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Objective: Gap in knowledge on benefit/risk ratio of second generation antipsychotics (SGA) in the paediatric population represents a challenge for the scientific community. This study aims to analyse all suspected adverse drug reactions (ADRs) to SGA observed during the study period; compare the safety profiles of risperidone and aripiprazole; evaluate the effect of switching from risperidone to aripiprazole or to a first generation antipsychotic (FGA). Methods: Prospective analysis of spontaneously reported ADRs concerning 184 paediatric outpatients between 2012 and 2014.; clinical outcomes of drug switch were evaluated. Results: Out of the 184 patients, 130 experienced at least one ADR; ADRs were usually not serious and more frequently associated with aripiprazole. Switching to aripiprazole was associated with better results than switching to FGAs in the Clinical Global Impression scale- Efficacy (CGI-E) scores (p = 0.018), Disturbed behaviour checklist-parents (DBC-P) self-absorption subscale (p = 0.010); only a trend for difference between changing to aripiprazole vs FGAs in the DBC-P total score (p = 0.054) and social relating subscale (p = 0.053) was observed. Conclusions: SGAs safety data were consistent with the ones already known; however, there is still a need to improve the knowledge in pharmacovigilance field among clinicians. Switching to aripiprazole may be a valid alternative to risperidone.

Objective: The practical effectiveness of second-generation antipsychotics in children and adolescents is an understudied issue. It is a crucial area of study, though, because such patients are often treated for long-lasting disorders. Methods: We carried out a 24-month (March 2012-March 2014) observational study on an unselected population of pediatric outpatients treated with risperidone, aripiprazole, olanzapine, or quetiapine aiming to (1) describe drug use, (2) compare post hoc the discontinuation rates due to specific causes and dose adjustments by Kaplan-Meier analyses between drugs, and (3) analyze predictors influencing these outcomes by Cox multivariate models. Results: Among 184 pediatric patients, 77% patients were prescribed risperidone, and 18% were prescribed aripiprazole. Olanzapine or quetiapine were scantly used; therefore, they were excluded from analyses. Risperidone was prevalent in younger, male patients with disruptive behavioral disorders; aripiprazole, in patients with tic disorders. Overall, discontinuations occurred mostly in the first 6 months, and, at 24 months, the discontinuation numbers were similar between users of risperidone and aripiprazole (41.5% vs 39.4%). In univariate analyses, dose reduction was higher for aripiprazole (P = .033). Multivariate analyses yielded the following predictors: for all-cause discontinuation, baseline severity (hazard ratio [HR] = 1.48, P = .001) and dose increase (HR = 3.55, P = .001); for patient-decided discontinuation, dose change (increase: HR = 6.43, P = .004; reduction: HR = 7.89, P = .049) and the presence of concomitant drugs (HR = 4.03, P = .034), while autistic patients discontinued less (HR = 0.23, P = .050); for clinician-decided discontinuation due to adverse drug reactions, baseline severity (HR = 1.96, P = .005) and dose increase (HR = 5.09, P = .016); for clinician-decided discontinuation due to inefficacy, baseline severity (HR = 2.88, P = .014) and the use of aripiprazole (HR = 5.55, P = .013); for dose increase, none; for dose reduction, the occurrence of adverse drug reactions (HR = 4.74, P = .046), while dose reduction was less probable in autistic patients (HR = 0.22, P = .042). Conclusions: The findings of this study show a similarity between the overall effectiveness of risperidone and aripiprazole in a real-life pediatric outpatient setting.

Purpose: Available guidelines on therapeutic drug monitoring of second-generation antipsychotics were designed for adults; therefore, they cannot be transferred as such in pediatric patients, who may have different drug absorption, distribution, metabolism, and elimination. Moreover, available tools that guide dosing in neuropsychiatric pediatric patients are scant, leading to the possibility of reduced efficacy and/or increased risks of toxicity. Here we describe the results of observational therapeutic drug monitoring conducted in three pediatric neuropsychiatry units across Italy in 2012-2014, with the following aims: (1) to describe the distribution of plasma concentrations of second-generation antipsychotics in our pediatric patients and (2) to identify clinical covariates associated with plasma drug levels. Methods: Five hundred fifty-six plasma trough concentrations of the second-generation antipsychotics risperidone (plus 9-hydroxy-risperidone), aripiprazole, olanzapine, and quetiapine were measured from 172 pediatric outpatients overall. The distribution of drug concentrations was described and correlated with drug doses and clinical variables. Results: Risperidone plasma levels were lower than in adults (median 13.6 ng/ml), with a high inter-patient (78.9 %) but lower intra-patient (34.2 %) variability. In multiple regression analyses, risperidone plasma levels depended only on drug dose (p < 0.001). Aripiprazole plasma levels were similar to those described in adults (median 165.8 ng/ml) and were widely distributed, with an inter-patient variability of 81.1 %, while the intra-patient variability was much lower (29.3 %). Multiple regression analyses indicated that aripiprazole plasma levels were influenced by the daily doses (p < 0.001) and by the number of concomitant drugs (p < 0.01). Conclusion: Our study described the distribution of plasma levels of SGAs in a real-life setting involving pediatric patients, significantly increasing the amount of available data for this fragile population. If confirmed in larger dataset, these data may contribute to the definition of optimal therapeutic window for risperidone and aripiprazole plasma levels in pediatric patients.

[Author Affiliation]Marco Pozzi. 1 Istituto Di Ricovero e Cura a Carattere Scientifico ( IRCCS) Eugenio Medea, Lecco, Italy.Simone Pisano. 2 Department of Medicine and Public Health, Second University of Naples, Naples, Italy.Silvana Bertella. 1 Istituto Di Ricovero e Cura a Carattere Scientifico ( IRCCS) Eugenio Medea, Lecco, Italy.Paola Lombardi. 2 Department of Medicine and Public Health, Second University of Naples, Naples, Italy.Paolo Pellegrino. 3 Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Universita di Milano, Milan, Italy.Massimo Molteni. 1 Istituto Di Ricovero e Cura a Carattere Scientifico ( IRCCS) Eugenio Medea, Lecco, Italy.Emilio Clementi. 1 Istituto Di Ricovero e Cura a Carattere Scientifico ( IRCCS) Eugenio Medea, Lecco, Italy. 4 Unit of Clinical Pharmacology, National Research Council ( CNR) Institute of Neuroscience, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Universita di Milano, Milan, Italy.Carmela Bravaccio. 5 Department of Translational Medical Sciences, University Federico II of Naples, Naples, Italy.Sonia Radice. 3 Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Universita di Milano, Milan, Italy.* The first two authors contributed equally.Funding: This work was supported by Agenzia Italiana del Farmaco (AIFA) and by the Italian Ministry of Health (Ricerca Corrente 2015, to E.C.). The funding public institutions had no role in any part of the work.Address correspondence to: Emilio Clementi, PhD, Department of Biomedical and Clinical Sciences, University of Milano, Via GB Grassi 74, 20157 Milano, Italy, E-mail: emilio.clementi@unimi.itTo The Editor:Renewed interest in the relationship between autoimmune diseases and psychiatric disorders has been raised by a recent consensus paper describing pediatric acute-onset neuropsychiatric syndrome (PANS) (Chang et al. 2014), which also includes the previously known pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) (Swedo et al. 1998). Although the diagnostic process is still debated and differential diagnosis may be challenging, several features of both disorders have been described. PANDAS is characterized by an infection-mediated (by group A-β hemolytic Streptococcus) abrupt, dramatic onset of neuropsychiatric symptoms mainly including, but not limited to, tics and obsessive-compulsive behaviors, whereas PANS may be caused by several triggers, not only postinfectious ones, and may present, together with obsessive-compulsive behaviors, with the predominant feature of acute-onset food refusal, rather than tics (Murphy et al. 2014). Anti-streptolysin O (ASO) titration is supportive of the diagnosis of PANDAS or PANS, and should be performed when they are suspected (Kiessling et al. 1993; Murphy et al. 2015; Pozzi et al. 2014). In the case of isolated measurements, the diagnostic threshold has been set at 400 U/mL, whereas the normality threshold is generally 200 U/mL, although it may be adjusted by age (Chang et al. 2014). It is also known that elevated ASO titers may be linked with a plurality of conditions that are not always pathological; however, scant data are available on the possible association of group A Streptococcus and ASO titers with the occurrence of neuropsychiatric manifestations other than Sydenham's chorea and PANDAS or PANS (Pozzi et al. 2014).Autoimmunity-based etiological hypotheses are increasingly being probed for neuropsychiatric diseases, such as autism spectrum disorders (ASD) (Keil et al. 2010). We have explored the distribution of ASO titers in a wide pediatric neuropsychiatric population, aiming to check for differences among groups of patients with different psychiatric diagnoses. …