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Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youths: A Placebo-Controlled Randomized Clinical Trial.
Johnstone, JM, Hatsu, I, Tost, G, Srikanth, P, Eiterman, LP, Bruton, AM, Ast, HK, Robinette, LM, Stern, MM, Millington, EG, et al
Journal of the American Academy of Child and Adolescent Psychiatry. 2022;61(5):647-661
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Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that affects about 5-7% of children. Characteristics of ADHD are age-inappropriate hyperactivity, impulsivity, and difficulties in focusing attention which arise from an impaired ability to regulate executive and emotional functions. The condition often persists into adulthood, where it presents an increased risk for poor educational achievements, substance abuse, incarceration, and mental health problems. In many cases, drug treatment can improve ADHD symptoms, yet concern remains about the side effects of these treatments. Some research has investigated the impact of nutrient supplementation on ADHD management, as many nutrients are essential for healthy brain function and are also involved in the production of neurotransmitters. In previous studies, supplementation with nutrients has shown some benefits but likewise also inconsistent results. This eight-week randomised placebo-controlled clinical trial evaluated the effects of a multi-nutrient supplement in 135 children with ADHD, aged 6-12 years. The study specifically focused on irritable mood symptoms. The multi-nutrient formula contained vitamins, minerals, amino acids, and antioxidants. Outcomes were measured by scores rated by clinicians (Clinical Global Impression-Improvement aka CGI-I) and scores rated by parents (Child and Adolescent Symptom Inventory-5 aka CASI-5). The multi-nutrient formula showed overall benefit in the blinded clinician rating but not by parental reports. According to the parents, overall improvement was reported, both in the placebo and intervention groups. The authors discussed how this absence of difference can be explained. Yet, on a subscale, the multi-nutrient group parents were more likely to report improvements. In addition, children with the additional micronutrients demonstrated greater height growth during the intervention. The supplement was well tolerated with good adherence and the monitored blood markers demonstrated safety of use.
Expert Review
Conflicts of interest:
None
Take Home Message:
This fully-blinded RCT of micronutrients addresses several concerns related to existing ADHD treatment, including the possibility of counteracting height suppression and treating associated irritable mood, emotional dysregulation, and aggression.
Although further research is needed, multinutrient supplementation should be considered for children with ADHD.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric condition that can result in low educational performance and achievement. Around 5-7% of children are believed to be affected. Alongside inattention and hyperactivity, emotional dysregulation is a common feature of ADHD. Psychiatric problems can continue into adulthood and an increased risk of incarceration and substance abuse have been reported.
Treatment with prescription medications may improve symptoms of ADHD, however, potential side effects include mild growth suppression, and mood and emotional dysregulation. Non-pharmacological treatments are therefore being investigated.
Previous research on single nutrients have shown mixed results for emotional dysregulation and mood issues in ADHD. The aim of this study was to test whether supplementation with a multi-nutrient could be beneficial to children aged 6-12 years with ADHD and irritability.
Methods
126 unmedicated children from North America with ADHD (mean age 9.8 years) completed this 8-week study. All participants had at least 1 symptom of anger, irritability, peer conflict or Disruptive Mood Dysregulation Disorder (DMDD).
Randomisation was into an intervention (n=71) or placebo (N=55) group with a 3:2 ratio to promote enrolment. Participants were required to take 6-12 capsules daily, depending on age and tolerance, of micronutrients or a placebo. Micronutrient dosages were above the recommended dietary allowance (RDA). Outcomes were measured using clinician and parent rated assessments and by a further adult who knew the child well.
The trial was blinded to all participants, parents and study staff.
Results
The clinician-rated results found 54% of the micronutrient group and 18% of the placebo group had improvements in irritability symptoms (Risk ratio =2.97, 97.5% CI: 1.5, 5.90, p<0.001). This was not replicated in the parent/adult rated results. Children in the micronutrient group grew on average 6mm more than the placebo group (p=0.002). No serious adverse treatment effects were reported. Adherence to protocol was met by >74% of participants (n=93).
Conclusions
In this study, clinicians reported that micronutrients showed greater benefits than placebo for treating irritability and supporting growth in children with ADHD.
The study and authors received funding from several research and association bodies. However, no funder was involved in the study design or reporting. No conflicts of interest were declared.
Clinical practice applications:
- Multinutrient supplementation including vitamins, minerals, amino acids, and antioxidants may support height growth in children who take pharmacologic treatment
- Multi nutrient supplementation may also help with irritable mood, emotional dysregulation, and aggression in ADHD children
- Micronutrients given at doses between the Recommended Dietary Allowance and Upper Tolerable Intake Level appear safe and may be developed into an alternative or complementary treatment for ADHD.
Considerations for future research:
- Further large scale research is needed into the potential benefits of micronutrients for children with ADHD and irritability
Abstract
OBJECTIVE To evaluate whether micronutrients (vitamins/minerals) benefit attention-deficit/hyperactivity disorder (ADHD) and irritability in a North American pediatric sample. METHOD A 3-site, 8-week, placebo-controlled, randomized clinical trial of micronutrients was conducted in nonmedicated children aged 6 to 12 years with ADHD and at least 1 impairing irritability symptom by parent report on the Child and Adolescent Symptom Inventory-5 (CASI-5). A priori-defined primary outcomes were Clinical Global Impression-Improvement (CGI-I) (CGI-I of 1 or 2 = treatment responder) and parent-rated CASI-5 composite score of ADHD, oppositional defiant, disruptive mood dysregulation, and peer conflict symptoms, including impairment scores. RESULTS Of 135 randomized (mean age 9.8 years), 126 youths (93%) comprised the modified intention-to-treat population. Blinding was maintained. For the CGI-I, 54% of the micronutrient and 18% of the placebo group were responders (risk ratio = 2.97, 97.5% CI = 1.50, 5.90, p < .001). CASI-5 composite scores improved significantly for both groups (p < .01), with a mean change of -0.31 (95% CI = -0.39, -0.23) in the micronutrient group and a mean change of -0.28 (95% CI = -0.38, -0.19) in the placebo group. However, the between-group difference was not significant (mean change = -0.02; 97.5% CI = -0.16, 0.12, effect size = 0.07, p = .70). The micronutrient group grew 6 mm more than the placebo group (p = .002). No serious adverse events or clinically significant changes from baseline in blood and urine tests occurred. CONCLUSION Micronutrients showed global benefit over placebo by blinded clinician rating, but not by parent-report CASI-5 composite rating in a population with ADHD and irritability. Micronutrients showed greater height growth. Micronutrients were well tolerated, and the majority of participants adhered to the number of capsules prescribed. This randomized controlled trial replicates safety and efficacy reported for ADHD in 2 smaller trials of a similar formula containing all vitamins and known essential minerals in amounts between the Recommended Dietary Allowance and Upper Tolerable Intake Level. CLINICAL TRIAL REGISTRATION INFORMATION Micronutrients for ADHD in Youth (MADDY) Study; https://clinicaltrials.gov; NCT03252522.
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Vegan diet in young children remodels metabolism and challenges the statuses of essential nutrients.
Hovinen, T, Korkalo, L, Freese, R, Skaffari, E, Isohanni, P, Niemi, M, Nevalainen, J, Gylling, H, Zamboni, N, Erkkola, M, et al
EMBO molecular medicine. 2021;13(2):e13492
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As vegan diets gain popularity amongst families, there is little known about the impact of strict plant-based diets on metabolism and micronutrient status in children, apart from reduced average growth within the norm. This small study looked at 40 Finnish children from one day centre, and compared children following an omnivore or vegetarian diet to those raised on a vegan diet. The diets were analysed, and biomarkers and metabolites were measured. The metabolic profile and nutrient status of children who followed a vegan diet from birth were distinctively different to other diet patterns, including vegetarians. The authors suggest that little animal source foods are enough to shift the metabolism of children. Dietary analysis showed that vegan children had higher folate consumption and lower protein and saturated fats intake. Despite intake appearing adequate, serum markers for fat-soluble vitamins A and D were low. While the fatty acid ALA was higher compared to omnivores, DHA and overall cholesterol were decreased. The authors concluded that the bodies own cholesterol production does not seem to compensate for a lack of dietary cholesterol in this case and it remains to be established whether lower cholesterol in vegan children are negative to health. Furthermore, the circulating amino acids pool was decreased in vegan children, particularly branch chained amino acids. The most distinct difference, however, was seen in the variance of bile acid patterns. The physiological functions of bile acids go beyond digestion, yet the consequences of diverging bile acid profiles in children’s health are unknown. In conclusion, the data shows that a strict vegan diet affects the metabolism of healthy children, but much of the long-term impact on health is currently still unclear. This article highlights some of the differences, risks and uncertainties that come with raising young children on a strictly vegan diet.
Abstract
Vegan diets are gaining popularity, also in families with young children. However, the effects of strict plant-based diets on metabolism and micronutrient status of children are unknown. We recruited 40 Finnish children with a median age 3.5 years-vegans, vegetarians, or omnivores from same daycare centers-for a cross-sectional study. They enjoyed nutritionist-planned vegan or omnivore meals in daycare, and the full diets were analyzed with questionnaires and food records. Detailed analysis of serum metabolomics and biomarkers indicated vitamin A insufficiency and border-line sufficient vitamin D in all vegan participants. Their serum total, HDL and LDL cholesterol, essential amino acid, and docosahexaenoic n-3 fatty acid (DHA) levels were markedly low and primary bile acid biosynthesis, and phospholipid balance was distinct from omnivores. Possible combination of low vitamin A and DHA status raise concern for their visual health. Our evidence indicates that (i) vitamin A and D status of vegan children requires special attention; (ii) dietary recommendations for children cannot be extrapolated from adult vegan studies; and (iii) longitudinal studies on infant-onset vegan diets are warranted.
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A 2 year physical activity and dietary intervention attenuates the increase in insulin resistance in a general population of children: the PANIC study.
Lakka, TA, Lintu, N, Väistö, J, Viitasalo, A, Sallinen, T, Haapala, EA, Tompuri, TT, Soininen, S, Karjalainen, P, Schnurr, TM, et al
Diabetologia. 2020;63(11):2270-2281
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The number of children and adolescents with type 2 diabetes and prediabetes has increased over the past decades which is likely due to decreased physical activity, increased sedentary time, unhealthy diet and consequently increased body fat content. Insulin resistance plays an important role in the development of type 2 diabetes. The aim of this 2 year non-randomised, controlled trial was to investigate the long-term effects of a combined physical activity and dietary intervention programme on insulin resistance in a general population of children, most of whom had a normal body weight. Children in the intervention group had six intervention visits which included 30–45 min of physical activity counselling and 30–45 min of dietary counselling for the children and their parents/carers. Fasting insulin and HOMA-IR (a measure for insulin resistance) increased significantly less in the intervention group than in the control group, whilst there were no significant differences in fasting glucose, body fat or lean body mass after 2 years. The effects on insulin resistance were mediated by changes in physical activity, sedentary time and diet. The authors conclude that the prevention of type 2 diabetes should begin in childhood by increasing physical activity, decreasing sedentary time and improving diet in the general paediatric population and not just among overweight and obese children.
Abstract
AIMS/HYPOTHESIS We studied for the first time the long-term effects of a combined physical activity and dietary intervention on insulin resistance and fasting plasma glucose in a general population of predominantly normal-weight children. METHODS We carried out a 2 year non-randomised controlled trial in a population sample of 504 children aged 6-9 years at baseline. The children were allocated to a combined physical activity and dietary intervention group (306 children at baseline, 261 children at 2-year follow-up) or a control group (198 children, 177 children) without blinding. We measured fasting insulin and fasting glucose, calculated HOMA-IR, assessed physical activity and sedentary time by combined heart rate and body movement monitoring, assessed dietary factors by a 4 day food record, used the Finnish Children Healthy Eating Index (FCHEI) as a measure of overall diet quality, and measured body fat percentage (BF%) and lean body mass by dual-energy x-ray absorptiometry. The intervention effects on insulin, glucose and HOMA-IR were analysed using the intention-to-treat principle and linear mixed-effects models after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The measures of physical activity, sedentary time, diet and body composition at baseline and 2 year follow-up were entered one-by-one as covariates into the models to study whether changes in these variables might partly explain the observed intervention effects. RESULTS Compared with the control group, fasting insulin increased 4.65 pmol/l less (absolute change +8.96 vs +13.61 pmol/l) and HOMA-IR increased 0.18 units less (+0.31 vs +0.49 units) over 2 years in the combined physical activity and dietary intervention group. The intervention effects on fasting insulin (regression coefficient β for intervention effect -0.33 [95% CI -0.62, -0.04], p = 0.026) and HOMA-IR (β for intervention effect -0.084 [95% CI -0.156, -0.012], p = 0.023) were statistically significant after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The intervention had no effect on fasting glucose, BF% or lean body mass. Changes in total physical activity energy expenditure, light physical activity, moderate-to-vigorous physical activity, total sedentary time, the reported consumption of high-fat (≥60%) vegetable oil-based spreads, and FCHEI, but not a change in BF% or lean body mass, partly explained the intervention effects on fasting insulin and HOMA-IR. CONCLUSIONS/INTERPRETATION The combined physical activity and dietary intervention attenuated the increase in insulin resistance over 2 years in a general population of predominantly normal-weight children. This beneficial effect was partly mediated by changes in physical activity, sedentary time and diet but not changes in body composition. TRIAL REGISTRATION ClinicalTrials.gov NCT01803776 Graphical abstract.
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Associations of dietary intake with cardiometabolic risk in a multi-ethnic cohort: a longitudinal analysis of the Determinants of Adolescence, now young Adults, Social well-being and Health (DASH) study.
Goff, LM, Huang, P, Silva, MJ, Bordoli, C, Enayat, EZ, Molaodi, OR, Cassidy, A, Maynard, M, Harding, S
The British journal of nutrition. 2019;121(9):1069-1079
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Ethnic inequalities in a wide range of chronic diseases are well documented. Poor dietary habits in childhood may contribute to higher rates of chronic diseases such as type 2 diabetes (T2D), hypertension and Coronary Heart Disease (CHD). This study was a longitudinal follow-up of a subsample of the Determinants of Adolescent Social well-being and Health (DASH) study. The researchers aimed to identify dietary patterns and investigate their impact on chronic diseases in young adulthood. The study participants were 107 White British, 102 Black Caribbean, 132 Black African, 98 Indian, 111 Bangladeshi/Pakistani and 115 other/mixed ethnicity. Participants completed a 24-hour dietary intake recall and behaviour questionnaire at age 11-13yrs, and then again at age 21-23yrs. Body mass index (BMI), blood pressure, blood cholesterol and blood sugar were measured. The researchers found that dietary behaviours such as skipping breakfast and a low intake of fruit and vegetables were common. Rates of skipping breakfast and low fruit and vegetable consumption were highest among Black African and Black Caribbean participants. BMI and cholesterol levels in young adults were higher among those who regularly skipped breakfast. The researchers concluded that skipping breakfast is more common in certain ethnic groups and is associated with risk factors for chronic disease in young adults. They suggest that interventions to improve dietary habits could be targeted at specific population groups.
Abstract
Unfavourable dietary habits, such as skipping breakfast, are common among ethnic minority children and may contribute to inequalities in cardiometabolic disease. We conducted a longitudinal follow-up of a subsample of the UK multi-ethnic Determinants of Adolescent Social well-being and Health cohort, which represents the main UK ethnic groups and is now aged 21-23 years. We aimed to describe longitudinal patterns of dietary intake and investigate their impact on cardiometabolic risk in young adulthood. Participants completed a dietary behaviour questionnaire and a 24 h dietary intake recall; anthropometry, blood pressure, total cholesterol and HDL-cholesterol and HbA1c were measured. The cohort consisted of 107 White British, 102 Black Caribbean, 132 Black African, 98 Indian, 111 Bangladeshi/Pakistani and 115 other/mixed ethnicity. Unhealthful dietary behaviours such as skipping breakfast and low intake of fruits and vegetables were common (56, 57 and 63 %, respectively). Rates of skipping breakfast and low fruit and vegetable consumption were highest among Black African and Black Caribbean participants. BMI and cholesterol levels at 21-23 years were higher among those who regularly skipped breakfast at 11-13 years (BMI 1·41 (95 % CI 0·57, 2·26), P=0·001; cholesterol 0·15 (95 % CI -0·01, 0·31), P=0·063) and at 21-23 years (BMI 1·05 (95 % CI 0·22, 1·89), P=0·014; cholesterol 0·22 (95 % CI 0·06, 0·37), P=0·007). Childhood breakfast skipping is more common in certain ethnic groups and is associated with cardiometabolic risk factors in young adulthood. Our findings highlight the importance of targeting interventions to improve dietary behaviours such as breakfast consumption at specific population groups.
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Maternal allergen-specific IgG might protect the child against allergic sensitization.
Lupinek, C, Hochwallner, H, Johansson, C, Mie, A, Rigler, E, Scheynius, A, Alm, J, Valenta, R
The Journal of allergy and clinical immunology. 2019;144(2):536-548
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Analysis of allergen-specific IgE responses in birth cohorts with allergens has provided detailed information regarding the development of specific IgE responses in children. Data regarding early development of allergen-specific IgG is needed. The aim of this study is to investigate whether maternal allergen-specific IgG can protect against IgE sensitization in their children. Plasma samples were taken from mothers during the third trimester, cord blood, breast milk collected 2 months after delivery; and from children at 6, 12, and 60 months of age. These samples were analysed for IgG reactivity to 164 allergens in 99 families. IgE sensitizations to allergens were determined at 5 years of age in the children. Children who were IgE sensitized against an allergen at 5 years of age had significantly higher allergen-specific IgG levels than non-sensitised children. For all 164 tested allergens, children from mothers with higher levels of specific plasma IgG levels against an allergen had no IgE sensitizations against that allergen at 5 years of age. High levels of allergen-specific IgG in mothers during the third trimester and in cord blood seem to protect against allergic sensitization in offspring. This finding has implications for allergy prevention.
Abstract
BACKGROUND Analysis of allergen-specific IgE responses in birth cohorts with microarrayed allergens has provided detailed information regarding the evolution of specific IgE responses in children. High-resolution data regarding early development of allergen-specific IgG are needed. OBJECTIVE We sought to analyze IgG reactivity to microarrayed allergens in mothers during pregnancy, in cord blood samples, in breast milk, and in infants in the first years of life with the aim to investigate whether maternal allergen-specific IgG can protect against IgE sensitization in the offspring. METHODS Plasma samples from mothers during the third trimester, cord blood, breast milk collected 2 months after delivery, and plasma samples from children at 6, 12, and 60 months of age were analyzed for IgG reactivity to 164 microarrayed allergens (ImmunoCAP ISAC technology) in 99 families of the Swedish birth cohort Assessment of Lifestyle and Allergic Disease During Infancy (ALADDIN). IgE sensitizations to microarrayed allergens were determined at 5 years of age in the children. RESULTS Allergen-specific IgG reactivity profiles in mothers, cord blood, and breast milk were highly correlated. Maternal allergen-specific IgG persisted in some children at 6 months. Children's allergen-specific IgG production occurred at 6 months and reflected allergen exposure. Children who were IgE sensitized against an allergen at 5 years of age had significantly higher allergen-specific IgG levels than nonsensitized children. For all 164 tested allergens, children from mothers with increased (>30 ISAC standardized units) specific plasma IgG levels against an allergen had no IgE sensitizations against that allergen at 5 years of age. CONCLUSION This is the first detailed analysis of the molecular IgG recognition profile in mothers and their children in early life. High allergen-specific IgG reactivity in the mother's plasma and breast milk and in cord blood seemed to protect against allergic sensitization at 5 years of age.
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Effects of fasting and preoperative feeding in children.
Yurtcu, M, Gunel, E, Sahin, TK, Sivrikaya, A
World journal of gastroenterology. 2009;15(39):4919-22
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Preoperative fasting is usually carried out to prevent the risk of vomiting during anaesthesia. The study investigated whether children should have a long period of fasting before surgery. Eight groups of 10 children (aged 1-10 years) with disorders of groin and scrotum were orally fed normal liquid food (NLF) or a high calorie diet (HCD) in 2 divided doses at 6 hour intervals, then fasted for 2, 3, 4 or 5 hours prior to surgery. Four groups had NLF and 4 groups had HCD. All children had their glucose, prealbumin and cortisol levels measured twice, just after the oral feeding and just before surgery. Once anaesthesia was sufficient and stable, gastric liquid was collected and measured. Patients with disease that could delay gastric emptying, had high acid production or were on medication were excluded from the trial. The researchers found that there was no significant difference in blood prealbumin levels in all groups. There was significant increase in blood cortisol in 4 groups when fasted (NLF-2h fasted, HCD-2h fasted, NLF-3h fasted and HCD-5h fasted). Stomach aid residue liquids were at tolerable levels of 1-2ml in all children. Anaesthesia was uneventful, with no coughing, laryngospasm or vomiting reported, and outcomes of surgery and wound healing were not affected. The authors noted that drinking clear liquids up to 2 hours before surgery was unlikely to substantially affect the volume of gastric fluids, and did not appear to increase the risk of vomiting in normal, healthy children. Glucose and insulin infusions appeared to minimise endocrine stress response and normalised post-op insulin sensitivity. Additionally, there may be a psychological benefit for children as irritability appeared to decrease prior to surgery. The study concluded that there was no need for fasting longer than 2 hours prior to inguinoscrotal region surgery.
Abstract
AIM: To investigate whether children should undergo surgery without a long period of fasting after feeding. METHODS Eighty children with inguinoscrotal disorders (aged 1-10 years) were studied prospectively. They were divided into eight groups that each contained 10 children who were fed normal liquid food (NLF) and a high-calorie diet (HCD) 2, 3, 4 and 5 h before surgery, in two doses at 6-h intervals. NLF was given to four groups and HCD to the other four. In all groups, glucose, prealbumin and cortisol levels in the blood were measured twice: just after oral feeding and just before the operation. After the establishment of adequate anesthesia, gastric residue liquid was measured with a syringe. RESULTS Blood glucose levels in all patients fed NLF and HCD were high, except in patients in the HCD-4 group. There was no significant difference in the blood prealbumin levels. There was a significant increase in the blood cortisol levels in the NLF-2 (14.4 +/- 5.7), HCD-2 (13.2 +/- 6.0), NLF-3 (10.9 +/- 6.4), and HCD-5 (6.8 +/- 5.7) groups (P < 0.05). CONCLUSION The stress of surgery may be tolerated by children when they are fed up to 2 h before elective surgery.