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Objective: To examine how changes in sleep patterns and sleep problems occurring between the pre-pandemic and the Covid-19 lockdown period influenced mood-behavioral functioning of children with Attention Deficit Hyperactivity Disorder (ADHD)., Methods: Parents of 992 children with ADHD (85.4% boys, mean age: 11.52 years, SD = 3.17), recruited from the Italian ADHD family association, completed a modified version of the Sleep Disturbance Scale for Children and filled out 11 emotional behavioral items selected from the Child Behavior Checklist (CBCL) 6-18 questionnaire. Subgroups identified based on sleep duration changes ("maintained", "increased", "reduced") and of sleep problems during lockdown ("onset", "remission", "maintained", "no sleep problem") were analyzed to evaluate the association with internalizing and externalizing scores., Results: Sleep duration showed no or low influence on internalizing and externalizing behaviors after control for age, sex, and socioeconomic status. Patients with ADHD with "no sleep problem" showed significant lower scores in internalizing and externalizing behaviors than those who "maintained" or had "onset" of different sleep problems. The effect sizes were higher for internalizing than externalizing behaviors. Lower internalizing scores were found in those who remitted difficulty in falling asleep, daytime sleepiness, nightmares, vs. the "maintained" or "onset" groups and those who remitted hypnic jerks vs. the "onset" group. Children with ADHD who "maintained" sleep terrors reported higher internalizing and mainly externalizing scores than the other groups., Conclusion: Sleep problems negatively influence daytime functioning of patients with ADHD. but mood and behavioral domains show different susceptibility to the changes of sleep problems, and different vulnerability to specific sleep problems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Inflammation may represent a common underlying mechanism in a wide range of diseases, including neuropsychiatric disorders. Cytokine involvement has been investigated in some studies on patients with childhood neuropsychiatric diseases. The aim of this study was to determine whether cytokines are involved in ADHD to provide a rationale for immune-based therapeutic strategies in this disorder., Methods: Sixty children were studied: 34 consecutive drug-naïve children with ADHD (30 males and 4 females; mean age of 10.10 years, SD=2.43 age) and 26 healthy control children (22 males and 4 females; mean age of 10.70 years, SD=1.81). All cytokines but IL-2 (IL4-IL6-IL10- IL17-TNFA and IFNG) were studied by ELISAs; IL-2 was instead studied by means of paired anti-cytokine Abs and cytokine standards obtained from PharMingen., Results: Data reveal higher IL-6 and IL-10 levels in ADHD patients than in the control group (P=0.03). No differences emerged between the two groups for the other cytokines., Conclusions: Our study showed an imbalance between pro- and anti-inflammatory cytokines that may play a pivotal role in the pathogenesis of ADHD.

Objective: We investigated whether ADHD children who are positive to Purkinje cell antibodies display pro-inflammatory activity associated with high cytokine serum levels. Method: Fifty-eight ADHD outpatients were compared with 36 healthy, age- and sex-matched children. Forty-five of the ADHD children were positive to anti-Yo antibodies, whereas 34 of the control children were negative. Interleukin 4 (IL-4), IL-6, IL-10, IL-17, tumor necrosis factor alpha (TNFα), and interferon gamma (IFNγ) cytokine serum levels were tested in ADHD children who were positive to anti-Yo antibodies and in the control children who were negative. Results: Anti-Yo antibodies were present to a greater extent in the ADHD group: 77.58% versus 22.42%. Significant differences emerged between the two groups in IL-6 and IL-10, with higher cytokine levels being detected in ADHD children than in controls. Conclusion: Immune processes in ADHD are likely to be associated with mediators of inflammation, such as cytokines. These results contribute to our understanding of action of neural antibodies and cytokines in ADHD.

The aim of the study is to explore the impact of Generalized Anxiety Disorder (GAD) comorbidity in children with Attention Deficit Hyperactivity Disorder (ADHD). Six hundred children with ADHD (mean age = 9.12 years), recruited from 2013 to 2017, participated in the study. A total of 96 (16%) children with ADHD displayed a comorbidity with GAD. ADHD + GAD were compared to 504 ADHD children without GAD in terms of cognitive and psychiatric profile, ADHD subtype and family psychiatric history. The ADHD + GAD, predominantly represented from ADHD combined (72.6%), displayed higher psychiatry comorbidity, in particular with depressive disorders, and were associated with higher rates of maternal depression, of ADHD in fathers, and bipolar disorders in second degree relatives. Moreover, younger preschool-primary school age children with ADHD + GAD showed significant higher frequency of depressive disorders versus younger preschool-primary children with ADHD without GAD. ADHD + GAD comorbidity represents a more complex clinical condition compared to ADHD without GAD, characterized by the higher frequency of multiple comorbidities and by a psychiatric family with higher rates of mood and disruptive disorders., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study aims at determining serum levels of tryptophan and other metabolites of the kynurenine pathway in children with attention deficit hyperactivity disorder (ADHD) compared to healthy controls. Such metabolites interact with glutamate receptors in the central nervous system, potentially modulating mechanisms that are pivotal in ADHD and thus potentially representing peripheral biomarkers of the disorder. We measured serum levels of tryptophan and some metabolites of the kynurenine pathway in 102 children with ADHD and 62 healthy controls by liquid chromatography-tandem mass spectrometry (LC-MS/MS). As compared to healthy controls, children with ADHD showed a reduction in serum levels of anthranilic acid (-60%), kynurenic acid (-11.2%), and xanthurenic acid (-12.5%). In contrast, serum levels of tryptophan (+11.0%) and kynurenine (+48.6%) were significantly enhanced, and levels of quinolinic acid were unchanged in children with ADHD. In a logistic regression model, the presence of ADHD was predicted by low anthranilic acid and high tryptophan levels. These findings support the involvement of the kynurenine pathway in the pathophysiology of ADHD and suggest that anthranilic acid and tryptophan levels should be investigated as potential peripheral biomarker for ADHD.

Objective: To explore the impact of early-onset bipolar disorder (pediatric bipolar disorder [PBD]) on ADHD., Method: We compared ADHD symptom severity, ADHD subtype distribution, and rates of comorbid and familial psychiatric disorders between 49 ADHD children with comorbid PBD and 320 ADHD children without PBD., Results: Children with ADHD and PBD showed higher scores in the Hyperactive and Inattentive subscales of the ADHD Rating Scale, than children with ADHD alone. The frequency of combined subtype was significantly higher in ADHD children with PBD, than in those with ADHD alone. ADHD children with PBD showed a higher rate of familial psychiatric disorders than ADHD children without PBD. The rate of conduct disorder was significantly greater in children with PBD and ADHD compared with children with ADHD alone., Conclusion: ADHD along with PBD presents with several characteristics that distinguish it from ADHD alone, suggesting that these may be distinct disorders.

Aim: In Italy, attention-deficit/hyperactivity disorder (ADHD) remains under-diagnosed. The Lifetime Impairment Survey assessed impairments/symptoms of ADHD in children across six European countries. Results relating to the Italian sample are discussed here., Methods: Parents/caregivers of children aged <20 years with ADHD (ADHD group) and without ADHD (control group) were invited to participate in an online survey. Participants answered questions relating to their eldest/only child. History of ADHD diagnosis was self-reported. Eight impairment and symptom scales and two summed scores were created to compare the ADHD and control groups; higher scores indicate greater impairment., Results: In Italy, 104 parents/caregivers of children with ADHD and 105 parents/caregivers of children without ADHD participated in the survey (N.=83 and N.=84, respectively, after exclusion of participants with implausible answers). The ADHD group had higher mean (standard deviation) scores than the control group for home impairment (2.1 [0.5]) vs. 1.9 [0.4]; P<0.001), school impairment (2.8 [0.6] vs. 2.1 [0.6]; P<0.001), relationship impairment (2.3 [0.8] vs. 1.9 [0.7]; P<0.001) and comorbid symptoms (3.3 [0.7] vs. 2.5 [0.7]; P<0.001). Impairment at home and at school were correlated with each other (r=0.478; P<0.001) and with ADHD symptoms (r=0.321; P<0.001 and r=0.462; P<0.001, respectively), comorbid symptoms (r=0.231; P<0.05 and r=0.420; P<0.001), school failure (r=0.208; P<0.02 and r=0.320; P<0.001) and relationship impairments (r=0.432; P<0.01 and r=0.645; P<0.001)., Conclusion: The daily lives of children with ADHD in Italy are significantly affected by impairments associated with ADHD. Children and adolescents with ADHD in Italy should receive prompt diagnosis and appropriate therapy.

Objective: A unique profile of the empirically derived Child Behavior Checklist-anxious/depressed, attention, and aggression-deficient emotional self-regulation (CBCL-AAA-DESR profile: ≥180 and ≤210) may be used to identify a sizable minority of children with ADHD with associated DESR. The main aim of this study was to replicate these findings in an Italian sample., Method: The sample consisted of 358 children and teenagers aged 6 to 17 years of both sexes with (n = 190) and without a diagnosis of ADHD (n = 168)., Results: In all, 40.0% of children with ADHD had a positive CBCL-DESR profile compared with 3.5% of controls. Receiver-operating characteristic analysis showed that the CBCL-DESR profile cut-off (sensitivity = 97.33, specificity = 79.66, criterion ≥179, ≤210) discriminated the two subsamples., Conclusion: The findings replicate previous results highlighting the utility of the CBCL as a means of identifying DESR in children with ADHD., (© 2012 SAGE Publications.)

Some clinical studies on attention deficit hyperactivity disorder (ADHD) have been found to overlap those of studies on personality, particularly those on the Novelty Seeking trait (NS) as measured by the Junior Temperament and Character Inventory (JTCI). The aim of this study was to evaluate the potential role of NS in clinical research on ADHD. We enroled 146 ADHD children (125 boys; mean age=9.61, S.D.=2.50) and 223 age- and gender-matched control children (178 boys; mean age=9.41, S.D.=2.30). All the parents filled in the JTCI for the evaluation of personality according to Cloninger׳s model. An exploratory factor analysis differentiated the NS items that concern "Impulsivity" (NS1) from those that concern other features (NS2). Multivariate Analysis of Variance (MANOVAs) revealed significant differences between ADHD children and non-ADHD children in temperamental dimensions: the scores of ADHD children were higher than those of non-ADHD children in Total NS, NS1-Impulsivity and NS2. Our results show that the NS dimension of the JTCI in ADHD children is higher than in non-ADHD children, even when a correction is made for impulsivity items. This finding suggests that the NS trait plays a central role in ADHD diagnosis even when items referred to impulsivity are removed from the NS scale., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: The aim of the present research was to identify profiles of Cloninger's temperament and character dimensions associated with anxiety disorders, oppositional defiant disorder (ODD) and attention- deficit/hyperactive disorder (ADHD) in preschoolers., Method: The parents of 120 children (mean age=4.65 years; S.D.=.88) completed the Preschool Temperament and Character Inventory (PsTCI). The sample consisted of 4 groups (n=30 per group): ADHD, anxious, ODD and control children. To diagnose the different disorders, the Preschool Age Psychiatric Assessment and Child Behavior Checklist 1.5-5 was administered to the parents., Results: The discriminant analysis showed that three temperamental dimensions (Harm Avoidance, Novelty Seeking and Persistence) enabled the correct classification of 75% of cases within their own group, which demonstrated an adequate accuracy rate. The ADHD children showed a temperamental profile that was characterized by high Novelty Seeking, low Reward Dependence and low Persistence, while the anxious children obtained high scores in Harm Avoidance. The profiles of the ODD children shared some common features (high Novelty Seeking) with the ADHD children, but the ODD children were characterized by higher Persistence and Harm Avoidance compared with ADHD children., Conclusions: The present results indicate that Cloninger's temperamental dimensions allow to differentiate the three most frequent psychiatric disorders in preschoolers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: The Lifetime Impairment Survey, conducted in Europe, assessed impairment and symptoms of attention-deficit/hyperactivity disorder (ADHD) in childhood, and experiences of ADHD diagnosis and treatment, as recalled by adults., Methods: Adults with ADHD and without ADHD (control group) were invited to participate in an internet-based survey and report on their childhood experiences. History of ADHD diagnosis was self-reported. Groups were compared using impairment and symptom scales., Results: Overall, 588 adults with ADHD and 736 without ADHD participated. Mean (standard deviation [SD]) age at diagnosis of ADHD was 20.0 (12.6) years (median 18.0) following consultation with 3.8 (5.1) doctors (median 2) over 44.6 (69.3) months (median 17.0). A total of 64.1% (377/588) of adults with ADHD reported frustration or difficulties during the diagnostic process. The ADHD group had a higher mean (SD) score versus control for general (3.3 [1.2] vs 2.1 [1.2]; p < 0.001) and school impairment (2.8 [0.7] vs 2.3 [0.6]; p < 0.001) but not home impairment (2.1 [0.5] for both groups). Discussion The survey demonstrated that ADHD had a negative impact on all aspects of childhood investigated, as recalled by adults., Conclusions: These data provide insights into childhood impairments and identify areas for improvement in the management and treatment of ADHD.

The Lifetime Impairment Survey assessed impairment and symptoms of attention-deficit/hyperactivity disorder (ADHD) in children/adolescents from six European countries. Parents/caregivers of children/adolescents aged<20 years with ADHD (ADHD group; n = 535) and without ADHD (control group; n=424) participated in an online survey. History of ADHD diagnosis was self-reported. ADHD and control groups were compared using impairment and symptom scales; higher scores indicate greater impairment. Mean (SD) age at ADHD diagnosis was 7.0 (2.8) years, following consultation of 2.7 (2.6) doctors over 20.4 (23.9) months. Parents/caregivers (64%; 344/535) reported frustration with some aspect of the diagnostic procedure; 74% (222/298) were satisfied with their child's current medication. ADHD had a negative impact on children/adolescents in all aspects of life investigated. The ADHD group had a higher mean (SD) school impairment score (2.7 [0.7]) compared with the control group (2.1 [0.7]; P<0.001) and were more likely to be in the bottom of their class (P<0.001). These data provide insights into impairments associated with ADHD in childhood/adolescence, and identify areas for improvement in its management and treatment., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Although the relationship between alexithymia and psychopathology has been studied extensively in adults, research is lacking on alexithymia in childhood psychopathology. The aim of this study was to investigate the relationship between alexithymia and attention-deficit/hyperactivity disorder (ADHD). The Italian version of the Alexithymia Questionnaire for Children was administered to a sample of 50 children with a DSM-IV diagnosis of ADHD, as assessed by means of the K-SADS PL, and to 100 healthy, age- and sex-matched children without ADHD. The total alexithymia score as well as the difficulty in identifying feelings (DIF) and externally oriented thinking factors were significantly associated with ADHD. The total alexithymia score, the DIF, and the difficulty in describing feelings factors were also significantly associated with symptoms of hyperactivity/impulsivity. No significant relationship between alexithymia and inattentiveness symptoms emerged. Results provide preliminary data on the relationship between alexithymia and ADHD. Findings point to an association between difficulty in identifying emotions and hyperactivity/impulsivity. Future studies conducted on larger patient samples, as well as longitudinal designs, are warranted to confirm our findings.

Objective: Five sleep ADHD phenotypes have been hypothesized: (a) the hypo-arousal state of the "primary" form of ADHD, (b) the sleep phase advanced disorder, (c) sleep disordered breathing (SDB), (d) restless legs syndrome and/or periodic limb movements disorder (PLMD), and (e) epilepsy., Method: Five case reports are presented; each child but one underwent video-polysomnography., Results: The first case report is an example of ADHD and SDB, with improvement of hypersomnolence after resolution of sleep apnea. The second case shows the impact of delayed sleep onset latency in the pathogenesis of ADHD, and the efficacy of melatonin. The third case report describes the association with PLMD, with amelioration after iron supplementation. The other two cases are examples of ADHD and epilepsy, with clinical improvement after antiepileptic treatment was started., Conclusion: A diagnostic and therapeutic algorithm should be designed to find the best first-line treatment for ADHD and sleep problems/epilepsy.

An autoimmune hypothesis has been suggested for several disorders in childhood. The aim of the study was to clarify the role of the cerebellum in ADHD and to evaluate the possible association between anti-Yo antibodies and ADHD. The presence/absence of antibodies was tested by indirect immunofluorescence assay on 30 combined subtype ADHD children, on 19 children with other psychiatric disorders (Oppositional-defiant and Conduct Disorders, Dyslexia) and 27 healthy controls. Results showed a significant positive response to the anti-Yo antibody immunoreactivity in the Purkinje cells of the cerebellum of ADHD children, compared with the control group and the psychiatric non-ADHD children. This association points to an immune dysregulation and the involvement of the cerebellum in ADHD., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: (a) To compare serum ferritin levels in a sample of stimulant-naïve children with ADHD and matched controls and (b) to assess the association of serum ferritin to ADHD symptoms severity, ADHD subtypes, and IQ., Method: The ADHD and the control groups included 101 and 93 children, respectively. Serum ferritin levels were determined with the enzyme-linked immunosorbent assay method., Results: Serum ferritin did not significantly differ between children with ADHD and controls, as well as among ADHD subtypes. Correlations between serum ferritin levels and measures related to IQ or ADHD severity were not significant., Conclusion: This is the largest controlled study that assessed ferritin levels in stimulant-naïve ADHD children. The findings of this study do not support a significant relationship between serum ferritin levels and ADHD. However, the authors' results based on peripheral measures of iron do not rule out a possible implication of brain iron deficiency in ADHD, grounded on neurobiological hypotheses and preliminary empirical evidence.

Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common childhood-onset neuropsychiatric conditions. Despite extensive research, the etiopathophysiological factors underlying ADHD are not completely understood. It has been suggested that iron deficiency may contribute to ADHD symptoms severity. Whereas evidence from studies based on serum ferritin measures, a marker of peripheral iron status, is somewhat mixed, preliminary recent evidence suggests a deficiency of brain iron in individuals with ADHD. Therefore, it has been proposed that either a deficiency of peripheral iron or a dysfunction of the blood-brain barrier, in the presence of normal peripheral iron levels, may contribute to low brain iron levels, which, in turn, would increase the risk for ADHD symptoms in a subgroup of individuals with this disorder. It has also been found that individuals with ADHD may be at increased risk of severe cardiovascular events during treatment with ADHD drugs, although the extent to which this occurs in ADHD patients compared to non-ADHD individuals is still matter of investigation. Since iron depletion has been recently reported as a risk factor for adverse prognosis in heart failure, iron deficiency might contribute both to ADHD symptoms severity before treatment and to increased risk of severe cardiovascular events during treatment with ADHD drugs in a selected subgroup of patients. Therefore, we hypothesize that the effective treatment of iron deficiency might lead both to improvement of ADHD symptoms severity and to a decrease of the risk of cardiovascular events during treatment with ADHD drugs. If empirical studies confirm this hypothesis, the clinician would be advised to systematically check iron status and effectively treat iron deficiency before starting a pharmacological treatment with ADHD drugs., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The present study aimed at: (1) exploring rate and clinical features of superimposed bipolar disorder (BD) in Italian children with attention deficit hyperactivity disorder (ADHD), compared with a community sample, matched for age and gender; (2) exploring predictors of BD in ADHD children, by comparing ADHD children with or without superimposed BD. We studied 173 consecutive drug-naïve outpatients with ADHD (156 males and 17 females, mean age of 9.2 ± 2.3years, age range 6-17.5 years), diagnosed with a clinical interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL)); the control group consisted of a community-based sample of 100 healthy children. The rate of children with a diagnosis of BD was higher in the ADHD group (29/173, 16.7%) compared with controls (1/100, 1%), (P<0.001). Among the 29 children with ADHD+BD, 16 (55.2%) had a Bipolar Disorder-Not Otherwise Specified (BD-NOS), and 11 (37.9%) showed ultrarapid cycling. Compared with children with ADHD without BD, they showed a higher rate of combined sub-type (21/29, 72.4%), a higher score at ADHD-Rating Scale (total score and hyperactivity subscale), higher rates of major depression, oppositional defiant disorder and conduct disorder. In summary, children with ADHD present a higher risk for developing a superimposed BD. The identification of clinical features with an increased risk of BD can improve diagnosis, prognosis and treatments., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The purpose of this study was to explore the possible efficacy and tolerability of amantadine in the treatment of attention-deficit/hyperactivity disorder (ADHD) in stimulant-naïve children., Methods: Twenty four children (5-13 years old) with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) ADHD (4 inattentive, 2 hyperactive, and 18 combined type) entered a 6-week open-label treatment with amantadine (50-150 mg) given as a single morning dose. Parent and teacher ADHD rating scales and the parent Child Behavior Checklist (CBCL) were administered at baseline and at week 6., Results: Twenty three subjects completed the 6-week treatment. One child dropped out at week 2 because of persistent headache, and another 12 children reported adverse effects, most commonly transient appetite decrease. The parent ADHD score decreased from mean 41.04 +/- D 6.9 at baseline to 28.9 +/- 8.7 at week 6 (p < 0.001, effect size d = 1.5), and the teacher ADHD score from 35.8 +/- 9.6 to 26.2 +/- 9.5 (p < 0.001, effect size d = 1.0). Response rate (a 25% or greater decline in ADHD score) was 58% based on parents and 46% based on teachers., Conclusions: These data suggest that amantadine has acceptable acute tolerability at single doses up to 150 mg/day and is possibly efficacious in decreasing ADHD symptoms, although its activity appears to be more modest than that of stimulant medications.

Study Objectives: To evaluate non-rapid eye movement sleep instability (NREM), as measured by the cyclic alternating pattern (CAP), in a cohort of children with attention-deficit/hyperactivity disorder (ADHD) and normal controls., Design: Prospective study., Settings: Sleep laboratory., Participants: Twenty consecutive outpatients with ADHD (18 boys and 2 girls; age range 6-13 years, mean age 9.3 years) and 20 normal children matched for age and socioeconomic status underwent polysomnographic recordings for 2 consecutive nights in a standard laboratory setting. Sleep was visually scored for sleep macrostructure and CAP, according to standard criteria., Measurements and Results: Children with ADHD showed significantly reduced sleep duration and increased rate of stage shifts. All children with ADHD had an apnea-hypopnea index less than 1. Those with ADHD presented lower total CAP rates and lower CAP rates during sleep stage 2 than did normal controls. Moreover, in children with ADHD, we found a lower number of CAP sequences and a reduced total A1 index, mainly in light sleep (sleep stages 1 and 2). We did not find differences in A subtype percentages, but there was a longer duration of A1 subtypes in children with ADHD., Conclusions: Children with ADHD showed a lower CAP rate and a lower number of CAP sequences; this supports the hypothesis of the existence of a hypoarousal state in these patients.