Carlos G. Fernandez-Robles, William F. Pirl
INTRODUCTION
Depression, anxiety, and fatigue are frequent complications of cancer and cancer treatment. Although fatigue can be caused by depression and anxiety, it is a separate symptom that often does not have psychological origins.
An estimated one-third of all people with cancer experience psychosocial distress. Psychosocial distress encompasses both psychiatric disorders as well as emotional states that do not meet full criteria for psychiatric illnesses. Depression, anxiety disorders, and adjustment disorders are the most common psychiatric disorders in cancer patients. Delirium, however, may be more prevalent in hospitalized cancer patients, affecting almost 25%.
REACTION TO DIAGNOSIS OF CANCER
A diagnosis of cancer can elicit a variety of emotions, including sadness, anxiety, anger, and fear. People may have difficulty sleeping, loss of appetite, anxious thoughts about their cancer, poor concentration, and low mood. These symptoms can persist for 3 weeks after diagnosis. Usually by 4 weeks after diagnosis, people have their coping mechanisms in place and the depressive and anxiety symptoms have resolved. Unless the psychological symptoms are severe or are markedly impairing functioning, the diagnosis of a psychiatric disorder is usually reserved during the first 4 weeks after diagnosis, while people are coping with learning they have cancer.
DEPRESSION
Depression can be used to describe a symptom, feeling sad, as well as a serious illness, major depressive disorder (MDD). MDD is associated with poor quality of life, worse adherence to treatment, longer hospital stays, greater desire for death, suicide, and, possibly, increased mortality (1).
PREVALENCE
In a recent meta-analysis the prevalence of depression in individuals with cancer by DSM or ICD criteria was 16.3% (13.4–19.5) and for DSM-defined major depression it was 14.9% (12.2–17.7); similarly the prevalence of clinical levels of depressive symptoms, not necessarily MDD, was 19.2% (9.1–31.9) (2).
DIAGNOSIS
The diagnosis of MDD is made by using a set of diagnostic criteria that include having a persistently low mood and 5 of the following symptoms for at least 2 weeks: sleep disturbance; loss of interest or anhedonia (inability to experience pleasure); feelings of hopelessness, helplessness, or guilt; low energy; poor concentration; appetite disturbance; psychomotor retardation/agitation; and suicidal ideation. Because many of these symptoms overlap with cancer and cancer treatments, substitutive criteria have been proposed, such as the Endicott criteria. However, the different sets of criteria may not yield markedly different results and in clinical practice physical symptoms that could be related to cancer or cancer treatment are included in making the diagnosis of MDD (3).
DIFFERENTIAL DIAGNOSIS
It is important to evaluate possible medical contributions to low mood and to consider the differential diagnosis. Untreated pain, hypothyroidism, and medications such as glucocorticoids and certain chemotherapies (alpha interferon, pemetrexed, and procarbazine) may contribute to MDD. The differential diagnosis includes:
• Adjustment disorder: Low mood has been present for less than 2 weeks or there are less than 5 of the symptoms needed for the diagnosis of MDD. Adjustment disorders are usually in response to a negative event. Treatment usually focuses on symptoms such as sleep disturbance, and antidepressants are usually not prescribed unless the symptoms persist or there is significant impairment in functioning.
• Delirium: Defined as a transient disturbance consciousness with reduced attention and generalized impairment of cognition, can present with waxing and waning severity of symptoms, and be accompanied by sleep-wake disturbance, language impairment, and psychotic symptoms, especially visual hallucinations and paranoid delusions. Agitation does not need to be present and in fact, one subtype of delirium, hypoactive delirium, presents with social withdrawal and inactivity, which is often mistaken for MDD. Addressing the underlying cause and the use of anti-psychotics, not antidepressants, are the treatment for delirium.
• Fatigue: Although difficult to tease apart from MDD, because of overlapping symptoms, attention to clinical symptoms can facilitate its diagnosis. Anhedonia (markedly diminished interest or pleasure in activities) may be the best distinguishing factor for MDD. Depressed patients usually complain of fatigue early in the day, whereas energy levels in cancer-related fatigue are at its best at this time of the day. Severe hopelessness and suicidal ideation are usually less frequent in fatigue.
• Anxiety: Tearfulness and depressed mood can occur in anticipation of negative events, like disease progression or cancer recurrence. In this case the low mood is not persistent and is usually triggered by the anxious thoughts. However, anxiety and MDD often occur together.
• Personality disorders: Can present with depressed mood, but the mood symptoms are not usually constant and persistent. Mood changes are usually triggered by a perceived injury or threat of abandonment. People with personality disorders can have difficulties maintaining stable social support and a history of self-harmful behavior like cutting. Although antidepressants and other psychotropic medications may be useful in managing specific symptoms, the treatment of personality disorders is primarily behavioral.
• Apathy: A neurological symptom that can also look like MDD and it is associated with a lesion in the frontal or temporal lobes. There is little spontaneous action or speech; responses are delayed, short, slowed, or absent; and it is usually associated with cognitive impairment and older age. Stimulants and dopaminergic medications may be helpful.
TREATMENT
Treatment for MDD consists of antidepressants and/or psychotherapy. Severe cases of MDD, especially those that endanger a patient’s life, may be treated with electroconvulsive therapy. Although complementary treatments such as herbal preparations, acupuncture, and massage are available, there is currently little data on their efficacy for treating MDD in cancer patients. Suicidal ideation should be assessed and, if present, a referral to a mental health professional should be made.
Antidepressants
Antidepressants are commonly used to treat MDD comorbid with cancer (Table 23-1). Overall, limited evidence from three randomized trials and two trials comparing active treatments suggest that cancer patients may benefit from pharmacological treatments of depression (4). Antidepressants should be selected with potential side effects in mind. Side effects can impact tolerability, but also be helpful with accompanying symptoms such as sleep disturbance and poor appetite. Some of the selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine, and paroxetine) and buproprion may interfere with the metabolism of commonly used medications in oncology because of their effects on cytochrome p450 2D6 system (5). Additionally, the FDA recently warned of higher doses of citalopram leading to QT prolongation and arrhythmias, especially when used with medications altering its metabolism (6). Antidepressants usually take about 4 weeks to see full benefit, but some patients may show signs of improvement earlier. Antidepressants should be continued for 9–12 months after remission of depressive symptoms if this has been the person’s first episode. Patients with recurrent MDD should continue the medication longer in order to lessen the chances of recurrence.
TABLE 23-1 SELECTED ANTIDEPRESSANTS COMMONLY USED IN CANCER PATIENTS
Stimulant medications may be beneficial for MDD in medically ill patients, but the evidence to supporting this practice is derived from case series and no trials have been reported in cancer patients. Stimulants, such as methylphenidate and dextroamphetamine, may lift mood, increase appetite, and improve fatigue. Effects of stimulants are usually seen within 1 week.
Psychotherapy
Psychotherapy often needs to take a flexible approach because of medical morbidity and the demands of cancer treatment. Referrals should be made to trained therapists with experience in working with medically ill patients, if possible. Because issues around coping with cancer are often the focus, certain short-term therapies that target current life stresses and strengthen coping skills, such as cognitive-behavioral therapy, may be beneficial. Similar to antidepressants, these short-term therapies may still take weeks to see improvement.
ANXIETY
Anxiety can also be used to describe an emotional experience, feeling nervous, and also to refer to set of psychiatric disorders. Anxiety becomes a psychiatric disorder when it leads to functional impairment. Several kinds of anxiety disorders are seen in people with cancer, such as phobias, panic disorder, generalized anxiety disorder, and post-traumatic stress disorder (PTSD), as well as some presentations of anxiety that do not fit into the current diagnostic system, like persistent anxiety around cancer recurrence.
PREVALENCE
In a large-scale study of adult outpatients at a tertiary cancer center, clinical levels of anxiety were present in 34% of patients (7). A meta-analysis of 70 studies found that actual anxiety disorders were present in 10.3% of patients, whereas 19.4% patients meet criteria for adjustment disorders (2).
DIAGNOSIS
• Phobia: extreme anxiety about a specific thing that leads to avoidance. Common phobias in medical settings include needles, blood, and confined spaces. Although the use of anxiolytic medication, like lorazepam, before entering into a phobic situation may be helpful, the primary treatment is behavioral therapy.
• Panic: a constellation of physical symptoms (shortness of breath, palpitations, chest pain, abdominal discomfort, nausea, headache, and numbness/tingling) along with anxious cognitions, such as “I am dying” or “I need to get out of here immediately.” Panic attacks are recurrent, unexpected, and usually last less than 30 min. Panic usually first presents in early adulthood and onset late in life is unusual. Pulmonary emboli, which can have similar symptoms, can be misdiagnosed as a panic attack.
• Generalized anxiety disorder: unrealistic and excessive worry for at least 6 months that is accompanied by motor tension, autonomic hyperactivity, or excessive vigilance.
• PTSD: a constellation of symptoms that persist months after a traumatic event. Symptoms include nightmares, flashbacks, avoidance behaviors related to the trauma, and hypervigilance. Although having cancer can be thought of as “traumatic,” the specific event is usually a particular point in time, such as waking up intubated and restrained in an intensive care unit.
TREATMENT
Similar to MDD, anxiety is treated with medications, psychotherapy, or both.
Medications
Because anxiety symptoms in cancer patients are often time limited or episodic, quick onset of action makes benzodiazepines particularly useful. These agents should be selected on the basis of their half-lives and duration of action. Short- or intermediate-acting lorazepam may be useful for situational anxiety around receiving a MRI, while longer acting clonazepam may be useful for preventing panic attacks throughout the day. In patients with impaired hepatic function, lorazepam, oxazepam, and temazepam are preferred because they undergo glucuronide conjugation. Side effects include sedation, ataxia, disinhibition, and confusion, especially in the elderly. Benzodiazepines can cause dependence and withdrawal, which is more likely with the shorter acting ones, like alprazolam.
Low-dose atypical antipsychotic medications, such as olanzapine and quetiapine, can also be useful for the immediate treatment of anxiety. They may be used for anxiety resistant to benzodiazepines or in people in whom benzodiazepines should be avoided, such as someone who developed confusion from a benzodiazepine or someone with serious substance abuse.
Antidepressants are effective for the treatment of anxiety disorders, but do not provide immediate relief. Higher doses and longer duration of treatment may be required compared to the treatment of MDD. Additional medications, like benzodiazepines, may be needed for more immediate relief while waiting at least 4 weeks for effects. Other agents such as buspirone, anticonvulsants (gabapentin and pregabalin), hydroxyzine, propanolol, and clonidine are sometimes used in the clinical practice of managing anxiety; these agents do not have US Food and Drug Administration indications for anxiety treatment and have not been systematically studied in anxiety treatment trials in cancer.
Psychotherapy
Short-term targeted therapies that include increasing distress tolerance and strengthening coping skills; identifying cognitive distortions and catastrophizing; and systematic desensitization may be particularly beneficial. Other techniques such as distraction, relaxation exercises, and visualization are also helpful.
FATIGUE
Cancer-related fatigue (CRF) is the most commonly reported symptom in people with cancer and it is the symptom that causes the most functional impairment (8). CRF may be the presenting symptom at the time of cancer diagnosis, occur during treatment, and persist into survivorship in some people. Often CRF will have identifiable causes that can be treated. Although psychiatric disorders, especially MDD and anxiety, can contribute to CFR, they are often not present.
REVALENCE
Reports on the rate of CFR in people affected by cancer vary widely because of differing measures of fatigue and heterogeneous populations. It is estimated that 60%–90% of patients have fatigue (9, 10).
DIAGNOSIS
CFR is characterized by a pervasive and persistent sense of tiredness not relieved by sleep or rest. Its diagnosis is largely clinical. The National Comprehensive Cancer Network (NCCN) recommends screening for fatigue at visits with a one-item, 0–10 scale, similar to screening for pain, with “0” being “no fatigue,” and “10” being “the most severe fatigue.” Scores of 4 or greater are recommended to have further evaluation.
Evaluation should consist of identifying any possibly modifiable causes of fatigue such as anemia, pain, sleep disturbance (insomnia, difficulty staying asleep, and sleep apnea), emotional distress (major depressive disorder and anxiety), poor nutrition, inactivity/deconditioning, medications and chemotherapies that cause fatigue (e.g., gemcitabine, glucocorticoids, narcotics, antiemetics, and beta-blockers), and other medical conditions such as hypothyroidism, hypogonadism, adrenal insufficiency, hypercalcemia, hepatic failure, and cardiovascular or pulmonary compromise. Fatigue can also be a side effect of radiation therapy. The time course of the onset of fatigue is important in trying to identify possible causes as well as detecting preexisting fatigue in people with fibromyalgia and chronic fatigue syndrome.
TREATMENT
NCCN guidelines suggest initially treating any underlying reversible cause of fatigue as described above. Persistent fatigue may be treated with stimulants, exercise, and behavioral interventions.
Medications
A recent Cochrane Review of drug treatment of CFR (11), after combining five randomized controlled studies, concluded that current evidence supports the use of psychostimulants for this condition. NCCN guidelines recommend the use of methylphenidate after other non-pharmacological approaches have failed. Other agents, such as dextroamphetamine and modafinil, have also been commonly used in the clinical treatment of CRF. Stimulants may raise blood pressure and heart rate and should be used with caution in patients with cardiac disease. Multiple studies have found a recognizable reduction in fatigue with erythropoietin; however, new safety concerns suggest that any seen benefit is outweighed by the increase risk of harm from these drugs in patients with mild anemia (12). Additional studies with selective serotonin reuptake inhibitors and glucocorticoids have failed to demonstrate any superiority over placebo for these classes of drugs.
Exercise
Several studies have demonstrated the benefit of exercise for fatigue in people with cancer (12). A physical therapist can design an exercise program, containing both strength training and cardiovascular, that is appropriate for a person with physical limitations from cancer or cancer treatments. For medically complicated patients, exercise might best be done in a cardiovascular or pulmonary rehabilitation center.
Behavioral Interventions
Behavioral interventions have focused on energy conservation; prioritizing activities and delegating if possible; problem solving around difficulties caused by the fatigue; improving organizational skills; and trying to maximize functioning through careful observation of symptoms and planning activities around them.
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