as the most common psychiatric complication encountered in primary care,1 major depression poses considerable diagnostic and treatment challenges to clinicians caring for medically ill patients. Moreover, accurate diagnosis and treatment of major depression in medically ill individuals is crucial because depressive disorders have been noted to adversely affect survival,2'6 length of hospital stays,6 compliance with treatment,7 ability to care for oneself, and quality of life.8 Because the prevalence of depression has been shown to increase with increased severity of medical illness,9,10 cancer remains a critical area of study with regard to diagnosis, treatment, and disease correlates In fact, illness severity has been found to be the most important variable associated with depression in patients with cancer.11,12
PREVALENCE OF DEPRESSION IN PATIENTS WITH CANCER
Among studies that have examined rates of depression in patients with cancer, a wide variability in prevalence can be categorized according to such domains as tumor site, disease stage, study cohort, and diagnostic method.1314 A recent literature review found rates of depression ranging from 1.5% to 50% (mean 24%) depending on tumor site, with the highest rates of depression reported for pancreatic cancer (50%), oropharyngeal cancer (22% to 40%), and breast cancer (13% to 26%).15 Among studies that have examined rates of depression in cancer patients referred for psychiatric consultation (therefore samples biased through selection by referral), a range of 9% to 58% has been reported.14 Although significant méthodologie variability exists among studies examining depression and cancer, rates of major depression among cancer patients are considerably higher than for patients with many other medical illnesses,16 and a clear spectrum of depressive symptom severity is recognized among these individuals.15
DIAGNOSIS OF DEPRESSION IN PATIENTS WITH CANCER
Because pharmacologic treatment of major depression in patients with cancer has been shown to improve life quality,17·18 and because some supportive psychological interventions have resulted in increased survival rates in patients with cancer,19'21 identification of depression in affected individuals is critical. Although reactions of sadness, shock, and disbelief may be expected responses to the painful experience of receiving a diagnosis of cancer, depressive symptoms must be monitored closely because they may reach the magnitude and duration to fulfill the Diagnostic and Statistical Manual, 4th edition (DSM-IV)22 criteria for major depression, A major depressive syndrome, in contrast to sad feelings, is not an expected complication of cancer, but rather a comorbid illness. Therefore, attentive, respectful approaches to patient care highlight the need for accurate diagnosis of depressive syndromes.
Numerous diagnostic approaches have been utilized to attempt to address the quandary of whether or not to include neurovegetative symptoms as part of a depressive syndrome in the medically ill.2325 As in other medical conditions, diagnosing depression in patients with cancer requires a thoughtful approach that takes into account the similarities of neurovegetative symptoms of depression and symptoms attributed to cancer or treatment side effects (eg, appetite loss, weight loss, insomnia, and loss of energy). One approach excludes the neurovegetative symptoms of anorexia and fatigue from the DSM-IV list of nine depressive criteria and requires four of the remaining symptoms for a diagnosis.26 This approach has been particularly useful for research purposes because it clearly increases specificity. However, Cohen-Cole and colleagues27 have suggested an approach that includes all relevant depressive symptoms regardless of whether there is reason to attribute the symptom to the medical illness or its treatment. Generally, this approach is useful in clinical settings because it reduces the number of patients who may be underdiagnosed and therefore untreated. Mermelstein and Lesko28 recommend focusing on the psychological symptoms of dysphoria, feelings of helplessness or hopelessness, loss of self-esteem, feelings of worthlessness, and suicidal ideation. Regardless of one's diagnostic approach, clinicians should maintain a lower threshold for diagnosing major depression in patients with cancer, particularly in view of evidence that even in patients with subsyndromal depression, antidepressant therapy improves fife quality. 18,29
When making a diagnosis, depression becomes complicated in the medical setting; clinicians may find that addressing known risk factors for depression in patients with cancer is a useful diagnostic adjunct. Investigators have identified the following risk factors that predispose cancer patients to the development of major depression: social isolation, recent losses, a tendency toward pessimism, socioeconomic factors, comorbid substance abuse, and previous history of mood disorder or suicide attempts.30' 33 Family psychiatric histories may be helpful because our research group has found that firstdegree relatives of patients with cancer and depression have a higher rate of psychiatric disorders than those of nondepressed patients with cancer (McDaniel, unpublished data, 1994). Recent studies suggest that although small numbers of cancer patients commit suicide, their relative risk is twice that of the general population, suggesting the need to carefully monitor suicide potential.34"36 The presence of pain, a frequent complication in advanced cancer, has been found to pose a significant risk for the development of depression.35 Other factors that may increase the risk of depression are linked to the use of such agents as corticosteroids and opiate analgesics in cancer treatment, medications with high rates of depression as side effects.37
Other diagnostic adjuncts available to clinicians treating depressed cancer patients include numerous biological markers reflecting neurochemical, neuroendocrine, and neuroanatomical alterations. As state-dependent variables, some of these markers may reflect and even portend treatment response in patients with depression.38 Although few of these markers have been systematically studied in medically ill populations, literally hundreds of reports document hypothalamicpituitary-adrenal (HPA) axis hyperactivity in patients with unipolar depression. This hyperactivity is currently thought to be due largely to hypersecretion of corticotropin-releasing factor (CRF) from paraventricular hypothalamic neurons, which results in anterior pituitary hypersecretion of corticotropin, which in turn results in adrenocortical glucocorticoid (Cortisol) hypersecretion.39 The dexamethasone suppression test (DST) is one of the most widely used laboratory assessments of Cortisol hypersecretion.38 In the standard DST paradigm, patients ingest 1 mg of dexamethasone, a synthetic glucocorticoid, by mouth at 11 PM. Blood samples for measurement of Cortisol concentrations are obtained at 4 PM and 11 PM the next day. One half to two thirds of depressed patients exhibit dexamethasone nonsuppression.40 Among cancer patients, one group of investigators has prospectively examined depressed patients for HPA hyperactivity utilizing the DST; their findings have important implications.41 Evans and colleagues41 studied 83 women with non-ovarian gynecological cancer and found that 40% of the depressed cancer patients exhibited DST nonsuppression, a rate of nonsuppression similar to depressed patients without cancer. Their findings, although preliminary, suggest that the DST may be a useful aid in the diagnosis of depression in patients with cancer, particularly those whose diagnosis is clouded by neurovegetative symptoms of unclear etiology.41
TREATMENT OF DEPRESSION IN PATIENTS WITH CANCER
Because the presence of depression in patients with cancer may adversely impact survival,2"6 appropriate treatment is of paramount importance. Treatment generally includes both psychopharmacologic management and psychosocial treatment.42 Antidepressant treatment of depressed cancer patients has been shown to be efficacious and well tolerated.17,18,23 Moreover, investigators have shown that effective treatment of major depression in cancer patients significantly enhances quality of life.17,18 Massie and Lesko44 outlined a number of important basic principles to keep in mind when using antidepressants in patients with cancer: (1) start with a lower dose than ordinarily indicated in physically healthy patients, (2) increase the drug dose more slowly, (3) administer a lower therapeutic maintenance dose, and (4) for any antidepressants under consideration, know of any major side effects that could have a deleterious effect on organ function related to tumor site or treatment. Generally, utilization of antidepressants with shorter half-lives and inactive metabolites, which have minimal effects on the hepatic cytochrome P450 system, will reduce the occurrence of drug-drug interactions.45 Neither tricyclic medications nor selective serotonin reuptake inhibitors (SSRIs) typically interact with chemotherapeutic agents.46 Newer agents such as the SSRIs can be administered with fewer side effects than tricyclic agents, which may cause anticholinergic, antihistaminic, antiadrenergic, sedative, and hypotensive side effects. A typical starting dose may be 25 to 50 mg of sertraline or 10 mg of paroxetine slowly titrated to produce a therapeutic response. In an effort to establish empirical data to standardize care, our center is currently one of three national sites conducting a placebo-controlled, double-blind trial of paroxetine and desipramine in depressed women with breast cancer. Other treatment options, particularly in patients who are in terminal stages of illness, include the use of psychostimulants, which can produce a safe, rapid improvement in mood, interest, and appetite.47,48 As in other medically ill patients who do not respond to conventional pharmacotherapy, electroconvulsive therapy remains a safe, effective alternative.49
A variety of psychosocial interventions are available for patients with cancer, including education, behavioral training, individual psychotherapy, and group interventions. The outcomes of each type of intervention have been reviewed recently by Fawzy and colleagues50 to reveal a wide range of treatment options. These investigators found that all four types of intervention had a positive effect on the treatment groups in the alleviation of emotional distress. Although the benefits of these interventions overlapped, each treatment modality also exhibited relatively specific effects. The educational approach stood out as the most beneficial method for improving treatment compliance, whereas the behavioral training modality proved uniquely advantageous in helping patients control the effects of cancer treatment and improving patients' perception of control of their treatment. Individual psychotherapy was shown to be effective in increasing patients' overall quality of life; group interventions appeared to have the most all-encompassing benefits, including increased knowledge of cancer and cancer treatment, enhanced physical capabilities, improved interpersonal relationships, better coping skills, decreased reported pain, and increased survival.30
Although most psychosocial interventions are aimed at providing psychological support rather than direct treatment of major depression, important clinical observations have emerged that focus on such variables as cancer outcome and psychoneuroimmunology.51 For example, Spiegel and colleagues19 demonstrated that women with metastatic breast cancer who received weekly group psychotherapy survived an average of 18 months longer than control patients who were randomly assigned to routine care. One group of investigators found that patients with lymphomas and leukemias who received in-home supportive interventions had significantly longer survival times than patients who did not receive these interventions.20 In their study of patients with malignant melanoma, Fawzy and colleagues21 found that for control patients who did not receive a structured group intervention, there was a statistically significant recurrence of cancer and a greater mortality rate than for patients who did receive such therapy. The malignant melanoma patients who received the group intervention also exhibited a significant increase in the number of large granular lymphocytes and natural killer (NK) cells and indications of increased NK activity.52 Another group of investigators have utilized group behavioral intervention (relaxation, guided imagery, and biofeedback training) in patients with breast cancer to demonstrate increases in NK activity and lymphocyte mitogen responses in patients receiving treatment compared with controls.53
A growing literature has examined aspects of psychoneuroimmunology in cancer patients.54 Levy and colleagues55,56 found that psychosocial variables such as lack of social support and depressive symptoms may be linked to reduced NK activity in women with breast cancer, and that more metastatic nodes and decreased NK activity are associated with depressive symptoms in these patients, illuminating the need for more research in the area. Addressing Psychoneuroimmunologie aspects of depression in patients with cancer may have important treatment implications, particularly regarding HPA hyperactivity associated with depression.39 In fact, HPA hyperactivity in depressed cancer patients may have important prognostic implications, particularly with regard to findings that in rats, HPA hyperactivity induced by exposure to stress is associated with increased tumor growth, especially in older rats.57
Only recently have investigators begun to address the complex interactions of immune functioning and the neuroendocrine system in psychosocial treatment interventions with cancer patients. In their behavioral group intervention with breast cancer patients, Schedlowski and colleagues58 found short- and longer-term reductions in plasma Cortisol levels and shortterm increases in lymphocyte numbers in those patients who received the intervention as compared with controls. Although such research examining neuroendocrine and immune aspects of treatment interventions is critical, the clinical implications of such findings, particularly with regard to depressed patients with cancer, remain to be studied.
A comprehensive, biopsychosocial approach to the management of depression in patients with cancer includes an appreciation for diagnostic complexity, neuroendocrine alterations, and psychoneuroimmune implications of comorbid depression and cancer. Effective treatment is critical and may impact such variables as quality of life, treatment compliance, length of hospital stays, and even survival. Numerous treatment strategies are available to clinicians ranging from psychopharmacologic approaches* which minimize medication side effects, to psychosocial interventions utilizing individual and group modalities. As future research illuminates the interplay between neuroendocrine and immunologic processes, particularly in those patients with major depression and cancer, new treatment modalities for depression will undoubtedly emerge, which will take into account medical morbidity and long-term survival.
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