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      High-dose eicosapentaenoic acid (EPA) improves attention and vigilance in children and adolescents with attention deficit hyperactivity disorder (ADHD) and low endogenous EPA levels

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          Abstract

          No studies have examined the relationship between endogenous polyunsaturated fatty acids (PUFAs) levels and treatment response to PUFAs. We conducted a 12-week, double-blind, placebo-controlled trial comparing the effects of high-dose eicosapentaenoic acid (EPA, 1.2 g) and placebo on cognitive function (continuous performance test) in n= 92 youth (age 6–18-years-old) with Attention Deficit Hyperactivity Disorder (ADHD). Blood erythrocytes PUFAs were measured before and after treatment, to examine the effects of baseline endogenous EPA levels on treatment response and the effects of EPA treatment on PUFAs levels. Secondary measures included other ADHD symptoms, emotional symptoms, and levels of plasma high-sensitivity c-reactive protein (hs-CRP) and brain-derived neurotrophic factor (BDNF). Overall, EPA group improved more than placebo group on focused attention (variability, Effect size (ES) = 0.38, p = 0.041); moreover, within youth with the lowest baseline endogenous EPA levels, EPA group improved more than placebo group in another measure of focused attention (hit reaction time, HRT, ES = 0.89, p = 0.015) and in vigilance (HRT interstimulus interval changes, HRTISIC, ES = 0.83, p = 0.036). Interestingly, EPA group improved less than placebo group in impulsivity (commission errors), both overall and in youth with the highest baseline EPA levels, who also showed less improvement in other ADHD and emotional symptoms. EPA increased blood erythrocytes EPA by 1.6-fold but not DHA levels, and did not affect hs-CRP and BDNF plasma levels. In conclusion, EPA treatment improves cognitive symptoms in ADHD youth, especially if they have a low baseline endogenous EPA level, while youth with high EPA levels may be negatively affected by this treatment.

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          Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis

          Summary Background The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. Methods We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976. Findings 133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD −1·02, 95% CI −1·19 to −0·85 for amphetamines, −0·78, −0·93 to −0·62 for methylphenidate, −0·56, −0·66 to −0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD −0·82, 95% CI −1·16 to −0·48) and modafinil (−0·76, −1·15 to −0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD −0·79, 95% CI −0·99 to −0·58), methylphenidate (−0·49, −0·64 to −0·35), bupropion (−0·46, −0·85 to −0·07), and atomoxetine (−0·45, −0·58 to −0·32), but not modafinil (0·16, −0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36–3·89) and adults (3·26, 1·54–6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20–5·81); and atomoxetine (2·33, 1·28–4·25), methylphenidate (2·39, 1·40–4·08), and modafinil (4·01, 1·42–11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs −0·46 to −0·24) and adults (−0·94 to −0·29). We did not find sufficient data for the 26-week and 52-week timepoints. Interpretation Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs. Funding Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.
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            Distribution, interconversion, and dose response of n−3 fatty acids in humans

            n-3 Fatty acids have important visual, mental, and cardiovascular health benefits throughout the life cycle. Biodistribution, interconversion, and dose response data are reviewed herein to provide a basis for more rational n-3 dose selections. Docosahexaenoic acid (DHA) is the principal n-3 fatty acid in tissues and is particularly abundant in neural and retinal tissue. Limited storage of the n-3 fatty acids in adipose tissue suggests that a continued dietary supply is needed. A large proportion of dietary alpha-linolenic acid (ALA) is oxidized, and because of limited interconversion of n-3 fatty acids in humans, ALA supplementation does not result in appreciable accumulation of long-chain n-3 fatty acids in plasma. Eicosapentaenoic acid (EPA) but not DHA concentrations in plasma increase in response to dietary EPA. Dietary DHA results in a dose-dependent, saturable increase in plasma DHA concentrations and modest increases in EPA concentrations. Plasma DHA concentrations equilibrate in approximately 1 mo and then remain at steady state throughout supplementation. DHA doses of approximately 2 g/d result in a near maximal plasma response. Both dietary DHA and EPA reduce plasma arachidonic acid concentrations. Tissue contents of DHA and EPA also increase in response to supplementation with these fatty acids. Human milk contents of DHA are dependent on diet, and infant DHA concentrations are determined by their dietary intake of this fatty acid. We conclude that the most predictable way to increase a specific long-chain n-3 fatty acid in plasma, tissues, or human milk is to supplement with the fatty acid of interest.
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              Genetic variants of the FADS1 FADS2 gene cluster are associated with altered (n-6) and (n-3) essential fatty acids in plasma and erythrocyte phospholipids in women during pregnancy and in breast milk during lactation.

              The enzymes encoded by fatty acid desaturase (FADS) 1 and FADS2 are rate-limiting enzymes in the desaturation of linoleic acid [LA; 18:2(n-6)] to arachidonic acid [ARA; 20:4(n-6)], and alpha-linolenic acid [ALA; 18:3(n-3)] to eicosapentaenoic acid [EPA; 20:5(n-3)] and docosahexaenoic acid [DHA; 22:6(n-3)]. ARA, EPA, and DHA play central roles in infant growth, neural development, and immune function. The maternal ARA, EPA, and DHA status in gestation influences maternal-to-infant transfer and breast milk provides fatty acids for infants after birth. We determined if single nucleotide polymorphisms in FADS1 and FADS2 influence plasma phospholipid and erythrocyte ethanolamine phosphoglyceride (EPG) (n-6) and (n-3) fatty acids of women in pregnancy or their breast milk during lactation. We genotyped rs174553, rs99780, rs174575, and rs174583 in the FADS1 FADS2 gene cluster and analyzed plasma and erythrocyte fatty acids and dietary intake for 69 pregnant women and breast milk for a subset of 54 women exclusively breast-feeding at 1 mo postpartum. Minor allele homozygotes of rs174553(GG), rs99780(TT), and rs174583(TT) had lower ARA but higher LA in plasma phospholipids and erythrocyte EPG and decreased (n-6) and (n-3) fatty acid product:precursor ratios at 16 and 36 wk of gestation. Breast milk fatty acids were influenced by genotype, with significantly lower 14:0, ARA, and EPA but higher 20:2(n-6) in the minor allele homozygotes of rs174553(GG), rs99780(TT), and rs174583(TT) and lower ARA, EPA, 22:5(n-3), and DHA in the minor allele homozygotes G/G of rs174575. We showed that genetic variants of FADS1 and FADS2 influence blood lipid and breast milk essential fatty acids in pregnancy and lactation.
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                Author and article information

                Contributors
                +886422052121 , cobolsu@gmail.com
                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group UK (London )
                2158-3188
                20 November 2019
                20 November 2019
                2019
                : 9
                : 303
                Affiliations
                [1 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, , King’s College London, ; London, WC2R 2LS UK
                [2 ]ISNI 0000 0004 0572 9415, GRID grid.411508.9, Department of Psychiatry, , China Medical University Hospital, ; Taichung, Taiwan
                [3 ]ISNI 0000 0001 0083 6092, GRID grid.254145.3, College of Medicine, , China Medical University, ; Taichung, Taiwan
                [4 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, College of Nutrition, , Taipei Medical University, ; Taipei, Taiwan
                Author information
                http://orcid.org/0000-0001-5582-0928
                http://orcid.org/0000-0002-4501-2502
                http://orcid.org/0000-0002-0513-4943
                http://orcid.org/0000-0002-9132-5091
                Article
                633
                10.1038/s41398-019-0633-0
                6864068
                31745072
                e9cfd00c-5b1d-4057-8e0d-a8312b0ac7db
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 26 April 2019
                : 13 September 2019
                : 20 October 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan);
                Award ID: 106-2314-B-039-027-MY3
                Award ID: 106-2314-B-038-049
                Award ID: 106-2314-B-039-031
                Award ID: 106-2314-B-039-035
                Award ID: 105-2918-I-039-001
                Award ID: 104-2314-B-039-022-MY2,
                Award ID: 103-2320-B-039-036
                Award ID: 103-2923-B-039-002-MY3
                Award ID: 106-2314-B-039-027-MY3
                Award ID: 106-2314-B-038-049
                Award ID: 106-2314-B-039-031
                Award ID: 106-2314-B-039-035
                Award ID: 105-2918-I-039-001;
                Award ID: 104-2314-B-039-022-MY2
                Award ID: 104-2314-B-039-050-MY3
                Award ID: 103-2320-B-039-036
                Award ID: 103-2923-B-039-002-MY3
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004737, National Health Research Institutes (NHRI);
                Award ID: NHRI-EX105-10528NI
                Award ID: NHRI-EX105-10528NI
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004391, China Medical University Hospital (CMUH);
                Award ID: CRS-106-063
                Award ID: DMR-107-202
                Award ID: DMR-107-204
                Award ID: CRS-106-063
                Award ID: DMR-107-202
                Award ID: DMR-107-204
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000265, RCUK | Medical Research Council (MRC);
                Award ID: MR/L014815/1
                Award ID: MR/J002739/1
                Award ID: MR/L014815/1
                Award ID: MR/J002739/1
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000272, DH | National Institute for Health Research (NIHR);
                Award ID: MR/L014815/1
                Award ID: MR/J002739/1
                Award ID: MR/L014815/1
                Award ID: MR/J002739/1
                Award Recipient :
                Categories
                Article
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                © The Author(s) 2019

                Clinical Psychology & Psychiatry
                pathogenesis,learning and memory
                Clinical Psychology & Psychiatry
                pathogenesis, learning and memory

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