Incidence of adverse events in antipsychotic-naïve children and adolescents treated with antipsychotic drugs: a French multicentre naturalistic study protocol (ETAPE)

ETAPE Study groupInternational audienceIntroduction: In France, over recent years, the prescription rate of antipsychotic (AP) remained stable in children and adolescents. Prescription of second-generation antipsychotics increased, whereas prescription of first-generation antipsychotics decreased. Off-label prescriptions are very frequent in this population. Adverse events (AEs) in youth treated with AP are common and may be severe. AEs have hitherto been poorly monitored in naturalistic studies independent from industry.Method and analysis: We describe a French prospective multicentre study in an AP-naïve paediatric population named Etude de la Tolérance des AntiPsychotique chez l'Enfant (ETAPE). The study started in April 2013. So far, 200 patients have been included. The inclusion criteria are: male or female inpatients aged from 6 to 18 years, treated with an AP drug for less than 28 days, never been treated or having received AP for less than 3 months, discontinued at least 6 months prior to inclusion. These assessments of AE are performed at inclusion, as well as at 3, 6, 9 and 12 months after the introduction of the AP. The monitoring period will end in May 2016.Ethics and dissemination: The study protocol was approved by the Ethics Committee 'Sud Méditerrané V' (number 12.082) and by the French National Agency for Medicines and Health Products Safety (number 2012-004546-15). All patients and their parents signed informed consent on enrolment in the study. We will submit the results of the study to relevant journals and offer national and international presentations. This study will enable better characterisation of the prescription of AP drugs. The results will further help to develop quality standards and recommendations for monitoring AE during the prescription of AP

Indication of Hyperthermic Intraperitoneal Chemotherapy in Gastric Cancer (Gastripec, Gastrichip)

Background: Gastric cancer (GC) is associated with a poor prognosis mostly due to peritoneal metastasis, which will develop in time during the patient's disease history. To prevent and treat peritoneal metastasis, different kinds of treatment regimens have been described. Summary: In this review, we addressed two main topics - prophylaxis and treatment of peritoneal metastasis in GC. Prevention should be directed towards diminishing cancer cell spillage and reducing adherence of cancer cells to the abdominal cavity. Postoperative washing of the abdomen with or without chemotherapy and additional heat are herein discussed. Key Messages: Treatment of existing peritoneal metastasis is effective in patients with limited disease and tumour spread. Cytoreductive surgery including resection of peritoneal metastasis followed directly with hyperthermic intraperitoneal chemotherapy can increase overall survival and progression-free survival in selected patients. Drugs, duration and time schedules of intraperitoneal chemotherapy are reviewed and presented. Intraperitoneal chemotherapy seems to improve the prognosis of patients with GC and peritoneal metastasis after complete resection of both primary and metastatic tumours

Malignant catatonia due to anti-NMDA-receptor encephalitis in a 17-year-old girl: case report

Anti-NMDA-Receptor encephalitis is a severe form of encephalitis that was recently identified in the context of acute neuropsychiatric presentation. Here, we describe the case of a 17-year-old girl referred for an acute mania with psychotic features and a clinical picture deteriorated to a catatonic state. Positive diagnosis of anti-NMDA-receptor encephalitis suggested specific treatment. She improved after plasma exchange and immunosuppressive therapy. Post-cognitive sequelae (memory impairment) disappeared within 2-year follow-up and intensive cognitive rehabilitation

Digital phenotype of mood disorders: A conceptual and critical review

BackgroundMood disorders are commonly diagnosed and staged using clinical features that rely merely on subjective data. The concept of digital phenotyping is based on the idea that collecting real-time markers of human behavior allows us to determine the digital signature of a pathology. This strategy assumes that behaviors are quantifiable from data extracted and analyzed through digital sensors, wearable devices, or smartphones. That concept could bring a shift in the diagnosis of mood disorders, introducing for the first time additional examinations on psychiatric routine care.ObjectiveThe main objective of this review was to propose a conceptual and critical review of the literature regarding the theoretical and technical principles of the digital phenotypes applied to mood disorders.MethodsWe conducted a review of the literature by updating a previous article and querying the PubMed database between February 2017 and November 2021 on titles with relevant keywords regarding digital phenotyping, mood disorders and artificial intelligence.ResultsOut of 884 articles included for evaluation, 45 articles were taken into account and classified by data source (multimodal, actigraphy, ECG, smartphone use, voice analysis, or body temperature). For depressive episodes, the main finding is a decrease in terms of functional and biological parameters [decrease in activities and walking, decrease in the number of calls and SMS messages, decrease in temperature and heart rate variability (HRV)], while the manic phase produces the reverse phenomenon (increase in activities, number of calls and HRV).ConclusionThe various studies presented support the potential interest in digital phenotyping to computerize the clinical characteristics of mood disorders

Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of ASD

Pain Reactivity and Plasma β-Endorphin in Children and Adolescents with Autistic Disorder

International audienceBackground: Reports of reduced pain sensitivity in autism have prompted opioid theories of autism and have practical care ramifications. Our objective was to examine behavioral and physiological pain responses, plasma β-endorphin levels and their relationship in a large group of individuals with autism.Methodology/Principal Findings: The study was conducted on 73 children and adolescents with autism and 115 normal individuals matched for age, sex and pubertal stage. Behavioral pain reactivity of individuals with autism was assessed in three observational situations (parents at home, two caregivers at day-care, a nurse and child psychiatrist during blood drawing), and compared to controls during venepuncture. Plasma β-endorphin concentrations were measured by radioimmunoassay. A high proportion of individuals with autism displayed absent or reduced behavioral pain reactivity at home (68.6%), at day-care (34.2%) and during venepuncture (55.6%). Despite their high rate of absent behavioral pain reactivity during venepuncture (41.3 vs. 8.7% of controls, P<0.0001), individuals with autism displayed a significantly increased heart rate in response to venepuncture (P<0.05). Moreover, this response (Δ heart rate) was significantly greater than for controls (mean±SEM; 6.4±2.5 vs. 1.3±0.8 beats/min, P<0.05). Plasma β-endorphin levels were higher in the autistic group (P<0.001) and were positively associated with autism severity (P<0.001) and heart rate before or after venepuncture (P<0.05), but not with behavioral pain reactivity.Conclusions/Significance: The greater heart rate response to venepuncture and the elevated plasma β-endorphin found in individuals with autism reflect enhanced physiological and biological stress responses that are dissociated from observable emotional and behavioral reactions. The results suggest strongly that prior reports of reduced pain sensitivity in autism are related to a different mode of pain expression rather than to an insensitivity or endogenous analgesia, and do not support opioid theories of autism. Clinical care practice and hypotheses regarding underlying mechanisms need to assume that children with autism are sensitive to pain

Modulation of Brain β-Endorphin Concentration by the Specific Part of the Y Chromosome in Mice

International audienceBackground: Several studies in animal models suggest a possible effect of the specific part of the Y-chromosome (Y NPAR) on brain opioid, and more specifically on brain b-endorphin (BE). In humans, male prevalence is found in autistic disorder in which observation of abnormal peripheral or central BE levels are also reported. This suggests gender differences in BE associated with genetic factors and more precisely with Y NPAR. Methodology/Principal Findings: Brain BE levels and plasma testosterone concentrations were measured in two highly inbred strains of mice, NZB/BlNJ (N) and CBA/HGnc (H), and their consomic strains for the Y NPAR. An indirect effect of the Y NPAR on brain BE level via plasma testosterone was also tested by studying the correlation between brain BE concentration and plasma testosterone concentration in eleven highly inbred strains. There was a significant and major effect (P,0.0001) of the Y NPAR in interaction with the genetic background on brain BE levels. Effect size calculated using Cohen's procedure was large (56% of the total variance). The variations of BE levels were not correlated with plasma testosterone which was also dependent of the Y NPAR. Conclusions/Significance: The contribution of Y NPAR on brain BE concentration in interaction with the genetic background is the first demonstration of Y-chromosome mediated control of brain opioid. Given that none of the genes encompassed by the Y NPAR encodes for BE or its precursor, our results suggest a contribution of the sex-determining region (Sry, carried by Y NPAR) to brain BE concentration. Indeed, the transcription of the Melanocortin 2 receptor gene (Mc2R gene, identified as the proopiomelanocortin receptor gene) depends on the presence of Sry and BE is derived directly from proopiomelanocortin. The results shed light on the sex dependent differences in brain functioning and the role of Sry in the BE system might be related to the higher frequency of autistic disorder in males

ETUDE DU STRESS PSYCHOSOCIAL, PHYSIQUE ET NOCICEPTIF DANS LES SCHIZOPHRENIES A DEBUT PRECOCE ET L'AUTISME

Background: Clinical and experimental studies suggest that autistic and schizophrenic patients are insensitive to pain. Stress plays a key role in onset or relapse of symptoms of autism or schizophrenia, but mechanisms are unclear. We studied reactivity to psychosocial, physical and nociceptif stress in patients with autism and early onset schizophrenia (EOS) by assessing behavioural, electrophysiological and neurovegetative responses. Objectives: (1) To study the circadian rhythm of salivary cortisol reflecting hypothalamo-pitiutary axis (HTA) (2) To show a higher response of HTA axis during psychosocial stress procedure and not during a physical stress procedure (cortisol study) (3) Obtain, by RIII reflex assessment, an objective measure of pain perception in autism and EOS, this study should show normal RIII threshold. (4) Showing higher nociceptif inducted vegetative nervous system (VNS) responses in patients with autism and EOS in the same time as lower verbal or emotional reactivity. (5) Showing dissociation between behavioural responses and RIII responses. Methodology: Population: Patients with EOS (n=16), Autism (n=20) and healthy subject (n=22) were compared. Diagnostic was assessed according to DSM IV criteria. Clinical assessments: BPRS, SANS, SAPS, TAS, Coping, STAI, C-GAS, CGI, MADRS, ADI-R and Wechsler scales for EOS patients and ADOS-G and Wechsler scales for Autistic patients. Protocol: Patients with EOS were included for psychosocial stress procedure (P, camera speaking task) and physical stress procedure (B, apartment bicycle riding). P and B procedure were scheduled twice (between 7am and 9am and between 4pm and 6pm) in one day (afternoon session following morning session) or in two days (morning session following afternoon session). During session assessment of cardiac frequency and salivary cortisol sample were collected. Autistic patients and EOS patients (n=10) were included in nociceptif procedure (consisting in progressive electric stimulation in order to raise RIII reflex threshold, capsaicin test to release substance P and EMG for sensitive and motor speed conduction assessment). During this procedure, cardiac and respiratory frequency, psychogalvanic reflex and behavioural reactivity (assessed with PL-BPRS) were measured. Results: EOS patient's cortisol basal profile and circadian rhythm were significatively higher in the morning when compared to healthy subjects. EOS patients starting psychosocial stress procedure in the morning session show an elevated cortisol response in the morning and a lower cortisol response in the afternoon. This difference was not found for healthy subject. All patients (Autism and EOS) had RIII threshold showing no difference when compared to healthy subjects. A sub-group of autistic patients with severe self-injury behaviour show low RIII threshold. We found dissociation between low behavioural reactivity and VNS responses for all patients. This dissociation is particularly notable for cardiac frequency in EOS patients and for respiratory frequency for autistic patients. Discussion: Biological response to stress is more elevated if stress occurs in the morning, linked to psychosocial dimension and novelty. HTA axis may be more solicited in the morning leading to an elevated release of cortisol. Our results suggest that apparent pain insensibility to pain in autism and EOS is more related to cognitive impairments than real endogen analgesia. Preferred responses are from VNS, algic stress couldn't be expressed by verbal or non-verbal behaviour. Psychosocial and nociceptive stress procedure shows in patients (EOS and Autism) higher responses of VNS and HTA axis, particularly in the morning. These results suggest a common dimension between EOS and Autism, particularly about novelty and immuability. These results need further research and are opening therapeutic options.Des observations cliniques et travaux de recherche suggèrent des réponses au stress perturbées dans l'autisme et les schizophrénies à début précoce (SDP). Nous avons étudié la réactivité au stress physique, psychosocial et nociceptif dans ces deux pathologies en évaluant les réponses comportementales, électrophysiologiques et neurovégétatives. Objectif général : Mettre en évidence chez les patients autistes et SDP des réponses anormalement élevées au stress, en particulier dans les situations de stress psychosocial ou nociceptif. Objectifs spécifiques (1) Etudier le rythme circadien du cortisol salivaire qui reflète la fonctionnement de l'axe hypothalamo-hypophysiaire (HPA) dans les SDP. (2) Mettre en évidence une réponse au stress anormalement élevée de l'axe HPA (étude du cortisol) à la situation de stress psychosocial mais pas à la situation de stress physique chez les patients SDP. (3) Obtenir, grâce à l'étude du réflexe RIII, une mesure objective de la perception de la douleur chez les patients autistes et SDP (4) Mettre en évidence des réponses du système nerveux SNV, à la suite d'un stimulus nociceptif, anormalement augmentées aussi bien chez les patients autistes que SDP, alors que l'expression verbale et émotionnelle serait diminuée. (5) De même, objectiver une dissociation entre les réponses comportementales extériorisées à la douleur et la réponse neurophysiologique réflexe infraclinique (RIII) chez les patients autistes et SDP. Méthodologie Population : Groupes de patients SDP (n=16), autistes (n=20) et témoins (n=22) diagnostiqués selon les critères du DSM IV-R. Les caractéristiques phénotypiques ont été précisées avec les instruments d'évaluation suivants : BPRS, SANS, SAPS, TAS, Coping, STAI, C-GAS, CGI, MADRS pour les patients SDP, et ADOS-G, ADI-R et échelles de Weschler pour les patients autistes. Protocole : Les patients SDP ont participé à des épreuves de stress psychosocial (discours devant un jury) et à des épreuves de stress physique (vélo). Ces épreuves ont eu lieu à deux reprises, soit sur une journée (matin puis après midi), soit sur deux jours (après midi puis matin). Durant les épreuves nous avons mesuré la fréquence cardiaque et le taux de cortisol salivaire. Le stress nociceptif a été étudié par la mesure du réflexe RIII chez les patients autistes (n=20) et SDP (n=10) comparés aux témoin (n=22) Durant l'étude du RIII, ont été mesurés les réponses neurovégétatives (rythme cardiaque, fréquence respiratoire et réflexe psychogalvanique) et la réactivité comportementale à la douleur (PL-BPRS). Cette étude neurophysiologique a été complétée par un test à la capsaïcine (sensibilité thermoalgique) et un électromyogramme. Résultats Le rythme circadien et le profil de sécrétion du cortisol (ligne de base) des patients SDP sont significativement différents de ceux des témoins (taux significativement plus élevés le matin). L'étude du stress physique et psychosocial met en évidence chez les patients SDP des réponses anormalement augmentées du cortisol lorsqu'il s'agit d'une situation nouvelle, se déroulant le matin et relevant d'un stress psychosocial, alors que les réponses l'après midi sont normales ou diminuées Concernant l'étude du stress nociceptif, tous les patients autistes et SDP ont des seuils de réflexe RIII qui ne diffèrent pas significativement de ceux des témoins. Cependant, certains patients autistes avec des automutilations sévères présentent un seuil de réflexe anormalement bas. Enfin, Il existe une dissociation entre une réduction des réponses comportementales à la douleur (expression émotionnelle) observables et les réponses augmentées du système nerveux végétatif chez les patients autistes et SDP. Cette dissociation est plus marquée pour la fréquence respiratoire chez les patients autistes et pour le rythme cardiaque chez les patients SDP. Discussion Nos résultats suggèrent que l'apparente insensibilité à la douleur chez les patients autistes et SDP n'est pas en rapport avec une analgésie endogène, mais relèverait de leurs troubles cognitifs (troubles de la communication sociale et de l'image du corps). . Le mode de réponse préférentiel à la douleur serait neurovégétatif, le stress algique ne pouvant s'extérioriser au moyen de la communication verbale et non-verbale. Par ailleurs, l'axe HPA serait sur-sollicité le matin chez les patients SDP, entraînant une décharge excessive du cortisol, ce qui expliquerait les réponses anormalement basses au test psychosocial l'après midi. Les études du stress psychosocial et nociceptif mettent en évidence chez les patients autistes et SDP des réponses anormalement élevées du système nerveux végétatif et de l'axe hypothalamo-hypophysaire, notamment le matin. Ces résultats suggèrent l'existence de dimensions communes à l'autiste et la SDP, notamment concernant des réponses au stress anormalement augmentées, et la réactivité à la nouveauté avec un besoin d'immuabilité passant par une recherche d'avariant. Ceci ouvre sur des perspectives thérapeutiques et des recherches ultérieures de façon à mieux comprendre les mécanismes sous-tendant ces résultat