2012. Vol.3, Special Issue, 787-794
Published Online September 2012 in SciRes (
Copyright © 2012 SciRes. 787
Comorbidity of Depression and Diabetes: In a Nutshell
Anisha Heeramun-Aubeeluck1, Zheng Lu1,2*, Yanli Luo1
1Department of Psychosomatic Medicine, Tongji Hospital, Shanghai, China
2Department of Adult Psychiatry, Shanghai Mental Health Center, Shanghai, China
Email: *
Received June 2nd, 2012; revised July 1st, 2012; accepted August 2nd, 2012
Depression and diabetes mellitus (DM) have existed since ages. Yet, the etiologies of both diseases are
unclear till date. However, the effects resulting from these diseases are well documented. Comorbidity of
both disorders leads to increase disability and mortality rates. Besides presenting the epidemiological
status of depression in DM, this review aims to highlight the different hypotheses governing the associa-
tion of depression in DM and summarize the current trend in detection and management of depression. A
high index of suspicion is required to detect depression in diabetic patients. There seems to be higher
prevalence of depression in type 2 diabetes than in type 1 diabetes. Treatment should be tailored as per the
individual needs and presence of comorbidity. Though there is no gold standard treatment for depressive
diabetics, combinations of both pharmacological and non-pharmacological interventions are likely to im-
prove outcomes. Selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake
inhibitors (SNRIs) are preferred to conventional antidepressants. Collaborative care, psychoeducation and
behavioral interventions are helpful in motivating patients to maintain treatment and improve psycho-
logical well-being and quality of life. Untreated depression in diabetics is costly to the health care and
economic system as there is an increase in functional impairment and mortality rate. More efforts need to
be made to effectively screen, diagnose and treat patients with comorbidity of diabetes and depression.
Keywords: Diabetes Mellitus; Depression; Management; Epidemiology
Thomas Willis (1621-1675), a famous British physician, was
the first to describe the relationship between depression and
diabetes mellitus. He claimed that diabetes was a consequence
of prolonged sorrows (Willis, 1675). This concept has flour-
ished over the past three centuries and still remains a hotly
debated subject amongst researchers in psychosomatic medi-
cine. Though the concept of mind-body unity and the effect of
psychological factors on the course of general medical condi-
tions are the crux of psychosomatic medicine, the exact mecha-
nisms underlying depression in diabetes mellitus (DM) is yet
unknown. Depression as per the World Health Organization
(WHO) represents a common mental disorder. It is character-
ized by depressed mood, loss of interest or pleasure, feelings of
guilt or low self-worth, disturbed sleep or appetite, low energy,
and poor concentration. On a darker side, it is also associated
with increased risk of suicidal behavior estimated at approxi-
mately 850,000 lives per year (WHO, 2012). As per the Diag-
nostic and Statistical Manual of Mental Disorders, 4th Edition,
Text Revision (DSM-IV-TR), depression is classified as major
depressive disorder. It can be further sub classified as single or
recurrent episode. Degree of severity can also be specified and
include mild, moderate and severe with/without psychotic fea-
tures. The International Classification of Disease, 10th Edition
(ICD-10) subdivides depression into depressive episode and
recurrent depressive episode. Each type can be graded depend-
ing on severity namely mild, moderate, and severe with or
without psychotic symptoms. Furthermore, each diagnosis may
be rated as with or without somatic syndrome. The diagnostic
criteria between ICD-10 and DSM-IV have some differences.
Depressive episode as per ICD-10 should last at least 2 weeks
and for mild, moderate and severe episodes a total of at least 6,
8 and >8 symptoms must be met. Irrespective of the degree of
the severity, ICD-10 requires any 2 of these core symptoms to
be present:
1) Depressed mood sustained during almost all days for at
least 2 weeks;
2) Loss of interest or pleasure;
3) Decreased energy or increased fatigability.
Recurrent depressive disorder (ICD-10) is diagnosed when
there has been one previous episode (mild, moderate or severe)
which lasted at least 2 weeks and time period between the pre-
vious episode and current one is a minimum of 2 months. The
degree of severity is rated similar to depressive episode. On the
other hand, as per DSM-IV-TR, major depressive disorder is
characterized by a total of 5 or more symptoms lasting for a
continuous 2 week period and a change from previous func-
tioning. The core symptom of depression as per DSM-IV is one
of these 2:
1) Depressed mood;
2) Loss of interest or pleasure.
Recurrent major depressive disorder (DSM-IV-TR) repre-
sents 2 more or previous episodes separated by a continuous 2
month period without depression. Severity is graded upon num-
ber of symptoms and degree of impairment in social and occu-
pational functioning.
Dysthymia, which represents a chronic and milder depression
is grouped under the depressive disorders constellation in
DSM-IV-TR while in ICD-10, it represents persistent mood
disorders. The diagnostic criteria for dysthymia in ICD-10 re-
*Corresponding author.
quire a minimum of 3 symptoms while DSM-IV-TR requires 2
symptoms. Though the duration is similar in both classification
systems, the list of symptoms differ.
DM is a metabolic disorder of multiple etiologies character-
ized by chronic hyperglycemia with disturbances of carbohy-
drate, fat and protein metabolism resulting from defects in insu-
lin secretion, insulin action, or both. DM can be broadly classi-
fied into four main categories namely:
1) Type 1 diabetesonset usually in childhood and adoles-
cence and results in β cell destruction leading to absolute insu-
lin deficiency.
2) Type 2 diabetesdue to progressive insulin secretory de-
fect superimposed on insulin resistance; common in adult with
obesity, unhealthy diets and lack of physical activity.
3) Gestational diabetes mellitusdiabetes diagnosed during
pregnancy but which has not yet reached overt diabetes).
4) Other categories such as drug-induced, genetic disorders,
and exocrine pancreatic disorders.
The diagnostic criteria for diabetes is either one of the fol-
1) A1C 6.5%. The test should be performed in a laboratory
using a method that is National Glycohemoglobin Standardiza-
tion Program (NGSP) certified and standardized to the Diabetes
Control and Complications Trial (DCCT) reference assay.
2) FPG 126 mg/dL (7.0 mmol/L). Fasting is defined as no
caloric intake for at least 8 hours.
3) 2 hour plasma glucose 200 mg/dL (11.1 mmol/L) during
an Oral Glucose Tolerance Test (OGTT). The test should be
performed as described by the WHO, using a glucose load con-
taining the equivalent of 75 g anhydrous glucose dissolved in
The diagnosis of DM itself can be a major life stress event to
an individual. Vulnerable subjects fail to cope with the complex
and wide-arrayed physical and mental accommodations re-
quired. Consequently, the affected individual may lose interest
or lack energy in maintaining his diabetic management. Un-
healthy eating habits are also frequent and may contribute to
jeopardizing the control of DM. Risks of suicide through insu-
lin overdose may also increase due to easy access to insulin.
Furthermore, the complications of DM such as retinopathy,
neuropathy and nephropathy overwhelm the already vulnerable
subjects. These scenarios accentuate the seriousness of detect-
ing and treating depression in DM.
Besides presenting the epidemiological status of depression
in DM, this review aims to highlight the different hypotheses
governing the association of depression in DM and summarize
the current trend in detection and management of depression.
Epidemiological Status of Depression and DM
As per Greden et al. (2003) depression was a serious global
health issue affecting approximately 340 million people world-
wide. The WHO survey conducted in 2000, depression was the
4th leading factor to global burden of disease in women while in
men it was on 7th position (Ustun et al., 2004). The lifetime pre-
valence of depression in different countries varied: US 16.6%,
Europe 14%, Asia-Pacific 1.1% - 19.9% and South Africa 9.7%
(Kessler et al., 2005; Alonso et al., 2005; Chui, 2004; Tomlin-
son et al., 2009).
A meta-analytical study had previously reported 11% of
people with DM suffered from depression and that 31% of them
had clinically relevant depression (Anderson et al., 2001).
In a more recent systematic review the co-existence of DM
and depression was confirmed (Egede & Ellis, 2010). Interest-
ingly rates for undiagnosed depression in DM patients as per
the study conducted by Li et al. (2008) equaled to 45%. The
WHO World Health Survey studied adults aged 18 and above
in 60 different countries worldwide and concluded that 1 year
prevalence for depression in diabetes was 2% (Moussavi et al.,
2007). TA systematic review reported the prevalence of depres-
sion in young adults with type 1 diabetes as inconclusive
(Johnson et al., 2012). On the other hand, a meta-analytic re-
view supported claim for raised rate of depression in type 2
diabetes, which is also the most common type of diabetes (Ali
et al., 2006).
The International Diabetes Federation (IDF) estimated
around 280 million people with DM in 2010 and this figure is
thought to increase to 439 million in 2030 (IDF, 2009). DM
currently holds the 7th place in cause of death (Murphy et al.,
2012). With depression superimposed in DM, the mortality rate
is likely to increase. Furthermore, there is evidence showing
that depression was significantly associated with a wide range
of diabetes complications with effect sizes of .17 - .32 (Groot et
al., 2001). In sum, untreated depression is one of contributing
factors for increased mortality rate in DM.
Risk Factors for Depression in DM
The feeling of “sadness” is a normal emotional reaction elic-
ited by many events such as loss and disease. This reaction
produces a variety of effects on the subject affecting his physi-
cal appearance, physical and mental functioning (neurobiologi-
cal, hormonal and psychological) as well as his family, social
and occupational activities and relationships (Levenson, 2001).
Genetic predisposition and/or childhood adverse events leading
to maladaptive coping strategies increase the vulnerability of a
person to depression. Coupled with multiple or recurrent
stressful events, the subject with the above characteristics has a
higher probability of developing depression. Furthermore, vul-
nerability might also be increased due to unhealthy life style or
behavior such as obesity, inadequate exercise, poor diet and
smoking. There are several predisposing factors for comorbid-
ity of depression and diabetes and include:
1) AgeA Canadian survey suggested that prevalence of
depression in diabetic patients is higher in the younger age
group (20 - 39 years) as compared to the middle aged groups
(40 - 64 years). This finding has been supported by study con-
ducted by Katon et al. (2004). In a survey of However, Trief
(2007) argued that elderly (above 65 years) were also at high
risk. A study in elderly Spanish revealed that diabetes was as-
sociated with an increased risk of prevalent (odds ratio = 1.47)
and incident (odds ratio = 1.40) depression. Another survey in
elderly Chinese on Homg Kong found that of that 26% of eld-
erly had diabetes and elevated depressive symptoms (Chou &
Chi., 2005).
2) GenderThe impact of depression in diabetes is thought
to be higher in females. A large prospective women cohort
conducted in 11 US states found that women with diabetes and
comorbid depression had increased mortality rate (95% C.I of
3.11) (Pan et al., 2011). However, it should be pointed out that
generally fewer males than females seek treatment for depres-
sion. Furthermore, depression in males is more likely to pro-
duce irritability, anger or violent behavior rather than depressed
Copyright © 2012 SciRes.
Copyright © 2012 SciRes. 789
mood and thus depression might be missed on screening as
irritability/anger are not hallmark features of depression.
3) Ethnicity-Li et al. (2009) in a large standardized telephone
survey covering 50 states in the US found a difference of 25
fold in rates prevailing among ethnic subgroups (lowest: Asian
1.1% and highest: 27.8% in American Indians/Alaska Natives).
Another study found increased depressive symptoms in African
Americans (Kogan et al., 2007).
4) Other factorsNever married and lower education level
had also been reported to influence the status of depression in
DM (Katon et al., 2004). Another large population-based study
demonstrated that depression in type 2 DM was associated with
lower level of education, lack of physical activity, physical
impairment and somatic complaints whilst type 1 DM was cor-
related with physical impairment and lower levels of education
(Engum et al., 2005). Few studies have focused on the inter-
relationship between depression and DM in pregnancy. Kozhi-
mannil et al. (2009) reported a two fold increase in odds ratio of
perinatal depression (ICD 9 code) in women with gestational
diabetes. However, another study conducted by Katon et al.
(2011) showed that antenatal depression (DSM-IV) and gesta-
tional diabetes was not independently associated.
Causal Links between Depression and DM
As described in the previous section, vulnerable individuals
have difficulties ending the normal process of sadness or grief
and thus are predisposed to experience depression. Figure 1
summarizes the hypothesized pathways to depression.
The exact etiologies and mechanisms behind depression in
DM are yet unknown. However, research in that field has
yielded some hypotheses regarding the relationship between
depression and DM. The most popular theory states that the
link between depression and DM is bidirectional, that is, DM
may predispose or induce depression and depression may pre-
dispose or induce DM. A meta-analytic review examining the
Behavioral risks :
1. Obesity
2. Smoking
3. Sedentary lifestyle/lack
of physical exercise
4. Chronic stress
Maladaptive coping style
Low social support;
Younger age;
Stigma and personal meaning
attached to medical condition
Physical effects of illness and treatment;
Proinflammatory factors;
Autonomic nervous system changes;
Metabolic syndrome;
Biological changes in brain resulting from chronic illness;
lications and other chronic medical conditions
Genetic predisposition;
Family history of mood disorders;
Adverse life events in childhood/adulthood;
Multiple stressors such as illness/treatment
Figure 1.
Factors causing and influencing depression (Peveler et al., 2002; Katon, 2003).
relationship between depression and DM from 1950-2007 de-
monstrated that depression was correlated with 60% increase
in type 2 diabetes whilst type 2 DM shared a correlation of 15%
with depression (Mezuk et al., 2008). Kohl et al. (2006) claim
that depression is not only a consequence of DM but might al-
so predispose to onset of type 2 DM. After controlling for so-
ciodemographic and other clinical health variables, depress-
sion was an independently associated with onset of type 2 dia-
betes (Musselman et al., 2003; Williams et al., 2006). On the
other hand, depression might also predict the number and se-
verity of diabetic complications (Groot et al., 2001; Ludman et
al., 2004).
Proposed biological links between depression and DM are
illustrated in Figures 2 and 3.
Screening for Depressive Diabetics
The need to detect depression in diabetic patients is impor-
tant in order to help them achieve a better quality of life. In a
primary care setting, patients with family history of mood dis-
orders, previous history of depression or anxiety or history of
substance abuse should alert the physician of possibility of
depression (Lustman & Clouse, 1997). Other symptoms that
might tip off the probability of depression are unexplained hy-
perglycemia or hypoglycemia and their related symptoms de-
spite appropriate pharmacotherapy, persistent somatic com-
plaints, chronic pain and sexual dysfunction. These patients are
good candidates for screening for depression.
A recent review on screening of depression in diabetic pa-
tients suggested that the following scales are the most popular
screening instruments: the Center for Epidemiological Stud-
ies-Depression Scale (CES-D), the Beck Depression Inventory
(BDI), and the Patient Health Questionnaire (PHQ-9) (van der
Feltz-Cornelis, 2011). However, with regard to detecting de-
pression in DM, data on the validity and reliability of these
screening tools as well as their cultural applicability are scarce.
Evidence suggested that the CES-D was the best predictor of
depression in type 2 diabetes (McHale et al., 2008). Further-
more, as there was an elevated association between symptoms
of depression and diabetes-related distress, the CES-D proved
to be efficient in distinguishing between depressive and
non-depressive symptoms. In clinical setting, use of the BDI
was likely to detect more than 70% of the patients with depression
while providing a sensitivity of greater than 70% (Lustman &
Hyperactivity of the
ary axis (HPA)
Activation of
sympathetic nervous
Oxidative stress
Increased cortisol Increased cytokines;
Increased catecholamines
Beta cell destruction in pancreas and hyperglycemia
Type 1 diabetes
Disease and related complications as stressor
Figure 2.
Biological links between depression and type 1diabetes (Ref: korczak et al., 2011).
Copyright © 2012 SciRes.
Type 2 diabetes
Increased cortisol
Family history;
Multiple stressors;
Increasing age;
Sedentary lifestyle/Lack of exercise;
Unhealthy diets and eating habits;
Metabolic syndrome
Increased cytokines;
Increased catecholamines
Ins u li n
Disease and related complications as stressor
Hyperactivity of
(HPA) axis
Activation of
nervous system
Figure 3.
Summary of causal links between type 2 diabetes and depression (Ref. Champani et al., 2010).
Clouse, 2004). The PHQ-9 is based on the DSM-IV major de-
pressive disorder criteria. The advantages of the PHQ-9 include
availability in 27 languages, brief, and also measurement of the
severity of depression. Van Steenbergen-Weijenburg et al.
(2010) found that the PHQ-9 was more accurate than the MINI
(Mini International Neuropsychiatric Interview) in assessing
depression in type 2 diabetes. Other screening instruments
comprise of the following scales: the World Health Organiza-
tion Five Wellbeing questionnaire (WHO-5), the Psychoso-
matic Evaluation of Problem areas in Diabetes (PAID), the
Hamilton rating Scale for Depression (HAM-D), and the two
screening questions.
It should be stressed that screening instruments are not diag-
nostic of depressive disorder and a thorough interview needs to
be conducted for a formal diagnosis of depression. The diag-
nostic criteria for depression and diabetes have been summa-
rized in section 1.
Clinical Goals and Treatment Strategies
Irrespective of the age group of patients, the management of
DM consists of these general goals:
1) Regulate blood glucose, blood pressure and lipid profile
and their associated symptoms;
Copyright © 2012 SciRes. 791
2) Identify and treat macrovascular and microvascular com-
3) Effective self-management by patients and
4) Improve or stabilize the general health status of patients.
However, in practice only a small percentage of patients are
able to reach the desired clinical goals. Various factors are
thought to be implicated such as patient’s beliefs about disease,
the severity of the disease, comorbid disorders, financial and
economic status and availability of support. Qaseem et al.
(2007) recommend that glycemic control should be based upon
severity of disease and risk of complications, comorbidity, life
expectancy, and patient’s preferences—thus treatment goals
ought to be individualized.
Diabetes coupled with depression tends to increase the dis-
ease burden and functional impairment. As mentioned above
primary care physicians need to have a high index of suspicion
in detecting underlying depression in diabetic patients. In a
longitudinal assessment of 998 adults with type 2 diabetes,
Chui et al. (2010) found that general health behaviors (physical
exercise, weight control, and smoking) explained 13% of the
depression-hyperglycemic link. The association between de-
pression and hyperglycemia has been replicated in other studies
(Rush et al., 2008; Katon et al., 2004). Interestingly, Lustman et
al., (2005) failed to establish diabetes self-care as a mediator
between depression and hyperglycemia in type 1 diabetes.
Nonetheless, lifestyle and health behaviors modification are
essential in the management of depressive diabetic patients.
Proposed strategies include:
1) Weight loss and exercise. Older patients are more likely to
successfully meet these goals (Diabetes Prevention Program
Research Group, 2004). Other beneficial effects of exercise
include reduced abdominal adiposity, improved lipid profile,
enhanced cardiac function and coronary blood flow and de-
crease blood pressure. All these factors are directly and indi-
rectly related to diabetes and its complications;
2) Reducing or quitting cigarette smoking and alcohol con-
3) Healthy diet: Increasing consumption of vegetables and
fruits, reducing intake of fatty foods, monitoring caloric intake
based on height and occupational requirement. Aggressive diets
can lead to disastrous consequences in patient with low hypo-
glycemic awareness. Furthermore, the adverse effects of tight
glycemic control is said to increase exponentially with age.
Treatment can be pharmacological, psychotherapeutic or
combined interventions. A recent meta-analysis has deemed it
effective to treat depression in diabetic patients (van der Feltz-
Cornelis et al., 2010). The role of antidepressant and whether
the class of antidepressant used had an influence on the glyce-
mic control was not clarified in the meta-analysis. Echeverry et
al. (2009) found significant association between treatment of
depression with sertraline and decrease in A1C levels as well as
systolic pressure in a low income Hispanic and African Ameri-
can sample. The Pathways study, on the other hand, in its one
year study did not find significant differences in A1C levels in
between treatment group for depression and placebo group
(Katon et al., 2004). Concern has also been raised regarding the
role of antidepressant in causing DM. A large well-conducted
trial found significant association between antidepressant use
for depression and diabetes was nullified by lifestyle/risk fac-
tors (Wilkins & Sambamoorthi, 2011). Another large trial in
middle-aged patients also supported the theory of no causal
relationship between antidepressant and DM (Kivimäki et al.,
2011). Interestingly, in a large sample of multi-ethnic post-
menopausal women, the use of antidepressants in women with
longstanding or elevated depressive symptoms was signifi-
cantly associated with a higher risk of DM (Ma et al., 2011).
A review on antidepressant use in DM showed that selective
serotonin reuptake inhibitors (SSRIs) such as fluoxetine, par-
oxetine, citalopram and sertraline not only improved depression
but also helped in reducing glucose levels while nortriptyline
(norepinephrine reuptake inhibitor, NRI) worsened the glucose
control (Goodnick, 2001). Studies on conventional antidepres-
sants have shown that they are liable to increase the risk of
metabolic syndrome and hence DM (van Reedt Dortland et al.,
2010; Mcintyre et al., 2010). Another antidepressant that has
proved to be beneficial in comorbid depression and DM is mil-
nacipran which is a serotonin and norepinephrine reuptake in-
hibitor (SNRI) (Hoffman, 2010). Depressive diabetic patients
with sexual dysfunction might benefit from the use of bu-
propion which is a norepinephrine-dopamine reuptake inhibitor
(Sayuk et al., 2011). Inadequate response to antidepressants in
depressive type 2 diabetics might benefit from treating co-exist-
ing symptoms such as pain and impairment (Anderson et al.,
Regarding psychotherapeutic interventions, as evidenced by
findings of a systematic review, they helped improve the sever-
ity of depression and had limited effects on the reduction of
A1C levels (Wang et al., 2008). Nevertheless, studies which
had focused on behavioral modifications or collaborative care
in depressive diabetics had improved outcomes and adherence
to medications. A combination of both pharmacotherapy and
psychotherapeutic interventions might lead to better outcome
measures and quality of life. Unfortunately, in real life, patients
with new-onset depression and medical comorbidities might not
be receiving adequate treatment (Gill et al., 2010).
Functional impairment as well as adverse effects caused by
comorbidity of DM and depression is a fact. Due to the in-
creasing number of both DM and depression and their hypothe-
sized associations, identification and treatment is a must. How-
ever, since DM has its own related diabetes-distress syndrome,
diagnosis is tricky. A high index of suspicion is required as at
times patients are unaware of their latent depression. Another
difficulty likely to be encountered is that many diabetic patients
have depressive symptoms which do not meet the criteria for a
diagnosis of depression as per DSM-IV-TR or ICD-10. Fur-
thermore, there is growing evidence that many patients given
the diagnosis of depression are in fact having Bipolar II disor-
der. Unfortunately, research on comorbidity of Bipolar II and
diabetes is scarce. Since antidepressants are not the first choice
for managing mild depression, patients with either subsyndro-
mal depression or mild depression are more likely to benefit
from added non-pharmacological approaches such as psy-
choeducation, coping skills strategies and behavioral interven-
tions to their regular treatment. These strategies could also be
added to the treatment of diabetic patients with a formal diag-
nosis of depression. Whatever strategies employed, they should
be individualized to the person. From a different angle, in the
long run, treated depressive diabetics might reduce the eco-
nomic burden of these 2 diseases by reducing complications
and functional impairment.
Copyright © 2012 SciRes.
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