A biobehavioral perspective on depressive symptoms in patients with cerebral astrocytoma.
Article Type: Clinical report
Subject: Radiotherapy (Health aspects)
Tumor necrosis factor (Health aspects)
Metastasis (Development and progression)
Metastasis (Risk factors)
Metastasis (Prognosis)
Metastasis (Care and treatment)
Metastasis (Health aspects)
Cancer patients (Prognosis)
Cancer patients (Care and treatment)
Cancer patients (Health aspects)
Mental health (Health aspects)
Oncology, Experimental (Health aspects)
Highly active antiretroviral therapy (Health aspects)
Stress management (Health aspects)
Depression, Mental (Development and progression)
Depression, Mental (Risk factors)
Depression, Mental (Prognosis)
Depression, Mental (Care and treatment)
Depression, Mental (Health aspects)
Anxiety (Development and progression)
Anxiety (Risk factors)
Anxiety (Prognosis)
Anxiety (Care and treatment)
Anxiety (Health aspects)
Family (Health aspects)
Intermediate filament proteins (Health aspects)
Gliomas (Development and progression)
Gliomas (Risk factors)
Gliomas (Prognosis)
Gliomas (Care and treatment)
Gliomas (Health aspects)
Glutamate (Health aspects)
Cancer (Diagnosis)
Cancer (Health aspects)
Cancer (Research)
Cancer (Adjuvant treatment)
Authors: Starkweather, Angela R.
Sherwood, Paula
Lyon, Debra E.
McCain, Nancy L.
Bovbjerg, Dana H.
Broaddus, William C.
Pub Date: 02/01/2011
Publication: Name: Journal of Neuroscience Nursing Publisher: American Association of Neuroscience Nurses Audience: Professional Format: Magazine/Journal Subject: Health care industry Copyright: COPYRIGHT 2011 American Association of Neuroscience Nurses ISSN: 0888-0395
Issue: Date: Feb, 2011 Source Volume: 43 Source Issue: 1
Topic: Canadian Subject Form: Tumour necrosis factor; Tumour removal
Product: Product Code: 8000421 Cancer Diagnosis; 8000220 Cancer & Cell R&D NAICS Code: 6215 Medical and Diagnostic Laboratories; 54171 Research and Development in the Physical, Engineering, and Life Sciences SIC Code: 8731 Commercial physical research; 8733 Noncommercial research organizations
Accession Number: 248333662
Full Text: ABSTRACT

More than 51,000 individuals are diagnosed with a primary brain tumor in the United States each year, and for those with the most common type of malignant tumor, an astrocytoma, almost 75% will die within 5 years of diagnosis. Although surgery, radiation, and chemotherapy have improved length of survival, mortality remains high, which underscores the need to understand how other factors affect the disease trajectory. Several recent studies have shown that depressive symptoms are independently associated with reduced quality of life and survival time after controlling for other variables in patients with an astrocytoma. Thus, depressive symptoms represent a significant risk factor for adverse outcomes in this patient population. A growing body of evidence indicates that depressive symptoms are linked to underlying biological phenomena, particularly inflammatory activation modulated through increased peripheral levels of proinflammatory cytokines. Recent research has shown that neoplastic astrocytes respond to elevated proinflammatory cytokine levels by secreting immune mediators within the central nervous system, including cytokines and glial fibrillary acidic protein that promote astrogliosis and angiogenesis and may increase tumor growth and metastasis. However, because these biological factors have not as yet been measured in conjunction with depressive symptoms in these patients, little is known about the interactions that potentially influence the treatment trajectory. To guide future research and to provide a deeper understanding of the factors that may influence depressive symptoms and length of survival in patients with an astrocytoma, a review of the literature was undertaken. Publications over the past 10 years were analyzed to examine the theoretical models and measures of depressive symptoms used in previous research. Although numerous studies have documented the relationship between depression and reduced length of survival, there were several methodological concerns identified, and there were no studies that biological variables. Yet, research in the basic sciences provides compelling evidence of specific included neuroendocrine-immune interactions orchestrated by astrocytes that can cause depressive symptoms and alter the tumor microenvironment so that standard treatments are not as effective. These findings support the need for clinically based research so that we can begin to understand the potentially modifiable biobehavioral mechanisms underlying depressive symptoms in patients with an astrocytoma. Grounded in the biobehavioral research paradigm of psychoneuroimmunology, a novel research program is presented that may provide a new level of understanding regarding the high prevalence of depressive symptoms in patients with an astrocytoma and lead to new treatment strategies, with possible implications for improved symptom management and quality of life in patients with brain tumors.

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Astrocytomas are a complex group of low- and high-grade tumors that comprise more than half of all primary brain tumors (Bondy et al., 2008). They are the most frequent cerebral tumor, with an incidence estimated at 1/12,500. Most patients diagnosed with an astrocytoma, regardless of the tumor grade, will not live beyond 5 years (Lin et al., 2002). Affecting primarily middle-aged adults, astrocytomas disrupt the lives of thousands of individuals and families each year as neurocognitive and functional status often deteriorate rapidly over the ensuing months. Besides the grade of astrocytoma, patient age and functional status remain the known preoperative prognostic indicators of survival (Lutterbach, Sauerbrei, & Guttenberg, 2003; McCarter et al., 2006). However, several recent studies have found that preoperative depressive symptoms are predictive of shorter survival time specifically among patients with an astrocytoma as opposed to other types of brain tumors (Gathinji et al., 2008; Litofsky et al., 2004; Mainio et al., 2006). Depressive symptoms have long been regarded as part of the normal emotional response to cancer diagnosis or a side effect of treatment (Gross, Smith, & Stem, 2007). Intriguing recent evidence, however, suggests that a biological pathway involving immune mediators may not only cause or worsen depressive symptoms but also may increase tumor treatment resistance (Litofsky & Resnick, 2009; Miller & Raison, 2008; Samaras et al., 2007). Although the grade of astrocytoma portends the disease trajectory and modalities of treatment, the proposed mechanisms underlying depressive symptoms may be present across grades because of the central role of astrocytes in regulating immune interactions within the central nervous system (CNS).

Epidemiological Overview of Astrocytoma

Astrocytomas represent 60% of all primary malignant brain tumors, and they are diagnosed in more than 24,000 people each year (American Cancer Society, 2007). Despite aggressive treatment, malignant astrocytomas cause more than 14,000 deaths annually. Astrocytomas are classified by tumor grade using the World Health Organization (WHO) system, which provides a prediction of their growth rate and ability to spread (Jemal et al., 2007). WHO grade I pilocytic astrocytomas and grade II diffuse astrocytomas are considered low grade, whereas the highly malignant forms, grade III anaplastic astrocytomas and grade IV glioblastoma multiforme (GBM), are high grade. The annual incidence of astrocytoma in the United States is 4 of every 100,000 people, with a male-to-female ratio of 3:2 (Central Brain Tumor Registry of the United States, 2008). Low-grade astrocytomas are more common in young adults, whereas high-grade astrocytomas primarily affect older adults. Caucasians are affected more often than any other race, and they occur more frequently in White non-Hispanics (American Cancer Society, 2007).

Pilocytic astrocytoma (WHO grade I) is a slow-growing cystic tumor occurring most often in young adulthood, with only a small portion (10%) located in the cerebral hemispheres (Jemal et al., 2007). Diffuse astrocytomas (WHO grade II), which include fibrillary astrocytoma, gemistocytic astrocytoma, and protoplasmic astrocytoma, affect primarily young adults and have a tendency for malignant progression to anaplastic astrocytoma and, ultimately, GBM. These tumors develop most commonly in the cerebrum and represent 35% of all astrocytic brain tumors. Anaplastic astrocytomas (WHO grade III) are most commonly located in the cerebral hemispheres and have a tendency to progress to GBM. The mean age at biopsy is approximately 41 years. GBM (WHO grade IV) is the most frequent malignant brain tumor, accounting for 15% of all brain tumors and 60% of all astrocytic tumors. The peak incidence occurs between the ages of 45 and 70 years, and these tumors are primarily found in the cerebral hemispheres (American Cancer Society, 2007).

Mean survival time varies by tumor grade, with the 5-year survival of grades I and II being 38% to 45%, respectively, whereas grade III is 29% and grade IV is 3% (Bondy et al., 2008). The median survival of patients with low-grade astrocytomas is 5 years, and most patients die from progression of their disease to a high-grade astrocytoma. The median survival for anaplastic astrocytoma is 3 years from time of diagnosis. Grade IV astrocytoma, GBM, is the most common type of glioma and has a survival time varying from less than 1 year to 3 years after initial diagnosis. Patients with a GBM usually have tumor recurrence, often within a year after completion of first-line therapy (Lin et al., 2002).

Although magnetic resonance imaging and positron emission tomography are used to provide a preliminary diagnosis, a biopsy must be performed to confirm diagnosis (Bondy et al., 2008). This typically occurs along with resection of the tumor. Tumor debulking or resection is the initial treatment for astrocytoma with the exception of tumors located in an area that would cause neurological devastation or when there is extensive metastasis (Claus & Black, 2006). Gross total resection has been associated with longer survival and improved neurological function (Brown et al., 2005). Surgery is followed by involved-field radiotherapy ranging from a total dose of 54 to 60 Gy, depending on tumor grade (Bondy et al., 2008). Adjuvant chemotherapy is not indicated for astrocytoma grades I to III but may be used to treat recurrent grade III tumors. Chemotherapy is typically used for grade IV astrocytomas, with temozolomide being the currently preferred agent because it is administered orally, has a favorable side effect profile, and is generally well tolerated by patients (Claus & Black, 2006). Unfortunately, despite advances in treatment modalities, little progress has been made in improving length of survival. Moreover, recent studies have shown that, regardless of the type and intensity of treatment, depressive symptoms are associated with shorter survival in patients with an astrocytoma (Gathinji et al., 2008; Litofsky et al., 2004; Mainio et al., 2005).

Literature Review

To guide future research and to provide a deeper understanding of the factors that may influence depressive symptoms and length of survival in patients with an astrocytoma, a review of the literature was undertaken. The questions of interest were the following: Is there an optimal theoretical model or framework used in prior studies that may inform future biobehavioral-based research? What methods or instruments have been used to measure depressive symptoms in patients with an astrocytoma? What other factors have been associated with depressive symptoms in previous research?

The following databases were used to obtain relevant research studies that address the questions of interest: CINAHL Plus, PsychINFO, OVID, and PubMed Central. The databases were searched for publications ranging from 1999 to 2009 using a combination of the following keywords or MeSH terms: brain neoplasms depression, depressive disorder, cytokines, and biological factors, with the following restrictions: English and research articles.

Results of the Literature Review

From the initial search, 18 articles were identified that measured depression or depressive symptoms in patients with a brain tumor. These publications were initially perused to inspect the study design and measurement of depressive symptoms. A more thorough examination was then conducted to identify the theoretical model of the study, the methods used to measure depressive symptoms, and other variables measured. The data from each article are listed in Table 1.

Theoretical Models of Previous Research

The theoretical model most often identified in the literature review was the biopsychosocial framework (Armstrong, Goldstein, Cohen, Jo, & Tallent, 2002; Arnold et al., 2008; Brown et al., 2006; Brown et al., 2005; D'Angelo et al., 2008; Davies, Hall, & Clarke, 2003; Giovagnoli, 1999; Giovagnoli, Silvani, Colombo, & Boiardi, 2005; Mainio et al., 2005, 2006; Wellisch, Kaleita, Freeman, Cloughesy, & Goldman, 2002). The remaining studies did not indicate or refer to a theoretical model when describing the study or in the discussion of the study results.

Methods Used to Measure Depressive Symptoms

Only one study included a diagnostic evaluation of depression by a neuropsychologist using major depressive disorder (MDD) criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Wellisch et al. (2002) evaluated depressive symptoms in 89 patients with a brain tumor, 70% of whom had an astrocytoma. Relevant symptoms of depression in these patients included energy loss, concentration problems, weight change, sadness, sleep disorder, motoric slowing, motivation loss/diminished interest in activities, guilt, and death ruminations. Six of the nine symptoms were reported by 50% or more of the patients. Of the sample, 28% were diagnosed with MDD by the neuropsychologist, indicating that this patient population was more than nine times more likely to have MDD than the general U.S. population.

Other studies used well-established screening instruments for depression, such as the Beck Depression Inventory (Armstrong et al., 2002; Hahn et al., 2003; Mainio et al., 2005, 2006; Pelletier, Verhoef, Khatri, & Hagen, 2002), the Multiphasic Personality Inventory-2 Depression (Armstrong et al., 2002), the Brief Patient Health Questionnaire (Arnold et al., 2008), the Hospital Anxiety and Depression Scale (Kilbride, Otellin, & Grigor'ev, 2007; Pringle, Taylor, & Whittle, 1999), and the Zung Self-rating Depression Scale (D'Angelo et al., 2008; Giovagnoli 1999; Giovagnoli et al., 2005). The remaining studies used mood assessment instruments, such as the Profile of Mood States, Short Form (Brown et al., 2005, 2006), the patient interviews (Davies et al., 2003), or the documentation of clinical depression in the patient's medical record by the physician or data suggestive of depression (Appleby, Appleby, & Rabin, 2008; Gathinji et al., 2008; Litofsky et al., 2004).

Other Factors That Influence Depressive Symptoms

Of the demographic variables measured, female gender (Armstrong et al., 2002; Arnold et al., 2008) and those with a lower educational level (Arnold et al., 2008) reported more symptoms of depression. A premorbid diagnosis of depression or diagnosis of active depression at the time of surgery were associated with more depressive symptoms in four studies (Appleby et al., 2008; Arnold et al., 2008; Gathinji et al., 2008; Kilbride et al., 2007). Tumor characteristics, such as lower grade (Arnold et al., 2008; Manio et al., 2005) or left hemisphere location (Armstrong et al., 2002; Hahn et al., 2003; Wellisch et al., 2002), were related to increased severity of depressive symptoms. The severity of other symptoms, including fatigue (Armstrong et al., 2002), cognitive impairment (Armstrong et al., 2002; Brown et al., 2006), and physical impairment (Brown et al., 2006; Davies et al., 2003; Giovagnoli, 1999; Giovagnoli et al., 2005), were found to increase depressive symptoms. Greater family support (Armstrong et al., 2002) and trait anxiety (D'Angelo et al., 2008; Giovagnoli, 1999) were found to be significantly related to depressive symptoms. And finally, a greater extent of surgery was related to decreased depressive symptoms in two studies (Brown et al., 2005; Gathinji et al., 2008) and increased depressive symptom in one study (Armstrong et al., 2002).

Discussion

Theoretical Models of Previous Research

The literature review revealed that the biopsychosocial framework of depression was the most common theoretical model used in exploring the relationships among depressive symptoms and outcomes in patients with a cerebral tumor. This framework emphasizes the dynamic interactions among neurocognitive factors, psychological processes, and the social environment and is particularly useful for exploring the factors associated with depression. However, the biopsychosocial model does not incorporate the biological interactions occurring within the individual, which may modulate neurocognitive factors and psychological processes.

In addition, although most studies that used the biopsychosocial framework documented the tumor type or histology, the analyses did not appear to control for this variable, which may dilute the significance of tumor biology on depressive symptoms. For example, gliomas (e.g., astrocytomas, oligodendrogliomas, and ependymomas) may be associated with depressive symptoms because of the involvement of immunocompetent cells, whereas other types of primary brain tumors (e.g., meningiomas or acoustic neuromas) may not (Litofsky & Resnick, 2009). Two studies reported that the association between depressive symptoms and decreased length of survival was more evident in low-grade tumors (Arnold et al., 2008; Mainio et al., 2005), whereas two studies controlled for tumor type and grade in the inclusion criteria and analyses (Gathinji et al., 2008; Litofsky et al., 2004). Because tumor histology and grade may affect the production and release of biological factors that cause depressive symptoms, these variables should be included in the theoretical framework.

None of the research studies reviewed measured biological factors in conjunction with depressive symptoms in patients with a brain tumor. Yet, extensive research in psychiatry and other areas of health science have shown that biological factors can trigger the onset of depressive symptoms (Dantzer & Kelley, 2007; Kelley et al., 2003; Muller & Schwartz, 2007). Proinflammatory cytokines (particularly interleukin [IL]-I, IL-6, and tumor necrosis factor [alpha]), molecules involved in the initiation of the inflammatory response, cause or exacerbate depressive symptoms and activate astrocytes to release cytokines within the CNS (Raghavendra, Tanga, & DeLeo, 2004; Vollmer-Conna et al., 2004; Wichers & Maes, 2002).

Astrocytes are the major glial cell population within the CNS and act as immunocompetent cells; that is, they regulate local immune responses through the production and release of cytokines, such as IL-l, IL-6, and tumor necrosis factor ct (Dong & Benveniste, 2001). When the integrity of astrocytes is compromised, such as occurs with neoplasia, astrocytes also release glial acidic fibrillary protein (GFAP) into the CNS in addition to increased cytokines. GFAP is a Type III intermediate filament protein, the major protein component of the astrocyte cytoskeleton (Laping, Teter, Nichols, Rozorski, & Finch, 2008). Thus, GFAP serves as a biomarker of astrogliosis, and serum levels have been found to be highly correlated with astrocytoma volume (Brommeland, Rosengran, Fridland, Hennig, & Isaksen, 2007). Local levels of GFAP along with elevated cytokines have been implicated as driving factors in astrocytic differentiation and growth, angiogenesis, and astrogliosis and may alter the tumor microenvironment so that immune cells do not attack the tumor cells (Korzhevskii, Otellin, & Grigor'ev, 2005; Radeff Huang, Seasholtz, & Brown, 2005; Schneider, Sailer, Ansorge, Firsching, & Reinhold, 2006). Altered GFAP levels have also been described in postmortem samples of brain tissue from physically healthy individuals with MDD (Davis et al., 2002; Muguel-Hidalso et al., 2000). Because GFAP levels have been found to rise with tumor progression (Brommeland et al., 2007), the relationship to depressive symptoms warrants further exploration.

Although increased secretion of several specific cytokines from astrocytoma cells have been described, there is mounting evidence that cytokine patterns or the balance between pro- and anti-inflammatory cytokines may be more important than isolated, individual cytokine levels in understanding astrocytoma growth and resistance to treatment (Hao et al., 2002). Indeed, Samaras et al. (2007) recently compared levels of IL-6 and IL-10 in astrocytic neoplasms and in peripheral blood. They found that levels of both cytokines were higher in peripheral blood compared with healthy controls and that tumor and peripheral levels were highly correlated. The median IL-10 expression level by the neoplastic cells was significantly lower than that of IE-6, suggesting a localized cellular mechanism of immune suppression. Moreover, the principal IL-6-positive cell type was the neoplastic astrocyte, whereas microglial cells and macrophages appeared to be the major source of IE-10. Similarly, Kumar et al. (2006) documented significantly lower levels of serum IL-12 and higher levels of IL-10 among newly diagnosed patients with anaplastic astrocytoma and GBM. The authors concluded that astrocytomas cause a Th1/Th2 cytokine imbalance. Although these particular cytokines are implicated in regulating cell growth, resistance to chemotherapy, and angiogenesis (Liebrich et al., 2007), the possible involvement of other cytokines has yet to be determined.

Within the past few years, advances in technology have enabled a broad spectrum of cytokine measurements from a single specimen, which could be used to study pro- and anti-inflammatory cytokine interactions in the blood and tissue. Immunohistochemistry or genetic biomarkers may be used to identify the specific cytokine-releasing cells, providing a new level of understanding about the biological interactions that affect depressive symptoms, quality of life, and the disease trajectory.

[FIGURE 1 OMITTED]

To incorporate the possible multiple interactions among depressive symptoms, biological factors, and outcomes, the integrative paradigm of psychoneuroimmunology (PNI) could be used to guide a program of research in this area (Fox, Shepherd, & McCain, 1999; Starkweather, Witek-Janusek, & Mathews, 2005). PNI is a biobehavioral framework focused on the mechanisms of multidimensional psychobehavioral--neuroendocrine--immune system interactions that influence disease-specific outcomes (McCain, Gray, Walter, & Robins, 2005). Critical cofactors are viewed as moderators of neuroendocrine-immune (biological) interactions that potentially predispose the individual to depressive symptoms (see Figure 1). These may include personal characteristics (demographics, comorbidities, current symptoms, or social support), disease characteristics (tumor type and location), and treatment characteristics (extent of surgery, radiation, and chemotherapy). Neuroendocrine-immune interactions are central to the framework, denoting their importance in mediating states of health and disease. As noted earlier, for patients with an astrocytoma, specific biological factors have been implicated: glial fibrillary acidic protein, a biomarker of astrocytic activation, and local and circulating cytokines (Brommeland et al., 2007; Kumar et al., 2006; Liebrich et al., 2007; Samaras et al., 2007). Use of the PNI framework allows an examination of the psychosocial and biological factors affecting symptoms of depression and a method to develop hypotheses regarding the interactions that affect clinical outcomes.

Methods Used to Measure Depressive Symptoms

Although most, if not all, studies purported to be measuring depression, only one study included a diagnostic neuropsychological examination, the gold standard method of diagnosing clinical depression (Wellisch et al., 2002). In addition, there was a wide range of instruments used, with most relying on self-report questionnaires or chart review, making comparisons among studies impossible. Because of these discrepancies in the definition of depression and depressive symptoms, it remains unclear whether patients with clinical depression are at risk of decreased survival time or whether those who have a high severity of depressive symptoms but do not qualify as clinically depressed are also at risk.

Depressive symptoms include emotional, cognitive, and physical effects, and many symptoms overlap with those engendered by the disease process or as side effects of treatment in patients with an astrocytoma. Although the detrimental effects of clinical depression on health is well recognized, there remains controversy over the significance of depressive symptoms in this population because symptoms caused by the presence of an astrocytoma, such as fatigue and insomnia, may be part of their disease process (somatic symptoms) as opposed to an emotional aspect of depression (affective symptoms; Pasquini & Biondi, 2007). Thus, the measurement of depressive symptoms in patients with an astrocytoma may grossly overestimate the presence of clinical depression.

Recent opinions within the oncology literature, however, encourage the use of an inclusive approach toward identifying depressed individuals by counting the number of depressive symptoms, even if they may be disease or treatment related (Guo et al., 2006; Pasquini & Biondi, 2007; Reich, 2008). Much data demonstrate that subsyndromal depression is associated with significant subsequent morbidity in individuals both with and without cancer (Goodwin, Zhang, & Ostir, 2004; Myers, 2008). Likewise, depressive symptoms, even when not qualifying as clinical depression or MDD, are predictive of increased morbidity and mortality across a range of medical conditions (Hjerl et al., 2003; Lima et al., 2007).

The findings of Litofsky et al. (2004) underscore the need to understand the symptom manifestations of depression versus depressive symptoms, the effect of depression and/or depressive symptoms on the treatment trajectory, and the type of interventions that may be effective. In their prospective study of 598 patients with high-grade glioma, they found that whereas physicians reported depression in 15% of patients during the early postoperative period, 93% of patients reported symptoms consistent with depression. Symptoms of depression increased across the 6-month period after surgery and were associated with reduced quality of life scores. The length of survival was significantly shorter among patients with depression, even among those who received anti-depressant therapy, compared with patients who were not depressed.

These findings support the need to measure depressive symptoms and to include serial diagnostic neuropsychological evaluations over time so that we can begin to understand the differences between patients who experience clinical depression versus depressive symptoms. The measurement of biological factors may also provide insight on the associated mechanisms so that new treatment strategies can begin to be developed. For instance, proinflammatory cytokines can cause different behavioral features, including both a depressive syndrome, distinguished primarily by affective symptoms, and a neurovegetative syndrome characterized by somatic symptoms such as fatigue and loss of appetite (Anisman & Merali, 2003; Dantzer, 2006; Maletic et al., 2007; Miller & O'Callaghan, 2005; Reich, 2008). Although the depressive syndrome is typically responsive to antidepressants, the neurovegetative syndrome appears to be resistant to antidepressant treatment (Miller & Raison, 2008; Reich, 2008). Thus, antidepressants may provide only part of the solution to cytokine-associated behavioral disturbances.

Novel approaches to symptom management may include pharmacological agents that directly inhibit proinflammatory cytokines or enhance glucocorticoid signaling and inhibit inflammatory signaling (Chen et al., 2002). Biobehavioral nursing interventions may complement medical therapies. Mindfulness-based meditation has been shown to be an effective strategy for reducing depressive symptoms in patients with cancer and immune-based disease (McCain et al., 2003, 2008).

Other Factors That Influence Depressive Symptoms

Additional factors identified in the literature review that may influence depressive symptoms can be broadly categorized into patient characteristics (gender, educational level, premorbid diagnosis of depression, trait anxiety, current symptoms [fatigue, cognitive impairment, physical functioning], and family support], tumor characteristics (tumor grade and location), and treatment characteristics (extent of tumor resection). These factors were added into the proposed theoretical model developed by the authors, which will be used to guide future research in this area (Figure 1).

Summary

The literature review revealed several methodological concerns that should be addressed in future research. Most studies mixed tumor types into one sample, which could dilute the significance of the study findings for patients with an astrocytoma. The measurement of depression or depressive symptoms was inconsistent between studies, creating variability in how patients are categorized (as depressed or nondepressed). It would be helpful if researchers could agree to use one method or instrument to measure depression and/or depressive symptoms in future studies so that results can be compared and the effect of various treatment modalities between sites can be more fully examined.

The pervasive nature of depressive symptoms over the disease trajectory, the recent evidence indicating a relationship between depressive symptoms and reduced length of survival, and the research showing that astrocytes orchestrate local cytokine concentrations suggest a common biobehavioral mechanism underlying the presence of depressive symptoms in patients with an astrocytoma. The literature review supports the need to gain a better understanding of how neuroendocrine-immune interactions influence outcomes with the goal of facilitating the development of effective treatment strategies. An initial step of a possible program of research would be to determine the relationships among the depressive symptoms, the selected biological factors, and the patient-reported, functional, and treatment-related outcomes over time in patients with a cerebral astrocytoma. The relationship between cytokine and GFAP levels in tumor tissue and serum could be evaluated to determine whether systemic concentrations correlate with concentrations within the CNS. Although previous studies have shown that tumor tissue and serum levels of some individual cytokines are highly correlated, a PNI-based program of research would examine a broader range of both pro- and anti-inflammatory cytokines. Without a clear understanding of how inflammatory mediators affect somatic versus affective symptoms and clinical outcomes over time, there is a great risk that these patients will continue to suffer from a potentially treatable aspect of the disease process.

Characterization of the cytokine profile and the balance between pro- and anti-inflammatory cytokines over time should be established to determine how cytokine interactions affect depressive symptoms, astrocytoma growth and recurrence, and length of survival. Application of the PNI framework will provide an integrated perspective, enhancing the exploration of the multiple interactions among biological factors, depressive symptoms, and critical cofactors so that the effect on outcomes can be better understood. The results of such a program of research might potentially provide empirical evidence regarding the biological mechanisms underlying depressive symptoms, which may ultimately lead to better symptom management and more speculatively to reduced morbidity and mortality in patients with an astrocytoma.

DOI: 10.1097/J NN.0b013e3182029859

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Questions or comments about this article may be directed to Angela R. Starkweather, PhD MSN ACNP-BC CNRN, at astarkweathe@ vcu.edu. She is an assistant professor at the Virginia Commonwealth University School of Nursing, Richmond, VA.

Paula Sherwood, PhD RN CNRN, is an associate professor at the University of Pittsburgh School of Nursing, Pittsburgh, PA.

Debra E. Lyon, PhD RN FNP-BC, is an associate professor and a chair at the Department of Family and Community Health Nursing, Virginia Commonwealth University School of Nursing, Richmond, VA.

Nancy L. McCain, DSN RN FAAN, is a professor at the Virginia Commonwealth University School of Nursing, Richmond, VA. Dana Howard Bovbjerg, PhD, is director at the Biobehavioral Medicine in Oncology Program, and a visiting professor at the Departments of Psychiatry, Psychology, and Behavioral & Community Health Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA.

William C. Broaddus, MD PhD, is a professor at the Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA.
TABLE 1. Literature Review Findings

Authors
and Year of   Study Design and Theoretical
Publication   Framework                    Factors Measured

Appleby       Retrospective review of      Age, gender, race, marital
et al.        patients with primary or     status, tumor type,
(2008)        metastatic brain tumors;     location, and size,
              theoretical framework not    premorbid psychiatric
              identified                   diagnoses, treatment
                                           modalities

Armstrong     Cross-sectional study of 57  Age, gender, marital
et al.        patients with low-grade      status, hand dominance,
(2002)        brain tumors following       fatigue, tumor type and
              surgery; biopsychosocial     location, extent of
              framework                    surgery, cognitive
                                           function, vocational
                                           status, family support,
                                           psychological defenses,
                                           physical symptoms

Arnold        Cross-sectional study of     Age, gender, marital
et al.        363 patients with a primary  status, ethnicity,
(2008)        brain tumor;                 education, tumor type,
              biopsychosocial framework    grade, and site, previous
                                           psychiatric illness,
                                           anxiety, and depression

Brown         Longitudinal study of 194    Age, gender, previous
et al.        patients with high-grade     radiotherapy, tumor grade,
(2006)        gliomas; biopsychosocial     location, laterality,
              framework                    extent of resection,
                                           medication, cognitive
                                           function, physical
                                           function, fatigue,
                                           depression, and QOL

Brown         Longitudinal study of 124    Extent of surgery,
et al.        patients with high-grade     medication, fatigue,
(2005)        gliomas before surgery and   depression, QOL
              at 2 and 4 months
              postsurgery;
              biopsychosocial framework

D'Angelo      Longitudinal study of 72     Age, gender, tumor type,
et al.        patients with a primary      location, and laterality,
(2008)        brain tumor before surgery   anxiety, depression, and
              and at 1, 3, 6, and 12       cognitive impairment
              months postsurgery;
              biopsychosocial framework

Davies        Cross-sectional study of 12  Age, gender, functional
et al.        patients with a malignant    status, work status, social
(2003)        brain tumor 24 months after  activities, and
              surgery; biopsychosocial     neuropsychological testing
              framework

Gathinji      Retrospective study of       Age, gender, marital
et al.        1,052 patients with          status, tumor type, size,
(2008)        malignant astrocytoma (WHO   location, and laterality
              grade III or IV);            and treatment modalities
              theoretical framework not
              identified

Giovagnoli    Cross-sectional study of 57  Age, gender, marital
(1999)        patients with primary        status, education,
              malignant brain tumor;       cognitive functioning,
              biopsychosocial framework    and work performance, QOL,
                                           tumor duration, type, and
                                           location

Giovagnoli    Cross-sectional study of 94  Age, gender, marital
et al.        patients with grades III to  status, education, tumor
(2005)        IV anaplastic astrocytoma;   grade and location,
              biopsychosocial framework    cognition, physical
                                           performance, mood, and QOL

Hahn et al.   Cross-sectional study of 68  Age, education, tumor type,
(2003)        patients with a primary      lateralization, size,
              brain tumor with no prior    functional status,
              radiotherapy; theoretical    neuropsychological testing,
              framework not identified     and depression

Kilbride      Longitudinal study of 51     Age, gender, tumor site,
et al.        patients with primary        laterality, grade,
(2007)        malignant brain tumor        functional status,
              postsurgery, 3 weeks         depression, and anxiety
              postsurgery, and
              preradiation treatment;
              biopsychosocial framework

Litofsky      Longitudinal study of 598    Age, gender, marital
et al.        patients with high-grade     status, tumor grade,
(2004)        glioma before surgery and    location, size, and
              1, 3, and 6 months           laterality and treatment
              postsurgery; theoretical     modalities
              framework not identified

Mainio        Longitudinal study of 77     Age, gender, education,
et al.        patients with grades I-IV    employment status, marital
(2006)        brain tumor before surgery   status, premorbid
              and 3 and 12 months          depression, tumor type,
              postsurgery;                 volume, and location,
              biopsychosocial framework    functional performance,
                                           premorbid depression, and
                                           active depression

Mainio        Longitudinal study of 77     Age, gender, education,
et al.        patients with grades I-IV    employment status, marital
(2005)        brain tumor before surgery   status, premorbid
              and 3 and 12 months          depression, tumor type,
              postsurgery;                 volume, and location,
              biopsychosocial framework    functional performance,
                                           premorbid depression, and
                                           active depression

Pelletier     Cross-sectional study among  Age, gender, marital
et al.        73 patients with a primary   status, education, tumor
(2002)        brain tumor; theoretical     type, depression, fatigue,
              framework not identified     emotional distress,
                                           existential well-being, and
                                           QOL

Pringle       Cross-sectional study of     Age, gender, marital
et al.        109 patients with an         status, education, tumor
(1999)        intracranial neoplasm;       type, location, and
              theoretical framework not    laterality
              identified

Wellisch      Cross-sectional study of 89  Age, marital status,
et al.        patients with PMBT           personal and family
(2002)        postsurgery or radiation;    psychiatric history, tumor
              biopsychosocial framework    location,
                                           neuropsychological testing,
                                           and self-reported symptoms

Authors
and Year of
Publication   Measurement of Depression    Significant Findings

Appleby       Treating physicians'         Depression and anxiety
et al.        diagnosis of depression and  rates, as detected by
(2008)        anxiety or data in the       physicians' assessment,
              chart that were suggestive   were similar to the
              of either disorder           12-month prevalence rate in
              according to the DSM-IV      the general population; the
              criteria                     most common correlate of
                                           reported depression and
                                           anxiety was a premorbid
                                           diagnosis of either
                                           disorder

Armstrong     BDI, MPI-2D                  After controlling for
et al.                                     fatigue, tumor location
(2002)                                     (posterior) and greater
                                           extent of surgery predicted
                                           a higher level of
                                           depression on MPI-2D;
                                           higher BDI scores were
                                           associated with female
                                           gender, greater fatigue,
                                           more cognitive impairment,
                                           and greater family support

Arnold        Brief Patient Health         Female gender, lower tumor
et al.        Questionnaire                grade, lower education
(2008)                                     level, and a history of
                                           psychiatric illness were
                                           predictors of symptoms
                                           consistent with anxiety
                                           and/ or depression

Brown         Profile of Mood States,      QOL was positively
et al.        Short Form                   associated with cognitive
(2006)                                     and physical function but
                                           not demographic variables
                                           or tumor characteristics

Brown         Profile of Mood States,      Patients who received
et al.        Short Form                   greater extent of surgery
(2005)                                     (gross total resection vs.
                                           subtotal resection or
                                           biopsy) had higher QOL and
                                           were less likely to
                                           experience worsening
                                           depression over time

D'Angelo      Zung Self-rating Depression  A significant increase in
et al.        Scale, State-Trait Anxiety   the number of patients with
(2008)        Inventory                    depression was found at 1
                                           and 3 months postsurgery; a
                                           positive relationship
                                           between trait anxiety at
                                           enrollment and depression
                                           after surgery was found

Davies        Home-based interviews        Patients with a lower level
et al.                                     of functioning were more
(2003)                                     likely to report symptoms
                                           of depression

Gathinji      Clinical diagnosis and       Preoperative depression was
et al.        treatment by the primary     associated with reduced
(2008)        provider or psychiatric      length of survival; the
              physician                    difference in percent
                                           survival between the
                                           depressed and nondepressed
                                           cohorts was particularly
                                           evident at 12 months (15%
                                           vs. 41 %) and 20 months (0%
                                           vs. 21 %)

Giovagnoli    Zung Self-rating Depression  Significant predictors of
(1999)        Scale, State-Trait Anxiety   QOL included level of
              Scale                        depression and anxiety and
                                           daily and work performance

Giovagnoli    Zung Self-rating Depression  QOL scores were
et al.        Scale, State-Trait Anxiety   significantly related to
(2005)        Inventory                    greater cognition, physical
                                           performance, and mood

Hahn et al.   BDI                          Patients with left
(2003)                                     hemisphere tumors reported
                                           significantly more memory
                                           problems and depressive
                                           symptoms

Kilbride      HADS and unstructured        HADS underestimated the
et al.        interviews                   presence of depression;
(2007)                                     patients who had suffered
                                           from depressive illness in
                                           the past were more likely
                                           to exhibit depression in
                                           the period between surgery
                                           and radiotherapy

Litofsky      Primary physician diagnosis  Depressive symptoms were
et al.        using the DSM-IV criteria,   associated with shorter
(2004)        patient report using the     survival in patients with a
              SF-36 Mental Health score,   glioblastoma (grade IV) but
              or a positive patient        not for those with grade
              response to one of three     III astrocytoma; mean
              questions related to         survival time was
              depressive symptoms          significantly shorter among
                                           patients identified as
                                           depressed (34.0 weeks)
                                           compared with those who
                                           were identified as
                                           nondepressed by their
                                           physician (41.1 weeks)

Mainio        Premorbid depression         After controlling for
et al.        measured with the            demographic f variables,
(2006)        Crown-Crisp Experiential     preinjury depression, and
              Index, active depression     tumor characteristics, the
              measured with BDI            level of depression
                                           predicted QOL at all
                                           treatment time intervals

Mainio        Premorbid depression         A BDI score >10 was
et al.        measured with the            significantly related to
(2005)        Crown-Crisp Experiential     decreased survival time in
              Index, active, and           low-grade gliomas but not
              depression measured with     in high grade gliomas;
              BDI                          patients with a
                                           preoperative BDI <10 or
                                           with a previous lifetime
                                           history of depression had a
                                           significantly longer
                                           survival time r than those
                                           with higher preoperative
                                           depressive symptoms (60 vs.
                                           51.7 months)

Pelletier     BDI-II                       Of the sample, 38% had a
et al.                                     BDI-II score in the
(2002)                                     clinically depressed range;
                                           the presence of depressive
                                           symptoms was the single
                                           most important independent
                                           predictor of QOL

Pringle       HADS                         Anxiety was reported by 30%
et al.                                     and depression by 16% of
(1999)                                     patients; findings were not
                                           significantly different
                                           than other surgical groups

Wellisch      MDD diagnosed by structured  Significant predictors of
et al.        psychiatric interview using  MDD included frontal
(2002)        the DSM-IV criteria          location of tumor, sadness
                                           and lack of motivation
                                           symptoms, and family
                                           psychiatric history

Note. DSM-IV= Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition; BDI = Beck Depression Inventory; MPI-
2D = Multiphasic Personality Inventory-2 Depression; QOL =
quality of  life; WHO = World Health Organization; HADS =
Hospital Anxiety and Depression Scale; PMBT = primary malignant
brain tumor; MDD = major depressive disorder.
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