Depression, anxiety, and delirium

Although many cancer patients cope well with their disease, psychiatric disorders occur in almost 50% of patients in the setting of malignancy. Untreated psychological and neuropsychiatric disorders can compromise quality of life as well as treatment compliance. Three behavioral syndromes that are often encountered in clinical practice will be discussed here: depression, anxiety, and delirium.

Depression

Sadness exists on a continuum, ranging from an emotion common in daily life to a syndrome of severe physical and psychological symptoms consistent with a defined psychiatric disorder (Major Depressive Disorder). Several studies of cancer inpatients report Major Depression prevalence rates of 25% to 42%.

SIGNS AND SYMPTOMS/DIAGNOSIS

Patients with depressive syndromes may experience an array of psychological and somatic symptoms.

Psychological symptoms include dysphoria (sadness), anhedonia (pervasive loss of pleasure in activities), feelings of guilt or low self-esteem, and thoughts of death or suicide.

Somatic symptoms include sleep disturbance (ie, sleeping too much or too little), change in appetite, fatigue, diminished concentration, and psychomotor agitation or withdrawal.

Focus of diagnostic evaluation Although the diagnosis of Major Depressive Disorder requires that greater than half of these symptoms (including dysphoria or anhedonia) be present for at least 2 weeks, patients who do not meet these criteria may be in significant distress, and may be described as having an Adjustment Disorder. In medically ill patients, diagnosis is complicated by the fact that somatic symptoms may also arise as a result of disease and treatment. For this reason, when evaluating the depressed cancer patient, special attention should be paid to those psychological symptoms that are less likely to be directly related to somatic disease or treatment.

ETIOLOGY

Psychological causes

Major depressive disorder is common in the general population (point prevalence, ~6%) and is a recurrent disease. Patients with a history of mood disorder are at risk for relapse in the face of a cancer diagnosis. In the setting of malignancy, obvious stressors include news of initial diagnosis, treatment failure, or disease progression. Patients may also confront more subtle stressors, including loss of independence, financial woes, diminished body image, family strain, and existential angst.

Disease- and treatment-related causes

Presenting symptom of malignancy Depression may be a presenting symptom of some primary malignancies, most notably pancreatic carcinoma. Primary and metastatic brain tumors can cause frontal lobe disinhibition syndromes or personality changes that mimic depression and other psychiatric disorders.

Drugs Many drugs used in general medical practice are associated with psychiatric syndromes. The most common of these drugs are β-blockers, anti-hypertensives, barbiturates, opioids, and benzodiazepines. Many primary and supportive therapies for cancer are also commonly associated with depression. They include corticosteroids (also possibly associated with mania), cytokines (especially interferon-alfa and interleukin-2), whole-brain radiation therapy, and chemotherapeutic agents, including procarbazine (Matulane). Patients treated with tamoxifen may complain of depression or “chemo brain.” The latter term usually refers to cognitive slowing. Treatment of tamoxifen-related depression raises particular challenges. Recent evidence suggests that many antidepressants used to treat these symptoms inhibit tamoxifen’s anti-cancer effect through P450 interactions.

MANAGEMENT

Management of depressive syndromes begins with accurate diagnosis. Clinicians should assess for somatic and psychological symptoms of the syndrome and should always ask about suicidal thoughts or intent. In addition to medication, laboratory assessments should be reviewed, as metabolic disarray, anemia, low B12 levels, and thyroid dysfunction can all contribute to the development of depressive symptoms. Once depression is diagnosed, treatment involves antidepressant medication, sleep aids, when possible, removal of exacerbating agents, and psychotherapy.

In cancer patients, diagnosis and treatment of depression require a high index of suspicion and regular, careful follow-up. Ideally, only patients with clinically significant or progressive symptoms are offered antidepressant therapy. When the diagnosis of depression is in doubt, however, it may be best to seek psychiatric consultation.

Antidepressants

Selected antidepressants used in cancer patients are listed in Table 1. No antidepressant has been shown to be more effective than any other in the cancer setting. Often, the choice of an antidepressant is based on side-effect profile.

In the general population, antidepressants often take at least 2 weeks or longer to produce initial relief of symptoms. As a general rule, antidepressant therapy should continue for 4 to 6 months after symptoms stabilize.

Selective serotonin reuptake inhibitors (SSRIs), such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), paroxetine, and sertraline (Zoloft), are often used in patients with cancer because of their benign side-effect profile. In particular, their lack of anticholinergic and α-adrenergic–blocking properties makes them attractive options for patients with a serious medical illness. SSRIs are rarely lethal in overdose, making them a reasonably safe choice in the treatment of patients experiencing suicidal ideations.

Side effects Common side effects of SSRIs include mild nausea, which tends to improve with continued use; reduced appetite; sexual dysfunction, including decreased libido, impotence, and anorgasmia; jitteriness; and insomnia. Paroxetine, in particular, may cause sedation; other side effects include dry mouth, rash, and weight gain.

Dosage In ambulatory patients with normal metabolic function, SSRIs can be started at the same doses used in general psychiatry (10 mg once daily for escitalopram; 20 mg once daily for citalopram, fluoxetine, and paroxetine; 50 mg once daily for sertraline). These doses can be increased if there is no response within 2 to 3 weeks.

Hospitalized or elderly patients, those with compromised renal or hepatic function, and those receiving highly emetogenic treatments should be started at one-half or even one-quarter of these starting doses, which can then be increased if tolerated.

Atypical and newer antidepressants Bupropion (Wellbutrin) is a well-tolerated medication that works to increase norepinephrine levels in the brain. In addition to its antidepressant effects, bupropion is activating and may help to improve attention. Unlike SSRIs, it is rarely associated with sexual dysfunction. A note of caution, however, is that bupropian lowers the seizure threshold and should not be used in patients with a history of seizures.

Venlafaxine (Effexor), mirtazapine (Remeron), and duloxetine (Cymbalta) are newer agents with selective effects on serotonin and norepinephrine metabolism. They should be started at low doses in order to establish tolerability. Venlafaxine may be quite effective against treatment-induced hot flashes. It tends to have an intense discontinuation syndrome, and patients should be titrated off slowly. Mirtazapine has sedative, appetite-stimulating, and antiemetic effects, which can all be useful in selected cases. Duloxetine is approved for treatment of diabetic neuropathy and may have applications in the depressed cancer patient with neuropathic pain.

Psychostimulants

Psychostimulants that have direct or indirect dopamine-agonistic properties, such as methylphenidate, have established role in the treatment of depression in the medically ill. Psychostimulants are activating agents useful in patients with psychomotor retardation, deconditioning, or apathy states associated with depression, as well as in those with CNS disease or treatment side effects.

The antidepressant effects of psychostimulants may be seen more quickly than those of first-line antidepressants. Improvements in mood, physical activity, well-being, and appetite are sometimes observed within 24 to 48 hours of the initiation of psychostimulant treatment.

Side effects Like other activating agents, psychostimulants may cause insomnia, decreased appetite, GI upset, anxiety, palpitations, and even arrhythmia. Pulses should be monitored with their use.

Dosage Initial dosing should be conservative (ie, 2.5–5 mg/d, the latter in divided doses) for methylphenidate. If tolerated, stimulant doses can be increased until a therapeutic effect is achieved or side effects develop. To prevent insomnia, afternoon doses should not be administered after 2 pm.

Psychotherapy

Although antidepressants alone are effective in the treatment of depression, they are often synergistic with psychotherapy. Talk therapy may provide patients with basic support and encouragement during cancer treatment. Cognitive-behavioral therapy may help them tackle fundamental misperceptions about themselves and their disease and to develop new coping skills.

Anxiety

Like depression, “anxiety” refers to both a subjective emotion and a constellation of signs and symptoms that can be of physical or psychological origin.

Especially in seriously ill patients, subjective anxiety may be the first sign of a serious or catastrophic physiologic derangement (ie, sepsis or pulmonary embolus). It is also common at disease milestones, especially at initial diagnosis, time of recurrence, and progression to the terminal phase. In patients whose disease is stable or in remission, anxiety frequently occurs in conjunction with routine reevaluation.

SIGNS AND SYMPTOMS/DIAGNOSIS

Psychological symptoms Patients with anxiety typically report worry, irritability, insomnia, and even depression, as there is considerable overlap between the two syndromes. They may appear hypervigilant or emotionally labile, crying unexpectedly or growing suddenly enraged. Typically, their thought processes are ruminative.

If anxiety proceeds to panic, patients may report time-limited feelings of impending doom, suffocation, or annihilation. Occasionally, distress is so intense that patients experience suicidal thoughts.

Physical symptoms A variety of somatic symptoms can be associated with anxiety. Cardiovascular signs and symptoms include palpitations and tachycardia, as well as subjective chest tightness or even pain. Respiratory symptoms include dyspnea, hyperventilation, and, as a result, light-headedness and dizziness. GI symptoms are common and include difficulty swallowing, abdominal cramping, nausea, diarrhea, and constipation. Patients may become diaphoretic. Preexisting pain may be aggravated.

ETIOLOGY

Psychological causes

Generalized anxiety disorder, panic disorder, and specific phobias (ie, to blood, needles, and even hospitals) are relatively common in the general population. Affected individuals are at risk for exacerbations of their anxiety disorders in the setting of cancer treatment. The stress associated with a cancer diagnosis can also trigger the onset of an anxiety disorder in a patient without a pre-morbid psychiatric diagnosis.

Cancer patients fear pain, suffering, disfigurement, and even death. Their concerns frequently center on loss of control or independence, strained finances, and family dynamics. Unpleasant procedures or medications can trigger anxiety, and this response can become conditioned, as in the case of anticipatory nausea. Even patients in the surveillance stage of treatment may find themselves suffering with considerable anxiety. In the absence of active treatment, these individuals become ruminative and fearful as they “wait for the other shoe to drop.” Anxiety of this type often peaks in anticipation of follow-up appointments.

Disease and treatment-related causes

Life-threatening causes of anxiety include hypoxia, (secondary to pulmonary edema, pulmonary embolus or sepsis). Other possible medical etiologies include severe anemia, electrolyte disturbances, endocrine disorders such as hyperthyroidism, hypercalcemia, hyperadrenalism, pain syndromes, and the presence of hormone-secreting neoplasms, such as pheochromocytomas.

Cancer-related medications can also cause or exacerbate anxiety. Frequent offending agents include corticosteroids, which can trigger nervousness, agitation, and even frank mania, and antiemetics, including promethazine, and metoclopramide, which can produce akathisia, a subjective sense of restlessness. Other medications such as anticholinergics (ie, benztropine [Cogentin]), opioids, and benzodiazepines can produce paradoxical reactions including anxiety states. These paradoxical reactions occur more frequently in geriatric and in CNS-impaired populations. Finally, drug toxicity (ie, from immunosuppressants, bronchodilators, or psychostimulants) and drug withdrawal states (ie, from opioids, benzodiazepines, and alcohol) can also trigger significant anxiety.

MANAGEMENT

Initial approaches to anxious patients vary with the severity of the symptom and the medical status of the patient. In all cases, medical underpinnings for anxiety should be considered and corrected when possible.

Psychotherapy

Talk therapy for anxious patients is universally appropriate. This intervention can take several forms. Supportive psychotherapy may enable an anxious patient to ventilate emotion in a safe setting. Cognitive-behavioral therapy may aid a patient in developing new coping skills through relaxation therapy, guided imagery training, or through a careful review of the patient’s core beliefs and the behaviors that help to trigger the emotion.

MEDICATIONS

The pharmacologic mainstay of anxiety disorders is antidepressant medication. These agents may take 4 to 6 weeks for maximal effect but promise long-lasting symptom amelioration once fully active. Currently, escitalopram, paroxetine, and venlafaxine have FDA (US Food and Drug Administration) indications for the management of generalized anxiety disorder. Most SSRIs have been used successfully in the treatment of panic disorder. Typical dose ranges for these agents follow: paroxetine, 20 to 60 mg/d; escitalopram, 10 to 20 mg/d; sertraline, 50 to 200 mg/d; and extended-release venlafaxine, 75 to 375 mg/d (see Table 1).

Benzodiazepines Because of the delayed onset of antidepressant action, benzodiazepines are often useful adjuncts to initial treatment. These medications have variable hypnotic, antiemetic, and muscle-relaxant effects useful in other aspects of supportive cancer care. Caution is required when using these agents in the settings of serious illness (because of the risk of additive sedation with other medications), advanced age, or CNS impairment (because of the risk of disinhibition or delirium). Benzodiazepines commonly used to treat anxiety in cancer patients are listed in Table 2.

Short-acting benzodiazepines, such as lorazepam and alprazolam, have a rapid onset but relatively short duration of action, making them useful for treating intermittent paroxysmal anxiety or panic attacks. For the same reason, they are also useful in patients with severe medical illness. Typical doses are lorazepam 0.5 to 1.0 mg PO (by mouth)/IM (intramuscular)/IV (intravenous) every 4 to 12 hours or alprazolam 0.25 to 0.5 mg PO every 6 to 8 hours as needed. For patients with persistent anxiety, these medications can be given on a regular schedule. Lorazepam’s lack of active metabolites makes it a good choice in patients with hepatic or renal compromise.

Withdrawal develops more rapidly to short-acting benzodiazepines than to their longer-acting counterparts. Therefore, if short-acting agents are used for any length of time, they should be discontinued gradually.

Longer-acting benzodiazepines, such as diazepam and clonazepam, are useful for persistent anxiety. Their longer duration of action is such that they do not “wear off” quickly and leave patients unprotected.

Clonazepam is typically given at a dose of 0.25 to 1.0 mg every 8 to 24 hours and diazepam at a dose of 2 to 10 mg every 6 to 24 hours. These drugs have multiple active metabolites that can adversely affect the elderly and patients with renal or hepatic impairment. In such patients, it is best to avoid these medications if at all possible.

Other medications At low doses, antipsychotic medications, such as haloperidol (Haldol), olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal), may be used as anxiolytics. These agents are most appropriate for patients with a history of, or at high risk for, adverse reactions to benzodiazepines.

Delirium

Delirium is a syndrome of diffuse brain dysfunction incited, typically acutely, by aspects of medical illness or treatment. In some surveys, 15%–30% of cancer inpatients and up to 85% of those who are terminally ill experience the syndrome. Its presence is linked to increased length of hospital stays, morbidity, and mortality. For this reason, accurate diagnosis and identification of causes are critical. With neutralization of inciting factors, many cases of delirium are reversible.

SIGNS AND SYMPTOMS

Waxing and waning impairments in attention, orientation, and memory are the hallmarks of the syndrome. Other features that occur more variably include disturbances in affect, mood, sleep pattern, level of agitation, insight, and perception; a delirious patient may, for instance, experience an altered sense of reality, whether in the form of an illusion or a hallucination. The presence of several of these signs and symptoms or history or an exam should raise the specter of the diagnosis.

Distractibility is the sine qua non of the syndrome. Delirious patients perform poorly on tasks requiring concentration. They may have trouble naming the months of the year in reverse, counting backward by 7’s from 100, or drawing a clock face set to a particular hour. Memory impairment is also prominent. Delirious patients often encounter difficulty encoding new information, for instance, registering three new words if specifically asked to remember them or recalling them after 5 minutes. They may also have difficulty with biographical information, such as their phone number or the ages of their children. Not infrequently, delirious patients prove to be amnestic to their delirious episodes. They are typically disoriented to time and place but rarely to person. These deficits wax and wane, and the presence of lucid intervals may seem to discount the diagnosis. For this reason, serial examinations are useful.

ETIOLOGY

Organic disturbances that can produce a state of delirium are multifold and range from primary intracranial abnormalities such as tumors to systemic diseases that secondarily affect the brain to substance intoxication or substance withdrawal. Life-threatening causes that are potentially reversible include substance withdrawal (including from alcohol, prescription drugs, and illicit drugs), hypertensive encephalopathy, Wernicke’s encephalopathy, hypoxia, hypoglycemia, intracranial bleeding, meningitis, encephalitis, and poisoning. Another potentially reversible cause is substance intoxication. Many medications used commonly in the context of cancer can trigger delirium. They include benzodiazepines, opioids, anticholinergic medications, corticosteroids, and chemotherapeutics.

MANAGEMENT

Treatment

The management of delirium centers on identifying and addressing the causative medical factors. Work-up should explore potential infectious, metabolic, neurologic, and biochemical causes. Imaging of the head may be indicated. In more than half of delirium cases, no definitive etiology can be identified. In these instances, care is supportive.

Behavioral management

Delirious patients should be managed in a setting of moderate stimulation. As much as possible, they should be provided with appropriate environmental cues: lights should be shut off during the night; they should be frequently reminded of the day and date, and, if possible, should be surrounded by family and other familiar faces. Their safety must be guarded, and close observation may be required. Some afflicted patients may lie listlessly, whereas others may become agitated and even violent. In these instances, chemical and even physical restraints may be required.

MEDICATIONS

Antipsychotics

If more conservative measures are ineffective, pharmacotherapy may be required to manage the behavioral disturbances associated with delirium. Antipsychotic medications may help to treat sensory misperceptions, as well as provide a degree of anxiolysis. Table 3 lists selected drugs often used to treat delirium in cancer patients. Because of a growing understanding of the health risks associated with use of these drugs (ranging from extrapyramidal symptoms to hyperglycemia, stroke, and increased risk of death in the elderly), antipsychotics should be reserved for use in patients with hyperactivity, for instance those who pull out blood access lines or those who wander.

Haloperidol is a potent antipsychotic that may be administered PO, IM, or IV. The IV formulation is twice as potent as the PO preparation.

Side effects Haloperidol is usually well tolerated, although it does carry a risk of akathisia and Parkinsonian side effects. The risk of these adverse reactions can be minimized by IV administration.

Dosage Elderly patients or patients with end-stage disease usually require very modest doses (0.5 to 1.0 mg PO or IV at night or twice daily) to control delirium. Especially in hyperactive delirium, higher and more frequent dosing is usually required (ie, 2 to 5 mg IV every 6 hours). In unusual cases, total doses of ≥ 50 mg/d may be administered via continuous infusion.

Risperidone is given orally. At doses of 0.5 to 3.0 mg once or twice daily, it is useful in managing delirium or delusional symptoms, especially in elderly patients, in whom it may have fewer adverse effects than oral haloperidol.

Olanzapine has been shown to be effective in the management of delirious cancer patients and is available for administration PO or IM in cases of severe agitation. The Zydis formulation of olanzapine is an orally disintegrating tablet that easily dissolves in the mouth and may be useful for some agitated patients and for those with swallowing difficulties.

Quetiapine is fairly sedating and is an attractive option for treatment of low-intensity delirium, especially when given at night to control behavior and promote sleep.

SUGGESTED READING

ON DEPRESSION

Jacobsen PB, Donovan KA, Weitzner MA: Distinguishing fatigue and depression in patients with cancer. Semin Clin Neuropsychiatry 8:229–240, 2003.

Spiegel D, Giese-Davis J: Depression and cancer: Mechanisms and disease progression. Biol Psychiatry 54:269–282, 2003.

Trask PC: Assessment of depression in cancer patients. J Natl Cancer Inst 32:80–92, 2004.

ON ANXIETY

Stark D, Kiely M, Smith A, et al: Anxiety disorders in cancer patients: Their nature, associations, and relation to quality of life. J Clin Oncol 20:3137–3148, 2002.

ON DELIRIUM

Centeno C, Sanz A, Bruera E: Delirium in advanced cancer patients. Palliat Med 18:184–194, 2004.

Fann JR, Sullivan AK: Delirium in the course of cancer treatment. Semin Clin Neuropsychiatry 8:217–228, 2003.

Gaudreau J-D, Gagnon P, Harel F, et al: Psychoactive medications and risk of delirium in hospitalized cancer patients. J Clin Oncol 23:6712–6718, 2005.

ON PSYCHOTROPIC DRUGS

Buclin T, Mazzocato C, Berney A, et al: Psychopharmacology in supportive care of cancer: A review for the clinician, IV. Other psychotropic agents. Support Care Cancer 9:213–222, 2001.

Fisch MJ, Kim HF: Use of atypical antipsychotic agents for symptom control in patients with advanced cancer. J Support Oncol 2:447–452, 2004.

Jin Y, Desta Z, Stearns V, et al: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30–39, 2005.

Joshi N, Breitbart WS: Psychopharmacologic management during cancer treatment. Semin Clin Neuropsychiatry 8:241–252, 2003.