Changes in serum levels of kynurenine metabolites in paediatric patients affected by ADHD.

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.

Daily life impairments associated with childhood/adolescent attention-deficit/hyperactivity disorder as recalled by adults: results from the European Lifetime Impairment Survey.

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.

Temperamental and character profiles of preschool children with ODD, ADHD, and anxiety disorders.

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.

Changes in sleep duration and disturbances during Covid-19 lockdown and internalizing-externalizing behaviors in children with attention deficit hyperactivity disorders.

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.

The Junior Temperament and Character Inventory: Italian validation of a questionnaire for the measurement of personality from ages 6 to 16 years.

The Junior Temperament and Character Inventory (JTCI) has been developed for the assessment of the personality in individuals 6 to 14 years old according to the psychobiological model of Cloninger. The aim of the present study was to evaluate the psychometric properties of an Italian version of JTCI. The sample included 459 subjects ranging in age from 6 to 15.9 years. Starting from the original parent version, an Italian version of JTCI was developed and administered to parents recruited in primary schools of Lazio and Campania. Using statistically appropriate methods for the analysis of dichotomous variables (binary coded), we analyzed the factor structure, the internal consistency, and the test-retest reliability. The architecture of the JTCI was consistent with the original hypothesis of the Cloninger model. Parent reports of each of the JTCI dimensions had good internal consistency and test-retest reliability over 3 months. Regarding the analysis of risk personality traits, significant correlations were found between several JTCI factors and Strengths and Difficulties Questionnaire scales. The JTCI is useful in research and in clinical practice to evaluate the role of temperament and character dimensions in psychopathology.

Body image distortion: validation of a new scale for children and adolescents.

BACKGROUND: A possible definition of body image is the picture that an individual has of her/his own body, irrespective of how her/his body actually is. Body image is a competence that develops in children similar to many other skills. The aim of this study was to validate a new rapid 20-items questionnaire to study the body image distortion in children and adolescents: the Strange Sensations Questionnaire (SSQ). A secondary aim was to improve the knowledge about body image distortion and about depersonalization symptoms,and their correlation with possible hallucinations, in children and adolescents, as it can be investigated using a scale. METHODS: 1557 children and adolescents, balanced for sex and age filled out a new 20-items questionnaire (SSQ) about body image, and a second validated questionnaire about fantasy with a Reality/Unreality distinction subscale to study the relationship with hallucinations (Free Fantasy Questionnaire-FFQ). RESULTS: Results showed a good validation of SSQ with three subscales: depersonalization, fragility and other shapes. We found a relative high frequency of proneness to out-of-body experiences. Children of primary school age have a higher mean score than pre-adolescents and adolescents in the total score of all the three subscales of SSG. Adolescents seem to have a significantly higher mean score in Fragility subscale. The mean total score and the mean scores of all the three subscales have a significant correlation with the Reality/Unreality subscale of FFQ. CONCLUSIONS: SSQ was validated. The research could confirm also the high frequency of body image distortion in developmental age, suggesting the possibility of a specific retardation as a possible origin of some body image distortion disorders. Data also confirm the proneness for hallucination of adolescents with body image distortion.

Bipolar disorder co-morbidity in children with attention deficit hyperactivity disorder.

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.

Serum cytokines in pediatric neuropsychiatric syndromes: focus on Attention Deficit Hyperactivity Disorder.

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.

Anti-Yo Antibodies in Children With ADHD: First Results About Serum Cytokines.

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 Validation of the Free Fantasy Questionnaire for Children and Adolescents: From Imaginary Playmate to "Dreamtime".

Fantasy in children is a precocious and important skill. In normal subjects some imaginative events, very close to hallucinations (perception-like experiences), have been found. Therefore, a better knowledge on both fantasy and the difference between imagination and the external world is needed. The aims of this study are: (a) to validate a new questionnaire for fantasy in children and adolescents; (b) to test its clinical application in ADHD children. 1.707 participants aged 8-18 years were enrolled: 1557 were recruited from a survey in six schools, whereas 150 participants were recruited in an ADHD Center. They filled out a new questionnaire, the Free Fantasy Questionnaire for Children and Adolescents, FFQ. Statistical analyses were performed to validate the FFQ and to study five parameters of fantasy. Analyses showed good properties of the FFQ as regards factor structure and reliability. Descriptive analysis showed that: 10% of the adolescents frequently have fantasy with paracosmos and 9.5% sometimes have a fantasy with imaginary relatives. Moreover, in the 64.3% of participants of primary school, in the 34.5% of lower-secondary, and in the 27.4% of upper-secondary school Perception-like experiences, involving invisible but real personages, were found. Quality of fantasy and Lack of control on imagination are correlated with a high score in the Reality/Unreality Dimension and Perception-like experiences. As regards ADHD participants, the 40% of the group showed Perception-like experiences: the 21.66% of them reported a very high score in the dimension Reality/Unreality, have some dissociative symptoms, and the 3.33% presented a clear dissociative identity disorder. All were free from psychosis or neurologic disorders. A new questionnaire to study fantasy in children and adolescents was validated. Many children and adolescents of the general population declared Perception-like experiences. These events seem to be specific, and probably normal, features of the mind; they could be better named as "Dreamtime," whereas only in extreme conditions they could represent a risk for dissociation.

Open-label amantadine in children with attention-deficit/hyperactivity disorder.

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.

Bipolar Disorder in Children With ADHD: A Clinical Sample Study.

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.

NREM sleep instability is reduced in children with attention-deficit/hyperactivity disorder.

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.

Might the temperament be a bias in clinical study on attention-deficit hyperactivity disorder (ADHD)?: Novelty Seeking dimension as a core feature of ADHD.

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.

Application of the seven-factor-model of personality to an italian preschool sample.

OBJECTIVE: Advances in dimensional assessment of children in healthy and clinical populations has renewed interest in the study of temperament. Cloninger's Temperament and Character Inventory (TCI) has shown high reliability and internal consistency. Adult and adolescent versions have been translated into a number of languages and validated in cross-cultural studies worldwide. To date only one preschool-TCI-based study has been conducted in early infancy with teachers as observers. The present study is aimed to test an Italian Preschool version of the Temperament and Character Inventory (PsTCI). This is the first replication and the first validation study of TCI on preschoolers with parents as observers. METHODS: 395 preschool children, recruited from pediatric communities and day-care centres throughout Italy, participated in the study. Parents of each child enrolled in the study and completed a PsTCI about the child. Standard psychometric tests of reliability and validation were performed. RESULTS: Exploratory factor analyses demonstrated the presence of distinct domains for temperament and character. TCI dimensions had good internal consistency with Cronbach's alpha ranging values (|0.60|-|0.81|). Gender differences were found for Harm Avoidance (ß=-0.186; p≤0.001) and Self-Directedness (ß=-0.216; p≤0.01), and accounted for 5-35arm-38-702- of the observed variance. CONCLUSION: The present work suggests the psychological complexity of Cloninger's model and confirms its application in pre-school children from diverse environmental and cultural backgrounds. The results confirm that Cloninger's instrument for temperament and character evaluations can also be used with different observers and highlight the importance of considering cultural and demographic differences in the assessment of temperament and character in preschoolers.

Comorbid Depressive Disorders in ADHD: The Role of ADHD Severity, Subtypes and Familial Psychiatric Disorders.

OBJECTIVE: To evaluate the presence of Major Depressive Disorder (MDD) and Dysthymic Disorder (DD) in a sample of Italian children with Attention Deficit Hyperactivity Disorder (ADHD) and to explore specific features of comorbid depressive disorders in ADHD. METHODS: Three hundred and sixty-six consecutive, drug-naïve Caucasian Italian outpatients with ADHD were recruited and comorbid disorders were evaluated using DSM-IV-TR criteria. To evaluate ADHD severity, parents of all children filled out the ADHD Rating Scale. Thirty-seven children with comorbid MDD or DD were compared with 118 children with comorbid conduct disorder and 122 without comorbidity for age, sex, IQ level, family psychiatric history, and ADHD subtypes and severity. RESULTS: 42 of the ADHD children displayed comorbid depressive disorders: 16 exhibited MDD, 21 DD, and 5 both MDD and DD. The frequency of hyperactive-impulsive subtypes was significantly lower in ADHD children with depressive disorders, than in those without any comorbidity. ADHD children with depressive disorders showed a higher number of familial psychiatric disorders and higher score in the Inattentive scale of the ADHD Rating Scale, than children without any comorbidity. No differences were found for age, sex and IQ level between the three groups. CONCLUSION: Consistent with previous studies in other countries, depressive disorders affect a significant proportion of ADHD children in Italy. Patient assessment and subsequent treatment should take into consideration the possible presence of this comorbidity, which could specifically increase the severity of ADHD attention problems.

Iron and ADHD: time to move beyond serum ferritin levels.

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.

Anti-Purkinje cell antibody as a biological marker in attention deficit/hyperactivity disorder: a pilot study.

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.

Case reports of sleep phenotypes of ADHD: from hypothesis to clinical practice.

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.