Mainio, Arja M.D.; Hakko, Helinä Ph.D.; Timonen, Markku M.D.; Niemelä, Asko M.D.; Koivukangas, John M.D., Ph.D.; Räsänen, Pirkko M.D., Ph.D.
Recently, in this journal, Litofsky et al. (26) reported depression to be a common complication and predictor for shorter survival among patients with high-grade glioma. In that study, both those patients whose depression was diagnosed by physician according to Diagnostic and Statistical Manual IV criteria and those who self-reported their depression had significantly shorter survival (34 wk) compared with nondepressed patients (41 wk). Treatment of depression with antidepressants was not related to the length survival of the depressive patients (26).
Depression is a common psychiatric disorder in patients with any type of cancer, and as many as one-quarter of cancer patients may be severely depressed (4, 44). Furthermore, a neoplasm in the central nervous system is considered to be a special risk factor for developing depression (44). In different types of samples of patients with a primary brain tumor, the prevalence of depressive symptoms varies from 15% to 38% (2, 26, 36, 39, 52). The great prevalence of depression among brain tumor patients is easy to understand because the biological roots of depression are related to dysfunction in neurotransmitter metabolism such as serotonin and norepinephrine in the brain (32, 41).
The brain tumor, being an expansive process, is both a progressive disease (51) and one that causes focal cerebral dysfunction, depending on the site of lesion (43). However, the level of depression among neurosurgical patients with a brain tumor was not shown to differ from that observed in patients with elective lumbar spinal surgery (39).
Several biopsychosocial risk factors are suggested to be related to increased mortality among brain tumor patients. Lutterbach et al. (27) reported that predictors for better survival in patients with glioblastoma multiforme were: age (<50 yr), good clinical condition (Karnofsky Performance Scale status >70), and tumor location only in the hemispheres versus those with central tumor location. In patients with low-grade astrocytoma (34), good prognosis was associated with young age, female sex, and good success of tumor extirpation, whereas cognitive impairment and tumor involvement of two or more lobes were risk factors for shorter survival. In a population-based study, the risk of death among patients with malignant histological features of the tumor (glioblastoma, astrocytoma, or glioma) was six to eight times more than among those with benign neuromas or meningiomas (25). However, the effect of depression on cancer mortality was not investigated in any of these studies.
The impact of depression or depressive mood on cancer survival thus far has not yet been clarified sufficiently (45, 46); in particular, studies on patients with brain tumor are mainly lacking. In this study, we examined a putative association of depression to the survival after removal of tumor. Our study population included patients with gliomas, as did the study by Litofsky et al. (26), but also patients with other types of brain tumors. We were able to follow the length of survival for more than 60 months after surgery and also to control for sociodemographic factors as well as previous patient history of depression and tumor characteristics.
PATIENTS AND METHODS
The original study population consisted of 101 patients with a solitary primary brain tumor treated surgically at the Oulu Clinic for Neurosurgery, Oulu University Hospital, Northern Finland, between February 1990 and March 1992 (28). From an epidemiological point of view, the cohort was a comprehensive and unselected sample of the population because the Oulu Clinic for Neurosurgery performs all resections of brain tumors in its catchment area. Geographically, this area covers approximately 49% of Finland. Written informed consent was obtained from all the participants, and the Ethics Committee of the Oulu University Hospital approved the study protocol.
The complete database of depressive status was available for 75 patients. Those who were excluded (n = 26) had tumor-induced motor aphasia, were confused, or their level of consciousness was reduced because of raised intracranial pressure. The final database consisted of 29 men and 46 women. The mean age before operation was 48.3 years (standard deviation [SD], 11.4 yr) for men and 45.9 years (SD, 11.9 yr) for women (P = 0.197; Z = −1.290, Mann-Whitney U test). Sociodemographic information was collected during admission to hospital for the tumor surgery; the patients were interviewed by a trained physician.
The radiological diagnosis of the brain tumor was carried out by computed tomographic (CT) scanning or magnetic resonance imaging (MRI). The histological features of the tumor were defined according to World Health Organization classification (22): Grade I–II (low-grade) gliomas (n = 16), Grade III–IV (high-grade) gliomas (n = 15), meningiomas (n = 22), pituitary adenomas (n = 6), acoustic neuromas (n = 12), and other solitary tumors (n = 4).
The brain tumor of the patient was specified as being located in the left or the right hemisphere or bilaterally. The anatomic classification of the brain developed by Matsui et al. (29) was used to define the location of various brain structures. The tumors were divided into those located in the left or right hemisphere as well as anteriorly or posteriorly if they reached the supratentorial space, as described by Salo et al. (42). The distance of the tumor from the apex of the frontal lobe was determined by calculating, from each CT or MRI slice, the ratio of the distance between the anterior part of the tumor and the apex of the frontal lobe to the anteroposterior diameter of the entire brain. The mean of these percentages was used to describe the distance from the apex of the frontal lobe to the tumor (29). Because central tumor location and tumor expansion in both hemispheres have been identified as risk factors for shorter survival (27, 34), we categorized the tumors as 1) bilateral tumors if they were located in central regions or reached the two hemispheres (n = 11; 14.7%), and 2) hemispheric tumors (n = 64; 85.3%) if they were located in only the left or right hemisphere.
The volume of each tumor was determined manually from the CT or MRI scan by the same method as that of Salo et al. (42). In this study, the tumors were divided in two size classes according to the volume of the tumor: 1) tumors with volume ≤25 ml (n = 40; 53.3%), and 2) tumors with volume >25 ml (n = 35; 46.7%).
Marital status of the patient was determined before surgery and patients were classified as being married (n = 60; 80%) or not married (n = 15; 20.0%). The group of patients who were not married included six unmarried, three divorced, and six widowed patients.
Twenty-nine patients (38.7%) were considered to be employed; the remaining 46 patients (61.3%) were considered to be unemployed, regardless of whether they had worked full-time or part-time. The unemployed group included 3 unemployed patients, 23 patients on medical leave, 4 students, and 16 pensioners.
Definition of Depression
Preoperative depressive symptoms were evaluated by the Beck Depression Inventory (BDI) before the patients were aware of the histological diagnosis of the tumor. The BDI is a widely used screening instrument for depressive symptoms, and it is reported to correspond to diagnostic criteria for depression found in the Diagnostic and Statistical Manual IV (3). The BDI has been used in evaluating depressive symptoms among patients with a primary brain tumor (19, 36). According to the BDI scale, depression is present if the BDI scores are 10 or more; the same classification was used in our study.
The patients also were asked to report whether they had ever experienced depressive periods during their lifetime. This previous depression was evaluated by using the depression scale of the Crown-Crisp Experiential Index (CCEI) (1). The CCEI, earlier called the Middlesex Hospital Questionnaire, is a clinical self-rating diagnostic scale that differentiates healthy patients and psychoneurotic patients at a statistically significant level (1, 5). The CCEI has been used in studies on patients with psychiatric (7) or somatic (13) diseases, and it also has been validated for the Finnish population (18).
The patients completed both depression questionnaires during admission for the surgical operation of the brain tumor, within 1 to 5 days before the operation. A trained psychologist administered both the BDI and the CCEI questionnaire before the patients knew the level of malignancy of the tumor.
Three study groups were formed based on the information on current and previous depression of the patients. The first group included patients who had been experiencing depression immediately before surgery. The second group covered those patients who had experienced depression previously but were not depressive immediately before the surgery. The last group consisted of patients without any current or past history of depression. This categorization was chosen because in the literature, depression is reported to be a recurrent disorder (11, 21). Therefore, current depression in the patients can be considered to have been induced by the tumor.
Assessment of Survival
The survival status of each patient was calculated from the date of surgery to the time of death or to the end of the follow-up after 60 months. The information on the 5-year survival (gross survival) was obtained from the Cause of Death Register, provided by Statistics Finland.
Group differences in continuous variables were tested with the Mann-Whitney U test (two independent groups) and Kruskal-Wallis test (three independent groups), and categorical variables were tested with the χ2 and Fisher’s exact tests. The Kaplan-Meier survival analysis and log-rank test were used to assess the statistical significance of difference in the length of survival between the subgroups of depression (no depression, previous depression, current depression). Survival curves in patients with Grade III–IV glioma and Grade I–II glioma were estimated separately for the subgroups of the depression after adjustment for patient age, sex, and employment status. All statistical analyses were performed using the SPSS statistical software, version 10 (SPSS, Inc., Chicago, IL).
Malignant tumors were statistically significantly associated with shorter survival: the patients with a malignant glioma (Grade III–IV) had a survival time of 22.5 months (SD, 21.4 mo), whereas the corresponding time for patients with Grade I–II glioma was 50.2 months (SD, 19.9 mo) and for patients with a histologically benign tumor was 58.2 months (SD, 9.4 mo; P < 0.001, difference between groups, Kruskal-Wallis test).
Table 1 shows the sociodemographic and clinical characteristics of the patients with a primary brain tumor according to their survival status in different histological subgroups. In the patients with a Grade I–II glioma or a benign tumor, the location of tumor and extent of surgery were significantly associated with survival time. A corresponding association was not found in the patients with a Grade III–IV glioma.
As shown in Table 2, the proportion of patients alive in the group with Grade III–IV gliomas was 20%, whereas the corresponding proportion was 68.7% among the patients with Grade I–II gliomas and 95.4% among the rest of the patients (P < 0.001, χ2 test; df = 2).
The association of current depression with decreased survival time was most prevalent among patients with a low-grade glioma. In pairwise comparisons, a statistically significant difference in survival distributions was found in the low-grade glioma group between patients with current depression compared with those without any history of depression (P = 0.031, Kaplan-Meier survival analysis). Figure 1 demonstrates the survival estimates among patients with a high-grade glioma and a low-grade glioma after adjustment for patient age, sex, and employment status.
The prevalence of current depression in different treatment groups varied from 2.5% to 15.4%. The prevalence was lowest in the patients with total extirpation of the tumor (n = 40) and the highest among the patients with subtotal resection and those whose tumors were inoperable (n = 35). Furthermore, the proportion of currently depressive patients was 6.5% in the radiotherapy group (n = 31) and 8.6% among those who did not receive radiotherapy (n = 44). The prevalence of depression did not differ statistically significantly according to treatment groups.
In recent years, increased attention has been focused on pretreatment factors as predictors for survival among brain tumor patients (25, 27). Similarly, the concurrence of depression and cancer has gained a great deal of interest in psychiatric research (8, 15, 20, 26, 46).
Adverse Impact of Depression on Survival
In this study, we were able to establish that current, preoperative depression, assessed soon after brain tumor diagnosis, was a significant predictor for shorter survival among patients with a low-grade glioma. Our finding is in line with the study of Litofsky et al. (26) in which depression was associated with shorter survival among high-grade glioma patients; however, in our study, the follow-up was 10 times longer. Furthermore, what is novel is that our study highlights the importance of current but not previous depression on the length of survival after brain tumor operation.
It is known that there is concurrence between cancer and depression and that the prevalence of depression in cancer patients increases with disease severity and symptoms (8). With regard to the role of depression as a predisposing factor for cancer, earlier findings are contradictory to some extent (46). Instead, there is stronger evidence that depression predicts cancer progression and mortality, as reviewed by Spiegel and Giese-Davis (46). The pathophysiology behind the association between cancer and depression is most probably multifactorial (20). It has been proposed that depression is not merely a purely psychological reaction to the cancer, but that the association between these disorders has biochemical roots (15, 46). For example, dysregulation of the hypothalamic-pituitary-adrenal axis, changes in cytokine levels in brain, and disturbed fatty acid and phospholipid metabolism have been suggested as explanations for the association between depression and cancer (8, 15, 46). These theories also may explain our findings, but unfortunately, our data did not include measurement of the biochemical markers mentioned above.
In general, the finding of an association between cancer and depression may be nonspecific. An increased risk of depression also has been noted in connection with many other physical diseases as well. There may also be other intervening factors besides depression explaining the shorter survival of depressive brain tumor patients.
Association of Depression and Brain Tumor
Current depressive symptoms before tumor operation or previous patient depression were not directly related to malignancy of the brain tumor in this study sample. It is understandable that awareness of malignancy was not associated with depression because the patients did not know at the measurement point whether their tumor was benign or malignant by histological evaluation. Serotonin and norepinephrine as well as dysfunction in interactions between these systems have fundamental roles in the cause of depression (32, 41). Furthermore, changes in these neurotransmitters and in neurotransmitter metabolite concentrations, reuptake sites, and receptors support the hypothesis of serotonergic and noradrenergic neuronal dysfunction in depression patients. There is evidence of underactivation of serotonergic function and complex dysregulation of noradrenergic function (32, 41).
In addition, 5-hydroxytryptamine receptors have been found in human glioma cells, and serotonin has been found to positively modulate glioma cell proliferation, migration, and invasion in vitro (30). It has been suggested that serotonin has an important role in the control of the biological properties of human glioma cells, and the serotonergic system in the brain area surrounding tumor may change (30, 33). In addition, patients with lesions in the ventral frontal cortex or lesions in the temporoparietal cortex have been reported to have statistically significantly worse mood states after surgery than those with lesions in other regions of the brain (17). It is suggested that lesions in cortical interconnection with limbic structures are important for the development of neuropsychiatric symptoms such as depression in brain tumor patients (51). Psychiatric symptoms most probably originate from dysregulation in the frontal and/or limbic release or disinhibition system in which serotonin and norepinephrine may play a significant role (24). Thus, we speculate that a brain tumor, per se, may have a direct pathophysiological effect on the brain because of the dysfunction in the serotonergic system caused by the glioma and thus may predispose a person to depression. The literature about psychiatric disorders in patients with a primary brain tumor has varied concerning the conceptualization and measurement of depression (36). Also, it is not yet known whether mood symptoms such as depression are the result of the direct effects of the tumor or whether they are psychological reactions in adapting to the diagnosis of severe disease (39).
Psychological Coping and Cancer Survival
From a psychological perspective, there is a popular belief that a depressive person with cancer may concede and surrender his life to cancer. In the literature, the association between psychological coping factors and cancer survival is to some extent inconsistent: fighting spirit (12, 38, 49) has been suggested to be associated with better survival, whereas helplessness/hopelessness (12, 31) has been suggested to be linked with a poorer chance of cancer survival. Petticrew et al. (37) in their systematic review focused on the fact that no consistent association exists between different psychological coping styles and cancer survival. However, there is evidence that supportive/expressive or cognitive-behavioral therapy for depressive cancer patients has led to normalized cortisol levels and increased survival time of these patients (6, 50).
Other Predisposing Factors for Survival
It is self-evident that the main predictor for survival among patients with a primary brain tumor is the malignancy of the tumor, as found previously (25). In our study, the length of survival was more than two times higher among the patients with a benign tumor compared with those with a malignant tumor. We found that prognostic factors for better survival were tumor location in one hemisphere compared with bilaterality of tumor and wider extent of surgery in patients with low-grade gliomas and benign tumors. These findings earlier have been reported among astrocytoma and glioblastoma patients (16, 25, 34).
Limitations of Our Study
A small number of cases in different histological groups was a limitation of our study, and thus our findings are preliminary. Another limitation was that in our database, the information on tumor location as well as dichotomized information on tumor volume was rough. From a psychiatric perspective, a major deficit in this database was that psychiatric diagnosis by any structured diagnostic interview was not available in this study. Also, any information of lifetime therapeutic interventions or psychological treatments was lacking. Thus, unfortunately no adjustment for treatment factors or later depression could be performed.
Nevertheless, the adaptive reaction of a patient is to be shocked or saddened when confronted with a serious disease. In our opinion, regardless of tumor malignancy, all the patients and their families would benefit from guidance concerning normal human psychological reactions and thus from a supportive intervention. If clinical depression is evident in the brain tumor patient, it is essential to treat it. The evidence-based treatment of depression consists of medical care, such as administration of selective serotonin reuptake inhibitors (14, 40, 48). Among psychosocial therapies, cognitive psychotherapy is the treatment of choice (10, 35). Although Litofsky et al. (26) found no association with depression treatment and survival, it was reported earlier that adequate treatment improves the prognosis of disease (23) and also the patient’s quality of life (9, 47).
More research is needed to evaluate depression among brain tumor patients by structured and standardized diagnostic methods to distinguish the patients whose depression actually needs treatment. It is also essential to study the effective treatment of clinical depression among brain tumor patients and the impact of treatment on the patients’ chances of survival.
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The authors address a relevant area of investigation that has received little attention in the literature. In a 5-year follow-up study involving brain tumor patients, they reported that depression at the time of diagnosis but before surgical intervention was a significant prognostic factor for worse survival among 16 patients with low-grade gliomas. Depression did not predict survival in either high-grade glioma or benign tumor patients. Tumors restricted to one hemisphere and with a greater extent of surgical resection were associated with increased survival among patients with low-grade gliomas and benign tumors. However, the validity of the comparisons according to tumor location was limited by the fact that 15 of the 16 patients had tumors in one hemisphere.
As the authors acknowledged, the findings are preliminary given several limitations to the study, the most significant being the small number of patients available to perform group comparisons. The absence of more detailed information regarding tumor location within each hemisphere makes it unclear whether most patients had tumors involving the frontal lobes. As noted by the authors, lesions that disrupt frontal-limbic connectivity can be associated with the development of psychiatric symptoms. The presence of cognitive dysfunction and degree of insight, seizures, and anti-epileptic or other pharmacological treatments (e.g., corticosteroids) may also have affected the mood of the patients studied. Finally, it is unclear why depression would affect survival only in low-grade glioma patients. Nevertheless, this study represents an initial step in trying to understand the possible role of mood in the survival of brain tumor patients. As depression can be treated with psychopharmacological and psychotherapeutic interventions, its contribution to brain tumor patients’ survival warrants further investigation. Future prospective studies that identify relevant contributing variables and assess specific neurotransmitters would make a significant contribution to our understanding of the role of depression in both survival and quality of life of brain tumor patients, and would assist in the implementation of guidelines for early treatment interventions.
Denise D. Correa
Philip H. Gutin
New York, New York
In this study, the authors bring to our attention an unfortunate association between primary brain tumors and depression, both past and present. Moreover, they suggest that the presence of depression, at least in the subgroup of patients with a low-grade glioma, is likely to result in a shorter lifespan.
The authors proactively assess the depressive symptoms of brain tumor patients at presentation using the Beck Depression Inventory. The assessment of past depressive episodes is unfortunately not as well-documented and is, by necessity, retrospective in nature. Another weakness of the study is in the limited number of patients, so that by the end, the authors’ hypothesis could not be confirmed. What must be recognized, however, is the deleterious effect that the depression has on the quality of life of brain tumor patients and therefore, the need to routinely incorporate a detailed assessment of the cognitive and mood dysfunctions in the initial evaluation of all brain tumor patients, so that such dysfunctions are properly diagnosed and managed.
This informative study of depression in 75 surgically-treated brain tumor patients is valuable because of several favorable design features usually not present in similar studies. Patients were followed up for a 5-year duration and baseline self-report measures were obtained preoperatively within 1 to 5 days of surgery, thereby minimizing the interference from the emotional aspects of the initial formal diagnosis. Additionally, a relatively large number of patients were studied and the study population was homogeneous because the institutional study site covers half of Finland.
The authors reported a correlation between preoperative depressive symptoms and shorter survival in adult patients being treated for low grade gliomas, a finding deserving further scientific inquiry and verification. Interestingly, this correlation was not observed with patients being treated for either high-grade gliomas or benign tumors, which necessitates cautious interpretation and generalization of these results. The remaining findings in low-grade gliomas and benign tumors have been previously reported, including increased survival with tumors limited to one cerebral hemisphere or with greater extent of resection.
Psychocognitive studies of this type must account for tumor location because tumors involving the frontal lobe region can significantly impact upon behavior and personality. According to The Mental Status Examination in Neurology (5), lesions involving the dorsolateral convexities tend to produce apathy, reduced drive, depressed mentation, and impaired planning, all of which are changes sometimes misconstrued as depression. Although the authors calculated the distance of the tumor from the apex of the frontal lobe using computed tomographic or magnetic resonance imaging scans, this information was unfortunately not included in the analysis or discussion of the results.
Both self-reported and clinician-rated measures are commonly used to assess depression, each having benefits and drawbacks. Self-report measures, although they are not diagnostic tools, enable clinicians to screen a large number of patients and focus their attention on those who are more likely to be depressed. The authors elected to use the Beck Depression Inventory (1), although the Hospital Anxiety and Depression Scale, (6) and the Beck Depression Inventory-Fast Screen for Medical Patients (2) are self-report depression questionnaires that have been specifically designed to avoid the confounding influence of somatic symptoms, which is commonly a critical variable with a medically ill populations.
A significant limitation of all the self-report measures is the difficulty in converting a symptom severity rating to a clinical diagnosis. Although various cutoff scores exist, pinpointing the exact cutoff that optimizes the classification of depression while minimizing false positives and false negatives can be somewhat arbitrary. In this study, a cutoff score of 10 was used, which, according to the manual represents minimal depression (10–15), as compared to mild to moderate depression (16–19), moderate to severe depression (20–29), or severe depression (30–63). It is therefore difficult to interpret the findings in terms of the severity of depressive symptoms because of possible confounding influences from somatic complaints, as well as the lack of clarity on the severity of the symptoms. Because of these drawbacks in interpretation, many researchers elect to use clinician-rated diagnostic interviews, as the authors have appropriately recommended for future studies. The most commonly used are the Diagnostic Interview Schedule (3) and the Structured Clinical Interview for DSM (4). These diagnostic interviews, while informative, are much more time consuming than either an unstructured clinical interview or a brief screening questionnaire.
One of the stronger aspects of this article is its detailed inquiry into the pathophysiology behind the association between cancer and depression, providing an excellent framework for future scientific studies by hypothesizing the possible dysregulation of the serotonergic system by gliomas. The authors conclude by making the appropriate recommendation for further research to include a treatment arm to provide interventions such as psychopharmacologic medications and psychotherapy or counseling to address the symptoms of depression, along with biochemical markers and multiple assessment points to better understand the trajectory of these symptoms across time and treatment.
Jeffrey N. Bruce
New York, New York
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