Variabilité de réponse aux psychotropes
Présentation
l'unité est constituée de 45 membres, chercheurs, enseignants-chercheurs, hospitalo-universitaires et personnels d’appui à la recherche des Facultés de Pharmacie Paris Descartes et de Médecine Paris Diderot.
Elle met son potentiel de recherche en neuropsychopharmacologie pré-clinique et clinique au service d’une recherche translationnelle visant à la personnalisation du traitement en psychiatrie et addictologie.
Ce projet très structurant s’appuie à la fois sur une plate-forme expérimentale in vivo et in vitro spécialisée dans l’étude de la barrière hémato-encéphalique, située à la Faculté de Pharmacie Paris Descartes, et sur les cohortes de patients des centres experts du service de psychiatrie et d’addictologie ainsi que du service de réanimation toxicologique du groupe hospitalier Saint-Louis-Lariboisière-Fernand Widal.
Les objectifs principaux du projet qui porte sur la compréhension des mécanismes responsables de la variabilité de réponse aux psychotropes en vue d’optimiser les traitements peuvent se résumer de la façon suivante :
- Caractériser les changements structuraux et moléculaires de la barrière hémato-encéphalique (BHE) en contexte pathologique ou exposée de façon chronique ou toxique aux psychotropes et identifier de nouveaux mécanismes de régulation d’échange et de transport à la BHE susceptibles d’expliquer la variabilité de réponse ;
- Identifier des signatures périphériques ou centrales prédictives de la rechute et de l’échec au traitement dans les conduites addictives et les troubles de l’humeur ;
- Caractériser les mécanismes de toxicité des psychotropes, seuls ou en association, en usage normal ou lors des surexpositions ainsi que ceux des nouvelles drogues « légales ou festives », et identifier les facteurs de vulnérabilité individuels.
Thèmes de recherche
Mécanismes de toxicité et optimisation thérapeutique des psychotropes
(Equipe 2, Bruno Mégarbane, Paris Diderot)
L’équipe est orientée vers l’identification des mécanismes de toxicité des psychotropes (y compris à potentiel d’abus et antalgiques centraux), en situation d'intoxication aigüe et de prescription. L’identification des facteurs de variabilité individuelle aux effets toxiques d’un psychotrope implique une approche transversale intégrant pharmacogénétique, pharmacocinétique (PK) et pharmacodynamie (PD) ainsi que l’étude des mécanismes d’interactions médicamenteuses, source importante de variabilité de réponse chez des patients polymédiqués.
Deux thèmes de recherche sont particulièrement développés :
- Thème 1: Vulnérabilité aux psychotropes
- Thème 2 : Neurotoxicité du lithium
Mots-clés : Toxicologie clinique - Opioïdes - Nouvelles drogues récréatives - Interactions drogues-drogues - Modèles animaux d'intoxication - Toxicocinétique - Pléthysmographie.
Physiopathologie et cibles thérapeutiques de la barrière hémato-encéphalique
(Equipe 3, Xavier Declèves, Paris Descartes)
L’équipe 3 développe une recherche fondamentale visant à étudier deux fonctions essentielles de la BHE : le maintien de l’homéostasie cérébrale vis-à-vis de composés endogènes et le contrôle de l’exposition cérébrale aux médicaments psychotropes.
Grâce à une approche expérimentale intégrée du gène à la fonction dans des modèles rongeurs in vivo et in vitro (tissus isolés et modèles cellulaires humains), les mécanismes moléculaires régulant l’expression et l’activité des transporteurs et enzymes de la BHE ainsi que les conséquences fonctionnelles de ces modulations sont étudiés dans le cadre d’exposition à des drogues d’abus, de pathologies psychiatriques et/ou de leurs traitements en lien avec les deux orientations de recherche « addiction » et « maladie bipolaire » de l’Unité.
- Thème 1: Nouveaux mécanismes de transport et d’échange à la BHE
- Thème 2 : Dynamique et hétérogénéité de l’endothélium cérébral
Mots-clés : Physiologie et Physiopathologie de la barrière hémato-encéphalique - Signalisation et différenciation - Cellules endothéliales cérébrales - Transport et Métabolisme des psychotropes - Passage membranaire - Protéomique quantitative - Modélisation en Pharmacocinétique et Pharmacodynamie
Biomarqueurs de la rechute et de la réponse aux traitements dans les addictions et les troubles de l'humeur
(Equipe 1, Frank Bellivier, Paris Diderot)
La variabilité de la réponse de même que la prédiction de la rechute dans les pathologies récurrentes sont de vastes questions scientifiques. Cette variabilité de la réponse est particulièrement importante et imprévisible dans les addictions et dans les troubles de l’humeur rendant en grand partie compte des difficultés de prise en charge de ces pathologies. Pouvoir la prédire pour mieux la prévenir est un enjeu majeur pour le développement d'une médecine personnalisée.
Les thèmes développés par l’équipe 1 en collaboration avec les équipes 2 et 3 reposent sur l’étude et l’analyse de cohortes de patients recrutés à l’hôpital Fernand Widal, au centre Murger et dans le service de Psychiatrie, centre expert de la fondation Fondamental :
- Thème 1: Variabilité de la réponse thérapeutique aux psychotropes et identification de biomarqueurs prédictifs
- Thème 2 : Biomarqueurs prédictifs de la rechute dans les addictions et les troubles bipolaires
Mots-clés : Psychiatrie - Dépression bipolaire - Addiction - Rechute Neuropsychopharmacologie - Cohortes - Génomique - Essais cliniques.
[hal-02361850] Pharmacokinetics and Pharmacodynamics of Once-daily Prolonged-release Tacrolimus in Liver Transplant Recipients.
Date: 22 Oct 2021 - 22:42
Desc: PURPOSE: Limited published data are available regarding the pharmacokinetic (PK) and pharmacodynamic (PD) variables of prolonged-release tacrolimus (PRT) after liver transplantations. The goal of this study was to compare the PK and PD profiles of PRT in early and stable liver transplant recipients by developing a population PK model of PRT and investigating the profile of calcineurin activity (CNA) in the peripheral blood mononuclear cells.METHODS: A conversion from BID immediate-release tacrolimus (IRT) to once-daily PRT based on a one-to-one daily dose was performed at day 7 (D7) and D90 posttransplantation in groups A (n = 12) and B (n = 12), respectively. Extensive PK samplings, including whole-blood tacrolimus (TAC) concentration, and CNA assessments were performed at D14 and D104 in groups A and B, respectively. TAC concentration-time data (N = 221) were analyzed by using nonlinear mixed effects modeling.FINDINGS: A 2-compartment model with linear elimination and a delayed first-order absorption characterized by 2 transit compartments best described the PK data. Model-predicted dose-normalized (6.0 mg/d) area under the TAC concentration-time curve over the dosing interval in groups A and B was similar (geometric mean, 235.6 ng/mL · h [95% CI, 139.6-598.7] vs 224.6 ng/mL · h [95% CI, 117.6-421.5], respectively; P = 0.94). Area under the CNA versus time curve over the dosing interval did not differ between groups (4897 [3437] and 4079 [1008] pmol/min/106 cells; P = 0.50). In group A, trough CNA at D14 posttransplantation was statistically higher than that measured just before the switch to PRT (ie, D7 posttransplantation) (198 [92] vs 124 [72] pmol/min/106cells, n = 8; P = 0.048); no statistical difference in TAC concentration was observed (P = 0.11). In group B, no statistical difference between D90 and D104 was observed in either trough CNA (149 [78] vs 172 [82] pmol/min/106 cells, n = 6; P = 0.18) or TAC (P = 0.17) concentration. No graft rejection was observed in either of the groups.IMPLICATIONS: This study suggests that one-to-one dosage conversion to once-daily PRT during the early posttransplantation period could result in significant CNA variations but without causing graft rejection. Further investigations in larger cohorts are warranted to confirm these results.
[hal-01862276] Prevalence and outcome of heparin-induced thrombocytopenia diagnosed under veno-arterial extracorporeal membrane oxygenation a retrospective nationwide study
Date: 27 Aug 2018 - 12:26
Desc: Purpose - Thrombocytopenia is a frequent and serious adverse event in patients treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for refractory cardiogenic shock. Similarly to postcardiac surgery patients, heparin-induced thrombocytopenia (HIT) could represent the causative underlying mechanism. However, the epidemiology as well as related mortality regarding HIT and VA-ECMO remains largely unknown. We aimed to define the prevalence and associated 90-day mortality of HIT diagnosed under VA-ECMO. Methods - This retrospective study included patients under VA-ECMO from 20 French centers between 2012 and 2016. Selected patients were hospitalized for more than 3 days with high clinical suspicion of HIT and positive anti-PF4/heparin antibodies. Patients were classified according to results of functional tests as having either Confirmed or Excluded HIT. Results - A total of 5797 patients under VA-ECMO were screened; 39/5797 met the inclusion criteria, with HIT confirmed in 21/5797 patients (0.36% [95% CI] [0.21-0.52]). Fourteen of 39 patients (35.9% [20.8-50.9]) with suspected HIT were ultimately excluded because of negative functional assays. Drug-induced thrombocytopenia tended to be more frequent in Excluded HIT at the time of HIT suspicion (p = 0.073). The platelet course was similar between Confirmed and Excluded HIT (p = 0.65). Mortality rate was 33.3% [13.2-53.5] in Confirmed and 50% [23.8-76.2] in Excluded HIT (p = 0.48). Conclusions - Prevalence of HIT among patients under VA-ECMO is extremely low at 0.36% with an associated mortality rate of 33.3%, which appears to be in the same range as that observed in patients treated with VA-ECMO without HIT. In addition, HIT was ultimately ruled out in one-third of patients with clinical suspicion of HIT and positive anti-PF4/heparin antibodies.
[inserm-01339482] Utility of CSF biomarkers in psychiatric disorders: a national multicentre prospective study
Date: 29 Jun 2016 - 19:03
Desc: AbstractBackgroundAffective and psychotic disorders are mental or behavioural patterns resulting in an inability to cope with life’s ordinary demands and routines. These conditions can be a prodromal event of Alzheimer’s disease (AD). The prevalence of underlying AD lesions in psychiatric diseases is unknown, and it would be helpful to determine them in patients. AD cerebrospinal fluid (CSF) biomarkers (amyloid β, tau and phosphorylated tau) have high diagnostic accuracy, both for AD with dementia and to predict incipient AD (mild cognitive impairment due to AD), and they are sometimes used to discriminate psychiatric diseases from AD. Our objective in the present study was to evaluate the clinical utility of CSF biomarkers in a group of patients with psychiatric disease as the main diagnosis.MethodsIn a multicentre prospective study, clinicians filled out an anonymous questionnaire about all of their patients who had undergone CSF biomarker evaluation. Before and after CSF biomarker results were obtained, clinicians provided a diagnosis with their level of confidence and information about the treatment. We included patients with a psychiatric disorder as the initial diagnosis. In a second part of the study conducted retrospectively in a followed subgroup, clinicians detailed the psychiatric history and we classified patients into three categories: (1) psychiatric symptoms associated with AD, (2) dual diagnosis and (3) cognitive decline not linked to a neurodegenerative disorder.ResultsOf 957 patients, 69 had an initial diagnosis of a psychiatric disorder. Among these 69 patients, 14 (20.2 %) had a CSF AD profile, 5 (7.2 %) presented with an intermediate CSF profile and 50 (72.4 %) had a non-AD CSF profile. Ultimately, 13 (18.8 %) patients were diagnosed with AD. We show that in the AD group psychiatric symptoms occurred later and the delay between the first psychiatric symptoms and the cognitive decline was shorter.ConclusionsThis study revealed that about 20 % of patients with a primary psychiatric disorder diagnosis before undergoing a CSF exploration for cognitive disorder displayed a CSF biomarker AD profile. In memory clinics, it seems important to consider AD as a possible diagnosis before finalizing a diagnosis of a psychiatric disorder.
[hal-01798415] Les biomarqueurs du liquide cérébro-spinal dans la maladie d’Alzheimer : un outil de recherche utile dans la pratique clinique courante des consultations mémoire pour les cas complexes
Date: 9 May 2023 - 10:17
Desc: The role of biomarkers in clinical research was recently highlighted in the new criteria for the diagnosis of Alzheimer's disease. Cerebro-spinal fluid (CSF) biomarkers (total Tau protein, threonine 181 phosphorylated Tau protein and amyloid Aβ1-42 peptide) are associated with cerebral neuropathological lesions observed in Alzheimer's disease (neuronal death, neurofibrillary tangle with abnormal Tau deposits and amyloid plaque). Aβ1-40 amyloid peptide dosage helps to interpret Aβ1-42 results. As suggested in the latest international criteria and the French HAS (Haute Autorité de santé) recommendations, using theses CSF biomarkers should not be systematic but sometimes could be performed to improve confidence about the diagnostic of Alzheimer's disease in young subjects or in complex clinical situations. Future biomarkers actually in development will additionally help in diagnostic process (differential diagnosis) and in prognostic evaluation of neurodegenerative diseases.
[hal-01904767] Circadian genes and lithium response in bipolar disorders: associations with PPARGC1A (PGC-1 α ) and RORA
Date: 25 Oct 2018 - 12:53
Desc: Preliminary studies suggest that lithium (Li) response might be associated with some circadian gene polymorphisms, we therefore performed a pharmacogenetic study on the core clock genes in two independent samples suffering from bipolar disorder (BD) and thoroughly characterized for their Li response. Two independent Caucasian samples (165 and 58 bipolar patients) treated with Li were selected from samples recruited in a French multicenter study and assessed for their Li response using the Alda scale. The two samples were genotyped using the Human660 (H660) and OmniExpress (OE) BeadChips and gene-based association analyses of 22 core clock genes were conducted. In the first sample (H660 chip), the RAR-related orphan receptor-a gene (RORA) and the Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha gene (PPARGC1A or PGC-1α) were significantly associated with the Li response (empirical P-value = 0.0015 and 0.04, respectively), and remained significant only for RORA after Bonferroni correction. In the second sample (OE chip), PPARGC1A was significantly associated with the Li response (empirical P-value = 0.04), and did not remain significant after Bonferroni correction. PPARGC1A is a master regulator of mitochondrial function and a key component of the endogenous clock that stimulates the expression of Bmal1 and Rev-erb-alpha through coactivation of RORA. Although the observed associations deserve further replication and investigation, our results suggest genetic associations between Li response and these two close biological partners: PPARGC1A and RORA involved in circadian rhythms and bioenergetics processes in Li response.
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