Diabetes and depression: a review

Diabetes mellitus and depression

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DIABETES AND DEPRESSION: A REVIEW

Diabetes and depression are both common conditions particularly in the western world and are frequently co-morbidities. For this reason we chose to conduct our research and produce a website highlighting these facts.

The aim of the study was to create a website targeted at primary care teams in order to highlight the link between diabetes mellitus and depression.  In order to do this we researched these subjects in detail whilst conducting small reviews on each paper to determine its weight. From this research this website was created including our conclusions on the topic.

Our review is split in the top menu as follows:

• 
  Introduction
  
• 
  Epidemiology and Prevalence
  
• 
  Impact
  
  • 
    Distribution of Mortality
    
  • 
    Mechanism of Disease Synergy
    
• 
  Treatment
  
  • 
    Pharmacotherapy
    
  • 
    Pharmacotherapy – Implications for Diabetes Development
    
  • 
    Psychotherapy
    
• 
  Conclusion
  

 

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  This site was made by a group of University of Edinburgh medical students who studied this subject over 10 weeks as part of SSC2a.
  
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  This website has not been peer reviewed.
  
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  We certify that this website is our own work and that we have authorisation to use all the content (e.g. figures / images) used in this website
  
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  We would like to thank Dr. Werner Pretorius for his tutorship and guidance during the project
  
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  Word Count: [insert here]
  

Introduction

Diabetes mellitus (DM) is one of the most commonly diagnosed chronic conditions, particularly in the western world, and thus is an area for extended study.

The characteristic symptom of DM is chronic hyperglycaemia, defined as a random plasma glucose of higher than 11 mmol/L (1) or fasting glucose of 6.1-6.9 mmol/L. Around 3-4% of the general population are diagnosed with DM due to this elevated level of glucose being present (2). The treatment for hyperglycaemia is insulin injections, most commonly carried out by the patient at regular intervals. It is therefore very important to educate the patient on how to accurately measure doses of insulin, how to adjust these doses dependant on blood glucose, and also how to inject the insulin. (1) Patients with DM have an increased risk of strokes, myocardial infarction and vascular diseases. (3) Because of this it is important to retain glycaemic control so as to prevent these occurring.

Along with the physical health complications that DM brings, there are commonly mental health problems that can impact on the quality of life of the patient. (2) One of the most common psychiatric condition that is present in patients with DM is depression. Depression can decrease patients’ quality of life, and often requires long term treatment with a combination of medication and therapy. This long term treatment for depression alone is projected to cost the National Health Service (4)(NHS) 2.96 billion pounds by 2026 despite the cost in 2007 being 1.68 billion (an increase of 56.8%) (5). The diagnosis of depression is classified by Alder et al as a person having a collection of symptoms including insomnia, unplanned weight loss and reduced ability to concentrate over a period of two weeks. These symptoms are only included if they are not due to the effects of drugs or explained by recent bereavement.

Not only are there effects causing those with DM to develop depression, but it has also been proven that the use of antidepressants can induce the onset of DM by affecting weight and glycaemic control. As depression is becoming much more prevalent worldwide, this is an important factor to take into consideration when prescribing appropriate treatments (6). We have also looked into the preferred treatment for people who develop depressive symptoms having already been diagnosed with DM, and which treatments would have the least negative effects on weight fluctuations and glycaemic control (7).

It is crucial to look into the effects that co-morbid depression and DM have on the body, as having both these conditions leads to a markedly higher mortality, as explained later in this analysis (8).

Due to these co-morbidities and the cost of treatment of both, it is postulated that by providing psychological care regarding depression at the first point someone is diagnosed with DM, morbidity and mortality of these conditions may be reduced. This would alleviate the financial strain that these comorbidities place on the NHS by reducing the number of hospital visits these patients may have.

Epidemiology and Prevalence

Over recent years our understanding of mental health disorders has increased, allowing those individuals suffering from such conditions to seek more effective treatment and feel able to talk freely about their condition, with less of the social stigma traditionally associated with mental health disorders (although it is important to note that some stigma still remains). Depression is the most common of all mental illnesses, affecting approximately 350 million people worldwide (9). Most of those diagnosed are living in western cultures where there is also a wide prevalence of DM. It is therefore important to recognise any association between these two commonly occurring diseases to ensure effective treatment and control, enabling patients to live the best quality of life.

Studies have been conducted to determine an association or cause between DM and depression. The WHO (World Health Organisation) conducted a World Health Survey focusing on Asian, African, South American and European low- and middle- income countries (10). Their analysis identified an increased prevalence of depression amongst those with DM in all continents (except Africa). Despite a drastic increase in prevalence of DM in the populations of Asia, South America and Africa over recent years, the associated secondary morbidity of depression is not as prevalent as it is in western populations. This may be because the stigma associated with mental illness in countries such as Africa acts as a barrier to treatment-seeking, resulting in under-diagnosis.

Prevalence of depression as a co-morbidity of DM tends to be greater in women compared to men (11). This is particularly apparent in type 2 DM; potentially related to the impacts of other co-morbidities of type 2 DM, such as obesity. As women are more likely to approach their doctor for treatment of depression, this gender gap may realistically be much smaller than reported.

The link between DM and depression is only partially understood, and the correlation between them has been shown to be bi-directional (12). Depression has been demonstrated to be associated with a 60% raised risk of developing type 2 DM; the relationship between depression and type 1 DM, however, is still unclear.

Depression can affect an individual’s health in numerous ways, many of which are significant risk factors in the development of type 2 DM. Depression has been proven to be a clinical risk factor in the development of adolescent obesity (13) and a cause of poor glycaemic control (14). Poor health behaviours, such as physical inactivity and smoking, manifest in depression and all increase risk of developing type 2 DM. This finding is supported by further studies that demonstrate how depression is a vital predictor in poor adherence to medical self-care: Gonzalez (2007) highlights how this is particularly noticeable in a depressed individual’s adherence to diet, exercise programmes and medication control (in this case glycaemic control)(15); all of which are significant risk factors in developing DM in the future.

Various hypotheses have been formulated to try and explain the physiology behind the increased rate of DM in depressed patients: most notably the increased activity of the hypothalamic-pituitary-adrenal axis which can result in insulin resistance (16). More specifically, the HPA releases more glucocorticoids (cortisol) around the body. Raised cortisol levels damage the function of glucose transporter type 4 proteins (GLUT4), altering the homeostatic control of glucose in the blood and resulting clinically in hyperglycaemia. Hyperglycaemia can lead to glucotoxicity and ultimately insulin resistance. Another possible pathophysiological link involves inflammatory processes in the body. The ‘cytokine-hypothesis’ of depression associated with co-morbidities such as DM has come about due to the increase in cytokine levels as a result of inflammatory responses which are more pronounced in depressed patients. An increase of cytokines with pro-inflammatory actions, such as interleukin-1 (IL-1), IL-6 and TNF-α have been associated with mood changes in patients who have never experienced any mental illness in the past (17). This may be because serotonin - the mood improving neurotransmitter - is broken down by cytokines. Therefore as DM (particularly type 1) has been associated with an increased inflammatory response, this would increase cytokine levels, resulting in greater breakdown in serotonin and thus lower mood. This would increase the risk of depression, especially if other risk factors are also present (17).

Studies have approximated that depression is present in 5%-10% of primary care patients and as many as 10%-14% of all medical inpatients (18). The increased prevalence of type 2 DM in depressed patients relative to the increased risk of other chronic diseases is still unclear but it is important to note both the widespread prevalence of depression throughout primary care and specifically the relationship between depression and the raised risk of developing DM.

Created using data from: T. Gadalla. 2008. Association of Comorbid Mood Disorders and Chronic Illness with Disability and Quality of Life in Ontario, Canada, Chronic Diseases in Canada 28 (4): 148-154  (Click to enlarge)

Distribution of Mortality

There are a number of studies which look into the relationship between DM and depression and the effect of this co-morbidity on mortality in a population. A study by Ismail et al, entitled “A Cohort Study of People with Diabetes and Their First Foot Ulcer” found that not only did having the co-morbidity have a strong link with developing foot ulcers, but having depression which was clinically significant tripled the mortality risk. (19) Another such study conducted found a strong worsening effect on mortality risk, measured in days until death. It concluded that there was a 49% greater mortality risk in patients with both depression and DM than in patients with DM alone. The evidence was particularly strong for the elderly, with the mortality risk being 78% greater in elderly patients with both conditions compared to younger patients with just DM. This highlights the need for depression screening especially amongst elderly diabetic patients, compared with younger diabetics (8).

Another study entitled “Diabetes, Depression, and Death” investigated the difference in mortality risk between patients with the co-morbidity and those with DM alone. It concluded that over a 5-year interval, patients who were treated for both DM and depression were less likely to die than patients who had both conditions, but were being treated only for DM. It too found a strong link for this especially in the elderly. However the study did acknowledge that the results may have been slightly flawed as all the results were obtained from greater metropolitan areas, not taking into account data from other areas in the U.S. As well as this, the self-reported nature of the questionnaires in the study may have also skewed results. There were a number of reasons given for the high mortality rates in diabetic depressed patients. The study suggested that a combination of increased inflammation due to DM and poor adherence to treatment may be responsible (20).

Figure 1 – Created using data from: Black S, Markides K, Ray L. Depression Predicts Increased Incidence of Adverse Health Outcomes in Older Mexican Americans With Type 2 Diabetes. Diabetes Care. 2003;26(10):2822-2828. (Click to Enlarge)

There is significant evidence to suggest that DM combined with depression increases all-cause mortality. In particular, looking at suicide alone as a cause of death showed interesting results. A cross-sectional study by Radobuljac et al investigated the link between suicidal and self-injurious behaviour and DM in Slovenian adolescents. The study was conducted by means of a self-reported questionnaire, originally designed by Kienhorst et al, and compared adolescents with Type 1 DM to those without it. The questionnaire was quite thorough, taking 45 minutes to complete and covering a range of topics such as demographic and family characteristics, possible future suicide, and self-injurious behaviour. When dividing the patients into subgroups by gender and performing further statistical analysis, the results proved highly interesting. Type 1 DM was found to protect against suicide in adolescent males; contradicting other studies that the burden of having a chronic illness such as DM would increase rates of depression, which goes hand in hand with suicide and self-destructive behaviour. The reason given for this finding is that the structure implemented on the patient’s life in managing DM in terms of diet, exercise and frequent medical contact may impact positively on their mental health, making them less prone to developing depression or resorting to self-destructive behaviour, as well staying away from “risky” behaviours such as smoking or drinking alcohol (21).

Mechanism of Disease Synergy

Previous chapters in this review have looked at the epidemiology of DM and depression comorbidity and its effect on mortality. This section aims to review possible reconciliatory models which may explain the (so far poorly understood) synergistic detrimental effect of DM and depression on patient outcome.
Biochemical:
Both depression and DM display serological profiles of chronic inflammatory disease. Cytokines such as IL-1, IL-6, IL-8 and TNF –α, and activation and production of various acute phase proteins such as activated CRP, amyloid A, and α1-acid glycoprotein have been shown to be elevated in both conditions individually, and excessively elevated in those suffering from the comorbidity (22-26). The literature base for this assertion is robust; most significant in establishing the hypothesis was perhaps Pickup et al’s study into association of non-insulin dependent DM/Metabolic syndrome X with inflammatory markers in 1997. Although the study used a small case population (n=19) the authors were able to show a significant relationship by: using well validated and extensively described assay techniques; validated diagnoses of DM/metabolic syndrome; control subjects and only accepting associations with p<0.01 or 0.001. The vascular implications of a sustained systemic inflammatory response are, in general terms, ones of adhesion, immune recruitment, and atherogenesis (27-30). How the inflammatory milieu arises in both conditions is relatively unknown, although evidence suggests that elevated serum cytokines and acute phase proteins both predict and are caused by diabetic and depressed states (31-34), indicating a bidirectional and reciprocal relationship. An interesting therapeutic feature of TNF-α serum levels has been exhibited in one study, in which successful antidepressant treatment led to reduction of both TNF-α serum levels and depressive symptoms. This strengthens the evidence for either a causative or resultant link between the cytokine and depression (35). As an end-note on cytokine involvement, the role of obesity as a primary disease course which may encourage the development of low-level chronic inflammation should not be overlooked. Studies have shown constitutive adipocyte production of TNF-α (36) and subsequent dose-related and reversible insulin resistance development; interesting considering the rate of coincidence of obesity with type 2 DM in particular (37, 38).
Stimulation of the HPA axis and cortisol release, with resulting increased sympathetic tone and catecholamine production, has also been noted in both diseases (22). Mechanisms of activation are unclear, but studies have shown a dose related activation of the HPA axis by inflammatory markers, some of which are present in diabetic and depressed individuals. This indicates another facet to the self-perpetuating cycle that a chronic inflammatory disease seems to present (39). It has also been shown that in depressed patients the normal inhibitory effects of cortisol in the HPA axis negative feedback loop are suppressed, leaving unfettered expression and activation (40).
A low level chronic increase of allostatic load, as presented by the above mechanisms, has various implications for vascular health. Biochemically at least it appears that an accentuated cytokine mediated inflammatory response, coupled with HPA axis hyperactivity and cortisol negative feedback attenuation, is the primary catalyst of the micro/macro vascular damage. This ultimately leads to the cardiovascular and cerebrovascular events that lead to adverse outcomes in depressed diabetic populations (41, 42).
Behavioural
Routes by which the depression-DM comorbidity impacts patient mortality appear to be focused on the negative impacts of the depressive state on diabetic self-care behaviour, the result being decreased glycaemic control and increased incidence of DM-related morbidities.
Among the most common behavioural factors induced or at least promoted by depression are a sedentary lifestyle, lack of medication/diet adherence, inconsistent glucose monitoring and smoking (43, 44). All the above factors are also commonly associated with a myriad of other determinants such as socioeconomic standing, distress caused by having DM itself, personal relationships and other lifestyle factors that often also show association with DM and depression individually (45, 46). As such it is difficult to tease apart a definitive and causative pathway by which behavioural changes and tendencies may result in increased mortality, but what evidence does show is a significant negative modification of diabetic control behaviour strongly associated with major depression.

Various behavioural and psychosocial factors are included in the below schematic in order to try and convey some level of the complexities of the DM and depression comorbidity.