Diabetes mellitus and depression
Website - Homepage
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





This site was made by a group of University of Edinburgh medical students who studied
this subject over 10 weeks as part of SSC2a.
This website has not been peer reviewed.
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
We would like to thank Dr. Werner Pretorius for his tutorship and guidance during the
project
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 ‘cytokinehypothesis’ 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 allcause 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.
Schematic Representation of the above text produced by Oliver Shipston-Sharman (Click to
Enlarge)
Although research into the synergistic mechanism by which depression and DM causes
increased mortality is ongoing, large scale controlled studies have already conclusively
proven a common mechanism. Prolonged low level inflammation influenced by HPA axis
activation, increased sympathetic tone, obesity, and damaging behavioural patterns all result
in a chronic affront to the vascular systems of diabetic depressed individuals. The body of
evidence that this leads to the greatly increased mortality and morbidities in such populations
is significant.
Pharmacotherapy
Antidepressant therapy in patients with DM who suffer from depression is an effective way
of reducing depressive symptoms. This has been proven for SSRIs such as fluoxetine and
citalopram (47), sertraline (48) and paroxetine (49); and tricyclic antidepressants such as
nortriptyline (7). However, the evidence as to whether antidepressant therapy is useful in
improving glycaemic control is fairly inconclusive. Certainly, remission of depression is
beneficial for glycaemic control, as the presence of psychiatric illness in diabetic patients is
associated with poorer glucose homeostasis, health behaviours and adherence to medication
(50). However, it is important that the potential benefits of treating depression for metabolic
control are not cancelled out by adverse effects of antidepressant drugs.
Some drug classes, such as tricyclic antidepressants (TCAs), have been shown to have
deteriorative effects on glycaemic control – this was the case with nortriptyline, which was
found to cause hyperglycaemia. This hyperglycaemia was not attributable to weight gain;
however, weight gain is a well-documented side effect of tricyclic antidepressants (7), and as
a result they should be avoided in diabetic patients. Another tricyclic antidepressant,
imipramine, may also have a negative impact on glycaemic control by increasing fasting
blood glucose levels (51). Although no longer widely prescribed due to its adverse effects
and the development of newer and safer drugs, it is especially important that MAOIs are not
prescribed for depression in diabetic patients, as they increase sensitivity to insulin and can
directly induce hypoglycaemia (52).
SSRIs may be a preferable option for the treatment of depression in diabetic patients, as
evidence suggests that drugs such as citalopram and fluoxetine may improve parameters such
as fasting blood glucose and HbA1c (47). Fluoxetine in particular was found to have a
favourable impact on glycaemic control (53, 54), as was sertraline (55). However, the
evidence on this is still somewhat lacking, as several studies found that there was no
significant change in glucose control when patients were prescribed SSRIs. This has been
found with sertraline (56) and citalopram (57). Despite the conflicting information, it is likely
that SSRIs are a better choice for depression in diabetic patients than drugs such as TCAs and
MAOIs, given the evidence available to date.
Several studies have shown that an integrated approach to the care of patients with comorbid
depression and DM could be very useful in improving clinical outcomes (58). Collaborative
care is highly likely to improve recovery from depression as a direct outcome (59), thereby
enabling diabetic patients to achieve better glycaemic control due to absence or lessened
severity of psychiatric comorbidities (60). Patients who are given a personalised care plan,
involving education about their comorbidity and the importance of managing depression in
order to keep DM under control, may be more likely to achieve desired HbA1c levels,
remission of depression, and satisfactory medication adherence (61).
Pharmacotherapy - Implications for Diabetes Development
It is important to consider how the treatment of mental illness may affect the risk of
developing DM; particularly with respect to antidepressants and antipsychotics.
Being overweight or obese strongly influences the likelihood of developing DM. If none of
the population had a BMI of over 25, then 64% of males and 74% of females could have been
prevented from developing non-insulin dependent DM (62). A major concern for physicians
now is the prescription of antidepressants and antipsychotics, as a variety of these are known
to induce weight gain (6).
Antidepressants
Some antidepressants, particularly those used in persistent depression where other treatments
have failed, are likely to cause considerable weight gain and thus predispose patients to DM.
However, patients with the same depressive symptoms who were not treated with
antidepressants had a lower prevalence of type 2 DM. This suggests that there is a stronger
correlation between depression and DM when antidepressant therapy is given, compared to
when it is not. This study involved a large cohort of 151,347 participants, which makes the
results reliable by reducing the influence of chance (63). Antidepressants which are linked
with weight gain include those with antihistamine mechanisms, tricyclic antidepressants
(TCAs), and monoamine oxidase inhibitors (MAOIs) (64). The antidepressant which has
been proven to have the greatest effect on weight gain in Mirtazapine, which has interactions
with specific serotonin receptors, as well as histaminergic receptors. The effects of these
interactions include an increased appetite which causes the weight gain (65).
Antipsychotics
There are 2 strands of antipsychotic medications; First Generation Antipsychotics (FGAs),
and Second Generation Antipsychotics (SGAs). FGAs are also known as typical
antipsychotics, and SGAs as atypical antipsychotics. The difference with adverse effects
appear to be that SGAs carry an increased risk of weight gain and Type II DM compared to
FGAs (66). However, they have a lesser effect on the extrapyramidal system, and a more
positive effect on depressive symptoms (compared to FGAs) and are therefore important in
the treatment of some depressed patients (67). Olanzapine and Clozapine have been shown to
cause patients to gain roughly 6kg in the first year of use. These drugs have also affect
glucose regulation, which can induce the onset of DM. This is because dysregulation of
glucose occurs as a result of insulin dysfunction, which can lead to hyperglycaemia - a sign
of untreated DM (68).
One study has found that Clozapine in particular has a significant effect on the onset of DM
in younger people (20-34 years old), with 5% of those taking Clozapine developing DM
compared with only 2% of those using other antipsychotics. However, in other age groups
there was no marked difference between using Clozapine versus any other antipsychotic (69).
It has been found that in patients taking atypical antipsychotics (SGAs) there is weight gain
due to increased fat deposition in the body, leading to insulin resistance which causes DM
(70). Another study found that Clozapine gives rise to a 7 fold greater chance of developing
DM compared with conventional antipsychotics; Risperidone a 3.4 times greater risk; and
Olanzapine a 3.2 times greater risk (71). Analysis of an UK General Practice Database,
showed a six fold increase in the incidence of diabetes in those who had been prescribed
Olanzapine at any point compared to controls not taking any antipsychotics and a fourfold
increase compared to controls taking first generation antipsychotics (72, 73).
Data regarding the links between both antidepressants and antipsychotics with DM is
somewhat limited to an extent. Trends suggest that they do induce the onset of DM, however
evidence as to why this actually happens is inconclusive. Drugs must be further examined
individually in order to understand the mechanisms by which they can encourage onset of
DM.
Psychotherapy
For those in the diabetic and depressed population, the treatment options without
pharmacological intervention usually lean towards the use of cognitive behavioural therapy
(CBT) in an effort to decrease the depressive symptoms and improve glycaemic control.
Many studies have been conducted in order to determine the effectiveness of CBT in the
treatment of DM related depression, and to ascertain whether the solution is cost effective.
CBT is the name given to a series of discussions with a patient that explore the thoughts they
are experiencing, with specific emphasis on the negative and positive thoughts they have
regarding their condition (74). CBT does not, however, focus only on thoughts; it also
explores the patient’s physical reactions to thoughts, and the environment that the patient is
in. The idea of CBT is to manage the patient’s emotional response to their condition in order
to reduce depressive symptoms (74).
Trials investigating the effects of CBT on glycaemic control and depressive symptoms in
depressed diabetic patients have had fairly mixed results. An early prominent study by
Lustman et al. was conducted in this area, and found that at follow-up 70% of depressed
diabetic patients in the CBT group achieved remission compared to only 33.3% in the control
(75). Glycaemic control was also better in the CBT group; glycated haemoglobin (GHb)
levels decreased by 0.7% in the CBT group, whereas they increased by 0.9% in the control. A
possible association was also found between depression and glycaemic control. The
experiment was well-planned, with confounding factors accounted for, and only included
patients who were diagnosed with depression. However, the sample size for the Lustman
study was quite small (with 51 participants) and the follow-up period was only 6 months,
raising the question of whether the positive results would have been sustained (especially as
the percentage of patients with depression in remission decreased from post-treatment to
follow-up).
The results from other studies have been varied. A randomized controlled trial by Penckofer
et al. tested the efficacy of group CBT and found that within a group of 74 women, there was
a lasting change in depression for the CBT group (76). Conversely, there was no indication
that CBT was more effective in decreasing HbA1c over time than the control. On the other
hand, a study by Snoek et al. (77) comparing CBT to blood glucose awareness training
(BGAT) found a significant decrease in HbA1c in the CBT group, and a non-significant
reduction of depression in both groups, raising the question of why glycaemic control was
superior in the intervention group, despite no difference between the two in psychological
outcome.
An interesting point made in Lustman et al’s study, however, was that adherence to selfmonitoring of glucose actually declined in the CBT group (75). In response to the
inconsistent findings of other trials in the improvement of glycaemic control, a study was
conducted by Safren et al. (78) which tested an integrative treatment of CBT for adherence
and depression (CBT-AD) in type 2 DM. Unsurprisingly, this proved much more successful
in improving adherence to glucose monitoring, with the CBT-AD achieving 30.2% points
higher than the control group, even though this declined to 16.9% points after a 4 month
follow-up.
A randomised controlled trial by N C W Van der Ven et al (79) looked at adult type 1 DM
patients with prolonged poor glycaemic control. They found results similar to Lustman et al,
which showed that CBT was of some benefit when measuring glycaemic control using
HbAC1 as an indicator (75). Additionally, it found that along with depressive symptoms
being reduced in patients receiving CBT, there was an increase in DM management selfefficacy from 71.6 to 74.3 using the confidence in DM self-care scale.
Unlike the other studies, in which the education level of the intervention and control groups
were relatively equal, a study by Bosma et al. (80) examined patients with either type 2 DM
or COPD to see whether the benefits of self-management intervention (including CBT)
would differ across education levels. Contrary to their hypothesis, it was found that the only
group who showed a significant improvement (a 50% or greater reduction in depression
compared to baseline) was the intervention group for those with the highest level of
education. Despite having a mix of COPD and DM patients, stratification (dividing COPD
and DM patients and choosing equal numbers of each strata at random) was utilised to ensure
an equal spread of patients with both underlying diseases in all groups. Analysis showed that
findings did not differ significantly by disease or severity of disease.
A study by Lamers et al (81) also found that those of a higher education level are more likely
to benefit from CBT; over 9 months, only those of a high education level showed a
statistically significant (P=0.03) reduction in both emotional distress and symptom distress.
However, the study concluded that nurse administered CBT had limited effects on diabetic
specific quality of life, despite the fact that it is potentially beneficial in glycaemic control.
From reviewing the literature on the subject there is little evidence to prove that CBT affects
diabetic control in all patients with DM. However there is potential for CBT to be used as a
first line prophylactic intervention by GPs or mental health professionals, in order to prevent
deterioration in glycaemic control in diabetic patients with depression. The use of CBT to
decrease depressive symptoms in diabetic patients and increase their quality of life is a topic
that may require more research. Using CBT as a prophylactic measure in diabetic patients
with depression may be appropriate and cost effective, as it could reduce admissions for
depression and events from these co-morbidities.
Conclusion
The increase in obesity in the Western world has in turn led to a rise in DM. There is also a
well-established link between DM and depression. This link is bi-directional, with the
presence of one dramatically increasing the likelihood of developing the other. There are
many possible explanations for the presence of depression increasing the risk of developing
DM, though the most apparent seems to be the presence of worse health behaviours in the
depressed, including smoking and lack of exercise. Poor adherence to medical self-care also
contributes. Additionally, some classes of anti-depressants have been shown to lead to weight
gain and therefore should be avoided in diabetics. This is primarily evident in people between
the ages of 20 and 34, and careful consideration should be given to alternative treatments
accordingly, for example CBT. Conversely, in diabetics, the burden of having to live with a
chronic condition predisposes to depression. Furthermore, both DM and depression increase
cortisol levels in the body, increasing inflammatory stress. Because of the overlapping
pathogenic mechanisms, the combination of the two diseases increases the risk of death.
People living with the co-morbidity have a 40% greater risk of mortality than patients living
with just one of the two. Particular attention should be paid to the elderly age bracket, and
depression screening should be performed in this patient group in order to reduce mortality,
as there is a 78% greater risk of death in elderly patients with the co-morbidity compared
with patients without the co-morbidity. Although importance must be given to treating DM,
as it is a persisting chronic illness, treating depression should not be neglected as patients
being treated for both depression and DM are less likely to die. Interestingly, adolescent
males with type 1 DM are shown to have better health behaviours in order to control their
disease. This acts almost as a protective mechanism against depression as the positive attitude
towards their health makes them less likely to get depressed.
Antidepressants have been shown to indirectly improve glycaemic control, by directly
improving symptoms of depression. A reduction in depressive symptoms enhances patients’
control of their DM and manifests in individuals being more likely to self-manage their
condition effectively. A strong correlation has been demonstrated between antidepressants
and antipsychotics causing weight gain. These treatments should be carefully prescribed for
depression because they are predisposing risk factors in the development of DM.
Nortriptyline (TCA), for example, has been shown to directly induce hyperglycaemia.
Clinicians should also be wary of prescribing MAOIs for depressed patients suffering from
DM, as they increase sensitivity to insulin and have been shown to induce hypoglycaemia.
SSRIs are a better treatment choice for depressed diabetics than the previous mentioned
classes of drugs. Primary care workers should also be aware of the increased risk of weight
gain associated with 2nd generation anti-psychotics. In particular, commonly prescribed
antipsychotics such as olanzapine and clozapine exhibit similar weight gain side effects as
many antidepressants.
CBT is the gold standard psychotherapy for depression, with those undergoing CBT being
twice as likely to achieve remission. GPs should note that CBT is not successful on all
patients, however, and alternatives may be necessary. CBT may also be clinically relevant as
preventive intervention, as a method of preventing the deterioration of glycaemic control.
Patients suffering comorbid depression and DM who are treated with a personalised and
integrated approach to care exhibit improved clinical outcomes. A collaborative care
approach increases remission from depression, and consequently patients achieve improved
glycaemic control through better health behaviours.
1.
Pearson, McCrimmon. Davidson's Principles and Practice of Medicine. 22 ed. Walker
B, Colledge N, Ralston S, Penman I, editors: Churchill Livingston; 2014.
2.
Ismail K, Peveler R. Handbook of Liaison Psychiatry. Lloyd G, Guthrie E, editors:
Cambridge University Press; 2007.
3.
Naish J, Revest P, Syndercombe Court D. Medical Sciences: Sauders/Elsevier; 2009.
4.
NHS. Clinical Depression NHS Online2013. Available from:
http://www.nhs.uk/Conditions/Depression/Pages/Introduction.aspx.
5.
McCrone P, Dhanasiri S, Patel A, Knapp M, Lawton-Smith S. Paying The Price: The
cost of mental health care in England to 2026. British Library: King's Fund, 2008.
6.
Andersohn F, Schade R, Suissa S, Garbe E. Long-term use of antidepressants for
depressive disorders and the risk of diabetes mellitus. The American journal of psychiatry.
2009;166(5):591-8.
7.
Lustman PJ, Griffith LS, Clouse RE, Freedland KE, Eisen SA, Rubin EH, et al.
Effects of Nortriptyline on Depression and Glycemic Control in Diabetes: Results of a
Double-blind, Placebo-controlled Trial. Psychosomatic Medicine. 1997;59(3):241-50.
8.
Kimbro LB, Mangione CM, Steers WN, Duru OK, McEwen L, Karter A, et al.
Depression and All-Cause Mortality in Persons with Diabetes Mellitus: Are Older Adults at
Higher Risk? Results from the Translating Research Into Action for Diabetes Study. Journal
of the American Geriatrics Society. 2014;62(6):1017-22.
9.
WHO. Depression. World Health Organisation, 2012.
10.
Mommersteeg PMC, Herr R, Pouwer F, Holt RIG, Loerbroks A. The association
between diabetes and an episode of depressive symptoms in the 2002 World Health Survey:
an analysis of 231 797 individuals from 47 countries. Diabetic Medicine. 2013;30(6):e208e14.
11.
Pouwer F, Geelhoed-Duijvestijn PHLM, Tack CJ, Bazelmans E, Beekman AJ, Heine
RJ, et al. Prevalence of comorbid depression is high in out-patients with Type 1 or Type 2
diabetes mellitus. Results from three out-patient clinics in the Netherlands. Diabetic
Medicine. 2010;27(2):217-24.
12.
Golden SH, Lazo M, Carnethon M, Bertoni AG, Schreiner PJ, Roux AVD, et al.
Examining a Bidirectional Association Between Depressive Symptoms and Diabetes. JAMA
: the journal of the American Medical Association. 2008;299(23):2751-9.
13.
Goodman E, Whitaker RC. A Prospective Study of the Role of Depression in the
Development and Persistence of Adolescent Obesity. Pediatrics. 2002;110(3):497-504.
14.
Lustman PJ, Clouse RE. Depression in diabetic patients: the relationship between
mood and glycemic control. Journal of Diabetes and its Complications. 2005;19(2):113-22.
15.
Gonzalez JS, Safren SA, Cagliero E, Wexler DJ, Delahanty L, Wittenberg E, et al.
Depression, self-care, and medication adherence in type 2 diabetes: relationships across the
full range of symptom severity. Diabetes care. 2007;30(9):2222-7.
16.
Tsigos C, Chrousos GP. Hypothalamic–pituitary–adrenal axis, neuroendocrine factors
and stress. Journal of Psychosomatic Research. 2002;53(4):865-71.
17.
Himmerich H, Fulda S, Linseisen J, Seiler H, Wolfram G, Himmerich S, et al.
Depression, comorbidities and the TNF-α system. European Psychiatry. 2008;23(6):421-9.
18.
Katon W, Schulberg H. Epidemiology of depression in primary care. General hospital
psychiatry. 1992;14(4):237-47.
19.
Ismail K, Winkley K, Stahl D, Chalder T, Edmonds M. A Cohort Study of People
With Diabetes and Their First Foot Ulcer: The role of depression on mortality. Diabetes care.
2007;30(6):1473-9.
20.
Bogner HR, Morales KH, Post EP, Bruce ML. DIABETES, DEPRESSION, AND
DEATH: A RANDOMIZED CONTROLLED TRIAL OF A DEPRESSION TREATMENT
PROGRAM FOR OLDER ADULTS BASED IN PRIMARY CARE (PROSPECT). Diabetes
care. 2007;30(12):3005-10.
21.
Radobuljac MD, Bratina NU, Battelino T, Tomori M. Lifetime prevalence of suicidal
and self-injurious behaviors in a representative cohort of Slovenian adolescents with type 1
diabetes. Pediatric Diabetes. 2009;10(7):424-31.
22.
Steptoe A, Hackett RA, Lazzarino AI, Bostock S, La Marca R, Carvalho LA, et al.
Disruption of multisystem responses to stress in type 2 diabetes: Investigating the dynamics
of allostatic load. Proceedings of the National Academy of Sciences. 2014;111(44):15693-8.
23.
Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate
immune system: association of acute-phase reactants and interleukin-6 with metabolic
syndrome X. Diabetologia. 1997;40(11):1286-92.
24.
Suarez EC, Krishnan RR, Lewis JG. The relation of severity of depressive symptoms
to monocyte-associated proinflammatory cytokines and chemokines in apparently healthy
men. Psychosom Med. 2003;65(3):362-8.
25.
Miller AH, Maletic V, Raison CL. Inflammation and Its Discontents: The Role of
Cytokines in the Pathophysiology of Major Depression. Biological psychiatry.
2009;65(9):732-41.
26.
Laake J-PS, Stahl D, Amiel SA, Petrak F, Sherwood RA, Pickup JC, et al. The
Association Between Depressive Symptoms and Systemic Inflammation in People With Type
2 Diabetes: Findings From the South London Diabetes Study. Diabetes care.
2014;37(8):2186-92.
27.
Stehouwer CD, Gall MA, Twisk JW, Knudsen E, Emeis JJ, Parving HH. Increased
urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in
type 2 diabetes: progressive, interrelated, and independently associated with risk of death.
Diabetes. 2002;51(4):1157-65.
28.
Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator
inhibitor-1 expression and activity in human aortic endothelial cells: implications for the
metabolic syndrome and atherothrombosis. Circulation. 2003;107(3):398-404.
29.
Festa A, D’Agostino R, Howard G, Mykkänen L, Tracy RP, Haffner SM. Chronic
Subclinical Inflammation as Part of the Insulin Resistance Syndrome: The Insulin Resistance
Atherosclerosis Study (IRAS). Circulation. 2000;102(1):42-7.
30.
Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. Journal of Clinical
Investigation. 2005;115(5):1111-9.
31.
Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, et al. Lowgrade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk
in communities study. Diabetes. 2003;52(7):1799-805.
32.
Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, et al.
Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective
population-based European Prospective Investigation into Cancer and Nutrition (EPIC)Potsdam Study. Diabetes. 2003;52(3):812-7.
33.
Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, et al.
Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans:
Role of Oxidative Stress. Circulation. 2002;106(16):2067-72.
34.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein,
interleukin 6, and risk of developing type 2 diabetes mellitus. Jama. 2001;286(3):327-34.
35.
Tuglu C, Kara SH, Caliyurt O, Vardar E, Abay E. Increased serum tumor necrosis
factor-alpha levels and treatment response in major depressive disorder.
Psychopharmacology. 2003;170(4):429-33.
36.
Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression
of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and
relationship to lipoprotein lipase. The Journal of clinical investigation. 1995;95(5):2111-9.
37.
Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose
tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.
Journal of Clinical Investigation. 1995;95(5):2409-15.
38.
Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis
factor-alpha: direct role in obesity-linked insulin resistance. Science (New York, NY).
1993;259(5091):87-91.
39.
Chrousos GP. The Hypothalamic–Pituitary–Adrenal Axis and Immune-Mediated
Inflammation. New England Journal of Medicine. 1995;332(20):1351-63.
40.
Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and
new developments. Trends in Neurosciences. 2008;31(9):464-8.
41.
Bruce DG, Davis WA, Starkstein SE, Davis TME. A prospective study of depression
and mortality in patients with type 2 diabetes: the Fremantle Diabetes Study. Diabetologia.
2005;48(12):2532-9.
42.
Lin E, Heckbert S, Rutter C, Katon W, Ciechanowski P, Ludman E, et al. Depression
and Increased Mortality in Diabetes: Unexpected Causes of Death. Annals of family
medicine. 2009;7(5):414-21.
43.
Ciechanowski PS, Katon WJ, Russo JE. Depression and diabetes: impact of
depressive symptoms on adherence, function, and costs. Archives of internal medicine.
2000;160(21):3278-85.
44.
Lin EH, Katon W, Von Korff M, Rutter C, Simon GE, Oliver M, et al. Relationship of
depression and diabetes self-care, medication adherence, and preventive care. Diabetes care.
2004;27(9):2154-60.
45.
Stringhini S, Dugravot A, Shipley M, Goldberg M, Zins M, Kivimaki M, et al. Health
behaviours, socioeconomic status, and mortality: further analyses of the British Whitehall II
and the French GAZEL prospective cohorts. PLoS medicine. 2011;8(2):e1000419.
46.
Everson S, Maty S, Lynch J, Kaplan G. Epidemiologic Evidence for the Relation
Between Socioeconomic Status and Depression, Obesity, and Diabetes. Journal of
Psychosomatic Research. 2002;53(4):891-5.
47.
Khazaie H, Rahimi M, Tatari F, Rezaei M, Najafi F, Tahmasian M. Treatment of
depression in type 2 diabetes with Fluoxetine or Citalopram? Neurosciences (Riyadh, Saudi
Arabia). 2011;16(1):42-5.
48.
Lustman PJ, Clouse RE, Nix BD, Freedland KE, Rubin EH, McGill JB, et al.
Sertraline for prevention of depression recurrence in diabetes mellitus: a randomized, doubleblind, placebo-controlled trial. Arch Gen Psychiatry. 2006;63(5):521-9.
49.
Gulseren L, Gulseren S, Hekimsoy Z, Mete L. Comparison of fluoxetine and
paroxetine in type II diabetes mellitus patients. Archives of medical research.
2005;36(2):159-65.
50.
Dirmaier J, Watzke B, Koch U, Schulz H, Lehnert H, Pieper L, et al. Diabetes in
primary care: prospective associations between depression, nonadherence and glycemic
control. Psychotherapy and psychosomatics. 2010;79(3):172-8.
51.
Ghaeli P, Shahsavand E, Mesbahi M, Kamkar M-Z, Sadeghi M, Dashti-Khavidaki S.
Comparing the effects of 8-week treatment with fluoxetine and imipramine on fasting blood
glucose of patients with major depressive disorder. Journal of clinical psychopharmacology.
2004;24(4):386-8.
52.
Adnitt PI. Hypoglycemic Action of Monoamineoxidase Inhibitors (MAOI'S).
Diabetes. 1968;17(10):628-33.
53.
Breum L, Bjerre U, Bak JF, Jacobsen S, Astrup A. Long-term effects of fluoxetine on
glycemic control in obese patients with non-insulin-dependent diabetes mellitus or glucose
intolerance: influence on muscle glycogen synthase and insulin receptor kinase activity.
Metabolism: clinical and experimental. 1995;44(12):1570-6.
54.
O'Kane M, Wiles PG, Wales JK. Fluoxetine in the treatment of obese type 2 diabetic
patients. Diabetic medicine : a journal of the British Diabetic Association. 1994;11(1):10510.
55.
Goodnick PJ, Kumar A, Henry JH, Buki VM, Goldberg RB. Sertraline in coexisting
major depression and diabetes mellitus. Psychopharmacology bulletin. 1997;33(2):261-4.
56.
Karaiskos D, Tzavellas E, Ilias I, Liappas I, Paparrigopoulos T. Agomelatine and
sertraline for the treatment of depression in type 2 diabetes mellitus. International journal of
clinical practice. 2013;67(3):257-60.
57.
Nicolau J, Rivera R, Francés C, Chacártegui B, Masmiquel L. Treatment of
depression in type 2 diabetic patients: Effects on depressive symptoms, quality of life and
metabolic control. Diabetes Research and Clinical Practice. 2013;101(2):148-52.
58.
McGregor M, Lin EH, Katon WJ. TEAMcare: an integrated multicondition
collaborative care program for chronic illnesses and depression. The Journal of ambulatory
care management. 2011;34(2):152-62.
59.
Williams JW, Jr., Katon W, Lin EH, Noel PH, Worchel J, Cornell J, et al. The
effectiveness of depression care management on diabetes-related outcomes in older patients.
Annals of internal medicine. 2004;140(12):1015-24.
60.
Lustman PJ, Griffith LS, Clouse RE, Cryer PE. Psychiatric illness in diabetes
mellitus. Relationship to symptoms and glucose control. The Journal of nervous and mental
disease. 1986;174(12):736-42.
61.
Bogner HR, Morales KH, de Vries HF, Cappola AR. Integrated management of type
2 diabetes mellitus and depression treatment to improve medication adherence: a randomized
controlled trial. Annals of family medicine. 2012;10(1):15-22.
62.
WHO. Obesity: preventing and managing the global epidemic. Technical Report
Series. World Health Organisation, 2000.
63.
Kivimaki M, Hamer M, Batty GD, Geddes JR, Tabak AG, Pentti J, et al.
Antidepressant medication use, weight gain, and risk of type 2 diabetes: a population-based
study. Diabetes care. 2010;33(12):2611-6.
64.
Schultz E, Malone DA. A practical approach to prescribing antidepressants.
Cleveland Clinic Journal of Medicine. 2013;80(10):625-31.
65.
Chiu H, Li T. Rapid Weight Gain During Mirtazapine Treatment. The Journal of
Neuropsychiatry and Clinical Neurosciences. 2011;23(1):E7-E.
66.
Moore R, 2nd, DeJoseph D, Simmons BB. Managing patients on antipsychotics: your
domain, too. The Journal Of Family Practice. 2014;63(3):142-9.
67.
Farah A. Atypicality of atypical antipsychotics. Primary care companion to the
Journal of clinical psychiatry. 2005;7(6):268-74.
68.
Vieweg V, Hasnain N. Schizophrenia, Antipsychotic Drugs, and Drug Induced
Weight Gain and Obesity. Healthy Body- Healthy Mind. 2012;26(1):19-22.
69.
Lund BC, Perry PJ, Brooks JM, Arndt S. Clozapine use in patients with schizophrenia
and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach. Arch
Gen Psychiatry. 2001;58:1172-6.
70.
Bergman RN, Ader M. Atypical antipsychotics and glucose homeostasis. The Journal
of clinical psychiatry. 2005;66(4):504-14.
71.
Guo JJ, Keck PE, Jr., Corey-Lisle PK, Li H, Jiang D, Jang R, et al. Risk of diabetes
mellitus associated with atypical antipsychotic use among patients with bipolar disorder: A
retrospective, population-based, case-control study. The Journal of clinical psychiatry.
2006;67(7):1055-61.
72.
Dixon L, Weiden P, Delahanty J, Goldberg R, Postrado L, Lucksted A, et al.
Prevalence and correlates of diabetes in national schizophrenia samples. Schizophrenia
bulletin. 2000;26(4):903-12.
73.
Koro CE, Fedder DO, L'Italien GJ, Weiss SS, Magder LS, Kreyenbuhl J, et al.
Assessment of independent effect of olanzapine and risperidone on risk of diabetes among
patients with schizophrenia: population based nested case-control study. BMJ : British
Medical Journal. 2002;325(7358):243-.
74.
David L. 10-Minute CBT in Primary Care: a brief introduction.
75.
Lustman PJ, Griffith LS, Freedland KE, Kissel SS, Clouse RE. Cognitive behavior
therapy for depression in type 2 diabetes mellitus. A randomized, controlled trial. Annals of
internal medicine. 1998;129(8):613-21.
76.
Penckofer SM, Ferrans C, Mumby P, Byrn M, Emanuele MA, Harrison PR, et al. A
psychoeducational intervention (SWEEP) for depressed women with diabetes. Annals of
behavioral medicine : a publication of the Society of Behavioral Medicine. 2012;44(2):192206.
77.
Snoek FJ, van der Ven NC, Twisk JW, Hogenelst MH, Tromp-Wever AM, van der
Ploeg HM, et al. Cognitive behavioural therapy (CBT) compared with blood glucose
awareness training (BGAT) in poorly controlled Type 1 diabetic patients: long-term effects
on HbA moderated by depression. A randomized controlled trial. Diabetic medicine : a
journal of the British Diabetic Association. 2008;25(11):1337-42.
78.
Safren SA, Gonzalez JS, Wexler DJ, Psaros C, Delahanty LM, Blashill AJ, et al. A
Randomized Controlled Trial of Cognitive Behavioral Therapy for Adherence and
Depression (CBT-AD) in Patients With Uncontrolled Type 2 Diabetes. Diabetes care.
2014;37(3):625-33.
79.
van Der Ven NCW, Hogenelst MHE, Tromp-Wever AME, Twisk JWR, van Der
Ploeg HM, Heine RJ, et al. Short-term effects of cognitive behavioural group training
(CBGT) in adult Type 1 diabetes patients in prolonged poor glycaemic control. A
randomized controlled trial. Diabetic Medicine. 2005;22(11):1619-23.
80.
Bosma H, Lamers F, Jonkers C, van Eijk J. Disparities by Education Level in
Outcomes of a Self-Management Intervention: The DELTA Trial in the Netherlands.
Psychiatric Services. 2011;62(7):793-5.
81.
Lamers F, Jonkers CCM, Bosma H, Knottnerus JA, van Eijk JTM. Treating
depression in diabetes patients: does a nurse-administered minimal psychological
intervention affect diabetes-specific quality of life and glycaemic control? A randomized
controlled trial. Journal of Advanced Nursing. 2011;67(4):788-99.