions requires coordination among many physicians from multiple specialties, as well as support personnel, such as diabetes nurse educators, dieticians, and psychologists. "These patients will have to be treated in a multidimensional, multidisciplinary way," says Riba. "It is not like looking at just your part of the elephant anymore."
  
• Handling multiple referrals. Patients need varying types of referrals based on their disease profiles. "In general, the more complex the therapy becomes and the more treatments are added, the more appropriate it becomes to refer this patient to specialists," says Abrahamson. Multiple referrals also bring their own set of concerns. The PCP may need to coordinate care among three different specialists, which involves assessing patients for medication side effects, ensuring appropriate laboratory studies are drawn at the right times, assessing compliance with many medication and lifestyle recommendations, and answering patient questions.
  

"The challenges are many," says Golden. "Helping patients to recognize that depression is more than a psychiatric disorder and that it has medical implications is an important point the PCP can reinforce. Present it to the patient as another way to improve outcomes, just like treating blood glucose or cholesterol."

Footnotes

FYI

The MacArthur Initiative on Depression and Primary Care offers a Depression Tool Kit to help clinicians recognize and manage depression. The kit includes downloadable versions of PRIME-MD in Spanish and English, available at www.depression-primarycare.org.

The National Institute of Mental Health offers extensive information about treating depression at www.nimh.nih.gov/healthinformation/depressionmenu.cfm.

National Depression Screening Day is October 11. A free kit to help primary care providers screen for mood and anxiety disorders, as well as postpartum depression, is available to download at www.mentalhealthscreening.org.

References

1. Katon WJ, Lin, EHB, Russo J, et al.: Cardiac risk factors in patients with diabetes mellitus and major depression. J Gen Intern Med 19:1192–1199, 2004.[Medline]

2. Eaton WW, Fogel W, Armenian H, et al.: The consequences of psychopathology in the Baltimore Epidemiological Catchment Area follow-up. In Medical and Psychiatric Comorbidity Over the Lifespan. Eaton WW, Ed. Washington, D.C., American Psychiatric Association Publishing, Inc., pp. 21–38, 2006.

3. Eaton WW.: Epidemiologic evidence on the comorbidity of depression and diabetes. J Psychosom Res 53: 903–906, 2002.[Medline]

4. Fenton WS: Mood disorders: Cardiovascular and diabetes comorbidity. Curr Opin Psychiatry 19:421–427, 2006.[Medline]

5. Lustman PJ, Anderson, RJ, Freedland KE, et al.: Depression and poor glycemic control: A meta-analytic review of the literature. Diabetes Care 23:934–942, 2000.[Abstract]

6. Lanqillon S, Krieg, JC, Bening-Abu-Shach U, et al.: Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 22:370–379, 2000.[Medline]

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Services Email this article to a friend Similar articles in this journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ullman, K. Search for Related Content PubMed Articles by Ullman, K. Social Bookmarking                What's this?