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Depression, anxiety, and delirium

Depression, anxiety, and delirium

Psychiatric disorders are common in the setting of malignant disease, occurring
in almost 50% of patients. Many cancer patients cope well with their
disease. For those who do not, untreated psychological and neuropsychiatric
disorders can seriously compromise quality of life and treatment compliance.
Although there is a wide variety of presentations, three behavioral syndromes
that are often encountered in clinical practice will be discussed here: depression,
anxiety, and delirium.

Depression

"Depression" exists on a continuum ranging from an emotion common in daily
life (sadness) to a syndrome of severe physical and psychological symptoms
consistent with a defined psychiatric disorder (major depressive disorder).

In cancer patients, identical symptoms may be caused or influenced by physical
(eg, tumor site, pain), psychological (eg, stress, premorbid function, maturity),
and social (eg, finances, interpersonal relationships) factors. Depression
occurs more frequently in the setting of severe illness; several studies of cancer
inpatients report a prevalence of 25%-42%.

SIGNS AND SYMPTOMS/DIAGNOSIS
Patients with depressive syndromes experience specific symptoms that vary
in intensity and severity.

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, change in appetite, loss of
libido, fatigue, diminished concentration, and psychomotor agitation or withdrawal.

Focus of diagnostic evaluation Although the diagnosis of major depressive
disorder requires that multiple symptoms (including dysphoria or anhedonia)
must be present for at least 2 weeks, patients who do not meet these criteria
may be in significant distress. The diagnosis of depression in medically ill
patients is complicated by the fact that somatic symptoms of depression may
also be caused by factors related to disease and treatment. For this reason,
when evaluating the depressed cancer patient, special attention should be
paid to psychological symptoms, which are less likely to be directly related
to treatment.

ETIOLOGYPsychological causes
Isolated symptoms Isolated depressive symptoms, if temporally related to
an identifiable stressor, may be classified as adjustment disorders. In the setting
of malignancy, obvious stressors include the initial diagnosis, treatment
failure, or disease progression. Patients may also face potential psychosocial
stressors, including changes in independence, body image, finances, and family
function, as well as issues related to death and dying.

Persistent symptoms Persistent mood symptoms may indicate the presence
of an evolving major depressive disorder. 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.

Disease- and treatment-related causes
Presenting symptom of malignancy Depression may be a presenting symptom
of some primary malignancies, including primary pancreatic and gastric
carcinomas. Primary and metastatic brain tumors may cause frontal lobe 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 -blockers, antihypertensives,
barbiturates, opioids, and benzodiazepines.

In contrast, few drugs used as primary and supportive therapies for cancer
are commonly associated with depression. The exceptions to this rule are
corticosteroids, cytokines (especially interferon-alfa [IFN-α Intron A, Roferon-
A] and interleukin-2 [aldesleukin, Proleukin]), and whole-brain radiation
therapy. Depressive syndromes may also be seen with certain chemotherapeutic
agents, including asparaginase (Elspar) and procarbazine (Matulane).
Patients treated with tamoxifen may complain of depression or "chemobrain."
The latter term usually refers to cognitive slowing. Day and colleagues have
shown a lack of association between tamoxifen treatment and depression,
even in women at higher risk for mood disorders.

MANAGEMENT
Management of depressive syndromes involves accurate diagnosis, use of antidepressant
medication, and psychotherapy. Patients should be assessed for
somatic and psychological symptoms of depression. The clinician should always
ask about suicidal thoughts or intent. Metabolic and thyroid function
should be evaluated and medications reviewed.

The decision to treat depression is a matter of clinical judgment. If mood disorder
symptoms adversely affect quality of life, work or family relationships, or
ability to participate in cancer therapy, intervention is indicated. Because the
diagnosis of depression can be difficult to make in patients with cancer, it is
best to have a low threshold for the initiation of treatment to minimize the risk
of missing a reversible disorder

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. There is some anecdotal evidence that
a more rapid effect is seen in cancer patients. As a general rule, antidepressant
therapy should continue for 4-6 months after symptoms stabilize.

Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine
(Prozac, Sarafem), sertraline (Zoloft), paroxetine (Paxil), and escitalopram
(Lexapro), are often used in patients with cancer because of their benign sideeffect
profile. In particular, their lack of anticholinergic and -adrenergic-blocking
properties makes them attractive options for patients with a serious medical
illness.

Unlike the tricyclic agents (discussed below), the SSRIs are not lethal in overdose,
making them a safe choice in the treatment of patients experiencing
suicidal ideations.

Side effects Mild nausea and anxiety are common side effects of all SSRIs,
which vary in severity from patient to patient. Sexual dysfunction may occur
with fluoxetine and paroxetine. Sedation may occur with paroxetine.

Dosage In ambulatory patients with normal metabolic function, SSRIs can be
started at the same doses used in general psychiatry (ie, 20 mg/d qAM for
fluoxetine, 50 mg/d qAM for sertraline, 20 mg/d qAM for paroxetine). These
doses can be increased if there is no response within 2-3 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.

Tricyclic antidepressants (TCAs) These older antidepressants (eg, amitriptyline,
nortriptyline, and desipramine) remain effective options for the
treatment of depression in cancer patients. The sedative properties of TCAs
can be useful in the treatment of insomnia associated with depression. In
addition, TCAs are useful adjuncts in the treatment of neuropathic pain.

TCAs have the advantage of established therapeutic blood levels, although
the applicability of these levels to cancer patients is uncertain.

Side effects The common side effects of TCAs include sedation, dry mouth,
orthostatic hypotension, constipation, and blurred vision. These side effects
are related to anticholinergic, -adrenergic-blocking, and antihistaminic properties
of TCAs and are often the reason these drugs are not used as the first
line of treatment in depressed medically ill patients. TCAs must be used cautiously
in patients with active suicidal ideations and in those with cardiac
conduction abnormalities.

Dosage Initial dosing of TCAs should be conservative (25-50 mg PO qhs for
nortriptyline, 25-50 mg qhs for amitriptyline, 25-50 mg qAM or hs for desipramine),
with escalation of doses if tolerated every 4-7 days. Therapeutic
response is sometimes seen at doses lower than those used in the general
population, that is lower than 75-150 mg/d for nortriptyline, 150-300 mg/d
for amitriptyline, and 200-300 mg/d for desipramine.

Atypical and newer antidepressants Bupropion (Wellbutrin) is activating,
which may be of potential benefit in patients with psychomotor slowing. Another
advantage is that it is not associated with sexual dysfunction. However,
bupropion has been associated with seizures and therefore should be used
with caution (if at all) in patients who suffer from seizures or who have a history
of seizures.

Venlafaxine (Effexor), nefazodone (Serzone), and mirtazapine (Remeron) are
newer agents with selective effects on serotonin and norepinephrine metabolism.
They should be started at low doses to establish whether they can be
tolerated. Venlafaxine may be effective against treatment-induced hot flashes.
Mirtazapine has sedative, appetite-stimulant, and antiemetic effects, which
can be very useful in selected cases.

Psychostimulants
Psychostimulants that have direct or indirect dopamine-agonistic properties,
such as dextroamphetamine, methylphenidate, and pemoline, have an 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 24-48 hours of
the initiation of psychostimulant treatment.

Side effects Like other activating agents, psychostimulants may cause insomnia,
anxiety, palpitations, and GI upset. Hypertension or hypotension may
also occur.

Dosage Initial dosing should be conservative (eg, 5 mg/d in two divided doses
every morning and noon for methylphenidate, 5 mg/d qAM for dextroamphetamine).
If tolerated, stimulant doses can be increased until a therapeutic
effect is achieved or side effects develop.

Psychotherapy
Although antidepressants alone are effective in the treatment of depression,
patients often require and benefit from psychotherapy.

In some cases, such therapy can be limited to support while response to medication
is monitored. Other patients may require cognitive-behavioral interventions
to help them deal with misperceptions about their disease status or
to resolve preexisting issues.

For some patients, group therapy can be helpful, although others find it difficult
to interact with patients who are equally or more severely ill.

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