Promoting emotional and behavioral interventions in ASD treatment: Evidence from EPIGRAM, A naturalistic, prospective and longitudinal study.

BACKGROUND: Prognostic factors from naturalistic treatment studies of children with Autism Spectrum Disorder (ASD) remain largely unknown. We aimed to identify baseline and treatment-related prognostic predictors at 1-year follow-up after Integrative Care Practices (ICPs). METHODS: Eighty-nine preschool children with severe ASD were given ICP combining nine therapeutic workshops based on children's needs. Participants were assessed at baseline and during 12 months follow-up with the Psycho-educational Profile-3-R, Children Autism Rating Scale, Parental Global Impression, and the Autistic Behaviors Scale. We assessed prognostic predictors using multivariable regression models and explored treatment ingredients influencing outcome using Classification and Regression Trees (CART). RESULTS: Multivariable models showed that being a child from first generation immigrant parents predicted increased maladaptive behaviors, whereas play activities had an opposite effect; severity of ASD symptoms and impaired cognitive functions predicted worse autism severity at follow-up; and lower play activities predicted worse parent impression. Regarding treatment effects, more emotion/behavioral interventions predicted better outcomes, and more communication interventions predicted lower autism severity, whereas more education and cognitive interventions had an opposite effect. CART confirmed that more hours of intervention in the emotion/behavioral domain helped classifying cases with better outcomes. More parental support was associated with decreased maladaptive behaviors. Sensorimotor and education interventions also significantly contributed to classifying cases according to outcomes but defined subgroups with opposite prognosis. CONCLUSION: Children who exhibited the best prognosis following ICPs had less autism severity, better cognition, and non-immigrant parents at baseline. Emotion/behavior interventions appeared key across all outcomes and should be promoted.

Prospective associations between ADHD symptoms and physical conditions from early childhood to adolescence: a population-based longitudinal study.

BACKGROUND: The co-occurrence between attention-deficit hyperactivity disorder (ADHD) and physical conditions is frequent but often goes unrecognised. Most available evidence on the links between ADHD and physical conditions relies on cross-sectional studies. Understanding temporal sequences of associations is key to inform appropriate treatment and preventive strategies. We aimed to assess possible longitudinal associations between ADHD symptoms and a broad range of physical conditions, adjusting for several confounding factors. METHODS: Participants came from the population-based Quebec Longitudinal Study of Child Development. Participants were selected from the Quebec Birth Registry, recruited between October, 1997, and July, 1998, from the province of Quebec, Canada, and followed up in early childhood (n=2120; age 5 months-5 years), middle childhood (n=1750; age 6-12 years), and adolescence (n=1573; age 13-17 years). Main outcome measures included ADHD symptom severity and physical conditions, which were reported by the person most knowledgeable of the child in early childhood, by teachers in middle childhood, and self-reported in adolescence. Multivariable regression analyses were conducted to study the prospective associations between ADHD symptoms and later physical conditions, and physical conditions and later ADHD symptoms, adjusting for multiple confounders. FINDINGS: We found several prospective associations between ADHD symptoms and physical conditions including asthma, high BMI (≥1 SD above the mean), epilepsy, dental caries, acute infections, injuries, and sleep problems. After adjusting for key confounding factors, several associations remained: ADHD symptoms in early childhood were associated with later high BMI during middle childhood (odds ratio [OR] 1·19 [95% CI 1·05-1·35]) and adolescence (OR 1·14 [1·01-1·29]), and with unintentional injuries during adolescence (OR 1·10 [1·01-1·21]). ADHD symptoms in middle childhood were significantly associated with later dental caries during adolescence (OR 1·10 [1·01-1·20]). Unintentional injuries in early childhood were associated with later ADHD symptoms in middle childhood (standardised mean difference [SMD] 0·15 [0·05-0·24]) and adolescence (SMD 0·13 [0·04-0·23]), and restless legs syndrome symptoms in middle childhood were associated with later ADHD symptoms in adolescence (SMD 0·15 [0·05-0·25]). INTERPRETATION: Our results point to the need to carefully monitor children with ADHD in early or middle childhood for several physical conditions, and to monitor children with particular physical conditions for ADHD symptoms. Our study also calls for policies to promote more integrated health-care systems for children with complex mental and physical needs, bridging the current gap between mental and physical health-care services. FUNDING: Québec Government's Ministry of Health, Ministry of Education, and Ministry of Family Affairs; The Lucie and André Chagnon Foundation; the Robert-Sauvé Research Institute of Health and Safety at Work; the Québec Statistics Institute; the Fonds de Recherche du Québec-Santé; the Fonds de Recherche du Québec-Societé et Culture; Canada's Social Science and Humanities Research Council; the Canadian Institutes of Health Research, the Sainte-Justine Research Center; and the French National Research Agency. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Half a century of research on Attention-Deficit/Hyperactivity Disorder: A scientometric study.

We performed a scientometric analysis of the scientific literature on ADHD to evaluate key themes and trends over the past decades, informing future lines of research. We conducted a systematic search in Web of Science Core Collection up to 15 November, 2021 for scientific publications on ADHD. We retrieved 28,381 publications. We identified four major research trends: 1) ADHD treatment, risks factors and evidence synthesis; 2) neurophysiology, neuropsychology and neuroimaging; 3) genetics; 4) comorbidity. In chronological order, identified clusters of themes included: tricyclic antidepressants, ADHD diagnosis/treatment, bipolar disorder, EEG, polymorphisms, sleep, executive functions, pharmacology, genetics, environmental risk factors, emotional dysregulation, neuroimaging, non-pharmacological interventions, default mode network, Tourette, polygenic risk score, sluggish cognitive tempo, evidence-synthesis, toxins/chemicals, psychoneuroimmunology, Covid-19, and physical exercise. In conclusion, research on ADHD over the past decades has been driven mainly by a medical model. Whereas the neurobiological correlates of ADHD are undeniable and crucial, we look forward to further research on relevant psychosocial aspects related to ADHD, such as societal pressure, the concept of neurodiversity, and stigma.

Brain stimulation and other biological non-pharmacological interventions in mental disorders: An umbrella review.

BACKGROUND: The degree of efficacy, safety, quality, and certainty of meta-analytic evidence of biological non-pharmacological treatments in mental disorders is unclear. METHODS: We conducted an umbrella review (PubMed/Cochrane Library/PsycINFO-04-Jul-2021, PROSPERO/CRD42020158827) for meta-analyses of randomized controlled trials (RCTs) on deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), electro-convulsive therapy (ECT), and others. Co-primary outcomes were standardized mean differences (SMD) of disease-specific symptoms, and acceptability (for all-cause discontinuation). Evidence was assessed with AMSTAR/AMSTAR-Content/GRADE. RESULTS: We selected 102 meta-analyses. Effective interventions compared to sham were in depressive disorders: ECT (SMD=0.91/GRADE=moderate), TMS (SMD=0.51/GRADE=moderate), tDCS (SMD=0.46/GRADE=low), DBS (SMD=0.42/GRADE=very low), light therapy (SMD=0.41/GRADE=low); schizophrenia: ECT (SMD=0.88/GRADE=moderate), tDCS (SMD=0.45/GRADE=very low), TMS (prefrontal theta-burst, SMD=0.58/GRADE=low; left-temporoparietal, SMD=0.42/GRADE=low); substance use disorder: TMS (high frequency-dorsolateral-prefrontal-deep (SMD=1.16/GRADE=moderate), high frequency-left dorsolateral-prefrontal (SMD=0.77/GRADE=very low); OCD: DBS (SMD=0.89/GRADE=moderate), TMS (SMD=0.64/GRADE=very low); PTSD: TMS (SMD=0.46/GRADE=moderate); generalized anxiety disorder: TMS (SMD=0.68/GRADE=low); ADHD: tDCS (SMD=0.23/GRADE=moderate); autism: tDCS (SMD=0.97/GRADE=very low). No significant differences for acceptability emerged. Median AMSTAR/AMSTAR-Content was 8/2 (suggesting high-quality meta-analyses/low-quality RCTs), GRADE low. DISCUSSION: Despite limited certainty, biological non-pharmacological interventions are effective and safe for numerous mental conditions. Results inform future research, and guidelines. FUNDING: None.

Beyond stimulants: a systematic review of randomised controlled trials assessing novel compounds for ADHD.

Introduction: Despite stimulants being highly efficacious in short-term randomized controlled trials (RCTs), not all patients respond or can successfully tolerate them. A number of novel non-stimulant options are currently in the pipeline for the treatment of attention-deficit/hyperactivity disorder (ADHD). Areas covered: The authors conducted a systematic review of RCTs registered in ClinicalTrials.gov in the past 5 years (January 2014 and February 2019), supplemented by searches in PubMed, Web of Science, and drug manufacturer websites to find recent RCTs on novel non-stimulant ADHD medications. Expert opinion: The authors found 28 pertinent RCTs of compounds acting on a variety of biological targets, including Dasotraline, Viloxazine (SPN-812), Centanafadine SR (CTN SR), OPC-64005, Fasoracetam (NFC-1, AEVI-001), Metadoxine (MDX), Vortioxetine, Tipepidine Hibenzate, Oxytocin, Sativex (delta-9-tetrahydrocannabinol (THC) plus cannabidiol), Mazindol, and Molindone hydrochloride (SPN-810). Given the high effect size found in RCTs of stimulants in terms of efficacy on ADHD core symptoms, it is unlikely that these novel agents will show better efficacy than stimulants, at the group level. However, they may offer comparable or better tolerability. Additionally, agents acting on etiopathophysiological targets disrupted in specific subgroups of patients with ADHD will move forward the pharmacotherapy of ADHD from a 'one size fits all' to a 'precision medicine' approach.

A 9-Year Follow-Up of Attention-Deficit/Hyperactivity Disorder in a Population Sample.

BACKGROUND: Prior follow-up studies of attention-deficit/hyperactivity disorder (ADHD) have mostly been from North America. They have provided a good deal of information about ADHD, but whether these results generalize to population samples and to other countries is not certain. Most prior studies have also not assessed predictors of possible new onsets of ADHD in non-ADHD youth or the validity of subthreshold forms of the disorder. METHODS: 1,012 families were recruited at baseline, when a telephone interview assessed a child in the 6-12 years age range. The interview covered symptoms of ADHD, conduct disorder, and oppositional defiant disorder as well as family living situation, school performance, sleep disturbance, eating habits, use of supplemental iron, and history of ADHD treatment. Nine years later, the persistence of ADHD and its impairments and the emergence of new conditions were assessed. DSM-5 diagnostic criteria were used to diagnose ADHD. RESULTS: 492 of the 1,012 participants seen at baseline were followed up 9 years later, at a mean age of 18 years. At follow-up, 16.7% of the children diagnosed with ADHD at baseline met full criteria for ADHD and 11.1% met criteria for subthreshold ADHD, yielding a persistence rate of 27.8%. Among children not diagnosed with ADHD at baseline, 1.1% met criteria for ADHD at follow-up. The persistence of ADHD and new onsets of ADHD were predicted by several baseline clinical features and by a family history of ADHD. CONCLUSIONS: We replicated predictors of the persistence of ADHD found in prior studies and provide new data about predictors of new ADHD onsets in the population. Our findings about subthreshold ADHD support a dimensional conceptualization of the disorder, highlighting the potential clinical utility of a subthreshold diagnostic category. This study also contributes to the ongoing debate regarding adult-onset ADHD.

Effects of neurofeedback versus methylphenidate for the treatment of attention-deficit/hyperactivity disorder protocol for a systematic review and meta-analysis of head-to-head trials.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is developmental disorder characterized by inattention and/or hyperactivity/impulsivity. Psychostimulants, including methylphenidate (MPH), are recommended as a first-line pharmacological intervention, whereas neurofeedback (NF) has been proposed as a nonpharmacological option. The comparative effects of MPH and NF need further exploration. We will conduct a systematic review and meta-analysis of head-to-head randomized controlled trials (RCTs) comparing the efficacy and/or tolerability of MPH and NF in children/adolescents and adults with ADHD. METHOD AND ANALYSIS: We will include published as well as unpublished data. Two investigators will independently search PubMed, OVID, ERIC, Web of Science, ClinialTrials.gov, and a set of Chinese databases, including CNKI, CQVIP, and WanFang for head-to-head RCTs comparing MPH and NF. Experts will be contacted for unpublished data. The primary outcome will be the efficacy on ADHD core symptoms, measured by the change in the severity of ADHD symptoms, from baseline to endpoint and, if available, at follow-up (at any available time point). Secondary outcomes will be: dropouts for any reasons; efficacy on neuropsychological measures (working memory, inattention, and inhibition). We will conduct subgroup analyses to assess the impact of the following variables: age; type of NF; language of publication; comorbidities. Additionally, we will carry out meta-regression analyses to investigate the effect of sponsorship, year of publication, duration of intervention, and age of participants. Sensitivity analyses will be conducted to test the robustness of the findings. Risk of bias of individual studies will be assessed using the Cochrane risk of bias tool. Analyses will be performed using Comprehensive Meta-Analysis Software. ETHICS AND DISSEMINATION: No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and presented at relevant national and international conferences. TRIALS REGISTRATION NUMBER: PROSPERO CRD42018090256.

Meditation-based therapies for attention-deficit/hyperactivity disorder in children, adolescents and adults: a systematic review and meta-analysis.

BACKGROUND: The efficacy of meditation-based therapies for attention deficit/hyperactivity disorder (ADHD) across the lifespan remains uncertain. OBJECTIVE: To conduct a systematic review and meta-analysis of randomised controlled trials (RCTs) assessing the efficacy of meditation-based therapies for ADHD core symptoms and associated neuropsychological dysfunctions in children/adolescents or adults with ADHD. METHODS: We searched Pubmed, PsycInfo, Embase+Embase Classic, Ovid Medline and Web of Knowledge with no language, date or type of document restriction, up to 5 May 2018. Random-effects model was used. Heterogeneity was assessed with Cochran's Q and I2 statistics. Publication (small studies) bias was assessed with funnel plots and the Egger's test. Studies were evaluated with the Cochrane risk of bias (RoB) tool. Analyses were conducted using Comprehensive Meta-Analysis. FINDINGS: 13 RCTs (seven in children/adolescents, n=270 and six in adults, n=339) were retained. Only one RCT was double-blind.Meditation-based therapies were significantly more efficacious than the control conditions in decreasing the severity of ADHD core symptoms (inattention+hyperactivity/impulsivity: children/adolescents: Hedge's g=-0.44, 95% CI -0.69 to -0.19, I20%; adults: Hedge's g=-0.66, 95% CI -1.21 to -0.11, I281.81%). No significant effects were found on neuropsychological measures of inattention and inhibition in children/adolescents. In adults, significant effects were detected on working memory and inhibition, although these results were based on a small number of studies (n=3). 57% and 43% of the studies in children/adolescents were rated at overall unclear and high risk of bias, respectively. In adults, 33% and 67% of the studies were deemed at overall unclear and high risk of bias, respectively. No evidence of publication bias was found. CONCLUSIONS: Despite statistically significant effects on ADHD combined core symptoms, due to paucity of RCTs, heterogeneity across studies and lack of studies at low risk of bias, there is insufficient methodologically sound evidence to support meditation-based therapies for ADHD. TRIAL REGISTRATION NUMBER: PROSPERO 2018 [CRD42018096156].

Neurofeedback for Attention-Deficit/Hyperactivity Disorder: Meta-Analysis of Clinical and Neuropsychological Outcomes From Randomized Controlled Trials.

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.

Neurofeedback for ADHD: a review of current evidence.

Considerable scientific effort has been directed at developing effective treatments for attention-deficit/hyperactivity disorder (ADHD). Among alternative treatment approaches, neurofeedback has gained some promising empirical support in recent years from controlled studies as a treatment of core ADHD symptoms. However, a recent stringent meta-analysis of 8 randomized controlled trials published in 2013 found that the effects were stronger for unblinded measures and 3 recent subsequently published well-controlled trials found no effects for the most blinded ADHD outcome. Firmer conclusions must await upcoming evidence from larger controlled studies and future meta-analyses contrasting different forms of neurofeedback and different outcome measures.

Research review: the role of diet in the treatment of attention-deficit/hyperactivity disorder--an appraisal of the evidence on efficacy and recommendations on the design of future studies.

BACKGROUND: The efficacy of three dietary treatments for ADHD has been repeatedly tested in randomized controlled trials (RCTs). These interventions are restricted elimination diets (RED), artificial food colour elimination (AFCE) and supplementation with free fatty acids (SFFA). There have been three systematic reviews and associated meta-analyses of the RCTs for each of these treatments. SCOPE: The aim of this review is to critically appraise the studies on the dietary treatments of ADHD, to compare the various meta-analyses of their efficacy that have been published and to identify where the design of such RCTs could be improved and where further investigations are needed. FINDINGS: The meta-analyses differ in the inclusion and exclusion criteria applied to potentially eligible studies. The range of average effect sizes in standard deviation units is RED (0.29-1.2), AFCE (0.18-0.42) and SFFA (0.17-0.31). The methodology of many of the trials on which the meta-analyses are based is weak. CONCLUSIONS: Nevertheless, there is evidence from well-conducted studies for a small effect of SFFA. Restricted elimination diets may be beneficial, but large-scale studies are needed on unselected children, using blind assessment and including assessment of long-term outcome. Artificial food colour elimination is a potentially valuable treatment but its effect size remains uncertain, as does the type of child for whom it is likely to be efficacious. There are additional dietary supplements that have been used with children with ADHD. A systematic search identified 11 RCTs that investigated the effects of these food supplements. Despite positive results for some individual trials, more studies are required before conclusions can be reached on the value in reducing ADHD symptoms of any of these additional supplements.

Nonpharmacological interventions for ADHD: systematic review and meta-analyses of randomized controlled trials of dietary and psychological treatments.

OBJECTIVE: Nonpharmacological treatments are available for attention deficit hyperactivity disorder (ADHD), although their efficacy remains uncertain. The authors undertook meta-analyses of the efficacy of dietary (restricted elimination diets, artificial food color exclusions, and free fatty acid supplementation) and psychological (cognitive training, neurofeedback, and behavioral interventions) ADHD treatments. METHOD: Using a common systematic search and a rigorous coding and data extraction strategy across domains, the authors searched electronic databases to identify published randomized controlled trials that involved individuals who were diagnosed with ADHD (or who met a validated cutoff on a recognized rating scale) and that included an ADHD outcome. RESULTS: Fifty-four of the 2,904 nonduplicate screened records were included in the analyses. Two different analyses were performed. When the outcome measure was based on ADHD assessments by raters closest to the therapeutic setting, all dietary (standardized mean differences=0.21-0.48) and psychological (standardized mean differences=0.40-0.64) treatments produced statistically significant effects. However, when the best probably blinded assessment was employed, effects remained significant for free fatty acid supplementation (standardized mean difference=0.16) and artificial food color exclusion (standardized mean difference=0.42) but were substantially attenuated to nonsignificant levels for other treatments. CONCLUSIONS: Free fatty acid supplementation produced small but significant reductions in ADHD symptoms even with probably blinded assessments, although the clinical significance of these effects remains to be determined. Artificial food color exclusion produced larger effects but often in individuals selected for food sensitivities. Better evidence for efficacy from blinded assessments is required for behavioral interventions, neurofeedback, cognitive training, and restricted elimination diets before they can be supported as treatments for core ADHD symptoms.

Iron and attention deficit/hyperactivity disorder: What is the empirical evidence so far? A systematic review of the literature.

The authors systematically reviewed evidence on iron status, as well as studies of iron supplementation, in individuals with attention deficit/hyperactivity disorder (ADHD). PubMed, Ovid, EMBASE and Web of Knowledge were searched on 4 July 2012. Quantitative appraisal of trials was performed using Jadad's score. Most (n = 20) of the retrieved studies assessed an index of peripheral iron status (i.e., serum ferritin), with overall mixed results - that is, both significant and nonsignificant association between ADHD symptoms and serum ferritin levels. One MRI study reported significantly lower indices of thalamic iron in ADHD versus comparison subjects. Two trials, an open-label and a pilot randomized placebo-controlled study with high Jaded score (4), showed improvement in some but not all measures of ADHD symptoms. Three studies showed that children with ADHD plus sleep disorders, in particular restless legs syndrome, are at risk of iron deficiency. Finally, two studies suggested that iron deficiency might decrease the effectiveness of psychostimulant treatment. The authors discussed how the field could move from initial research mainly focused on serum ferritin towards a more comprehensive and translational investigation of iron in ADHD, with the potential to inform clinical practice in terms of screening and treating iron deficiency in individuals with ADHD.

Brain iron levels in attention-deficit/hyperactivity disorder: a pilot MRI study.

OBJECTIVE: Brain iron deficiency has been supposed to be involved in the pathophysiology of ADHD. Available studies assessing iron in ADHD are based on serum ferritin, a peripheral marker of iron status. To what extent serum ferritin correlates with brain iron (BI) is unclear. The main aim of this study was to compare BI, estimated with magnetic resonance imaging (MRI) in the putamen, pallidum, caudate, and thalamus, between children with and without ADHD. The secondary aim was to assess the correlation between serum ferritin and BI levels. METHODS: Thirty-six children (18 with and 18 without ADHD, the latter including nine healthy controls and nine psychiatric controls) completed MRI and blood sampling. Brain iron levels were estimated by imaging T2*. RESULTS: Children with ADHD showed significantly lower estimated BI in right and left thalamus compared to healthy controls. Estimated BI did not differ significantly between children with ADHD and psychiatric controls. Children with ADHD had significantly lower levels of serum ferritin than healthy as well as psychiatric controls. Serum ferritin and T2* values did not correlate significantly in most regions. CONCLUSIONS: Low iron in the thalamus may contribute to ADHD pathophysiology.

Sleep disturbances and serum ferritin levels in children with attention-deficit/hyperactivity disorder.

BACKGROUND: A subset of children with attention-deficit/hyperactivity disorder (ADHD) may present with impairing sleep disturbances. While preliminary evidence suggests that iron deficiency might be involved into the pathophysiology of daytime ADHD symptoms, no research has been conducted to explore the relationship between iron deficiency and sleep disturbances in patients with ADHD. The aim of this study was to assess the association between serum ferritin levels and parent reports of sleep disturbances in a sample of children with ADHD. SUBJECTS: Sixty-eight consecutively referred children (6-14 years) with ADHD diagnosed according to DSM-IV criteria using the semi-structured interview Kiddie-SADS-PL. MEASURES: parents filled out the Sleep Disturbance Scale for Children (SDSC) and the Conners Parent Rating Scale (CPRS). Serum ferritin levels were determined using the Tinaquant method. RESULTS: Compared to children with serum ferritin levels >or=45 microg/l, those with serum ferritin levels <45 microg/l had significantly higher scores on the SDSC subscale "Sleep wake transition disorders" (SWTD) (P = 0.042), which includes items on abnormal movements in sleep, as well as significantly higher scores on the CPRS-ADHD index (P = 0.034). The mean scores on the other SDSC subscales did not significantly differ between children with serum ferritin >or=45 and <45 microg/l. Serum ferritin levels were inversely correlated to SWTD scores (P = 0.043). CONCLUSION: Serum ferritin levels <45 microg/l might indicate a risk for sleep wake transition disorders, including abnormal sleep movements, in children with ADHD. Our results based on questionnaires set the basis for further actigraphic and polysomnographic studies on nighttime activity and iron deficiency in ADHD. Research in this field may suggest future trials of iron supplementation (possibly in association with ADHD medications) for abnormal sleep motor activity in children with ADHD.

Alertness and feeding behaviors in ADHD: does the hypocretin/orexin system play a role?

Increasing evidence has suggested that patients with attention-deficit/hyperactivity disorder (ADHD) may present with a deficit of alertness and sleep disturbances. Recent studies have also pointed out a previously underestimated association between ADHD and abnormal eating behaviors, including binge eating. Since sleep/alertness disturbances and eating disorders may significantly increase the functional impairment of ADHD, gaining insight into their pathophysiology as well as into their treatment is of relevance to provide a better clinical management of patients suffering from ADHD. The hypocretin/orexin system comprises two distinct peptides, located in the hypothalamus, which are involved in several homeostatic functions. In particular, it has been suggested that hypocretin/orexin neurons located in perifornical and dorsomedial hypothalamic nuclei increase arousal, whereas those located in the lateral hypothalamus are primarily implicated in reward processing, stimulating feeding and other reward seeking behaviors. Given the involvement of the hypocretin/orexin system in the control of alertness and reward seeking (including feeding), we hypothesize that hypocretin/orexin neurons located in perifornical and dorsomedial hypothalamic areas are hypoactivated, while those located in the lateral hypothalamus are overactivated in patients with ADHD. If confirmed by further neurophysiological, imaging, and genetics studies, our hypothesis may help us progress in the understanding of the complex pathophysiology of ADHD. This might set the basis for the study of novel molecules, acting on the hypocretin/orexin system, aimed at increasing wakefulness and reducing binge eating and other abnormal reward seeking behaviors in patients with ADHD. We also suggest future studies on the potential therapeutic role of other molecules which have a complex interplay with the hypocretin/orexin system, such as the histamine H(1) receptor agonists, the histamine H(3) receptor antagonists, and the neuropeptide Y receptor antagonists. All this body of research would provide a tremendous opportunity to improve the quality of life of patients with ADHD by means of pathophysiologically oriented treatment.

Attention-deficit/hyperactivity disorder, Tourette's syndrome, and restless legs syndrome: the iron hypothesis.

Preliminary but increasing evidence suggests that attention-deficit/hyperactivity disorder (ADHD), Tourette's syndrome (TS), and restless legs syndrome (RLS) may be comorbid. In the present article, we hypothesize that ADHD, TS, and RLS may be part of a spectrum, and that iron deficiency contributes to the pathophysiology underlying this spectrum. Iron deficiency might lead to ADHD, RLS and TS symptoms via its impact on the metabolism of dopamine and other catecholamines, which have been involved into the pathophysiology of ADHD, TS, and RLS. We speculate that the catecholaminergic systems are differently impacted in each of the three disorders, contributing to a different specific phenotypic expression of iron deficiency. MRI studies assessing brain iron levels in ADHD, TS, and childhood RLS, as well as genetic studies on the specific molecular pathways involved in iron deficiency, are greatly needed to confirm the iron hypothesis underlying ADHD, TS, and RLS. This body of research may set the basis for controlled trials assessing the effectiveness and tolerability, as well as the most appropriate dose, duration and type (oral vs. intravenous) of iron supplementation. In conclusion, the iron hypothesis may help us progress in the understanding of pathophysiological links between ADHD, RLS, and TS, suggesting that iron supplementation might be effective for all these three impairing conditions.

Effects of iron supplementation on attention deficit hyperactivity disorder in children.

Iron deficiency has been suggested as a possible contributing cause of attention deficit hyperactivity disorder (ADHD) in children. This present study examined the effects of iron supplementation on ADHD in children. Twenty-three nonanemic children (aged 5-8 years) with serum ferritin levels <30 ng/mL who met DSM-IV criteria for ADHD were randomized (3:1 ratio) to either oral iron (ferrous sulfate, 80 mg/day, n = 18) or placebo (n = 5) for 12 weeks. There was a progressive significant decrease in the ADHD Rating Scale after 12 weeks on iron (-11.0 +/- 13.9; P < 0.008), but not on placebo (3.0 +/- 5.7; P = 0.308). Improvement on Conners' Parent Rating Scale (P = 0.055) and Conners' Teacher Rating Scale (P = 0.076) with iron supplementation therapy failed to reach significance. The mean Clinical Global Impression-Severity significantly decreased at 12 weeks (P < 0.01) with iron, without change in the placebo group. Iron supplementation (80 mg/day) appeared to improve ADHD symptoms in children with low serum ferritin levels suggesting a need for future investigations with larger controlled trials. Iron therapy was well tolerated and effectiveness is comparable to stimulants.

Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children.

OBJECTIVE: Increasing evidence suggests a significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and restless legs syndrome (RLS). Iron deficiency may underlie common pathophysiological mechanisms in subjects with ADHD plus RLS (ADHD+RLS). To date, the impact of iron deficiency, RLS and familial history of RLS on ADHD severity has been scarcely examined in children. These issues are addressed in the present study. METHODS: Serum ferritin levels, familial history of RLS (diagnosed using National Institutes of Health (NIH) criteria) and previous iron supplementation in infancy were assessed in 12 ADHD+RLS children, 10 ADHD children and 10 controls. RLS was diagnosed using NIH-specific pediatric criteria, and ADHD severity was assessed using the Conners' Parent Rating scale. RESULTS: ADHD symptom severity was higher, although not significantly, in children with ADHD+RLS compared to ADHD. The mean serum ferritin levels were significantly lower in children with ADHD than in the control group (p<0.0005). There was a trend for lower ferritin levels in ADHD+RLS subjects versus ADHD. Both a positive family history of RLS and previous iron supplementation in infancy were associated with more severe ADHD scores. CONCLUSIONS: Children with ADHD and a positive family history of RLS appear to represent a subgroup particularly at risk for severe ADHD symptoms. Iron deficiency may contribute to the severity of symptoms. We suggest that clinicians consider assessing children with ADHD for RLS, a family history of RLS, and iron deficiency.