ABSTRACT

In people with diabetes the comorbidity with depression is associated with micro- and macrovascular complications and increased mortality. Health-related quality of life is often reduced, and the adherence to treatment is generally low. Screening and diagnostic tools for depression are widely available. However, their use is only effective if subsequent treatment pathways are provided, which is often not the case. Meta-analyses on the treatment of depression in diabetes indicate that depression can be effectively treated with a variety of psychological and/or psychopharmacological interventions. However, results from the most frequently studied psychological treatment, cognitive behavioral therapy (CBT), have revealed decreasing effects ranging from large to low-grade, the longer the studies’ follow-up lasts. This may indicate CBT’s reduced long-term efficacy in diabetes patients with depression compared to depressive people without diabetes. As few data are available on the long-term effects of drug treatments, the studies’ conclusiveness is limited. Regarding the amelioration of glycemic control, the treatment results are heterogeneous, indicating a slight improvement by selective serotonin reuptake inhibitors and contradictory evidence for psychological interventions. This chapter concludes with a practice-oriented model of stepped care for depression treatment in people with diabetes. For complete coverage of this and all related areas of Endocrinology, please visit our FREE on-line web-textbook, www.endotext.org.

INTRODUCTION

Diabetes mellitus can be considered a paradigm of a 21st century chronic disease where prognosis and progression are significantly dependent on the patients’ lifestyle and self- management behaviors. Treatment requires lifelong planning and controlling both one’s food intake and making multiple changes to other lifestyles such as physical activity. The patient bears a high degree of personal responsibility, and many patients have trouble implementing treatment recommendations successfully. Comorbid mental disorders, which often hinder the smooth integration of diabetes into everyday life, constitute a major barrier to successful diabetes self-management.

As one of the most common mental disorders, depression occurs frequently in patients with diabetes and has a bi-directional relationship: diabetes raises the risk of depression, and depressed individuals also have an increased risk of developing type 2 diabetes. Since the co-morbidity of diabetes and depression has been understood for many years as a "hen-egg problem", recent findings imply parallel development of biological mechanisms thought to be responsible for both the development of depressive disorders and type 2 diabetes. Among other factors, it is assumed that the hypothalamic pituitary adrenal axis is dysregulated and that the immune system is overactivated over the life span, factors promoting insulin resistance, endothelial dysfunction, and cardiovascular disease, all of which raise the risk of depression, type 2 diabetes, and premature mortality. A direct depression-promoting effect of inflammatory processes on the brain is also assumed. Apart from these biological factors, numerous findings indicate that the psychosocial stress caused by diabetes and its complications also contribute to increased depression rates.

The comorbidity of depression and diabetes impacts medical outcome of people suffering from both conditions. More specifically, symptoms of depression are associated with hyperglycemia, micro- and macrovascular complications, and significantly increased mortality in people with diabetes. Patients often suffer from lower general and diabetes-specific quality of life, making how they manage their diabetes and adhere to therapy recommendations much more difficult.

The detection rate for depression in patients with diabetes is low and this inevitably goes hand-in-hand with inadequate therapy. Several screening and diagnostic tools have been developed that enable the rapid and reliable diagnosis of depression and are not costly to implement. But, if depression screening and subsequent diagnosis fail to lead to adequate care through an established treatment pathway, the potential adverse effects of not providing an evidence based intervention may outweigh the benefit of screening for depression.

The treatment of comorbid depression in diabetes differs mainly in its objectives from those of depression not accompanied by chronic physical illness. In view of the complex psychological and somatic interactions, depression treatment targets not only mental symptoms and problems, it also includes diabetes-related medical goals that focus particularly on improving the patient’s adherence to treatment and glycemic control to help prevent diabetes-related complications. The models of care for depression in diabetes include various approaches ranging from psychopharmacological treatment to psychological interventions. These are complemented by algorithm-based interventions delivered by different professional groups (e.g., collaborative care or stepped-care approaches). These are now being supplemented by telemedical or web-based interventions. Current scientific evidence demonstrated good treatment results regarding depression outcome in diabetes patients with comorbid depression. This applies to a variety of psychopharmacological or psychological interventions or a combination of both. Results are much less consistent regarding the physical targets of diabetes therapy, as contradictory findings reveal that we still do not know which is the most effective therapeutic approach in this field.

Based on existing guidelines and updated by current research, we suggest a practice oriented model of stepped care for patients with diabetes and depression that could be adapted to the individual patient’s care requirements.

This ENDOTEXT chapter aims to summarize the current state of research on the co-morbidity of diabetes and depression in adult patients with type 1 and type 2 diabetes.

Since a great deal of published research does not differentiate between the different types of diabetes, both types are addressed in this chapter as well. However, where differentiated information is possible, it is specified in the text. The concept that diabetes distress overlaps with depression but should be distinguished from depression as a mental disorder (1, 2) is not the subject of this chapter.

DEPRESSION

As depression is one of the mental disorders often overlooked by non-psychiatric physicians, it is frequently treated inadequately (3). This is also the case for patients with diabetes and comorbid depression; their diagnostic rate for depression ranges from 45% (4) to 50% (5). The dangerous interactions with diabetes and the frequent disregard of depression highlight the importance of informing healthcare professionals about the diagnostic criteria of depressive disorders.

According to the ICD-10 classification of the World Health Organization, depressive symptoms can be assigned to different categories of mental disorders (6). One essential distinguishing feature concerns the course of the depression. For the most part, a distinction is made between depressive episodes of varying degrees of severity that occur for the first time, and recurrent or persistent disorders. In addition, depressive symptoms are treated in the context of adaptation disorders, other diseases and various diagnostic "residual categories". The present chapter deals only with unipolar depression and not with bipolar affective disorders, cyclothymia, or manic episodes.

The main focus of the ICD-10 classification is on the depressive episode, which distinguishes at least two weeks of major symptoms from additional symptoms.

Main symptoms

• depressed mood,
• loss of interest and enjoyment
• reduced energy leading to increased fatigability and diminished activity

Other common symptoms

• reduced concentration and attention
• reduced self-esteem and self-confidence
• feeling guilty and worthless
• bleak and pessimistic views of the future;
• ideas or acts of self-harm or suicide;
• disturbed sleep;
• diminished appetite.

The severity of the depressive episode is specified by counting the number of current depression symptoms:

• mild (4-5 symptoms): 2 main and to 2-3 additional symptoms
• moderate (6-7 symptoms): 2 main and 3-5 additional symptoms
• severe (at least 8 symptoms): 3 main and at least 4 additional symptoms

In addition, a mild or moderate depressive episode can be described as coinciding with "somatic syndrome" or not. This applies if at least four characteristics of the somatic syndrome are fulfilled (in case of severe depressive episodes, the somatic syndrome is generally assumed due to the variety of symptoms).

Characteristics of Somatic Syndrome

• loss of interest or pleasure in normally enjoyable activities
• inability to react emotionally to a friendly environment or joyful events
• early morning awakening (two or more hours before the usual time)
• morning low
• psychomotor inhibition or agitation
• significant loss of appetite
• weight loss, often more than 5% of body weight in the past month;
• significant loss of libido

Furthermore, regarding a severe depressive episode: a distinction between patients "with" and "without" psychotic symptoms can be made. If the patient presents any psychotic symptoms (e g, impoverishment or delusional delusions), hallucinations, or depressive stupor, the patient is additionally referred to as "with psychotic symptoms".

The most important diagnostic categories of ICD 10 in which symptoms of unipolar depression occur are the

• Depressive episode during which the above-mentioned symptoms occur for the first time for at least two weeks;
• Recurrent depressive disorder diagnosed if a depressive episode has already occurred in the patient’s past;
• Dysthymia, a persistent affective disorder in which symptoms of depression persist for at least two years but do not or rarely fulfill the criteria of a depressive episode; and
• Adjustment disorders in which depressive symptoms may occur as part of a disturbed adaptation process following a stressful life event, but at no time are all the criteria of a complete depressive episode fulfilled. A distinction is made between the short depressive reaction (duration shorter than one month), the longer depressive reaction (lasting up to two years) or the adjustment disorder with mixed anxiety and depressed mood.

For a comprehensive description of the criteria for each category of specific disorders, see ICD-10 Clinical descriptions and diagnostic guidelines (6). More detailed criteria are defined in the ICD 10 Diagnostic criteria for research (7).

EPIDEMIOLOGY OF DEPRESSION IN DIABETES

DEPRESSION DIAGNOSIS AND SCREENING IN DIABETES

At most, half of depressed patients with diabetes in primary care are acknowledged to be depressed and insufficiently treated (40). Such inadequate diagnostic rates of depressive disorders are not specific to people with diabetes - they are a major problem in medical care (41, 42).

However, if patients with diabetes suffer from comorbid depression, diagnosing a depressive disorder can be made even harder because of the two conditions’ overlapping symptoms. Non-depressed individuals with diabetes, especially those with poor glycemic control, may suffer from fatigue, appetite change, or libido reduction (43) - typical symptoms of depression. Yet other symptoms of depression do not overlap with the physical symptoms of diabetes, and their detection by clinicians can facilitate the correct diagnosis of depression. This applies to the cognitive and affective symptoms of depression (e.g., depressive mood, anxiety, diminished self-esteem, feelings of guilt, pessimism, anhedonia, suicidal thoughts) (44). Another difficulty in diagnosing depression in patients with diabetes is that those affected are often unaware they are suffering from depression. They are often more apt to complain about diffuse physical maladies during medical consultation, while psychological symptoms are frequently concealed or trivialized (45).

Clinical interviews such as the Structured Clinical Interview for DSM-IV-TR Axis I Disorders SCID interview (46) SKID or the Schedule for Clinical Assessment in Neuropsychiatry 2.1 (47), are considered the gold standard for diagnosing mental disorders like depression. Being time-consuming and requiring appropriate training, they are mainly used in research. In some cases, questionnaires alone are used to screen and diagnose depression concurrently. However, as this method is associated with exaggerated rates of depression (48, 49), it is not an advisable diagnostic option.

Given the time constraints of medical consultation in primary care, offering screening questionnaires as the first step can be a time-saving alternative. Only a positive screening result would then be followed by a clinical diagnostic procedure to confirm the diagnosis and consider differential diagnoses. For the subsequent diagnosis of a depressive episode after positive screening, it can be useful to go through the individual items on the Patient Health Questionnaire PHQ-9 (50) together with the patient in conversation to check whether the criteria for a depressive disorder are fulfilled. To diagnose more complex forms of depression, it is advisable to refer the patient to a specialist such as a psychiatrist or clinical psychologist.

A confirmed diagnosis of depression must always be followed by a clear treatment pathway and continuous monitoring of therapy results (51).

THE LINK BETWEEN DEPRESSION AND DIABETES IN TYPE 1 DIABETES

The link between depression and diabetes in type 2 diabetes

PREVENTION OF DEPRESSION IN PEOPLE WITH DIABETES

Given the increased risk of depression in people with diabetes, it seems necessary to offer interventions to prevent depression for this high-risk group of patients. In fact, as results from a meta-analysis demonstrated, there are effective approaches to prevent depression in people without diabetes (141). However, there is presently no scientific evidence on such interventions in people with diabetes (142).

Two recent trials focused on the secondary prevention of major depression for patients with diabetes already affected by minor depression, a group with a substantially higher risk for exacerbated depression. In the first trial, a stepped-care program for subthreshold depression was compared with usual care in patients with type 2 diabetes and/or coronary heart disease. Their results indicated that this intervention was no more effective than usual care in preventing major depression (143). In contrast, results from a multicentric, randomized, controlled trial including elderly patients with type 2 diabetes and minor depression demonstrated that after 15 months, cognitive behavioral therapy (CBT) was more effective than treatment as usual to prevent the progression or conversion to major depression (144).

TREATMENT OF DEPRESSION IN DIABETES

RECOMMENDATIONS FOR CLINICAL PRACTICE

The implementation of medical standards is constrained by limited resources in many parts of the developing world, leading to different levels of medical care worldwide. The International Diabetes Federation (IDF) classifies levels of care as ranging from ‘limited care’ (with insufficient medical resources and too little qualified medical staff), to ‘recommended care’ (evidence-based cost-effective care), and finally, ‘comprehensive care’ (most up-to-date, all necessary health technologies available) (75). Until now, only one evidence-based guideline specifically addressing the treatment for depression in people with diabetes has been published in Germany within a healthcare system at the IDF level of ‘recommended’ or ‘comprehensive care’ (145, 162). Other guidelines from the UK National Institute for Health and Care Excellence (NICE) address the treatment of depression in people with chronic physical disorders, including patients with diabetes (163).

There is still insufficient scientific evidence to make concrete recommendations regarding the treatment of depression in diabetes patients with specific characteristics such as the type of diabetes, quality of glycemic control, diabetes complications, etc. Nevertheless, such characteristics must be considered when treating individual patients. Diabetes therapy as such does not differ from the treatment of non-depressive patients with comorbid depression, and should follow national and international guidelines, e.g., (164-166).

A Practice-Oriented Stepped-Care Model for the Treatment of Depression in Patients with Diabetes

In the following, we present a stepped-care model of the treatment of depression in patients with diabetes developed based on current scientific evidence and guidelines from the German Diabetes Society (51, 145); it can be adapted to specific levels of care (see figure 1). The treatment steps are determined by the severity and duration of depressive symptoms and are summarized in four stages. During therapy, it is recommended to regularly monitor response and suicidal ideation through all phases and, depending on the severity and development of depression, the intervention step should be changed. This stepped-care approach should enable flexible and individually-adjustable treatment with the overall goal of complete remission of depression.

Figure 1Model of stepped care for the treatment of depression in diabetes

adapted from (51, 145, 162)

1) Mild depression (or impairing subthreshold depressive symptoms):

A depression of this severity can usually be treated within the framework of primary care, provided there are no acute crises or suicidal thoughts. The consultation style should be flexible and supportive, and oriented towards problem-solving. It is important to inform patients about their depression and the potential links between depression and diabetes. If possible, individual explanations should be worked out with the patient from which starting points for different interventions can be derived. These could be, for example, identifying dysfunctional thoughts, interpersonal problems, or insufficient adherence to diabetes therapy. Self-help materials or web-based self-help tools for depression can be a useful to overcome the depression at this stage.

If there is a history of severe recurrent depression, SSRI medication or psychotherapy should be considered already at this stage of treatment. The course of the depressive symptoms should be carefully monitored over a 2- to 4-week period. If there is no improvement by then, the next step must be initiated, which is also the starting point for moderate depression.

2) Moderate depression (or persistent mild depression not responding to step 1):

Depression of moderate severity requires specific treatment, and the patient should be informed of the various treatment options so that informed decision-making is facilitated.

Cognitive behavioral therapy is considered the first-choice psychotherapeutic treatment, whereas SSRIs should be given priority in psychopharmacological treatment. The combination of medication and psychotherapy is particularly recommended for recurrent depressive disorders. Psychopharmacological treatment requires continued monitoring so that a change in dosage or medication can be considered after 2-4 weeks of treatment if the response remains insufficient. Psychotherapeutic treatment should also be monitored, but with individualized time frames for the transition to the next treatment stage, which must be initiated if the treatment outcome is inadequate.

3) Severe depression (or moderate depression not responding to step 2):

With this severity level, the treatment options include antidepressants, which are often combined with psychotherapy or psychotherapy without medication. Depending on the patient’s individual requirements, outpatient or inpatient therapy can be carried out.

4) Very severe depression (or severe depression not responding to step 3):

In case of a very severe depression, psychotherapy will usually not suffice and is often impossible. Treatment should usually be provided on an in-patient basis and often involves a complex medication regime. Depending on the patient’s individual requirements, psychotherapy can be offered concomitantly or frequently after an initial improvement through medication.

CONCLUSION

The comorbidity of diabetes and depression remains a considerable clinical challenge for patients and healthcare professionals. While the means of screening and diagnosing depressive disorders in people with diabetes have improved significantly in recent years, this does not automatically lead to better care, as clear treatment pathways after a positive diagnosis are often lacking or are rejected by the affected individuals.

Taken together, the scientific evidence on various treatments for depression in diabetes is somewhat encouraging, as it demonstrates that depression is treatable with moderate to good results in depressed people with diabetes. However, we still need efficient treatments to achieve simultaneous a long-term improvement in glycemic control.

A positive development is that the awareness of the importance of depression in diabetes has grown, and that many treatment alternatives for patients are now available. Although the scientific evidence still has much room for improvement in this area of research, there are many options for individualized treatment that give cause for optimism for the individual patient.

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