In addition to these psychiatric conditions, non-specific distress and anxiety are very common in cancer patients, in addition to formal psychiatric diagnoses. Distress is the summation of multiple psychological, social, and spiritual factors. If severe enough, distress can interfere with the patient's ability to deal effectively with the illness, its symptoms, and the complications of treatment.

Specific issues regarding the management of psychiatric illness in patients with cancer are reviewed here.

ADJUSTMENT DISORDER — The identification and diagnosis of adjustment disorder is not straightforward, but is important since many of these patients will benefit from counseling. Physicians attempting to identify individuals who could benefit from counseling should focus upon a lack of patient flexibility. Those who develop adjustment disorder may be more rigid in their thinking and determined to address their cancer-related problems in the same manner as they have for prior stressors. If the old coping and problem-solving strategies fail, the person may begin to exhibit depressed mood and anxiety associated with adjustment disorder. In contrast, patients who successfully adapt typically have a flexible style.

People with adjustment disorder have positive outcomes when they are treated with brief psychotherapy. Early treatment using counselors, nurses, and other staff is helpful before the problem expands to the point of requiring more intensive care.

Psychotherapy for adjustment disorder addresses cancer-related stressors directly by teaching enhanced coping skills, focusing upon immediate problems in living caused by the disease. Establishing social support networks and psychoeducation are also important. Informal support groups and more formal group therapy are highly effective for improving quality of life and decreasing depression and anxiety symptoms.

MANAGEMENT OF DEPRESSION — Similar to physically healthy patients, depression in patients with cancer is best managed utilizing a combination of supportive psychotherapy, cognitive-behavioral techniques, and antidepressant medications.

Pharmacologic therapy — Psychopharmacologic interventions are the mainstay of management for patients with moderate to severe levels of depression; antidepressants are safe and effective in this setting. These drugs can alleviate depressive affect, emotional lability, irritability, and social withdrawal. Medication also may help increase an individual's ability to participate in rehabilitation services and improve overall functioning.

A systematic review of randomized trials conducted exclusively in cancer patients suggested that drug therapy is well tolerated and useful in treating symptoms of depression. However, the trials were small and unable to distinguish between different pharmacologic approaches.

Patients with early stage cancer are similar to the average individual who needs an antidepressant; they can be safely and effectively treated with selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) with similar dose titrations as the physically healthy population. In patients with more advanced disease and increased levels of physical distress, the pharmacologic management is more complex and challenging.

Antidepressant selection — Selection of an antidepressant depends upon a number of factors. Among the considerations are

• The type of depressive symptoms
• Current medical problems
• Side effect profiles

The depressed patient who is experiencing agitation or insomnia may benefit from the more sedating antidepressants (eg, TCAs, trazodone, or mirtazapine) (show table). A better choice for patients with fatigue or psychomotor slowing would be compounds with the least sedating effects (eg, SSRIs, stimulants).

A number of coexisting medical problems may influence antidepressant selection.

• In addition to their antidepressant action, the TCAs have analgesic properties and the ability to potentiate the effects of opioid analgesics.  Thus, patients who are experiencing pain, particularly neuropathic pain, may benefit from these agents alone or in combination with other drugs.

• Patients with cardiovascular disease and older patients should take drugs that cause the least orthostatic hypotension (eg, fluoxetine, sertraline).

• Patients with slow intestinal motility or urinary retention, or with stomatitis secondary to chemotherapy or radiotherapy, should receive medications with the least anticholinergic effects (eg, SSRIs).

• Patients at risk for seizures or who may have a lower seizure threshold because of other medications are more safely treated with agents that will not exacerbate the problem (eg, neuroleptics). Virtually any antidepressant can have a small effect on lowering the seizure threshold. However, bupropion has been associated with the highest incidence of seizures and should be used cautiously in patients with CNS disease.

• Liquid formulations available for some antidepressants may be better options for patients who cannot swallow pills.

While attention to potentially upsetting or adverse effects of the different classes of antidepressants is warranted, many times side effects can be used to the patient's advantage (show table). As an example, sedation may be useful to the agitated patient who is anxious and cannot sleep, while the side effect of activation may be useful to the hypersomnolent, withdrawn patient with lethargy. In addition, some antidepressants stimulate appetite, a useful effect when appetite is decreased.

Tricyclic antidepressants — TCAs have been used frequently in the cancer setting. The TCAs should be started at a low dose (10 to 25 mg at bedtime) and increased slowly by 10 to 25 mg increments every one to two days until a beneficial effect is achieved. This slow titration is especially important for debilitated patients with advanced disease. Patients with cancer may exhibit a therapeutic response to the TCAs at lower doses than physically healthy individuals. Serial plasma drug levels can be utilized to monitor the effective and safe administration of the drugs, minimizing the risk of side effects or toxicity. A cardiac history and electrocardiogram should be obtained prior to prescribing TCAs since these drugs can have an adverse effect on cardiac rhythm.

The tertiary amines (eg, imipramine, amitriptyline, and doxepin) tend to sedate patients, stimulate appetite, and cause anticholinergic side effects (eg, dry mouth, blurred vision, constipation, nausea, urinary retention, and tachycardia). Their metabolites, the secondary amines (eg, desipramine and nortriptyline) are less sedating and less anticholinergic. Many times patients can tolerate secondary amines in higher doses, allowing for greater therapeutic benefit.

Selective serotonin reuptake inhibitors — SSRIs have become the most widely used antidepressants. Their efficacy and side effect profiles in particular make them attractive agents for some patients with cancer. One study found that both fluoxetine and desipramine led to improvements in depression, anxiety, and overall quality of life in depressed women with advanced cancer, and were well tolerated. A larger double-blind study suggested that fluoxetine (20 mg daily) was superior to placebo in improving depression and overall quality of life in outpatients with advanced cancer.

SSRIS cause fewer problems with cardiac arrhythmias, hypotension, and anticholinergic effects than the TCAs. In addition, the SSRIs generally have less sedative, autonomic, and anticholinergic effects.

The SSRIs may increase blood levels of other drugs by dislodging them from blood proteins. They also inhibit the cytochrome P450 isoenzymes. Thus, blood levels of any medications that are metabolized by the P450 system may be increased. This is an important consideration in the cancer population since many of these patients are on warfarin or cisapride, two medications that are substrates for the P450 system.

Other antidepressants — The other available antidepressants vary widely in their mechanism of action and side effects and show table).

• Bupropion is both an antidepressant and central nervous system stimulant that does not interact with other medications. It is very useful in depressed patients with psychomotor retardation and can be used in a wide variety of patients with few side effects. The drug is thought to act through the dopamine pathways, but its precise mechanism of action is not known. It cannot be used in patients who have a history of a seizure disorder and should be used with caution in patients with possible CNS disease that may be prone to seizures.

• Venlafaxine is a mixed serotonin and norepinephrine reuptake inhibitor that is well tolerated by cancer patients. It is not significantly active at the cytochrome P450 system and is somewhat less protein bound than the other antidepressants. Venlafaxine has been associated with safe but uncomfortable withdrawal symptoms (anxiety, nausea, insomnia) at discontinuation, suggesting that the drug should be tapered rather than stopped abruptly.

• Mirtazapine is an antidepressant with a novel mechanism of action. The cell receptors that regulate production of norepinephrine and serotonin are blocked so that the neurotransmitters continue to be produced even when their concentrations might normally shut down production by the cell. In addition, mirtazapine has 5HT2 and 5HT3 blocking action that may make it useful as a coanalgesic and antiemetic; clinical trials are underway to evaluate its potential in these two important areas for cancer patients. Mirtazapine also appears to block the H1 receptor in the CNS. It has some sedative side effects and stimulates appetite, side effects that may be very useful in some patients. It can be administered as a single dose at bedtime.

One open label pilot study of mirtazapine (15 to 30 mg at bedtime) suggests that patients with advanced cancer may derive benefit from this drug with regard to mood, weight loss and insomnia. Treatment was well-tolerated at either starting dose.

• Trazodone and nefazodone are related antidepressants that are SSRIs in part, but also have some other actions. Trazodone is typically sedating and is used frequently to help with sleep disturbance. It can be associated with priapism. Nefazodone has blocking action at the 5HT2 receptor which may make it useful for patients with anxiety. It is an active inhibitor of the 3A4 isoenzyme and thus may increase the concentration of other medications.

Psychostimulants — The psychostimulants methylphenidate, dextroamphetamine, and modafinil are an alternative for depressed patients with cancer. These drugs improve attention, concentration, and overall performance on neurologic testing in the medically ill . Mood, appetite and sense of well being can be improved for the patient at the same time the medication is decreasing feelings of weakness and fatigue. An additional benefit of methylphenidate and dextroamphetamine is reduction of the sedation caused by opioid analgesics; they also provide adjuvant analgesia in patients with cancer. The psychostimulants may play a useful role in helping cancer patients feel energetic enough to engage in rehabilitation efforts until their energy level ultimately improves from the direct effects of such efforts.

The starting dose of methylphenidate and dextroamphetamine is 5 to 10 mg QD or BID. Maximum doses may range as high as 60 mg per day. Typically patients are maintained on the stimulant for one to two months or longer. Tolerance can develop and dose adjustment may be necessary over time. Most patients respond quickly to these agents and, if taken in the morning and early afternoon, they should not interfere with sleep. Side effects include anxiety, overstimulation, headache, increase in blood pressure, and tremors; however, these are rarely a problem with the typically low doses used.

Modafinil, a benzhydryl sulfinylacetamide non-amphetamine "wake-promoting agent," was introduced to the world market in 1994 for the treatment of narcolepsy and idiopathic hypersomnia, and was approved for use in the United States in 1999. Modafinil has not been directly compared with amphetamines in patients with narcolepsy, but early indications are that it is better tolerated and has less abuse potential. It is usually administered in a single morning dose of 100 or 200 mg.

Anecdotal experience suggests that modafanil may be a useful treatment for fatigue, depression, and opioid-induced sedation, and is well tolerated. Although modafinil may offer similar benefit to the amphetamines in patients with cancer, no published studies are available.

Combined therapy — Combined antidepressant therapy may provide certain advantages in select patients, particularly those experiencing distressing physical symptoms. Patients with depression and severe fatigue or psychomotor slowing, for example, may gain the most from the use of TCAs, SSRIs, or mirtazapine plus psychostimulants. Patients with depression and anxiety or insomnia may gain the most from the combination of TCAs and SSRIs, or an SSRI with mirtazapine.

Many antidepressants require weeks to reach peak efficacy. Thus, augmentation with another medication directed at the most distressful symptom not only leads to a quicker benefit to the patient, but also may improve compliance. This symptom driven approach is particularly helpful in patients with advanced cancer in whom treatment is often complex, but immediate relief of symptom distress is a priority.

Nonpharmacologic therapy — Patients with cancer and depression are often reacting to the burden of the illness and the effect it has on their lives. Psychosocial interventions are used to help individuals, families, and groups. The general objective of this therapy is to improve coping skills through educational, behavioral, or psychodynamic approaches.

Crisis intervention — Clinicians working in oncology rely primarily upon short-term supportive psychotherapy based on a crisis intervention model to help patients with depressive symptomatology. Crisis intervention is a process of actively influencing psychosocial functioning during a period of disequilibrium. It is directed at alleviating the immediate impact of disruptive stressful events. The aim is to reduce emotional distress while working toward strengthening the patient's psychological and social resources. Crisis therapy is generally time limited and asserts clear-cut goals

Supportive/crisis intervention psychotherapy involves clarifying information and answering questions about the illness and its treatment, correcting misunderstanding, and giving reassurance about the situation. Describing common reactions to illness may help the patient and family to normalize their experience. The patients' usual adaptive strategies should be explored and strengths supported as needed in adjustment. Patients are encouraged to discuss how they feel about their lifestyle modifications, family role changes, and fears of dependency and abandonment. Themes of loss and anticipatory grief are also explored. Patients often experience loss of good health, body integrity, and self-esteem, along with losses secondary to cancer (eg, financial, social, and occupational). Therapy seeks to improve a sense of control and morale. When the focus of treatment changes from cure to palliation, it is important for patients to know that they will not be abandoned and that their comfort, pain control, and dignity will receive continued attention.

Cognitive-behavioral therapy — Cognitive-behavioral techniques are often integrated into depression therapy and are very useful and effective. These approaches explore patients' beliefs about the cancer diagnosis and its treatment in order to elicit irrational or unhelpful thoughts that lead to feelings of helplessness and hopelessness. Therapy then leads to the correction of these maladaptive thoughts along with providing new coping skills (eg, relaxation). Both group and individual treatment are effective for reducing depressive symptoms and distress and improving quality of life

Cognitive-behavioral interventions help patients allay exaggerated fears by encouraging them to consider different possible outcomes for their situation. Helping the patient focus upon aspects of the disease and its treatment that they have control over and encouraging behavior modification that will keep them involved and positive could provide a better quality of life.

Relaxation techniques and imagery may enhance any of these therapeutic interventions. Simple focused breathing exercises, meditation, and progressive muscle relaxation can be used to lessen the episodic anxiety that many cancer patients experience. Pleasant imagery, such as visualizing a gentle stream flowing through a beautiful landscape, may also ease the tension that some patients feel.

Support groups — Support groups are important adjunctive intervention modalities for cancer patients and family members who are distressed. Hospitals and community organizations will often sponsor groups that are professionally run and/or self-help. The professionally run groups usually use educational, supportive, or cognitive-behavioral methods, while lay groups focus upon education, practical advice and modeling, and serve as a source of mutual support and advocacy.

ANXIETY — Treatment of anxiety in patients with cancer involves the combination of psychotherapy and a range of anxiolytic medications. . Pharmacotherapy in patients with more advanced illness includes the judicious use of benzodiazepines, neuroleptics, antihistamines, antidepressants, and opioid analgesics

Pharmacotherapy

Benzodiazepines — Benzodiazepines are the mainstay of pharmacologic therapy for anxiety disorders. The shorter acting benzodiazepines such as lorazepam (Ativan) , alprazolam (Xanax) , and oxazepam (Serax)  are safest in patients with cancer since they are least likely to lead to toxic accumulation due to impaired metabolism in debilitated patients. Lorazepam and oxazepam are metabolized by conjugation in the liver and are therefore the safest choice in patients with hepatic disease.

The disadvantage of using short-acting benzodiazepines is that patients often experience breakthrough anxiety or end of dose failure. Such patients may benefit from switching to longer acting benzodiazepines such as diazepam (Valium)  or clonazepam (Klonopin) we have found clonazepam to be particularly useful in this setting. We also frequently switch patients from alprazolam to clonazepam when attempting to taper off the former. Clonazepam may have additional uses in patients with organic mood disorders who have symptoms of mania, and as an adjuvant analgesic in patients with neuropathic pain

Fears of causing respiratory depression should not prevent the clinician from using adequate doses of benzodiazepines to control anxiety. The likelihood of respiratory depression is minimized with shorter acting drugs and small dose increments; ultimately the switch can be made to longer acting drugs. Common dosage regimens include: lorazepam 0.5 mg to 2.0 mg PO, IV or IM, every three to six hours; alprazolam 0.25 mg to 1.0 mg PO, TID to QID; diazepam 2.5 mg to 10 mg PO, PR, IM, or IV every 3 to 6 hours; clonazepam 1 to 2 mg PO, BID to TID.

Other anxiolytics — Neuroleptics such as thioridazine, haloperidol, and olanzapine are useful in the treatment of anxiety when benzodiazepines are not sufficient for symptom control. They are also indicated when an organic etiology is suspected or when psychotic symptoms such as delusions or hallucinations accompany anxiety. Neuroleptics are probably the safest class of anxiolytics in patients for whom there is a legitimate concern of respiratory depression or compromise.

Haloperidol 0.5 mg to 5 mg PO, IV, or SC every 2 to 12 hours, typically is sufficient to control anxious symptoms and avoid excessive sedation. Low potency neuroleptics such as thioridazine (10 mg to 25 mg PO TID) also are effective anxiolytics and can help with insomnia and agitation.

Methotrimeprazine (10 mg to 20 mg every four to eight hours, IM, IV, or SC) is a phenothiazine with unique analgesic and anxiolytic properties that is often used for the treatment of pain and anxiety in patients with advanced cancer. Its side effects include sedation, anticholinergic symptoms, and hypotension. Intravenous administration by slow infusion is preferable to avoid problems with hypotension.

Chlorpromazine (12.5 mg to 50 mg PO, IM or IV, every 4 to 12 hours) has similar side effects to methotrimeprazine that often limit its application in patients with cancer. However, it can be useful in patients in whom sedation is desirable. This class of drugs is associated with extrapyramidal side effects (particularly when patients are taking additional neuroleptics for antiemetic purposes) and the remote possibility of neuroleptic malignant syndrome. Tardive dyskinesia is rarely a concern given the generally short-term use and low doses employed in this population

Hydroxyzine is an antihistamine with mild anxiolytic, sedative, and analgesic properties. It is particularly useful when treating anxious cancer patients with pain. A dose of 100 mg administered parenterally has analgesic potency equivalent to 8 mg of morphine, and also potentiates the analgesic effects of morphine. As an anxiolytic, 25 mg to 50 mg of hydroxyzine every four to six hours PO, IV, or SC is effective.

The atypical antipsychotics are useful in the treatment of both "functional" and "organic" anxiety syndromes, especially in older and/or frail patients. (

Although not extensively studied in patients with cancer, anecdotal experience suggests that low doses of olanzapine or risperidone are effective and well-tolerated for the treatment of delirium and organic mental phenomena in patients with cancer, improving anxiety related to confusional states, delusions, and nausea. In addition, they offer the advantage of not causing extrapyramidal symptoms in the doses generally used, ranging from 2.5 to 10 mg of olanzapine QD to BID, and for risperidone, 0.5 to 4.0 mg QD to BID.

TCAs, SSRIs, and heterocyclic antidepressants are the most effective treatment for anxiety accompanying depression and also are helpful in treating panic disorder

Buspirone is a non-benzodiazepine anxiolytic that is useful along with psychotherapy in patients with chronic anxiety or anxiety related to adjustment disorders. The onset of anxiolytic action is delayed in comparison with the benzodiazepines, taking 5 to 10 days for relief of anxiety to begin. Buspirone is not a benzodiazepine; thus, it will not block benzodiazepine withdrawal, and caution must be used when switching from a benzodiazepine to this drug. The effective dose of buspirone is 10 mg PO TID Its delayed onset of action and indication for use in chronic anxiety states limit its usefulness in patients with cancer.

Nonpharmacologic therapy — Nonpharmacologic interventions for anxiety and distress include supportive psychotherapy and behavioral interventions used alone or in combination. Brief supportive psychotherapy is often useful in dealing with both crisis-related issues as well as existential issues. Psychotherapeutic interventions can include both the patient and family, particularly as the patient with cancer becomes increasingly debilitated and less able to interact.

The goals of psychotherapy for the anxious patient are to establish a bond that decreases the sense of isolation, to help the patient face cancer with a sense of integrity and self worth, to correct misconceptions about the past and present, to integrate the present illness into a continuum of life experiences, and to explore issues of separation, loss, and the unknown that lies ahead. As in the treatment of depression, the therapist should emphasize past strengths and support previously successful ways of coping. This helps the patient mobilize inner resources, modify plans for the future, and perhaps even accept the inevitability of death.

Relaxation, guided imagery, and hypnosis may help reduce anxiety and thereby increase the patient's sense of control. Most patients with cancer, even those with advanced disease, are candidates for behavioral techniques despite physical debilitation. In assessing the utility of such interventions for a given patient, the clinician should take into account the patient's mental clarity. Confusional states interfere dramatically with the ability to focus attention and thereby limit the usefulness of these techniques, although occasionally they can be modified to include the mildly cognitively impaired. This often involves the therapist taking a more active role by orienting the patient, creating a safe and secure environment, and evoking a conditioned response to the therapist's voice or presence.

A typical behavioral intervention for anxiety includes a relaxation exercise combined with some distraction or imagery technique. The patient is first taught to relax with passive breathing accompanied by either passive or active muscle relaxation. Once in a relaxed state, the patient is taught a pleasant, distracting imagery exercise. In a randomized study comparing a relaxation technique with alprazolam in the treatment of anxiety and distress in cancer patients, both treatments were effective for mild to moderate degrees of anxiety or distress. Alprazolam was more effective for greater levels of distress or anxiety and had a more rapid onset of beneficial effect. Relaxation techniques can be used in combination with anxiolytic medications for highly anxious patients.

DELIRIUM — The standard approach for managing delirium in the cancer patient includes a search for underlying causes, correction of those factors, and management of symptoms. Symptomatic and supportive therapies also are important , and fluid and electrolyte balance, nutrition, and vitamins may be helpful. (

Measures to help reduce anxiety and disorientation include a quiet, well-lit room with familiar objects, a visible clock or calendar, and the presence of family. Judicious use of physical restraints, along with one-to-one nursing observation may be necessary. When supportive techniques alone are not effective, symptomatic treatment with neuroleptic or sedative medications are necessary. Sedation may be required to relieve severe agitation or insomnia

Haloperidol is the drug of choice for treatment of delirium in the medically ill . Low doses (1 to 3 mg) are usually effective for agitation, paranoia, and fear. Typically 0.5 mg to 1.0 mg haloperidol (PO, IV, IM, SC) is administered, with repeat doses every 45 to 60 minutes titrated against symptoms. Lorazepam 0.5 mg to 1.0 mg every one to two hours PO or IV, plus haloperidol, may be more effective than the latter alone in rapidly sedating the agitated delirious patient. In a double-blind, randomized trial of haloperidol versus chlorpromazine versus lorazepam, lorazepam alone, in doses up to 8 mg in a 12 hour period, was ineffective in the treatment of delirium and contributed to worsening delirium and cognitive impairment. Both neuroleptic drugs however, in low doses (approximately 2 mg of haloperidol equivalent/per 24 hours), were highly effective in controlling the symptoms of delirium and improving cognitive function. The atypical antipsychotics may have an as yet under-appreciated role in the management of cognitive disorders in cancer patients.

Delirium during treatment for malignancy has been associated with an adverse outcome. In patients undergoing hematopoietic stem cell transplantation, those who have experienced delirium have significantly worse symptoms of depression, fatigue, and anxiety at 30 days. These signs and symptoms persisted at 80 days, including multiple impairment of neurocognitive function. Delirium may also be more frequent in patients with more severe disease, and at least two studies found that cancer patients experiencing delirium have an increased mortality .