Fatigue and Psychiatric Morbidity Among Hodgkin s Disease Survivors

Vol. 19 No. 2 February 2000 Journal of Pain and Symptom Management 91 Original Article Fatigue and Psychiatric Morbidity Among Hodgkin s Disease Survivors Jon Håvard Loge, MD, Arne Foss Abrahamsen, MD, PhD, Øivind Ekeberg, MD, PhD, and Stein Kaasa, MD, PhD Department of Behavioral Sciences in Medicine (J.H.L., Ø.E.), University of Oslo, Oslo, Norway; The Norwegian Radium Hospital (A.F.A.), University of Oslo, Oslo, Norway; Palliative Medicine Unit (S.K.), Department of Oncology and Radiotherapy, Trondheim University Hospital, Trondheim, Norway; Unit for Applied Clinical Research (J.H.L., S.K.), The Norwegian University for Science and Technology, Trondheim, Norway Abstract Fatigue is prevalent among cancer patients, including Hodgkin s disease survivors (HDS). Fatigue is poorly understood, and the clinical management is consequently difficult. This cross-sectional study examined how fatigue related to psychiatric morbidity among 457 HDS (aged 19 74 years, 56% males) treated during the period 1971 1991. The subjects were mailed a questionnaire including the Fatigue Questionnaire, the Hospital Anxiety and Depression Scale, and measures of previous psychiatric problems. Fatigue correlated moderately with anxiety and depression (r 0.44 and 0.41 respectively). Twenty-six percent of the HDS had substantial fatigue for 6 months or longer ( cases). They had higher levels of anxiety (mean 7.3, 95% CI 6.4 8.1) and depression (mean 4.5, 95% CI 3.8 5.2) than the noncases (anxiety: mean 4.3, 95% CI 3.9 4.7; depression: mean 2.1, 95% CI 1.8 2.5). Past psychiatric problems were not reported more commonly among the fatigue cases than among the non-cases. A multiple logistic regression analysis identified age (OR 1.04, 95% CI 1.02 1.06), anxiety (OR 1.2, 95% CI 1.2 1.3), and no self-reported psychiatric symptoms during treatment (OR 2.3, 95% CI 1.3 4.2) as predictors of fatigue caseness. One-half of the fatigue cases among HDS have psychological distress that might respond to treatment. Chronic fatigue among HDS is not predicted by previous psychiatric problems. J Pain Symptom Manage 2000;19:91 99. U.S. Cancer Pain Relief Committee, 1999. Key Words Anxiety, depression, fatigue, Hodgkin s disease, neoplasms/psychology Introduction Fatigue is a taxing experience with serious functional consequences such as reduced Address reprint requests to: Jon Håvard Loge, MD, Dept. of Behavioral Sciences in Medicine, University of Oslo, P.O.Box 1111 Blindern, N-0317 Oslo, Norway. Accepted for publication: March 24, 1999. working capacity. 1 Fatigue is also prevalent: 11 20% in the general population, 2,3 50 80% in patients with medical conditions such as multiple sclerosis, rheumatoid arthritis or systemic lupus erythematosus (SLE), 4 7 and 70% in cancer patients. 8 The mechanisms or precise etiology of fatigue are at present poorly understood. Even in SLE, in which fatigue is the predominant symptom, the pathophysiology is not fully understood. 4,5 If treatment is to U.S. Cancer Pain Relief Committee, 2000 0885-3924/00/$ see front matter Published by Elsevier, New York, New York PII S0885-3924(99)00148-7

92 Loge et al. Vol. 19 No. 2 February 2000 be implemented, better understanding of what constitutes fatigue is essential. 9 Fatigue has been associated with psychiatric morbidity, such as depressed mood or anxiety, in the general population, 2 in patients with multiple sclerosis, 6 and in breast cancer patients. 10 Still, the association between fatigue and psychiatric morbidity is debated, 11 and the relation between fatigue and depression represents a special diagnostic and clinical challenge. This is partly related to the present ways of measuring fatigue and depression. Measurement of fatigue, like psychiatric symptoms, relies on subjective report. 12 In the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), psychomotor retardation, fatigue or energy loss, and diminished ability to think are inclusion criteria for a major depressive episode. 13 Most self-report measures of depression also include symptoms of fatigue. The similarities between depression and fatigue may be attributed to a common denominator or to an overlap between the current operational concepts of psychiatric disorders and fatigue. 11 Among medically ill patients, fatigue is the most controversial symptom of depression, and it has been suggested to exclude fatigue as a symptom of depression in cancer patients due to the similarities between fatigue and the effects of the disease process or the treatment. 14 Fatigue is distributed as a continuous dimension rather than a discrete variable, 2,3 and most probably fatigue and depression will overlap. Fatigue characteristics do not differentiate between fatigue of physical or psychological origin, 15 and empirical studies are therefore needed to determine the relative contributions of the physical and psychological aspects of fatigue. Among cancer patients, several factors such as severe anemia, pain, chemotherapy, radiotherapy, medications such as analgesics or sedatives, nutritional status, and psychological factors may all contribute to the subjective experience of fatigue. 16 Correlates of fatigue may also vary with tumor type, disease dissemination, or type of treatment. 8 Hayes described how depression and fatigue might co-occur because both may result from the same biological factors. 17 However, few studies have systematically explored the relation between anxiety, depression, and fatigue. 16 Anxiety and depression correlated moderately (r 0.40 and 0.46 respectively) with fatigue during chemo- and/or radiotherapy. 18 In a prospective study, the level of fatigue increased during radiotherapy without accompanying increase in depressive symptoms. 19 Fatigue is also a common problem among cancer survivors. Hodgkin s disease survivors (HDS) 20 22 and breast cancer patients treated with adjuvant chemotherapy 10,23 have increased levels of fatigue. In a recent study, we demonstrated that the prevalence of substantial fatigue of duration 6 months or longer was increased among HDS (26%) compared to general population controls (11%). 24 Such chronic fatigue was not related to type of primary treatment, and was most commonly found in subjects with disease stage IB/IIB. 24 When fatigue persists after cancer cure, somatic factors related to fatigue during active disease such as pain, nutritional status, or anemia are probably negligible. Empirical data on factors related to fatigue after cancer cure are scarce. 16 Fobair et al. found that lacking return of energy among HDS was associated with a high score of depression, stage of the disease, and combined chemo- and radiotherapy. 20 Broeckel et al. found that fatigue after adjuvant chemotherapy for breast cancer was related to poorer sleep quality and presence of a current psychiatric disorder. They concluded that fatigue probably was not merely a symptom of psychiatric disorder. 10 We have also demonstrated high levels of anxiety and low levels of depression in the HDS cohort. 25 Both post-treatment anxiety and depression were related to psychiatric symptoms experienced before or during treatment. 25 The present study was performed to explore the relationship between fatigue and psychiatric morbidity in a cohort of HDS. More specifically, we wanted to examine how fatigue related to present anxiety and depression and how fatigue related to indicators of previous psychiatric morbidity, i.e., self-reported psychiatric symptoms, use of psychotropic medication, and consulting a psychiatrist/psychologist. Finally, we wanted to identify predictors of fatigue caseness ( substantial fatigue of duration 6 months or longer). Methods Patients A cross-sectional study was performed by approaching patients who were admitted for

Vol. 19 No. 2 February 2000 Fatigue and Psychiatric Morbidity 93 Hodgkin s disease to the Norwegian Radium Hospital (NRH) 1971 1991, were alive by the end of 1993, and were between 15 and 61 years at time of diagnosis and 74 years or younger by the end of 1993. The latter was chosen due to the decreasing response rate and the poorer data quality among the oldest. 3 The subjects were approached by mail and received a selfreport questionnaire. Nonresponders received one written reminder. Totally, 557 former patients were eligible, and 459 replied (response rate 82%). The response rate tended to be higher among the women than among the men (86% vs. 80%, P 0.05). Otherwise, the nonresponders did not differ from the responders in terms of sociodemographic or medical characteristics. Two subjects had received no treatment after surgical removal of lymph nodes and were excluded from the analyses. Measures The Tumor Registry of NRH supported data on age, gender, and disease/treatment characteristics. 26 Educational status was assessed in the questionnaire. Age, gender, and educational status were included to control for the known associations with anxiety, depression, or fatigue. 24,25 Fatigue was assessed by the Norwegian version of the Fatigue Questionnaire (FQ). 2,3,24,27,28 The FQ is a self-report questionnaire (11 items) intended for assessment of fatigue severity and case detection in clinical and epidemiological studies. 27 Two additional items ask about the duration and the extent of fatigue. Item content and response categories are reported elsewhere. 27 The FQ has good face and discriminant validity. 27 Two independent translators translated the FQ into Norwegian. An agreed upon version was back translated by a native English speaker, and this version was conceptually equivalent to the original version. The psychometric properties of the Norwegian version correspond well to the English version. 2,3 The responses are scored in two ways. 2,27 Likertscoring (0,1,2,3) is used for the construction of physical fatigue ( PF) (7 items), mental fatigue (MF) (4 items), and total fatigue (TF) (all items) by simple addition. Higher scores imply more fatigue. A dichotomized score is used for the definition of cases. The responses are then scored 0, 0, 1, 1, and all the scores are summed. When the sum is 4 or higher and the duration is 6 months or longer, a case is defined. 3,27 In questionnaires with missing data in four or less items, missing values were replaced with the items means. Current anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS). 29 In the HADS, anxiety and depression are measured in two separate subscales (7 items each). Each response is scored on a four-point scale (0 3). Scores for either subscale are calculated by simple addition. A higher score implies more distress. A case refers to a score of 8 or higher on either subscale. 29 The subjects were asked about possible psychiatric disorder and psychiatric treatment during the treatment period: Did you experience psychiatric symptoms when you were treated for Hodgkin s disease? If yes, which was the dominating symptom (anxiety, restless, depressed, difficulties sleeping, psychotic, other symptoms (such as abuse of drugs or alcohol)? Did you consult a psychologist or a psychiatrist when you were treated for Hodgkin s disease? Did you receive any of the following drugs when you were treated for Hodgkin s disease (hypnotics, sedatives, antidepressants, other psychotropics, no such medicines)? The subjects were also asked if they had ever experienced psychiatric symptoms (plus type of symptom), consulted a psychologist or a psychiatrist, used the above-mentioned psychotropic drugs, had consulted a physician for psychiatric problems or been hospitalized for psychiatric problems before they received the diagnosis of Hodgkin s disease. Analysis The level of significance was set at P 0.05. Statistical procedures included chi-square statistics (categorical variables), two-sided t-tests (independent samples), one-way analyses of variance (ANOVAs), Pearson s correlations, and logistic multiple regression analysis. The data were analyzed using the SPSS for Windows Version 7.5 software (SPSS Inc., Chicago, IL). Results In total, 421 (92%) subjects had complete sets of both questionnaires after substituting the missing values. The characteristics of the subjects and their relation to fatigue (TF and

94 Loge et al. Vol. 19 No. 2 February 2000 fatigue caseness), anxiety, and depression are presented in Table 1. Both age and educational level were associated with significant differences in the level of fatigue or in proportions of fatigue cases. The highest scores were found among the oldest (aged 60 74 years) and the poorest educated (10 years or less). Most cases were found among the oldest. More patients in Stage IB/ IIB were classified as cases as compared to the other staging groups. Statistically significant differences in the level of anxiety and depression were found in relation to educational level (highest levels among the poorest educated). The level of depression also differed in relation to age, observational period, and stage of the disease. The highest levels were found among the oldest, among subjects 7 10 years off treatment, and among subjects with disease stage IB/IIB. Fatigue and Current Anxiety and Depression As presented in Table 2, both HADS-anxiety (r: 0.38, 0.40, 0.44) and HADS-depression (r: 0.39, 0.46, 0.49) correlated moderately with MF, PF, and TF respectively. Anxiety and depression correlated 0.63. When removing the HADS-depression item on retardation ( I feel as if I am slowed down ), HADS-depression s correlations with MF, PF, and TF were 0.33, 0.39, and 0.41 respectively. In the subsequent analysis, the HADS-depression item on retardation was removed and the sum of the remaining items multiplied with 7/6. In total, 113 subjects (26%) were fatigue cases and 114 (26%) subjects had case scores (8 or more) on the HADS. Eight percent had case scores on both HADS subscales, 15% were anxiety cases, and 3% were depression cases. Sixty-one percent did not have case scores in any of the instruments. Table 1 Subject Characteristics and Their Relation to Fatigue, Anxiety and Depression (n 421) Fatigue N (%) TF-mean (SD) %cases Anxiety Mean (SD) Depression Mean (SD) Age groups (at study) * * n.s. * 19 29 years 47 (11%) 12.6 (4.4) 11% 5.2 (4.1) 1.9 (1.9) 30 39 years 110 (26%) 14.5 (5.0) 26% 5.0 (4.3) 2.6 (3.5) 40 49 years 158 (38%) 14.1 (4.2) 22% 5.3 (3.9) 3.3 (3.3) 50 59 years 62 (15%) 14.7 (4.5) 32% 4.8 (4.3) 3.9 (3.4) 60 74 years 44 (11%) 15.8 (4.4) 48% 4.2 (3.3) 4.2 (3.3) Gender n.s. n.s. n.s. n.s Male 234 (56%) 14.1 (4.5) 25% 4.7 (4.2) 3.3 (3.4) Female 187 (44%) 14.5 (4.7) 27% 5.4 (3.9) 3.0 (3.2) Educational status * n.s. * * 10 years or less 146 (35%) 15.0 (4.8) 30% 5.6 (4.5) 3.9 (3.6) 11 years or more 164 (39%) 14.2 (4.4) 28% 5.2 (3.9) 3.1 (3.2) University 110 (26%) 13.5 (4.3) 18% 4.0 (3.4) 2.2 (2.7) Observational period n.s. n.s. n.s. * 3 6 years 84 (20%) 14.0 (4.0) 26% 4.3 (3.7) 2.2 (2.4) 7 10 years 91 (22%) 14.3 (4.9) 21% 5.7 (4.2) 3.7 (3.7) 11 14 years 100 (24%) 14.4 (5.0) 28% 5.1 (4.6) 3.1 (3.6) 15 23 years 146 (35%) 14.3 (4.3) 27% 4.9 (3.7) 3.4 (3.2) Stage/substage n.s * n.s. * IA/IIA 203 (48%) 14.0 (4.3) 23% 5.0 (3.9) 2.9 (3.1) IB/IIB 51 (12%) 15.7 (5.1) 41% 5.2 (4.8) 4.1 (3.8) IIIA/IVA 83 (20%) 14.2 (4.8) 29% 4.6 (3.6) 2.6 (3.1) IIIB/IVB 84 (20%) 14.3 (4.5) 21% 5.5 (4.3) 3.7 (3.4) Primary treatment n.s. n.s n.s. n.s. Chemotherapy only 62 (15%) 13.8 (4.4) 24% 4.6 (3.7) 2.9 (3.1) Irradiation only 156 (37%) 14.4 (4.5) 25% 4.9 (3.8) 3.0 (3.1) Irradiation chemotherapy 203 (48%) 14.4 (4.6) 27% 5.2 (4.3) 3.4 (3.5) Relapsed n.s. n.s. n.s. n.s. Yes 49 (12%) 15.1 (4.9) 29% 4.5 (3.5) 2.8 (2.6) No 372 (88%) 14.2 (4.5) 26% 5.1 (4.1) 3.2 (3.4) n.s. Not statistically significant differences in means between groups by t-tests, one-way ANOVAs, or in proportions of cases by Chi-square statistics. *P 0.05 for differences in means between groups by one-way ANOVAs or in proportions of cases by Chi-square statistics.

Vol. 19 No. 2 February 2000 Fatigue and Psychiatric Morbidity 95 Table 2 Correlations (Pearson s) Between Fatigue, Anxiety, and Depression a TF Anxiety Depression PF MF TF 0.44 0.49 0.96 0.77 Anxiety 0.63 0.40 0.38 Depression 0.46 0.39 PF 0.55 MF TF Total fatigue; MF Mental fatigue; PF Physical fatigue. a All correlations: P 0. 001. As presented in Table 3, 48% of the fatigue cases were not cases on the HADS. Among the fatigue cases, 28% were anxiety cases, 6% were depression cases, and 17% were both anxiety and depression cases. HADS-caseness significantly predicted fatigue caseness (OR 5.2, 95% CI: 3.3 8.4). The subjects with case scores on the HADS had statistically significantly higher PF-, MF-, and TF-scores than the non-cases (P 0.001). The highest TF-score was found among the subjects who had case scores on both HADS subscales (mean 18.8, 95% CI 17.0 20.6). The subjects with caseness score on the FQ had statistically significantly higher scores on HADS-anxiety (mean 7.3, 95% CI 6.4 8.1) and on HADS-depression (mean 4.5, 95% CI 3.8 5.2) than the non-cases (anxiety: mean 4.3, 95% CI 3.9 4.7; depression: mean 2.1, 95% CI 1.8 2.5) (t: 7.0 and 5.9 respectively, P 0.001). Fatigue and Previous Psychiatric Symptoms and Treatment Seventy-eight subjects (17%) reported psychiatric symptoms before their diagnosis of HD. Depression (10%) and anxiety (10%) were reported most commonly. Forty-seven subjects (11%) had received psychotropic medication. Hypnotics (4%) and antidepressants (3%) were the most frequently used drugs. Twenty-two subjects (5%) had consulted a psychiatrist or a psychologist. During treatment, 151 subjects (33%) had experienced psychiatric symptoms. Anxiety (18%), depression (12%), and sleeping difficulties (11%) were the commonest reported symptoms. In total, 143 (32%) had received psychotropic medication during treatment. Hypnotics (20%), minor tranquilizers (18%), and antidepressants (2%) were the most frequently used drugs. There were no statistically significant associations between psychiatric symptoms before diagnosis or during treatment and fatigue caseness (Table 4). There was a weak association between the use of psychotropic medication before the diagnosis of HD and fatigue caseness (OR 1.9, 95% CI 1.0 3.7, P 0.03). No statistically significant associations were found between the other types of psychiatric treatment and fatigue caseness. Subjects reporting psychiatric symptoms before diagnosis had higher TF-scores (mean 15.4, 95% CI 14.3 16.5) than the subjects with- Table 3 Fatigue Caseness, Physical Fatigue (PF), Mental Fatigue (MF) and Total Fatigue (TF) in Relation to HADS Caseness Anxiety cases (n 64) Depression cases (n 13) Anxiety and depression cases (n 34) Not HADS-cases (n 310) Fatigue cases a Yes (n 109 ) 31 (28%) 7 (6%) 19 (17%) 52 (48%) No (n 312) 33 (11%) 6 (2%) 15 (5%) 258 (83%) PF a Mean 11.0 11.5 12.6 8.6 95% CI 10.0 11.9 9.5 13.5 11.4 13.9 8.2 8.9 MF a Mean 5.7 5.8 6.1 4.6 95% CI 5.3 6.1 4.5 7.1 5.5 6.8 4.4 4.8 TF a Mean 16.7 17.3 18.8 13.2 95% CI 15.5 17.8 14.4 20.1 17.0 20.6 12.7 13.6 TF, PF, and MF: mean (95% confidence interval). HADS cases: n (% of row s total). a P 0.001 for differences in proportions by Chi-square statistics or in means by one-way ANOVAs.

96 Loge et al. Vol. 19 No. 2 February 2000 Table 4 Previous Psychiatric Symptoms and Treatment in Relation to Fatigue Caseness [n (% of columns total)] Previous psychiatric symptoms Before diagnosis (n 78) During treatment (n 151) Before diagnosis (n 47) Psychotropic medication During treatment (n 143) Consulted psychiatrist/ psychologist Before diagnosis (n 22) During treatment (n 30) Fatigue cases No 54 (69%) 112 (74%) 29 (62%) 100 (70%) 15 (68%) 19 (63%) Yes 24 (31%) 39 (26%) 18 (38%) 43 (30%) 7 (32%) 11 (37%) OR (95% CI) a 1.4 (0.8 2.3) 1.0 (0.6-1.6) 1.9 (1.0 3.7) 1.5 (0.9 2.3) 1.4 (0.6 3.5) 1.8 (0.8 3.9) a Odds ratio for fatigue caseness with 95% confidence interval compared to subjects without condition. out such symptoms (mean 14.1, 95% CI 13.6 14.5) (t: 2.3, P 0.02). The use of psychotropic medication before diagnosis (mean 16.0, 95% CI 14.6 17.3) and during treatment (mean 15.3, 95% CI 14.5 16.1) was associated with higher TF-scores (t: 2.7 and 3.4, P 0.008 and 0.001 respectively). Predictors of Fatigue Caseness A multivariate logistic regression analysis with a forward stepwise selection of variables was performed to examine predictors of fatigue caseness. All variables found to be significantly (P 0.05) associated with fatigue caseness in the univariate analyses were included: age, HADS-anxiety, HADS-depression, stage/ substage, and use of psychotropic medication prior to the diagnosis of HDS. Because of the strong relationship between past psychiatric morbidity and fatigue in the general population, we also included three other indicators of psychiatric morbidity before diagnosis and during treatment (psychiatric problems before diagnosis and during treatment and use of psychotropic medication during treatment) as predictors. Increasing age, no self-reported psychiatric symptoms during treatment, and increasing level of anxiety were all statistically significant predictors of fatigue caseness (Table 5). The other variables were not entered into the equation. Discussion The present study demonstrates that fatigue and psychological distress among HDS are separate phenomena. Still, chronic fatigue is associated with increased levels of psychological distress. We found weak associations between indicators of previous psychiatric morbidity and fatigue. In the multivariate analysis after accounting for the predictive value of HADS anxiety and age, there was a negative relation between self-reported psychiatric symptoms during treatment and fatigue caseness. The limitations of the present study mainly fall into two categories. Firstly, the cross-sectional retrospective design implied limited data on the course of distress and fatigue during treatment and after termination of treatment. Firm conclusions of the causal relation between fatigue and psychiatric morbidity can therefore not be drawn. Secondly, except for the data on disease and treatment characteristics, all our data were based on self-reports. Our measures of psychiatric morbidity do not give exact psychiatric diagnosis. Psychiatric morbidity such as use of psychotropic medica- Table 5 Predictors of Fatigue Caseness, Forward Stepwise Logistic Regression (n 373) Predictor variables Number of cases OR (P-value) 95% CI HADS-anxiety (continuous) 1.2 ( 0.001) 1.2 1.3 Age (continuous) 1.04 ( 0.001) 1.02 1.06 Psychiatric symptoms during treatment Yes (reference) 130 No 243 2.3 (0.006) 1.3 4.2 Abbreviations: OR odds ratio; CI confidence interval.

Vol. 19 No. 2 February 2000 Fatigue and Psychiatric Morbidity 97 tion is often underreported in surveys possibly due to social desirability. 30 Time since exposure may negatively affect recall, while frequency, duration, and extent of the exposition positively affect recall. 30 The prevalence of psychiatric morbidity before diagnosis and during treatment may therefore have been underestimated. However, the prevalence of psychiatric problems during treatment is similar to that demonstrated among lymphoma patients in a prospective study. 21 The unselected sample and its size, the high compliance rate, and the use of standardized instruments (FQ and HADS), that allow for comparison with other studies, are considered the main strengths. The fatigue cases among the HDS had significantly lower scores on HADS-anxiety (7.3 versus 9.9) and HADS-depression (4.5 versus 9.0) than the subjects in a recent prospective primary care based study of chronic fatigue. 31 That study applied similar measures as the present, including the FQ with the same casedefinition, the HADS and self-reported measures of previous psychiatric disorders. Broeckel et al. also reported a negative correlation between fatigue and past psychiatric disorders in their study of breast cancer patients after adjuvant treatment. 10 They assessed past psychiatric problems by the Structured Clinical Interview for the DSM-IV. 10 In relation to anxiety and depression, we have previously demonstrated that the well-known association between past psychiatric problems and current psychiatric morbidity also holds true among these HDS. 25 In the prospective primary care based study of chronic fatigue, Wessely et al. demonstrated a strong association between previous psychiatric morbidity and chronic fatigue. 31 These findings indicate that mechanisms related to fatigue among the HDS (either psychological or physical) are different from mechanisms related to fatigue in the general population. There is considerable evidence that supports a dimensional rather than a categorical view of fatigue. 11 This implies that the same level of fatigue may have different etiologies in the same way as the level of blood pressure does not differentiate between renal, endocrine, or essential hypertension. Both physiological and psychological mechanisms of fatigue among HDS can be hypothesized from the present study. The substantial number of fatigued subjects without concordant or previous psychiatric morbidity indicates that biological correlates of fatigue among HDS should be addressed in future studies. The effect of age upon fatigue has been demonstrated in the general population 3 and in a previous study of HDS. 20 Whether this effect is direct or a confounding effect (i.e., increased morbidity) was not available for analysis in the present study. However, in the general Norwegian population we demonstrated an independent effect of age upon fatigue. 3 The different treatment regimens were not associated with significant differences in level of fatigue or in proportion of cases. 24 Fatigue may therefore be related to aspects of the disease itself, and comparable data on fatigue from other cancer survivors should then show higher levels of fatigue among the HDS. To our knowledge only one previous study has compared the level of fatigue among HDS to other cancer survivors (testicular cancer). 32 That study demonstrated significantly higher levels of fatigue among the HDS. 32 The Epstein-Barr virus (EBV) has been considered a causative agent both in chronic fatigue syndrome (CFS) 11 and in HD. Further, the immune system is activated in HD, and cytokines are probably related to fatigue during irradiation. 33 Altered neuroendocrinological functioning has been found among sufferers of CFS, 34 and could also be a relevant factor in maintaining fatigue among HDS. Generally, the psychological mechanisms behind fatigue are as poorly understood as the physiological ones. If fatigue among HDS is related to psychological mechanisms, the inverse relationship between perceived distress during treatment and post-treatment fatigue indicates that other psychological mechanisms are involved in the development of post-treatment fatigue than in the development of post-treatment anxiety and depression. This effect first emerged after adjusting for the level of anxiety, and was repeated in separate analyses including present anxiety and perceived distress during treatment as predictors. Sufferers of CFS have increased current psychiatric morbidity but also a tendency to amplify bodily sensations and to perceive stress as bodily sensations. 35 Such mechanisms may explain the inverse relation between perceived distress during treatment and chronic fatigue. Other mechanisms of relevance in CFS such as per-

98 Loge et al. Vol. 19 No. 2 February 2000 sonality traits, coping strategies, illness behavior, and somatic attribution styles 35 may therefore be of significance for chronic fatigue in HDS but have not been addressed yet. In the present study, we have treated fatigue as the dependent variable and anxiety/depression as explanatory variables, as done by others. 36 However, the causal relationship between fatigue and psychological distress is not clarified. Chronic fatigue may lead to psychological distress, and chronic anxiety or depression may lead to exhaustion, i.e. fatigue. Whether there is a relation between psychological vulnerability and the development of chronic fatigue in general is consequently controversial. Sufferers of chronic fatigue have increased risk of past psychiatric disorders. 37 This may be related to confounding, i.e., past psychiatric disorders only predict current psychiatric disorder. 31 Better understanding of what constitutes fatigue among HDS may therefore reveal different patterns in fatigued HDS with or without psychiatric morbidity. Still, the high levels of anxiety and depression among the fatigued are highly relevant in clinical practice. In conclusion, fatigue and psychological distress coexist but differ on several central aspects among HDS. In clinical practice, addressing fatigue is recommended, since uncertainty is a stressor, which may add to the subjective burden of being fatigued. Anxiety and depression should be looked for and if necessary treated. Still, better understanding of what constitutes fatigue is called for. Acknowledgment The Regional Committee for Ethics in Medical Research approved the study. Financial support by Grant 96028/003 from the Norwegian Cancer Society. References 1. Kroenke K, Wood DR, Mangelsdorff AD, et al. Chronic fatigue in primary care. JAMA 1988;260: 929 934. 2. Pawlikowska T, Chalder T, Hirsch SR, Wallace P, Wright DJM, Wessely S. Population based study of fatigue and psychological distress. BMJ 1994;308: 763 766. 3. Loge JH, Ekeberg Ø, Kaasa S. Fatigue in the general Norwegian population: normative data and associations. J Psychosom Res 1998;45:53 65. 4. Krupp LB, Larocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale: application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121 1123. 5. Wysenbeek AJ, Leibovici L, Weinberger A, Guedj D. Fatigue in systemic lupus erythematosus: prevalence and relation to disease expression. Br J Rheumatol 1993;32:633 635. 6. Ford H, Trigwell P, Johnson M. The nature of fatigue in multiple sclerosis. J Psychosom Res 1998; 45:33 38. 7. Krupp LB, Mendelson WB, Friedman R. An overview of chronic fatigue syndrome. J Clin Psychiatry 1991;52:403 410. 8. Irvine DM, Vincent L, Bubela N, Thompson L, Graydon J. A critical appraisal of the research literature investigating fatigue in the individual with cancer. Cancer Nursing 1991;14:188 199. 9. Shapiro M. Fatigue: how many types and how common? J Psychosom Res 1998;45:1 3. 10. Broeckel JA, Jacobsen PB, Horton J, Balducci L, Lyman GH. Characteristics and correlates of fatigue after adjuvant chemotherapy for breast cancer. J Clin Oncol 1998;16:1689 1696. 11. Wessely S. The epidemiology of chronic fatigue syndrome. Epidemiol Rev 1995;17:139 151. 12. Wessely S. The measurement of fatigue and chronic fatigue syndrome. J R Soc Med 1992;85: 189 190. 13. American Psychiatric Association. DSM-IV: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: APA, 1994. 14. McDaniel JS, Musselman DL, Porter MR, Reed DA, Nemeroff CB. Depression in patients with cancer. Arch Gen Psychiatry 1995;52:89 99. 15. Katerndahl DA. Differentiation of physical and psychological fatigue. Fam Pract Res J 1993;13:81 91. 16. Smets EMA, Garssen B, Schuster-Uitterhoeve ALJ, de Haes JCJM. Fatigue in cancer patients. Br J Cancer 1993;68:220 224. 17. Hayes JR. Depression and chronic fatigue in cancer patients. Primary Care 1991;18:327 339. 18. Blesch KS, Paice RW, Wickham R, Harte N, Schnoor DK, Purl S, et al. Correlates of fatigue in people with breast or lung cancer. Oncol Nurs Forum 1991:18;81 87. 19. Greenberg DB, Sawicka J, Eisenthal S, Ross D. Fatigue syndrome due to localized radiation. J Pain Symptom Manage 1992;7:38 45. 20. Fobair P, Hoppe RT, Bloom J, Cox R, Varghese A, Spiegel D. Psychosocial problems among survivors of Hodgkin s disease. J Clin Oncol 1986;4:805 814. 21. Devlen J, Maguire P, Phillips P, Crowther D, Chambers H. Psychological problems associated with diagnosis and treatment of lymphomas. BMJ 1987;295:953 957.

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