The Role Of Inflammation In The Pathaphysiology Of Treatment Resistant Depression

The research on depression, especially treatment resistant depression(TRD)is one of the most exciting and challenging topics in the world. Depression is a common and chronic neurological disorder characterized by recurrent depressive mood, including sleep and appetite disturbances, loss of interest and pleasure, negative rumination, fatigue and poor concentration, even the recurrent suicidal idea. It is estimated that by 2020 major depression will be the second most disabling condition in the world. Despite considerable stride has been made over the recent years in the development of treatments for depressive disorder, treatment resistant depression (TRD) remains a common condition which accounts for approximately 30% of the depressed population. Currently available therapeutic interventions for those patients including multiple trials of high-dose antidepressants, varying combinations of antidepressants, augmenting agents and psychotherapy, are less than ideal. A large body of evidence supports the acute efficacy of ECT in treatment-resistant depression. However memory loss and the need for repeated treatments to maintain efficacy preclude the use of ECT as a long-term treatment option. The illness not only affects quality of life but is also a major cause of suicide. Meanwhile, it contributes to increase mortality in the context of comorbid disorders including diabetes and cardiovascular disease. There is pressing need to identify novel pathophysiologic pathways to depression to reveal neurobiological targets for the development of new medications.Indeed, numerous studies have demonstrated the relationship between the inflammation and the development of treatment resistant depression. Major depressive patients with a history of nonresponsive to antidepressants have been found to demonstrate increased plasma concentration of IL-6, TNF-αand acute phase reactants when compared with treatment responsive patients Similarly, patients with increased inflammatory cytokines before treatment have been reported to be less responsive to antidepressant treatment. However, there are still negative data on the link between inflammation and depression.In this paper, we aimed to further investigate the role of inflammation in the pathophysiology of treatment resistant depression. In our study, the depressive rats were induced by chronic unpredictable mild stress (CUMS) and administered with fluoxetine. For observing the effects of inflammation on the treatment resistant depression, we performed the sequential three parts of the experiments by using behavioral testing and multiple neurobiological techniques. Thus, we hope to shed light on more detailed understanding of potential mechanisms in treatment resistant depression and provide a newly target of depression treatment. In addition, the modified CUMS regimen pretreatment with LPS may be served as a useful model for a type of treatment resistant depression.1. The Expression of Inflammatory Cytokines in the Peripheral Blood and Hippocampus of Fluoxetine Treatment Resistant Depressive RatsClinical studies have reported that major depressive patients with a history of nonresponsive to antidepressants have been found to demonstrate increased plasma concentration of IL-6, TNF-αand acute phase reactants when compared with treatment responsive patients. So, whether we can investigate this phenomenon in experimental depressive rats?In this study, rats were subjected to chronic unpredictable mild stress (CUMS) and administered with fluoxetine. The CUMS regimen and fluoxetine treatment were assessed by behavioral testing. And then, we examined the expressions of inflammatory cytokines by immunohistochemistry, western blot and ELISA in the peripheral blood and hippocampus of fluoxetine treatment resistant depressive rats.The results were as followings:(1) 4-week fluoxetine treatment reversed the behavioral changes in approximately 70-80% depressive rats.(2) 20-30% depressive rats were resistant to fluoxetine treatment, namely fluoxetine treatment resistant depressive rats.(3) The levels of IL-1βin the peripheral blood and the hippocampus of fluoxetine treatment resistant depressive rats were higher than those of control and fluoxetine treatment responsive rats.(4) In the hippocampus of fluoxetine treatment resistant depressive rats, a significant upregulation of COX-2 level and PGE2 concentration was observed than that of fluoxetine responsive rats.These results suggest that we can choose the fluoxetine treatment resistant depressive rats by CUMS despite of poor rate. The higher expression of inflammatory cytokines exists in the peripheral blood and hippocampus of fluoxetine treatment resistant depressive rats, which may play a role in the pathophysiology of treatment resistance.2. Acetylsalicylic acid as an Augmentation Agent in Fluoxetine Treatment Resistant Depressive RatsThe results from the first part of this study indicated that the inflammation may affect the antidepressant action of fluoxtine in CUMS induced depressive rats. Therefore, we investigated whether further investigate whether aspirin can be used as an augmentation agent in fluoxetine treatment resistant depressive rats induced by CUMS.The results were as followings:(1) In these rats, adjunctive aspirin treatment significantly improved the depressive behaviors including the sucrose preference and immobility time in the forced swimming test.(2) Adjunctive aspirin treatment can downregulate the expression of COX-2 and PGE2 in the hippocampus of fluoxetine treatment resistant depressive rats.These results indicate that aspirin can be served as an effective adjunctive agent in the treatment resistant depression which may be mediated by inhibiting the expression of COX-2 and PGE2 in the hippocampus. In addition, these results also further verify the role of inflammation in the pathophysiology of treatment resistance. 3. LPS Reverses the Effects of Fluoxetine on Depression-like BehaviorThe results from the former parts of this study indicated that the inflammation play a role in the pathophysiology of treatment resistance. Clinical depressive patients with increased inflammatory cytokines before treatment have been reported to be less responsive to antidepressant treatment. In this part of study, we employed LPS to mimic inflammatory reaction and investigated whether pretreatment with inflammation can affect the antidepressant action of fluoxetine in reversal the depressive behavior and downregulation of hippocampal nueorgenesis in CUMS induced depressive rats.The results were as followings:(1) LPS(0.1mg/kg)increased the levels of IL-1βin the peripheral blood and hippocampus of rats. No significant behavioral changes can be found in this dose of LPS administration.(2) LPS did not affect the effect of fluoxetine on the immobility time in the forced swimming test.(3) Chronic LPS administration before the stressor daily can inhibit the effects of fluoxetine on depression-like behavior induced by chronic unpredictable mild stress.(4) The behavioral changes induced by CUMS pretreatment with LPS can be reversed by adjunctive aspirin therapy conjunction with fluoxetine in depressive rats. These resultd indicated that"LPS+CUMS"may be served as a modified treatment resistant depressive model.4. The possible mechanismFluoxetine can stimulate proliferation of progenitor cells in the dentate gyrus of the adult hippocampus. There are suggestions that this action may underlie the therapeutic effects of such drugs in depression. The results from the former parts of this study indicated that chronic but not acute inflammation reaction can affect the antidepressant effects of fluoxetine. Based on the above demonstrations, we hypothized wether inflammation influenced the antidepressant action of fluoxetine by inhibiting the hippocampal neurogenesis.The results were as followings:(1) Stress exposure decreased the number of BrdU+ cells in the DG(2) Fluoxetine can increased the number of BrdU+ cells in FLX(+) rats(3) The number of BrdU+ cells in the DG is much less than that of control and FLX(+) rats(4) Chronic LPS injection did not decrease the newborn cells in the dentate gyrus of CUMS-induced depressive rats but significantly inhibited the effects of fluoxetine on the hippocampal neurogenesis.(5) No difference can be found in the number of BrdU/NeuN(+) cells among groupsThese results indicated that inflammation may influence the antidepressant action of fluoxetine by inhibiting the hippocampal neurogenesis.In this study, we found that CUMS can recapitulate the depressive changes in a rat model, and CUMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by 4-week fluoxetine treatment. Pretreatment with LPS, to mimic inflammation, had no significant effect on CUMS-induced depressive behavior but attenuated the antidepressant action of fluoxetine significantly. These results may point to a new understanding of why some patients fail to respond to SSRIs and suggest that concurrent manipulation of the inflammation might improve the efficacy of SSRIs in some treatment resistant patients. In addition, the modified CUMS regimen may be served as a useful model for some kind of treatment resistant depression.