Low-grade inflammation as a predictor of antidepressant and anti- inflammatory therapy response in MDD patients: a systematic review of the literature in combination with an analysis of experimental data collected in the EU-MOODINFLAME consortium

Terapia antiinflamatoria; Terapia antidepresiva; InflamaciónAnti-inflammatory therapy; Antidepressant therapy; InflammationTeràpia antiinflamatòria; Teràpia antidepressiva; InflamacióLow-grade inflammation plays a role not only in the pathogenesis of major depressive disorder (MDD) but probably also in the poor responsiveness to regular antidepressants. There are also indications that anti-inflammatory agents improve the outcomes of antidepressants. Aim: To study whether the presence of low-grade inflammation predicts the outcome of antidepressants, anti-inflammatory agents, or combinations thereof. Methods: We carried out a systematic review of the literature on the prediction capability of the serum levels of inflammatory compounds and/or the inflammatory state of circulating leukocytes for the outcome of antidepressant/anti-inflammatory treatment in MDD. We compared outcomes of the review with original data (collected in two limited trials carried out in the EU project MOODINFLAME) on the prediction capability of the inflammatory state of monocytes (as measured by inflammatory gene expression) for the outcome of venlafaxine, imipramine, or sertraline treatment, the latter with and without celecoxib added. Results: Collectively, the literature and original data showed that: 1) raised serum levels of pro-inflammatory compounds (in particular of CRP/IL-6) characterize an inflammatory form of MDD with poor responsiveness to predominately serotonergic agents, but a better responsiveness to antidepressant regimens with a) (add-on) noradrenergic, dopaminergic, or glutamatergic action or b) (add-on) anti-inflammatory agents such as infliximab, minocycline, or eicosapentaenoic acid, showing—next to anti-inflammatory—dopaminergic or lipid corrective action; 2) these successful anti-inflammatory (add-on) agents, when used in patients with low serum levels of CRP/IL-6, decreased response rates in comparison to placebo. Add-on aspirin, in contrast, improved responsiveness in such “non-inflammatory” patients; 3) patients with increased inflammatory gene expression in circulating leukocytes had a poor responsiveness to serotonergic/noradrenergic agents. Conclusions: The presence of inflammation in patients with MDD heralds a poor outcome of first-line antidepressant therapies. Immediate step-ups to dopaminergic or glutamatergic regimens or to (add-on) anti-inflammatory agents are most likely indicated. However, at present, insufficient data exist to design protocols with reliable inflammation parameter cutoff points to guide such therapies, the more since detrimental outcomes are possible of anti-inflammatory agents in “non-inflamed” patients.This study was financially supported by the EU via the MOODINFLAME project (EU-FP7-HEALTH-F2-2008-222963), the PSYCHAID (EU-FP7-PEOPLE-2009-IAPP-MarieCurie-286334), and the MOODSTRATIFICATION project (H2020-EU. 3.1.1., GA754740). NM and GA were additionally supported by the foundation "Immunitat und Seele." The funders had no role in study design, data collection, analysis and interpretation of data, the writing of the report, and the decision to submit the paper for publication

Efficacy of Sertraline Plus Placebo or Add-On Celecoxib in Major Depressive Disorder: Macrophage Migration Inhibitory Factor as a Promising Biomarker for Remission After Sertraline-Results From a Randomized Controlled Clinical Trial

Trastorno depresivo mayor; Tratamiento antiinflamatorio; CitocinaTrastorn depressiu major; Tractament antiinflamatori; CitocinaMajor depressive disorder; Anti-inflammatory treatment; CytokineIntroduction: Previous research delivers strong indications that inflammatory activation leads to treatment resistance in a subgroup of patients with Major Depressive Disorder (MDD). Thus, tailored interventions are needed. The present study aimed to find potential biomarkers that may enable patients to be stratified according to immune activation. Methods: A phase IIa randomized placebo-controlled trial was performed to assess levels of inflammatory compounds in responders/remitters and non-responders/non-remitters to sertraline plus celecoxib (n = 20) and sertraline plus placebo (n = 23). Levels of macrophage migration inhibitory factor, neopterin, and tumor necrosis factor alpha were determined by enzyme-linked immunosorbent assay; response and remission were measured by reduction of the Montgomery Åsberg Depression Rating Scale score. Results: Both treatment groups showed a significant decline in depression symptoms, but no difference was found between groups. A clear pattern emerged only for macrophage migration inhibitory factor: placebo remitters showed significantly lower baseline levels than non-remitters (a similar trend was seen in responders and non-responders) while celecoxib responders showed a trend for higher baseline levels than non-responders. Conclusion: Small subsample sizes are a notable limitation, wherefore results are preliminary. However, the present study provides novel insights by suggesting macrophage migration inhibitory factor as a promising biomarker for treatment choice.This present work was funded by the EU 7th Framework program (grant number EU-FP7-CP-IP-2008-222963/EU-FP7-PEOPLE-2009-IAPP-MarieCurie-286334) and Horizon 2020 (grant number H2020-SC1-2016-2017/H2020-SC1-2017-Two-Stage-RTD). Further, part of this work was supported by the foundation Immunität und Seele. The funders had no role in the study design, data collection and analysis, or decision to publish

Transcranial Direct Current Stimulation (tDCS) for Depression during Pregnancy: Scientific Evidence and What Is Being Said in the Media - A Systematic Review

Major depression is the most frequent morbidity in pregnancy. The first-line therapies, psychopharmacologic treatment and psychotherapy, are either insufficient or may cause severe or teratogenic adverse events. As a result of its local limitation to the patient's brain, transcranial direct current stimulation (tDCS) could potentially be an ideal treatment for pregnant women with depression. A literature search was conducted in medical databases, globally published newspapers, search engines, and clinical trial registers to collect all articles on tDCS for the treatment of depression during pregnancy. The aim of this review was to investigate the scientific evidence of tDCS use for depression during pregnancy and to compare these results with the textual and emotional perception in the media as interventions during pregnancy are under particular surveillance. We detected 13 medical articles dealing with tDCS for depression in pregnancy. Overall, the scientific evidence as well as articles in the media for tDCS in pregnancy are sparse, but promising. Further studies are required in this specifically vulnerable population of pregnant women to generate evidence. It is likely that public interest will increase when the results of a pilot study in Canada are published

<i>Mycoplasma pneumoniae</i> IgG positivity is associated with tic severity in chronic tic disorders

Infectious pathogens may represent an environmental risk factor for chronic tic disorders (CTD). This cross-sectional study aimed to determine whether Mycoplasma pneumoniae (M. pneumoniae) IgG positivity is associated with the presence or severity of tics. We compared M. pneumoniae IgG positivity across three groups: children and adolescents (3-16 years) with CTD (CTD group; n=302); siblings (3-10 years) of people with CTD who developed tics within a seven-year follow-up period (tic onset group; n=51); siblings (4-10 years) who did not develop tics within the study period and were ≥ 10-years-old at their last assessment (unaffected group; n=88). The relationship between M. pneumoniae IgG positivity and the presence and severity of tics was analysed using multilevel models controlling for site, family relatedness, sex, age, presence of comorbid obsessive-compulsive and/or attention-deficit/hyperactivity disorder and use of psychotropic medication. M. pneumoniae IgG positivity was not associated with the presence of CTD, or the first onset of tics as compared to siblings who remained unaffected. M. pneumoniae IgG positivity was associated with a higher tic severity score within the CTD group (β=2.64, s.e.=1.15, p=0.02). It is possible that M. pneumoniae infection influences tic severity in CTD or, that having more severe tics, increases the risk of infection. However, it is more likely that the association observed in this study reflects a propensity toward enhanced immune responses in people with CTD and that, rather than a causal relationship, infection and greater tic severity are indirectly linked via shared underlying immune mechanisms

Cathodal tDCS Over Motor Cortex Does Not Improve Tourette Syndrome: Lessons Learned From a Case Series

Introduction: Current pathophysiological hypotheses of Gilles de la Tourette Syndrome (GTS) refer to temporally abnormal neuronal activation in cortico-striato-thalamo-cortical (CSTC) networks. Modifying cortical activity by non-invasive brain-stimulation appears to be a new treatment option in GTS. Background: Previous studies suggested therapeutic effects of cathodal transcranial direct current stimulation (tDCS) to pre-supplementary motor areas (SMA), however, treatment modalities concerning electrode placement, current intensity and stimulation-rate have not been systematically explored. Aim of this study was to assess efficacy of an alternative stimulation regime on GTS symptoms in a pilot study. To test a treatment protocol with tDCS twice a day, we administered 10 sessions over 5 days of bilateral cathodal tDCS (30 min, 2 mA) over the pre-SMA in three patients with severe GTS. Tic severity as well as obsessive-compulsive (OC) symptoms and affective scales were rated before and after tDCS treatment. Discussion: Only one out of three patients showed a 34.5% reduction in tic severity. The two other patients showed an increase in tic severity. All patients showed a mild increase in positive affect and a reduction in negative affect, OC symptom changes were heterogeneous. Our results do not support earlier findings of extensive therapeutic effects of cathodal tDCS on tics in patients with GTS and show that prediction of stimulation effects on a targeted brain area remains inaccurate. Concluding Remarks: Future research will have to focus on the determination of most effective stimulation modes regarding site, polarity and frequency of tDCS in GTS patients

Low-grade inflammation as a predictor of antidepressant and anti-inflammatory therapy response in MDD patients: A systematic review of the literature in combination with an analysis of experimental data collected in the EU-Moodinflame consortium

Low-grade inflammation plays a role not only in the pathogenesis of major depressive disorder (MDD) but probably also in the poor responsiveness to regular antidepressants. There are also indications that anti-inflammatory agents improve the outcomes of antidepressants. Aim: To study whether the presence of low-grade inflammation predicts the outcome of antidepressants, anti-inflammatory agents, or combinations thereof. Methods: We carried out a systematic review of the literature on the prediction capability of the serum levels of inflammatory compounds and/or the inflammatory state of circulating leukocytes for the outcome of antidepressant/anti-inflammatory treatment in MDD. We compared outcomes of the review with original data (collected in two limited trials carried out in the EU project MOODINFLAME) on the prediction capability of the inflammatory state of monocytes (as measured by inflammatory gene expression) for the outcome of venlafaxine, imipramine, or sertraline treatment, the latter with and without celecoxib added. Results: Collectively, the literature and original data showed that: 1) raised serum levels of pro-inflammatory compounds (in particular of CRP/IL-6) characterize an inflammatory form of MDD with poor responsiveness to predominately serotonergic agents, but a better responsiveness to antidepressant regimens with a) (add-on) noradrenergic, dopaminergic, or glutamatergic action or b) (add-on) anti-inflammatory agents such as infliximab, minocycline, o

Activation and deactivation steps in the tryptophan breakdown pathway in major depressive disorder: A link to the monocyte inflammatory state of patients

It is unclear how the tryptophan (TRP) breakdown pathway relates to the activated inflammatory state of patients with major depressive disorder (MDD). We determined in two different cohorts of patients with MDD (n = 281) and healthy controls (HCs) (n = 206) collected for the EU-MOODINFLAME project: a.) the monocyte expression levels of 5 key pro-inflammatory cytokine/chemokine genes (ICCGs), 5 type I interferon stimulated genes (ISGs), and 4 kynurenine pathway (KP) enzyme genes (i.e. IDO-1, KMO, CCBL1/KAT II and CCBL2/KAT III) by standard q-PCR, b.) serum levels of TRP, 5-HTrp, 5-HIAA, KYN, KYNA, 3-HK, XA, PIC, and QUIN by LC-MS/MS and/or HPLC, and calculated various TRP/KP metabolism ratios. We then correlated outcomes to each other, and to the clinical characteristics of patients. Both cohorts of patients differed clinically; patients of the Munich cohort (n = 50) were less overweight, less medicated, were less in the current episode and showed a higher HAM-D 17 score as compared with patients of the Muenster cohort (n = 231). An increased expression of ICCGs was found in the circulating monocytes of patients of both cohorts; this was in particular evident in the Munich cohort. In contrast, ISGs monocyte expression levels tended to be reduced (both cohorts). TRP serum levels were linked to the pro-inflammatory (ICCGs) monocyte state of patients; a decrease in TRP serum levels was found in the Munich cohort; TRP levels correlated negatively to patient's HAM-D 17 score. Contrary to what expected, KYN serum levels were not increased in patients (both cohorts); and an increased KYN/TRP ratio was only found in the Munich patients (who showed the lowest TRP serum levels). IDO-1 monocyte expression levels were decreased in patients (both cohorts) and negatively associated to their pro-inflammatory (ICCGs) monocyte state. Thus, a depletion of TRP via an ICCGs-inflammatory IDO activation is not likely in MDD. Downstream from KYN, and regarding compounds influencing glutamate receptors (GR), reduced serum levels of KYNA (NMDA-R antagonist), 3-HK (NMDA-R agonist), and XA (mGlu2/3 agonist) were found in patients of both cohorts; PIC serum levels (NMDA-R antagonist) were increased in patients of both cohorts. Reduced QUIN serum levels (NMDA-R agonist) were found in patients of the Muenster cohort,only. 3-HK levels correlated to the monocyte inflammatory ICCG state of patients. The ultimate effect on brain glutamate receptor triggering of this altered equilibrium between peripheral agonists and antagonists remains to be elucidated

Tic disorders in children and adolescents: does the clinical presentation differ in males and females? A report by the EMTICS group

Tic disorders have a strong male predominance, with a male-to-female ratio of 4:1 in Tourette syndrome (TS) and 2:1 in persistent tic disorders. In other neurodevelopmental conditions, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), the disparity in sex distribution has been partially related to differences in symptom presentation between males and females. In tic disorders, however, little research has been conducted on this topic, probably due to the limited access to large samples with a significant proportion of females. The aim of this study was to describe sex differences in the clinical presentation of tic disorders in children and adolescents in one of the largest pediatric samples with TS/persistent tic disorders (n = 709, 23.3% females) recruited as part of the European Multicenter Tics in Children Study (EMTICS). Validated measures assessed the severity of tics and comorbid psychiatric symptoms. Using mixed-effect models, we found that sex had a significant influence on the severity of tics, ADHD symptoms, ASD symptoms, and emotional problems. Males had more severe symptoms than females, except for emotional problems. We also observed a statistically significant interaction between sex and age on the severity of tics and compulsions, with females showing higher symptom severity with increasing age than males. These findings indicate that the clinical presentation of TS/persistent tic disorders varies with sex. Males seem to exhibit a more noticeable pattern of clinical symptoms at a younger age that may contribute to their earlier detection in comparison to females