Cognitive
Evaluation of the danger versus one’s coping resources. Focus is on the perceived threat while extraneous detail environmental details are blocked out (tunnel vision). For example, a patient may focus on the risk of stem cell transplant to the exclusion of marital or financial issues.
Emotional
Feeling nervous, edgy, scared, alarmed, terrified, worried, etc.
Behavioral
This refers to behaviors associated with anxiety: avoidance (e.g., nonadherence), flight (e.g., signing out against medical advice), fight (e.g., angry or litigious), immobility, unable to speak (e.g., a passive or overtly shy patient).
Physiological
Cardiovascular (palpitations, hypertension, faintness/fainting), respiratory (tachypnea, chest pain, lump in throat), neuromuscular (startle reflex, twitching muscles, tremor, unsteady, restless), gastrointestinal (discomfort, anorexia, nausea, diarrhea, vomiting), urinary (urgency, frequency), dermatological (flushed, pale, sweaty, itchy, hot, shivers, blushing).
Anxiety, like pain and fever, is not necessarily pathological. In the correct quantity it can motivate the individual to take action to minimize a threat. For example, worry is positively associated with increased breast cancer screening via both self-examination and mammography (r = 0.12) [2].
Anxiety becomes pathological when it is activated disproportionately to a threat, independently of an actual danger or when it becomes chronic. Such maladaptive anxiety has a noxious intensity that impairs a person’s functioning and also wears out their family and friends because, unlike effective problem solving, it serves no end point.
Consider an anxious chronic lymphocytic leukemia patient receiving watchful waiting treatment. Considerable effort may be expended on fruitless worry, hyper-vigilance, self-palpation of lymph nodes, and amplification of nonspecific physical symptoms. All of these do not improve prognosis beyond that of a rational surveillance program. In this chapter, the term anxiety refers to the maladaptive variety rather than normal anxiety.
Whether anxiety is adaptive or pathological is moderated by a person’s sense of self-efficacy or confidence in dealing with potential threats as well as the resources available to them. Loss of work or family roles, negative medical experiences such as misdiagnosis, or physical weakness leading to a self-image of a weak or vulnerable person can all erode confidence and increase anxiety. See Fig. 62.1.
Fig. 62.1
Self-portrait of the artist after hearing the news that his lymphoma has relapsed and he will require a second HSCT. He depicts himself lying naked, exposed, and impotent, floating on a river-like bed. Half his body is in darkness, reflecting paralysis. His eyes are hollow. His self-confidence eroded. All the hard fought gains recovering from the first transplant seem to have been in vain. (Reproduced with permission of the artist, Jeffery Toplin. Copyright © 2010.)
Prevalence of Anxiety
Risk Factors for Anxiety
Specific demographic factors such as younger age, female sex, separated, divorced, widowed, and lower socioeconomic status are associated with greater anxiety levels. Conversely, older, married, more experienced patients with social support and financial and educational resources can better manage anxiety [5, 6]. Approaching death or a worse prognosis is probably not associated with increased anxiety [7, 8]. Genetic factors are also increasingly recognized as contributing to the risk for anxiety disorders; however, genes are not always the answer. For example, a spider phobia may have greater valence to a child as compared to an adult but, with appropriate nurturing, an anxious child may grow into a confident young adult. In other words, experience and maturation can override a biological propensity towards anxiety.
Finally, childhood sexual abuse is associated with an increased risk for generalized anxiety disorder and panic disorder (also major depression, substance abuse, and bulimia nervosa). This risk is doubled when the victim is subjected to sexual intercourse [9], highlighting the importance of considering sexual abuse when interviewing anxious cancer patients. Furthermore, because trust in parental figures has been betrayed at an early age, sexually abused oncology patients may have difficulty trusting their physicians and may be more difficult to reassure.
Screening and Measuring Anxiety
Asking, “Are you worried?” or using the Distress Thermometer, where patients are asked to rate their distress from 0 to 10 [10], are simple ways of assessing anxiety. The Generalized Anxiety Disorder-7 scale (GAD-7), used widely in medical cohorts, matches DSM-IV criteria for generalized anxiety disorder (Table 62.2) [11]. It can be used to screen for anxiety where a cutoff of ≥5 represents significant anxiety. Alternatively it can be used to measure anxiety severity, e.g., before and after starting a benzodiazepine.
Table 62.2
Generalized anxiety disorder-7
Over the last 2 weeks, how often have you been bothered by the following problems? | |||||
---|---|---|---|---|---|
Not at all | Several days | More than half of the days | Nearly every day | ||
1. | Feeling nervous, anxious, or on edge | 0 | 1 | 2 | 3 |
2. | Not being able to stop or control worrying | 0 | 1 | 2 | 3 |
3. | Worrying too much about different things | 0 | 1 | 2 | 3 |
4. | Trouble relaxing | 0 | 1 | 2 | 3 |
5. | Being so restless that it is hard to sit still | 0 | 1 | 2 | 3 |
6. | Becoming easily annoyed or irritable | 0 | 1 | 2 | 3 |
7. | Feeling afraid as if something awful might happen | 0 | 1 | 2 | 3 |
Total _________=Add_________+ ______________+ _______________ Scorecolumns | |||||
If you checked off any problems, how difficult have these problems made it for you to do your work, take care of things at home, or get along with other people? | |||||
Not difficult at all | Somewhat difficult | Very difficult | Extremely difficult | ||
Specific anxiety syndromes are discussed next.
Generalized Anxiety Disorder
When diagnosing generalized anxiety disorder (GAD) in psycho-oncology settings, the usual 6-month duration of symptoms is impractical because it would lead to underdiagnosis. A sensible clinical modification is a 2-week symptom duration [11]. Nevertheless, most GAD patients will have suffered from generalized anxiety, on and off, for many years previously; average duration of symptoms before diagnosis is 5–10 years. These patients tend to be greater users of primary and specialist medical care, have greater social impairment, demonstrate less work productivity and more absenteeism [3], and frequently display intercurrent depression.
How is GAD colored by the oncology setting? These patients may worry excessively about prognosis, uncertainty or recurrence, treatments, role changes, loss of income and status, transportation, and dependency. “Markeritis” describes overly worrying about elevated cancer markers. The “tyranny of positive thinking” is where patients are told that they “must” think positively, implying that negative thinking will worsen the prognosis. It is, however, impossible to be perpetually optimistic, even in the best of times, but especially when seriously ill. Thoughts about mortality are normal and understandable. Telling a cancer patient “not to think negative” is similar to saying, “don’t think of a white elephant”—quite impossible, and this increases anxiety.
Adjustment Disorder with Anxiety
The cardinal features of this category are anxiety symptoms within 3 months of a stressor that should resolve within 6 months of termination of the stressful trigger. The presumption is that, without the stressor, the patient would not have anxiety or worry symptoms.
The advantages of this classification are that it is nonpejorative, semantically empathic with an expectation of recovery. Disadvantages are that it is hard to predict who will recover versus who will progress to chronic generalized anxiety. Even when cured, cancer remains a long-term stressor with multilevel effects on patient, family, employment, and finances, suggesting that it is overly simplistic to view the stressor as an on–off button. This categorization also invites the argument that anxiety is “normal” in a cancer setting, which may in turn lead to underrecognition and undertreatment, e.g., not initiating pharmacotherapy or psychotherapy.
Panic Disorder with or without Agoraphobia
Panic attacks are discrete episodes of intense apprehension, fear, terror, or a sense of impending doom that peak within 10 min. They are associated with physical symptoms such as chest pain, shortness of breath, choking or smothering sensations, and a fear of going crazy or losing control. Agoraphobia, fear of being trapped in a crowded place where escape might be difficult or embarrassing, often is a consequence of panic attacks. When panic attacks become recurrent, with persistent worry about additional attacks or concern about its implications (going crazy, heart attack) or significant “avoidance” because of the attacks, panic disorder can be diagnosed but an isolated panic attack may not have great clinical significance.
Panic in cancer patients may occur de novo or reflect an exacerbation of a preexisting panic. It is often underdiagnosed; one cancer center reported a fifth of referrals to its psycho-oncology service with panic symptoms [12]. Cognitively, panic is conceptualized as the misinterpretation of bodily symptoms, for example, a stem cell transplant patient who misinterprets pain and discomfort catastrophically. Occasionally, panic disorder presents as a patient who wants to leave hospital “against medical advice” or who suddenly refuses chemotherapy.
Social Anxiety Disorder
This is characterized by persistent fear that social scrutiny will be humiliating or embarrassing, resulting in severe anxiety or reactions such as avoidance, withdrawal, or paralysis. As this disorder is largely a chronic condition that starts in teenage years, these patients are often underachievers in life. The cancer journeys of such painfully shy and inhibited patients are uncomfortable. They have difficulty negotiating the medical bureaucracy and speaking up because their biggest fear is being the center of attention. Scars, radiations burns, disfiguring surgery, intrathecal catheters, or anything that makes the patient stand out in a crowd can exacerbate social anxiety. For these shy patients, obtaining a second opinion is commonly an anxiety wrought experience, which is often avoided, to the patient’s ultimate detriment.
Specific Phobia
Seen in 3.5 % of the general population, blood–injection–injury phobia may result in fainting during procedures and avoidance of injections, blood tests, or dental care. As self-injection becomes increasingly common, blood–injection–injury phobia should be considered in patients who refuse or have difficulty self-injecting. Claustrophobia is very common in the setting of imaging (e.g., closed MRI scans) and radiation treatments.
Anticipatory Anxiety and Nausea
Anticipatory anxiety and nausea are classically conditioned responses (Pavlovian conditioning) to nausea induced by oncology treatments. Anxiety and nausea are generalized beyond the cancer treatment so that all food cues result in anxiety and nausea, resulting in food avoidance. Preexisting anxiety, younger age, vulnerability to motion sickness, prior emetic chemotherapy, and abnormal taste sensations, all predispose to anticipatory nausea and anxiety [13].
Anxiety Due to a General Medical Condition
No oncologist wants to misattribute anxiety as psychological when it actually is due to an underlying medical illness [14]. Medical causes of anxiety are listed in Table 62.3. Treatment is primarily that of the underlying medical illness, although this may not necessarily eliminate the anxiety.
Table 62.3
Medical conditions and medications associated with anxiety
Metabolic | Hyperkalemia, porphyria, hypo- and hypercalcemia, hyperthermia, hypoglycemia, hyponatremia, vitamin deficiencies, hypovolemia, sepsis |
Neurological Conditions | Pain, raised intracranial pressure, central nervous system neoplasms, postconcussion syndrome, seizure disorder, vertigo |
Endocrine | Adrenal abnormalities, hyper/hypothyroidism, parathyroid abnormalities, pituitary abnormalities, pheochromocytoma, carcinoid syndrome |
Cardiovascular | Arrhythmia, congestive heart failure, coronary artery disease, anemia, valvular disease, cardiomyopathy |
Pulmonary | Hypoxia, pulmonary embolism, asthma, chronic obstructive pulmonary disease, pneumothorax, pulmonary edema |
Medications/toxic conditions | Corticosteroids, bronchodilators, antipsychotics, thyroid preparations, theophylline, sympathomimetic agents, levodopa, serotonergic agents, psychostimulants, antibiotics (cephalosporins, acyclovir, isoniazid), interferon, caffeine, cocaine, marijuana, withdrawal states (alcohol, opioid analgesics, benzodiazepines, caffeine) |
Shortness of breath is a common pathway that increases anxiety. It is rare to encounter a patient with shortness of breath from a pulmonary condition, arrhythmia, sepsis, or blood loss who does not feel more anxious.
Pain is a common cause of anxiety in cancer patients. In one study of hospitalized cancer patients, the prevalence of pain was 96 % for patients with anxiety as opposed to 80 % for patients without anxiety [15]. Patients in severe pain appear diaphoretic, restless, and nervous. Anxiety assessment can only be completed after adequate pain relief. Anxiety often resolves after the pain is treated.
Substance-Induced Anxiety Disorder
Substance-induced anxiety is the direct effect of a drug, medication, or toxin. Bronchodilators raise the pulse rate, compounding the anxiety caused by air hunger. Anti-inflammatory cytokines such as interferons can cause anxiety and panic, perhaps via serotonergic and dopaminergic pathways, although they may be better tolerated than previously thought [16, 17]. Corticosteroids commonly cause anxiety, emotional lability, insomnia, agitation, and restlessness. Thyroxine, psychostimulants, sympathomimetic agents, serotonergic agents, anticholinergics, immunosuppressants, antihistamines, and certain antibiotics may all produce symptoms of anxiety. Akathisia (motor restlessness), when an extrapyramidal side effect of the antiemetics prochlorperazine and metoclopramide, is often misdiagnosed as anxiety. Substance withdrawal (alcohol, benzodiazepines, barbiturates, opioids, nicotine), frequently unrecognized, may present with sudden, intense anxiety and agitation.
Depression
What Is Depression?
A depressed person feels down, sad, hopeless, and loses interest in life, hobbies, and things that previously were a source of pleasure (anhedonia). Their facial expressions (affect) are sad and their overall demeanor and posture reflect their morose mood. In severe depression, nothing can brighten the affect, not even a little humor or encouragement. Psychiatrists describe this as nonreactive affect. Irritability, decreased concentration (e.g., “I can’t read anything beyond the newspaper headlines”), middle insomnia (falling asleep but waking up after a few hours), loss of appetite or excessive eating, psychomotor slowing, and guilt (e.g., “If only I had not …..”) are other symptoms.
Prevalence and Impact of Depression
The prevalence of depression in oncology ranges from 10 to 25 %. It is frequently comorbid with anxiety. One study found that two-thirds of depressed oncology patients also met anxiety criteria [5]. The treatment implications of this are that depression and anxiety should be targeted simultaneously, e.g., by starting an antidepressant together with a benzodiazepine or behavioral therapy.
Depression is not more severe in early compared to advanced disease (e.g., watch and wait versus late stage CLL), nor in milder versus more demanding treatments (e.g., autologous stem cell transplant compared to allogeneic). Depression does not become more severe as death approaches [7], a fact that can be used to reassure patients and families who are concerned that depression is ubiquitous with the dying phase of an oncological illness.
Depression, however, can worsen an oncology patient’s quality of life and is associated with longer admissions and lesser adherence but, according to current research, does not trigger cancer or increase vulnerability to relapse [18].
Risk Factors for Depression
Of the malleable risk factors, substance abuse and withdrawal are common and of most concern. In addition, lack of social support has been associated with depression and an overall increase in mortality of cancer patients [19]. It is hard to battle cancer alone, when poverty limits access to treatments and resources, or when health literacy is low and you cannot, for example, understand medical instructions. This speaks to the importance of identifying and helping resource-deprived oncology subgroups.
Differential Diagnosis of Major Depression
Mood disorder due to a general medical condition is where the depression is judged to be a direct physiological effect of the medical condition, e.g., stroke, hypothyroidism. Hypoactive delirium is an important consideration in patients who are lethargic or labeled as “failure to thrive” or who seem depressed but are also disoriented (see “Discussion” later in this chapter).
A substance-induced mood disorder is where a drug of abuse or medication is causing depressive symptoms, e.g., alcohol or tobacco withdrawal. A number of medications have been associated with depression, but the strongest correlations are with steroids, interferon alpha, and taxanes. Smoking cessation predisposes an individual to a higher rate of major depression in the year subsequent to quitting [20].
Bipolar disorder is common and should be considered where there is a family history of bipolar or other affective disorders, or when depression does not respond to a standard 4-week antidepressant course.
Measuring and Screening for Depression
One measure for depression screening is the Patient Health Questionnaire-9 (PHQ-9) that has been widely validated in medical populations (Table 62.4) [21]. Items one (anhedonia) and two (depressed mood) must be positive in order to meet the depression threshold. In fact, Veterans Affairs hospitals in the USA use these first two items (known as the PHQ-2) to screen all of their patients. A score of ≥5 on the PHQ-9 represents significant depression and, thus, it can easily be used as a screening measure in oncology clinics. This measure can also be used to assess depression severity, e.g., before and 3 weeks after starting an antidepressant. Translations into other languages such as Spanish, Chinese, and Russian are widely available online and are another useful resource for oncologists. If a response to item nine (thoughts of being better off dead) is positive, further questions about suicidality are necessary. Even use of a single question, “Are you depressed?” had a specificity and sensitivity of 1.00 for identifying depression in a palliative care cohort [22].
Table 62.4
The PHQ-9
PHQ-9. Over the last 2 weeks, how often have you been bothered by any the following problems? | |||||
---|---|---|---|---|---|
Not at all | Several days | More than half of the days | Nearly every day | ||
1. | Little interest or pleasure in doing things | 0 | 1 | 2 | 3 |
2. | Feeling down, depressed, or hopeless | 0 | 1 | 2 | 3 |
3. | Trouble falling or staying asleep, or sleeping too much | 0 | 1 | 2 | 3 |
4. | Feeling tired or having little energy | 0 | 1 | 2 | 3 |
5. | Poor appetite or overeating | 0 | 1 | 2 | 3 |
6. | Feeling bad about yourself—or that you are a failure or have let yourself or your family down | 0 | 1 | 2 | 3 |
7. | Trouble concentrating on things, such as reading the newspaper or watching television | 0 | 1 | 2 | 3 |
8. | Moving or speaking so slowly that other people could have noticed. Or the opposite—being so fidgety or restless that you have been moving around a lot more than usual | 0 | 1 | 2 | 3 |
9. | Thoughts that you would be better off dead or of hurting yourself in some way | 0 | 1 | 2 | 3 |
Total ___________=Add_________ + ______________ + ______________ score columns | |||||
If you checked off any problems, how difficult have these problems made it for you to do your work, take care of things at home, or get along with other people? | |||||
Not difficult at all | Somewhat difficult | Very difficult | Extremely difficult | ||
Anxiety, Depression, and Suicide
Cancer patients have twice the risk of suicide compared to the general population, and risk factors include depression, hopelessness, helplessness, loss of control, perceived burden to others, pain, cognitive function and delirium, poor social support, personality disorders, and existential distress [23].
While the association between depression and suicide is well known, more recently, there has been an increasing awareness that anxiety is another risk factor for suicide [24]. It seems likely that interactions between other vulnerabilities such as younger age, less social support, and specific anxiety subtypes (e.g., panic) might confer increased risk of suicidality [6]. Depression is associated with a greater desire for physician assisted suicide and, conversely, treating depression decreases the number of such requests.
Medical Workup for Depression
A thorough medical history and physical examination should consider vital signs, cardiovascular, neurological, gastrointestinal, and respiratory systems. Diagnostic tests may include laboratory examination (such as electrolytes, thyroid function tests, liver function tests, albumin, blood urea nitrogen, creatinine), electrocardiogram, brain imaging studies to exclude structural CNS lesions, electroencephalogram when seizure activity is suspected, and cerebrospinal fluid analysis (if CNS infection, subarachnoid hemorrhage, or leptomeningeal disease is suspected).
Psychopharmacological Treatments of Anxiety and Depression
Because psychological symptoms occur in approximately one-third of cancer patients, oncologists should have demonstrable competency treating their patients with antidepressants and antianxiety agents. Starting an antidepressant together with a benzodiazepine makes clinical sense where there is comorbid anxiety or prominent sleep disturbance, as the patient will experience some relief straight away. Adherence with antidepressants is also improved when they are prescribed together with benzodiazepines.
Although serotonin norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) and other such medications are called antidepressants, when taken regularly, they also have significant antianxiety effects; hence, the term antidepressant does not entirely match the function of the drug class. They might be better described as antidepressant–antianxiety agents.
Antidepressants
SNRIs, such as venlafaxine and duloxetine, and SSRIs, such as citalopram and sertraline, are considered first-line agents for treating depression in patients with comorbid medical conditions. One advantage of using an SNRI is that they have been found to be helpful in reducing neuropathic pain associated with diabetic neuropathy; however, SSRIs have no impact on pain pathways.
Antidepressant Titration Protocol
A good rule of thumb is to prescribe half of the lowest starting dose for 3–7 days to ensure that the medication is well tolerated. To illustrate, venlafaxine XR 37.5 mg is given for 1 week, after which it is increased to 75 mg daily. The dose of an antidepressant is reevaluated every 3–4 weeks by a clinical examination and measuring the PHQ-9 and GAD-7 for a 50 % decrease in score. If there is no improvement, the dose is usually doubled, e.g., venlafaxine XR is increased from 75 to 150 mg/day after 1 month. If there is still no improvement after 2 months, the dose could be increased to 225 mg/day for a further month. If the depression still has not improved significantly by month three, the next step would be to (1) add an antidepressant from a different class (e.g., mirtazapine or bupropion), (2) switch antidepressants, or (3) augment with psychotherapy.
After symptoms remit (e.g., PHQ-9 score of <5) patients should continue the antidepressants for another 6–8 months to consolidate the remission. Discontinuing the antidepressant earlier increases the statistical chance of relapse. If depression is recurrent, the patient should continue treatment for 2–5 years. It is not recommended that an antidepressant be stopped during the winter months due to the tendency of symptoms to worsen when they overlap with seasonal affective disorder. Spring or summer months are better times to wean antidepressants.
Side Effects of Antidepressants
SNRIs and SSRIs should be taken with food to minimize the most common initial side effect, transient nausea. Patients should be warned about this and told not to stop the medication if they experience nausea or other gastrointestinal symptoms because tolerance usually develops after a day or two.
A serotonergic withdrawal reaction occurs in some patients when these medications are stopped suddenly. This presents as intense discomfort and flu-like symptoms. In this event, treatment with the antidepressant should be restarted and weaned slowly over the course of 2 weeks. If patients have skipped multiple doses accidently, without withdrawal symptoms, the chances are that the medication can be safely stopped suddenly. Generally, it is prudent to tell patients that when antidepressants are stopped, the dose should be weaned down gradually over 1–2 weeks.
Sexual side effects can be bothersome and manifest as decreased libido in both sexes or delayed ejaculation in males. This is not, however, universal; many patients experience an improvement in their libido as the depression lightens.
Hyponatremia secondary to syndrome of inappropriate antidiuretic hormone has been recognized with SNRIs, SSRIs, and mirtazapine with a mean time to onset of 13 days (range 3–120) [25]. Those older than 65 are at particular risk.
There is an increased risk of gastrointestinal and uterine bleeding with SSRIs and SNRIs. The mechanism is believed to be via depletion of platelet serotonin which impedes coagulation in vulnerable patients, e.g., those taking nonsteroidal anti-inflammatories.