Endocrine DOI 10.1007/s12020-014-0323-x

REVIEW

The association between diabetes and depression: a very disabling condition Vincenzo Fiore • Massimo Marci • Antonella Poggi • Vito Angelo Giagulli Brunella Licchelli • Massimo Iacoviello • Edoardo Guastamacchia • Giovanni De Pergola • Vincenzo Triggiani

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Received: 15 February 2014 / Accepted: 27 May 2014  Springer Science+Business Media New York 2014

Abstract Rates of depression are significantly increased in diabetic patients, and even more in the elderly. About 20–30 % of patients with diabetes suffer from clinically relevant depressive disorders, 10 % of which being affected by the major depression disorder. Moreover, people with depression seem to be more prone to develop an associated diabetes mellitus, and depression can worsen glycemic control in diabetes, with higher risk to develop complications and adverse outcomes, whereas improving depressive symptoms is generally associated with a better glycemic control. Thus, the coexistence of depression and diabetes has a negative impact on both lifestyle and quality of life, with a reduction of physical activity and an increase in the request for medical care and prescriptions, possibly increasing the healthcare costs and the susceptibility to further diseases. These negative aspects are particularly evident in the elderly, with further decrease in the mobility, worsening of disability, frailty, geriatric syndromes

V. Fiore
M. Marci
A. Poggi Unit of Internal Medicine-Geriatrics, ‘‘S. Giovanni Evangelista’’ Hospital, Via Parrozzani 3, 00019 Tivoli (RM), Italy V. A. Giagulli
B. Licchelli
E. Guastamacchia
V. Triggiani (&) Endocrinology and Metabolic Diseases, Interdisciplinary Department of Medicine, University of Bari ‘‘A. Moro’’, Piazza Giulio Cesare 11, 70124 Bari, Italy e-mail: [email protected] M. Iacoviello Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari ‘‘A. Moro’’, Piazza Giulio Cesare 11, 70124 Bari, Italy G. De Pergola Clinical Nutrition Unit, Department of Biomedical Sciences and Human Oncology, University of Bari ‘‘A. Moro’’, Piazza Giulio Cesare 11, 70124 Bari, Italy

and increased mortality. Healthcare providers should be aware of the possible coexistence of depression and diabetes and of the related consequences, to better manage the patients affected by these two pathological conditions. Keywords Diabetes mellitus
Depression
Cardiovascular risk
Quality of life

Introduction Current epidemiological evidence suggests that people with diabetes have an increased risk of experiencing a depressive condition in their lifetime. About one-third of diabetic patients suffer from clinically relevant depressive disorders that lead to greater morbidity and mortality and poorer quality of life. On the other hand, people with depression seem to be at increased risk of developing diabetes. The aim of this narrative review, based on a careful evaluation of the literature, was to revise the bidirectional relationships between diabetes and depression and the clinical implications of this association. Relevant studies published up to now have been identified from MEDLINE/PubMed and EMBASE, using key search words including: ‘‘diabetes mellitus,’’ ‘‘depression’’ and ‘‘depressive disorders.’’ Additional key words ‘‘glycemic control,’’ ‘‘cardiovascular risk,’’ ‘‘antidepressant drugs’’, and ‘‘quality of life’’ were used to further delineate relevant articles.

Background and epidemiology of the association between diabetes and depression Depression is defined as a pathological modification of mood. The DSM-IV criteria for the diagnosis of major

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depressive disorder (MDD) consist of the presence nearly every day and for 2 weeks of at least five of the following symptoms: depressed mood, markedly reduced interest or pleasure in all or almost all activities, significant weight loss or gain or decreased/increased appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or guilt, lower ability to concentrate or take decisions, recurrent thoughts of death or suicide [1]. Working and social activities are consequently compromised [1]. To diagnose primary depression, depressive conditions due to other diseases or certain drugs or mourning should be ruled out [1]. Depression is particularly common in the elderly, half of the cases being a first episode of depression in these patients; it commonly evolves in a chronic condition, with a higher tendency to recur when compared with younger people [2]. It is polymorphic in its presentation because of different medical comorbidities and socio-cultural factors [3]. Furthermore, there are frequent cognitive disorders, somatization and loss of interest in these patients. Predisposing factors are specific genetic traits, cognitive diathesis, age-related neurobiological modifications, insomnia, stressful life events, reduction in physical activities and retirement. Conversely, protective factors are higher scholar level and socio-economic status, involvement in worthwhile activities, religious or spiritual beliefs, and psychological resilience, which tend to increase with aging [3, 4]. If cognitive disorders are prevalent, it should be necessary to rule out dementia [1]. Finally, the so-called end-life depression is due to several medical comorbidities (cognitive disorders, cardiovascular diseases, diabetes), higher mortality risk [5–7], and poor physical performance, especially in institutionalized patients [8]. It has been estimated that 5–12 % of men and 10–15 % of women would experience a MDD during their lifespan, with an evident clinical syndrome in 3 % and 5–9 %, respectively [9, 10]. There are different tests for diagnosing and monitoring depressive disorders. The most utilized and powerful tests are the Back Depression Inventory (BDI-II) [11] and the 9-item Patient Health Questionnaire (PHQ-9) [12–14]. The former has been developed to evaluate the presence and severity of depressive symptoms according to the DSM-IV criteria; it is a scale test exploring somatic, affective and motivational aspects through 21 items; the PHQ-9 is a selfmanaged questionnaire exploring each of the 9 DSM-IV criteria for the diagnosis of depression. Another very sensitive diagnostic test, used either in clinical practice or for scientific purposes, is the MiniInternational Neuropsychiatric Interview (MINI); it is based on the DSM-IV criteria and is useful to diagnose also subclinical depressive conditions [15].

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Finally, the Center for Epidemiological Studies Depression Scale (CES-D) is a 20-items test useful for a preliminary screening, exploring the main aspects of depressive disorders: feelings of worthlessness/guilt, feeling of impotence and desperation, psychomotor agitation or retardation, loss of appetite and sleep disturbances [11, 16]. Also Diabetes mellitus is a very frequent pathologic condition and a chronic disabling disease. It has a prevalence approaching the epidemic proportion, with 285 million people (6.6 % of the world population) being affected [17]. The prevalence of diabetes mellitus is about 4.9 % in Italy, with type 2 (T2DM) accounting for about 95 % of the cases, and it is progressively higher with aging, reaching the level of 13 % in the elderly and 19.8 % over 75 years [18]. The evidence of a high frequent association between diabetes mellitus and depression has determined growing interest in the last few years, even though the relationship between these two conditions is incompletely understood. The rate of depression is significantly higher in diabetic patients, and even more in the elderly; in fact, from 20 to 30 % of patients with diabetes (both type 1 and type 2) suffer from clinically relevant depressive disorders [19, 20]. However, about two-third of patients are not correctly diagnosed and consequently treated for their depressive syndrome, possibly because the attention of physicians to psychological status is common lower. Moreover, people with depression seem to have an increased risk of developing diabetes mellitus [21], even up to 37 % of cases [22], and particularly in the elderly. Campayo et al. [23] reported a 65 % increment of the estimated risk to develop T2DM in clinical evident depression as well as in mild depressive disorders. Depression has also been shown to be an independent risk factor for the development of T2DM [19, 24, 25]. The depression in diabetic patients is a chronic and severe condition, which tends to recurrence after remission in up to 80 % of treated patients in a five-year period [26], and some authors consider depression as highly predictive of the number and the severity of diabetic complications [27–29]. A prospective study [30], performed in a cohort of 65,381 women (aged between 50–75 years), followed for 10 years, and classified on the basis of the severity of their depression (Mental Health Index 5—MHI-5 of 76–85 and 53–75) or of their depressed mood, showed that the relative risk (RR) of developing T2DM was 1.17, and even more whether diabetic subjects were treated with specific antidepressant drugs, such as noradrenergic substances and possibly dual acting antidepressants, because of their hyperglycemic effects [31] (Table 1). Golden et al. [32] evaluated the incidence of T2DM in a 3-year period in individuals with and without depressive

Endocrine Table 1 Most used antidepressant drugs and their effects on glycemic control [31, 128]

Category Serotonin reuptake inhibitor (SSRIs)

Drug

Main Effect on glycemia

Presumable mechanism

Sertraline

Hypoglycemia

Increasing insulin sensitivity

Hypoglycemia and hyperglycemia

Increasing insulin sensitivity Increasing weight

Hyperglycemia

Increasing glycogenolysis

Fluvoxamine Paroxetine Fluoxetine Citalopram Cloropropamin SRI and 5-HT 2c receptor binding

Amitriptyline Doxepin Imipramin

Norepinephrinic (NE)

Maprotiline

Reuptake transporter

Nortriptyline

Increasing gluconeogenesis

5-HT 2c receptor binding; H1 and M1 receptor Biding

Mianserin

Increasing weight

Mirtazapine

Decreasing insulin secretion

symptoms of the Multi Ethnic Study of Atherosclerosis, a longitudinal study involving 5,000 american people (age range 45–84 years) belonging to different ethnical groups, showing that the incidence of T2DM was 22/1,000 persons/ year and 16.6/1,000 persons/year for patients with and without depressive symptoms, respectively, with an increase of 1.10 times for an increase of 5 units in the CES-D. It is now clear that depression and diabetes influence each other, and this aspect has been well emphasized in the metanalysis by Mezuk et al. [33]. Considering the possibility that altered glucose metabolism is a risk factor for depression, a metanalysis by Nouwen has shown that patients with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or nondiagnosed diabetes mellitus had the same risk to develop depression as normal subjects, but lower than that of patients having the diagnosis of diabetes [34, 35]. Diabetic women showed an increased RR of developing depression (1.29) when compared with non-diabetic subjects, with differences related to the therapeutic regimen (1.25 without therapy; 1.24 oral hypoglycemic agents; 1.53 insulin-treated). These associations remained significant after adjusting data for associated comorbidities. Moreover, the Multi Ethnic Study of Atherosclerosis has shown that the incidence of severe depressive symptoms in treated T2DM patients was 61.9/1,000 persons/year that was significantly higher (RR 1.54, 95 % CI 0.44–1.27) than that of normal subjects or patients with IFG, IGT, or non-diagnosed T2DM [32]. The role played by psychological stress associated with the management of diabetic condition is critical [32] and,

in fact, intensively treated patients are more prone to develop symptoms of depression as compared to those less intensively treated in the first 3 year after the diagnosis [34]. Other main factors are the consciousness of being affected by diabetes, and chronic complications and disability related to it [36, 37]. In fact, several studies showed an association between depressive symptoms and diabetic complications (nephropathy, retinopathy, neuropathy, and macro-vascular disease), even though the findings are conflicting [28, 38–42]. In any case, even though the studies are based on a low number of patients and prospective studies are few, there is a strict correlation between the severity of depressive symptoms and that of diabetic complications [43]. The worsening of both microvascular (end-stage renal disease and death related to renal failure, blindness, amputations) and macro-vascular (stroke, myocardial infarction and cardiovascular disease mortality) diabetic complications is enhanced by the simultaneous presence of depression [28] either in type 1 or in type 2 diabetic patients. Interestingly, brain tissue vascular bed has been shown to be reduced in depressed elderly diabetic patients when compared with non-depressed patients [44]. The differences in the prevalence of depression in patients with diabetes (and vice versa) reported by epidemiological studies are related to different methods and related limits. For instance, a neglected previous episode of depression could have favored the onset of diabetes; in this case, a new episode of depression can be erroneously considered as a consequence of the diabetic condition, instead of a natural expression of a recurrent depression [33].

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Other important confounding factors are the use of different diagnostic criteria for depression and screening methods. For example, in some studies, the use of antidepressants is considered a marker of depression, even though they can have been prescribed for different, nondepressive disorders (anxiety, diabetic neuropathy, paraplegia …); furthermore, there are many depressed patients who are not treated with anti-depressive drugs [45]. Several studies, moreover, are based on the score of self-reported questionnaires (CES-D) [16] that are not specific for the diagnosis of the different depressive disorders. Another critical point is represented by the different criteria used to define the patient as affected by diabetes in several studies (self-reported diagnosis and use of hypoglycemic agents in particular) that is responsible of an underestimation of the real prevalence of DM as compared to diagnosis performed by fasting glucose or performing the oral glucose tolerance test. It is also important that well established risk factors for diabetes, such as obesity, low physical activity, and alcohol abuse may well be markers of an unrecognized depression [46], and that the distinction between T1 and T2DM is not reported in some studies, as well as the data about the prevalence of diabetes complications and other comorbidities.

Pathogenesis of the Depression–Diabetes link and predisposing conditions The mechanisms involved in the pathogenesis of the link between depression and diabetes are not yet definitely understood. There are several hypothesis, and since metabolic programming and mental health are both determined at genetic level and possibly influenced by hyponutrition during intrauterine life and/or childhood, it may well be that the same factors influence the development of both diabetes and depression [47]. An overactivity of the hypothalamus–pituitary–adrenal axis, with hypercortisolism and/or activation of sympathetic nervous system (SNS), has been observed in patients with either diabetes or depression [48, 49] and these hormone changes lead to visceral adiposity and insulin resistance, alterations promoting T2DM and cardiovascular risk factors associated with this disease. Hyperproduction of pro-inflammatory cytokines may be present in depression and diabetes and, in association with hypercortisolism and activation of SNS, may further worsen metabolic dysregulation (pancreatic beta-cell apoptosis, reduced insulin secretion, insulin resistance, and T2DM onset) and, at the same time, impair neurotrophic function and neuronal networks plasticity [50–52].

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A possible link between T2DM and depression in male subjects, especially in the elderly, might be represented by the testosterone deficiency syndrome (TDS) [53–55]. Moreover, the testosterone replacement therapy (TRT) in depressed men with TDS and T2DM seems to be less effective in improving HbA1c, fasting glucose, lipids, insulin levels etc., as well as markers of inflammation such as tumor necrosis factor alpha and C-reactive protein [56, 57]. As previously reported, depression could be linked to the awareness of the chronic and dangerous implications of diabetes per se, determining a psychological stress due to the sense of impotence and the fear of the development of chronic complications and the risk of cardiovascular events [58, 59]. Several factors should be taken into consideration when the pathogenesis of depression is investigated: duration of the disease, quality of glycemic control, adherence to changes of lifestyle, need of frequent clinical controls, self-monitoring, fear of cardiovascular and neurological complications and their consequences [60–62]. Lloyd showed that higher levels of depressive symptoms, measured by means of psychometric tests (Beck Depression Inventory, the Center for Epidemiologic Studies Depression Scale, and the Problem Areas in Diabetes), are independently associated with the disease-related distress and to the suggestions concerning physical activity, addressed to reach a better metabolic control, but they are not associated with the frequency of self-monitoring in type 1 diabetic patients. The disease-related stress and the presence of depression can lead to difficulty in the selfmanagement of these patients [63]. Trento et al. evaluated the prevalence of depression, anxiety and impairment in cognitive functions in a population (age range 40–80 years) of T2DM patients either on insulin therapy or not. Despite a higher prevalence of depression (20.9 %), there was not a higher prevalence of anxiety or cognitive disorders in patients with diabetes as compared to normal subjects. Moreover, even though insulin-treated patients have longer duration of diabetes, older mean age and worse metabolic control, they show a milder depressive condition than patients untreated with insulin. Confirming previous observations, the authors found a direct correlation between depressive disorders and both age and gender, while there was no correlation with duration of diabetes, HbA1c levels or vascular complications, suggesting that depression could even precede DM and its complications rather than being the consequence of them [64]. This could be due to unhealthy behaviors correlated with the depressive state (sedentary lifestyle, obesity, smoking, alcohol abuse) as well as to the use of antidepressants with consequent worsening of glucose metabolism [65] (Table 1).

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Finally, one must consider the fact that the outcomes and the consequences of both diseases may be influenced by social determinants, given that we have to deal with two important chronic illnesses that can mark the life of those affected subjects. Furthermore, since the costs of these diseases are still growing, the accessibility to care would seem to be the most important factor among the social determinants (age, education, gender, etc.) in Western societies [66]. In conclusion, there is a bidirectional influence between depression and diabetes with the possibility that one condition facilitates the development of the other one and the social determinants and the accessibility to care could play a key role in the health outcomes.

Antidepressant drugs and T2DM risk Antidepressants are nowadays among the most frequent prescribed drugs in outpatients medicine, but data are not homogenous to give evidence of the role of these drugs and the risk to develop T2DM [31] (Table 1). Indeed, some studies show an elevated risk of T2DM in treated patients [67], whereas others cannot confirm it [68]. The effects on glucose metabolism are different on the basis of the kind of antidepressant. Noradrenergic drugs and dual acting antidepressants may impair glucose tolerance and worsen glycemic control in diabetic patients, whereas hydrazine-type monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs) may even improve glucose homeostasis [31]. Further studies are required, especially for newer antidepressant drugs, to better choose the kind of antidepressant in diabetic patients.

Quality of life and adherence The presence of depression leads to amplification of some symptoms in diabetes [69], and diabetic patients have the tendency to complain more about symptoms typically related to diabetes (thirst, polyuria, polydipsia, etc.), even in the case of adequate glycemic control. Moreover, if we consider parameters such as clinical complications, response to the treatment, and mortality, the prognosis of DM and depression is worse when both conditions are associated. It is of interest that patients with both depression and diabetes have the perception of a worse health state as compared to people affected by depression associated with any other chronic disease (arthritis, asthma, angina, etc.) [50]. The impairment of the quality of life (QoL) is of particular importance in the elderly patients, because the

awareness of comorbid conditions has a more relevant impact, especially in the case of social and physical isolation, and even more in the oldest ones and when the disabling conditions (impairment of sight, deaf, hypomobility, falls, etc.) become evident. It has been suggested that both higher scholar level and socio-economic status are protective factors, attenuating the effects of the association between DM and depression, while psychological resilience, which tends to increase with aging, is characterized by a reduced response to negative emotions and better control of the stress [70, 71]. However, the reported data are conflicting. In the cohort study ESTHER, performed for 5 years in more than 1,000 elderly patients with diabetes and depression, mental scores (MCS) were the best predictor of the quality of life (HRQoL), minimizing the effects of the depression [72]. In other studies performed in USA, the physical and psychological impact of depressive symptoms was stronger in middle aged than in the elderly patients with diabetes, even though the latter group had a worse glycemic control [73, 74]. However, the distinction between T1 and T2DM patients was not described and the evaluation (self-evaluation) of depressive disorders in different ages was not homogeneous, thus arising some doubt on the reliability of the reported results [75–77]. In a very large group of elderly diabetic patients (more than 6,000 affected either by T1 and T2DM, age range 60–75) of the Diabetes and Aging Study, a lower HRQoL mental score was significantly associated with depression [78]. The association between DM and depression leads to lower adherence to hypoglycemic, antihypertensive, and hypolipidemic drugs [79] and to suggestions concerning diet, physical activity, smoking, alcohol restrictions, glucose self-monitoring and follow-up [80, 81], with deleterious effects on symptoms, QoL, the onset and progression of complications, morbidity and mortality [82–84]. The impact is even more evident in the elderly patients because of the frequent multiple disabling conditions and the related frailty, with reduction in the social contacts. The patient is often unable to follow the prescriptions, with consequent worsening of the symptoms and feelings of inadequacy, frustration, hopelessness, and he is even shame of the incapacity to reach an acceptable level of glycemic control. This can lead to further lowering of the adherence to prescriptions, further impairment of selfconfidence, decrease in the interactions with the healthcare provider and even missing of the therapeutic regimen. On the other hand, the clinician can also feel discouraged by the worsening of diabetic control when the depressive disorder has not been diagnosed, and he may blame the patient for not trying hard enough, thus further impairing the patient self-confidence. Then, clinicians

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should be aware that depressed patients with diabetes may lose the capacity of self-managing and should always consider the possibility of a depressive disorder in diabetic patients showing an impairment of glycemic control. The depressive symptoms can mimic those of the diabetes and, when the depressive disorder has not been correctly identified, they can lead to a worsening of the clinical picture as perceived by the patient without a correlation with both the clinical and laboratory findings [85]. It is, therefore, of crucial importance optimizing the relationship and the collaboration between the patient and the healthcare provider. Several psychotherapeutic regimens (cognitive–behavioral therapy, psychodynamic therapy, relaxing techniques) have been proposed in the treatment of depressive disorders in diabetic patients in addition to or instead of standard therapies. An improvement of both depressive symptoms and glycemic control has been observed [86–93]. Male diabetic patients, moreover, should be carefully evaluated for diabetic-related sexual disorders, such as retrograde ejaculation, libido reduction and erectile dysfunction, because they can seriously impair QoL and could be involved in the onset of a depression status, especially in young adult T2DM patients [94].

Diabetes, depression and cognitive dysfunction Data have been reported about the possible association of both diabetes mellitus (especially T2DM) and depression with cognitive dysfunction, either on vascular or degenerative basis. The risk of dementia is considerably increased in patients affected by T2DM and depression, with an HR of 2.02 in about 19,000 patients (age range 30–75 years, with a follow-up of 3–5 years) of The Diabetes and Aging Study, when compared with patients with diabetes and without depression [95]. Similar results were found in elderly diabetics of the Mexican Health and Aging Study, with a relative risk for dementia of 2.08, with an even higher risk (2.44) in the patients over 80 [96]. NT-proBNP is commonly known as a marker of congestive heart failure, but it has been suggested to be also a risk marker of the psychiatric sphere. Accordingly, a study performed in 1,066 patients affected by T2DM, with an age range of 60–75 years, has shown that those with the higher levels of serum NT-proBNP had higher probability to develop an impaired cognitive condition and/or depression [97].

Diabetes, depression and cardiovascular risk The cardiovascular diseases (CVD) are the most frequent causes of morbidity and mortality in patients with diabetes

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[98], with a twofold increased risk of myocardial infarction in T2DM patients, when compared with subjects nonaffected by diabetes [99, 100]. The depression is also a very common comorbid condition in CVD: in fact, patients affected by MDD or with a previous episode of depression have a twofold increased risk of myocardial infarction [101–103]. A significant association between previous depressive symptoms and coronary artery disease was found in prospective studies performed in subjects with diabetes [91]. When DM and MDD are associated, they independently influence the risk for CVD (myocardial infarction in particular) and the all-cause and CHD-related mortality are both increased [104]. In patients with diabetes and depression [105] there is a doubled probability to have other CV risk factors, such as smoking, obesity, a sedentary lifestyle, and HbA1c [8.0 %, thus having a higher risk to develop microvascular complications (24 %) [106], and a higher mortality rate for all-cause and CVD when compared with those without depression [59]. In a metanalysis by Fleur et al., evaluating data from 16 longitudinal studies, the CV and all-cause mortality risk was, respectively, 1.4 and 1.5 times higher in depressed patients with diabetes than in those non-depressed [107]. A severe depression leads to an increased risk of myocardial infarction and related mortality, especially in patients with diabetes, with a 2 to threefold increased risk of death in the following 3-year period [108]. These data were confirmed by another study [9]. In more than 7,000 women (age range 54–79 years, follow-up 6 years) participating to the Nurses Health Study, the age-adjusted RR for all-cause mortality was 1.76 for patients with depression alone, 1.71 for those with diabetes alone and 3.11 when the two conditions were associated. The RR for CV mortality was 1.81, 2.67 and 5.38, respectively. The CV mortality RR was even worse (4.90) when depression was associated with a long-standing diabetes or to insulin treatment [109]. The TRIAD Study confirmed the poor CV risk control in depressed patients with diabetes [110]. On the basis of all the cited studies, it seems very important to evaluate the possible association between DM and depression, with the aim to identify subgroups of patients with diabetes at higher CV and all-cause mortality risk [111]. Possible explanations for the increased CV risk in patients with the association between DM and depression are the frequent coexistence of dyslipidemia, higher BMI, visceral adiposity, insulin resistance and tobacco consumption [28]. Furthermore, they show the tendency to develop more frequently micro- and macro-vascular complications [28, 104], have a worse glycemic control and show a reduced adherence to diet, physical activity and

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pharmacological prescriptions as compared to patients with diabetes and without depression [29, 80, 81]. It is to take into account that depression is also associated with platelet function abnormalities [112], inflammation, autonomic nervous system dysfunction [113], reduced heart rate variability [114] and increased risk of experiencing malignant ventricular arrhythmias [115], all factors strictly correlated with an increased risk to develop CVD and a worse prognosis.

Medical costs of coexisting diabetes and depression Several studies have reported that the coexistence of diabetes and depression is associated with increased healthcare costs [116–119], and the treatment of depression could reduce the healthcare use and related costs in these patients. The systematic treatment of depression in elderly patients with diabetes showed clear-cut clinical benefits, without an increment in healthcare costs [120] and this finding is of particular relevance since the high frequency of this association [121, 122]. In a longitudinal study by Katon et al., the addition of a treatment for depression led to a decrease in global healthcare costs over the years [120, 123], and this is in line with the finding that treating depression can improve self-care, with a positive impact on both complications and mortality [79, 108, 124]. Walker et al. [66] have recently emphasized the impact of social determinants of health on outcomes for T2DM by an elegant systematic review, and next studies could clarify whether these social determinants may influence the relationship between diabetes and depression and the effects of this association.

Conclusions The prevalence of depression is almost twofold higher in patients with type 2 diabetes, and the association between depression and diabetes represents a challenging problem, because the high direct and indirect healthcare costs and the heavy impact on CV risk and mortality. The association of DM-depression is characterized by a low QoL [125], reduced adherence to prescriptions and self-management [126], and higher prevalence and impact of diabetic complications [28], thus leading to increased healthcare use and costs. Depression has a negative impact on physical activity, especially in the elderly [126], is associated with stable higher levels of HbA1c [24] and can negatively influence the glycemic control through interference with the central nervous system activity [125]. DM can negatively impact depression, and a bad glycemic control can further impair the mood. Elderly depressed patients with

diabetes have the tendency to complain more often of the typical diabetic symptoms (thirst, polyuria, polydipsia, etc.), even in the case of adequate glycemic control [125], and the impact of diabetes on the mood is even heavier when there are disabling conditions. However, only 1 patient out of 4 receives an adequate treatment [122]. Therefore, identifying and treating depressive disorders is very important in patients with diabetes, allowing a better management of DM, higher adherence to prescriptions and suggested behaviors, and a global improvement in the mood and QoL [127]. Further research is required to address open questions such as possible common pathogenetic factors, reciprocal influence between depression and glycemic control, interaction between depression and diabetic complications, and choice of different antidepressant drugs. In conclusion, we still need to better understand how depression and diabetes influence each other and how we can help our patients to better manage this association. Conflict of interest The authors declare that no competing financial interests or any conflict of interest exist.

References 1. American Psychiatric Association, Practice Guideline for Treatment of Patients with Major Depressive Disorder, 2nd edn. (American Psychiatric Association Press, Washington, DC, 2000) 2. A.J. Mitchell, H. Subramaniam, Prognosis of depression in old age compared to middle age: a systematic review of comparative studies. Am. J. Psychiatry 162(9), 1588–1601 (2005) 3. J.M. Hegeman, R.M. Kok, R.C. van der Mast, E.J. Giltay, Phenomenology of depression in older compared with younger adults: meta-analysis. Br. J. Psychiatry 200(4), 275–281 (2012). doi:10.1192/bjp.bp.111.095950 4. A. Fiske, J.L. Wetherell, M. Gatz, Depression in Older Adults. Annu. Rev. Clin. Psychol. 5, 363–389 (2009). doi:10.1146/ annurev.clinpsy.032408.153621 5. G. Schneider, A. Kruse, H.G. Nehen, W. Senf, G. Heuft, The prevalence and differential diagnosis of subclinical depressive syndromes in inpatients 60 years and older. Psychother. Psychosom. 69(5), 251–260 (2000) 6. S.R. Rapp, S.A. Parisi, D.A. Walsh, C.E. Wallace, Detecting depression in elderly medical inpatients. J. Consult. Clin. Psychol. 56(4), 509–513 (1988) 7. E. Linka, G. Bartko´, T. Aga´rdi, K. Keme´ny, Dementia and depression in elderly medical inpatients. Int. Psychogeriatr. 12(1), 67–75 (2000) 8. A. Conde Martel, M. Hemmersbach-Miller, B.J. Anı´a Lafuente, N. Sujanani Afonso, M. Serrano-Fuentes, Prevalence of depressive symptoms in hospitalized elderly medical patients. Rev. Esp. Geriatr. Gerontol. 48(5), 224–227 (2013). doi:10. 1016/j.regg.2012.10.003 9. M. Valenstein, S. Vijan, J.E. Zeber, K. Boehm, A. Buttar, The cost-utility of screening for depression in primary care. Ann. Intern. Med. 134(5), 345–360 (2001) 10. American Psychiatric Association, DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th edn. (American Psychiatric Assoc, Washington, DC, 1994)

123

Endocrine 11. A.T. Beck, C.H. Ward, M. Mendelson, J. Mock, J. Erbaugh, An inventory for measuring depression. Arch. Gen. Psychiatry 4, 561–571 (1961) 12. K. Kroenke, R.L. Spitzer, J.B. Williams, The PHQ-9: validity of a brief depression severity measure. J. Gen. Intern. Med. 16(9), 606–613 (2001) 13. B. Lo¨we, K. Kroenke, W. Herzog, K. Gra¨fe, Measuring depression outcome with a brief self-report instrument: sensitivity to change of the Patient Health Questionnaire (PHQ-9). J. Affect. Disord. 81(1), 61–66 (2004) 14. R.L. Spitzer, K. Kroenke, J.B. Williams, Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA 282(18), 1737–1744 (1999) 15. D.V. Sheehan, Y. Lecrubier, K.H. Sheehan, P. Amorim, J. Janavs, E. Weiller, T. Hergueta, R. Baker, G.C. Dunbar, The MiniInternational Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59(Suppl 20), 22–33, quiz 34–57 (1998) 16. L. Radloff, The CES-D scale: a self-report depression scale for research in the general population. Appl. Psychol. Meas. 1, 385–401 (1977) 17. International Diabetes Federation Diabetes Atlas, 4th edn. (2009). www.diabetesatlas.org 18. P. Marnini, P.M. Bollati, S. Tondini, Esiste un diabete dell’anziano? Il Giornale di AMD 16(S1), 5–10 (2013) 19. D.L. Musselman, E. Betan, H. Larsen, L.S. Phillips, Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment. Biol. Psychiatry 54(3), 317–329 (2003) 20. P.J. Lustman, L.S. Griffith, R.E. Clouse, Depression in adults with diabetes. Semin. Clin. Neuropsychiatry 2(1), 15–23 (1997) 21. F. Pouwer, A.T. Beekman, G. Nijpels, J.M. Dekker, F.J. Snoek, P.J. Kostense, R.J. Heine, D.J. Deeg, Rates and risks for comorbid depression in patients with Type 2 diabetes mellitus: results from a community-based study. Diabetologia 46(7), 892–898 (2003) 22. M.J. Knol, J.W. Twisk, A.T. Beekman, R.J. Heine, F.J. Snoek, F. Pouwer, Depression as a risk factor for the onset of type 2 diabetes mellitus: a meta-analysis. Diabetologia 49(5), 837–845 (2006) 23. A. Campayo, P. de Jonge, J.F. Roy, P. Saz, C. de la Ca´mara, M.A. Quintanilla, G. Marcos, J. Santaba´rbara, A. Lobo, ZARADEMP Project, depressive disorder and incident diabetes mellitus: the effect of characteristics of depression. Am. J. Psychiatry 167(5), 580–588 (2010). doi:10.1176/appi.ajp.2009. 09010038 24. M.M. Williams, R.E. Clouse, P.J. Lustman, Treating depression to prevent diabetes: understanding depression as a medical complication. Clin. Diabetes 24, 79–86 (2006) 25. W.W. Eaton, H. Armenian, J. Gallo, L. Pratt, D.E. Ford, Depression and risk for onset of type II diabetes: a prospective population-based study. Diabetes Care 19(10), 1097–1102 (1996) 26. P.J. Lustman, G.W. Harper, Nonpsychiatric physicians’ identification and treatment of depression in patients with diabetes. Compr. Psychiatry 28(1), 22–27 (1987) 27. M.D. Harris, Psychosocial aspects of diabetes with an emphasis on depression. Curr. Diab. Rep. 3(1), 49–55 (2003) 28. M. de Groot, R. Anderson, K.E. Freedland, R.E. Clouse, P.J. Lustman, Association of depression and diabetes complications: a meta-analysis. Psychosom. Med. 63(4), 619–630 (2001) 29. E.J. Ludman, W. Katon, J. Russo, M. Von Korff, G. Simon, P. Ciechanowski, E. Lin, T. Bush, E. Walker, B. Young, Depression and diabetes symptom burden. Gen. Hosp. Psychiatry 26(6), 430–436 (2004)

123

30. A. Pan, M. Lucas, Q. Sun, R.M. van Dam, O.H. Franco, J.E. Manson, W.C. Willett, A. Ascherio, F.B. Hu, Bidirectional association between depression and type 2 diabetes mellitus in women. Arch. Intern. Med. 170(21), 1884–1891 (2010). doi:10. 1001/archinternmed.2010.356 31. J.M. Hennings, L. Schaaf, S. Fulda, Glucose metabolism and antidepressant medication. Curr. Pharm. Des. 18(36), 5900–5919 (2012) 32. S.H. Golden, M. Lazo, M. Carnethon, A.G. Bertoni, P.J. Schreiner, A.V. Diez Roux, H.B. Lee, C. Lyketsos, Examining a bidirectional association between depressive symptoms and diabetes. JAMA 299(23), 2751–2759 (2008). doi:10.1001/jama. 299.23.2751 33. B. Mezuk, W.W. Eaton, S. Albrecht, S.H. Golden, Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 31(12), 2383–2390 (2008). doi:10.2337/dc08-0985 34. A. Nouwen, G. Nefs, I. Caramlau, M. Connock, K. Winkley, C.E. Lloyd, M. Peyrot, F. Pouwer, European Depression in Diabetes Research Consortium, Prevalence of depression in individuals with impaired glucose metabolism or undiagnosed diabetes: a systematic review and meta-analysis of the European Depression in Diabetes (EDID) Research Consortium. Diabetes Care 34(3), 752–762 (2011). doi:10.2337/dc10-1414 35. V. Fiore, D. Barbaro, P. Di Berardino, Diabete e depressione, 11 Congresso Nazionale AME, Udine 2011, Handout. pp. 247–250 (2011) 36. H.H. Pan, C.Y. Li, P.C. Chen, M.D. Lee, C.Y. Liang, W.H. Hou, K.Y. Wang, Contributions of diabetic macro-vascular complications and hip fracture to depression onset in elderly patients with diabetes: an 8-year population-based follow-up study. J. Psychosom. Res. 73(3), 180–184 (2012). doi:10.1016/j.jpsy chores.2012.06.003 37. Y. Du, C. Heidemann, A. Go¨ßwald, P. Schmich, C. ScheidtNave, Prevalence and comorbidity of diabetes mellitus among non-institutionalized older adults in Germany—results of the national telephone health interview survey ‘German Health Update (GEDA)’ 2009. BMC Public Health 13, 166 (2013). doi:10.1186/1471-2458-13-166 38. Y. Miyaoka, H. Miyaoka, T. Motomiya, S. Kitamura, M. Asai, Impact of socio demographic and diabetes-related characteristics on depressive state among non-insulin-dependent diabetic patients. Psychiatry Clin. Neurosci. 51(4), 203–206 (1997) 39. S.T. Cohen, G. Welch, A.M. Jacobson, M. De Groot, J. Samson, The association of lifetime psychiatric illness and increased retinopathy in patients with type I diabetes mellitus. Psychosomatics 38(2), 98–108 (1997) 40. H. Viinama¨ki, L. Niskanen, M. Uusitupa, Mental well-being in people with non-insulin-dependent diabetes. Acta Psychiatr. Scand. 92(5), 392–397 (1995) 41. E.S. Geringer, L.C. Perlmuter, T.A. Stern, D.M. Nathan, Depression and diabetic neuropathy: a complex relationship. J. Geriatr. Psychiatry Neurol. 1(1), 11–15 (1988) 42. S.A. Black, Increased health burden associated with comorbid depression in older diabetic Mexican Americans: results from the Hispanic Established Population for the Epidemiologic Study of the Elderly survey. Diabetes Care 22(1), 56–64 (1999) 43. C. Maraldi, S. Volpato, B.W. Penninx, K. Yaffe, E.M. Simonsick, E.S. Strotmeyer, M. Cesari, S.B. Kritchevsky, S. Perry, H.N. Ayonayon, M. Pahor, Diabetes mellitus, glycemic control, and incident depressive symptoms among 70- to 79-year-old persons: the health, aging, and body composition study. Arch. Intern. Med. 167(11), 1137–1144 (2007) 44. T. Desmidt, M.E. Hachemi, J.P. Remenieras, P. Lecomte, N. Ferreira-Maldent, F. Patat, V. Camus, Ultrasound Brain Tissue Pulsatility is decreased in middle aged and elderly type 2 diabetic patients with depression. Psychiatry Res. 193(1), 63–64 (2011). doi:10.1016/j.pscychresns.2011.01.002

Endocrine 45. L.S. Goldman, N.H. Nielsen, H.C. Champion, Awareness, diagnosis, and treatment of depression. J. Gen. Intern. Med. 14(9), 569–580 (1999) 46. F. Rotella, E. Mannucci, Depression as a risk factor for diabetes: a meta-analysis of longitudinal studies. J. Clin. Psychiatry 74(1), 31–37 (2013). doi:10.4088/JCP.12r07922 47. K. Ismail, Underavelling the pathogenesiis of the depression. Diabetes link, in Depression and Diabetes, ed. by W. Katon, M. Maj, N. Sartorius (Wiley, Chichester, 2010) 48. F. Talbot, A. Nouwen, A review of the relationship between depression and diabetes in adults. Diabetes Care 23(10), 1556–1562 (2000) 49. O.G. Cameron, Z. Kronfol, J.F. Greden, B.J. Carroll, Hypothalamic-pituitary-adrenocortical activity in patients with diabetes mellitus. Arch. Gen. Psychiatry 41(11), 1090–1095 (1984) 50. J.K. Rustad, D.L. Musselman, C.B. Nemeroff, The relationship of depression and diabetes: pathophysiological and treatment implications. Psychoneuroendocrinology 36(9), 1276–1286 (2011). doi:10.1016/j.psyneuen.2011.03.005 51. S. Champaneri, G.S. Wand, S.S. Malhotra, S.S. Casagrande, S.H. Golden, Biological basis of depression in adults with diabetes. Curr. Diabetes Rep. 10(6), 396–405 (2010). doi:10.1007/ s11892-010-0148-9 52. S.M. Markowitz, J.S. Gonzalez, J.L. Wilkinson, S.A. Safren, A review of treating depression in diabetes: emerging findings. Psychosomatics 52(1), 1–18 (2011). doi:10.1016/j.psym.2010. 11.007 53. M. Khera, Patients with testosterone deficit syndrome and depression. Arch. Esp. Urol. 66(7), 729–736 (2013) 54. F.A. Zarrouf, S. Artz, J. Griffith, C. Sirbu, M. Kommor, Testosterone and depression: systematic review and meta-analysis. J. Psychiatr. Pract. 15(4), 289–305 (2009). doi:10.1097/01.pra. 0000358315.88931.fc 55. U. Aydogan, A. Aydogdu, H. Akbulut, A. Sonmez, S. Yuksel, Y. Basaran, O. Uzun, E. Bolu, K. Saglam, Increased frequency of anxiety, depression, quality of life and sexual life in young hypogonadotropic hypogonadal males and impacts of testosterone replacement therapy on these conditions. Endocr. J. 59(12), 1099–1105 (2012) 56. V.A. Giagulli, V. Triggiani, G. Corona, D. Carbone, B. Licchelli, E. Tafaro, F. Resta, C. Sabba`, M. Maggi, E. Guastamacchia, Evidence-based medicine update on testosterone replacement therapy (TRT) in male hypogonadism: focus on new formulations. Curr. Pharm. Des. 17(15), 1500–1511 (2011) 57. G. Hackett, N. Cole, M. Bhartia, D. Kennedy, J. Raju, P. Wilkinson, BLAST Study Group. Testosterone replacement therapy improves metabolic parameters in Hypogonadal Men with Type 2 Diabetes but not in men with coexisting depression: the BLAST Study. J. Sex. Med. 11(3), 840–856 (2014). doi:10. 1111/jsm.12404 58. M.D. Sullivan, P. O’Connor, P. Feeney, D. Hire, D.L. Simmons, D.W. Raisch, L.J. Fine, K.M. Narayan, M.K. Ali, W.J. Katon, Depression Predicts All-Cause Mortality: epidemiological evaluation from the ACCORD HRQL substudy. Diabetes Care 35(8), 1708–1715 (2012). doi:10.2337/dc11-1791 59. E.H. Lin, S.R. Heckbert, C.M. Rutter, W.J. Katon, P. Ciechanowski, E.J. Ludman, M. Oliver, B.A. Young, D.K. McCulloch, M. Von Korff, Depression and increased mortality in diabetes: unexpected causes of death. Ann. Fam. Med. 7(5), 414–421 (2009). doi:10.1370/afm.998 60. A.M. Jacobson, Depression and diabetes. Diabetes Care 16(12), 1621–1623 (1993) 61. L.R. Wulsin, A.M. Jacobson, L.I. Rand, Psychosocial adjustment to advanced proliferative diabetic neuropathy. Diabetes Care 16(8), 1061–1066 (1993)

62. L.R. Wulsin, A.M. Jacobson, L.I. Rand, Psychological aspects of diabetic retinopathy. Diabetes Care 10(3), 367–373 (1987) 63. C.E. Lloyd, G. Pambianco, T.J. Orchard, Does diabetes-related distress explain the presence of depressive symptoms and selfcare in individuals with type 1 diabetes? Diabet. Med. 27(2), 234–237 (2010). doi:10.1111/j.1464-5491.2009.02896.x 64. M. Trento, M. Raballo, M. Trevisan, J. Sicuro, P. Passera, L. Cirio, L. Charrier, F. Cavallo, M. Porta, A cross-sectional survey of depression, anxiety, and cognitive function in patients with type 2 diabetes. Acta Diabetol. 49(3), 199–203 (2012). doi:10. 1007/s00592-011-0275-z 65. W. Katon, M. von Korff, P. Ciechanowski, J. Russo, E. Lin, G. Simon, E. Ludman, E. Walker, T. Bush, B. Young, Behavioral and clinical factors associated with depression among individuals with diabetes. Diabetes Care 27(4), 914–920 (2004) 66. R.J. Walker, B.L. Smalls, J.A. Campbell, J.L. Williams, L.E. Egede. Impact of social determinants of health on outcomes for type 2 diabetes: a systematic review. Endocrine (2014) [Epub ahead of print] 67. M. Kivima¨ki, M. Hamer, G.D. Batty, J.R. Geddes, A.G. Tabak, J. Pentti, M. Virtanen, J. Vahtera, Antidepressant medication use, weight gain, and risk of type 2 diabetes: a population-based study. Diabetes Care 33(12), 2611–2616 (2010). doi:10.2337/ dc10-1187 68. M.J. Knol, M.I. Geerlings, A.C. Egberts, K.J. Gorter, D.E. Grobbee, E.R. Heerdink, No increased incidence of diabetes in antidepressant users. Int. Clin. Psychopharmacol. 22(6), 382–386 (2007) 69. P.S. Ciechanowski, W.J. Katon, J.E. Russo, I.B. Hirsch, The relationship of depressive symptoms to symptom reporting, selfcare and glucose control in diabetes. Gen. Hosp. Psychiatry 25(4), 246–252 (2003) 70. A.F. Jorm, Does old age reduce the risk of anxiety and depression? A review of epidemiological studies across the adult life span. Psychol. Med. 30(1), 11–22 (2000) 71. B. Wild, W. Herzog, D. Schellberg, S. Lechner, D. Niehoff, H. Brenner, D. Rothenbacher, C. Stegmaier, E. Raum, Association between the prevalence of depression and age in a large representative German sample of people aged 53 to 80 years. Int. J. Geriatr. Psychiatry 27(4), 375–381 (2012). doi:10.1002/gps. 2728 72. I. Maatouk, B. Wild, D. Wesche, W. Herzog, E. Raum, H. Mu¨ller, D. Rothenbacher, C. Stegmaier, D. Schellberg, H. Brenner, Temporal predictors of health-related quality of life in elderly people with diabetes: results of a German cohort study. PLoS ONE 7(1), e31088 (2012). doi:10.1371/journal.pone. 0031088 73. E. Selvin, J. Coresh, F.L. Brancati, The burden and treatment of diabetes in elderly individuals in the U.S. Diabetes Care 29(11), 2415–2419 (2006) 74. D.C. Suh, C.M. Kim, I.S. Choi, C.A. Plauschinat, Comorbid conditions and glycemic control in elderly patients with type 2 diabetes mellitus, 1988 to 1994 to 1999 to 2004. J. Am. Geriatr. Soc. 56(3), 484–492 (2008). doi:10.1111/j.1532-5415.2007. 01563.x 75. C.T. Cigolle, P.G. Lee, K.M. Langa, Y.Y. Lee, Z. Tian, C.S. Blaum, Geriatric conditions develop in middle-aged adults with diabetes. J. Gen. Intern. Med. 26(3), 272–279 (2011). doi:10. 1007/s11606-010-1510-y 76. T.A. Reistetter, J.E. Graham, A. Deutsch, S.J. Markello, C.V. Granger, K.J. Ottenbacher, Diabetes comorbidity and age influence rehabilitation outcomes after hip fracture. Diabetes Care 34(6), 1375–1377 (2011). doi:10.2337/dc10-2220 77. D.J. Wexler, B. Porneala, Y. Chang, E.S. Huang, J.C. Huffman, R.W. Grant, Diabetes differentially affects depression and self-

123

Endocrine

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

rated health by age in the U.S. Diabetes Care 35(7), 1575–1577 (2012). doi:10.2337/dc11-2266 N. Laiteerapong, A.J. Karter, J.Y. Liu, H.H. Moffet, R. Sudore, D. Schillinger, P.M. John, E.S. Huang, Correlates of quality of life in older adults with diabetes. The diabetes & aging study. Diabetes Care 34(8), 1749–1753 (2011). doi:10.2337/dc10-2424 E.H. Lin, W. Katon, M. Von Korff, C. Rutter, G.E. Simon, M. Oliver, P. Ciechanowski, E.J. Ludman, T. Bush, B. Young, Relationship of depression and diabetes self-care, medication adherence, and preventive care. Diabetes Care 27(9), 2154–2160 (2004) I. Lerman, L. Lozano, A.R. Villa, S. Herna´ndez-Jime´nez, K. Weinger, A.E. Caballero, C.A. Salinas, M.L. Velasco, F.J. Go´mez-Pe´rez, J.A. Rull, Psychosocial factors associated with poor diabetes self-care management in a specialized center in Mexico City. Biomed. Pharmacother. 58(10), 566–570 (2004) H. Park, Y. Hong, H. Lee, E. Ha, Y. Sung, Individuals with type 2 diabetes and depressive symptoms exhibited lower adherence with self-care. J. Clin. Epidemiol. 57(9), 978–984 (2004) R. Alam, J. Sturt, R. Lall, K. Winkley, An updated meta-analysis to assess the effectiveness of psychological interventions delivered by psychological specialist and generalist clinicians on glycaemic control and on psychological status. Patient Educ. Couns. 75(1), 25–36 (2009). doi:10.1016/j.pec.2008.08.026 K. Ismail, K. Winkley, S. Rabe-Hesketh, Systematic review and meta-analysis of randomised controlled trials of psychological interventions to improve glycaemic control in patients with type 2 diabetes. Lancet 363(9421), 1589–1597 (2004) J. Cochran, V.S. Conn, Meta-analysis of quality of life outcomes following diabetes self- management training. Diabetes Educ. 34(5), 815–823 (2008). doi:10.1177/0145721708323640 R. Helleman, P. Ciechanowski, Diabetes and depression: management in ordinary clinical conditions, in Depression and Diabetes, ed. by W. Katon, M. Maj, N. Sartorius (Wiley, Chichester, 2010) P.J. Lustman, L.S. Griffith, K.E. Freedland, S.S. Kissel, R.E. Clouse, Cognitive behavior therapy for depression in type 2 diabetes mellitus. A randomized, controlled trial. Ann. Intern. Med. 129(8), 613–621 (1998) M.Y. Wang, P.S. Tsai, K.R. Chou, C.M. Chen, A systematic review of the efficacy of non-pharmacological treatments for depression on glycaemic control in type 2 diabetics. J. Clin. Nurs. 17(19), 2524–2530 (2008). doi:10.1111/j.1365-2702.2008. 02301.x E.H. Lin, W. Katon, C. Rutter, G.E. Simon, E.J. Ludman, M. Von Korff, B. Young, M. Oliver, P.C. Ciechanowski, L. Kinder, E. Walker, Effects of enhanced depression treatment on diabetes self-care. Ann. Fam. Med. 4(1), 46–53 (2006) G.E. Simon, W.J. Katon, E.H. Lin, C. Rutter, W.G. Manning, M. Von Korff, P. Ciechanowski, E.J. Ludman, B.A. Young, Costeffectiveness of systematic depression treatment among people with diabetes mellitus. Arch. Gen. Psychiatry 64(1), 65–72 (2007) S.F. Wu, S.Y. Liang, T.J. Wang, M.H. Chen, Y.M. Jian, K.C. Cheng, A self-management intervention to improve quality of life and psychosocial impact for people with type 2 diabetes. J. Clin. Nurs. 20(17–18), 2655–2665 (2011). doi:10.1111/j. 1365-2702.2010.03694.x C.M. van der Feltz-Cornelis, J. Nuyen, C. Stoop, J. Chan, A.M. Jacobson, W. Katon, F. Snoek, N. Sartorius, Effect of interventions for major depressive disorder and significant depressive symptoms in patients with diabetes mellitus: a systematic review and meta-analysis. Gen. Hosp. Psychiatry 32(4), 380–395 (2010). doi:10.1016/j.genhosppsych.2010.03.011 W.J. Katon, The comorbidity of diabetes mellitus and depression. Am. J. Med. 121(11 Suppl 2), S8–S15 (2008). doi:10.1016/ j.amjmed.2008.09.008

123

93. C.J. Chiu, L.A. Wray, E.A. Beverly, O.G. Dominic, The role of health behaviors in mediating the relationship between depressive symptoms and glycemic control in type 2 diabetes: a structural equation modeling approach. Soc. Psychiatry Psychiatr. Epidemiol. 45(1), 67–76 (2010). doi:10.1007/s00127009-0043-3 94. G. Corona, D.M. Lee, G. Forti, D.B. O’Connor, M. Maggi, T.W. O’Neill, N. Pendleton, G. Bartfai, S. Boonen, F.F. Casanueva, J.D. Finn, A. Giwercman, T.S. Han, I.T. Huhtaniemi, K. Kula, M.E. Lean, M. Punab, A.J. Silman, D. Vanderschueren, F.C. Wu, EMAS Study Group, Age-related changes in general and sexual health in middle-aged and older men: results from the European Male Ageing Study (EMAS). J. Sex. Med. 7(4 Pt 1), 1362–1380 (2010). doi:10.1111/j.1743-6109.2009.01601.x 95. W. Katon, C.R. Lyles, M.M. Parker, A.J. Karter, E.S. Huang, R.A. Whitmer, Association of depression with increased risk of dementia in patients with type 2 diabetes: the Diabetes and Aging Study. Arch. Gen. Psychiatry 69(4), 410–417 (2012). doi:10.1001/archgenpsychiatry.2011.154 96. S. Mejı´a-Arango, C. Zu´n˜iga-Gil, Diabetes mellitus as a risk factor for dementia in the Mexican elder population. Rev. Neurol. 53(7), 397–405 (2011) 97. I. Feinkohl, N. Sattar, P. Welsh, R.M. Reynolds, I.J. Deary, M.W. Strachan, J.F. Price, Edinburgh Type 2 Diabetes StudyET2DS Investigators, Association of N-terminal pro-brain natriuretic peptide with cognitive function and depression in elderly people with type 2 diabetes. PLoS ONE 7(9), e44569 (2012) 98. S.M. Marshall, A. Flyvbjerg, Prevention and early detection of vascular complications of diabetes. BMJ 333(7566), 475–480 (2006) 99. M. Laakso, Cardiovascular disease in type 2 diabetes from population to man to mechanisms: the Kelly West Award Lecture 2008. Diabetes Care 33(2), 442–449 (2010). doi:10.2337/ dc09-0749 100. T.K. Schramm, G.H. Gislason, L. Køber, S. Rasmussen, J.N. Rasmussen, S.Z. Abildstrøm, M.L. Hansen, F. Folke, P. Buch, M. Madsen, A. Vaag, C. Torp-Pedersen, Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation 117(15), 1945–1954 (2008). doi:10.1161/CIRCULATIONAHA.107. 720847 101. J.H. Thakore, Physical Consequences of Depression (Wrighton Biomedical Publishing LTD, Petersfield, 2001) 102. J.C. Barefoot, M. Schroll, Symptoms of depression, acute myocardial infarction, and total mortality in a community sample. Circulation 93(11), 1976–1980 (1996) 103. D.E. Ford, L.A. Mead, P.P. Chang, L. Cooper-Patrick, N.Y. Wang, M.J. Klag, Depression is a risk factor for coronary artery disease in men: the precursors study. Arch. Intern. Med. 158(13), 1422–1426 (1998) 104. L.E. Egede, P.J. Nietert, D. Zheng, Depression and all-cause and coronary heart disease mortality among adults with and without diabetes. Diabetes Care 28(6), 1339–1345 (2005) 105. W.J. Katon, E.H. Lin, J. Russo, M. Von Korff, P. Ciechanowski, G. Simon, E. Ludman, T. Bush, B. Young, Cardiac risk factors in patients with diabetes mellitus and major depression. J. Gen. Intern. Med. 19(12), 1192–1199 (2004) 106. E.H. Lin, C.M. Rutter, W. Katon, S.R. Heckbert, P. Ciechanowski, M.M. Oliver, E.J. Ludman, B.A. Young, L.H. Williams, D.K. McCulloch, M. Von Korff, Depression and advanced complications of diabetes: a prospective cohort study. Diabetes Care 33(2), 264–269 (2010). doi:10.2337/dc09-1068 107. E.H. Lin, S.R. Heckbert, C.M. Rutter, W.J. Katon, P. Ciechanowski, E.J. Ludman, M. Oliver, B.A. Young, D.K. McCulloch,

Endocrine

108.

109.

110.

111.

112.

113.

114.

115.

116.

M. Von Korff, Depression and increased mortality in diabetes: unexpected causes of death. Ann. Fam. Med. 7(5), 414–421 (2009). doi:10.1370/afm.998 W.J. Katon, C. Rutter, G. Simon, E.H. Lin, E. Ludman, P. Ciechanowski, L. Kinder, B. Young, M. Von Korff, The association of comorbid depression with mortality in patients with type 2 diabetes. Diabetes Care 28(11), 2668–2672 (2005) A. Pan, M. Lucas, Q. Sun, R.M. van Dam, O.H. Franco, W.C. Willett, J.E. Manson, K.M. Rexrode, A. Ascherio, F.B. Hu, Increased mortality risk in women with depression and diabetes mellitus. Arch. Gen. Psychiatry 68(1), 42–50 (2011). doi:10. 1001/archgenpsychiatry.2010.176 L.B. Kimbro, W.N. Steers, C.M. Mangione, O.K. Duru, S.L. Ettner, The Association of Depression and the Cardiovascular Risk Factors of Blood Pressure, HbA1c, and Body Mass Index among Patients with Diabetes: results from the Translating Research into Action for Diabetes Study. Int. J. Endocrinol. 2012, 747460 (2012). doi:10.1155/2012/747460 C. de Burgos-Lunar, P. Go´mez-Campelo, J. Ca´rdenas-Valladolid, C.Y. Fuentes-Rodrı´guez, M.I. Granados-Mene´ndez, F. Lo´pez-Lo´pez, M.A. Salinero-Fort, MADIABETES Group, effect of depression on mortality and cardiovascular morbidity in type 2 diabetes mellitus after 3 years follow up. The DIADEMA study protocol. BMC Psychiatry 12, 95 (2012). doi:10. 1186/1471-244X-12-95 D.L. Musselman, A. Tomer, A.K. Manatunga, B.T. Knight, M.R. Porter, S. Kasey, U. Marzec, L.A. Harker, C.B. Nemeroff, Exaggerated platelet reactivity in major depression. Am. J. Psychiatry 153, 1313–1317 (1996) R.C. Veith, L. Lewis, O.A. Linares, R.F. Barnes, M.A. Raskin, E.C. Villacres, M.M. Murburg, E.A. Ashleigh, S. Castillo, E.R. Peskind, M. Pascualy, J.B. Halter, Sympathetic nervous system activity in major depression: basal and desipramine-induced alterations in plasma norepinephrine kinetics. Arch. Gen. Psychiatry 51(5), 411–422 (1994) M.V. Pitzalis, M. Iacoviello, O. Todarello, A. Fioretti, P. Guida, F. Massari, F. Mastropasqua, G.D. Russo, P. Rizzon, Depression but not anxiety influences the autonomic control of heart rate after myocardial infarction. Am. Heart J. 141(5), 765–771 (2001) W. Whang, C.M. Albert Jr, S.F. Sears, R. Lampert, J.B. Conti, P.J. Wang, J.P. Singh, J.N. Ruskin, J.E. Muller, M.A. Mittleman, TOVA Study Investigators, depression as a predictor for appropriate shocks among patients with implantable cardioverter-defibrillators: results from the Triggers of Ventricular Arrhythmias (TOVA) study. J. Am. Coll. Cardiol. 45(7), 1090–1095 (2005) E.A. Finkelstein, J.W. Bray, H. Chen, M.J. Larson, K. Miller, C. Tompkins, A. Keme, R. Manderscheid, Prevalence and costs of major depression among elderly claimants with diabetes. Diabetes Care 26(2), 415–420 (2003)

117. S. Himelhoch, W.E. Weller, A.W. Wu, G.F. Anderson, L.A. Cooper, Chronic medical illness, depression, and use of acute medical services among medicare beneficiaries. Med. Care 42(6), 512–521 (2004) 118. L.E. Egede, D. Zheng, K. Simpson, Comorbid depression is associated with in- creased health care use and expenditures in individual with diabetes. Diabetes Care 25(3), 464–470 (2002) 119. G.E. Simon, W.J. Katon, E.H. Lin, E. Ludman, M. VonKorff, P. Ciechanowski, B.A. Young, Diabetes complications and depression as predictors of health service costs. Gen. Hosp. Psychiatry 27(5), 344–351 (2005) 120. W. Katon, J. Unu¨tzer, M.Y. Fan Jr, J.W. Williams, M. Schoenbaum, E.H. Lin, E.M. Hunkeler, Cost-effectiveness and net benefit of enhanced treatment of depression for older adults with diabetes and depression. Diabetes Care 29(2), 265–270 (2006) 121. A.H. Mokdad, B.A. Bowman, E.S. Ford, F. Vinicor, J.S. Marks, J.P. Koplan, The continuing epidemic of obesity and diabetes in the United States. JAMA 286(10), 1195–1200 (2001) 122. R.J. Anderson, K.E. Freedland, R.E. Clouse, P.J. Lustman, The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 24(6), 1069–1078 (2001) 123. G.E. Simon, W.J. Katon, E.H. Lin, C. Rutter, W.G. Manning, M. Von Korff, P. Ciechanowski, E.J. Ludman, B.A. Young, Costeffectiveness of systematic depression treatment among people with diabetes mellitus. Arch. Gen. Psychiatry 64(1), 65–72 (2007) 124. S.A. Black, K.S. Markides, L.A. Ray, Depression predicts increased incidence of ad- verse health outcomes in older Mexican Americans with type 2 diabetes. Diabetes Care 26, 2822–2828 (2003) 125. P.J. Lustman, R.E. Clouse, Depression in diabetic patients: the relationship between mood and glycemic control. J. Diabetes Complicat. 19(2), 113–122 (2005) 126. J.S. Gonzalez, S.A. Safren, E. Cagliero, D.J. Wexler, L. Delahanty, E. Wittenberg, M.A. Blais, J.B. Meigs, R.W. Grant, Depression, self-care, and medication adherence in type 2 diabetes: relationships across the full range of symptom severity. Diabetes Care 30(9), 2222–2227 (2007) 127. M. Bot, F. Pouwer, M. Zuidersma, J.P. van Melle, P. de Jonge, Association of coexisting diabetes and depression with mortality after myocardial infarction. Diabetes Care 35(3), 503–509 (2012). doi:10.2337/dc11-1749 128. H.J. Derijks, R.H. Meyboom, E.R. Heerdink, F.H. De Koning, R. Janknegt, M. Lindquist, A.C. Egberts, The association between antidepressant use and disturbances in glucose homeostasis: evidence from spontaneous reports. Eur. J. Clin. Pharmacol. 64(5), 531–538 (2008). doi:10.1007/s00228-0070441-y

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