1. Can Depression Cause Diabetes? Behavioral Health Symposium May 16, 2008 Mercedes R. Carnethon, Ph.D. Assistant Professor of Preventive Medicine Feinberg School of Medicine Northwestern University, Chicago, IL

2. Outline Type 2 Diabetes Depression and diabetes Depression and diabetes risk factors Depression as a cause of diabetes

3. Epidemiology of Type 2 Diabetes Non-insulin dependent diabetes 90-95% of all diagnosed cases 21 million adults (10%) have T2DM –Average age of onset: > 40 years –Typically overweight or obese –Higher Prevalence in non-white minorities –Roughly equal by sex

4. Age-Adjusted Prevalence of Diabetes in 2005 American Indian/ Native American Non-Hispanic Black Hispanic/ Latino Americans Non-Hispanic White Age > 20 years Overall prevalence ~ 10%

5. Pathogenesis of Type 2 Diabetes Defective Insulin Secretion Blunted insulin secretion Insulin Resistance Glucose can’t get to cells in the body Impaired glucose tolerance Insulin Secretion Glucose enters the bloodstream Glucose builds up in blood stream Type 2 Diabetes Impaired fasting glucose

7. Risk Factors for Type 2 Diabetes Osler’s Principles & Practice of Medicine, 1892 Heredity Ethnicity Social Class Adiposity Sedentary life Overindulgence Defective Assimilation Nervous strain Worry CNS Lesions Environment Infections Liver Disturbances Adiposity

8. Multiple Mechanistic Pathways for Diabetes Development Obesity Diabetes Autonomic Dysfunction Insulin Resistance Inflammation Endothelial Dysfunction

9. Depression and Diabetes

10. Major Depressive Disorder (MDD) Combination of somatic and mood symptoms –Symptoms persist for at least 2 weeks –Mood represents a change from person’s normal mood –Not due to bereavement Diagnosed by a structured clinical interview Diagnostic Interview Schedule (DIS) Structured Clinical Interview for Depression (SCID) Adapted from: DSM-IV

11. Estimated Prevalence DSM-IV Major Depressive Disorder in the US, 2005 Prevalence (%) Hasin DS. Arch of Gen Psychiatry 2005; 62: 1097

12. Depression and Diabetes Persons with diabetes up to three times more likely to suffer depression –Rate varies based on self-reported symptoms or diagnosed major depressive disorder

13. Prevalence (%) of Adults with Major Depressive Disorder in Adults, by Diabetes Egede LE. Diabetes Care 2003; 26: 104 Kessler RC. JAMA 2003; 289: 3095 (%)

14. Depression and Diabetes: Mechanisms Cross-sectional –Common neuroendocrine basis underlying both disorders –Depression and diabetes share somatic symptoms (e.g., fatigue) Temporal –Stress of coping with diabetes leads to symptoms of depression –Depression leads to physiologic or behavioral changes that lead to diabetes

15. Which comes first— depression or diabetes? Diabetes Depression ?

16. Depressive Illness Preceding Diabetes Onset Stress of coping with diabetes results in symptoms of depression Or Depression produces physiologic or behavioral changes that lead to diabetes

17. Diabetes Depression Diabetes HPA-axis alterations Cortisol Secretion Depressive Symptomatology Psychological Factors Confronting the “loss” of healthy function Changes in self esteem Complications decrease QOL Perceived Disability Coping Difficulties

18. Rate of Depression* Over 3.1 Years by Baseline Glucose Status Rate per 1000 Person-Years Multi-Ethnic Study of Atherosclerosis *Depression defined as CES-D>16 or initiation of depression meds 40% elevated following adjustment

19. Shared Symptoms of Diabetes and Depression DSM-IV excludes illness as criteria for defining major depressive disorder –Mood disorder due to a general medical condition –Diabetes and depression share symptoms (e.g., decreased energy, weight changes) “A prominent and persistent disturbance in mood that is judged to be due to the direct physiological effects of a general medical condition”

20. Average Ages of Onset for Diabetes and Depression Type 1 DM 5-14 Depression 18 - 39 Type 2 DM 40-60 Age 10 20 30 40 5060700 Depression 45 - 64

21. Plausibility of Diabetes leading to Depression Evidence suggests that it is the burden of treatment leading to depression –Inconsistent with the definition of MDD Average ages for developing both conditions not consistent with a causal model More longitudinal observational studies needed

22. Evidence for Depression Preceding the Onset of Diabetes Diabetes Depression

23. Behavioral Mechanisms Energy Balance If depression leads to decreased physical activity levels and increased energy intake... The scale tips and weight gain ensues

24. Behavioral Pathways for Depression to Precede the Onset of Diabetes Depressive Symptomatology Incident Diabetes Food Intake Physical Inactivity Poor Sleep Habits Cigarette Smoking Weight Gain Insulin Resistance

25. Multiple Mechanistic Pathways for Diabetes Development Obesity Diabetes Autonomic Dysfunction Insulin Resistance Inflammation Endothelial Dysfunction HPA-axis Dysregulation Cortisol release

26. Meta-Analysis of Longitudinal Studies of Depression and Incident Diabetes Knol MJ et al. Diabetologia 2006; 49: 837 26% elevated risk 37% elevated risk

27. Depressive Symptom Scores Over Time and the 10- Year Risk of Developing Diabetes: in Older Adults (Age > 65) Carnethon et. Archives Internal Medicine 2007; 167: 802

28. Association between Depressive Symptoms and Incident Diabetes over 16 years: NHEFS (n = 6190) Carnethon et al. Am J Epidemiol 2003: 158: 416 General Well Being Depression Subscale

29. Relative Risk of Incident Diabetes over 16 years by Depressive Symptoms Category and Education Carnethon et al. Am J Epidemiol 2003: 158: 416

30. Role of Covariates Mediating the Relationship between Depression and Diabetes What percent of the association between depressive symptoms and diabetes is attributable to a behavioral characteristic(s) or physiologic factor? Percent of excess risk explained by the addition of covariates to the model –% Excess Risk = (RR 1 – RR 2 )/(RR 1 – 1) RR1 = Unadjusted or minimally adjusted relative risk RR2 = Relative risk adjusted for covariates of interest

31. % Excess Risk Explained by Covariates: NHEFS ppt w/ < HS Education ModelModel TermsRR% Excess Risk 1Age, race, sex3.1Ref 21 + smoking status, ETOH, physical activity 2.96 32 + BMI2.337 “6% of the association between depressive symptoms and diabetes is explained by smoking status, alcohol intake, and physical activity... An additional 37% explained by BMI...”

32. Summary of Previous Findings: Depression and Incident Diabetes Depression consistently associated with the development of diabetes Traditional risk factors (e.g., BMI, physical activity) for diabetes mediate the association Few studies investigating physiological factors mediating the association Evidence of heterogeneity of effect by socio- demographic characteristics

33. Summary Conclusions about Temporal Relationship Weight of evidence suggests that depression precedes the onset of diabetes –Important in middle-aged and elderly –Present in men and women –Effect may be restricted to population subgroups with fewer socioeconomic resources Both behavioral and mechanistic pathways could explain the association

34. Future Research Needed Longitudinal evaluation of development of depressive symptoms in type 2 diabetes Rigorous definitions of depressive symptoms and diabetes Studies investigating biological mechanisms mediating assoc between depression and incident diabetes Experimental trials to treat depression and evaluate risk of diabetes development

35. Clinical Implications: Emphasis on Health Behaviors Move attention away from pharmacologic intervention and towards health behaviors –What pill has positive effects on mood, body weight, sleep quantity and quality, lowers blood pressure, lipids, blood glucose, the risk of heart disease, certain cancers, improves functional ability, overall quality of life, arthritis, and extends life? –Evidence for the exercise prescription!

36. Public Health Implications Large population at risk for the joint comorbidities of depression and diabetes –Prevalence of diabetes is rising with obesity epidemic –Large proportion of undiagnosed depression Suggests a need for cross-screening in persons with depression or diabetes –May be particularly important in at-risk subgroups