Clinical Studies | Attention Disorders


CLINICAL STUDY 1 — Attention-Deficit-Hyperactivity Disorder and Reward Deficiency Syndrome

—Blum K, Chen AL, Braverman ER, Comings DE, Chen TJ, Arcuri V, Blum SH, Downs BW, Waite RL, Notaro A, Lubar J, Williams L, Prihoda TJ, Palomo T, Oscar-Berman M. – Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC

Molecular genetic studies have identified several genes that may mediate susceptibility to attention deficit hyperactivity disorder (ADHD). A consensus of the literature suggests that when there is a dysfunction in the “brain reward cascade,” especially in the dopamine system, causing a low or hypo-dopaminergic trait, the brain may require dopamine for individuals to avoid unpleasant feelings. This high-risk genetic trait leads to multiple drug-seeking behaviors, because the drugs activate release of dopamine, which can diminish abnormal cravings. Moreover, this genetic trait is due in part to a form of a gene (DRD A1 allele) that prevents the expression of the normal laying down of dopamine receptors in brain reward sites. This gene, and others involved in neurophysiological processing of specific neurotransmitters, have been associated with deficient functions and predispose individuals to have a high risk for addictive, impulsive, and compulsive behavioral propensities. It has been proposed that genetic variants of dopaminergic genes and other “reward genes” are important common determinants of reward deficiency syndrome (RDS), which we hypothesize includes ADHD as a behavioral subtype. We further hypothesize that early diagnosis through genetic polymorphic identification in combination with DNA-based cusized nutraceutical administration to young children may attenuate behavioral symptoms associated with ADHD. Moreover, it is concluded that dopamine and serotonin releasers might be useful therapeutic adjuncts for the treatment of other RDS behavioral subtypes, including addictions. PMID: 19183781

CLINICAL STUDY 2 — Phenylethylaminergic Mechanisms in Attention-Deficit Disorder

—Baker GB, Bornstein RA, Rouget AC, Ashton SE, van Muyden JC, Coutts RT. – PMHAC Research Unit, University of Alberta, Edmonton, Canada

Urinary excretion (24-hr) of beta-phenylethylamine (PEA), phenylacetic acid (PAA), phenylalanine (PHE), and p-tyrosine (TYR), and plasma levels of PAA, PHE, and TYR were examined in 18 normal children and 26 children diagnosed as having attention-deficit hyperactivity disorder (ADHD). The results indicated that urinary excretion (expressed per g of creatinine) of free and total PEA was significantly lower in the ADHD patients, and plasma levels of PHE and TYR were also decreased in the ADHD subjects compared with the normal controls. PMID: 2001444

(phenylalanine is the precursor to tyrosine)

CLINICAL STUDY 3 — Imbalance of Plasma Amino Acids in Patients with Autism and Subjects with Attention Deficit/Hyperactivity Disorder

—Zavala M, Castejón HV, Ortega PA, Castejón OJ, Marcano de Hidalgo A, Montiel N. – Instituto de Investigaciones Biológicas, Facultad de Medicina, Universidad del Zulia. Maracaibo, Zulia, Venezuela

INTRODUCTION: Plasma and brain amino acids are influenced by dietary intake. Alterations of plasma amino acid concentrations have been reported in neuropsychiatric disorders. OBJECTIVE: To analyse the plasma amino acid values in subject diagnosed with autism, with attention deficit/hyperactivity disorder (ADHD), and healthy subjects as controls. PATIENTS AND METHODS: Forty subjects affected by autism, 11 with ADHD and 41 healthy subjects (age range 3 to 18 years old) were included in this study. Peripheral venous blood was obtained in fasting condition, collected in EDTA tubes and centrifuged. Plasma was de proteinised with sulfosalicylic acid. Amino acids were analysed by ion exchange liquid chromatography with an LKB amino acid analyser with sodium citrate elution system and ninhydrin reaction. Results were expressed as mmol/L. RESULTS AND CONCLUSIONS: In both disorders a diminution of phenylalanine and glutamine plasma concentrations was observed beside an increase of glycine. Lysine appeared increased only in autistic subjects. These alterations produce an imbalance with the rest of plasma amino acids competing at the brain blood barrier by the same transport system thus causing alterations in the metabolism and/or transport of amino acids to the brain, altering CNS functions. The phenylalanine decreasing, beside glycine increasing appears to support the hypothesis of a disorder in the inhibitory neurotransmission system, especially in ADHD. The diminution of phenylalanine and the increasing of lysine in autism are suggestive that these two amino acids are metabolically related. PMID: 11727202

CLINICAL STUDY 4 — Dopamine and the Regulation of Cognition and Attention

—Nieoullon A. – Neurobiology Unit at the CNRS, Université de La Méditerranée, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France

Dopamine (DA) acts as a key neurotransmitter in the brain. Numerous studies have shown its regulatory role for motor and limbic functions. However, in the early stages of Parkinson’s disease (PD), alterations of executive functions also suggest a role for DA in regulating cognitive functions. Some other diseases, which can also involve DA dysfunction, such as schizophrenia or attention deficit hyperactivity disorder (ADHD) in children, as shown from the ameliorative action of dopaminergic antagonists and agonists, respectively, also show alteration of cognitive functions. Experimental studies showed that selective lesions of the dopaminergic neurons in rats or primates can actually provide cognitive deficits, especially when the mesocorticolimbic component of the dopaminergic class=”small-red-titles” systems is altered. Data from the experiments also showed significant alteration in attentional processes, thus raising the question of direct involvement of DA in regulating attention. Since the dopaminergic influence is mainly exerted over the frontal lobe and basal ganglia, it has been suggested that cognitive deficits express alteration in these subcortical brain structures closely linked to cortical areas, more than simple deficit in dopaminergic transmission. This point is still a matter of debate but, undoubtedly, DA acts as a powerful regulator of different aspects of cognitive brain functions. In this respect, normalizing DA transmission will contribute to improve the cognitive deficits not only related to neurologic or psychiatric diseases, but also in normal aging. Ontogenic and phylogenetic analysis of dopaminergic systems can provide evidences for a role of DA in the development of cognitive general capacities. DA can have a trophic action during maturation, which may influence the later cortical specification, particularly of pre-frontal cortical areas. Moreover, the characteristic extension of the dopaminergic cortical innervation in the rostro-caudal direction during the last stages of evolution in mammals can also be related to the appearance of progressively more developed cognitive capacities. Such an extension of cortical DA innervation could be related to increase processing of cortical information through basal ganglia, either during the course of evolution or development. DA has thus to be considered as a key neuroregulator which contributes to behavioral adaptation and to anticipatory processes necessary for preparing voluntary action consequent upon intention. All together, it can be suggested that a correlation exists between DA innervation and expression of cognitive capacities. Altering the dopaminergic transmission could, therefore, contribute to cognitive impairment. PMID: 12126656

CLINICAL STUDY 5 — Neurochemical and Neurotransmitter Studies in Patients with Learning Disabilities

—Matsuishi T, Yamashita Y. – Department of Pediatrics and Child Health, Kurume University, School of Medicine, Fukuoka

To clarify the pathophysiology of learning disability (LD), we measured the urinary levels of 3-methoxy-4-hydroxyphenyl glycol (MHPG), and phenylethylamine (PEA) in urine samples collected in a 24 hour period. Findings were compared with those obtained in age-matched controls and diseased controls including patients with attention deficit-hyperactivity disorder (ADHD), infantile autism, and mental retardation. The mean urinary level of MHPG in LD (n = 6) were not significantly different from those in ADHD (n = 16), mental retardation (n = 4), infantile autism (n = 5), and the controls (n = 6), while the mean urinary levels of PEA were significantly lower in LD (n = 6, 91 +/- 17.3 micrograms/mg) and in ADHD (n = 5, 65 +/- 53.6 micrograms/mg) as compared to age-matched controls (n = 3, 340 +/- 264.5 micrograms/mg) ANOVA, (p < 0.05). PEA is considered to play an important role for the pathogenesis of LD and ADHD. PMID: 10355264

CLINICAL STUDY 6 — GABA and GABA Receptors in the Central Nervous System and other Organs

—Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H. – Anay Department, Osaka Medical College, Takatsuki, Japan

Gamma-aminobutyrate acid (GABA) is a major inhibitory neurotransmitter in the adult mammalian brain. GABA is also considered to be a multifunctional molecule that has different situational functions in the central nervous system, the peripheral nervous system, and in some nonneuronal tissues. GABA is synthesized primarily from glutamate by glutamate decarboxylase (GAD), but alternative pathways may be important under certain situations. Two types of GAD appear to have significant physiological roles. GABA functions appear to be triggered by binding of GABA to its ionotropic receptors, GABA (A) and GABA (C), which are ligand-gated chloride channels, and its metabotropic receptor, GABA (B). The physiological, pharmacological, and molecular characteristics of GABA (A) receptors are well documented, and diversity in the pharmacologic properties of the receptor subtypes is important clinically. In addition to its role in neural development, GABA appears to be involved in a wide variety of physiological functions in tissues and organs outside the brain. PMID: 11837891

(l-glutamine is the precursor to gamma-aminobutyric acid GABA)

CLINICAL STUDY 7 — Can micronutrients improve neurocognitive functioning in adults with ADHD and severe mood dysregulation? A pilot study.

—Rucklidge, J.J., Taylor, M. R., Whitehead, K. A. (2011). Journal of Attention Disorders. 2011;15(1):79-91.

OBJECTIVES: Little research has investigated how micronutrients (minerals and vitamins) affect cognitive functioning, despite preliminary studies showing they may improve psychiatric functioning. INTERVENTION: This pilot study investigated the impact of a 36-ingredient micronutrient formula consisting mainly of vitamins and minerals on neurocognitive functioning in 14 adults with attention-deficit/hyperactivity disorder (ADHD) and severe mood dysregulation. DESIGN: The formula was consumed in an open-label trial over an 8-week period. OUTCOME MEASURES: The participants completed tests of memory (Wide Range Assessment of Memory and Learning) and executive functioning (Delis-Kaplan Executive Functioning System and Conners Continuous Performance Test) at baseline and at the end of the trial. A gender- and age-matched control group of 14 non-ADHD adults not taking the formula were assessed on the same tests 8 weeks apart in order to investigate the impact of practice on the results. RESULTS: There were no group differences in ethnicity, socio-economic status and estimated IQ. Significant improvement was observed in the ADHD group, but not the control group, across a range of verbal abilities including verbal learning, verbal cognitive flexibility and fluency, and verbal inhibition. These neurocognitive improvements were large and consistent with improved psychiatric functioning. No changes were noted above a practice effect in visual-spatial memory and there were no improvements noted in reaction time, working memory, or rapid naming for either groups. CONCLUSIONS: Although the pilot and open-label design of the study limits the generalizability of the results, it supports a growing body of literature recognizing the importance of nutrients for mental health and cognition. The results also provide evidence supporting the need for randomized clinical trials of micronutrients as well as other experimental studies in order to better assess whether improved neurocognitive functioning may contribute to improved psychiatric symptoms. PMID: 22112202

CLINICAL STUDY 8 — Micronutrients reduce stress and anxiety in adults with Attention-Deficit/Hyperactivity Disorder following a 7.1 earthquake

—Rucklidge, J. J., Johnstone, J., Harrison, R., 8 Boggis, A. (2011). Psychiatry Research, 189:281-87.

The role of good nutrition for resilience in the face of stress is a topic of interest, but difficult to study. A 7.1 earthquake took place in the midst of research on a micronutrient treatment for Attention-Deficit/Hyperactivity Disorder (ADHD), providing a unique opportunity to examine whether individuals with ADHD taking micronutrients demonstrated more emotional resilience post-earthquake than individuals with ADHD not taking micronutrients. Thirty-three adults with ADHD were assessed twice following the earthquake using a measure of depression, anxiety and stress also completed at some point pre-earthquake (baseline). Seventeen were not taking micronutrients at the time of the earthquake (control group), 16 were (micronutrient group). While there were no between-group differences one week post-quake (Time 1), at two weeks post-quake (Time 2), the micronutrient group reported significantly less anxiety and stress than the controls (effect size 0.69). These between group differences could not be explained by other variables, such as pre-earthquake measures of emotions, demographics, psychiatric status, and personal loss or damage following the earthquake. The results suggest that micronutrients may increase resilience to ongoing stress and anxiety associated with a highly stressful event in individuals with ADHD and are consistent with controlled studies showing benefit of micronutrients for mental health. PMID: 21802745

CLINICAL STUDY 9 — Moderators of treatment response in adults with ADHD treated with a vitamin-mineral supplement

—Rucklidge JJ., Johnstone J., Gorman B., Boggis A. and Frampton CA. Prog Neuro-Psychopharmacol Biol Psychiatry (2013).

BACKGROUND: To date there has been no research investigating moderators of response to micronutrient treatment of mental illness, specifically baseline nutrient levels. METHOD: We conducted analyses of data from a randomized placebo-controlled trial (RCT) of 80 adults (≥16years) with Attention-Deficit/Hyperactivity Disorder (ADHD), whereby participants were treated acutely (8weeks) with micronutrients or placebo followed by an open-label (OL) phase of 8weeks whereby all participants received micronutrients. To ensure that all participants had been exposed to the micronutrients for 8weeks, only those 64 who had adhered to the treatment protocol and completed 8weeks on nutrients were included in the data analysis: 34 from the group that had been randomized to the micronutrient arm, and 30 from the group that had been randomized to the placebo group and hence had only received nutrients in the OL phase. Six outcomes were examined: change in ADHD symptoms (self/clinician), ADHD responder, Clinical Global Impression-Improvement (CGI-I), change in mood, and change in Global Assessment of Functioning (GAF). Demographic, developmental and psychiatric history, current clinical characteristics, and baseline nutrient levels were all considered as putative predictors. RESULTS: There were significant changes in all outcome variables after 8weeks exposure to the micronutrients. Among the nutrients recorded at baseline, substantial deficiencies (27%) were only observed for vitamin D. However, other than an association showing that higher iron at baseline was correlated with higher baseline depression scores, baseline nutrient levels were not correlated with baseline psychiatric variables/current clinical characteristics. Regression analyses revealed that higher baseline ferritin and lower baseline copper and vitamin D levels were associated with a better response to treatment for some but not all outcomes. None of the other nutrient levels was found to be associated with outcome, including zinc, vitamin B12, iron, and folate. There were no childhood risk factors, demographic variables or clinical correlates that contraindicated micronutrient treatment; more severe symptoms at baseline and greater number of developmental risk factors predicted greater treatment response. CONCLUSIONS: Further research looking at nutrients more broadly is required to confirm these initial observations about ferritin, vitamin D and copper; however, the results suggest that serum nutrient levels have limited value for identifying who will respond to treatment. PMID: 24374068

CLINICAL STUDY 10 — Nutrient supplementation approaches in the treatment of ADHD

—Rucklidge, J. J., Johnstone, J., & Kaplan, B. J. (2009). Expert Review of Neurotherapeutics, 9(4): 461-476.

Attention-deficit/hyperactivity disorder (ADHD) is a chronic, debilitating psychiatric illness that often co-occurs with other common psychiatric problems. Although empirical evidence supports pharmacological and behavioral treatments, side effects, concerns regarding safety and fears about long-term use all contribute to families searching for alternative methods of treating the symptoms of ADHD. This review presents the published evidence on supplementation, including single ingredients (e.g., minerals, vitamins, amino acids and essential fatty acids), botanicals and multi-ingredient formulas in the treatment of ADHD symptoms. In most cases, evidence is sparse, mixed and lacking information. Of those supplements where we found published studies, the evidence is best for zinc (two positive randomized, controlled trials); there is mixed evidence for carnitine, pycnogenol and essential fatty acids, and more research is needed before drawing conclusions about vitamins, magnesium, iron, SAM-e, tryptophan and Ginkgo biloba with ginseng. To date, there is no evidence to support the use of St John’s wort, tyrosine or phenylalanine in the treatment of ADHD symptoms. Multi-ingredient approaches are an intriguing yet under-researched area; we discuss the benefits of this approach considering the heterogeneous nature of ADHD. PMID: 19344299

CLINICAL STUDY 11 — Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial

—Rucklidge JJ., Frampton CA., Gorman B., and Boggis A. The British journal of Psychiatry 1-10.doi: 10.1192/bjp. 113.132126.

BACKGROUND: The role of nutrition in the treatment of attention-deficit hyperactivity disorder (ADHD) is gaining international attention; however, treatments have generally focused only on diet restriction or supplementing with one nutrient at a time. AIMS: To investigate the efficacy and safety of a broad-based micronutrient formula consisting mainly of vitamins and minerals, without omega fatty acids, in the treatment of ADHD in adults. METHOD: This double-blind randomised controlled trial assigned 80 adults with ADHD in a 1:1 ratio to either micronutrients (n = 42) or placebo (n = 38) for 8 weeks (trial registered with the Australian New Zealand Clinical Trials Registry: ACTRN12609000308291). RESULTS: Intent-to-treat analyses showed significant between-group differences favouring active treatment on self- and observer- but not clinician-ADHD rating scales. However, clinicians rated those receiving micronutrients as more improved than those on placebo both globally and on ADHD symptoms. Post hoc analyses showed that for those with moderate/severe depression at baseline, there was a greater change in mood favouring active treatment over placebo. There were no group differences in adverse events. CONCLUSIONS: This study provides preliminary evidence of efficacy for micronutrients in the treatment of ADHD symptoms in adults, with a reassuring safety profile. PMID: 24482441

CLINICAL STUDY 12 — A possible biological mechanism for the B Vitamins altering behaviour in ADHD

—Shaw, I., Rucklidge, J. J., Hughes, R. N. (2010). Pharmaceutical Medicine, 24 (5): 1-6.

There is a growing body of recent evidence showing that micronutrients (combinations of minerals, vitamins and amino acids) improve the symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). Dopamine (DA) agonists, such as methylphenidate, have long been identified as effective in treating ADHD symptoms, by inhibiting DA transporter function. This paper explores the role that B vitamins might have in the treatment of ADHD symptoms by investigating the structural similarities between B vitamins and methylphenidate. We suggest that the presence of B vitamins and their postulated structure activity relationships (SARs) with DA may be responsible for the observed pharmacological effect. This pharmacological activity is likely to be via their competitive binding to the DAT dopamine binding site with a concomitant increase in synaptic DA concentration which in turn might activate the postsynaptic dopamine receptor and thus ameliorate the symptoms of ADHD. Further research is required to assess the validity of the intriguing possibility that B vitamins and methylphenidate share a common neurochemical mechanism of action. Source:

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