Immune system dysfunction and its link to the monoaminergic theory of Major Depressive Disorder: Implications and therapeutic approaches

Major Depressive Disorder (MDD) is a complex and heterogeneous disease, with a so far poorly characterized underlying pathophysiology. This defaults diagnosis and therapy stratification of patients. Consequently, response rates to currently available treatments are far from being optimal, with up to 30% of patients not responding to conventional antidepressant agents. During past decades, increasing evidence has suggested that biological changes may underlie MDD. One of the established biological changes may arise from an abnormal inflammatory response system (IRS) that interacts with important neurotransmission systems (e.g., monoaminergic,glutamatergic). However, the extent and direction of these changes still remain unclear. During the MOODINFLAME project, a European-funded cooperation project aimed to identify biomarkers of mood disorders, data about the immune cell profile, the serum inflammatory state, and the serum levels of tryptophan (TRP) and kynurenine pathway (KP) metabolites were collected in both individuals with depression and healthy controls (HC). Part one of this doctoral thesis was to analyze these data, and to study how is the inflammatory state of individuals with depression related to TRP and KP abnormalities, and to their clinical characteristics. In a second project, we explored whether the existence of a pro-inflammatory monocyte and/or serum state could be used for prediction of antidepressant response, and/or to prediction of (add-on) treatment with anti-inflammatory agents. This included conducting a systematic review on inflammatory predictors of treatment response in patients with MDD and a clinical study, where the expression levels of key pro-inflammatory genes were determined in the circulating monocytes of individuals with depression, and related to response to treatment (as measured by the % of improvement in the HAM-D 17 score). Taken together, we found that individuals with depression that lack from other comorbid medical conditions show, in general, an increased expression of pro-inflammatory cytokine/chemokine genes in their circulating monocytes, but no serological markers of im-mune activation. These individuals are also characterized by decreased levels of TRP, and by a deactivation of the KP, and would benefit from treatment with primarily serotonergic antidepressants. On the contrary, individuals with depression that suffer from other comorbid medical conditions may be characterized by increased monocyte expression levels of pro-inflammatory genes, and by increased peripheral levels of pro-inflammatory compounds. In addition, they may exhibit, along with a decrease in the levels of TRP, an activation of the KP. These individuals would benefit from antidepressants and/or (add-on) therapy with anti-inflammatory/immunoregulatory agents with a strong action on other neurotransmitter systems, such as the glutamatergic system.Als Depressive Störung (oder Depression) bezeichnet man eine komplexe und heterogene Erkrankung mit einer bisher schlecht charakterisierten zugrundeliegenden Pathogenese. Letzteres erschwert Diagnose und Behandlung. Als Folge sind die Ansprechraten auf die derzeit verfügbaren Therapien bei weitem nicht optimal, da bis zu 30% der Patienten auf herkömmliche Antidepressiva nicht ansprechen. Während der MOODINFLAME-Studie, einem europäisch finanzierten Kooperationsprojekt das darauf abzielt, Biomarker affektiver Störungen zu identifizieren, wurden nicht nur Daten zum Immunzellprofil, sondern auch zu Blutspiegeln verschiedener Entzündungsparameter und von Tryptophan- (TRP) und Kynurenin-Pfad (KP) Metaboliten bei Patienten mit Depression und gesunden Kontrollen bestimmt. Teil eins dieser Arbeit bestand daraus, diese Daten zu analysieren und zu untersuchen, inwieweit Entzündungsparameter mit TRP und KP-Auffälligkeiten, und mit unterschiedlichen klinischen Merkmalen, korreliert. In einem zweiten Projekt wurde untersucht, ob diese Parameter bei Patienten zur Vorhersage der antidepressiven therapeutischen Wirkung verwendet werden können. Zu diesem Zweck wurde vor der Behandlung mit verschiedenen serotonergen Antidepressiva, oder mit dem Entzündungshemmer Celecoxib, die Expression wichtiger Entzündungs-Genen in Monozyten von Patienten bestimmt, und mit dem Ansprechen auf die Behandlung korreliert. Darüber hinaus wurde der aktuelle Stand der Literatur zusammengefasst. Wir konnten feststellen, dass Patienten mit einer Depressiven Störung nicht nur verringerte TRP-Spiegel in Serum zeigen, sondern auch, in etwa 30-40% der Fälle, eine erhöhte Ex-pression von pro-inflammatorischen Zytokin/Chemokin-Genen in ihren zirkulierenden Monozyten aufweisen. In Abwesenheit komorbider Erkrankungen zeigten sich keine Auffälligkeiten bei den serologischen Markern der Immunaktivierung. Diese Patienten weisen wei-terhin eine Deaktivierung des KP auf. Im Gegensatz dazu sind Patienten mit Depression, die an weiteren komorbiden Erkrankungen leiden, durch erhöhte Serum-Spiegel von Entzündungsparametern gekennzeichnet. Ausserdem zeigen sie neben der Abnahme der TRP-Spiegel, eine Aktivierung des KP. Dementsprechend fanden wir, dass sowohl die erhöhte monozytäre Expression von Entzündungs-Genen, als auch erhöhte Blutspiegel von Entzündungsparametern und verschiedener KP Metaboliten, das Nichtansprechen auf primär serotonerge Antidepressiva vorhersagen. Diese Patienten würden von Antidepressiva oder (Zusatz)-Therapie mit anti-entzündlichen/immunregulatorischen Wirk-stoffen, die auch Effekte mit starker Wirkung auf andere Neurotransmittersysteme wie das glutamaterge System haben, profitieren

Immunoregulatory and/or Anti-inflammatory Agents for the Management of Core and Associated Symptoms in Individuals with Autism Spectrum Disorder: A Narrative Review of Randomized, Placebo-Controlled Trials

Immunoregulatory agents; Autism spectrum disorderAgents immunoreguladors; Trastorn de l'espectre autistaAgentes inmunorreguladores; Trastorno del espectro autistaAutism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a so far poorly understood underlying pathogenesis, and few effective therapies for core symptoms. Accumulating evidence supports an association between ASD and immune/inflammatory processes, arising as a possible pathway for new drug intervention. However, current literature on the efficacy of immunoregulatory/anti-inflammatory interventions on ASD symptoms is still limited. The aim of this narrative review was to summarize and discuss the latest evidence on the use of immunoregulatory and/or anti-inflammatory agents for the management of this condition. During the last 10 years, several randomized, placebo-controlled trials on the effectiveness of (add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, N-acetylcysteine (NAC), sulforaphane (SFN), and/or omega-3 fatty acids have been performed. Overall, a beneficial effect of prednisolone, pregnenolone, celecoxib, and/or omega-3 fatty acids on several core symptoms, such as stereotyped behavior, was found. (Add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, NAC, SFN, and/or omega-3 fatty acids was also associated with a significantly higher improvement in other symptoms, such as irritability, hyperactivity, and/or lethargy when compared with placebo. The mechanisms by which these agents exert their action and improve symptoms of ASD are not fully understood. Interestingly, studies have suggested that all these agents may suppress microglial/monocyte proinflammatory activation and also restore several immune cell imbalances (e.g., T regulatory/T helper-17 cell imbalances), decreasing the levels of proinflammatory cytokines, such as interleukin (IL)-6 and/or IL-17A, both in the blood and in the brain of individuals with ASD. Although encouraging, the performance of larger randomized placebo-controlled trials, including more homogeneous populations, dosages, and longer periods of follow-up, are urgently needed in order to confirm the findings and to provide stronger evidence

Cariprazine Use in Combination With a Mood Stabilizer in First Episode Mania

Acute mania; Cariprazine; Precision medicineManía aguda; Cariprazina; Medicina de precisiónMania aguda; Cariprazina; Medicina de precisióBackground: Cariprazine's efficacy and safety have been previously tested in adult patients with acute mania associated with bipolar I disorder, but there is no available data in FEM. The objective of this study is to assess the efficacy and safety of cariprazine in combination with a mood stabilizer in treating FEM as well as to evaluate patients' adherence to the treatment. Methods: FEM patients were recruited from the acute inpatient unit at Lleida University Hospital Santa Maria, between January and June 2021. Their symptoms were evaluated using the Young Mania Rating Scale (YMRS) and the Clinical Global Impressions–Severity (CGI-S) scale at admission and at discharge. Akathisia was assessed using the Barnes Akathisia Rating Scale. Patient adherence to medication treatment was assessed 30 days after discharge using the Morisky, Green and Levine Medication Adherence Scale. Socio-demographic and clinical information were further collected. Results: Eleven patients with FEM were involved, seven women and four men. Their mean age was 26.00+/-6.37 years. Mean hospitalization was 17.36+/−4.7 days. Cariprazine was combined with a mood stabilizer: lithium in seven patients and divalproex in four. Mean YMRS change from baseline was −24.55+/−7.5 and the mean CGI-S change from baseline was −2.55+/−0.82. Regarding adverse events, two (18.2%) patients presented with akathisia. At the 30-day treatment-adherence assessment, six (54.5%) patients were adherent and four (36.4%) had moderate adherence. Conclusion: In this sample, cariprazine in combination with mood stabilizers proved to be safe and effective in the treatment of FEM with more than half the patients being adherent to treatment. Therefore, cariprazine add-on is a good choice for promoting the long-term adherence of patients, thus minimizing the risk of relapse and improving prognosis.Gedeon Richter provided funds for the open access publication fees

Immunoregulatory and/or Anti-inflammatory Agents for the Management of Core and Associated Symptoms in Individuals with Autism Spectrum Disorder : A Narrative Review of Randomized, Placebo-Controlled Trials

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a so far poorly understood underlying pathogenesis, and few effective therapies for core symptoms. Accumulating evidence supports an association between ASD and immune/inflammatory processes, arising as a possible pathway for new drug intervention. However, current literature on the efficacy of immunoregulatory/anti-inflammatory interventions on ASD symptoms is still limited. The aim of this narrative review was to summarize and discuss the latest evidence on the use of immunoregulatory and/or anti-inflammatory agents for the management of this condition. During the last 10 years, several randomized, placebo-controlled trials on the effectiveness of (add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, N -acetylcysteine (NAC), sulforaphane (SFN), and/or omega-3 fatty acids have been performed. Overall, a beneficial effect of prednisolone, pregnenolone, celecoxib, and/or omega-3 fatty acids on several core symptoms, such as stereotyped behavior, was found. (Add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, NAC, SFN, and/or omega-3 fatty acids was also associated with a significantly higher improvement in other symptoms, such as irritability, hyperactivity, and/or lethargy when compared with placebo. The mechanisms by which these agents exert their action and improve symptoms of ASD are not fully understood. Interestingly, studies have suggested that all these agents may suppress microglial/monocyte proinflammatory activation and also restore several immune cell imbalances (e.g., T regulatory/T helper-17 cell imbalances), decreasing the levels of proinflammatory cytokines, such as interleukin (IL)-6 and/or IL-17A, both in the blood and in the brain of individuals with ASD. Although encouraging, the performance of larger randomized placebo-controlled trials, including more homogeneous populations, dosages, and longer periods of follow-up, are urgently needed in order to confirm the findings and to provide stronger evidence

Premature T cell aging in major depression: A double hit by the state of disease and cytomegalovirus infection

Childhood trauma; Major depressive disorder; T cytotoxic cellTrauma infantil; Trastorn depressiu major; cèl·lula T citotòxicaTrauma infantil; Trastorno depresivo mayor; célula T citotóxicaIntroduction Previous research indicates that premature T cell senescence is a characteristic of major depressive disorder (MDD). However, known senescence inducing factors like cytomegalovirus (CMV) infection or, probably, childhood adversity (CA) have not been taken into consideration so far. Objective Differentiation and senescent characteristics of T cells of MDD patients were investigated in relation to healthy controls (HC), taking the CMV seropositivity and CA into account. Methods 127 MDD and 113 HC of the EU-MOODSTRATIFICATION cohort were analyzed. Fluorescence activated cell sorting (FACS) analysis was performed to determine B, NK, and T cell frequencies. In a second FACS analysis, naïve, effector memory (Tem), central memory (Tcm), effector memory cells re-expressing RA (TEMRA), as well as CD28+ and CD27+ memory populations, were determined of the CD4+ and CD8+ T cell populations in a subsample (N = 35 MDD and N = 36 HC). CMV-antibody state was measured by IgG ELISA and CA by the Childhood Trauma Questionnaire. Results We detected a CMV-antibody positivity in 40% of MDD patients (35% HC, n. s.) with seropositive MDD cases showing a higher total childhood trauma score. Second, a higher inflation of memory CD4+ T helper cells in CMV seronegative patients as compared to seronegative HC and reduced numbers of naïve CD4+ T helper cells in CMV seropositive patients (not in CMV seropositive HC) were found. Third, a higher inflation of memory CD8+ T cytotoxic cells in CMV seropositive cases as compared to CMV seropositive HC, particularly of the TEMRA cells, became apparent. Higher percentages of CD4+ TEMRA and late stage CD27−CD28− TEMRA cells were similar in both HC and MDD with CMV seropositivity. Overall, apportioning of T cell subpopulations did not differ between CA positive vs negative cases. Conclusions MDD patients show several signs of a CMV independent “MDD specific” premature T cell aging, such as a CMV independent increase in CD4+ T memory cells and a latent naïve CD4 T-cell reduction and a latent CD8+ T-cell increase. However, these two latent T cell senescence abnormalities only become evident with CMV infection (double hit).This work was supported by the European Commission: EU 7th Framework program (grant number EU-FP7-CP-IP-2008-222963) and Horizon 2020 (grant number H2020-SC1-2016-2017/H2020-SC1-2017-Two-Stage-RTD) grants were received by HAD, Erasmus Medical Center Rotterdam. The funding source had no role in the study design, the data collection, the analysis and interpretation of data, the manuscript writing, and in the decision to submit the article for publication

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

Improvement of functional neurological disorder after administration of esketamine nasal spray: a case report

Esketamina; Trastorn neurològic funcional; Paràlisi mixtaEsketamina; Trastorno neurológico funcional; Parálisis mixtaEsketamine; Functional neurological disorder; Mixed paralysisFunctional neurological disorder (FND) is a complex neuropsychiatric condition characterized by the presence of neurological symptoms and signs (either motor or sensory) that cannot be explained by any known medical or mental disease. It is frequently presented with psychiatric comorbidities, such as major depression. Its prognosis is poor, with low improvement or recovery rates at 1 year after their onset, and no particular treatment has demonstrated significant efficacy in this regard. Here, we describe the management of a patient affected by treatment-resistant depression (TRD) and FND characterized by mixed paralysis (sensory and motor) in the left arm, and who was successfully treated with esketamine nasal spray, achieving remission in both disorders. The US Food and Drug Administration and the European Medicines Agency recently approved esketamine, the S-enantiomer of ketamine, for treatment of TRD. It is a fast-acting drug that provides a rapid-onset improvement of depressive symptoms. We have presented the first case, to our knowledge, of functional neurological symptoms being successfully treated with esketamine in a patient with comorbid TRD. While the novelty of this data implies a clear need for further research, it is suggested that esketamine might be a useful tool for the treatment of FND, acting through different theorized mechanisms that are in tune with recent advances in knowledge of the etiopathology of FND.The authors received no financial support for the research, authorship, and/or publication of this article

Multifrequency microwave radiometry for characterizing the Internal temperature of biological tissues

The analysis of near-field radiometry is described for characterizing the internal temperature of biological tissues, for which a system based on multifrequency pseudo-correlation-type radiometers is proposed. The approach consists of a new topology with multiple output devices that enables real-time calibration and performance assessment, recalibrating the receiver through simultaneous measurable outputs. Experimental characterization of the prototypes includes a welldefined calibration procedure, which is described and demonstrated, as well as DC conversion from the microwave input power. Regarding performance, high sensitivity is provided in all the bands with noise temperatures around 100 K, reducing the impact of the receiver on the measurements and improving its sensitivity. Calibrated temperature retrievals exhibit outstanding results for several noise sources, for which temperature deviations are lower than 0.1% with regard to the expected temperature. Furthermore, a temperature recovery test for biological tissues, such as a human forearm, provides temperature values on the order of 310 K. In summary, the radiometers design, calibration method and temperature retrieval demonstrated significant results in all bands, validating their use for biomedical applications.This work was supported, in part, by the Council of Tenerife under IACTEC Technological Training Program, grant TF INNOVA 2016-2021, and, in part, by the Spanish Ministry of Science and Innovation, under grants ESP2015-70646-C2-2-R and PID2019-110610RB-C22

Activation of the Monocyte/Macrophage System and Abnormal Blood Levels of Lymphocyte Subpopulations in Individuals with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

Inflammation; Lymphocytes; MonocytesInflamació; Limfòcits; MonòcitsInflamación; Linfocitos; MonocitosAutism spectrum disorder (ASD) is a neurodevelopmental condition with a so far unknown etiology. Increasing evidence suggests that a state of systemic low-grade inflammation may be involved in the pathophysiology of this condition. However, studies investigating peripheral blood levels of immune cells, and/or of immune cell activation markers such as neopterin are lacking and have provided mixed findings. We performed a systematic review and meta-analysis of studies comparing total and differential white blood cell (WBC) counts, blood levels of lymphocyte subpopulations and of neopterin between individuals with ASD and typically developing (TD) controls (PROSPERO registration number: CRD CRD42019146472). Online searches covered publications from 1 January 1994 until 1 March 2022. Out of 1170 publication records identified, 25 studies were finally included. Random-effects meta-analyses were carried out, and sensitivity analyses were performed to control for potential moderators. Results: Individuals with ASD showed a significantly higher WBC count (k = 10, g = 0.29, p = 0.001, I2 = 34%), significantly higher levels of neutrophils (k = 6, g = 0.29, p = 0.005, I2 = 31%), monocytes (k = 11, g = 0.35, p < 0.001, I2 = 54%), NK cells (k = 7, g = 0.36, p = 0.037, I2 = 67%), Tc cells (k = 4, g = 0.73, p = 0.021, I2 = 82%), and a significantly lower Th/Tc cells ratio (k = 3, g = −0.42, p = 0.008, I2 = 0%), compared to TD controls. Subjects with ASD were also characterized by a significantly higher neutrophil-to-lymphocyte ratio (NLR) (k = 4, g = 0.69, p = 0.040, I2 = 90%), and significantly higher neopterin levels (k = 3, g = 1.16, p = 0.001, I2 = 97%) compared to TD controls. No significant differences were found with respect to the levels of lymphocytes, B cells, Th cells, Treg cells, and Th17 cells. Sensitivity analysis suggested that the findings for monocyte and neutrophil levels were robust, and independent of other factors, such as medication status, diagnostic criteria applied, and/or the difference in age or sex between subjects with ASD and TD controls. Taken together, our findings suggest the existence of a chronically (and systemically) activated inflammatory response system in, at least, a subgroup of individuals with ASD. This might have not only diagnostic, but also, therapeutic implications. However, larger longitudinal studies including more homogeneous samples and laboratory assessment methods and recording potential confounding factors such as body mass index, or the presence of comorbid psychiatric and/or medical conditions are urgently needed to confirm the findings