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.

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.

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.

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.

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).

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.

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.

[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.

Early-Onset Schizophrenia in a paediatric population of French psychiatric and medico-social care centres: A cross sectional study.

BACKGROUND: Early-Onset Schizophrenia (EOS) is rare but severe mental health disorder in children and adolescents. Diagnosis of schizophrenia before the age of 18 years remains complex and challenging, especially in young children. In France, there are no recent reliable epidemiological data about the prevalence of EOS. The present study evaluates the EOS rate in a target clinical population of children and adolescents in psychiatric and medico-social care centres in the South-East of France. METHODS: Psychiatric and medico-social centres for children and adolescent in the geographical area have been contacted, and after receiving their agreement to participate in the study, eligible patients corresponding to inclusion criteria were selected based on patients' medical records. Main inclusion criteria were age 7 to 17 years and intelligence quotient > 35. EOS categorical diagnosis was assessed by Kiddie-SADS Present and Lifetime psychosis section. RESULTS: 37 centres participated and 302 subjects have been included in the study. The main result was the categorical diagnosis of EOS in 27 subjects, corresponding to a rate of 8.9% in the study population. Half of the patients presented mild to moderate intellectual deficiency. Interestingly, only 2.3% had a diagnosis of schizophrenia spectrum disorder noted in their medical records before standardized assessment. CONCLUSIONS: The results of the study highlight the importance of using a standardized diagnostic tool for the diagnosis of schizophrenia in the paediatric population. In fact, EOS might be underdiagnosed in children and adolescents with neurodevelopmental disorders and subnormal cognitive functioning. TRIAL REGISTRATION: NCT01512641. Registered 19 January 2012; https://clinicaltrials.gov/ct2/show/NCT01512641.

Incidence of adverse events in antipsychotic-naïve children and adolescents treated with antipsychotic drugs: Results of a multicenter naturalistic study (ETAPE).

The main objective of ETAPE study was to determine the incidence of adverse events (AEs) potentially related to antipsychotic (AP) during a 12-months observational study of naturalistic treatment. ETAPE is a naturalistic prospective multicenter study conducted between April 2013 and May 2016. 200 patients were included. The mean age was 12 ± 3 years, with 73.6% being males. Patients presented a significant clinical improvement over time. At baseline, 92% of patients received a second generation AP, 74% AP monotherapy and 79.5% off-label AP prescriptions. Clinical diagnoses were heterogeneous including psychosis, anxiety, mood and neurodevelopmental disorders. The overall AE incidence rate was 11.52 AEs per person-years. Among AEs potentially attributable to AP, 15.4% were neuromotor, 14.8% gastroenterological, 12.2% metabolic and 11.8% general symptoms. Weight and body mass index increased significantly. More than half of AE appeared during the first 3 months, but onset of AE was noted all over follow-up. The presence of AEs was stable over time. ETAPE study highlights a high incidence rate of AE in children treated with AP. A careful and continuous clinical and biological monitoring is required to adapt treatment decisions based on benefice-risk-analysis. Moreover, additional research is warranted, also in regard of high proportion of off-label prescriptions.

Hormonal Risk Factors for Osteoporosis: Different Profile Among Antipsychotics.

Objectives: Osteoporosis is a major risk factor for fracture and treatment is mainly preventive. Patients with severe psychiatric condition and treated with antipsychotics are at risk for vitamin D deficiency and iatrogenic hyperprolactinemia, two serious risk factors of osteoporosis. We aim to determine whether all antipsychotics are similar regarding the risk of osteoporosis in young patients. Methods: From January 2009 to March 2015, we determined the vitamin D blood level (VDBL) among 484 inpatients and from January 2012 to March 2015, we determined the prolactin blood level (PBL) among 205 inpatients. We systematically recorded well-documented risk factors (e.g., age, gender, ethnic origin, body mass index, or season) and suspected risk factors (e.g., disease type or antipsychotic treatment). Results: Up to 89% of the inpatients had a VDBL under the recommended threshold. Up to 60% of the inpatients had hyperprolactinemia. The multivariate model found a significant effect on VDBL for seasonality (higher VDBL in summer), ethnicity (lower VDBL in Black individuals), and treatment exposure. The multivariate model found a significant effect on PBL for gender and treatment exposure. In both models, aripiprazole had a safer profile compared with other antipsychotics. Conclusion: Because adolescence is a period of bone construction and a critical window of opportunity for maximizing bone mass, we recommend vitamin D supplementation in young patients with severe mental condition. It could be interesting to reconsider to regularly monitor PBL among youth patients treated with antipsychotic, with the exception of aripiprazole.

Exploration and characterisation of the phenotypic and genetic profiles of patients with early onset schizophrenia associated with autism spectrum disorder and their first-degree relatives: a French multicentre case series study protocol (GenAuDiss).

INTRODUCTION: Early-onset schizophrenia (EOS) is a rare and severe condition. A higher rate of neurodevelopmental abnormalities, such as intellectual or communication impairments as well as attention deficit hyperactivity disorder, is observed in EOS compared with adult-onset schizophrenia. Early signs of autism spectrum disorders (ASD) are present in about 30% of patients. Genetic abnormalities, including copy number variations, are frequent in neurodevelopmental disorders and have been associated to ASD physiopathology. Implicated genes encode proteins involved in brain development, synapses morphology and plasticity and neurogenesis. In addition, an increasing number of genetic abnormalities are shared by EOS and ASD, underlying the neurodevelopmental hypothesis of EOS.The main objective of our study is to identify disease-causing genetic mutations in a cohort of patients affected by both EOS and ASD. Special attention will be paid to genes involved in neurodevelopmental pathways. METHODS AND ANALYSIS: We describe a multicentric study in a paediatric population. The study started in April 2014. Inclusion criteria are: age 7-22 years, diagnosis of EOS with comorbid ASD and IQ >50; Parents and siblings are also enrolled. We perform psychiatric assessments (Mini International Neuropsychiatric Interview, Kiddie Schedule for Affective Disorders and Schizophrenia -Present and Lifetime Version, Positive and Negative Syndrome Scale and Scale for the Assessment of Negative Symptoms) together with neurocognitive evaluations (IQ, Trail Making Test A/B and verbal fluency). Then, we study variants of the coding part of DNA (exome), using next-generation sequencing process on trio (mother, father and child). Bioinformatics tools (RVIS and PolyPhen-2) are used to prioritise disease-causing mutations in candidate genes. The inclusion period will end in November 2019. ETHICS AND DISSEMINATION: The study protocol was approved by the Local Ethic Committee and by the French National Agency for Medicines and Health Products Safety. All patients signed informed consent on enrolment in the study. Results of the present study should help to unravel the molecular pathology of EOS, paving the way for an early therapeutic intervention. TRIAL REGISTRATION NUMBER: NCT0256552; Pre-results.

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

INTRODUCTION: 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. TRIAL REGISTRATION NUMBER: NCT02007928.

Preliminary and ongoing French multicenter prospective naturalistic study of adverse events of antipsychotic treatment in naive children and adolescents.

BACKGROUND: The prescription of antipsychotics (AP), and especially second generation AP, is increasing worldwide in the pediatric population. Most prescriptions are off-label and despite the identification of frequent and potentially severe adverse events (AE), there are only a few guidelines for the safety management. France is one of the countries with no official safety guidelines. METHODS: Psychotropic drug-naive adolescents (13-18 years), hospitalized for an acute psychotic episode and treated with a second-generation antipsychotic were consecutively included in a prospective cohort study. Patients were assessed for their AE at baseline, 2, 6 and 12 weeks after the introduction of drug. RESULTS: The majority of patients was treated with risperidone (n = 13), 2 with aripiprazole. The principal findings are: (1) A high incidence of neuromuscular AE: 8/15 muscle weakness, 8/15 extrapyramidal syndrome, 6/15 akathisia, 3/15 oro-facial acute dystonia; (2) Severe catatonia symptoms in 2 patients despite a low to moderate treatment dose, requiring transfer in intensive care unit for one; (3) Weight gain and significant increase of the BMI for all 13 patients who had a 12 weeks follow-up. CONCLUSION: All adolescents experienced AE, with significant weight gain being observed in all patients who completed the 12-week follow-up. The fact that our patient population was first episode drug naïve may partially explain this observation. Despite the limitation due to the small sample size of this prospective short-term study, such findings are important to report and warrant further research. CLINICAL AND RESEARCH IMPLICATION: Because of the lack of naturalistic follow up studies of antipsychotic treatments in AP-naive children and adolescents and the absence of safety guidelines for the pediatric population in France, we decided to continue our research at a national level. We therefore started a prospective, naturalistic and multicenter study funded by the French National Agency for Medicines and Health Products Safety (ANSM). Study purpose is to evaluate the incidence of adverse events related to antipsychotic drugs in AP-naive children and adolescents. In addition, we aim to provide further evidence for the necessity of national safety guidelines for AP prescription in the pediatric population.