Kristi Skeel Williams and Kathleen S.N. Franco-Bronson
I. GENERAL PRINCIPLES
Clinical psychiatric disorders occur in up to half of patients with cancer at some point during their treatment. Delirium, depression, and anxiety are most frequently seen and may coexist in the same patient Vigilant monitoring for early symptoms of psychiatric distress is important in the care of these patients. The clinician should inquire regularly about symptoms in affective and cognitive domains. Symptom clusters help differentiate anxiety, depression, and acute confusional states from other psychiatric disorders. Once an accurate diagnosis is made, safety, toler-ability, efficacy, and price influence choice of medication. More than one psychiatric diagnosis maybe present, requiring a hierarchical approach. For example, if both delirium and depression are present, the cause of the delirium should be determined and treated before starting antidepressant therapy (which could worsen the delirium). Once the delirium has improved, treatment for the depression can be considered. When major depression and an anxiety disorder coexist, treatment for the depression is started first and may adequately manage both disorders.
II. ACUTE CONFUSIONAL STATES
Approximately 15% of hospitalized patients with cancer experience delirium, but this can increase to 80% to 85% in those receiving palliative care.
Attempting to treat delirium with psychotropic drugs, but without understanding the cause of the patient's confusion, can have serious consequences. Delirium is characterized by fluctuating levels of alertness and consciousness, shortened attention and concentration, rapidly changing moods, irregular sleep-wake cycles, garbled or slurred speech, hypervigilance, and behavior not consistent with good judgment. The delirious patient may also have delusional ideas or hallucinations or appear depressed. Visual, auditory, tactile, and occasionally olfactory hallucinations can be present. The more sensory modalities that are involved in the hallucinations, the greater the likelihood that the patient is experiencing a medically induced confusional state.
1. Medications remain the most common reason for acute confusional states. The most frequently identified medications to cause delirium are sedatives, narcotic analgesics, anxiolytics, anticholinergic drugs, and corticosteroids. Antineoplastic and immunotherapeutic agents can cause delirium: cytarabine, methotrexate, asparaginase, fluorouracil, interferon, and interleukin. Even histamine blockage from agents like diphenhydramine or famotidine can lead to delirium.
2. Metabolic causes are often seen in patients with cancer and include hypernatremia and hyponatremia, hyperthyroidism and hypothyroidism, poorly controlled diabetes mellitus, vitamin deficiencies (B12, folate, thiamine), and hypercalcemia.
3. Infections of the respiratory, urinary, central nervous, and other systems are common, especially in immunosuppressed patients.
4. Chemical withdrawal from benzodiazepines, alcohol, and other drugs can induce delirium.
5. Medical illness such as tumors, particularly primary brain tumors and brain metastases, cardiac arrhythmias, congestive heart failure, liver disease, trauma, strokes, and renal failure. Hyperviscosity syndrome with lymphoma, myeloma, and Waldenstrom macroglobulinemia are unusual causes. After radiation to the brain, confusional states can occur, especially if the patient received a small amount of steroid. An acute confusional state can occur secondary to a para-neoplastic syndrome frequently associated with lymphoma. In addition to the original illness, postoperative head and neck surgery, often for malignancy, carries a higher risk than many other surgical procedures for delirium.
C. Therapeutic approach
Once an acute confusional state is identified, the primary therapeutic approach is to treat the cause. The key is to determine when symptoms of delirium first occurred and to look for preceding changes in medications, vital signs, laboratory studies, or imagery/radiology. This helps to determine how to best proceed with treatment (e.g., withdrawing a medication or treating a urinary tract infection found on a urinalysis). When hypoactive delirium occurs, inclining the head to 30% reduces the risk for aspiration. Moving the patient frequently may prevent bed sores. Hyperactive patients with delirium are at high risk for falls and subsequent fractures. Research has demonstrated that a combined protocol of physical mobilization, cognitive exercise through conversation and reorientation, appropriate hydration, use of glasses or hearing aids from home, and minimizing sedatives at night can reduce the number, severity, and cost of delirium episodes. Antipsychotic medications may be helpful for managing symptoms such as hallucinations, delusions, and extreme agitation, but they do not treat the cause of the delirium.
1. Orientation (frequent reconnection) of the patient aids inreduction of confusion.
a. It is helpful to orient the patient frequently to place, time, and why they are at the hospital and to give current explanations of procedures. This routine should be done once or more per shift when the delirious patient is awake. Because the patient's attention, concentration, and recent memory are frequently impaired, the patient often does not recall instructions given earlier. Leaving a large, legibly written note card with the patient's name, date, hospital name, and other data is beneficial in some instances.
b. A large calendar, a clock, and family pictures or mementos can assist the patient in feeling less estranged from his or her environment. It can be very reassuring to a patient if a family member can stay with them overnight.
c. Some patients are reassured by a small night light in their room, which cuts down on illusions or misinterpretations. Patients with compromised vision or hearing are particularly distraught when they are even less able to discern what is happening around them, and they should be provided with their regular hearing aids and glasses.
2. Medication helps to control hallucinations, delusions, and psychotic agitation. The lowest dose to control symptoms is usually preferable.
a. Haloperidol (Haldol; Table 32.1) is a butyrophenone, an antipsychotic agent with potent dopamine-blocking action. It is less likely to produce cardiovascular, respiratory, gastrointestinal, and general anticholinergic side effects than many of the other antipsychotic medications. However, moderate doses may cause extrapyramidal symptoms. The starting dose in a patient with an acute confusional state is 0.25 to 2 mg by mouth or intramuscularly, on an as-needed or regular dosing schedule every 4 to 6 hours. A marked advantage of haloperidol is that sedation is minimized while controlling agitation. There are exceptions to the usually preferred low doses of antipsychotic medications. For example, if patients tolerate higher doses with few side effects, they may benefit by having improved pain control. Intravenous (IV) haloperidol has not been approved by the U.S. Food and Drug Administration, although it is commonly used in the seriously agitated patient. There are fewer extrapyramidal symptoms with IV haloperidol, but the half-life in this form is much shorter, requiring more frequent administration. Avoid very high doses in patients can also be given in a rapid onset intramuscular preparation. Quetiapine (Seroquel) is only available orally, as is aripiprazole (Abilify, Abilify Discmelt). Aripiprazole acts slowly and would not help reduce symptoms quickly. Some immediate antipsychotic preparations can be crushed and put in a feeding tube.
b. Risperidone, olanzapine, ziprasidone, quetiapine, and aripiprazole. Risperidone (Risperdal, Risperdal M-Tab) is less likely to produce extrapyramidal side effects, but is available only in oral form for acute (nondepot) use. Olanzapine (Zyprexa, Zydis) is sedating and can be given in a tablet that dissolves on the tongue or in an intramuscular form. Ziprasidone (Geodon) with alcoholic cardiomyopathy, those prone to torsades de pointes or similar arrhythmias, and those with an excessively long corrected QT interval.
c. A delirious patient with vision or hearing impairment is likely to hallucinate during periods of excessive sedation, especially if there is pulmonary compromise or a tendency toward hypoxia.
d. If the patient demonstrates a predictable period of confusion, such as during the early evening (“sun-downing”) when there is less environmental activity, a small once-a-day dose at that time may be adequate.
e. When increasing the dose of antipsychotic drugs, muscle spasms, restlessness, or pseudoparkinsonian symptoms may occur with older first-generation antipsychotics and some second-generation agents like risperidone or ziprasidone. Adding a small amount of trihexyphenidyl (Artane) 1 to 2 mg twice a day, benztropine (Cogentin) 1 mg twice a day, or diphenhydramine (Benadryl) 25 mg twice a day can often reduce the side effects. However, increasing the level of anticholinergic activity with these choices may cause an atropenic-like psychosis. Constipation, urinary retention, dry mouth, tachycardia, and increasing confusion are warnings of this potential problem, especially when multiple anticholinergic medications (e.g., antiemetics, analgesics) are being prescribed. Therefore, antiparkinsonian drugs are not prescribed prophylactically but only if clearly indicated. Ondansetron (Zofran), granisetron (Kytril), or dolasetron (Anzemet) may be substituted for other antiemetics, reducing extrapyramidal symptoms and avoiding the need for an antiparkinsonian medication. Some antiemetics (e.g., droperidol) are also antipsychotics, but these, like metoclopramide, can lead to extrapyramidal symptoms like akathisia or dystonias.
f. Benzodiazepines such as lorazepam (Ativan) can be given 0.5 to 2.0 mg every 8 hours. They can be administered in small doses to a patient who needs some sedation without added anticholinergic activity or those whose cardiac status is at risk (i.e., heart block) if some antipsychotic medications were increased. Using both benzodiazepines and antipsychotics is sometimes helpful.
g. Increasing delirium. Too much medication may have been given if the patient's agitation increases with higher doses. Secondary hypoxia and akathisia should be excluded. High blood levels of longer-acting medications can accumulate, particularly if serum albumin and protein is low and hepatic and renal functioning are compromised.
h. Hypotension. Avoid adding a second antipsychotic (e.g., chlorpromazine), as it may predispose to hypotension and shock. If the blood pressure does drop significantly, nor-epinephrine bitartrate (Levophed) or a similar choice may be necessary as antipsychotic medications like haloperidol also block some peripheral actions of dopamine.
Depression is roughly four times more common in patients with cancer than in age-matched controls. Oropharyngeal, pancreatic, lung, and breast cancer are associated with the highest rates of depression. Earlier studies indicated that patients with both cancer and depression had a higher risk of death, but larger meta-analysis did not find this to be true. However, patients who are depressed report poorer pain control, poorer compliance, and more often choose to discontinue treatment.
Patients with cancer have various emotional responses to their diagnoses. The mourning period for some is brief, does not inhibit their ability to interact with family and friends, and does not hinder participation in their own treatment. Support from others, acceptance of their feelings, and time may be all that is necessary for them to continue the emotional work ahead. However, about one-fourth of patients with cancer develop longer, more severe depression. The greatest risk of depression is at the time of first relapse. There are many variables that influence this process, including emotional conflicts with loved ones, disproportionate guilt, previous losses that were never resolved, long-standing debilitating illness, individual personality characteristics such as dependency, and inadequate support systems. Any of these factors, along with a family history of depression, are warnings for the physician to heed.
Besides emotional response to the stress of having cancer and undergoing treatment, other causes of depression should be considered. Folate or vitamin B12 deficiencies, thyroid or parathyroid disorders, adrenal insufficiency, leptomeningeal disease, and brain metastases can induce depression. Interferon can sometimes precipitate sadness to suicidal proportions in patients who have never previously experienced depression. Some recommend an antidepressant be started 2 weeks prior to starting interferon if a patient has a prior history of major depression.
Passive suicidal thoughts with depression are common. Patients who actually do commit suicide are more likely to be male, have advanced disease, and a history of psychiatric illness, substance abuse, and prior attempts. Good pain control and efforts to reduce isolation can lessen suicidal thoughts and behavior.
A. Therapeutic approach
1. Emotional support at frequent intervals from the physician is generally needed. Some patients explore old emotional conflicts, whereas others just need a safe person to whom they can express their feelings. It is important for patients to be able to hold on to hope. A degree of denial is acceptable, normal, and upheld. Only when this denial makes it impossible for a patient to make informed treatment decisions is it necessary to probe into the denial.
Psychotherapy of a supportive nature is often provided by the primary care physician, oncologist, psychiatrist, clergy, nurse, family, or friend individually or in any combination. For patients who wish to explore ambivalence, a professional psychotherapist trained in psychodynamic or interpersonal therapy is a good option. Cognitive therapy is helpful in letting go of detrimental interpretations while increasing one's ability to deal with emotional pain.
2. Psychiatric care may be particularly instrumental when the patient's pre-existing personality style is interfering with treatment. Anniversary responses to previous losses, important family events, or past hospitalizations may have a great impact on the presentation of the depression and deserve exploration by a psychotherapist if a pattern is found. If there is a designated psychiatric consultant, this individual must work closely with the rest of the oncology team, communicating in a helpful way to the patient, family, and staff.
If a patient has felt depressed, distressed, or irritable for some time or describes a loss of pleasure from formerly enjoyable relationships or activities, inquiry about the following symptoms is necessary: insomnia or hypersomnia; alteration in appetite with expected weight change; reduced interest in family, sexuality, work, or hobbies; increased guilt; low energy level; poor concentration; thoughts of death or suicide; frequent crying episodes; and psychomotor hypoactivity or hyperactivity. When the diagnosis of depression in the medically ill patient is being made, the emphasis is placed on psychological features as opposed to physical ones. These include rumination or repetitive negative thoughts, increased tearfulness, hopeless-helpless feelings, withdrawal from family or friends, and an hedonia. These symptoms are characteristic of a major depressive disorder for which antidepressant medications in addition to psychotherapy are recommended. In some studies, group therapy for patients with breast cancer has improved quality of life and may prolong survival.
It is important to screen for a past history of mania and hypomania in individuals with depression, as well as a family history of bipolar disorder, as antidepressants must be used with extreme caution, if used at all, for patients with a positive personal or family history.
3. Medications. In the past, patients with cancer were often under treated for major depression that was mistaken as an “understandable” consequence of their illness or as simple grief. Now, evidence exists that psychosocial adjustment and improved life adaptation, in general, occur when patients with cancer and major depression are treated with antidepressant medications.
a. Selection of agents and their side effects. In addition to efficacy, an antidepressant medication should be selected on the basis of its safety and tolerability, including any tendency to sedate or activate, cause orthostatic changes, or produce anticholinergic effects. Medication selection should also be tailored to the patient's symptom cluster such as the need for sedation or weight gain versus the need for activation (Tables 32.2 and 32.3). The route of metabolism and elimination, as well as any increased risk for seizures, should affect the choice. Agents like venlafaxine and duloxetine can reduce depression in patients with or without anxiety and improve pain control. Starting with lower doses and titrating up can lessen the risk of added nausea.
There is increasing evidence that selective serotonin reuptake inhibitors (SSRIs) inhibit platelet aggregation and prolong bleeding. Although this might be helpful to patients who also have cardiovascular disease, these agents should be discontinued when there is observed evidence of acute bleeding as indicated by rapid falls in hemoglobin and hematocrit. There is also some evidence that SSRIs inhibit CYP2D6 (see Table 32.3) and may interfere with the effectiveness of tamoxifen.
Highly anticholinergic medications frequently produce dry mouth, blurred vision, tachycardia, and constipation. They can also produce urinary retention, ileus, and acute confusion. Antihistaminergic drugs can increase sedation and appetite and worsen hypotension. Both H1- and H2-blocking agents can cause delirium, while a proton pump inhibitor will not. Medications that produce α-adrenergic receptor blockade are associated with increased orthostatic hypotension, dizziness, and reflex tachycardia. Stimulants such as methylphenidate and modafinil may be beneficial to treat depression and lethargy in the medically ill patient. Caution is advised in patients with cardiovascular disease or hepatic impairment.
b. Dosages (Table 32.4). Weak, debilitated, or elderly patients need protection from the side effects of psychotropic agents. Starting out with small doses and gradually increasing the dose is prudent. Splitting doses may also be helpful for minimizing side effects and maximizing pain relief from antidepressant medications.
If a patient has a personal history, family history, or previous response to medication (e.g., steroids) that reflects manic or hypomanic symptoms, proceed carefully. A mood stabilizer such as lithium or an anticonvulsant should be considered, as should consultation with a psychiatrist.
c. Monoamine oxidase inhibitors (MAOIs) may be used to treat major depression or panic disorder but are somewhat inconvenient owing to tyramine dietary restrictions and medication interactions requiring much attention. They are sometimes tried when other choices have failed. There is a transdermal form of selegiline (Emsam) available that does not require dietary modification at the lowest dose of 6 mg/24 h.
A. Approach to the problem
As grieving is described as normal, so is anxiety in patients with cancer. However, anxiety varies in its cause, severity, and treatment. A detailed history of the onset, characteristics, and length of distress is important. Knowledge of the patient's previous symptoms, current and past physical illness, substance abuse, and medication usage is essential to the evaluation process. Like depression, anxiety also amplifies pain. Antianxiety agents may be helpful for alleviating patients distress and helping them cope with other problems associated with their cancer (Table 32.5).
B. Problems that present as anxiety
The duration of the symptoms is one of the first factors to assess in the anxious patient.
1. Suspect an adjustment disorder when maladaptive anxious symptoms have persisted less than 6 months and apparently represent an adjustment to learning the diagnosis or reactions to the treatment. This kind of anxiety may benefit from supportive therapy, relaxation therapy, or benzodiazepines.
2. Generalized anxiety. If the anxiety has been present for more than 6 months, continuing no matter what environmental alterations occur, and is accompanied by signs of physical tension or poor attention to conversation or other daily activities, the patient is likely to have generalized anxiety. Supportive therapy, relaxation tapes, biofeedback, buspirone, gabapentin, and benzodiazepines such as clonazepam are useful.
3. Brief, isolated episodes of anxiety that come and go lead the examiner to consider other diagnoses.
a. Panic attacks. If the patient has repeated “attacks” that have a rapid onset and last 20 minutes to a few hours and if they are accompanied by tachycardia, palpitations, shortness of breath, hyperventilation, choking, sweating, dizziness, and the wish to flee, without a physical or chemical explanation, they are most likely panic attacks. They may be treated with benzodiazepines such as clonazepam and alprazolam; however, antide-pressants such as tricyclics, SSRIs, MAOIs, or mirtazapine are also effective. Antidepressants must be started at a very low dose (e.g., sertraline 12.5 mg, paroxetine 5 mg, or imipramine 10 mg) and increased slowly every 1 to 2 days to avoid increased anxiety. While the dose is brought up to that typically used in depression, benzodiazepines may be added if needed. Benzo-diazepines with a short half-life, like alprazolam, can induce breakthrough panic if tolerance develops, so those with longer half-lives, like clonazepam, may be preferred if tolerated. β-Blockers to block autonomic symptoms may be tried if performance anxiety around specific activities is identified, but they are less effective for panic disorder, as is buspirone.
b. Organic causes are often responsible for the anxiety
(1) Hypoxia. Repeating episodes of anxiety accompanied by alterations in intellectual functioning, poor orientation, reduced judgment, shortened attention, a rapidly fluctuating mood, and difficulty with memory suggest hypoxia. When anxiety is induced by hypoxia, it is wise to reduce central nervous system (CNS) depressant medications and give small doses of an antipsychotic drug if the anxiety is accompanied by delirium. However, older antipsychotic and antiemetic medications as well as metoclopramide often produce akathisia, an extrapyramidal restlessness that mimics anxiety. Alternating the antipsychotic drug with small doses of a benzodiazepine with a short half-life is one option for organically induced anxiety, as long as respiratory status or arterial blood gas measurements do not worsen. Newer antipsychotic agents are less likely to produce extrapyramidal akathisia but still should be monitored with pulse oximetry measurements.
(2) Liver disease and other physical disorders. If anxiety is associated with liver disease, start by reducing CNS depressant medications. When needed, small infrequent doses of a short-acting benzodiazepine that requires conjugation but not oxidation in the liver are prescribed. These include lorazepam, oxazepam, and temazepam. Many other physical disorders can also produce anxious symptoms, including various brain tumors, pheochromocytoma, carcinoid, hyperthyroidism, cardiac arrhythmias, drug or alcohol withdrawal, and hyperparathyroidism. Gabapentin, which is renally cleared, may help with anxiety, sleep, and pain. It can also help augment other medications for mood stabilization and panic disorder.
(3) Medications such as theophylline, corticosteroids, antidepressants, and antipsychotic drugs can produce anxiety. Anxiety is frequently one of multiple symptoms associated with benzodiazepine or narcotic analgesic withdrawal. Akathisia mimics anxiety and often occurs with prochlorperazine, promethazine, perphenazine, and metoclopramide. It is generally wise to stop these medications to avoid prolonging this very uncomfortable, involuntary condition and find a suitable alternative.
c. Precipitating events that initiate the previously discussed adjustment disorder lasting generally no longer than 6 months can be identified in patients with cancer. Posttraumatic stress disorder (PTSD), less often seen in patients with cancer, follows a distressing event beyond what would be expected. Younger women with breast cancer are at higher risk for PTSD, especially if they have less education and lower income. More advanced disease, medical sequelae of treatments, and longer hospital admissions also contribute. More frequently observed, however, are patients who describe intense fears of needles, radiotherapy rooms, or confined-space scanning devices. Often, the history unfolds to describe previously existing phobias. These patients, like those with anticipatory anxiety about procedures or chemotherapy, may be assisted with relaxation or desensitization techniques, imagery, anti-anxiety medications, and assurance. If patients begin to experience procedures, treatments, or interpersonal situations as being particularly stressful, anticipatory anxiety intensifies the requirement for larger doses of as-needed medication to attain some relief. Therefore, regular scheduling of antianxiety medication similar to that of pain medication is in order.
Difficulty falling asleep may be associated with anxiety, whereas awakening in the middle of the night is generally more closely related to depression. In addition, there are a variety of physical disorders that cause sleeping irregularities. The sleep–wake cycle is almost always disturbed in a delirious patient, no matter what the cause. Pain often awakens a patient with cancer. Medications can awaken some patients directly (e.g., fluoxetine) or indirectly (e.g., diuretics). Aside from sorting out these influences, the physician must take into account the environment. Is the patient too hot or cold? Is the ward too brightly lit or too noisy? Do the patients awaken each time they are checked by the night staff? When any or several of these concerns are corrected, sleeping medication may not be necessary, although the need for sedatives remains in some patients.
B. Benzodiazepines (Table 32.5)
This class of drugs is most often prescribed if a patient needs nighttime sedation. The benzodiazepines with shorter half-lives (i.e., lorazepam or temazepam) with a rapid onset produce less daytime grogginess than those with a longer half-life. Short-acting agents tend to accumulate less and are safer for patients with liver disease. On the other hand, drugs with longer half-lives (i.e., diazepam or flurazepam) with a rapid onset produce less unwanted awakening during the very early morning.
C. Nonbenzodiazepine hypnotics (see Table 32.5)
The four medications in this class help patients fall asleep quickly and do not leave the patient groggy in the morning. Clinical experience shows tolerance can also develop to zolpidem, zaleplon, and eszopiclone. Ramelteon, a melatonin receptor agonist, is contraindicated in patients taking fluvoxamine.
D. Antihistamines (see Table 32.5)
These medications may be chosen if physicians are hesitant to prescribe benzodiazepines, such as for patients with severe respiratory disease. A disadvantage may be the higher anticholinergic potential of these drugs, compared with the benzodiazepine family, which can increase the risk of delirium.
Chloral hydrate 500 to 1000 mg, an old standby hypnotic, is occasionally used as long as patients are free of gastrointestinal or liver disease. Barbiturates such as amobarbital sodium are occasionally used to treat some refractory sleeping disturbances for a short time but are not routinely used because they induce respiratory depression and have addictive potential. Gabapentin, which is renally cleared and has few drug interactions, has become increasingly popular. Doses may vary from 300 to 1200 mg at bedtime. It is always better to start with a lower dose.
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