Bethesda Handbook of Clinical Oncology, 2nd Edition

Supportive Care

39

Psychopharmacologic Management in Oncology

Donald L. Rosenstein*

Maryland Pao^†

June Cai^‡

*National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

^†National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

^‡Department of Pyschiatry and Human Behavior, Brown University Medical School, Providence, Rhode Island

Psychiatric syndromes, predominantly depression and anxiety, occur commonly in patients with cancer, and, if misdiagnosed or poorly managed, can have a profoundly negative effect on optimal oncologic care. The comprehensive psychiatric care of patients with cancer includes psychosocial, behavioral, and psychoeducational interventions as well as pharmacologic and psychotherapeutic treatment. This chapter focuses on the psychopharmacologic management of the major psychiatric syndromes encountered in the oncology setting and concludes with specific recommendations for psychopharmacologic management in pediatric oncology.

CONSIDERATIONS BEFORE PRESCRIBING PSYCHOPHARMACOLOGIC AGENTS

1. Psychiatric symptoms are often manifestations of an underlying medical disorder or are complications of its treatment (see Table 39.1). For example, specific malignancies (e.g., lung, breast, gastrointestinal, renal, and prostate cancers) are prone to metastasize to the central nervous system (CNS). In addition, any advanced cancer can result in structural or metabolic CNS insults that precipitate psychiatric symptoms. For those patients whose psychiatric symptoms fail to respond to psychopharmacologic treatment, CNS involvement should be reconsidered, even in malignancies that do not commonly metastasize to the brain.

TABLE 39.1. Medical Conditions in Oncologic and Other Disorders Associated with Anxiety and Depression

Neoplasms Cardiovascular Brain tumors Ischemic heart disease Insulinoma Arrhythmias Lymphoma Congestive heart failure Small cell carcinoma Pancreatic cancer Metabolic Leukemia Electrolyte disturbances Uremia Endocrinologic Vitamin B12 or folate deficiency Cushing syndrome Adrenal insufficiency Other Hypopituitarism Substance abuse and withdrawal Pheochromocytoma Pain (uncontrolled) Thyroid dysfunction Hematologic (e.g., anemia)

2. Medically ill patients are particularly susceptible to CNS adverse effects of medications. Specific examples of medications associated with mood, cognitive, and behavioral symptoms include the following: corticosteroids, interleukin-2, interferon-α, narcotics, and dopamine-blocking antiemetics. For patients who develop psychiatric symptoms after treatment with such agents, it is often more prudent to lower the dose or to discontinue the use of a currently prescribed medication than to introduce yet another agent (i.e., a psychotropic) that might exacerbate psychiatric symptoms.
3. Polypharmacy is often unavoidable in patients with cancer; however, most clinically significant interactions with psychotropic agents are predictable and can be avoided by choosing alternative agents or by making dose adjustments. The use of monoamine oxidase inhibitors (MAOIs) with either meperidine (Demerol) or selective serotonin reuptake inhibitors (SSRIs) is life threatening. Up-to-date drug interaction resources can be found at several internet websites (e.g., http://www.medicine.iupui.edu/flockhart/).

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4. Inadequate pain control frequently induces symptoms of anxiety, irritability, or depression. It is essential to have pain well-controlled so that the appropriate psychiatric diagnosis and treatment can proceed (see Chapter 37). One note of caution in this regard concerns the combined use of SSRIs and tricyclic antidepressants (TCAs), which are frequently used in the treatment of neuropathic pain. Some SSRIs (e.g., fluoxetine, paroxetine, and fluvoxamine) inhibit the metabolism of TCAs, which can in turn prolong the corrected QT interval (QTc) interval.

COMMON PSYCHIATRIC SYNDROMES IN THE ONCOLOGY SETTING

1. Adjustment disorder:This is a time-limited, maladaptive reaction to a specific stressor that typically involves symptoms of depression, anxiety, or behavioral changes and impairs psychosocial functioning. The diagnostic criteria include the onset of symptoms within 3 months of the stressor but the duration of symptoms is no more than 6 months. The differential diagnosis includes the following disorders:

• Bereavement
• Posttraumatic stress disorder
• Other mood and anxiety disorders

Management: The initial treatment approach consists of crisis intervention and brief psychotherapy. Time-limited symptom management with medications may be indicated. For example, anxiety, tearfulness, and insomnia are frequent reactions to the diagnosis of a new or recurrent malignancy. Short-term treatment of these symptoms with benzodiazepines (BZDs) (e.g., lorazepam and clonazepam) is appropriate, effective, and rarely associated with the development of abuse or dependence.

2. Major depression:Major depression and subsyndromal depressive disorders are common in patients with cancer. Prevalence rates vary between 5% and 50% depending on how depression is defined, whether study samples are drawn from outpatient clinics or hospital wards, and the type of cancer involved. Untreated depression has been correlated to poor compliance with medical care, increased pain and disability, and a greater likelihood to consider euthanasia and physician-assisted suicide.

A major diagnostic task in the oncology setting is assorting symptoms attributable to depression from those symptoms that are caused by the cancer or its treatment. The patient with disseminated cancer who is undergoing chemotherapy is likely to experience fatigue, anorexia, weight loss, and insomnia, whether a clinical depression is

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present or absent. Our practice is to institute empiric trials of antidepressants using a targeted symptom reduction approach. In borderline cases, a personal or family history of depression and symptoms of excessive guilt, poor self-esteem, anhedonia, and ruminative thinking strengthen the argument for a medication trial. Furthermore, because the number of well-tolerated, safe, and effective antidepressants has grown, we have lowered our threshold for treating subsyndromal depression in the oncology setting.

Particular attention should be paid to symptoms of hopelessness, helplessness, and suicidal ideation, accompanied by considerable increases in anxiety, because patients with cancer have an increased risk of suicide compared with the general population. The incidence of cancer at certain sites (e.g., head and neck, lung, gastrointestinal tract, urogenital tract, and breast) is associated with an even greater risk of suicide (see Table 39.2).

TABLE 39.2. Risk Factors for Suicide in Patients with Cancer

Historical considerations Clinical descriptors Prior suicide attempts Elderly men Family history of suicide Recent loss and poor social support Prior psychiatric illness Current depression, anxiety, substance abuse History of substance abuse Advanced cancer, pain, poor prognosis Impulsive behavior Delirium, psychosis, illogical thoughts

Differential diagnosis of major depression:

• Adjustment disorder
• Dysthymic disorder
• Delirium
• Dementia
• Substance abuse
• Bipolar disorder
• Bereavement
• Mood disorder caused by a medical disorder or medication (Table 39.1).

Management: Treatment modalities include pharmacotherapy (see Table 39.3), psychotherapy, and electroconvulsive therapy (ECT). Selection of an antidepressant should be based on a number of considerations such as prior treatment response, an optimal match between the patient's target symptoms and the side-effect profile of the antidepressant (e.g., using a sedating agent for the patient with anxiety and insomnia), and the potential for drug interactions. Mirtazapine (Remeron) has several properties that make it a particularly attractive antidepressant choice in patients with cancer: it is sedating, causes weight gain, has few significant drug interactions, and is a partial 5HT-3 receptor antagonist (i.e., has antiemtic properties).

TABLE 39.3. Commonly used Antidepressants in Patients with Cancer

Generic names (brand names) Dose range (mg) Important adverse effects and comments SSRI, selective serotonin reuptake inhibitor; GI, gastrointestinal; CYP, cytochrome P-450; CNS, central nervous system; ECG, electrocardiogram. a FDA approval for use in children/adolescents. b Orally disintegrating tablets or wafers available. c Sustained release and extended release formulations available. d Liquid formulation available. SSRIs Fluoxetine (Prozac)a,d 5–60 Sexual dysfunction, diarrhea, weight changes, insomnia, agitation, anxiety, hyponatremia, night sweats Sertraline (Zoloft)a,d 12.5–200 Sedation, weight gain, GI symptoms, sexual dysfunction, hyponatremia Paroxetine (Paxil)c,d 10–60 Sexual dysfunction, sedation, akathisia, anticholinergic effects, hyponatremia, withdrawal syndrome Citalopram (Celexa)d 10–60 Nausea, dry mouth, somnolence, ejaculation disorder, weak inhibition of CYP isoenzymes Escitalopram (Lexapro) 5–40 Nausea, dry mouth, somnolence, ejaculation disorder, weak inhibition of CYP isoenzymes Fluvoxamine (Luvox)a 25–300 Night sweats, sexual dysfunction, potent inhibitor of CYP1A2 and 3A3/4 Novel antidepressants Venlafaxine (Effexor)c 18.75–300 GI distress, sexual dysfunction, sedation, anticholinergic effects, hypertension at dose >225 mg Mirtazapine (Remeron)b 7.5–45 Sedation, dry mouth, increased appetite and weight gain, constipation, asthenia, dizziness Bupropion (Wellbutrin)c 37.5–450 GI distress, tremor, excitement, seizure at high dose or with brain tumors Trazodone (Desyrel) 25–200 Sedation, anticholinergic effects, orthostatic hypotension, priapism, useful for anxiety and insomnia at low doses CNS stimulants Methylphenidate (Ritalin)a,c 2.5–40 Insomnia, agitation, GI distress, headache, tics, rebound depression Dextroamphetamine (Dexedrine)a,c 2.5–30 Insomnia, agitation, confusion, delusion, psychosis, tics, rebound depression Tricyclic antidepressants Amitriptyline (Elavil)a 25–150 Dry mouth, sedation, weight gain, ECG changes, orthostatic hypotension, anticholinergic effects Desipramine (Norpramin) 25–150 Dry mouth, tachycardia, ECG changes Nortriptyline (Pamelor) 25–150 Tremor, confusion, anticholinergic effects

3. Anxiety disorders:Many medical conditions seen in the oncology setting, such as heart failure, respiratory compromise, seizure disorders, pheochromocytoma, and chemotherapy-induced ovarian failure, may cause anxiety. Additional conditions that may cause both anxiety and depression are listed in Table 39.1. Similarly, anxiety is an adverse effect of numerous medications. In particular, dopamine-blocking antiemetics such as metoclopramide (Reglan), prochlorperazine (Compazine), and promethazine (Phenergan) frequently cause akathisia, an adverse effect characterized by subjective restlessness and increased motor activity, which is commonly misdiagnosed as anxiety.

The differential diagnosis of anxiety disorders in the oncology setting includes the following:

• Exacerbation of medical illness
• Agitated depression

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• Adverse effects of medications
• Substance or alcohol abuse or withdrawal
• Adjustment disorder
• Delirium.

Management of anxiety: In addition to behavioral therapy and psychotherapy, BZDs are the medications that are most frequently used for the short-term treatment of anxiety (see Table 39.4). For anxiety that persists beyond a few weeks, treatment with an antidepressant (Table 39.3) is indicated. If the patient has already been taking an SSRI, it is important to not discontinue an SSRI (with the exception of fluoxetine because of its long half-life) abruptly to avoid rebound anxiety from withdrawal. Low-dose atypical antipsychotics are often useful for severe and persistent anxiety or for conditions such as anxiety secondary to steroids and delirium (see Table 39.5).

TABLE 39.4. Preferred BZDs in the Oncology Setting

Lorazepam (Ativan)a Clonazepam (Klonopin) BZD, benzodiazepines; PO, orally; i.m., intramuscularly; i.v., intravenously. a Liquid formulation available. Dose equivalency 1 mg 0.25 mg Dose range 0.25–2 mg PO, sublingual, i.m. or i.v. routes, every 1–6 h (maximum daily dose, 8 mg) 0.25–1 mg PO route only, every 12 h Advantages Rapid onset of action Less frequent dosing than with lorazepam

TABLE 39.5. Commonly Used Neuroleptics in the Oncology Setting

Initial dose (mg) Administrative routes and schedules Maximum daily dose (mg) Important adverse effects EPS, extrapyramidal symptoms; PO, orally; s.c., subcutaneously; i.m., intramuscularly; i.v., intravenously. a FDA approval for use in children/adolescents. b Liquid formulation available. haloperidol a,b(Haldol) 0.25–1 PO, or i.v. every 2–12 h s.c., i.m., 20 Hypotension, EPS, elevated prolactin chlorpromazine (Thorazine) 12.5–50 PO, i.m. or i.v. every 4–12 h 300 Decreased seizure threshold, EPS, hypotension risperidone a,b(Risperdal) 0.25–3 PO every 12 h 6 Hypotension, sedation, elevated prolactin, olanzapine (Zyprexa) 2.5–10 PO every 12–24 h 20 Sedation, anticholinergic, insulin resistance quetiapine (Seroquel) 25–50 PO every 12–24 h 800 Sedation, increased QTc

The following issues associated with BZD use require attention:

• BZDs are the treatment of choice for delirium caused by alcohol or sedative–hypnotic withdrawal, but typically worsen other types of delirium.
• In patients with hepatic failure, lorazepam, temazepam, or oxazepam are the preferred BZDs.

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• BZDs may result in “disinhibition,” especially in delirium, substance abuse, organic disorders, and preexisting personality disorders.
• The abrupt discontinuation of BZDs with short half-lives [e.g., alprazolam (Xanax) and triazolam (Halcion)] can cause rebound anxiety and precipitate a withdrawal syndrome.

4. Delirium:Delirium is an acute confusional state characterized by a fluctuating course of cognitive impairment, perceptual disturbances, mood changes, delusions, and sleep–wake cycle disruption. Patients can have a hyperactive (agitated) or hypoactive (quiet) delirium. Virtually any psychiatric symptom can be a manifestation of delirium, among which anxiety and/or labile mood are common presentations often misdiagnosed as “depression.” Patients who are elderly, who are on multiple medications, or who have underlying brain pathology are more prone to delirium. Delirium in terminally ill patients is common and often underdiagnosed. The differential diagnosis includes the following:

• Dementia
• Affective disorders with psychosis (mania or depression)
• Psychotic disorders
• Medication effects or substance or alcohol abuse or withdrawal.

Management: The first steps in the management of delirium are the identification and treatment of precipitating factors and the discontinuation of nonessential medications. Haloperidol (Haldol) continues to be the treatment of choice for delirium in most cases (Table 39.5). Newer atypical antipsychotics have fewer side effects and can be used as well, such as olanzapine (Zyprexa), quetiapine (seroquel) and risperidone (Risperdal). Delirium secondary to BZD, or sedative–hypnotic and alcohol withdrawal should be treated with BZDs.

ADDITIONAL CONSIDERATIONS FOR PSYCHOPHARMACOLOGIC MANAGEMENT IN PEDIATRIC ONCOLOGY

Cancer is the fourth leading cause of death, and the leading cause of nonacute death among children. Life-threatening illness in a child or an adolescent is traumatic and can be associated with anxiety and depression. Although many patients cope well with and adapt to the trauma, symptoms of depression such as fatigue, cognitive impairment, decreased social interaction and exploration, and anorexia may be part of a cytokine or immunologic response to cancer and its treatments. Psychotropic medications can dramatically improve the quality of life for children with cancer. These medications do not replace comprehensive, multimodal, multidisciplinary care, but are adjuncts to decrease discomfort and improve functioning of medically ill children.

Assessment and Diagnosis in Pediatric Oncology

A thorough psychiatric assessment is needed to make a correct diagnosis and to institute treatment. Typically, this assessment is based on multiple brief examinations of the child and information gathered from additional sources including family, staff, and teachers. A patient's biologic vulnerability to depression and anxiety may be inferred from (a) a family history of a mood or anxiety disorder, or other psychiatric disorder, and (b) previous psychiatric symptoms or psychiatric treatment.

Common complaints in medically ill children include:

• anxiety
• pain
• difficulty in sleeping
• fatigue
• feeling “bored.”

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Adult psychiatric syndromes of adjustment disorder, major depression, anxiety, and delirium apply to children as well, but anxiety, rather than depression, is the most frequent diagnosis. Important determining factors for pharmacologic intervention are severity and duration of psychiatric symptoms.

Psychopharmacologic Treatment of Pediatric Patients

In 1994, manufacturers and federally funded researchers were mandated to study medications such as antidepressants in children. Although there have been no well-controlled antidepressant trials in depressed medically ill children, and the dose of psychiatric medications for children with cancer has not been systematically studied, antidepressants have been useful for treating anxiety and depression. Body weight, Tanner staging, clinical status, and potential for medications to interact are weighed in deciding doses. See Tables 39.3 and 39.5 for psychotropics with U.S. Food and Drug Administration (FDA) approval for use in children and adolescents.

BZDs, such as lorazepam, used in low doses in conjunction with nonpharmacologic distraction techniques, may be appropriate for procedures that induce considerable anxiety in children. Clonazepam is longer acting and may be helpful with more pervasive and prolonged anxiety symptoms. BZDs can cause sedation, confusion, and behavioral disinhibition. Their use should be carefully monitored, especially in those patients with CNS dysfunction. BZD withdrawal precipitated by abrupt discontinuation occurs most frequently on transferring the patient from intensive care settings.

Antihistamines have been used to sedate anxious children. Diphenhydramine, hydroxyzine, and promethazine may be helpful for occasional insomnia. However, antihistamines are not helpful for persistent anxiety and their anticholinergic properties can precipitate or worsen delirium. Intravenous diphenhydramine may be sought because it can induce euphoria when given by i.v. push; very high doses can provoke seizures.

Fluoxetine is the only FDA-approved SSRI for depression in children older than 6 years. Fluoxetine and sertraline are approved for obsessive-compulsive disorder in children older than 6 years; fluvoxamine is approved for those who are 8 years and older. Fluoxetine, with its active metabolite norfluoxetine, and fluvoxamine are potent inhibitors of cytochrome P-450 (CYP) 3A3 and 3A4. They are contraindicated with macrolide antibiotics, azole antifungal agents, and several other medications. Amitriptyline is approved for depression in children who are 12 years or older. TCAs are useful for treating insomnia, weight loss, anxiety, and some pain syndromes.

Some antidepressants may contribute to suicidal thinking in children and adolescents. This possibility warrants careful monitoring of all children treated with antidepressants. Use of non-FDA approved psychopharmacologic agents in children with cancer may be considered in extreme or prolonged distress and poor functioning, but must be monitored closely. It is unusual for children with cancer to be suicidal in the absence of premorbid depression or inadequate pain management.

Children and adolescents who cannot tolerate antidepressants may benefit from stimulants for depression and apathy. Psychostimulants are generally well tolerated and have a rapid onset of action. Children with delirium, hallucinations, severe agitation, or aggression may be safely treated with low-dose antipsychotics such as haloperidol or atypical neuroleptics such as risperidone.

Although there is a dearth of research in pediatric cancer psychopharmacology, child psychiatry consultation may considerably improve the quality of life for children undergoing cancer treatment and dealing with cancer survival. Routine psychological screening of children with cancer and survivors can detect ongoing distress. Psychopharmacologic consultation may also help children with postradiation or postchemotherapy conditions related to attention, mood, and anxiety disorders.

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SUMMARY

Psychiatric syndromes are frequently misdiagnosed and poorly treated in patients with cancer. Before initiating psychopharmacologic therapy, underlying medical disorders and adverse effects of medication must be addressed and potential drug interactions anticipated. Psychiatric symptoms should then be treated promptly and aggressively. Consultation from a psychiatrist is indicated in the following circumstances when the patient (a) has a complex psychiatric history and is taking multiple psychotropic medications; (b) exhibits depressive symptoms associated with extreme guilt, anxiety, and/or suicidal thoughts; (c) is confused, hallucinating, agitated, or violent; and (d) is noncompliant with treatment or rejects treatment and seeks physician-assisted suicide.

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