The Two Hit Model of Cytokine-Induced-Depression

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Table of Contents

Induced depression including the role of vulnerability factors
Clinical implications
Conclusions
References

Induced depression including the role of vulnerability factors

Production of pro-inflammatory cytokines induces sickness behavior which is terminated by endogenous anti-inflammatory molecules. Sustained production of pro-inflammatory cytokines in the context of insufficient production of anti-inflammatory molecules causes depression in vulnerable individuals. Factors acquired or genetic can contribute to vulnerability. Vulnerability in the present context refers to an innate or acquired predisposition to develop a given pathology when causal factors are present. Dysfunction in genes controlling key proteins in cytokine production (e.g., IL-6) and serotoninergic neurotransmission (e.g., activity of the serotonin transporter) or serotonin receptor subtype are identified as vulnerability factors for cytokine-induced depression (Kraus et al., 2007).

The association between IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-alpha-induced depression. In contrast, the effect of the 5-HTT serotonin transporter gene was small and perhaps dependent on the status of the inflammatory response (Bull et al., 2009). There are several features that contribute to vulnerability and are considered markers of vulnerability. Firstly, psychological features can reveal vulnerability to cytokine-induced depression. Patients who have high scores on depression scales at the start of cytokine treatment are more likely to develop depressive syndrome in response to immunotherapy than patients who have a low score at baseline (Capuron and Ravaud, 1999; Miyaoka et al., 1999).

Another example of psychological features is childhood adversity and maltreatment. Danese et al. (2007) conducted a cohort study and followed 1000 individuals from birth to age 32, they found that patients with major depression and documented history of childhood maltreatment showed higher levels of peripheral blood concentrations of high-sensitivity CRP compared with depressed patients without a history of childhood maltreatment (Danese et al, 2008).

Secondly, physiological features can also reveal vulnerability. For example, patients who respond to the first injection of IFN-α by an exaggerated pituitary-adrenal response are more likely to become depressed in response to repeated administration of IFN-α than patients who display a lower pituitary-adrenal response (Capuron et al., 2003). Aging is accompanied by several changes in the immune system and reflect immunosenescence and an altered susceptibility of disease.

Thus, the elderly respond to stressful events with larger fluctuation of immune function and a greater propensity for the development or progression of disease in young or middle-aged individuals (Irwin & Vedhara, 2007). Godbout et al. (2005) investigated if aging exacerbated neuro-inflammation and sickness behavior after peripheral injection of lipopolysaccharide (LPS) in aged mice. Their data revealed that activation of the peripheral innate immune system leads to exacerbated neuro-inflammation in the aged compared with adult mice.

The dysregulation link between the peripheral and central innate immune system is likely to be involved in the severe behavioral deficits that frequently occur in older adults with systemic infections. Another example is obesity; O’Connor et al. (2005) tested the hypothesis that this inflammatory dysregulation affects the IL-1beta system and has functional consequences in the brain of obese mice. Their results indicate IL-1beta-mediated innate immunity is augmented in diabetic obese mice at the periphery and in the brain, and the mechanism is due to diabetes-associated loss of IL-1beta counter-regulation.

Obesity and aging is correlated with low-grade inflammation status because of the immune-to-brain communication which leads to priming or sensitization of brain microglial cells (Perry, 2004). Superimposed on this low-grade inflammation status, a peripheral infectious episode leads to exaggerated synthesis of inflammatory cytokines and other mediators in the brain which has an impact on behavior and mood or exacerbate the progression of chronic neurodegenerative disease. Finally, immuno-compromised individuals, patients taking certain medications or drug abusers can reveal vulnerability (Irwin & Vedhara, 2007).

Since, any alteration in the balance between pro-inflammatory and anti-inflammatory cytokines in the sense of a predominance of pro-inflammatory cytokines over anti-inflammatory cytokines, results in an exaggerated sickness response to activation of the peripheral immune system or direct activation of the brain cytokine system (Dantzer, 2009). Patients who respond to the first injection of IFN-alpha by an exaggerated pituitary-adrenal response are likely to become depressed in response to repeated administration of IFN-alpha than patients who display a lower pituitary-adrenal response (Capuron, Neurauter, and Musselman, 2003).

The third feature is Genetic predisposition to particular diseases (eg. autoimmune diseases, diabetes or cancer…) can lead to vulnerability (Irwin & Vedhara, 2007). Dysfunction in genes controlling key proteins in cytokine production and serotoninergic neurotransmission are identified as vulnerability factors for cytokine-induced depression (Krauset al., 2007, Bull et al, 2009). Krauset al. (2007) conducted a study to investigate the impact of functional gene variants of the cerebral serotonin (5-HT) signaling pathway previously implicated in depression risk in hepatitis C-infected outpatients treated with interferon alfa-2b.

Their findings suggest an impact of allelic variation in 5-HT1A receptor expression on the development of interferon alpha-induced depression during antiviral treatment of chronic hepatitis C. Prediction models of interferon-induced depressive symptoms based on HTR1A variation offer a perspective for an antidepressant selective serotonin reuptake inhibitor prophylaxis in patients genetically at risk for interferon-induced depression (Krauset al., 2007).

In another study, Bull et al (2009) conducted a study to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-alpha and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-alpha and ribavirin treatment for chronic hepatitis C virus participated in this prospective cohort study. The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-alpha-induced depression. In contrast, the effect of the 5-HTT genes was small and perhaps dependent on the status of the inflammatory response (Bull et al., 2009).

The interaction between psychosocial factors and other psychobiological vulnerably (e.g. depression) are characterized by alteration of immune function and increased susceptibility to or progression of disease (Irwin & Vedhara, 2007). Collectively, the above features may help while using markers for prediction of patients at risk for depressive symptoms and a guide in the development of interventions to prevent the occurrence of depression thus improving the quality of life.

Chronic administration of the inflammatory cytokine resulted in inducing depressive symptoms with 30–50% of cytokine-treated patients with major depression (Raison et al, 2005). Results from a randomized clinical trial showed patients with malignant melanoma and hepatitis-C have pre-administration of paroxetine; an antidepressant medication significantly reduced the development of depressive symptoms, especially in patients with elevated symptoms of depression at baseline (Raison et al, 2007).

In cardiac patients, Appels, Bär, Bär, Bruggeman, & de (2000) tested the hypothesis, depressive symptomatology is associated with levels of myocardial cytokines and higher antibody titers against microbial pathogens. They found that exhausted or depressed patients had higher antibody titers against cytomegalovirus, higher levels of C. pneumonia immunoglobulin G, and higher levels of IL-1b and TNF-a.

These findings indicate how the mental state of angioplasty patients is positively associated with serological markers of inflammation. However, it remains to be seen whether the inflammation causes feelings of exhaustion orr exhaustion and depression set the stage for inflammation, or existing feelings of exhaustion are amplified by the inflammation (Appels, Bär, Bär, Bruggeman, & de, 2000).

Along the same lines, Lespérance, Frasure-Smith, Théroux, & Irwin (2004) conducted another study to determine the association between depression and higher levels of inflammatory markers in patients recovering from acute coronary syndromes. There results suggest chronic endothelial activation among depressed patients after acute coronary syndromes (Lespérance, Frasure-Smith, Théroux, & Irwin, 2004)

Clinical implications

The model of cytokine-induced depression has the advantage of providing clinicians with the possibility of observing development of depressive symptoms over time in many patients who can be monitored closely while receiving immunotherapy. Furthermore, patients who develop depression can be compared transversally to patients who remain free from mood disorder. The model of cytokine-induced depression provides valuable insights into the relationship between cytokines and depression (Dantzer, 2009). Clinicians may explore the implications of sickness behavior related to depression and specific diseases related Symptoms.

Nurses would benefit from awareness and understanding of the relationship between pro-inflammatory cytokine and sickness behaviors. Enhanced knowledge in this arena will aid the nurses in assessing and identifying vulnerable patients and at risk for sickness behavior symptoms. Additionally, nurses can participate in educating patients to promote quality of life. There are several innervations that can interrupt the cytokine-brain signaling pathway, such as pharmacological and non-pharmacological interventions. Future research is warranted in this arena which will be addressed in this section.

First for pharmacological interventions, there is a crucial need in the discovery and the development of novel antidepressant drugs target the brain immune system or its secondary consequences of activating IDO or the enzymes responsible for degradation of kynurenine. These neural circuits process affective and reward-based information for optimal cost-benefit decision-making, a function may link cytokine-evoked changes in synaptic plasticity to translatable measures of specific behavioral impairments observed in depressed patients (Piser, 2010).

For example, the administration of insulin-like growth factor-I into the lateral ventricles of the brain inhibits sickness behavior induced by a central injection of LPS (Dantzer, Gheusi, Johnson, & Kelley, 1999). Furthermore, evidence shows central administration of IGF-I decrease depressive-like behavior and brain cytokine expression in mice (Park et al., 2011). The anti-depressant activity of IGF-I may have clinical implications for psychiatric conditions with or without the presence of inflammatory diseases (Park et al, 2011).

Park et al. (2011) conducted a study to investigate the extent to which central IGF-I would impair the development of depressive-like behavior by tempering the neuro-inflammatory processes within the brain. Additionally, they examined the extent it would do so by inducing expression of the brain-derived neurotropic factor while decreasing pro-inflammatory cytokine expression in the brain. Their results revealed that the central IGF-I significantly impaired development of depressive-like behavior in LPS-challenged mice by an anti-inflammatory response in the brain, which in return decreases the expression of inflammatory proteins in naïve and LPS-challenged mice.

In other words, these findings showed how IGF-I down regulates glial activation and induces expression of an endogenous growth factor that shares anti-depressant activity. This is the first study evaluates IGF-I for anti-depressive actions within the brain, which forms the basis for future studies defining the mechanism for IGF-I’s anti-depressant activity in human (Park et al., 2011).

Another example is the use of anti-cytokine therapies for depressed mood. In a large double-blind placebo-controlled trial, the administration of TNF-alpha antagonist in patients with psoriasis showed significant improvement in depressive symptoms independent of symptoms related to the disease etiology (Tyring et al., 2006). Furthermore, in a small double-blind placebo-controlled trial, the COX-2 inhibitor in healthy patients with major depression increased the antidepressant efficacy of the norepinephrine reuptake inhibitor, (Muller et al., 2006). These implications emphasize the importance and significance of targeting signaling pathways of cytokines can promote an antidepressant activity.

Additionally, chemokine such as MCP-1, which can attract monocytes to multiple tissue sites including the brain where they can perpetuate inflammatory responses (D’Mello et al., 2009), are another class of target that have unique applicability to behavioral disorders associated with increased inflammation (Capuron and Miller, 2011)

Finally, the cytosolic enzyme indoleamine 2, 3-dioxygenase (IDO) can be manipulated to treat a range of chronic inflammatory diseases. There are studies in IDO inhibitors to improve T cell activity in inflammatory states and cancer, thus indicating broad interest in the development of pharmacologic agents that target IDO (Johnson, Baban, & Mellor, 2009).

These are examples of the development of pharmacological interventions relevant to immuno-biology and neurobiology which emphasize the need for implication and support opportunities for collaborative effort between disciplines help in understanding the mind and body connection (Capuron and Miller, 2011).

For non-pharmacological intervention, the immune-modulatory and anti-inflammatory effects of specific nutritional factors helps prevent or modulate neuropsychiatric symptomatology in chronic low-grade inflammation using nutritional interventions. For example, Layé (2010) polyunsaturated fatty acids are essential nutrients and essential components of neuronal and glial cell membranes. These Polyunsaturated fatty acids regulate prostaglandin and pro-inflammatory cytokine production.

For example, n-3 fatty acids are anti-inflammatory while n-6 fatty acids are precursors of prostaglandins. Inappropriate amounts of dietary n-6 and n-3 fatty acids can lead to neuro-inflammation because of their abundance in the brain and reduced wellbeing. However, future investigations need to account for the two key enzymes in the metabolism of polyunsaturated fatty acids; Phospholipase A2 (PLA2) and cyclooxygenase 2 (COX2).

These enzymes have significantly crucial roles in cytokine-induced depression. Elucidation the genetic variations in the COX2 and PLA2 genes increase the risk of IFN-alpha-induced depression, possibly by affecting the levels of docosahexaenoic and eicosapentaenoic acid (Su et al., 2010). Collectively, the above vulnerability features may help in using markers for prediction of patients at risk for depressive symptoms and r guide in the development of interventions to prevent the occurrence of depression and improve life. Since obesity is correlated with low-grade inflammation status that (Perry, 2004), weight loss intervention will benefit obese vulnerable patient accordingly.

Finally, it is well established that stress predisposes laboratory animals and humans to activate the inflammatory response (Miller, Maletic, and Raison 2009). Behavioral interventions focused on stress management, coping and therapies that modulate sympathetic and parasympathetic tone (e.g. meditation, behavioral cognitive therapies, and yoga) should also be implemented and considered for further research.

Conclusions

The presented evidence in this paper reveal the increasing knowledge regarding the immune-to-brain communication, but evidence needs to be implicated in clinical practice. Symptoms of sickness negatively affect patients with chronic inflammatory disorders. Therefore, controlled studies are necessary to validate the beneficial value of various interventions (for example, physical exercise) to alleviate the symptoms of sickness (Dantzer, O’Connor, Freund, Johnson, and Kelley, 2008).

Furthermore, the neurobiological mechanisms underlying the behavioral effects of pro-inflammatory cytokines have not been investigated vigorously to correlate a given behavioral effect of a cytokine to a specific action in a well-defined area in the brain. For this reason, micro-pharmacology experiments that target inflammatory mediators in specific brain areas must be implemented to define the cause-effect relationships (Dantzer, O’Connor, Freund, Johnson, and Kelley, 2008).

The identification of the intracellular association between inflammation and depression will provide valuable targets for the development of new antidepressant drugs if the activation of brain pro-inflammatory cytokine signaling is proven to represent the final common pathway for the various conditions that lead to depression (Dantzer, O’Connor, Freund, Johnson, and Kelley, 2008).

Investigation of acute circulating inflammatory marker’s responses is a fruitful area may provide insight into the role of psycho neuro-immunological processes in patients. Standardization of appropriate markers of inflammation and a systematic approach for investigation of the risk factors will improve life. Furthermore, it is possible to develop clinical trials aimed at blocking cytokine production or action, attenuating the production of second messengers or deactivating glial cells produce excessive quantities of pro-inflammatory cytokines.

More research is needed in this area to enhance its innovative potential and avoid the duplication of efforts likely to occur because of the diversity of pathological conditions lead to non-specific clinical signs of sickness behavior (Dantzer and Kelly, 2007). Future studies are warranted to illuminate the precise effects of certain cytokines and explore targets for interventions and therapies. Taken together, future studies are warranted to illuminate the precise effects of certain cytokines and explore targets for interventions and therapies.

For example, the potential targeting of inflammatory pathways for depression treatment, such treatments can provide valuable starting points for the identification of vulnerable subgroups of depressed patients who may be most appropriate for immune-targeted therapies (Danese et al, 2008).

For example, the potential targeting of inflammatory pathways for depression treatment can provide valuable starting points for the identification of vulnerable subgroups of depressed patients who may be most appropriate for immune-targeted therapies (Danese et al, 2008). Finally, findings from warranted studies can lead to the development of feasible effective interventions aimed to identifying patients at risk for sickness behaviors, preventing or decreasing the negative effects of cytokine-induced inflammatory responses to improve life.

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The Two Hit Model of Cytokine-Induced-Depression

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