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Predictors of Changes in Height, Weight, and Body Mass Index After Initiation of Central Nervous System Stimulants in Children with Attention Deficit Hyperactivity Disorder.
Waxmonsky, JG, Pelham, WE, Baweja, R, Hale, D, Pelham, WE
The Journal of pediatrics. 2022;:115-125.e2
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Abstract
OBJECTIVE To identify predictors of changes in height, weight, and body mass index (BMI) in children with attention deficit hyperactivity disorder (ADHD) starting central nervous system (CNS) stimulants. STUDY DESIGN There were 230 medication-naïve children aged 5-12 years with ADHD who participated in a randomized trial evaluating the impact of CNS stimulants on growth over 30 months. This observational analysis focused on the 141 participants using study medication for 65 or more days in the first 6-months after starting medication. Biometric variables, ADHD, and oppositional defiant disorder symptom scores at medication initiation, and medication use over the study were examined as predictors of changes in standardized (z) height, weight, and BMI. RESULTS Mean changes in z-BMI, z-weight. and z-height were negative throughout the study. The most consistent predictors of change in z-BMI, z-weight, and z-height were percent days medicated and total medication exposure. Children with lower z-height and z-weight at medication initiation experienced greater z-BMI and z-weight decreases over the first 6 months on medication. Greater appetite suppression during dose optimization predicted greater decreases in z-weight over the entire study and a greater decrease in z-height over the first 6 months on medication. z-weight change correlated with z-height change. Behavioral symptoms did not predict changes in z-BMI, z-weight, or z-height. CONCLUSIONS How much and how often CNS stimulants are used predicts changes in z-BMI, z-weight, and z-height in children. Even smaller and lighter children may be at risk for decreases in z-weight and z-BMI. Parent ratings of appetite during dose titration may serve as feasible indicators of future weight and height change in children using CNS stimulants. TRIAL REGISTRATION Clinicialtrials.gov: NCT01109849.
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Translating Attention-Deficit/Hyperactivity Disorder Rating Scale-5 and Weiss Functional Impairment Rating Scale-Parent Effectiveness Scores into Clinical Global Impressions Clinical Significance Levels in Four Randomized Clinical Trials of SPN-812 (Viloxazine Extended-Release) in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.
Nasser, A, Kosheleff, AR, Hull, JT, Liranso, T, Qin, P, Busse, GD, O'Neal, W, Fava, M, Faraone, SV, Rubin, J
Journal of child and adolescent psychopharmacology. 2021;(3):214-226
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Objectives: Clinical trials in psychiatry frequently report results from lengthy, comprehensive assessments to characterize a subject emotionally, cognitively, and behaviorally before and after treatment. However, the potential treatment implications of these results and how they translate into clinical practice remain unclear. Conversely, the Clinical Global Impressions (CGI) scales are quick, intuitive assessments used to assess the functional impact of a treatment in clinically relevant terms. The objectives of the present analyses are to translate scores from comprehensive assessments of symptom severity and functional impairment into clinically meaningful CGI levels. Methods: These post-hoc analyses use data integrated from four pivotal Phase 3 trials in attention-deficit/hyperactivity disorder (ADHD) in children and adolescents treated with the novel nonstimulant SPN-812 (Viloxazine Extended-Release). In this study, we evaluated the ADHD Rating Scale-5 (ADHD-RS-5) and Weiss Functional Impairment Rating Scale-Parent (WFIRS-P), assessments of symptom severity and functional impairment, respectively, by linking these scales with the CGI scales at baseline and end of study. Results: For participants that improved, a one-level change on the CGI-Improvement (CGI-I) was associated with a 10-15-point change on the ADHD-RS-5, and a 0.2-0.5-point change on the WFIRS-P. On the CGI-I, ratings of much improved and very much improved were associated with a percent score decrease (i.e., improvement) of ∼55% and 80% on the ADHD-RS-5 and ∼40% and 70% on the WFIRS-P, respectively. Differences between children and adolescents were minor and are unlikely to be clinically meaningful. Conclusion: These post-hoc analyses provide clinically meaningful benchmarks for the interpretation of scores on the ADHD-RS-5 and WFIRS-P in terms of CGI evaluations in subjects with ADHD. These results may be useful for physicians seeking to understand a treatment's potential impact on their ADHD patients or for researchers looking to define their study results within a clinically relevant context. Data are from clinical trials NCT03247530, NCT03247543, NCT03247517, and NCT03247556.
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Complementary effects of pine bark extract supplementation on inattention, impulsivity, and antioxidative status in children with attention-deficit hyperactivity disorder: A double-blinded randomized placebo-controlled cross-over study.
Hsu, CD, Hsieh, LH, Chen, YL, Lin, IC, Chen, YR, Chen, CC, Shirakawa, H, Yang, SC
Phytotherapy research : PTR. 2021;(6):3226-3235
Abstract
The purpose of this study was to investigate the complementary effects of polyphenolic compounds from pine bark extract (PE) as a strong antioxidative substrate on the symptoms of inattention and impulsivity in children with attention-deficit hyperactivity disorder (ADHD). This was a randomized, double-blind, crossover, placebo-controlled study that included two experimental units (4 weeks with PE supplementation and 4 weeks with placebo supplementation) separated by a 2-week washout period. ADHD participants were supplemented with 25 mg or 50 mg PE. We recruited 20 participants (17 boys and 3 girls) with a mean age of 10.0 ± 2.1 years. PE supplementation caused a significant reduction in the inattention and hyperactivity-impulsivity items of SNAP-IV. During the period of PE supplementation, the item of commissions in the Continuous Performance Test III (CPT III) significantly decreased, which was used to evaluate the symptoms of inattention and impulsivity. In addition, the erythrocytic reduced glutathione/oxidized glutathione ratio significantly increased, and the plasma TBARs level significantly decreased after 4 weeks of PE supplementation. However, there was no significant correlation between CPT III (commission) and antioxidative status indictors. PE supplementation may have potential effects of ameliorating inattention and impulsivity, and elevating the antioxidative status in children with ADHD.
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Zinc status in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis of observational studies.
Ghoreishy, SM, Ebrahimi Mousavi, S, Asoudeh, F, Mohammadi, H
Scientific reports. 2021;(1):14612
Abstract
Previous studies regarding the zinc status in attention-deficit/hyperactivity disorder (ADHD) yielded inconsistent results. Thus, the present meta-analysis was aimed to estimate the association between hair and serum/plasma zinc levels and ADHD. Online databases of Medline, EMBASE, and Scopus were searched up to October 2020 with no limitation in time and language. Weighted mean differences (WMDs) of hair and serum/plasma zinc levels were calculated using a random-effects model. Overall, 22 articles with 1280 subjects with ADHD and 1200 controls were included. The pooled effect size indicated that serum/plasma zinc levels in subjects with ADHD were not statistically different than their controls (WMD = - 1.26 µmol/L; 95% CI - 3.72, 1.20). Interestingly, the exclusion of one study from the analysis showed that people with ADHD significantly have lower circulating levels of zinc compared to their controls (WMD: - 2.49 µmol/L; 95% CI - 4.29, - 0.69). Also, the pooled effect size indicated that hair zinc levels in cases with ADHD were not statistically different than their controls (WMD = - 24.19 μg/g; 95% CI - 61.80, 13.42). Present meta-analysis raises the possibility that subjects with ADHD are prone to have declined levels of zinc levels. Based on current findings, screening the zinc levels in subjects with ADHD could be reasonable. Further well-designed studies are needed to clarify the role of zinc in the etiology of ADHD.
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The Role of Iron and Zinc in the Treatment of ADHD among Children and Adolescents: A Systematic Review of Randomized Clinical Trials.
Granero, R, Pardo-Garrido, A, Carpio-Toro, IL, Ramírez-Coronel, AA, Martínez-Suárez, PC, Reivan-Ortiz, GG
Nutrients. 2021;(11)
Abstract
UNLABELLED Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder common from childhood to adulthood, affecting 5% to 12% among the general population in developed countries. Potential etiological factors have been identified, including genetic causes, environmental elements and epigenetic components. Nutrition is currently considered an influencing factor, and several studies have explored the contribution of restriction and dietary supplements in ADHD treatments. Iron is an essential cofactor required for a number of functions, such as transport of oxygen, immune function, cellular respiration, neurotransmitter metabolism (dopamine production), and DNA synthesis. Zinc is also an essential trace element, required for cellular functions related to the metabolism of neurotransmitters, melatonin, and prostaglandins. Epidemiological studies have found that iron and zinc deficiencies are common nutritional deficits worldwide, with important roles on neurologic functions (poor memory, inattentiveness, and impulsiveness), finicky appetite, and mood changes (sadness and irritability). Altered levels of iron and zinc have been related with the aggravation and progression of ADHD. OBJECTIVE This is a systematic review focused on the contribution of iron and zinc in the progression of ADHD among children and adolescents, and how therapies including these elements are tolerated along with its effectiveness (according to PRISMA guidelines). METHOD The scientific literature was screened for randomized controlled trials published between January 2000 to July 2021. The databases consulted were Medline, PsycINFO, Web of Science, and Google Scholar. Two independent reviewers screened studies, extracted data, and assessed quality and risk of bias (CONSORT, NICE, and Cochrane checklists used). CONCLUSION Nine studies met the eligibility criteria and were selected. Evidence was obtained regarding the contribution of iron-zinc supplementation in the treatment of ADHD among young individuals. The discussion was focused on how the deficits of these elements contribute to affectation on multiple ADHD correlates, and potential mechanisms explaining the mediational pathways. Evidence also suggested that treating ADHD with diet interventions might be particularly useful for specific subgroups of children and adolescents, but further investigations of the effects of these diet interventions are needed.
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Resveratrol adjunct to methylphenidate improves symptoms of attention-deficit/hyperactivity disorder: a randomized, double-blinded, placebo-controlled clinical trial.
Rafeiy-Torghabeh, M, Ashraf-Ganjouei, A, Moradi, K, Bagheri, S, Mohammadi, MR, Akhondzadeh, S
European child & adolescent psychiatry. 2021;(5):799-807
Abstract
Current pharmacological approaches have failed to provide complete remission for patients with Attention-Deficit/Hyperactivity Disorder (ADHD). This study aimed to evaluate the efficacy and tolerability of resveratrol (that have been shown to have antioxidative, anti-inflammatory, and anti-apoptotic effects) as an adjunct to methylphenidate in pharmacologic treatment of ADHD. This 8-week, double-blinded, placebo-controlled trial randomized 66 participants to receive either 500 mg/day resveratrol or matched placebo in addition to methylphenidate. ADHD symptoms were evaluated in the patients using the Parent and Teacher versions of ADHD-Rating Scale (ADHD-RS) at three measurement points with time intervals of 4 weeks. Furthermore, the tolerability of the treatment strategies was systematically compared. Repeated measures analysis demonstrated a significant effect for time-treatment interaction on all three subscales of the Parent ADHD-RS during the trial period (total: p = 0.015; inattention: p = 0.032; hyperactivity/impulsivity: p = 0.036). Nevertheless, the effect for time-treatment interaction was not significant for the Teacher version of ADHD-RS (total: F = 0.81, df = 1.33, p = 0.401; inattention: F = 0.57, df = 1.37, p = 0.507; hyperactivity/impulsivity: F = 0.65, df = 1.34, p = 0.466). The frequencies of complications in the treatment groups were similar. Resveratrol administration for a duration of 8 weeks improved characteristic symptoms in patients with ADHD according to their parents. Further investigations containing larger sample sizes, longer supplementation periods, and dose-response evaluations are required to replicate these findings in ADHD children more confidently.
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Effect of Delayed-Release and Extended-Release Methylphenidate on Caregiver Strain and Validation of Psychometric Properties of the Caregiver Strain Questionnaire: Results from a Phase 3 Trial in Children with Attention-Deficit/Hyperactivity Disorder.
López, FA, Faraone, SV, Newcorn, JH, Doll, HA, Rhoten, S, Lewis, HB, Khan, TF, DeSousa, NJ, Sallee, FR, Incledon, B
Journal of child and adolescent psychopharmacology. 2021;(3):179-186
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Objectives: Inadequately controlled symptoms and associated impaired functioning have a significant negative impact on caregivers of children with attention-deficit/hyperactivity disorder (ADHD). This study aimed to assess the impact of evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) treatment on caregiver strain, measured by the Caregiver Strain Questionnaire (CGSQ), and present post hoc psychometric analyses assessing the reliability and validity of the CGSQ, its ability to detect change (responsiveness), and to derive responder definitions. Methods: The CGSQ was an exploratory efficacy endpoint in a phase 3, 3-week, randomized, double-blind, multicenter, placebo-controlled, forced-dose titration trial of DR/ER-MPH in children aged 6-12 years with ADHD (NCT02520388). Psychometric properties of the CGSQ evaluated post hoc included internal consistency using Cronbach's alpha; test/retest reliability using intraclass correlation coefficients (ICCs); construct validity (known groups and convergent/divergent validity); responsiveness to changes in assessments of ADHD severity (ADHD Rating Scale-IV [ADHD-RS-IV], Conners' Global Index-Parent [CGI-P], and Clinical Global Impression-Severity [CGI-S]/CGI-Improvement [CGI-I]); and meaningful change threshold (MCT) using receiver operating characteristic curves, which were used to compare response between DR/ER-MPH and placebo groups. Results: Randomized DR/ER-MPH (54.5) and placebo (54.9) groups had similar mean CGSQ scores at screening. Caregivers of children on DR/ER-MPH reported significant reductions in CGSQ scores after 3 weeks of DR/ER-MPH treatment versus placebo (least-squares mean: 41.2 vs. 49.1; p < 0.001). The CGSQ demonstrated strong internal consistency (Cronbach's alpha = 0.93) and good test/retest reliability (ICC = 0.72). Known groups, convergent/divergent validity, and responsiveness were demonstrated from relationships between the CGSQ and the CGI-S, ADHD-RS-IV, and CGI-P. The mean anchor-based MCT for CGSQ total score was estimated as -9.0 (DR/ER-MPH vs. placebo: 53.2% vs. 29.9% p = 0.003). Conclusions: CGSQ scores significantly decreased after 3 weeks of DR/ER-MPH treatment versus placebo, and the CGSQ was found to be a valid and reliable measure of strain in caregivers of children with ADHD. Clinical trial registration identification number: NCT02520388.
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Environmental risk factors, protective factors, and peripheral biomarkers for ADHD: an umbrella review.
Kim, JH, Kim, JY, Lee, J, Jeong, GH, Lee, E, Lee, S, Lee, KH, Kronbichler, A, Stubbs, B, Solmi, M, et al
The lancet. Psychiatry. 2020;(11):955-970
Abstract
BACKGROUND Many potential environmental risk factors, environmental protective factors, and peripheral biomarkers for ADHD have been investigated, but the consistency and magnitude of their effects are unclear. We aimed to systematically appraise the published evidence of association between potential risk factors, protective factors, or peripheral biomarkers, and ADHD. METHODS In this umbrella review of meta-analyses, we searched PubMed including MEDLINE, Embase, and the Cochrane Database of Systematic Reviews, from database inception to Oct 31, 2019, and screened the references of relevant articles. We included systematic reviews that provided meta-analyses of observational studies that examined associations of potential environmental risk factors, environmental protective factors, or peripheral biomarkers with diagnosis of ADHD. We included meta-analyses that used categorical ADHD diagnosis criteria according to DSM, hyperkinetic disorder according to ICD, or criteria that were less rigorous than DSM or ICD, such as self-report. We excluded articles that did not examine environmental risk factors, environmental protective factors, or peripheral biomarkers of ADHD; articles that did not include a meta-analysis; and articles that did not present enough data for re-analysis. We excluded non-human studies, primary studies, genetic studies, and conference abstracts. We calculated summary effect estimates (odds ratio [OR], relative risk [RR], weighted mean difference [WMD], Cohen's d, and Hedges' g), 95% CI, heterogeneity I2 statistic, 95% prediction interval, small study effects, and excess significance biases. We did analyses under credibility ceilings, and assessed the quality of the meta-analyses with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). This study is registered with PROSPERO, number CRD42019145032. FINDINGS We identified 1839 articles, of which 35 were eligible for inclusion. These 35 articles yielded 63 meta-analyses encompassing 40 environmental risk factors and environmental protective factors (median cases 16 850, median population 91 954) and 23 peripheral biomarkers (median cases 175, median controls 187). Evidence of association was convincing (class I) for maternal pre-pregnancy obesity (OR 1·63, 95% CI 1·49 to 1·77), childhood eczema (1·31, 1·20 to 1·44), hypertensive disorders during pregnancy (1·29, 1·22 to 1·36), pre-eclampsia (1·28, 1·21 to 1·35), and maternal acetaminophen exposure during pregnancy (RR 1·25, 95% CI 1·17 to 1·34). Evidence of association was highly suggestive (class II) for maternal smoking during pregnancy (OR 1·6, 95% CI 1·45 to 1·76), childhood asthma (1·51, 1·4 to 1·63), maternal pre-pregnancy overweight (1·28, 1·21 to 1·35), and serum vitamin D (WMD -6·93, 95% CI -9·34 to -4·51). INTERPRETATION Maternal pre-pregnancy obesity and overweight; pre-eclampsia, hypertension, acetaminophen exposure, and smoking during pregnancy; and childhood atopic diseases were strongly associated with ADHD. Previous familial studies suggest that maternal pre-pregnancy obesity, overweight, and smoking during pregnancy are confounded by familial or genetic factors, and further high-quality studies are therefore required to establish causality. FUNDING None.
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Maternal Iodine Status During Pregnancy Is Not Consistently Associated with Attention-Deficit Hyperactivity Disorder or Autistic Traits in Children.
Levie, D, Bath, SC, Guxens, M, Korevaar, TIM, Dineva, M, Fano, E, Ibarluzea, JM, Llop, S, Murcia, M, Rayman, MP, et al
The Journal of nutrition. 2020;(6):1516-1528
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BACKGROUND Severe iodine deficiency during pregnancy can cause intellectual disability, presumably through inadequate placental transfer of maternal thyroid hormone to the fetus. The association between mild-to-moderate iodine deficiency and child neurodevelopmental problems is not well understood. OBJECTIVES We investigated the association of maternal iodine status during pregnancy with child attention-deficit hyperactivity disorder (ADHD) and autistic traits. METHODS This was a collaborative study of 3 population-based birth cohorts: Generation R (n = 1634), INfancia y Medio Ambiente (n = 1293), and the Avon Longitudinal Study of Parents and Children (n = 2619). Exclusion criteria were multiple fetuses, fertility treatment, thyroid-interfering medication use, and pre-existing thyroid disease. The mean age of assessment in the cohorts was between 4.4 and 7.7 y for ADHD symptoms and 4.5 and 7.6 y for autistic traits. We studied the association of the urinary iodine-to-creatinine ratio (UI/Creat) <150 μg/g-in all mother-child pairs, and in those with a urinary-iodine measurement at ≤18 weeks and ≤14 weeks of gestation-with the risk of ADHD or a high autistic-trait score (≥93rd percentile cutoff), using logistic regression. The cohort-specific effect estimates were combined by random-effects meta-analyses. We also investigated whether UI/Creat modified the associations of maternal free thyroxine (FT4) or thyroid-stimulating hormone concentrations with ADHD or autistic traits. RESULTS UI/Creat <150 μg/g was not associated with ADHD (OR: 1.2; 95% CI: 0.7, 2.2; P = 0.56) or with a high autistic-trait score (OR: 0.8; 95% CI: 0.6, 1.1; P = 0.22). UI/Creat <150 μg/g in early pregnancy (i.e., ≤18 weeks or ≤14 weeks of gestation) was not associated with a higher risk of behavioral problems. The association between a higher FT4 and a greater risk of ADHD (OR: 1.3; 95% CI: 1.0, 1.6; P = 0.017) was not modified by iodine status. CONCLUSIONS There is no consistent evidence to support an association of mild-to-moderate iodine deficiency during pregnancy with child ADHD or autistic traits.
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Sugar consumption, sugar sweetened beverages and Attention Deficit Hyperactivity Disorder: A systematic review and meta-analysis.
Farsad-Naeimi, A, Asjodi, F, Omidian, M, Askari, M, Nouri, M, Pizarro, AB, Daneshzad, E
Complementary therapies in medicine. 2020;:102512
Abstract
BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is a significant neurobehavioral disorder in children and adolescence which may be affected by diet. OBJECTIVE To evaluate the possible relationship between sugar consumption and the development of symptoms of ADHD. METHODS In March 2020, an exhaustive systematic literature search was conducted using Google Scholar, PubMed, and Scopus. In this meta-analysis of observational studies, odds ratios, relative risks, hazard ratios, and their 95% confidence intervals, which was reported for ADHD regarding SSBS, soft drink consumption, and dietary sugars, were used to calculate ORs and standard errors. At first, a fixed-effects model was used to drive the overall effect sizes using log ORs and SEs. If there was any significant between-studies heterogeneity, the random-effects model was conducted. Cochran's Q test and I2 were used to measure potential sources of heterogeneity across studies. The Newcastle-Ottawa scale was used to assess the quality of the included articles. RESULTS Seven studies, two cross-sectional, two case-control, and three prospective with a total of 25,945 individuals were eligible to include in the current meta-analysis. The association between sugar and soft drink consumption and the risk of ADHD symptoms were provided based on the random-effects model (pooled effect size: 1.22, 95%CI: 1.04-1.42, P = 0.01) (I² = 81.9%, P heterogeneity< 0.0001). CONCLUSION This meta-analysis indicated a positive relationship between overall sugar and sugar-sweetened beverages consumption and symptoms of ADHD; however, there was heterogeneity among included studies. Future well-designed studies that can account for confounds are necessary to confirm the effect of sugar on ADHD.