Traitement pharmacologique de la schizophrénie : évaluation comparative de la qualité des recommandations de pratique clinique = Comparative evaluation of clinical practice guidelines for the treatment of schizophrenia

De nombreuses recommandations de pratique clinique (RPC) ont été publiées, en réponse au développement du concept de la médecine fondée sur les preuves et comme solution à la difficulté de synthétiser et trier l'abondante littérature médicale. Pour faire un choix parmi le foisonnement de nouvelles RPC, il est primordial d'évaluer leur qualité. Récemment, le premier instrument d'évaluation standardisée de la qualité des RPC, appelé " AGREE " pour appraisal of guidelines for research and evaluation, a été validé. Nous avons comparé - avec l'aide de la grille " AGREE " - les six principales RPC publiées depuis une dizaine d'années sur le traitement de la schizophrénie : (1) les Recommandations de l'Agence nationale pour le développement de l'évaluation médicale (ANDEM) ; (2) The American Psychiatric Association (APA) practice guideline for the treatment of patients with schizophrenia ; (3) The quick reference guide of APA practice guideline for the treatment of patients with schizophrenia [APA - guide rapide de référence] ; (4) The schizophrenia patient outcomes research team (PORT) treatment recommandations ; (5) The Texas medication algorithm project " T-MAP " ; (6) The expert consensus guideline for the treatment of schizophrenia. Les résultats de notre étude ont ensuite été comparés avec ceux d'une étude similaire publiée en 2005 par Gæbel et al. portant sur 24 RPC abordant le traitement de la schizophrénie, réalisée également avec l'aide de la grille " AGREE " et deux évaluateurs [Br J Psychiatry 187 (2005) 248-255]. De manière générale, les scores des deux études ne sont pas trop éloignés et les deux évaluations globales des RPC convergent : chacune des six RPC est perfectible et présente différemment des points faibles et des points forts. La rigueur d'élaboration des six RPC est dans l'ensemble très moyenne, la prise en compte de l'opinion des utilisateurs potentiels est lacunaire et un effort sur la présentation des recommandations faciliterait leur utilisation clinique. L'applicabilité des recommandations est également peu considérée par les auteurs. Globalement, deux RPC se distinguent et peuvent être fortement recommandées selon les critères de la grille " AGREE " : " l'APA - guide rapide de référence " et le " T-MAP ".

Glutathione deficit in schizophrenia: strategies to increase glutathione levels in " in vitro " and clinical studies

Summary: Decrease in glutathione (GSH) levels was observed in cerebrospinal fluid, prefrontal cortex and post-mortem striatum of schizophrenia patients. Evidences suggest a defect in GSH synthesis at the levels of the rate-limiting synthesizing enzyme, glutamate cysteine ligase (GCL). Indeed, polymorphisms in the gene of the modifier subunit of GCL (GCLM) was shown to be associated with the disease in three different populations, GCLM gene expression is decreaséd in fibroblasts from patients and the increase in GCL activity induced by an oxidative stress is lower in patients' fibroblasts compared to controls. GSH being a major antioxydant and redox regulator, its presence is of high importance for protecting cells against oxidative stress. The aim of the present work was to use various substances to increase GSH levels by diverse strategies. Since the synthesizing enzyme GCL is defective, bypassing this enzyme was the first strategy we used. GSH ethyl ester (GSHEE), a membrane permeable analog of GSH, succeeded in replenishing GSH levels in cultured neurons and astrocytes previously depleted in GSH by L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of GCL. GSHEE also abolished dopamine-induced decrease of NMDA-mediated calcium response observed in BSO-treated neurons. y-Glutamylcysteine ethyl ester (GCSE), a membrane permeable analog of the product of GCL, increased GSH levels only in astrocytes. The second strategy was to boost the defective enzyme GCL. While quercetin (flavonoid) could increase GSH levels only in astrocytes, curcumin (polyphenol) and tertbutylhydroquinone (quinone) were successful in both neurons and astrocytes, via an increase in the gene expression of the two subunits of GCL and, consequently, an increase in the activity of the enzyme. However, FK506, an immunosupressant, was unefficient. Treating astrocytes from GCLM KO mice showed that the modulatory subunit is necessary for the action of the substances. Finally, since cysteine is the limiting precursor in the synthesis of GSH, we hypothesized that we could increase GSH levels by providing more of this precursor. N-acetyl-cysteine (NAC), a cysteine donor, was administered to schizophrenia patients, using adouble-blind and cross-over protocol. NAC significantly improved the mismatch negativity (MMN), a component of the auditory evoked potentials, thought to reflect selective current flowing through open, unblocked NMDA channels. Considering that NMDA function is reduced when GSH levels are low, increasing these levels with NAC could improve NMDA function as reflected by the improvement in the generation of the MMN. Résumé: Les taux de glutathion (GSH) dans le liquide céphalo-rachidien, le cortex préfrontal ainsi que le striatum post-mortem de patients schizophrènes, sont diminués. L'enzyme limitante dans la synthèse du GSH, la glutamyl-cysteine ligase (GCL), est défectueuse. En effet, des polymorphismes dans le gène de la sous-unité modulatrice de GCL (GCLM) sont associés à la maladie, l'expression du gène GCLM est diminuée dans les fibroblastes de patients et, lors d'un stress oxidative, l'augmentation de l'activité de GCL est plus faible chez les patients que chez les contrôles. Le GSH étant un important antioxydant et régulateur du status redox, sa présence est primordiale afin de protéger les cellules contre les stress oxydatifs. Au cours du présent travail, une variété de substances ont été utilisées dans le but d'augmenter les taux de GSH. Passer outre l'enzyme de synthèse GCL qui est défectueuse fut la première stratégie utilisée. L'éthylester de GSH (GSHEE), un analogue du GSH qui pénètre la membrane cellulaire, a augmenté les taux de GSH dans des neurones et des astrocytes déficitaires en GSH dû au L-buthionine-(S,R)-sulfoximine (BSO), un inhibiteur du GCL. Dans ces neurones, le GSHEE a aussi aboli la diminution de la réponse NMDA, induite parla dopamine. L'éthyl-ester de y-glutamylcysteine (GCEE), un analogue du produit de la GCL qui pénètre la membrane cellulaire, a augmenté les taux de GSH seulement dans les astrocytes. La seconde stratégie était d'augmenter l'activité de l'enzyme GCL. Tandis que la quercétine (flavonoïde) n'a pu augmenter les taux de GSH que dans les astrocytes, la curcumin (polyphénol) et le tert-butylhydroquinone (quinone) furent efficaces dans les deux types de cellules, via une augmentation de l'expression des gènes des deux sous-unités de GCL et de l'activité de l'enzyme. Le FK506 (immunosupresseur) n' a démontré aucune efficacité. Traiter des astrocytes provenant de souris GCLM KO a permis d'observer que la sous-unité modulatoire est nécessaire à l'action des substances. Enfin, puisque la cysteine est le substrat limitant dans la synthèse du GSH, fournir plus de ce présurseur pourrait augmenter les taux de GSH. Nacétyl-cystéine (NAC), un donneur de cystéine, a été administrée à des schizophrènes, lors d'une étude en double-aveugle et cross-over. NAC a amélioré le mismatch negativity (MMN), un composant des potentials évoqués auditifs, qui reflète le courant circulant via les canaux NMDA. Puisque la fonctionnalité des R-NMDA est diminuée lorsque les taux de GSH sont bas, augmenter ces taux avec NAC pourrait améliorer la fonction des R-NMDA, réflété par une augmentation de l'amplitude du MMN.

Up-regulated 14-3-3β and 14-3-3ζ proteins in prefrontal cortex of subjects with schizophrenia: effect of psychotropic treatment.

14-3-3 is a family of conserved regulatory proteins that bind to a multitude of functionally diverse signalling proteins. Various genetic studies and gene expression and proteomic analyses have involved 14-3-3 proteins in schizophrenia (SZ). On the other hand, studies about the status of these proteins in major depressive disorder (MD) are still missing. Immunoreactivity values of cytosolic 14-3-3&#946; and 14-3-3&#950; proteins were evaluated by Western blot in prefrontal cortex (PFC) of subjects with schizophrenia (SZ; n=22), subjects with major depressive disorder (MD; n=21) and age-, gender- and postmortem delay-matched control subjects (n=52). The modulation of 14-3-3&#946; and 14-3-3&#950; proteins by psychotropic medication was also assessed. The analysis of both proteins in SZ subjects with respect to matched control subjects showed increased 14-3-3&#946; (&#916;=33±10%, p<0.05) and 14-3-3&#950; (&#916;=29±6%, p<0.05) immunoreactivity in antipsychotic-free but not in antipsychotic-treated SZ subjects. Immunoreactivity values of 14-3-3&#946; and 14-3-3&#950; were not altered in MD subjects. These results show the specific up-regulation of 14-3-3&#946; and 14-3-3&#950; proteins in PFC of SZ subjects and suggest a possible down-regulation of both proteins by antipsychotic treatment.

Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia.

Schizophrenia is a neurodevelopmental disorder reflecting a convergence of genetic risk and early life stress. The slow progression to first psychotic episode represents both a window of vulnerability as well as opportunity for therapeutic intervention. Here, we consider recent neurobiological insight into the cellular and molecular components of developmental critical periods and their vulnerability to redox dysregulation. In particular, the consistent loss of parvalbumin-positive interneuron (PVI) function and their surrounding perineuronal nets (PNNs) as well as myelination in patient brains is consistent with a delayed or extended period of circuit instability. This linkage to critical period triggers (PVI) and brakes (PNN, myelin) implicates mistimed trajectories of brain development in mental illness. Strategically introduced antioxidant treatment or later reinforcement of molecular brakes may then offer a novel prophylactic psychiatry.

Does chronic nicotine consumption influence visual backward masking in schizophrenia and schizotypy ?

Nicotine consumption is higher for people within the schizophrenia spectrum compared to controls. This observation supports the self-medication hypothesis, that nicotine relieves symptoms in, for example, schizophrenia patients. We tested whether performance in an endophenotype of schizophrenia (visual backward masking, VBM) is modulated by nicotine consumption in i) smoking and non-smoking schizophrenia patients, their first-degree relatives, and age-matched controls, ii) non-smoking and smoking university students, and iii) non-smoking, early and late onset nicotine smokers. Overall, our results confirmed that VBM deficits are an endophenotype of schizophrenia, i.e., deficits were highest in patients, followed by their relatives, students scoring high in Cognitive Disorganisation, and controls. Moreover, we found i) beneficial effects of chronic nicotine consumption on VBM performance, in particular with increasing age, and ii) little impact of clinical status. alone or in interactionwith nicotine consumption on VBMperformance. Given the younger age of undergraduate students (up to 30 years) versus controls and patients (up to 66 years),we propose that age-dependent VBMdeficits emergewhen schizotypy effects are targeted in populations of a larger age range, but that nicotine consumption might counteract these deficits (supporting the self-medication hypothesis).

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients.

Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

Analysis of the mitochondrial DNA of Schizophrenia patients by next generation sequencing

Mitochondrial DNA (mtDNA), a maternally inherited 16.6-Kb molecule crucial for energy production, is implicated in numerous human traits and disorders. It has been hypothesized that the presence of mutations in the mtDNA may contribute to the complex genetic basis of schizophreniadisease, due to the evidence of maternal inheritance and the presence of schizophrenia symptoms in patients affected of a mitochondrial disorder related to a mtDNA mutation. The present project aims to study the association of variants of mitochondrial DNA (mtDNA), and an increased risk of schizophrenia in a cohort of patients and controls from the same population. The entire mtDNA of 55 schizophrenia patients with an apparent maternal transmission of the disease and 38 controls was sequenced by Next Generation Sequencing (Ion Torrent PGM, Life Technologies) and compared to the reference sequence. The current method for establishing mtDNA haplotypes is Sanger sequencing, which is laborious, timeconsuming, and expensive. With the emergence of Next Generation Sequencing technologies, this sequencing process can be much more quickly and cost-efficiently. We have identified 14 variants that have not been previously reported. Two of them were missense variants: MTATP6 p.V113M and MTND5 p.F334L ,and also three variants encoding rRNA and one variant encoding tRNA. Not significant differences have been found in the number of variants between the two groups. We found that the sequence alignment algorithm employed to align NGS reads played a significant role in the analysis of the data and the resulting mtDNA haplotypes. Further development of the bioinformatics analysis and annotation step would be desirable to facilitate the application of NGS in mtDNA analysis.

Inflammation in schizophrenia: A question of balance.

In the past decade, there has been renewed interest in immune/inflammatory changes and their associated oxidative/nitrosative consequences as key pathophysiological mechanisms in schizophrenia and related disorders. Both brain cell components (microglia, astrocytes, and neurons) and peripheral immune cells have been implicated in inflammation and the resulting oxidative/nitrosative stress (O&amp;NS) in schizophrenia. Furthermore, down-regulation of endogenous antioxidant and anti-inflammatory mechanisms has been identified in biological samples from patients, although the degree and progression of the inflammatory process and the nature of its self-regulatory mechanisms vary from early onset to full-blown disease. This review focuses on the interactions between inflammation and O&amp;NS, their damaging consequences for brain cells in schizophrenia, the possible origins of inflammation and increased O&amp;NS in the disorder, and current pharmacological strategies to deal with these processes (mainly treatments with anti-inflammatory or antioxidant drugs as add-ons to antipsychotics).

Positive Emotions Program for Schizophrenia (PEPS): a pilot intervention to reduce anhedonia and apathy.

BACKGROUND: Recent literature has distinguished the negative symptoms associated with a diminished capacity to experience (apathy, anhedonia) from symptoms associated with a limited capacity for expression (emotional blunting, alogia). The apathy-anhedonia syndrome tends to be associated with a poorer prognosis than the symptoms related to diminished expression. The efficacy of drug-based treatments and psychological interventions for these symptoms in schizophrenia remains limited. There is a clear clinical need for new treatments. METHODS: This pilot study tested the feasibility of a program to reduce anhedonia and apathy in schizophrenia and assessed its impact on 37 participants meeting the ICD-10 criteria for schizophrenia or schizoaffective disorders. Participants were pre- and post-tested using the Scale for the Assessment of Negative Symptoms (SANS) and the Calgary Depression Scale for Schizophrenia (CDSS). They took part in eight sessions of the Positive Emotions Program for Schizophrenia (PEPS)--an intervention that teaches participants skills to help overcome defeatist thinking and to increase the anticipation and maintenance of positive emotions. RESULTS: Thirty-one participants completed the program; those who dropped out did not differ from completers. Participation in the program was accompanied by statistically significant reductions in the total scores for Avolition-Apathy and Anhedonia-Asociality on the SANS, with moderate effect sizes. Furthermore, there was a statistically significant reduction of depression on the CDSS, with a large effect size. Emotional blunting and alogia remain stable during the intervention. DISCUSSION: Findings indicate that PEPS is both a feasible intervention and is associated with an apparently specific reduction of anhedonia and apathy. However, these findings are limited by the absence of control group and the fact that the rater was not blind to the treatment objectives. CONCLUSIONS: PEPS is a promising intervention to improve anhedonia and apathy which need to be tested further in a controlled study. TRIAL REGISTRATION NUMBER: ISRCTN registry ISRCTN74048461, registered 18 may 2015.

Executive dysfunction and memory impairment in schizoaffective disorder: a comparison with bipolar disorder, schizophrenia and healthy controls.

BACKGROUND: Deficits in memory and executive performance are well-established features of bipolar disorder and schizophrenia. By contrast, data on cognitive impairment in schizoaffective disorder are scarce and the findings are conflicting. METHOD: We used the Wechsler Memory Scale (WMS-III) and the Behavioural Assessment of the Dysexecutive Syndrome (BADS) to test memory and executive function in 45 schizophrenic patients, 26 schizomanic patients and 51 manic bipolar patients in comparison to 65 healthy controls. The patients were tested when acutely ill. RESULTS: All three patient groups performed significantly more poorly than the controls on global measures of memory and executive functioning, but there were no differences among the patient groups. There were few differences in memory and executive function subtest scores within the patient groups. There were no differences in any test scores between manic patients with and without psychotic symptoms. CONCLUSIONS: Schizophrenic, schizomanic and manic patients show a broadly similar degree of executive and memory deficits in the acute phase of illness. Our results do not support a categorical differentiation across different psychotic categories with regard to neuropsychological deficits.

A thematic analysis of delusion with religious content in schizophrenia: open, closed, and mixed dynamics

The aim of the present study was to elicit how patients with delusions with religious contents conceptualized or experienced their spirituality and religiousness. Sixty-two patients with present or past religious delusions went through semistructured interviews, which were analyzed using the three coding steps described in the grounded theory. Three major themes were found in religious delusions: ''spiritual identity,'' ''meaning of illness,'' and ''spiritual figures.'' One higher-order concept was found: ''structure of beliefs.'' We identified dynamics that put these personal beliefs into a constant reconstruction through interaction with the world and others (i.e., open dynamics) and conversely structural dynamics that created a complete rupture with the surrounding world and others (i.e., closed structural dynamics); those dynamics may coexist. These analyses may help to identify psychological functions of delusions with religious content and, therefore, to better conceptualize interventions when dealing with it in psychotherapy.

Attachment and spiritual coping in patients with chronic schizophrenia

Many studies on spirituality in psychosis have shown that, compared to a nonclinical population, patients make more use of spiritual beliefs/religious practices to deal with their problems. Our research question was to test whether attachment to spiritual figures could be a good explanation for religious coping strategies in patients with psychosis. First, adult attachment was investigated in 28 patients with chronic psychosis and 18 controls, using the Adult Attachment Interview. Diagnostic evaluations were performed with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (4th edition, Text Revision) Axis I disorders and symptomatic evaluation with the Brief Psychiatric Rating Scale. Results also show a high prevalence of insecure avoidant attachment in patients, and suggest that a significant part of religious coping might be explained by the theory of attachment (64% of the patients, 78% of controls). The implications of these results are interpreted in light of correspondence and compensation hypotheses.