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This document reviews evidence that increased glutamate receptor activation and immune system alterations play a role in major depression alongside serotonin deficiencies. The hypothesis is presented that proinflammatory cytokines activate the enzyme IDO, leading to increased consumption of tryptophan and serotonin as well as increased production of quinolinic acid, a potent NMDA receptor agonist. This imbalance in type 1/type 2 immune response is associated with reduced astrocytes and increased microglia, contributing to serotonin deficiency, glutamate overproduction, and altered neurotransmission. Targeting inflammation with anti-inflammatory drugs may exert antidepressant effects through these mechanisms.
This document reviews evidence that increased glutamate receptor activation and immune system alterations play a role in major depression alongside serotonin deficiencies. The hypothesis is presented that proinflammatory cytokines activate the enzyme IDO, leading to increased consumption of tryptophan and serotonin as well as increased production of quinolinic acid, a potent NMDA receptor agonist. This imbalance in type 1/type 2 immune response is associated with reduced astrocytes and increased microglia, contributing to serotonin deficiency, glutamate overproduction, and altered neurotransmission. Targeting inflammation with anti-inflammatory drugs may exert antidepressant effects through these mechanisms.
This document reviews evidence that increased glutamate receptor activation and immune system alterations play a role in major depression alongside serotonin deficiencies. The hypothesis is presented that proinflammatory cytokines activate the enzyme IDO, leading to increased consumption of tryptophan and serotonin as well as increased production of quinolinic acid, a potent NMDA receptor agonist. This imbalance in type 1/type 2 immune response is associated with reduced astrocytes and increased microglia, contributing to serotonin deficiency, glutamate overproduction, and altered neurotransmission. Targeting inflammation with anti-inflammatory drugs may exert antidepressant effects through these mechanisms.
glutamate: towards an integrated view of depression N Mu ller and MJ Schwarz Department for Psychiatry and Psychotherapy, Ludwig-Maximilians-Universita t Mu nchen, Mu nchen, Germany Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotrans- mitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamuspituitaryadrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, inter- feron-c, or tumor necrosis factor-a activate the tryptophan- and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes counteracting this metabolism due to the lack of an enzyme of this metabolism have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 9881000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depression Glutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepres- sant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression (MD) focused on the serotonergic and noradrenergic neuro- transmission during the last four decades. 1,2 Intense research, however, has not yet discovered the mechanisms causing disturbances of the monoami- nergic neurotransmission. Moreover, the regularly occurring non-response rate of about 30% for any given antidepressant drug and several other consid- erations have led to the conclusion that the mono- amine hypothesis alone cannot explain the complete pathomechanism of MD. As early as in 1959, Crane 3 reported the anti- depressant efficacy of high doses of D-cycloserine. D- cycloserine, a partial N-methyl-D-aspartate (NMDA) receptor agonist, acts as a NMDA receptor antagonist in high doses. NMDA receptors are a class of ionotropic glutamate receptors, and in recent years, the role of an increased glutamatergic neurotransmission in the pathophysiology of MD was brought into focus. Consistent with the view that an increased activity of the glutamatergic system and NMDA receptor Received 1 February 2006; revised and accepted 8 February 2007; published online 24 April 2007 Correspondence: Dr N Mu ller, Department for Psychiatry and Psychotherapy, Ludwig-Maximilians-Universitat Mu nchen, Nussbaumstr. 7, Mu nchen 80336, Germany. E-mail: Norbert.Mueller@med.uni-muenchen.de Molecular Psychiatry (2007) 12, 9881000 & 2007 Nature Publishing Group All rights reserved 1359-4184/07 $30.00 www.nature.com/mp agonism is associated with depressed mood, a reduc- tion of the glutamatergic activity, that is NMDA receptor antagonismmight exert antidepressant effects. NMDA antagonists such as MK-801, 4,5 ketamine, 6 amantadine 7 and others 8,9 exhibited antidepressant effects in different animal models. Beside the above- mentioned report on D-cycloserine, slight antidepres- sant effects in humans have also been observed with the NMDA receptor antagonists amantadine 10,11 and ketamine. 12,13 Riluzole, an antiglutamatergic agent believed to increase the glutamatergic uptake into the astrocytes, is under intensive investigation for its antidepressant potential. 14 A recent series of open- labelled studies and case reports demonstrated its efficacy. 1519 Although the glutamatergic system may influence directly or indirectly the serotonergic and noradre- nergic neurotransmission, there are only few data in the literature dealing with this interaction. NMDA receptor antagonists increase the serotonin levels in the brain. 20,21 Several studies showed an increased activity of the glutamatergic system in the peripheral blood of depressive patients, 2224 although this result could not be replicated by all authors. 25 The incon- sistency of the findings, however, might be due to medication effects, low statistical power and a lack of appropriate control of diagnosis. 9 Support for increased glutamatergic activity in depression comes from magnetic resonance spectro- scopy: elevated glutamate levels were found in the occipital cortex of unmedicated subjects with MD. 16 Associated with an increased level of certain neuro- transmitter is often a downregulation of the respective receptor. Accordingly, in the brains of suicide victims and patients with depression, a reduced glycine binding site of the NMDA receptor was found. 26,27 Moreover, a decrease in the NMDA agonistic MK-801 binding in bipolar patients was observed. 28 The glutamate system in depression: quinolinic acid as a depressiogenic NMDA receptor agonist Investigating the glutamatergic neurotransmission and activation of the NMDA receptors, neurochemists often forget to include the potential endogenous NMDA agonist quinolinic acid into their considera- tions. The essential amino acid tryptophan is not only the precursor of serotonin (5-hydroxytrypamine) and melatonin, but also of the so-called kynurenine (KYN) pathway. This quantitatively most prominent metabolism pathway of tryptophan includes several neuroactive intermediates, of which kynurenic acid (KYN-A) and quinolinic acid act on the NMDA receptor in an opposing mode. These two intermedi- ates are alternative products of KYN degradation and while KYN-A is an NMDA receptor antagonist, quinolinic acid acts as an NMDA receptor agonist via ligation at the glycine binding site. An increase of quinolinic acid is strongly asso- ciated with several prominent features of depression: decrease in reaction time 2931 and cognitive deficits, in particular difficulties in learning. 32 In an animal model, an increase of quinolinic acid and 3-hydroxy- kynurenine was shown to be associated with anxi- ety. 33 A recent study in 16 patients treated with interferon-g (IFN-a) showed that the depressive symptoms were related to the increase of the ratio of KYN/KYN-A. Five patients met criteria for MD. KYN itself, however, showed no significant increase. 34 The increase of the ratio, however, reflects that in depressed states KYN is preferentially metabolized to quinolinic acid compared to the KYN-A pathway. The preferred metabolism to quinolinic acid is related to the depressive symptoms, but not the metabolism to KYN-A. A recent study revealed that the trypto- phan degradation in patients suffering from MD was increased compared with controls, whereas the KYN- A concentration was lower. This combination of findings suggests that the metabolism of KYN is preferentially directed to the quinolinic pathway, although quinolinic acid itself was not determined. 35 Beside the direct action of quinolinic acid as an NMDA receptor agonist, increased levels of the quinolinic acid lead to increased levels of glutamate. The induction of quinolinic acid was shown to cause an overrelease of glutamate in the striatum and in the cortex, presumably by presynaptic mechanisms. 36,37 The quinolinic pathway could thus be the mechanism involved in the increased glutamatergic neurotrans- mission in MD. 16 Moreover, owing to the well-known neurotoxic effects of quinolinic acid, it is discussed that quinolinic acid is beside cortisone respon- sible for neurodegeneration observed in chronic depressive patients. 38 The role of indoleamine 2,3-dioxygenase in depression The rate-limiting step in initialization of the KYN pathway is the nearly ubiquitously expressed indole- amine 2,3-dioxygenase (IDO) (or the tryptophan dioxygenase in the liver). The further conversion of KYN to either KYN-A or 3-hydroxykynurenine, the precursor of quinolinic acid, is mediated by the enzymes kynurenine aminotransferase and kynure- nine monooxygenase, (KMO, sometimes reffered to as kynurenine hydroxylase), respectively. The activity of both, IDO and KMO, underlie strong regulation by cytokines. Proinflammatory cytokines such as IFN-g, interleukin-1 (IL-1), or tumor necrosis factor-a (TNF-a) are potent inducers of IDO, whereas anti- inflammatory cytokines such as IL-4 and IL-10 are IDO inhibitors. 39 Besides IFN-g and TNF-a, other proinflammatory molecules such as prostaglandin E 2 (PGE 2 ) synergistically induce an increase of IDO activity. 4042 This close relationship between immune system and the KYN pathway is reflected by its crucial role in inflammation. Tryptophan is essential for the survival of infectious microbes, such as bacteria, and the consumption of tryptophan plays a pivotal role during infectious diseases. 4345 Owing to this need, the withdrawal of tryptophan from an inflammatory locus is part of the immune defense. Moreover, the Immune-mediated alteration of serotonin and glutamate N Muller and MJ Schwarz 989 Molecular Psychiatry activity of IDO is an important regulatory component in the control of the bodies own defense system, since IDO activity induces a halt in the lymphocyte cell cycle due to the catabolism of tryptophan. 46,47 Within the central nervous system (CNS), only microglial cells and invading monocytes have the complete set of enzymes in the pathway necessary to produce quinolinic acid. 48,49 In a model of infection, the highest concentrations of quinolinic acid are found in the gray and white matter of the cortex but not in subcortical areas indicating that high levels of quinolinic acid may lead to cortical dysfunction. 32 Peripheral immune stimulation, however, under certain conditions also lead to increased CNS con- centration of quinolinic acid. 48 During a local inflam- matory CNS process, the quinolinic acid production in the CNS increases, but the blood levels remain unchanged. 32 The local quinolinic acid production correlates with the inflammatory marker b2-micro- globulin. Local CNS concentrations of quinolinic acid are able to exceed the blood levels by far. 32 Owing to the fact that tryptophan availability is the rate-limiting factor in the serotonin synthesis, 45 it has been hypothesized that a cytokine-induced, IDO- mediated decrease of central nervous tryptophan availability may lead to a serotonergic deficiency. 45 Moreover, serotonin can be directly metabolized by IDO (IDO catalyses the oxidative cleavage of the indole ring, its substrate specificity also includes serotonin.). 50 Therefore, an enhanced production of quinolinic acid through increased IDO activity may not only lead to an amplified glutamatergic neuro- transmission as stated above, but may also influence the serotonergic neurotransmission. Considering the important role of the immune system in the regulation of quinolinic acid formation, the question arises, if an immune activation is associated with MD. The following section will provide some evidence for the functional relationship between inflammation and depression. The inflammatory hypothesis of depression Sickness behavior An immunological model of MD is sickness beha- vior, the non-specific reaction of the organism to infection and inflammation. Sickness behavior is characterized by weakness, malaise, listlessness, inability to concentrate, lethargy, decreased interest in the surroundings and reduced food intake all of which are depression-like symptoms. The sickness- related psychopathological symptomatology during infection and inflammation is mediated by proin- flammatory cytokines such as IL-1, IL-6, TNF-a and IFN-g. Their active pathway from the peripheral immune system to the brain is via afferent neurons and through direct targeting of the amygdala and other brain regions after diffusion at the circumven- tricular organs and choroid plexus. 51 Undoubtedly, there is a strong relationship between the cytokine system and the neurotransmitter system, but a more differentiated analysis may be required to understand the specific mechanisms underlying the heterogenous disease entity of MD. In humans, the involvement of cytokines in the regulation of the behavioral symptoms of sickness behavior has been studied by application of the bacterial endotoxin lipopolysaccharide (LPS) to human volunteers. 52 LPS, a potent activator of proinflam- matory cytokines, was found to induce mild fever, anorexia, anxiety, depressed mood, and cognitive impairment. The levels of anxiety, depression and cognitive impairment were found to be related to the levels of circulating cytokines (see Table 1). 52,53 Side effects of cytokine therapies A depressive syndrome including suicidal ideations is a common side effect of cytokine administration, for example, IFN-a in the therapy of hepatitis C or malignant melanoma. 5458 During these therapies, IDO is activated and the tryptophan metabolism increases. The psychopathological changes seem to be closely related to the tryptophan metabolism: patients devel- oping more severe depressive symptoms during IFN-a showed a more pronounced increase in tryptophan metabolism. 59,60 Moreover, two distinct psychopatho- logical syndromes induced by IFN-a therapy have been described: one syndrome characterized by changes in mood and cognition, and another char- acterized by psychomotor slowing, fatigue, sleep disturbances and anorexia. 61 The mechanism, how- ever, is not yet fully elucidated. 62,63 Activation of the immune system in MD The characteristics of the immune activation in MD include increased numbers of circulating lympho- cytes and phagocytic cells, upregulated serum levels of parameters indicating activated immune cells (for example, soluble IL-2 receptor), higher serum con- centrations of positive acute phase proteins (APP), coupled with reduced levels of negative APP, as well as an increased release of proinflammatory cytokines, such as IL-1, IL-2, TNF-a and IL-6 through activated macrophages and IFN-g through activated T cells. 6470 Increased numbers of peripheral mononuclear cells have been described by different groups of research- ers. 7173 According to these findings, an increased secretion of neopterin has been described by several Table 1 Cytokines of the polarized immune response Type 1 cytokines Type 2 cytokines Monocyte-derived proinflammatory cytokines IL-2 IL-4 IL-1 IL-12 IL-13 IL-6 IFN-g [IL-10] Abbreviations: IFN-g; interferon-g; IL, interleukin. IL-10 is partly a Type 2 cytokine. Immune-mediated alteration of serotonin and glutamate N Muller and MJ Schwarz 990 Molecular Psychiatry groups of researchers. 7477 Neopterin is a sensitive marker of the cell-mediated immunity. The main source of neopterin is monocytes/macrophages. In particular, the group of Maes described an increase of the inflammatory response system and observed a relationship between proinflammatory immune markers, the severity of depression and measures of hypothalamuspituitaryadrenal (HPA) axis hyperactivity. 7880 As genetics play a role in MD, the genetics of the immune system in relation to MD has also been investigated. Certain cytokine gene polymorphisms, for example, in genes coding for IL-1 and TNF-a, may confer a greater susceptibility to develop MD. 8183 The production of IL-2 and IFN-g is the typical marker of a type 1 immune response. IFN-g is produced in greater amounts by lymphocytes of patients with MD compared to healthy controls. 84 In depressed patients, higher plasma levels of IFN-g accompanied by lower plasma tryptophan availabil- ity, 76 as well as increased IFN-g/IL-4 and IFN-g/TGF-b ratios 85 have been described. However, a recent study inversely reported an enhancement of type 2 cyto- kines IL-4 and IL-13 together with a reduction of type 1 cytokines IL-2 and IFN-g in depression. 86 The latter findings were discussed as being related to the elevated cortisol levels, which were accompanied by elevated TNF-a levels. On the other hand, the washout time for antidepressant medication anti- depressants increase the type 2 cytokine production was only 3 weeks in this study. Data on IL-2 in MD are mainly restricted to the estimation of its soluble receptor, sIL-2R, in the peripheral blood. Increased soluble IL-2-receptors (sIL-2R) levels reflect an in- creased production of IL-2. The blood levels of sIL-2R were repeatedly found to be higher in MD pa- tients 65,66,87 as well as the in vitro production of IL-2. 88 According to the sickness behavior hypothesis, the cytokines TNF-a, IL-1 and IL-6 have frequently been investigated in MD. A considerable number of studies showed elevated serum levels of TNF-a 70,86,8993 and IL-1b 9496 in depressed patients, whereas only few investigators reported unchanged levels of these cytokines. 97 A study on elevated mRNA levels of TNF-a in peripheral mononuclear cells of depressed patients confirms the majority of findings on elevated serum levels. 98 Levels of IL-1b are also elevated in cerebrospinal fluid (CSF), whereas TNF-a levels are not altered in CSF of depressed patients. 89 As a product of activated monocytes and macro- phages, IL-6 is one of the most frequently investigated immune parameters in MD. The majority of reports demonstrate a markedly higher in vitro IL-6 produc- tion, 80,94 or higher serum IL-6 levels in depressed patients 65,87,93,99104 as well as IL-6 mRNA expression in leukocytes. 98 The elevation of IL-6 seems to be especially profound in the morning. Additionally, the circadian rhythm of IL-6 secretion is altered in depressed patients. 105 Elevated whole blood IL-6 levels in unmedicated depressed patients were demonstrated to be related to treatment non-response to antidepressant administration, whereas patients with subsequent remission showed markedly lower IL-6 levels. 90 Higher plasma IL-6 concentrations were also found in cancer patients with depression, compared with cancer patients without depression or healthy control subjects. 106 Contradictory results are very few indicating reduced, 107 or not altered, serum IL-6 levels. 97,108,109 The potential influence of possibly interfering variables, such as age, smoking, gender, recent infections and prior medication (in- cluding insufficient washout period) to IL-6 release and concentration must be considered. 110 An age- related increase of IL-6 serum values was reported in patients with MD, 111 but also elderly depressed patients exhibit higher IL-6 serum levels compared with control persons of comparable age. 92 In contrast, CSF levels of IL-6 and soluble IL-6 receptor were found to be markedly reduced in geriatric patients suffering from depression. 112 Another study investi- gating depressed patients of age 1866 could not find any alteration of IL-6 levels in the CSF. 113 Levine et al. 89 compared serum and CSF cytokine levels in depressed patients and healthy control persons and found significantly elevated serum levels of IL-6, but de- creased IL-6 levels in CSF. Thus, the elevated IL-6 secretion may be restricted to the peripheral compart- ment. On the other hand, IL-6 acts locally in a paracrine manner and CSF levels may not be representative for local cellular effects of IL-6 in the CNS. Altogether, the three cytokines, typically inducing sickness behavior appear to be elevated at least in the peripheral blood of depressed patients. Both, IL-1 and TNF-a are strong inducers of IDO. Thus IDO activity may be enhanced in depressed patients through these cytokines. Although IL-6 does not directly act on IDO, its elevated levels in serum may contribute to IDO activation within the CNS by the stimulatory effect on PGE 2 , which acts as cofactor in the activation of IDO. Recent investigations confirmed that the bloodbrain barrier (BBB) is not a divider preventing signal transduction, but rather the transducer itself. In the endothelial and perivascular cells of the BBB, up- stream signaling molecules such as proinflammatory cytokines are switched to the downstream mediator PGE 2 . 114 This fits with a report on the correlation of increased in vitro IL-6 production with decreased tryptophan levels in depressed patients emphasizing the influence of IL-6 on the serotonin metabolism (see Table 2). 80 Moreover, clinical studies have observed higher levels of type 1 cytokines in suicidal patients. In a small study, distinct associations between suicidality and type 1 immune response and a predominance of type 2 immune parameters in non-suicidal patients were observed. 115 An epidemiological study also hypothezized that high IL-2 levels are associated with suicidality. 116 One study showed increased levels of serum sIL-2R in medication-free suicide attempters irrespective of the psychiatric diagnosis, 117 and treatment with high-dose IL-2 has been associated with suicide in a case report. 118 Immune-mediated alteration of serotonin and glutamate N Muller and MJ Schwarz 991 Molecular Psychiatry Different types of MD were observed to exhibit different immune profiles, the subgroup of melan- cholic depressed patients showed a decreased type 1 activation accompanied with a marked activation of the HPA axis, whereas the non-melancholic de- pressed patients showed signs of inflammation such as increased monocyte count and increased levels of IL-1b and a2-macroglobulin. 73,119 Moreover, the plasma levels and expression in the brain of intercellular adhesion molecule-1 (ICAM-1) seem to be related to depression: both, in patients treated with IFN-a 57 and in patients after acute coronary syndromes, 120 soluble ICAM-1 levels were observed to be associated with depressive symptoms. Moreover, increased expression of ICAM-1 was found in the prefrontal cortex of elder depressive patients. 121 ICAM-1 is a type 1 related protein and a cell adhesion molecule expressed on macrophages and lympho- cytes. Increased expression of ICAM-1 is observed in inflammatory processes, it promotes the influx of peripheral immune cells through the BBB. 122 By this mechanism, macrophages and co-stimulatory lym- phocytes can invade the CNS, further increasing the proinflammatory immune response. Inflammation is associated with increased invasion of macrophages/ microglia in the CNS. 123 Beside the above-mentioned signal transducing effect of the BBB, the direct entry of activated immune cells may therefore also con- tribute to an enhanced proinflammatory signal in the CNS. Postpartum depression as model for type 1/type 2 imbalance Pregnancy is immunologically characterized by a dominance of the type 2 immune response of the mother to protect the fetus from abortion, the maternal organism developing immune tolerance against the non-self-organism of the baby. 124,125 After delivery, an activation of the type 1 response of the maternal immune system takes place. 126,127 This type 1-dominated maternal immune re-balancing was found to be associated with the postpartum blues, 126 a state found in 2075% of mothers, 128,129 or the postpartum depression, a state found in 1015% of mothers. 130 After delivery, an increase of the proin- flammatory immune response was described. 126,127 Accordingly, postpartum blues is associated with increased activation of the proinflammatory immune response, increased activity of the IDO and a delay in the increase of postpartum tryptophan levels com- pared with mothers without the blues. 126,131 Symp- toms of depression and anxiety in the early puerperum are significantly related to the increase of the proinflammatory cytokine IL-8. 126 Postpartum depression is associated with the activation of the proinflammatory type 1 immune response and a lack of tryptophan. 132,133 Prostaglandins and depression PGE 2 is a molecule of the proinflammatory cascade. It stimulates the production of proinflammatory cyto- kines, for example, IL-6, the expression of cycloox- ygenase-2 (COX-2), and as a cofactor the expression of IDO. Therefore an increased secretion of PGE 2 would be expected in depressive disorders. Increased levels of PGE 2 have indeed been observed in CSF, in serum and in saliva of depressed patients. 134136 In vitro studies likewise show an increased PGE 2 secretion from lymphocytes of de- pressed patients compared with healthy controls. 102 Twenty years ago, it was suggested that antidepres- sants inhibit PGE 2 . 137 A recent in vitro study has shown that both tricyclic antidepressants and selec- tive serotonin inhibitors attenuated cytokine-induced PGE 2 and nitric oxide production by inflammatory cells from synovial tissue. 138 Stress and the immune system in MD Stress, cytokines and HPA axis activation It has been proposed that stress may act as a predisposing factor for MD. An impaired ability of Table 2 Major cytokine alterations in major depression Cytokine In vitro production Peripheral blood CSF Unmedicated Effect of antidepressants Unmedicated Effect of antidepressants Unmedicated IL-1b mm kk mm m IL-2 and sIL-2R m k m m IL-4 k mk m IL-6 and sIL-6R mm kk mm kk mk IL-10 m mm IFN-g m kk m k TNF-a mm kk mm kk 2 TGF-b m k m Abbreviations: IFN-g; interferon-g; IL, interleukin; sIL-6R, soluble IL-6-receptors; TNF-a, tumor necrosis factor-a; TNF-b, tumor necrosis factor-b. mm or kk means frequently repeated, relatively consistent data for elevation or decrease, respectively; m or k means less consistent data; 2 means no changes; km means controversial results. Immune-mediated alteration of serotonin and glutamate N Muller and MJ Schwarz 992 Molecular Psychiatry stress coping has repeatedly been described in patients with MD, even before the first exacerbation of the disorder, and psychosocial stressors frequently precede the onset of MD. 139 Additionally, an altered HPA axis physiology and dysfunctions of the extra- hypothalamic corticotrophin-releasing hormone (CRH) system have been consistently found in subjects with MD. 140 Activation of the HPA axis is one of the best-documented changes in MD. 141 Several studies demonstrate that MD patients exhibit higher baseline cortisol levels or at least much higher cortisol levels during the recovery period after psychological stress. 142 Proinflammatory cytokines such as IL-1 and IL-6 are known to stimulate the HPA axis via hypothala- mic neurons. For example, the release of the CRH and growth hormone-releasing hormone (GHRH) is stimu- lated by IL-1, 143,144 the central IL-1 upregulation leads to stimulation of CRH, the HPA axis and the sympathetic nervous system. 145,146 IL-6 is also in- volved in modulation of the HPA axis and increased availability of IL-6 in the hypothalamus is associated with increased HPA activity. 147 Proinflammatory cytokines additionally inhibit the function of the glucocorticoid receptor (GR). 148 This functional rela- tionship was demonstrated recently by Fitzgerald et al., 93 who demonstrated a reduced vasoconstriction response upon topical corticosterone application on the skin in antidepressant-resistant depressive pa- tients. This reduced GR response was related to high serum TNF-a and IL-6 levels. Since psychological or physical stress was shown to result in an enhanced IL-6 secretion in the peripheral immune system, 149151 the functional relationship between cytokines and HPA axis activity is of pivotal interest in MD research. Psychological stress not only directly induce the activity of the HPA axis, but may also induce it indirectly through increased IL-6 levels. An activa- tion of the immune system and psychological stress together may, therefore, lead to an overwhelming HPA axis stimulation. Beside the relationship between HPA axis hormones and cytokines, glucocorticoids stimulate the tryptophan metabolism through the KYN pathway in the liver, directly resulting in decreased CNS concentrations of serotonin. 152 Stress and CNS immune system The effect of chronic stress on the peripheral immune system and its relevance for MD has extensively been discussed. 153 Recent in vivo evidence now suggests that stress-induced elevation of glucocorticoids also enhances immune function within the CNS through microglia activation and proliferation. According to the type 1/type 2 hypothesis of astrocytes and microglia, stress is associated with microglia activa- tion, but also with a loss in the number and volume of astrocytes. 154 Animal studies show that stress induces an enhanced expression of proinflammatory factors such as IL-1b, 155,156 macrophage migration inhibitory factor 157159 and COX-2 160 in the brain. Elevation of these proinflammatory factors is accompanied with dendritic atrophy and neuronal death within the hippocampus, 161,162 which are also found in brains of subjects with MD. These detrimental effects of glucocorticoids in the CNS are mediated by a rise in extracellular glutamate 163,164 and subsequent over- stimulation of the NMDA receptor. Such an over- stimulation of the NMDA receptor results in excitotoxic neuronal damage. 165 Nair and Bonneau 166 could demonstrate that restraint-induced psychologi- cal stress stimulates proliferation of microglia, which was prevented by blockade of corticosterone synth- esis, the GR or the NMDA receptor. These data show that stress-induced microglia proliferation is mediated by corticosterone-induced, NMDA recep- tor-mediated activation within the CNS. Moreover, NMDA receptor activation during stress leads again to increased expression of COX-2 and PGE 2 . Both, COX-2 and PGE 2 per se are able to stimulate microglia activation. Therefore, a vicious circle may be in- duced, if the stress response is not limited, as it is discussed in MD. Astrocytes, microglia and type 1/type 2 response The cellular sources for the polarized immune response in the CNS are astrocytes and microglia cells. 167 Microglial cells, deriving from peripheral macrophages, secrete preferably Th1 cytokines such as IL-12, whereas astrocytes inhibit the produc- tion of IL-12 and other type 1 cytokines and secrete the type 2 cytokine IL-10. 168,169 The type 1/type 2 imbalance in the CNS might be represented by an imbalance in the activation of microglial cells and astrocytes. Since the type 1 activation predominates the response in the peripheral immune system in depression, a dominance of microglial activation compared to astrocyte activation should be observed in depression. Glial reductions were consistently found in brain circuits known to be involved in mood disorders, such as in the limbic and prefrontal cortex. 170174 Although some reports did not differentiate between the loss of microglial cells or astrocytes, this differ- ence is crucial due to the different effects of the type 1/type 2 immune response. Recent studies show that in particular astrocytes are diminished in MD, 175177 although the data are not fully consistent. 178 A loss of astrocytes was particularly observed in younger depressed patients: the lack of glial fibrillary acidic acid (GFAP)-immunoreactive astrocytes reflects a lowered activity of responsiveness in those cells. 176 A reduced expression of the astrocyte-specific GFAP indicating a loss of astrocytes, 179 was found in many cortical layers and in different sections of the dorsolateral prefrontal cortex, but also in the cerebel- lum in MD. 179,180 Loss of astrocytes seems also to be associated with an impaired re-uptake of glutamate from the extra- cellular space into astrocytes by high-affinity gluta- mate transporters, which are primarily found on astrocytes. 181,182 Impaired glutamate re-uptake from Immune-mediated alteration of serotonin and glutamate N Muller and MJ Schwarz 993 Molecular Psychiatry the synaptic cleft by astroglia prolongs synaptic activation by glutamate. 183,184 Pharmacologic intervention in MD is associated with downregulation of the proinflammatory immune response Antidepressant pharmacotherapy In animal experiments, a modulatory, mostly inhibi- tory effect of serotonin reuptake inhibiting drugs on activation of proinflammatory immune parameters was demonstrated. 185188 Several antidepressants induce in vitro a shift from a type 1 to a type 2, that is from a proinflammatory to an antiinflammatory immune response. 189 Antide- pressants such as clomipramine, fluoxetine, imipra- mine, mianserine, sertraline, trazodone and venlafaxine significantly reduced the IFN-g/IL-10 ratio, reflecting the type 1/type 2 relationship. 190192 Even in depressed patients suffering from multiple sclerosis, antidepressant treatment was associated with a reduced in vitro IFN-g production. 193 Other in vitro studies found a significantly reduced produc- tion of IFN-g, IL-2, sIL-2R, and IL-10 after antidepres- sant treatment compared to pre-treatment values in whole blood assays. 72,194 Another study observed a downregulation of the IL-6 production during amitriptyine treatment, whereas the TNF-a produc- tion decreased significantly only in treatment responders. 90 However, there are also studies showing no effect of antidepressants on the in vitro production of cytokines. 195 Methodological differ- ences may be accounted for these inconclusive results. Overall, it can be concluded that antidepres- sants of different classes show a downregulation of the type 1 cytokine production in vitro. 195 In micro- glial and in mixed glial cultures, amitriptylin and nortriptylin were observed to inhibit the release of IL-1b and TNF-a. 196 Regarding the serum levels of MD patients, several researchers reported a decrease of IL-6 during treat- ment with serotonin re-uptake inhibitors 197,198 and other antidepressants. 101 Myint et al. 85 reported an increase of the regulating, anti-inflammatory Th3- cytokine TGF-b together with a reduction of the IFN-g/IL-4 ratio after antidepressant therapy. Mark- edly reduced TNF-a serum levels were found in remitted depressed patients after chronic antidepres- sant therapy for at least half a year. 199 However, there are again some conflicting results, showing no effect of certain antidepressants on serum levels of different cytokines. 65,100 Regarding the relationship between IL-6 and PGE 2 as mentioned above, an inhibiting action of anti- depressants on PGE 2 would be expected. 200 Twenty years ago, it was suggested that antidepressants inhibit PGE 2 . 137 A recent in vitro study has shown that both tricyclic antidepressants and selective serotonin inhibitors attenuated cytokine-induced PGE 2 and nitric oxide production by inflammatory cells from synovial tissue. 138 Immunological effects of non-pharmacologic treatment strategies Electroconvulsive therapy was found do downregu- late increased levels of the proinflammatory cytokine TNF-a in patients with MD as antidepressant phar- macotherapy. 201 During sleep, a shift to the type 1 immune response takes place, 202 for example, an increase of TNF-a and IL-12 and a decrease of the type 2 IL-10-producing monocytes were observed. In contrary, sleep depriva- tion a therapeutic paradigma in depression blocked the increase of type 1 and decrease of type 2 cytokines (T Lange and S Dimitrov, personal communication). Thus, sleep deprivation may exert therapeutic effects through a low suppression of type 1 cytokines in MD. Cyclooxygenase-2 inhibition as a possible anti- inflammatory therapeutic approach in depression Owing to the increase of proinflammatory cytokines and PGE 2 in depressed patients and the relationship to depressive symptoms, anti-inflammatory treatment would be expected to show antidepressant effects in these patients. In particular, the COX-2 inhibitors seem to show advantageous results: animal studies show that COX-2 inhibition can lower the increase of the proinflammatory cytokines IL-1b, TNF-a and of PGE 2 , but it can also prevent clinical symptoms such as anxiety and cognitive decline, which are associated with this increase of proinflammatory cytokines. 203 Moreover, treatment with the COX-2 inhibitor celecoxib but not with a COX-1 inhibitor prevented the dysregulation of the HPA axis, in particular the increase of cortisol, one of the biological key features associated with depression. 203,204 This effect can be expected because PGE 2 stimulates the HPA axis in the CNS 205 and PGE 2 is inhibited by COX-2 inhibition. Moreover, the functional effects of IL-1 in the CNS sickness behavior being one of these effects were also shown to be antagonized by treatment with a selective COX-2 inhibitor. 206 Additionally, COX-2 inhibitors influence either directly or via CNS immune mechanisms the CNS serotonergic system. In a rat model, treatment with rofecoxib was followed by an increase of serotonin in the frontal- and the temporo-parietal cortex, 207 and the non-specific COX-inhibitor diclofenac attenuated the IFN-a-induced enhancement of serotonin turn- over in rat prefrontal cortex. 208 Since the lack of serotonin is one of the pinpoints in the pathophysio- logy of depression, a clinical antidepressive effect of COX-2 inhibitors would be expected due to this effect. In an other animal model of depression, an increased expression of COX-2 in the hippocampus was observed; preliminary data from this group point to an antidepressant effect of COX-2 inhibitors in this model. 209 A possible mechanism of the antidepressant action of COX-2 inhibitors is the inhibition of the release of IL-1 and IL-6. Moreover, COX-2 inhibitors also protect the CNS from effects of quinolinic acid. 210 Immune-mediated alteration of serotonin and glutamate N Muller and MJ Schwarz 994 Molecular Psychiatry Accordingly, a clinical antidepressant effect of rofecoxib was found in 2228 patients with osteoar- thritis, 15% of them showing a comorbid depressive syndrome, which was evaluated by a specific depres- sion self-report. Comorbid depression was a signifi- cant predictor for worse outcome regarding the ostheoarthritis-related pain to rofecoxib therapy. Surprisingly, there was a significant decrease in the rate of substantive depression during therapy with 25 mg rofecoxib from 15% to 3% of the patients. 211 Moreover, an own randomized double-blind pilot add-on study using the selective COX-2 inhibitor celecoxib in MD showed a significant therapeutic effect of the COX-2 inhibitors on depressive symp- toms. 212 Although those preliminary data have to be interpreted cautiously and intense research has to be provided to evaluate further the therapeutic effects of COX-2 inhibitors or other anti-inflammatory drugs in MD, those results are encouraging for further studies dealing with the inflammatory hypothesis of depres- sion with regard to pathogenesis, course and therapy. The class of COX-2 inhibitors, however, may exert antidepressant effects not only by regulation of cytokines and PGE 2 , but also by effects on the GR of the HPA axis, 204 and the effects of COX-2 inhibition to NMDA receptor and glutamatergic neurotrans- mission. 213 Conclusion There is strong evidence for the view, that the interactions of the immune system, IDO and the serotonergic system, and the glutamatergic neuro- transmission play a key role in depression. These factors contribute to the overweight of NMDA agon- ism in depression. The differential activation of microglia cells and astrocytes may be an additional mechanism contributing to this imbalance. The immunological imbalance results in an increased PGE 2 production and probably also in an increased COX-2 expression. However, several gaps, for exam- ple, the roles of genetics, disease course, sex, different psychopathological states, and so on have to be bridged by intense further research. 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