Lines of evidence coming from many branches of neuroscience indicate that anxiety disorders arise from a dysfunction in the modulation of brain circuits which regulate emotional responses to ...potentially threatening stimuli. The concept of anxiety disorders as a disturbance of emotional response regulation is a useful one as it allows anxiety to be explained in terms of a more general model of aberrant salience and also because it identifies avenues for developing psychological, behavioral, and pharmacological strategies for the treatment of anxiety disorder. These circuits involve bottom-up activity from the amygdala, indicating the presence of potentially threatening stimuli, and top-down control mechanisms originating in the prefrontal cortex, signaling the emotional salience of stimuli. Understanding the factors that control cortical mechanisms may open the way to identification of more effective cognitive behavioral strategies for managing anxiety disorders. The brain circuits in the amygdala are thought to comprise inhibitory networks of γ-aminobutyric acid-ergic (GABAergic) interneurons and this neurotransmitter thus plays a key role in the modulation of anxiety responses both in the normal and pathological state. The presence of allosteric sites on the GABAA receptor allows the level of inhibition of neurons in the amygdala to be regulated with exquisite precision, and these sites are the molecular targets of the principal classes of anxiolytic drugs. Changes in the levels of endogenous modulators of these allosteric sites as well as changes in the subunit composition of the GABAA receptor may represent mechanisms whereby the level of neuronal inhibition is downregulated in pathological anxiety states. Neurosteroids are synthesized in the brain and act as allosteric modulators of the GABAA receptor. Since their synthesis is itself regulated by stress and by anxiogenic stimuli, targeting the neurosteroid-GABAA receptor axis represents an attractive target for the modulation of anxiety.
The understanding of the functional role of the lipid diversity in biological membranes is a major challenge. Lipid models have been developed to address this issue by using lipid mixtures generating ...liquid-ordered (Lo)/liquid-disordered (Ld) immiscibility. The present study examined mixtures comprising Egg sphingomyelin (SM), cholesterol (chol) and phosphatidylcholine (PC) either containing docosahexaenoic (PDPC) or oleic acid (POPC). The mixtures were examined in terms of their capability to induce phase separation at the micron- and nano-scales. Fluorescence microscopy, electron spin resonance (ESR), X-ray diffraction (XRD) and calorimetry methods were used to analyze the lateral organization of the mixtures. Fluorescence microscopy of giant vesicles could show that the temperature of the micron-scale Lo/Ld miscibility is higher for PDPC than for POPC ternary mixtures. At 37°C, no micron-scale Lo/Ld phase separation could be identified in the POPC containing mixtures while it was evident for PDPC. In contrast, a phase separation was distinguished for both PC mixtures by ESR and XRD, indicative that PDPC and POPC mixtures differed in micron vs nano domain organization. Compared to POPC, the higher line tension of the Lo domains observed in PDPC mixtures is assumed to result from the higher difference in Lo/Ld order parameter rather than hydrophobic mismatch.
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•A higher Lo/Ld demixing temperature is observed for PDPC vs POPC.•PDPC and POPC mixtures differ in micron vs nano domain pattern.•Lo order parameter is higher for PDPC compared to POPC.•Lo fraction is larger for POPC vs PDPC below 37°C and smaller above 37°C.
Schizophrenia is a severe mental condition in which several lipid abnormalities-either structural or metabolic-have been described. We tested the hypothesis that an abnormality in membrane lipid ...composition may contribute to aberrant dopamine signaling, and thereby symptoms and cognitive impairment, in schizophrenia (SCZ) patients. Antipsychotic-medicated and clinically stable SCZ outpatients (n=74) were compared with matched healthy subjects (HC, n=40). A lipidomic analysis was performed in red blood cell (RBC) membranes examining the major phospholipid (PL) classes and their associated fatty acids (FAs). Clinical manifestations were examined using the positive and negative syndrome scale (PANSS). Cognitive function was assessed using the Continuous Performance Test, Salience Attribution Test and Wisconsin Card Sorting Test. Sphingomyelin (SM) percentage was the lipid abnormality most robustly associated with a schizophrenia diagnosis. Two groups of patients were defined. The first group (SCZ c/SM-) is characterized by a low SM membrane content. In this group, all other PL classes, plasmalogen and key polyunsaturated FAs known to be involved in brain function, were significantly modified, identifying a very specific membrane lipid cluster. The second patient group (SCZ c/SM+) was similar to HCs in terms of RBC membrane SM composition. Compared with SCZ c/SM+, SCZ c/SM- patients were characterized by significantly more severe PANSS total, positive, disorganized/cognitive and excited psychopathology. Cognitive performance was also significantly poorer in this subgroup. These data show that a specific RBC membrane lipid cluster is associated with clinical and cognitive manifestations of dopamine dysfunction in schizophrenia patients. We speculate that this membrane lipid abnormality influences presynaptic dopamine signaling.
The various roles of membrane lipids in human health has urged researchers to study their impact in neuropsychiatric diseases, especially in schizophrenia spectrum disorders and more recently in ...early stages of psychosis. The progress in mass spectrometry technologies now allows a more comprehensive analysis of phospholipids (PL) and their fatty acid (FA) molecular species. FA are defined by a carbon chain of variable length and are said to be unsaturated when their chain has one or more carbon-carbon double bonds. The PL are composed of a hydrophilic polar head with a phosphoric acid group and an hydrophobic part with FAs; they encompass glycerophospholipids and sphingolipids. The plasma membrane is a complex and dynamic structure consisting of a lipid bilayer composed of an outer layer and an inner layer of specific lipid composition. The permanent remodeling of membrane lipids involves phospholipases especially the phospholipase A2. Seventy percent of the brain consists of lipids from different classes and molecular species. Most of the brain lipids are composed of polyunsaturated fatty acid (PUFA)-enriched diacyl classes where omega-3 and omega-6 molecular species predominate. The balance between omega-3 and omega-6 is important for the neurodevelopment. PUFA are also involved in neurogenesis and neurotransmission. Sphingomyelin (SM) is a sphingolipid that influences inflammation, cell proliferation and lipid rafts formation. It is an important component of myelin sheaths of white matter and therefore is involved in cerebral connectivity. In rat models, deficiency in omega-3 causes abnormalities in dopaminergic neurotransmission, impacts on the functioning of some receptors (including cannabinoids CB1, glutamatergic N-methyl-D-aspartate receptor, NMDA), and increases sensitivity to hallucinogens. In contrast, omega-3 supplementation improves cognitive function and prevents psychotic-like behavior in some animal models for schizophrenia. It also reduces oxidative stress and prevents demyelination. The historical membrane hypothesis of schizophrenia has led to explore the lipids abnormality in this disorder. This hypothesis was initially based on the observation of an abnormal membrane prostaglandin production in schizophrenia caused by a membrane arachidonic acid deficiency. It has evolved emphasizing the various PUFA membrane's roles in particular regarding oxidative stress, inflammation and regulation of the NMDA receptors. In patients with mental disorders, low omega-3 index is more frequent than in the general population. This lipid abnormality could lead to myelination abnormalities and cognitive deficits observed in patients. It could also participate in oxidative stress abnormalities and inflammation reported in schizophrenia. On the other hand, low omega-3 index deficit was reported to be associated with an increased cardiovascular risk, and omega-3 supplementation may also have a positive cardiovascular impact in psychiatric patients, even more than in the general population. The presence of membrane lipid abnormalities is also found in patients during the first psychotic episode (FEP). The omega-3 supplementation improved the recovery rate and prevented the loss of gray matter in FEP. In patients at ultra-high risk to develop a psychotic disorder (UHR), omega-3 supplementation has been associated with a reduction of the rate of conversion to psychosis and with metabolic changes, such as decreased activity of phospholipase A2. However, this study has not as yet been replicated. Not all patients exhibit lipid abnormalities. Several studies, including studies from our team, have found a bimodal distribution of lipids in patients with schizophrenia. But some studies have found differences (in PUFA) in the acute phase whereas our studies (on phospholipids) are in chronic phases. It will be interesting to study in more depth the links between these two parameters. Furthermore, we identified a subgroup which was identified with a deficit in sphingomyelin and PUFA whereas others have found an increase of sphingomyelin. Individuals with this abnormal lipid cluster had more cognitive impairments and more severe clinical symptoms. Because the niacin test is an indirect reflection of arachidonic acid levels, it has been proposed to identify a subset of patients with membrane lipids anomalies. Niacin test response is influenced by several factors related to lipid metabolism, including cannabis use and phospholipase A2 activity. Despite progress, the function and impact of membrane lipids are still poorly understood in schizophrenia. They could serve as biomarkers for identifying biological subgroups among patients with schizophrenia. In UHR patients, their predictive value on the conversion to psychosis should be tested. Omega-3 supplementation could be a promising treatment thanks to its good tolerance and acceptability. It could be more appropriate for patients with PUFA anomalies in a more personalized medical approach.
Prevention of the risk of recurrence of depressive episodes is a dynamic process that begins early in the management. Although complete remission is obtained for almost half of the treated depressive ...episodes, a heuristic conceptual thinking apprehends depression as a potentially chronic disorder when considering relapse and recurrence prevention. Multiple actions of care have to be initiated. They are formalised, but also adjustable to the needs of a critical management period throughout the follow-up. These actions include the prescription of an antidepressant at an effective dosage. They also consider the preventative and therapeutic impact of psychotherapy. The search for residual symptoms of depression is the rule, and addition of other medication should be considered if needed. These recommendations are evidence-based in the context of recurrence prevention. Nevertheless, many other initiatives are equally important recommendations in terms of therapeutic impact. Thus, rigorous evaluation of the initial symptomatology, promotion of information on disease, health-care advices, as well as implementation of family and other networks are good-practices. Such actions should be conducted in a relationship based on a therapeutic alliance. These elements need to be adjusted and contextualised in line with the Health System, mode of medical practice and unique style of the therapist. Proactive and sustainable implementations of these guidelines are required in the context of a unique and open therapeutic relationship for both therapist and patient.
Stigma associated with depression and antidepressants is strong among the general population but also among patients and health professionals.
This cross-sectional study is aimed at: 1) evaluating ...the knowledge and attitude towards antidepressant by nursing student; 2) exploring the association between instruction in psychiatry and representation of depression and antidepressants.
2037 undergraduate students from 10 French nursing schools were invited to participate in 2017, 1475 (73%) completed the questionnaire.
The self-report questionnaire included the Drug Attitude Inventory (DAI) and questions about representation on depression and antidepressant. Four groups of students were built: 1) pre-teaching group (PT) as a reference group, 2) clinical training in psychiatry (CT), 3) receiving mental health theoretical education (TE), 4) receiving both (CT + TE).
The mean (standard deviation) DAI score was negative: -1.9 (±4.4) with only 40% of the nursing students conveying a positive attitude towards antidepressant. A combination of CT and TE was associated with a more positive attitude towards antidepressant in comparison with the PT condition. The CT + TE group was more prone to view antidepressants as effective and safe.
There is strong stigma against depression/antidepressants among nursing student. Education combined with clinical experiences in psychiatry improved these representations.
•60% of the nursing students had a negative attitude to antidepressant.•Students showed a stronger mistrust in antidepressant than general population.•Theoretical education + clinical practicum improved antidepressants representations.
Introduction La non-adhésion diminue largement l’efficacité des antidépresseurs 1,2 , dont la représentation évolue dans un contexte particulièrement défiant et médiatiquement tendu. Objectif ...L’objectif de cette étude est de : – évaluer l’adhésion aux antidépresseurs chez des patients hospitalisés pour épisode dépressif majeur ; – explorer les représentations que les patients ont des antidépresseurs et de la dépression, ainsi que la perception de la stigmatisation aux troubles mentaux ; – analyser la relation entre les attitudes face aux antidépresseurs et des paramètres sociodémographiques et cliniques. Méthode L’adhérence était évaluée chez 40 patients en utilisant la version courte du Drug Attitude Inventory (DAI-10), complétée par un questionnaire mesurant les connaissances, craintes, impact des média et stigmatisation liés aux antidépresseurs. Des entretiens d’investigation étaient ensuite menés à l’aide de celui-ci. Résultats L’âge moyen de l’échantillon est de 43 ans, dont 27 % d’homme. Il s’agit d’un premier épisode pour 40 % des patients. La médiane du DAI est de 3,5 (échelle de −10 à +10), et 30 % des patients ne sont pas adhérents. Les hommes de l’échantillon ont une plus mauvaise représentation des antidépresseurs (−2 VS 4 ; U de Mann-Whitney = 90,50 ; p = 0,0035). Soixante-dix pour cent des patients ont des craintes par rapport à leur antidépresseur (prise de poids et dépendance au premier rang). Vingt pour cent des patients n’ont pas dit à leur entourage qu’ils prenaient des médicaments contre la dépression. Discussion Une intervention à de multiples niveaux pourrait augmenter les connaissances des patients ainsi que de l’opinion publique 3 . Une collaboration spécifique entre journalistes et psychiatres permettrait une meilleure connaissance et une diffusion plus représentative des enjeux de santé mentale dans les média 4 . Des actions de santé publique et initiatives citoyennes pourraient aussi être profitables aux patients. Conclusion L’adhérence aux antidépresseurs peut largement être améliorée, la stigmatisation restant une barrière aux traitements et à la prise en charge.
TEMPPO is an observational, cross-sectional and multicentre study, initiated in the French metropolitan territory in 2009. Set up from a random sample of 135 psychiatrists, it has observed the ...procedures for therapeutic management of a population (n=619) of their outpatients (respectively 197 and 422 in public and private practice) with bipolar disorder type I or II disorders (DSM-IV). The patients who were followed were mostly very sick. Every patient received a pharmacological treatment. The prescription included at least one mood stabilizer or an antipsychotic (71 % atypical) in 78 % and 56 % of cases respectively. Treatment regimen changes were frequent (61 % of patients had at least one change in treatment during the last 12 months). A single molecule by therapeutic class was generally prescribed. The presence of an antipsychotic in combination therapy was often associated with the severity or difficulty of care of the patient (mixed states, severity of the global functioning impairment, manic states, high number of hospitalizations and history of suicide attempt). The combination of two antipsychotics is found only in the difficult situations of manic states. Patients with severe depressive phase are those who benefit from the combination mood stabilizer+antipsychotic+antidepressant (16 % of the sample). In this study, the prescription of antidepressants significantly differs from recommendations for good prescribing practices. Indeed antidepressants were commonly prescribed in mixed-phase (63 %), particularly as a monotherapy in 5 % of cases. It was also found in patients in euthymic phase (48 %), manic phase (12 %) and hypomanic phase (29 %). The prescription of atypical antipsychotics (monotherapy or combination) is now fully established in the management of all phases of the disease. The importance of non-pharmacological treatment is acknowledged by psychiatrists and proposed whether a psychotherapeutic support, information about the disease and/or lifestyle changes. The data collected in this study allowed to demonstrate that the participant psychiatrists have a pharmacological management of patients with bipolar disorder mostly in line with national and international guidelines.
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