Assessment and management of depression in palliative care

INTRODUCTION — Patients with advanced illness often experience psychological distress. While emotional distress is natural and expected in individuals experiencing serious illness and confronting the end of their lives, the differentiation between a normal and appropriate reaction to dying versus a more serious psychiatric disorder such as major depression can be clinically challenging.

This topic reviews assessment and management of depression in patients receiving palliative care for serious illness. The basic principles of palliative care, assessment and management of other symptoms that are prevalent among patients with advanced illness, and psychosocial, existential, and spiritual issues in palliative care are discussed separately. (See "Benefits, services, and models of subspecialty palliative care" and "Overview of comprehensive patient assessment in palliative care" and "Approach to symptom assessment in palliative care" and "Overview of managing common non-pain symptoms in palliative care" and "Psychosocial issues in advanced illness" and "Overview of spirituality in palliative care".)

SCOPE OF THE PROBLEM — Depressive syndromes are a common mental health problem in palliative medicine, yet they are widely misunderstood, underdiagnosed, and undertreated [1-5]. Data on the prevalence of moderate to severe depression in the last six months of life for patients with terminal cancer were provided by a unique observational cohort study of all cancer decedents in Ontario Canada between 2007 and 2009 (figure 1) [6].

Clinicians often fail to recognize the extent of a patient's depression until too late in the course of the disease. As an example, in a survey of 1046 consecutive hospice patients, only 10 percent were prescribed antidepressants at some point during hospice care [3]. Patients prescribed tricyclic antidepressants were nearly always underdosed, and three-fourths of those started on antidepressants died within two weeks.

Among the many barriers to the recognition and treatment of psychological symptoms in patients with advanced illness are the following:

●The mistaken belief that all patients facing or contemplating the end of life are "depressed"

●The clinician's lack of knowledge and skill at recognizing and treating major depression [7]

●Fear of upsetting the patient or intruding at an emotionally vulnerable time

●The stigma associated with psychiatric diagnoses such as major depression

●Apprehension about possible drug-drug interactions with psychotropic agents

●When caring for patients with advanced illness, clinicians themselves may feel a sense of hopelessness that can lead to therapeutic nihilism [8]

Burden of depression — Psychological distress is a major cause of suffering among patients with advanced disease or terminal illness [9,10]. Depressive syndromes are highly correlated with a reduced quality of life, greater difficulty in managing the course of the patient's illness, decreased adherence to treatment, and earlier admission to inpatient or hospice care [1,11-16]. Depression also impairs the patient's capacity for pleasure, meaning, connection, and doing the emotional work of separating and saying goodbye; it amplifies pain and other symptoms, and causes anguish and worry in family members and friends [8].

Depression, suicide, and desire for a hastened death — Individuals with advanced illness who suffer from depressive syndromes are also at high risk of suicide and suicidal ideation, and they have an increased desire for a hastened death [4,17-23]. (See "Suicidal ideation and behavior in adults".)

●One study concluded that suicidal ideation was relatively infrequent in cancer and limited to those who were significantly depressed [22].

●In a review of psychiatric consultation data from Memorial Sloan-Kettering Cancer Center, one-third of suicidal cancer patients had major depression, and 50 percent were diagnosed with an adjustment disorder with features of both anxiety and depression at the time of evaluation [21,24].

●Although some studies suggest that hopelessness is a significantly better predictor of completed suicide than is depression alone [25-27], others have found that a clinical diagnosis of depression, the severity of depressive symptoms, and a sense of hopelessness are all strong and independent predictors of a desire for hastened death in the terminally ill [20,28]. Depression, hopelessness, and general psychological distress are also consistently associated with interest in physician-assisted dying and euthanasia; as many as 59 percent of patients requesting physician-assisted dying are depressed [29].

Prevalence of depression in palliative care — The prevalence of depressive syndromes in patients with advanced or terminal illness varies widely.

Cancer patients — The reported prevalence of major depression in individuals with cancer varies from 3 to 38 percent [30-36]. This wide variability is explained by the lack of agreement as to appropriate diagnostic criteria to be used in the setting of advanced illness (table 1), differences in patient populations (ie, demographics, type and stage of disease, treatment versus no treatment), and variation in assessment methods. In general, rates are higher in populations with advanced cancer, greater levels of disability, and/or unrelieved pain [33,35,37-39]. (See 'Assessment and diagnosis' below.)

Even when the most stringent criteria are used, major depression is diagnosed in approximately 7 percent, and minor depression in 11 percent, of patients with advanced cancer [33,38-40]. The reported prevalence of depression in terminally ill cancer patients is between 13 and 26 percent [12,20,41,42]. These rates are significantly higher than one-month prevalence rates of depression in the general North American population, which range from 1.6 to 4.9 percent [30,31]. (See "Patients with cancer: Overview of the clinical features and diagnosis of psychiatric disorders", section on 'Prevalence of psychiatric comorbidity'.)

The clinical features, prevalence, and diagnosis of depressive disorders in patients with cancer are discussed in more detail elsewhere. (See "Patients with cancer: Overview of the clinical features and diagnosis of psychiatric disorders".)

Non-cancer populations — Similarly, patients with other advanced medical illnesses also appear to have elevated rates of depression. Within non-cancer populations, depression has been identified in up to 27 percent of patients with end-stage kidney disease and those seeking to discontinue dialysis [43,44], 20 to 40 percent of those with Parkinson disease [45,46], 35 percent of patients with advanced multiple sclerosis [47], and 22 to 46 percent of patients with advanced heart failure [48,49]. Depression is also a common symptom in patients with AIDS, affecting 23 to 52 percent of those with end-stage disease [50,51]. (See "Depression, mania, and schizophrenia in patients with HIV" and "Kidney palliative care: Principles, benefits, and core components".)

Risk factors — An awareness of the specific risk factors for depressive disorders in patients receiving end-of-life care may facilitate early diagnosis and intervention [52].

Age and gender — In several (but not all [53]) studies, younger cancer patients have higher rates of depressive disorders and self-reported distress [54-58]. While depression is twice as common in women as compared with men in the general population, gender is not consistently reported to be a risk factor for depression in cancer patients [33,59].

Prior history of depression — A past history of depression is a risk factor for major depression in cancer patients [5,60].

Uncontrolled symptoms — The presence of uncontrolled symptoms, particularly pain, is a major risk factor for depression and suicide among patients with cancer [61-63]. Some speculate that depression may result in an amplification of pain, while others suggest that it lessens the ability to tolerate the stress of physical symptoms [64,65]. Thus, the causal pathway may be bidirectional [66].

Type of illness — The incidence of depression also depends upon the patient's particular illness. Among cancer patients, those with head and neck and pancreatic cancers are at a particularly high risk [33,67]. For patients with pancreatic cancer, psychiatric symptoms may precede the physical symptoms of the disease by several months, leading some to propose that tumor-induced changes in the neuroendocrine system may contribute to depression [61,67,68].

Illness and treatment-related factors — Certain factors associated with the patient's illness or its treatment may be associated with depression. Tumors arising within or metastasizing to the central nervous system can cause depression [15,58,69,70]. In the case of pituitary tumors, this may be related to excess cortisol production [71-73]. Metabolic complications such as hypercalcemia, often associated with breast and lung cancers, can also be associated with depression. (See "Clinical manifestations of hypercalcemia".)

Depression is common among patients with HIV/AIDS. HIV infection increases the risk of depression both through direct damage to subcortical brain areas and by disease-related chronic stress, social isolation, and intense demoralization. (See "Overview of the neuropsychiatric aspects of HIV infection and AIDS", section on 'Major Depression'.)

Other causes of depression in cancer patients include toxins created by a tumor, possibly autoimmune reactions [74], viral infections, and nutritional deficiencies. Depression can also represent an adverse effect from certain treatments, including glucocorticoids; chemotherapy drugs (vincristine, vinblastine, asparaginase, intrathecal methotrexate, interferon, and tamoxifen [75-82]); as well as radiotherapy to the brain or head and neck [83-87]. (See "Major adverse effects of systemic glucocorticoids".)

Existential concerns and spirituality — The recognition of a life-threatening crisis brings existential concerns (unfulfilled ambitions, the meaning of life, maintaining dignity at the end of life) to the forefront [1]. Existential suffering and deep personal anguish are some of the most distressing experiences that occur in the dying [88]. The relationship between existential distress and depressive syndromes among the terminally ill is not well studied. In one study, existential distress (ie, concerns related to loss of meaning in life) showed a higher correlation with scores on depression scales than did items pertaining to physical symptoms, medical treatment, or social isolation [57].

Patients who have high levels of spiritual wellbeing tend to be less depressed. The inverse correlation between religious beliefs/spirituality and severity of depressive symptoms was shown in a sample of 162 terminally ill patients with cancer and AIDS [89]. The beneficial aspects of religion related primarily to spiritual wellbeing rather than to formal religious practice. (See "Psychosocial issues in advanced illness" and "Overview of spirituality in palliative care".)

ASSESSMENT AND DIAGNOSIS — Screening for depression should be carried out in all palliative care patients given the high prevalence of symptoms. For patients with cancer, the American Society of Clinical Oncology has issued recommendations for the assessment and diagnosis of depression, endorsing practice guidelines from the Pan-Canadian Guideline on Screening, Assessment and Care of Psychosocial Distress (Depression, Anxiety) in Adults with Cancer [90]. The recommendations state that every patient with cancer should be screened for depression when the initial diagnosis of cancer is made and periodically thereafter as clinically indicated, especially with changes in cancer or treatment status (eg, posttreatment, recurrence, or progression) as well as transition to palliative care. We agree with this recommendation.

The two-item Patient Health Questionnaire (PHQ-2) (table 2) can be used to screen for depression. Patients who screen positive (a single "yes" response) should be interviewed to diagnose depression; the interview can be facilitated with the PHQ-9 (table 3). Additional information about screening for depression is discussed separately. (See "Screening for depression in adults".)

Depressed mood, sadness, grief, and anticipatory feelings of loss are all appropriate responses to advanced disease and dying. However, feelings of hopelessness, helplessness, worthlessness, guilt, lack of pleasure, and suicidal ideation (even mild or passive) are among the best indicators of depressive syndromes in these patients [21,24,91]. Passive suicidal ideation ("I'd be better off dead") should be distinguished from active suicidal ideation ("I’m going to kill myself"). (See "Bereavement and grief in adults: Clinical features", section on 'Unipolar major depression'.)

A summary of some of the contrasting characteristics of normal grief versus depression in terminally ill patients is provided in a table (table 4) [8].

There are two important caveats:

●Feelings of hopelessness, helplessness, and guilt must be considered in the context of the patient's illness. Hopelessness may be difficult to interpret in the setting of a disease where there is no hope for cure or recovery [27]. Furthermore, patients may feel helpless because of their physical condition, or there may be a sense of guilt if the illness is related to certain behaviors (eg, cirrhosis and hepatocellular cancer in alcoholics, lung cancer in smokers). Symptoms that seem out of proportion to the patient's actual situation should prompt concern for major depression.

●There is considerable overlap between the neurovegetative or somatic symptoms of major depression (eg, fatigue, insomnia, anorexia, and weight loss) and those associated with any serious illness and/or its treatment. This has led some to exclude these symptoms from diagnostic criteria for depression in medically ill patients, a subject that is discussed in detail below. (See 'Criterion-based diagnosis' below.)

Tools for assessment and diagnosis — There are two major types of research methods that are available for the assessment of depression in advanced illness: criterion-based instruments, which may be based upon a diagnostic classification scheme or the outcome of a structured diagnostic interview, and self-report measures. The available tools are summarized in a table (table 5).

Criterion-based diagnosis — The most widely used criteria to diagnose depression in non-terminally ill patients are those outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [92]. If sufficient criteria are not met for the diagnosis of major depression, then patients may be classified as "adjustment disorder" with depressive features, or mood disorder secondary to medical condition.

Small differences between investigators in the application of symptom severity thresholds (eg, the severity with which symptoms must be expressed before they are considered clinically significant) can result in large differences in prevalence rates for depression in studied populations. Furthermore, as noted previously, because somatic complaints in medically ill patients may also be attributable to the physical effects of the illness or its treatment, their use as diagnostic criteria can also affect the rate of diagnosis of major depression in medically ill patients, particularly when they are used in conjunction with a low-threshold symptom severity approach [32].

Because of these issues, several general approaches to the diagnosis of major depression in the medically ill have evolved, which differ in how they deal with somatic symptoms and in the definition of symptom severity. These approaches are outlined in a table (table 1).

The most widely used is the substitutive approach of Endicott [93]. The Endicott scale replaces four of the DSM-IV-TR somatic criteria thought most likely attributable to medical illness or its treatment (ie, change of weight/appetite, sleep disturbance, loss of energy/fatigue, difficulty thinking or concentrating) with cognitive substitutes (depressed appearance, social withdrawal, brooding/self-pity/pessimism, and lack of reactivity in situations that would normally be pleasurable) (table 6).

Although the substitutive approach is used most often for research purposes, most experts agree that for clinical purposes, the use of a modified inclusive set of diagnostic criteria that incorporates both neurovegetative and psychological symptoms of depression, and emphasizes the presence of hopelessness, worthlessness, guilt, and suicidal ideation is most appropriate for the palliative care population [1,94].

Self-report instruments — Criterion-based diagnostic systems require an in-depth clinical interview. Self-report methods (eg, the PHQ-9 (table 3) [95,96], 21-item Beck Depression Inventory [BDI] or the shorter 13-item scale [97,98], or visual analog scales [99,100]) may be used if a direct face-to-face interview is not feasible. However, these self-report scales are only a crude substitute for a careful diagnostic interview. The efficacy of these tools as a diagnostic aid in the palliative care setting is not as good as a brief interview directly addressing the commonly accepted diagnostic criteria. Situations where they might be useful include providing additional information in difficult cases, quantifying the severity of a depressive syndrome after initial diagnosis, or monitoring changes in depression over time.

A self-report measure designed to differentiate between preparatory grief and depression in adults, the Terminally Ill Grief or Depression Scale (TIGDS), has been developed and validated in a small series of 47 adult inpatients [101]. The tool is comprised of grief and depression subscales totaling 47 questions and is described as easy to administer and acceptable to patients. However, the TIGDS has not been tested in other clinical settings and requires validation in larger samples.

Simple screening instruments — A careful diagnostic interview remains the gold standard method for assessment of depression in medically ill patients [8]. However, direct face-to-face interviews are time-consuming, thus limiting their usefulness in palliative care settings.

More than 50 questionnaires have been developed to aid the detection of depression or severe distress, but most have been validated in primary care patients. Few have been studied specifically in palliative care settings [102-104], and most of these are too long for routine use. Assessment of depression in advanced illness requires instruments that are not only valid and reliable but also minimally burdensome, acceptable to patients, and easy to administer and score. A detailed discussion of depression assessment in cancer patients is provided elsewhere. (See "Patients with cancer: Overview of the clinical features and diagnosis of psychiatric disorders", section on 'Assessment of psychiatric symptoms' and "Patients with cancer: Overview of the clinical features and diagnosis of psychiatric disorders", section on 'Depressive disorders'.)

Simple one- or two-question and other abbreviated assessments appear to be as effective as longer instruments in screening for depression in most (table 7) [97,99,105-111] but not all studies [112]. The single-item screen is adapted from the Schedule for Affective Disorders and Schizophrenia (SADS) depression criteria [105] and consists simply of asking the question: "Have you been depressed most of the time for the past two weeks?"

This method appears to be accurate for identifying patients who might qualify for a diagnosis of depression on the basis of a full interview covering all of the criterion symptoms, and thus is a useful screening tool to select patients who need further evaluation [97-99,102,106,107,113,114].

The utility of this approach was shown in a study of 200 palliative care in patients with terminal cancer that compared the performance of four brief screen measures for depression, including the single-item question "Are you depressed?", a two-item question assessing depressed mood and loss of interest or pleasure in activities, a visual analog scale (VAS) for mood based on the Memorial Pain Assessment Card [107], and the BDI short version [99]. Using a semi-structured diagnostic interview as the gold standard for diagnosis, the single-item interview (using a threshold stringency equivalent to patients feeling depressed "most of the time") outperformed both the BDI and the VAS. The two-item scale did not identify more depressed patients, and it characterized four patients as being depressed who were classified as not depressed after the full interview.

The sensitivity and specificity of a single-item question as a screen for depression have been shown by others in diverse cohorts [102,113,114], although conflicting results have been observed in palliative care populations in the United Kingdom [104,112,115] and in Japan [116]. This is perhaps not surprising. While some patients may readily verbalize that they are depressed, others, no matter how despairing, may never acknowledge it or may label it something else (eg, nervousness) [94].

Guidelines for distress management from the National Comprehensive Cancer Network (NCCN) suggest the use of a VAS (ranging from no distress to extreme distress) as well as patient self-report of depression, sadness, and loss of interest in usual activities (yes or no) as a screen for depression [117]. Both methods are reasonable as screening tools.

TREATMENT — Major depression in palliative care or terminally ill patients is treatable, although some data suggest that these patients may not be adequately managed. For example, one cross-sectional analysis of patients with cancer with depression (n = 1538) being treated in Scotland found that over 70 percent of those with depression were not receiving potentially effective therapy [118].

The more favorable side effect profile of newer antidepressants (eg, selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]) has facilitated their use in older adults and the medically ill. Because treatment with these agents is relatively benign and well tolerated, clinicians should have a low threshold for initiating therapy. Psychostimulants, in comparison with other antidepressants, have a faster onset of activity and are the preferred initial option for palliative care patients whose life expectancy is less than two to four months or for those in need of urgent treatment.

General treatment principles — The first step in treating depression is to relieve uncontrolled symptoms, particularly pain. Although pain is most often an issue in the setting of cancer, patients who have diseases that are not usually considered painful (eg, cardiac disease) may also experience moderate to severe pain at the end of life [119]. (See "Assessment of cancer pain".)

All patients should have a complete medical evaluation to assess possible general medical contributors to depressed mood. (See 'Illness and treatment-related factors' above.)

If depression persists once pain is controlled, and a potentially reversible general medical cause of depressed mood cannot be identified, specific therapy is warranted. Treatment should be tailored to the individual needs of the patient. In addition to drug therapy, effective psychosocial interventions include individual or group psychotherapy, hypnotherapy, cognitive-behavioral therapy (eg, relaxation training and biofeedback), existential therapy, and self-help groups [120-124]. (See "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm".)

There are no randomized trials that specifically address the benefit of psychotherapy for palliative care patients with depression, and there are few that address pharmacologic treatment [125]. As a result, therapy for depression in these patients is generally based upon the larger body of evidence on effective treatments in patients with cancer, or primary care populations with either no physical illness or less severe medical conditions. Although there is a lack of controlled trials to support the efficacy of combined therapy, most experts recommend an approach that combines supportive psychotherapy with patient and family education and judicious use of antidepressant medication [8]. (See "Management of psychiatric disorders in patients with cancer" and "Major depressive disorder in adults: Approach to initial management" and "Unipolar depression in adults: Supportive psychotherapy".)

It is important to note that for patients in palliative care, the data support the use of integrated treatment delivered collaboratively between disease-specific specialists, primary care providers, and mental health specialists. While best studied in patients with cancer [126], it is likely that patients with other life-threatening illnesses may derive a similar benefit.

Psychosocial interventions — A broad range of psychological interventions have been found to be effective for the treatment of major depression in a variety of patients, including those with cancer [127-131]. (See "Management of psychiatric disorders in patients with cancer", section on 'Psychotherapy' and "Overview of psychotherapies".)

Psychotherapy increases the effectiveness of drug therapy for major depression in older primary care patients [132,133], and most experts recommend a combined approach in medically ill patients as well, despite the lack of evidence from randomized trials to support this practice. However, patients with severe depressive symptoms may be too immobilized and/or dysphoric to effectively engage in psychotherapy; such patients may first need to receive appropriate pharmacotherapy.

Supportive psychotherapy — The single most important aspect of psychotherapeutic support for depressed terminally ill patients is the therapeutic alliance between the patient and the primary medical caregiver [134]. Optimally, this relationship will be one of mutual trust, respect, and sensitivity. Maintaining ongoing contact with the patient both ensures that symptoms and treatment efficacy will be continuously reevaluated and reassures the patient that they will not be abandoned throughout the course of the terminal illness.

Supportive psychotherapy aims to support adaptive coping mechanisms, minimize maladaptive ones, and decrease adverse psychological reactions such as fear, shame, self-loathing, and withdrawal. The main components of psychotherapy are active listening, supportive verbal interventions, and occasional interpretation.

Clinicians should elicit from the patient their concerns about death and the dying process but need not focus solely on the issue of death. Patients should be encouraged to talk about their lives and experiences, fears about the impact of illness on family members, and past experiences of coping with loss. Patients should be encouraged to freely talk about or ask questions about their prognosis, with their therapist taking an interested and interactive role in the discussion. Reassurance is useful when it is based on a specific understanding of the individual's status and is not clinically unrealistic.

Supportive therapy can be provided by the primary medical caregiver, psychiatrist, psychologist, hospice nurse, or social worker, depending on time, interest, training, and the severity of the patient's condition. Sometimes, supportive psychotherapy alone is sufficient to treat depression. Treating major depression with supportive psychotherapy is discussed in more detail separately. (See "Unipolar depression in adults: Supportive psychotherapy".)

Structured cognitive therapies — Cognitive-behavioral techniques, which focus on distorted thoughts that adversely affect mood, are often integrated into depression therapy. These approaches explore patients' beliefs about the cancer diagnosis and its treatment and attempt to elicit irrational or unhelpful thoughts that lead to feelings of helplessness and hopelessness. Therapy then leads to the correction of these maladaptive thoughts along with providing new coping skills (eg, relaxation). (See "Management of psychiatric disorders in patients with cancer", section on 'Cognitive-behavioral therapy'.)

Existential psychotherapy — Serious illness has a profound impact on the sense of self; the physical and psychological losses that are often part of the illness challenge one's sense of wholeness and integrity, which are key components of emotional health. Serious illness also challenges personal values of independence and control (which together form the construct of dignity) as well as self-determination and self-worth.

Existential therapies such as dignity therapy [135-139], meaning-centered psychotherapy [140,141], and therapeutic life review [142] may represent appropriate choices for some terminally ill patients who confront daily choices that affect quality of life and who often have questions about the meaning, purpose, and value of their lives. Such therapy can improve spiritual wellbeing, lessen sadness and depression, and sustain or enhance a sense of meaning, peace, and purpose at the end of life. (See "Overview of spirituality in palliative care", section on 'Spiritual distress and existential suffering' and "Psychosocial issues in advanced illness", section on 'Common issues for patients with advanced illness'.)

Pharmacotherapy — As with psychotherapy, there is a general lack of high-quality evidence regarding the effectiveness of antidepressants in patients with major depression who are receiving end-of-life care [124,125]. There are no randomized trials focusing on this population. However, randomized trials and meta-analyses have documented the efficacy of antidepressants in depressed patients with physical illness, including those with "life-threatening" physical illness [143]. Furthermore, a systematic review of antidepressants for treatment of depression in palliative care, which included 25 placebo-controlled randomized trials, demonstrated significant benefit of treatment over placebo within four to five weeks, with continued improvement over time [144]. (See "Management of psychiatric disorders in patients with cancer", section on 'Pharmacotherapy'.)

Drug selection — There are several classes of antidepressants, including:

●Psychostimulants (eg, dextroamphetamine, methylphenidate, and modafinil)

●SSRIs (see "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects")

●Tricyclic antidepressants (TCAs) and tetracyclic antidepressants (see "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects")

●SNRIs (see "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects")

●Serotonin modulators (eg, nefazodone, trazodone, and vilazodone) (see "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects")

●Atypical antidepressants (eg, agomelatine, bupropion, and mirtazapine) (see "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects")

●Monoamine oxidase inhibitors (MAOIs), which are rarely used in palliative care (see "Monoamine oxidase inhibitors (MAOIs): Pharmacology, administration, safety, and side effects")

The agents used most commonly in palliative care patients are psychostimulants, SSRIs, and TCAs (table 8). Although there is no evidence that any particular antidepressant or class of antidepressants is preferable for patients receiving end-of-life or palliative care, the 2008 clinical practice guidelines for initial treatment of depression in primary care patients from the American College of Physicians make a strong recommendation to initiate an SSRI, SNRI, or atypical antidepressant [145]. The most compelling reason why SSRIs are usually selected for initial therapy in depressed primary care patients is not because of demonstrated greater efficacy but because of their more favorable side effect profile [146,147] and the markedly lower danger with overdose. (See "Major depressive disorder in adults: Approach to initial management" and "Tricyclic antidepressant poisoning".)

However, there is some evidence that TCAs might be preferred for severely depressed patients. In general, patients with severe depression are less likely to drop out of treatment trials because of unacceptable side effects when taking an SSRI as compared with a TCA, but they are more likely to drop out because of treatment inefficacy. Evidence-based European guidelines for management of depression in palliative cancer care do not endorse any one category of antidepressants for initial therapy [148]. (See "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Patients with severe major depression'.)

In addition to these drugs, psychostimulants are an important option for treatment of depression at the end of life because, unlike classic antidepressants, they take effect quickly.

For palliative care patients, the factors that influence the choice of initial agent in addition to side effect profile (table 9) are the available timeframe for treatment, coexisting medical problems and symptoms, and pharmacologic properties (eg, half-life, potential for drug-drug interactions, and availability of liquid formulation):

●While patients with an anticipated life expectancy of several months can afford to wait one or two weeks for a TCA or SSRI to begin working (as long as immediate onset of action is not essential), those with a shorter remaining lifespan (or severe depression requiring urgent treatment) do better with rapidly acting psychostimulants [149-153]. Psychostimulants can be useful for the treatment of depressive symptoms in patients who are weeks from death. Even patients who are extremely debilitated and fatigued may experience improvement in mood and energy within 24 to 48 hours of starting treatment (table 8).

Psychostimulants may also be useful as initial agents for patients with a relatively long estimated lifespan who have severe depression and require urgent treatment and a rapid response [154]. An antidepressant such as an SSRI can be introduced concurrently and the dose increased to therapeutic levels over one to two weeks while the dose of the psychostimulant is gradually decreased.

●Older adult patients and those with cardiovascular disease should avoid drugs that cause orthostatic hypotension (eg, TCAs) (table 9). Similarly, because they lack anticholinergic effects, SSRIs are preferred for patients with slowed intestinal motility or urinary retention, as well as those who have stomatitis or chronic dry mouth secondary to chemotherapy or radiotherapy.

●For patients who are at risk for seizures or who may have a lower seizure threshold because of other medications, maprotiline (where available) and bupropion should be avoided as they are associated with the highest seizure risk (table 9). However, virtually any antidepressant can have a small effect on lowering the seizure threshold, and all agents should be used cautiously in patients with central nervous system (CNS) disease.

●Side effects may sometimes be used to the patient's advantage. As an example, the depressed patient who is experiencing agitation or insomnia may benefit from the more sedating antidepressants (eg, TCAs, trazodone, or mirtazapine) (table 9). By contrast, patients with fatigue or psychomotor slowing may do better with compounds that have the least sedating effects (eg, SSRIs and psychostimulants).

In addition to their antidepressant action, the TCAs have analgesic properties (as do SNRIs such as venlafaxine and duloxetine), and they potentiate the effects of opioid analgesics. Thus, patients who are experiencing pain, particularly neuropathic pain, may benefit from these agents alone or in combination with other drugs. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Antidepressants'.)

●Liquid formulations are available for some antidepressants (eg, fluoxetine, sertraline, paroxetine, citalopram, escitalopram, doxepin, and nortriptyline) and may be preferred for patients who cannot swallow pills.

●Rather than continuously experimenting with a range of different drugs, clinicians should become comfortable with prescribing a single drug from each class in order to become familiar with dosing regimens, actions, interactions, and side effects. Specific interactions of antidepressants with other medications may be determined using the drug interactions program included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on drug interactions.

Selective serotonin reuptake inhibitors — In most cases, SSRIs are preferred for first-line therapy. SSRIs are generally as effective as TCAs for the treatment of depression, and they have a wider margin of safety than TCAs in the event of an overdose.

There are currently several SSRIs marketed in the United States: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline (table 8). All have similar efficacy but differ in pharmacokinetics, drug interactions, and side effect profile. Although SSRIs are generally well tolerated, dose-related side effects such as jitteriness, restlessness, anxiety, agitation, headache, sexual dysfunction, gastrointestinal symptoms (diarrhea and nausea), and insomnia are common and may be problematic in debilitated patients (table 9). Headache and jitteriness often subside after the first four to seven days of antidepressant initiation. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".)

Fluoxetine was shown to significantly improve quality of life and depressive symptoms in patients with advanced cancer in two of the only controlled trials carried out in this population [155,156]. However, the clinical use of this agent in palliative care is limited by its long half-life (it takes five to six weeks to reach steady state drug concentrations) and the potential for significant drug-drug interactions because it inhibits hepatic drug metabolizing enzymes such as cytochrome P450 [157,158]. Specific interactions of fluoxetine and other SSRIs with other medications may be determined using the drug interactions program included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on drug interactions. The specific cytochrome enzymes that each SSRI and their metabolites potently or moderately inhibit are summarized elsewhere. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Drug-drug interactions'.)

In contrast to the long half-life of fluoxetine, steady state levels are reached in 4 to 14 days with paroxetine, fluvoxamine, and sertraline. However, the advantages of a shorter half-life SSRI such as paroxetine and fluvoxamine in ill cancer patients is counterbalanced by the fact that a missed dose may result in fairly rapid and unpleasant withdrawal syndrome. This does not tend to happen with sertraline.

Paroxetine, fluvoxamine, and sertraline are also likely to be better tolerated by terminally ill patients than other SSRIs because they have fewer active metabolites, which can accumulate and cause toxicity. Citalopram and escitalopram have significantly fewer interactions with hepatic metabolizing enzymes than the other SSRIs, making them appealing choices in patients who are on other medications where drug-drug interactions are a concern.

As in older adults, the initial SSRI dose for patients with advanced or end-stage medical illness should be approximately one-half that used in otherwise healthy patients (table 8). (See "Diagnosis and management of late-life unipolar depression".)

Tricyclic antidepressants — Many studies have demonstrated the efficacy of TCAs in depressed, medically ill patients, although none are controlled trials.

Although TCAs are still used in terminally ill cancer patients, they are not as well tolerated as SSRIs because of their sedating and autonomic effects, which can be particularly troublesome for terminally ill patients (table 8). The major side effects are anticholinergic effects, including dry mouth, blurred vision, constipation, urinary retention, tachycardia, orthostatic hypotension, impaired memory, confusion, or delirium (table 9). These adverse effects can be particularly problematic for patients receiving other medications with anticholinergic properties. Such patients are at risk for developing anticholinergic delirium [159]. Desipramine and nortriptyline are less anticholinergic than other tricyclics.

Older adults are particularly susceptible to memory impairment, confusion, and hallucinations. Sedation is a particular problem with the tertiary amine tricyclics (ie, imipramine, amitriptyline, and doxepin), which can exacerbate the sedating effects of other medications [149].

Older patients and those with advanced medical illness have a higher likelihood of drug intolerance and drug-drug interactions. Specific interactions of these agents with other medications may be determined using the drug interactions program included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on drug interactions. (See "Diagnosis and management of late-life unipolar depression".)

If TCAs are chosen as the initial agent for older patients, they should be started at low doses and slowly titrated (table 8). In order to minimize drug toxicity and more carefully guide the drug titration process, TCAs with well-established therapeutic plasma levels and generally better tolerance profiles, such as desipramine and nortriptyline, should be prescribed [160]. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects".)

Other antidepressants — Venlafaxine is a potent SNRI (table 8). Its use in terminally ill depressed patients has not been studied, but its pharmacokinetic properties and generally well-tolerated side effect profile suggest that it is a potentially useful agent [134]. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Venlafaxine'.)

Mirtazapine has also been shown to be effective for improving multiple symptoms, depression, and quality of life in patients with advanced cancer, although it is relatively sedating [161,162]. (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Mirtazapine'.)

Similarly, trazodone can be an effective antidepressant, but it is also sedating (table 8). It may be given at low doses to treat depressed cancer patients with insomnia, and it may also be useful for patients who require adjunct analgesic effects in addition to antidepressant effects [134]. Trazodone has also been associated with priapism and should thus be used with caution in male patients [163]. Nefazodone has been associated with liver failure and probably should not be used in this patient population. (See "Serotonin modulators: Pharmacology, administration, and side effects", section on 'Trazodone' and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Antidepressants'.)

Bupropion is not the first drug of choice for the treatment of depression in terminally ill patients, although it may be considered for patients who have a poor response to the trial of other antidepressants (see "Switching antidepressant medications in adults"). The energizing effects of bupropion are similar to the stimulant drugs (table 8) [164,165]. However, it is contraindicated for cancer patients with CNS disorders, due to its association with increased incidence of seizures [166]. (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Bupropion'.)

Heterocyclic antidepressants have side effect profiles similar to those for the TCAs [134]. As noted above, maprotiline (where available) should be avoided in patients with brain tumors and patients susceptible to seizures, as seizure incidence is increased with this medication [167]. Mianserin, a serotonergic antidepressant with adjuvant analgesic properties, is widely used in Europe and Latin America but not available in the United States. It is safe and effective for the treatment of depression in cancer [168].

As a drug class, the MAOIs are generally considered a less desirable alternative for treating depression in the terminally ill, due to the large number of adverse interactions associated with these drugs [149,169]. Thus, MAOIs are generally reserved in this patient population for those who have shown past preferential responses to them for treatment of their depression [134]. (See "Monoamine oxidase inhibitors (MAOIs): Pharmacology, administration, safety, and side effects".)

Although it is not a classic antidepressant, the triazolobenzodiazepine alprazolam is a mildly effective antidepressant as well as an anxiolytic and may be particularly useful in medically ill patients who have mixed symptoms of anxiety and depression [123]. A meta-analysis of randomized trials comparing alprazolam with placebo in patients with major depression (not limited to patients in the palliative care population) found greater symptom response with alprazolam [170].

Psychostimulants — The efficacy of psychostimulants (dextroamphetamine, methylphenidate, and modafinil) for the treatment of depression in medically ill patients is supported by small prospective controlled trials [150,171-174]. The main benefit of these agents over TCAs and SSRIs is their more rapid onset of action (often within 24 to 48 hours). (See 'Drug selection' above.)

Psychostimulants may also be helpful in cases where dysphoric mood is associated with opioid-related sedation, severe psychomotor slowing, and even mild cognitive impairment, because stimulants are often energizing and improve overall performance on neuropsychological testing in the medically ill [172,173,175]. At relatively low doses, these medications also stimulate appetite, promote a sense of wellbeing, and relieve feelings of weakness and fatigue in cancer patients [134]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Somnolence and mental clouding' and "Cancer-related fatigue: Treatment".)

Although generally well tolerated, side effects may include agitation, insomnia (particularly if administered within six to eight hours of bedtime), anxiety, and tremor. Cardiac decompensation can occur in older adult patients and in those with heart disease. Rarely, confusion or delirium may occur in older adults or cognitively impaired individuals.

Side effects are uncommon but include headache, nausea, dry mouth, anorexia, and diarrhea. Modafinil has less sympathomimetic effects than amphetamines and is often a good choice for older patients. However, it has been associated with a mild increase in blood pressure and should be used cautiously in people with a history of arrhythmias or heart disease. (See "Treatment of narcolepsy in adults", section on 'Modafinil'.)

Ketamine — Meta-analyses of randomized trials that compared intravenous ketamine with placebo in physically healthy patients with treatment-resistant depression have found rapid, clinically moderate to large benefits with N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine; however, the long-term benefits and risks are unknown. Case reports and one small placebo-controlled trial of intravenous ketamine also suggest that ketamine can rapidly improve depressive symptoms in patients with refractory depression in the setting of a terminal illness, particularly in the setting of chronic pain [176-184]. However, the optimal selection of patients for this approach and the best way in which to administer ketamine in this situation are unclear. (See "Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects" and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Ketamine and other NMDA receptor antagonists'.)

Emerging psychopharmacologic interventions

Psilocybin-assisted psychotherapy — Psilocybin is a Schedule I substance used only in research settings and is not approved by the US Food and Drug Administration (FDA) for any indication. Psilocybin safety has been tested over several decades (although it has not been studied in patients with brain cancer, psychotic disorders, or psychotic disorders in first-degree relatives) [185]. The potential effectiveness of psychedelics has been investigated in several studies for cancer-related existential distress [186]. Psilocybin-assisted psychotherapy specifically has been studied in randomized Phase II trials for the treatment of existential distress in patients with life-threatening cancer [187-189] and unipolar major depression [190], and in open trials for demoralized long-term AIDS survivors [191] as well as treatment-resistant depression [192], with promising results [193-196], showing acute and sustained reductions in measures of depression and existential distress while also improving quality-of-life metrics such as psychologic and spiritual wellbeing.

Additional information about treating unipolar major depression with psilocybin is discussed separately in the context of highly resistant depression. (See "Unipolar depression in adults: Choosing treatment for resistant depression".)

MDMA-assisted psychotherapy — 3,4-Methylenedioxy​methamphetamine (MDMA) is a Schedule I substance and is only used in the context of research or expanded access (granted for compassionate use) [197]. Recreational use of the substance (also known as ecstasy) has been associated with cardiotoxicity, neurotoxicity, and death [198-200]. Adverse events in clinical trials have typically been transient, mild to moderate in severity, and have included muscle tightness, decreased appetite, nausea, hyperhidrosis, and feeling cold [201]. MDMA-assisted psychotherapy has shown acute and sustained reduction of posttraumatic stress disorder (PTSD) symptoms in a Phase III clinical trial [201], described in detail elsewhere (see "Posttraumatic stress disorder in adults: Treatment overview", section on 'Medications with limited supporting evidence'). Future directions in palliative care research could include its use for unipolar major depression, PTSD secondary to life-threatening diagnoses, and cancer recurrence fears.

Electroconvulsive therapy — It is rarely necessary to use electroconvulsive therapy (ECT) for medically ill patients who have depression with psychotic features or in whom treatment with antidepressants is either ineffective or poses unacceptable side effects. ECT is safe for use in the medically ill, but its use in patients near the end of life may be inconsistent with the goal of providing noninvasive and nonintrusive comfort care [202]. (See "Unipolar depression in adults: Choosing treatment for resistant depression".)

INDICATIONS FOR PSYCHIATRIC REFERRAL — When assessing and treating depression in palliative care patients, several circumstances should prompt referral to a psychiatrist for an in-depth assessment of the patient's judgment, decision-making capacity, and mood. These include:

●Uncertainty as to the psychiatric diagnosis

●History of a major psychiatric disorder

●Patient is suicidal or requesting assisted suicide or euthanasia

●Patient is psychotic (hallucinations, delusions) or delirious

●Patient is unresponsive to therapy with first-line antidepressants

●Significant family conflict interferes with wellbeing, treatment, or decision-making

The approach to terminally ill patients who ask about hastening death is addressed elsewhere. (See "Medical aid in dying: Ethical and legal issues".)

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: Palliative care".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Medical care during advanced illness (The Basics)" and "Patient education: Advance directives (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Depression is the most common mental health problem encountered in palliative medicine, yet it is widely misunderstood, underdiagnosed, and undertreated. Individuals who suffer from depression are at high risk of suicide and suicidal ideation, and they have an increased desire for a hastened death. Failure to diagnose and treat depression impairs the quality of life of dying patients and adds to their burden of suffering. (See 'Scope of the problem' above.)

●Screening for depression should be carried out in all palliative care patients. Screening is conducted when the initial diagnosis of cancer is made and periodically thereafter as clinically indicated, especially with changes in cancer or treatment status (eg, posttreatment, recurrence, or progression), as well as transition to palliative care. (See 'Assessment and diagnosis' above.)

●Depressed mood, sadness, grief, and anticipatory feelings of loss are appropriate responses in patients with a serious, life-threatening illness. Feelings of hopelessness, helplessness, worthlessness, guilt, and suicidal ideation (even mild or passive) are among the best indicators of depressive disorders in such patients. (See 'Assessment and diagnosis' above.)

●A careful diagnostic interview is the gold standard method for assessing whether patients are clinically depressed. However, a simple single question ("Have you been depressed most of the time for the past two weeks?") and other abbreviated screening methods appear to be as effective as longer instruments in identifying those patients who require further assessment for depression. (See 'Tools for assessment and diagnosis' above.)

●Major depression in terminally ill patients is treatable. The first step in treating depression is to relieve uncontrolled symptoms, particularly pain. (See 'General treatment principles' above.)

●Supportive psychotherapy can be provided by the primary medical caregiver, psychiatrist, psychologist, hospice nurse, or social worker. While supportive therapy may be sufficient to treat depression, most experts recommend an approach that combines supportive psychotherapy with patient and family education and judicious use of antidepressant medication. (See 'Psychosocial interventions' above.)

●Clinicians should have a low threshold to initiate pharmacologic treatment, even if the diagnosis of a depressive syndrome is in question, because both psychostimulants and newer drugs such as selective serotonin receptor inhibitors (SSRIs) are relatively safe, effective, and well tolerated. (See 'Pharmacotherapy' above.)

●For moderately to severely depressed patients who have an estimated life expectancy of at least two to four months, we recommend both pharmacotherapy and psychotherapy (Grade 1A). For patients whose life expectancy is at least two to four months, we typically initiate therapy with an antidepressant and choose an SSRI rather than a tricyclic antidepressant (TCA) because of their wider safety margin. Patients with more acute depressive symptoms may also benefit from use of a psychostimulant. (See 'Drug selection' above and 'Selective serotonin reuptake inhibitors' above.)

●For patients with a shorter life expectancy (less than two to four months), or who need urgent treatment, we suggest a psychostimulant rather than other drugs (Grade 2C). For patients who have an estimated life expectancy of longer than two to four months, an SSRI is then started, and the dose gradually titrated upwards, while the dose of the psychostimulant is gradually reduced. (See 'Drug selection' above.)

●Regardless of the initial agent chosen, the starting dose should be approximately one-half that used in non-terminally ill patients, and then slowly and carefully titrated. During this time, maintaining ongoing contact with the patient both ensures that symptoms and treatment efficacy will be continuously reevaluated, and it reassures the patient that they will not be abandoned throughout the course of the terminal illness. (See 'Supportive psychotherapy' above.)

●Among the indications for referral to a psychiatrist are the following (see 'Indications for psychiatric referral' above):

•Uncertainty as to the psychiatric diagnosis

•History of a major psychiatric disorder

•Patient is suicidal or requesting assisted suicide or euthanasia

•Patient is psychotic (hallucinations, delusions) or delirious

•Patient is unresponsive to therapy with first-line antidepressants