Antonella Gagliano

Effects of Methylphenidate on Cognitive Functions in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Evidence from a Systematic Review and a Meta-Analysis

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of neuropsychological impairments. The relationship between these neuropsychological deficits and the defining symptoms of ADHD seems more complex than originally thought. Methylphenidate (MPH) is an effective treatment for ADHD symptoms, but its impact on cognition is less clearly understood. METHODS With a common systematic search strategy and a rigorous coding and data extraction strategy across domains, we searched electronic databases to identify published placebo controlled trials that compared MPH and placebo on executive and nonexecutive memory, reaction time, reaction time variability and response inhibition in children and adolescents (5-18 years) with a formal diagnosis of ADHD. RESULTS Sixty studies were included in the review, of which 36 contained sufficient data for meta-analysis. Methylphenidate was superior to placebo in all five meta-analyses: executive memory, standardized mean difference (SMD) .26, 95% confidence interval (CI): -.39 to -.13; non-executive memory, SMD .60, 95% CI: -.79 to -.41; reaction time, SMD .24, 95% CI: -.33 to -.15; reaction time variability, SMD .62, 95% CI: -.90 to -.34; response inhibition, SMD .41, 95% CI: -.55 to -.27. CONCLUSIONS These data support the potentially important effects of MPH on various aspects of cognition known to be associated with ADHD. Consideration should be given to adding cognitive outcomes to the assessment of treatment outcome in ADHD, considering the complexity of the relationship between ADHD symptoms and cognition.

Sleep disorders in children with Attention-Deficit/Hyperactivity Disorder (ADHD) recorded overnight by video-polysomnography

OBJECTIVE To outline specific sleep disturbances in different clinical subsets of Attention Deficit/Hyperactivity Disorder (ADHD) and to confirm, by means of nocturnal video-polysomnography (video-PSG), a variety of sleep disorders in ADHD besides the classically described periodic leg movement disorder (PLMD), restless legs syndrome (RLS) and sleep related breathing disorder (SRBD). METHODS Fifty-five ADHD children (47 M, 8F; mean age=8.9 y) were included: 16 had Inattentive and 39 Hyperactive/Impulsive or Combined ADHD subtype. Behavior assessment by Conners and SNAP-IV Scales, a structured sleep interview and a nocturnal video-PSG were administered. RESULTS Most children/parents reported disturbed, fragmentary sleep at night; complaints were motor restlessness (50%), sleep walking (47.6%), night terrors (38%), confusional arousals (28.5%), snoring (21.4%), and leg discomfort at night associated with RLS (11.9%). There is a significant difference (p value <0.05 or <0.001) in almost all the studied sleep variables between ADHD children and controls. International RLS Rating Scale scoring, Periodic Limb Movements during Sleep (PLMS) and Wake (PLMW) indexes, hyperactivity and opposition scores and ADHD subtype appear related. Different sleep disorders seem to address specific ADHD phenotypes and correlate with severity of symptoms as in sleep related movement disorders occurring in Hyperactive/Impulsive and Combined ADHD subtypes. Besides, an abnormality of the arousal process in slow wave sleep with consequent abnormal prevalence of disorders of arousal possibly enhanced by SRBD has also been detected in 52% of our sample. CONCLUSIONS This study underlines the opportunity to propose and promote the inclusion of sleep studies, possibly by video-PSG, as part of the diagnostic screening for ADHD. This strategy could address the diagnosis and treatment of different specific ADHD phenotypic expressions that might be relevant to childrens symptoms and contribute to ADHD severity.

Risperidone Treatment of Children with Autistic Disorder: Effectiveness, Tolerability, and Pharmacokinetic Implications

BACKGROUND Recent evidence indicates that atypical antipsychotics represent a promising option for the treatment of autistic disorder. In particular, risperidone appears to be effective in treating aggressiveness, hyperactivity, irritability, stereotypies, social withdrawal, and lack of interests. OBJECTIVE The aim of the present study was to evaluate the effectiveness and tolerability of risperidone in children with autistic disorder and to examine the correlation between plasma levels of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) and the clinical response. METHODS The effect of treatment with risperidone (0.75-2 mg/day; mean +/- SD dose = 1.26 +/- 0.42 mg/day) was studied for 24 weeks in 20 children (14 boys, 6 girls) ages 3 to 10 years (mean age 6.0 +/- 2.4 years), diagnosed with autistic disorder. Fourteen items selected from the Childrens Psychiatric Rating Scale (CPRS-14) and Clinical Global Impression (CGI) were used for behavioral evaluation. Patients were classified as responders if they showed a 25% or greater decrease on CPRS-14 total score at final evaluation compared with baseline and a final CGI rating of 1 or 2. Patients were rated for extrapyramidal side effects on the Abnormal Involuntary Movement Scale (AIMS). Other side effects, including the expected side effects of atypical antipsychotics drugs, were assessed by a checklist. Blood samples for determination of risperidone and its active metabolite 9-OH-risperidone were obtained after 12 weeks, and serum prolactin levels were measured on admission and at weeks 12 and 24. RESULTS The psychopathological state, as assessed by CPRS, improved significantly over the duration of treatment. The mean CPRS-14 scores decreased significantly from 63.7 +/- 10.0 at baseline to 52.9 +/- 14.3 at week 12 (p < 0.01). At the end of 12 weeks of treatment, 8 patients were considered responders, and 10 patients reached a minimal improvement. No further improvement was observed in the following 12 weeks. In all children, serum prolactin levels increased significantly (p < 0.001) from 166 +/- 88 UI/mL at baseline to 504 +/- 207 UI/mL at week 12 of risperidone treatment. Weight gain and increased appetite were the most common unwanted effects. A mean increase of 3.7 +/- 1.7 kg in body weight was observed at final evaluation as compared with baseline. There was no significant correlation between percent improvement in total CPRS score and the plasma level of risperidones active fractions (the sum of the risperidone and 9-OH-risperidone plasma concentration). CONCLUSIONS This study provides further evidence of the beneficial effects of risperidone in children diagnosed with autistic disorder. However, the potential advantages of risperidone should be weighed against the risk of unwanted effects, such as an increase in serum prolactin levels and weight gain. No relation was observed between total plasma risperidone and 9-OH-risperidone concentrations and clinical response.

Ictal and interictal EEG abnormalities in ADHD children recorded over night by video-polysomnography

In this paper we explore the prevalence of ictal and interictal epileptiform discharges (IEDs) and sleep disorders in ADHD children referred to a sleep clinic for all night video-PSG. Forty-two ADHD outpatients (35 males and 7 females) underwent video-PSG and a behavioural/neuropsychological assessment. Spearman correlation coefficients (p<0.05 criterion level) were used to assess the association between cognitive, behavioural, clinical (co-morbidity), sleep (sleep efficiency) and EEG (seizures, IEDs, localization of IEDs foci) variables. Sleep disorders were found in 86% of ADHD children; among these, 26% had RLS. 53.1% of ADHD children had IEDs (28.2% centro-temporal spikes, 12.5% frontal spikes, 9.3% temporal-occipital spikes and 2.3% generalized S-W). Nocturnal seizures were recorded in three patients: two with atypical interictal rolandic spikes and one with left frontal slow abnormalities. A significant relationship (p<0.05) emerges between nocturnal seizures and WISC-R IQ score and visual-spatial memory test and between some cognitive variables and interictal rolandic spikes. High levels of inattention, impulsivity/hyperactivity and oppositional behaviours were related (p<0.01 or 0.05) with Restless Leg Syndrome diagnosis. In conclusion, ADHD is a condition often associated with EEG epileptiform abnormalities. Seizures/IEDs presence seems to play a role on cognitive abilities, conversely sleep disorders have a stronger impact on behavioural rather than cognitive indicators.

No evidence for association between dyslexia and DYX1C1 functional variants in a group of children and adolescents from Southern Italy

Recently, DYX1C1, a candidate gene for developmental dyslexia, encoding a nuclear tetratricopepetide repeat domain protein dynamically regulated in brain, has been characterized through a translocation breakpoint in a Finnish family. Two putatively functional variants, −3G/A and 1249G/T, have been reported to be significantly associated with dyslexia in this population. Further studies, conducted on different ethnic groups (English and Canadian), have not confirmed a role for DYX1C1 variants in increasing the risk for dyslexia. We investigated the role of these variants in dyslexic children and adolescents from Southern Italy. No significant evidence for association between dyslexia and these DYX1C1 putative functional variants has been shown. We argue that the different DYX1C allele frequencies shown among Italian and Finnish subjects with dyslexia could be attributable to the different linkage disequilibrium structure of these populations.

Erratum to: Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies.

Background: The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed. The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection. Methods: A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included. Results: Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study. Conclusions: Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation. No formulation is clearly superior to another; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment. For patients achieving suboptimal symptom control, switching long-acting MPH formulations may be beneficial. When switching formulations, it is usually appropriate to titrate the immediate-release component of the formulation; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components. Further studies are necessary to provide guidance in clinical practice, particularly in the treatment of adults and pre-school children and the impact of comorbidities and symptom severity on treatment response.

Short- and long-term effects on prolactin of risperidone and olanzapine treatments in children and adolescents.

This study investigated prolactin levels in two groups of children and adolescents receiving risperidone (N=29) or olanzapine (N=13). It focused not only on significant differences but also on effect sizes; took into account dose effects and gender differences; used a longitudinal design (months 1, 3, 6 and 12) that helped control for individual differences; and took into account response differences due to the duration of antipsychotic treatment. Additionally, this study investigated tolerance development using statistical tests, and explored the effect of antipsychotic plasma concentrations at months 1 and 3. After adjusting for gender, treatment duration and individual effects, mean prolactin levels on risperidone were 4.9 ng/mL higher than on olanzapine (10.3 times higher after controlling for dosing potency). On risperidone treatment, the adjusted mean prolactin level at the 3rd month of treatment was significantly higher than at the 1st month; at the 12th month it was significantly lower than at the 1st month; the 1st and 6th months were not significantly different. On olanzapine treatment, adjusted mean prolactin levels at the 3rd and 6th months of treatment were significantly higher than at the 1st month; at the 12th month it was lower than at the 1st month, but the difference was not significant. In males, at the 3rd month, an increase of 1 ng/mL in plasma 9-hydroxyrisperidone concentrations raised prolactin levels significantly by 0.44 ng/mL. In females, independently of duration (1 or 3 months), an increase of 1 ng/mL in plasma olanzapine concentrations raised prolactin levels significantly by 2.1 ng/mL. After adjusting for dose and the greater potency of risperidone, the increase in prolactin levels during risperidone treatment appeared to be 10.3 times higher than that during olanzapine treatment. Our study showed a pattern consistent with the development of prolactin tolerance over time. Future prolactin studies in children and adolescents taking antipsychotics need to include larger samples with more frequent prolactin measures and long-term plasma concentrations.

Pharmacological response in juvenile bipolar disorder subtypes: A naturalistic retrospective examination

This study reports on the naturalistic pharmacotherapy of 266 youths with bipolar disorder (BP), manic or hypomanic episode (158 males and 108 females, 13.8+/-2.8 years), first treated with monotherapy on valproic acid (VPA) (n=158, 59.4%), lithium (n=90, 33.8%) or atypical antipsychotics (n=18, 6.8%). Among the patients receiving mood stabilizers, 59.5% of those treated with VPA and 47.8% of those receiving lithium did not need other antimanic agents (mood stabilizers and/or atypical antipsychotics). Lower severity was associated with a greater persistence of both VPA and lithium monotherapy. Factors associated with greater persistence of VPA monotherapy were BP II and co-occurring generalized anxiety disorder, separation anxiety disorder and simple phobias. On the contrary, BP I and co-occurring psychotic symptoms and/or conduct disorder were associated with a lower persistence of VPA monotherapy. Factors associated with lower persistence of lithium monotherapy were younger age and the association with attention deficit hyper-activity disorder (ADHD). Type of BP and presence of psychotic symptoms and conduct disorder did not affect the lithium monotherapy. Overall, predictors of non-response (multiple stepwise logistic regression) in both VPA and lithium groups were baseline Clinical Global Impression (CGI) Severity score and comorbid conduct disorder; while psychotic symptoms and absence of comorbid generalized anxiety disorder were predictors of poorer treatment response only in the VPA group, and chronic course, comorbid ADHD and absence of comorbid panic disorder were predictors only in the lithium group. Such naturalistic data from an ordinary clinical setting have relevance to clinical practice.

Aripiprazole in Children with Tourette's Disorder and Co-morbid Attention-Deficit/Hyperactivity Disorder: A 12-Week, Open-Label, Preliminary Study

Tourettes disorder (TD) in children and adolescents is frequently co-morbid with attention-deficit/hyperactivity disorder (ADHD). Dopamine-blockers are the first line treatment for TD, whereas dopamine-agonists, such as stimulants, are the gold-standard in the treatment of ADHD. These contrasting effects supported concerns about the risk that stimulants for treating ADHD may trigger or worsen co-morbid tics. Aripiprazole, a partial dopamine agonist, acts as an antagonist at dopamine D2 receptors in hyperdopaminergic conditions and displays agonist properties under hypodopaminergic conditions. The present study describes the use of aripiprazole (10.0 ± 4.8 mg/day) in a consecutive group of 28 patients with a primary diagnosis of TD and co-morbid ADHD, combined subtype. The Yale Global Tic Severity Scale (YGTSS) and the ADHD-Rating Scale (ADHD-RS-IV) were used as primary outcome measures and both significantly improved (p<0.001) after the treatment. Global measures of severity (Clinical Global Impressions-Severity) and of functional impairment (Childrens Global Assessment Scale) also significantly improved during the treatment (p<0.001). At the YGTSS there was a reduction of 42.5%, in motor tics, of 47.9% in phonic tics (44.7% for the combined scores), and of 32.3% in tic impairment. Nineteen patients (67.9%) had a reduction of at least 50% of the YGTSS score (motor+phonic tics). The improvement at the ADHD-RS-IV score was 22.5%, 12 patients (42.8%) presented an improvement of 30%, but only 2 (7.1%) an improvement greater than 50%. Using a logistic regression model, a reduction of at least 30% in ADHD-RS-IV score was more likely to occur in the obsessive-compulsive disorder co-morbid group. Aripiprazole was well tolerated and none of the patients discontinued medication because of side effects. In summary, aripiprazole resulted in an effective treatment for TD, but it was only moderately effective on co-occurring ADHD symptomatology. Our preliminary data suggest that aripiprazole may represent a possible therapeutic option, among other possible monotherapies addressing both tics and ADHD.

Difference in Visual Social Predispositions Between Newborns at Low- and High-risk for Autism

Some key behavioural traits of Autism Spectrum Disorders (ASD) have been hypothesized to be due to impairments in the early activation of subcortical orienting mechanisms, which in typical development bias newborns to orient to relevant social visual stimuli. A challenge to testing this hypothesis is that autism is usually not diagnosed until a child is at least 3 years old. Here, we circumvented this difficulty by studying for the very first time, the predispositions to pay attention to social stimuli in newborns with a high familial risk of autism. Results showed that visual preferences to social stimuli strikingly differed between high-risk and low-risk newborns. Significant predictors for high-risk newborns were obtained and an accurate biomarker was identified. The results revealed early behavioural characteristics of newborns with familial risk for ASD, allowing for a prospective approach to the emergence of autism in early infancy.