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Depression in the Cancer Patient: Diagnostic, Biological, and Treatment Aspects

In recent years, an extensive body of literature has accumulated that examines depression in patients with medical illness and, more specifically, the diagnosis and treatment of depression in patients with cancer. Investigators have found a relatively high prevalence rate of depression in patients with certain types of cancer, and some reports have suggested an association between depression and increased morbidity in cancer patients. One obstacle in studying depression in cancer patients has been the difficulty detecting depression because the diagnostic criteria for major depression include a number of signs and symptoms that have been attributed to the patient's malignancy (e.g., appetite loss, weight loss, insomnia, loss of interest, and loss of energy). A potential aid in the diagnosis of major depression in medically ill patients is the use of biological markers, particularly measures of neurochemical and neuroendocrine alterations, and abnormalities in sleep architecture. This chapter reviews current perspectives in diagnosing depression in cancer patients, prevalence data on depression in patients with cancer, recent advances in biological markers, treatment of depression in cancer patients, and future research in the area of depression in cancer.

DIAGNOSING DEPRESSION IN PATIENTS WITH CANCER

Chapter 1 Table 1. DSM-III-R criteria for major depressive syndrome

There has been considerable controversy as to how to most effectively diagnose depression in patients with medical illness. Kathol and colleagues (45) recently discussed this in detail. They reported the following problems associated with diagnosing depression in patients with medical illness: (i) depressive symptoms are often appropriate to the stress of having a serious medical illness; (ii) many symptoms of depression are similar to those of medical illness itself; and (iii) there have been numerous diagnostic symptoms proposed to diagnose depression, some of them with overlapping populations. Cohen-Cole and colleagues (11) have reviewed four different conceptual approaches to the diagnosis of major depression in medically ill patients. They are as follows:

1. The inclusive approach, which includes all symptoms and signs presented by the patient, whether or not they may be secondary to the physical illness.
2. The exclusive approach, which disregards symptoms such as anorexia in cancer patients and does not allow them to contribute to a diagnosis of major depression.
3. The etiological approach, which attempts to operationalize the guidelines of DSM-III-R, in which the clinician tries to determine whether the problematic symptom is secondary to the physical illness or secondary to a mood disorder.
4. The substitutive approach, which suggests substituting additional cognitive symptoms of depression such as brooding or pessimism for vegetative symptoms of uncertain or mixed etiology.

However, for clinical purposes the inclusive approach, which maximizes sensitivity, best protects from the problem of underdiagnosing depression, so-called false negatives. This approach guides clinicians in the diagnosis of depression by counting all relevant symptoms if there is any reason to believe that they may be part of a depressive syndrome, even if the etiology of the symptom may result from either a physical or psychiatric process. Available data currently indicate that the risk of overdiagnosis is small, between 1.5% and 8% (30,44). the particular diagnostic approach may be most influenced by whether the assessment is primarily for research or clinical purposes. For research purposes, the exclusive approach first proposed by investigators at the Memorial Sloan-Kettering Cancer Center clearly maximizes specificity. This diagnostic approach eliminates anorexia and fatigue from the list of nine depressive criteria and requires four of the remaining symptoms for a diagnosis of major depression

Wells and colleagues (88) reported that depression in the context of physical illness is associated with increased morbidity, length of hospital stay, and overall disability. They have further convincingly shown that symptom complexes suggestive of depression, but not meeting full criteria for major depression, are still associated with significant social impairment and disability. Quitkin and colleagues (74) and Evans and colleagues (23) have demonstrated that minor depressions may still respond to antidepressants, therefore calling into question the need to more aggressively identify depressed patients in the medical setting.

PREVALENCE OF DEPRESSION IN THE CANCER PATIENT

Chapter 1 Table 2. Prevalence studies of depression in patients with cancer

MMPI, Minnesota Multiphasic Personality Inventory; DRS, Depression Rating Scale; SCL-90, Symptom Checklist-90; BDI, Beck Depression Inventory; HDS, Hamilton Depression Scale; SADS-L, Schedule of Affective Disorders and Schizophrenia-Lifetime Version; STAI, Spielberger State-Trait Anxiety Inventory.

Depression is a common, potentially lethal but eminently treatable disease. The prevalence of depression in the general population has been found to be approximately 6%, according to a multicenter study sponsored by the National Institute of Mental Health in which 10,000 individuals in three cities were interviewed (55). Most studies that have examined the prevalence of depression in the context of other medical illnesses, especially cancer, have found the rate to be significantly higher than the 6% found in the general population. Table 2 chronologically outlines those studies in the psychiatric literature that have examined depression in the context of patients with cancer. The rate of depression has been quite variable, most likely owing to such factors as hospitalization status, sites of cancer, and diagnostic methods used to assess depression. The frequency of depression has ranged from as high as 50% to as low as 4.5%. In the study by Craig and Abeloff (15) of 30 inpatients with various types of cancer, a self-report symptom checklist (SCL-90) was utilized to determine that one-half of their patient sample met criteria for major depression. Lanksy et al. (52) used DSM-III criteria to find a depression rate of 4.5% in their sample of 500 female outpatients with various cancer types. In a recent study of 100 inpatients with acute leukemia, Colon et al. (12) utilized DSM-III-R criteria and reported a lower rate of depression than other studies: 1%, major depression; 2%, organic affective syndrome; and 8%, adjustment disorder.

All but two of the 22 reported studies found rates of depression significantly higher than those found in the general population. In considering the studies that reported lower rates, Lansky et al. (52) utilized predefined criteria for the diagnosis of major depression, and the sample included ambulatory patients with good physical performance status. Colon et al. (12) evaluated acute leukemia patients prior to allogenic bone marrow transplantation. Although this study did find that depressed mood appeared to independently affect outcome, this particular patient group was different from all other studies in that they were studied prior to receiving a bone marrow transplant, a potentially curative procedure. Peck and Boland (69) report the highest percentage of depressive symptoms in their postradiation radiotherapy outpatients. This early study used a semistructured interview for diagnostic assessment rather than a self- or observer-rated interview. Further, this study included a variety of cancer types and stages.

Of those studies that have specifically looked at cancer sites, pancreatic cancer remains the type most associated with the highest prevalence of depression. In their study of 46 inpatients with pancreatic cancer, Fras et al. (32) found a 50% rate of depression in pancreatic cancer patients compared to 13% in patients with colon cancer. Similarly, Joffe et al. (43) found in their study of 12 pancreatic cancer patients that 50% of the sample met criteria for major depression compared to 11% of their comparison group with gastric cancer. Holland et al. (41), in their study of 218 patients with pancreatic and gastric cancer, found by using the Profile of Mood States that depressive symptoms, as well as disturbance of fatigue, tension-anxiety, and confusion-bewilderment, were significantly more prevalent in patients with pancreatic cancer. Our preliminary data support a high prevalence rate of major depression in pancreatic cancer patients compared to patients with gastric or esophageal cancer (Nemeroff et al., unpublished data). A number of investigators have studied depressive symptoms in patients with head and neck cancer. This population also seems to represent a clinical sample in which depression is of primary concern. Both Morton et al. (59) and Baile et al. (2) found a 40% rate of depression in their outpatient populations with oropharyngeal cancer.

Psychiatric Consultation Studies

Further insight into the role of depression in patients with cancer can be ascertained by reviewing those studies classified as psychiatric consultation studies. These investigations represent studies of cancer patients referred to psychiatrists for consultation for a variety of reasons (Table 3). The five studies in the literature all represent patient samples in which the cancers are of various types, and all studies use a variety of clinical interviews. Hinton (40) found that 58% of patient referrals met criteria for major depression and 42% of these patients were specifically referred for the purpose of evaluating depression. Similarly, Levine et al. (53) found that 56% of their inpatient referrals met criteria for major depression. Massie et al. (57) found that 49% of their patient sample met criteria for either major depression or adjustment disorder. In the largest reported study, of 546 patient referrals, Massie and Holland (58) found that 20% of their referral sample met criteria for major depression and 27% met criteria for adjustment disorder. Of their total patient sample, 59% were referred for evaluation of depression. In the most recent consultation study, Razavi et al. (77) reported that in their sample of 88 inpatient referrals, 26% fulfilled criteria for major depression and 46% for an adjustment disorder. Although these reports represent biased samples in that all patients in the studies were referred for specific psychiatric evaluation, it is of importance that the rate of depression in these referrals ranges from 20% to 58% (excluding adjustment disorders) or 47% to 72% (including adjustment disorders), a significant rate of comorbid psychiatric impairment.

UTILITY OF BIOLOGICAL MARKERS IN THE DIAGNOSIS OF DEPRESSION

In the past decade, a number of biological alterations have been described in drug-free patients with depression (Table 4). These biological markers have potential as diagnostic adjuncts and in some cases to monitor treatment responses in patients with depression. Among the prevalence studies of depression in patients with cancer reviewed in Table 2, only two in the past 25 years have examined biological markers in this patient population. There is an important need for such tests in patients in whom the diagnosis of depression is confounded by neurovegetative symptoms sometimes attributed to manifestations of cancer. The two prevalence studies utilizing biological markers will be described in more detail in the following discussion.

The major biological markers under continued investigation include:

1. Neuroendocrine alterations such as increased activity of the hypothalamic-pituitary-adrenal (HPA) axis and abnormalities of the hypothalamic-pituitary-thyroid (HPT) axis,
2. Alterations in serotonergic neurotransmission,
3. Alterations in sleep architecture,
4. Structural brain abnormalities associated with mood disorders.

Neuroendocrine Alterations

It is now well established that HPA axis hyperactivity occurs in patients with major depression, especially those with melancholic and/or psychotic features (9,54,62,79). Predominant abnormalities of HPA dysfunction in these subtypes of depressed patients include hypercortisolemia, increased 24-hr urinary excretion of cortisol, resistance to suppression of cortisol by dexamethasone, a blunted adrenocorticotropic hormone (ACTH) response to corticotropin-releasing factor (CRF), and hypersecretion of CRF as evidenced by increased concentration of CRF in cerebrospinal fluid (CSF) of depressed patients (66). Recently Nemeroff and colleagues (66) documented adrenal gland enlargement in depressed patients to further document hyperactivity of the HPA axis. In their study of 38 patients with major depression, 12 were found to exhibit adrenal hypertrophy, thus providing support for the hypothesis that chronic ACTH hypersecretion associated with depression results in adrenocortical hypertrophy. They have postulated that adrenal gland enlargement may be a measure of cumulative lifetime depression. Krishnan et al. (49) recently reported findings of increased pituitary gland size as measured by magnetic resonance imaging (MRI) in a group of 20 depressed patients compared to controls, possibly due in part to CRF hypersecretion.

With regard to the literature on depression in cancer patients, the HPA axis has been studied by two groups of investigators. A sample consisting of 21 patients with pancreatic or gastric cancer was studied; rates of 50% and 11% of major depression were observed, respectively (43). Dexamethasone suppression tests (DST) were obtained in only a small subgroup of these patients. All six patients with pancreatic cancer exhibited DST nonsuppression (only one of the six had a diagnosis of major depression). Similarly, six patients with gastric cancer were tested and five of these six patients showed nonsuppression; however, none of these six patients had a diagnosis of major depression. These findings remain difficult to interpret because of the small sample size, lack of representation of depressed patients in the study sample, and absence of dexamethasone plasma measurements in the study.

In a study of 83 women with gynecological cancer, Evans et al. (22,24) administered the DST and found that 40% of the depressed patients exhibited DST nonsuppression. Moreover, many patients with a diagnosis of adjustment disorder with depressed mood also exhibited DST nonsuppression. This rate (40%) of nonsuppression is very similar to that observed by these investigators in depressed psychiatric inpatients (25). These preliminary results complement the clinical findings and suggest a similar neuroendocrine alteration in primary depression and depressed cancer patients.

Corticotropin-Releasing Factor

With further investigations of the HPA axis, it has become clear that CRF, the major physiological regulator of release of ACTH from the anterior pituitary gland, plays a major role in the pathophysiology of depression (66). It is hypothesized that CRF plays a preeminent role in the hypercortisolemia observed in patients with major depression. Further, the stress-diathesis model of major depression states that stress precipitates depressive episodes in genetically vulnerable individuals, and CRF is known to mediate the major physiological and behavioral responses to stress (67).

Thus, the central administration of CRF in laboratory animals produces a behavioral profile that is similar to that observed in stressed animals (64). These behaviors include reduced food consumption, diminished sexual behavior, sleep disruption, and alterations in locomotor activity similar to the neurovegetative symptoms of depression in humans. These studies lend further support to the hypothesis that CRF hypersecretion mediates both the endocrine alterations and certain of the signs and symptoms of depression.

There has now been a series of studies in which CSF/CRF concentrations have been measured in drug-free depressed patients (60). In general, depressed patients exhibit elevated CSF/CRF concentrations when compared to nondepressed psychiatric patients, as well as normal controls. Nemeroff and colleagues (63) have shown that following electroconvulsive therapy (ECT) depressed patients who had pre-ECT elevated CSF/CRF concentrations exhibited reductions after treatment and clinical recovery. These findings indicate that CSF/CRF concentrations in depressed patients may represent a state, rather than a trait, marker.

HPT Axis Alterations

Like the HPA axis, the HPT axis has been extensively studied to ascertain its role in the biology of mood disorders. Prange et al. (72) first reported that approximately 25% of patients with major depression and normal baseline plasma concentrations of thyroid-stimulating hormone (TSH) and thyroid hormones exhibit a blunted TSH response after exogenous administration of thyrotropin-releasing hormone (TRH). This finding has been widely replicated and has resulted in the use of the TRH stimulation test in identifying some populations of depressed patients. In this test, a fixed dose of TRH is administered intravenously, usually in the morning, and blood samples for TSH assay are obtained every 30 min over a 2- to 3-hr period.

Only one study that has examined depression in cancer patients has utilized the TRH stimulation test. Evans and colleagues (24) administered the TRH stimulation test and found that there was a blunted response in 29% of those patients with a diagnosis of major depression and a blunted response in 43% of those patients who had a diagnosis of adjustment disorder with depressed mood. This rate of TSH blunting in cancer patients with major depression is similar to the 25% rate observed in primary major depression.

The mechanism underlying this endocrinopathy remains elusive. Kirkegaard et al. (47) reported that, when compared to controls, drug-free depressed patients have increased CSF concentrations of TRH. Similarly, Banki and colleagues (3) found that depressed patients exhibited an almost threefold increase in CSF/TRH concentrations compared to controls. These findings lend support to the hypothesis that certain TRH-containing neurons hypersecrete TRH in depression; this may contribute to the pituitary gland enlargement noted above.

In contrast to the blunted TSH response to TRH in depressed patients noted earlier, some depressed patients have been found to exhibit an exaggerated TSH response. Gold and Pearsall (34) studied this subpopulation and concluded that this group largely represents patients with grade-III hypothyroidism. Nemeroff et al. (67) confirmed and extended these observations, finding that 20% of 45 consecutively admitted psychiatric inpatients with prominent depressive symptoms had evidence of symptomless autoimmune thyroiditis. In a further study, Haggerty et al. (37) determined the relationship between DST nonsuppression and symptomless autoimmune thyroiditis. These investigators found a higher incidence of symptomless autoimmune thyroiditis in depressed patients with abnormal DST results. These findings of abnormalities of the HPT axis in depression warrant further scrutiny of the HPT axis in depression, particularly in those patients with comorbid medical illness.

Somatostatin

Somatostatin (SRIF) is known to inhibit the secretion of growth hormone, as well as the release of TSH, prolactin, cholecystokinin, vasoactive-intestinal peptide, and glycogen. Gerner and Yamada (33) reported reduced CSF concentrations of SRIF in patients with major depression when compared to controls. Further studies have universally confirmed these findings. Doran et al. (21) measured CSF/SRIF concentrations in patients with schizophrenia and depression who also had had a DST. These investigators found that patients who exhibited DST nonsuppression also exhibited lower CSF/SRIF concentrations, and CSF/SRIF concentrations were negatively correlated with the maximal post-DST plasma cortisol concentrations. There appears to be a relationship between low CSF/SRIF levels and increased activity of the HPA axis. These findings are of interest because SRIF inhibits ACTH secretion from the anterior pituitary. Unfortunately, studies have not correlated CSF/SRIF concentrations with severity of depression; however, some investigators have postulated a role of reduced SRIF synaptic availability in the cognitive dysfunction associated with a variety of neuropsychiatric disorders, including depression (13).

Serotonergic Neurotransmission

The involvement of serotonergic neurotransmission in mood disorders has been postulated by a number of investigators. This area of interest is based largely on early measurements of decreased concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the CSF of depressed patients (87). Further, there is now widespread evidence provided by clinical studies that tricyclic antidepressants, monoamine oxidase inhibitors, and serotonin reuptake inhibitors all are effective antidepressants and increase the efficacy of serotonergic neurotransmission.

A number of investigators have confirmed the original observation by Langer and colleagues (51) of reductions in the number of platelet [³H]imipramine binding sites in drug-free depressed patients (6). Laboratory animal experiments have demonstrated that [³H]imipramine binds to presynaptic serotonergic nerve terminals in the CNS, with kinetic characteristics that are nearly identical to those found in platelets (5). Therefore, studies of the binding of [³H]imipramine to platelets in depressed patients were conducted. It is now known that the [³H]imipramine binding site is identical to the serotonin transporter site in platelets and neurons. Although there have been a few discordant reports, most investigators have reported significant reductions in the number of [³H]imipramine binding sites on platelets of depressed patients (68,75,76,86). In their study of geriatric depressed patients, Nemeroff and colleagues (65) found their depressed sample groups to exhibit significant reductions in the number (B_max) of platelet [³H]imipramine binding sites with, however, no change in affinity ( K _d) when compared to age-matched controls. Other investigators have reported a reduced number of [³H]imipramine binding sites in the cerebral cortex and hypothalamus of suicide victims when compared to controls (70,83).

Although there have been no studies to date examining the role of platelet [³H]imipramine binding in depressed patients with cancer, these findings of reduced platelet serotonin transporter sites suggest that this is a topic worthy of study. More recently [³H]paroxetine, a selective ligand for the serotonin (5-HT) transporter, has been utilized in these studies with similar results.

Sleep Architecture

The development of all-night electroencephalographic (EEG) recording methods has enabled investigators to objectively and precisely measure sleep disturbances in patients with a variety of mood disorders. Over the past 25 years, considerable attention has been devoted to the use of EEG sleep studies, both to more accurately quantify sleep disturbances and to look for abnormalities more specific to mood states. There are now commonly accepted and well-replicated EEG sleep characteristics for patients with depression that have utility as diagnostic adjuncts. A substantial body of research across diverse settings in patient populations has established the following four EEG sleep abnormalities commonly found in depressed patients: (i) shortened rapid eye movement (REM) latency, (ii) increased REM activity, (iii) reduced delta (slow wave) sleep time, and (iv) sleep continuity disturbances (50).

Buysse and Kupfer (8) warn that the appraisals of the utility of sleep studies may be affected by the competing needs of clinical and research studies and by focusing too narrowly on the diagnostic use of such studies, rather than on their wider clinical and research applications. They further comment, however, that sleep EEG studies are playing an increasingly important role in examining both clinical and theoretical aspects of the neurobiology of depression. Thus, sleep EEG measures at baseline and following the acute administration of tricyclic antidepressants may predict response to antidepressant treatment. Similarly, pretreatment REM latency may identify patients at risk for earlier and more frequent recurrences following successful psychotherapeutic treatment. There is also a potential role for sleep studies to be used to examine the familial and genetic aspects of depression with regard to recent studies suggesting that the REM sleep abnormalities of depressed patients may be found in their biological relatives as well (10). There are no sleep EEG studies of cancer patients with depression.

Structural Brain Abnormalities

Several investigators have now documented structural abnormalities in the CNS of depressed patients. Figiel et al. (31) have recently reviewed this topic in detail. A number of investigators have found enlarged lateral ventricular size, as well as enlarged third ventricles when utilizing both computed axial tomography as well as MRI. Generally, it appears that enlarged lateral ventricles are present in a subgroup of young affective disorder patients and are more consistently observed in older patients. Of those studies that have investigated the structure of the cerebellum in patients with mood disorders, the vast majority of studies to date suggest that the cerebellar vermis may be smaller in patients with mood disorders compared to controls. Similarly, studies that have examined the temporal lobes, caudate, and putamen have all revealed data consistent with decreased volume in patients with depression (31). In addition, a higher prevalence rate of subcortical and periventricular hyperintensities has been observed in depressed patients compared to controls, particularly in the elderly. Clearly, there is a diverse array of structural brain changes in patients with mood disorders. However, the significance of these observations in many cases remains undetermined, and the utility of these structural changes with regard to biological markers remains an important area of investigation. No studies of this kind have been conducted in depressed cancer patients.

TREATMENT OF DEPRESSION IN THE CANCER PATIENT

Antidepressant Medications

There is considerable evidence that depression is both underdiagnosed and inadequately treated in many patients with cancer (17,18,46). Antidepressant medications have been extensively used in depressed patients with medical illness (38), and empirical evidence has suggested that antidepressants are useful in treating depressed cancer patients (85). Although numerous publications address the need for psychosocial support and assistance with coping, the literature examining antidepressant treatment response is sparse.

Purohit and colleagues (73) first reported the efficacy of low-dose (75 mg/day) imipramine in a study of a small number of cancer patients. Two studies to date have prospectively evaluated antidepressant treatment response in depressed cancer patients. Costa et al. (14) studied the use of mianserin, a tetracyclic second-generation antidepressant unavailable in the United States, in a randomized, placebo-controlled trial of 73 depressed women with cancer. They found significant improvement in depressed mood in the treatment group compared to the placebo group. The report of Evans et al. (23) is the only published report that has attempted to assess the effects of antidepressant treatment on life adaptation in depressed cancer patients. These investigators studied a subset of their original 83 patients consecutively admitted to a gynecological tumor service for staging workup of their cancer. This naturalistic pilot study followed 22 depressed patients longitudinally for an average of 9 months following their initial evaluation and treatment. Of these 22 patients, 13 fulfilled DSM-III criteria for major depression; nine patients had significant depressive symptoms but did not meet full criteria. Satisfactory antidepressant treatment was defined as treatment with imipramine (or its equivalent) at doses of at least 150 mg per day for at least 4 weeks. Each patient was contacted at approximately monthly intervals following discharge from her initial hospitalization. Each patient was evaluated on the Hamilton Depression Rating Scale and on the Psychosocial Adjustment to Illness Scale. Within the course of this study, two comparison groups developed. One group received adequate treatment and one group either did not follow the recommendations for treatment or received inadequate treatment. The depressed patients who received adequate treatment demonstrated significant improvement in depression, as well as better life adaptation when compared to depressed cancer patients who remained untreated. Similarly, patients with depressive symptoms who did not fulfill criteria for major depression but received somatic treatment had levels of adaptation similar to those of treated patients with major depression. These preliminary findings suggest that cancer patients with major depression (and perhaps cancer patients with significant depressive symptoms) will benefit from antidepressant treatment and experience a better quality of life than depressed cancer patients who do not receive antidepressant treatment or who receive inadequate treatment.

Studies evaluating the role of newer antidepressant agents such as fluoxetine, sertraline, and buproprion are clearly needed. Because of fewer potential side effects, these agents may offer significant treatment advantages. Similarly, controlled studies that examine the primary or adjunctive use of psychostimulants in depressed cancer patients are needed. Psychostimulants have proven useful in treating some depressed patients with medical illness (89). Finally, electroconvulsive shock therapy remains a viable treatment option for many patients with comorbid depression and medical illness including cancer.

Psychosocial Interventions

There has been a growing interest in the use of psychosocial treatments not only to assist patients in coping with cancer, but also to perhaps extend survival time among certain cancer patients. A number of therapeutic interventions including individual psychotherapy, group psychotherapy, psychoanalysis, hypnosis, guided imagery, education, relaxation training, and self-help groups have been implemented to deal with the psychological reactions of patients with cancer (4,29,35,42,56,90). However, the literature remains largely descriptive, and few studies have investigated long-term effectiveness. There are three randomized prospective trials of psychosocial treatment; two of these studies utilized group intervention.

Spiegel and colleagues (80-82) showed that 50 women with metastatic breast cancer randomly assigned to a year of weekly support groups with training in self-hypnosis for pain control survived an average of 18 months longer than 36 control patients randomly assigned to routine care. Richardson et al. (78) utilized a four-cell design in studying patients with lymphomas and leukemias. These investigators assigned patients either to a routine care condition or to one of three educational in-home visiting supportive interventions. The control group had significantly shorter survival time than patients allocated to the intervention. There were also differences in patients' compliance with medical treatment. These survival differences remained significant even when differences in medication compliance were controlled.

Recently, Fawzy et al. (27,28) utilized a series of six weekly structured support groups to assess the psychosocial and immunological benefits when treating patients with malignant melanoma. Half of the patients were assigned to routine care, and the other half to weekly support groups designed to facilitate better coping with cancer. These investigators found significant reductions in mood disturbance on the Profile of Mood States and the use of more active coping strategies in the intervention sample. They further found differences in immune function at 3-month follow-up, but not earlier. They specifically found a significant increase in the percentage of large granular lymphocytes and natural killer cells, along with indications of an increase in natural killer cytotoxic activity. A small decrease in the percentage of CD-4 (helper/inducer) T cells was also documented.

Current research in this area is attempting to continue to study the effects of psychosocial support on survival time in various types of cancer. Studies similar to those of Spiegel et al. and Fawzy et al. are currently being expanded to involve multicenter patient sampling.

UTURE RESEARCH IMPLICATIONS

Appropriate diagnosis and management of depression are integral components in the overall treatment of patients with cancer. Although the best method of diagnosing depression in cancer patients remains somewhat controversial, a review of prevalence studies clearly documents that the rate of depression in cancer patients is significantly higher than in the general population. Particularly for some cancer types such as pancreatic cancer and tumors of the head and neck, rates of depression appear to far exceed those for other types of cancer. As more data become available, the use of biological markers such as neuroendocrine alterations, alterations in serotonergic neurotransmission, abnormalities of sleep architecture, and brain structure abnormalities may be of more use both in diagnosing depression and determining treatment response in depressed cancer patients. The studies by Evans et al. (23) and Costa et al. (14) are important in that they provide clear evidence that cancer patients with major depression, and perhaps cancer patients with minor depression, benefit from antidepressant medication treatment and experience a better quality of life than untreated depressed cancer patients. Further, those studies that have examined the effectiveness of prospective group interventions offer great optimism, not just in facilitating coping and reducing mood disturbance, but in potentially increasing survival. This phenomenon may in part be due to the reductions in immune function in depressed patients reported by several investigators.

Far more research is needed in this exciting area of psycho-oncology. Future studies must continue to strive for a standardized method of diagnosis, further evaluating the role of biological markers. Such parameters as age, sex, hospitalization status, tumor site, tumor stage, time since knowledge of diagnosis, pain, previous psychiatric history, vulnerability to mood disorders, and measures of immune status must be incorporated in future studies. To more adequately assess treatment responses, double-blind studies with larger sample sizes are needed. Larger investigations to study the effects of psychosocial interventions on survival time must continue to examine possible mechanisms that might mediate such effects, particularly the psychoneuroimmune pathway. What becomes clear in reviewing the role of depression in cancer patients is that a true biopsychosocial approach to treatment is an important addition to the standard biomedical treatment from both a psychological and physiological perspective.

ACKNOWLEDGMENT

The authors' research is supported by National Institute of Mental Health grants MH-46791 and MH-42088.

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