Jean Naudin

A differential role for interleukin-6 and tumor necrosis factor-α in schizophrenia?

Pro-inflammatory cytokines are dysregulated in schizophrenia. To determine the nature of the so-called inflammatory syndrome in schizophrenia, we investigated the circulating levels of various cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)α), their natural antagonists (IL1-ra, TNF-RI, TNF-RII) and leukocyte activation markers (the soluble receptor of interleukin-2, soluble CD14 and soluble CD23) in subjects with chronic schizophrenia (n=18) and in normal controls (n=21). The levels of IL-1β and its antagonist and the levels of leukocyte activation markers were not significantly differents between patients and controls. Circulating levels of TNFα were significantly (p<0.05) higher in patients than in controls and did not result from variations of its antagonist levels. The significant (p<0.05) increase in patient IL-6 was related specifically to clinical status, i.e. illness duration. These data suggest a specific cytokine-mediated syndrome in schizophrenia. We hypothesize that TNFα and IL-6 reflect the genetic background of disease suceptibility.

Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.

To date, it remains impossible to guarantee that short-term treatment given to a patient suffering from a major depressive episode (MDE) will improve long-term efficacy. Objective biological measurements and biomarkers that could help in predicting the clinical evolution of MDE are still warranted. To better understand the reason nearly half of MDE patients respond poorly to current antidepressive treatments, we examined the gene expression profile of peripheral blood samples collected from 16 severe MDE patients and 13 matched controls. Using a naturalistic and longitudinal design, we ascertained mRNA and microRNA (miRNA) expression at baseline, 2 and 8 weeks later. On a genome-wide scale, we detected transcripts with roles in various biological processes as significantly dysregulated between MDE patients and controls, notably those involved in nucleotide binding and chromatin assembly. We also established putative interactions between dysregulated mRNAs and miRNAs that may contribute to MDE physiopathology. We selected a set of mRNA candidates for quantitative reverse transcriptase PCR (RT-qPCR) to validate that the transcriptional signatures observed in responders is different from nonresponders. Furthermore, we identified a combination of four mRNAs (PPT1, TNF, IL1B and HIST1H1E) that could be predictive of treatment response. Altogether, these results highlight the importance of studies investigating the tight relationship between peripheral transcriptional changes and the dynamic clinical progression of MDE patients to provide biomarkers of MDE evolution and prognosis.

Elevated circulating levels of IL-6 in schizophrenia

Schizophrenia may result from immune or inflammatory disorders, which are mediated by cytokines. Data in this field are heterogeneous and often contradictory. We investigated circulating levels of IL-6 and TNF-alpha, two distinct proinflammatory cytokines. Using immunoassay, we assessed IL-6 and TNF-alpha in serum from chronic schizophrenic patients (n = 30) and normal controls (n = 15). Circulating levels of IL-6 were higher in patients than in controls; those of TNF-alpha were not significantly higher than in controls. In addition, IL-6 levels were higher in patients with acute exacerbation of schizophrenia than in patients with remissions. Our results suggest that immunologic abnormalities in schizophrenia may be related to a specific inflammatory process mediated by IL-6. An interesting line of research would be the evaluation of IL-6 cerebral production in CSF.

Clinical variations modulate patterns of gene expression and define blood biomarkers in major depression

The aim of the study is to compare the expression level of candidate genes between patients suffering from a severe major depressive episode (MDE) and controls, and also among patients during MDE evolution. After a comprehensive review of the biological data related to mood disorders, we initiated a hypothesis-driven exploration of candidate mRNAs. Using RT-qPCR, we analyzed peripheral blood mononuclear cells (PBMCs) mRNA obtained from a homogeneous population of 11 patients who suffered from severe melancholic MDE. To assess the evolution of MDE, we analyzed PBMC mRNAs that were collected on Day 1 and 8 weeks later. Data from these patient samples were analyzed in comparison to age- and sex-matched healthy controls. Among 40 candidate genes consistently transcribed in PBMCs, 10 were differentially expressed in at least one comparison. We found that variations of mRNA levels for NRG1, SORT1 and TPH1 were interesting state-dependent biological markers of the disease. We also observed that variations in other mRNA expression were associated with treatment efficacy or clinical improvement (CREB1, HDAC5, HSPA2, HTR1B, HTR2A, and SLC6A4/5HTT). Significantly, 5HTT exhibited a strong correlation with clinical score evolution. We also found a state-independent marker, IL10. Moreover, the analysis of 2 separate MDEs concerning a same patient revealed comparable results for the expression of CREB1, HSPA2, HTR1B, NRG1 and TPH1. Overall, our results indicate that PBMCs obtained at different time points during MDE progression represent a promising avenue to discover biological markers for depression.

Forging the links between phenomenology, cognitive neuroscience, and psychopathology: the emergence of a new discipline

Debates in the philosophy of mind and cognitive sciences in the anglo-american tradition of analytic philosophy have been venturing into new topics: consciousness, the self, common sense theories of mind (intersubjectivity) and the timing of distributed processes in the brain as they may be correlated with a subjective sense of time. There have been appeals to phenomenology from various directions. In addition, there has been a sudden burst of monographs, edited books and articles which actually apply philosophical phenomenology and continental philosophy to cognitive neuroscience. A new triangulating discipline linking phenomenology, cognitive neuroscience and psychopathology is tentatively emerging. In this article, we examine how phenomenological approaches to subjective experience (i.e. first person data) are becoming increasingly important to cognitive neuroscience and its application to psychopathology. Phenomenological studies of disturbances in different mental disorders to body-schema, intentionality (i.e. self-world relationship), time-consciousness and intersubjectivity are found to have particularly promising applications to the research of their neurobiological correlates. A relationship between these disciplines which does not restrict itself to mutual constraint but allows for mutual enrichment is proposed. Curr Opin Psychiatry 11:567-573.

Schizophrenia and common sense: study of 3 single cases.

There is new interest in subjective experiences of schizophrenia. This kind of analysis emphasizes the subjective stories of patients, and the methods do not pretend to have the objectivity of science. However, the plausibility and the empathetic resonance of the single case may bring subjective confirmation to the validity of an insight and indicate new directions of research. Following this line, the authors present a study of 3 single cases of ‘reflexive’ residual type of schizophrenia. The methods for selecting the cases and the philosophical groundings of the concept of ‘reflexive schizophrenia’ are explained. The analysis of the single cases revealed that (1) schizophrenic persons’ cognitive deficit is related to the constitution of common sense; (2) some schizophrenics cope with the cognitive deficit by creating a theoretical corpus of axioms stemming from common sense, namely the ‘axioms of everyday life’; (3) this mechanism of coping is described as an inflexible attachment to ‘axioms of everydayness’, and (4) this attachment to common sense releases the patient from all personal investment of self in the process of anchoring in the living world and, on this basis, allows a relatively solid, although distant, attachment to reality. The nature of deficit in schizophrenia is also discussed by confronting the phenomenological point of view and the neuropsychological, that is the so-called ‘theory of mind’.

Natural speech comprehension in bipolar disorders: An event-related brain potential study among manic patients

BACKGROUND Thought and language disturbances are crucial clinical features in Bipolar Disorders (BD), and constitute a fundamental basis for social cognition. In BD, clinical manifestations such as disorganization and formal thought disorders may play a role in communication disturbances. However, only few studies have explored language disturbances in BD at a neurophysiological level. Two main Event-Related brain Potentials (ERPs) have been used in language comprehension research: the N400 component, elicited by incongruous word with the preceding semantic context, and the Late Positive Component (LPC), associated with non-specifically semantic and more general cognitive processes. Previous studies provided contradictory results regarding N400 in mood disorders, showing either preserved N400 in depression or dysthymia, or altered N400 in BD during semantic priming paradigm. The aim of our study was to explore N400 and LPC among patients with BD in natural speech conditions. METHODS ERPs from 19 bipolar type I patients with manic or hypomanic symptomatology and 19 healthy controls were recorded. Participants were asked to listen to congruous and incongruous complete sentences and to judge the match between the final word and the sentence context. Behavioral results and ERPs data were analyzed. RESULTS At the behavioral level, patients with BD show worst performances than healthy participants. At the electrophysiological level, our results show preserved N400 component in BD. LPC elicited under natural speech conditions shows preserved amplitude but delayed latency in difference waves. LIMITATIONS Small size of samples, absence of schizophrenic group and medication status. CONCLUSIONS In contrast with the only previous N400 study in BD that uses written semantic priming, our results show a preserved N400 component in ecological and natural speech conditions among patients with BD. Possible implications in terms of clinical specificity are discussed.

How to: Measuring blood cytokines in biological psychiatry using commercially available multiplex immunoassays

Cytokines produced by both immune and non-immune cells are likely to play roles in the development and/or progression of psychiatric disorders. Indeed, many investigators have compared the blood cytokine levels in psychiatric patients with those of healthy controls or monitored their levels in patients during disease progression to identify biomarkers. Nevertheless, very few studies have confirmed that such cytokines remain stable in healthy individuals through periods of weeks and months. This is an important issue to consider before using blood cytokine levels as biomarkers of disease traits, disease state, or treatment response. Although multiplex assay technology represents an advance in identifying biomarkers because it allows simultaneous examination of large panels of analytes from a small volume of sample, it is necessary to verify whether these assays yield enough sensitivity and reproducibility when applied to the blood from neuropsychiatric patients. Therefore, we compared two multiplex immunoassays, the bead-based Luminex® (Bio-Rad) and the electro-chemiluminescence-based V-plex® (MesoScaleDiscovery), for the detection and quantification of 31 cytokines, chemokines and growth factors in both the sera and plasma of patients with major depressive episodes (MDE) and age- and sex-matched healthy control subjects during a 30-week period. Although both platforms exhibited low coefficients of variability (CV) between the duplicates in the calibration curves, the linearity was better in general for the V-PLEX® platform. However, neither platform was able to detect the absolute values for all of the tested analytes. Among the 16 analytes that were detected by both assays, the intra-assay reproducibility was in general better with the V-PLEX® platform. Although it is not a general rule that the results from sera and plasma will be correlated, consistent results were more frequent with the V-PLEX® platform. Furthermore, the V-PLEX® results were more consistent with the gold standard ELISA simplex assay for IL-6 in both sera and plasma. The intra-individual variability of the measurements, among the sera and plasma for the 4 samples harvested from each healthy individual, was low for Eotaxin, G-CSF, IL-4, IL-7, IL-9, IL-12p40, IL-12p70, IL-15, MIP-1β, PDGF-BB, TNF, TNF-β and VEGF, but intermediate or high for IFN-γ, IL-6, IL-8, IL-10, and IP10. Together, these data suggest that extreme caution is needed in translating the results of multiplex cytokine profiling into biomarker discovery in psychiatry.

Longitudinal Monitoring of the Serotonin Transporter Gene Expression to Assess Major Depressive Episode Evolution

Background: Mood disorders are frequently characterized by uncertain prognosis and studying mRNA expression variations in blood cells represents a promising avenue of identifying biomarkers for mood disorders. State-dependent gene expression variations have been described during a major depressive episode (MDE), in particular for SLC6A4 mRNA, but how this transcript varies in relation to MDE evolution remains unclear. In this study, we prospectively assessed time trends of SCL6A4 mRNA expression in responder and nonresponder patients. Methods: We examined SLC6A4 mRNA expression in blood samples from 13 patients treated for severe MDE and their matched controls by reverse transcription and quantitative PCR. All subjects were followed for 30 weeks. Patients were classified as either responders or nonresponders based on improvement of depression according to the 17-item Hamilton Depression Rating Scale. Using a longitudinal design, we ascertained mRNA expression at baseline, 2, 8, and 30 weeks and compared mRNA expression between responder and nonresponder patients, and matched controls. Results: We observed a decrease of SLC6A4 mRNA expression in responder patients across a 30-week follow-up, while nonresponder patients exhibited up-regulated SLC6A4 mRNA. Conclusion: Peripheral SLC6A4 mRNA expression could serve as a biomarker for monitoring and follow-up during an MDE and may help to more appropriately select individualized treatments.

Serotonin transporter gene expression predicts the worsening of suicidal ideation and suicide attempts along a long-term follow-up of a Major Depressive Episode

The quest for biomarkers in suicidal behaviors has been elusive so far, despite their potential utility in clinical practice. One of the most robust biological findings in suicidal behaviors is the alteration of the serotonin transporter function in suicidal individuals. Our main objective was to investigate the predictive value of the serotonin transporter gene expression (SLC6A4) for suicidal ideation and as secondary, for suicide attempts in individuals with a major depressive episode (MDE). A 30-week prospective study was conducted on 148 patients with a MDE and 100 healthy controls including 4 evaluation times (0, 2, 8 and 30 weeks). Blood samples and clinical data were collected and SLC6A4 mRNA levels were measured from peripheral blood mononuclear cells using RT-qPCR. We first demonstrated the stability and reproducibility of SLC6A4 mRNA expression measures over time in healthy controls (F=0.658; p=0.579; η2=0.008; ICC=0.91, 95% CI [0.87-0.94]). Baseline SLC6A4 expression level (OR=0.563 [0.340-0.932], p=0.026) as well as early changes in SLC6A4 expression between baseline and the 2nd week (β=0.200, p=0.042) predicted the worsening of suicidal ideation (WSI) in the following 8 weeks. Moreover, changes in SLC6A4 expression between the 2nd and 8th weeks predicted the occurrence of a suicide attempt within 30 weeks (OR=10.976 [1.438-83.768], p=0.021). Altogether, the baseline level and the changes in SLC6A4 mRNA expression during a MDE might predict the WSI and the occurrence of suicidal attempts and could be a useful biomarker in clinical practice.