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Depression in adults receiving maintenance dialysis

Depression in adults receiving maintenance dialysis
Literature review current through: Jan 2024.
This topic last updated: Sep 01, 2022.

INTRODUCTION — The most common psychiatric disorders observed in patients treated with maintenance dialysis are unipolar major depression (major depressive disorder) and other depressive syndromes [1-4]. Depression is associated with reduced adherence to treatment for end-stage kidney disease, as well as increased hospitalization and mortality, possibly independent of dialysis adequacy.

Other psychiatric disorders in patients on maintenance dialysis, as well as the risk of suicide, are discussed separately. (See "Psychiatric illness in adults receiving maintenance dialysis".)

EPIDEMIOLOGY

Prevalence — In patients who are treated with maintenance dialysis, multiple studies indicate that the point prevalence of unipolar major depression (major depressive disorder) plus other depressive syndromes is approximately 25 percent [3,5-7]. As an example, a meta-analysis included 28 studies in which dialysis patients (n >2800) were clinically interviewed, and estimated that the point prevalence of depressive syndromes diagnosed according to standardized criteria was 23 percent [8]. This appears to be consistent with the prevalence of depression observed across all general medical disorders, and seems to be greater than the point prevalence in the general population. (See "Unipolar depression in adults: Epidemiology", section on 'Prevalence'.)

Although other studies report that the point prevalence of depression in dialysis patients may be as high as 35 to 50 percent, these estimates are largely based upon either patient self-report or clinician-administered instruments [8-12]. These instruments, especially self-report scales, may overestimate the prevalence because symptoms such as anergia, anorexia, and insomnia that are secondary to inadequate dialysis may be incorrectly attributed to depression.

Time of onset — Observational studies suggest that onset of depression may occur prior to or at commencement of dialysis in approximately 40 to 45 percent of patients. In two prospective studies of patients starting dialysis (n = 182 and 123), assessment with a self-report questionnaire found that clinically significant symptoms of depression were present at baseline in 40 and 44 percent [11,13]. Consistent with these results is the finding that among patients with chronic kidney disease who are not receiving dialysis, comorbid unipolar major depression increases the risk that patients will progress to dialysis [14].

Risk factors — The risk of depression in dialysis patients may be increased in those who are married. A meta-analysis of 169 studies (n >39,000 patients), which were largely based upon patient self-report or clinician-administered instruments, found that the prevalence of depression increased approximately 1 percent for each 1 percent increase in the proportion of patients who were married [8]. By contrast, age, sex, race, employment status, and diabetic status were not associated with an increased risk of depression. In addition, the risk of depression was comparable in patients treated with hemodialysis or peritoneal dialysis.

SCREENING — We suggest that primary care clinicians or the nephrology treatment team screen all patients on dialysis for depression every 6 to 12 months, provided that services are in place to ensure follow-up for diagnosis and treatment [5,6]. Clinicians should interview patients who screen positive to establish or rule out the diagnosis because screening is not sufficient for case-finding. Immediate referral to emergency psychiatric services is indicated for patients who endorse suicidal ideation with a plan and intent.

Screening for depression in end-stage kidney disease (ESKD) is mandatory for dialysis facilities in the United States [4,15,16]. In addition, practice guidelines issued by the US Preventive Services Task Force recommend screening all adults for depression [17,18] (the full guideline can be accessed through the website for the US Preventive Services Task Force [19]), as do guidelines from the Kidney Disease Outcomes Quality Initiative (National Kidney Foundation) [20]. The rationale for screening is that depression is serious, prevalent, underrecognized, readily diagnosed, and treatable, and that standardized, valid screening tools are available and feasible to use. However, the benefit of screening for depression in ESKD remains uncertain because there are no data that demonstrate screening improves outcomes in this patient population [3,21].

We typically use the self-report Patient Health Questionnaire – Nine Item (PHQ-9) (table 1) to screen for depressive disorders in ESKD. A study that validated the instrument in dialysis patients found that the optimal cutoff score was 10 or greater; the sensitivity and specificity were each 92 percent and the positive predictive value was 71 percent [6,22]. Reasonable alternatives include the 21-item Beck Depression Inventory and the 20-item Center for Epidemiologic Studies Depression Scale, both of which are also self-report measures that have been validated in ESKD. Results from the three scales should be interpreted judiciously because the instruments include items about appetite, energy, and sleep, impairment of which may reflect symptoms related to kidney failure and inadequate dialysis rather than depression [6].

A reasonable alternative to a screening tool is to ask questions such as, “During the last month, have you often been bothered by feeling down, depressed, or hopeless?” and “During the last month, have you often been bothered by having little interest or pleasure in doing things?” [5]. For patients who endorse dysphoria or anhedonia, follow-up questions can better determine the patient's clinical status, including questions as to whether patients have thoughts about harming themselves.

Information about screening for depression in the general population, including implementation and efficacy, is discussed separately. (See "Screening for depression in adults".)

ASSESSMENT

When to suspect the disorder — The presence of major depression in patients on maintenance dialysis is suggested by the following clues [1]:

Prior history of depression

Symptoms such as anergia, anorexia, and sleep disturbance, which may suggest inadequate dialysis, depression, or both disorders

Misuse of alcohol or other substances

Reduced quality of life

Poor adherence to dialysis

Requesting to withdraw from dialysis

Initial evaluation — The evaluation for unipolar major depression (major depressive disorder) (table 2), persistent depressive disorder (dysthymia) (table 3), minor depression (table 4), and other depressive syndromes is generally similar in patients treated with maintenance dialysis and individuals in the general population [6]. (See "Unipolar depression in adults: Assessment and diagnosis", section on 'Assessment'.)

However, evaluating dialysis patients for depression is complicated because some patients are unaware that they are depressed, deny it when asked, or refuse to acknowledge it. In a study of 186 patients who were treated with dialysis and screened positive for major depression, 55 percent declined further evaluation to confirm the diagnosis [23]. The inability to accept a diagnosis of depression may be due in part to the stigma of mental illness as a sign of weakness. For patients who positive screen but refuse further assessment for depression, ongoing intermittent education may eventually make additional assessment more palatable.

Another difficulty in assessing dialysis patients for major depression is that some symptoms of depression, such as anergia, anorexia, sleep disturbance, and psychomotor retardation can overlap with symptoms commonly observed in patients on dialysis, which may reflect inadequate dialysis or medication adverse effects [1]. To manage this problem, clinicians can focus upon the five mood and cognitive symptoms of depression. (See 'Diagnosis' below.)

One of the cognitive symptoms of major depression involves impairment of concentration, memory, and decision making. More specific aspects of this impairment were examined in a prospective study of dialysis patients who either screened positive for depression (n = 220) or did not (n = 238); all patients underwent neuropsychological testing [24]. After controlling for potential confounding factors such as demographics, general medical comorbidities, and laboratory parameters, the analyses showed that depressive symptoms were associated with general cognitive dysfunction as well as impairment of executive function (eg, planning, problem solving, and sequencing actions), immediate memory, delayed memory, and language. In addition, even relatively mild depression was associated with cognitive dysfunction.

Although neuropsychological testing is typically not part of the initial evaluation for depression in dialysis patients, it can be useful for cases in which it is difficult to differentiate major depression from neurodegenerative disorders such as delirium or dementia. However, assessing cognitive function in dialysis patients is often difficult because of patient limitations. In a prospective study that examined cognitive function in 767 patients on dialysis, data were missing in 48 percent [25]. The reasons for missing data included visual impairment, lack of motivation, and motor impairment. In addition, patients with missing data were more likely to have depression than patients with complete cognitive testing data. Additional information about cognitive impairment in patients treated with dialysis, as well as assessing cognition, is discussed separately. (See "Psychiatric illness in adults receiving maintenance dialysis", section on 'Neurocognitive disorders' and "The mental status examination in adults".)

DIAGNOSIS — Among patients who are treated with maintenance dialysis, the diagnostic criteria for unipolar major depression (major depressive disorder) (table 2), persistent depressive disorder (dysthymia) (table 3), minor depression (table 4), and other depressive syndromes are identical to those used in the general population [6,26]. The criteria are elicited through clinical interviews with patients, as well as family members who can help in establishing the diagnosis [6]. (See "Unipolar depression in adults: Assessment and diagnosis", section on 'Diagnostic criteria and classification'.)

Diagnosing depressive syndromes in dialysis patients can be difficult because some symptoms of depression (table 2) may be attributable to inadequate dialysis and complications of end-stage kidney disease (ESKD) [1,7,27]. As an example, one review found that among patients with ESKD, the prevalence of anorexia and sleep disturbances were each approximately 50 percent [2].

In some studies, the diagnosis of major depression in patients with general medical disorders such as ESKD has focused upon the five mood and cognitive symptoms of depression [5,28]:

Dysphoria

Anhedonia

Worthlessness or excessive guilt

Cognitive dysfunction

Suicidal ideation and behavior

Less emphasis was placed upon the four somatic symptoms of depression that may be caused by medical conditions [5,28]:

Anorexia

Sleep disturbance

Fatigue

Psychomotor retardation

Support for this approach includes multiple observational studies [29,30], including two (n = 2510 and 1594 psychiatric outpatients) that diagnosed major depression in patients who had three out of the five mood and cognitive symptoms, at least one of which was dysphoria or anhedonia [31,32]. Approximately 95 percent of patients who endorsed five or more of the nine symptoms (ie, the standard definition of major depression) also endorsed three of the five mood and cognitive symptoms.

POTENTIAL ADVERSE CONSEQUENCES — In patients who are treated with maintenance dialysis, unipolar major depression (major depressive disorder) is associated with multiple adverse medical outcomes. Across different studies, depression predicted pain, peritonitis, pruritus, cardiovascular events, emergency department visits, hospitalizations, withdrawal from dialysis, and all-cause mortality, as well as sleep disturbance, sexual dysfunction, diminished cognitive functioning, decreased quality of life, and suicide [6,33,34].

Poor medical outcomes may be increased in dialysis patients with depression because dialysis is a complex treatment, and depression may interfere with the patient’s ability to follow treatment recommendations and lead to poor adherence [3,27]. In addition, depression may be associated with other adverse health-related behaviors such as inadequate dietary intake or substance use disorders, or depression may reflect general physical deterioration or a specific disease process such as cardiovascular illness or abnormal functioning of the immune system.

Hospitalization — Depression in dialysis patients is associated with an increased risk of hospitalization for any cause, independent of demographic variables, comorbid illnesses, and duration of dialysis [35]. The risk is increased by at least 10 percent:

A prospective study evaluated 6987 patients with a self-report measure and found that clinically relevant depressive symptoms were present in 43 percent [36]. After adjusting for potential confounding factors such as demographics, general medical comorbidities, and time on dialysis, the analyses showed that hospitalization was 12 percent greater in patients with depressive symptoms (relative risk 1.12, 95% CI 1.03-1.22).

A study prospectively followed dialysis patients (n = 286) for up to two years and assessed them for depressive symptoms, using the self-report Patient Health Questionnaire – Nine Item (PHQ-9) (table 1) [37]. After adjusting for potential confounding factors such as demographics, comorbid illnesses, and lifetime duration of dialysis, the analyses found that moderate to severe depression was associated with an increased risk of hospitalization (hazard ratio 1.4, 95% CI 1.2-1.8). In addition, the study found that depression was associated with missed dialysis treatments, which may partially explain the risk of hospitalization.

A retrospective study examined patients who started hemodialysis (n >8000) and were followed for up to one year; the analyses controlled for potential confounding factors, including demographics and physical and mental health problems [38]. The estimated probability of hospitalization was 13 percent greater in patients with depressed affect (dysphoria; relative risk 1.13, 95% CI 1.02-1.25), compared with patients who were not dysphoric, and the median length of hospitalization was twice as long in dysphoric patients (four versus two days).

Withdrawal from dialysis — Among patients who are treated with maintenance dialysis, the risk of withdrawal from dialysis is greater in those with depressive symptoms:

In a prospective study of 6987 patients, clinically relevant depressive symptoms were present in 43 percent [36]. After adjusting for potential confounding factors, the analyses showed that withdrawal of dialysis was 60 percent greater in patients with depressive symptoms (relative risk 1.6, 95% CI 1.3-1.9).

A retrospective study included patients (n >6400) who initiated maintenance dialysis and were followed for up to one year [39]. Baseline depression was rated by patients on a self-report scale from one (none of the time) to six (all the time). After controlling for potential confounding factors such as age, diabetes, and physical functioning and pain, the analyses found that each one-point increase in the depression score was associated with a 20 percent increase in the risk of discontinuing dialysis (hazard ratio 1.2, 95% CI 1.1-1.3). Withdrawal of dialysis most often led to death.

All-cause mortality — In patients treated with maintenance dialysis, depression is independently associated with a 40 to 50 percent increased risk of all-cause mortality:

A meta-analysis of 14 observational studies (n >33,000 dialysis patients) found that mortality was greater in depressed patients than nondepressed patients (relative risk 1.4, 95% CI 1.2-1.5) [40]. Heterogeneity across studies was moderate.

In a meta-analysis of 12 observational studies that included more than 21,000 dialysis patients and adjusted for covariates, depression was associated with an increased risk of death (hazard ratio 1.5, 95% CI 1.4-1.7) [41]. Heterogeneity across studies was moderate.

A subsequent study prospectively followed dialysis patients (n = 286) for up to two years and assessed them for depressive symptoms with the PHQ-9 (table 1) [37]. After adjusting for potential confounding factors such as demographics, comorbid illnesses, and lifetime duration of dialysis, the analyses found that each five-point increase in the PHQ-9 score was associated with an increased risk of all-cause mortality (hazard ratio 1.4, 95% CI 1.1-1.8).

The association between depression and mortality in the general population of depressed patients is discussed separately. (See "Unipolar depression in adults: Course of illness", section on 'Mortality'.)

Suicide — The increased risk of suicide in patients on maintenance dialysis who have depression or other psychiatric disorders is discussed separately. (See "Psychiatric illness in adults receiving maintenance dialysis", section on 'Suicide'.)

COURSE OF ILLNESS — Onset of depression in dialysis patients may occur prior to or at commencement of dialysis and persist during dialysis. A prospective study enrolled 182 patients who were starting dialysis and followed them for a median of 20 months; assessments included a self-report questionnaire at baseline and during follow-up [11]. Clinically significant symptoms of depression were present at baseline in 40 percent, and the symptoms did not improve during the first year of follow-up and dialysis.

In a prospective study that used a semi-structured interview and standardized diagnostic criteria at study intake to diagnose a depressive disorder in 12 dialysis patients, follow-up interviews 16 months later found that a depression diagnosis was still present in 5 patients (42 percent) [42]. Higher depression rating scale scores at baseline were associated with persistence of depression.

CHOOSING TREATMENT

Overview — Multiple studies have found that depression in patients receiving maintenance dialysis is undertreated [6,7]. As an example, a retrospective study of 928 dialysis patients with clinician-diagnosed depression found that antidepressants were prescribed for only 35 percent [36]; in a prospective study of 54 depressed patients who were initiating dialysis, only 16 percent were receiving treatment for depression at baseline [13].

Engaging dialysis patients in treatment of comorbid unipolar major depression (major depressive disorder) can be difficult [4,23]. As an example, an open-label, randomized trial enrolled patients (n = 170) treated with hemodialysis who had unipolar major depression or persistent depressive disorder (dysthymia), and assigned them to a single engagement interview or control visit [16]. The engagement interview used motivational interviewing to help patients accept the diagnosis of depression and engage in treatment of depression; during the control visit, the depression diagnosis and available treatment options were discussed. Both the engagement interview and control visit occurred at the bedside while the patient received hemodialysis. The number of patients who accepted treatment for depression within one month was similar for the engagement interview and control visit (66 and 64 percent).

Patients on maintenance dialysis with depression may refuse starting treatment for depression or modifying existing treatment that is ineffective because they attribute the depressive syndrome to a recent acute event, chronic illness, or dialysis [43]. In addition, patients may not want to take yet another medication or exert the effort required by psychotherapy, or psychotherapy may not be available [6]. Nephrologists may also decline initiating or modifying treatment for depression.

For patients on maintenance dialysis who have acute unipolar major depression, we suggest treating the depressive syndrome with an antidepressant plus psychotherapy. However, pharmacotherapy alone is reasonable for patients who decline or do not have access to psychotherapy, and antidepressant monotherapy may be superior to psychotherapy alone. In addition, psychotherapy alone is reasonable for patients who want to avoid the adverse effects of antidepressants and drug-drug interactions. Relatively few head-to-head, randomized trials have compared these three standard treatment regimens in dialysis patients, and clinicians should attempt to accommodate patient preferences. Other factors that help determine which treatment to prescribe are prior treatment history and cost.

Referral — Nephrologists often have the requisite training and experience to manage unipolar major depression in patients on maintenance dialysis. However, there may be uncertainty about the diagnosis, or these clinicians may not be comfortable treating depression and thus refer patients to psychiatrists or other mental health clinicians if these specialists are available; referrals are also made if requested by patients. Indications for referral include:

Suicidal ideation and behavior (see "Suicidal ideation and behavior in adults")

Psychotic features (eg, auditory hallucinations commanding patients to kill themselves) (see "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis", section on 'Clinical features')

Catatonia – Prominent psychomotor disturbances, such as immobility, mutism, and posturing, which occur during most of the mood episode (see "Catatonia in adults: Epidemiology, clinical features, assessment, and diagnosis")

Impulsive and dangerous behavior (eg, significant aggression)

Fluctuating depressive symptoms

Functional impairment (eg, chronic marital conflicts or unemployment)

Comorbid psychopathology (eg, anxiety disorders and substance-related and addictive disorders)

Administering psychotherapy

Prior history of recurrent depressive episodes

Poor adherence to psychiatric treatment

Discontinuing treatment following a period of stability

In addition, referral to social work may be appropriate; indications include problematic social circumstances, such as intimate partner violence or other trauma, poverty, or homelessness. Social workers may also facilitate treatment uptake.

Nephrologists who refer patients to psychiatric specialists are encouraged to remain involved in management. The nephrologist can help educate patients and families about pharmacotherapy and psychotherapy, reinforce the need for adherence, and typically collaborate in evaluating patients prior to treatment by obtaining a general medical history and performing a physical examination, and monitoring vital signs, weight, height, waist size, and laboratory tests during treatment.

Initial therapy — For patients on maintenance dialysis who have unipolar major depression, we suggest treating the depressive syndrome with an antidepressant plus psychotherapy. We typically use a selective serotonin reuptake inhibitor (SSRI) such as sertraline plus cognitive-behavioral therapy (CBT). However, there are several reasonable alternatives to SSRIs, including serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, and the atypical antidepressants bupropion and mirtazapine. In addition, there are several reasonable alternatives to CBT, including interpersonal psychotherapy and problem-solving therapy. Additional information about choosing an antidepressant and a psychotherapy is discussed separately. (See 'Alternatives' below.)

Evidence supporting the combination of an antidepressant plus psychotherapy for comorbid major depression in dialysis patients includes randomized trials in the general population of depressed patients. (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Efficacy of antidepressants plus psychotherapy'.)

In addition, low-quality studies in maintenance dialysis patients with major depression suggest that pharmacotherapy plus psychotherapy may be beneficial:

In an eight-week, prospective observational study, 34 hemodialysis patients with unipolar major depression were treated with paroxetine 10 mg/day and supportive psychotherapy [44]. Improvement of depression was statistically significant. In addition, nutritional status improved, including the normalized protein catabolic rate and serum albumin levels.

A 12-week observational study of 71 peritoneal dialysis patients found that response (reduction of baseline symptoms ≥50 percent) to antidepressants (eg, an SSRI or bupropion) plus psychotherapy occurred in approximately 50 percent [23].

Indirect evidence supporting combination therapy includes a study of overall health care expenditures in patients (n >33,000) with chronic general medical disorders such as cardiovascular disease and diabetes [45]. Patients who received pharmacotherapy plus psychotherapy in one year had lower health care costs in the subsequent year, compared with patients who received only monotherapy.

Alternatives — Alternatives to the combination of an antidepressant plus psychotherapy include medication monotherapy and psychotherapy monotherapy.

Medication monotherapy – For patients on maintenance dialysis who have unipolar major depression, treating the depressive syndrome with antidepressant monotherapy is a reasonable alternative to the combination of an antidepressant plus psychotherapy. Patients may prefer using medication alone or have a prior history of poor response to psychotherapy, or psychotherapy may not be available.

Choosing a drug – SSRIs are generally recommended as first-line agents for major depression in dialysis patients [3,5,46]. However, no head-to-head trials in dialysis patients have compared the efficacy of different antidepressants. Thus, the choice is often guided by side effect profile and cost.

-SSRIs – In treating comorbid major depression in dialysis patients who prefer antidepressant monotherapy, we generally select an SSRI because SSRIs have demonstrated efficacy, are well tolerated, and have been more widely studied and may be more cost effective than other antidepressants [5,6]. One review noted that SSRIs are among the top 10 drugs prescribed to dialysis patients [47].

Although there is no evidence that one SSRI is more efficacious than another, we typically choose sertraline because of its demonstrated efficacy in dialysis patients treated for depression. In addition, the dose of sertraline does not need to be adjusted in patients undergoing hemodialysis or peritoneal dialysis, and sertraline is not likely to cause drug-drug interactions that can lead to adverse side effects. Reasonable alternatives to sertraline include fluoxetine and paroxetine.

Citalopram is generally avoided in patients with end-stage kidney disease (ESKD), based upon a warning by the US Food and Drug Administration (FDA) that citalopram causes dose-dependent QT interval prolongation that can lead to arrhythmias [48]. Although the FDA also found that escitalopram, which is the single isomer formulation of citalopram, may also prolong the corrected QT interval, the FDA concluded that the finding was not clinically significant and did not justify a warning. Nevertheless, we also avoid escitalopram in patients with ESKD because patients receiving maintenance dialysis are at increased risk of adverse cardiac events due to comorbid cardiovascular disease, electrolyte shifts during dialysis, and use of other medications that can prolong the QT interval [49].

Evidence regarding QT prolongation with citalopram or escitalopram in dialysis patients includes a retrospective study that used a national registry to identify hemodialysis patients who initiated citalopram or escitalopram (n >31,000) and hemodialysis patients who initiated fluoxetine, fluvoxamine, paroxetine, or sertraline (n >34,000) [49]. After controlling for potential confounding factors (eg, demographics, comorbid disorders, and concurrent medications), the analyses found that the one-year risk of sudden cardiac death following onset of antidepressant treatment was greater with citalopram or escitalopram than fluoxetine, fluvoxamine, paroxetine, or sertraline (hazard ratio 1.2, 95% CI 1.1-1.3). The association between citalopram or escitalopram and sudden cardiac death appeared to be stronger in patients aged 65 years or more, females, patients with conduction disorders, or patients prescribed other QT-prolonging drugs.

Some patients may discontinue SSRIs due to adverse effects (table 5) [50]. The incidence of adverse effects secondary to SSRIs in dialysis patients is likely to be at least comparable to the incidence in patients without ESKD. Detailed information about the adverse effects of SSRIs in the general population of depressed patients is discussed separately. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Side effects'.)

Other factors beyond side effects that are associated with poor adherence to antidepressants are acute general medical problems not secondary to the antidepressant [23].

-Other drug classes – Reasonable alternatives to SSRIs for the initial treatment of major depression include other second-generation antidepressants, such as SNRIs (eg, venlafaxine), atypical antidepressants (eg, bupropion or mirtazapine), and serotonin modulators (eg, vilazodone and vortioxetine) (table 6). In addition, these alternatives are suitable for patients who have not responded to SSRIs for past episodes of unipolar depression, as well as patients who do not respond to initial treatment of the current depressive episode with one or two trials of an SSRI. Information about the adverse effects of these other, non-SSRI antidepressants in the general population of depressed patients is discussed separately (table 5). (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects" and "Atypical antidepressants: Pharmacology, administration, and side effects" and "Serotonin modulators: Pharmacology, administration, and side effects".)

Tricyclics are often poorly tolerated (table 5), particularly due to their anticholinergic effects and potential for causing orthostatic hypotension [2,5,7,47]. They are also potentially cardiotoxic (eg, may prolong the QT interval) and generally avoided in patients with heart disease, which is common in dialysis patients. In addition, tricyclics have a narrow therapeutic index and are potentially lethal in overdose. Nevertheless, their sedating effects and potential efficacy in treating neuropathic pain may be beneficial, in which case the preferred agents are desipramine or nortriptyline because they are less likely to cause anticholinergic effects and orthostatic hypotension. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects".)

Monoamine oxidase inhibitors (MAOIs) are also avoided in patients with ESKD because these medications can cause episodes of hypotension. In addition, MAOIs can cause lethal drug-drug and drug-food interactions, and overdoses with these drugs are dangerous. (See "Monoamine oxidase inhibitors (MAOIs): Pharmacology, administration, safety, and side effects".)

Administration – Antidepressants can be started once the diagnosis of unipolar major depression has been made. Following administration of starting doses (table 6), clinicians should titrate the dose up to therapeutic doses, rather than using subtherapeutic doses to avoid adverse effects. Depression is often undertreated in dialysis patients and inadequate dosing of antidepressants is a common cause of therapeutic failure [51]. We generally treat unipolar major depression for 6 to 12 weeks at therapeutic doses before deciding whether antidepressants have sufficiently relieved symptoms [3].

Following response, full therapeutic doses should be anticipated for at least 6 to 12 months in patients to reduce the probability of relapse. (See "Unipolar depression in adults: Continuation and maintenance treatment", section on 'Duration'.)

It is unlikely that dialysis will remove meaningful amounts of antidepressants because they typically have a large volume of distribution, are highly bound to plasma proteins, and are metabolized in the liver [6]. Thus, clinicians may need to reduce the dose of antidepressants for patients treated with maintenance dialysis. For some individual drugs, dosing recommendations that are specific for hemodialysis and peritoneal dialysis can be found in the Lexicomp drug information topic for that drug, in the section on dosing in renal impairment. Some of the dose recommendations are based upon the European Renal Best Practice guideline [46]. The Lexicomp drug information topics are included in UpToDate. (See "Psychiatric illness in adults receiving maintenance dialysis", section on 'Psychopharmacology'.)

Drug-drug interactions can occur between psychotropic medications and other medications that may be prescribed for patients with ESKD [2,5,7]. Interactions of a specific drug with other medications may be determined by using the drug interactions program included in UpToDate.

Efficacy – Evidence supporting the use of antidepressants for treating unipolar major depression in dialysis patients includes meta-analyses of randomized trials in the general population of adults with unipolar major depression, which demonstrate that antidepressants such as SSRIs are more efficacious than placebo. (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Efficacy of antidepressants'.)

Other trials in the general population of patients with chronic general medical illnesses indicate that antidepressants are efficacious for depressive syndromes such as unipolar major depression and persistent depressive disorder (dysthymia) [6]. As an example, a meta-analysis of 25 trials compared antidepressants with placebo for depression in patients (n >1600 patients) with physical illnesses such as HIV, Parkinson disease, and diabetes [52]. After six to eight weeks, response (reduction of baseline depression ≥50 percent) was more likely with antidepressants (odds ratio 2.3, 95% CI 1.8-3.0). In the subgroup of patients treated with SSRIs (16 trials, n >1100), response occurred more often with active treatment than placebo (odds ratio 1.9, 95% CI 1.5-2.5). However, all-cause discontinuation of SSRIs was more likely in patients treated with antidepressants, as was dry mouth and sexual dysfunction.

In addition, randomized trials suggest that pharmacotherapy can be efficacious for treating unipolar major depression in patients on maintenance dialysis:

-A 12-week, open-label trial enrolled hemodialysis patients (n = 120) with unipolar major depression or persistent depressive disorder (dysthymia), and randomly assigned them to sertraline or CBT [16]. The target dose of sertraline was 200 mg/day. CBT included standard components adapted for maintenance dialysis, and consisted of 10 sessions, each lasting 60 minutes and administered at the chairside while patients received dialysis. Improvement of depression was modestly superior with sertraline than CBT. In addition, functioning at work and home and interpersonally were better in the sertraline group, as was satisfaction with life. However, adverse effects occurred more frequently with sertraline.

Limitations of the study included the use of chairside CBT during dialysis sessions [4]. Although this format is convenient for patients and may thus increase treatment uptake and adherence to treatment, it is not clear that this is the optimal setting for administering CBT, compared with the therapist’s office, given the lack of privacy between dialysis stations. In addition, hemodynamic shifts during dialysis may induce cerebral hypoperfusion and transient cognitive impairment.

-Another 12-week trial included hemodialysis patients (n = 43) with unipolar depressive syndromes and randomly assigned them to sertraline (100 mg/day) or placebo [53]. Response (reduction of baseline depression ≥50 percent) occurred in more patients who received sertraline than placebo (48 versus 9 percent [10/21 versus 2/22]). Although nausea occurred in more patients with sertraline than placebo (33 versus 14 percent), discontinuation of treatment was comparable for the two groups.

-An eight-week trial (n = 58) compared escitalopram with placebo in dialysis patients with unipolar depressive syndromes [54]. Improvement of depression posttreatment was assessed with the Hamilton Rating Scale for Depression (table 7), which ranges from 0 to 52, with higher scores indicating greater depression. Reduction of baseline depression rating scale scores was greater with escitalopram than placebo (posttreatment mean score 11 versus 28).

Randomized trials that failed to demonstrate a benefit for antidepressants include a six-month study (n = 30 dialysis patients) that found the efficacy of sertraline (maximum dose 100 mg/day) and placebo for depression was comparable [50]. Study limitations include the small sample size and the relatively low dose of sertraline, which is often given at 200 mg/day.

In addition, a 12-week trial compared sertraline (median dose 150 mg/day) with placebo in patients with nondialysis dependent chronic kidney disease and unipolar major depression (n = 193); improvement of depression was comparable for the two groups [55]. However, chronic kidney disease is often more benign than ESKD in terms of morbidity, psychosocial impairment, and quality of life [56]. In addition, 73 percent of study patients were male, whereas major depression occurs twice as often in women than men. (See "Unipolar depression in adults: Epidemiology", section on 'Sex'.)

Psychotherapy monotherapy – Patients on maintenance dialysis who have unipolar major depression may decline treatment with antidepressant drugs and prefer treatment with psychotherapy alone, due to reasons such as a prior history of poor response to antidepressants, and concerns about their adverse effects (table 5) and drug-drug interactions with other medications. For these patients, we suggest monotherapy with CBT or another psychotherapy, such as interpersonal psychotherapy and problem-solving therapy. Other reasonable choices include behavioral activation, family and couples therapy, psychodynamic psychotherapy, and supportive psychotherapy. (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Treatment options'.)

Evidence supporting the use of psychotherapy for depression in dialysis patients includes meta-analyses of randomized trials in the general population of adults with unipolar major depression, which indicate that psychotherapy (eg, CBT) is more efficacious than a control condition (eg, waiting list or usual care). (See "Unipolar major depression in adults: Choosing initial treatment" and "Unipolar major depression in adults: Choosing initial treatment", section on 'Psychotherapy'.)

Other trials in the general population of patients with chronic general medical illnesses indicate that psychotherapy is efficacious for depressive syndromes [6]. As an example, a meta-analysis of four trials compared psychotherapy with usual care or a waiting list control group for treating depression in patients (n >600 patients) with diabetes, which is often present in dialysis patients [57]. Posttreatment, remission was more likely with psychotherapy (odds ratio 3, 95% CI 2-5). In addition, follow-up one to six months later showed more patients had remitted with psychotherapy. However, heterogeneity across studies was moderate.

In addition, randomized trials suggest that psychotherapy can be efficacious for treating unipolar major depression in patients on maintenance dialysis:

A meta-analysis of four trials, lasting five weeks to three months, compared CBT with usual care (eg, waiting list) in depressed hemodialysis patients (n = 230) [58]. Improvement of depression was greater with CBT than usual care, and the benefit persisted three to six months posttreatment [59,60]. In addition, quality of life was superior with psychotherapy [58].

A meta-analysis of three trials lasting six weeks to three months compared psychotherapies other than CBT with usual care in hemodialysis patients with depression (n = 99) [58]. The psychotherapies included problem-solving therapy, supportive therapy, and group therapy, and usual care included no treatment or was not reported. Improvement of depression was greater with psychotherapy than usual care.

Other options — For patients on maintenance dialysis who have unipolar major depression, options beyond standard treatment with pharmacotherapy and psychotherapy are available. Although we suggest that these alternative treatments be used adjunctively with standard treatment, it is reasonable to use them alone in patients with mild to moderate depression who prefer this approach. During monotherapy with one of these alternative approaches, clinicians can continue to educate patients about depression and the potential benefits of standard treatments.

Exercise – Exercise may alleviate unipolar depressive symptoms in dialysis patients [3]. A systematic review included a meta-analysis of three randomized trials lasting 6 to 12 months, which compared exercise (eg, cycling and flexibility) with usual care (no intentional exercise) in hemodialysis patients with major depression (n = 108) [58]. Improvement of depression was greater with exercise than usual care and the clinical benefit was moderate. In addition, quality of life was better with exercise, and no adverse effects occurred. The same review reported that one small trial (n = 17) found improvement of depression in dialysis patients was superior with exercise than a support group.

Exercise programs for treating depression may need to be specifically tailored for dialysis patients, who often have relatively poor tolerance for exercise due to factors such as anemia and diminished cardiovascular function [3]. One small trial (n = 28) found improvement of depression was comparable with endurance training and resistance training [58].

Relaxation techniques – Relaxation may be beneficial for unipolar depressive syndromes. A meta-analysis of two randomized trials compared relaxation techniques (eg, progressively relaxing the muscles from the feet to the head) with usual care in 122 hemodialysis patients with depression [58]. Improvement of depression was greater with relaxation than usual care.

One of the trials, lasting four weeks, compared a relaxation technique involving diaphragmatic breathing with a wait-list control condition in hemodialysis patients with depressive symptoms (n = 57) [61]. Active treatment involved patients learning deep, slow diaphragmatic breathing sessions (two sessions per week, each lasting 30 minutes) while undergoing hemodialysis. After adjusting for potential confounding factors (sex, education, and general medical comorbidities), the analyses found that improvement of depressive symptoms one-week posttreatment was greater with active treatment, as was perceived role limitations and quality of life.

Other possible options for depression in dialysis patients include acupuncture, massage therapy, and meditation, but there are no compelling data to support their use [62,63].

Multiple studies have examined increasing the frequency of hemodialysis (eg, six times/week) to treat depression, but have failed to find a beneficial effect [3,6].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Depressive disorders".)

SUMMARY AND RECOMMENDATIONS

Prevalence – In patients who are treated with maintenance dialysis, the point prevalence of unipolar major depression (major depressive disorder) plus other depressive syndromes is approximately 25 percent. (See 'Epidemiology' above.)

Screening – We suggest that primary care clinicians or the nephrology treatment team screen all patients on dialysis for depression every 6 to 12 months, provided that services are in place to ensure follow-up for diagnosis and treatment (Grade 2C). We typically use the self-report Patient Health Questionnaire – Nine Item (PHQ-9) (table 1). (See 'Screening' above.)

Assessment – The evaluation for depressive syndromes is generally similar in patients treated with maintenance dialysis and individuals in the general population. (See 'Assessment' above.)

Diagnosis – Among patients who are treated with maintenance dialysis, the diagnostic criteria for unipolar major depression (table 2), persistent depressive disorder (dysthymia) (table 3), minor depression (table 4), and other depressive syndromes are identical to those used in the general population. (See 'Diagnosis' above.)

Potential adverse consequences – Major depression in the context of maintenance dialysis is associated with an increased risk of hospitalization, withdrawal from dialysis, and all-cause mortality. (See 'Potential adverse consequences' above.)

Treatment

Preferred – For patients on maintenance dialysis who have unipolar major depression, we suggest treating the depressive syndrome with an antidepressant plus psychotherapy rather than monotherapy (Grade 2C). We typically use a selective serotonin reuptake inhibitor (SSRI) such as sertraline plus cognitive-behavioral therapy (CBT). (See 'Initial therapy' above.)

Alternatives – Alternatives to the combination of an antidepressant plus psychotherapy include medication monotherapy and psychotherapy monotherapy.

-Medication monotherapy – Patients on maintenance dialysis who have unipolar major depression may prefer using medication monotherapy due to a prior history of poor response to psychotherapy, or psychotherapy may not be available. For these patients, we suggest an SSRI (Grade 2C). We typically use sertraline, but fluoxetine or paroxetine are reasonable alternatives. In addition, reasonable alternatives to SSRIs include other second-generation antidepressants, such as serotonin-norepinephrine reuptake inhibitors, atypical antidepressants, and serotonin modulators (table 6). Conversely, we generally avoid citalopram, escitalopram, tricyclics, and monoamine oxidase inhibitors due to potential harms.

-Psychotherapy monotherapy – Patients on maintenance dialysis who have unipolar major depression may decline treatment with antidepressant drugs and prefer treatment with psychotherapy alone, due to a prior history of poor response to antidepressants and concerns about their adverse effects (table 5). For these patients, monotherapy with CBT or another psychotherapy, such as interpersonal psychotherapy and problem-solving therapy, can be helpful. Other reasonable choices include behavioral activation, family and couples therapy, psychodynamic psychotherapy, and supportive psychotherapy. (See 'Alternatives' above.)

Adjunctive options – Adjunctive exercise and relaxation techniques may be helpful. (See 'Other options' above.)

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Topic 132291 Version 7.0

References

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