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Antidepressant drugs and cytokines in mood disorders
International Immunopharmacology 2 (2002) 1619 – 1626 www.elsevier.com/locate/intimp
Review
Antidepressant drugs and cytokines in mood disorders Akira Nishida a,*, Kazue Hisaoka a, Hidenobu Zensho a, Yousuke Uchitomi b, Shigeru Morinobu c, Shigeto Yamawaki c a
Department of Psychiatry and Neuroscience, Institute of Clinical Research, National Kure Medical Center, 3-1 Aoyama, Kure 737-0023, Japan b Psycho-Oncology Division, National Cancer Center Research Institute East, 6-5-1, Kashiwanoha, Kashiwa 277-8577, Japan c Department of Psychiatry and Neurosciences, Hiroshima University Graduate School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan Received 30 April 2002; received in revised form 23 September 2002; accepted 24 September 2002
Abstract This article reviews recent developments in cytokine research that pertain to pharmacological treatment of mood disorders such as antidepressants and lithium. We review the possible involvement of cytokines in mood disorders and their role in the therapeutic effects of antidepressant drugs. Growing evidence suggests that specific cytokines signal the brain to generate neurochemical, neuroimmune, neuroendocrine and behavior changes. An imbalance of cytokines within the central nervous system (CNS), or even systemically, may play a role in the pathophysiology of mood disorders. Modulation of these cytokines by chronic antidepressant treatment may result in restored balance. However, the effect of antidepressants on cytokines is still unclear both in clinical and preclinical research due to limited data. Further research is needed to clarify the involvement of cytokines in mood disorders. Understanding this relationship may lead to rational, therapeutic improvements in antidepressant and mood stabilizing drugs. D 2002 Published by Elsevier Science B.V. Keywords: Mood disorder; Bipolar disorder; Depression; Antidepressant; Cytokine; Interleukin; Interferon; Sickness behavior
1. Introduction Mood disorder is a common, often overlooked, illness that should be recognized and treated. The World Health Organization (WHO) has estimated that depression will be one of the two major illness burdens confronting the world by 2020. Marked increases in the incidence and prevalence of this
* Corresponding author. Tel.: +81-823-22-3111x7404; fax: +81-823-21-0478. E-mail address: [email protected] (A. Nishida).
psychiatric illness present serious problems. The most severe problem is that only fewer than 25% of those affected have access to effective treatment. A barrier to effective care includes the social stigma associated with mental disorders including mood disorders. A better understanding of the biological causes of mood disorders may help to overcome this stigma. Over the last three or four decades, some key hypotheses regarding the etiology of depression have been advanced [1]. The neurotransmitter – receptor hypothesis of depression postulates that an imbalance of catecholamine neurotransmitters and/or their receptors results in depression. The intracellular messenger
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hypothesis of depression derives from data showing that lithium inhibits inositol monophosphatase. Much research on the involvement of second messengers in mood disorders has taken place and this hypothesis has become widely accepted in the last decade. Even so, this hypothesis and the neurotransmitter – receptor hypothesis do not completely explain the molecular mechanisms underlying mood disorders. Recent investigations have shown that mood disorder is associated with the immune system [2 – 7]. Several researchers have proposed the hypothesis that the immune system might be involved in the pathophysiology of mood disorders because some immune parameters (cell counts, cell responses to mitogens and antigen expression) are aberrant in depressed patients. Many researchers have enthusiastically accepted this hypothesis. The concept is strongly supported by the observation that cytokine-induced ‘‘sickness behavior’’ is somewhat symptomatically similar to depression and includes such behaviors as anhedonia, reduced appetite, helplessness, dysphoria, apathy, mental slowing and fatigue [8]. The objective of this paper is to review the literature concerning changes in cytokine expression and activity associated with mood disorders and to focus on the effects of treatment with antidepressants or mood stabilizers on cytokines both in clinical and preclinical research.
2. Alteration of cytokines in mood disorders The potential association between the immune system and mood disorders is a hot issue in biological psychiatry. In general, three immune measures have been examined in studies for patients of mood-disordered, enumerative measures like cell counts, functional measures such as natural killer cell (NK) activity, and cell markers like HLA. Taken together, the cumulative data suggest that depressed patients have decreased numbers of lymphocytes, reduced mitogen-induced lymphocyte proliferation, and lowered NK cell activity [2– 7]. However, this does not apply to all depressed patients since some depressed patients show increased or normal immune responses. Thus, a new perspective is needed to make progress in understanding the association between the immune system and mood disorders.
Newer technology in immunology research, such as ELISA and general molecular biology techniques, has made it possible to effectively study cytokine expression. These studies have suggested that cytokine expression may play an important role in the relationship between mood disorders and the immune system. Cytokines are multifunctional, pleiotropic proteins that play crucial roles in the immune system. They are not only immunoregulators but also neuromodulators in the central nervous system. Cytokines have been classified as being either pro-inflammatory (Th 1-type, stimulatory) or anti-inflammatory (Th 2type, inhibitory) depending on the final effects on the immune system [9]. In general, the pro-inflammatory cytokines consist of interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), etc., and the anti-inflammatory cytokines include IL-4, IL-10, IL-13, etc. Cytokines are involved not only in immune mechanisms but also in various physiological and pathological processes including events in the peripheral and the central nervous system. It has been hypothesized that aberrant production of cytokines may play a role in the etiopathology and symptomatology of mood disorders [2– 7]. There is increasing evidence for an association between the alteration of cytokine concentrations in blood and the pathophysiology of depressive disorders. The results of these studies suggest an involvement of the proinflammatory cytokines in mood disorders. In addition to blood studies, recent reports show that depressed patient groups have higher CSF concentrations of IL-1-beta, lower levels of IL-6 and sIL-2 receptor, and no change in TNF-alpha, compared to control groups [10,11]. The process of neural damage to specific brain areas in depressed patients seems to be closely related to the shift of cytokine balance towards pro-inflammatory cytokines such as IL-1beta, IL-6 or TNF-alpha independent of whether they are produced within the central nervous system (CNS) or systemically.
3. Antidepressants and cytokines in humans Various antidepressant treatments may affect cytokine production and action both in the peripheral immune system and in the CNS [12]. However, there are still only a few studies that have measured
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peripheral blood cytokines in mood-disordered patients before and after treatment with antidepressants (Table 1). In one study, a significant reduction in IL-1-beta, IL-2 and IL-3-like activity in peripheral blood mononuclear cells was observed in untreated depressed patients when compared to controls. Synthesis of IL-1-beta and IL-3-like activity was significantly increased after clomipramine treatment [13]. Another study showed that increased plasma levels of IL-6 observed during acute depression were normalized after an 8-week period of fluoxetine treatment [4]. A more recent study showed that, compared to
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controls, unstimulated pretreatment production of IL6 was significantly decreased in patients who responded to treatment, whereas it was significantly increased in patients who did not respond to treatment. Post-treatment values did not differ significantly between patient and control groups [15]. These authors also reported that pretreatment levels of TNF-alpha were increased in both responding and non-responding patient subgroups, with a significant decrease during treatment only in the responder subgroup. Another study showed that TNF-alpha levels in depressed patients increased after pharmacotherapy,
Table 1 Results of selected studies of antidepressant drugs and cytokine in mood disorders Author
Year
Subject
Organ
Antidepressant
Cytokine
Pretreatment levelsa
Post-treatment results
Weizman et al. [13]
1994
major depressed patients
mononuclear cell
clomipramine (4 weeks)
interleukin-1h interleukin-2 interleukin-3-like activity
low low low
Sluzewska et al. [14] Lanquillon et al. [15]
1995
depressed patients major depressive disorder
serum
fluoxetine (8 weeks) amitriptyline (6 weeks)
interleukin-6
high
interleukin-6
low (responder)
high (nonresponder) no difference no difference no difference
increase (normalize) no change increase (normalize) decease (normalize) increase (responder, normalize) decease (nonresponder, normalize) decease (responder, normalize) no change (nonresponder) no change no change no change
no difference high high
increase no change no change
high
no change
high high high
no change no change no change
no difference high
no change no change
2000
whole blood
high (nonresponder) TNF-a
Kagaya et al. [16]
2001
major depressive and dysthymia
plasma
various antidepressant mainly clomipramine (4 weeks)
Maes et al. [17]
1995
major depressed patients
plasma
fluoxetine or tricyclic antidepressants (over 80 days on the average)
Maes et al. [18]
1997
major depressed patients
serum
maily trazodone (5 weeks)
Anisman et al. [19]
1999
dysthymic patients
mononuclear cell
sertraline (12 weeks)
a
interleukin-1h interleukin-6 soluble interleukin-2 receptor TNF-a interleukin-6 soluble interleukin-2 receptor soluble interleukin-6 receptor transferrin receptor interleukin-6 interleukin-1 receptor antagonist interleukin-6 receptor interleukin-1h
high (responder)
Pretreatment levels mean cytokine levels of subjects in comparison with normal subjects before treatment.
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but there was no change in plasma IL-1-beta, IL-6 or sIL-2 receptor [16]. Modulation of cytokine production in depressed patients may be attributed to the depression per se, or it may be related to depressionassociated hyperactivity of the hypothalamic –pituitary – adrenal axis. If cytokine expression is altered by antidepressants, it is still unknown whether it is due to direct effects of antidepressants or indirect effects after mood improvements. Further research is necessary to elucidate the mechanism of interaction between antidepressant drugs and cellular immune function and the mediators responsible for the aberrant cytokine production observed in patients with mood disorders. In contrast, there are some reports that antidepressants do not affect blood cytokine levels in depressed patients. One study showed that plasma concentrations of IL-6, sIL-6 receptor and sIL-2 receptor were significantly higher in major depressed subjects than in healthy controls. However, subchronic treatment with antidepressant drugs, such as fluoxetine or tricyclic antidepressants, did not significantly affect plasma IL-6, sIL-6 receptor or sIL-2 receptor levels [17]. In a follow-up study, these authors showed that serum IL-6 and IL-1 receptor antagonist were significantly higher in subjects with major depression compared to normal controls. However, subchronic treatment with antidepressants had no significant effects on serum IL-6 and IL-1 receptor antagonist, but did significantly reduce serum sIL-6 receptor levels [18]. Thus, these authors suggested that aberrant cytokine expression in depressed patients might be a trait-dependent but not a state-dependent biological marker of depression. Another study indicated that, in dysthymic patients, basal IL-1-beta was elevated relative to control subjects, but sertraline, which attenuated the symptoms of depression, did not normalize IL-1-beta production [19]. These results suggest that antidepressant drugs might exert their effects, at least in part, by affecting downstream signaling of cytokine receptors and not by affecting plasma concentrations of cytokines. It has been suggested that antidepressant drugs may alleviate the neuropsychiatric disturbances induced by interferon-alpha [20,21] and IL-1-beta [22]. These results imply that cytokines could play a role in mood disorders. An indirect effect of antidepressants on these cytokines may underlie the mech-
anism of neuropsychiatric symptom alleviation. However, due to the limited clinical studies available, it is not possible to conclude whether antidepressants modulate cytokine expression in depressed patients. Much more research is necessary to answer this question. To examine direct effects of antidepressants on cytokine production, in vitro studies have investigated the effects of antidepressants on immune cells from human volunteers. One such study indicates that clomipramine, imipramine and citalopram significantly suppress IL-2 and interferon-gamma release in T lymphocytes and IL-1-beta and TNF-alpha release in lipopolysaccharide (LPS)-treated monocytes [23]. Other investigators have found that different classes of antidepressants (clomipramine, sertraline, and trazodone) at plasma concentrations in the therapeutic range exert significant suppressive effects on the interferon-gamma/IL-10 ratio. This effect was attributable to both a suppression of the stimulated production of interferon-gamma and a significant stimulatory effect on IL-10 production [24]. These authors hypothesized that serotonin (5HT) may mediate the effects of antidepressants on immune cells. Specifically, they suggested that intracellular 5-HT may be necessary for an optimal synthesis of interferon-gamma and IL-10, and that extracellular 5-HT concentrations at or above serum values may suppress the production of interferongamma [25]. The studies described thus far have focused on the effects of antidepressant treatments on cytokine expression by peripheral blood cells. These studies have shown an effect of antidepressant treatments on the peripheral immune system. However, antidepressants may also affect cytokine expression and action in the CNS. Levine et al. [10,11] have reported that depressed patients, compared to controls, showed higher CSF concentrations of IL-1-beta, lower concentrations of IL-6 and sIL-2 receptor and no change in TNF-alpha. More research is needed to investigate expression of these cytokines in the CNS before and after antidepressant treatment. A recent report has examined the effects of lowdose endotoxemia, a well-established and safe model of host defense activation on emotional, cognitive, immunological and endocrine parameters in 20 healthy male volunteers [26]. Endotoxin increased
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circulating levels of TNF-alpha, soluble TNF receptors, IL-6, IL-1 receptor antagonist and cortisol. After endotoxin administration, the subjects showed a transient but significant increase in anxiety and depressed mood. In humans, mild stimulation of primary host defense has negative effects on emotional and memory functions, which are probably caused by cytokine release. These data suggest that cytokines represent a novel target for neuropsychopharmacological research. Future studies examining the effects of antidepressants on sickness behavior in LPS-administered volunteers will provide an important and interesting contribution to psychoimmulogical science.
4. Antidepressants and cytokines in experimental models Limited data exist examining the effects of antidepressant treatment on the immune system and cytokine action in experimental models. One study has shown that the chronic, mild stress-induced lymphocyte proliferation and synthesis of IL-1 and IL-2 from rat spleen cells are reversed following chronic treatment with imipramine [27]. These authors have also shown stimulatory effects on IL-10 secretion by repeated administration of tricyclic antidepressants or the selective serotonin reuptake inhibitors (SSRIs) in C57BL/6 mice [28 – 30]. Suzuki et al. [31] have shown that repeated administration of imipramine in the CNS induces IL-1 and IL-1 receptor antagonist mRNA in various regions of the rat brain. Imipramine induces a greater effect on IL-1 receptor antagonist mRNA than on IL-1 mRNA. Further basic research using experimental models is needed to fully examine the direct effects of antidepressants on cytokine expression. In another experimental paradigm, chronic but not acute antidepressant treatment abrogates symptoms of LPS-induced sickness behavior in rats [8,32,33]. In addition to behavioral endpoints, these studies have also focused on the effects of antidepressant treatments on cytokine expression in peripheral blood cells from LPS-treated animals. However, only a few studies have examined the effects of antidepressant treatment on the brain. These kinds of investigations are necessary to identify the precise mechanism underlying the effects of antidepressant treatments
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on cytokine expression. Yirmiya [32] found that chronic imipramine treatment abolishes the suppressive effect of LPS-induced anhedonia using a saccharine preference paradigm. Moreover, chronic but not acute treatment with imipramine reduces and facilitates recovery from the suppressive effects of LPS on food consumption, body weight, social interaction and activity in the open-field test. Chronic, but not acute treatment with tianeptine, attenuates the behavioral signs of sickness behavior induced by peripheral but not central LPS or IL-1-beta [34]. This work, which is the first in vivo study assessing the effect of an antidepressant on centrally induced immune activation, shows a clear dissociation between peripheral and central cytokine effects and suggests a peripheral site of action of tianeptine. It also provides the first evidence that the protective effects of classical antidepressants on LPS-induced sickness behavior extend to an atypical antidepressant and that the protective effect of antidepressants also applies to IL-1-beta. Rolipram, a selective type IV phosphodiesterase inhibitor, stereospecifically suppresses the production of TNF/lymphotoxin-alpha and albeit less strongly, interferon-gamma in human and rat auto-reactive T cells [35]. These experimental models provide useful tools for investigating the precise mechanisms of antidepressant action and may help to develop new treatments for mood disorders. However, other experimental studies of antidepressant and sickness behavior have given conflicting results. Shen et al. [36] reported that chronic treatment with the antidepressants paroxetine and venlafaxine failed to alter any of the LPS-induced behavioral responses, while chronic treatment with the tricyclic antidepressant desipramine prevented LPS-induced anorexia, loss of body weight, the antidipsogenic effect and hypoactivity in rats. In addition, a recent report cannot show the prevention by chronic treatment of antidepressants (imipramine and venlafaxine) against the reduction in sweetened milk intake induced by IL-1 and endotoxin in mice [37]. These results do not support the hypothesis that antidepressants may exert part of their antidepressive efficacy through modulation of cytokine action. Chronic treatment of some antidepressants may indeed alter some of the behavioral responses to LPS, but whether this is related to the antidepressant properties of the drugs remains to be determined.
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5. Effects of lithium and monoamine oxidase inhibitors on the immune system There are only a few reports that drugs for the treatment of mood disorders, other than antidepressants, affect cytokine actions. To our knowledge, only one study has examined the effects of lithium on cytokine expression in manic patients. This study found that sIL-2RS and sIL-6RS are increased in symptomatic rapid cycling patients and normalize with lithium treatment [38]. These authors have also shown that 5 days of lithium treatment increases IL-2, sIL-2RS and sIL-6RS in normal volunteers [38], and that lithium causes an increase in IL-4 and IL-10 levels and a decrease in IL-2 and interferon-gamma levels in whole blood cultures from normal control subjects [39]. Another researcher found that lithium exerts significant immunoregulatory effects by increasing the production of both pro-inflammatory cytokines (interferon-gamma, TNF-alpha and IL-8) and anti-inflammatory cytokines or proteins (IL-10 and the IL-1RA) in whole blood supernatants from healthy volunteers [40]. In studies of diluted whole blood stimulated with LPS plus phytohemagglutinin, moclobemide (a reversible monoamine oxidase A inhibitor) shows negative immunoregulatory capacities through inhibition of the production of proinflammatory cytokines (i.e. TNF-alpha and IL-8) and through enhancement of the production of IL10, an anti-inflammatory cytokine [41]. Much more research, including investigation of the effects of electroconvulsive shock therapy on cytokine expression, is necessary to elucidate the role of cytokine expression in antidepressive therapy.
6. How do antidepressants act on cytokines? A number of studies have shown an interaction between neurotransmission and the immune system in the brains of experimental animals [9,42]. Because immune cells express neurotransmitter and neuropeptide receptors, mediators such as noradrenaline and serotonin, other monoamines, nucleosides and acetylcholine are able to modulate the cytokine response to certain stimuli. Moreover, neurons and glial cells express cytokine receptors and the release and action of neurotransmitters are modulated by cytokines. Anti-
depressants appear to affect cytokine release and action by modulating neurotransmitter actions. Antidepressants may also modulate intracellular signals like cAMP and CREB and in this way affect cytokine function [9]. Indeed, antidepressant modulation of neurotransmitters that results in stimulation of adenylate-cyclase leads to a shift towards Th 2-type responses, which are anti-inflammatory and protective. Neuroprotection and/or proliferation of neuronal cells might be the most probable molecular mechanism of antidepressive therapy [1,43]. Adaptations at the cellular and molecular levels in response to stress and antidepressant treatment could represent a form of neural plasticity that contributes to the pathophysiology and/or treatment of depression. Neuroprotection and/or proliferation could be the result of an adjustment of the balance between pro- and anti-inflammatory cytokines after antidepressive therapy. As has been widely recognized during the last decade, neurotoxic and neuroprotective mechanisms are both closely related to the balance between pro- and antiinflammatory cytokines. A majority of researchers currently support the imbalance hypothesis of proand anti-inflammatory cytokines in depression. This hypothesis seems to be conceivable and drawn mostly on the concept of cytokine actions in peripheral tissues. However, there are still conflicting results of cytokine research both in blood and CSF in depression [10 –16]. Unfortunately, non-invasive methods for detection and quantification of cytokines in CNS have not devised. In addition, the evidence that proinflammatory cytokines such as IL-1 or TNF-alpha are neurotoxic is considerable but controversial. Proinflammatory cytokines are also likely to be involved in synaptic plasticity, neural transmission and Ca2 + signaling and thus perform neural functions in the normal brain. Thus, they should be thought of as neuromodulators in addition to inflammatory mediators [44]. We should continue to do much more investigations into the effects of antidepressive therapy on each cytokine and interaction among cytokines in both preclinical and clinical research.
7. Future perspective In this article, we have reviewed the association between cytokines and antidepressant therapy based
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on both clinical and preclinical research. A line of evidence suggests the modulation of cytokine signals by chronic antidepressant treatment. This may lead to the adjustment of an imbalance of cytokines in depression. However, the effect of antidepressant treatments on cytokines is still unclear in various aspects: (1) Does the modulation of cytokine signals by antidepressants occur in the periphery or in the brain? (2) How do antidepressants act on cytokines to cause mood change? (3) Is the modulation of cytokines causative or a result of mood change? (4) Why do only some patients show depressive symptoms in response to cytokine administration? Recent developments in molecular biology such as microarrays and/ or knockout animal models [45] of cytokines will provide useful tools to resolve these questions. Clinical research investigating single nucleotide polymorphisms for cytokines, their receptors and signaling molecules will also provide great insight into these fundamental questions. Understanding the relationship between antidepressive therapy and cytokines may result in new, rational diagnostic and therapeutic improvements for the treatment of depression. Acknowledgements This work was supported in part by a research grant (13A-3) for Nervous and Mental Disorders and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan and grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. References [1] Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002 March 28;34:13 – 25. [2] Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 1995;19:11 – 38. [3] Mu¨ller N, Ackenheil M. Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 1998;22: 1 – 33. [4] Dantzer R, Wollman EE, Yirmiya R. Cytokines, stress, and depression. Adv Exp Med Biol, vol. 461. New York: Plenum; 1999.
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Review
Antidepressant drugs and cytokines in mood disorders Akira Nishida a,*, Kazue Hisaoka a, Hidenobu Zensho a, Yousuke Uchitomi b, Shigeru Morinobu c, Shigeto Yamawaki c a
Department of Psychiatry and Neuroscience, Institute of Clinical Research, National Kure Medical Center, 3-1 Aoyama, Kure 737-0023, Japan b Psycho-Oncology Division, National Cancer Center Research Institute East, 6-5-1, Kashiwanoha, Kashiwa 277-8577, Japan c Department of Psychiatry and Neurosciences, Hiroshima University Graduate School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan Received 30 April 2002; received in revised form 23 September 2002; accepted 24 September 2002
Abstract This article reviews recent developments in cytokine research that pertain to pharmacological treatment of mood disorders such as antidepressants and lithium. We review the possible involvement of cytokines in mood disorders and their role in the therapeutic effects of antidepressant drugs. Growing evidence suggests that specific cytokines signal the brain to generate neurochemical, neuroimmune, neuroendocrine and behavior changes. An imbalance of cytokines within the central nervous system (CNS), or even systemically, may play a role in the pathophysiology of mood disorders. Modulation of these cytokines by chronic antidepressant treatment may result in restored balance. However, the effect of antidepressants on cytokines is still unclear both in clinical and preclinical research due to limited data. Further research is needed to clarify the involvement of cytokines in mood disorders. Understanding this relationship may lead to rational, therapeutic improvements in antidepressant and mood stabilizing drugs. D 2002 Published by Elsevier Science B.V. Keywords: Mood disorder; Bipolar disorder; Depression; Antidepressant; Cytokine; Interleukin; Interferon; Sickness behavior
1. Introduction Mood disorder is a common, often overlooked, illness that should be recognized and treated. The World Health Organization (WHO) has estimated that depression will be one of the two major illness burdens confronting the world by 2020. Marked increases in the incidence and prevalence of this
* Corresponding author. Tel.: +81-823-22-3111x7404; fax: +81-823-21-0478. E-mail address: [email protected] (A. Nishida).
psychiatric illness present serious problems. The most severe problem is that only fewer than 25% of those affected have access to effective treatment. A barrier to effective care includes the social stigma associated with mental disorders including mood disorders. A better understanding of the biological causes of mood disorders may help to overcome this stigma. Over the last three or four decades, some key hypotheses regarding the etiology of depression have been advanced [1]. The neurotransmitter – receptor hypothesis of depression postulates that an imbalance of catecholamine neurotransmitters and/or their receptors results in depression. The intracellular messenger
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hypothesis of depression derives from data showing that lithium inhibits inositol monophosphatase. Much research on the involvement of second messengers in mood disorders has taken place and this hypothesis has become widely accepted in the last decade. Even so, this hypothesis and the neurotransmitter – receptor hypothesis do not completely explain the molecular mechanisms underlying mood disorders. Recent investigations have shown that mood disorder is associated with the immune system [2 – 7]. Several researchers have proposed the hypothesis that the immune system might be involved in the pathophysiology of mood disorders because some immune parameters (cell counts, cell responses to mitogens and antigen expression) are aberrant in depressed patients. Many researchers have enthusiastically accepted this hypothesis. The concept is strongly supported by the observation that cytokine-induced ‘‘sickness behavior’’ is somewhat symptomatically similar to depression and includes such behaviors as anhedonia, reduced appetite, helplessness, dysphoria, apathy, mental slowing and fatigue [8]. The objective of this paper is to review the literature concerning changes in cytokine expression and activity associated with mood disorders and to focus on the effects of treatment with antidepressants or mood stabilizers on cytokines both in clinical and preclinical research.
2. Alteration of cytokines in mood disorders The potential association between the immune system and mood disorders is a hot issue in biological psychiatry. In general, three immune measures have been examined in studies for patients of mood-disordered, enumerative measures like cell counts, functional measures such as natural killer cell (NK) activity, and cell markers like HLA. Taken together, the cumulative data suggest that depressed patients have decreased numbers of lymphocytes, reduced mitogen-induced lymphocyte proliferation, and lowered NK cell activity [2– 7]. However, this does not apply to all depressed patients since some depressed patients show increased or normal immune responses. Thus, a new perspective is needed to make progress in understanding the association between the immune system and mood disorders.
Newer technology in immunology research, such as ELISA and general molecular biology techniques, has made it possible to effectively study cytokine expression. These studies have suggested that cytokine expression may play an important role in the relationship between mood disorders and the immune system. Cytokines are multifunctional, pleiotropic proteins that play crucial roles in the immune system. They are not only immunoregulators but also neuromodulators in the central nervous system. Cytokines have been classified as being either pro-inflammatory (Th 1-type, stimulatory) or anti-inflammatory (Th 2type, inhibitory) depending on the final effects on the immune system [9]. In general, the pro-inflammatory cytokines consist of interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), etc., and the anti-inflammatory cytokines include IL-4, IL-10, IL-13, etc. Cytokines are involved not only in immune mechanisms but also in various physiological and pathological processes including events in the peripheral and the central nervous system. It has been hypothesized that aberrant production of cytokines may play a role in the etiopathology and symptomatology of mood disorders [2– 7]. There is increasing evidence for an association between the alteration of cytokine concentrations in blood and the pathophysiology of depressive disorders. The results of these studies suggest an involvement of the proinflammatory cytokines in mood disorders. In addition to blood studies, recent reports show that depressed patient groups have higher CSF concentrations of IL-1-beta, lower levels of IL-6 and sIL-2 receptor, and no change in TNF-alpha, compared to control groups [10,11]. The process of neural damage to specific brain areas in depressed patients seems to be closely related to the shift of cytokine balance towards pro-inflammatory cytokines such as IL-1beta, IL-6 or TNF-alpha independent of whether they are produced within the central nervous system (CNS) or systemically.
3. Antidepressants and cytokines in humans Various antidepressant treatments may affect cytokine production and action both in the peripheral immune system and in the CNS [12]. However, there are still only a few studies that have measured
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peripheral blood cytokines in mood-disordered patients before and after treatment with antidepressants (Table 1). In one study, a significant reduction in IL-1-beta, IL-2 and IL-3-like activity in peripheral blood mononuclear cells was observed in untreated depressed patients when compared to controls. Synthesis of IL-1-beta and IL-3-like activity was significantly increased after clomipramine treatment [13]. Another study showed that increased plasma levels of IL-6 observed during acute depression were normalized after an 8-week period of fluoxetine treatment [4]. A more recent study showed that, compared to
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controls, unstimulated pretreatment production of IL6 was significantly decreased in patients who responded to treatment, whereas it was significantly increased in patients who did not respond to treatment. Post-treatment values did not differ significantly between patient and control groups [15]. These authors also reported that pretreatment levels of TNF-alpha were increased in both responding and non-responding patient subgroups, with a significant decrease during treatment only in the responder subgroup. Another study showed that TNF-alpha levels in depressed patients increased after pharmacotherapy,
Table 1 Results of selected studies of antidepressant drugs and cytokine in mood disorders Author
Year
Subject
Organ
Antidepressant
Cytokine
Pretreatment levelsa
Post-treatment results
Weizman et al. [13]
1994
major depressed patients
mononuclear cell
clomipramine (4 weeks)
interleukin-1h interleukin-2 interleukin-3-like activity
low low low
Sluzewska et al. [14] Lanquillon et al. [15]
1995
depressed patients major depressive disorder
serum
fluoxetine (8 weeks) amitriptyline (6 weeks)
interleukin-6
high
interleukin-6
low (responder)
high (nonresponder) no difference no difference no difference
increase (normalize) no change increase (normalize) decease (normalize) increase (responder, normalize) decease (nonresponder, normalize) decease (responder, normalize) no change (nonresponder) no change no change no change
no difference high high
increase no change no change
high
no change
high high high
no change no change no change
no difference high
no change no change
2000
whole blood
high (nonresponder) TNF-a
Kagaya et al. [16]
2001
major depressive and dysthymia
plasma
various antidepressant mainly clomipramine (4 weeks)
Maes et al. [17]
1995
major depressed patients
plasma
fluoxetine or tricyclic antidepressants (over 80 days on the average)
Maes et al. [18]
1997
major depressed patients
serum
maily trazodone (5 weeks)
Anisman et al. [19]
1999
dysthymic patients
mononuclear cell
sertraline (12 weeks)
a
interleukin-1h interleukin-6 soluble interleukin-2 receptor TNF-a interleukin-6 soluble interleukin-2 receptor soluble interleukin-6 receptor transferrin receptor interleukin-6 interleukin-1 receptor antagonist interleukin-6 receptor interleukin-1h
high (responder)
Pretreatment levels mean cytokine levels of subjects in comparison with normal subjects before treatment.
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but there was no change in plasma IL-1-beta, IL-6 or sIL-2 receptor [16]. Modulation of cytokine production in depressed patients may be attributed to the depression per se, or it may be related to depressionassociated hyperactivity of the hypothalamic –pituitary – adrenal axis. If cytokine expression is altered by antidepressants, it is still unknown whether it is due to direct effects of antidepressants or indirect effects after mood improvements. Further research is necessary to elucidate the mechanism of interaction between antidepressant drugs and cellular immune function and the mediators responsible for the aberrant cytokine production observed in patients with mood disorders. In contrast, there are some reports that antidepressants do not affect blood cytokine levels in depressed patients. One study showed that plasma concentrations of IL-6, sIL-6 receptor and sIL-2 receptor were significantly higher in major depressed subjects than in healthy controls. However, subchronic treatment with antidepressant drugs, such as fluoxetine or tricyclic antidepressants, did not significantly affect plasma IL-6, sIL-6 receptor or sIL-2 receptor levels [17]. In a follow-up study, these authors showed that serum IL-6 and IL-1 receptor antagonist were significantly higher in subjects with major depression compared to normal controls. However, subchronic treatment with antidepressants had no significant effects on serum IL-6 and IL-1 receptor antagonist, but did significantly reduce serum sIL-6 receptor levels [18]. Thus, these authors suggested that aberrant cytokine expression in depressed patients might be a trait-dependent but not a state-dependent biological marker of depression. Another study indicated that, in dysthymic patients, basal IL-1-beta was elevated relative to control subjects, but sertraline, which attenuated the symptoms of depression, did not normalize IL-1-beta production [19]. These results suggest that antidepressant drugs might exert their effects, at least in part, by affecting downstream signaling of cytokine receptors and not by affecting plasma concentrations of cytokines. It has been suggested that antidepressant drugs may alleviate the neuropsychiatric disturbances induced by interferon-alpha [20,21] and IL-1-beta [22]. These results imply that cytokines could play a role in mood disorders. An indirect effect of antidepressants on these cytokines may underlie the mech-
anism of neuropsychiatric symptom alleviation. However, due to the limited clinical studies available, it is not possible to conclude whether antidepressants modulate cytokine expression in depressed patients. Much more research is necessary to answer this question. To examine direct effects of antidepressants on cytokine production, in vitro studies have investigated the effects of antidepressants on immune cells from human volunteers. One such study indicates that clomipramine, imipramine and citalopram significantly suppress IL-2 and interferon-gamma release in T lymphocytes and IL-1-beta and TNF-alpha release in lipopolysaccharide (LPS)-treated monocytes [23]. Other investigators have found that different classes of antidepressants (clomipramine, sertraline, and trazodone) at plasma concentrations in the therapeutic range exert significant suppressive effects on the interferon-gamma/IL-10 ratio. This effect was attributable to both a suppression of the stimulated production of interferon-gamma and a significant stimulatory effect on IL-10 production [24]. These authors hypothesized that serotonin (5HT) may mediate the effects of antidepressants on immune cells. Specifically, they suggested that intracellular 5-HT may be necessary for an optimal synthesis of interferon-gamma and IL-10, and that extracellular 5-HT concentrations at or above serum values may suppress the production of interferongamma [25]. The studies described thus far have focused on the effects of antidepressant treatments on cytokine expression by peripheral blood cells. These studies have shown an effect of antidepressant treatments on the peripheral immune system. However, antidepressants may also affect cytokine expression and action in the CNS. Levine et al. [10,11] have reported that depressed patients, compared to controls, showed higher CSF concentrations of IL-1-beta, lower concentrations of IL-6 and sIL-2 receptor and no change in TNF-alpha. More research is needed to investigate expression of these cytokines in the CNS before and after antidepressant treatment. A recent report has examined the effects of lowdose endotoxemia, a well-established and safe model of host defense activation on emotional, cognitive, immunological and endocrine parameters in 20 healthy male volunteers [26]. Endotoxin increased
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circulating levels of TNF-alpha, soluble TNF receptors, IL-6, IL-1 receptor antagonist and cortisol. After endotoxin administration, the subjects showed a transient but significant increase in anxiety and depressed mood. In humans, mild stimulation of primary host defense has negative effects on emotional and memory functions, which are probably caused by cytokine release. These data suggest that cytokines represent a novel target for neuropsychopharmacological research. Future studies examining the effects of antidepressants on sickness behavior in LPS-administered volunteers will provide an important and interesting contribution to psychoimmulogical science.
4. Antidepressants and cytokines in experimental models Limited data exist examining the effects of antidepressant treatment on the immune system and cytokine action in experimental models. One study has shown that the chronic, mild stress-induced lymphocyte proliferation and synthesis of IL-1 and IL-2 from rat spleen cells are reversed following chronic treatment with imipramine [27]. These authors have also shown stimulatory effects on IL-10 secretion by repeated administration of tricyclic antidepressants or the selective serotonin reuptake inhibitors (SSRIs) in C57BL/6 mice [28 – 30]. Suzuki et al. [31] have shown that repeated administration of imipramine in the CNS induces IL-1 and IL-1 receptor antagonist mRNA in various regions of the rat brain. Imipramine induces a greater effect on IL-1 receptor antagonist mRNA than on IL-1 mRNA. Further basic research using experimental models is needed to fully examine the direct effects of antidepressants on cytokine expression. In another experimental paradigm, chronic but not acute antidepressant treatment abrogates symptoms of LPS-induced sickness behavior in rats [8,32,33]. In addition to behavioral endpoints, these studies have also focused on the effects of antidepressant treatments on cytokine expression in peripheral blood cells from LPS-treated animals. However, only a few studies have examined the effects of antidepressant treatment on the brain. These kinds of investigations are necessary to identify the precise mechanism underlying the effects of antidepressant treatments
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on cytokine expression. Yirmiya [32] found that chronic imipramine treatment abolishes the suppressive effect of LPS-induced anhedonia using a saccharine preference paradigm. Moreover, chronic but not acute treatment with imipramine reduces and facilitates recovery from the suppressive effects of LPS on food consumption, body weight, social interaction and activity in the open-field test. Chronic, but not acute treatment with tianeptine, attenuates the behavioral signs of sickness behavior induced by peripheral but not central LPS or IL-1-beta [34]. This work, which is the first in vivo study assessing the effect of an antidepressant on centrally induced immune activation, shows a clear dissociation between peripheral and central cytokine effects and suggests a peripheral site of action of tianeptine. It also provides the first evidence that the protective effects of classical antidepressants on LPS-induced sickness behavior extend to an atypical antidepressant and that the protective effect of antidepressants also applies to IL-1-beta. Rolipram, a selective type IV phosphodiesterase inhibitor, stereospecifically suppresses the production of TNF/lymphotoxin-alpha and albeit less strongly, interferon-gamma in human and rat auto-reactive T cells [35]. These experimental models provide useful tools for investigating the precise mechanisms of antidepressant action and may help to develop new treatments for mood disorders. However, other experimental studies of antidepressant and sickness behavior have given conflicting results. Shen et al. [36] reported that chronic treatment with the antidepressants paroxetine and venlafaxine failed to alter any of the LPS-induced behavioral responses, while chronic treatment with the tricyclic antidepressant desipramine prevented LPS-induced anorexia, loss of body weight, the antidipsogenic effect and hypoactivity in rats. In addition, a recent report cannot show the prevention by chronic treatment of antidepressants (imipramine and venlafaxine) against the reduction in sweetened milk intake induced by IL-1 and endotoxin in mice [37]. These results do not support the hypothesis that antidepressants may exert part of their antidepressive efficacy through modulation of cytokine action. Chronic treatment of some antidepressants may indeed alter some of the behavioral responses to LPS, but whether this is related to the antidepressant properties of the drugs remains to be determined.
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5. Effects of lithium and monoamine oxidase inhibitors on the immune system There are only a few reports that drugs for the treatment of mood disorders, other than antidepressants, affect cytokine actions. To our knowledge, only one study has examined the effects of lithium on cytokine expression in manic patients. This study found that sIL-2RS and sIL-6RS are increased in symptomatic rapid cycling patients and normalize with lithium treatment [38]. These authors have also shown that 5 days of lithium treatment increases IL-2, sIL-2RS and sIL-6RS in normal volunteers [38], and that lithium causes an increase in IL-4 and IL-10 levels and a decrease in IL-2 and interferon-gamma levels in whole blood cultures from normal control subjects [39]. Another researcher found that lithium exerts significant immunoregulatory effects by increasing the production of both pro-inflammatory cytokines (interferon-gamma, TNF-alpha and IL-8) and anti-inflammatory cytokines or proteins (IL-10 and the IL-1RA) in whole blood supernatants from healthy volunteers [40]. In studies of diluted whole blood stimulated with LPS plus phytohemagglutinin, moclobemide (a reversible monoamine oxidase A inhibitor) shows negative immunoregulatory capacities through inhibition of the production of proinflammatory cytokines (i.e. TNF-alpha and IL-8) and through enhancement of the production of IL10, an anti-inflammatory cytokine [41]. Much more research, including investigation of the effects of electroconvulsive shock therapy on cytokine expression, is necessary to elucidate the role of cytokine expression in antidepressive therapy.
6. How do antidepressants act on cytokines? A number of studies have shown an interaction between neurotransmission and the immune system in the brains of experimental animals [9,42]. Because immune cells express neurotransmitter and neuropeptide receptors, mediators such as noradrenaline and serotonin, other monoamines, nucleosides and acetylcholine are able to modulate the cytokine response to certain stimuli. Moreover, neurons and glial cells express cytokine receptors and the release and action of neurotransmitters are modulated by cytokines. Anti-
depressants appear to affect cytokine release and action by modulating neurotransmitter actions. Antidepressants may also modulate intracellular signals like cAMP and CREB and in this way affect cytokine function [9]. Indeed, antidepressant modulation of neurotransmitters that results in stimulation of adenylate-cyclase leads to a shift towards Th 2-type responses, which are anti-inflammatory and protective. Neuroprotection and/or proliferation of neuronal cells might be the most probable molecular mechanism of antidepressive therapy [1,43]. Adaptations at the cellular and molecular levels in response to stress and antidepressant treatment could represent a form of neural plasticity that contributes to the pathophysiology and/or treatment of depression. Neuroprotection and/or proliferation could be the result of an adjustment of the balance between pro- and anti-inflammatory cytokines after antidepressive therapy. As has been widely recognized during the last decade, neurotoxic and neuroprotective mechanisms are both closely related to the balance between pro- and antiinflammatory cytokines. A majority of researchers currently support the imbalance hypothesis of proand anti-inflammatory cytokines in depression. This hypothesis seems to be conceivable and drawn mostly on the concept of cytokine actions in peripheral tissues. However, there are still conflicting results of cytokine research both in blood and CSF in depression [10 –16]. Unfortunately, non-invasive methods for detection and quantification of cytokines in CNS have not devised. In addition, the evidence that proinflammatory cytokines such as IL-1 or TNF-alpha are neurotoxic is considerable but controversial. Proinflammatory cytokines are also likely to be involved in synaptic plasticity, neural transmission and Ca2 + signaling and thus perform neural functions in the normal brain. Thus, they should be thought of as neuromodulators in addition to inflammatory mediators [44]. We should continue to do much more investigations into the effects of antidepressive therapy on each cytokine and interaction among cytokines in both preclinical and clinical research.
7. Future perspective In this article, we have reviewed the association between cytokines and antidepressant therapy based
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on both clinical and preclinical research. A line of evidence suggests the modulation of cytokine signals by chronic antidepressant treatment. This may lead to the adjustment of an imbalance of cytokines in depression. However, the effect of antidepressant treatments on cytokines is still unclear in various aspects: (1) Does the modulation of cytokine signals by antidepressants occur in the periphery or in the brain? (2) How do antidepressants act on cytokines to cause mood change? (3) Is the modulation of cytokines causative or a result of mood change? (4) Why do only some patients show depressive symptoms in response to cytokine administration? Recent developments in molecular biology such as microarrays and/ or knockout animal models [45] of cytokines will provide useful tools to resolve these questions. Clinical research investigating single nucleotide polymorphisms for cytokines, their receptors and signaling molecules will also provide great insight into these fundamental questions. Understanding the relationship between antidepressive therapy and cytokines may result in new, rational diagnostic and therapeutic improvements for the treatment of depression. Acknowledgements This work was supported in part by a research grant (13A-3) for Nervous and Mental Disorders and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan and grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. References [1] Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002 March 28;34:13 – 25. [2] Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 1995;19:11 – 38. [3] Mu¨ller N, Ackenheil M. Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 1998;22: 1 – 33. [4] Dantzer R, Wollman EE, Yirmiya R. Cytokines, stress, and depression. Adv Exp Med Biol, vol. 461. New York: Plenum; 1999.
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