Tra gli articoli di recente pubblicazione segnalo il seguente Divalproex Sodium vs Placebo for the Treatment of Irritability in Children and Adolescents with Autism Spectrum Disorders, Eric Hollander*,1,5, William Chaplin2, Latha Soorya3, Stacey Wasserman3, Sherry Novotny3, Jade Rusoff3, Nicole Feirsen3, Lauren Pepa3 and Evdokia Anagnostou4,5, Neuropsychopharmacology advance online publication, 9 December 2009; doi:10.1038/npp.2009.202 Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by social and language deficits and by repetitive behaviors and interests. Irritability/aggression is a significant comorbid symptom in this population, which greatly impacts burden of care. This study examined the effect of divalproex sodium for irritability/aggression in children and adolescents with ASD. This was a 12-week randomized, double-blind, placebo-controlled trial. All efficacy measures were obtained by an independent evaluator blinded to randomization condition and side effects. A total of 55 subjects gavetheir consent and 27 were randomized in a 1 : 1 manner (mean age 9.46+/-2.46, mean nonverbal IQ 63.3+/-23.9). Two subjects from the active group and one subject from the placebo group discontinued the study because of either a lack of efficacy or side effects (increased irritability). Primary outcome measures were Aberrant Behavior Checklist-Irritability subscale and Clinical Global Impression-Improvement, which focused on irritability. Overall, 62.5% of divalproex subjects vs 9% of placebo subjects were responders (CGI-irritability OR: 16.7, Fisher's exact p=0.008). A statistically significant improvement was also noted on the ABC-Irritability subscale (p=0.048). There was a trend for responders to have higher valproate blood levels compared with nonresponders. This study suggests the efficacy of divalproex for the treatment of irritability in children and adolescents with ASD. Larger sample follow-up studies are warranted.Neuropsychopharmacology advance online publication, La sperimentazione del divalproato per l’irritabilità/aggressività associata all’autismo nasce dai seguenti dati di fatto: la gravità del sintomo e il fatto che sia i trattamenti farmacologici che quelli comportamentali attualmente in uso hanno un’efficacia molto limitata. I farmaci che sino ad ora si sono mostrati superiori al placebo appartengono tutti alla classe dei neurolettici, i limiti dei quali sono ben noti: efficacia scarsa ed effetti collaterali tutt’altro che trascurabili. Da qui l’esigenza di avere farmaci diversi, appartenenti a classi farmacologiche che presentino un minor carico di effetti indesiderabili. Il razionale per la scelta di questo farmaco così viene spiegato nel testo dell’articolo “It potentiates GABA inhibitory effects in the CNS (Soderpalm, 2002) and is likely to have epigenetic effects, as it is a histone deacetylase inhibitor (Go¨ttlicher, 2004). These two mechanisms are of specific interest in ASD, given theories of decreased inhibitory control in autism (Casanova et al, 2003), high frequency of seizures, and epileptiform EEGs in this population, especially in individuals with lower IQs (Amiet et al, 2008), and the increasing evidence to support a role of gene expression abnormalities in the pathophysiology of multiple neuropsychiatric disorders (Szyf, 2009). In adults, valproate has shown to have some efficacy at reducing aggressive behaviors across diagnostic groups, and controlled trials have documented a reduction in irritability in cluster B personality disorders (Hollander et al, 2003, 2005)” Un altro dato riferito come premessa alla sperimentazione è il fatto che molti pazienti con autismo hanno un eeg epilettiforme, anche in assenza di chiare crisi epilettiche e da molto tempo in letteratura ci si domanda se questo dato strumentale abbia dei corrispettivi clinici e se possa essere un fattore predittivo di risposta agli antiepilettici. Dice il testo “explores the effect of baseline epileptiform activity on treatment response for irritability.” L’abstract presenta la sperimenazione come positiva. Se tuttavia leggiamo il full text, troviamo che i risultati sono molto modesti. “CGI-I for Irritability. On the basis of intent-to treat analyses, 10 of the 16 active treatment subjects (62.5%) showed a response to irritability, whereas only one of the placebo subjects (9.09%) showed a response (OR¼16.66). This effect is significant by Fisher’s exact test (p¼0.008)” Secondary. OAS-M Irritability subscale. For two of the time points (weeks 0 and 8), the scale has a negative skew 4|1.0|. On the basis of both winsorized (t¼_1.09, df¼23.44, p¼0.28) and nonwinsorized (t¼_1.37, df¼24.01, p¼0.181) data, no statistically significant improvement in this measure was noted in subjects receiving divalproex vs placebo. Controlling for the IQ differences did not change these conclusions. The mean irritability scores at baseline and end point were the following: divalproexbaseline 6.43 (1.41), divalproex end 5.42 (2.17), placebobaseline 5.36 (2.2), placeboend 6.25 (1.28) DUNQUE, MENTRE PER LA SCALA CGI-I C’E’ UNA DIFFERENZA TRA IL GRUPPO TRATTATO E IL PLACEBO, PER LA SCALA OAS-M , NON CI SONO MIGLIORAMENTI SIGNIFICATIVI NEL GRUPPO TRATTATO. CYBOCS. Mixed model analysis was used to examine the effect of divalproex sodium vs placebo on repetitive behaviors as measured by CYBOCS. There were no statistically significant differences between groups (p¼0.748). NON C’E’ MIGLIORAMENTO RISPETTOI AL PLACEBO NEI COMPORTAMENTI RIPETITIVI. Vineland adaptive behavioral scale, YMRS. There were no statistically significant differences between groups in either the Vineland domains (communication: p¼0.865, daily living: p¼0.77, socialization: p¼0.119) or the YMRS (p¼0.987). Table 3 suggests that subjects with abnormal/ epileptiform EEGs (2/3), especially those with epileptiform EEGs (2/2), may be more likely to respond to divalproex sodium than subjects with normal EEG records (4/7). , the treatment of underlying epileptiform abnormalities may contribute to behavioral response This theory, although controversial, is supported by our very preliminary data that showed that children randomized to divalproex sodium with epileptiform EEGs were classified as responders. QUESTA TENDENZA, OSSIA IL RILIEVO DI UN MAGGIOR NUMERO DI RESPONDERS NEI PAZIENTI CON EEG EPILETTIFORME, E’ UN DATO MOLTO INTERESSANTE. PECCATO CHE NEL CAMPIONE DI PROBANDI, GIA’ MOLTO PICCOLO (27), L’EEG SIA STATO FATTO SOLO A UN NUMERO PICCOLISSIMO DI PARTECIPANTI E SOLO ALL’INIZIO, MENTRE SAREBBE STATO MOLTO INTERESSANTE VEDERE SE, ANCHE SOLO IN QUEI POCHI, VI FOSSE STATA UNA CORRELAZIONE TRA RISPOSTA E ALTERAZIONI EEG INZIALE E TRA RISPOSTA POSITIVA E MIGLIORAMENTO DELL’EEG FINALE. GLI AUTORI AUSPICANO CHE SI FACCIANO ALTRI STUDI CHE ESPLORINO QUESTA IPOTESI. In addition, a larger sample study powered to address the question of whether the presence of epileptiform abnormalities, while controlling for IQ, affects differential treatment response to anticonvulsants compared with atypicals, and whether treatment response is mediated by improvements in epileptiform abnormalities is required. Limitations of our study include the relatively small sample size, which did not allow for a complete analysis of EEG and valproate blood level data In addition, the absence of an EEG record at the end of the study makes it impossible for investigators to determine whether an improvement in EEG patterns correlated with treatment response The only treatment emergent side effect that was cited as a reason for discontinuation was a paradoxical increase in irritability associated with insomnia on just 250 mg of active compound in one participant. Increased aggression was reported as a side effect in two subjects in the active group and in one subject in the placebo group ANCHE PER IL VALPROATO SI è AVUTO L’EFFETTO PARADOSSO, OVVERO IL PEGGIORAMENTO DEL SINTOMO STESSO CHE IL FARMACO AVREBBE DOVUTO CURARE. E QUESTO SI E’ EVIDENZIATO GIA’ IN UN CAMPIONE COSI’ MODESTO (27 PAZIENTI) NELLE CONCLUSIONI GLI AUTORI RIPORTANO, TRA LE CRITICITA’ EVIDENZIATE DALLA SPERIMENTAZIONE, IL FATTO CHE LA DIMINUZIONE DELL’IRRITABILITà DOCUMENTATA DA UNA SCALA NON ABBIA AVUTO QUALE CORRELATO UN MIGLIORAMENTO DELLA SCALA VINELAND Of interest, there was no change in Vineland scores in this acute trial. Qualitative reports of relief due to decreased aggression did not seem to affect the scores on Vineland. ANCHE IN QUESTO LAVORO, COME NEI PRECEDENTI FATTI CON ALTRI FARMACI, IL FARMACO NON INCIDE SUI SINTOMI NUCLEARI DELL’AUTISMO There was also no change in CGI-I autism, which is not surprising, given that core symptom domain severity was scored within this measure Insomma: dalla lettura dell’abstract pare che il trial abbia dato risultati positivi, mentre la lettura del full text ridimensiona di molto tali risultati. Vorremmo che l’affermazione fatta da Michael Rutter molti anni fa “Drug therapy of autism is disappointing” non fosse più attuale, mentre purtroppo lo è ancora e la strada da fare per renderla obsoleta pare che sia ancora molto lunga. Alla prossima Daniela