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Cytokines and depression: an analogic approach
Biomed Pharmacother 2002 ; 56 : 105-10 © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S0753332201001561/DIS
Point of view
Cytokines and depression: an analogic approach M. Corcos*, O. Guilbaud, L. Hjalmarsson, J. Chambry, Ph. Jeammet Department of Adolescent and Young Adult Psychiatry, Pr. Jeammet, Institut Mutualiste Montsouris, 42 Bd Jourdan, 75014 Paris, France (Received 22 June 2001; accepted 17 December 2001)
Summary – A growing body of evidence suggests that major depressive disorders may be accompanied by immune dysfunction and more particularly by an enhanced production of pro-inflammatory cytokines. The possible involvement of cytokines in depressive illness are based upon an analogic model. Pro-inflammatory cytokines are known to induce behavioral effects, and neuro-endocrine and immune activation similar to those observed in depression; these can be alleviated by antidepressant treatment. In this paper, we review research literature on the links between depressive illness and cytokine production and address further questions on this cytokine pathway . Further research is needed to see whether cytokines sustain specific depressive syndromes or whether cytokines induce depressive-like symptoms. © 2002 Éditions scientifiques et médicales Elsevier SAS cytokines / depression / psychoneuroimmunoendocrinology
Psychoneuroimmunoendocrinology has yielded a new holistic vision of the mind-body problem distinct from a dualistic separation between mind and body. Through recent progress in immunology, increasing attention has focused on the view that cytokines may contribute to psychological disturbances such as depressive illness. Cytokines are low molecular-weight proteins or glycoproteins that were initially thought to be restricted to the immune system as mediators of communication between immune cells. However, it is clearly known that many cytokines also play a key role in the central nervous and endocrine system. It has been reported that cytokines were produced by brain cells and interact closely with neurohormones, neurotransmitters and the neuroendocrine system [33]. During the last decade, it has been hypothesized that pro-inflammatory cytokines and immune mediators contribute to the biology of depression. It has *Correspondence and reprints. E-mail address: [email protected] (M. Corcos).
generated a new etiological pathway of depression consistent with some data in the literature. This paper reviews research literature on the links between human and animal cytokine functioning and mood disorders. CYTOKINE PATHWAYS IN MAJOR DEPRESSIVE DISORDERS (MDD) Several line of evidence suggest that depression may be associated with increased production of proinflammatory cytokines such as Il-1, IL-6, IFN, TNF in humans and experimental animals. It has been hypothesized [20, 25] that major depression is accompanied by an acute phase response and peripheral immune activation sustained by an increased production of pro-inflammatory cytokines such as Il-1 and Il-6. According to this peripheral immune theory of depression, depressive disorder would be a consequence of the increased monocytic production of proinflammatory cytokines (notably Il-1 and Il-6 but also Il-2, IFN and TNFα by activated T cells) leading to
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an activation of the immune system with elevated rates of antinuclear antibody, increased rates of lymphocyte subsets, such as CD4, decreased numbers of CD8 and an acute phase response characterized by a peripheral inflammatory syndrome (increased plasma levels of haptoglobulin, C-reactive protein [13, 45] and decreased plasma levels of albumin and transferin [26]. Abnormalities of the endocrine system, especially the hyperactivity of the corticotrope axis, could be secondary to the elevated rates of Il-1. The psychoneuroendocrinoimmunological model of depression was built: – on experimental work assessing the depressed effects of immunological therapies (interferon-alpha therapy, interleukin-2 therapy) on patients suffering from cancer or infectious viral diseases (AIDS, chronic hepatitis C, etc.) and/or the depressed effects of cytokines in experimental animals; – on investigation of the reciprocal interaction between pro-inflammatory cytokines such as Il-1 and the hypothalamo-pituitary-adrenocorticotrope axis in depressed patients or in experimental animals; and – from studies assessing circulating levels, or cytokine production in spontaneous or mitogen-stimulated lymphocytes among depressed patients compared to non-depressed control subjects. SICKNESS BEHAVIOUR AND CYTOKINES Infectious diseases are associated with nonspecific symptoms of infection including fever, hypersomnia or hyposomnia, anorexia, fatigue, decreased physical and social activity and loss of interest. These non specific changes are collectively termed ‘sickness behaviour’. Several lines of evidence suggest that pro-inflammatory cytokines such as interleukin (Il-1, Il-6), tumor necrosis factor (TNF) or interferon (IFN) can underlie sickness behaviour mechanisms. Studies in experimental animals indicate that peripheral or central administration of interleukin 1 (Il-1β, Il-1α) and TNFα induce sickness behaviours in mice and rats [3, 8] with decreased social exploration and weight loss. For instance, symptoms of systemic illness can be reproduced by central injection of Il-1β and prevented by high levels of Il-1 receptor antagonist (Il-1ra) [39]. For Wong et al. [49], Il-1ra antagonist receptor may be secreted by the anterior pituitary as an anti-inflammatory hormone in response to Il-1β effects. Moreover, Il-1β knockout mice have
no fever and no alterations in ingestive behavior in response to some peripheral inflammation [51]. In experimental animals, Il-1 is known to have pyrogenic, somnogenic, anorectic and depressed effects. Clinical studies [6, 34, 47] have shown within patients treated with interferon-α the onset of flulike symptoms including fever, anorexia, fatigue, and also severe neuropsychiatric manifestations (such as depression, anxiety, sleep disorders, cognitive impairment). For instance, repeated injections of high doses of interferon-alpha in patients with chronic viral hepatitis (or with malignant melanoma) have been associated with a high frequency of neuropsychiatric complications including symptoms sufficient to meet diagnostic criteria for major depression. Severe depressed symptoms are dose-dependent and diminish a few days to few weeks after cessation of treatment. Many medical conditions are accompanied by a cytokine-mediated depressive-like syndrome [50]. Due to the behavioral effects of cytokines that mimic the vegetative or somatic symptoms of depressive illness (anorexia, sleep disorders, fatigue, motor retardation, anhedonia), a pathophysiological parallel has been made between the profound depressive effects of cytokines and their potent etiological implications in depressive illness. CYTOKINES IN THE BRAIN, CYTOKINES AND SEROTONIN SYNTHESIS Dysregulation of the hypothalamo-pituitaryadrenocortical (HPA) axis is an important key element in the biology of major depression which could result in the atrophy of hippocampus and amygdala [43]. Cytokines are known to disrupt the endocrine system and act in the brain as neurotransmitter [1]. For example, Il-1 is a potent activator of the HPA axis via the stimulation of the corticotropin-releasing hormone (CRH) [9, 19]. In major depression increased levels of Il-1β could stimulate HPA activity [10]. Il-1 is also known to increase the noradrenergic catabolites in the medial hypothalamus [9, 15]. Pro-inflammatory cytokines can also modify serotonin mechanisms in the brain [37]. Il-1 (and to a lesser degree Il-6 and TNFα) increase free tryptophan and the serotonin catabolites [10]. Moreover, Il-1β has been reported to be a potent regulator of the serotonin transporter [38].
Analogic approach to cytokines and depression
Other authors were interested in the loops of immune regulation between the interferon-γ pathway and serotonin synthesis. A peripheral model of immunomodulation concerning interferon was relatively well documented. It has been shown that there was a feedback of serotonin synthesis by interferon-γ [11]. IFN-γ increases the tryptophan uptake by lymphocytes and macrophages, which could lead to an enhanced production of serotonin, while high levels of indolamines such as serotonin inhibit IFN-γ synthesis [11]. On the other hand, interferon-γ also enhances tryptophan degradation via the kynurenine catabolic pathway with an induction of the enzyme indolamine 2,3 dioxygenase [5]. These new models of interaction between interferon and serotonin regulation could be the reflect of some immunoregulatory pathway relevant to the central nervous system that might be disturbed within patients under interferon treatment. These findings are quite relevant because the serotonin transporter and metabolism in the brain are primary targets for a number of antidepressants. DATA IN THE LITERATURE It has been hypothesized that some of the neuroendocrine and immune disorders observed in major depression could be related to an acute phase response with an activation of the inflammatory response in that illness [25], but the results of the literature conflict. The acute phase response in major depressive disorders (MDD) Several authors have reported increased plasma levels of positive acute phase proteins such as haptoglobulin, C-reactive protein, α1-acid glycoprotein and α1- or α2-globulin in major depression [13, 20, 35, 41, 45]. For instance, Maes et al. [22] found that the vegetative symptoms of major depression (insomnia, reduced locomotion) were correlated with higher levels of haptoglobulinemia but not with mood state. This could be related [21, 28] to a specific activation of peripheral pro-inflammatory cytokines, notably Il-6, Il-1, which may underlie the immune and acute phase response of major depression [25]. For Van West and Maes [48] the neuroendocrine changes in depression (HPA-axis hyperactivity, lower activity
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of the hypo-pituitary-thyroid axis) are indicators of the activation of the inflammatory response system. It has been shown in severe depressive episode that Il-6 or Il-1 production by mitogen-stimulated peripheral leukocytes was significantly and positively correlated with the activity of the HPA-axis [21, 24], haptoglobulinemia [21] or alpha-1 acid glycoprotein [44], while Il-6 activity and haptoglobulinemia have been reported to be significantly and negatively correlated with lower plasma L-tryptophan levels [23]. These clinical studies support the hypothesis that increased production of pro-inflammatory cytokines such as Il-6 in depressive disorders may disturb the pathophysiological loop of regulation within the neuroendocrinoimmune system and thus be responsible of the immune activation with an acute phase response, hyperactivity of the HPA-axis and deregulation of the turn over of serotonin. Cytokine production in MDD However, the results concerning the production of pro-inflammatory cytokines are still inconstant; some authors have reported elevated rates of Il-1 or Il-6 ( in peripheral blood mononuclear cells [PBMCs] stimulated by mitogens: [23, 41]; in serum: [2, 27, 29, 36, 40, 44]), while others did not find significant differences (in stimulated PBMCs: [40]; in serum: [4, 12, 14]), or found significantly decreased Il-6 levels in cerebral spinal fluid of geriatric patients with major depression [46] while Levine et al. [18] found higher cerebrospinal fluid (CSF) Il-1 concentrations and lower CSF Il-6 levels in depressed patients. Moreover, the association between depression and activated immunity has not been constantly demonstrated. In a meta-analysis concerning the relationship between depression and immunological assays, Zorilla et al. [52] found that depression was associated with a relative leukocytosis, a slightly increased CD4/CD8 ratios, a moderately reduced T and natural killer (NK) cell cytotoxicity and reduced lymphoproliferative response. However, the lowered proliferative response and the reduced NK cytotoxicity might not necessarily fit with the theory of an immune activation. The results are highly variable and are not always consistent with the monocyte-T-lymphocyte theory of depression. The discrepancies between the clinical studies could be related to the heterogeneous psychiatric samples, the duration of illness, the age of onset, the
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different subtypes of depressive disorders (dysthymia, melancholia, etc.) and also to some confounding variables such as weight loss or sleep disorders. Cytokine balance and antidepressants in MDD More recently, investigators have focused on the proand anti-inflammatory cytokine balance in major depressive disorders. Anti-inflammatory cytokines or cytokine receptors are known to induce an antiinflammatory state on their own (Il-10, TGFβ) and also to block the binding of pro-inflammatory stimuli to their cell surface receptors (Il-1ra, soluble TNF receptors II). They have generated a new comprehension of the cytokines’ profile in depressive illness. In a previous study we found decreased levels of TGFβ2 in depressed bulimic patients compared to non-depressed bulimics [7]. A dysregulation within the cytokine balance could induce depressive symptoms due to lower levels of anti-inflammatory cytokines and higher levels of pro-inflammatory cytokines. In some clinical studies [17, 30], it has been reported that antidepressants may attenuate the effects of proinflammatory cytokines by increasing the production of anti-inflammatory cytokines such as Il-10 and Il-1ra. Most antidepressant treatments could significantly reduce the IFNγ/Il-10 ratio and have negative immunoregulatory effects [30]. A number of studies support the idea of an anti-inflammatory action of antidepressants that could explain their efficiency on depressive symptoms. But it still raises a question: if the efficiency of antidepressants is primarily realised by their anti-inflammatory effects why haven’t antiinflammatory drugs been reported to be effective in the treatment of major depressive disorder? According to other authors [32, 42], proinflammatory cytokines could be perturbed only within the central nervous system (notably within the hypothalamic area) and could be responsible in the longer term for a peripheral inflammatory syndrome independently of the activation of the HPA corticotroph axis. Thus, there would be no peripheral rise of the cytokines. METHODOLOGICAL LIMITATION OF PSYCHONEUROIMMUNOLOGY Moreover, many variables interact with the various measurable parameters of immunity such as age, sex,
circadian rhythm, body mass index (BMI), individual genetic factors, any pathology modifying the immune profile (flu, infectious, immune pathology, cancer, etc.), alcohol consumption, tobacco, the status of inpatients or outpatients and the psychotropic drug used. There are many variables which are not easily controllable and constitute many confounding factors. Data of these clinical or experimental studies must thus be interpreted with the greatest prudence, in spite of their major importance in the fields of psychopathology. The reason for the discrepant immune findings could be also related, despite the particularity of each sample, to the different mitogens used for the stimulation of PBMCs. Methodological limitations are also related to the threshold of the tests which vary according to the kits used and to the method of dosage (ELISA, RIA). The biological assessment of cytokines can also differ, ranging from direct measurement of cytokines in body fluid (cerebrospinal, plasma) to the measurement of the in vitro production by PBMCs. Plasma levels of cytokines are highly variable. An analysis of the results in terms of circulating levels of cytokines remains complex. Nevertheless, in vitro cytokine production provides more useful information regarding the capacity of immune cells to produce cytokines [16] but is tightly bound to the activation of the peripheral immune system and not the exact reflection of neuroimmunomodulation. Indeed, only a few peripheral cytokines can cross the brain-blood barrier, and the serum level of cytokines (or the in vitro production by PBMCs) is obviously not the best way to investigate their relevance to the function of the central nervous system. TOWARD A NEW APPROACH TO THE CLINICAL CHARACTERISTICS OF DEPRESSIVE DISORDERS It is thus unclear to what extent depression-related cytokine alterations would be generalizable to most clinically depressed individuals. It can be argued that the cytokine theory of depression has shifted the core symptom of depression from sadness of mood to the vegetative and somatic symptoms of depression. A psychosomatic approach to major depressive disorder might highlight the pathophysiology of specific subtypes of depression, which may be defined as cytokine-induced depressive disorder with prominent
Analogic approach to cytokines and depression
signs of vegetative symptoms rather than depressed mood. Regardless to the putative causal role of proinflammatory cytokines, it is noteworthy that this kind of depressive disorder could be related to the so-called depression essentielle defined by the French psychosomatic school of Paris [31]. This subtype of depression is marked by the somatic component of depression (fatigue, exhaustion) without its emotional component (sadness). It might be accompanied by a specific dysregulation of the pro- and anticytokine profile.
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32 Morimoto A, Watanabe T, Sakata Y, Murakami N. Leukocytosis induced by microinjection of endogenous pyrogen or interleukin-1 into the preoptic and anterior hypothalamus. Brain Res 1989 ; 475 : 345-8. 33 Müller N, Ackeinheil M. Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog Neuropsychoparmacol Biol Psychiatry 1998 ; 22 : 1-33. 34 Musselman DL, Lawson D, Gumnick J, Manatunga A, Penna S, Goodkin RS, et al. Paroxetine for the prevention of the depression and neurotoxicity induced by high dose interferon-alpha therapy. N Engl J Med 2001 ; 344 : 961-6. 35 Nieto E, Vieta E, Alvarez L, Torra M, Colom F, Gasto C. Alpha1acid glycoprotein in major depressive disorder. Relationship to severity, response to treatment and imipramine plasma levels. J Affect Disord 2000 ; 59 : 159-64. 36 Owen BM, Eccleston D, Ferrier IN, Young AH. Raised levels of plasma interleukin-1beta in major and postviral depression. Acta Psychiatr Scand 2001 ; 103 : 226-8. 37 Plata-Salaman CR. Anorexia during acute and chronic disease: relevance of neurotransmitter-peptide-cytokine interactions. Nutrition 1997 ; 13 : 159-60. 38 Ramamoorty S, Ramamoorty JD, Prasad PD, Bhat GK, Mahesh VB, Leibach FH, et al. Regulation of the human serotonin transporter by interleukin-1 beta. Biochem Biophys Res Commun 1995 ; 216 : 560-7. 39 Rothwell NJ, Hopkins SJ. Cytokines and the nervous system II: actions and mechanisms of action. Trends Neurosci 1995 ; 18 : 130-6. 40 Rothermundt M, Arolt V, Peters M, Gutbrodt H, Fenker J, Kersting A, et al. Inflammatory markers in major depression and melancholia. J Affect Disord 2001 ; 63 : 93-102. 41 Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H. Cytokine production and serum proteins in depression. Scand J Immunol 1995 ; 41 : 534-8. 42 Sellami S, de Beaurepaire R. Hypothalamic and thalamic sites of action of interleukin-1ß on food intake, body temperature and pain sensitivity in the rat. Brain Res 1995 ; 694 : 69-77.
43 Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 1996 ; 93 : 3908-13. 44 Sluzewska A, Rybakowski J, Bosmans E, Sobieska M, Berghmans R, Maes M, et al. Indicators of immune activation in major depression. Psychiatry Res 1996 ; 64 : 161-7. 45 Song C, Dinan T, Leonard BE. Changes in immunoglobulin, complement and acute phase protein levels in depressed patients and normal controls. J Affect Disord 1994 ; 30 : 283-8. 46 Stubner S, Schon T, Padberg F, Teipel SJ, Schwarz MJ, Haslinger A, et al. Interleukin-6 and the soluble Il-6 receptor are decreased in cerebrospinal fluid of geriatric patients with major depression: no alteration of soluble gp130. Neurosci Lett 1999 ; 259 : 145-8. 47 Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P. Mood and cognitive side effects of interferon-alpha therapy. Semin Oncol 1998 ; 25 (Suppl 1) : 39-47. 48 Van West Maes M. Activation of the inflammatory response system: a new look at the etiopathogenesis of major depression. Neuroendocrinol Lett 1999 ; 20 : 11-7. 49 Wong ML, Bongiorno PB, Rettori V, McCann SM, Licinio J. Interleukin (Il) 1ß, Il-1 receptor antagonist, Il-10, and Il-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: Pathophysiological implications. Proc Natl Acad Sci U S A 1997 ; 94 : 227-32. 50 Yirmiya R. Behavioral and psychological effects of immune activation: implications for depression due to general medical condition. Curr Opin Psychology 1997 ; 10 : 470-6. 51 Zheng H, Fletcher D, Kozak W, Jiang M, Hofmann KJ, Conn CA, et al. Resistance to fever induction and impaired acutephase response in interleukin-1 beta-deficient mice. Immunity 1995 ; 3 : 9-19. 52 Zorrilla EP, Luborsky L, McKay JR, Rosenthal R, Houldin A, Tax A, et al. The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun 2001 ; 15 : 199-206.
Point of view
Cytokines and depression: an analogic approach M. Corcos*, O. Guilbaud, L. Hjalmarsson, J. Chambry, Ph. Jeammet Department of Adolescent and Young Adult Psychiatry, Pr. Jeammet, Institut Mutualiste Montsouris, 42 Bd Jourdan, 75014 Paris, France (Received 22 June 2001; accepted 17 December 2001)
Summary – A growing body of evidence suggests that major depressive disorders may be accompanied by immune dysfunction and more particularly by an enhanced production of pro-inflammatory cytokines. The possible involvement of cytokines in depressive illness are based upon an analogic model. Pro-inflammatory cytokines are known to induce behavioral effects, and neuro-endocrine and immune activation similar to those observed in depression; these can be alleviated by antidepressant treatment. In this paper, we review research literature on the links between depressive illness and cytokine production and address further questions on this cytokine pathway . Further research is needed to see whether cytokines sustain specific depressive syndromes or whether cytokines induce depressive-like symptoms. © 2002 Éditions scientifiques et médicales Elsevier SAS cytokines / depression / psychoneuroimmunoendocrinology
Psychoneuroimmunoendocrinology has yielded a new holistic vision of the mind-body problem distinct from a dualistic separation between mind and body. Through recent progress in immunology, increasing attention has focused on the view that cytokines may contribute to psychological disturbances such as depressive illness. Cytokines are low molecular-weight proteins or glycoproteins that were initially thought to be restricted to the immune system as mediators of communication between immune cells. However, it is clearly known that many cytokines also play a key role in the central nervous and endocrine system. It has been reported that cytokines were produced by brain cells and interact closely with neurohormones, neurotransmitters and the neuroendocrine system [33]. During the last decade, it has been hypothesized that pro-inflammatory cytokines and immune mediators contribute to the biology of depression. It has *Correspondence and reprints. E-mail address: [email protected] (M. Corcos).
generated a new etiological pathway of depression consistent with some data in the literature. This paper reviews research literature on the links between human and animal cytokine functioning and mood disorders. CYTOKINE PATHWAYS IN MAJOR DEPRESSIVE DISORDERS (MDD) Several line of evidence suggest that depression may be associated with increased production of proinflammatory cytokines such as Il-1, IL-6, IFN, TNF in humans and experimental animals. It has been hypothesized [20, 25] that major depression is accompanied by an acute phase response and peripheral immune activation sustained by an increased production of pro-inflammatory cytokines such as Il-1 and Il-6. According to this peripheral immune theory of depression, depressive disorder would be a consequence of the increased monocytic production of proinflammatory cytokines (notably Il-1 and Il-6 but also Il-2, IFN and TNFα by activated T cells) leading to
106
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an activation of the immune system with elevated rates of antinuclear antibody, increased rates of lymphocyte subsets, such as CD4, decreased numbers of CD8 and an acute phase response characterized by a peripheral inflammatory syndrome (increased plasma levels of haptoglobulin, C-reactive protein [13, 45] and decreased plasma levels of albumin and transferin [26]. Abnormalities of the endocrine system, especially the hyperactivity of the corticotrope axis, could be secondary to the elevated rates of Il-1. The psychoneuroendocrinoimmunological model of depression was built: – on experimental work assessing the depressed effects of immunological therapies (interferon-alpha therapy, interleukin-2 therapy) on patients suffering from cancer or infectious viral diseases (AIDS, chronic hepatitis C, etc.) and/or the depressed effects of cytokines in experimental animals; – on investigation of the reciprocal interaction between pro-inflammatory cytokines such as Il-1 and the hypothalamo-pituitary-adrenocorticotrope axis in depressed patients or in experimental animals; and – from studies assessing circulating levels, or cytokine production in spontaneous or mitogen-stimulated lymphocytes among depressed patients compared to non-depressed control subjects. SICKNESS BEHAVIOUR AND CYTOKINES Infectious diseases are associated with nonspecific symptoms of infection including fever, hypersomnia or hyposomnia, anorexia, fatigue, decreased physical and social activity and loss of interest. These non specific changes are collectively termed ‘sickness behaviour’. Several lines of evidence suggest that pro-inflammatory cytokines such as interleukin (Il-1, Il-6), tumor necrosis factor (TNF) or interferon (IFN) can underlie sickness behaviour mechanisms. Studies in experimental animals indicate that peripheral or central administration of interleukin 1 (Il-1β, Il-1α) and TNFα induce sickness behaviours in mice and rats [3, 8] with decreased social exploration and weight loss. For instance, symptoms of systemic illness can be reproduced by central injection of Il-1β and prevented by high levels of Il-1 receptor antagonist (Il-1ra) [39]. For Wong et al. [49], Il-1ra antagonist receptor may be secreted by the anterior pituitary as an anti-inflammatory hormone in response to Il-1β effects. Moreover, Il-1β knockout mice have
no fever and no alterations in ingestive behavior in response to some peripheral inflammation [51]. In experimental animals, Il-1 is known to have pyrogenic, somnogenic, anorectic and depressed effects. Clinical studies [6, 34, 47] have shown within patients treated with interferon-α the onset of flulike symptoms including fever, anorexia, fatigue, and also severe neuropsychiatric manifestations (such as depression, anxiety, sleep disorders, cognitive impairment). For instance, repeated injections of high doses of interferon-alpha in patients with chronic viral hepatitis (or with malignant melanoma) have been associated with a high frequency of neuropsychiatric complications including symptoms sufficient to meet diagnostic criteria for major depression. Severe depressed symptoms are dose-dependent and diminish a few days to few weeks after cessation of treatment. Many medical conditions are accompanied by a cytokine-mediated depressive-like syndrome [50]. Due to the behavioral effects of cytokines that mimic the vegetative or somatic symptoms of depressive illness (anorexia, sleep disorders, fatigue, motor retardation, anhedonia), a pathophysiological parallel has been made between the profound depressive effects of cytokines and their potent etiological implications in depressive illness. CYTOKINES IN THE BRAIN, CYTOKINES AND SEROTONIN SYNTHESIS Dysregulation of the hypothalamo-pituitaryadrenocortical (HPA) axis is an important key element in the biology of major depression which could result in the atrophy of hippocampus and amygdala [43]. Cytokines are known to disrupt the endocrine system and act in the brain as neurotransmitter [1]. For example, Il-1 is a potent activator of the HPA axis via the stimulation of the corticotropin-releasing hormone (CRH) [9, 19]. In major depression increased levels of Il-1β could stimulate HPA activity [10]. Il-1 is also known to increase the noradrenergic catabolites in the medial hypothalamus [9, 15]. Pro-inflammatory cytokines can also modify serotonin mechanisms in the brain [37]. Il-1 (and to a lesser degree Il-6 and TNFα) increase free tryptophan and the serotonin catabolites [10]. Moreover, Il-1β has been reported to be a potent regulator of the serotonin transporter [38].
Analogic approach to cytokines and depression
Other authors were interested in the loops of immune regulation between the interferon-γ pathway and serotonin synthesis. A peripheral model of immunomodulation concerning interferon was relatively well documented. It has been shown that there was a feedback of serotonin synthesis by interferon-γ [11]. IFN-γ increases the tryptophan uptake by lymphocytes and macrophages, which could lead to an enhanced production of serotonin, while high levels of indolamines such as serotonin inhibit IFN-γ synthesis [11]. On the other hand, interferon-γ also enhances tryptophan degradation via the kynurenine catabolic pathway with an induction of the enzyme indolamine 2,3 dioxygenase [5]. These new models of interaction between interferon and serotonin regulation could be the reflect of some immunoregulatory pathway relevant to the central nervous system that might be disturbed within patients under interferon treatment. These findings are quite relevant because the serotonin transporter and metabolism in the brain are primary targets for a number of antidepressants. DATA IN THE LITERATURE It has been hypothesized that some of the neuroendocrine and immune disorders observed in major depression could be related to an acute phase response with an activation of the inflammatory response in that illness [25], but the results of the literature conflict. The acute phase response in major depressive disorders (MDD) Several authors have reported increased plasma levels of positive acute phase proteins such as haptoglobulin, C-reactive protein, α1-acid glycoprotein and α1- or α2-globulin in major depression [13, 20, 35, 41, 45]. For instance, Maes et al. [22] found that the vegetative symptoms of major depression (insomnia, reduced locomotion) were correlated with higher levels of haptoglobulinemia but not with mood state. This could be related [21, 28] to a specific activation of peripheral pro-inflammatory cytokines, notably Il-6, Il-1, which may underlie the immune and acute phase response of major depression [25]. For Van West and Maes [48] the neuroendocrine changes in depression (HPA-axis hyperactivity, lower activity
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of the hypo-pituitary-thyroid axis) are indicators of the activation of the inflammatory response system. It has been shown in severe depressive episode that Il-6 or Il-1 production by mitogen-stimulated peripheral leukocytes was significantly and positively correlated with the activity of the HPA-axis [21, 24], haptoglobulinemia [21] or alpha-1 acid glycoprotein [44], while Il-6 activity and haptoglobulinemia have been reported to be significantly and negatively correlated with lower plasma L-tryptophan levels [23]. These clinical studies support the hypothesis that increased production of pro-inflammatory cytokines such as Il-6 in depressive disorders may disturb the pathophysiological loop of regulation within the neuroendocrinoimmune system and thus be responsible of the immune activation with an acute phase response, hyperactivity of the HPA-axis and deregulation of the turn over of serotonin. Cytokine production in MDD However, the results concerning the production of pro-inflammatory cytokines are still inconstant; some authors have reported elevated rates of Il-1 or Il-6 ( in peripheral blood mononuclear cells [PBMCs] stimulated by mitogens: [23, 41]; in serum: [2, 27, 29, 36, 40, 44]), while others did not find significant differences (in stimulated PBMCs: [40]; in serum: [4, 12, 14]), or found significantly decreased Il-6 levels in cerebral spinal fluid of geriatric patients with major depression [46] while Levine et al. [18] found higher cerebrospinal fluid (CSF) Il-1 concentrations and lower CSF Il-6 levels in depressed patients. Moreover, the association between depression and activated immunity has not been constantly demonstrated. In a meta-analysis concerning the relationship between depression and immunological assays, Zorilla et al. [52] found that depression was associated with a relative leukocytosis, a slightly increased CD4/CD8 ratios, a moderately reduced T and natural killer (NK) cell cytotoxicity and reduced lymphoproliferative response. However, the lowered proliferative response and the reduced NK cytotoxicity might not necessarily fit with the theory of an immune activation. The results are highly variable and are not always consistent with the monocyte-T-lymphocyte theory of depression. The discrepancies between the clinical studies could be related to the heterogeneous psychiatric samples, the duration of illness, the age of onset, the
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different subtypes of depressive disorders (dysthymia, melancholia, etc.) and also to some confounding variables such as weight loss or sleep disorders. Cytokine balance and antidepressants in MDD More recently, investigators have focused on the proand anti-inflammatory cytokine balance in major depressive disorders. Anti-inflammatory cytokines or cytokine receptors are known to induce an antiinflammatory state on their own (Il-10, TGFβ) and also to block the binding of pro-inflammatory stimuli to their cell surface receptors (Il-1ra, soluble TNF receptors II). They have generated a new comprehension of the cytokines’ profile in depressive illness. In a previous study we found decreased levels of TGFβ2 in depressed bulimic patients compared to non-depressed bulimics [7]. A dysregulation within the cytokine balance could induce depressive symptoms due to lower levels of anti-inflammatory cytokines and higher levels of pro-inflammatory cytokines. In some clinical studies [17, 30], it has been reported that antidepressants may attenuate the effects of proinflammatory cytokines by increasing the production of anti-inflammatory cytokines such as Il-10 and Il-1ra. Most antidepressant treatments could significantly reduce the IFNγ/Il-10 ratio and have negative immunoregulatory effects [30]. A number of studies support the idea of an anti-inflammatory action of antidepressants that could explain their efficiency on depressive symptoms. But it still raises a question: if the efficiency of antidepressants is primarily realised by their anti-inflammatory effects why haven’t antiinflammatory drugs been reported to be effective in the treatment of major depressive disorder? According to other authors [32, 42], proinflammatory cytokines could be perturbed only within the central nervous system (notably within the hypothalamic area) and could be responsible in the longer term for a peripheral inflammatory syndrome independently of the activation of the HPA corticotroph axis. Thus, there would be no peripheral rise of the cytokines. METHODOLOGICAL LIMITATION OF PSYCHONEUROIMMUNOLOGY Moreover, many variables interact with the various measurable parameters of immunity such as age, sex,
circadian rhythm, body mass index (BMI), individual genetic factors, any pathology modifying the immune profile (flu, infectious, immune pathology, cancer, etc.), alcohol consumption, tobacco, the status of inpatients or outpatients and the psychotropic drug used. There are many variables which are not easily controllable and constitute many confounding factors. Data of these clinical or experimental studies must thus be interpreted with the greatest prudence, in spite of their major importance in the fields of psychopathology. The reason for the discrepant immune findings could be also related, despite the particularity of each sample, to the different mitogens used for the stimulation of PBMCs. Methodological limitations are also related to the threshold of the tests which vary according to the kits used and to the method of dosage (ELISA, RIA). The biological assessment of cytokines can also differ, ranging from direct measurement of cytokines in body fluid (cerebrospinal, plasma) to the measurement of the in vitro production by PBMCs. Plasma levels of cytokines are highly variable. An analysis of the results in terms of circulating levels of cytokines remains complex. Nevertheless, in vitro cytokine production provides more useful information regarding the capacity of immune cells to produce cytokines [16] but is tightly bound to the activation of the peripheral immune system and not the exact reflection of neuroimmunomodulation. Indeed, only a few peripheral cytokines can cross the brain-blood barrier, and the serum level of cytokines (or the in vitro production by PBMCs) is obviously not the best way to investigate their relevance to the function of the central nervous system. TOWARD A NEW APPROACH TO THE CLINICAL CHARACTERISTICS OF DEPRESSIVE DISORDERS It is thus unclear to what extent depression-related cytokine alterations would be generalizable to most clinically depressed individuals. It can be argued that the cytokine theory of depression has shifted the core symptom of depression from sadness of mood to the vegetative and somatic symptoms of depression. A psychosomatic approach to major depressive disorder might highlight the pathophysiology of specific subtypes of depression, which may be defined as cytokine-induced depressive disorder with prominent
Analogic approach to cytokines and depression
signs of vegetative symptoms rather than depressed mood. Regardless to the putative causal role of proinflammatory cytokines, it is noteworthy that this kind of depressive disorder could be related to the so-called depression essentielle defined by the French psychosomatic school of Paris [31]. This subtype of depression is marked by the somatic component of depression (fatigue, exhaustion) without its emotional component (sadness). It might be accompanied by a specific dysregulation of the pro- and anticytokine profile.
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