Massimo Molteni

Prevalence and correlates of mental disorders among adolescents in Italy: the PrISMA study

BackgroundWhile in the last 5xa0years several studies have been conducted in Italy on the prevalence of mental disorders in adults, to date no epidemiological study has been targeted on mental disorders in adolescents.MethodA two-phase study was conducted on 3,418 participants using the child behavior checklist/6–18 (CBCL) and the development and well-being assessment (DAWBA), a structured interview with verbatim reports reviewed by clinicians.ResultsThe prevalence of CBCL caseness and DSM-IV disorders was 9.8% (CI 8.8–10.8%) and 8.2% (CI 4.2–12.3%), respectively. DSM-IV Emotional disorders were more frequently observed (6.5% CI 2.2–10.8%) than externalizing disorders (1.2% CI 0.2–2.3%). In girls, prevalence estimates increased significantly with age; furthermore, living with a single parent, low level of maternal education, and low family income were associated with a higher likelihood of suffering from emotional or behavioral problems.ConclusionsApproximately one in ten adolescents has psychological problems. Teachers and clinicians should focus on boys and girls living with a single parent and/or in disadvantaged socioeconomic conditions.

Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 ( CDH8 ) in susceptibility to autism and learning disability

Background Autism spectrum disorder (ASD) is characterised by impairments in social communication and by a pattern of repetitive behaviours, with learning disability (LD) typically seen in up to 70% of cases. A recent study using the PPL statistical framework identified a novel region of genetic linkage on chromosome 16q21 that is limited to ASD families with LD. Methods In this study, two families with autism and/or LD are described which harbour rare >1.6u2005Mb microdeletions located within this linkage region. The deletion breakpoints are mapped at base-pair resolution and segregation analysis is performed using a combination of 1M single nucleotide polymorphism (SNP) technology, array comparative genomic hybridisation (CGH), long-range PCR, and Sanger sequencing. The frequency of similar genomic variants in control subjects is determined through analysis of published SNP array data. Expression of CDH8, the only gene disrupted by these microdeletions, is assessed using reverse transcriptase PCR and in situ hybridisation analysis of 9u2005week human embryos. Results The deletion of chr16: 60u2008025u2008584–61u2008667u2008839 was transmitted to three of three boys with autism and LD and none of four unaffected siblings, from their unaffected mother. In a second family, an overlapping deletion of chr16: 58u2008724u2008527–60u2008547u2008472 was transmitted to an individual with severe LD from his father with moderate LD. No copy number variations (CNVs) disrupting CDH8 were observed in 5023 controls. Expression analysis indicates that the two CDH8 isoforms are present in the developing human cortex. Conclusion Rare familial 16q21 microdeletions and expression analysis implicate CDH8 in susceptibility to autism and LD.

Altered white matter integrity and development in children with autism: A combined voxel-based morphometry and diffusion imaging study

BACKGROUNDnA combined protocol of voxel-based morphometry (VBM) and diffusion-weighted imaging (DWI) was applied to investigate the neurodevelopment of gray and white matter in autism.nnnMETHODSnTwenty children with autism (mean age= 7 ± 2.75 years old; age range: 4-14; 2 girls) and 22 matched normally developing children (mean age = 7.68 ± 2.03 years old; age range: 4-11; 2 girls) underwent magnetic resonance imaging (MRI). VBM was employed by applying the Template-o-Matic toolbox (TOM), a new approach which constructs the age-matched customized template for tissue segmentation. Also, the apparent diffusion coefficients (ADC) of water molecules were obtained from the analysis of DWI. Regions of interests (ROIs), standardized at 5 pixels, were placed in cortical lobes and corpus callosum on the non-diffusion weighted echo-planar images (b = 0) and were then automatically transferred to the corresponding maps to obtain the ADC values.nnnRESULTSnCompared to normal children, individuals with autism had significantly: (1) increased white matter volumes in the right inferior frontal gyrus, the right fusiform gyrus, the left precentral and supplementary motor area and the left hippocampus, (2) increased gray matter volumes in the inferior temporal gyri bilaterally, the right inferior parietal cortex, the right superior occipital lobe and the left superior parietal lobule, and (3) decreased gray matter volumes in the right inferior frontal gyrus and the left supplementary motor area. Abnormally increased ADC values in the bilateral frontal cortex and in the left side of the genu of the corpus callosum were also reported in autism. Finally, age correlated negatively with lobar and callosal ADC measurements in individuals with autism, but not in children with normal development.nnnCONCLUSIONSnThese findings suggest cerebral dysconnectivity in the early phases of autism coupled with an altered white matter maturation trajectory during childhood potentially taking place in the frontal and parietal lobes, which may represent a neurodevelopmental marker of the disorder, possibly accounting for the cognitive and social deficits.

DCDC2 Genetic Variants and Susceptibility to Developmental Dyslexia

Objective(s) Developmental dyslexia is a heritable condition, with genetic factors accounting for 44–75% of the variance in performance tests of reading component subphenotypes. Compelling genetic linkage and association evidence supports a quantitative trait locus in the 6p21.3 region that encodes a gene called DCDC2. In this study, we explored the contribution of two DCDC2 markers to dyslexia, related reading and memory phenotypes in nuclear families of Italian origin. Methods The 303 nuclear families recruited on the basis of having a proband with developmental dyslexia have been studied with 6p21.3 markers, BV677278 and rs793862. Marker-trait association was investigated by the quantitative transmission disequilibrium test (version 2.5.1) that allows for the analyses of quantitative traits. Seven phenotypes were used in association analyses, that is, word and nonword reading, word and nonword spelling, orthographic choice, memory, and the affected status based on inclusion criteria. Results Quantitative transmission disequilibrium test analyses yielded evidence for association between reading skills and the BV677278 deletion (empirical P-values=0.025–0.029) and between memory and BV677278 allele 10 (empirical P-value=0.0001). Conclusion Our result adds further evidence in support of DCDC2 contributing to the deficits in developmental dyslexia. More specifically, our data support the view that DCDC2 influences both reading and memory impairments thus shedding further light into the etiologic basis and the phenotypic complexity of developmental dyslexia.

A locus on 15q15-15qter influences dyslexia: further support from a transmission/disequilibrium study in an Italian speaking population

Developmental dyslexia (dyslexia) is a heritable condition typically diagnosed in the first school years, characterised by an impairment of reading abilities in spite of normal intelligence and adequate educational opportunities.nnWhile the exact neurobiological mechanisms underlying this condition remain obscure, the most convincing current aetiopathogenetic view of dyslexia is that impaired reading stems from a defective representation and manipulation of phonemes, —that is, the sounds that we combine to build words.1 There are at least two major complications when studying the ultimate causes of dyslexia. Firstly, the composite neuropsychological picture that often marks dyslexia may lead people to consider reading problems as a part of a more extended neurobiological syndrome whose phenotypic boundaries are blurred, and whose genetic determinants may be especially difficult to identify with certainty.2 Secondly, the leading criterion to diagnose dyslexia remains that of a reading performance below the population mean (typically, a reading score two standard deviations below the general population mean). While reading performance is distributed normally in the population,3 the prevalence of dyslexics will vary considerably across different cultures, because it depends on the complexity of orthographic rules specific to a given language to which a subject is exposed.4 Contradicting a culturally bound identity of dyslexia is a recent, functional brain imaging study of adult subjects with dyslexia from different cultures and languages (English, French, Italian) that showed the same abnormal patterns of brain activation during implicit and explicit reading.5 This suggests common neurobiological causes for dyslexia regardless of a person’s spoken language, while variation in prevalence estimates across different cultures could at least partially reflect local difficulties specific to each language, when homogenous diagnostic criteria are applied.5nnWhile functional brain imaging findings suggest biological unity for dyslexia, evidence based on genetic analyses of common determinants of dyslexia …

No evidence for association and linkage disequilibrium between dyslexia and markers of four dopamine-related genes

Abstract.Dopamine genes are candidate genes for dyslexia in thenlight of the well-known comorbidity between dyslexia and ADHD.nWithin-family association and linkage disequilibrium were testednbetween four genetic markers at DRD4, DRD3, DRD2, and DAT loci,nand dyslexia, in a sample of 130 Italian dyslexic children,n16.9% of whom had comorbid ADHD.No evidence of eithernassociation or linkage disequilibrium was found, neither in thentotal sample nor in the comorbid subgroup. Negative results donnot support a common genetic basis between these two disordersnfor these markers.

Update on the safety of second generation antipsychotics in youths: a call for collaboration among paediatricians and child psychiatrists

During the past decade, a substantial increase in the use of second generation antipsychotics (SGAs) has occurred for a number of juvenile psychiatric disorders, often as off-label prescriptions. Although they were thought to be safer than older, first generation antipsychotics, mainly due to a lower risk of neurological adverse reactions, recent studies have raised significant concerns regarding their safety regarding metabolic, endocrinological and cardiovascular side effects. Aim of this paper is to update with a narrative review, the latest findings on safety of SGAs in youths. Results suggest that different SGAs may present different safety profiles. Metabolic adverse events are the most frequent and troublesome, with increasing evidences of heightened risk for type II diabetes mellitus. Results are discussed with specific emphasis on possible strategies of an active monitoring, which could enable both paediatricians and child psychiatrists to a possible prevention, early detection, and a timely management of such effects.

Second generation antipsychotics in ‘real-life’ paediatric patients. Adverse drug reactions and clinical outcomes of drug switch

ABSTRACT 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.

Therapeutic drug monitoring of second-generation antipsychotics in pediatric patients: an observational study in real-life settings

PurposeAvailable 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.MethodsFive 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.ResultsRisperidone plasma levels were lower than in adults (median 13.6xa0ng/ml), with a high inter-patient (78.9xa0%) but lower intra-patient (34.2xa0%) variability. In multiple regression analyses, risperidone plasma levels depended only on drug dose (pxa0<xa00.001). Aripiprazole plasma levels were similar to those described in adults (median 165.8xa0ng/ml) and were widely distributed, with an inter-patient variability of 81.1xa0%, while the intra-patient variability was much lower (29.3xa0%). Multiple regression analyses indicated that aripiprazole plasma levels were influenced by the daily doses (pxa0<xa00.001) and by the number of concomitant drugs (pxa0<xa00.01).ConclusionOur 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.

The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions

We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c.421 non-CA/AA genotypes (P-value: 0.008). Multivariate analysis revealed that the ABCG2 c.421 CA/AA genotype was found associated to a higher hazard (P-value: 0.004) of developing adverse drug reactions classified as metabolism and nutrition disorders. The ABCB1 2677TT/3435TT genotype had a statistically significant lower aripiprazole Ct/ds if compared with patients with others ABCB1 genotypes (P-value: 0.026). Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients.