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Psychological depression and cancer
Psychological Depression and Cancer* Linas A. Bieliauskas, Ph.D. and David C. Garron, Ph.D. Rush-Presbyterian-St.
Luke‘s Medical Center, Chicago, lllinois
Abstract: Studies are reviewed which relate to five basic content areas of research concerning depression and cancer: significant loss experience, emotional inhibition, hopelessness, psychiatric assessment of depression, and test measurement of depression. Methodological issues within each area are addressed as they relate to the potential validity and generalizability of findings. In general, there is no support for increased loss experience in cancer patients and mild support for increased emotional inhibition and hopelessness in these individuals. Traditional psychiatric assessment approaches are not seen as providing solid evidencefor a depression/cancer relationship due to reliability and design issues, while psychometric assessment provides mild support for a prospective relationship between depression and later cancer. Issues relating to approaches to research, means of measurement of depression, design issues, and questions of conceptualization of depression are discussed.
Depression has been linked to the occurrence of cancer through anecdotal and scientific reports for a number of years (l-3). Nevertheless, empirical support for either an increased prevalence of depression in cancer patients or an increased prevalenc& or incidence of cancer in depressed individuals has proved to be only suggestive. Difficulties in assessing any relationship between psychological factors and cancer are considerable, and there are excellent reviews treating the issues (l/3). However, the widespread indictment of depression as either a concomitant or premorbid factor in cancer necessitates a comprehensive examination of conceptual and methodological questions. This report provides a critical review of the research on depression and cancer, expanding on earlier general critical issues and including more recent investigations. Specific goals are to provide a *This research was supported in part by grant CA-22536 from the National Cancer Institute. general HospitalPsychiatry 4, 187-195, 1982 0 Elsevier North Holland, Inc., 1982 52 Vanderbilt Avenue, New York, NY 10017
brief review of significant loss experience, inhibition of emotion, hopelessness, clinical psychiatric depression, and psychometrically assessed depression. In addition, we will attempt to clarify the current status of general knowledge about depression and cancer, and discuss implications for future depression and cancer research. The effect of depression on adaptation or survival in cancer patients will not be discussed, since recent reviews are available (4-6).
Content Categories Since depression is by no means a uniformly defined concept (7), measures of it depend on the investigator’s viewpoint. In cancer research, approaches to depression can generally be classified as either indirect or direct. The former is derived from the notion of depression as resulting from loss of a significant emotional relationship, an intemalization of anger tied to the loss of that relationship, and a lack of investment in the environment (8-9). Related research efforts have tried to identify significant losses, a lack of emotional expressiveness, and a sense of hopelessness in cancer patients. The direct approach, on the other hand, is primarily concerned with documentation of various signs and symptoms of depression (10) without reference to etiology or theoretical considerations. This approach has generally investigated depression by using psychiatric criteria or standardized test procedures. Significant
Loss
Green and his co-workers (ll-14), and LeShan and Worthington (15) have reported that loss of a major emotional relationship, including death of a relative or occupational loss, precedes cancer by periods 187 ISSN OKi-8343/82/030187-09/$2.50
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and D. C. Garron
ranging from several days to eight years. While provocative, these case-control studies have a number of difficulties. Patient selection procedures include cancers of mixed sites, types, and stages, confounding different etiological considerations and course of disease (1). The sex, education, and social class of patients are seldom accounted for (1, 3) even though they may be independently related to incidence of significant loss (16). There are difficulties with subject selection in control groups, or a failure to provide any control groups (3). As mentioned by others (1, 3), these studies used either interview data or semistructured questionnaires to assess loss, and data gathering was not blind to patient or control subject status. Thus, a reliable, standard set of questions was not asked and there was no objective definition of significant loss. Muslin et al. (17) conducted a study of significant loss in cancer patients which attended to major design and methodology considerations. They used a standard questionnaire to examine 165 consecutive female patients admitted for breast biopsy. This questionnaire named all first-degree relatives and close friends and documented permanent separations from them during the first nine years of the patient’s life and the last three years preceding biopsy. After diagnosis and surgery, 37 pairs of subjects were matched for age and education, one member of each pair having a biopsy showing malignancy and the other showing a benign growth. Loss was defined as “the permanent loss of a firstdegree relative or other person whom the subject stated was emotionally important to her.” These data were analyzed independently by two psychiatrists, who had no information about subject assignment. They found no significant differences in loss experience between patients with malignant versus benign biopsy results. Questions might be raised about the limited range of loss experience documented, and the restricted time intervals for which loss was measured, but Muslin et al. (17) clearly addressed themselves to selection procedures, blind assessment, standard measures, and objective definition of significant loss. Their negative results, in conjunction with weaknesses in studies reporting increased prevalence of significant loss in cancer patients, suggest that there is no firm basis on which to postulate such a relationship.
Emotional Inhibition A second class of indirect studies investigated the hypothesis that internalization of anger, man188
ifested by an inhibition of emotions or absence of affectively related activities, has an increased prevalence in cancer patients. Kissen and his co-workers (18-22) consistently found that lung cancer patients averaged significantly lower on measures of emotional expression than other chest disease and nonchest-disease patient controls. The case-control design of these studies minimized possible bias, controlling site and stage of disease, and patients were evaluated before final diagnosis was made. Fox (1) nevertheless, has questioned the actual ability to control patient knowledge of probable diagnosis, the possibility of confounding effects of smoking behavior, and the validity of the measures used by Kissen and his colleagues to assess emotional expressivity [the “neuroticism” scale of the Maudsley Personality Inventory (MPI) (23) and the Eysenck Personality Inventory (EPI) (24)]. Kissen defined the “neuroticism” factor as an index of emotional lability and overresponsivity; lower scores on this factor were interpreted as a lessened ability to discharge emotion. However, the “neuroticism” factor was developed to detect “emotionally overresponsive” individuals with high scores and “better adjusted and emotionally stable” individuals with lower scores (25). Kissen’s cancer patients, therefore might be described as better adjusted than other patients, or the test results might reflect a desire to look good to the experimenter (1). Nevertheless, the consistency of Kissen’s findings and his careful design suggest that some systematic differences were being detected. Greer and Morris (26) also used the EPI to evaluate women admitted consecutively for breast biopsy prior to operation. Women who later proved to have cancer did not differ significantly in terms of marital or social status or intelligence test scores from those with benign breast disease. In contrast to Kissen’s findings, Greer and Morris did not find significant differences between their groups on any EPI factor, including “neuroticism,” though they did find differences between groups in the number of times they openly displayed anger or other feelings during their adult lives. On this latter measure, which was assessed by interview independent of the EPI, cancer patients were categorized as both more often and less often expressing anger than benign breast disease patients. They concluded that cancer patients demonstrated an abnormal release of emotions, in most cases an extreme suppression of anger. Kissen and his co-workers examined only men and Greer and Morris only women; site of disease also differed between studies. The latter also evaluated a small number of cancer patients (61
Psychological
as compared to 214), and their patients likely also had a better sense of general well-being than would be expected in chest-disease patients. These differences may account for the discrepancies in EPI scores between studies, though there remains a question about the actual validity of EPI factors (25). The other measures employed by Greer and Morris are also somewhat questionable in that reports of expression of feelings are necessarily subjective and difficult to compare. However, both sets of studies used careful case-control designs, and suggest a decreased emotional responsivity in cancer patients. There are several additional case-control studies which report increased emotional inhibition in cancer patients (27-30) but these have selection, measurement, or design difficulties described elsewhere (l), making their results questionable. Particular mention should be made of a Swedish study by Hagnell (31) using a prospective design to evaluate cancer incidence. Ten years after the gathering of personality data, 20 men and 22 women of 2,550 subjects had cancer. Of importance to this review is a dimension designated as “stability” (32). The higher an individual rated on this factor the less he was emotionally affected by events, and the more cool and stable his mood; while the lower he was on this factor, the more intense was his affective tone and potential for dysthymic (mild depressive) reactions. Hagnell found a significantly greater proportion of cancer in women who had low ratings on the stability factor, while no differences in cancer incidence were found for men. Prospectively, therefore, Hagnell reports that women with greater emotional reactions have increased cancer incidence. These results are provocative because of the prospective design, but the differences by sex are difficult to explain and relate to other case-control studies. In addition, the nature of the measurements and calculations of incidence rates in Hagnell’s study is questionnable (1). Most studies evaluating emotional inhibition in cancer patients, therefore, report a positive relationship. A generally sound design in several studies and the quantity of research suggest moderate support for the notion that cancer patients tend to be less responsive emotionally than patients with other diseases or healthy controls, Any prospective relationship between emotional expression and cancer remains unproven. Hopelessness A third major area of indirect research concerns the prevalence of hopelessness and despair in cancer
Depression
and Cancer
patients compared to various control groups. Greene (13) described leukemia and lymphoma patient samples as hopeless about psychosocial losses, though difficulty with the interpretation of the results has been discussed earlier. In a careful investigation, Schmale and Iker (33, 34) evaluated 60 women referred for biopsy because of abnormal cervical cytology and predicted positive biopsies through knowledge of recently expressed hopelessness as assessed by admission interview. They predicted true positives in eight of 14 women, and the absence of malignancy in 23 of 46 women. This study is impressive in its case selection procedures, that is, single disease site, relatively similar extent of disease, and blind assessment. However, the authors did not use standard interviews to gather their data (to ensure all patients were asked the same questions) and although a general description of what was regarded as hopelessness was given, criteria for defining hopelessness were not identified objectively; the findings of Schamale and Iker are thus difficult to generalize. Before the results can be regarded as firm, they need to be replicated using standard techniques and objective criteria. Thomas and co-workers (35-37) used prospective data to examine psychological predecessors of five disease states: suicide, mental illness, hypertension, coronary heart disease, and tumor. Questionnaire data were gathered on 1130 white male graduating medical students between 1946 and 1964; incidence of disease was eventually assessed through 1978. The results are viewed as supporting a hypothesis of damaging emotional life history patterns leading to feelings of isolation and hopelessness and despair in both cancer and suicidal patients. Though the prospective approach employed by Thomas et al. is impressive, the measures used (questionnaires which were not well validated), the relatively small subjects/variable ratio, and use of case-control data analyses with a prospective design (1) prevent confidence in any interpretation of the results as being strongly supportive of hopelessness as a predecessor of cancer. In summary, there is support for increased hopelessness in cancer patients, though it is weak and requires considerable verification before it can be accepted. Psychiatrically
Assessed Depression
Though all clinicians do not agree about all characteristics of depression, there are (38) research criteria established which are generally in agreement with the clinical descriptions provided by Beck (39) 189
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and Becker (40). Unfortunately, such explicit criteria have seldom been applied in depression/cancer research. Large clinical studies using psychiatric criteria to assess depression generally report its presence in a majority of cancer patients (3,40-43). However, interview structure and diagnostic criteria are poorly specified, control samples are often lacking or inadequate, and statistical analyses are suspect (3). Such factors prevent these studies from providing convincing evidence of increased prevalence of depression among cancer patients. Psychiatric criteria have also been used prospectively to assess depression in groups of subjects in which an attempt has been made to assess cancer incidence. Kerr et al. (44) conducted a four-year followup of 135 psychiatric admissions in Newcastle-upon-Tyne during 1963-1965 who had been diagnosed as evidencing anxiety or depression. Five of 28 depressed males died of cancer during the followup period: none of the 28 depressed females or any anxious patients died of cancer. The incidence of cancer among depressed males was significantly greater (P < ,001) than the 1965 British national death rates from cancer. However, there were small numbers of patients in each psychiatric group and there can be some question about the reliability of patient assignments to groups, this being done only by structured interview which attended primarily to mood changes without use of formal diagnostic criteria. Comparison of cancer mortality in such groups to general population figures is not justified because cancer risk factors (e.g., smoking, alcohol use, age) are not controlled. It is also likely that the use of psychiatrically depressed populations excludes consideration of individuals in the general population who may have depressive symptoms but who are not hospitalized. Similar studies of cancer incidence in large groups of psychiatrically depressed patients have not found any increase compared to the general population (45-46) * At this time, most case-control studies using psychiatric impression report an association between depression and cancer while prospective studies do not. However, design difficulties are such that neither an increased prevalence of depression among cancer patients nor an increased incidence of cancer among depressed patients has been demonstrated.
Psychometrically Assessed Depression An alternative to clinical assessment of depression in cancer patients has been the use of standardized
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measures. The advantages include use of a standardized questionnaire, often with reliability and validity data available for response, and easily quantifiable results. The Minnesota Multiphasic Personality Inventory (MMPI) (47) includes a clinical scale for measurement of depression which covers a range of obvious and subtle signs and symptoms (48,49). Blumberg et al. (50), in an early use of the MMPI, reported differences in depression between patients with “fast” versus “slow” growing tumors. However, others found major methodological and statistical flaws in their study, invalidating the findings (51, 52). Schmale and Iker (33) suggested that the MMPI depression scale was elevated in a group of females later found to have malignant cell changes following cervical biopsy when compared to those who had negative biopsies; however, the difference was not significant (P < .09). A more recent study by Koenig et al. (53) reported that patients with incurable intestinal cancer did not differ from a group of tuberculosis patients, and were lower than a group of psychiatric patients on the MMPI depression scale. The lack of specified selection procedures for stage of disease, age, education, or socioeconomic status, however, prevents conclusive interpretation. Watson and Schuld (52) used a prospective approach to assess differences in MMPI scores in a group of psychiatric patients with either malignant or benign tumors diagnosed at least two years posttest; another control group consisted of psychiatric admissions who were within five years of age of the neoplasm subjects but who had no evidence of tumor. Twenty-one pairs of malignant/control and benign/control subjects were selected; tumor diagnosis included varied sites, types, and stages for both cancer and benign groups. The authors found no significant differences between tumor and control groups on any of the MMPI scales, including depression. KeIIerman (54) has questioned the Watson and Schuld findings because they employed psychiatric patients, whose personality characteristics might be expected to obscure any relationships between MMM scores and other factors. The Watson and Schuld study was also limited to a two-year prospective period, a questionably effective time interval since many cancers are known to have extended incubation periods (1). More recently, Shekelle and his co-workers (55) conducted a prospective analysis of incidence of mortality from cancer in a population of 2020 men in whom depression had been measured 17 years earlier using the MMPI. Risk of death from cancer
PsychologicalDepression and Cancer
in the groups scoring highest on the depression scale was approximately twice that for those who did not score highest on this scale (see Table 1). This risk was constant at l-5, 6-11, and 12-17 years following measurement of depression (Table 2) and it was not affected when known risk factors of smoking, alcohol use, and age were controlled. Because of the prospective nature, the long period, the use of quantitative measures, attention to other risk factors, and the large number of subjects, this study provides significant evidence of prospective increase in risk of cancer death with increased depression. This study also presents data which may explain some difficulties of other studies in finding relationships between cancer and depression. Even though high scores on the MMPI depression scale were associated with increased mortality from cancer, Shekelle et al. (55) found that the absolute scale scores were not in the pathological range of scaled scores (pathological range T score = 70; depression scale scores for subjects with cancer death, mean T score = 60.7). We have made a recent analysis of the data utilizing a formula developed by Mezzich et al. (56) to discriminate simple pathological depression from nondepressive states using the entire MMPI. There was no increase in risk of cancer death using this formula for depression (Table 3). Thus, while increased depression did increase risk of death from cancer, that depression was not necessarily in the pathological range. Psychiatric criteria for depression may therefore not be entirely applicable to cancer research At this time, these data do not address the issue of cancer morbidity, the next important step in extending these results, and the test subjects indude a variety of types of sites of cancer. in general, there is some support for a prospective relationship between cancer and depression as measured by the MMPI, but extension and replication will be necessary before they can be regarded as established.
Another standardized instrument used to measure depression in cancer research is the Beck Depression Inventory (BDI) (57). This test questions the patient about the degree of depression-related symptomatology. Plumb and Holland (58) found no differences on BDI scores between a group of consecutively hospitalized cancer patients (mixed site, type, and stage of disease) and their next of kin. In addition, the authors found the cancer patients to have significantly lower BDI scores than a group of physically healthy patients hospitalized for suicide attempts. Lieber et al. (59) also found no difference on BDI scores between patients receiving chemotherapy for advanced cancer of various types and stages and their spouses. In both studies, the BDI scores of the cancer patients were not in the pathological ranges, consistent with Shekelle et al (55). In the BDI studies, there is some question about the comparison between cancer patients and next of kin on personality measures since both might be presumed to be experiencing considerable distress at hospitalization. However, use of the BDI in cancer patients has not generally supported increased depression as a characteristic feature. The Hamilton Rating Scale (60), another measure of depression, was used by Greer and .Morris (26) in their study of patients with positive and negative biopsies for breast cancer. Depression ratings were
Table 1. Percentage mortality, 1958-1974
Table 3. Percentage cancer mortality 1958-74
1958 MMPI
high-point scale
Depression
Other Total
Odds ratio P
Number at risk 379 1641 2020
Cancer deaths @) 7.1 3.4 4.1 2.2 0.001
Other deaths PJ) 16.4 13.2 13.8 1.3 0.104
Table 2. Odds of death associated with 1958 MMPI high-point D Year of death
Cancer death
Other death
1958-1962 1963-1968 1969-1974 Total
2.2 2.6 2.0 2.2
1.7 1.8 0.9 1.3
1958 Mezzich cutoff score Depression Other Total Odds ratio
Number at risk 453 1507 2020
Cancer deaths (%) 5.07 3.83 4.11 1.33
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generally low for both cancer patients and controls. However, the Hamilton scale may not be an appropriate measure of depression in a cancer population since it was developed for use in hospitalized psychiatric inpatients, and it is primarily sensitive to depressive symptomatology of degrees not commonly seen outside of such settings. At this time, the Greer and Morris findings must therefore be cautiously interpreted. Overall, standardized tests do not support increased depression in patients with cancer, though there is some evidence that a nonpathological increase in depression symptomatology may be prospectively related to mortality from cancer. However, in many of these studies, selection procedures have not controlled for disease and demographic characteristics, thus preventing conculsive interpretations.
Current Status and Discussion The following points characterize the current status of knowledge regarding depression and cancer: (a) There is no evidence that cancer patients have an increased experience of emotional loss prior to their disease, while there is some support for increased emotional inhibition and hopelessness in patients who already have cancer: (b) There is no solid evidence that cancer patients have increased depression in a psychiatric sense when compared to other patients, relatives, or normal control groups: (c) Psychometric assessment of depression also does not indicate increased prevalence of pathologic depression in cancer patients, though there is some suggestion that mild elevations in depressive symptomatology may be prospectively related to cancer incidence. Several issues regarding the research and interpretation of evidence relating to depression and cancer have emerged. First, indirect approaches to measurement of depression have been contrasted with more direct symptomatic assessment approaches. In general, the indirect method is justified if the theoretical relationships on which it is based are valid and if effective measures of the variables are available. Unfortunately, there is some question about the relationship of variables such as emotional loss and emotional inhibition to depression. Akiskal and McKinney (7), for instance, conclude that separation from others and inhibition of anger need not be increased in depression. Hopelessness is often described as a symptom of depression, however, and may be a more direct
measure than an indirect one. Beyond these difficulties, the criteria for assessing variables such as loss, emotional inhibition, and hopelessness are not agreed upon or standardized, and are difficult to compare among studies. These theoretical and practical considerations make it unlikely that indirect approaches to future research in depression and cancer will be fruitful. The more direct approaches to measuring psychological depression in cancer patients generally involve either clinical psychiatric criteria or objective psychometric testing. Though purely clinical studies are among the most common in testifying to increased depression in cancer patients, they have been plagued by design and methodological difficulties. At present, there is no clear evidence that cancer patients are more depressed in a clinical psychiatric sense than anyone else. The use of standardized tests, the other direct approach to assessment of depression in cancer, has raised hopes that quantifiable measures would answer specific questions about any relationship between depression and cancer. While such studies have generally been superior to more inferential approaches, there have been methodological questions raised in traditional areas of difficulty, such as subject selection procedures. Comparisons between cancer patients and other subject groups have not supported an increased depression in individuals with cancer. However, a recent prospective study has suggested an increased risk for mortality from cancer in subjects scoring higher on the MMPI depression scale than those who do not (55). Further research, including data on cancer morbidity will be necessary before full implications for any relationship between depression and cancer can be realized. In general, psychometrically-based studies of depression offer the best opportunity to elucidate the depression/cancer relationship because of standardization of measurement, resultant comparability between studies or over time with the same subjects, objective definitions of depression, and easy quantification. A second issue discussed was the difference in approach to experimental design exemplified by case-control versus cohort studies. Fox (1) strongly supports the latter because of its inherent control advantages and freedom from bias in investigations of prospective issues. However, case-control studies are appropriate if one wishes to learn about the relationship between depression and cancer during acute stages of the cancer process. This would have implications for how a patient is best treated from a
Psychological Depression and Cancer
psychological standpoint, how quality of life is conceptualized for a patient undergoing treatment for cancer, and even for compliance with medical regimen (61). While certain cancer patients may be significantly depressed, it is clear that the widespread notion that cancer patients are generally depressed is not supported by the evidence. Continued casecontrol studies would be in order to further evaluate issues relating to depression or other psychological reactions in cancer patients. Cohort studies, on the other hand, are designed to evaluate the risk status for cancer incidence which may be affected by depression (1); this is a question that case-control studies have difficulty answering because of the problem of inferring cause-effect relationships. Because cohort studies are prospective in nature, they require large numbers of subjects and lengthy followup of the subjects, resulting in high cost. Consequently, in spite of the inherent advantages of such an approach, few such studies have been conducted. The studies by Thomas and her co-workers (35-37) and Shekelle and his colleagues (55) provide evidence linking depression to cancer prospectively. To establish an increased risk of cancer resulting from depression, it will be necessary to conduct prospective studies with different populations of subjects and with attention to disease sites and different types of cancer. Costs can be somewhat limited by studying populations at high risk for cancer (1). A caution in the conduct of prospective studies is suggested by the results of the work of Shekelle and co-workers (55) where relationships between depression and mortality from cancer were found to exist for periods as long as 17 years prior to death; any relationship between depression and cancer may be an extended one and not demonstrable in studies which look at acute depression or use short prospective periods. Another issue which deserves close attention has been raised by psychometric research. The study by Shekelle and colleagues (55) reports a positive premorbid relationship between depression and later mortality from cancer; this depression was not of pathological proportions, however, but rather simply an elevated characteristic when compared to other clinical measures. This finding suggests that cancer researchers should consider depression not solely as an either/or phenomenon but as a continuous variable, a view proposed by Hoch (62). The need for more extensive measures may explain why so much of the psychometrically
and psychiatrically based research on depression and cancer does not provide conclusive evidence: many studies are designed primarily to identify the presence or absence of pathological depression with inadequate attention to the broad range of depression-associated symptoms which may not necessarily be pathological. A test such as the MMPI addresses these issues as it measures the “depth’ of depression (63) as a continuous variable and measures many subtle depressive symptoms covering a wide range of behaviors (48). Instruments such as the MMPI depression scale should be included to ensure that significant relationships of mild or moderate depression to cancer are not neglected. A final general issue in this area of research is the need for attention to important methodological and design questions. These will not be belabored here, excellent reviews address them elsewhere (1,3,17). However, with the currently nebulous state of knowledge in this area, attention to subject and control selection procedures, use of judicious response measures, and appropriate data analyses must continue to be strongly encouraged. There is no reason to expect a relationship between depression and cancer to be as sturdy as that between cigarette smoking and cancer (cancer mortality ratios ranging from 10 to 30). The preponderance of anecdoctal evidence supporting a positive relationship between depression and cancer, suggestive prospective evidence of a possible relationship, and possible links between depression and constitutional changes which may be linked with cancer (1, 7) increase the likelihood that one is affected by the other. However, it seems clear that a relationship between depression and cancer, if it is present, is of a magnitude which cannot overcome design and methodology difficulties which have been present in much of this most interesting area of research. It is hoped that the issues highlighted in this review will be useful in its continuing exploration. Critiqueof this manuscript and suggesfions for its improvement from Richard B. Shekelle, Ph.D. are gratefully acknowledged.
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56. Mezzich JE, Damarin FL, Erickson JR: Comparative validity of strategies and indicies for differential diagnosis of depressive states from their psychiatric conditions using the MMPI. J. Consult Clin Psycho1 42:691-698, 1974 57. Beck AT, Ward CH, Mendelson M, et al: An inventory for measuring depression. Arch Gen Psychiat 4:561-571, 1961 58. Plumb MM, Holland J: Comparative studies of psychological functioning in patients with advanced cancer I. Self-reported depressive symptoms. Psychosom Med 393264-276, 1977 59. Leiber L, Plumb MM, Gerstenzang ML, Holland J: The communication of affection between cancer patients and their spouses. Psychosom Med 38: 379-389, 1976 60. Hamilton M: Development of a rating scale for primary depressive illness. Br J Sot Clin Psycho1 6:278-296, 1967 61. Freeman AM, Sack RL, Berger PA: Psychiatry for the primary care physician. Baltimore, Williams & Wilkins, 1979 62. Hoch PA: Differential diagnosis in clinical psychiatry. New York, Aronson, 1972 63. Endicott NA, Jortner S: Objective measures of depression. Arch Gen Psychiatr 15:249-255, 1966 Direct reprint requests to: Linas A. Bieliauskas, Ph.D. Department of Psychology and Social Sciences Rush-Presbyterian-St. Luke’s Medical Center 1753 West Congress Parkway Chicago, Illinois 60612
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Abstract: Studies are reviewed which relate to five basic content areas of research concerning depression and cancer: significant loss experience, emotional inhibition, hopelessness, psychiatric assessment of depression, and test measurement of depression. Methodological issues within each area are addressed as they relate to the potential validity and generalizability of findings. In general, there is no support for increased loss experience in cancer patients and mild support for increased emotional inhibition and hopelessness in these individuals. Traditional psychiatric assessment approaches are not seen as providing solid evidencefor a depression/cancer relationship due to reliability and design issues, while psychometric assessment provides mild support for a prospective relationship between depression and later cancer. Issues relating to approaches to research, means of measurement of depression, design issues, and questions of conceptualization of depression are discussed.
Depression has been linked to the occurrence of cancer through anecdotal and scientific reports for a number of years (l-3). Nevertheless, empirical support for either an increased prevalence of depression in cancer patients or an increased prevalenc& or incidence of cancer in depressed individuals has proved to be only suggestive. Difficulties in assessing any relationship between psychological factors and cancer are considerable, and there are excellent reviews treating the issues (l/3). However, the widespread indictment of depression as either a concomitant or premorbid factor in cancer necessitates a comprehensive examination of conceptual and methodological questions. This report provides a critical review of the research on depression and cancer, expanding on earlier general critical issues and including more recent investigations. Specific goals are to provide a *This research was supported in part by grant CA-22536 from the National Cancer Institute. general HospitalPsychiatry 4, 187-195, 1982 0 Elsevier North Holland, Inc., 1982 52 Vanderbilt Avenue, New York, NY 10017
brief review of significant loss experience, inhibition of emotion, hopelessness, clinical psychiatric depression, and psychometrically assessed depression. In addition, we will attempt to clarify the current status of general knowledge about depression and cancer, and discuss implications for future depression and cancer research. The effect of depression on adaptation or survival in cancer patients will not be discussed, since recent reviews are available (4-6).
Content Categories Since depression is by no means a uniformly defined concept (7), measures of it depend on the investigator’s viewpoint. In cancer research, approaches to depression can generally be classified as either indirect or direct. The former is derived from the notion of depression as resulting from loss of a significant emotional relationship, an intemalization of anger tied to the loss of that relationship, and a lack of investment in the environment (8-9). Related research efforts have tried to identify significant losses, a lack of emotional expressiveness, and a sense of hopelessness in cancer patients. The direct approach, on the other hand, is primarily concerned with documentation of various signs and symptoms of depression (10) without reference to etiology or theoretical considerations. This approach has generally investigated depression by using psychiatric criteria or standardized test procedures. Significant
Loss
Green and his co-workers (ll-14), and LeShan and Worthington (15) have reported that loss of a major emotional relationship, including death of a relative or occupational loss, precedes cancer by periods 187 ISSN OKi-8343/82/030187-09/$2.50
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and D. C. Garron
ranging from several days to eight years. While provocative, these case-control studies have a number of difficulties. Patient selection procedures include cancers of mixed sites, types, and stages, confounding different etiological considerations and course of disease (1). The sex, education, and social class of patients are seldom accounted for (1, 3) even though they may be independently related to incidence of significant loss (16). There are difficulties with subject selection in control groups, or a failure to provide any control groups (3). As mentioned by others (1, 3), these studies used either interview data or semistructured questionnaires to assess loss, and data gathering was not blind to patient or control subject status. Thus, a reliable, standard set of questions was not asked and there was no objective definition of significant loss. Muslin et al. (17) conducted a study of significant loss in cancer patients which attended to major design and methodology considerations. They used a standard questionnaire to examine 165 consecutive female patients admitted for breast biopsy. This questionnaire named all first-degree relatives and close friends and documented permanent separations from them during the first nine years of the patient’s life and the last three years preceding biopsy. After diagnosis and surgery, 37 pairs of subjects were matched for age and education, one member of each pair having a biopsy showing malignancy and the other showing a benign growth. Loss was defined as “the permanent loss of a firstdegree relative or other person whom the subject stated was emotionally important to her.” These data were analyzed independently by two psychiatrists, who had no information about subject assignment. They found no significant differences in loss experience between patients with malignant versus benign biopsy results. Questions might be raised about the limited range of loss experience documented, and the restricted time intervals for which loss was measured, but Muslin et al. (17) clearly addressed themselves to selection procedures, blind assessment, standard measures, and objective definition of significant loss. Their negative results, in conjunction with weaknesses in studies reporting increased prevalence of significant loss in cancer patients, suggest that there is no firm basis on which to postulate such a relationship.
Emotional Inhibition A second class of indirect studies investigated the hypothesis that internalization of anger, man188
ifested by an inhibition of emotions or absence of affectively related activities, has an increased prevalence in cancer patients. Kissen and his co-workers (18-22) consistently found that lung cancer patients averaged significantly lower on measures of emotional expression than other chest disease and nonchest-disease patient controls. The case-control design of these studies minimized possible bias, controlling site and stage of disease, and patients were evaluated before final diagnosis was made. Fox (1) nevertheless, has questioned the actual ability to control patient knowledge of probable diagnosis, the possibility of confounding effects of smoking behavior, and the validity of the measures used by Kissen and his colleagues to assess emotional expressivity [the “neuroticism” scale of the Maudsley Personality Inventory (MPI) (23) and the Eysenck Personality Inventory (EPI) (24)]. Kissen defined the “neuroticism” factor as an index of emotional lability and overresponsivity; lower scores on this factor were interpreted as a lessened ability to discharge emotion. However, the “neuroticism” factor was developed to detect “emotionally overresponsive” individuals with high scores and “better adjusted and emotionally stable” individuals with lower scores (25). Kissen’s cancer patients, therefore might be described as better adjusted than other patients, or the test results might reflect a desire to look good to the experimenter (1). Nevertheless, the consistency of Kissen’s findings and his careful design suggest that some systematic differences were being detected. Greer and Morris (26) also used the EPI to evaluate women admitted consecutively for breast biopsy prior to operation. Women who later proved to have cancer did not differ significantly in terms of marital or social status or intelligence test scores from those with benign breast disease. In contrast to Kissen’s findings, Greer and Morris did not find significant differences between their groups on any EPI factor, including “neuroticism,” though they did find differences between groups in the number of times they openly displayed anger or other feelings during their adult lives. On this latter measure, which was assessed by interview independent of the EPI, cancer patients were categorized as both more often and less often expressing anger than benign breast disease patients. They concluded that cancer patients demonstrated an abnormal release of emotions, in most cases an extreme suppression of anger. Kissen and his co-workers examined only men and Greer and Morris only women; site of disease also differed between studies. The latter also evaluated a small number of cancer patients (61
Psychological
as compared to 214), and their patients likely also had a better sense of general well-being than would be expected in chest-disease patients. These differences may account for the discrepancies in EPI scores between studies, though there remains a question about the actual validity of EPI factors (25). The other measures employed by Greer and Morris are also somewhat questionable in that reports of expression of feelings are necessarily subjective and difficult to compare. However, both sets of studies used careful case-control designs, and suggest a decreased emotional responsivity in cancer patients. There are several additional case-control studies which report increased emotional inhibition in cancer patients (27-30) but these have selection, measurement, or design difficulties described elsewhere (l), making their results questionable. Particular mention should be made of a Swedish study by Hagnell (31) using a prospective design to evaluate cancer incidence. Ten years after the gathering of personality data, 20 men and 22 women of 2,550 subjects had cancer. Of importance to this review is a dimension designated as “stability” (32). The higher an individual rated on this factor the less he was emotionally affected by events, and the more cool and stable his mood; while the lower he was on this factor, the more intense was his affective tone and potential for dysthymic (mild depressive) reactions. Hagnell found a significantly greater proportion of cancer in women who had low ratings on the stability factor, while no differences in cancer incidence were found for men. Prospectively, therefore, Hagnell reports that women with greater emotional reactions have increased cancer incidence. These results are provocative because of the prospective design, but the differences by sex are difficult to explain and relate to other case-control studies. In addition, the nature of the measurements and calculations of incidence rates in Hagnell’s study is questionnable (1). Most studies evaluating emotional inhibition in cancer patients, therefore, report a positive relationship. A generally sound design in several studies and the quantity of research suggest moderate support for the notion that cancer patients tend to be less responsive emotionally than patients with other diseases or healthy controls, Any prospective relationship between emotional expression and cancer remains unproven. Hopelessness A third major area of indirect research concerns the prevalence of hopelessness and despair in cancer
Depression
and Cancer
patients compared to various control groups. Greene (13) described leukemia and lymphoma patient samples as hopeless about psychosocial losses, though difficulty with the interpretation of the results has been discussed earlier. In a careful investigation, Schmale and Iker (33, 34) evaluated 60 women referred for biopsy because of abnormal cervical cytology and predicted positive biopsies through knowledge of recently expressed hopelessness as assessed by admission interview. They predicted true positives in eight of 14 women, and the absence of malignancy in 23 of 46 women. This study is impressive in its case selection procedures, that is, single disease site, relatively similar extent of disease, and blind assessment. However, the authors did not use standard interviews to gather their data (to ensure all patients were asked the same questions) and although a general description of what was regarded as hopelessness was given, criteria for defining hopelessness were not identified objectively; the findings of Schamale and Iker are thus difficult to generalize. Before the results can be regarded as firm, they need to be replicated using standard techniques and objective criteria. Thomas and co-workers (35-37) used prospective data to examine psychological predecessors of five disease states: suicide, mental illness, hypertension, coronary heart disease, and tumor. Questionnaire data were gathered on 1130 white male graduating medical students between 1946 and 1964; incidence of disease was eventually assessed through 1978. The results are viewed as supporting a hypothesis of damaging emotional life history patterns leading to feelings of isolation and hopelessness and despair in both cancer and suicidal patients. Though the prospective approach employed by Thomas et al. is impressive, the measures used (questionnaires which were not well validated), the relatively small subjects/variable ratio, and use of case-control data analyses with a prospective design (1) prevent confidence in any interpretation of the results as being strongly supportive of hopelessness as a predecessor of cancer. In summary, there is support for increased hopelessness in cancer patients, though it is weak and requires considerable verification before it can be accepted. Psychiatrically
Assessed Depression
Though all clinicians do not agree about all characteristics of depression, there are (38) research criteria established which are generally in agreement with the clinical descriptions provided by Beck (39) 189
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and Becker (40). Unfortunately, such explicit criteria have seldom been applied in depression/cancer research. Large clinical studies using psychiatric criteria to assess depression generally report its presence in a majority of cancer patients (3,40-43). However, interview structure and diagnostic criteria are poorly specified, control samples are often lacking or inadequate, and statistical analyses are suspect (3). Such factors prevent these studies from providing convincing evidence of increased prevalence of depression among cancer patients. Psychiatric criteria have also been used prospectively to assess depression in groups of subjects in which an attempt has been made to assess cancer incidence. Kerr et al. (44) conducted a four-year followup of 135 psychiatric admissions in Newcastle-upon-Tyne during 1963-1965 who had been diagnosed as evidencing anxiety or depression. Five of 28 depressed males died of cancer during the followup period: none of the 28 depressed females or any anxious patients died of cancer. The incidence of cancer among depressed males was significantly greater (P < ,001) than the 1965 British national death rates from cancer. However, there were small numbers of patients in each psychiatric group and there can be some question about the reliability of patient assignments to groups, this being done only by structured interview which attended primarily to mood changes without use of formal diagnostic criteria. Comparison of cancer mortality in such groups to general population figures is not justified because cancer risk factors (e.g., smoking, alcohol use, age) are not controlled. It is also likely that the use of psychiatrically depressed populations excludes consideration of individuals in the general population who may have depressive symptoms but who are not hospitalized. Similar studies of cancer incidence in large groups of psychiatrically depressed patients have not found any increase compared to the general population (45-46) * At this time, most case-control studies using psychiatric impression report an association between depression and cancer while prospective studies do not. However, design difficulties are such that neither an increased prevalence of depression among cancer patients nor an increased incidence of cancer among depressed patients has been demonstrated.
Psychometrically Assessed Depression An alternative to clinical assessment of depression in cancer patients has been the use of standardized
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measures. The advantages include use of a standardized questionnaire, often with reliability and validity data available for response, and easily quantifiable results. The Minnesota Multiphasic Personality Inventory (MMPI) (47) includes a clinical scale for measurement of depression which covers a range of obvious and subtle signs and symptoms (48,49). Blumberg et al. (50), in an early use of the MMPI, reported differences in depression between patients with “fast” versus “slow” growing tumors. However, others found major methodological and statistical flaws in their study, invalidating the findings (51, 52). Schmale and Iker (33) suggested that the MMPI depression scale was elevated in a group of females later found to have malignant cell changes following cervical biopsy when compared to those who had negative biopsies; however, the difference was not significant (P < .09). A more recent study by Koenig et al. (53) reported that patients with incurable intestinal cancer did not differ from a group of tuberculosis patients, and were lower than a group of psychiatric patients on the MMPI depression scale. The lack of specified selection procedures for stage of disease, age, education, or socioeconomic status, however, prevents conclusive interpretation. Watson and Schuld (52) used a prospective approach to assess differences in MMPI scores in a group of psychiatric patients with either malignant or benign tumors diagnosed at least two years posttest; another control group consisted of psychiatric admissions who were within five years of age of the neoplasm subjects but who had no evidence of tumor. Twenty-one pairs of malignant/control and benign/control subjects were selected; tumor diagnosis included varied sites, types, and stages for both cancer and benign groups. The authors found no significant differences between tumor and control groups on any of the MMPI scales, including depression. KeIIerman (54) has questioned the Watson and Schuld findings because they employed psychiatric patients, whose personality characteristics might be expected to obscure any relationships between MMM scores and other factors. The Watson and Schuld study was also limited to a two-year prospective period, a questionably effective time interval since many cancers are known to have extended incubation periods (1). More recently, Shekelle and his co-workers (55) conducted a prospective analysis of incidence of mortality from cancer in a population of 2020 men in whom depression had been measured 17 years earlier using the MMPI. Risk of death from cancer
PsychologicalDepression and Cancer
in the groups scoring highest on the depression scale was approximately twice that for those who did not score highest on this scale (see Table 1). This risk was constant at l-5, 6-11, and 12-17 years following measurement of depression (Table 2) and it was not affected when known risk factors of smoking, alcohol use, and age were controlled. Because of the prospective nature, the long period, the use of quantitative measures, attention to other risk factors, and the large number of subjects, this study provides significant evidence of prospective increase in risk of cancer death with increased depression. This study also presents data which may explain some difficulties of other studies in finding relationships between cancer and depression. Even though high scores on the MMPI depression scale were associated with increased mortality from cancer, Shekelle et al. (55) found that the absolute scale scores were not in the pathological range of scaled scores (pathological range T score = 70; depression scale scores for subjects with cancer death, mean T score = 60.7). We have made a recent analysis of the data utilizing a formula developed by Mezzich et al. (56) to discriminate simple pathological depression from nondepressive states using the entire MMPI. There was no increase in risk of cancer death using this formula for depression (Table 3). Thus, while increased depression did increase risk of death from cancer, that depression was not necessarily in the pathological range. Psychiatric criteria for depression may therefore not be entirely applicable to cancer research At this time, these data do not address the issue of cancer morbidity, the next important step in extending these results, and the test subjects indude a variety of types of sites of cancer. in general, there is some support for a prospective relationship between cancer and depression as measured by the MMPI, but extension and replication will be necessary before they can be regarded as established.
Another standardized instrument used to measure depression in cancer research is the Beck Depression Inventory (BDI) (57). This test questions the patient about the degree of depression-related symptomatology. Plumb and Holland (58) found no differences on BDI scores between a group of consecutively hospitalized cancer patients (mixed site, type, and stage of disease) and their next of kin. In addition, the authors found the cancer patients to have significantly lower BDI scores than a group of physically healthy patients hospitalized for suicide attempts. Lieber et al. (59) also found no difference on BDI scores between patients receiving chemotherapy for advanced cancer of various types and stages and their spouses. In both studies, the BDI scores of the cancer patients were not in the pathological ranges, consistent with Shekelle et al (55). In the BDI studies, there is some question about the comparison between cancer patients and next of kin on personality measures since both might be presumed to be experiencing considerable distress at hospitalization. However, use of the BDI in cancer patients has not generally supported increased depression as a characteristic feature. The Hamilton Rating Scale (60), another measure of depression, was used by Greer and .Morris (26) in their study of patients with positive and negative biopsies for breast cancer. Depression ratings were
Table 1. Percentage mortality, 1958-1974
Table 3. Percentage cancer mortality 1958-74
1958 MMPI
high-point scale
Depression
Other Total
Odds ratio P
Number at risk 379 1641 2020
Cancer deaths @) 7.1 3.4 4.1 2.2 0.001
Other deaths PJ) 16.4 13.2 13.8 1.3 0.104
Table 2. Odds of death associated with 1958 MMPI high-point D Year of death
Cancer death
Other death
1958-1962 1963-1968 1969-1974 Total
2.2 2.6 2.0 2.2
1.7 1.8 0.9 1.3
1958 Mezzich cutoff score Depression Other Total Odds ratio
Number at risk 453 1507 2020
Cancer deaths (%) 5.07 3.83 4.11 1.33
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generally low for both cancer patients and controls. However, the Hamilton scale may not be an appropriate measure of depression in a cancer population since it was developed for use in hospitalized psychiatric inpatients, and it is primarily sensitive to depressive symptomatology of degrees not commonly seen outside of such settings. At this time, the Greer and Morris findings must therefore be cautiously interpreted. Overall, standardized tests do not support increased depression in patients with cancer, though there is some evidence that a nonpathological increase in depression symptomatology may be prospectively related to mortality from cancer. However, in many of these studies, selection procedures have not controlled for disease and demographic characteristics, thus preventing conculsive interpretations.
Current Status and Discussion The following points characterize the current status of knowledge regarding depression and cancer: (a) There is no evidence that cancer patients have an increased experience of emotional loss prior to their disease, while there is some support for increased emotional inhibition and hopelessness in patients who already have cancer: (b) There is no solid evidence that cancer patients have increased depression in a psychiatric sense when compared to other patients, relatives, or normal control groups: (c) Psychometric assessment of depression also does not indicate increased prevalence of pathologic depression in cancer patients, though there is some suggestion that mild elevations in depressive symptomatology may be prospectively related to cancer incidence. Several issues regarding the research and interpretation of evidence relating to depression and cancer have emerged. First, indirect approaches to measurement of depression have been contrasted with more direct symptomatic assessment approaches. In general, the indirect method is justified if the theoretical relationships on which it is based are valid and if effective measures of the variables are available. Unfortunately, there is some question about the relationship of variables such as emotional loss and emotional inhibition to depression. Akiskal and McKinney (7), for instance, conclude that separation from others and inhibition of anger need not be increased in depression. Hopelessness is often described as a symptom of depression, however, and may be a more direct
measure than an indirect one. Beyond these difficulties, the criteria for assessing variables such as loss, emotional inhibition, and hopelessness are not agreed upon or standardized, and are difficult to compare among studies. These theoretical and practical considerations make it unlikely that indirect approaches to future research in depression and cancer will be fruitful. The more direct approaches to measuring psychological depression in cancer patients generally involve either clinical psychiatric criteria or objective psychometric testing. Though purely clinical studies are among the most common in testifying to increased depression in cancer patients, they have been plagued by design and methodological difficulties. At present, there is no clear evidence that cancer patients are more depressed in a clinical psychiatric sense than anyone else. The use of standardized tests, the other direct approach to assessment of depression in cancer, has raised hopes that quantifiable measures would answer specific questions about any relationship between depression and cancer. While such studies have generally been superior to more inferential approaches, there have been methodological questions raised in traditional areas of difficulty, such as subject selection procedures. Comparisons between cancer patients and other subject groups have not supported an increased depression in individuals with cancer. However, a recent prospective study has suggested an increased risk for mortality from cancer in subjects scoring higher on the MMPI depression scale than those who do not (55). Further research, including data on cancer morbidity will be necessary before full implications for any relationship between depression and cancer can be realized. In general, psychometrically-based studies of depression offer the best opportunity to elucidate the depression/cancer relationship because of standardization of measurement, resultant comparability between studies or over time with the same subjects, objective definitions of depression, and easy quantification. A second issue discussed was the difference in approach to experimental design exemplified by case-control versus cohort studies. Fox (1) strongly supports the latter because of its inherent control advantages and freedom from bias in investigations of prospective issues. However, case-control studies are appropriate if one wishes to learn about the relationship between depression and cancer during acute stages of the cancer process. This would have implications for how a patient is best treated from a
Psychological Depression and Cancer
psychological standpoint, how quality of life is conceptualized for a patient undergoing treatment for cancer, and even for compliance with medical regimen (61). While certain cancer patients may be significantly depressed, it is clear that the widespread notion that cancer patients are generally depressed is not supported by the evidence. Continued casecontrol studies would be in order to further evaluate issues relating to depression or other psychological reactions in cancer patients. Cohort studies, on the other hand, are designed to evaluate the risk status for cancer incidence which may be affected by depression (1); this is a question that case-control studies have difficulty answering because of the problem of inferring cause-effect relationships. Because cohort studies are prospective in nature, they require large numbers of subjects and lengthy followup of the subjects, resulting in high cost. Consequently, in spite of the inherent advantages of such an approach, few such studies have been conducted. The studies by Thomas and her co-workers (35-37) and Shekelle and his colleagues (55) provide evidence linking depression to cancer prospectively. To establish an increased risk of cancer resulting from depression, it will be necessary to conduct prospective studies with different populations of subjects and with attention to disease sites and different types of cancer. Costs can be somewhat limited by studying populations at high risk for cancer (1). A caution in the conduct of prospective studies is suggested by the results of the work of Shekelle and co-workers (55) where relationships between depression and mortality from cancer were found to exist for periods as long as 17 years prior to death; any relationship between depression and cancer may be an extended one and not demonstrable in studies which look at acute depression or use short prospective periods. Another issue which deserves close attention has been raised by psychometric research. The study by Shekelle and colleagues (55) reports a positive premorbid relationship between depression and later mortality from cancer; this depression was not of pathological proportions, however, but rather simply an elevated characteristic when compared to other clinical measures. This finding suggests that cancer researchers should consider depression not solely as an either/or phenomenon but as a continuous variable, a view proposed by Hoch (62). The need for more extensive measures may explain why so much of the psychometrically
and psychiatrically based research on depression and cancer does not provide conclusive evidence: many studies are designed primarily to identify the presence or absence of pathological depression with inadequate attention to the broad range of depression-associated symptoms which may not necessarily be pathological. A test such as the MMPI addresses these issues as it measures the “depth’ of depression (63) as a continuous variable and measures many subtle depressive symptoms covering a wide range of behaviors (48). Instruments such as the MMPI depression scale should be included to ensure that significant relationships of mild or moderate depression to cancer are not neglected. A final general issue in this area of research is the need for attention to important methodological and design questions. These will not be belabored here, excellent reviews address them elsewhere (1,3,17). However, with the currently nebulous state of knowledge in this area, attention to subject and control selection procedures, use of judicious response measures, and appropriate data analyses must continue to be strongly encouraged. There is no reason to expect a relationship between depression and cancer to be as sturdy as that between cigarette smoking and cancer (cancer mortality ratios ranging from 10 to 30). The preponderance of anecdoctal evidence supporting a positive relationship between depression and cancer, suggestive prospective evidence of a possible relationship, and possible links between depression and constitutional changes which may be linked with cancer (1, 7) increase the likelihood that one is affected by the other. However, it seems clear that a relationship between depression and cancer, if it is present, is of a magnitude which cannot overcome design and methodology difficulties which have been present in much of this most interesting area of research. It is hoped that the issues highlighted in this review will be useful in its continuing exploration. Critiqueof this manuscript and suggesfions for its improvement from Richard B. Shekelle, Ph.D. are gratefully acknowledged.
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