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Anxiety and Depression in Patients with Serious Illness

Oncology
Mental Health
Internal Medicine
Palliative Care

Authors

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Ariel Shalev, MD
Author
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Daniel Shalev, MD
Author
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Introduction

Anxiety and depression are common and impactful among individuals with serious medical illnesses like cancer. Approximately 40% of individuals with serious or life-limiting illnesses experience clinically significant anxiety or depression.[1–7]
However, it is worth noting significant heterogeneity in epidemiologic data on psychiatric comorbidities; for instance, among cancer patients, prevalence of depression ranges from 2 to >50% across data sets.[8–10]
Heterogeneity in epidemiologic data is a result of variations in the characteristics of the sample (disease stage, setting of care, geographic location etc.) and wide variations in approaches to measurement.[11]
Among patients with serious illness, depression and anxiety may be part of a mental health disorder such as major depressive disorder or generalized anxiety disorder. However, patients who do not meet full Diagnostic and Statistical Manual of Mental Disorder (DSM) or International Classification of Diseases (ICD) criteria for a psychiatric disorder may nonetheless experience distressing mood or anxiety symptoms. Furthermore, both depression and anxiety may represent exacerbations of symptoms or disorders that pre-date the serious illness diagnosis or de novo symptoms or disorders occurring in the setting of serious medical illness. [8,12]
The etiology of depression and anxiety among individuals with serious illness is multifactorial. [10] Contributors may include psychosocial stressors (e.g., managing dependence or financial insecurity), the underlying serious illness (e.g., through neuroinflammation), and iatrogenic effects of treatment (e.g., through chemotherapy regimens with neuropsychiatric side effects).
In our clinical experience, most patients with serious illness and depression or anxiety do not evidence a single contributing factor but rather a constellation of possible contributors from a range of psychological, social, and biological domains.
Regardless of their etiology, both depression and anxiety among patients living with serious illnesses are highly impactful. There is a preponderance of evidence that depression and/or anxiety among patients receiving life-prolonging or curative treatment for serious illness impacts outcomes such as treatment adherence, quality of life, and survival.[13–18]
Among patients with serious illness receiving palliative or end-of-life care, both depression and anxiety are also highly impactful. In a systematic review of 43 studies, depression and anxiety were associated with myriad poor outcomes in palliative and end-of-life care including poor quality of life, poor function, high symptom burden, and differential care utilization.[19]

Symptoms

The core symptoms of depression are either persistently low mood or anhedonia (a loss of interest or pleasure in previously enjoyable activities).[20] Either one or both of these core symptoms must be present among patients experiencing depression.
Several additional signs and symptoms are common in depression. These include changes in weight or appetite (either gain or reduction in weight/appetite), changes in sleep (either insomnia or hypersomnia), changes in psychomotor activity level (either agitation or slowing), fatigue, feelings of guilt or low-self-worth, decreased concentration, and thoughts of death or suicidal ideation. These associated signs and symptoms are necessary for the diagnosis of certain depressive disorders (see below) but may also accompany symptoms of depression that do not meet the threshold for diagnosis of a disorder due to severity or duration.
The core symptom of anxiety is persistent worry or fear. [20] This is often accompanied by restlessness, fatigue, decreased concentration, irritability, muscle tension, and sleep disturbances. Of note, these symptoms describe general anxiety. Anxiety may also manifest as sudden, brief, intense attacks of anxiety with multiple somatic symptoms (panic attacks) or as fear of a specific object or situation (e.g, specific phobia, social anxiety). This chapter focuses predominantly on general anxiety.

Diagnostic Workup

Assessment of anxiety and depression among patients with serious illness may be complex but is imperative for delivering effective interventions and stratifying risk. Below, I discuss general diagnostic considerations followed by specific information about assessment procedures.
Diagnostic Criteria in Brief:
Both depression and anxiety may be components of several different psychiatric disorders — or may be clinically significant symptoms that are distressing to patients but fail to meet criteria for a diagnosable psychiatric disorder.
The DSM differentiates depressive episodes from major depressive disorder because many related disorders (such as bipolar affective disorder) may also manifest with depression. The DSM diagnosis of a major depressive episode is contingent on five or more core symptoms, one of which must be either depressed mood or anhedonia, for at least two weeks (though most major depressive episodes last significantly longer).
SymptomFrequency (if applicable)
Depressed mood (or irritability in children and adolescents)Most of the day nearly every day
Loss of interest or pleasureMost of the day nearly every day
Change in appetite and/or weight 
Persistent insomnia/hypersomniaNearly every day
Psychomotor agitation or slowing observable by othersNearly every day
Fatigue or anergiaNearly every day
Feelings of guilt or low self-worthNearly every day
Difficult with concentration or decision-makingNearly every day
Recurrent thoughts of death or suicidal ideation, plan, or attempt 
For patients who meet criteria for a major depressive episode, history and context are required to accurately make a diagnosis. Depressive episodes are a feature of several psychiatric illnesses and not all patients who experience depressive episodes are diagnosed with major depressive disorder. It is important to assess whether a diagnosis of bipolar affective disorder, schizoaffective disorder, substance/medication-induced mood disorders, or depressive disorder due to another medical condition may be more accurate.[20]
Unlike depression, the DSM-5 diagnostic classification of generalized anxiety does not differentiate an episode and a disorder. DSM-5 diagnostic criteria for generalized anxiety disorder are excessive anxiety or worry occurring on most days over six months, difficulty controlling the worry, and three or more associated symptoms.
Excessive anxiety or worry and three or more of the following:
Restlessness or feeling edgy
Fatigue
Difficulty with concentration
Irritability
Muscle tension
Sleep disturbance
As with Major Depressive Disorder, a diagnosis of generalized anxiety disorder is contingent on exclusion of an anxiety disorder due to another medical condition and/or of substance or medication-induced anxiety disorder. The diagnosis of panic disorder and other anxiety disorders is outside the scope of this chapter but should be considered in patients who experience anxiety either in intensely episodic form or with respect to a circumscribed situation or object.
Note that major depressive disorder and generalized anxiety disorder can be co-diagnosed if criteria are met and commonly co-occur.[21]
Patients who do not meet criteria for generalized anxiety or a major depressive episode but who experience clinically significant symptoms in the context of a recent stressor (for instance, a serious medical diagnosis, a change in treatment plan, or a complication of a serious illness) may meet criteria for adjustment disorder.[20]
Adjustment disorders describe emotional or behavioral symptoms (including anxiety and/or depression) that develop in response to and within three months of a stressor. The symptoms must cause marked distress and/or impairment, as described above, but not meet full criteria for another psychiatric diagnosis such as major depressive disorder or generalized anxiety disorder.
Adjustment disorder may describe a significant subset of patients with serious illness and symptoms of anxiety and/or depression. Though some patients with clinically significant symptoms may fail to meet criteria for this diagnosis by virtue of the stipulation that symptoms occur within three months of a new stressor, our experience is that patients with serious illness are almost always within three months of a multiple potential stressors.
Diagnostic assessment of psychiatric disorders among patients with cancer or other serious illnesses may be challenging for several reasons. Below, we briefly discuss some unique diagnostic considerations in this patient population.
Normative versus Non-normative:
Feelings of sadness, disinterest, worry, and fear are a normal part of human experience. In the context of a serious illness, such feelings may become more common or pronounced. These normative reactions — and the attitudes that we as clinicians bring to our assessment — can make identifying patients who would benefit from further assessment and intervention challenging. Individual clinicians may be prone to underdiagnosis by virtue of false beliefs that it is normative to suffer depression or anxiety in the context of serious illness.[22]
Conversely, other clinicians may falsely believe that all patients with serious illness experience psychiatric morbidity and require treatment. In distinguishing patients who may benefit from intervention, the authors rely on the DSM’s broad approach to psychiatric diagnosis: that the symptoms must cause significant distress or impairment in key areas of function.
Patients with serious illness who experience depression or anxiety that is negatively impacting their quality of life or their ability to engage in treatment or otherwise function merit further assessment and intervention. Assessing the degree of distress and/or impairment requires a holistic approach that may include operationalized screening or symptom scales, patient interview, clinician observation, and engagement of other relevant input from family caregivers and/or other clinicians involved in a patients’ care.
Etiology and Differential Diagnosis
Among patients who meet criteria for a mood or anxiety disorder, clinicians may struggle to distinguish generalized anxiety disorder and major depressive disorder from anxiety and/or depression due to substances/medication or due to a general medical condition. As noted above, among patients with serious illness, it can be difficult to differentiate discrete causative factors.
Our approach to diagnosis in such cases is to err on the side of the more general diagnosis (e.g., major depressive disorder rather) unless there is an extremely clear causal relationship between a medical event or substance exposure and symptoms. Examples of such clear causality might include the development of new-onset severe depression within several months of starting treatment with interferon or severe anxiety in the setting of a new cerebral lesion which resolves following gamma knife radiosurgery.
Significant attention has been paid to the diagnostic complication of overlapping symptoms between psychiatric disorders and serious illness. This is particularly germane for depression as many of the diagnostic symptoms of depression such as fatigue, anorexia, and anergia may be expected to occur in the context of serious illness. As such, a number of alternative criteria have been formulated that de-emphasize somatic symptoms of depressive and focus on those findings most indicative of depression among individuals with serious medical illness (hopelessness, low self-worth, suicidal ideation).[23,24]
However, there is increasingly robust evidence that diagnostic criteria and existing screening tools are valid as-is among patients with serious illness.[25,26] As such, our recommendation is to utilize validated diagnostic criteria and scales in the context of clinical judgement about specific patient cases (e.g., recognizing if an overlapping symptom is clearly due to an underlying medical illness).
In addition to the mood and anxiety disorders described above, the differential diagnosis of mood and anxiety symptoms among individuals with serious illness also includes a range of medical and neuropsychiatric conditions which should be considered as appropriate. Examples of medical causes or mimics of depression or anxiety among patients with serious illness include endocrinopathies (e.g., hypo or hyperthyroidism), anemia, medications (e.g., corticosteroids, opioids), and neurologic lesions (e.g., brain metastasis).
Among patients with serious illness, special attention must be paid to differentiating delirium from other potential causes of depression or anxiety because of the high prevalence and overlapping symptomatology of delirium.[27] This is particularly true in patients in acute care settings and approaching the end-of-life.
Assessment
The gold standard for the assessment of psychiatric symptoms among individuals with serious illness — and in general — is a comprehensive diagnostic assessment by a trained mental health professional.[28,29] Assessment, even when supported by the use of structured diagnostic tools, should be guided by clinical history and examination.
A description of a full psychiatric history and examination are outside the scope of this chapter, however important history to gather in addition to a general thorough medical history includes core and associated symptoms; duration, frequency, and severity of symptoms; associated medical and psychosocial stressors; safety risks (e.g., suicidal ideation); and psychiatric history. A mental status and physical examination can be clarifying, particularly with respect to differentiating mood and anxiety disorders from other medical or neuropsychiatric disorders.
The use of screening and symptom scales to identify and monitor severity of depression and anxiety is helpful in the clinical setting.

This is particularly true among patients with serious illness in whom the burden of depression and anxiety is so significant; all patients receiving oncologic or palliative care should be screened for depression and anxiety.[30,31]
There is not compelling evidence to suggest the use of one screening/symptom-tracking tool over another. In general diagnosis of depression and anxiety among patients with serious illness is more limited by lack of screening than by using an incorrect or inappropriate screening tool.[29] We suggest the use of instruments that impose a limited burden on clinicians and on patients and that are validated in the context of patients with serious medical illnesses.
Our screening tools of choice are
  • the Generalized Anxiety Disorder Screener (GAD-7) for anxiety,
  • the Patient Health Questionnaire-9 (PHQ-9) for depression,
  • the Hospital Anxiety and Depression Scale (HADS) for both anxiety and depression.[25,26,32–36]
While very brief or single-item screening scales may be useful in lieu of no screening, they tend to have poor positive predictive value.[29]

Management

Even patients with serious medical illnesses and/or limited prognoses can benefit from treatment or anxiety and depression.[2,37,38]
Psychotherapy: A variety of psychotherapy interventions have shown efficacy in improving depression and anxiety among individuals with serious illness.[37] Such interventions range from behavioral interventions including relaxation or exercise interventions, genera support interventions including support group, and formal, structured psychotherapies like cognitive-behavioral therapy and problem-solving therapy.
In general, we recommend that patients with more severe symptoms be treated with interventions delivered by trained mental health clinicians like psychiatrists or psychologists. Patients with mild or subsyndromal symptoms may benefit from less intensive and less structured interventions.
Psychopharmacology: In general, pharmacologic treatment is effective for patients with depression and anxiety with serious medical illnesses. As is the case in general practice, patients may benefit most robustly from combined psychosocial and pharmacologic treatment. We suggest selecting patients for pharmacologic treatment based on: severity (patients with more severe symptoms tend to experience the highest benefit), co-existing medical problems or symptoms (is medication safe and can it be leveraged to treat somatic symptoms concurrently with depression or anxiety), patient preference, availability (patients with inability to tolerate medications by mouth or enterally may have few agents available to them).
Oral antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, other atypical antidepressants, tricyclic antidepressants, and monoamine oxidase inhibitors. We consider SSRIs, SNRIs, and mirtazapine appropriate first line agents for depression and anxiety in patients with a prognosis of months or greater.
Bupropion may also be appropriate as a first-line agent, but it is a poor anxiolytic and is associated with risk of seizures that may be more significant than other antidepressants. These medications, though diverse in structure and mechanism, share key features. Most notably, all must be taken regularly for 4-8 weeks before full therapeutic effect. Under the guidance of a psychiatrist, antidepressant medications can be augmented with a range of other pharmacologic agents including antipsychotics and mood stabilizers.
Management of depression among patients with a short prognosis poses a challenge as many of the most commonly utilized medications have a 1-2 lag time in effect. Patients with a prognosis of under 8-12 weeks should be managed with optimal multi-modal supportive care to improve symptoms and other contributors to quality of life, psychosocial interventions, and, at times psychostimulants.
Psychostimulants are safe and well-tolerated in most patients with serious illness and may improve symptoms of depression.[42–44] However, it is worth noting that their efficacy in improving depression symptoms is controversial and likely short-lived.
As such, we recommend only utilizing psychostimulants as primary antidepressant treatment among patients with prognoses of under 3 months (though it may be appropriate to use them in patients with longer prognoses for management of fatigue). Clinicians using psychostimulants should be aware of their penchant to cause insomnia and precipitate anxiety.
Below we summarize a few preferred first line agents we recommend, the dosing range, and the situations in which we do and do not use them.
MedicationRecommended DosingWhen and why to use
Escitalopram2.5-20mg/dailyOur recommended SSRI in the absence of compelling indications to use other SSRIs. It has fewer potential interactions than other SSRIs and does not have anticholinergic properties.
Mirtazapine7.5-45mg/daily (usually at bedtime)An excellent first-line agent for patients with concurrent insomnia. It may cause weight gain and increase appetite but this has been shown not to be the case among patients with serious illness and it should not be used for this indication.[39]
Duloxetine20-90mg/dailyA good choice for patients with depression/anxiety and neuropathic pain given its role as an adjunctive agent for such pain.[40]
Methylphenidate5mg-40mg, generally BIDOur preferred agent for depression among patients with a prognosis of under 8 weeks. Effects tend to be seen much more quickly (within 1-4 days) than with traditional antidepressants.
For anxiety, in addition to antidepressants, benzodiazepines may also be appropriate. Benzodiazepines are sedative-hypnotics which induce anxiolysis and sedation by serving as positive allosteric modulators of the GABA-A receptor.[41]
Unlike antidepressants, benzodiazepines work rapidly (as quickly as minutes after administration depending on the specific drug and formulation).
As such, they are useful as both stand-alone and adjunctive anxiolytics. For patients with anxiety and a prognosis of months of greater, benzodiazepines may be prescribed concurrently with an antidepressant to “bridge” patients until the antidepressant takes effect (often a 4-8 prescription followed by a trial of weaning).
Alternatively, for patients with a short prognosis or with very episodic anxiety for whom a daily medication may be inappropriate, benzodiazepines can be used as a primary anxiolytic. We recommend prudence with the use of benzodiazepines because they can induce delirium, increase risk of falls, and induce dependence (with potential for severe withdrawal reactions akin to alcohol withdrawal).
The choice of benzodiazepine should be guided by a number of factors including the mode of administration, the half-life of the medication, the metabolism of the medication (e.g., hepatic versus renal). We find that the majority of patients benefit from either lorazepam or clonazepam and we often recommend against use of alprazolam because of its tendency to induce rebound anxiety and be habituating.
Several other pharmacologic modalities have been used to manage anxiety and depression in patients with serious illness. These include ketamine, which may induce a rapid antidepressant and anti-suicidal response and hallucinogens. Discussion of these more complex management approaches is outside the scope of this chapter but may be considered in situations.

Other Interventions

Little data exist on the benefit of complementary and alternative medicine (CAM) for the management of depression and anxiety in serious illness.
Patients with severe depression and serious illness may benefit from interventional psychiatry modalities such as electroconvulsive therapy or transcranial magnetic stimulation. Such modalities should be considered in close consultation with a psychiatrist. [45,46]
Of note, while most anxiety or depression can be managed in the outpatient or general medical setting by either a serious illness clinician (e.g., medical specialist, palliative care) or a psychiatrist, unremitting severe symptoms, suicidality, psychotic symptoms, and other emergent symptoms may benefit from management in a psychiatric emergency or inpatient setting.

Controversies/Limitations

Evidence supporting interventions for depression and anxiety for patients with serious illness are limited. Many of the care recommendations provided in this chapter and in general are generated from small studies of limited quality, from studies focused only on patients with oncologic disease, and/or from inferences drawn from studies of individuals without medical illness. There is little data on the efficacy of psychopharmacologic approaches to depression and anxiety among patients with serious illness.
However, although there are significant research gaps, there is no question that patients with serious illness and comorbid anxiety and depression merit treatment and that clinical experience and research demonstrate the potential efficacy of both psychosocial and psychopharmacologic interventions.

Summary

Depression and anxiety are common among individuals with serious illness. They impact myriad outcomes including survival, quality of life, symptom burden, caregiver distress, and engagement with medical treatment.
Though the diagnostic assessment of anxiety and depression may be complicated in the context of serious illness, standard diagnostic criteria and screening scales are generally valid even among individuals with somatic symptoms. Treatment options include psychosocial and psychopharmacologic options.
Among patients with severe symptoms, combined treatment approaches are more efficacious. Treatment decisions should also be made in the context of the patient’s medical context including their prognosis and potential medication interactions.

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