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Clément Nathou,1,2 Olivier Etard,2,3 Sonia Dollfus1,21Normandie Univ, UNICAEN, CHU de Caen, Service de Psychiatrie Adulte, Caen, F-14000, France; 2Normandie Univ, UNICAEN, ISTS, EA 7466, GIP Cyceron, Caen 14000, France; 3Normandie Univ, UNICAEN, CHU de Caen, Service des Explorations Fonctionnelles du Système Nerveux, CHU de Caen, Caen, F-14000, FrancePurpose: This review reports the current perspectives of brain stimulation techniques in the treatment of auditory verbal hallucinations (AVH) in schizophrenia.Methods: A systematic search of the literature in the PubMed database revealed that the most studied techniques are noninvasive techniques (NIBS), including electroconvulsive therapy (ECT), transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS).Results: The results showed that ECT could have great clinical efficacy but is currently underused in practice perhaps due to the costs associated with its limited implementation and potential associated risks. tDCS is still poorly studied and does not demonstrate sufficiently homogeneous or conclusive results yet to prove its efficacy in the treatment of AVH. However, its safe and simple implementation allows us to recommend it to patients who are refractory to other stimulation techniques. Finally, rTMS seems to be the most efficacious NIBS to offer patients with persistent AVH as an add-on therapeutic strategy. Its implementation has a non negligible cost but can be performed by a single practitioner. Great evolution in these techniques with technological progress, robotics and computer science are currently being tested and will undoubtedly improve the clinical efficacy of these procedures, particularly towards more personalized treatments such as individual rTMS targets and intensities. There are also new techniques for deep brain stimulation based on focused ultrasound that could provide much insight into the treatment of AVH in schizophrenia.Conclusion: This review suggests that add-on brain stimulation treatments could play a key role among the therapeutic strategies for auditory hallucinations reduction in schizophrenia.Keywords: electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, auditory hallucinations, schizophrenia

Background. During the last decades, a renewed interest for negative symptoms (NS) was brought about by the increased awareness that they interfere severely with real-life functioning, particularly when they are primary and persistent. Methods. In this guidance paper, we provide a systematic review of the evidence and elaborate several recommendations for the conceptualization and assessment of NS in clinical trials and practice. Results. Expert consensus and systematic reviews have provided guidance for the optimal assessment of primary and persistent negative symptoms; second-generation rating scales, which provide a better assessment of the experiential domains, are available; however, NS are still poorly assessed both in research and clinical settings. This European Psychiatric Association (EPA) guidance recommends the use of persistent negative symptoms (PNS) construct in the context of clinical trials and highlights the need for further efforts to make the definition of PNS consistent across studies in order to exclude as much as possible secondary negative symptoms. We also encourage clinicians to use secondgeneration scales, at least to complement first-generation ones. The EPA guidance further recommends the evidence-based exclusion of several items included in first-generation scales from any NS summary or factor score to improve NS measurement in research and clinical settings. Self-rated instruments are suggested to further complement observer-rated scales in NS assessment. Several recommendations are provided for the identification of secondary negative symptoms in clinical settings. Conclusions. The dissemination of this guidance paper may promote the development of national guidelines on negative symptom assessment and ultimately improve the care of people with schizophrenia. [ABSTRACT FROM AUTHOR]

Negative symptoms of schizophrenia remain a major therapeutic challenge. The progress in the conceptualization and assessment is not yet fully reflected by treatment research. Nevertheless, there is a growing evidence base regarding the effects of biological and psychosocial interventions on negative symptoms. The importance of the distinction between primary and secondary negative symptoms for treatment selection might seem evident, but the currently available evidence remains limited. Good clinical practice is recommended for the treatment of secondary negative symptoms. Antipsychotic treatment should be optimized to avoid secondary negative symptoms due to side effects and due to positive symptoms. For most available interventions, further evidence is needed to formulate sound recommendations for primary, persistent, or predominant negative symptoms. However, based on currently available evidence recommendations for the treatment of undifferentiated negative symptoms (including both primary and secondary negative symptoms) are provided. Although it has proven difficult to formulate an evidence-based recommendation for the choice of an antipsychotic, a switch to a second-generation antipsychotic should be considered for patients who are treated with a first-generation antipsychotic. Antidepressant add-on to antipsychotic treatment is an option. Social skills training is recommended as well as cognitive remediation for patients who also show cognitive impairment. Exercise interventions also have shown promise. Finally, access to treatment and to psychosocial rehabilitation should be ensured for patients with negative symptoms. Overall, there is definitive progress in the field, but further research is clearly needed to develop specific treatments for negative symptoms. [ABSTRACT FROM AUTHOR]

NonInvasive Brain Stimulation (NIBS) is a potential therapeutic tool with growing interest, but neuronavigation-guided software and tools available for the target determination are mostly either expensive or closed proprietary applications. To address these limitations, we propose GeodesicSlicer, a customizable, free, and open-source NIBS therapy research toolkit. GeodesicSlicer is implemented as an extension for the widely used 3D Slicer medical image visualization and analysis application platform. GeodesicSlicer uses cortical stimulation target from either functional or anatomical images to provide functionality specifically designed for NIBS therapy research. The provided algorithms are tested and they are accessible through a convenient graphical user interface. Modules have been created for NIBS target determination according to the position of the electrodes in the 10–20 system electroencephalogram and calculating correction factors to adjust the repetitive Transcranial Magnetic Stimulation (rTMS) dose for the treatment. Two illustrative examples are processing with the module. This new open-source software has been developed for NIBS therapy: GeodesicSlicer is an alternative for laboratories that do not have access to neuronavigation system. The triangulation-based MRI-guided method presented here provides a reproducible and inexpensive way to position the TMS coil that may be used without the use of a neuronavigation system. [ABSTRACT FROM AUTHOR]

The population with schizophrenia is characterised by a leftward shift in handedness—sinistrality. However, findings are inconsistent in chronic patients, and familial sinistrality (FS), defined as the presence of left-handed close relatives, might contribute to the discrepancies. Therefore the aim of this study was to investigate the strength of manual lateralisation in patients with first episode schizophrenia, taking into account familial sinistrality. The Edinburgh Inventory (EI) allowed us to categorise 179 patients from the EUFEST study and 189 controls presenting “strong handedness” (SH: EI absolute value between ∣81∣ and ∣100∣) or “weak-handedness” (WH: EI value between −80 and +80). The nominal logistic regression did not show an FS effect, but a nearly significant interaction between illness and FS (p =.07). There were fewer participants without FS presenting SH among patients (99/151: 65.6%) than among controls (134/164: 81.7%, p =.001). In contrast, the number of participants with FS presenting SH was similar between controls (68%) and patients (75%, p =.57). The presence of left-handed relatives (FS + ) tended to reduce manual lateralisation, but only in controls. This supports the notion that reduced manual lateralisation in schizophrenia is related to the illness rather than to familial left-handedness. [ABSTRACT FROM PUBLISHER]

OBJECTIVE: Cognitive impairment, manifested as mild to moderate deviations from psychometric norms, is present in many but not all schizophrenia patients. The purpose of the present study was to compare the effect of haloperidol with that of second-generation antipsychotic drugs on the cognitive performance of patients with schizophreniform disorder or first-episode schizophrenia. METHODS: Subjects were 498 patients with schizophreniform disorder or first-episode schizophrenia who were randomly assigned to open-label haloperidol (1 to 4 mg/day [N=103]), amisulpride (200 to 800 mg/day [N=104]), olanzapine (5 to 20 mg/day [N=105]), quetiapine (200 to 750 mg/day [N=104]), or ziprasidone (40 to 160 mg/day [N=82]). The Rey Auditory Verbal Learning Test, Trail Making Test Part A and Part B, WAIS Digit Symbol Test, and Purdue Pegboard Test were administered at baseline and the 6-month follow-up evaluation. RESULTS: Compared with scores at baseline, composite cognitive test scores improved for all five treatment groups at the 6-month follow-up evaluation. However, there were no overall differences among the treatment groups. In addition, there was a weak correlation between the degree of cognitive improvement and changes in Positive and Negative Syndrome Scale scores. CONCLUSION: Treatment with antipsychotic medication is associated with moderate improvement in the cognitive test performance of patients who have schizophreniform disorder or who are in their first episode of schizophrenia. The magnitude of improvement does not differ between treatment with haloperidol and treatment with second-generation antipsychotics. Moreover, cognitive improvement is weakly related to symptom change. [ABSTRACT FROM AUTHOR]

Standardized assessments for negative symptoms are necessary in clinical practice, Research and therapeutic trials. As numerous scales have been developed, their advantages, limitations and some recommendations need to be described. Most of the scales are based on observer ratings but self-reports on negative symptoms have been recently developed. The NIMH-Negative Symptom Consensus Development Conference (Kirkpatrick, et al., 2006) has been a milestone for the development of a second generation of scales. These scales such as BNSS (Kirkpatrick et al., 2011) and CAINS (Blanchard et al., 2011) assess the 5 negative dimensions (alogia, social withdrawal, anhedonia, blunted affect and avolition) as recommended by the conference and also assess internal experiences for avolition and social withdrawal. Due to their good psychometric properties, they should be recommended for the assessment of negative symptoms. They supplant the first generation scales such as PANSS negative, SANS, NSA-16, SDS. These scales, although widely used, should not be recommended due to their limits according to the present concept on negative symptoms. However, SDS should be still considered for categorizing patients into deficit and no deficit sub-groups. Two recent self-assessment scales, the MAP-SR (Llerena et al., 2013) and the SNS (Dollfus et al., 2016) have been also developed. Due to the limits of first-generation self-assessments, they should be used for self-assessing negative symptoms as complementary measure of observer-ratings. Finally, other scales assessing anhedonia and avolition, initially developed in disorders other than schizophrenia, can also be considered since good psychometric properties have been observed in patients with schizophrenia. Disclosure: S. Dollfus received honoraria as expert/consultant by Fabre, Gedeon; invited Conferences: Lundbeck, Otsuka, Janssen, and has contracts with Prophase MedAvances and NeuroCog-Trials. [ABSTRACT FROM AUTHOR]

Introduction Negative symptoms are found in many patients with schizophrenia, but their assessment remains delicate. Standardized assessments are therefore needed to facilitate their identification. Many tools have been developed but most of them are assessments based on observer rating. Nevertheless, patient subjective evaluation can provide an additional outcome measure and allow patients to be more engaged in their treatment. Therefore, the aim of this study is to present past and recent tools assessing the subjective experience of negative symptoms; we will particularly focus on a novel tool, the Self-evaluation of Negative Symptoms (SNS). Methods Forty-nine patients with schizophrenia and schizoaffective disorders (DSMIV) were evaluated in order to demonstrate three components of the scale's validity: face and content validities and reliability. Results Cronbach's coefficient showed good internal consistency. Factor analysis extracted 2 factors (apathy and emotional). SNS was significantly correlated with the Scale of Assessment of Negative Symptoms and the Clinician Global Impression on severity of negative symptoms supporting good convergent validity. SNS scores were not correlated with level of insight, Parkinsonism, or with BPRS positive sub-scores in favor of good discriminant validity. Intra-subject reliability of SNS revealed excellent intraclass correlation coefficients. Conclusion This study shows good psychometric properties of SNS as well as quite satisfactory acceptance by patients. It also demonstrates the ability of patients with schizophrenia to accurately report their own experience. Self-assessments of negative symptoms should be used more in clinical practice since they might allow patients with schizophrenia to develop appropriate coping strategies. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS) shows a high inter-subjects variability in the efficacy of treatment of auditory verbal hallucinations (AVH) in schizophrenia. The aim of this presentation is to demonstrate the involvement of several factors in the efficacy of rTMS such as the frequency of stimulation, the placebo effect and the brain morphology underlying the target of stimulation. Methods A meta-analysis was conducted to determine the effect sizes of placebo effect in 21 controlled studies on rTMS in the treatment of AVH in schizophrenia. MRI was also acquired in patients treated by rTMS to evaluate the scalp to cortex distances (SDCs) and the gray matter densities (GMDs) at the target of stimulation. Finally, we evaluated the efficacy of high (20 Hz) frequency stimulation in a controlled placebo study. Results Weak or no placebo effect in the control groups led to reveal a superiority of active rTMS over sham rTMS in the treatment of AVH. Clinical efficacy of rTMS was also correlated with the SCD or the GMD at the region of the target stimulation. Finally, we also demonstrated that more responders were observed after 2 weeks in the active group treated by 20 Hz than in the placebo group. Conclusion We clearly demonstrated that several factors such as high frequency, the placebo effect, anatomical cortical variations can impact on the efficacy of rTMS. These results fundamentally inform the design and the method of further controlled studies, particularly with respect to studies of rTMS in the treatment of AVH. [ABSTRACT FROM AUTHOR]

Negative symptoms are a fundamental dimension of schizophrenia despite of their limited role in the international diagnostic classifications. Eighteen instruments are identified of which 11 assess specifically the negative symptoms. The assessment of subjective experience is neglected in most of these negative symptom rating scales. Consequently, we present a new scale, the Self-report of Negative Symptoms (SNS), assessing the 5 consensual negative dimensions (emotional blunting, alogia, social withdrawal, anhedonia and avolition). This scale is an auto-evaluation constituted of 20 questions with a score ranging from 0 to 40. Forty nine patients with schizophrenia and schizoaffective disorders (DSMIV) were evaluated in order to demonstrate three components of the scale’s validity: face and content validities and reliability. No item was judged inappropriate or poorly formulated (face validity). According to experts, the universe of items clearly covers all the negative symptoms (content validity). The Cronbach’s coefficient (α=0.784) showed a good internal consistency (reliability). Factor analysis extracted 1 factor which accounted for 56.75% of the variance. Moreover, the SNS scores were significantly correlated with the SANS scores (r=0.526, p<0.001) and the negative CGI scores (r=0.599, p<0.001) supporting a good convergent validity. In contrast, there was no correlation between the SNS scores and the self-report insight scores demonstrating that patients with negative symptoms can evaluate themselves their negative symptoms independently of their level of insight of illness. In conclusion, self-report of negative symptoms should be more used in clinical practice since it might allow the patients with schizophrenia to develop appropriate coping strategies. [ABSTRACT FROM AUTHOR]

Les traitements correcteurs de certains effets secondaires neurologiques induits par les traitements antipsychotiques peuvent être à l'origine d'effets indésirables de type anticholinergiques. Cependant, le risque de survenue ou d'exacerbation de symptômes psychotiques induits par ces traitements est beaucoup moins connu avec seulement quelques cas publiés concernant la tropatépine. De plus, les recommandations d'utilisation de ces traitements restent imprécises, aussi bien concernant leur indication que concernant leur effets indésirables, anticholinergiques ou non. Nous rapportons le cas d'un épisode psychotique chez un patient de 18 ans potentiellement acutisé suite à une intoxication médicamenteuse volontaire par la tropatépine. À dose élevée, les traitements anticholinergiques, tropatépine incluse, pourraient induire l'exacerbation d'épisodes psychotiques. De plus, les données épidémiologiques disponibles mettent en évidence une prescription inadaptée et excessive de ces traitements. Leur utilisation et leurs risques devraient être mieux connus des praticiens et nécessitent une mise à jour des recommandations disponibles. Corrective treatments for some neurological side effects due to antipsychotic treatments can induce anticholinergic adverse effects. However, the risk of triggering or increasing psychotic symptoms induced by these drugs is unknown with only one case-report concerning the tropatepine. In addition, recommendations for the use of these drugs remain imprecise regarding the management of this type of adverse effect. We report the case of a psychotic episode in an 18-year-old patient potentially acutised after an auto-intoxication with tropatepine. At high doses, anticholinergic treatments, including tropatepine, might increase psychotic episodes. In addition, the available epidemiological data reveal an inappropriate and excessive prescription of these drugs. Their use and risks should be better known and need an update of the available recommendations. [ABSTRACT FROM AUTHOR]

This exploratory study investigated the functional connectivity (FC) in the language network in schizophrenia patients (SZ) with auditory verbal hallucinations (AVHs), and the therapeutic efficacy of rTMS on it. Eleven SZ with AVHs and 10 healthy controls (HC) underwent two fMRI sessions using a speech listening paradigm. SZ received 20Hz rTMS following the first fMRI session. Compared to HC, SZ showed a reduced FC in the language network. While AVHs improved after 12days, no changes in FC were observed. This suggests the efficacy of high-frequency rTMS on AVH without any impact for rTMS on FC within the language network. [ABSTRACT FROM AUTHOR]