Depression and diabetes – the terrible twins?

Those with depressive disorders have an increased risk of developing diabetes.¹ Despite the huge impact of the co-existence of depression with diabetes on an individual and its enormous importance as a public health problem, there are unanswered questions as to the nature of the link, causes, consequences and possible management of these two conditions.

Epidemiology of depression and diabetes

In people with diabetes, the prevalence of clinically relevant depressive disorders is up to one third.^2,3,4 The prognosis of both diabetes and depression is worse when the two diseases are comorbid than when they occur separately.^5,6 Rates of depression are particularly high in patients with type 2 diabetes with less evidence for type 1.⁴

There is a variation in the prevalence rates of depression across Europe but it is consistently higher in people with diabetes compared to those without.^7,8 Confounding factors in this variation may be a reflection of differences in socioeconomic, environmental and cultural factors and variation in assessment methods. The frequency of recurrence and duration of episodes of depression tend to be higher in patients with diabetes.^9,10,11 The risk factors for depression in diabetes can be divided into two:^12,13

• Non-diabetes-specific risk factors which include female gender, lack of social supports, low socio-economic status and critical life events

• Diabetes-specific risk factors which include poor glycaemic control, late complications of diabetes, need for insulin in type 2 and hypoglycaemic episodes. 

Depression is associated with poorer outcomes for diabetes and evidence suggests that poor self-care in depression leads to poor glycaemic control, along with the increased use of health services.^14,15 There is a three-fold risk of mortality caused by depressive episodes in diabetes, which was demonstrated in a UK study.¹⁶

The Pathways study in the US showed a 1.67 and 2.30-fold increase in mortality.¹⁷ The US National Health and Nutritional Examination Survey (NHANES) compared people with diabetes and depression to diabetics without depression and people without diabetes and showed a 2.50-fold increase in mortality over an eight-year follow-up study. It has also been shown that people with depressive disorders have an increased risk of developing diabetes.^1,18

Pathogenesis of depression-diabetes link

The psychological model

The psychological model is the traditional explanation for the association between depression and diabetes, in that the emotional and practical burden of diabetes care leads to depression. In other words, depression is caused by diabetes. This is however, not supported by any literature.^16,17

Also, at present there is very little evidence that treating only depression improves glycaemic control, although it does improve mood. There are arguments that the direction of association is reversed or bidirectional.^18,19 

Depression and insulin resistance

The diabetes spectrum ranges from insulin resistance to impaired glucose tolerance and frank diabetes due to failure of secretion of insulin. Insulin resistance is reduced sensitivity of receptors to the available insulin and it can be peripheral or central. Insulin resistance is a determinant in availability of free fatty acids in blood which are needed for tryptophan and serotonin concentration in the brain. Finnish, Dutch and Chinese studies showed a positive correlation between depression and insulin resistance.^20,21,22

However, the limitation to these studies was the utilisation of self-reported depression which may have inadvertently classified symptoms of undiagnosed diabetes as depressive. There was a Japanese case-control study which showed improvement in insulin resistance in depressed patients with antidepressant treatment.²³

Depression and HPA axis

The HPA axis (hypothalamic-pituitary-adrenal) is activated by stress and this leads to a cascade of reactions that returns the body to a homeostatic state. First of all, CRH (corticotropin-releasing hormone) is released onto the pituitary receptors which leads to the secretion of corticotropin into plasma and ultimately results in cortisol secretion into the blood. This inhibits the gonadal, growth hormone and thyroid axes and at certain levels activates the inflammatory response. 

The HPA axis also activates the sympathetic nervous system, which increases catecholamines (adrenaline and noradrenaline), stimulates the immune response and increases cognitive functioning. The collective metabolic effects are gluconeogenesis, glycogenolysis and insulin resistance.²⁴ There is substantial evidence that cortisol and CRH are involved in depression, as high levels of cortisol have been observed in depressed patients.^25,26,27,28

Diabetes-depression links

Autonomic nervous system

The autonomic nervous system (ANS) is divided into the sympathetic and parasympathetic systems which function in opposition to each other to preserve the dynamic balance of the body’s vital functions. The sympathetic nervous system (SNS) increases the heart rate, ventilation and causes dilatation of the bronchi. It releases adrenaline and noradrenaline. 

The parasympathetic system (PSS) on the other hand, slows the ventilatory rhythm and causes contraction of the bronchi using acetylcholine as its neurotransmitter. In stressful states, the HPA activates the SNS and causes the immediate anxiety response. Irregular sympathetic tone may result from excessive or persistent activation which in turn may lead to dysfunction in metabolic parameters.

Heart rate variability (HRV) is a measure of cardiac vagal tone and also serves as a sensitive indicator of how well the central nervous system controls the ANS. There is an established link between HRV and depression as decreased levels of HRV are known to be associated with depression.^29,30,31

It has also been suggested that acute alterations in the cardiac autonomic tone may be responsible for the increased risk of coronary heart disease (CHD) events and mortality in patients with depression.^32,33  However, it is yet to be clarified whether HRV can serve as a clinical predictor of worse depression. There may be a plausible link between depression and diabetes mediated through ANS, although very limited literature is available to support this.

Innate inflammatory response

A biologically plausible hypothesis known as the ‘macrophage theory of depression’³⁴ says that depression is associated with a cytokine-induced acute phase response. The latter is postulated in the pathogenesis of type 2 diabetes and its associated clinical and biochemical features.³⁵ The acute phase response leads to production of pro-inflammatory cytokines which are associated with pancreatic beta cells apoptosis, reduced insulin secretion and insulin resistance with onset of type 2 diabetes. There is growing evidence that stress and depression are associated with acute phase response.³⁶

Genetics

There appear to be genetic traits in type 2 diabetes and major depression, which aggregate in families due to a complex interaction between the environment and genetic risk.³⁷ To date, little research has been carried out to investigate the direct link between depression and diabetes. 

Due to the human genome sequencing project it is now possible to carry out genome-wide surveys of common variant associations and to assess the combined genetic risk for common complex traits such as depression and diabetes.

Birth weight

There is some evidence to suggest a relationship between birth weight and type 2 diabetes later in life.³⁸ There is some evidence, though weak, to suggest a link between low birth weight and depression in later life.³⁹ It is however, yet to be determined whether overweight babies have increased risk for depression.

Early childhood adversity

While a systematic review was consistent for the adverse impact of the accumulation of negative socioeconomic status for CHD risk, the same has not been found to be true for diabetes.⁴⁰ An important factor for later life depression–diabetes comorbidity may be educational attainment in childhood.⁴¹ In a birth cohort study which was followed up to age 32 years, it was found that children who suffered maltreatment showed a significant and dose response increase in CRP levels by 80%, independent of health behaviours in adult life.^42,43 Unfortunately, there are no studies to date which compare the risk factors for diabetes and depression over the life course in the same sample.

The role of antidepressants

Antidepressants have an important role in aiding the understanding of the pathogenesis of the depression-diabetes link. Anecdotal evidence and a small number of randomised controlled trials show that MAOIs (monoamine oxidase inhibitors)and TCAs (tricyclic antidepressants) have a hyperglycaemic effect, while SSRIs (selective serotonin reuptake inhibitors, especially fluoxetine and sertraline) are anorectic, improve insulin sensitivity and reduce glucose levels. Partial evidence does exist that treatment of depression with antidepressants does improve insulin resistance and possibly weight loss.^44,45,46

On the other hand, there is negative evidence from the US Diabetes Prevention Program for antidepressants.⁴⁷ A small proportion of sample self-reported use of antidepressants had a two to threefold rise in diabetes risk in those randomised to placebo and to the lifestyle intervention. There was no observed increased risk in the metformin group with antidepressants.⁴⁷ Antidepressants may also have an immunomodulating effect which has been observed in animal models. This has a positive effect on glucose metabolism.⁴⁸

Practical considerations

In a large meta-analysis conducted by Anderson et al in 2001, the prevalence of depression in people with diabetes was 11% while the prevalence of depression that was clinically relevant was 31%.⁴⁹ Worldwide estimates of depression prevalence among people with diabetes vary by diabetes type. 

Depression and diabetes symptoms overlap, hence the patient and clinician may be unaware of depression and may primarily attribute the changed status to worsening diabetes self-care. Secondly, depression may be associated with onset or amplification of physical symptoms in which case the patient may not sense that they are fully understood or supported by their clinician during healthcare visits when the physical or laboratory results do not correspond to subjective complaints. Thirdly, depression is commonly associated with difficulties with diabetes self-management and treatment adherence. 

The patient may feel resigned about their lack of ability to make changes. The clinician may feel discouraged about the ability of the patient to make changes in their care. Fourthly, individuals with depression may attempt to regulate emotions with food and substances and the clinician is not able to understand the underlying depressive symptoms. Next is the problem of stressors which impact both on the patient and clinician, who may attribute poor diabetes outcomes to a decrease in self-management because of a busy lifestyle, but who may not appreciate the insidious development of depression and its consequences. 

Depression is commonly associated with changes in healthcare-seeking patterns. The patient may be reluctant to make appointments, show up for appointments, seek support or collaborate with healthcare providers during appointments. 

Another problem is that depression may be associated with poor blood glucose control irrespective of behavioural actions. This may lead to a decreased sense of control of illness and may influence the motivation of the patient to engage in further clinical treatment recommendations. Depression is also commonly associated with difficulty organising tasks; hence clinical instructions may need to be written, repeated and checked for comprehension.  

Also, depression leads to increased pessimism. Thus, clinicians may need to help depressed patients break down tasks into manageable steps that may have shorter-term pay-off (eg. reduction of physical symptoms). Clinicians also need to consider the presence of anxiety which heightens a patient’s uncertainty around decision-making and increases a general sense of dread about the likelihood of success.

Management guidelines

In a review, Gilbody et al⁵⁰ found that screening for depression is effective only if aimed to find patients with sufficient severity of depressive symptoms that warrant treatment and if the appropriate treatment is subsequently offered as a result of the outcome of the screening.

Several systematic reviews have been completed evaluating effect sizes of pharmacological treatments in patients with comorbid depression and diabetes. The results of a systematic review of efficacy trials showed that sertraline improved depression with increased time to recurrence; however glycaemic control was poor. It showed a lower HbA1c when patients were depression-free.^51,52,53,54

Escitalopram was shown to reduce the depression ratings and improve glycaemic control.⁵⁵ Depression and anxiety as well as glycaemic control improved with paroxetine.^56,57,58 Fluoxetine showed conflicting data in adolescents but it was shown to improve the severity of depression and anxiety and reduced HbA1c levels.^59,60,61,62 Bupropion improved the severity of depression, glycaemic control and BMI as well as diabetes self-care.⁶³ MAOIs reduced blood glucose levels; however they can potentiate hypoglycaemia because of their interaction with sulphonylureas.^64,65 Last but not least, nortriptyline and amitriptyline were shown to improve depression but had a negative impact on glycaemic control. 

There was possible interaction with sulphonylureas, thereby causing symptomatic hypoglycaemia and possibly hypoglycaemic unawareness. The efficacy trials ranged from two weeks to three years. The clinician needs to tailor the therapy to suit the specific needs of the individual. 

Studies in support of cognitive behavioural therapy (CBT) varied from 10-24 weeks duration of study and it showed reduced severity and increased remission rates for depression as well as improved glycaemic control.^67,68 Because depressed patients with diabetes more often have an increased severity and high rate of recurrence of depression, the healthcare provider will often find that the medication course is more prolonged and the use of behavioural therapies is more crucial. 

There should be a more comprehensive approach to improve psychiatric and medical outcomes, which includes both evidence-based depression treatment and interventions aimed at improving diabetes self-care and glucose control. There is an association between ineffective provider-patient collaboration and lower levels of trust, poor information exchange and decreased satisfaction. The latter may lead to poorer adherence and poorer outcomes.⁶⁹

Successful management of both conditions requires intensification of efforts in the therapy for depression and diabetes as well as a much higher level of prolonged cooperation between different disciplines for optimal results for the patient.

In summary, active screening for depression in patients with diabetes should be carried out. Emphasis should be on improved self-management of both illnesses and there should be adequate support from the clinician/team, both phamacologically and psychologically.

References

1. Pouwer F, Beekmann TF, Nijpels G et al. Rates and risks for co-morbid depression in patients with type 2 diabetes mellitus: results from a community based study. Diabetologia, 2009; 46: 892-898
2. Anderson RJ, Freedland KE, Clouse RE and Lustman PJ. The prevalence of co-morbid depression in adults with diabetes. Diabetes care 2001; 6: 1069-1078
3. Ali S, Stone M, Peters J et al. The prevalence of co-morbid depression in adults with type 2 diabetes: a systematic review and meta-analysis. Diabet. Med. 2006; 23: 1165-1173
4. Barnard K, Skinnner T and Peveler R. The prevalence of co-morbid depression in adults with type 1 diabetes: systematic literature review. Diabet. Med. 2006; 23: 445-448
5. Simon G, Katon W, Lin E et al. Diabetes complications and depresssion as predictors of health service costs. Gen Hosp. Psychiatry 2005; 27:  344-351
6. Egede LE, Nietert PJ and Zheng D. Depression and all cause and coronary mortality among adults with and without diabetes. Diabetes care 2005; 28: 1339-1345
7. Pouwer F, Skinner T, Pibernik-Okanovic M et al. Serious diabetes- specific emotional problems and depression in a Croatian-Dutch-English survey from the European Depression in Diabetes (EDID) Research Consortium. Diabetes Res.Clin. Pract 2005; 70: 166-173
8. de Jonge P, Roy J, Saz P et al. Prevalent and incident depression in community-dwelling elderly persons with diabetes mellitus: results from the ZARADEMP project. Diabetologia 2006; 49: 2627-2633
9. Lustman P, Griffith L and Clouse R. Depression in adults with diabetes. Results of a 5-year follow-up study. Diabetes Care 1988; 11: 605-612
10. Kovacs M, Obrosky DS, Goldston D and Drash A. Major depressive disorder in youths with IDDM: a controlled prospective study of course and outcome. Diabetes Care 1997; 20: 45-51
11. Peyrot M and Rubin RR. Persistence of depressive symptoms in diabetic adults. Diabetes Care 1999; 22: 448-452
12. Peyrot M and Rubin RR. Levels and risk of depression and anxiety symptomatology among diabetic adults. Diabetes Care 1997; 20: 585-590
13. Hermanns N, Kulzer B, Krichbaum M et al. Affective and anxiety disorders in a German sample of diabetic patients: prevalence, comorbidity and risk factors. Diabetes Care 2005; 22: 293-300
14. Ciechanowski PS, Katon WJ and Russo JE. Depression and diabetes: impact of depressive symptoms on adherence, function and costs. Arch. Intern. Med. 2000; 160: 3278-3285
15. Hampson S, Glasgow R and Strycker L. Beliefs versus feelings: a comparison of personal models and depression for predicting multiple outcomes in diabetes. Br.J. Health Psychol. 2000; 5: 27-29
16. Ismail K, Winkey K, Stahl D et al. A cohort study of people with diabetes and their first foot ulcer: the role of depression on mortality. Diabetes Care 2007; 30: 1473-1479
17. Katon WJ, Ruter C, Simon G et al. The association of comorbid depression with mortality in patients with type 2 diabetes. Diabetes Care 2005; 28: 934-942
18. Mezuk B, Eaton WW, Albrecht S and Golden SH. Depression and type 2 diabetes over the lifespan: a meta–analysis. Diabetes Care 2008; 31: 2382-2390
19. Knol MJ, Twisk JWR, Beekman ATF et al. Depression as a rick factor for the onset of type 2 diabetes mellitus. A meta-analysis. Diabetologia 2006; 49: 837-845
20. Timonem M, Laakso M, Jokelainen J et al. Insulin resistance and depression: cross sectional study. BMJ 2005; 330: 17-18
21. Adriaanse M, Dekker J, Nijpels G et al. Association between depressive symptoms and insulin resistance: the Hoorn study. Diabetologia 2006; 49: 2874-2877
22. Pan A, Ye X, Franco OH et al. Insulin resistance and depressive symptoms in middle-aged and elderly Chinese: finding from the nutrition and health of aging population in China study. J.Affect. Disord. 2008; 109: 75-82
23. Okamura F, Tashiro A, Utumi A et al. Insulin resistance in patients with depression and its changes during the clinical course of depression: minimal model analysis. Metabolism 2000; 49: 1255-1260
24. Brotman D, Golden S and Wittstein I. The cardiovascular toll of stress. Lancet 2007; 370: 1089-1100
25. Pariante CM and Miller AH. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol. Psychiatry 2001; 49: 391-404
26. Burke H, Davis M, Otte C and Mohr D. Depression and cortisol responses to psychological stress; a meta-analysis. Psychoneuroendocrinology 2005; 30: 846-856
27. Shea A, Walsh C, MacMillan H and Steiner M. Child maltreatment and HPA axis dysregulation: relationship to major depressive disorder and post-traumatic stress disorder in females. Psychoneuroendocrinology 2005; 30: 162-178
28. Belmaker RH and Agam G. Major depressive disorder. N.Engl.J.Med. 2008; 358: 55-68
29. Rottenberg J. Cardiac vagal control in depression: a critical analysis. Biol. Psychol. 2007; 74: 200-211
30. Licht CMM, de Geus EJC, Zitman FG et al. Association between major depressive disorder and heart rate variability in the Netherlands study of depression and anxiety (NESDA). Arch. Gen. Psychiatry 2008; 65: 1358-1367
31. Ohira T, Roux AVD, Prineas RJ et al. Associations of psychosocial factors with heart rate and its short term variability: multiethnic study of atherosclerosis. Psychosom. Med. 2008; 70: 141-146
32. Pickup J. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 2004; 27: 813-823
33. Carney RM, Freedland KE and Veith RC. Depression, the autonomic nervous system, and coronary heart disease. Psychosom. Med 2005; 67: S29-S33
34. Smith R. The macrophage theory of depression. Med. Hypotheses 1991; 36: 178
35. Pickup J and Crook M. Is type II diabetes a disease of the innate immune system? Diabetologia 1998; 41: 1241-1248
36. Davidson KW, Schwartz JE, Kirkland SA et al. Relation of inflammation to depression and incident coronary heart disease (from the Canadian Nova Scotia Health Survey (NSHS95) prospective population study). Am.J. Cardiol. 2009; 103: 755-761
37. McCarthy M and Eleftheria Zeggini E. Genome-wide association studies in type 2 diabetes. Curr. Diabetes Rep. 2009; 9: 164-171
38. Barker D. Foetal origins of coronary heart disease. BMJ 1995; 311: 171-174
39. Gale C and Martyn C. Birth weight and later risk of depression in a national birth cohort. Br. J. Psychiatry 2004; 184: 28-33
40. Whincup PH, Kaye SJ, Owen CG et al. Birth weight and risk of type 2 diabetes: a systematic review. JAMA 2008; 300: 2886-2897
41. Mezuk B, Eaton WW, Golden SH and Ding Y. The influence of educational attainment on depression and risk of type 2 diabetes. Am.J. Public Health 2008; 98: 1480-1485
42. Golden SH, Lee HB, Schreiner PJ et al. Depression and type 2 diabetes mellitus: the Multiethnic Study of Atherosclerosis. Psychosom. Med. 2007; 69: 529-536
43. Maes M, Yirmyia R, Noraberg J et al. The inflammatory and neurodegenerative (I &ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab. Brain Dis. 2009; 24: 27-53
44. Okamura F, Tashiro A, Utumi A et al. Insulin resistance in patients with depression and its changs during the clinical course of depression: minimal model analysis. Metabolism 2000; 49: 1255-1260
45. Weber-Hamann B, Gilles M, Lederbogen F et al. Improved insulin sensitivity in 80 nondiabetic patients with MDD after clinical remission in a double blind, randomised trial of amitriptyline and paroxetine. J. Clin. Psychiatry 2006; 67: 1856-1861
46. Kauffman RP, Castracane, VD, White DL et al. Impact of the selective serotonin uptake inhibitor citalopram on insulin sensitivity, leptin and basal cortisol secretion in depressed and non-depressed euglycemic women of reproductive age. Gynecol. Endocrinol. 2005; 21: 129-137
47. Rubin RR, Ma Y, Marrero DG et al. Elevated depression symptoms, antidepressant medicine use, and risk of developing diabetes during the diabetes prevention program. Diabetes Care 2008; 31: 420-426
48. Maes M, Song C, Lin A et al. Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychoopharmacology 1999; 20: 370-379
49. Anderson RJ, Freedlandd KE, Clouse RE and Lustman PJ. The prevalence of comorbid depression in adults with diabetes: a meta –analysis. Diabetes Care 2001; 24: 1069-1078
50. Gilbody S, Sheldon T and House A. Screening and case finding instruments for depression: a meta-analysis. CMAJ 2008; 178: 997-1003
51. Goodnick PJ, Kumar A, Henry JH, Buki VMV, Goldberg RB. Sertraline in coexisting major depression and diabetes mellitus. Psychopharmacology Bulletin 33.2 (1997): 261-264
52. Sansone Randy A, Sansone Lori A. Sertraline-induced hyperglycemia: case report. Int J Psychiatry Med March 2003; Vol. 33 no.1 103-105
53. Lustman PJ, Clouse RE, Nix BD et al. Sertraline for prevention of depression recurrence in diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry; 2006; 63:521-529
54. Williams MM, Clouse RE, Nix BD et al. Efficacy of sertraline in prevention of depression recurrence in older versus younger adults with diabetes. Diabetes Care. 2007; 30:801-806
55. Amsterdam JD, Shults J, Rutherford N, Schwartz S. Safety and efficacy of escitalopram in patients with co-morbid major depression and diabetes mellitus. Neuropsychobiology. 2006; 54(4): 208-214
56. Paile-Hyvärinen M, Wahlbeck K, Eriksson JG. Quality of life and metabolic status in mildly depressed women with Type 2 diabetes treated with paroxetine: A single-blind randomised placebo controlled trial. BMC Fam Pract. 2003; 4:7
57. Gülseren L, Gülseren S, Hekimsoy Z, Mete L. Comparison of fluoxetine and paroxetine in type II diabetes mellitus patients. Arch Med Res. 2005; 36(2):159-165
58. Qu W, Meng P. Relationship between blood glucose levels in patients with type 2 diabetes mellitus. Depression and anxiety and the ant-depression/anxiety intervention. Zhongguo Linchuang Kangfu. 2005; 9:213-215
59. Katz LM, Fochtmann LJ, Pato MT (1991). Clomipramine, fluoxetine and glucose control. Ann Clin Psychiatry 3: 271-274
60. Ghaziuddin N, Naylor MW, King CA, Segal HG. Fluoxetine and blood glucose control in adolescents with major depression and insulin-dependent diabetes mellitus. J Child Adolesc Psychopharmacol. 1994; 4:87-92
61. Deeg MA, Lipkin EW (1996). Hypoglycemia associated with the use of fluoxetine. West J Med 164: 262-263
62. Lustman PJ, Griffith LS, Freedland KE et al (1998b). Cognitive behavior therapy for depression in type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 129: 613-621 
63. Lustman PJ, Williams MM, Sayuk GS et al (2007). Factors influencing glycemic control in type 2 diabetes during acute- and maintenance-phase treatment of major depressive disorder with bupropion. Diabetes Care 30: 459-466
64. Wickstrom L, Pettersson K. Treatment of Diabetics with Monoamine Oxidase Inhibitors. (1964). Lancet 2: 995-997
65. Cooper AJ (1966). The action of mebanazine, a mono amine oxidase inhibitor antidepressant drug in diabetes. II. Int J Neuropsychiatry 2: 342-345
66. Lustman PJ, Griffith LS, Freedland KE et al (1998). Cognitive behavioural therapy for Depression in type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med; 129; 613-621
67. Georgiades A, Zucker N, Friedman KE, Mosunic CJ, Applegate K, Lane JD, Feinglos MN, Surwit RS. Changes in depressive symptoms and glycemic control in diabetes mellitus. Psychosom Med. 2007 Apr; 69(3):235-241. Epub 2007 Apr 9
68. Glasgow RE, Price DW (2005). Individualised treatment improves depression in people with depression and diabetes Evid Based Ment Health 8:40
69. Ciechanowski PS, Russo JE, Katon WJ (2006). The association of patient relationship style and outcomes in collaborative care treatment for depression in patients with diabetes.Med Care 44: 283-291