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.
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 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.
