Depression in Cancer Patients

ABSTRACT: Depression is seen in many cancer patients. It is an especially importantissue in palliative care, as depression can be more common inpatients who are at the end of life. Accurate assessment and treatmentcan have a powerful impact on improving a patient’s quality of life.This article reviews the definition and the differential diagnosis of depressionin cancer patients. It then focuses on some of the treatmentoptions available, including pharmacotherapy and psychotherapy.

Wouldn't you feel depressed if you had cancer?" This question is one that is often heard from patients, family, and friends as well as from nursing staff and physicians. It may seem logical to expect that someone facing a lifethreatening illness would experience some sadness or depression. However, the problem of depression in cancer patients is a more complex issue. It can span from normal reactions to bad news to clinically significant disorders that can benefit from a variety of treatments. Depression is an important concern in palliative and supportive care, as up to 17% of terminally ill cancer patients have expressed a desire for hastened death.[1] This article will focus on how to recognize depression in cancer patients as well as outline some of the treatment options available to the clinician.

Prevalence and Definition

Estimates of prevalence for depression vary from as low as 1% to greater than 50%.[2] This wide variation is due to several factors. Different diagnostic assessments, inclusion criteria the reported prevalence of depression. Mental health professionals typically use the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) to diagnose depression.[3]

Table 1 lists the symptoms used to make a diagnosis of depression. A person must have either consistently depressed mood or anhedonia in addition to four of the other symptoms listed in Table 1 for at least a 2-week period in order to make a diagnosis of a major depressive episode. Symptoms such as fatigue, weight loss/appetite, and psychomotor retardation can be thought of as the physical or somatic symptoms of depression that are useful criteria in a non-medically ill population. Using these symptoms in cancer patients to diagnosis depression, however, can be problematic, as these physical symptoms are often also associated with treatments for cancer or with the cancer itself.

A recent article by Trask outlines several diagnostic approaches that have been used to aid in evaluating depression in cancer patients given this problem.[4] These include the inclusive, etiologic, substitutive, and exclusive approaches. The inclusive approach uses all the criteria of depression regardless of the etiology. The etiologic approach seeks to determine whether a somatic symptom is illness- or treatment-related, or due to depression. The substitutive approach replaces the somatic symptoms of depression such as fatigue with additional cognitive symptoms such as indecisiveness, hopelessness, and pessimism. The exclusive approach excludes the somatic symptoms of fatigue and appetite/weight change that can be seen in many cancer patients.

Diagnosis

In the clinical setting, a few questions can help determine who may be at risk for major depression and there by prompt referral for further evaluation. Simply asking the patient if he or she is depressed has been shown in one small study to be highly correlated with the presence of major depression.[ 5] Table 2 lists some questions that the clinician can ask to help determine if further investigation or referral is needed.[6]

An important part of any assessment is an evaluation of suicidality. In addition to asking questions about an individual's thoughts of suicide, it is important to keep in mind several factors that are associated with increased risk of suicide. These factors are listed in Table 3.[6] If suicidal ideation is present, the patient should be referred for psychiatric evaluation. In the palliative care setting, it is especially important to consider and assess for suicidal thoughts and the desire for hastened death. Patients with advanced illness are at the highest risk for depression and suicidal ideation. In terminally ill cancer patients, depression and hopelessness were the strongest predictors of a desire for hastened death.[1]

Once a clinician has noted a patient's distress, they should try to determine if there are other possible explanations for the symptoms besides a diagnosis of major depression. Several differential diagnoses should be considered when working with cancer patients.

Normal Reaction to Bad News

Immediately following bad news, most patients will experience a brief period of distress. Examples of such news would be the initial diagnosis of cancer, the news of cancer spread or relapse, or the news that care will be shifted from a focus on cure to a focus on comfort measures. During these periods, many of the symptoms of depression may be present such as sad mood, decreased appetite, poor sleep, difficulty concentrating, and uncertainty about the future. Patients may be preoccupied with thoughts of death and grieve for their current or anticipated losses. Patients may also experience a sense of helplessness and despair with debilitating symptoms such as pain, nausea/vomiting, and recurrent fevers that necessitate long hospital stays. These feelings are normal and may last for a few weeks depending on the medical and treatment circumstances.

After this initial period, most patients will begin to adapt to this new reality and their symptoms will gradually remit.[7] This often takes place as a new cancer treatment plan is undertaken. It is important not to mistakenly label this period as a major depression. This could unnecessarily lead to starting the patient on an antidepressant for symptoms that are limited in duration. It also increases the likelihood of morbidity from medication side effects and drug-drug interactions.

An appropriate response to these circumstances is the provision by the oncologist or nurse of brief support and reassurance. The aim of this support is to "normalize" the patient's feelings. This validation can go a long way toward helping alleviate a patient's distress.

Adjustment Disorder

When a patient's symptoms of distress do not remit after a couple of weeks and are clearly related in onset to an identifiable stressor such as diagnosis or relapse, a diagnosis of an adjustment disorder should be considered. Many of the symptoms in an adjustment disorder overlap with those of a diagnosis of major depression. The main difference is that in an adjustment disorder, the symptom number or severity will not be great enough to qualify for a diagnosis of major depression. Sometimes an adjustment disorder can progress to a major depressive episode. In cases where the symptoms of an adjustment disorder have persisted for some time or have been quite distressing, a trial of an antidepressant may be warranted.

Medical Causes of Depressive Symptoms

Table 4 outlines some of the important medical causes of depressive symptoms, including those related to treatment side effects.[6] In these cases, the patient would be considered to have a mood disorder secondary to a general medical condition. Treatment would involve first attempting to correct the medical cause; however, in many cases, it may also be necessary to utilize psychotropic interventions such as antidepressants.

• Pain-The most common cause of depressed mood in cancer patients is uncontrolled pain. It is also something feared by many patients as they approach death. A commitment on the part of the physician to always work with the patient to control their pain, even if it cannot be completely eliminated, often leads to relief of anxiety for patients. The proper treatment of pain can help to alleviate depressive symptoms.

• Metabolic and Endocrine Abnormalities-Calcium, potassium, and sodium imbalances, as well as thyroid dysfunction and vitamin deficiencies, have all been associated with depression. They are part of the routine screening suggested by mental health providers as part of a work-up to rule out medical causes of depression. Cushing's syndrome, hyperparathyroidism, and adrenal insufficiency have also been associated with depression. There is some evidence that depression has occurred with greater frequency and severity in patients with pancreatic cancer, although the mechanism is not well understood.

Some interesting new studies are examining inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6. The inflammatory cytokines may play a role in the development of depression, specifically in relation to the physical symptoms such as fatigue and sleep and appetite changes.[8]

• Neurologic Abnormalities-Primary brain tumors and brain metastases can produce a variety of symptoms.Right-sided and frontal lesions are particularly associated with mood symptoms.

• Cancer Treatments-Many of the medications used to treat cancer patients can cause depressive symptoms. Particularly common are steroids, such as prednisone and dexamethasone, which are sometimes used as antiemetics prior to chemotherapy agents. Steroids have been known to cause euphoria, irritability, and depression as well as delirium and psychosis. Interferon and IL-2 are also associated with causing depressive symptoms.

Chemotherapy agents are known to have many side effects. However, the few agents listed in Table 4 are the ones that have been linked with depressive symptoms. Often stopping the causative agent or reducing the dose can alleviate the depressive symptoms. In cases where there is no alternative, antidepressant therapy may be needed. There is some evidence to show that prophylaxis against depression in these treatment circumstances may be helpful. A study by Musselman found that giving the antidepressant paroxetine prophylactically to patients with melanoma receiving interferon-alpha significantly lowered the incidence of depression when compared to placebo.[9]

• Delirium-Patients who have delirium can present with psychomotor slowing, decreased concentration, crying, and depressed mood. However, a delirious patient will have a generally characteristic rapid onset in addition to a fluctuating course with varying levels of arousal. Delirious patients may also experience visual hallucinations, which are uncommon in depression.

• Dementia-There is usually a history of a slow cognitive decline in patients with dementia as opposed to a more rapid onset of cognitive difficulties coinciding with depressive symptoms in patients with depression. In addition, neuropsychological testing may be helpful to distinguish between depression and dementia, as depressed patients are often able to complete cognitive tasks with significant encouragement.

Management of Depression

Once a diagnosis of depression has been made, there are several modalities available to treat these patients. Often a combination of pharmacologic and psychotherapeutic interventions will be utilized. As outlined above, when there is a reversible medical cause such as thyroid function abnormalities, correction of these should be the first focus of treatment.

Pharmacologic Treatments

A medication trial is often the primary treatment for depression in cancer patients. However, the use of pharmacotherapy in cancer patients can pose unique challenges. Patients who are at the end of life, possibly entering hospice care, may not be able to wait the 4 to 8 weeks it can take for some of the medications to work at any particular dose. The choice of antidepressant should be based on matching the potential side effects of each medication with the patient's primary symptoms, prognosis, and any comorbid symptoms or conditions. In some cases a side effect such as weight gain or sedation may be beneficial to cancer patients who have difficulty with appetite or sleep.

There are five categories of pharmacotherapy that have typically been used in the cancer setting (see Table 5): selective serotonin reuptake inhibitors (SSRIs), atypical antidepressants, tricyclic antidepressants, psychostimulants, and monoamine oxidase inhibitors (MAOIs).[10] The use of MAOIs has greatly diminished in the past few years due to their unfavorable side-effect profile and the numerous drug and food interactions that exist with these medicines. They have been mostly replaced with the now numerous SSRIs and atypical antidepressants on the market that are easier to use and have fewer side effects. The MAOIs are therefore not discussed here further, and do not appear in the table.

• Selective Serotonin Reuptake Inhibitors-SSRIs have become the first line of treatment for depression as well as many anxiety disorders. They are efficacious, well tolerated, and not as toxic in overdose as the older tricyclic antidepressants. The SSRI fluvoxamine is intentionally omitted from Table 5 as it is mainly used in treating obsessive compulsive disorder and is not often used in the cancer setting.

Some SSRIs, such as fluoxetine, are inhibitors of cytochrome P450 isoenzymes. The clinician must therefore monitor for the possibility of drug-drug interactions between the SSRIs and a patient's other medications. Drugs that are less protein bound may have a lower risk of drug interactions with the P450 system. SSRIs that are less protein bound and therefore less likely to have significant drug-drug interactions include sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro).[11] This may make these medications a better choice for those patients on numerous other medications.

Almost all of the SSRIs are available in liquid form, making it possible for patients who cannot swallow pills to still receive an antidepressant. SSRIs should typically be started at lower doses than are used in a healthy population and they should be titrated slowly. Once a patient has been on an SSRI for some time, it is recommended that the medication be tapered slowly if the medicine is to be stopped. This is because some of the SSRIs with short half-lives, such as paroxetine, can be associated with flu-like withdrawal symptoms if stopped abruptly. As a group, the SSRIs can also be associated with sexual dysfunction.

• Atypical Antidepressants-Although these medications are grouped together, they actually have quite differing therapeutic mechanisms and side-effect profiles. Nefazodone (Serzone), which has some similarities to trazodone, is not listed in Table 5 as it received a black box warning from the US Food and Drug Administration (FDA) for cases of hepatic failure and is now rarely used.?

Bupropion (Wellbutrin) primarily works on the dopamine system and can have a stimulant-like effect. This can be a helpful side effect for individuals with significant fatigue. It is generally weight-neutral and has an additional FDA indication as a treatment for smoking cessation. It has little to no effect on sexual functioning, which often makes it a good choice for patients concerned about loss of libido or sexual dysfunction. Bupropion has been associated with seizures; it is therefore contraindicated in patients with seizure disorders or those at risk for seizures, such as those with central nervous system disorders or eating disorders.

Mirtazapine (Remeron) acts by blocking the 5-HT2, 5-HT3, and alpha- 2 adrenergic receptor sites. The main side effects of this medication are sedation and weight gain. Many cancer patients suffer from weight loss and insomnia, making this antidepressant's side-effect profile a useful one in this population. Remeron Sol TAB is a dissolvable tablet form of mirtazapine that melts on the tongue. This makes mirtazapine additionally useful, as it can be given to patients who cannot swallow.

Venlafaxine (Effexor) is a reuptake inhibitor of both serotonin and norepinephrine. It is often used when patients fail to respond to other antidepressants. Blood pressure monitoring is recommended, as venlafaxine can cause hypertension as a side effect, especially at high doses. Duloxetine (Cymbalta) is another serotonin and norepinephrine reuptake inhibitor that has just been released to market. Clinical experience with this agent is therefore limited, although there may be some use for this medication as an adjunctive treatment for pain syndromes.

Trazodone works by blocking postsynaptic serotonin 5-HT2 receptors. Its main side effect is sedation. Because the dose of trazodone needs to be fairly high for a full antidepressant effect, it is rarely used as a primary antidepressant. However, its sedative effects at low doses make it very useful as a nonaddictive sleep aid. Trazodone has rarely been associated with priapism and cardiac arrhythmias.

• Tricyclic Antidepressants-This is the oldest group of medications used to treat depression. Three of the most common tricyclics used are listed in Table 5. They are much less expensive than the SSRIs, but their use has greatly diminished as they are associated with a greater potential for side effects and toxicity. These side effects include the anticholinergic symptoms of urinary retention, constipation, blurred vision, and dry mouth, as well as orthostatic hypotension and arrhythmias. They are also highly cardiotoxic in overdose. Tricyclics are currently mostly used as adjunctive pain medications, especially for neuropathic pain. Their sedative effects can also be exploited when insomnia is a problem for the patient. A cancer patient with difficult to control pain, insomnia, and some depressive symptoms may be one that is a good candidate for a trial of a tricyclic.

• Psychostimulants-This is a very important class of medications for patients in the palliative care setting. A major drawback for many of the traditional antidepressants is the weeks to months it can take for them to reach a therapeutic effect. The stimulants can provide relief for the cancer patient's symptoms of fatigue, depressed mood, and poor concentration in a matter of days. They are also useful for counteracting the sedating side effects of opioid medications that many patients require at the end of life. Pemoline (Cylert) is an older medication that is not listed in Table 5, as it has been associated with liver and renal toxicity and has fallen out of favor. Side effects of the psychostimulants can include anorexia, insomnia, euphoria, irritability, and mood lability. Modafinil (Provigil) is a newer agent that is called a "wakefulness promoting agent" that works by a different mechanism than the other stimulants. It is rapidly growing in popularity for use in treating cancerrelated fatigue.

Psychotherapy

Psychotherapy is frequently used in combination with pharmacologic intervention. There are several psychotherapeutic techniques that have been successfully used with cancer patients suffering from depressive symptoms. Two common forms of psychotherapy are supportive psychotherapy and cognitive-behavioral therapy. Supportive psychotherapy aims to help the patient focus on adaptive coping strategies. It attempts to identify and support those strategies that have helped the patient in the past, with the goal of strengthening selfesteem and a sense of control. Cognitive- behavioral therapy focuses on altering a patient's maladaptive or negative thoughts and behaviors, with the premise that these thoughts and behaviors influence how the patient is feeling.

Group psychotherapy is another valuable source of support that helps to improve patients' social networks and decrease a sense of isolation. Other forms of therapy that have been used to treat depression include existential therapy, interpersonal therapy, and the therapeutic life narrative.[12]

Addressing spirituality and meaning for patients with advanced cancer is a growing area of interest and research. Patients at the end of life may experience spiritual suffering, demoralization, hopelessness, and a loss of meaning. On the other hand, spiritual well-being has been shown to offer some protection against end-of-life despair.[13] Breitbart has outlined a meaning-centered group psychotherapy intervention for patients with advanced cancer that focuses on addressing these spiritual issues.[14] Further study is needed, but this work suggests that interventions aimed at addressing spiritual issues may be helpful in treating and preventing depression at the end of life.

Summary

Patients with advanced cancer are at particular risk for the development of depressive symptoms. Routine assessment for depression can lead to the early identification of distress in these patients. Reviewing the differential causes for a patient's symptoms can lead to appropriate treatment of underlying medical causes or pain. For those patients who do develop significant symptoms of depression, a variety of effective interventions are available. When depression is deemed to be severe or when a patient expresses suicidal ideation, he or she should be referred to a psychiatrist for a more in-depth evaluation. Depression is treatable in cancer patients, even at the end of life. Accurate assessment and a careful approach to management in these patients can greatly improve their quality of life.

Disclosures:

The authors have nosignificant financial interest or other relationshipwith the manufacturers of any productsor providers of any service mentioned in thisarticle.

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