Relationship between social cognition and emotional markers and acoustic-verbal hallucination in youth with post-traumatic stress disorder: Protocol for a prospective, 2-year, longitudinal case-control study.

INTRODUCTION: Auditory-verbal hallucinatory experiences (AVH) have a 12% prevalence in the general pediatric population. Literature reports a higher risk of developing AVH in post-traumatic stress disorder (PTSD). The persistence of AVHs during adolescence represents a risk of evolution into psychotic disorders. Social cognition and emotional markers could be considered prodromes markers of this evolution. The objectives of this prospective observational study are to observe social cognition and emotional markers correlation with the presence and persistence of AVH over two years and with the evolution of PTSD and psychotic diagnosis. METHODS AND ANALYSIS: This prospective case-control study, longitudinal over two years (with an interim reassessment at six months and one year), will include 40 participants aged 8 to 16 years old with a diagnosis of PTSD and without a diagnosis of psychosis according to the criteria of DSM-5 (K-SADS-PL). Subjects included are divided into two groups with AVH and without AVH matched by gender, age and diagnosis. The primary outcome measure will be the correlation between social cognition and emotional makers and the presence of AVH in the PTSD pediatric population without psychotic disorders. The social cognition marker is assessed with the NEPSY II test. The emotional marker is assessed with the Differential Emotion Scale IV and the Revised Beliefs About Voices Questionnaire. The secondary outcome measures are the correlation of these markers with the persistence of AVH and the evolution of the patient's initial diagnosis two years later. DISCUSSION: The originality of our protocol is to explore the potential progression to psychosis from PTSD by cognitive biases. This study supports the hypothesis of connections between PTSD and AVH through sensory, emotional and cognitive biases. It proposes a continuum model from PTSD to psychotic disorder due to impaired perception like AVH. TRIAL REGISTRATION: Clinical trial registration: ClinicalTrials.gov Identifier: NCT03356028.

Somatic and Posttraumatic Stress Symptoms in Children and Adolescents in France.

Importance: Somatic symptoms are a major concern among the pediatric population because of frequency and burden. The association between adverse childhood experiences and somatic symptoms in adults is well established but less is known concerning somatic symptoms in young people. Objective: To explore the frequency and intensity of somatic symptoms in children and adolescents exposed to traumatic events. Design, Setting, and Participants: This cross-sectional study was conducted from January 1 to December 31, 2021, at the Nice Pediatric Psychotrauma Referral Center in Nice, France. Participants included pediatric outpatients, aged 7 to 17 years, who were referred to the center. Statistical analysis was performed in January 2022. Exposure: All participants experienced at least 1 traumatic event during life. Main Outcome and Measure: Somatic and posttraumatic stress symptoms were assessed using the Patient Health Questionnaire-13 (PHQ-13) and Child PTSD Checklist (CPC). Posttraumatic stress disorder (PTSD) and non-PTSD groups were defined based on CPC symptoms severity score. In the hypothesized association between somatic symptoms and posttraumatic stress symptoms (PTSS), PTSD and non-PTSD groups were compared, correlations between PTSS and severity of CPC were analyzed, and a regression model was performed. Results: There were 363 participants included (mean [SD] age, 13.58 [0.25] years; 174 [47.9%] female, 189 [52.1%] male). Compared with the non-PTSD group, the PTSD group presented with a higher mean (SD) number of somatic symptoms (7.0 [2.5] vs 4.0 [2.5] symptoms; t360 = 11.7; P < .001), and higher mean (SD) intensity (10.4 [4.6] vs 4.8 [3.7] points; t360 = 12.6; P < .001). Most of the explored somatic symptoms positively correlated with the intensity of PTSS and their functional alterations (eg, PTSS intensity correlated with stomach pain symptoms [r = .30; P < .001]; and with headaches symptoms [r = .44; P < .001]). In the regression model, the combination of migraines, palpitation, nausea, tiredness, and sleep disorders explained 6.5% of the variance in the PTSD group. (F1,341 = 22.651; P < .001). Conclusions and Relevance: In this cross-sectional study, somatic symptoms were positively correlated with PTSS both in frequency and intensity among youths. These results suggest that the systematic screening for somatic symptoms in youths with traumatic exposure should be a routine evaluation procedure.

Impact of post-COVID-19 olfactory disorders on quality of life, hedonic experiences and psychiatric dimensions in general population.

BACKGROUND AND OBJECTIVE: Olfactory disorders in COVID-19 impact quality of life and may lead to psychological impairments. Prevalence ranges from 8 to 85%, persisting in about 30% of cases. This study aimed to evaluate the 6-month post-COVID-19 impact on quality of life, hedonic experiences, anxiety and depression due to olfactory disorders. Additionally, it sought to compare psychophysical tests and self-perceived olfactory evaluations. METHODS: A prospective, longitudinal study was conducted over baseline (T0) and 6 months (T1) on individuals with persistent olfactory disorders post-COVID-19 for more than 6 weeks. Psychophysical tests employed the Sniffin' Sticks Test® (TDI score), and self-perceived olfactory evaluation used a Visual Analogue Scale. Quality of life was assessed with an Olfactive Disorder Questionnaire and the French version of the Quality of Life and Diet Questionnaire. Hedonic experiences were gauged using the Snaith-Hamilton Pleasure Scale, while anxiety and depression dimensions were measured by The State-Trait Anxiety Inventory, The Post Traumatic Stress Checklist Scale, and Hamilton Rating Scale for Depression. Participants were classified into the "normosmic group" (NG) and the "olfactory disorders group" (ODG) at T0 and T1 based on the TDI score. RESULTS: Were included 56 participants (58.93% women, 41.07% men) with a mean age of 39.04 years and a mean duration of post-COVID-19 olfactory disorders of 5.32 months. At T1, ODG had a significantly lower quality of life and hedonic experiences than NG. No significant differences in anxiety and depression dimensions were observed between groups. At T0, psychophysical tests and self-perceived olfactory evaluations were significantly correlated with quality of life and hedonic experiences in both groups. At T1, self-perceived olfactory evaluation in NG correlated significantly with quality of life, hedonic experiences, anxiety and depression dimensions, whereas ODG only correlated with hedonic experiences. CONCLUSION: Individuals with persistent post-COVID-19 olfactory disorders after six months demonstrated compromised quality of life and hedonic experiences. Self-perceived olfactory evaluation played a more significant role in influencing quality of life and the dimension of anxiety and depression than the psychophysical presence of olfactory disorders. These findings emphasize the importance of considering patients' perceptions to comprehensively assess the impact of olfactory disorders on their well-being. TRIAL REGISTRATION: ClinicalTrials.gov number (ID: NCT04799977).

July 14th 2016 Nice Terrorist Attack Court Trial: A Protocol on Sleep Quality and Somatic Symptoms as Markers of Risk for Traumatic Reactivation in Adolescents Exposed to This Attack.

The court trial of the 14th of July 2016 terrorist attack in Nice (France) opened in September 2022 and ended in December 2022. Engaging in court proceedings, whether as a victim or a witness, can lead to a significant risk of traumatic reactivation (i.e., the re-emergence of post-traumatic stress symptoms). The present protocol aimed to improve knowledge of the pathophysiology of traumatic reactivation due to the media coverage of the trial by assessing sleep disturbances and somatic symptoms that could reappear if there is a traumatic reactivation. Method and Analysis: This is a monocentric longitudinal study, with recruitment solely planned at the Nice Pediatric Psychotrauma Center (NPPC). We intended to include 100 adolescents aged 12 to 17 years who were directly or indirectly exposed to the attack and included in the "14-7" program). Assessments began one month before the trial, in August 2022, and were scheduled once a month until the end of the trial. A smartwatch recorded sleep activity. Somatic and PTSD symptoms and sleep were assessed through validated questionnaires. The main analyses comprised the variance and regression analyses of predictors of clinical evolution over time. Ethics and Dissemination: The National Ethics Committee "NORD OUEST III" approved the "14-7" program protocol (number 2017-A02212-51). The specific amendment for this research was approved in April 2022 by the same national ethical committee. Inclusions started in August 2022.

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.

A 6-Month Open-Label Extension Study of Vortioxetine in Pediatric Patients with Depressive or Anxiety Disorders.

OBJECTIVES: In this 6-month open-label extension (OLE) of NCT01491035 (a 14-day, open-label, pharmacokinetic/safety lead-in study), the long-term safety and tolerability of vortioxetine (5-20 mg/day) were investigated in children and adolescents with a DSM-IV-TR™ diagnosis of depressive or anxiety disorder in the United States or Germany. The study also was designed to provide data to inform dose selection and titration in future pediatric studies with vortioxetine. METHODS: Safety evaluations included spontaneously reported adverse events (AEs), the Columbia Suicide Severity Rating Scale (C-SSRS), and the Pediatric Adverse Events Rating Scale (PAERS; clinician administered). Clinical effectiveness was determined by Clinical Global Impressions. Comorbid attention-deficit/hyperactivity disorder was permitted, including concomitant use of stimulant medication (US sites only). RESULTS: Of the 47 patients who completed the lead-in period, 41 continued into the OLE. Most patients (n = 39 [95%]) continued their previous dose regimen. Twenty-one patients (51%) withdrew during the OLE; the most common primary reasons were administrative [n = 8], AEs [n = 4], and lack of efficacy [n = 3]. Thirty-five patients (85%) had ≥1 AE, 86% of which were mild or moderate in severity. Five patients (12%) reported a severe AE, none of which was considered related to study medication. The most common AEs (≥10%) were headache (27%), nausea (20%), dysmenorrhea (females; 19%), and vomiting (15%), with no relationship between AE intensity and age or dose. Five patients reported instances of suicidal ideation during the OLE, one of whom also reported this during the lead-in period. Two patients had nonsuicidal self-injurious behavior; one had a nonfatal suicide attempt. Throughout the study, there was a decrease over time in the incidence and intensity of AEs collected using the PAERS. Effectiveness assessment indicated a trend toward improvement based on numeric results. CONCLUSION: This OLE confirms the findings from the lead-in study, which concluded that a dosing strategy of 5-20 mg/day is safe, well tolerated, and suitable for future clinical studies of vortioxetine in pediatric patients.

Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients.

OBJECTIVE: The primary objectives of this study were to evaluate the pharmacokinetics (PK) and tolerability of single and multiple doses of vortioxetine in children and adolescents with a depressive or anxiety disorder and to provide supportive information for appropriate dosing regimens for pediatric clinical trials. METHODS: This prospective, open-label, multinational, multisite, multiple-dose trial enrolled 48 patients (children and adolescents; 1:1 ratio) divided into 8 cohorts (4 adolescent and 4 child), with each cohort including 6 patients. The cohorts in each age group were assigned to receive one of four dosing regimens: vortioxetine 5, 10, 15, or 20 mg q.d. for 14 days. The total treatment period lasted 14-20 days with patients in the higher dose cohorts uptitrated over 2-6 days. Plasma samples for PK analysis were obtained on the first and last days of dosing. RESULTS: Among children and adolescents, respectively, 62% and 92% had depression and 58% and 33% had anxiety disorder. Comorbid attention-deficit/hyperactivity disorder (ADHD) was present in 50% of children and 38% of adolescents. After 14 days q.d. at the target dose, the PK of vortioxetine concentrations was generally proportional to the dose in both age groups. Exposure, as assessed by maximum plasma concentrations and area under the plasma concentration-time curve from time 0 to 24 hours, was 30%-40% lower in adolescents than in children. There was no significant relationship between sex, height, or ADHD diagnosis and PK parameters. Most adverse events were mild in severity and consistent with those seen in adults. CONCLUSION: The results suggest that the dosages of vortioxetine evaluated (5-20 mg q.d.; approved for treatment in adults) and the uptitration schedule used are appropriate for pediatric efficacy and safety trials.

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.

Pharmaceutical research in paediatric populations and the new EU Paediatric Legislation: an industry perspective.

A large proportion of medicines used in children are prescribed off-label, and children have often been denied access to new or innovative medications. Because such situation is unethical, the need to obtain paediatric information for medicines used in children seems nowadays a matter of consensus on a global basis. Based on this, it was clear in EU, like what has happened in the US, that there was a need for a legal obligation for Pharmaceutical Companies to perform studies. This new European Paediatric Regulation that entered into force in 2007 opens a new era of European drug regulatory history and will offer a major opportunity to improve children's health through advancements in research by providing a new framework for evaluating the efficacy and safety of medicines for children. But, paediatric development remains challenging and the hurdles of conducting research in paediatric population are numerous. The article presents the new European Paediatric Regulation, illustrates its rationale through paediatric psychopharmacology, and discusses some of its consequences on paediatric research from an industry perspective. Recommendations for further international collaboration are also suggested to make global paediatric development plans.

Management of acute agitation in patients with bipolar disorder: efficacy and safety of intramuscular aripiprazole.

To investigate the efficacy and safety of intramuscular (IM) aripiprazole for the treatment of agitation in patients with bipolar I disorder, manic or mixed episodes. In total, 301 patients experiencing acute agitation were randomized to IM aripiprazole 9.75 mg per injection (n = 78), IM aripiprazole 15 mg per injection (n = 78), IM lorazepam 2 mg per injection (n = 70), or IM placebo (n = 75) in this double-blind multicenter study. Patients could receive up to 3 injections over 24 hours. Primary efficacy measure was mean change in Positive and Negative Syndrome Scale Excited Component score from baseline at 2 hours after first injection. Mean improvements in Positive and Negative Syndrome Scale Excited Component score at 2 hours were significantly greater with IM aripiprazole (9.75 mg, -8.7; 15 mg, -8.7) and IM lorazepam (-9.6) versus IM placebo (-5.8; P

Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: This multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of intramuscular (IM) aripiprazole in patients with acute agitation with a DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or schizo-phreniform disorder. METHOD: Patients were randomly assigned to IM aripiprazole 1 mg, 5.25 mg, 9.75 mg, or 15 mg; IM haloperidol 7.5 mg; or placebo and observed for 24 hours. The primary efficacy measure was mean change in the Positive and Negative Syndrome Scale-Excited Component (PEC) score from baseline to 2 hours after initial dosing. Secondary measures included the Agitation-Calmness Evaluation Scale (ACES) score. The study was carried out at 50 centers worldwide between April 2002 and January 2003. RESULTS: A total of 357 patients were randomly assigned to treatment. Intramuscular aripiprazole 5.25 mg, 9.75 mg, and 15 mg and IM haloperidol 7.5 mg demonstrated significantly greater reduction in the primary efficacy measure versus placebo. These changes were statistically significant as early as 45 minutes for the IM aripiprazole 9.75-mg group, with a trend toward significance (p = .051) at 30 minutes. Intramuscular haloperidol 7.5 mg first showed a significant reduction in PEC score versus placebo at 105 minutes. At 30 minutes, significantly more patients responded (defined as a greater than or equal to 40% reduction in PEC score) to IM aripiprazole 9.75 mg versus placebo (27% vs. 13%, p = .05). Intramuscular aripiprazole 9.75 mg significantly improved agitation, without oversedation, as measured by change in ACES score from baseline to 2 hours versus placebo (p = .003). No patient discontinued the study because of treatment-emergent adverse events. Extrapyramidal symptoms occurred most frequently in the IM haloperidol group. The most common adverse event in IM aripiprazole recipients was headache. CONCLUSION: Intramuscular aripiprazole 9.75 mg is a rapidly effective and well-tolerated alternative to IM haloperidol for the control of agitation, without oversedation, in patients with schizophrenia, schizo-affective disorder, or schizophreniform disorder. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00036127.

Antipsychotic prescribing patterns in Germany: a retrospective analysis using a large outpatient prescription database.

Data of prescribing practices for antipsychotics are of great interest with respect to quality of care. Consequently, we analysed all prescriptions under the statutory health insurance redeemed at pharmacies in Southern Germany between July 1999 and December 2001. The database covers prescriptions for approximately 25 million people. Up to 6% of the population were prescribed an antipsychotic at least once during the study period. Most prescriptions were for conventional antipsychotics and written by non-specialists. Patients receiving second generation antipsychotics were more likely to receive continuous antipsychotic therapy. For a large proportion of patients, antipsychotic polypharmacy, as well as comedication for somatic illnesses, were observed. In particular, drugs for the treatment of cardiovascular and metabolic disorders were frequently co-prescribed. Physicians should consider patients' cardiovascular and metabolic risk profile when making treatment choices. The data suggest that the majority of antipsychotics are used for the treatment of disorders other than schizophrenia. It is important to raise awareness among non-specialists about the indications, efficacy and side-effects of the antipsychotics because these physicians account for the majority of antipsychotic prescriptions.