One in five patients with chronic kidney disease (CKD) will experience at least one major depressive episode, which is likely to be detrimental to the course of their kidney disease and significantly limit their quality of life. Most patients with major depressive disorder (MDD) in the setting of CKD are undiagnosed and untreated, which suggests a significant opportunity for psychiatrists to work collaboratively to optimize the treatment of depression in this high-risk population and provide guidance for both patients and their families around complex issues like dialysis withdrawal.

There is clearly a direct association between depression and hypertension as both have been identified as risk factors in precipitating the occurrence of the other. Psychiatrists should be vigilant about the appropriate management of hypertension and be familiar with medications that can exacerbate hypertension.

As many as four out of five adults in the United States report inadequate intake of fruits and vegetables according to national dietary standards and there are direct relationships between vitamin deficiencies and depressive symptoms. Psychiatrists have the opportunity to educate patients about appropriate nutrition and should be especially careful to recognize and appropriately treat nutritional deficiencies.

EPIDEMIOLOGY

Chronic kidney disease (CKD) is defined as the presence of kidney damage or decreased kidney function (glomerular filtration rate [GFR] <60 mL/min/1.73m²) for 3 or more months. It is a highly prevalent condition affecting over 8 million Americans each year.¹ Common etiologies include diabetes mellitus, hypertension, generalized arteriosclerosis, lupus, AIDS, and primary renal diseases, such as chronic glomerulonephritis, polycystic kidney disease, and other congenital and hereditary renal disorders. Around 80,000 Americans will progress to end-stage renal disease (ESRD) each year joining the more than 500,000 who are being treated for ESRD. Seventy-five percent of those with ESRD are on maintenance dialysis. The majority of these are treated with hemodialysis (HD), with less than 10% by home peritoneal dialysis (PD). The remaining 25% have a functioning kidney transplant, which is the treatment of choice for patients as it increases survival and quality of life.²

Depression is the most common psychiatric disorder in the CKD and ESRD population, with prevalence rates as high as 20% to 25% in recent studies, although many of these studies have used nonstandard measures for assessing depression.^3,4 In one study, 27.4% of CKD patients had evidence of depressive symptoms,⁵ while in others, 20% to 22% of patients with CKD have major depressive disorder.^6,7 The prevalence does not appear to vary widely with the stage of renal disease.⁸ Variables associated with a major depressive episode were diabetes mellitus, comorbid psychiatric illness, and history of drug or alcohol abuse. Taken together, the current data suggest that one in five patients with CKD will have at least one major depressive episode.⁸

Early studies on suicide in ESRD patients reported very high rates (100- to 400-fold greater risk than the general population), but these studies did not distinguish suicide from dialysis withdrawal, now considered to be distinct entities.⁹ In addition, early data were drawn from a highly select population undergoing a much more rudimentary and arduous dialysis procedure.⁹ Since 1990, the ESRD Death Notification Form has listed dialysis withdrawal and suicide as separate causes of death, allowing for more accurate data collection.⁹ What is unique about suicide consideration in this population is the ease of access to lethal methods that dialysis allows, either by noncompliance with medications or dialysis therapy, dietary excess, or by manipulating one’s shunt. Despite this, more recent data from the US Renal Data System (USRDS) indicate that suicide occurs at a modestly increased rate compared to the general population.^9,10 Data from the USRDS indicated that patients with ESRD had an 84% higher rate of suicide compared to the general population, but this rate is comparable to that of other chronic or debilitating illnesses, such as HIV, chronic lung disease, and stroke.⁹

ESRD appears to exacerbate a pre-existing vulnerability or tendency toward suicidal behavior among certain high-risks groups, particularly individuals with a history of alcohol dependence and previous hospitalizations for substance abuse and/or mental illness.¹⁰ The increased risk for suicide is associated with age >75, male gender, white or Asian race, ischemic heart disease, peripheral vascular disease, cancer, COPD, alcohol or drug dependence, low serum albumin, and hospitalization within the preceding 12 months.⁹ For example, prior psychiatric hospitalization is associated with a fivefold increase in suicide risk. The risk for suicide is highest in the first 3 months of dialysis initiation but then diminishes steadily over time, and it has been suggested that suicide may be driven by a failure to cope with the stress of adjusting to the lifestyle demands of dialysis.⁹ Clearly, the ESRD population deserves thoughtful assessment of suicide risk, especially those with a history of mental illness in addition to a high global burden of disease.⁹

The incidence of ESRD is disproportionately higher in African Americans and Hispanic Americans (compared with Caucasian Americans) and is thought to be related to both genetic and socioeconomic factors.¹¹ African-American patients comprise approximately one-third of ESRD patients in the United States and have an incidence of disease about threefold that of Caucasian patients.¹⁰ There is an increased prevalence of the APOL1 gene among those of West African ancestry, which appears to contribute to the higher frequency of certain common etiologies of CKD (e.g., focal segmental glomerulosclerosis) observed among African and Hispanic Americans.¹¹

Patients with CKD and depression are also more likely to be of lower socioeconomic status (Box 15-1). Patients with moderate to severe depressive symptoms were found more likely to lack a high school diploma, have an annual income of $20,000 or less, and receive public aid for health insurance.⁵ Indeed, socioeconomic factors such as low income, poor education, residence in low-income areas, and poor access to healthcare are strong predictors of the development of ESRD.¹² Minority populations in the ESRD program were at twice the risk of low socioeconomic status. This may contribute to the increased prevalence of depression among minority patients with CKD, who are also much less likely to seek mental health treatment and be prescribed antidepressants.^5,12 Other risk factors for depression in patients with CKD are being old, female, single, and unemployed. Among individuals with chronic HD, those who were female, unemployed, and had less education were over-represented in the subgroup with comorbid depression. Sixty percent of those who screened positive for depression were either single or widowed.^6,11,13

Finally, some data suggest that depression itself may be a risk factor for the development of CKD. Depressed patients have a higher prevalence of CKD at baseline compared with nondepressed participants in one multivariable analysis. Depression has been prospectively associated with incident ESRD, a rapid decline in estimated GFR, and acute kidney injury (AKI).¹⁴ The authors also found that elevated depressive symptoms are associated with subsequent adverse renal disease outcomes.¹⁴ Depression has been shown to precede a decrease in serum albumin concentration in dialysis patients, implying that the depression may result in malnutrition.¹²

Depressive symptoms also substantially increase the risk of adverse renal outcomes in adults with CKD. A major depressive episode is associated with nearly doubling the risk of death, dialysis therapy initiation, or hospitalization in male veterans with CKD.⁴ Patients with comorbid CKD and MDD were twice as likely to be admitted to the hospital and more than 3 times as likely to progress to ESRD and maintenance dialysis initiation as CKD patients without depression, even after adjusting for other medical comorbidity.⁷ In a prospective cohort of diabetic patients with stage 5 CKD, those with comorbid major depression had an almost threefold greater risk of mortality compared to those without major depression.⁶ What’s more, depression has been shown to be a risk factor for subsequent peritonitis rates and to independently correlate with mortality in PD patients.¹⁵

Additional risk factors that can affect the development of CKD include hypertension, diabetes mellitus, autoimmune disease, family history of renal disease, a previous episode of AKI, presence of proteinuria, abnormal urinary sediment, or structural abnormalities of the urinary tract.¹¹ In the United States, the leading cause of ESRD is diabetes mellitus, currently accounting for nearly 55% of newly diagnosed cases of ESRD and associated with a 15% to 25% greater mortality risk among ESRD patients compared to those without diabetes.^6,16 Depression has been found to be commonly comorbid with both diabetes and hypertension. Symptoms of chronic pain and insomnia in addition to a past history of depression are also associated with increased risk of depression in patients with CKD.^10,12

PATHOPHYSIOLOGY

While most of the risk factors for CKD are relatively fixed, depression remains an important modifiable risk factor in patients with ESRD (Box 15-2).³ Several behavioral and physiologic factors have been proposed as mechanisms through which depression can influence outcomes in patients with renal diseases.

Depression has been shown to negatively influence adherence with all the components of ESRD treatment, including medical appointments, the dialysis procedure itself, dietary control, fluid restriction, and the medication regimen.⁵ High rates of nonadherence to antihypertensives (85.2%) and oral phosphate binders (72.9%) have been found in depressed dialysis patients, and depression, anxiety, and stress have been negatively correlated with adherence.¹⁷ In addition, depression has been found to be negatively correlated with adherence to the dialysis regimen.¹⁰ Finally, depressed patients are more likely to engage in unhealthy behaviors, including a sedentary lifestyle, cigarette smoking, and alcohol overuse.^6,14

There is increasing evidence to support a direct physiologic effect of depression and stress on the immune system and internal cytokine milieu.^3,12 Depression has been shown to increase inflammation, alter platelet reactivity, lead to dysregulation of the autonomic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis, and contribute to endothelial dysfunction.⁵ Kimmel et al. showed elevations in proinflammatory cytokines such as IL-1 and β-endorphin correlated with increasing levels of depression and marital discord, and was associated with increased mortality.^3,10 C-reactive protein (CRP), another inflammatory biomarker, has been linked to depression in patients without CKD. This is of particular importance as elevations of CRP in ESRD has been associated with increased mortality.¹⁸ Research has revealed alterations in tumor necrosis factor (TNF-α) and IL-6 in setting of uremia, and evidence suggests that increased levels of TNF-α may drive the cachexia that occurs in CKD patients.¹² Since peptide and steroid hormones (e.g., cortisol) undergo metabolism by the kidney, they often circulate at much higher levels in patients with renal disease as than in patients without renal disease, and thus create an internal biochemical milieu similar to that of a chronic stress response.¹² This chronic proinflammatory state intrinsic to ESRD, and exacerbated by the presence of depression, likely contributes to the higher than expected rates of cardiovascular disease and other medical comorbidity, leading to increased mortality in this population.¹²

CLINICAL PRESENTATION

Assessment of clinical depression in the setting of CKD can be challenging and major depression should be distinguished from subthreshold depression and dysthymia (Box 15-3). Exploring the cognitive rather than somatic symptoms of depression may be useful in differentiating between an appropriate adaptive reaction to the physiologic effects of CKD and a maladaptive cognitive schema that would suggest a depressive disorder.¹⁹ Hallmark symptoms suggesting major depression in ESRD patients include worthlessness, guilt, thoughts of death, and suicidal ideation.¹⁰ It is also important to consider the time course of depressive symptoms in making the diagnosis. For example, the transition to dialysis can be an exceptionally stressful time. In this context, it has been suggested that a diagnosis of major depression should not be made until 3 to 6 months after beginning dialysis, as there seems to be a normal “settling in period” following which depressive symptoms tend to decrease. Depressive symptoms that improve following adaptation to an acute stressor would suggest an adjustment disorder whereas those that continue to persist would indicate a more severe clinical depression.¹⁰

One of the shortcomings of the literature is the use of widely differing instruments for assessing depression in CKD.¹⁵ Earlier studies have mostly relied on screening tools such as the Hamilton Rating Scale for Depression (HRSD) or the Beck Depression Inventory^© (BDI) to quantify depressive symptoms rather than on making a clinical diagnosis of depressive disorder.³ The BDI has been used extensively in the ESRD populations and many authors suggest higher cutoffs (i.e., BDI >15) than are used in the general population (BDI >10) because of the higher prevalence of somatic symptoms in patients with ESRD, including fatigue, loss of energy, decreased appetite, sleep disturbance, and difficulty concentrating.⁴ Wuerth et al. demonstrated a BDI cutoff of 11 has 84% sensitivity in predicting a diagnosis of depression.¹⁸ More recent studies have used the BDI to screen patients for referral to psychiatric providers who then confirm the diagnosis with a clinical evaluation utilizing DSM criteria.⁴ Scales assessing quality of life in CKD are often inversely related to dimensional measures of depression, as both chronic pain and insomnia frequently complicate depression in patients with renal disease.³

Negative affect due to depression can be difficult to distinguish from the known uremic symptoms of irritability, cognitive dysfunction, and encephalopathy.¹⁹ While the early stages of CKD are usually not associated with somatic symptoms, patients in the later stages may develop the uremic syndrome, whose clinical features include anorexia, dysguesia, nausea, vomiting, constipation, lassitude, pruritus, disturbances in memory and concentration, and sleep changes. Neuromuscular effects include muscle twitching, muscle cramps, restless leg syndrome, and peripheral neuropathy.^8,11,12

The initiation of dialysis in the setting of ESRD is often associated with significant psychological and biological stress, lifestyle changes, and decreased quality of life.⁶ Several factors contributing to emotional distress include impairments in physical and cognitive functioning, decreased mobility, decreased role function within the family, loss of occupation, and loss of independence.^8,20 Decreased marital satisfaction, disturbances in family dynamics, and lower socioeconomic status have been associated with poorer health outcomes. These factors may also effect patients’ perception of social support and increase depression.¹² ESRD and dialysis can also impact the patient’s family. Over 40% of spouses of patients on dialysis experience moderate to severe degrees of distress resulting from role changes, loss of employment or income, increasing household responsibilities, and reduced recreational and social activity.²¹ PD, which is often preferred because it can be done at home and allows for more autonomy, still places many demands on the patient and his/her support system. PD requires a substantial time commitment, can cause disruption of the home environment, requires a large bedroom machine (which can affect the bed partner), and a surgically implanted catheter (which can affect self-esteem, body image, and sexual functioning).²¹ Moreover, dialysis patients have significant sexual dysfunction in part due to hormone dysregulation.¹⁵ Sexual dysfunction is related to quality of life, and improvement in sexual function results in improvement in quality of life.²¹ Finally, the perception of disability and the discomfort associated with the peritoneal procedure can also drive symptoms of depression and hopelessness.¹⁵

Depressed patients with CKD may also suffer from comorbid symptoms of anxiety (Box 15-4). Various stresses appear to drive anxiety in this population, most notably impaired functioning, time constraints, fear of disability and death, loss of supportive relationships, loss of employment, and financial stressors.²¹ Rates of anxiety in CKD have been estimated as high as 27% but rates of comorbid depression and anxiety are substantially lower, and it appears that anxiety exists independently of depression in this population.¹⁹ In a study of urban HD patients, 29% had a current depressive disorder, 27% had a current anxiety disorder, up to 19% had a substance use disorder, and 10% had a current psychotic disorder (Box 15-5).¹⁹

COURSE AND NATURAL HISTORY

Depression results in substantial functional impairment and decreased quality of life in ESRD patients, and symptoms of depression do not appear to remit spontaneously in untreated patients.⁴ Untreated depression is likely to adversely affect progression of kidney disease. Kop et al. showed that depressive symptoms pose an increased risk for the development of poor kidney function and clinical progression to ESRD and AKI.¹⁴ It is hypothesized that effective treatment of depression will improve adverse ESRD outcomes, including poor nutritional status and treatment adherence, which will in turn affect survival.¹² However, this remains unproven given the existing low rates of adequate treatment. While nearly one in four patients with stage 5 CKD qualify for a DSM diagnosis of MDD, estimates suggest that only 16% to 20% of these patients are being treated with antidepressants.^4,15,19 More research is needed to demonstrate the benefit of effective treatment, but it is likely that adequate therapy would ameliorate depressive symptoms, which in turn would improve quality of life and functioning.¹⁸

As CKD progresses, the presence of depressive symptoms has been shown to increase. Fischer et al. demonstrated that for every 10 mL/min/1.73m² decrease in GFR, there was a 9% increased odds of elevated depressive symptoms. These authors also found a significantly greater frequency of BDI scores >11 (positive screen for depression) in patients with GFR <30 mL.⁵

Finally, progressive renal dysfunction leads to poorer health status. In the setting of comorbid depression, this CKD progression is significantly associated with a perception of lower quality of life.¹⁹ Depressed individuals have a higher expectation that their needs for security, safety, acceptance, and respect will not be met. Patients with depression also demonstrate impaired autonomy that interferes with their perceived ability to survive, function independently, or perform successfully.¹⁹ These findings are consistent with the psychodynamic literature, which discusses themes of “aloneness” and “ineffectiveness” as hallmarks of the depressogenic changes associated with ESRD treatment.¹⁹

WITHDRAWAL FROM DIALYSIS

Despite major technological advances over past 30 years, the short- and long-term adjustments to dialysis still exact a heavy toll on ESRD patients. Withdrawal from dialysis is common; approximately 20% of patients withdraw voluntarily, leading to about 10,000 deaths in the United States each year.^10,22 Although there has long been controversy around patient decision-making capacity to discontinue dialysis, cessation of dialysis is now recognized as an appropriate treatment option. Clinical practice guidelines²³ on dialysis withdrawal recommend a shared decision-making process, which takes into account prognostic information along with individual treatment preferences, ideally through an advanced directive. Less than one-third of ESRD patients complete advanced directives. At the time of dialysis withdrawal, nearly half of patients will lack the capacity to participate in this complex decision and, consequently, the burden will fall to their surrogates.²³ Reassurance can be offered that dialysis withdrawal generally results in a peaceful and pain-free death, and the average duration from the last day of cessation until death is 8 days.²³ (Practice guidelines from the American Society of Nephrology and Renal Physicians Association are available at http://www.renalmd.org).²³

Age, medical complications, dementia, and failure to thrive are common important reasons associated with the decision to withdraw ESRD therapy.¹⁰ In a retrospective review of over 460, 000 patients in the USRDS those withdrawing from dialysis had mean age of 71, were predominately white, more likely to be on HD (rather than PD), and had a higher burden of illness, malnutrition, physical impairment, dementia, malignancy, and other comorbid chronic diseases. African-American patients are half as likely to withdraw as white or Asian patients and the likelihood of dialysis withdrawal is the highest within the first year after initiating dialysis.^9,22

Depression is also an important factor affecting the decision to withdraw from dialysis. Patients with depression are more likely to eventually withdraw from dialysis compared to those without depression.^22,23 While concern has been raised that depression may lead to a premature decision to withdraw, it is not known whether this would decrease with improved recognition and treatment of depression. Despite this, it is prudent to consider psychiatric evaluation for depression when ESRD patients make an unexpected decision to discontinue dialysis. A low threshold for treatment, either psychotherapy, pharmacotherapy, or both, is indicated when patients meet criteria for major depression.

ASSESSMENT AND DIFFERENTIAL DIAGNOSIS

The assessment and differential diagnosis of depression in patients with CKD is similar to that for all medically ill patients (see chapter on Assessment of Depression) (Box 15-6). Prior history of depression, family history, and other comorbid medical illnesses associated with depression should not be overlooked. Differential diagnoses that should always be considered include other mood disorders, particularly bipolar affective disorder, anxiety disorders, and substance use disorders. In patients with chronic or ESRD, additional consideration should include sleep disorders, dementia or other cognitive disorder, and delirium.

TREATMENT

Chronic kidney disease may affect antidepressant (AD) pharmacokinetics unpredictably (Box 15-7). Most importantly, decreases in GFR may result in impaired drug excretion. Unless more than 70% of a drug excretion is by a nonrenal route, such as hepatic elimination, the maintenance doses of many drugs will likely need to be adjusted.¹¹ Antidepressants are highly protein bound and not significantly cleared by the dialysis procedure and as such do not require substitution dosing following dialysis. They commonly undergo hepatic metabolism, but many have active metabolites that are excreted renally, leading to accumulation of potentially toxic metabolites in patients with decreased GFR (Table 15-1).⁴ Specific agents with reduced clearance in advanced CKD include selegiline, amitriptyline, venlafaxine, desvenlafaxine, and bupropion. Dose reduction is recommended with these agents. Mirtazapine has a reduced plasma clearance after oral intake but not a prolonged elimination half-life so dose adjustment may not be needed (Table 15-2).²⁴

There is a paucity of data describing the safety and efficacy of AD medications in patients with advanced CKD and ESRD as these patients have generally been excluded from large AD trials because of concern for adverse effects. In addition, there are insufficient data to clearly suggest that the treatment of MDD is either effective in CKD or that treatment of depression changes outcomes in advanced CKD or ESRD.⁴ Most of the known studies are small, lack placebo control, and fail to utilize DSM-based criteria for diagnosing depression.⁴

Although there is limited evidence suggesting that ADs are more effective than placebo in treating patients with CKD, they are still recommended as first-line treatment of depression.²⁴ A recent review of AD drug therapy in CKD patients showed that ADs were more effective that placebo, with NNT = 6.²⁴ A systematic review of RCTs and observational studies of AD use in patients with CKD stages 3 to 5 found only 28 studies, and the data in these studies were so sparse and heterogeneous that they precluded a meta-analysis.²⁴ Nine nonrandomized trials all suggested benefit for the AD under investigation but the response was not significantly greater than placebo, with up to one-third of patients responding to placebo. Even though side effects were considered mild in most patients, an average of 21% discontinued treatment making it even more difficult to accurately assess outcomes.²⁴ The authors concluded that current evidence was insufficient, but still advised active treatment for depression given its negative influence on survival and quality of life. When choosing an agent, SSRIs are preferred and the authors recommend an 8–12-week trial and a reduction in starting dosage by one-third.^12,24 Once medication is initiated, response to treatment, need for dose adjustment, and the development of side effects should be monitored closely. Dose escalation should not be done sooner than 1 to 2 weeks and only as tolerated, with special attention to drug interactions and to assessment of suicidal ideation (Box 15-8).⁴

Many barriers prevent patients who do get diagnosed with depression from obtaining the appropriate treatment. These include patient refusal of psychiatric referral, reluctance to accept AD therapy in the context of an already complex pharmacologic regimen, and medication side effects.¹⁵ In a study of the efficacy of several different ADs over 12 weeks, improvement in depressive symptoms was observed in all groups. However, only 50% of patients who screened positive for depression agreed to referral, and nearly 25% of that group refused to initiate pharmacotherapy. Of those who did take medication, only 50% successfully completed a 12-week trial.²⁵

Depression treatment seems to vary with sociodemographic factors and comorbid psychiatric disorders. Female patients with depression are more likely to be on medication than males. Minority populations, who have up to 1.5-fold increased prevalence of depressive symptoms, are much less likely to be on medication.⁵ Patients with depression who use tobacco or illicit drugs are more likely to receive AD treatment. It is reassuring that those with more severe depressive symptoms are more likely to be on an antidepressant medication.⁵ Patients with comorbid substance abuse and with axis II personality disorders are much more likely to prematurely discontinue antidepressant therapy.¹⁸

There are limited data to suggest a direct effect of renal medications on symptoms of depression, except for the antihypertensives (which are reviewed elsewhere in this chapter). However, there is an increased risk of drug–drug interactions in patients with CKD as they are commonly on multiple medications, frequently have other medical comorbidity, and have increased risk of metabolic derangements.