Anxiety Disorders: Description and Etiology
Anxiety Disorder Caused by Other General Medical Conditions
Primary Anxiety Disorders
Generalized anxiety disorder
Screening and Assessment
Current Clinical Trials
Anxiety occurs to varying degrees in patients with cancer and may increase as the disease progresses or as treatment becomes more aggressive. Investigators have found that 44% of patients with cancer reported some anxiety, and 23% reported significant anxiety.[2,3]
Anxiety can be part of normal adaptation to cancer. In most cases, the reactions are time limited and may motivate patients and families to take steps to reduce anxiety (e.g., gain information), which may assist in adjusting to the illness. However, as discussed above, anxiety reactions that are more prolonged or intense are classified as adjustment disorders. These disorders can negatively affect quality of life and interfere with a cancer patient’s ability to function socially and emotionally. These anxiety reactions require intervention. Anxiety disorders may also be secondary to other aspects of the medical condition, such as uncontrolled pain, certain metabolic states, or medication side effects.
Other specific anxiety disorders—such as generalized anxiety, phobia, or panic disorder—are not as common among cancer patients and usually predate the cancer diagnosis, but deserve further attention to facilitate cancer care. The stress caused by a diagnosis of cancer and its treatment may precipitate a relapse of pre-existing anxiety disorders. These disorders can be disabling and can interfere with treatment. They require prompt diagnosis and effective management.
Factors that can increase the likelihood of developing anxiety disorders during cancer treatment include the following:
- History of anxiety disorders.
- Severe pain.
- Anxiety at time of diagnosis.
- Functional limitations.
- Lack of social support.
- Advancing disease.
- History of trauma.[1,7]
Some medical conditions and interventions are associated with symptoms that present as anxiety disorders, including central nervous system metastases, dyspnea associated with lung cancer, and treatment with corticosteroids and other medications. A patient’s experience with cancer or other illnesses may reactivate associations and memories of previous illness and contribute to acute anxiety. Certain demographic factors, such as being female and developing cancer at a young age, are associated with increased anxiety in medical situations.[2,8] Patients who have problems communicating with their families, friends, and physicians are also more at risk of developing anxiety.
Anxiety, on the other hand, can lead to overestimation of negative prognosis. A longitudinal study of women with ductal carcinoma in situ (N = 487) found that anxiety as measured by the Hospital Anxiety and Depression Scale was the factor that was most consistently and strongly associated with inaccurate perception of and overestimation of future breast cancer–related risks.
In the patient with advanced disease, anxiety is often not caused by the fear of death but by the issues of uncontrolled pain, isolation, abandonment, and dependency. Many of these factors can be managed when adequately assessed and properly treated.Anxiety Disorder Caused by Other General Medical Conditions
The following table highlights possible causes of anxiety in cancer patients.Table 2. Possible Causes of Anxietya
|aAdapted from Massie.|
|Poorly controlled pain||Insufficient or as-needed pain medications.|
|Abnormal metabolic states||Hypoxia, pulmonary embolus, sepsis, delirium, hypoglycemia, bleeding, coronary occlusion, or heart failure.|
|Hormone-secreting tumors||Pheochromocytoma, thyroid adenoma or carcinoma, parathyroid adenoma, corticotropin-producing tumors, and insulinoma.|
|Anxiety-producing drugs||Corticosteroids, neuroleptics used as antiemetics, thyroxine, bronchodilators, beta-adrenergic stimulants, antihistamines, and benzodiazepines (paradoxical reactions are often seen in older persons).|
|Anxiety-producing conditions||Substance withdrawal (from alcohol, opioids, or sedative-hypnotics).|
Acute onset of anxiety may be a precursor of a change in metabolic state or of another impending medical event such as myocardial infarction, infection, or pneumonia. Sepsis and electrolyte abnormalities can also cause anxiety symptoms. Sudden anxiety with chest pain or respiratory distress may suggest a pulmonary embolism. Patients who are hypoxic can experience anxiety; they may fear that they are suffocating.
Many drugs can precipitate anxiety in persons who are ill. For example, corticosteroids can produce motor restlessness, agitation, and mania as well as depression and thoughts of suicide. Bronchodilators and B-adrenergic receptor stimulants used for chronic respiratory conditions can cause anxiety, irritability, and tremulousness. Akathisia, motor restlessness accompanied by subjective feelings of distress, is a side effect of neuroleptic drugs, which are commonly used for control of emesis. Withdrawal from opioids, benzodiazepines, barbiturates, nicotine, and alcohol can result in anxiety, agitation, and behaviors that may be problematic for the patient who is in active treatment.
Certain tumor sites can produce symptoms that resemble anxiety disorders. Pheochromocytomas and pituitary microadenomas can present as episodes of panic and anxiety. Non–hormone-secreting pancreatic cancers can cause anxiety symptoms. Primary lung tumors and lung metastases can often cause shortness of breath, which can lead to anxiety.Primary Anxiety Disorders
Patients who have the following symptoms may be experiencing a specific anxiety disorder that was present before they became ill with cancer and that recurs because of the stress of the diagnosis and treatment:
- Intense fear.
- Inability to absorb information.
- Inability to cooperate with medical procedures.
Somatic symptoms include the following:
- Shortness of breath.
Patients with cancer can present with the following anxiety disorders:
- Panic disorder.
- Generalized anxiety disorder.
- Obsessive-compulsive disorder.
- Adjustment disorder.
- Post-traumatic stress disorder.
- Anxiety disorder that is caused by other general medical conditions.
Patients with these anxiety disorders are generally distressed about their symptoms and are usually compliant with behavioral and psychopharmacologic intervention.Phobias
Phobias are persistent fears or avoidance of a circumscribed object or situation. People with phobias usually experience intense anxiety and avoid potentially frightening situations. Phobias are experienced by cancer patients in a number of ways, such as fear of witnessing blood or tissue injury (also known as needle phobia) or claustrophobia (for example, during a magnetic resonance imaging scan). Phobias can complicate medical procedures and can result in the refusal of necessary medical intervention or tests. Phobias generally respond well to exposure therapy and cognitive behavioral therapy (CBT).Panic disorder
In panic disorder, intense anxiety is the predominant symptom, virtually always accompanied by severe somatic symptoms that include the following:
- Shortness of breath.
- Tingling sensations.
- Fears of going crazy or that a heart attack is occurring.
Panic disorder is characterized by discrete panic “attacks” that are experienced as happening suddenly, often without a specific trigger, and become intense very quickly. Attacks or discrete periods of intense discomfort generally last for several minutes or longer, but the discomfort generally lasts for hours. A common complication is agoraphobia or avoidance of open places, caused by fear of situations that might trigger attacks. Patients with panic attacks often present with symptoms that can be difficult to differentiate from other medical disorders, though a known history of panic disorder can help clarify the diagnosis. Panic disorder in patients with cancer is most often managed with benzodiazepines and antidepressant medications  but also responds well to CBT.Generalized anxiety disorder
Generalized anxiety disorder is characterized by ongoing, unrealistic, and excessive anxiety and worry about two or more life circumstances, to a degree that is pervasive and does not respond to either reassurance or contrary evidence. The following physical symptoms may be reported but do not have the sudden onset or intensity of panic attacks:
- Motor tension (restlessness, muscle tension, and being easily fatigued).
- Autonomic hyperactivity (shortness of breath, heart palpitations, sweating, and dizziness).
- Vigilance in scanning (feeling keyed up and on edge, irritability, and having exaggerated startle responses).
Some examples of generalized anxiety disorder are patients’ fears that no one will care for them, even though they have adequate and willing social support; and the fear of exhausting their finances, even though adequate insurance and financial coverage is available. Frequently, a generalized anxiety disorder is preceded by a major depressive episode.Obsessive-compulsive disorder
Obsessive-compulsive disorder (OCD) is characterized by persistent thoughts, ideas, or images (obsessions) and by repetitive, purposeful, and intentional behaviors (compulsions) that a person performs to manage his or her intense distress. To qualify as OCD, the obsessive thoughts and compulsive behaviors must be time-consuming and sufficiently distracting to interfere with the person’s ability to function in employment, academic, or social situations.
Patients with cancer who have a history of OCD may engage in compulsive behaviors such as hand washing, checking, or counting to such an extent that they cannot comply with treatment. For such patients, normal worry about the cancer diagnosis and prognosis can develop into full obsessive-compulsive symptoms and be severely disabling. OCD is most often managed with serotonergic antidepressant medications (selective serotonin reuptake inhibitors [SSRIs] and clomipramine) and CBT. Milder obsessive thoughts or use of rituals that are not interfering might be addressed with CBT, but medications are not indicated. This disorder is rare in cancer patients who do not have a premorbid history.Screening and Assessment
Effective management of anxiety disorders begins with a thorough and comprehensive assessment and an accurate diagnosis. The normal fears and uncertainties associated with cancer are often intense. Frequently not clear is the distinction between normal fears and fears that are more severe and reach the criteria for an anxiety disorder (see Table 3 for more information).
Treatment should consider the patient’s quality of life, not be based solely on the disorder. To assess the severity of the anxiety, it is important to understand to what extent the symptoms of anxiety are interfering with activities of daily living. Screening for anxiety could include a brief self-report questionnaire that, if a defined cutoff score is exceeded, could then be followed by a more thorough clinical interview. A variety of general screening questionnaires have been used for identification of distress. (Refer to the section on Self-report screening instruments in this summary for more information.) Other anxiety-specific self-report questionnaires (e.g., State-Trait Anxiety Inventory) have also been used, and a questionnaire for the assessment of prostate cancer–related anxiety has been developed and validated.[2,15,16]
The following is a list of symptoms designed to distinguish common or normal worry from more serious symptoms of anxiety. When patients are reporting the more serious symptoms, referral to a qualified mental health professional may be warranted.Table 3. Common Worry versus Anxiety Disordersa
|Symptoms of Common or Normal Worry||More Serious Symptoms of Anxiety Disorders|
|aAdapted from Nicholas.|
|Worry comes and goes.||Worry seems constant.|
|Has some difficulty in concentrating.||Is unable to concentrate.|
|Is able to "turn off thoughts" most of the time.||Is unable to "turn off thoughts" most of the time.|
|Has occasional trouble falling asleep.||Has trouble falling asleep and/or wakes up early most nights.|
|Has occasional crying spells that seem to provide some relief.||Has frequent crying spells that interfere with daily activities.|
|Fear and apprehension are clearly connected to some upcoming event (e.g., start of treatment, doctor appointment, or receipt of test results).||Fear and apprehension are more "free floating" and seem to be present most of the time.|
|Has few, if any, physical symptoms (e.g., racing heart, dry mouth, shaky hands, or restlessness).||Has many physical symptoms (e.g., racing heart, dry mouth, shaky hands, restlessness, fidgetiness, or feeling keyed up).|
|Has ways to reduce anxiety (e.g., distraction by staying busy).||Has few, if any, ways to reduce anxiety.|
When anxiety is situational (i.e., produced by pain, another underlying medical condition, a hormone-secreting tumor, or a side effect of medication), the prompt treatment of the cause usually leads to immediate control of the symptoms. Some effective coping strategies include encouraging fearful patients to:
- Confront the problem directly.
- Try to view the situation as a problem to be solved or as a challenge.
- Try to obtain complete information.
- Try to be flexible (taking things as they come).
- Think of major events as a series of step-by-step tasks.
- Use resources and support.
Initial management of anxiety includes providing adequate information and support to the patient. Initial symptoms, which may warrant a psychiatric or psychological consultation, may first be reported to the primary oncologist or surgeon.[Level of evidence: IV]Psychosocial interventions
Psychological approaches include combinations of cognitive behavioral therapy techniques, insight-oriented psychotherapy, crisis intervention, couple and family therapy, group therapy, self-help groups, and relaxation-based interventions. These approaches (hypnosis, meditation, progressive relaxation, guided imagery, and biofeedback) can be used to treat anxiety symptoms that are associated with painful procedures, pain syndromes, crisis situations, anticipatory fears, and depressive syndromes.
Combining different approaches can be beneficial for some patients. (Refer to the Psychosocial Interventions for Distress section of this summary for more information.) Individuals who may be struggling with anxiety disorders should be referred for full assessment and psychological treatment.
One study of 509 recurrence-free breast cancer survivors at 5 to 9 years posttreatment examined the usefulness of a comprehensive intervention that combined positive coping strategies based on CBT (e.g., calming self-talk or relaxation) with education about the disease, treatment, and potential side effects. Findings from this study indicate that women in the intervention group (n = 244) regularly used the intervention components to deal with triggers of fears of breast cancer recurrence and long-term treatment side effects. Most women in the intervention group found the strategies very helpful.[Level of evidence: I]
Preliminary evidence suggests racial differences in the use and benefit of specific coping strategies (e.g., religious coping strategies such as prayer and hopefulness are used more by African American women and provide greater benefit for these women).[Level of evidence: I];[Level of evidence: II]Pharmacologic interventions
Patients with cancer often have symptoms of both anxiety and depression that are caused by stressors related to cancer treatment. Such symptoms of distress often are resolved with psychologic support alone. However, in some cases, pharmacologic interventions are required to address these symptoms. (Refer to Table 3 for descriptions of symptoms of anxiety disorders possibly requiring pharmacological treatment.)
Following are brief descriptions of pharmacological treatment options and potential indications for their use. These descriptions are based on evidence derived from studies conducted in patients without cancer because of the lack of such studies in patients with cancer. However, it is important to note that clinicians have used some of these medications for several decades to treat anxiety symptoms in patients with cancer. The treatment options and their use in the situations described below are also based on clinical experience with these agents in patients with cancer.
The use of medications to treat anxiety disorders is considered when patients are experiencing more severe symptoms or when their responses to psychosocial interventions are inadequate. When counseling resources are not available or are declined by the patient, medication may be considered sooner rather than later. In certain cases, medications are started simultaneously with psychosocial interventions when it is likely that psychosocial support alone will be inadequate to provide relief or to provide it soon enough.
Pharmacological interventions can be used short-term or long-term, depending on individual patient and illness factors, including the following:
- Severity of anxiety symptoms.
- Level of functional/social impairment.
- Psychiatric history.
- Continued presence of cancer.
- Cancer treatment–related factors contributing to anxiety directly or indirectly (e.g., high-intensity or long-term cancer treatments or treatment with agents known to cause to psychiatric symptoms [e.g., cytokines]).
Specific anxiety medications—i.e., medications from the benzodiazepine class, as listed in Table 4—are frequently used alone or in combination with psychological approaches to provide relief from anxiety symptoms. These medications are effective in the acute treatment of anxiety disorders because of their rapid onset of action. They are frequently used as monotherapy or as adjunctive agents in the short-term management (<4 months) of anxiety disorders. Their long-term use (>4 months) is limited by the potential for abuse and dependence and by their lack of antidepressant effects, as depression is often comorbid with anxiety disorders. Following are some of the indications and safety considerations for the use of benzodiazepines in patients with cancer:[23,24]
- Short-acting benzodiazepines such as alprazolam and lorazepam can be effectively used to provide short-term relief at specific points in the cancer continuum of diagnosis, treatment, and recurrence. Examples of such short-term use include the treatment of anxiety during diagnostic procedures (e.g., certain radioimaging procedures) and the treatment of patient anxiety about pending test results (e.g., for yearly mammograms in patients with histories of breast cancer).
- Cancer treatments such as intensive chemotherapeutic regimens can cause significant physical and emotional distress and thus exacerbate anxiety. Short-acting or intermediate-acting agents (e.g.,clonazepam) can provide significant relief of anxiety and other symptoms (e.g., insomnia secondary to anxiety) during active cancer treatments.
- Longer-acting medications (e.g., diazepam and clorazepate) should generally be avoided because of their long half-lives. These medications can cause or exacerbate cognitive impairment, disorientation, and drowsiness because of their potential for accumulation.
- Patients with medical conditions such as delirium can present with anxiety and agitation. Benzodiazepine use in patients with such conditions is counterindicated because these agents can cause or exacerbate confusion and disorientation.
- All patients, especially elderly patients, receiving benzodiazepines should be closely monitored for cognitive impairment, daytime sedation, and fall risks. Use of these agents should be optimized in elderly patients, patients with multiple comorbidities, patients with liver disease, and patients receiving multiple medications.
- Use of these agents should be closely monitored and optimized in patients receiving other sedating medications, central nervous system depressants, and agents with potential for causing respiratory depression (e.g., opiates).
- It is important to continuously monitor and reevaluate anxiety symptoms in all patients receiving benzodiazepines. Use of these medications can be tapered off if anxiety symptoms resolve with the conclusion of cancer treatments.
- In some patients, the use of benzodiazepines is continued (as monotherapy or as adjunctive treatment) over a longer period (>4 months) because of persistent and debilitating anxiety symptoms. It is important to monitor the development of tolerance, abuse, and dependence issues as well as comorbid depressive symptoms in such patients. Long-term and sometimes chronic use of these agents might be indicated in a subpopulation of patients, with close monitoring and frequent risk-benefit assessments. Persistent (after 3 or 4 months) anxiety symptoms frequently lead to depression. Patients with persistent anxiety symptoms with or without depression might benefit from alternative treatments (e.g., paroxetine, sertraline).
|Drug Equivalent||Approximate Oral Dose (mg)b||Initial Dose (mg)||Elimination Half-life of Drug Metabolites (h)|
|Alprazolam (Xanax)||0.5||0.25–2.0 tid–qid||10–15|
|Oxazepam (Serax)||10.5||10–15 tid–qid||5–15|
|Lorazepam (Ativan)||1.0||0.5–2.0 tid–qid||10–20|
|Temazepam (Restoril)||15.0||15–30 at bedtime||10–15|
|Alprazolam (Xanax XR)||1.0||1–6 qd||10–15|
|Clonazepam (Klonopin)||1.0||0.5–2.0 bid–tid||19–50|
|Chlordiazepoxide (Librium)||10.0||10–50 tid–qid||10–40|
|Diazepam (Valium)||5.0||5–10 bid–qid||20–100|
|Clorazepate (Tranxene)||7.5||7.5–15.0 bid||30–200|
|bid = twice a day; qd = once a day; qid = 4 times a day; tid = 3 times a day.|
|aAdapted from Breitbart et al.|
|bRefer to the PDQ summary on Depression for dosing information on antidepressants used for anxiety as described in this summary.|
The choice of a benzodiazepine depends on the following:
- Duration of action that is best suited to the patient.
- Desired rapidity of onset needed.
- Route of administration available.
- Presence or absence of active metabolites.
- Metabolic problems.
Dosing schedules depend on patient tolerance and require individual titration. The shorter-acting benzodiazepines (alprazolam and lorazepam) are given 3 to 4 times per day. Short-acting benzodiazepines, particularly those that can be administered by multiple routes (lorazepam and diazepam), are effective for high levels of distress. Benzodiazepines decrease daytime anxiety and reduce insomnia. (Refer to the PDQ summary on Sleep Disorders for more information.) The most common side effects of benzodiazepines are dose dependent and are controlled by titrating the dose to avoid drowsiness, confusion, motor incoordination, and sedation.
All benzodiazepines can cause some degree of respiratory depression, which is generally minimal in patients who have not used benzodiazepines in the past. Benzodiazepines should be used cautiously (or not at all) in cases of respiratory impairment.
Standard precautions should be considered when any sedative drug is used in patients who have borderline respiratory function. Ongoing assessment of this population is important. Low doses of the antihistamine hydroxyzine (25 mg, 2–3 times a day) can be used safely in such situations. In patients with hepatic dysfunction, it is best to use short-acting benzodiazepines that are metabolized primarily by conjugation and excreted by the kidneys (e.g., oxazepam, temazepam, or lorazepam). Another advantage of using lorazepam is its lack of active metabolites. Conversely, other benzodiazepines should be selected in cases of renal dysfunction.
SSRIs (e.g., fluoxetine and sertraline) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine) are considered first-line pharmacotherapy for long-term management of anxiety disorders. SSRIs and SNRIs are also effective in the treatment of depressive symptoms frequently comorbid with persistent anxiety disorders. SSRIs and SNRIs can take approximately 4 to 6 weeks to take effect because of their slow onset of action. Benzodiazepines are frequently used as adjunctive agents to stabilize symptoms in the initial period of treatment with SSRIs and SNRIs.
Atypical antidepressants (e.g., mirtazapine) are sometimes used to treat anxiety disorders because of their added effects on comorbid symptoms such as insomnia. Older medications such as tricyclic antidepressants (e.g., imipramine and clomipramine) and monoamine oxidase inhibitors (e.g., phenelzine) are also effective in treating anxiety disorders. The use of antidepressants in clinical practice is limited by their unfavorable side effects, poorer tolerability, and higher risks of toxicity.
(Refer to Table 2 in the PDQ summary on Depression for antidepressant dosing. Refer to the Suicide Risk in Cancer Patients section in the PDQ summary on Depression for risk of suicidality and other neuropsychiatric side effects.)
Buspirone, a nonbenzodiazepine, is useful in patients who have not previously been treated with a benzodiazepine and in those who may abuse benzodiazepines (e.g., those with a history of illicit substance abuse or alcoholism). Buspirone is also useful in the geriatric population to augment fluoxetine for the treatment of anxiety and depression. The beginning dose is 5 mg 3 times a day and can be increased to 15 mg 3 times a day. Buspirone can also be given twice a day.
The use of specific classes of medications is considered for managing treatment-refractory anxiety symptoms or in certain special clinical situations. Low-dose neuroleptics (e.g., thioridazine, 10 mg 3 times a day; and risperidone, 1 mg twice a day) are used to treat severe anxiety when an adequate dose of a benzodiazepine is ineffective or if the patient might be expected to respond poorly to benzodiazepines (e.g., patients with brain metastases). Low-dose neuroleptics can also be used when benzodiazepines are not helpful or when there is the possibility of delirium, dementia, or other complications. Low-dose anticonvulsants (e.g., pregabalin, 200 mg per day) are sometimes used to treat severe treatment-resistant anxiety when other medications are ineffective or contraindicated because of certain associated risks. Generally, the use of neuroleptics or anticonvulsants is considered after adequate trials with several first-line agents (e.g., SSRIs, SNRIs, and benzodiazepines) because of the significant side effect burden and potential for drug-drug interactions with these agents. Consultation with a psychiatric clinician is strongly recommended before these medications are used. Direct involvement of a psychiatric clinician is imperative for the management of patients receiving these medications.
The presence or absence of specific psychiatric or medical comorbidities is frequently a critical factor in the selection of pharmacological treatments. Pharmacokinetic and pharmacodynamic interactions with other medications are also important factors to be considered in the selection of agents. Following are some examples of such factors and clinical situations driving the selection of pharmacological treatments:
- When depressive symptoms are comorbid with anxiety, treatment with SSRIs, SNRIs, or other antidepressants is strongly considered.
- When neuropathic pain is comorbid with anxiety symptoms, specific antidepressants with known efficacy in treating neuropathic pain (e.g., duloxetine and venlafaxine) are considered.
- When hot flashes are comorbid with anxiety symptoms, specific agents with known efficacy in treating hot flashes (e.g., venlafaxine) are considered.
- Specific medications with known side effects (e.g., nausea with duloxetine or risk of sedation with mirtazapine) are avoided when patients are already experiencing these side effects from their cancer treatments and because of the possible exacerbation of these side effects.
- Treatment with significant CYP2D6 inhibitors (e.g., paroxetine) is not recommended when patients are receiving tamoxifen because of the risk of significant drug-drug interactions. (Refer to the PDQ summary on Sweats and Hot Flashes for more information.)
No pharmacological treatment studies have been conducted in children and adolescents with cancer. Furthermore, evidence on pharmacological treatment of anxiety disorders in pediatric patients without cancer is also limited. One meta-analysis of pediatric antidepressant clinical trials [Level of evidence: I] found antidepressants efficacious relative to placebo in the treatment of anxiety disorders, with strongest effects in non-OCD anxiety disorders (e.g., generalized anxiety disorder or social anxiety disorder) and intermediate effects in OCD. (Refer to the PDQ summary on Depression for a discussion of the risk of suicidal ideation/suicide attempt associated with antidepressant use.)
In general, patients with cancer need to be encouraged to take enough medication to relieve anxiety. Medications are readily tapered and discontinued when symptoms subside. Concerns about addiction are exaggerated in patients with cancer and often interfere with adequate symptom relief.Current Clinical Trials
Check NCI’s list of cancer clinical trials for U.S. supportive and palliative care trials about anxiety disorder that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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