A self-observation by a French cardiologist was published in 2004 which highlighted the benefit of high-dose baclofen for alcohol use disorder. The therapeutic benefit of this GABAB agonist had already been identified, but only at doses not exceeding 30 mg per day, compared to 270 mg per day in the 2004 observation. Over the 20 years that followed, the repositioning of baclofen in alcohol use disorder was the subject of scientific works having clarified its effectiveness and its tolerance, but also of medical controversies and regulatory twists traced out in this review. (c) 2024 l'Academie nationale de medecine. Published by Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

En 2004 paraissait une auto-observation d’un cardiologue français soulignant l’intérêt du baclofène à hautes doses dans le trouble de l’usage de l’alcool. L’intérêt thérapeutique de cet agoniste GABA-B avait déjà été repéré mais uniquement à des doses n’excédant pas 30mg par jour, contre 270mg par jour dans l’observation de 2004. Au cours des 20 ans qui ont suivi, le repositionnement du baclofène dans l’indication du trouble de l’usage de l’alcool a été l’objet de travaux scientifiques ayant précisé son efficacité et sa tolérance, mais aussi de polémiques médicales et de rebondissements réglementaires retracés dans cet article.

Les unités de soins de rééducation post-réanimation accueillent des patients ayant effectué un séjour prolongé en réanimation. Ces patients présentent de manière quasi constante une dénutrition, parfois sévère. Les escarres de stade 3 et 4 sont fréquentes. Les troubles de la déglutition sont très répandus, de même que diverses pathologies neurologiques ou rhumatologiques compliquant la reprise d’une alimentation per os autonome. La prise en charge nutritionnelle constitue un des axes thérapeutiques principaux. Pour autant, peu de données sont disponibles au sujet de cette population particulière de patients. Les objectifs sont de : – décrire l’état nutritionnel des patients à l’admission et à la sortie de l’unité ; – présenter la prise en charge effectuée dans l’Unité de SRPR (objectifs, moyens) ; – décrire l’évolution de l’assistance nutritionnelle des patients dans le temps, en décrivant en parallèle l’évolution des paramètres nutritionnels ainsi que l’évolution dans les autres axes majeurs de la prise en charge (troubles de la déglutition, sevrage ventilatoire, motricité) ; – décrire l’adéquation entre les objectifs nutritionnels (Kcal, protides) calculés et les ingestas estimés ; – déterminer des profils-type de patients. Il s’agit d’une étude descriptive prospective des patients admis sur 1 an. Des statistiques usuelles et une analyse par un modèle en classe latente ont été appliquées. 87 patients ont été inclus. A l’admission, 91 % des patients sont dénutris (47 % dénutrition sévère), 57 % présentent des troubles de déglutition. 29 % sont sous nutrition entérale (NE) exclusive, 36 % en nutrition per os (PO) exclusive et 35 % en mixte. Les apports caloriques et protidiques moyennés sur le séjour restent respectivement inférieur à 30 kcal/kg/j pour 41 % des patients et inférieur à 1 g/kg/j pour 26 %. L’analyse en classe latente identifie un profil de patients caractérisés par une dépendance forte et prolongée à la NE (26 % des patients). La prévalence des trachéotomies, antécédents de cancer ou chirurgicaux et des troubles de déglutition sont plus élevés dans ce groupe. Un second groupe (38 % des patients) est composé de patients sans NE ou rapidement sevrés de la NE : l’IMC est plus élevé (24 vs 21,9), la durée de séjour plus courte (22 vs 30 jours), les apports caloriques sont plus bas (1350 vs 2000 kcal/j). A la sortie, la dénutrition sévère a régressé (17 % non dénutris, 42 % de dénutrition sévère). La NE est poursuivie chez 44 % des patients. Cette étude a permis de décrire la prévalence de la dénutrition dans cette population et de distinguer plusieurs profils évolutifs pour lesquels les enjeux de prise en charge nutritionnelle sont différents. Les apports calorico-protidiques restent inférieurs aux recommandations pour certains patients, en particulier après sevrage de la nutrition entérale. Ce travail confirme l’importance du versant nutritionnel de la prise en charge en post réanimation.

BACKGROUND:The spatial functional chronnectome is an innovative mathematical model designed to capture dynamic features in the organization of brain function derived from resting-state functional magnetic resonance imaging data. Measurements of dynamic functional connectivity have been developed from this model to quantify the brain dynamical self-reconfigurations at different spatial and temporal scales. This study examined whether two spatiotemporal dynamic functional connectivity quantifications were linked to late adolescence-onset major depressive disorder (AO-MDD), and scaled with depression and symptom severity measured with the Montgomery-Åsberg Depression Rating Scale.METHODS:Thirty-five patients with AO-MDD (21 ± 6 years of age) and 53 age- and sex-matched healthy young participants (20 ± 3 years of age) underwent 3T magnetic resonance imaging structural and resting-state functional magnetic resonance imaging acquisitions. The chronnectome here comprised seven individualized functional networks portrayed along 132 temporal overlapping windows, each framing 110 seconds of resting brain activity.RESULTS:Based on voxelwise analyses, patients with AO-MDD demonstrated significantly reduced temporal variability within the bilateral prefrontal cortex in five functional networks including the limbic network, default mode network, and frontoparietal network. Furthermore, the limbic network appeared to be particularly involved in this sample and was associated with Montgomery-Åsberg Depression Rating Scale scores, and its progressive dynamic inflexibility was linked to sadness. Default mode network and frontoparietal network dynamics scaled with negative thoughts and neurovegetative symptoms, respectively.CONCLUSIONS:This triple-network imbalance could delay spatiotemporal integration, while across-subject symptom variability would be network specific. Therefore, the present approach supports that brain network dynamics underlie patients' symptom heterogeneity in AO-MDD.

BACKGROUND:A reduced presynaptic dopamine neurotransmission has long been implicated in major depressive disorder (MDD). However, molecular imaging studies that assessed the dopamine transporter (DAT) availability have led to inconsistent results, partly due to methodological considerations, and to exclusive focus on the striatum, precluding findings in extra-striatal regions. METHODS:Herein, we leveraged our database of high-resolution Positron Emission Tomography (PET) images acquired with a highly selective radiotracer, [11C]PE2I, to assess striatal and extra-striatal DAT availability in eight patients treated for depression compared to twenty-four healthy controls. RESULTS:Statistical parametric mapping and voxel-based analyses of PET images detected a significant lower DAT availability in depressed patients within the superior part of the midbrain (right, pFWE = 0.002; left, pFWE = 0.006), a region including the ventral tegmental area and the substantia nigra from where the mesocorticolimbic and nigrostriatal dopamine pathways originate. A similar difference was found in the right dorsal putamen (pFWE = 0.012). LIMITATIONS:The statistical power was limited to detect only large effects, due to the size of the patients' sample. CONCLUSIONS:The findings support the hypothesis that a reduced presynaptic dopamine function plays a role in the pathophysiology of depression, and that extra-striatal dopamine function should be further investigated.

Schizophrénie : tout le monde a déjà entendu ce terme qui est passé dans le langage courant sans que l'on sache précisément ce qu'il recouvre. Rien d'étonnant d'ailleurs, car la plupart des travaux sur la schizophrénie revêtent d'emblée un caractère ­spécialisé. Cet ouvrage se propose de répondre aux questions les plus simples que le public se pose à propos d'une maladie qu'il sait grave et stigmatisante : à quels signes reconnaît-on la schizo­phrénie ? Quels sont les causes, les traitements ? Que peut faire l'entourage pour aider le patient ? Et pour le patient lui-même, comment vivre avec cette maladie ? Faut-il renommer la maladie ? Bernard Granger et Jean Naudin mettent en commun leur expérience de praticiens et d'enseignants pour analyser les mécanismes de cette maladie mentale et en détailler les traitements. 3e édition revue et augmentée Bernard Granger, psychiatre et psychothérapeute, est professeur de psy­chiatrie à l'université René Descartes (Paris 5) et dirige l'unité de psychiatrie de l'hôpital Tarnier (AP-HP). Jean Naudin est professeur de psychiatrie à l'université de la Méditerranée et Chef de service au CHU Sainte-Marguerite à Marseille. Il est également docteur en philosophie et chercheur permanent au CNRS (EA 3279).

Cet ouvrage presente les fondements des "nouveaux modeles de soins", une thematique en plein essor sur le plan international. Jusqu'alors, le modele traditionnel des soins etait tourne vers les notions de maladie et de traitement curatif, occultant progressivement la personne soignee sous le poids de la technicite scientifique. 4 contrario, tout en assumant pleinement les exigences d'ordre scientifique, ces nouveaux modeles convergent autour de preoccupations au cœur des exigences de la clinique et des attentes societales : appui sur les ressources et aspirations de la personne soignee, reconnaissance de son histoire et de son experience comme sources essentielles de savoir, implication de cette personne comme acteur decisionnel en fonction de ses valeurs, attention au clinicien comme personne et a l'impact de la relation soignant-soigne, rehabilitation des methodes qualitatives et du recours aux sciences humaines. L'influence de ce changement de paradigme, veritable revolution scientifique, est appelee a s'exercer sur toutes les disciplines concernees par les soins, en particulier celles relevant directement des sciences medicales, sociales ou infirmieres. Pour la premiere fois, cet ouvrage met en relation les principes communs a ces modeles, presente les plus dynamiques d'entre eux, met en evidence leurs developpements cliniques concrets et souligne leur synergie avec la clinique fondee sur les donnees probantes. Rassemblant des auteurs de reference issus de multiples disciplines, cet ouvrage s'adresse aux professionnels intervenant dans les domaines medical, sanitaire et medico-social (medecins de toutes specialites, infirmiers, psychologues, educateurs), mais aussi aux chercheurs en sciences sociales (philosophes, sociologues), acteurs institutionnels et decideurs en sante. Il sera egalement d'un grand interet pour les etudiants qui se destinent a ces professions en les ouvrant aux horizons les plus prometteurs pour un exercice correspondant a leur vocation.

Background: More information is needed about the efficacy and safety of long-term baclofen in the treatment of alcohol use disorders. The objective of this study was to assess the effect of treatment with tailored-dose baclofen on alcohol consumption in patients with alcohol use disorders followed for 3 years after first initiating baclofen treatment. Methods: This retrospective descriptive cohort included outpatients followed in a French general practice clinic for 3 years and treated with tailored-dose baclofen to reduce or eliminate alcohol consumption. At 3 years, treatment was considered successful if alcohol consumption was at or below levels defined as low-risk by the WHO (≤ 40 g/d in men and ≤ 20 g/d in women). Results: The study population included 144 patients (88 men and 56 women). The participants' mean age was 46 ± 11 years and mean daily alcohol intake before treatment was 167 ± 77 grams. At the end of the study, treatment was successful for 91 (63.2%) patients. Participants' mean dose of baclofen at the end of study period was 100 ± 101 mg/d. We identified 75 (52.1%) patients for whom treatment was successful at each annual follow-up appointment: at 1, 2, and 3 years. The mean maximum dose of baclofen over follow-up of the 144 patients was 211 ± 99 mg/d (dose range: 40 mg/d to 520 mg/d). Conclusion: In this study, tailored-dose baclofen appears to be an effective treatment in patients with alcohol use disorders, with sustainable effect over time (3 years). There are many adverse effects but they are consistent with those already described in the literature.

Dopamine function and reward processing are highly interrelated and involve common brain regions afferent to the nucleus accumbens, within the mesolimbic pathway. Although dopamine function and reward system neural activity are impaired in most psychiatric disorders, it is unknown whether alterations in the dopamine system underlie variations in reward processing across a continuum encompassing health and these disorders. We explored the relationship between dopamine function and neural activity during reward anticipation in 27 participants including healthy volunteers and psychiatric patients with schizophrenia, depression, or cocaine addiction, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) multimodal imaging with a voxel-based statistical approach. Dopamine transporter (DAT) availability was assessed with PET and [11C]PE2I as a marker of presynaptic dopamine function, and reward-related neural response was assessed using fMRI with a modified Monetary Incentive Delay task. Across all the participants, DAT availability in the midbrain correlated positively with the neural response to anticipation of reward in the nucleus accumbens. Moreover, this relationship was conserved in each clinical subgroup, despite the heterogeneity of mental illnesses examined. For the first time, a direct link between DAT availability and reward anticipation was detected within the mesolimbic pathway in healthy and psychiatric participants, and suggests that dopaminergic dysfunction is a common mechanism underlying the alterations of reward processing observed in patients across diagnostic categories. The findings support the use of a dimensional approach in psychiatry, as promoted by the Research Domain Criteria project to identify neurobiological signatures of core dysfunctions underling mental illnesses.

BACKGROUND:Although treatment-resistant and nontreatment-resistant depressed patients show structural brain anomalies relative to healthy controls, the difference in regional volumetry between these two groups remains undocumented.METHODS:A whole-brain voxel-based morphometry (VBM) analysis of regional volumes was performed in 125 participants' magnetic resonance images obtained on a 1.5 Tesla scanner; 41 had treatment-resistant depression (TRD), 40 nontreatment-resistant depression (non-TRD), and 44 were healthy controls. The groups were comparable for age and gender. Bipolar/unipolar features as well as pharmacological treatment classes were taken into account as covariates.RESULTS:TRD patients had higher gray matter (GM) volume in the left and right amygdala than non-TRD patients. No difference was found between the TRD bipolar and the TRD unipolar patients, or between the non-TRD bipolar and non-TRD unipolar patients. An exploratory analysis showed that lithium-treated patients in both groups had higher GM volume in the superior and middle frontal gyri in both hemispheres.CONCLUSIONS:Higher GM volume in amygdala detected in TRD patients might be seen in perspective with vulnerability to chronicity, revealed by medication resistance.

Baclofen has been proposed for few years to help treating alcohol dependence at higher doses than those used in neurology. Baclofen pharmacokinetics has been previously well described at low oral or intravenous doses but remains poorly investigated with such high oral doses. We here describe dose regimens of baclofen in 143 alcohol-dependent patients treated with steady-state oral doses of baclofen. Plasma baclofen levels were measured in blood samples using liquid chromatography coupled with tandem mass spectrometry. One hundred and forty-nine baclofen concentrations were sampled 30 min to 15 h after the last dose, and baclofen pharmacokinetics was determined using population pharmacokinetics approach. Our population, whose average age and BMI were 51.5 years and 25.5 kg/m(2), respectively, was composed of two-thirds of men. Daily baclofen doses ranged from 15 to 250 mg and 26% were higher than 120 mg. A one-compartment model with first-order absorption and elimination allowed to determine mean values for clearance (CL/F), volume of distribution (V/F) and absorption rate constant at 8.0 L/h, 44.5 L and 2.23 h(-1), respectively. Inter-individual variability on CL/F and V/F was 27.4 and 86% for the parameters. None of the demographic and biological covariates significantly decreased inter-individual variability. A proportional relationship between oral dose and plasma baclofen exposure indicated a linear pharmacokinetics of baclofen even at doses over 120 mg/day. Our large population study evidenced a linear pharmacokinetics of oral baclofen even at high daily doses with an inter-individual variability of baclofen exposure that could not be explained by demographic and biological data.

Neuroimaging studies investigating dopamine (DA) function widely support the hypothesis of presynaptic striatal DA hyperactivity in schizophrenia. However, published data on the striatal DA transporter (DAT) appear less consistent with this hypothesis, probably partly due to methodological limitations. Moreover, DAT in extrastriatal regions has been very poorly investigated in the context of schizophrenia. In order to address these issues, we used a high resolution positron emission tomograph and the selective DAT radioligand [11C]PE2I, coupled with a whole brain voxel-based analysis method to investigate DAT availability in striatal but also extra-striatal regions in 21 male chronic schizophrenia patients compared to 30 healthy male controls matched by age. We found higher DAT availability in schizophrenia patients in midbrain, striatal, and limbic regions. DAT availability in amygdala/hippocampus and putamen/pallidum was positively correlated with hallucinations and suspiciousness/persecution, respectively. These results are consistent with an increase of presynaptic DA function in patients with schizophrenia, and support the involvement of both striatal and extrastriatal DA dysfunction in positive psychotic symptoms. The study also highlights the whole brain voxel-based analysis method to explore DA dysfunction in schizophrenia.

Baclofen is used to manage alcohol dependence. This study describes a simple method using liquid chromatography coupled to high-resolution mass spectrometry (LC-HR-MS) developed in plasma samples. This method was optimized to allow quantification of baclofen and determination of metabolic ratio of its metabolites, an oxidative deaminated metabolite of baclofen (M1) and its glucuronide form (M2). The LC-HR-MS method on Exactive® apparatus is a newly developed method with all the advantages of high resolution in full-scan mode for the quantification of baclofen and detection of its metabolites in plasma. The present assay provides a protein precipitation method starting with 100 μL plasma giving a wide polynomial dynamic range (R2  > 0.999) between 10 and 2000 ng/mL and a lower limit of quantitation of 3 ng/mL for baclofen. Intra- and inter-day precisions were <8.1% and accuracies were between 91.2 and 103.3% for baclofen. No matrix effect was observed. The assay was successfully applied to 36 patients following baclofen administration. Plasma concentrations of baclofen were determined between 12.2 and 1399.9 ng/mL and metabolic ratios were estimated between 0.4 and 81.8% for M1 metabolite and on the order of 0.3% for M2 in two samples.

The article by Laramee et al . (2016) concerning ‘the cost-effectiveness of the integration of nalmefene for alcohol dependence’ deserves careful attention because it is one of the few and very similar decision-modelling studies available supporting nalmefene use for harm reduction among people treated for alcohol dependency. But can results derived from models replace evidence? Indeed, the nalmefene Phase 3 programme was controversial. When the whole body of evidence derived from randomised controlled trials (RCTs) is considered, a meta-analysis (Palpacuer et al. , 2015) found that ‘the value of nalmefene for treatment of alcohol addiction is not established’ and that ‘nalmefene has limited efficacy in reducing alcohol consumption’. In addition, an attrition bias could not be excluded in these studies, with more withdrawals for nalmefene than for placebo, including more withdrawals for safety reasons. Thus, because of these concerns, …