We have all bemoaned non-adherent patients with out-of-control blood sugars who nod agreeably and then ignore everything we say. Not surprisingly, their wounds heal poorly and discouragement sets in with these patients. Their behavior appears to defy logic until we look at how prevalent depression and anxiety disorders are among patents with diabetes and how these disorders affect healing. The picture begins to make even more sense when we consider the effect of prolonged hyperglycemia on the brain.
Extensive studies have established a strong link between diabetes and depression. Patients with diabetes are twice as likely to be depressed as the general population with their estimated prevalence of depression ranging from an estimated 11.4 percent to as high as 31.7 percent, depending on the survey methodology and the subpopulation studied.1
Peyrot and Rubin found a substantially higher prevalence of depressive symptoms among patients with diabetes (41.3 percent) than that estimated for the general population (16.7 percent). They found even higher rates among patients with multiple complications (47.1 percent) or hemoglobin A1c levels above 12 (43.6 percent).2 In a 2007 cohort study of patients with diabetes with their first foot ulcer, Ismail found that one-third of patients with their first diabetic foot ulcer had clinically significant depression and a threefold risk of death after 18 months.3
The effect of depression on our patients includes non-adherence to treatment regimens for diabetes and their foot ulcers, as well as significantly impaired wound healing.4,5,6 Monami and his colleagues studied 80 patients 60 years and older with chronic foot ulcers and found that the risk of non-healing within six months was significantly higher among those patients with Geriatric Depression Scale (GDS) scores over 10 (30.2 percent vs. 10.8 percent).5 Adherence, as measured by the percent of patients wearing prescribed footwear at follow-up, was significantly lower among patients with a GDS score over 10 (21.4 percent versus 53.8 percent).5 
In addition to depression, diabetes is associated with a higher prevalence of anxiety disorders. Li and associates estimated that the overall age adjusted prevalence of lifetime diagnosis of anxiety was 19.5 percent in people with diabetes and 10.9 percent in people without diabetes.9 Even after adjusting for education, marital status, employment, smoking, leisure activities, physical activity and body mass index (BMI), patients with diabetes had a 20 percent higher prevalence of diagnosed anxiety.9
The comorbidity of a mood or anxiety disorder exacerbates the patient’s already impaired wound healing. Researchers have shown this in numerous animal and human studies investigating psychological stress and wound healing. Mice subjected to restraint stress healed 27 percent more slowly than control mice and had serum levels of corticosterone that were four times higher. Human studies have shown stress-induced increases in glucocorticoids suppress IL-1B, TNF and PDGF.10
Using a skin blister model to collect wound fluid from people during periods of high and low stress (university exam periods versus non-exam periods), Roy found stress to be associated with decreased growth hormone levels and impaired wound healing.11
Keicolt-Glaser, et al., reported similar findings in their investigation of wound healing among patients stressed by their roles as caregivers versus a control group. Wound healing took significantly longer in the stressed group than the control (an average of 48.7 days versus 39.3 days) and stressed patients produced less interleukin-1 beta than the control group. Research has shown that interleukin-1 beta regulates the production, release and activation of metalloproteinases, which play an important role in the formation of the connective tissue matrix.11 
Finally, Broadbent studied the effect of stress on surgical wound healing by analyzing wound fluid for the levels of specific cytokines and used regression analysis to quantify the effect of stress on those levels. The study correlated perceived stress with lower levels of IL-1 and MMP-9, indicating that stress impairs the inflammatory responses and matrix degradation processes that one sees in the early stages of normal wound healing.12
In addition to an increased incidence of anxiety and depression, patients with diabetes also face cognitive and behavioral impairments related to the effect of prolonged hyperglycemia on the brain. Specifically, diabetes impairs hippocampus-dependent memory, perforant path synaptic plasticity and adult neurogenesis.13
Hyperglycemia triggered excesses of the adrenal glucocorticoids appear to play a role in these adverse effects.14 Impaired hippocampal synaptic plasticity ultimately results in impaired cognitive and behavioral functioning.13,14 Additionally, oxidative stress and reactive oxygen species are increased in patients with diabetes and both reduce the activity of a variety of proteins that are crucial to neuronal homeostasis.15
Recognizing these less frequently discussed complications of diabetes suggests several ways we can strengthen our practices. Now more than ever, we must insist on tight glycemic control. No diabetic patient should ever leave our office without at least two staff members asking about the patient’s most recent hemoglobin A1c. Patients failing to achieve the American Diabetes Association (ADA) 2009 target of 7 or lower need to hear how critical it is to lower their levels. Explaining the damaging effect of hyperglycemia on brain function should now be a part of that discussion. One should also refer these patients to diabetes support services and encourage them to pursue new glycemic control strategies with their primary care provider .
Secondly, as much as we would rather leave it up to primary care, we should screen our patients for depression and anxiety. There is a significant under-detection of these disorders among primary care physicians, and the majority of individuals with depression and anxiety do not access effective treatment.16 When it comes to this under-detection among primary care physicians, many of us may be affected by provider perceived stigma concerning emotional issues and the avoidance of asking questions for fear of harming the relationship.16 The link between emotional illness and poor wound healing behooves us to get past our discomfort and develop a non-threatening, expeditious way to screen for the problem.
There are several accurate depression and anxiety screening tools available that use a quick self-assessment questionnaire. One can distribute these tools at patient registration and a staff member can score them before one sees the patient.17,18 The Hospital Anxiety and Depression Scale (HADS) and the Generalized Anxiety Disorder (GAD-7) scale are two such tools that have been used effectively in primary care settings.17,18
Incorporating these screening tools in our office protocols also makes a clear statement to our patients that we understand chronic wound healing requires attention to psychological as well as physical health. By modeling behavior that destigmatizes and stresses the importance of mental health, and by insisting on tight glycemic control, we have an opportunity to make real progress with our patients with diabetes.
Ms. Megas is a nurse practitioner with the Center for Wound Healing at Georgetown University Hospital in Washington, DC.
Dr. Steinberg is an Assistant Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C. Dr. Steinberg is a Fellow of the American College of Foot and Ankle Surgeons.
1. Anderson RJ, et al. The prevalence of comorbid depression in adults with diabetes: A meta-analysis. Diabetes Care, 24(6):1069-78, 2001.
2. Payrot M, et al. Levels and risks of depression and anxiety symptomatology among diabetic adults. Diabetes Care, 20(4):585-90, 1997.
3. Ismail K, et al. A cohort study of people with diabetes and their first foot ulcer: The role of depression on mortality. Diabetes Care, 30(6):1473-1479, 2007.
4. Bosch JA, et al. Depressive symptoms predict mucosal wound healing. Psychosomatic Medicine 69(7): 596-605, 2007.
5. Monami M, et al. The diabetic person beyond a foot ulcer. JAPMA 98(2):130-136, 2008.
6. Gonzalez JS, et al. Depression and diabetes treatment non-adherence: A meta-analysis. Diabetes Care 31(12):2398-2403, 2008.
7. Glaser R and Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nature Reviews Immunology. 5(3):243-51, 2005.
8. Padgett DA, et al. Restraint stress slows cutaneous wound healing in mice. Brain Behavior and Immunity 12(1):64-73, 1998.
9. Li C, et al. Diabetes and Anxiety in US adults: findings from the 2006 Behavioral Risk Factor Survelliance System, Diabetes Medicine 25(7):878-881, 2008.
10. Keicolt-Glaser JK, et al. Slowing of wound healing by psychological stress. The Lancet, 346(8984):1194-1197, 1995.
11. Roy S, et al. Wound site neutrophil transcriptome in response to psychological stress in young men. Gene Expression 12(4-6):273-287, 2005.
12. Broadbent E, et al. Psychological stress impairs early wound repair following surgery. Psychosomatic Medicine 65(5):865-869, 2003.
13. Stranahan AM, et al. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nature Neuroscience, 11(3):309-17, 2008.
14. Reagan LP. Insulin signaling effects on memory and mood. Current Opinions in Pharmacology. 7(6):633-637,2007.
15. Reagan LP, et al. The A’s and D’s of stress: metabolic, morphological and behavioral consequences. European Journal of Pharmacology 585(1):64-75, 2008.
16. Collins KA, et al. Gaps in accessing treatment for anxiety and depression: Challenges for the delivery of care. Clinical Psychology Review 24(5):583-616, 2004.
17. Bunevicius A, et al. Screening for depression and anxiety disorders in primary care patients. Depression and Anxiety 24(7):455-460, 2007.
18. Spitzer RL, et al. A brief measure for assessing generalized anxiety disorder. Archives of Internal Medicine 166(10):1092-1097, 2006.