[Pharmacoresistance to psychotropic drugs in children and adolescents: Pharmacogenetic anomalies of cytochrome P450 2D6]. / La pharmacorésistance aux psychotropes chez l'enfant et l'adolescent : recherche d'anomalies pharmacogénétiques du cytochrome P450 2D6.

OBJECTIVES: Some patients in child and adolescent psychiatry present resistance to psychotropic drugs, often resulting in polytherapy, an increased risk of adverse events, and more frequent and longer hospitalisation. Psychotropic drugs are mainly metabolised in the liver, in particular by the CYP2D6 subunit of cytochrome P450. Anomalies such as a duplication of the CYP2D6 gene related to an ultra-rapid metaboliser phenotype has been described to be linked to clinical efficacy. However, little research has been done in child and adolescent psychiatry. METHODS: A multi-centric cross-sectional study in the southeast of France explored the relation between pharmaco-resistance to psychotropic drugs and the prevalence of duplications or polymorphisms of CYP2D6 associated with an ultra-rapid phenotype in children and adolescents with severe mental health disease. RESULTS: Twenty-two patients have been included. The presence of an ultra-rapid phenotype concerns one patient in our study. A second patient presents a slow metaboliser phenotype. CONCLUSIONS: This study allows a clinical characterisation of the population of pediatric drug-resistant patients whose severity and the impact of their pathology are major and require long-term care associated with repeated hospitalisations, multiple drug prescriptions and numerous side effects. However, a link between drug resistance to psychotropic drugs and CYP2D6 UFM abnormalities could not be confirmed. An additional pharmacogenetic analysis by a panel of genes applied in the metabolism, transport and action of psychotropic drugs should be considered to answer questions about the resistance and independent effects of CYP2D6.

[Neurodevelopmental Disorders, Psychiatric Comorbidities and Associated Pathologies in Patients with Childhood-Onset Schizophrenia and Premorbid Autistic Symptoms.] / Atteintes Neurodéveloppementales, Comorbidités Psychiatriques Et Pathologies Associées Chez Des Patients Atteints de Schizophrénie Très Précoce Avec Symptômes Autistiques Prémorbides.

INTRODUCTION: Childhood-Onset Schizophrenia (COS) is a rare (1/40000), severe and neurodevelopmental form of schizophrenia beginning before 13 years of age. Little is known about comorbidities and specific COS-related disorders. Thus, the objective of our study was to evaluate them from a psychiatric, neurodevelopmental and somatic perspective. METHOD: This is an ancillary study of the GenAuDiss protocol. A standardized psychiatric interview (K-SADS-PL DSM5) and a neuropsychological assessment (WISC-V/WAIS-IV) were carried out in outpatients with COS as well as a medical history collection concerning pregnancy, perinatal period, development, biography and medical and psychiatric, personal, and family history. RESULTS: 20 outpatients were included. The mean age of onset of COS was 8.90 years (+/- 2.30). Psychiatric comorbidities (DSM5) were Attention Deficit Hyperactivity Disorder (15/20 patients), Anxiety Disorders (14/20) and Autism Spectrum Disorder (13/20). The average IQ was 70.26 (+/- 18.09). A language delay and a break in school career were noted in 18/20 patients. Finally, the main associated somatic disorder was asthma (15/20 patients). DISCUSSION: We highlighted in our patients with COS a high frequency of comorbidities including at least one systematic psychiatric disorder. However, although COS is a severe condition impacting the patient, his family and society, its management remains essentially symptomatic. In clinical practice, it is necessary to look for all these comorbidities and to manage them in order to improve the overall quality of care.

INTRODUCTION: La schizophrénie très précoce (STP) est une forme rare (1/40000), grave et neurodéveloppementale de schizophrénie débutant avant 13 ans. Les comorbidités et atteintes associées spécifiques des STP étant peu étudiées, l'objectif de notre étude a été de les évaluer sur le plan psychiatrique, neurodéveloppemental et somatique. MÉTHODE: Il s'agit d'une étude ancillaire du protocole GenAuDiss. Un entretien psychiatrique standardisé (K-SADS-PL DSM5) et un bilan neuropsychologique (WISC-V/WAIS-IV) ont été effectués chez les patients atteints de STP ainsi qu'une anamnèse concernant la grossesse, la périnatalité, le développement, la biographie et les antécédents médicaux et psychiatriques, personnels et familiaux. RÉSULTATS: 20 sujets ont été inclus. L'âge moyen de début du trouble était de 8,90 ans (+/−2,30). Les comorbidités psychiatriques (DSM5) étaient le Trouble Déficitaire de l'Attention avec Hyperactivité (15/20 patients), les troubles anxieux (14/20) et le Trouble du Spectre de l'Autisme (13/20). Le QI moyen était de 70,26 (+/−18,09). Un retard de langage et une rupture de parcours scolaire étaient notés chez 18/20 patients. Enfin, l'affection somatique principale associée était l'asthme (15/20 patients). DISCUSSION: Nous avons mis en évidence chez nos patients atteints de STP une fréquence élevée de comorbidités dont au moins un trouble psychiatrique systématique. Or, bien que la schizophrénie infantile soit une pathologie de pronostic sévère impactant le patient, sa famille et la société, sa prise en charge demeure essentiellement symptomatique. En pratique clinique, il apparaît nécessaire de rechercher systématiquement ces comorbidités et de les prendre en charge pour améliorer la qualité globale des soins.

Sex ratio in dementia with Lewy bodies balanced between Alzheimer's disease and Parkinson's disease dementia: a cross-sectional study.

BACKGROUND: Gender distribution varies across neurodegenerative disorders, with, traditionally, a higher female frequency reported in Alzheimer's disease (AD) and a higher male frequency in Parkinson's disease (PD). Conflicting results on gender distribution are reported concerning dementia with Lewy bodies (DLB), usually considered as an intermediate disease between AD and PD. The aim of the present study was to investigate gender differences in DLB in French specialized memory settings using data from the French national database spanning from 2010 to 2015 and to compare sex ratio in DLB with that in AD, Parkinson's disease dementia (PDD), and PD. Our hypothesis was that there is a balanced sex ratio in DLB, different from that found in AD and PD. METHODS: We conducted a repeated cross-sectional study. The study population comprised individuals with a DLB, AD, PDD, or PD diagnosis according to the International Classification of Diseases, Tenth Revision, in the French National Alzheimer Database between 2010 and 2015. Sex ratio and demographic data were compared using multinomial logistic regression and a Bayesian statistical model. RESULTS: From 2010 to 2015 in French specialized memory settings, sex ratios (female percent/male percent) were found as follows: 1.21 (54.7%/45.3%) for DLB (n = 10,309), 2.34 (70.1%/29.9%) for AD (n = 135,664), 0.76 (43.1%/56.9%) for PD (n = 8744), and 0.83 (45.4%/54.6%) for PDD (n = 3198). Significant differences were found between each group, but not between PDD and PD, which had a similar sex ratio. CONCLUSIONS: This large-sample prevalence study confirms the balanced gender distribution in the DLB population compared with AD and PD-PDD. Gender distribution and general demographic characteristics differed between DLB and PDD. This is consistent with the hypothesis that DLB is a distinct disease with characteristics intermediate between AD and PD, as well as with the hypothesis that DLB could have at least partially distinct neuropathological correlates.

[Suicidal attempts in child and adolescent and bipolar disorders]. / Tentative de suicide chez l'enfant et l'adolescent et bipolarité.

BACKGROUND: Child and adolescent psychiatrists are frequently confronted with suicide attempts and comorbid mood disorders. Diagnoses of juvenile bipolar disorders (BD) are rare and controversial and standardized assessment is helpful for a reliable diagnosis. The main objective of this study was to identify the number of juvenile bipolar disorder diagnoses according to DSM-5 criteria in a population of children and adolescents hospitalized for suicide attempts. Secondary objectives were the assessment of a patient's characteristics and the comparison of suicide attempt recurrence during 12 months of follow-up. METHODS: This current practice study consecutively included children and adolescents aged 6 to 18 years and hospitalized for a suicide attempt in a French University Pediatric Hospital over a 4-month period. Patients were assessed at baseline, at 3 months and at 12 months. The standardized assessment was realized by the investigator using semi-structured interview K-SADS-PL (2013) to diagnose juvenile bipolar disorders based on DSM-5 criteria. Clinical diagnoses based on medical charts and according to ICD-10 criteria were also collected at 12-month follow-up. Standardized assessment was completed by the French validated K-SADS-PL (2004) for comorbidities (DSM-IV), dimensional assessment by MADRS-YMRS-ARI-C-SSR, and C-GAS at inclusion. Patients were divided into two groups: (1) those presenting juvenile bipolar disorder according to DSM 5 (BD+) and (2) those without criteria for bipolar disorder (BD-). Suicide risk factors and suicide attempt relapse were assessed at 3 and 12 months of follow-up. RESULTS: Twenty-six inpatients (22 female and 4 male) aged 14.5 years (SD 1,5) were consecutively included. Twenty patients were followed up during the 12-month period. At baseline, 5 patients (19.2 %) presented a diagnosis of BD (DSM-5): 1 BD type 2, 2 non specified BD, 2 cyclothymic disorders. According to the medical charts (ICD-10), none of the patients had been diagnosed with BD but had diagnoses of dysthymia, of borderline personality disorder and of conduct disorder corresponding to DMDD in 3, 2 and 1 patient respectively. During the 12-month follow-up, 9 patients of the BD- group and none of the BD+ presented recurrence of suicide attempt with 67 % during the first 3 months and 3 patients with multi-relapses. These 3 patients were female adolescents out of care and carrying at least three suicide risk factors. Six patients have been lost to follow-up (1 BD+, 5 BD-). In the BD+ group, 3 patients out of 4 had a persistent diagnosis (DSM-5) of BD at 12 months. CONCLUSION: In our adolescent population hospitalized for suicidal attempt, 19,2 % present BD using DSM-5 criteria. Diagnoses are stable during 12 months of follow-up, but under diagnosed in current clinical practice. DSM-5 standardized assessment appears to be very important to diagnose juvenile BD, mandatory for medium and long-term psychiatric follow-up, especially for suicide prevention and psychopharmacologic therapeutics. Nevertheless, no recurrence of suicide attempts has been observed in our BP+ group, contrary to BP-, possibly due the absence of BP 1 disorder.

[Emergency child psychiatry response following the 14 July 2016 terrorist attack in Nice, France]. / Réponse pédopsychiatrique d'urgence à la suite de l'attentat terroriste du 14 juillet 2016 à Nice, en France.

The attack on 14 July 2016 in Nice on the Promenade des Anglais caused major trauma for individuals directly or indirectly impacted by the horror of the terrorist attack, mainly families and children. It was the first time in France that a pediatric population aged from several months to 18 years was impacted by an event of such magnitude. The literature underlines the importance of taking into account, over the longer term, the side effects of such a psychotrauma in the pediatric population, especially in children under 6 years of age. From the night of 14 July 2016, a pediatric medical and psychological emergency unit (CUMP) was set up within the CHU-Lenval pediatric hospital. This has been a unique experience in Europe, which mobilized 227 caregivers. A total of 728 individuals were seen in consultations, including 385 children between 3 months and 17.7 years. The article outlines the main lines of its organization and its objectives.

Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders.

In animal models of autism spectrum disorder (ASD), the NKCC1 chloride-importer inhibitor bumetanide restores physiological (Cl-)i levels, enhances GABAergic inhibition and attenuates electrical and behavioral symptoms of ASD. In an earlier phase 2 trial; bumetanide reduced the severity of ASD in children and adolescents (3-11 years old). Here we report the results of a multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide. Efficacy outcome measures included the Childhood Autism Rating Scale (CARS), the Social Responsive Scale (SRS) and the Clinical Global Impressions (CGI) Improvement scale (CGI-I). Eighty-eight patients with ASD spanning across the entire pediatric population (2-18 years old) were subdivided in four age groups and randomized to receive bumetanide (0.5, 1.0 or 2.0 mg twice daily) or placebo for 3 months. The mean CARS value was significantly improved in the completers group (P: 0.015). Also, 23 treated children had more than a six-point improvement in the CARS compared with only one placebo-treated individual. Bumetanide significantly improved CGI (P: 0.0043) and the SRS score by more than 10 points (P: 0.02). The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia. Hypokalemia occurred mainly at the beginning of the treatment at 1.0 and 2.0 mg twice-daily doses and improved gradually with oral potassium supplements. The frequency and incidence of adverse event were directly correlated with the dose of bumetanide. Therefore, bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily.

[Carbamazepine and psychotropic treatment interaction: Two case studies of carbamazepine overdosage]. / Surdosage en carbamazépine par interaction avec les psychotropes : à propos de deux cas.

Drug interaction is a frequent situation in pediatrics and child psychiatry. Carbamazepine (CBZ) is an antiepileptic drug used as a mood stabilizer in child psychiatry. CBZ is known to be a potent inducer of various CYP isoenzymes of cytochrome P450, which might result in a decrease in the plasma concentration of associated treatments. We describe two cases of CBZ overdosage in adolescent inpatients (14 and 16 years). The patients were treated with risperidone associated with fluoxetine in one and with loxapine in the other case, and CBZ was introduced as a mood stabilizer. Patients presented typical clinical symptoms (fatigue, dizziness, gastrointestinal signs, blurred vision). Overdosage was confirmed by an elevated CBZ plasma concentration (17 and 15.5 mg/L, therapeutic range 4-12 mg/L). We recommend introducing CBZ very progressively in patients treated with psychotropics, particularly when it is associated to several treatments. An intensification of clinical and biological follow-up with early plasma concentration testing should allow for better treatment adjustment.

[Congenital syphilis: a case report]. / Syphilis congénitale: à propos d'un cas.

Syphilis is a re-emerging infectious disease in Western Europe. Congenital syphilis is a potentially serious pathology affecting newborns of infected mothers. This disease is easily curable by a simple antibiotic treatment. Because of systematic antenatal screening it should no longer exist in industrialized countries. Nevertheless, we report a case of a six-week-old infant with a delayed diagnosis of congenital syphilis. Physicians, especially gynaecologists, obstetricians and paediatricians, have to be vigilant in order to allow for early diagnosis and appropriate treatment of congenital syphilis.

Adenosine receptor antagonists induce persistent bursting in the rat hippocampal CA3 region via an NMDA receptor-dependent mechanism.

Adenosine receptor antagonists initiate repetitive bursting activity in the CA3 region of hippocampal slices. Although some studies have suggested that this effect is irreversible, this has been difficult to establish because many adenosine antagonists wash out of brain slices extremely slowly. Furthermore the cellular mechanism that underlies persistent bursting is unknown. To resolve these issues, we studied the effects of nonselective (8-p-sulfophenyltheophylline, 8SPT, 50-100 microM), A(l)-selective (8-cyclopentyl-1, 3-dipropylxanthine, 100 nM; xanthine carboxylic acid congener, 200 nM), and A(2A)-selective (chlorostyryl-caffeine; 200 nM) adenosine antagonists in the CA3 region of rat hippocampal slices using extracellular recording. Superfusion with all of the adenosine antagonists except chlorostyryl-caffeine induced bursting, and the burst frequency after 30 min drug superfusion did not differ for the different antagonists. Most slices showed a period of rapid initial bursting, followed either by stable bursting at a lower frequency or a pattern of oscillating burst frequency. In either case, the bursting continued after drug washout. Virtually identical patterns of long-term bursting activity were observed when 8SPT was washed out or applied continuously. Control experiments using exogenous adenosine to characterize the persistence of 8SPT in tissue demonstrated >95% washout at 60 min, a time when nearly all slices still showed regular bursting activity. When the N-methyl-D-aspartate (NMDA) antagonists DL-2-amino-5-phosphonovaleric acid (AP5; 50 microM) or dizocilpine (10 microM) were applied before and during 8SPT superfusion, bursting occurred in the presence of the NMDA antagonists but did not persist once the 8SPT was washed out. AP5 had no effect on persistent bursting when applied after the initiation of spiking. The selective calcium/calmodulin-dependent protein kinase inhibitor 1-[N, O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62; 3 microM), which has been shown to block NMDA receptor-dependent synaptic plasticity in the CA1 region, also significantly decreased the long-term effect of 8SPT. Thus adenosine antagonists initiate persistent spiking in the CA3 region; this activity does not depend on continued occupation of adenosine receptors by antagonists, and can be blocked by treatments that prevent NMDA receptor-dependent plasticity.