Broad-Spectrum Micronutrients or Antidepressants for Antenatal Depression: Effect on Maternal and Infant Birth Outcomes in an Observational Secondary Analysis of NUTRIMUM

Abstract

Purpose/background: One-fifth of women experience antenatal depression. Untreated antenatal depression is associated with increased risk of adverse birth outcomes. This study investigated the effect of broad-spectrum micronutrients (BSM; vitamins and minerals), used to treat antenatal depression (NUTRIMUM trial), on birth outcomes.

Methods/procedures: Birth outcomes of 129 mother-infant pairs were obtained from hospital medical records or personal health records for home births. Pairs from NUTRIMUM exposed to ≥8 weeks of BSM antenatally (MN; n = 55) were compared to pairs exposed to antidepressants antenatally (MED; n = 20) and a reference group (REF; n = 54) of pairs not exposed to trial BSM or antidepressants.

Findings/results: Groups were comparable on demographic variables. At study entry, MN and MED had depression scores in the moderate range, statistically higher than REF (nonclinical range). MN and REF did not differ significantly for gestational age, preterm births, infant size, or infant resuscitation. There were significantly lower rates of postpartum hemorrhage in MN relative to REF (7.7% vs 30%; RR = 0.26, 95% CI [0.08-0.84]). Gestational age at birth was higher for MN (39.5 weeks) than MED (38.5 weeks; d = 0.67, 95% CI [0.15-1.20], P = 0.03) as well as infant birth length (52.2 vs 50.0 cm; d = 0.77, 95% CI [0.21-1.33], P = 0.02), and rates of infant resuscitation were lower (14.5% vs 45%; RR = 0.33, 95% CI [0.15-0.73]). Days of BSM exposure was positively associated with birth weight (r = 0.32, P = 0.008) and length (r = 0.25, P = 0.04).

Implications/conclusions: Micronutrients used to alleviate antenatal depression may mitigate negative effects of depression on birth outcomes and showed more favorable birth outcomes compared with antidepressants.

Broad-Spectrum Micronutrients or Antidepressants for Antenatal Depression: Effect on Maternal and Infant Birth Outcomes in an Observational Secondary Analysis of NUTRIMUM

Heaton JL, Campbell SA, Bradley HA, Mulder RT, Dixon L, Henderson J, Rucklidge JJ. Broad-Spectrum Micronutrients or Antidepressants for Antenatal Depression: Effect on Maternal and Infant Birth Outcomes in an Observational Secondary Analysis of NUTRIMUM. J Clin Psychopharmacol. 2024 Dec 2.

Efficacy and safety of a mineral and vitamin treatment on symptoms of antenatal depression: 12-week fully blinded randomised placebo-controlled trial (NUTRIMUM)

Background

Broad-spectrum micronutrients (minerals and vitamins) have shown benefit for treatment of depressive symptoms.

Aims

To determine whether additional micronutrients reduce symptoms of antenatal depression.

Method

Eighty-eight medication-free pregnant women at 12–24 weeks gestation, who scored ≥13 on the Edinburgh Postnatal Depression Scale (EPDS), were randomised 1:1 to micronutrients or active placebo (containing iodine and riboflavin), for 12 weeks. Micronutrient doses were generally between recommended dietary allowance and tolerable upper level. Primary outcomes (EPDS and Clinical Global Impression – Improvement Scale (CGI-I)) were analysed with constrained longitudinal data analysis.

Results

Seventeen (19%) women dropped out, with no group differences, and four (4.5%) gave birth before trial completion. Both groups improved on the EPDS, with no group differences (P = 0.1018); 77.3% taking micronutrients and 72.7% taking placebos were considered recovered. However, the micronutrient group demonstrated significantly greater improvement, based on CGI-I clinician ratings, over time (P = 0.0196). The micronutrient group had significantly greater improvement on sleep and global assessment of functioning, and were more likely to identify themselves as ‘much’ to ‘very much’ improved (68.8%) compared with placebo (38.5%) (odds ratio 3.52, P = 0.011; number needed to treat: 3). There were no significant group differences on treatment-emergent adverse events, including suicidal ideation. Homocysteine decreased significantly more in the micronutrient group. Presence of personality difficulties, history of psychiatric medication use and higher social support tended to increase micronutrient response compared with placebo.

Conclusions

This study highlights the benefits of active monitoring on antenatal depression, with added efficacy for overall functioning when taking micronutrients, with no evidence of harm. Trial replication with larger samples and clinically diagnosed depression are needed.

Efficacy and safety of a mineral and vitamin treatment on symptoms of antenatal depression: 12-week fully blinded randomised placebo-controlled trial (NUTRIMUM)

Bradley HA, Moltchanova E, Mulder RT, Dixon L, Henderson J, Rucklidge JJ. Efficacy and safety of a mineral and vitamin treatment on symptoms of antenatal depression: 12-week fully blinded randomised placebo-controlled trial (NUTRIMUM). BJPsych Open. 2024;10(4):e119.

Problems most concerning to parents of children with ADHD and emotional dysregulation in a randomized controlled trial of multinutrients: MADDY secondary analysis

Abstract

Objective: With dual focus on structured, objective quantification of parent observations of child's behavior and identifying behaviors most amenable to change, this report examines Parent Target Problems (PTP) as a secondary outcome in a randomized clinical trial (RCT) of children with attention-deficit/ hyperactivity disorder (ADHD) in which one primary outcome, Clinical Global Impression-Improvement, showed a significant advantage of multinutrients over placebo and the other, Likert-type parent ratings, showed significant improvement in both groups, without significant difference between them.

Method: In a multisite 8-week RCT of broad-spectrum micronutrients ("multinutrients"), parents of children ages 6-12 (N = 126, 73% male, 88% white) with ADHD and emotional dysregulation nominated their child's most concerning problem(s) at baseline and quantified them by frequency, duration, impairment, and consequences. At subsequent visits, parents re-quantified the problem(s). Blinded child psychiatrists independently reviewed the PTPs and rated change at two timepoints compared to baseline. PTPs were grouped into 9 categories. Mean ratings were compared between active and placebo groups and explored by category.

Results: By week 8, a significant separation favored multinutrients: 38% of the multinutrient group were "definitely improved" or better, compared to 25% of the placebo group, and ratings of "no change" or "worse" occurred in 35% with placebo versus 23% with multinutrients (p = 0.04). Inattention (72.2%) and emotional dysregulation (69.1%) were the most frequently reported PTP categories. Inattention and internalizing symptoms improved more with multinutrients than placebo (p = 0.01, d = 0.55; p = 0.03, d = 0.80, respectively). The multinutrient advantage was not significant for 7 other symptoms, including hyperactivity/impulsivity, aggression, autistic symptoms, or emotional dysregulation/irritable oppositionality.

Conclusions: This secondary analysis found that the multinutrients, compared to placebo, were associated with improvements in parental concerns overall, and in two domains specifically: inattention and internalizing symptoms (anxiety/depression), but not in seven domains: hyperactivity/impulsivity, aggression, autistic symptoms or physiological symptoms, peer relationships or emotional dysregulation/irritable oppositionality.

Problems most concerning to parents of children with ADHD and emotional dysregulation in a randomized controlled trial of multinutrients: MADDY secondary analysis

Tost G, Srikanth P, Bruton A, Hatsu IE, Leung BM, Ast HK, Eiterman LP, Robinette LM, Williams C, Gracious B, Eugene Arnold L, Johnstone JM. Eur Child Adolesc Psychiatry. 2024 May 31.

Treatment response to supplemental nutrients for ADHD is independent of diet quality: the MADDY Study RCT

Abstract

Objectives: The 8-week Micronutrients for ADHD in Youth (MADDY) randomized controlled trial (N = 126, age 6-12) of broad-spectrum multinutrients for ADHD with emotional dysregulation found 3 times as many responders with multinutrients (54%) compared to placebo (18%) by Clinical Global Impression-Improvement (CGI-I). Our primary aim for this analysis tests the hypothesis that those with poor overall diet quality at baseline benefit more. The second aim is to explore whether specific components of diet quality moderate treatment response.

Methods: 124 children (69 multinutrients, 55 placebo) had diet quality assessed using the Healthy Eating Index-2015 (HEI-2015). For each potential moderator, the outcome CGI-I at week 8 (RCT-end), was modeled two ways: (1) as a dichotomous variable: responder/non-responder, with responders defined by a rating of 1 or 2 'very much' or 'much improved,' all else equals non-responder using logistic regression, and (2) as a dimensional improvement outcome from 1 = very much improved to 7 = very much worse, using linear regression.

Results: HEI-2015 total score did not moderate treatment response [odds ratio = 1.00 (95% CI: 0.90,1.10), p = 0.984] or improvement [β = -0.01 (95% CI: -0.06,0.04), p = 0.648]. However, total vegetable intake moderated level of improvement in exploratory analysis [β = -0.48 (95% CI: -0.82, -0.13), p = 0.007]: those with higher baseline vegetable intake showed greater benefit from multinutrients compared to placebo.

Conclusions: Multinutrients may benefit children with ADHD and irritability regardless of overall diet quality. The finding that higher baseline vegetable intake may improve response to multinutrients deserves further exploration, including dietary effect on gut microbiota and absorption of multinutrients and parental factors.

Treatment response to supplemental nutrients for ADHD is independent of diet quality: the MADDY Study RCT

Robinette LM, Hatsu IE, Johnstone JM, Bruton AM, Leung BMY, Arnold LE. Treatment response to supplemental nutrients for ADHD is independent of diet quality: the MADDY Study RCT. Nutr Neurosci. 2024 Apr;27(4):319-328.

Exploring the impact of antenatal micronutrients used as a treatment for maternal depression on infant temperament in the first year of life

Abstract

Antenatal depression and maternal nutrition can influence infant temperament. Although broad-spectrum-micronutrients (BSM: vitamins and minerals) given above Recommended Dietary Allowances during pregnancy can mitigate symptoms of antenatal depression, their associated effects on infant temperament are unknown. One hundred and fourteen New Zealand mother-infant dyads (45 infants exposed to BSM during pregnancy (range of exposure during pregnancy: 12-182 days) to treat antenatal depressive symptoms (measured by Edinburgh Postnatal Depression Scale) and 69 non-exposed infants) were followed antenatally and for 12 months postpartum to determine the influence of in utero BSM exposure on infant temperament. The Infant Behavior Questionnaire-Revised: Very Short-Form assessed temperament at 4 (T1), 6 (T2) and 12 (T3) months postpartum via online questionnaire. Latent growth curve modeling showed BSM exposure, antenatal depression and infant sex did not statistically significantly predict initial levels or longitudinal changes in orienting/regulatory capacity (ORC), positive affectivity/surgency (PAS) or negative affectivity (NEG). Higher gestational age was positively associated with initial PAS, and smaller increases between T1 and T3. Breastfeeding occurrence was positively associated with initial NEG. Although not significant, BSM exposure exerted small, positive effects on initial NEG (β = -0.116) and longitudinal changes in ORC (β = 0.266) and NEG (β = -0.235). While BSM exposure did not significantly predict infant temperament, it may mitigate risks associated with antenatal depression. BSM-exposed infants displayed temperamental characteristics on par with typical pregnancies, supporting the safety of BSM treatment for antenatal depression.

Exploring the impact of antenatal micronutrients used as a treatment for maternal depression on infant temperament in the first year of life

Campbell SA, Dys SP, Henderson JMT, Bradley HA, Rucklidge JJ. Front Nutr. 2024 Apr 22;11:1307701.

Effect of antenatal micronutrient or antidepressant exposure on Brazelton neonatal behavioral assessment scale (NBAS) performance within one-month of birth

Abstract

Background: Antenatal depression is a risk factor for poor infant outcomes. Broad-spectrum-micronutrients (vitamins and minerals) have shown efficacy in treating psychiatric symptoms in non-pregnant populations and are associated with reduced incidence of adverse birth outcomes, and improvements in neonatal development. We investigated the effects of treatment of antenatal depression with micronutrients above the Recommended Dietary Allowance on infant development compared to treatment with antidepressant medications and controls.

Method: One-hundred-and-three infants were assessed using the Brazelton Neonatal Behavioral Assessment Scale (NBAS) within 28 days of birth: 37 exposed to micronutrients in-utero (50-182 days exposure), 18 to antidepressants in-utero (exposure for full gestation), and 48 controls whose mothers received neither treatment nor experienced depressive symptoms.

Results: Controlling for gestational age and parity, there were significant group differences on habituation, orientation, motor, state regulation, autonomic stability and reflexes (p < .05). Micronutrient-exposed performed better than antidepressant-exposed and controls on habituation, motor and autonomic stability (p < .05), effect sizes ranged 1.0-1.7 and 0.5-1.0, respectively. Antidepressant-exposed performed significantly worse on orientation and reflexes compared to micronutrient-exposed and controls. Micronutrient-exposed had significantly better state regulation compared to antidepressant-exposed. There was an association between micronutrient exposure length and better habituation (r = 0.41, p = .028). Micronutrient exposure was generally identified as a stronger predictor of neonatal performance over maternal depression, social adversity, gestational age and infant sex.

Conclusion: In-utero micronutrient exposure appears to mitigate risks of depression on infant outcomes showing positive effects on infant behavior, on par with or better than typical pregnancies and superior to antidepressants. Limitations include differential exposure to micronutrients/antidepressants and lack of group blinding.

Effect of antenatal micronutrient or antidepressant exposure on Brazelton neonatal behavioral assessment scale (NBAS) performance within one-month of birth

Campbell SA, Bradley HA, Mulder RT, Henderson JMT, Dixon L, Haslett LC, Rucklidge JJ. Effect of antenatal micronutrient or antidepressant exposure on Brazelton neonatal behavioral assessment scale (NBAS) performance within one-month of birth. Early Hum Dev. 2024 Mar;190:105948.

Efficacy and safety of a vitamin-mineral intervention for symptoms of anxiety and depression in adults: A randomised placebo-controlled trial "NoMAD"

Abstract

Background: Anxiety and depression are increasingly burdening society. We investigated whether micronutrients (vitamins and minerals), improve anxiety and depression symptoms in an adult community setting.

Methods: Participants (n = 150) describing functionally-impairing symptoms of anxiety/depression randomly received micronutrients or placebo for 10 weeks. Primary outcome measures were Patient Health Questionnaire-9 (PHQ-9), Generalised Anxiety Disorder Scale-7 (GAD-7), and Clinical Global Impression-Improvement scale (CGII). They were monitored online with regular phone contact with a clinical psychologist.

Results: Linear mixed-effects modelling showed significant improvements in both groups, with the micronutrient group improving significantly more quickly on both the PHQ-9 (t = -2.17, p = 0.03) and the GAD-7 (t = -2.23, p = 0.03). Subsequent models with covariates showed that participant characteristics moderated time-by-group interactions; micronutrients provided fastest improvement relative to placebo for younger participants, those from lower socioeconomic groups and those who had previously tried psychiatric medication. On the CGII, there were no group differences at end-point ((F1,148) = 1.36, p = 0.25, d = 0.19, 95 % CI [-0.13 to 0.51]), with 49 % of the micronutrient and 44 % of the placebo groups being identified responders. Participants on micronutrients had significantly increased bowel motions compared with placebo. There was no increased suicidal ideation, no serious adverse events and the blind was adequately maintained. Drop out was low at 8.7 %.

Limitations: The improvement under placebo and lack of formal diagnoses limit generalizability.

Conclusions: Despite limited clinician contact, all participants improved significantly, though improvements were faster with micronutrients. Participants in some subgroups demonstrated a lower response to placebo, identifying where micronutrients may offer greatest potential as an intervention.

Journal of Affective Disorders

Efficacy and safety of a vitamin-mineral intervention for symptoms of anxiety and depression in adults: A randomised placebo-controlled trial “NoMAD”

Blampied FM, Tylianakis JM, Bell C, Gilbert C, Rucklidge JJ. Efficacy and safety of a vitamin-mineral intervention for symptoms of anxiety and depression in adults: A randomised placebo-controlled trial "NoMAD". J Affect Disord. 2023 May 31:S0165-0327(23)00718-8.

Non-pharmacological interventions for attention-deficit hyperactivity disorder in children and adolescents

Conclusions

Multinutrients combining 4 or more ingredients, mindfulness, and polyunsaturated fatty acids showed replicated, consistent moderate effects and can be encouraged as secondary treatments in combination with primary treatments or if a primary treatment is not a fit for the participant and their family.

Summary

Attention-deficit hyperactivity disorder (ADHD) affects approximately 5% of children and adolescents globally and
is associated with negative life outcomes and socioeconomic costs. First-generation ADHD treatments were
predominantly pharmacological; however, increased understanding of biological, psychological, and environmental
factors contributing to ADHD has expanded non-pharmacological treatment possibilities. This Review provides
an updated evaluation of the efficacy and safety of non-pharmacological treatments for paediatric ADHD,
discussing the quality and level of evidence for nine intervention categories. Unlike medication, no
non-pharmacological treatments showed a consistent strong effect on ADHD symptoms. When considering broad
outcomes (eg, impairment, caregiver stress, and behavioural improvement), multicomponent (cognitive)
behaviour therapy joined medication as a primary ADHD treatment. With respect to secondary treatments,
polyunsaturated fatty acids showed a consistent modest effect on ADHD symptoms when taken for at least
3 months. Additionally, mindfulness and multinutrient supplementation with four or more ingredients showed
modest efficacy on non-symptom outcomes. All other non-pharmacological treatments were safe; clinicians might
tolerate their use but should educate families of childrenand adolescents with ADHD on the disadvantages,
including costs, burden to the service user, absence of proven efficacy relative to other treatments, and delay of
proven treatment.

Non-pharmacological interventions for attention-deficit hyperactivity disorder in children and adolescents

Sibley MH, Bruton AM, Zhao X, Johnstone JM, Mitchell J, Hatsu I, Arnold LE, Basu HH, Levy L, Vyas P, Macphee F, Gonzalez ES, Kelley M, Jusko ML, Bolden CR, Zulauf-McCurdy C, Manzano M, Torres G. Non-pharmacological interventions for attention-deficit hyperactivity disorder in children and adolescents. Lancet Child Adolesc Health. 2023 Mar 9:S2352-4642(22)00381-9.

Inflammation and Vitamin C in Women with Prenatal Depression and Anxiety: Effect of Multinutrient Supplementation.

Abstract

Elevated inflammation has been associated with adverse mood states, such as depression and anxiety, and antioxidant nutrients, such as vitamin C, have been associated with decreased inflammation and improved mood. In the current study comprising a cohort of pregnant women with depression and anxiety, we hypothesised that elevated inflammation would be associated with adverse mood states and inversely associated with vitamin C status and that multinutrient supplementation would optimise vitamin concentrations and attenuate inflammation. Sixty-one participants from the NUTRIMUM trial had blood samples collected between 12 and 24 weeks gestation (baseline) and following 12 weeks of daily supplementation with a multinutrient formula containing 600 mg of vitamin C or active placebo. The samples were analysed for inflammatory biomarkers (C-reactive protein (CRP) and cytokines) and vitamin C content and were related to scales of depression and anxiety. Positive correlations were observed between interleukin-6 (IL-6) and all of the mood scales administered (p < 0.05), including the Edinburgh Postnatal Depression Scale, the Clinical Global Impressions-Severity Scale, the Montgomery and Åsberg Depression Rating Scale, the Depression Anxiety Stress Scale 21, and the Generalized Anxiety Disorder-7 (GAD-7). CRP correlated weakly with GAD-7 (p = 0.05). There was an inverse correlation between CRP and the vitamin C status of the cohort (p = 0.045), although there was no association of the latter with the mood scales (p > 0.05). Supplementation with the multinutrient formula resulted in a significant increase in the vitamin C status of the cohort (p = 0.007) but did not affect the inflammatory biomarker concentrations (p > 0.05). In conclusion, greater systemic inflammation was associated with worse mood states; however, 12-week multinutrient supplementation did not alter inflammatory biomarker concentrations. Nevertheless, the vitamin C status of the cohort was improved with supplementation, which may aid pregnancy and infant outcomes.

Inflammation and Vitamin C in Women with Prenatal Depression and Anxiety: Effect of Multinutrient Supplementation.

Carr AC, Bradley HA, Vlasiuk E, Pierard H, Beddow J, Rucklidge JJ. Inflammation and Vitamin C in Women with Prenatal Depression and Anxiety: Effect of Multinutrient Supplementation. Antioxidants (Basel). 2023 Apr 17;12(4):941.

Diet Quality as a Moderator of Response to Multinutrients for ADHD and Emotional Dysregulation: The MADDY RCT.

Abstract

Objectives

The Micronutrients for ADHD in Youth (MADDY) study was an 8-week double-blind RCT of broad spectrum multinutrients (BSMN) for ADHD with emotional dysregulation in children ages 6–12. Primary outcome Clinical Global Impressions-Improvement (CGI-I) showed 3 times as many responders with BSMN (54%) as placebo (18%). Since diet is the primary source of nutrients intake, and diet quality corresponds with nutritional outcomes, this study seeks to determine the role of baseline diet quality as a moderator of treatment response to test the hypothesis that those with poor diet quality should benefit more.

Methods

124 children (69 BSMN, 55 placebo) in the intent-to-treat analysis had diet quality assessed by Healthy Eating Index-2015 (HEI-2015) component and total scores from the VioscreenTM FFQ. Primary outcome was odds of treatment response, defined by a rating of 1 or 2 (very much or much improved) on CGI-I at week 8. Sensitivity analysis used CGI-I at week 8 as a dimensional outcome (from 1 = very much improved to 7 = very much worse). Logistic regressions were conducted for the primary analysis and linear regressions for the sensitivity analysis, with HEI scores entered as potential moderators.

Results

Total HEI-2015 score did not moderate treatment response [odds ratio = 1.00 (95% CI: 0.90,1.10), p = 0.994] or improvement [β= −0.01 (95% CI: −0.06,0.04), p = 0.655]. HEI component scores also did not moderate treatment response, though total vegetable intake moderated level of improvement [β= −0.48 (95% CI: −0.82, −0.13), p = 0.007]: those with higher vegetable intake showed greater improvement with BSMN but not with placebo.

Conclusions

BSMN may benefit children with ADHD and irritability regardless of diet quality. The finding that higher baseline vegetable intake possibly predisposes to improvement with BSMN is puzzling and worth further exploration of potential mechanisms such that a higher vegetable intake may promote the absorption or utilization of the multinutrients.

Diet Quality as a Moderator of Response to Multinutrients for ADHD and Emotional Dysregulation: The MADDY RCT.

Robinette L, Hatsu I, Johnstone J, Leung B, Arnold LE. Diet Quality as a Moderator of Response to Multinutrients for ADHD and Emotional Dysregulation: The MADDY RCT. Curr Dev Nutr. 2022 Jun 14;6(Suppl 1):395.

Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youth: A Placebo-Controlled Randomized Clinical Trial

Abstract

Objective: To evaluate whether micronutrients (vitamins/minerals) benefit attention-deficit/hyperactivity disorder (ADHD) and irritability in a North American pediatric sample.

Method: A three-site 8-week placebo-controlled randomized clinical trial of micronutrients was conducted in unmedicated children ages 6-12 with ADHD and at least one 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 (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<0.001). CASI-5 composite scores improved significantly for both groups (p<0.01) 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. But the between group difference was not significant (mean change = -0.02; 97.5% CI: -0.16, 0.12, ES = 0.07, p=0.70). The micronutrient group grew six millimeters more than the placebo group (p=0.002). No serious adverse events nor 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 adhered to the number of capsules prescribed. This RCT replicates safety and efficacy reported for ADHD in two 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.

Journal of the American Academy of Child & Adolescent Psychiatry

Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youth: A Placebo-Controlled Randomized Clinical Trial

Johnstone JM, Hatsu I, Tost G, Srikanth P, Eiterman LP, Bruton A, Ast HK, Robinette LM, Stern MM, Millington EG, Gracious B, Hughes AJ, Leung BM, Arnold LE. Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youth: A Placebo-Controlled Randomized Clinical Trial. J Am Acad Child Adolesc Psychiatry. 2021 Jul 21:S0890-8567(21)00473-1.

Paediatric adverse event rating scale: a measure of safety or efficacy? Novel analysis from the MADDY study

ABSTRACT
Objective: The Pediatric Adverse Event Rating Scale (PAERS) measured adverse events of children
aged 6–12 years with ADHD and emotional dysregulation in the Micronutrients for ADHD in Youth
(MADDY) study, an eight week multi-site randomized clinical trial of a broad-spectrum multinutrient
treatment. Treatment sensitivity of the PAERS was assessed by calculating the treatment difference in
change of the item scores from baseline to end of the RCT.

Methods: Principal component analysis retained 14 “adverse events” (out of 43 in the PAERS) that
reflected ADHD symptoms and emotional dysregulation and was used to group the variables of interest.
A combined score ranging from 0 to 5 was created based on symptom presence, functional
impairment, and severity. Mean score change was calculated from baseline to week 8 by treatment
(multinutrient vs placebo) with intention-to-treat and per-protocol samples. The study has been registered
on clinicaltrials.gov as Micronutrients for ADHD in Youth (MADDY) Study, trial registration #
NCT03252522 (https://clinicaltrials.gov/ct2/show/NCT03252522).

Results: The 126 children in the ITT sample had a mean age of 9.8 (SD = 1.7), with majority (73%)
male, and 72% diagnosed with ADHD prior to the study screening. Baseline presence of PAERS symptoms
was similar between treatment groups: the highest proportion was ADHD symptoms, followed
by Irritable symptoms. The micronutrient group showed a greater decrease (improvement) in the
mean anxiety combined score than the placebo group with a between-group difference in change of
- 0.36 (95% CI: - 0.67, - 0.04; p¼.03) with ITT data and - 0.48 (95% CI: - 0.81, - 0.15; p = .005) with
per-protocol (n = 93) data.

Conclusion: The multinutrient supplement did not result in more adverse events than placebo, suggesting
it is a safe intervention. In addition to assessing actual adverse events, the PAERS may be a
useful adjunct outcome measure for ADHD behaviors.

CMRO

Paediatric adverse event rating scale: a measure of safety or efficacy? Novel analysis from the MADDY study

Brenda M. Y. Leung, Priya Srikanth, Barbara Gracious, Irene E. Hatsu, Gabriella Tost, Valerie Conrad, Jeanette M. Johnstone & L. Eugene Arnold (2022) Paediatric adverse event rating scale: a measure of safety or efficacy? Novel analysis from the MADDY study, Current Medical Research and Opinion, 2022 Sep;38:9, 1595-1602.

Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce

The 'Micronutrient Formula' rated by this international taskforce was Daily Essential Nutrients, and was given an 'Evidence Grade' of 'A', due to a statistically significant meta-analysis (k = 2, n = 173) with statistically significant RCTs in adult and child samples. They gave the following supporting statements for Daily Essential Nutrients:

  • Meta-analytic level results have shown supportive evidence for efficacy in ADHD as a monotherapy

  • More replicated evidence required (in both adults and children)

  • This particular micronutrient formula’s efficacy cannot necessarily be extended to other multi-nutrient formulas

  • Dosing may need to be supervised (and titrated) via a health profession

  • Cost and compliance may be an issue due to a recommended dosage of 8–12 capsules per day

  • Acceptable safety data

Abstract

Objectives: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations.

Methods: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed.

Conclusions: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.

Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce

Sarris J, Ravindran A, Yatham LN, Marx W, Rucklidge JJ, McIntyre RS, Akhondzadeh S, Benedetti F, Caneo C, Cramer H, Cribb L, de Manincor M, Dean O, Deslandes AC, Freeman MP, Gangadhar B, Harvey BH, Kasper S, Lake J, Lopresti A, Lu L, Metri NJ, Mischoulon D, Ng CH, Nishi D, Rahimi R, Seedat S, Sinclair J, Su KP, Zhang ZJ, Berk M. Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce. World J Biol Psychiatry. 2022 Jul;23(6):424-455.

Parents' priorities and preferences for treatment of children with ADHD: Qualitative inquiry in the MADDY study

Abstract

Background: Parents' lived experiences of having a child with ADHD may shape their decision making regarding ADHD treatment options for their child. The aim of this study was to explore parents' experiences of living with a child with ADHD in the family and how their experiences influence their perspectives on treatment preferences and priorities.

Methods: A phenomenological qualitative design was used. Semistructured interviews were conducted with parents of children with ADHD who were enrolled in a multisite randomized controlled trial. Interviews were transcribed verbatim, and transcripts at each site were double coded. Initial codes were derived directly from the text. Qualitative data were analysed with an inductive approach.

Results: Twenty-three parents were interviewed: eight from Alberta, Canada; eight from Portland, Oregon, USA; and seven from Columbus, Ohio, USA. Among the parents, 69% were married, 86% completed college education and 52% reported household income over $80,000. Among the children, the mean age was 9.6 years (SD = 1.8 years), 78% were boys and 48% were never medicated for their ADHD. Two major themes emerged from the analysis. Theme 1 was 'impact of ADHD on families within and outside the home' with the following subthemes: 'reconfiguring the home life', 'trial-and-error of accommodations at school' and 'responding to social pressures to fit in'. Theme 2 was 'enabling appropriate and accessible treatments for families' with the following subthemes: 'finding the "right fit" with professionals and treatments' and 'factors influencing inequitable access to treatments'.

Conclusions: Parents described shared experiences and identified similar barriers, preferences and priorities for ADHD treatments regardless of demographic differences by site. Families desired access to family-centred, multimodal approaches to ADHD treatment. Further research is needed to identify the specific structural changes to healthcare, services and policies that will better support this approach.

Parents' priorities and preferences for treatment of children with ADHD: Qualitative inquiry in the MADDY study

Lu SV, Leung BMY, Bruton AM, Millington E, Alexander E, Camden K, Hatsu I, Johnstone JM, Arnold LE. Parents' priorities and preferences for treatment of children with ADHD: Qualitative inquiry in the MADDY study. Child Care Health Dev. 2022 Sep;48(5):852-861.

Do Changes in Blood Nutrient Levels Mediate Treatment Response in Children and Adults With ADHD Consuming a Vitamin-Mineral Supplement?

Abstract

Objective: We investigated whether changes in serum nutrient levels mediate clinical response to a micronutrient intervention for ADHD. Method: Data were compiled from two ADHD trials (8-10 weeks), one in adults (n = 53) and one in children (n = 38). Seven outcomes included change in ADHD symptoms, mood, overall functioning (all clinician-rated) as well as response status. Change in serum/plasma nutrient levels (vitamins B12 and D, folate, ferritin, iron, zinc, and copper) were considered putative mediators. Results: A decrease in ferritin and an increase in copper were weakly associated with greater likelihood of being identified as an ADHD responder; none of the other nutrient biomarkers served as mediators. Conclusion: Further research looking at nutrients more broadly from other tissues are required to confirm these initial observations of the limited value of nutrient levels in deciphering mechanism of action. Monitoring these biomarkers on their own is unlikely helpful in understanding clinical response to a broad-spectrum micronutrient approach.

Do Changes in Blood Nutrient Levels Mediate Treatment Response in Children and Adults With ADHD Consuming a Vitamin-Mineral Supplement?

Rucklidge JJ, Eggleston MJF, Boggis A, Darling K, Gorman B, Frampton CM. J Atten Disord. 2021 Jun;25(8):1107-1119. Epub 2019 Nov 9.

Multinutrients for the Treatment of Psychiatric Symptoms in Clinical Samples: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

This systematic review and meta-analysis focused on randomized controlled trials (RCT) of multinutrients consisting of at least four vitamins and/or minerals as interventions for participants with psychiatric symptoms. A systematic search identified 16 RCTs that fit the inclusion criteria (n = 1719 participants) in six psychiatric categories: depression, post-disaster stress, antisocial behavior, behavioral deficits in dementia, attention-deficit/hyperactivity disorder, and autism. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to rate the evidence base. Significant clinical benefit was assessed using minimal clinically important differences (MIDs). Due to heterogeneity in participants, multinutrient formulas, outcome measures, and absence of complete data, only the Attention-Deficit/Hyperactivity Disorder (ADHD) category was eligible for meta-analyses. In ADHD populations, statistically and clinically significant improvements were found in global functioning, Mean Difference (MD) -3.3, p = 0.001, MID -3.26; Standardized Mean Difference (SMD) -0.49 p = 0.001 MD -0.5), clinician ratings of global improvement (MD -0.58, p = 0.001, MID -0.5) and ADHD improvement (MD -0.54, p = 0.002, MID -0.5), and clinician (but not observer) measures of ADHD inattentive symptoms (MD -1.53, p = 0.05, MID -0.5). Narrative synthesis also revealed a pattern of benefit for global measures of improvement, for example: in autism, and in participants with behavioral deficits in dementia. Post-natural disaster anxiety and the number of violent incidents in prison populations also improved. Broad-spectrum formulas (vitamins + minerals) demonstrated more robust effects than formulas with fewer ingredients. This review highlights the need for robust methodology-RCTs that report full data, including means and standard deviations for all outcomes-in order to further elucidate the effects of multinutrients for psychiatric symptoms.

Multinutrients for the Treatment of Psychiatric Symptoms in Clinical Samples: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Jeanette M Johnstone, Andrew Hughes, Joshua Z Goldenberg, Amy R Romijn, Julia J Rucklidge. Nutrients. 2020 Nov 4;12(11):3394.

Resting-state networks and neurometabolites in children with ADHD after 10 weeks of treatment with micronutrients: results of a randomised placebo-controlled trial

Abstract

Children with attention-deficit/hyperactivity disorder (ADHD) show significant abnormalities on MR imaging in network communication and connectivity. The prefrontal-striatal-cerebella circuitry, involved in attention is particularly disrupted. Neurometabolites, the biochemical structures that support neurological structural integrity, particularly in the prefrontal cortex and striatum are associated with symptoms. This study aimed to explore changes in neurometabolite levels through treatment with vitamins and minerals (micronutrients), hypothesising that treatment would impact neural circuitry and correspond to a reduction in symptoms. Twenty-seven non-medicated children (M = 10.75 years) with DSM5 diagnosed ADHD were randomised to receive daily micronutrients or placebo for 10 weeks. Main outcome measures included the Clinical Global Impression-Improvement Scale and ADHD-RS-IV Clinician Ratings of ADHD symptoms. Magnetic resonance spectroscopy of the bilateral pre-frontal cortex and bilateral striatum, resting state fMRI and structural images were acquired 1 week pre-treatment, and in the last week of intervention. Results did not show any significant differences in the measured brain metrics and the levels of neurometabolites between treatment and placebo groups after ten weeks of treatment with micronutrients. In the treatment group there was a trend for: decreased choline in the striatum; decreased glutamate in the prefrontal cortex; increased grey matter in the anterior thalamus; increased white matter in the fornix and improved network integrity of the default mode network, dorsal attention network and frontal executive network. The small sample size of the current study limits results, future studies with higher power are warranted to explore any association between micronutrient treatment and neurological changes.

Resting-state networks and neurometabolites in children with ADHD after 10 weeks of treatment with micronutrients: results of a randomised placebo-controlled trial

Borlase N, Melzer TR, Eggleston MJF, Darling KA, Rucklidge JJ. Nutr Neurosci. 2020 Nov;23(11):876-886.

Novel Mineral–Vitamin Treatment for Reduction in Cigarette Smoking: A Fully Blinded Randomized Placebo-Controlled Trial

Introduction

Many smokers do not achieve abstinence using current smoking cessation options. This randomized controlled trial (RCT) investigated a novel nutritional supplement to assist with quitting smoking.

Methods

Following a baseline phase where cigarettes per day and nicotine dependence were measured, participants (n = 107) were randomized to placebo (n = 50) or micronutrient conditions (n = 57). A 4-week pre-quit phase permitted titration up to 12 capsules/day. During the quit phase (12 weeks), participants were registered with a public Quitline while consuming micronutrients or placebo. Carbon monoxide levels were measured to confirm smoking cessation.

Results

Forty-five (42%) participants completed the trial. Treatment and placebo groups did not differ on the primary outcome of continuous abstinence at 12 weeks using intention-to-treat analysis; however, 28% of the micronutrient-treated group had quit versus 18% for placebo (odds ratio [OR] = 1.78, 95% confidence interval [CI] = 0.71 to 4.48), with number needed to treat = 10. Comparison of cigarette consumption (cigarettes per day) between micronutrient and placebo groups showed that those taking micronutrients reported reduced consumption throughout the trial, notably at pre-quit weeks 1 and 4, and at quit phase week 4. There were no serious adverse events, blinding was successful, and there were no substantive group differences in side effects or dropout rate.

Conclusion

This is the first RCT investigating the impact of micronutrients on smoking reduction, finding that micronutrients reduced harm through reduction in number of cigarettes smoked relative to placebo. The small sample and high dropout rate limit confidence in the conclusions and generalizability of the study; however, assessed by number needed to treat, micronutrients are comparable to other smoking cessation treatments but with fewer side effects. Future research using larger and longer trials including cost-effectiveness and biomarker measures is encouraged.

Implications

Micronutrients are being increasingly studied for the treatment of psychiatric conditions, but direct application of micronutrients as a treatment for addictions is novel. There is extensive evidence that micronutrients alleviate stress. Given that tobacco smoking is often used to cope with stress, taking micronutrients may moderate the stress of withdrawal and increase the chance of a successful quit attempt. This study is the first known RCT to investigate the use of micronutrients to support smoking cessation. Treatments that are safe, effective, relatively inexpensive, and readily available are needed and micronutrient supplements offer one such possible alternative.

Novel Mineral–Vitamin Treatment for Reduction in Cigarette Smoking: A Fully Blinded Randomized Placebo-Controlled Trial

Phillipa K Reihana, Neville M Blampied, Julia J Rucklidge. Nicotine Tob Res. 2019 Oct 26;21(11):1496-1505.

Human gut microbiome changes during a 10 week Randomised Control Trial for micronutrient supplementation in children with attention deficit hyperactivity disorder

Abstract

It has been widely hypothesized that both diet and the microbiome play a role in the regulation of attention-deficit/hyperactivity disorder (ADHD) behaviour. However, there has been very limited scientific investigation into the potential biological connection. We performed a 10-week pilot study investigating the effects of a broad spectrum micronutrient administration on faecal microbiome content, using 16S rRNA gene sequencing.

The study consisted of 17 children (seven in the placebo and ten in the treatment group) between the ages of seven and 12 years, who were diagnosed with ADHD. We found that micronutrient treatment did not drive large-scale changes in composition or structure of the microbiome.

However, observed OTUs significantly increased in the treatment group, and showed no mean change in the placebo group. The differential abundance and relative frequency of Actinobacteria significantly decreased post- micronutrient treatment, and this was largely attributed to species from the genus Bifidobacterium. This was compensated by an increase in the relative frequency of species from the genus Collinsella.

Further research is required to establish the role that Bifidobacterium contribute towards neuropsychiatric disorders; however, these findings suggest that micronutrient administration could be used as a safe, therapeutic method to modulate Bifidobacterium abundance, which could have potential implications for modulating and regulating ADHD behaviour.

Our pilot study provides an initial observation into this area of research, and highlights an interesting avenue for further investigation in a larger cohort. Furthermore, these novel results provide a basis for future research on the biological connection between ADHD, diet and the microbiome.

Human gut microbiome changes during a 10 week Randomised Control Trial for micronutrient supplementation in children with attention deficit hyperactivity disorder

Aaron J. Stevens, Rachel V. Purcell, Kathryn A. Darling, Matthew J. F. Eggleston, Martin A. Kennedy & Julia J. Rucklidge. Scientific Reportsvolume 9, Article number: 10128, 2019

An Observational Preliminary Study on the Safety of Long-Term Consumption of Micronutrients for the Treatment of Psychiatric Symptoms

Abstract

Objectives: There is an increasing body of literature documenting the efficacy of micronutrients (vitamins and minerals) interventions for the treatment of psychiatric problems in the short term; however, long-term safety is largely unexplored. The goal of this observational study was to investigate the safety of two commercially available broad-spectrum micronutrient formulas (EMPowerplus and Daily Essential Nutrients) given at doses above the Recommended Dietary Allowances for the long-term treatment of individuals with psychiatric symptoms. 

Design: Participants on long-term treatment with micronutrients (medication-free) for psychiatric problems (attention-deficit hyperactivity disorder [ADHD, n = 21], anxiety/depression [n = 13]) were identified from ongoing research studies and the community through purchasing records. Seventeen children and 17 adults had blood tests to assess their full blood count, coagulation profile, liver and kidney function, fasting glucose, iron studies, key nutrients, and prolactin. Questionnaires assessed psychological/psychiatric functioning. Seventeen of the participants had completed the same measures pretreatment. 

Results: The average length of consuming micronutrients was 2.66 years (standard deviation = 2.86). Excluding B12 (which was elevated for almost all participants), 94.6% of all blood test results were within the test reference ranges. One participant was diagnosed with hemochromatosis based on iron studies. No other clinically relevant adverse changes in blood results were identified pre- and post-treatment. No clinically significant adverse effects were reported. Post-treatment psychometrics identified that 85% of the participants were in nonclinical ranges for measures of ADHD, depression, anxiety, and stress. 

Conclusions: We report preliminary evidence for the safety of long-term commercially available micronutrients, although questions remain. Overall, the substantial psychiatric benefits observed appear to outweigh the minimal observed risks in these participants. Screening for potential medical problems is recommended before initiating treatment. Long-term pharmacovigilance monitoring is required to ascertain any rare but significant adverse events.

An Observational Preliminary Study on the Safety of Long-Term Consumption of Micronutrients for the Treatment of Psychiatric Symptoms

Julia J. Rucklidge, PhD, Matthew J. F. Eggleston, MD, Breanne Ealam, BA (Hons), Ben Beaglehole, MD, and Roger T. Mulder, MD. J Altern Complement Med. 2019 Jun;25(6):613-622. doi: 10.1089/acm.2018.0352. Epub 2019 May 13.

Methylomic changes in response to micronutrient supplementation and MTHFR genotype.

Abstract

Exposure times and dosage required for dietary components to modify DNA methylation patterns are largely unknown.

Aim: This exploratory research represents the first genome-wide analysis of DNA methylation changes during a randomized-controlled-trial (RCT) for dietary supplementation with broad spectrum vitamins, minerals and amino acids in humans.

Methods: Genome-wide changes in methylation from paired, peripheral blood samples were assessed using the Infinium Methylation EPIC 850 K array.

Results: Methylation increased at 84% of the most significant differentially methylated CpGs; however, none showed significance after adjustment for genome-wide testing.

Conclusion: Micronutrient supplementation is unlikely to have a substantial biological effect on DNA methylation over 10 weeks; however, the trend toward hypermethylation that we observed is likely to become more marked with longer exposure periods.

Methylomic changes in response to micronutrient supplementation and MTHFR genotype.

Stevens AJ, Rucklidge JJ, Darling KA, Eggleston MJ, Pearson JF, Kennedy MA. Epigenomics. 2018 Sep 4;10(09):1201-14.

Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: a fully blinded, randomized, placebo-controlled trial.

BACKGROUND:
Evaluation of broad-spectrum micronutrient (vitamins and minerals) treatment for childhood ADHD has been limited to open-label studies that highlight beneficial effects across many aspects of psychological functioning.

METHOD:
This is the first fully blinded randomized controlled trial of medication-free children (n = 93) with ADHD (7-12 years) assigned to either micronutrients (n = 47) or placebo (n = 46) in a 1:1 ratio, for 10 weeks. All children received standardized ADHD assessments. Data were collected from clinicians, parents, participants and teachers across a range of measures assessing ADHD symptoms, general functioning and impairment, mood, aggression and emotional regulation.

RESULTS:
Intent-to-treat analyses showed significant between-group differences favouring micronutrient treatment on the Clinical Global Impression-Improvement (ES = 0.46), with 47% of those on micronutrients identified as 'much' to 'very much' improved versus 28% on placebo. No group differences were identified on clinician, parent and teacher ratings of overall ADHD symptoms (ES ranged 0.03-0.17). However, according to clinicians, 32% of those on micronutrients versus 9% of those on placebo showed a clinically meaningful improvement on inattentive (OR = 4.9; 95% CI: 1.5-16.3), but no group differences on improvement in hyperactive-impulsive symptoms (OR = 1.0; 95% CI: 0.4-2.5). Based on clinician, parent and teacher report, those on micronutrients showed greater improvements in emotional regulation, aggression and general functioning compared to placebo (ES ranged 0.35-0.66). There were two dropouts per group, no group differences in adverse events and no serious adverse events identified. Blinding was successful with guessing no better than chance.

CONCLUSIONS:
Micronutrients improved overall function, reduced impairment and improved inattention, emotional regulation and aggression, but not hyperactive/impulsive symptoms, in this sample of children with ADHD. Although direct benefit for core ADHD symptoms was modest, with mixed findings across raters, the low rate of adverse effects and the benefits reported across multiple areas of functioning indicate micronutrients may be a favourable option for some children, particularly those with both ADHD and emotional dysregulation. Trial registered with the Australian New Zealand Clinical Trials Registry ACTRN12613000896774.

 

Journal of Child Psychology and Psychiatry

Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: a fully blinded, randomized, placebo-controlled trial.

Rucklidge JJ, Eggleston MJF, Johnstone JM, Darling K, Frampton CM. J Child Psychol Psychiatry. 2017 Oct 2.

†The micronutrient formulation studied was a pre-2013 version of Truehope EMPowerplus which was co-formulated by David Hardy and Anthony Stephan. Truehope EMPowerplus is a registered trademark of The Synergy Group of Canada Inc., which was co-founded by David Hardy and Anthony Stephan in 1999. David Hardy officially resigned as a shareholder of The Synergy Group of Canada Inc. and director of Truehope Nutritional Support Ltd. in 2013 to focus his efforts exclusively on Hardy Nutritionals®.