Cytokines are molecules produced by the innate immune system in response to recognition of pathogen-associated molecular patterns (PAMPs) by toll-like receptors (TLRs). The pro-inflammatory cytokines IL-1, IL-6 and TNF-α initiate a cascade, the function of which is to aid the body in fighting infection. Physiological effects of these cytokines include up-regulation of body temperature (fever) and cortisol release. Behavioural effects include symptoms of sickness such as decreased activity and food intake, often referred to as 'sickness behaviour'. Various aspects of major depression, such as anhedonia, fatigue and decreased appetite, seem to mimic this cytokine-induced 'sickness behaviour'. Several clinical specialities including cardiology and endocrinology have taken an increased interest in the role of pro-inflammatory cytokines in contributing to the pathophysiology of diseases such as atherosclerosis and diabetes (1). This has led to a general interest across clinical medicine into how cytokines may influence a wide range of disease processes.
Clinical observations and experimental evidence have led to interest in the idea the cytokine production has a role to play in the generation of mood disorders, particularly major depression. Increased cytokine levels, the inhibitory effect of antidepressants on cytokine levels and increased levels of depression in medically ill patients are among the observations that link cytokines with depression. The mechanisms by which cytokines interact with the central nervous system (CNS) to affect behaviour may include altered hypothalamic-pituitary axis (HPA) function and disruption to neurotransmitter systems.
Research linking cytokines to depression/mood disorder
Observational Cytokine Studies
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It has been observed that people suffering from major depressive episodes have increased levels of pro-inflammatory cytokines and other inflammatory markers. Patients with melancholic depression were found to have Increased IL-6 production by peripheral blood mononuclear cells (PBMC) (2). The reliability of these findings must be questioned due to the fact that IL-6 levels were measured ex-vivo. Another study detected significantly raised levels of IL-6 in the serum of depressed patients, however this study could only detect IL-6 in 50% of depressed patients (3). Furthermore, one study found no difference in IL-1β and IL-6 between depressed and control subjects (4). IFN-γ, IL-1β and IL-6 levels were found to be raised in patients with major depression, in the same study neopterin levels were found to be raised in 60% of melancholic patients. Neopterin is reliably found to be stimulated by IFN-γ so these results indicate increased inflammatory activation in depressed subjects (5). A study by Motivala et al. found that sleep disturbance, a common complaint in major depression, was associated with increased IL-6 and soluble intercellular adhesion molecules (sICAM) (6). Raised levels of inflammatory markers have also been found in older populations of depressed patients, one study found raised plasma levels of IL-6 and TNF-α was associated with significantly increased risk of depression (7). The authors note that as a cross-sectional study, no causal link can be inferred from the results, a common complaint for several studies investigating cytokines and depression.
Antidepressant effects on Cytokines
Studies investigating the effects of antidepressant medication on levels of inflammatory cytokines in subjects with major depression have produced positive results. One study looked at changes in IL-6 concentration in depressed patients following 8 weeks of treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Levels of IL-6 were found to be decreased following the treatment, however a decrease in the patients' symptoms of depression was not reported on. The fact that only 6 of 22 depressed subjects were found to have raised baseline IL-6 levels before the treatment raises questions the validity of its conclusions (8). Another study similarly found a decrease in levels of IL-6 in subjects treated with SSRIs for 6 weeks. However, a small sample size and lack of significant baseline differences in IL-6 between control and patient group lessens the relevance of this study (9).
An in vitro study found that tricyclic antidepressants (TCAs) significantly inhibit the release of IL-1β, IL-6 and TNF-α from monocytes which may suggest a further mechanism of action for these antidepressants (10).
The difficulty of reproducing models of complex psychiatric disorders in animals poses a problem for experimental research into depression. Lipopolysaccharide (LPS), an endotoxin, has been shown to induce symptoms in rodents similar to some of those seen in depression in humans. These include reduced consumption of sugar solution, compared to anhedonia in humans, and decreased sexual behaviour. LPS is known to cause activation of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α in humans (11). In a study by Yirmiya et al. it was shown that LPS-induced symptoms of anhedonia in rats could be reversed with chronic TCA treatment (12). The study did not measure cytokine levels in rats with LPS-induced behavioural changes before or after treatment. Further studies are needed to help clarify this link. These results could not be replicated during LPS-induced sickness behaviour studies in mice treated with the TCA imipramine and the SSRI venlafaxine (13).
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Evidence has pointed to involvement of the hypothalamic-pituitary-adrenal (HPA) axis in the pathophysiology of depression. Corticotropin releasing factor (CRF) is released from the paraventricular nucleus (PVN) of the hypothalamus in response to stressful stimuli. Approximately 50% of patients with depression have an over-active HPA axis, while some patients show decreased inhibitory response to dexamethasone suppression (14). Evidence for increased hypothalamic neuronal activity following immune stimulation (15) has led to investigations into the role of cytokines in mediating HPA axis abnormalities in depressed patients. In rodents, experiments measuring levels of CRF in the hypophyseal portal system found significantly raised levels after administration of IL-1 (16). The mechanism by which peripherally released cytokines act on neurones in the hypothalamus is unclear as the molecules are too large to pass through the blood-brain barrier and the PVN hasn't been shown to possess cytokine receptors. There is some evidence however, that cytokines can act on the hypothalamus by increasing levels of prostaglandins in the brain (17). It has been suggested that early exposure to the cytokine IL-1 can result in long-term alterations to the HPA axis in rodents, however further research is needed to determine any link this may have to behavioural abnormalities (18). A study involving patients treated with IFN-α for malignant melanoma measured levels of adrenocorticotropic hormone (ACTH), cortisol and IL-6 while also recording depressive symptoms. A significant association was found between higher ACTH and cortisol response to short-term treatment and depressive symptoms. No difference however was found in cytokine levels between the depressed and non-depressed patients and with chronic IFN-α treatment there was no significant association (19). These results, while suggesting some link between HPA axis and immune response, are far from conclusive.
Cytokines and Depression in Medically Ill
Depression rates are found to be up to 10 times greater in medically ill patient groups (depending on the disorder studied) compared to the general population (20). Interest into depression in the medical setting has increased greatly following observations that mortality rates are higher among depressed patients than non-depressed (21). From a neuroimmunological view these obvservations have added significance given the finding that cytokines and other immune markers are raised in many medical disorders where depression rates are particularly high. In the context of medical illness, behavioural, affective and cognitive symptoms are often referred to as 'sickness behaviour' although most of the features are the same as those found in major depression (22) (see table 1).
Table 1. Comparison of symptoms found in sickness behaviour and major depression (adapted from Raison et al. 2003 (22))
A study looking at depression in cancer patients found increased levels of IL-6 in depressed patients compared to non-depressed cancer patients. The authors acknowledged however that this rise could be an effect of the disease process in those patients. The same study failed to find a significant link between raised IL-6 levels and HPA axis activation and the small sample size used limits the possible conclusions that can be drawn regarding a link between IL-6 and depression in cancer patients (23). Other studies have found links between specific symptoms found in cancer sickness behaviour and raised cytokine levels. Raised IL-6 levels were linked to cognitive disturbances while both IL-6 and TNF-α were linked to fatigue in cancer patients before the onset of treatment (24).
Depression in Cytokine Therapy
The finding that cytokine treatment for disorders such as malignant melanoma and hepatitis C causes depressive symptoms has provided further evidence for a link between cytokines and mood disorders. Frequency varies between symptoms with fatigue reported up 80% of patients, depressed mood in 60% and loss of concentration in 30% (25). In one double-blind placebo study, 45% of patients treated with IFN-α and placebo developed symptoms of major depression compared to 11% who received paroxetine (an SSRI) (26). The response of these depressive symptoms to antidepressant drugs could suggest common mechanisms between cytokine-induced depression and major depression. However, the validity of these observations in providing a causal link between cytokines and major depression is diminished due to the high-doses of cytokines used in these treatments.
Mechanisms of action of cytokines in depression/mood disorder
How Peripheral Cytokines access the CNS
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Several problems must be overcome to provide a coherent theory for how cytokines can contribute to the pathophysiology of major depression. It has been shown experimentally that LPS administration in mice results in local production of cytokines in the hypothalamus and pituitary (27). There are believed to be two main mechanisms by which peripherally produced cytokines can influence structures in the brain linked to depression. Studies suggest there is a relatively slow-acting process whereby blood-borne cytokines pass through endothelial cells of the circumventricular organs (CVOs) where the blood-brain barrier is more permeable. Movement of IL-1β has been shown to occur in this way at the area postrema and it is then thought to act on microglial cells to promote further release of cytokines (28). It has been noted that the majority of IL-1β found in the brain is produced in this way, through glial cell activity, rather than entering from the periphery (29). IL-1 can then diffuse through the brain parenchyma to affect different brain areas such as the amygdala or activate specific neurons in the brainstem that possess IL-1 receptors (30), (31). The exact mechanisms by which cytokines produced in the brain act to bring about behavioural changes is far from clear and further research is required to clarify this.
A fast-acting mechanism is thought to occur, whereby peripheral cytokines stimulate the vagus nerve to bring about stimulation of the nucleus tractus solitarius and in turn various hypothalamic nuclei. Intraperitoneal injection of IL-1β was shown to induce cFos immunoreactivity in vagal afferents indicating stimulation of these nerves by IL-1β.
How Cytokines act on the CNS
Once peripheral cytokines have been produced in the CNS there are thought to be several ways in which they can affect CNS structures and systems to bring about physiological and behavioural changes. Evidence for alterations to neuroendocrine systems, namely the HPA axis, have been mentioned already although mechanisms by which these alterations occur are unclear. Glucocorticoid receptor (GR) abnormalities have been suggested as a means by which cytokines can affect neuroendocrine function. IL-1 administration to mouse cells in vitro results in decreased translocation of GRs to the cell membrane associated with decreased GR-DNA binding, these effects were found to be blocked by IL-1 receptor antagonist (32). This effect is thought to be mediated by p38 mitogen-activated protein kinase (MAPK), which has been shown to disrupt GR function (33). In this way IL-1 is believed to contribute to development of glucocorticoid resistance as found clinically during dexamethasone suppression tests in patients with depression. This may also explain how high levels of glucocorticoids, which normally have anti-inflammatory effects, can be found in conjunction with pro-inflammatory cytokines.
As well as disrupting neuroendocrine systems, cytokines are believed to significantly alter metabolism of neurotransmitters crucial to the regulation of mood and behaviour. Deficiencies of serotonin have been strongly implicated in the pathophysiology of depression and this is backed up by the efficacy of SSRIs in treatment (34). A study looking at patients with Hepatitis C receiving IFN-α found decreased tryptophan levels and increases in kynurenine, indicating increased breakdown of tryptophan (35). Another study suggested that decreases in tryptophan during IFN-α therapy directly correlated with symptoms of depression. These studies looked at relatively small numbers of patients and taken alone, don't provide strong evidence for the role of cytokines in serotonin depletion (36). The strongest evidence comes from studies showing that cytokines can induce the enzyme indoleamine 2,3 dioxygenase (IDO), which breaks down tryptophan to kynurenine, reducing the amount available for conversion to 5-HT (37). While these studies provided evidence that cytokines could induce IDO in macrophages, another study showed that IDO was also expressed in the mouse brain after exposure to peripheral LPS administration. This study found an increase in plasma IFN-γ in these mice followed by a large rise in brain IDO levels, indicating that the cytokine played a role in the induction of IDO (38).