Donald L. Rosenstein*
*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
TABLE 39.1. Medical Conditions in Oncologic and Other Disorders Associated with Anxiety and Depression
COMMON PSYCHIATRIC SYNDROMES IN THE ONCOLOGY SETTING
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.
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
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
Differential diagnosis of major depression:
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
The differential diagnosis of anxiety disorders in the oncology setting includes the following:
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
TABLE 39.5. Commonly Used Neuroleptics in the Oncology Setting
The following issues associated with BZD use require attention:
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:
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.
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.
Academy of Psychosomatic Medicine. Psychiatric aspects of excellent end-of-life care: a position statement of the Academy of Psychosomatic Medicine. Available at: http://www.apm.org/eol-care.html. Accessed March 14, 2005.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994.
Cassem EH. Depressive disorders in the medically ill: an overview. Psychosomatics 1995;36:S2–S10.
Cleeland CS, Bennett GJ, Dantzer R, et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer 2003;97:2919.
Coyle N, Adelhardt J, Foley KM, et al. Character of terminal illness in the advanced patient with cancer: pain and other symptoms during the last four weeks of life. J Pain Symptom Manage 1990;5:83.
Emanuel EJ, Fairclough DL, Daniels ER, et al. Euthanasia and physician-assisted suicide: attitudes and experiences of oncology patients, oncologists, and the public. Lancet 1996;347:1805.
Endicott J. Measurement of depression in patients with cancer. Cancer 1984;53:2243.
Fawzy I, Greenburg D. Oncology. Textbook of consultation-liaison psychiatry. Washington, DC: American Psychiatric Press, 2001.
Goldman LS, Wise TN, Brody DS. Psychiatry for primary care physicians. Washington, DC: American Psychiatric Press, 1997.
Holland J. Psycho-oncology. New York: Oxford University Press, 1998.
Lipsett DR, Payne EC, Cassem NH. On death and dying. Discussion. J Geriatr Psychiatry 1974;7:108.
Lynch ME. The assessment and prevalence of affective disorders in advanced cancer. J Palliat Care 1995;11:10.
McDaniel JS, Musselman DL, Porter MR, et al. Depression in patients with cancer: diagnosis, biology, and treatment. Arch Gen Psychiatry 1995;52:89.
Recklitis C, O'Leary T, Diller L. Utility of routine psychological screening in the childhood cancer survivor clinic. J Clin Oncol 2003;21:787.
Spiegel D, Sands S, Koopman C. Pain and depression in patients with cancer. Cancer 1994;74:2570.
Spiegel L. Pediatric psychopharmacology. Psycho-oncology. New York: Oxford University Press, 1998; Wise TN. The physician and his patient with cancer. Prim Care 1974;1:407.