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.

[Prosocial intervention in children and adolescents with autism spectrum disorder without intellectual disability: benefits of videotaping therapy sessions]. / Intervention pro-sociale chez l'enfant et l'adolescent avec trouble du spectre autistique sans déficit intellectuel : intérêt du support vidéo.

INTRODUCTION: The category of pervasive developmental disorders (PDD) without intellectual disability (including Asperger syndrome and high-functioning autism) has increased steadily among individuals since the 1980s. Although some symptoms may decrease with age, functional disability persists and is largely related to abnormalities in social interaction. Within the framework of PDD without intellectual disability, improving social skills appears to be a primary target for intervention programs. Despite a recent increase in the number of studies on this topic, few validated programs are yet available for clinical settings. BACKGROUND: We have developed an intervention targeting the improvement of social skills from the analysis of video sequences. The goal of this intervention is to promote communication within the group through sharing their interests and emotions, and to enhance the understanding of social situations. In order to assess the efficiency of this intervention, we have conducted a prospective, open, and uncontrolled study. First, it aimed at assessing the immediate effect of our intervention on a single social skill (communication) in an experimental situation (in the group) and in an ecological situations (family and school). Second, this study aimed at assessing the effects of this intervention on the subjects' social adjustment. METHOD: This study included 16 individuals with high-functioning autism/Asperger syndrome. Participants were evaluated before and after a 6-month video-based training using measures of socio-communicative and adaptive skills. RESULTS: Results revealed a statistically significant increase in the communication skills not only in the group (15.5%), but also at home (13.7%) and at school (8.7%). The evaluation of socio-adaptive behavior indicates a statistically significant increase in communication (12%), family (7%) and social autonomy (8%), and leisure activities (8%). DISCUSSION: The communication and social adjustment scores obtained upon inclusion were low, despite low autistic intensity scores. However, the improvement at six months was significant for most studied variables. These results are consistent with our clinical findings and seem partly explained by the use of video supports as the mediator of exchanges within the group. However, because of some methodological limitations, the conclusions on the effects of the intervention should be nuanced. CONCLUSIONS: This type of intervention seems to be an interesting therapeutic indication for individuals with high-functioning autism/Asperger syndrome. The first results are encouraging, and all participants enjoyed attending the meetings. These conclusion elements encourage us to continue this intervention and to pursue further research by studying the impact on the individuals' quality of life.

[Catatonia in a 14 year-old girl: treatment with clorazepam and carbamazepine, a 10-year follow-up]. / Catatonie chez une adolescente de 14 ans: traitement par clorazépam et carbamazépine et évolution à dix ans.

INTRODUCTION: Child and adolescent catatonia has been poorly investigated. Moreover, diagnosis criteria only exist for adult psychiatry, and there are no therapeutic guidelines. The aim of this paper is to describe the case of a 14-year-old girl presenting an overlap between psychogenic and neuroleptic induced catatonia, acute treatment and ten year's follow-up. CASE REPORT: A 14-year-old Caucasian French girl, Elsa, was admitted in February 1998 to a University adolescent mental health center with an acute psychotic disorder. She showed agitation, impulsivity (sudden engagement in inappropriate behaviour), paranoid delusions, visual and auditory hallucinations, diurnal and nocturnal urinary incontinence, lack of self-care, inadequate food intake because of fear of poisoning, and vomiting after meals leading to rapid weight loss of 5 kg. Clinical examination, laboratory tests, EEG and RMI were normal. Toxicological tests were negative. Her IQ, assessed six months before admission, was in the dull average range (70-75). Elsa was treated with loxapine 150 mg per day for one week without improvement and this was then replaced by haloperidol 30 mg per day. One week after the start of haloperidol her agitation, impulsivity, and hallucinatory symptoms decreased. Twenty four days after loxapine introduction and 17 days after the haloperidol, her condition deteriorated rapidly over less than 48 hours. She exhibited immobility, minimal response to stimuli, staring and catalepsy with waxy flexibility. The diagnosis of catatonia was established. Examination revealed tremulous extremities, tachychardia (110 pm) and apyrexia. Creatine phosphokinase levels were 106 UI/l (normal range 0-250). Human immunodeficiency virus, hepatitis, listeria and Lyme serology were negative. Cerebrospinal fluid analysis was normal. Haloperidol was stopped and intravenous clonazepam 5mg/kg was begun. It was not possible to obtain signed consent from the two parents for Electroconvulsive therapy. The patient was transferred to a pediatric intensive care unit. The treatment was standard parenteral nutrition, nursing, intravenous clonazepam 0.05 mg/kg, with regular attendance by a child psychiatrist. Elsa stayed three weeks in this condition. She then began to notice the child psychiatrist, and a few days later she was able to carry out simple requests. Elsa was transferred to an adolescent psychiatric unit. As soon as she could eat by herself again, carbamazepine 400mg per day was begun. Her agitation reduced at a carbamazepine level of 7 mg/l. One month later her condition was stable. However, language difficulties persisted for a further six months. One year after the episode she scored 66 on a repeat IQ test and her RMI was normal. She exhibited no significant residual symptoms except some cognitive impairment. She integrated into a special education facility. These attempts to stop the carbamazepine were followed by depressed mood, aggressiveness and impulsivity; carbamazepine was finally stopped successfully after seven years. Ten years later, Elsa is the mother of two young children and is able to take care of them. She has never had a relapse of her psychotic disorder or catatonic state. DISCUSSION: The etiopathogenic diagnosis is problematic. Some indices in the familial history may suggest a traumatic event. But one to the total residual amnesia it was never confirmed, and traumatic catatonia are extremely rare. Normal CPK levels, with autonomic disturbance limited to tachycardia and the lack of resolution after discontinuance of medication, argues against a diagnosis of neuroleptic malignant syndrome (NMS). But CPK levels are non specific, and NMS without pyrexia has been described. The occurrence of the catatonic syndrome 21 days after the first dose of a neuroleptic could be diagnostic. This case involved a non organic catatonic psychosis followed by neuroleptic induced catatonia. Catatonia is described as a risk factor for the development of NMS and some consider NMS to be a variant of malignant catatonia. The interest of this report is (1) it reinforces the need to be cautious before prescribing neuroleptics in adolescents presenting with symptoms of catatonia; (2) the complete recovery from catatonia after treatment with intensive care and more than three weeks of intravenous clonazepam without the use of ECT and (3) the effectiveness of carbamazepine over a long period of follow-up. Although trials on carbamazepine in catatonia are published, there are no data available for the control of residual symptoms or the long term prognosis, especially in child and adolescent psychiatry.