Faculty Bibliography

A recent Cochrane review assessed the efficacy of methylphenidate for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. Notwithstanding the moderate-to-large effect sizes for ADHD symptom reduction found in the meta-analysis, the authors concluded that the quality of the evidence is low and therefore the true magnitude of these effects remains uncertain. We identified a number of major concerns with the review, in the domains of study inclusion, approaches to quality assessment and interpretation of data relating to serious adverse events as well as of the clinical implications of the reported effects. We also found errors in the extraction of data used to estimate the effect size of the primary outcome. Considering all the shortcomings, the conclusion in the Cochrane review that the status of the evidence is uncertain is misplaced. Professionals, parents and patients should refer to previous reviews and existing guidelines, which include methylphenidate as one of the safe and efficacious treatment strategies for ADHD.

Until recently, no comprehensive guidance specifically on the conduction of systematic reviews and meta-analyses of pharmacoepidemiological studies of safety outcomes was available. In December 2015, the European Network of Centres for Pharmacoepidemiology and Pharamacovigilance (ENCePP), a network coordinated by the European Medicines Agency, published their 'Guidance on conducting systematic reviews and meta-analyses of completed comparative pharmacoepidemiological studies of safety outcomes', filling an important gap in the field. This paper highlights the ENCePP recommendations in terms of study identification, data extraction, study quality appraisal and analytical plan. Although the ENCePP document should not be considered as definitive, since it will likely be refined following researchers' feedback, it is expected that it will be highly influential and useful for the field, with the ultimate goal to improve and standardise the conduction and reporting of systematic reviews/meta-analyses of pharmacoepidemiological studies of safety outcomes.

AIM: Although there have been frequent clinical reports about sleep disturbances in children with learning disabilities, no data are available about the prevalence of sleep disturbances in children with developmental dyslexia (DD). This study evaluated sleep disturbances in children with DD referred to a hospital clinic and compared their scores with healthy controls. METHODS: We consecutively enrolled 147 children (66% male) aged 10.26 +/- 2.63 years who were referred by clinical paediatricians to the Clinic for Child and Adolescent Neuropsychiatry at the Second University of Naples with DD and 766 children without DD (60% male) aged 10.49 +/- 2.39 years recruited from schools in the same urban area. Sleep disturbances were assessed with the Sleep Disturbances Scale for Children (SDSC), which was filled out by the children's main carers. RESULTS: Compared with the controls, the children with DD showed significantly higher rates of above threshold scores on the total SDSC score (p < 0.001) and on the subscales for disorders in initiating and maintaining sleep (p < 0.001), sleep breathing disorders (p < 0.001) and disorders of arousal (p < 0.001). CONCLUSION: Sleep disorders were significantly more frequent in children with DD than in healthy controls. A possible relationship between dyslexia and sleep disorders may have relevant clinical implications.

The study by Leventakou and colleagues is emblematic of a welcome change in focus in attention-deficit/hyperactivity disorder (ADHD) research. First, the authors focused on the overlooked association between ADHD and aberrant eating patterns, reflecting an emerging change in the conceptualization of ADHD as a condition affecting not only high-level cognitive processes but also more basic functions such as eating and sleeping, as well as the underlying complex metabolic and possibly inflammatory pathways. Second, the authors focused, for the first time, on the relationship between ADHD and eating disorders in preschoolers, which is of relevance for the design of preventive strategies. Third, they zoomed closely to several types of aberrant eating behaviours; besides confirming the association of ADHD symptoms to emotional overeating, they also found an intriguing relationship between impulsivity and food fussiness. Further changes in perspective focusing on the underlying mechanisms, as well as using a wide-angle lens to capture the longitudinal relationship between ADHD and aberrant eating behaviours will not only provide a more detailed (clinical) picture of individuals with ADHD but will also hopefully lead to more effective preventive/treatment strategies.

OBJECTIVE: We performed meta-analyses of randomized controlled trials to examine the effects of neurofeedback on attention-deficit/hyperactivity disorder (ADHD) symptoms and neuropsychological deficits in children and adolescents with ADHD. METHOD: We searched PubMed, Ovid, Web of Science, ERIC, and CINAHAL through August 30, 2015. Random-effects models were employed. Studies were evaluated with the Cochrane Risk of Bias tool. RESULTS: We included 13 trials (520 participants with ADHD). Significant effects were found on ADHD symptoms rated by assessors most proximal to the treatment setting, that is, the least blinded outcome measure (standardized mean difference [SMD]: ADHD total symptoms = 0.35, 95% CI = 0.11-0.59; inattention = 0.36, 95% CI = 0.09-0.63; hyperactivity/impulsivity = 0.26, 95% CI = 0.08-0.43). Effects were not significant when probably blinded ratings were the outcome or in trials with active/sham controls. Results were similar when only frequency band training trials, the most common neurofeedback approach, were analyzed separately. Effects on laboratory measures of inhibition (SMD = 0.30, 95% CI = -0.10 to 0.70) and attention (SMD = 0.13, 95% CI = -0.09 to 0.36) were not significant. Only 4 studies directly assessed whether learning occurred after neurofeedback training. The risk of bias was unclear for many Cochrane Risk of Bias domains in most studies. CONCLUSION: Evidence from well-controlled trials with probably blinded outcomes currently fails to support neurofeedback as an effective treatment for ADHD. Future efforts should focus on implementing standard neurofeedback protocols, ensuring learning, and optimizing clinically relevant transfer.

Children with ADHD may present with sleep disturbances that add to the impairment of the disorder. The long-term sleep effects of the first-line pharmacological treatment for ADHD, i.e., psychostimulants, are unclear. In this pilot study, we compared polysomnographic variables in children with ADHD (n = 11, aged 6-15 years), before pharmacological treatment, and in children without ADHD (n = 22, aged 5-14 years); we also assessed polysomnographic changes in children with ADHD (n = 7) after a 6-month treatment with methylphenidate immediate-release (once or twice daily). Compared to children without ADHD, those with ADHD at baseline presented with significantly increased duration of awakenings (p = 0.02), reduction in sleep efficiency (p = 0.03), and increase in stage I (N1) (p < 0.01) and reduction in stage II (N2) (p = 0.02) and stage III-IV (N3) percentages. Methylphenidate treatment did not significantly change any parameter of sleep architecture. CONCLUSION: Preliminary evidence from this pilot study shows that, compared to children without ADHD, those with ADHD presented a more fragmented and less effective sleep at baseline and that the 6-month methylphenidate treatment did not further negatively impact on sleep architecture. What is known: * Children with ADHD may present with subjectively reported and/or objectively confirmed disturbances of sleep. * The long-term effects on sleep of the first-line pharmacological treatment for ADHD, i.e., psychostimulants, are not clear. What is new: * Our study showed that the 6-month continuous treatment with methylphenidate did not further negatively impact on sleep architecture in children with ADHD.

Mitochondrial dysfunction has been reported to be involved in the pathophysiology of autism spectrum disorder (ASD). Studies investigating the possible association between ASD and polymorphism in SLC25A12, which encodes the mitochondrial aspartate/glutamate carrier, have yielded inconsistent results. We conducted a systematic review and meta-analysis of such studies to elucidate if and which SLC25A12 single nucleotide polymorphisms (SNPs) are associated with ASD. We searched PubMed, Ovid, Web of Science, and ERIC databases through September 20th, 2014. Odds ratios (ORs) were aggregated using random effect models. Sensitivity analyses were conducted based on study design (family-based or case-control). Fifteen out of 79 non-duplicate records were retained for qualitative synthesis. We pooled 10 datasets from 9 studies with 2001 families, 735 individuals with ASD and 632 typically developing (TD) individuals for the meta-analysis of rs2292813, as well as 11 datasets from 10 studies with 2016 families, 852 individuals with ASD and 1058 TD individuals for the meta-analysis of rs2056202. We found a statistically significant association between ASD and variant in rs2292813 (OR = 1.190, 95 % CI 1.052-1.346, P = 0.006) as well as in rs2056202 (OR = 1.206, 95 % CI 1.035-1.405, P = 0.016). Sensitivity analyses including only studies with family-based design demonstrated significant association between ASD and polymorphism in rs2292813 (OR = 1.216, 95 % CI 1.075-1.376, P = 0.002) and rs2056202 (OR = 1.267, 95 % CI 1.041-1.542, P = 0.018). In contrast, sensitivity analyses including case-control design studies only failed to find a significant association. Further research on the role of SLC25A12 and ASD may pave the way for potential innovative therapeutic interventions.

BACKGROUND: Gaining insight into possible gender differences in the clinical presentation of adults with attention-deficit/hyperactivity disorder (ADHD) is of relevance in order to conduct appropriate screening and treatment interventions in both genders. METHOD: The analyses compared (1) prevalence and sociodemographic correlates, (2) frequency of ADHD core symptoms, (3) rates of subtypes, (4) prevalence of comorbid mental health conditions, and (5) rates of risky/impulsive behaviors, as well as health and social correlates, in men and women with ADHD in a nationally representative, US population-based sample. Face-to-face psychiatric interviews were conducted according to DSM-IV criteria in 34,653 adults from the US National Epidemiologic Survey on Alcohol and Related Conditions (Wave 2, 2004-2005). RESULTS: While the prevalence of lifetime ADHD was significantly higher in men than in women (OR = 1.46, 95% CI = 1.22-1.76), the rate of persistent ADHD did not significantly differ across genders (OR = 1.23, 95% CI = 0.96-1.58). Compared to men with persistent ADHD, women with persistent ADHD, despite having lower rates of hyperactive symptoms, presented with similar ADHD subtypes profile and rates of risky behaviors (except for reckless driving), as well as with significantly more anxiety and perceived mental health impairment (P = .032). Results were similar when considering lifetime ADHD. CONCLUSIONS: Our findings show that, despite different symptom profiles and comorbidities, men and women have similar rates of current ADHD and of risky behaviors associated with the disorder. Women with ADHD should receive as much attention as their male counterparts.