There are no sources in the current document.The purpose of this essay is to explain the role of cytokines in depression. Over the last few decades there have been many controversial hypotheses put forward to explain the observation of depressive symptoms in people, who have a physical injury or are under psychological stress (Schiepers, et al., 2008). Research shows that most controversy was over how the messages from the immune system were interpreted or translated into being a signal to the central nervous system (CNS). While most research agreed that there was a correlation in data between cytokines and depressive symptoms, they did not believe this indicated a causal link (Anisman, 2002). I have chosen to focus one of the most popular theories, the “cytokine theory of depression”, as I believe the research shows that it has a causal link between inflammation, cytokine activity and depressive symptoms (Roque, et al., 2009). This hypothesis recognises and explains the highly integrated processes and mechanisms that a person or animal goes through, from the initial stressor to displaying the depressive symptoms, termed as “sickness behaviour” (Dantzer, 2006).
“Sickness Behaviour” is the term given to the symptoms caused by high levels of pro-inflammatory cytokines in the periphery of the body; these symptoms overlap with the general characteristics of depression and include; decreased appetite, increased desire to sleep, cognitive dysfunction, social withdrawal and decreased sexual drive. It is believed that these symptoms result from the response by the body’s healing mechanisms, to ensure people with illnesses take respite during their recovery and healing phase (Wilson & Warise, 2008).
The activation of the immune system is shown to have neural, neuroendocrine and behavioural effects, which may be responsible for the sickness behaviour symptoms (Wilson & Warise, 2008). Patients diagnosed with depression are reported to have high serum levels of inflammatory markers, including; complement proteins C3, C4 and Immunoglobulin-M (IGM), as well as elevated levels of pro-inflammatory cytokines in their peripheral blood, indicating an immune response to an injury, infection or a stressor. These same patients also display lower level of T lymphocyte and natural killer (NK) cell activity in the serum. While most immune responses begin in the periphery of the body, there is an almost instantaneous, sensory-like transmission of the immune response sent to the brain, where the information is used to activate neurons and cells to further release local cytokines, which can then regulate and modulate neurotransmitters in the brain. Immune dysfunction has been reported in patients before symptoms of depression were observed. These patients began with a medical illness, usually an acute viral infection, or a chronic autoimmune or neurodegenerative disease, a tumour, tissue damage, or a psychological stressor, all of which would have initiated an immune response by the body, and the illnesses or injuries were symptomatic and diagnosed before any depressive symptoms were observed (Yirmiya, et al., 2006).
The main cytokine types that mediate the inflammation process are interferons and interleukins, and these are believed to interact with corticosteroids and serotonin (5-HT) levels in the brain. The proimflammatory cytokines; Interleukin (IL) -1, IL- 6 and interferons, are all reported as being at increased levels in patients with depressive symptoms. High levels of circulating pro-inflammatory cytokines also affect the body’s feedback loop to reduce corticosteroids, which in turn leads to lower levels of serotonin, possibly causing depression in patients (Wilson & Warise, 2008).
Depression is a major burden of disease; it is one of the most common psychiatric disorders in the Western World, and a current leading cause of disability around the globe (Zunszain, et al., 2011). The most common type of depression, and the one I will be addressing throughout this paper, is associated with changes to levels of adrenocorticotrophic hormone (ACTH) and cortisol, which both are capable of affecting the levels of neurotransmitters in the brain.
Depression has typical symptoms which include; sleep disturbance, fatigue, loss of appetite, psychomotor retardation, somnolence and cognitive disturbances, as well as possible muscle aches, increased cigarette smoking or alcohol consumption, and hygiene changes. The prevalence of major episodes of depression reported in patients with a physical illness varies from 5% to 40%, although this number is most likely underestimated as ill patients are not likely to be diagnosed as having depression, or therefore treated for the disorder (Yirmiya, et al., 2006). Most depression is treated with antidepressants that target the monoamine pathways, but unfortunately this fails to attain a remissive state for around 30% of sufferers. Research has shown that cytokines can access the brain and affect almost all of the pathophysiological areas that are involved in the psychiatric disorder depression (Miller, et al., 2009).
Research indicates that inflammation, which is a common mechanism for the body to respond to disease, plays a role in depression, and other neuropsychiatric diseases. Inflammation occurs when cells secrete cytokine proteins that start the immune response process after an initial insult (Miller, et al., 2009). Cytokines are glycoprotein hormones that act as inter-cellular signalling molecules that can regulate, inhibit or stimulate proteins in neighbouring cells. Cytokines are produced during immune responses and are mostly synthesized by activated macrophages in innate defence responses, and T lymphocytes in adaptive immune responses, following acute or chronic insult from a stressor. Cytokines can also be anti-inflammatory or pro-inflammatory. Pro-inflammatory cytokines include; IL-1, IL-2, IL-6, IL-8, IL-12, tumour necrosis factor (TNF) a, TNFb, and interferon (IFN) a, and IFNy. Anti-inflammatory cytokines include; IL-4, IL-8 and IL-10. There are several major functional groups of cytokines, the main two for our purposes in relation to depressive symptoms, are interleukins and interferons (Wilson & Warise, 2008).
Interleukins are a group of chemical messengers in the immune system that can be synthesized by macrophages and lymphocytes, as well as astrocytes, fibroblasts and endothelial cells. IL’s can either suppress or increase immune responses. IL-1 is an endogenous protein mainly produced by activated macrophages. In relation to the inflammatory response it reacts with hypothalamus cell receptors, which produce fever by affecting the body’s internal thermostat. IL-1 also helps to moderate the immune response, by stimulating B lymphocytes and increasing T lymphocytes antigen sensitivity (Wilson & Warise, 2008). IL-1 is commonly released in the hypothalamus and hippocampus of the brain (Schiepers, et al., 2008).The hypothalamus and hippocampus have many IL-1 binding sites, and IL-1 is capable of stimulating secretion of the corticotrophin-releasing hormone (CRH) from the hypothalamus. Increased IL-1 can be responsible for the depressive symptom of fatigue and CRH can induce restlessness, symptoms which can both occur simultaneously in a depressive patient (Corrigan, 1998).
Another important cytokine is IL-6, which signals hepatocytes to produce proteins required in the inflammation process (Wilson & Warise, 2008). Corrigan (1998), reports that there is an increase in IL-6 activity in patients with depressive symptoms. IL-6 is associated with the development of the symptoms; fatigue, sleep disturbance and cognitive dysfunction, again all symptoms of depression (Miller, et al., 2009). IL-1 and IL-6 therefore, are both capable of producing symptoms found in depressive patients and can stimulate the synthesis of CRH in the hypothalamus, to decrease the intensity of the immune response via the pituitary adrenal axis (Corrigan, 1998).
Interferons (IFN) are produced by the body to regulate immunity and respond to viral and tumour insults, these IFN are also recognised as initiating depressive symptoms in patients. There are three main classes of INF: alpha, beta and gamma, both alpha and gamma stimulate and attract natural killer (NK) cells, and beta is associated with decelerating the inflammation progress of viral infections (Wilson & Warise, 2008). Lower levels of NK cells activity is reported in patients during a depressive episode (Corrigan, 1998).
The cytokine theory of depression proposes that there is an interaction between the central nervous system, the endocrine system and cytokines. This occurs through regulation of the hypothalamic- pituitary- adrenal (HPA) axis and the modulation of the monoamine neurotransmitters (Schiepers, et al., 2008). The neurotransmitters; nor-adrenaline (NA), dopamine, (DA) and serotonin (5-HT), can all be influenced by cytokine activity, and are all involved in the disorder of depression. Cytokines, especially IFN, interfere with the metabolism of 5-HT, and its dietary precursor tryptophan, which is lower in depressed patients and is indicated in the relationship between low mood and 5-HT levels. Lower levels of tryptophan are linked with depressive symptoms, including; inability to concentrate, loss of appetite, suicidal ideation and pessimism. The alteration of tryptophan levels, occur as a result of the competition between tryptophan and other large amino acids to cross the blood-brain barrier (BBB), resulting in tryptophan levels being lowered (Wilson & Warise, 2008).
There has been great controversy over the last few decades of how the cytokines could reach the brain and breach the BBB, to allow bidirectional communication between the immune, neural and endocrine systems, and the central nervous system. Cytokines are large polypeptides, and there are several ways that their signals could reach the brain. One way is that the cytokines can bind with receptors of the Autonomic Nervous System (ANS) on peripheral nerve fibres, like on the vagus nerve, which would then allow the cytokines to relay signals via the neurotransmitter Acetylcholine (ACh) to the brain, especially the hypothalamus. Cytokines could also signal and activate endothelial cells lining the cerebral vasculature, to produce inflammatory mediators and local cytokines. Astrocytes and microglia in the Central Nervous System (CNS) are capable of producing these cytokines. Nuclear factor kappa B (NF-kB) would be required, as it is a molecule which is necessary to mediate the inflammatory signals at the BBB, between the CNS and the periphery (Schiepers, et al., 2008). Cytokines could also enter the brain itself through leaky regions in the BBB, or via active transport on saturable transport molecules (Miller, et al., 2009) at sites of the brain like the median eminence. The pro-inflammatory cytokine TNFa is also reported to be capable of promoting degeneration of the BBB itself (Schiepers, et al., 2008).
Research shows that cytokines after reaching the brain can influence the hypothalamic- pituitary- adrenal axis. The cytokine theory of depression theorises that a person with depressive symptoms would show hyperactivity of the HPA axis, with increased concentrations of IL-1 and IL-6 in the plasma concentrations (Schiepers, et al., 2008). The adrenal cortex secretes the class of hormones known as glucocorticoids (GC), these GC’s are involved in regulating the immune systems’ inflammation process, by being able to decrease the immune and inflammatory response in conjunction with the HPA feed-back mechanism (Corrigan, 1998).
Cortisol is a GC, and in depressive patients is seen to secrete larger amounts of its hormone, more often and for longer periods, and at times of the day when the cortisol production does not normally occur at the higher levels. The hypersecretion of the GC hormones, which can be caused by stress, can lead to immunosuppression and feed-back resistance in the hippocampus (Corrigan, 1998). GC’s have lower responsiveness during a depressive episode, which is caused by the cytokines impairing the negative feed-back regulation of the HPA axis (Miller, et al., 2009). Low levels of cortisol lead to an increase in production of pro-inflammatory cytokines (Schiepers, et al., 2008).
Corticotropin-releasing hormone (CRH) is a neurotransmitter that is secreted from the hypothalamus, in the HPA axis, in reaction to stress. Modulation of CRH secretion from the hypothalamus is mediated by the neurotransmitters; ACh, DA and NA, which all stimulate CRH secretion, and 5-HT which suppresses the CRH hormone secretion. CRH stimulates the production of Adrenocorticotropic hormone (ACTH) from the anterior pituitary gland, and ACTH stimulates the synthesis of cortisol and is capable of altering the immune system response by adjusting the amount of cortisol secreted by the adrenal glands, as part of the feed-back loop (Schiepers, et al., 2008).
Cytokines can affect the brain in many ways. The symptoms of sickness behaviour are related to the peripheral pro-inflammatory cytokines, which are mostly mediated by the hypothalamus. Inflammation leading to brain injury could be caused by IL-1 stimulating production of IL-6 and TNFa, by the microglia and astrocytes. Cytokines can also affect the neurotransmitters in the brain. IL-6 is capable of increasing secretion of the monoamine 5-HT, while IL-1 can raise levels of 5-HT as well as the catecholamines DA and NA in the hippocampus and hypothalamus (Schiepers, et al., 2008).
Patients who are treated with cytokine therapy for cancer or viruses, including hepatitis C, report depressive like symptoms after commencing treatment, which usually subside when the cytokine treatment is ceased. Studies have shown that after acute administration of cytokines, levels of CRH, ACTH and cortisol are elevated, which are also indicated in the depressive patients serum levels (Schiepers, et al., 2008). The behavioural changes reported by patients are cognitive dysfunction, insomnia and social withdrawl (Wilson & Warise, 2008). Schiepers et al. (2008) report that 20-50% of patients receiving long term IFNa therapy for infectious disease or cancer, acquire clinically significant depression.
There has been a lot of research on animals and testing in patients, which support the cytokine theory of depression. A study of rodents supported the link between immune activation and depressive symptoms, when rodents who were subjected to various acute or chronic physical and psychological challenges, were reported to develop; lack of appetite, reduced social and locomotor exploratory behaviour, body weight loss and anhedonia. (Yirmiya, et al., 2006).
Evidence which further supports the cytokine theory of depression, includes experiments involving the administration via injection of Lipopolysaccharides (LPS’s) to patients who had no health issues before they received the LPS injections. LPS’s have the ability to increase the levels of cytokines in the body, and the LPS-induced increase in levels of cytokines and cortisol where highly correlated with mild fever, anorexia, increased levels of depression, memory deficits and anxiety, which were reported in the same patients during the follow up examination. A study involving rodents that had received LPS’s to induce their levels of cytokines, displayed similar depressive symptoms to the human samples, as well as increases in their body temperature. Treatment with the antidepressants, Imipramine or Fluoxetine, was administered to the rodents over a period of time, which alleviated the symptoms associated with the increased levels of cytokines (Yirmiya, et al., 2006).
Imipramine is a tri-cyclic antidepressant medication, which after three to five weeks of daily injections, was shown to completely dispel all of the behavioural symptoms in the rodents who had previously received chronic administration of LPS’s. Fluoxetine is a selective seritonin reuptake inhibitor (SSRI) antidepressant medication, which when provided to the rodents, significantly changed their behaviour, they displayed an increase in appetite and regained body weight, as well as considerable effects on the change of body temperature were reported (Yirmiya, et al., 2006). Research suggests that human patients who display depressive symptoms and do not respond to straight fluoxetine treatment, may receive positive benefit and increased remission rates of symptoms, when fluoxetine is administered with Acetylsalicyclic Acid, commonly known as Aspirin, which is used in this case as an anti-inflammatory treatment. Antidepressant’s are also reported to be effective in patients who have inflammatory or immune disorders, as an anti-inflammatory treatment (Miller, et al., 2009).
Multiple studies of animals and humans have shown the causal link between an immune response producing increased levels of pro-inflammatory cytokines and depression. This paper has shown how the cytokine theory of depression is supported with the current data and research of the symptomology and aetiology of depression following a stressor initiating an immune reaction (Yirmiya, et al., 2006). Once stimulated, pro-inflammatory cytokines, undeniably have the ability to affect many body mechanisms that control the two major neurotransmitters which are known to moderate depression, DA and 5-HT. I argue that there is not just a correlation in the data between the cytokines and depressive symptoms, but that the affects that the pro-inflammatory cytokines have upon activity of the HPA axis and its ability to alter the levels of the hormones that stimulate or suppress brain neurotransmitters, also have a causal link with depression (Anisman, 2002).