Integrative approach of biological and psychological factors associated to the prognosis of mood disorders

Les troubles de l’humeur sont des troubles psychiatriques fréquents et constituent un ensemble hétérogène caractérisés par un fardeau personnel, sanitaire et social considérable. Le pronostic de ces troubles est aggravé par un risque suicidaire accru, la présence de comorbidités psychiatriques et somatiques. Dans une démarche préventive, il parait essentiel d’identifier des facteurs biologiques ou psychologiques pouvant prédire l’aggravation du pronostic de ces troubles. Cette thèse porte sur des éléments majeurs du pronostic des deux principaux troubles de l’humeur à savoir, le trouble dépressif caractérisé et le trouble bipolaire. Dans un premier temps, nous avons tenté d’identifier un biomarqueur du risque suicidaire chez les patients dépressifs à partir d’une approche gène-candidat. Nous avons montré que l’expression génétique de l’ARN messager de SLC6A4 obtenu à partir du sang périphérique, permet de prédire l’aggravation des idées suicidaires au cours du suivi de patients souffrant d’un épisode dépressif majeur. Dans un second temps, nous avons exploré les facteurs cliniques et neuropsychologiques associés à une faible qualité de l’observance médicamenteuse chez les patients bipolaires euthymiques. Les résultats de notre étude suggèrent que les patients bipolaires auraient plus de risque de rencontrer des problèmes d’observance lorsqu’ils rapportent de nombreux effets indésirables liés aux traitements et un faible nombre d’hospitalisations antérieures. De plus, chez les patients bipolaires les plus âgés uniquement, la qualité de l’observance semble également associée aux capacités cognitives des patients et plus spécifiquement au fonctionnement exécutif.Mood disorders are frequent and heterogeneous psychiatric illnesses associated to a huge functional, social and economic burden. Different factors such as a higher risk of suicide, the higher frequency of psychiatric and somatic comorbidities are worsening the prognosis of these diseases. Within a preventive approach, it is essential to identify biological, psychological or environmental factors that might influence or predict such prognosis. This thesis focused on major elements of the prognosis of the two main mood disorders: major depression and bipolar disorder. Firstly, using a candidate-gene approach, we have tried to identify a biomarker of suicide risk in patients with a major depressive episode. We have found that SLC6A4 (gene coding for the serotonin transporter protein) mRNA expression levels extracted from the peripheral blood was able to predict the worsening of suicidal ideation in a 30 weeks follow-up. Secondly, we explored the clinical and neuropsychological factors associated to medication adherence in euthymic bipolar patients. The results of our study highlighted that bipolar patients who experienced a higher number of adverse side effects and a smaller number of previous hospitalizations are more likely to be low adherent. Moreover, in the older bipolar patients only, poor executive functioning predicted low adherence

Biomarker development: current issues and perspectives

International audienceWe have read the letter of Ho et al. in response to our work with great interest. We agree with their general comment regarding the interest of evaluating agreement between two multiplex immunoassays. Ho et al. reminds us that correlation analysis suffers from limitations in assessing agreement between methods. Such agreement should be assessed using Bland-Altman plots. This method is largely known as the original 1986 paper of Bland and Altman has been the most frequently cited article ever to appear in the Lancet and is one of the ten most frequently cited statistical articles ever (Bland and Altman, 2012). Nevertheless, we decided to use Spearman’s rank correlation, since our original intent was to compare methods and biological fluids, which is not exactly the same as assessing the degree of agreement. Ultimately, several conditions are required to evaluate agreement with Bland-Altman graphics

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

International audienceCytokines 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

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

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Trajectories of medication adherence in patients with Bipolar Disorder along 2 years-follow-up

Background: Bipolar disorder (BD) is a chronic and severe mental illness. It requires a non-discontinued pharmacological treatment to prevent mood recurrences but nonadherence to medication is frequent. To this date, medication adherence in BD has been mostly evaluated in cross-sectional studies and often considered as a stable trait. We aimed to study medication adherence using a prospective person-oriented approach. Methods: 1627 BD patients were followed on a 2 years period and assessed every 6 months. Medication adherence was evaluated at each visit with the Medication Adherence Rating Scale (MARS). A latent class mixed model (LCMM) was used to identify trajectory classes of adherence over time. Regression analyses and linear mixed model were used to search for predictors and covariables of the trajectories. Results: Three distinct and robust trajectories of medication adherence have been identified: one that starts poorly and keeps deteriorating (4.8%), one that starts poorly but improves (9%) and one that starts well and keeps improving (86.2%). A good tolerance to psychotropic medications, low depressive symptoms, the absence of comorbid eating disorders and anticonvulsant medication were associated to a better prognosis of adherence. Along the follow-up, the lower were the depressive symptoms, the better was the medication adherence (p <.001) Limitations: The use of a single measure of medication adherence although it is a validated instrument and a possible positive selection bias that might limit the generalization of our findings. Conclusions: This study demonstrates that medication adherence in BD patients is a heterogeneous and potentially variable phenomenon.Sorbonne Universités à Paris pour l'Enseignement et la RechercheFondaMental-Cohorte

Neuropsychological functioning, age, and medication adherence in bipolar disorder

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Separate multiple logistic regressions to predict low adherence (versus high adherence) in young (<i>16–46 years)</i> and old (<i>47–71 years</i>) bipolar patients’ subgroups before and after backward selection procedures.

<p>Separate multiple logistic regressions to predict low adherence (versus high adherence) in young (<i>16–46 years)</i> and old (<i>47–71 years</i>) bipolar patients’ subgroups before and after backward selection procedures.</p

Selection procedure.

<p>Selection procedure of the final sample of bipolar outpatients (N = 353) from the FondaMental Advanced Centers of Expertise in Bipolar Disorders (FACE-BD) cohort.</p

Socio-demographic and clinical description of the sample by age groups.

<p>Socio-demographic and clinical description of the sample by age groups.</p