Etiology of Depression

Depression has long been identified as the primary mental health issue for patients with chronic kidney disease (CKD) and specifically end-stage renal disease (ESRD). It is unclear what etiological factors contribute to the increased vulnerability to depression, but understanding the biological, psychological, and social context in which the depression develops is essential. The biopsychosocial model proposes that various etiological factors play roles in establishing vulnerability to depression. The diathesis-stress model posits that depression results when preexisting vulnerability is activated by stressful life events. This predisposition can be either genetic, implying an interaction of nature and nurture, or cognitive, involving a lasting influence of attitudes and beliefs formed in childhood, or perhaps both.

Several biological theories for vulnerability to depression have been proposed, including a monoamine hypothesis, abnormalities in neurogenesis, known side effects of commonly prescribed medications for ESRD or common comorbid illnesses, an overactive hypothalamic-pituitary-adrenal (HPA) axis, hormonal dysregulation, as well as certain vitamin deficiencies. Although all these theories have a substantial basis, none have emerged as a singular explanation for the increased biological vulnerability. At core of these theories is the concept of stress and the ability to achieve stability through change, or “allostasis.” McEwen and Stellar developed the construct of allostatic load to express the vulnerability to disease that continuous physiological and psychological demand creates. The stress response of the CKD or ESRD patient may be impaired or overwhelmed due to the biochemical milieu created by renal disease or by the broad range of psychosocial threats the ESRD patient encounters. The expressed psychological reaction can be viewed as the combination of the biological and psychosocial threats in the context of the patient’s resources to cope with these increased demands.

Another way to conceptualize the psychological vulnerability to depression may be through noxious learning experiences. Beck and colleagues developed the cognitive model of depression in which he proposed three concepts as the hallmarks of depression: a triad of negative thoughts that comprise a negative bias about oneself, one’s world, and one’s future; distorted information processing and recurrent patterns of depressive thinking; and distorted cognitive schema. These patterns of maladaptive thinking often begin in childhood or adolescence and serve as a risk factor for the future development of the full depressive syndrome.

What these theories share in common is predicated on the acknowledgment that life on dialysis for patients with ESRD is demanding. Although kidney disease shares similarities with other chronic disorders, there may be other substantial losses associated with ESRD, beyond the loss of kidney function. Patients can undergo profound changes in role functioning, work status, autonomy, intimate relationships, and body image. The treatment burden of hemodialysis (HD) is also demanding. The weekly time demand is substantial and lifelong, without successful transplantation. Patients with ESRD report fatigue, pain, sexual dysfunction, gastrointestinal symptoms (nausea, vomiting, and anorexia), dermatological changes, and appetite changes. These ongoing challenges of living with ESRD can serve as the trigger that interacts with the person’s previous vulnerabilities and induce depression. There are a variety of psychological pathways in which the challenges of ESRD can affect a person. It is possible that patients with ESRD are put into a state of “learned helplessness” because treatment options are limited, and they are forced indefinitely to remain in their difficult situations with little hope for improvement or control over their outcomes. Threats to the patient’s autonomy and control as a result of the demanding course of treatment can serve as the precipitating stressor for a depressive episode.

The onset of depressive symptoms and depression can also be associated with changes in interpersonal factors, including strained or critical personal relationships. Patients with ESRD may experience changes in social role functioning, relationships with a spouse or adult children as a result of the transition to a caregiving or care-needing role, the death of a significant other, or the availability or quality of social relationships with friends because of their own health-related life events. These types of change have been associated with late-life depression.

One new integrative theory of depression, the social signal transduction theory of depression, posits that life stressors, particularly ones that involve interpersonal threat initiate a cascade of neural, physiological, molecular, and genomic processes that lead to the development and maintenance of depression. The stress response is not specific but initiates survival mechanisms in which proinflammatory cytokines upregulate components of the immune system, which then can lead to profound changes in behavior, which can be essential in the face of immediate physical threat, but maladaptive in the chronic state or in the context of prolonged social stress.

Suicide

The most acute danger that depression presents is the increased risk of suicide. Patients with ESRD may be particularly at risk because they can commit suicide through passive means, by no longer receiving dialysis or by manipulating a functional vascular access site. This makes suicide in this population readily available and complicates assessment and intervention strategies. Increased levels of depression have been associated with higher levels of suicidality. Patients with ESRD had an 84% increased rate of suicide compared with the general US population. Important risk factors for suicide in the ESRD population include a previous history of mental illness, recent hospitalization, age greater than 75 years, male gender, white or Asian race, and alcohol or drug dependence. Because of the increased prevalence and the relative ease with which patients with ESRD can commit suicide, screening for depression and suicidal ideation should be an essential part of the treatment plan in depressed patients with ESRD.

Malnutrition

A possible route through which depression could influence the course of ESRD is malnutrition. Some exploratory studies have found negative correlations between BDI scores and serum albumin levels, protein catabolic rate, and nutritional status scores in small samples, whereas others have not. The reasons for these disparate findings remain unclear, but may be related to differences in composition of the study samples, cultural and socioeconomic factors, or treatment conditions. The causal pathways between increased depressive affect and decreased appetite or nutrition have not yet been determined but may be bidirectional. Careful longitudinal or interventional studies will be needed to establish causal relationships.

Treatment Compliance

Another route through which depression can exert an influence on ESRD outcomes is through impairing treatment compliance. Better adherence to the HD prescription has been associated with improved survival. Studies have indicated a relationship between depressive affect and laboratory and behavioral markers of poor compliance in dialysis patients. Decreased behavioral compliance with the dialysis prescription correlated with increased depressive affect is prevalent HD patients. Initial findings suggest that successful treatment of depression may, at least temporarily, be associated with improved fluid compliance.

Social Support

Patients with depression may be more likely to feel less connected to their existing relationships and isolated from social connections. In chronic illness, this can lead to deleterious consequences. Several studies have shown an association between survival and perception of social support in patients with ESRD of different ethnic backgrounds. McClellan and colleagues used a prospective design and demonstrated that social support predicted survival of HD patients. Christensen and colleagues showed that a social support indicator, measured by family cohesion, predicted survival in HD patients. The result of these studies remain tentative, because the effects of medical and treatment parameters were not controlled. Kimmel and colleagues showed increased perception of social support, measured by the Multidimensional Scale of Perceived Social Support, predicted survival even when variation in age, severity of comorbid illness, serum albumin concentration, dialysis membrane type, and study site were controlled. In an analysis of the Dialysis Outcomes and Practice Patterns Study (DOPPS) on over 30,000 patients from a multinational sample, higher mortality rates were found among patients reporting less social support. Lower levels of perceived family support were also associated with decreased adherence to fluid and weight gain recommendations. It is unclear to what extent the quality of one’s social support is mutable and whether interventions designed to promote social support will have an effect on other outcomes such as mood, adherence, and survival.

Immunological Response

Depression may affect the course of ESRD through its impact on immunological factors and inflammation. Stress has long been linked to the dysregulation of the HPA axis, and depression has long been associated with abnormal glucocorticoid metabolism in healthy people. The precise mechanisms through which depression may modulate the immune system are still unclear, but one proposed theory is that depression increases cytokine activity, which may disrupt the HPA axis by impairing negative feedback of circulating corticosteroids.

There is also some evidence that inflammatory biomarkers, such as proinflammatory cytokines and C-reactive protein, are dysregulated and predict outcome in patients with ESRD. In one small study, there was an association between genetic predisposition to produce low levels of interleukin (IL)-10 (A/A genotype for the IL-10—1082 polymorphism) and increased chance of depression. The reasons for the increased risk of chronic inflammation in ESRD are complex; however, it has been suggested that a proinflammatory state is intrinsic to ESRD and is related to the higher-than-expected rates of cardiovascular disease and other causes of increased mortality in this population. Antiinflammatory agents may be a new frontier in treating depression in comorbid medical illnesses.

Mortality

There has been a great deal of scientific discussion regarding the association between depression and mortality in patients with ESRD. Some initial studies in ESRD patients found associations between depressive affect and mortality. However, these studies were preliminary and used comparisons of means between groups of deceased and surviving patients, without accounting for confounding medical and demographic factors. Other studies have been unable to detect simple associations between depression or depressive affect and survival in patients with ESRD. The Dialysis Outcomes and Practice Patterns Study, an observational study on a large multinational sample, has provided information regarding screening questions related to depressive affect and survival in patients with ESRD treated with HD. They used statements from the KDQOL regarding depressive affect and found that those who answered affirmatively to having more frequently experienced depressive affect had a higher risk of mortality, withdrawal from dialysis therapy, and hospitalization. Despite the nature of their nonstandard assessment, the study findings seem to indicate a robust relationship between depressive affect and medical sequelae. One prospective longitudinal study found that when subjects were divided by affect severity based on a single depression score, those with severe depressive affect had significantly shorter time to death. Kimmel and colleagues were initially unable to demonstrate a relationship between increased level of baseline depressive affect and mortality in a sample of almost 300 HD patients. They did report associations between the perception of increased burden of illness and mortality and between the perception of a high level of social support and improved survival. The group subsequently performed longitudinal assessments of the study population, evaluating BDI scores up to six times over a period of 20 months to 5 years (mean 38.6 months). The data were analyzed using Cox regression models to predict the length of survival. They found that an increased level of depressive affect over time was associated with an increased risk of mortality, even when the analysis was controlled for medical parameters. Boulware and colleagues generated similar results when they evaluated baseline and longitudinal data from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) study, a large cohort of incident patients starting dialysis. They determined that levels of depressive affect, measured by non-validated mood questions from the SF-36, at the beginning of the study were not associated with increased overall mortality. However, similar to Kimmel’s findings, using several different time-dependent analyses, the investigators demonstrated that persistently higher levels of depressive affect over time were associated with increased risk of death and cardiovascular events in both adjusted and unadjusted analyses.

There is also evidence that the repeated measurement of a depression diagnosis is more informative than cross-sectional assessments. Patients with ESRD who were depressed at two diagnostic interviews, spaced 16 months apart, exhibited correlations with lower quality of life and more reported health problems. Although the limited study duration prevented these results from being extended directly to mortality, it appears that a persistent course of depression represents an increased risk of morbidity and mortality for patients with ESRD treated with HD.

Hedayati and colleagues reported on time to death or hospitalization in an ESRD sample. They found a hazard ratio of about 2 for patients with ESRD with depression, compared with patients with ESRD without depression. A metaanalysis concluded that the conflicting research reports are likely due to the use of different depression scales and the ability of the studies to meaningfully correct for illness variables, but that there appears to be need to elucidate the mechanisms underscoring such relationships.

Marital Issues

Depressed ESRD patients may be at particular risk for marital difficulty. In addition to the typical strain that the development of a chronic illness places on a couple, the depressed patient could feel more easily overwhelmed and can be perceived as not being invested in the relationship. Role changes can be profound because spouses can now become caregivers or wage earners, which may promote further depression or resentment. There have been only a few studies that assess marital relationships in patients with ESRD, with one study reporting that greater than 50% of couples that included a patient with ESRD experienced marital discord. In a study of Indian HD patients and their spouses, marital discord was reported in about one-third of the sample, which had a strong relationship to either individual’s depression. Marital support and conflict may also be associated with the degree to which a patient adheres to the dialysis prescription.

Substance Use

All ESRD patients should be carefully screened for substance abuse because of the potentially nephrotoxic effects of some illicit drugs. Patients with depression are often unsure regarding how to effectively cope with their mood and may turn to drugs or alcohol to “self-medicate”. One study found that in a sample of 145 HD patients, 28% were judged to have a problem with chronic alcohol abuse. The study further found that the alcoholic group had poorer nutritional markers than the nonalcoholics.

Little is known about the effect of intravenous drug use on dialysis or vascular access; however, active substance abuse should be considered an acute situation, and coordination of care with addiction specialists should be undertaken. In a systematic review of opioid and benzodiazepine use, the authors found wide variability between centers, due to varying assessment techniques. They concluded that more precision in substance research and overall, more attention is required to further elucidate rates of substance use, the reasons for use and the consequences of use/over use. Recent findings suggest prescription of opioid medication in ESRD dialysis patients is common and associated with increased morbidity and mortality.

Anxiety Disorders

Anxiety is a complicating comorbid diagnosis for many patients with medical illness. Anxiety often occurs with depression in ESRD populations. Anxiety is consistently ranked as a major cause of years lost to disability in the United States. There is relatively little anxiety research specific to ESRD patients, but it appears that an anxiety diagnosis exerts a powerful negative effect on quality of life. Compound depression and anxiety might represent a clinical entity that has a synergistic, negative effect on patients’ perception of quality of life. One must consider that anxious patients can have characteristics on a spectrum from the more classic worried and withdrawn to agitated or angry.

When disruptive behavior presents in ESRD patients, it is important to try to understand the cause of the patient’s distress and to explore whether stress and anxiety may lead to undesirable outcomes. Similarly, excessive anxiety might lead to somatic vigilance, a discomfort with changes in bodily sensations. This may be particularly important to evaluate in patients who often prematurely end dialysis sessions because pain or discomfort might be a concomitant of anxiety.

Dementia/Delirium

Neurocognitive disorders are common in patients with ESRD. Depression can be a precipitant for neurocognitive decline, and the evaluation of any patient who reports a change in his or her mental acuity should include screening for depression. Withdrawal from dialysis is relatively common, especially in elderly patients or patients who fail to thrive, and the physician should try to determine the patient’s wishes before the patient’s mood and mental status may compromise his or her ability to provide a meaningful directive. A full discussion of neurocognitive changes in ESRD is in the following section.

Psychotherapeutic Options

There are several forms of psychotherapies (cognitive-behavioral, interpersonal, supportive, group therapy) that have demonstrated consistent and substantial efficacy in the treatment of depression in general populations, which may well be effective tools for patients with ESRD as well. In comparison to pharmacological interventions, psychotherapy has the advantage of few deleterious side effects, frequently introducing benefits such as improved sleep, improved interpersonal relationships, and improved regimen compliance. However, a significant disadvantage is that therapy typically requires the patient to be motivated to change. The first step in wanting to change is acknowledging the presence of a problem. Denial, an unconscious mental operation that allows the person to avoid facing harsh realities, is a considerable obstacle. Incorporating a mental health evaluation as a standard of care is one strategy to reduce barriers to psychological care and to minimize patients’ resistance to psychotherapeutic interventions. In addition, referring clinicians should explain their biopsychosocial conceptualization of disease and how treating psychological components is essential for good medical care.

There is an insufficient amount of literature on psychotherapeutic intervention in HD populations, but there is increasing interest in psychotherapeutic interventions for ESRD patients treated with HD. There is increasing literature indicating that psychosocial interventions, such as cognitive behavioral therapy, are effective for treating depression. In two small randomized controlled trials (RCTs) cognitive-behavioral therapy was shown to be effective in reducing depression when administered in both individual and group formats. Although this initial evidence is encouraging, larger scale trials are needed, and some are underway.

Pharmacotherapy

In today’s healthcare environment, nephrologists have, in many ways, become primary care providers for ESRD patients and often find themselves prescribing medications usually prescribed in primary care or other settings. When considering a psychotropic medication for patients with ESRD, it is important for nephrologists to balance their familiarity with the pharmacokinetics of psychotropic agents against the probability of the patient accepting a psychiatric referral, attending the appointment, and following through on the recommendations. Nephrologists must be aware of whether a drug is cleared through renal or hepatic metabolism and whether the drug clearance is affected by HD or peritoneal dialysis (PD). Most psychotropic medications are protein-bound, lipid soluble, penetrate the blood–brain barrier, and are cleared by the liver, with the notable exception of lithium. Protein binding may be impaired in ESRD, which can affect drug metabolism. Therefore, to reduce the potential for overdosing, consideration should be given to the reduction of the initial dose of psychotropic medications in this patient population. Clinical responses should be carefully monitored as doses are increased, and drug levels should be obtained if available.

Antidepressants have a potentially essential role in treating unipolar depression in patients with ESRD, with selective serotonin reuptake inhibitors (SSRIs) being the first line of pharmacological treatment. Tricyclic antidepressants (TCAs) and SSRIs are typically cleared by the liver, and therefore require only a minimal dose adjustment in patients without liver disease. For patients with ESRD, the initial dose of an SSRI is often one-half to two-thirds the usual dose. Typically, treatment with SSRIs should be continued for at least 4 to 6 weeks before deciding whether there has been a therapeutic benefit. If improvement is not achieved after 3 to 4 months, then consideration should be given to switching to another antidepressant. Establishing an appropriate antidepressant regimen may involve trial and error. The nephrologist and patient should expect that adjustments will need to be made to identify the optimal medication and dosing.

There is some evidence that SSRIs are effective in the treatment of depression in patients with ESRD. An early study found a treatment advantage in 12 depressed patients with ESRD treated with the SSRI fluoxetine over those given a placebo. Wuerth and colleagues found that depressive symptoms were markedly ameliorated in PD patients who completed a 12-week course of treatment with sertraline, bupropion, or nefazodone, despite low rates of compliance overall. Researchers in Korea found that fluoxetine significantly reduced HAM-D scores in patients with ESRD.

For a variety of reasons, SSRIs are the preferred medication for the treatment of ESRD patients with depression. SSRIs typically cause fewer anticholinergic symptoms than TCAs, are not associated with cardiac conduction abnormalities, and are less lethal in large doses compared with TCAs, which are lethal in large doses and can be used in suicide attempts. An additional benefit of SSRIs in this patient population is that they may reduce postural hypotension, presumably through effects on vascular tone. Fluoxetine, the first available SSRI, is the best-studied drug in this family. Other medications in this family include paroxetine, sertraline, and citalopram.

Venlafaxine and bupropion hydrochloride are examples of a different class of antidepressants called selective norepinephrine reuptake inhibitors (SNRIs). The SNRIs should be used with caution in ESRD patients because these drugs are primarily cleared by the kidneys. Bupropion has active metabolites that are almost completely excreted through the kidney. These may accumulate in dialysis patients, predisposing them to developing seizures.

Monoamine oxidase inhibitors (MAOs) have numerous side effects and should be avoided if possible in ESRD patients because of their potential to cause hypotension. All medications carry the risk of adverse effects, and patients’ regimens need to be carefully selected and then closely monitored. If the nephrologist does not believe that the regimen is sufficiently improving the depression, or he or she is not comfortable with the multiple iterations that are often required in gaining efficacy from antidepressants, a psychiatric consultation is warranted.

The literature has highlighted the challenges in having patients effectively accept an SSRI prescription at the dialysis center. Wuerth and colleagues documented some of the barriers to patient acceptance, but data from two studies emphasize the significant role of the patient’s willingness to take the medication. Successfully prescribing a medication for depression includes appropriate diagnosis, appropriate selection of an agent and dose, as well as patient education regarding the need for and potential benefits and harms of the intervention choice.

Etiology of Neurocognitive Impairment

Cognitive impairment poses many challenges to the CKD or ESRD patient, their caregivers, and their families. Depending on the severity of impairment, activities of daily living, such as ability to manage medications or even driving to medical appointments may become unsafe. Remembering to take one’s medication or even attend dialysis sessions may become problematic. The burden of impairment often falls on those who take on caregiving responsibilities, and the stress of witnessing a loved one undergo cognitive decline can be devastating.

The assessment of neurocognitive functioning is a vital part of the comprehensive care of the CKD patient. Aside from the impact on activities of daily life, cognitive dysfunction can be associated with disease progression and affect the likelihood of adherence to the medical regimen, or it can serve as a gross measure of adjustment. Tables 16.3 and 16.4 provide, respectively, lists of cognitive domains and tests that can be used in the evaluation of cognition. Cognitive impairment can range from subtle, with only minor impairment in a circumscribed domain, to gross diffuse dysfunction. Major neurocognitive disorder, or “dementia,” is used when there is a decline in cognitive functioning in one or more areas of cognition that affects independence in daily activities, such as remembering to pay bills and managing medication. If the cognitive decline is transient and abrupt, and there is a change in attention or awareness, the impairment is referred to as delirium . Delirium may occur with a concurrent neurocognitive disorder. The most common type of dementia is Alzheimer disease. Alzheimer disease can be progressive and, in advanced stages, result in profound impairment in memory and language and visuoperceptual ability. Another common cause of dementia is vascular neurocognitive disorder, which is often characterized by significant impairment in executive functioning.

TABLE 16.3

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