Needs Assessment: Twenty percent to 40% of patients on renal replacement therapy suffer from depressive disorders. These conditions increase the burden of kidney disease, adversely affect quality of life, and may increase the mortality of these patients. Despite their significance, depressive disorders are largely underdiagnosed and undertreated in the chronic kidney disease population. Physicians should know the triggers, diagnostic issues, and treatment options of depression in this special context.

Learning Objectives:
• Describe how depression effects chronic kidney disease (CKD) outcome measures.
• List the risk factors and critical periods for depression in the CKD population.
• Provide examples for the overlapping symptoms of depression and uremia.
• List the most effective interventions for depression in the CKD population.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: November 8, 2007.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by January 1, 2010 to be eligible for credit. Release date: January 1, 2008. Termination date: January 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Zalai is research fellow in the Department of Psychiatry at the University of Toronto in Ontario, Canada. Dr. Novak is assistant professor in the Department of Psychiatry at the University Health Network and University of Toronto in Ontario, Canada, and associate professor at the Institute of Behavioral Sciences at Semmelweis University in Budapest, Hungary.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Acknowledgments: The authors thank the Department of Psychiatry in the Center for Integrative Mood Research at the University Health Network in Toronto, Canada, and the Hungarian Kidney Foundation.

Please direct all correspondence to: Marta Novak, MD, PhD, Department of Psychiatry, University Health Network, Toronto General Hospital, 200 Elizabeth St. EN 8-212, Toronto, ON, M5T 2S8, Canada; Tel: 416-340-3043; Fax: 416-340-4198; E-mail: marta.novak@uhn.on.ca.

 

 
 

Abstract

Depressive disorders have been shown to be present in 20% to 40% of the population receiving renal-replacement therapy, and this figure may be even higher in the pre-dialysis chronic kidney disease (CKD) population. Psychosocial factors (eg, unemployment, low income, young age, female gender, low-perceived social support, lack of adjustment to the hardship of dialysis, role transitions) make patients vulnerable to depression. Although it is often impossible to tell whether some symptoms originate primary in CKD or depressive disorders, if they meet the diagnostic criteria of depressive disorders then adequate therapy should be initiated. Screening tools can help in the identification of patients with depressive disorders. Prevention and treatment of depression is crucial because it is strongly associated with several important CKD outcomes. Monitoring the presence of depressive symptoms and enhancing social support should be part of the routine care in the CKD population.

 

Introduction

Chronic kidney disease (CKD) is a progressive, life-threatening illness, and a variety of biologic, psychological, and social stressors may trigger depression at any point during this life-long illness. Certain periods of the disease cycle and biopsychosocial factors make some patients especially vulnerable to depression. The diagnosis of depressive disorders may be challenging in this population. Clinicians sometimes experience difficulties to distinguish between the symptoms of uremia and somatic symptoms of depression. Furthermore, it may be questionable whether social withdrawal, decline in vocational activities, marital discord, and sadness are all expressions of depression or of the known burden of CKD. The literature in this respect is often confusing. On the one hand, the concept of “depression” is sometimes used in terms of “depressive affect” or “high scores on self-report questionnaires” and only rarely classified according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; Table 1).1 On the other hand, there has been no consensus, whether the shared somatic symptoms of depression and uremia should be included into the assessment and diagnosis. This article reviews the information concerning the triggers and risk factors of depressive disorders and addresses the above diagnostic issues. It also summarizes evidence on the association between depressive disorders and CKD outcomes in order to shed light on the importance of accurate diagnosis of depressive disorders in this population as well as review the few treatment studies available, with special emphasis on psychotherapy. The terms depression and depressive disorders are used interchangeably.

 

 

  

Etiology of Depression in Chronic Kidney Disease

CKD is a progressive, life-threatening illness, posing a fundamental existential problem on individuals and a burden on their families. The interplay between the person’s genetic susceptibility, his or her socioeconomic circumstances, and biopsychosocial impact of the kidney disease and its treatment may trigger depression in patients at any point of the disease.

The potential biologic pathways that link CKD and depressive disorders are important issues yet to be fully explored. Presumably, several biologic conditions associated with kidney disease (ie, uremia, anemia, impaired glucose metabolism, endocrine and immunologic changes, chronic inflammation) may play a role in the pathomechanism of mood disorders in CKD. So far, the most attention has been paid to the potential pathophysiologic link between immunologic stress factors and depression. The cytokine theory of depression assumes that inflammatory cytokines can trigger depression acting on the central nervous system. Chronic inflammation is common in dialysis patients and there is evidence to suggest that depression correlates with markers of inflammation in this population.2-5 Inflammation, malnutrition, and depression may have a complex, multi-dimensional relationship in CKD; pro-inflammatory markers may contribute to mood changes and malnutrition, whereas malnutrition can lead to inflammation and depression may result in malnutrition. This triad—often referred to as inflammation-malnutrition-depression complex—is a major determinant of a patient’s health status and mortality.2,6,7

On the psychological level, starting dialysis requires a complex emotional and cognitive-behavioral adaptation from patients. Profound experience of role transitions is common among people in this period. People whose kidney functions decline fast or who are not aware of their illness until its final stage become suddenly “severely ill.” Autonomous adults who used to exercise control over their lives become dependent on healthcare professionals and on their own family members. Those used to maintain households may become unemployed. People’s roles as sexually active, fertile males and females may be damaged. Bereavement is a natural reaction to these role changes and multiple losses that can resolve sadness and lead to healing. With some patients, however, mourning may progress to a major depressive episode (MDE) that requires treatment.

Although transplantation usually results in improved quality of life (QOL) in many aspects, it also requires special behavioral adaptation and psychological adjustment. Patients’ uncertainty about their future health and finances are the two leading stressors in the post-transplant period.8 Side effects of medications and physical problems also cause psychological strain after transplantation.9-10 Data from the few studies on this issue suggest that transplantation does not necessarily alleviate depression and anxiety; in fact, it may even amplify them.9,11,12

Re-starting dialysis after a graft rejection may again be a crisis point in the CKD “disease cycle.” A comparison between people with well-functioning graft, dialysis patients on transplant waiting list, and dialysis patients with chronic graft failure found that in the latter group the incidence of depression was significantly higher (>60%) than in the other two groups.11

Female gender, unemployment, low income, and living alone are risk factors for depression both in the general and CKD populations.13-15 Dialysis patients often have to give up their jobs. Although transplantation gives more independence to patients, the vocational activity level stays low.16

The studies on the relationship between age and the psychological impact of CKD generally concluded that younger age is associated with more mental distress than older age.15,17 Younger patients may experience dramatic role transitions in areas of health, employment, family and sexual roles, and fertility, and may feel that the illness shatters their future aspirations. In contrast, elderly patients usually compare themselves to their peers who often suffer from other chronic illnesses, and the onset of CKD may be an acceptable life event at this stage of their lives.18

Perceived social support has consistently been shown to have a strong correlation with depression and CKD outcomes.5,19,20 In particular, patients with history of suicidal thoughts or attempts in the pre-transplant and post-transplant period have found to perceive less social support than those who did not think of suicide.21 Low perceived social support is also correlated with low life satisfaction. Marital problems are common in the dialysis population.22 In a sample of mostly African-American hemodialysis patients, dyadic dissatisfaction was associated with depressive symptoms, although only in women.5

Awareness of the above factors may facilitate the utilization of appropriate preventive methods. Psychotherapy was shown to support adjustment to dialysis and transplantation and to prevent psychological deterioration.23,24 The primary care physician (PCP), who has trusting relationships with the patients, can be the first healthcare professional recognizing the risk factors for depression and to whom the patients disclose their distress.

 

Prevalence of Depression in Patients with Chronic Kidney Disease

Depressive disorders and anxiety disorders are the most common mental health problems in the CKD population,12,25,26 Most epidemiologic studies in this respect suffer from small and non-representative samples and from the use of instruments that had not been validated for the particular population. The largest study so far has been the Dialysis Outcomes and Practice Patterns Study that assessed the symptoms of depression with >9,000 participants from 12 countries.15 This study, using the Center for Epidemiologic Studies Depression Scale, reported that 43% of patients had scores indicating depression. There was also a large variation in the prevalence of physician-diagnosed depression; the two extremes were Japan (2%) and the United States (21.7%). The discrepancy between the reported symptoms and physician diagnosis may reflect cultural factors and diagnostic difficulties. A study that validated the same questionnaire in hemodialysis patients found depressive disorders in 26.7% of patients, including major depressive disorder (65%; MDD), dysthymia (27%) and minor depression (8%).27 In two other recent studies using validated instruments, the prevalence of depressive disorders have been 26% and 27%, respectively; the majority of patients suffered from MDD.28,29 The few studies available in transplanted patients suggested that the prevalence of depression is similar (20% to 35%) to that of the dialysis population.11,12

The assessment of psychological distress in the earlier stages of CKD has been largely neglected. In an unpublished study by Zalai and colleagues conducted in a pre-dialysis clinic, approximately 50% of patients reported severe depressive symptoms (unpublished data, November 2005). An earlier study arrived at similar results.30

The above evidence suggest that CKD patients can be regarded as a high-risk population for depressive disorders. Considering the enormous burden of depression both for the individual and the society, its large prevalence in CKD alone calls for special attention and effective intervention.13,31,32

 

Significance of Depression in Chronic Kidney Disease

The life expectancy of dialysis patients is one-third to one-sixth of the non-dialysis patients of the same age in the United States.33 Age, comorbidity, malnutrition, anemia, and functional status have been consistently shown to be associated with mortality.34 Depressive disorders, however, are not included in the most frequently used comorbidity indexes.

The prognostic significance of depression has been the focus of several studies, but these reports arrived at conflicting conclusions. Some studies did not find an association between depression and mortality.25,35,36 However, a large international study on dialysis outcomes concluded that both physician-diagnosed depression and depressive affect were independent predictors of survival in all countries.17 In addition, depression was associated with higher withdrawal rate and higher death rate from cardiac, vascular, and infectious diseases. The shortcoming of the above studies is that depression was assessed only at one point in time. Kimmel and colleagues37 showed that depressive affect, if measured only once, was not associated with mortality, but the time variation of depressive symptoms over a period of 2–5 years predicted survival.5 A further theoretical and methodologic issue is whether MDD and depressive affect has different effects on CKD outcomes. A recent retrospective study of a large sample of male veterans receiving long-term hemodialysis did not find association between mortality and physician-diagnosed depression, whereas other authors described that current symptoms of depression were associated with fourfold increase in mortality.29,38 Further large, multi-center studies are needed to assess the impact of clinical depression and depressive affect on mortality in CKD. Depression may increase mortality through various mechanisms, including malnutrition, immunologic changes, and increased risk for coronary heart disease and myocardial infarction.

It has been suggested that incidence of suicide is 84% higher in the dialysis than in the general population and is associated with mental illnesses.39 More passive behavior forms, eg, self-neglect, non-adherence to the treatments, may be expressions of suicidal ideation. The association between hospitalization and depression is more lucid; depression was found to increase the number of hospitalizations and length of stay in the hemodialysis population.17,38

For those living with CKD for months, years, or decades, the impact of disease and of kidney replacement therapies on their lives is an essential issue. Depression and anxiety are predictors of poor QOL in the hemodialysis, peritoneal dialysis, and transplanted populations.29,40-42 Depression and anxiety have found to be a stronger impact on QOL than clinical and sociodemographic variables (ie, comorbidity, hemoglobin, albumin, age, gender, employment status) taken together.40

 

Diagnosis of Depression in Patients with Chronic Kidney Disease

The DSM-IV classifies depressive disorders into MDD, dysthymic disorder and depressive disorder not otherwise specified (NOS). MDD is characterized by MDEs (Table 1). Dysthymic disorder features non-episodic symptoms that are present for at least 2 years (Table 1). Depressive disorders NOS are disorders with depressive features that do not meet the criteria for MDD or dysthymic disorder.

MDEs are characterized with depressed mood and/or anhedonia accompanied by decreased or increased appetite, significant weight gain or weight loss, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, diminished ability to think or concentrate, feelings of worthlessness, guilt, and recurrent thoughts of death. Some of these symptoms, however, can also be attributed to CKD or can simply be regarded as understandable reactions to the overwhelming burden of this illness (Table 2).

 

 

Fatigue, for example is one of the most prevalent symptoms of stage 5 CKD, affecting approximately 70% of patients.43 It may be caused by the consequences of renal failure, including anemia, malnutrition, hemodialysis-related hypotension and electrolyte shifts, medication side effects, and sleep disorders.34 However, loss of energy is among the leading symptoms of depressive disorders.44 Sleep disturbances occur in 45% to 80% in stage 5 CKD. The most frequent sleep disorders in the dialysis population are insomnia, sleep apnea, restless-leg syndrome, and periodic limb movements.45 The relationship between sleep disturbances and depression is two-directional; sleep problems can trigger depression and depression often results in insomnia.46 It is also important to note that the neuropsychological symptoms of sleep apnea, which is very frequent in the renal population, resemble the symptoms of depression or even uremia.47

Anorexia is yet another devastating symptom in about half of the patients with advanced stages of CKD.22 Depressive disorders are also often associated with decreased appetite. Sexual problems may appear in the early stages of CKD and their prevalence increases with the progression of the disease.43 Depression is one among the multiple factors that may contribute to the development of sexual dysfunctions, especially to loss of libido. Finkelstein and colleagues2 suggested that pharmacotherapy and psychiatric counseling may improve sexual functions in CKD patients with depression.

Pain is highly prevalent from the early stages of CKD.48 Chronic pain increases the burden of CKD, decreases QOL, and correlates with psychological distress in the early stages of the CKD. The prevalence of chronic pain is >50% in end-stage CKD, but it is often under-recognized even in the dialysis settings.43,49 Pain management also seems to be inadequate; according to a Canadian study,50 >40% of those in pain (musculoskeletal, ischemic, and neuropathic of origin) report moderate-to-severe pain and nearly 75% of patients find pain analgesic treatment inadequate. In the study, the severity of pain was positively correlated with the severity of self-reported depression symptoms. Patients who reported moderate-severe pain had higher score on the Beck Depression Inventory than those who had only mild or no pain.50

The presence of cognitive-emotional symptoms can help in directing attention to an underlying depressive disorder. However, some patients may not be able to identify or express emotional distress, or may be reluctant to share these psychological problems with their physicians. In addition to this, both physicians and patients often share the belief that depression is an “understandable” or “inevitable” condition in severe chronic illness.51,52

Sadness, anhedonia, anxiety, and thoughts of death are common at the onset of severe illnesses. The distinction of depression from normal bereavement and from adjustment disorders is important. DSM-IV makes a distinction between normal bereavement and “complicated bereavement.” The former refers to a normal, profound sadness caused by the loss of a loved one, whereas complicated bereavement is a reaction that triggers MDD. DSM-IV classifies bereavement as an MDE if symptoms of bereavement last for >2 months, or if there is a marked functional impairment, psychomotor retardation, morbid preoccupation with worthlessness, suicidal ideation, or psychotic symptoms. Although DSM-IV does not exclude normal, intense sadness caused by losses other than loss of a loved person from MDD criteria, it has been proposed that these reactions be treated similarly to bereavement.53,54 In this spirit, when patients react with intense sadness to the losses associated with CKD, those symptoms could be classified as MDD if the symptoms last for >2 months or are as extreme as described above. Adjustment disorders may develop in 3 months after stressful life events such as, for example, the initiation of dialysis. Adjustment disorders may manifest with depressive symptoms, most often with depressed mood, tearfulness, and hopelessness. Other maladaptive symptoms, such as chronic denial, noncompliance with treatment, and social withdrawal may also dominate the clinical presentation. In adjustment disorder with depressed mood, the symptoms do not meet the diagnostic criteria of an MDE. Somatic symptoms and suicidal ideation are also less common than in MDD.

Depression is largely under-diagnosed in CKD populations.15,55 Full assessment of the emotional, cognitive, and somatic symptoms of depressive disorders is strongly suggested in this population. The National Institute of Health and Clinical Excellence (Canada) advised that screening for depression should include at least two questions about the mood and interest of the patients.56 Although this may be a valid, quick screening method, it is important to know that patients who cannot or do not want to disclose emotions may give denying answers for these questions.57 Self-report screening instruments can also aid the recognition of depressive disorders. These tools cannot be used for diagnosis, but help to identify people with the symptoms of depression and indicate the severity of these symptoms. Some of these instruments have already been validated in dialysis patients (Table 3).27,28,58-60 Structured interviews validated against DSM-IV can reliably aid the diagnosis of depression. Referral to a psychiatrist who has experience with the medically ill population might be necessary.

 

 

 

Therapy of Depression in Patients with Chronic Kidney Disease

Despite of the association of depression with outcomes of the disease, only a few studies have been published on the treatment of depression in CKD patients.

Antidepressant pharmacotherapy is discussed by McIntyre and colleagues.61 Preliminary evidence suggests that selective serotonin reuptake inhibitors, in particular fluoxetine, sertraline, and paroxetine, seem to be safe choices for treatment of CKD.62,63 Tricyclic antidepressants, however, may have severe side effects in patients with CKD, and should be used mainly for the treatment of insomnia and neuropathic pain, under close monitoring. Pain management and the treatment of sleep disturbances should also be considered when starting antidepressant therapy.

Non-pharmacologic therapeutic approaches, such as counseling or psychotherapy, may be a more appealing choice of treatment for patients who suffer from several medical conditions and already receive multiple medications. Cognitive-behavioral therapy (CBT) and interpersonal psychotherapy (IPT) are both effective for the treatment of mild and moderate depression in other patient populations64 and can be combined with pharmacotherapy for the treatment of severe depression. Cognitive psychotherapy aims at identifying and modifying patients’ maladaptive beliefs about the self and the world, whereas IPT focuses on the identification and resolution of the main interpersonal problem areas in the patients` lives that are assumed to be related to the onset of depressive symptoms. Supportive psychotherapy is widely used to facilitate adjustment to chronic illness. Empathetic listening, cognitive and emotional support, reinforcement of adaptive strategies, and direct environmental intervention by the therapist are its main features. Psychotherapy can be conducted either in an individual, couple, family, or group setting. Group therapy is more cost effective than individual therapy and can also have additional benefits in that, for example, patients can share experiences and develop supportive relationships. However, individual therapy may better suit those patients who find public psychological disclosure difficult or intimidating. Psychotherapy might have to be modified to meet the needs of this population. Therapy, for example, could be delivered over the phone, or conducted with dialysis patients during the dialysis sessions, although issues about privacy in that setting may present a problem.

The few studies on the effectiveness of psychotherapy have promising outcomes in different CKD treatment groups. In a recent study of hemodialysis patients, 15 weeks of CBT reduced the depressive symptoms measured with the Beck Depression Inventory, and this effect was maintained for 3 months.52 Furthermore, a Korean group showed that a combination of pharmacotherapy and supportive psychotherapy reduced depressive affect and improved nutritional status of hemodialysis patients who previously had been diagnosed with MDD.63 Appropriate counseling may also be beneficial for people at the time of diagnosis of CKD as well as before the initiation of kidney replacement therapy. Studies in this area are very much needed. For PCPs and psychiatrists, it is also important to know that >40% of married dialysis patients report moderate-to-severe marital discord.22 Counseling with spouses or main caregivers could be an important part of the prevention and treatment of depression in this subgroup of patients. Well-designed, prospective, randomized studies are badly needed to establish the effectiveness of the above interventions and treatments in the CKD population.

 

Conclusion    

Depressive disorders are common in patients with CKD. Regular screening of depressive disorders in this population is essential. Appropriate use of validated screening instruments and structured clinical interviews help identify individuals with depression. Further studies are still needed to assess the association of the different depressive disorders with outcome of CKD, but the available evidence suggests that both depressive affect and clinical depression are associated with impaired QOL and poorer survival in these patient groups. Both pharmacotherapy and psychotherapy should be considered for the treatment of depression. Individual and group psychotherapy can be applied not only as effective treatment methods but also as preventive tools during the transition to dialysis and transplantation. Spouses or main caregivers of dialysis patients often play active roles in the treatment process and share the psychological strain of the disease. Thus, involving them in the counseling sessions may also be an important element of prevention and treatment of depression. PP

 

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