Antidepressants induce autophagy dependent-NLRP3-inflammasome inhibition in Major depressive disorder.

Major Depressive Disorder (MDD, ICD-10: F-33) is a prevalent illness in which the pathogenic mechanism remains elusive. Recently an important role has been attributed to neuro-inflammation, and specifically the NLRP3-inflammasome complex, in the pathogenesis of MDD. This suggests a key role for immunomodulation as a key pathway in the treatment of this disorder. This study evaluates the involvement of nine common antidepressants in the NLRP3-inflammasome complex (fluoxetine, paroxetine, mianserin, mirtazapine, venlafaxine, desvenlafaxine, amitriptyline, imipramine and agomelatine), both in in vitro THP-1 cells stimulated by ATP, and in a stress-induced depressive animal or MDD patients. Antidepressant treatment induced inflammasome inhibition was observed by decreased serum levels of IL-1ß and IL-18 and decrease of NLRP3 and IL-1ß (p17) protein expression. This was also observed under stress-induced depressive behaviour and inflammasome activation in C57Bl/6 mice in vivo. Deletion of key autophagy mediator Atg5 in embryonic fibroblasts (MEF cells) showed an autophagy dependent-NLRP3-inflammasome inhibition by antidepressant treatment. These results suggest the NLRP3-inflammasome could be a biomarker for antidepressant treatment response in MDD patients, and therefore the monitoring of NLRP3 expression levels and/or IL-1ß/IL-18 release may have clinical value in drug selection. Existing evidence suggests an anti-inflammatory effect of some antidepressants shown by IL-1ß, IL-6 and TNF-α. Our data have shown that antidepressant-mediated autophagy may have a role in restoration of certain metabolic and immunological pathways in MDD patients.

Stress-Induced Depressive Behaviors Require a Functional NLRP3 Inflammasome.

Depression is a major public health concern in modern society, yet little is known about the molecular link between this condition and neuroinflammation. The inflammasome complex was recently shown to be implicated in depression. The present study shows the implication of NLRP3 inflammasome in animal model of stress-induced depression. Accordingly, we show here that in the absence of a NLRP3 inflammasome, prolonged stress does not provoke depressive behaviors or microglial activation in mice or dampen hippocampal neurogenesis. Indeed, NLRP3 deletion or inhibition of microglial activation impairs the stress-induced alterations associated with depression. According to these findings in animal model, the inflammasome could be a target for new therapeutic interventions to prevent depression in patients.

NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) is a very prevalent disease which pathogenic mechanism remains elusive. There are some hypotheses and pilot studies suggesting that cytokines may play an important role in MDD. In this respect, we have investigated the role of NLRP3 inflammasome complex in the maturation of caspase-1 and the processing of its substrates, IL-1ß and IL-18, in blood cells from MDD patients. METHODS: Forty MDD patients were selected for this study, twenty without treatments and twenty treated with amitriptyline, a common tricyclic antidepressant. Blood samples from twenty healthy volunteers were included in the study. The inflammasome activation was studied by Western blot and real-time PCR of NLRP3 and caspase 1 and serum levels of IL-1ß and 18. RESULTS: We observed increased gene expression of NLRP3 and caspase-1 in blood cells, and increased serum levels of IL-1ß and IL-18 in non-treated patients. IL-1ß and IL-18 correlated with Beck Depression Inventory (BDI) scores of MDD patients. Interestingly, amitriptyline treatment reduced NLRP3 and caspase-1 gene expression, and IL-1ß and IL-18 serum levels. As it is well established that oxidative stress is associated with NLRP3 inflammasome activation, we next studied mitochondrial ROS and lipid peroxidation (LPO) levels in MDD patients. Increased levels of mitochondrial ROS and LPO were observed in MDD patients, however oxidative damage was higher in MDD patients treated with amitriptyline. CONCLUSIONS: These findings provide new insight into the pathogenesis of MDD and the effects of amitriptyline treatment on NLRP3 inflammasome activation and IL-1ß and IL-18 serum levels.

Oral treatment with amitriptyline induces coenzyme Q deficiency and oxidative stress in psychiatric patients.

Amitriptyline is a commonly prescribed tricyclic antidepressant, which has been shown to impair mitochondrial function and increase oxidative stress in a variety of in vitro assays. Coenzyme Q(10) (CoQ(10)), an essential component of the mitochondrial respiratory chain and a potent antioxidant, has been proposed as a mitochondrial dysfunction marker. In order to evaluate the putative mitochondrial toxicity of amitriptyline, we have analyzed CoQ(10) and ATP levels, oxidative damage and mitochondrial mass in peripheral blood cells from control healthy volunteers and psychiatric patients with depressive episodes treated or non-treated with amitriptyline. In patients not following amitriptyline treatment, CoQ(10) and ATP levels and mitochondrial mass were reduced when compared to normal individuals while lipid peroxidation was clearly increased. All these alterations were aggravated in patients following oral amitriptyline therapy. These results suggest that mitochondrial dysfunction could be involved in the pathophysiology of depression and may be worsened by amitriptyline treatment. CoQ(10) supplementation is postulated to counteract the adverse effects of amitriptyline treatment in psychiatric patients.

Clinical variables and implications of the personality on the outcome of bipolar illness: a pilot study.

Outcome in bipolar patients is affected by comorbidity. Comorbid personality disorders are frequent and may complicate the course of bipolar illness. This pilot study examined a series of 40 euthymic bipolar patients (DSM-IV criteria) (bipolar I disorder 31, bipolar II disorder 9) to assess the effect of clinical variables and the influence of comorbid personality on the clinical course of bipolar illness. Bipolar patients with a diagnosis of comorbid personality disorder (n = 30) were compared with "pure" bipolar patients (n = 10) with regard to demographic, clinical, and course of illness variables. Comorbid personality disorder was diagnosed in 75% of patients according to ICD-10 criteria, with obsessive-compulsive personality disorder being the most frequent type. Sixty-three per cent of subjects had more than one comorbid personality disorder. Bipolar patients with and without comorbid personality disorder showed no significant differences regarding features of the bipolar illness, although the group with comorbid personality disorder showed a younger age at onset, more depressive episodes, and longer duration of bipolar illness. In subjects with comorbid personality disorders, the number of hospitalizations correlated significantly with depressive episodes and there was an inverse correlation between age at the first episode and duration of bipolar illness. These findings, however, should be interpreted taking into account the preliminary nature of a pilot study and the contamination of the sample with too many bipolar II patients.