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Cytokines and depression: The need for a new paradigm
BRAIN, BEHAVIOR, and IMMUNITY Brain, Behavior, and Immunity 17 (2003) S119–S124 www.elsevier.com/locate/ybrbi
Cytokines and depression: The need for a new paradigm Lucile Capurona and Robert Dantzerb,* a
Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Atlanta, GA 30322, USA b INSERM-INRA U394, Integrative Neurobiology, Institut Francois Magendie, Rue Camille Saint-Saens, 33077 Bordeaux Cedex, France Received 1 April 2002; received in revised form 15 August 2002; accepted 15 August 2002
Abstract Considerable clinical and experimental data support the existence of a relationship between cytokines and depression. At the experimental level, proinflammatory cytokines have been found to induce alterations in brain function analogous to the behavioral and biological abnormalities occurring in depressed patients, including social withdrawal, cognitive impairment, anhedonia, increased activity of the hypothalamus–pituitary–adrenal axis, altered neurotransmission, and cross-sensitization with stressors. At the clinical level, the evidence in favor of innate immune system activation in depressed patients is still controversial, despite accumulating evidence for an increased risk of depressive disorders in patients receiving recombinant cytokines for the treatment of cancer and viral infection. This last issue has received significant attention recently, given that the administration of therapeutic cytokines provides a quasi-experimental model for studying the mechanisms which underlie the effects of cytokines on mood, cognition, and neurovegetative functions. Although the vulnerability factors that account for the risk of depression have yet to be identified, tryptophan depletion, likely related to the induction of indoleamine 2,3-dioxygenase enzyme, may represent an important mediator for the development of depressed mood in cytokine-treated patients. This paper discusses ways in which these emerging data may lead to advances in the recognition and management of non-specific neurobehavioral symptoms associated with the development and progression of cancer. Ó 2003 Elsevier Science (USA). All rights reserved. Keywords: Cytokine; Depression; Cancer; Antidepressants; Symptoms; Tryptophan; Indoleamine 2,3 deoxygenase
1. Introduction In the early 1980s, cytokines were characterized as communication molecules between immune cells, immunocytes, and other peripheral cells such as fibroblasts and endothelial cells. Cytokines were demonstrated to play a key role in the regulation of the immune response and the coordination of the host response to infection. No one would have predicted, based on these biological properties, that within a decade cytokines would become
*
Corresponding author. Fax: 33-5-56989029. E-mail address: [email protected] (R. Dantzer).
a major focus in neuroscience, in the process permeating several avenues of current research in neuropsychiatry. The first indication that cytokines might be involved in psychopathology came from oncology and internal medicine. Clinicians who were treating patients afflicted with cancer or hepatitis B or C with purified or recombinant cytokines to stimulate the immune system observed a rapid induction of flu-like symptoms in response to treatment, followed after several weeks of treatment by the appearance of psychiatric disorders (especially in the form of acute psychosis and major depression) in a significant proportion of patients. These side effects of cytokine therapy obliged clinicians to reduce doses and find safer routes of administration than the intracerebral and intravenous routes used initially.
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However, these observations did not have an impact on the world of psychiatry, given that the relationship between immunity and mental disorders was seen more as a coincidence than a causal chain of events. In 1991, Smith (1991) proposed what he called the ‘‘macrophage theory of depression’’. Based on the potent brain effects of proinflammatory cytokines, such as interleukin-1 (IL1), and the anecdotally reported association between pathological states of immune activation and depression, he proposed that excessive secretion of IL-1 and other macrophage products causes depression. Since the discovery of proinflammatory cytokines, many reports have shown that the administration of these molecules to experimental animals and human volunteers induces depressive symptoms, including depressed mood, anhedonia, suppression of food intake, psychomotor retardation, sleep abnormalities, fatigue, confusion, and alterations in cognition. It has also been reported that cytokines are able to activate the hypothalamic–pituitary–adrenal axis (HPA), a physiological finding frequently reported in depression. However, there was no evidence that depression was associated with immune activation. On the contrary, the predominant view at that time was that depressed patients were immunosuppressed, as evidenced, for example, by reduced natural killer cell activity and lymphocyte proliferation in response to mitogens. It took several years after the publication of SmithÕs provocative hypothesis to collect data sufficient for accepting the possibility that depression was associated not just with immunosuppression, but also with an imbalance in immune system function characterized by activation of the monocyte/ macrophage arm of the immune response and relative inhibition of lymphocyte functions. Evidence for immune activation in depressed patients was first collected by Maes and was mainly based on the measurement of acute phase proteins and cytokines in the plasma of patients with major depressive disorders and treatment resistant depression (Maes, 1995). If cytokines are involved in the pathogenesis of depressive symptoms, one might expect that antidepressant drugs would attenuate cytokine production and action and, conversely, that cytokine antagonists should alleviate symptoms of depression in clinical populations and animal models. Studies testing these predictions have been recently initiated, and the first demonstration that chronic antidepressant treatment alleviated the anhedonic effects of cytokines in laboratory rodents was provided by Yirmiya in 1996. Moreover, other reports have indicated that, in addition to immune stimuli, psychological stressors, which have long been regarded as contributors to the development and maintenance of depression, can induce cytokine expression in the brain. The early literature on the intersection between cytokines and depression has already been amply reviewed
(Dantzer, Wollman, Vitkovic, & Yirmiya, 1999a; Dantzer, Wollman, & Yirmiya, 1999b). The objective of the present paper is to present what has been learned since and, on this basis, to propose a theoretical framework for making sense of the possible role of cytokines in depression.
2. Are cytokines involved in the pathogenesis of depression? The possibility that cytokines are involved in the pathogenesis of depression has been examined from several angles. At the clinical level, the data in favor of an enhancement of innate immunity in depressed patients appear less persuasive than previously thought. In line with the proposed association between activation of the monocyte/macrophage component of immunity and depression, Levine et al. (1999) reported that levels of IL-1b were higher in the cerebrospinal fluid of 13 hospitalized patients with acute untreated severe depression, whereas IL-6 levels were lower and TNF-a levels unchanged in comparison with 10 control subjects. In this study, serum IL-1b concentrations were positively correlated with the severity of depression. On the other hand, however, Haack et al. (1999) did not find any evidence for depression-related alterations in plasma levels of various cytokines in 361 psychiatric patients compared with 64 healthy controls, after controlling for potentially confounding factors such as age, body mass index, smoking habits, ongoing or recent infectious disease, and prior medication. Moreover, when an association between immune activation and depression was observed, it was not necessarily associated with the presence of depressive symptoms per se. For example, Anisman, Ravindran, Griffiths, and Merali (1999) examined the role of illness chronicity and neurovegetative symptomatology by comparing the circulating levels of stress hormones and the production of IL-1b by mitogen-stimulated lymphocytes in patients suffering from classical unipolar major depression, atypical depression or dysthymia with either typical or atypical profiles. They observed that IL-1b was increased in dysthymic patients and highly correlated with the age-of-onset and duration of the illness. In another study on major depression, melancholic patients did not differ from nonmelancholic patients and healthy controls in IL-1b production upon mitogen stimulation in a whole blood assay, and the only indirect evidence for an inflammatory response was found in non-melancholic major depressed patients in the form of increased absolute monocyte count and a-2-macroglobulin (Rothermundt et al., 2001). At the experimental level, results have been more encouraging. Studies addressing the effects of chronic antidepressant treatment on cytokine action in the brain
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have shown that all antidepressant drugs, irrespective of their pharmacological class, are able to attenuate the behavioral and neuroendocrine effects of immune activation (Castanon, Bluthe, & Dantzer, 2001; Yirmiya et al., 2001). These effects appear in general more marked with tricyclic and atypical antidepressants, such as tianeptine than with selective serotonin reuptake inhibitors (Dunn & Swiergiel, 2001). In addition, it has been shown that antidepressant treatment causes a shift in the balance between pro- and anti-inflammatory cytokine production within the brain (Castanon et al., 2001), and perhaps also at the periphery, although contradictory results have been obtained (Connor, Harkin, Kelly, & Leonard, 2000; Yirmiya et al., 2001). Whether the effect of antidepressants on immune function is an epiphenomenon or contributes to the efficacy of antidepressant drugs in clinical practice is still unknown and certainly deserves further investigation. Alterations in cytokine production have also been observed in animal models of depression. In mice, mild chronic stress was associated with increased IL-1 and IL-2 production in concert with decreased NK cell activity and mitogen-induced lymphoproliferation (Kubera et al., 1998). In addition, it has been shown that bulbectomized rats (an animal model for depression) exhibit an attenuated proinflammatory cytokine response to lipopolysaccharide, an effect that is accentuated by chronic treatment with desipramine (Connor et al., 2000). More relevant in terms of psychopathology is the demonstration of a cross-sensitization between cytokines and stressors, which implies that cytokines might alter brain circuitry, changing its sensitivity to seemingly unrelated subsequent stimuli or events. For example, rats injected with a dose of IL-6 that had a minor effect on locomotion per se exhibited an enhanced response to the locomotor-stimulating effects of amphetamine administered 5–14 days post IL-6 (Zalcman, Savina, & Wise, 1999). The same phenomenon was observed in mice treated with IL-2 and subsequently challenged with GBR 12909, a highly selective dopamine uptake inhibitor (Zalcman, 2001). The relationship between behavioral sensitization and monoamine turnover has been examined by Anisman et al., with little or no evidence for a clear-cut association (Anisman, Kokkinidis, Borowski, & Merali, 1998; Hayley, Brebner, Lacosta, Merali, & Anisman, 1999; Hayley, Lacosta, Merali, van Rooijen, & Anisman, 2001). In contrast, mechanisms of IL-1-induced sensitization of the HPA axis to novelty appear to be mediated by an increase in the proportion of CRH neurons in the paraventricular nucleus of the hypothalamus expressing vasopressin. This increase is associated with a sensitization of stimulus-secretion coupling in brain stem noradrenergic neurons innervating the PVN (Schmidt et al., 2001).
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3. Cytokines induce the neuropsychiatric and neurovegetative features of depression The characterization of the neurobehavioral effects of cytokines in clinical populations and laboratory animals has aided in our understanding of the relationship between cytokines and depression. Cytokines administered exogenously induce a large set of symptoms, referred to as sickness behavior, including malaise, weakness, fatigue, sleepiness, and disinterest for usual activities, including feeding, drinking, and social interactions (Dantzer, 2001). Neurovegetative symptoms are clearly prominent in this description. Both in clinical populations and laboratory animals, activation of the immune system is associated with reduced food intake and altered sleep patterns (Plata-Salaman, 1998; Pollmacher et al., 2000). In addition, fatigue is frequent in patients suffering from immune-based illnesses, as well as in patients treated with cytokines (Kurzrock, 2001; Malik, Makower, & Wadler, 2001). For instance, 80% of patients undergoing IFN-a therapy report fatigue from moderate to severe intensity (Capuron et al., 2002a). In addition, it has been shown that feelings of exhaustion are associated with serological markers of inflammation in patients with coronary artery disease (Appels, Bar, Bar, Bruggeman, & de Baets, 2000). In animals, reduced activity, anorexia, and flu-like symptoms appear after acute administration of many cytokines and endotoxins, whereas anhedonia is induced by chronic administration of IL-2, but not IL-1b nor IL-6 (Anisman et al., 1998). Cytokine-induced depression clearly requires qualification. According to the DSM-IV classification, the diagnosis of major depression requires a two week period of either depressed mood or loss of interest and pleasure in activities, associated with at least five additional symptoms; including both psychological symptoms (feelings of worthlessness or guilt, loss of concentration or indecisiveness, recurrent thoughts of death or suicidal ideation) and somatic/neurovegetative symptoms (changes in appetite and/or weight, altered sleep patterns, fatigue/loss of energy, psychomotor agitation or retardation) (American Psychiatric Association, 1994). Under DSM-IV criteria, a depressive episode that occurs during the course of either endogenous immune activation or exogenous cytokine administration is considered to be a medical condition- or substance-induced mood disorder. Dimensional analyses have shown that cytokines are able to induce both the neurovegetative and psychological symptoms of depression. Patients undergoing interleukin-2 (IL-2) or interferon-a (IFN-a) therapy for the treatment of cancer develop not only sadness and loss of interest, but also cognitive disturbances and neurovegetative symptoms, such as loss of appetite, fatigue or altered sleep during the course of the therapy (Capuron, Ravaud, & Dantzer, 2000; Capuron et al.,
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The fact that cytokine system activation induces mood symptoms less frequently than neurovegetative symptoms, points to the existence of vulnerability factors for cytokine-induced depression. Consistent with this, cancer patients who develop significant depressive symptoms during cytokine therapy display elevated pretreatment scores in the Montgomery–Asberg Depression Rating Scale compared to patients who do not develop depressive symptomatology (Capuron & Ravaud, 1999). Similar results have been found in studies using other scales for depression (Miyaoka et al., 1999; Musselman et al., 2001). Preliminary data indicate that risk factors for the development of depressive symptoms in cancer patients undergoing cytokine therapy include cognitive disturbances, sleep difficulties or lassitude, together with poor social support (unpublished results). These results suggest that personality traits may represent vulnerability factors for cytokine-induced depression. The specificity of this vulnerability and its biological basis remain to be elucidated. Future investigations aiming at assessing the psychological and biological factors of vulnerability are of important conceptual and practical value since the knowledge gained would allow for better detection and treatment of patients at risk for depressive disorders in the context of immune activation.
kines lead to the development of depressive symptoms by modulating the activity of the HPA axis. Cytokines are able to induce glucocorticoid resistance, potentially leading to hyper-activity of the HPA axis and suppression of glucocorticoid negative feedback on the release of the corticotropin-releasing hormone (CRH) (Miller, Pariante, & Pierce, 1999). Clinical and preclinical evidence supports the concept that impaired corticosteroid receptor signaling is a key mechanism in the pathogenesis of depression (Holsboer, 2000; Pariante & Miller, 2001). Interestingly, IL-1 has been found to impair glucocorticoid receptor (GR) translocation and function, suggesting that cytokines might mediate GR resistance in relevant cell types by direct effects on the GR (Pariante et al., 1999). Neurochemical transmission represents another nonexclusive potential target. Cytokines may induce depressive symptoms by down-regulating the synthesis of serotonin, whereas psychomotor retardation and anhedonia may be mediated by aberrant functioning of the basal ganglia, especially in its dopaminergic component. Immune activation is associated with the induction of indoleamine 2,3-dioxygenase (IDO), an enzyme that switches the metabolism of tryptophan (TRP) toward the synthesis of kynurenine and quinolinic acid, to the detriment of serotonin synthesis. IDO is induced both at the periphery and in the brain of cytokine-treated animals (Lestage, Verrier, Palin, & Dantzer, 2002). Consistent with this hypothesis, intracerebroventricular injection of IFN-a was found to reduce brain levels of serotonin in several regions of the rat brain (Kamata, Higuchi, Yoshimoto, Yoshida, & Shimizu, 2000). Cancer patients undergoing cytokine therapy were also found to display significant decreases in serum TRP concentrations during the course of therapy (Capuron et al., 2002b). The amplitude of TRP decreases was correlated with the severity of depressive symptoms. Given the many data indicating that TRP depletion is associated with the development of depressive symptoms and associated behavioral disturbances in vulnerable patients (Moore et al., 2000; Moreno et al., 1999; Delgado et al., 1991), it is possible that at least some of cytokine-induced depressive symptoms are mediated by IDO-induced TRP depletion. This hypothesis is supported by recent data indicating a significant reduction in TRP/kynurenine ratio associated with inflammatory signs in patients with chronic hepatitis C undergoing IFN-a therapy (Maes et al., 2001). Therefore, IDO could represent a possible link between cytokines and depression. This target is therefore of considerable value and interest for future investigation.
5. Possible mechanisms of cytokine-induced depression
6. Conclusion and implications
There are several mechanisms by which cytokines may induce depression. A first possibility is that cyto-
Converging evidence for an association between cytokines and depression has been at the source of a
2002a). The onset of these symptoms appears to be dependent on which treatment modality is used. For instance, depressive symptoms and fronto-subcortical-like cognitive alterations develop early (first week of treatment) in patients receiving IL-2. In contrast, depressive symptoms develop only after several weeks (4–8 weeks) of treatment in patients treated with IFN-a. Interestingly and more frequently, neurovegetative symptoms occur significantly sooner than mood symptoms in both treatment modalities. This distinction between neurovegetative symptoms and mood alterations is supported by recent findings showing that prophylactic treatment with the antidepressant paroxetine blocks the development of major depression in patients undergoing IFN-a therapy, whereas it has a minor effect on neurovegetative symptoms, including fatigue (Musselman et al., 2001; Capuron et al., 2002a). In view of these data, it appears possible that cytokines exert differential effects on mood and neurovegetative functions, probably through distinct mechanisms. This hypothesis merits further investigation.
4. Vulnerability factors for cytokine-induced depression
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number of clinical investigations aiming at assessing the immune status of depressed patients. In view of the various confounding factors that inevitably bias this type of research and the heterogeneity of the major depression syndrome, it is time to switch gears and study independently the physical symptoms and mood/cognitive alterations that occur in patients afflicted with chronic inflammation, so as to be able to dissect the intricate relationships that certainly exist between endogenous cytokines and specific subcategories of symptoms. This type of research will certainly allow provide insight into understanding how non-specific physical and psychological symptoms of disease develop and how specific targets for alleviating therapies can be identified. In the case of cancer, cytokines are not only produced by tumor cells and inflammatory cells infiltrating or surrounding the tumor, but also by medical interventions such as radiotherapy and surgery. Cytokines undoubtedly play a key role in pain, fatigue, anorexia/cachexia, and alterations in mood and cognition that impact on the quality of life of cancer patients. Identification of their role and mode of action requires a concerted effort to relate well-defined symptoms in clinically homogenous populations to biological markers of inflammation and putative intermediate mechanisms, including vulnerability factors. Such a task is at hand, and the expected results would not only serve the population under study but certainly also other clinical populations afflicted with organic or psychiatric diseases.
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Cytokines and depression: The need for a new paradigm Lucile Capurona and Robert Dantzerb,* a
Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Atlanta, GA 30322, USA b INSERM-INRA U394, Integrative Neurobiology, Institut Francois Magendie, Rue Camille Saint-Saens, 33077 Bordeaux Cedex, France Received 1 April 2002; received in revised form 15 August 2002; accepted 15 August 2002
Abstract Considerable clinical and experimental data support the existence of a relationship between cytokines and depression. At the experimental level, proinflammatory cytokines have been found to induce alterations in brain function analogous to the behavioral and biological abnormalities occurring in depressed patients, including social withdrawal, cognitive impairment, anhedonia, increased activity of the hypothalamus–pituitary–adrenal axis, altered neurotransmission, and cross-sensitization with stressors. At the clinical level, the evidence in favor of innate immune system activation in depressed patients is still controversial, despite accumulating evidence for an increased risk of depressive disorders in patients receiving recombinant cytokines for the treatment of cancer and viral infection. This last issue has received significant attention recently, given that the administration of therapeutic cytokines provides a quasi-experimental model for studying the mechanisms which underlie the effects of cytokines on mood, cognition, and neurovegetative functions. Although the vulnerability factors that account for the risk of depression have yet to be identified, tryptophan depletion, likely related to the induction of indoleamine 2,3-dioxygenase enzyme, may represent an important mediator for the development of depressed mood in cytokine-treated patients. This paper discusses ways in which these emerging data may lead to advances in the recognition and management of non-specific neurobehavioral symptoms associated with the development and progression of cancer. Ó 2003 Elsevier Science (USA). All rights reserved. Keywords: Cytokine; Depression; Cancer; Antidepressants; Symptoms; Tryptophan; Indoleamine 2,3 deoxygenase
1. Introduction In the early 1980s, cytokines were characterized as communication molecules between immune cells, immunocytes, and other peripheral cells such as fibroblasts and endothelial cells. Cytokines were demonstrated to play a key role in the regulation of the immune response and the coordination of the host response to infection. No one would have predicted, based on these biological properties, that within a decade cytokines would become
*
Corresponding author. Fax: 33-5-56989029. E-mail address: [email protected] (R. Dantzer).
a major focus in neuroscience, in the process permeating several avenues of current research in neuropsychiatry. The first indication that cytokines might be involved in psychopathology came from oncology and internal medicine. Clinicians who were treating patients afflicted with cancer or hepatitis B or C with purified or recombinant cytokines to stimulate the immune system observed a rapid induction of flu-like symptoms in response to treatment, followed after several weeks of treatment by the appearance of psychiatric disorders (especially in the form of acute psychosis and major depression) in a significant proportion of patients. These side effects of cytokine therapy obliged clinicians to reduce doses and find safer routes of administration than the intracerebral and intravenous routes used initially.
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However, these observations did not have an impact on the world of psychiatry, given that the relationship between immunity and mental disorders was seen more as a coincidence than a causal chain of events. In 1991, Smith (1991) proposed what he called the ‘‘macrophage theory of depression’’. Based on the potent brain effects of proinflammatory cytokines, such as interleukin-1 (IL1), and the anecdotally reported association between pathological states of immune activation and depression, he proposed that excessive secretion of IL-1 and other macrophage products causes depression. Since the discovery of proinflammatory cytokines, many reports have shown that the administration of these molecules to experimental animals and human volunteers induces depressive symptoms, including depressed mood, anhedonia, suppression of food intake, psychomotor retardation, sleep abnormalities, fatigue, confusion, and alterations in cognition. It has also been reported that cytokines are able to activate the hypothalamic–pituitary–adrenal axis (HPA), a physiological finding frequently reported in depression. However, there was no evidence that depression was associated with immune activation. On the contrary, the predominant view at that time was that depressed patients were immunosuppressed, as evidenced, for example, by reduced natural killer cell activity and lymphocyte proliferation in response to mitogens. It took several years after the publication of SmithÕs provocative hypothesis to collect data sufficient for accepting the possibility that depression was associated not just with immunosuppression, but also with an imbalance in immune system function characterized by activation of the monocyte/ macrophage arm of the immune response and relative inhibition of lymphocyte functions. Evidence for immune activation in depressed patients was first collected by Maes and was mainly based on the measurement of acute phase proteins and cytokines in the plasma of patients with major depressive disorders and treatment resistant depression (Maes, 1995). If cytokines are involved in the pathogenesis of depressive symptoms, one might expect that antidepressant drugs would attenuate cytokine production and action and, conversely, that cytokine antagonists should alleviate symptoms of depression in clinical populations and animal models. Studies testing these predictions have been recently initiated, and the first demonstration that chronic antidepressant treatment alleviated the anhedonic effects of cytokines in laboratory rodents was provided by Yirmiya in 1996. Moreover, other reports have indicated that, in addition to immune stimuli, psychological stressors, which have long been regarded as contributors to the development and maintenance of depression, can induce cytokine expression in the brain. The early literature on the intersection between cytokines and depression has already been amply reviewed
(Dantzer, Wollman, Vitkovic, & Yirmiya, 1999a; Dantzer, Wollman, & Yirmiya, 1999b). The objective of the present paper is to present what has been learned since and, on this basis, to propose a theoretical framework for making sense of the possible role of cytokines in depression.
2. Are cytokines involved in the pathogenesis of depression? The possibility that cytokines are involved in the pathogenesis of depression has been examined from several angles. At the clinical level, the data in favor of an enhancement of innate immunity in depressed patients appear less persuasive than previously thought. In line with the proposed association between activation of the monocyte/macrophage component of immunity and depression, Levine et al. (1999) reported that levels of IL-1b were higher in the cerebrospinal fluid of 13 hospitalized patients with acute untreated severe depression, whereas IL-6 levels were lower and TNF-a levels unchanged in comparison with 10 control subjects. In this study, serum IL-1b concentrations were positively correlated with the severity of depression. On the other hand, however, Haack et al. (1999) did not find any evidence for depression-related alterations in plasma levels of various cytokines in 361 psychiatric patients compared with 64 healthy controls, after controlling for potentially confounding factors such as age, body mass index, smoking habits, ongoing or recent infectious disease, and prior medication. Moreover, when an association between immune activation and depression was observed, it was not necessarily associated with the presence of depressive symptoms per se. For example, Anisman, Ravindran, Griffiths, and Merali (1999) examined the role of illness chronicity and neurovegetative symptomatology by comparing the circulating levels of stress hormones and the production of IL-1b by mitogen-stimulated lymphocytes in patients suffering from classical unipolar major depression, atypical depression or dysthymia with either typical or atypical profiles. They observed that IL-1b was increased in dysthymic patients and highly correlated with the age-of-onset and duration of the illness. In another study on major depression, melancholic patients did not differ from nonmelancholic patients and healthy controls in IL-1b production upon mitogen stimulation in a whole blood assay, and the only indirect evidence for an inflammatory response was found in non-melancholic major depressed patients in the form of increased absolute monocyte count and a-2-macroglobulin (Rothermundt et al., 2001). At the experimental level, results have been more encouraging. Studies addressing the effects of chronic antidepressant treatment on cytokine action in the brain
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have shown that all antidepressant drugs, irrespective of their pharmacological class, are able to attenuate the behavioral and neuroendocrine effects of immune activation (Castanon, Bluthe, & Dantzer, 2001; Yirmiya et al., 2001). These effects appear in general more marked with tricyclic and atypical antidepressants, such as tianeptine than with selective serotonin reuptake inhibitors (Dunn & Swiergiel, 2001). In addition, it has been shown that antidepressant treatment causes a shift in the balance between pro- and anti-inflammatory cytokine production within the brain (Castanon et al., 2001), and perhaps also at the periphery, although contradictory results have been obtained (Connor, Harkin, Kelly, & Leonard, 2000; Yirmiya et al., 2001). Whether the effect of antidepressants on immune function is an epiphenomenon or contributes to the efficacy of antidepressant drugs in clinical practice is still unknown and certainly deserves further investigation. Alterations in cytokine production have also been observed in animal models of depression. In mice, mild chronic stress was associated with increased IL-1 and IL-2 production in concert with decreased NK cell activity and mitogen-induced lymphoproliferation (Kubera et al., 1998). In addition, it has been shown that bulbectomized rats (an animal model for depression) exhibit an attenuated proinflammatory cytokine response to lipopolysaccharide, an effect that is accentuated by chronic treatment with desipramine (Connor et al., 2000). More relevant in terms of psychopathology is the demonstration of a cross-sensitization between cytokines and stressors, which implies that cytokines might alter brain circuitry, changing its sensitivity to seemingly unrelated subsequent stimuli or events. For example, rats injected with a dose of IL-6 that had a minor effect on locomotion per se exhibited an enhanced response to the locomotor-stimulating effects of amphetamine administered 5–14 days post IL-6 (Zalcman, Savina, & Wise, 1999). The same phenomenon was observed in mice treated with IL-2 and subsequently challenged with GBR 12909, a highly selective dopamine uptake inhibitor (Zalcman, 2001). The relationship between behavioral sensitization and monoamine turnover has been examined by Anisman et al., with little or no evidence for a clear-cut association (Anisman, Kokkinidis, Borowski, & Merali, 1998; Hayley, Brebner, Lacosta, Merali, & Anisman, 1999; Hayley, Lacosta, Merali, van Rooijen, & Anisman, 2001). In contrast, mechanisms of IL-1-induced sensitization of the HPA axis to novelty appear to be mediated by an increase in the proportion of CRH neurons in the paraventricular nucleus of the hypothalamus expressing vasopressin. This increase is associated with a sensitization of stimulus-secretion coupling in brain stem noradrenergic neurons innervating the PVN (Schmidt et al., 2001).
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3. Cytokines induce the neuropsychiatric and neurovegetative features of depression The characterization of the neurobehavioral effects of cytokines in clinical populations and laboratory animals has aided in our understanding of the relationship between cytokines and depression. Cytokines administered exogenously induce a large set of symptoms, referred to as sickness behavior, including malaise, weakness, fatigue, sleepiness, and disinterest for usual activities, including feeding, drinking, and social interactions (Dantzer, 2001). Neurovegetative symptoms are clearly prominent in this description. Both in clinical populations and laboratory animals, activation of the immune system is associated with reduced food intake and altered sleep patterns (Plata-Salaman, 1998; Pollmacher et al., 2000). In addition, fatigue is frequent in patients suffering from immune-based illnesses, as well as in patients treated with cytokines (Kurzrock, 2001; Malik, Makower, & Wadler, 2001). For instance, 80% of patients undergoing IFN-a therapy report fatigue from moderate to severe intensity (Capuron et al., 2002a). In addition, it has been shown that feelings of exhaustion are associated with serological markers of inflammation in patients with coronary artery disease (Appels, Bar, Bar, Bruggeman, & de Baets, 2000). In animals, reduced activity, anorexia, and flu-like symptoms appear after acute administration of many cytokines and endotoxins, whereas anhedonia is induced by chronic administration of IL-2, but not IL-1b nor IL-6 (Anisman et al., 1998). Cytokine-induced depression clearly requires qualification. According to the DSM-IV classification, the diagnosis of major depression requires a two week period of either depressed mood or loss of interest and pleasure in activities, associated with at least five additional symptoms; including both psychological symptoms (feelings of worthlessness or guilt, loss of concentration or indecisiveness, recurrent thoughts of death or suicidal ideation) and somatic/neurovegetative symptoms (changes in appetite and/or weight, altered sleep patterns, fatigue/loss of energy, psychomotor agitation or retardation) (American Psychiatric Association, 1994). Under DSM-IV criteria, a depressive episode that occurs during the course of either endogenous immune activation or exogenous cytokine administration is considered to be a medical condition- or substance-induced mood disorder. Dimensional analyses have shown that cytokines are able to induce both the neurovegetative and psychological symptoms of depression. Patients undergoing interleukin-2 (IL-2) or interferon-a (IFN-a) therapy for the treatment of cancer develop not only sadness and loss of interest, but also cognitive disturbances and neurovegetative symptoms, such as loss of appetite, fatigue or altered sleep during the course of the therapy (Capuron, Ravaud, & Dantzer, 2000; Capuron et al.,
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The fact that cytokine system activation induces mood symptoms less frequently than neurovegetative symptoms, points to the existence of vulnerability factors for cytokine-induced depression. Consistent with this, cancer patients who develop significant depressive symptoms during cytokine therapy display elevated pretreatment scores in the Montgomery–Asberg Depression Rating Scale compared to patients who do not develop depressive symptomatology (Capuron & Ravaud, 1999). Similar results have been found in studies using other scales for depression (Miyaoka et al., 1999; Musselman et al., 2001). Preliminary data indicate that risk factors for the development of depressive symptoms in cancer patients undergoing cytokine therapy include cognitive disturbances, sleep difficulties or lassitude, together with poor social support (unpublished results). These results suggest that personality traits may represent vulnerability factors for cytokine-induced depression. The specificity of this vulnerability and its biological basis remain to be elucidated. Future investigations aiming at assessing the psychological and biological factors of vulnerability are of important conceptual and practical value since the knowledge gained would allow for better detection and treatment of patients at risk for depressive disorders in the context of immune activation.
kines lead to the development of depressive symptoms by modulating the activity of the HPA axis. Cytokines are able to induce glucocorticoid resistance, potentially leading to hyper-activity of the HPA axis and suppression of glucocorticoid negative feedback on the release of the corticotropin-releasing hormone (CRH) (Miller, Pariante, & Pierce, 1999). Clinical and preclinical evidence supports the concept that impaired corticosteroid receptor signaling is a key mechanism in the pathogenesis of depression (Holsboer, 2000; Pariante & Miller, 2001). Interestingly, IL-1 has been found to impair glucocorticoid receptor (GR) translocation and function, suggesting that cytokines might mediate GR resistance in relevant cell types by direct effects on the GR (Pariante et al., 1999). Neurochemical transmission represents another nonexclusive potential target. Cytokines may induce depressive symptoms by down-regulating the synthesis of serotonin, whereas psychomotor retardation and anhedonia may be mediated by aberrant functioning of the basal ganglia, especially in its dopaminergic component. Immune activation is associated with the induction of indoleamine 2,3-dioxygenase (IDO), an enzyme that switches the metabolism of tryptophan (TRP) toward the synthesis of kynurenine and quinolinic acid, to the detriment of serotonin synthesis. IDO is induced both at the periphery and in the brain of cytokine-treated animals (Lestage, Verrier, Palin, & Dantzer, 2002). Consistent with this hypothesis, intracerebroventricular injection of IFN-a was found to reduce brain levels of serotonin in several regions of the rat brain (Kamata, Higuchi, Yoshimoto, Yoshida, & Shimizu, 2000). Cancer patients undergoing cytokine therapy were also found to display significant decreases in serum TRP concentrations during the course of therapy (Capuron et al., 2002b). The amplitude of TRP decreases was correlated with the severity of depressive symptoms. Given the many data indicating that TRP depletion is associated with the development of depressive symptoms and associated behavioral disturbances in vulnerable patients (Moore et al., 2000; Moreno et al., 1999; Delgado et al., 1991), it is possible that at least some of cytokine-induced depressive symptoms are mediated by IDO-induced TRP depletion. This hypothesis is supported by recent data indicating a significant reduction in TRP/kynurenine ratio associated with inflammatory signs in patients with chronic hepatitis C undergoing IFN-a therapy (Maes et al., 2001). Therefore, IDO could represent a possible link between cytokines and depression. This target is therefore of considerable value and interest for future investigation.
5. Possible mechanisms of cytokine-induced depression
6. Conclusion and implications
There are several mechanisms by which cytokines may induce depression. A first possibility is that cyto-
Converging evidence for an association between cytokines and depression has been at the source of a
2002a). The onset of these symptoms appears to be dependent on which treatment modality is used. For instance, depressive symptoms and fronto-subcortical-like cognitive alterations develop early (first week of treatment) in patients receiving IL-2. In contrast, depressive symptoms develop only after several weeks (4–8 weeks) of treatment in patients treated with IFN-a. Interestingly and more frequently, neurovegetative symptoms occur significantly sooner than mood symptoms in both treatment modalities. This distinction between neurovegetative symptoms and mood alterations is supported by recent findings showing that prophylactic treatment with the antidepressant paroxetine blocks the development of major depression in patients undergoing IFN-a therapy, whereas it has a minor effect on neurovegetative symptoms, including fatigue (Musselman et al., 2001; Capuron et al., 2002a). In view of these data, it appears possible that cytokines exert differential effects on mood and neurovegetative functions, probably through distinct mechanisms. This hypothesis merits further investigation.
4. Vulnerability factors for cytokine-induced depression
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number of clinical investigations aiming at assessing the immune status of depressed patients. In view of the various confounding factors that inevitably bias this type of research and the heterogeneity of the major depression syndrome, it is time to switch gears and study independently the physical symptoms and mood/cognitive alterations that occur in patients afflicted with chronic inflammation, so as to be able to dissect the intricate relationships that certainly exist between endogenous cytokines and specific subcategories of symptoms. This type of research will certainly allow provide insight into understanding how non-specific physical and psychological symptoms of disease develop and how specific targets for alleviating therapies can be identified. In the case of cancer, cytokines are not only produced by tumor cells and inflammatory cells infiltrating or surrounding the tumor, but also by medical interventions such as radiotherapy and surgery. Cytokines undoubtedly play a key role in pain, fatigue, anorexia/cachexia, and alterations in mood and cognition that impact on the quality of life of cancer patients. Identification of their role and mode of action requires a concerted effort to relate well-defined symptoms in clinically homogenous populations to biological markers of inflammation and putative intermediate mechanisms, including vulnerability factors. Such a task is at hand, and the expected results would not only serve the population under study but certainly also other clinical populations afflicted with organic or psychiatric diseases.
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