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S.15.03 Combined effect of antidepressant and anti-inflammatory drugs in an animal model of depression
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S.15 Stress and mood disorders: neuroimmunological aspects
S.15.03 Combined effect of antidepressant and anti-inflammatory drugs in an animal model of depression N. Brunello1 ° , S. Alboni1 , C. Benatti1 , D. Corsini1 , G. Capone1 , F. Tascedda1 , J. Mendlewicz2 . 1 University of Modena, Dept. Biomedical Sciences, Modena, Italy; 2 ULB Erasme, Dept. Psychiatry, Brussels, Belgium The delay in the onset of action of antidepressants remains one of the unsolved issues in the treatment of depression despite the availability of safe and effective drugs. It has been known for years that depression may share identical symptoms as those in inflammatory reaction and that immune function and inflammation markers are altered in psychiatric patients. This suggests to use anti-inflammatory drugs as an adjunctive therapy for depression. We previously demonstrated that the combination of acetylsalicylic acid (ASA) with Fluoxetine (FLX) accelerated and potentiated the effect of the antidepressant in the chronic escape model of depression (Brunello et al., 2006). These results, together with preliminary clinical data in major depressed nonresponder patients, suggest that ASA might accelerate the onset of action of SSRIs (Mendlewicz et al., 2006). Preclinical and clinical studies have recently reported that Escitalopram (ESC), the active enantiomer of citalopram, shows a faster onset of action compared to other antidepressants. The aim of our study was to compare the effect of one week of combined treatment with ESC plus ASA vs. ESC alone in the chronic escape deficit model of depression. Significant response after one week of treatment was present in about 50% of the animals receiving ESC (10 mg/kg/day) alone and in about 75% of the rats receiving ESC plus ASA (45 mg/kg/day). These results suggest that the co-administration of ASA with ESC increased the response to treatment in reverting the behavioural despair induced by stress in rats, thus confirming the specific effect of combined therapy. References [1] Brunello N, Alboni S, Capone G, Benatti C, Blom JMC, Tascedda F, Kriwin P, Mendlewicz J, 2006, Acetylsalicylic acid accelerates the antidepressant effect of fluoxetina in the chronic escape deficit model of depression. Int Clin Psychopharmacol 21(4), 219−25. [2] Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N, 2006, Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol 21(4), 227−31.
S.15.04 Cytokines as mediators of depression: the involvement of the HPA axis and the serotonergic system M. Kubera ° . Institute of Pharmacology Polish Academy of Sciences, Department of Neuroendocrinology, 31–343 Krak´ow, Poland Current hypotheses on the etiology of the depressive disorder tend to integrate monoaminoergic, neuroendocrine and immunological concept of depression. A number of research papers emphasize a significant increase in pro-inflammatory cytokines levels in depressed patients. The main target of cytokines are hypothalamic CRH/AVP neurons in the paraventricular nucleus. Cytokines enter the brain via capillary endothelium of the circumventricular organs and other sites where BBB permeability is increased, via
limited specific transport or they influence hypothalamic function indirectly via soluble mediators produced by perivascular cells of BBB. Chronic stressors and environmental insults which augment proinflammatory cytokine expression concomitantly induce hypersecretion of CRH and increase CRH1 receptors expression, and decrease number and sensitivity of glucocorticoid receptors in immune cells, hippocampus and HPA axis thereby leading to attenuation of cortisol induced suppression of pro-inflammatory cytokine production and negative feedback inhibition of HPA axis. In addition, they lower levels of beneficial growth or neuroprotective factors including brain-derived neurotrophic factor and anti-apoptotic factors, and impair process of neuronal branching and neurogenesis. Cytokines reduce the production of 5-HT by stimulating the enzyme indoleamine 2,3-dioxygenase which converts tryptophan into kynurenine. Kynurenine metabolites like3hydroxy-kynurenine and quinolinic acid, promote tissue damage. Cytokines up-regulate the serotonin transporter causing a depletion of extracellular 5-HT. IL-1 suppresses 5-HT production by serotoninergic neurons. Chronic elevation of proinflammotory cytokines, via glucocorticoids, increase expression of 5HT1A auto-receptors in raphe nucleus and decrease expression of post-synaptic 5HT1A hetero-receptors in hipoccampus leading to inhibition of serotoninergic neurotransmission.Cytokines induce pathophysiological changes in HPA axis and 5-HT system typical for depression. References [1] Hayley S, Poulter MO, Merali Z, Anisman H, 2005, The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity. Neuroscience 135, 659–678.
S.15.05 Molecular mechanisms of GR sensitivity in vitro and in vivo C. Pariante ° . King’s College London, Division of Psychological Medicine Section of Stress Psychiatry and Immunology, London, United Kingdom Clinical studies have demonstrated an impairment of glucocorticoid receptor (GR)-mediated negative feedback on the hypothalamic–pituitary–adrenal (HPA) axis in patients with major depression (GR resistance), and its resolution by antidepressant treatment. Accordingly, reduced GR function have also been demonstrated in vitro, in peripheral tissues of depressed patients, as shown by reduced sensitivity to the effects of glucocorticoids on immune and metabolic functions. We and others have shown that antidepressants in vitro are able to increase GR expression, induce GR upregulation and also increase GR function. Interestingly, these in vitro effects are in the same direction as the in vivo ones – towards overcoming glucocorticoid resistance – although the molecular mechanisms underlying these effects are unclear. Our work has also shown that depressed patients, as well as subjects with a history of childhood abuse, have increased evidence of inflammation, and that inflammation in turn is associated with both depression in medically-ill patients and with GR resistance. The GR, and its modulation by antidepressants and inflammation, in human and animals’ cell lines have been studied. Several mechanisms could be involved in modulation of GR function, including changes in GR expression, GR translocation, GRmediated gene transcription, as well as changes in the availability of glucocorticoids hormones inside the cells. These studies might help clarify the pathophysiology of GR resistance in depression and the mechanisms of therapeutic action of antidepressants drugs.
S.15 Stress and mood disorders: neuroimmunological aspects
S.15.03 Combined effect of antidepressant and anti-inflammatory drugs in an animal model of depression N. Brunello1 ° , S. Alboni1 , C. Benatti1 , D. Corsini1 , G. Capone1 , F. Tascedda1 , J. Mendlewicz2 . 1 University of Modena, Dept. Biomedical Sciences, Modena, Italy; 2 ULB Erasme, Dept. Psychiatry, Brussels, Belgium The delay in the onset of action of antidepressants remains one of the unsolved issues in the treatment of depression despite the availability of safe and effective drugs. It has been known for years that depression may share identical symptoms as those in inflammatory reaction and that immune function and inflammation markers are altered in psychiatric patients. This suggests to use anti-inflammatory drugs as an adjunctive therapy for depression. We previously demonstrated that the combination of acetylsalicylic acid (ASA) with Fluoxetine (FLX) accelerated and potentiated the effect of the antidepressant in the chronic escape model of depression (Brunello et al., 2006). These results, together with preliminary clinical data in major depressed nonresponder patients, suggest that ASA might accelerate the onset of action of SSRIs (Mendlewicz et al., 2006). Preclinical and clinical studies have recently reported that Escitalopram (ESC), the active enantiomer of citalopram, shows a faster onset of action compared to other antidepressants. The aim of our study was to compare the effect of one week of combined treatment with ESC plus ASA vs. ESC alone in the chronic escape deficit model of depression. Significant response after one week of treatment was present in about 50% of the animals receiving ESC (10 mg/kg/day) alone and in about 75% of the rats receiving ESC plus ASA (45 mg/kg/day). These results suggest that the co-administration of ASA with ESC increased the response to treatment in reverting the behavioural despair induced by stress in rats, thus confirming the specific effect of combined therapy. References [1] Brunello N, Alboni S, Capone G, Benatti C, Blom JMC, Tascedda F, Kriwin P, Mendlewicz J, 2006, Acetylsalicylic acid accelerates the antidepressant effect of fluoxetina in the chronic escape deficit model of depression. Int Clin Psychopharmacol 21(4), 219−25. [2] Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N, 2006, Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol 21(4), 227−31.
S.15.04 Cytokines as mediators of depression: the involvement of the HPA axis and the serotonergic system M. Kubera ° . Institute of Pharmacology Polish Academy of Sciences, Department of Neuroendocrinology, 31–343 Krak´ow, Poland Current hypotheses on the etiology of the depressive disorder tend to integrate monoaminoergic, neuroendocrine and immunological concept of depression. A number of research papers emphasize a significant increase in pro-inflammatory cytokines levels in depressed patients. The main target of cytokines are hypothalamic CRH/AVP neurons in the paraventricular nucleus. Cytokines enter the brain via capillary endothelium of the circumventricular organs and other sites where BBB permeability is increased, via
limited specific transport or they influence hypothalamic function indirectly via soluble mediators produced by perivascular cells of BBB. Chronic stressors and environmental insults which augment proinflammatory cytokine expression concomitantly induce hypersecretion of CRH and increase CRH1 receptors expression, and decrease number and sensitivity of glucocorticoid receptors in immune cells, hippocampus and HPA axis thereby leading to attenuation of cortisol induced suppression of pro-inflammatory cytokine production and negative feedback inhibition of HPA axis. In addition, they lower levels of beneficial growth or neuroprotective factors including brain-derived neurotrophic factor and anti-apoptotic factors, and impair process of neuronal branching and neurogenesis. Cytokines reduce the production of 5-HT by stimulating the enzyme indoleamine 2,3-dioxygenase which converts tryptophan into kynurenine. Kynurenine metabolites like3hydroxy-kynurenine and quinolinic acid, promote tissue damage. Cytokines up-regulate the serotonin transporter causing a depletion of extracellular 5-HT. IL-1 suppresses 5-HT production by serotoninergic neurons. Chronic elevation of proinflammotory cytokines, via glucocorticoids, increase expression of 5HT1A auto-receptors in raphe nucleus and decrease expression of post-synaptic 5HT1A hetero-receptors in hipoccampus leading to inhibition of serotoninergic neurotransmission.Cytokines induce pathophysiological changes in HPA axis and 5-HT system typical for depression. References [1] Hayley S, Poulter MO, Merali Z, Anisman H, 2005, The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity. Neuroscience 135, 659–678.
S.15.05 Molecular mechanisms of GR sensitivity in vitro and in vivo C. Pariante ° . King’s College London, Division of Psychological Medicine Section of Stress Psychiatry and Immunology, London, United Kingdom Clinical studies have demonstrated an impairment of glucocorticoid receptor (GR)-mediated negative feedback on the hypothalamic–pituitary–adrenal (HPA) axis in patients with major depression (GR resistance), and its resolution by antidepressant treatment. Accordingly, reduced GR function have also been demonstrated in vitro, in peripheral tissues of depressed patients, as shown by reduced sensitivity to the effects of glucocorticoids on immune and metabolic functions. We and others have shown that antidepressants in vitro are able to increase GR expression, induce GR upregulation and also increase GR function. Interestingly, these in vitro effects are in the same direction as the in vivo ones – towards overcoming glucocorticoid resistance – although the molecular mechanisms underlying these effects are unclear. Our work has also shown that depressed patients, as well as subjects with a history of childhood abuse, have increased evidence of inflammation, and that inflammation in turn is associated with both depression in medically-ill patients and with GR resistance. The GR, and its modulation by antidepressants and inflammation, in human and animals’ cell lines have been studied. Several mechanisms could be involved in modulation of GR function, including changes in GR expression, GR translocation, GRmediated gene transcription, as well as changes in the availability of glucocorticoids hormones inside the cells. These studies might help clarify the pathophysiology of GR resistance in depression and the mechanisms of therapeutic action of antidepressants drugs.