Psychology of Affective Disorders - Neuroinflammation PDF

Module: Psychology and Neuroscience of Affective Disorders Week 3 Cognitive and biological alterations of affective disorders Topic 3 The role of neuroinflammation in affective disorders - Part 2 of 2 Dr Naghmeh Nikkheslat Post-Doctoral Researcher, Depa...

Module: Psychology and Neuroscience of Affective Disorders Week 3 Cognitive and biological alterations of affective disorders Topic 3 The role of neuroinflammation in affective disorders - Part 2 of 2 Dr Naghmeh Nikkheslat Post-Doctoral Researcher, Department of Psychological Medicine Lecture transcript Slide 2: So, from what we went through so far, it appears that depressed patients show elevated cortisol concentration, and at the same time, increased inflammation. In fact, we see the coexistence of two quite opposite factors. In one hand, the cortisol, which is the most potent anti- inflammatory hormone, is increased. And in the other hand, inflammation, instead of being decreased, is elevated, as evidenced in both CSF and periphery. So how we can explain the coexistence of these two phenomenon? We might know the answer now, but this has puzzled scientists at the time. The answer is the presence of glucocorticoid, or GR resistance, in depression. Evidence suggests that glucocorticoid resistance is observed in about 80% of patients with major depression. Slide 3: Back to our previous diagram, what we see in depression is that the hyperactivity of the HPA axis and increased production of cortisol seems to reflect and impair the ability of glucocorticoid hormones to exert their physiological effects through the negative feedback on the HPA axis. What we see is that HPA axis produces cortisol in response to stress, and the levels go up. But the problem is that the hormone cannot regulate its own production, as seen in normal conditions, and is not affected due to the GR resistance. In fact, the receptors show less sensitivity and not being able to inhibit the production of CRH and ACTH effectively. Slide 4: Elevated inflammation found in patients with major depression can be also due to impaired glucocorticoid receptor sensitivity. Indeed, the inflammatory response, which is regulated by the effect of glucocorticoid hormones in normal condition, cannot be terminated due to GR resistance and diminished sensitivity of immune cells to the hormones. And so, the immune system fails to induce an appropriate anti-inflammatory response to inhibit excessive release of pre-inflammatory cytokines. Indeed, depressed people show high circulating pre-inflammatory cytokines, such as interleukins, higher clinical inflammatory biomarkers, such as C-reactive proteins, or CRP, and also, they show association with inflammatory genes. Slide 5: Having high levels of inflammation can have consequences as small increases in C- reactive protein greatly increases your risk of heart attack, angina, and other cardiac events. There is overwhelming evidence that depression is associated with CHD, or coronary heart disease. Depression and heart disease are very common and often coexist. According to the World Health Organisation, chronic heart disease and depression are currently the first and second causes of disability in developed countries. And it is estimated that this will apply to all countries throughout the world by the year 2020. Slide 6: Converging lines of evidence from both experimental and epidemiological studies indicate that there is bi-directional association between these two common disorders. Cardiovascular disease characterised by changes in homeostatic and neuroendocrine function is a significant risk Transcripts by 3Playmedia Week 3 © King’s College London 1.  factor for depression. Also, depression is recognised as an independent risk factor for cardiovascular disease, increasing the risk of heart-related morbidity and mortality. Slide 7: In a recent study, we have looked at heart disease and depression in relation to inflammation and neuroendocrine responses. And it was found that CHD patients with depression has even higher levels of inflammation in the context of HPA axis alteration, and GR resistance, as compared to CHD patients without depression. In fact, CHD depressed patients showed attenuated glucocorticoid responsiveness, leading to insufficient glucocorticoid signalling, and so, elevation of inflammation. Slide 8: Although once it was believed that due to presence of blood brain barrier the brain is protected from peripheral inflammatory activation, the concept has been challenged due to the development in neuroimmunology research and evidence showing the presence of inflammatory responses within the central nervous system. Recently, attention has been paid to the blood brain barrier hypotheses as one of the potential mechanism underlying pathogenesis of psychiatric conditions, including depression in relation to inflammation. The hypotheses suggest breakdown of blood brain barrier and its abnormal communication, leading to breaching the gates and permitting penetration of inflammatory molecules into the brain. Studies reveal that cytokine, in fact, are able to penetrate the brain via specific mechanism. The communication between cytokine and the brain can be facilitated by transport mechanism passive diffusion at the sides where the barrier is deficient, and passive penetration of inflammatory cytokines into the central nervous system through their binding to transport molecules. It has been also postulated that glucocorticoid resistance itself may occur as a result of chronic stress and prolonged exposure to inflammatory cytokines. Inflammation has a direct effect in reducing GR sensitivity through the interaction of cytokines signalling pathway with the GR signalling pathway, thereby, disruption of functional properties of the receptors. So, the effect is bi-directional. Inflammation could potentially affect GR. And reduced GR sensitivity leads to elevation of inflammation. Furthermore, in animal models exposed to either acute or chronic stress, excessive production of cytokines causes diminished neurotropic support and neurogenesis. Moreover, neuroinflammatory activation enhances oxidative status in the central nervous system, stimulating the production of nitric oxide, the characteristic that is observed in neuropathophysiology of depression. Slide 9: Increased inflammation has been suggested to induce depressive symptoms, not only by directly affecting the brain, but also modulating the serotonergic system by affecting the kynurenine pathway of tryptophan metabolise. Tryptophan is a precursor of serotonin. Enzyme IDO can also convert tryptophan into kynurenine or kynurenic acid. Following IDO activation, both the reduced peripheral availability of tryptophan that putatively leading to reduce serotonin synthesis in the brain, and the production of neurotoxic tryptophan metabolites are considered essential steps in the pathophysiological processes. In fact, kynurenic acid is NMDA receptor antagonists and is generally considered neuroprotective. Whereas 3-hydroxykynurenine and quinolinic acid are NMDA receptor agonists-- potentially neurotoxic-- and so contributing to depression. In case of inflammation, pre-inflammatory cytokines enhance the activation of IDO and KMO enzymes and so divert the kynurenic pathway more into the neurotoxic path with diversion of kynurenine into 3-hydrokynurenine. Slide 10: Overall, we know that chronic stress and inflammatory exposure is one of the challenges that patients with depression face. And adaptation to such condition require involvement of neural endocrine immune mechanism. This is how we see that one-third of patients with depression fail to respond to conventional antidepressant therapies, and this is due to the complexity of the disorder. And therefore, to target depression, we need to consider neuroendocrine abnormalities and immune activation also presented in these patients. Slide 11: So, the ultimate goal is targeting inflammation-induced depression, identification of inflammatory biomarkers, prevention of future developments of depression, detection of biomarkers used for monitoring changes in vulnerability, and also inflammation as a pharmacological target to develop new antidepressants. Slide 12: But from evolutionary perspective, why inflammation and depression has evolved? Even though the fight and flight response is automatic, it isn’t always accurate. In fact, most of the time when the fight and flight response is triggered, it is a false alarm. There is no threat to survival. Transcripts by 3Playmedia Week 3 © King’s College London 2.  The part of the brain that initiates the automatic part of the fight and flight response, the amygdala, can’t distinguish between a real threat and a perceived threat. For example, in the lab when we are trying to induce the stress environment-- delivering speech to a judgmental panel, which in this case could be behavioural experts, subject will experience the classic fight and flight response characterised by increase in heart rate and blood pressure, as well as cortisol and catecholamines. But what is also happening as a result of such a stress is activation of key inflammatory pathway at periphery, including increased levels of inflammatory cytokines. But this immune response is not against a pathogen, but against a threat to the subject’s self-esteem. Based on adaptive theories of depression, there is a potential benefit of depressive symptoms. More modern theories believe that human inherited genes for inflammation because this response, and depressive symptoms, enhance host survival and reproduction in a highly pathogenetic and stressful environment. Association between stress perception and risk of subsequent harm to the subject was reliable enough that evolution favoured organism with activated inflammatory systems in response to a wide array of environmental threats and challenges, including psychological stressor, even if this activation was often a false alarm. Slide 13: So, from what we have learned so far, we can now see clearly the link between inflammation and depression. Transcripts by 3Playmedia Week 3 © King’s College London 3.