Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Early-onset schizophrenia: studying the links between cognitive and clinical dimensions.

BACKGROUND: Early-onset schizophrenia (EOS), a rare and severe chronic psychiatric condition, is defined by an onset of schizophrenia symptoms before the age of 18. Core symptoms also include cognitive impairments. However, little is known about links between psychiatric symptoms of EOS and cognitive abilities. OBJECTIVE: To explore the clinical and neurocognitive profiles of EOS patients and their links. METHOD: EOS patients have been phenotyped using standardised psychiatric assessments for DSM-5 diagnoses (K-SADS-PL) and for symptoms (PANSS and SANS), together with neurocognitive evaluations. RESULTS: The EOS sample (n = 27, 12.4 +/-3.2 years) presented hallucinations (83%), negative symptoms (70%) and delusion (59%). 81% of patients presented comorbidities such as anxiety disorders (33%), autism spectrum disorder (26%) and attention-deficit hyperactivity disorder (26%). Patients presented borderline intellectual deficiency (total IQ = 72.5 +/-4.7), with low performances in working memory subtest. We highlight a positive correlation between the IQ and intensity of positive symptoms (PANSS) and between the IQ and a first treatment being administered at an older age. We also highlight a negative correlation between the IQ and attention items of SANS. CONCLUSION: Cognitive skills are correlated with symptom intensity in EOS patients. An older age of onset seems to be a protective factor for cognitive development.

Hey1- and p53-dependent TrkC proapoptotic activity controls neuroblastoma growth.

The neurotrophin-3 (NT-3) receptor tropomyosin receptor kinase C (TrkC/NTRK3) has been described as a dependence receptor and, as such, triggers apoptosis in the absence of its ligand NT-3. This proapoptotic activity has been proposed to confer a tumor suppressor activity to this classic tyrosine kinase receptor (RTK). By investigating interacting partners that might facilitate TrkC-induced cell death, we have identified the basic helix-loop-helix (bHLH) transcription factor Hey1 and importin-α3 (karyopherin alpha 4 [KPNA4]) as direct interactors of TrkC intracellular domain, and we show that Hey1 is required for TrkC-induced apoptosis. We propose here that the cleaved proapoptotic portion of TrkC intracellular domain (called TrkC killer-fragment [TrkC-KF]) is translocated to the nucleus by importins and interacts there with Hey1. We also demonstrate that Hey1 and TrkC-KF transcriptionally silence mouse double minute 2 homolog (MDM2), thus contributing to p53 stabilization. p53 transcriptionally regulates the expression of TrkC-KF cytoplasmic and mitochondrial interactors cofactor of breast cancer 1 (COBRA1) and B cell lymphoma 2-associated X (BAX), which will subsequently trigger the intrinsic pathway of apoptosis. Of interest, TrkC was proposed to constrain tumor progression in neuroblastoma (NB), and we demonstrate in an avian model that TrkC tumor suppressor activity requires Hey1 and p53.

The dependence receptor TrkC triggers mitochondria-dependent apoptosis upon Cobra-1 recruitment.

The neurotrophin receptor TrkC was recently identified as a dependence receptor, and, as such, it triggers apoptosis in the absence of its ligand, NT-3. The molecular mechanism for apoptotic engagement involves the double cleavage of the receptor's intracellular domain, leading to the formation of a proapoptotic "killer" fragment (TrkC KF). Here, we show that TrkC KF interacts with Cobra1, a putative cofactor of BRCA1, and that Cobra1 is required for TrkC-induced apoptosis. We also show that, in the developing chick neural tube, NT-3 silencing is associated with neuroepithelial cell death that is rescued by Cobra1 silencing. Cobra1 shuttles TrkC KF to the mitochondria, where it promotes Bax activation, cytochrome c release, and apoptosome-dependent apoptosis. Thus, we propose that, in the absence of NT-3, the proteolytic cleavage of TrkC leads to the release of a killer fragment that triggers mitochondria-dependent apoptosis via the recruitment of Cobra1.

Long-Term Metabolic Monitoring of Youths Treated with Second-Generation Antipsychotics 5 Years after Publication of the CAMESA Guidelines Are We Making Progress? Surveillance Métabolique à Long Terme des Jeunes Traités par Antipsychotiques de Deuxième Génération, Cinq ans Après la publication des Lignes Directrices Camesa: Faisons-Nous des Progrès?

OBJECTIVE: The potential metabolic adverse effects of second-generation antipsychotics (SGA) need to be monitored. The Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics (CAMESA) offers guidelines for this purpose. We aimed to evaluate the long-term rates of youths receiving monitoring in mental health clinics and document the factors that may influence them. METHOD: The charts of 180 patients (13.3 ± 3.1 years, 54.4% males) receiving SGA treatment for the first time between January 2016 and June 2018 were reviewed. Monitoring was divided into baseline and 1- to 6-month and 9- to 24-month periods. Population under study was stratified into children (4 to 12 years) and adolescents (13 to 18 years). Sociodemographic characteristics, psychiatric diagnosis and comorbidities, prescribed SGAs and comedications, anthropometric measures (AM), blood pressure (BP), blood tests (BT), electrocardiogram, and the psychiatrist's years of practice were collected. Cross tables were used to present the monitoring rates. Categories were compared by covariate analysis. Rates of patients monitored across categories were compared using Fisher exact test. RESULTS: Monitoring rates for AM, BT, and BP were 55%, 47.8%, and 46.7% at baseline; 50%, 41.7%, and 45.2% at 1 to 6 months; and 47.2%, 41.5%, and 40.6% at 9 to 24 months, respectively. Higher monitoring rates were significantly associated with adolescent status (baseline, 1 to 6 months), a diagnosis of psychotic and/or affective disorder (baseline, 1 to 6 months, 9 to 24 months), having ≤1 psychiatric comorbidities (1 to 6 months), high SGA dose (baseline, 1 to 6 months), and clinician's experience (baseline, 9 to 24 months). Significantly lower monitoring rates were associated with the psychostimulant/atomoxetine comedication (baseline, 1 to 6 months, 9 to 24 months). CONCLUSION: Five years after publication of the CAMESA guidelines, metabolic monitoring is conducted for less than half of patients. In our sample, age, diagnostic category, psychiatric comorbidities, SGA dose, clinician's experience, and comedications influenced the monitoring rates. Major progress still needs to be made before reaching a satisfactory level of monitoring.

The dependence receptor TrkC regulates the number of sensory neurons during DRG development.

The development of the sensory nervous system is the result of fine-tuned waves of neurogenesis and apoptosis which control the appropriate number of precursors and newly generated neurons and orient them toward a specific lineage. Neurotrophins and their tyrosine-kinase receptors (RTK) orchestrate this process. They have long been in the scope of the neurotrophic theory which established that a neuron is committed to die unless a trophic factor generated by its target provides it with a survival signal. The neural death has thus always been described as a "default" program, survival being the major player to control the number of cells. New insights have been brought by the gain of function studies which recently demonstrated that TrkC (NTRK3) is a "dependence receptor" able to actively trigger apoptosis in absence of its ligand NT-3. In order to address the role of TrkC pro-apoptotic activity in the control of sensory neurons number, we generated a TrkC gene-trap mutant mice. We found out that this new murine model recapitulates the sensory phenotype of TrkC constitutive mutants, with reduced DRG size and reduced number of DRG neurons. We engineered these mice strain with a lacZ reporter in order to follow the fate of neurons committed to a TrkC lineage and observed that they are specifically protected from NT-3 mediated apoptosis in NT-3/TrkC double knock-out embryos. Finally, using a chicken model we demonstrated that silencing NT-3 emanating from the ventral neural tube induced apoptosis in the DRG anlage. This apoptosis was inhibited by silencing TrkC. This work thus demonstrates that, during in vivo DRG development, TrkC behaves as a two-sided receptor transducing positive signals of neuronal survival in response to NT-3, but actively inducing neuronal cell death when unbound. This functional duality sets adequate number of neurons committed to a TrkC identity in the forming DRG.

Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane.

The pivotal step on the mitochondrial pathway to apoptosis is permeabilization of the mitochondrial outer membrane (MOM) by oligomers of the B-cell lymphoma-2 (Bcl-2) family members Bak or Bax. However, how they disrupt MOM integrity is unknown. A longstanding model is that activated Bak and Bax insert two α-helices, α5 and α6, as a hairpin across the MOM, but recent insights on the oligomer structures question this model. We have clarified how these helices contribute to MOM perforation by determining that, in the oligomers, Bak α5 (like Bax α5) remains part of the protein core and that a membrane-impermeable cysteine reagent can label cysteines placed at many positions in α5 and α6 of both Bak and Bax. The results are inconsistent with the hairpin insertion model but support an in-plane model in which α5 and α6 collapse onto the membrane and insert shallowly to drive formation of proteolipidic pores.

Pollen identification through convolutional neural networks: First application on a full fossil pollen sequence.

The automation of pollen identification has seen vast improvements in the past years, with Convolutional Neural Networks coming out as the preferred tool to train models. Still, only a small portion of works published on the matter address the identification of fossil pollen. Fossil pollen is commonly extracted from organic sediment cores and are used by paleoecologists to reconstruct past environments, flora, vegetation, and their evolution through time. The automation of fossil pollen identification would allow paleoecologists to save both time and money while reducing bias and uncertainty. However, Convolutional Neural Networks require a large amount of data for training and databases of fossilized pollen are rare and often incomplete. Since machine learning models are usually trained using labelled fresh pollen associated with many different species, there exists a gap between the training data and target data. We propose a method for a large-scale fossil pollen identification workflow. Our proposed method employs an accelerated fossil pollen extraction protocol and Convolutional Neural Networks trained on the labelled fresh pollen of the species most commonly found in Northeastern American organic sediments. We first test our model on fresh pollen and then on a full fossil pollen sequence totalling 196,526 images. Our model achieved an average per class accuracy of 91.2% when tested against fresh pollen. However, we find that our model does not perform as well when tested on fossil data. While our model is overconfident in its predictions, the general abundance patterns remain consistent with the traditional palynologist IDs. Although not yet capable of accurately classifying a whole fossil pollen sequence, our model serves as a proof of concept towards creating a full large-scale identification workflow.

Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.

RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985). SIGNIFICANCE: The discovery of RMC-6236 enables the first-ever therapeutic evaluation of targeted and concurrent inhibition of canonical mutant and wild-type RAS-GTP in RAS-driven cancers. We demonstrate that broad-spectrum RAS-GTP inhibition is tolerable at exposures that induce profound tumor regressions in preclinical models of, and in patients with, such tumors. This article is featured in Selected Articles from This Issue, p. 897.

Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma.

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

Emergence of psychiatric adverse events during antipsychotic treatment in AP-naïve children and adolescents.

BACKGROUND: Over the last decades, antipsychotic prescriptions in children have increased worldwide. However, adverse events are frequently observed, with some such as psychiatric adverse events remaining poorly documented. METHOD: The French ETAPE study is a 12-month naturalistic prospective multisite study that included 190 antipsychotic-naïve pediatric patients (mean age = 12 ± 3 years), treated by antipsychotic for psychotic or non-psychotic symptoms. From the ETAPE database, we performed additional analyses focusing on psychiatric adverse events. RESULTS: Children received mainly second-generation antipsychotic for conditions out of regulatory approval, with risperidone and aripiprazole being the most frequent (respectively 52.5% and 30.83%). Clinicians reported 2447 adverse events, mainly non-psychiatric (n = 2073, 84.72%), including neuromuscular, metabolic, gastroenterological, and (n = 374, 15.28%) psychiatric. 55.88% of psychiatric adverse events were attributable to antipsychotic by the clinician, compared to 89% of non-psychiatric adverse events (p < 0.001). 63.2% (n = 120) of the 190 children and adolescents presented at least one psychiatric adverse event. The most frequent were externalized behaviors such as aggressiveness or agitation (22.7%), mood changes (18.4%) and suicidal ideas or behaviors (11.8%). Half of psychiatric adverse events occurred during the first quarter, 49.46%, compared to 23.79% during the second, 15.77% during the third, and 10.96% during the fourth. CONCLUSION: This additional analysis from the French ETAPE study emphasizes that psychiatric adverse events might be more frequent than expected in the pediatric population. Also, the potential risk of psychiatric adverse events should be part of the benefit-risk evaluation and sub-sequent follow-up.

Decision making under uncertainty in the diagnosis and management of Alzheimer's Disease in primary care: A study protocol applying concepts from neuroeconomics.

Background: The current management of patients with Dementia, primarily with Alzheimer's Disease (AD) is rapidly evolving. However, limited information is available about the current gaps and decision-making in primary care. Objectives: To evaluate factors associated with gaps, risk preferences regarding diagnostic and therapeutic choices in the management of patients with AD by primary care physicians (PCP) from across Canada. Methods: We propose a non-interventional, cross-sectional pilot study involving 120 primary care physicians referred from the College of Family Physicians of Canada to assess diagnostic and therapeutic decisions in the management of ten simulated AD-related case-scenarios commonly encountered in clinical practice. We initially describe the current landscape and gaps regarding diagnostic and therapeutic challenges in the management of patients with AD in primary care. Then, we provide concepts from behavioral economics and neuroeconomics applied to medical decision-making. Specifically, we include standardized tests to measure risk aversion, physicians' reactions to uncertainty, and questions related to risk preferences in different domains. Finally, we summarize the protocol to be implemented to address our goals. The primary study outcome is the proportion of participants that elect to defer initial investigations to the specialist and the associated factors. Secondary outcomes include the proportion of PCP willing to order cerebral spinal fluid studies, PET scans, or initiate treatment according to the simulated case-scenarios. The study will be conducted in English and French. Conclusions: The study findings will contribute a better understanding of relevant factors associated with diagnostic and therapeutic decisions of PCP in the management of AD, identifying participant's preferences and evaluating the role of behavioral aspects such tolerance to uncertainty, aversion to ambiguity, and therapeutic inertia.

A 3-year retrospective study of 866 children and adolescent outpatients followed in the Nice Pediatric Psychotrauma Center created after the 2016 mass terror attack.

Background: The mass terrorist attack in Nice, France, in July 2016 caused deaths and injuries in a local population, including children and adolescents. The Nice Pediatric Psychotrauma Center (NPPC) was opened to provide mental health care to the pediatric population (0-18 years) who experienced traumatic events. Objectives: This study describes the specificity of the care pathway for young trauma victims, with an explanation of how the NPPC works during the first three years. Methods: In this retrospective study, we conducted quantitative and qualitative data collection about new and follow-up consultations, primary and comorbid diagnoses, and the kind of trauma (terrorist attack versus other kinds of trauma). Ethics approval was obtained from the local Ethics committee. Results: 866 children and adolescents were followed in the NPPC. We found a high rate of Post-Traumatic Stress Disorder (PTSD; 71%) in this population with a high rate of comorbidities (67%), mainly sleep disorders (34.7%) and mood and anxiety disorders (16.2%). A high number of children and adolescents impacted by the terrorist attack required follow-up consultations after exposure to the mass terrorist attack, the first care-seeking requests continued to occur three years later, although at a slower rate than in the first and second years. New consultations for other kinds of trauma were observed over time. Discussion: This study supports previous findings on the significant impact of mass trauma in the pediatric population showing even a higher level of PTSD and a high rate of comorbidities. This may be explained by the brutality of the traumatic event, particularly for this age group. The findings of this study have implications for early interventions and long-term care for children and adolescents to prevent the development of chronic PTSD into adulthood.

Storm Alex: acute stress responses in the pediatric population.

Introduction: On 2 October 2020, a violent storm (Alex) reached the French Riviera and caused significant damage in three inhabited valleys in the hinterland of the city of Nice. Entire populations were exposed to prolonged stress (no means of communication, electricity nor water) and were particularly at risk of suffering from psychological consequences. We first hypothesized that a majority of children would experience an acute stress reaction. However, we also hypothesized that their clinical expression would differ depending on their developmental age. Thus, we aimed to evaluate, according to the child's level of development, the presence of acute stress symptoms. Methods: Consecutive interviews with the child/adolescent and his/her parents were conducted by child and adolescent psychologists and psychiatrists to assess symptomatology following storm Alex (from day 1 to day 3). Each interview assessed nine classes of symptoms that have been compared according to age-groups. Results: 116 children have been evaluated (0.2-17.6 years, mean 9.1). The 0-5-years-old showed more agitation as well as developmental regression than children aged 6-11 (p = .011, p = .045) and 12-18 years (p < .001, p < .001). Anxiety was reported more frequently among the 6-11 years old than the 0-5 years children (p = .018). Overall, the interviewed children presented at least one manifestation of acute stress after the storm (94% for the 0-5 years; 83% for the 6-11 years and 74% for the 12-18 years). Discussion: The results highlight the high rate of acute stress symptoms in a natural disaster context, their specificity depending on children's age. Therefore; it emphasizes the need to develop, improve and validate specific assessment tools. Scheduled follow-up evaluations will help to understand, after a natural disaster, the long-term stress response in children, paving the way for targeting early, intensive, specific and multidisciplinary symptomatic treatment approaches.Trial registration: ClinicalTrials.gov identifier: NCT04850924. HIGHLIGHTS: Acute stress symptoms in children and adolescents are very frequent in the context of exposure to a natural disaster with specifications depending on the developmental age.

Governments' accountability for Canada's pandemic response.

The COVID-19 pandemic-with its wide-reaching social, political, and economic implications-showcases the importance of public health governance. Governmental accountability is at the forefront of societal preoccupations, as state actors attempt to manage the pandemic by using sweeping emergency powers which grant them significant discretion. Though emergency measures have tremendous impacts on citizens' lives, elected officials and civil society have little input in how governments wield these powers. We reviewed available mechanisms in Canadian private, constitutional, and criminal law and found them to be unlikely sources of much-needed accountability. Therefore, we propose that provincial and territorial legislatures modify public health legislation to expand mechanisms to foster public confidence in decision-makers, and bolster accountability to parliaments and citizens.

Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication.

The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2+ malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called 'Don't eat me' signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic 'Eat me' signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.

Loss of Gas7 Is a Key Metastatic Switch in Neuroblastoma.

Metastatic spread to distant tissues and organs is responsible for most cancer-related mortalities. Changes in the invasiveness ability of metastatic tumor cells often come with significantly altered gene expression profiles compared with primary tumor cells. Identifying the main actors involved in the metastatic switch of tumor cells is key to proposed new therapeutic approaches. In this issue, the loss of growth-arrest specific 7 is described as one of the main events driving metastatic spread in neuroblastoma.See related article by Dong et al., p. 2995.

Aripiprazole in Children and Adolescents.

Objective: To review the use of aripiprazole in children and adolescents. Methods: Medline and Embase databases were systematically searched using the keywords aripiprazole and child or adolescent over the period from 2000 to 2019. The initial screen yielded 163 publications, from which 99 studies were reviewed. Results: Aripiprazole is one of the most widely prescribed atypical antipsychotics. Like others, its use in children and adolescents is becoming commonplace and occurs in off-label indications. Aripiprazole has proven efficacy for several indications in children and adolescents, including schizophrenia, bipolar disorder, Tourette's syndrome, and behavioral impairments associated with autism and intellectual disability. Adverse effects are more important in children and adolescents than adults, particularly weight gain, drowsiness, extrapyramidal effects, and metabolic effects, even though the latter may appear less important than with other atypical antipsychotics. Severe adverse effects often occur in multiple-prescription settings. At present, postprescription monitoring is very poor. Conclusion: Aripiprazole has proven efficacy for several indications in children and adolescents. However, its use requires clinical and paraclinical monitoring to assess the occurrence of adverse events that may challenge the benefit/risk ratio. In addition, off-label prescriptions should be limited, as they appear to account for a significant proportion of aripiprazole use worldwide.

Monitoring of metabolic adverse events of second-generation antipsychotics in a naive paediatric population followed in mental health outpatient and inpatient clinical settings: MEMAS prospective study protocol.

INTRODUCTION: Second-generation antipsychotics (SGAs) are widely used in the paediatric population. It is currently established that SGAs may induce metabolic adverse events (AEs) such as weight gain, perturbation of blood lipids or glucose with risk of potential cardiovascular morbidity and mortality. The Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in children (CAMESA) has published recommendations for monitoring the metabolic AEs of SGAs. Factors that may be associated with the onset of SGA's metabolic AEs and long-term consequences are less studied in the literature. The objectives of our research are to evaluate some factors that can influence the development of the SGA's metabolic AEs and to study clinical adherence to CAMESA guidelines. METHODS AND ANALYSIS: The Monitoring des Effets Métaboliques des Antipsychotiques de Seconde Génération study is a multicenter, prospective, longitudinal observational study with repeated measures of metabolic monitoring over 24 months. Two recruiting centres have been selected for patients under 18 years of age, previously naive of antipsychotics, starting an SGA or who have started an SGA for less than 4 weeks regardless of the diagnosis that motivated the prescription. Assessments are performed for anthropometric measures, blood pressure, blood tests at baseline and 1, 2, 3, 6, 9, 12 and 24 months of follow-up. ETHICS AND DISSEMINATION: The study protocol was approved by the CHU Sainte-Justine's Research Ethics Board (MP-21-2016-1201) in 2016 and obtained institutional suitability for the 'Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l'Île-de-Montréal' Research Center in May 2018. For all participants, written consent will be obtained from parents/caregivers as well as the participant's assent in order to enable their participation in this research project. The results of this research will be published. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (number NCT04395326).

[Review of the prescription of antipsychotics in children]. / État des lieux de la prescription des antipsychotiques chez l'enfant.

Review of the prescription of antipsychotics in children. In France, as in the rest of the world, prescribing of antipsychotic drugs increases in children and adolescentsIndeed, antipsychotics are frequently prescribed in children and adolescents for both psychotic and non-psychotic disorders, with 36 to 93%o fprescriptionsbeingoff-label in this population. In addition, a high number of adverse events have been reported in the literature under antipsychotic treatment. The consequences of these adverse events are still poorly documented. In France, a 12-months national prospective study (ETAPE) observed a high incidence rate, severity and persistence of adverse events during first-time antipsychotic treatment in pediatric patients. Therefore, a careful and continuous clinical and biological monitoring all over the treatment period is required to adapt treatment decisions based on benefice-risk-analysis.

État des lieux de la prescription des antipsychotiques chez l'enfant. En France, comme dans le reste du monde, les prescriptions d'antipsychotiques augmentent chez l'enfant et l'adolescent. Les antipsychotiques sont fréquemment prescrits chez l'enfant et l'adolescent pour des troubles psychotiques et non psychotiques. Le taux de prescription effectué hors autorisation de mise sur le marché (AMM) s'étend de 36 à 93 % dans cette population. De plus, un nombre important d'effets secondaires sous antipsychotiques ont été rapportés dans la littérature. Les conséquences de ces effets secondaires sont encore insuffisamment documentées. En France, une étude nationale prospective sur 12 mois (ETAPE) réalisée en population pédiatrique exposée pour la première fois à un antipsychotique a montré un taux d'incidence d'effets secondaires élevé, une sévérité et la persistance de ces effets pendant toute la durée du suivi. Aussi une surveillance attentive et régulière, clinique et biologique, pendant toute la durée d'exposition au traitement est nécessaire afin d'adapter les décisions thérapeutiques en fonction de la balance bénéfice-risque.