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Depression in relation to anxiety, obsessionality and phobia among neurosurgical patients with a primary brain tumor: A 1-year follow-up study
Clinical Neurology and Neurosurgery 113 (2011) 649–653
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Depression in relation to anxiety, obsessionality and phobia among neurosurgical patients with a primary brain tumor: A 1-year follow-up study Arja Mainio a,b,∗ , Helinä Hakko a,b , Asko Niemelä a,b , John Koivukangas b,c , Pirkko Räsänen a,b a b c
University of Oulu, Department of Psychiatry, BOX 5000, 90014, Finland Oulu University Hospital, Department of Psychiatry, BOX 26, 90029 OYS, Finland Oulu University Hospital, Department of Neurosurgery, BOX 26, 90029 OYS, Finland
a r t i c l e
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Article history: Received 10 December 2009 Received in revised form 18 April 2011 Accepted 14 May 2011 Available online 12 June 2011 Keywords: Depression Anxiety Obsessive–compulsive symptoms Primary brain tumor
a b s t r a c t Depression is found to be present in up to 44% of brain tumor patients during their illness process. Anxiety as a comorbid psychiatric disorder with depression has formerly been studied, but phobia or obsessive–compulsive symptoms among brain tumor patients have not yet been noticed. By using a clinical prospective database of primary brain tumor patients (n = 77) we studied the level of depression, anxiety, obsessionality (traits and symptoms) and phobic anxiety symptoms. Psychiatric symptoms were assessed before tumor operation as well as at three months and at one year after operation. The presence of comorbid anxiety, obsessionality and phobic anxiety symptoms was assessed before operation and at follow-ups in depressed and non-depressed patients, separately. Before tumor operation 16% of the patients had depression according to Beck Depression Inventory (BDI), while 10% had depression at three months and 15% at one year after operation. The depressed patients had statistically significantly higher anxiety scores and phobic scores at all three measurement points compared to corresponding scores among non-depressed brain tumor patients. The mean obsessionality scores among depressed brain tumor patients were significantly higher when measured before operation and at one year after the operation compared to non-depressed patients. To our knowledge, this is the first study so far in which comorbidity of psychiatric symptoms has been shown among depressive brain tumor patients. Concurrent comorbid conditions have been shown to be associated with increased severity, morbidity and chronicity of depression. It is recommended that treatment of depressive patients complicated with comorbid psychiatric disorders be planned by psychiatric units. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Brain tumors are important from a psychiatric point of view since an unrecognized brain tumor can present as psychiatric symptoms only or psychiatric symptoms may arise during the illness process. The prevalence of depressive symptoms has varied from 5% to 44% in different samples of patients with a malignant or benign primary brain tumor [1–6]. Recent studies have shown that depression may be associated with shorter survival among patients with high-grade and low-grade gliomas [5–7]. According to case reports and study samples, anxiety or panic attacks have been reported to be present before diagnosis or treatment of a brain tumor [2,8–12]. Among brain tumor patients there are case reports of adult patients presenting with obsessional symptoms with a
∗ Corresponding author at: Oulu University Hospital, Department of Psychiatry, BOX 26, 90029 OYS, Finland. Tel.: +358 8 3156706. E-mail address: arja.mainio@oulu.fi (A. Mainio). 0303-8467/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2011.05.006
brain tumor located in the frontal, temporal or parietal regions of the brain [13–15]. Further, there are rare case reports describing specific phobias associated with primary brain tumor [16–18]. To the best of our knowledge, the literature on comorbid psychiatric disorders i.e. two or more disorders occurring at the same time among brain tumor patients is sparsely documented. However, it is known that most depressive patients in general suffer from concurrent psychiatric disorders, such as anxiety disorders [19]. The existence of another concurrent psychiatric disorder is known to be associated with decreased psychosocial capacity in patients, and treatment can be complicated or recovery delayed. The most usual comorbid anxiety disorders are panic disorders, phobias and generalized anxiety [19–21]. Our study group has already earlier studied on psychiatric symptoms among brain tumor patient [7,22–24]. On this study we aimed combine our findings and re-analyze specially comorbid psychiatric symptoms in patients: (1) the prevalence of depression, anxiety, obsessionality (traits and symptoms) and phobic anxiety symptoms before tumor operation as well as at three months and at
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A. Mainio et al. / Clinical Neurology and Neurosurgery 113 (2011) 649–653
one year after operation and (2) the presence of comorbid anxiety, obsessionality and phobic anxiety symptoms before operation and at follow-ups in depressed and non-depressed patients, separately. 2. Materials and methods The study population consisted of 77 patients, 30 males and 47 females, with a solitary primary brain tumor treated surgically at the Clinic for Neurosurgery, Oulu University Hospital, between February 1990 and March 1992. Written informed consent was obtained from all the participants. The Ethics Committee of Oulu University Hospital approved the study protocol. The data of our study have been fully documented earlier [22–24]. Epidemiologically the cohort is a comprehensive and unselected sample of population because the Oulu Clinic for Neurosurgery performs all resections of brain tumors in its catchments area. Geographically this area covers about 49% of Finland. The present study consisted of those brain tumor patients whose measurements for depression were available for each measurement point. 2.1. Tumor characteristics The radiological diagnosis of the brain tumor was carried out by computer tomography (CT) or magnetic resonance imaging (MRI). Histological grading was done according to the WHO classification [25]. Tumors were categorized into the following classes: grade I–II gliomas, grade III–IV gliomas, meningiomas, pituitary adenomas, acoustic neurinomas and other tumors (hemangiopericytomas, malignant lymphoma, craniopharyngeoma and two undefined tumors) [7]. Regarding the hemispheric lateralization the tumors were classified into three groups: tumors in the left hemisphere, tumors in the right hemisphere and tumors located bilaterally. Furthermore, if the tumors reached the supratentorial space, the location of the tumor was defined to be ‘anterior’ or ‘posterior’. Matsui’s anatomical location was used in defining the tumor location in the brain [26]. The distance of the tumor from the apex of the frontal lobe was determined by calculating from each CT or MRI slice ratio of the distance between the anterior part of the tumor and the apex of the frontal lobe to the anterior-posterior diameter of the whole brain. The mean of these percentages was used to describe the distance from the apex of the frontal lobe to the tumor. The volume of the tumor was determined manually from the CT or MRI by a trained physician in the neurosurgical ward. The tumors were categorized into two groups according to the tumor volume i.e. ≤25 ml, and >25 ml. 2.2. Assessment of anxiety, obsessionality and phobia The levels of anxiety, obsessive–compulsive symptoms and phobic anxiety were assessed using appropriate subscales of the Crown–Crisp Experiential Index (CCEI), earlier called the Middlesex Hospital Questionnaire [27]. According to Crown and Crisp, CCEI has been formulated for three different purposes: to describe normal and deviant groups, to study psychosomatic interrelationships, and as a clinical psychometric test to study personality change following either psychological or somatic therapies [28]. The levels of anxiety, obsessionality and phobic anxiety were based on the following subscales of the CCEI: the Free-Floating Anxiety (FFA), Obsessionality (OBS), and Phobic (PHO) subscale. In this study the sum score of the FFA, OBS and PHO subscales were used as a continuous variable in statistical analyses, since in the literature, there are neither standard reference values nor cut-off points for these subscales to indicate anxious, obsessive or phobic disorder in a person [28].
2.3. Assessment of depression Depressive symptoms were evaluated by the Beck Depression Inventory (BDI), which is a self-report rating inventory measuring characteristic attitudes and symptoms of depression [29]. In this study, depression was defined to be present if the patient’s BDI sum score was 15 or higher. It has been shown that with a cut-off point of 14/15 the BDI-21 can be used to indicate the presence of a major depressive episode regardless of the phase of the major depressive disorder [30]. 2.4. Statistical analyses Differences in categorical variables were tested with the Chi-Square test or Fischer exact test. Statistical significance of group differences in continuous variables was analyzed with the Mann–Whitney U-test or Student’s t-test. The statistical significance of differences between repeated measurements was assessed with Wilcoxon signed rank test (two repeated measurements). All statistical analyses were performed using the SPSS statistical software, version 11, and the results in this study were considered statistically significant when the appropriately calculated twotailed p-value was ≤0.05. 3. Results 3.1. Prevalence of depression In the total study population (n = 77), there were 16% patients indicating major depression according to BDI before tumor operation, compared to 10% at three months and 15% at one year after operation. The decrease in depression scores over time was not statistically significant. 3.2. Characteristics of depressed and non-depressed brain tumor patients Table 1 presents the tumor and patient characteristics of the study subjects according to their depression status. None of these characteristics differed statistically significantly between depressed and non-depressed brain tumor patients. 3.3. Prevalence of anxiety, obsessionality and phobia In the total data set the mean anxiety scores decreased statistically significantly when comparing the scores before operations to measurements made after the operation. Mean (sd) anxiety score before the operation was 4.4 (3.3), while it was 3.3 (2.3) at three months (Wilcoxon signed rank test, Z = −3.216, p-value = 0.001) and 3.2 (2.3) at one year after the operation (Wilcoxon signed rank test, Z = −3.051, p-value = 0.002). There were no statistically significant changes over time in the mean (sd) levels of obsessionality [baseline: 6.9 (3.2), 3 months: 7.3 (3.1), one year: 6.9 (3.2)] or in the levels of phobic anxiety [baseline: 3.3 (3.2), 3 months: 3.3 (2.4), one year: 3.4 (2.5)]. 3.4. Depression in relation to anxiety, obsessionality and phobia Table 2 shows the level of anxiety, obsessionality as well as phobic anxiety among depressed and non-depressed brain tumor patients. The depressed patients had statistically significantly higher anxiety scores at all three measurement points compared to corresponding scores among non-depressed brain tumor patients. The mean obsessionality scores among depressed brain tumor patients were significantly higher at the measurements before operation, and at one year after operation compared
A. Mainio et al. / Clinical Neurology and Neurosurgery 113 (2011) 649–653 Table 1 Patient and tumor characteristic of study subjects according to their depression status.
Patient characteristics Gender Male Female Age, mean (sd) Marital status Married Not married Employment status Employed Unemployed Sickness leave Pensioner Tumor characteristics Tumor histology Glioma grade I–II Glioma grade III–IV Meningioma Acoustic neurinoma Pituitary adenoma Other tumorsa Hemisphere In left hemisphere In right hemisphere Bilaterally Not identified Location Anteriorly Other Volume Under 25 ml 25 ml or more Not identified Extent of surgery Extirpation Resection Biopsy/unknown Chemotherapy Yes No Not reported Radiotherapy Yes No Not reported
Depressed patients (n = 12) BDI ≥ 15
Non-depressed patients (n = 65) BDI < 15
3 (25) 9 (75) 44.8 (11.4)
27 (41.5) 38 (58.5) 47.3 (11.6)
11 (92) 1 (8)
51 (78.5) 14 (21.5)
Group difference, p-value** 0.348
0.343 0.194
0.105 5 (41) 2 (17) 5 (42) –
22 (34) 11 (17) 18 (28) 14 (21)
2 (17) 4 (33) 4 (33) 1 (8) – 1 (8)
14 (22) 11 (17) 19 (29) 11 (17) 7 (11) 3 (5)
5 (42) 5 (42) 2 (16) –
31 (48) 20 (31) 9 (14) 5 (7)
8 (67) 4 (33)
31 (48) 34 (52)
4 (33) 8 (67) –
36 (55) 27 (42) 2 (3)
5 (42) 3 (25) 4 (33)
36 (55) 14 (22) 15 (23)
3 (25) 8 (67) 1 (8)
3 (5) 53 (81) 9 (14)
5 (42) 6 (50) 1 (8)
26 (40) 30 (46) 9 (14)
0.606
0.811
0.404
0.206
0.297
0.051
0.608
Note: Values are numbers (percentage in parenthesis) if not otherwise specified. a Others include two hemangiopericytomas, malignant lymphoma, craniopharyngeoma and two undefined tumors. ** Chi-square or Fischer Exact test in categorical variables, and Student’s t-test in continuous variables, two-tailed significance.
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to non-depressed patients. Furthermore, the phobic scores were statistically significantly higher among the depressed brain tumor patients before tumor operation and at one year after operation. Further, the gender difference in anxiety, obsessionality and phobic anxiety scores among depressed brain tumor patients was examined. There were no statistically significant gender differences at any measurement points according to different psychiatric subgroups (anxiety, obsessionality or phobic anxiety) in the depressed brain tumor patients. 4. Discussion We found in the present study that 16% of the brain tumor patients had clinical depression while waiting for tumor surgery. Although no statistically significant change in depression scores over time was observed, the proportion of depressed patients decreased slightly in the follow-up at three months after the operation, rising again at one year after the operation to the same level as before the operation. In our data the prevalence of depression was in the lowest level compared the corresponding proportion in earlier literature, which has reported the prevalence of depression being about 15–44% before tumor operation and up to 70% in the follow-up [2,4,5,31]. The depressed brain tumor patients did not differ from the nondepressed patients in terms of sociodemographic characteristics, nor did they differ significantly from the non-depressed patients according to tumor malignancy or tumor location. Similarly to our results, in a study by Madhusoodanan et al., depression among brain tumor patients was not found to be associated with tumor type or location [31]. We found a high level of anxiety before tumor operation in the patients of the study sample. Some studies have reported FFA norms for mentally healthy general practice patients, Finnish healthy controls and outpatients with psychoneurotic illness [28,32]. The level of anxiety among depressed patients in our data set reached the norms reported in psychoneurotic patients, norms being 9–11 for anxiety disorder [28]. The anxiety scores declined as soon as at three months after the operation to the level found in general population, norms being 3–5 for mentally healthy subjects. Our finding is in line with previous studies in which a high level of anxiety has also been found in patients waiting for tumor surgery [2,33]. D’Angelo et al. found that anxiety among brain tumor patients did not change at the follow-up [33]. Our findings confirm this only among the non-depressive patients. In our study the level of anxiety remained at the high level among the depressed patients and we emphasize, according to our findings that a great treatment attention in clinical practice have to be focused on those brain tumor patients with multiple psychiatric symptoms at the same time.
Table 2 Anxiety, obsessionality and phobic anxiety scores among depressed and non-depressed brain tumor patients before operation and at two follow-up measurement points. Depressed patients (n = 12)
Non-depressed patients (n = 65)
Group difference, p-value*
Mean (sd)
Median (IQR)
Mean (sd)
Median (IQR)
Anxiety sum-score Before operation At three months after operation At one year after operation
9.1(3.8) 4.8 (2.0) 6.4 (2.5)
10.0 (5.5–11.0) 4.5 (3.0–7.0) 6.0 (4.0–8.0)
3.6 (2.6) 3.2 (2.3) 2.6 (1.8)
3.0 (1.5–4.0) 3.0 (2.0–4.0) 2.0 (1.0–3.0)
0.000 0.043 0.000
Obsessionality sum-score Before operation At three months after operation At one year after operation
9.1(4.1) 7.0 (2.8) 9.5 (3.4)
10.0 (6.0–12.0) 6.5 (6.0–9.5) 9.0 (7.0–13.0)
6.6 (2.9) 7.3 (3.1) 6.5 (3.0)
7.0 (4.0–9.0) 7.0 (5.0–10.5) 7.0 (5.0–9.0)
0.018 0.805 0.024
Phobic anxiety sum-score Before operation At three months after operation At one year after operation
5.8 (2.1) 2.8 (1.5) 5.4 (2.1)
6.0 (5.0–7.0) 2.5 (2.0–3.0) 5.0 (4.0–7.0)
2.9 (2.1) 3.3 (2.4) 3.1 (2.3)
2.0 (1.0–4.0) 3.0 (1.0–5.0) 3.0 (1.0–5.0)
0.001 0.696 0.005
*
Mann–Whitney U-test, two-tailed significance.
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We found that in the total study sample, obsessionality and phobic anxiety did not change significantly during the follow-up in non-depressed patients. In addition, the level of these psychiatric symptoms was at the level found in reported norms for mentally healthy persons, i.e. 6–7 for obsessionality and 2.5–5 for phobic anxiety [28]. The main finding of the present study was that the depressed brain tumor patients had significantly higher scores of anxiety, obsessionality and phobic anxiety compared to non-depressed patients. This difference was found before tumor operation and also in the follow-up at one year after tumor surgery. To our knowledge, this is the first study so far in which comorbidity of psychiatric symptoms has been shown among depressive brain tumor patients. Earlier studies have indicated other problems associated with depression among brain tumor patients as well; depressive brain tumor patients have shorter survival compared to non-depressive brain tumor patients [5–7]. The quality of life of depressive brain tumor patients has also been shown to be lower compared to nondepressive patients [34,3]. None of these studies observed any other psychiatric symptoms besides depression. However, it has been documented that the course of disease in depressive patients with comorbid psychiatric disorder is more complicated compared to patients without other psychiatric disorders [35–37]. Concurrent comorbid conditions have been shown to be associated with increased severity, morbidity and chronicity of depression as well as with more social and occupational impairment [35,36]. Pharmacological treatment of depression in patients with physical illnesses is useful and has the same basic principles as the treatment of depression in general [38]. The drugs of choice in pharmacotherapeutic treatment of depression with anxiety are selective serotonin reuptake inhibitors (SSRIs), venlafaxine, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) [38–41]. However, according to a recent review, there are no randomized controlled trials (RCTs) evaluating the adequate treatment of depression in brain tumor patients. Thus, if brain tumor patients are treated with antidepressant drugs close follow up is needed due to high risk of side effects i.e. epilepsy, cognitive dysfunction or fatigue among these patients [42]. Also, as long as we have no special guide line for treating psychiatric disorders among patients with a brain tumor we have to turn to general guide lines. It has been recommended that the treatment of depressive patients complicated with comorbid psychiatric disorders should be planned in specialist medical care [43]. Psychotherapy and pharmacotherapy generally are of comparable efficacy, and both modalities are superior to usual care in treating depression [43]. We suggest that psychosocial interventions for brain tumor patients should consist of both psychotherapy and pharmacotherapy. The main psychological methods have to consist of crisis therapy with supportive elements and psychoeducational techniques. By supportive therapy the patient’s productive coping strategies are strengthened. In a dynamic approach of individual psychotherapy the patient is helped to bring meaning to the illness [44]. The limitations of this study must be acknowledged. From a psychiatric point of view it was unfortunate that the study protocol did not include any structured psychiatric diagnostic interviews. The existence of the patients’ psychiatric symptoms was based on self-administered questionnaires. In addition, no information was available concerning the patients’ previous history of psychiatric disorders, psychiatric treatment, family history of psychiatric diseases or corticosteroid therapy during data collection. It must be mentioned as a limitation of the CCEI questionnaire that there are no standard cut-off points or border values for the subscales used in the study with which the respective values observed in the studies of this thesis could have been directly compared. Nevertheless, it is reported that CCEI is a valid instrument for evaluating
psychiatric, neurotic psychopathology in psychiatric patients and somatically ill patients [45] as well as change in psychic state following either psychological or somatic therapies [24]. Further, our data has been collected on years from 1990 to 1992 but we suggest that it is not very assumable that major findings concerning the prevalence of psychiatric symptoms among brain tumor patients would have changed even if we have had a more recent data. The major strength of the present study was the prospective study design with repeated measurements. The patients were personally and carefully interviewed by a trained psychologist and by a trained physician at each measurement point. The histological grading of the tumors followed the WHO classification and it was thoroughly determined by a specialist in pathology. Furthermore, the tumors consisted of both benign and malignant brain tumors, which gave an opportunity to compare the effect of tumor malignancy on psychiatric symptoms. 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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Depression in relation to anxiety, obsessionality and phobia among neurosurgical patients with a primary brain tumor: A 1-year follow-up study Arja Mainio a,b,∗ , Helinä Hakko a,b , Asko Niemelä a,b , John Koivukangas b,c , Pirkko Räsänen a,b a b c
University of Oulu, Department of Psychiatry, BOX 5000, 90014, Finland Oulu University Hospital, Department of Psychiatry, BOX 26, 90029 OYS, Finland Oulu University Hospital, Department of Neurosurgery, BOX 26, 90029 OYS, Finland
a r t i c l e
i n f o
Article history: Received 10 December 2009 Received in revised form 18 April 2011 Accepted 14 May 2011 Available online 12 June 2011 Keywords: Depression Anxiety Obsessive–compulsive symptoms Primary brain tumor
a b s t r a c t Depression is found to be present in up to 44% of brain tumor patients during their illness process. Anxiety as a comorbid psychiatric disorder with depression has formerly been studied, but phobia or obsessive–compulsive symptoms among brain tumor patients have not yet been noticed. By using a clinical prospective database of primary brain tumor patients (n = 77) we studied the level of depression, anxiety, obsessionality (traits and symptoms) and phobic anxiety symptoms. Psychiatric symptoms were assessed before tumor operation as well as at three months and at one year after operation. The presence of comorbid anxiety, obsessionality and phobic anxiety symptoms was assessed before operation and at follow-ups in depressed and non-depressed patients, separately. Before tumor operation 16% of the patients had depression according to Beck Depression Inventory (BDI), while 10% had depression at three months and 15% at one year after operation. The depressed patients had statistically significantly higher anxiety scores and phobic scores at all three measurement points compared to corresponding scores among non-depressed brain tumor patients. The mean obsessionality scores among depressed brain tumor patients were significantly higher when measured before operation and at one year after the operation compared to non-depressed patients. To our knowledge, this is the first study so far in which comorbidity of psychiatric symptoms has been shown among depressive brain tumor patients. Concurrent comorbid conditions have been shown to be associated with increased severity, morbidity and chronicity of depression. It is recommended that treatment of depressive patients complicated with comorbid psychiatric disorders be planned by psychiatric units. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Brain tumors are important from a psychiatric point of view since an unrecognized brain tumor can present as psychiatric symptoms only or psychiatric symptoms may arise during the illness process. The prevalence of depressive symptoms has varied from 5% to 44% in different samples of patients with a malignant or benign primary brain tumor [1–6]. Recent studies have shown that depression may be associated with shorter survival among patients with high-grade and low-grade gliomas [5–7]. According to case reports and study samples, anxiety or panic attacks have been reported to be present before diagnosis or treatment of a brain tumor [2,8–12]. Among brain tumor patients there are case reports of adult patients presenting with obsessional symptoms with a
∗ Corresponding author at: Oulu University Hospital, Department of Psychiatry, BOX 26, 90029 OYS, Finland. Tel.: +358 8 3156706. E-mail address: arja.mainio@oulu.fi (A. Mainio). 0303-8467/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2011.05.006
brain tumor located in the frontal, temporal or parietal regions of the brain [13–15]. Further, there are rare case reports describing specific phobias associated with primary brain tumor [16–18]. To the best of our knowledge, the literature on comorbid psychiatric disorders i.e. two or more disorders occurring at the same time among brain tumor patients is sparsely documented. However, it is known that most depressive patients in general suffer from concurrent psychiatric disorders, such as anxiety disorders [19]. The existence of another concurrent psychiatric disorder is known to be associated with decreased psychosocial capacity in patients, and treatment can be complicated or recovery delayed. The most usual comorbid anxiety disorders are panic disorders, phobias and generalized anxiety [19–21]. Our study group has already earlier studied on psychiatric symptoms among brain tumor patient [7,22–24]. On this study we aimed combine our findings and re-analyze specially comorbid psychiatric symptoms in patients: (1) the prevalence of depression, anxiety, obsessionality (traits and symptoms) and phobic anxiety symptoms before tumor operation as well as at three months and at
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one year after operation and (2) the presence of comorbid anxiety, obsessionality and phobic anxiety symptoms before operation and at follow-ups in depressed and non-depressed patients, separately. 2. Materials and methods The study population consisted of 77 patients, 30 males and 47 females, with a solitary primary brain tumor treated surgically at the Clinic for Neurosurgery, Oulu University Hospital, between February 1990 and March 1992. Written informed consent was obtained from all the participants. The Ethics Committee of Oulu University Hospital approved the study protocol. The data of our study have been fully documented earlier [22–24]. Epidemiologically the cohort is a comprehensive and unselected sample of population because the Oulu Clinic for Neurosurgery performs all resections of brain tumors in its catchments area. Geographically this area covers about 49% of Finland. The present study consisted of those brain tumor patients whose measurements for depression were available for each measurement point. 2.1. Tumor characteristics The radiological diagnosis of the brain tumor was carried out by computer tomography (CT) or magnetic resonance imaging (MRI). Histological grading was done according to the WHO classification [25]. Tumors were categorized into the following classes: grade I–II gliomas, grade III–IV gliomas, meningiomas, pituitary adenomas, acoustic neurinomas and other tumors (hemangiopericytomas, malignant lymphoma, craniopharyngeoma and two undefined tumors) [7]. Regarding the hemispheric lateralization the tumors were classified into three groups: tumors in the left hemisphere, tumors in the right hemisphere and tumors located bilaterally. Furthermore, if the tumors reached the supratentorial space, the location of the tumor was defined to be ‘anterior’ or ‘posterior’. Matsui’s anatomical location was used in defining the tumor location in the brain [26]. The distance of the tumor from the apex of the frontal lobe was determined by calculating from each CT or MRI slice ratio of the distance between the anterior part of the tumor and the apex of the frontal lobe to the anterior-posterior diameter of the whole brain. The mean of these percentages was used to describe the distance from the apex of the frontal lobe to the tumor. The volume of the tumor was determined manually from the CT or MRI by a trained physician in the neurosurgical ward. The tumors were categorized into two groups according to the tumor volume i.e. ≤25 ml, and >25 ml. 2.2. Assessment of anxiety, obsessionality and phobia The levels of anxiety, obsessive–compulsive symptoms and phobic anxiety were assessed using appropriate subscales of the Crown–Crisp Experiential Index (CCEI), earlier called the Middlesex Hospital Questionnaire [27]. According to Crown and Crisp, CCEI has been formulated for three different purposes: to describe normal and deviant groups, to study psychosomatic interrelationships, and as a clinical psychometric test to study personality change following either psychological or somatic therapies [28]. The levels of anxiety, obsessionality and phobic anxiety were based on the following subscales of the CCEI: the Free-Floating Anxiety (FFA), Obsessionality (OBS), and Phobic (PHO) subscale. In this study the sum score of the FFA, OBS and PHO subscales were used as a continuous variable in statistical analyses, since in the literature, there are neither standard reference values nor cut-off points for these subscales to indicate anxious, obsessive or phobic disorder in a person [28].
2.3. Assessment of depression Depressive symptoms were evaluated by the Beck Depression Inventory (BDI), which is a self-report rating inventory measuring characteristic attitudes and symptoms of depression [29]. In this study, depression was defined to be present if the patient’s BDI sum score was 15 or higher. It has been shown that with a cut-off point of 14/15 the BDI-21 can be used to indicate the presence of a major depressive episode regardless of the phase of the major depressive disorder [30]. 2.4. Statistical analyses Differences in categorical variables were tested with the Chi-Square test or Fischer exact test. Statistical significance of group differences in continuous variables was analyzed with the Mann–Whitney U-test or Student’s t-test. The statistical significance of differences between repeated measurements was assessed with Wilcoxon signed rank test (two repeated measurements). All statistical analyses were performed using the SPSS statistical software, version 11, and the results in this study were considered statistically significant when the appropriately calculated twotailed p-value was ≤0.05. 3. Results 3.1. Prevalence of depression In the total study population (n = 77), there were 16% patients indicating major depression according to BDI before tumor operation, compared to 10% at three months and 15% at one year after operation. The decrease in depression scores over time was not statistically significant. 3.2. Characteristics of depressed and non-depressed brain tumor patients Table 1 presents the tumor and patient characteristics of the study subjects according to their depression status. None of these characteristics differed statistically significantly between depressed and non-depressed brain tumor patients. 3.3. Prevalence of anxiety, obsessionality and phobia In the total data set the mean anxiety scores decreased statistically significantly when comparing the scores before operations to measurements made after the operation. Mean (sd) anxiety score before the operation was 4.4 (3.3), while it was 3.3 (2.3) at three months (Wilcoxon signed rank test, Z = −3.216, p-value = 0.001) and 3.2 (2.3) at one year after the operation (Wilcoxon signed rank test, Z = −3.051, p-value = 0.002). There were no statistically significant changes over time in the mean (sd) levels of obsessionality [baseline: 6.9 (3.2), 3 months: 7.3 (3.1), one year: 6.9 (3.2)] or in the levels of phobic anxiety [baseline: 3.3 (3.2), 3 months: 3.3 (2.4), one year: 3.4 (2.5)]. 3.4. Depression in relation to anxiety, obsessionality and phobia Table 2 shows the level of anxiety, obsessionality as well as phobic anxiety among depressed and non-depressed brain tumor patients. The depressed patients had statistically significantly higher anxiety scores at all three measurement points compared to corresponding scores among non-depressed brain tumor patients. The mean obsessionality scores among depressed brain tumor patients were significantly higher at the measurements before operation, and at one year after operation compared
A. Mainio et al. / Clinical Neurology and Neurosurgery 113 (2011) 649–653 Table 1 Patient and tumor characteristic of study subjects according to their depression status.
Patient characteristics Gender Male Female Age, mean (sd) Marital status Married Not married Employment status Employed Unemployed Sickness leave Pensioner Tumor characteristics Tumor histology Glioma grade I–II Glioma grade III–IV Meningioma Acoustic neurinoma Pituitary adenoma Other tumorsa Hemisphere In left hemisphere In right hemisphere Bilaterally Not identified Location Anteriorly Other Volume Under 25 ml 25 ml or more Not identified Extent of surgery Extirpation Resection Biopsy/unknown Chemotherapy Yes No Not reported Radiotherapy Yes No Not reported
Depressed patients (n = 12) BDI ≥ 15
Non-depressed patients (n = 65) BDI < 15
3 (25) 9 (75) 44.8 (11.4)
27 (41.5) 38 (58.5) 47.3 (11.6)
11 (92) 1 (8)
51 (78.5) 14 (21.5)
Group difference, p-value** 0.348
0.343 0.194
0.105 5 (41) 2 (17) 5 (42) –
22 (34) 11 (17) 18 (28) 14 (21)
2 (17) 4 (33) 4 (33) 1 (8) – 1 (8)
14 (22) 11 (17) 19 (29) 11 (17) 7 (11) 3 (5)
5 (42) 5 (42) 2 (16) –
31 (48) 20 (31) 9 (14) 5 (7)
8 (67) 4 (33)
31 (48) 34 (52)
4 (33) 8 (67) –
36 (55) 27 (42) 2 (3)
5 (42) 3 (25) 4 (33)
36 (55) 14 (22) 15 (23)
3 (25) 8 (67) 1 (8)
3 (5) 53 (81) 9 (14)
5 (42) 6 (50) 1 (8)
26 (40) 30 (46) 9 (14)
0.606
0.811
0.404
0.206
0.297
0.051
0.608
Note: Values are numbers (percentage in parenthesis) if not otherwise specified. a Others include two hemangiopericytomas, malignant lymphoma, craniopharyngeoma and two undefined tumors. ** Chi-square or Fischer Exact test in categorical variables, and Student’s t-test in continuous variables, two-tailed significance.
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to non-depressed patients. Furthermore, the phobic scores were statistically significantly higher among the depressed brain tumor patients before tumor operation and at one year after operation. Further, the gender difference in anxiety, obsessionality and phobic anxiety scores among depressed brain tumor patients was examined. There were no statistically significant gender differences at any measurement points according to different psychiatric subgroups (anxiety, obsessionality or phobic anxiety) in the depressed brain tumor patients. 4. Discussion We found in the present study that 16% of the brain tumor patients had clinical depression while waiting for tumor surgery. Although no statistically significant change in depression scores over time was observed, the proportion of depressed patients decreased slightly in the follow-up at three months after the operation, rising again at one year after the operation to the same level as before the operation. In our data the prevalence of depression was in the lowest level compared the corresponding proportion in earlier literature, which has reported the prevalence of depression being about 15–44% before tumor operation and up to 70% in the follow-up [2,4,5,31]. The depressed brain tumor patients did not differ from the nondepressed patients in terms of sociodemographic characteristics, nor did they differ significantly from the non-depressed patients according to tumor malignancy or tumor location. Similarly to our results, in a study by Madhusoodanan et al., depression among brain tumor patients was not found to be associated with tumor type or location [31]. We found a high level of anxiety before tumor operation in the patients of the study sample. Some studies have reported FFA norms for mentally healthy general practice patients, Finnish healthy controls and outpatients with psychoneurotic illness [28,32]. The level of anxiety among depressed patients in our data set reached the norms reported in psychoneurotic patients, norms being 9–11 for anxiety disorder [28]. The anxiety scores declined as soon as at three months after the operation to the level found in general population, norms being 3–5 for mentally healthy subjects. Our finding is in line with previous studies in which a high level of anxiety has also been found in patients waiting for tumor surgery [2,33]. D’Angelo et al. found that anxiety among brain tumor patients did not change at the follow-up [33]. Our findings confirm this only among the non-depressive patients. In our study the level of anxiety remained at the high level among the depressed patients and we emphasize, according to our findings that a great treatment attention in clinical practice have to be focused on those brain tumor patients with multiple psychiatric symptoms at the same time.
Table 2 Anxiety, obsessionality and phobic anxiety scores among depressed and non-depressed brain tumor patients before operation and at two follow-up measurement points. Depressed patients (n = 12)
Non-depressed patients (n = 65)
Group difference, p-value*
Mean (sd)
Median (IQR)
Mean (sd)
Median (IQR)
Anxiety sum-score Before operation At three months after operation At one year after operation
9.1(3.8) 4.8 (2.0) 6.4 (2.5)
10.0 (5.5–11.0) 4.5 (3.0–7.0) 6.0 (4.0–8.0)
3.6 (2.6) 3.2 (2.3) 2.6 (1.8)
3.0 (1.5–4.0) 3.0 (2.0–4.0) 2.0 (1.0–3.0)
0.000 0.043 0.000
Obsessionality sum-score Before operation At three months after operation At one year after operation
9.1(4.1) 7.0 (2.8) 9.5 (3.4)
10.0 (6.0–12.0) 6.5 (6.0–9.5) 9.0 (7.0–13.0)
6.6 (2.9) 7.3 (3.1) 6.5 (3.0)
7.0 (4.0–9.0) 7.0 (5.0–10.5) 7.0 (5.0–9.0)
0.018 0.805 0.024
Phobic anxiety sum-score Before operation At three months after operation At one year after operation
5.8 (2.1) 2.8 (1.5) 5.4 (2.1)
6.0 (5.0–7.0) 2.5 (2.0–3.0) 5.0 (4.0–7.0)
2.9 (2.1) 3.3 (2.4) 3.1 (2.3)
2.0 (1.0–4.0) 3.0 (1.0–5.0) 3.0 (1.0–5.0)
0.001 0.696 0.005
*
Mann–Whitney U-test, two-tailed significance.
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We found that in the total study sample, obsessionality and phobic anxiety did not change significantly during the follow-up in non-depressed patients. In addition, the level of these psychiatric symptoms was at the level found in reported norms for mentally healthy persons, i.e. 6–7 for obsessionality and 2.5–5 for phobic anxiety [28]. The main finding of the present study was that the depressed brain tumor patients had significantly higher scores of anxiety, obsessionality and phobic anxiety compared to non-depressed patients. This difference was found before tumor operation and also in the follow-up at one year after tumor surgery. To our knowledge, this is the first study so far in which comorbidity of psychiatric symptoms has been shown among depressive brain tumor patients. Earlier studies have indicated other problems associated with depression among brain tumor patients as well; depressive brain tumor patients have shorter survival compared to non-depressive brain tumor patients [5–7]. The quality of life of depressive brain tumor patients has also been shown to be lower compared to nondepressive patients [34,3]. None of these studies observed any other psychiatric symptoms besides depression. However, it has been documented that the course of disease in depressive patients with comorbid psychiatric disorder is more complicated compared to patients without other psychiatric disorders [35–37]. Concurrent comorbid conditions have been shown to be associated with increased severity, morbidity and chronicity of depression as well as with more social and occupational impairment [35,36]. Pharmacological treatment of depression in patients with physical illnesses is useful and has the same basic principles as the treatment of depression in general [38]. The drugs of choice in pharmacotherapeutic treatment of depression with anxiety are selective serotonin reuptake inhibitors (SSRIs), venlafaxine, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) [38–41]. However, according to a recent review, there are no randomized controlled trials (RCTs) evaluating the adequate treatment of depression in brain tumor patients. Thus, if brain tumor patients are treated with antidepressant drugs close follow up is needed due to high risk of side effects i.e. epilepsy, cognitive dysfunction or fatigue among these patients [42]. Also, as long as we have no special guide line for treating psychiatric disorders among patients with a brain tumor we have to turn to general guide lines. It has been recommended that the treatment of depressive patients complicated with comorbid psychiatric disorders should be planned in specialist medical care [43]. Psychotherapy and pharmacotherapy generally are of comparable efficacy, and both modalities are superior to usual care in treating depression [43]. We suggest that psychosocial interventions for brain tumor patients should consist of both psychotherapy and pharmacotherapy. The main psychological methods have to consist of crisis therapy with supportive elements and psychoeducational techniques. By supportive therapy the patient’s productive coping strategies are strengthened. In a dynamic approach of individual psychotherapy the patient is helped to bring meaning to the illness [44]. The limitations of this study must be acknowledged. From a psychiatric point of view it was unfortunate that the study protocol did not include any structured psychiatric diagnostic interviews. The existence of the patients’ psychiatric symptoms was based on self-administered questionnaires. In addition, no information was available concerning the patients’ previous history of psychiatric disorders, psychiatric treatment, family history of psychiatric diseases or corticosteroid therapy during data collection. It must be mentioned as a limitation of the CCEI questionnaire that there are no standard cut-off points or border values for the subscales used in the study with which the respective values observed in the studies of this thesis could have been directly compared. Nevertheless, it is reported that CCEI is a valid instrument for evaluating
psychiatric, neurotic psychopathology in psychiatric patients and somatically ill patients [45] as well as change in psychic state following either psychological or somatic therapies [24]. Further, our data has been collected on years from 1990 to 1992 but we suggest that it is not very assumable that major findings concerning the prevalence of psychiatric symptoms among brain tumor patients would have changed even if we have had a more recent data. The major strength of the present study was the prospective study design with repeated measurements. The patients were personally and carefully interviewed by a trained psychologist and by a trained physician at each measurement point. The histological grading of the tumors followed the WHO classification and it was thoroughly determined by a specialist in pathology. Furthermore, the tumors consisted of both benign and malignant brain tumors, which gave an opportunity to compare the effect of tumor malignancy on psychiatric symptoms. 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