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Predictors of Changes in Height, Weight, and Body Mass Index After Initiation of Central Nervous System Stimulants in Children with Attention Deficit Hyperactivity Disorder.
Waxmonsky, JG, Pelham, WE, Baweja, R, Hale, D, Pelham, WE
The Journal of pediatrics. 2022;:115-125.e2
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OBJECTIVE To identify predictors of changes in height, weight, and body mass index (BMI) in children with attention deficit hyperactivity disorder (ADHD) starting central nervous system (CNS) stimulants. STUDY DESIGN There were 230 medication-naïve children aged 5-12 years with ADHD who participated in a randomized trial evaluating the impact of CNS stimulants on growth over 30 months. This observational analysis focused on the 141 participants using study medication for 65 or more days in the first 6-months after starting medication. Biometric variables, ADHD, and oppositional defiant disorder symptom scores at medication initiation, and medication use over the study were examined as predictors of changes in standardized (z) height, weight, and BMI. RESULTS Mean changes in z-BMI, z-weight. and z-height were negative throughout the study. The most consistent predictors of change in z-BMI, z-weight, and z-height were percent days medicated and total medication exposure. Children with lower z-height and z-weight at medication initiation experienced greater z-BMI and z-weight decreases over the first 6 months on medication. Greater appetite suppression during dose optimization predicted greater decreases in z-weight over the entire study and a greater decrease in z-height over the first 6 months on medication. z-weight change correlated with z-height change. Behavioral symptoms did not predict changes in z-BMI, z-weight, or z-height. CONCLUSIONS How much and how often CNS stimulants are used predicts changes in z-BMI, z-weight, and z-height in children. Even smaller and lighter children may be at risk for decreases in z-weight and z-BMI. Parent ratings of appetite during dose titration may serve as feasible indicators of future weight and height change in children using CNS stimulants. TRIAL REGISTRATION Clinicialtrials.gov: NCT01109849.
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Effect of Delayed-Release and Extended-Release Methylphenidate on Caregiver Strain and Validation of Psychometric Properties of the Caregiver Strain Questionnaire: Results from a Phase 3 Trial in Children with Attention-Deficit/Hyperactivity Disorder.
López, FA, Faraone, SV, Newcorn, JH, Doll, HA, Rhoten, S, Lewis, HB, Khan, TF, DeSousa, NJ, Sallee, FR, Incledon, B
Journal of child and adolescent psychopharmacology. 2021;(3):179-186
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Objectives: Inadequately controlled symptoms and associated impaired functioning have a significant negative impact on caregivers of children with attention-deficit/hyperactivity disorder (ADHD). This study aimed to assess the impact of evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) treatment on caregiver strain, measured by the Caregiver Strain Questionnaire (CGSQ), and present post hoc psychometric analyses assessing the reliability and validity of the CGSQ, its ability to detect change (responsiveness), and to derive responder definitions. Methods: The CGSQ was an exploratory efficacy endpoint in a phase 3, 3-week, randomized, double-blind, multicenter, placebo-controlled, forced-dose titration trial of DR/ER-MPH in children aged 6-12 years with ADHD (NCT02520388). Psychometric properties of the CGSQ evaluated post hoc included internal consistency using Cronbach's alpha; test/retest reliability using intraclass correlation coefficients (ICCs); construct validity (known groups and convergent/divergent validity); responsiveness to changes in assessments of ADHD severity (ADHD Rating Scale-IV [ADHD-RS-IV], Conners' Global Index-Parent [CGI-P], and Clinical Global Impression-Severity [CGI-S]/CGI-Improvement [CGI-I]); and meaningful change threshold (MCT) using receiver operating characteristic curves, which were used to compare response between DR/ER-MPH and placebo groups. Results: Randomized DR/ER-MPH (54.5) and placebo (54.9) groups had similar mean CGSQ scores at screening. Caregivers of children on DR/ER-MPH reported significant reductions in CGSQ scores after 3 weeks of DR/ER-MPH treatment versus placebo (least-squares mean: 41.2 vs. 49.1; p < 0.001). The CGSQ demonstrated strong internal consistency (Cronbach's alpha = 0.93) and good test/retest reliability (ICC = 0.72). Known groups, convergent/divergent validity, and responsiveness were demonstrated from relationships between the CGSQ and the CGI-S, ADHD-RS-IV, and CGI-P. The mean anchor-based MCT for CGSQ total score was estimated as -9.0 (DR/ER-MPH vs. placebo: 53.2% vs. 29.9% p = 0.003). Conclusions: CGSQ scores significantly decreased after 3 weeks of DR/ER-MPH treatment versus placebo, and the CGSQ was found to be a valid and reliable measure of strain in caregivers of children with ADHD. Clinical trial registration identification number: NCT02520388.
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Cognitive enhancement effects of stimulants: a randomized controlled trial testing methylphenidate, modafinil, and caffeine.
Repantis, D, Bovy, L, Ohla, K, Kühn, S, Dresler, M
Psychopharmacology. 2021;(2):441-451
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RATIONAL At all times humans have made attempts to improve their cognitive abilities by different means, among others, with the use of stimulants. Widely available stimulants such as caffeine, but also prescription substances such as methylphenidate and modafinil, are being used by healthy individuals to enhance cognitive performance. OBJECTIVES There is a lack of knowledge on the effects of prescription stimulants when taken by healthy individuals (as compared with patients) and especially on the effects of different substances across different cognitive domains. METHODS We conducted a pilot study with three arms in which male participants received placebo and one of three stimulants (caffeine, methylphenidate, modafinil) and assessed cognitive performance with a test battery that captures various cognitive domains. RESULTS Our study showed some moderate effects of the three stimulants tested. Methylphenidate had positive effects on self-reported fatigue as well as on declarative memory 24 hours after learning; caffeine had a positive effect on sustained attention; there was no significant effect of modafinil in any of the instruments of our test battery. All stimulants were well tolerated, and no trade-off negative effects on other cognitive domains were found. CONCLUSIONS The few observed significant positive effects of the tested stimulants were domain-specific and of rather low magnitude. The results can inform the use of stimulants for cognitive enhancement purposes as well as direct further research to investigate the effects of stimulants on specific cognitive domains that seem most promising, possibly by using tasks that are more demanding.
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Blue Monday: Co-occurring Stimulant Use and HIV Persistence Predict Dysregulated Catecholamine Synthesis.
Chahine, A, Koru-Sengul, T, Feaster, DJ, Dilworth, SE, Antoni, MH, Klatt, N, Roach, ME, Pallikkuth, S, Sharkey, M, Salinas, J, et al
Journal of acquired immune deficiency syndromes (1999). 2021;(3):353-360
Abstract
BACKGROUND This longitudinal study examined whether co-occurring stimulant use and HIV disease processes predicted greater risk for depression via dysregulated metabolism of amino acid precursors for neurotransmitters. METHODS In total, 110 sexual minority men (ie, gay, bisexual, and other men who have sex with men) living with HIV who had biologically confirmed recent methamphetamine use were enrolled in a randomized controlled trial. The kynurenine/tryptophan (K/T) and phenylalanine/tyrosine (P/T) ratios were measured over 15 months to index dysregulated metabolism of amino acid precursors for serotonin and catecholamines. Markers of gut-immune dysregulation such as lipopolysaccharide binding protein and soluble CD14 (sCD14), HIV persistence in immune cells (ie, proviral HIV DNA), and stimulant use were examined as predictors. These bio-behavioral measures, including the K/T and P/T ratios, were also examined as predictors of greater risk for depression over 15 months. RESULTS Higher time-varying sCD14 levels (β = 0.13; P = 0.04) and time-varying detectable viral loads (β = 0.71; P < 0.001) were independent predictors of a higher K/T ratio. Time-varying reactive urine toxicology results for stimulants (β = 0.53; P < 0.001) and greater proviral HIV DNA at baseline (β = 0.34; P < 0.001) independently predicted an increased P/T ratio. Greater time-varying, self-reported methamphetamine use uniquely predicted higher odds of screening positive for depression (Adjusted Odds Ratio = 1.08; 95% confidence interval: 1.01 to 1.17). CONCLUSIONS Ongoing stimulant use and HIV persistence independently predict dysregulated metabolism of amino acid precursors for catecholamines, but this did not explain amplified risk for depression.
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Caffeine Exacerbates Hyperventilation and Reductions in Cerebral Blood Flow in Physically Fit Men Exercising in the Heat.
Fujii, N, Fujimoto, T, Yinhang, C, Dobashi, K, Matsutake, R, Amano, T, Watanabe, K, Nishiyasu, T
Medicine and science in sports and exercise. 2021;(4):845-852
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INTRODUCTION Caffeine is an exercise performance enhancer widely used by individuals engaged in training or competition under heat-stressed conditions. Caffeine ingestion during exercise in the heat is believed to be safe because it does not greatly affect body temperature responses, heart rate, or body fluid status. However, it remains unknown whether caffeine affects hyperthermia-induced hyperventilation or reductions in the cerebral blood flow index. We tested the hypothesis that under conditions inducing severe hyperthermia, caffeine exacerbates hyperthermia-induced hyperventilation and reduces the cerebral blood flow index during exercise. METHODS Using a randomized, single-blind, crossover design, 12 physically active healthy young men (23 ± 2 yr) consumed a moderate dose of caffeine (5 mg·kg-1) or placebo in the heat (37°C). Approximately 60 min after the ingestion, they cycled for ~45 min at a workload equal to ~55% of their predetermined peak oxygen uptake (moderate intensity) until their core temperature increased to 2.0°C above its preexercise baseline level. RESULTS In both trials, ventilation increased and the cerebral blood flow index assessed by middle cerebral artery mean blood velocity decreased as core temperature rose during exercise (P < 0.05), indicating that hyperthermia-induced hyperventilation and lowering of the cerebral blood flow occurred. When core temperature was elevated by 1.5°C or more (P < 0.05), ventilation was higher and the cerebral blood flow was lower throughout the caffeine trial than the placebo trial (P < 0.05). CONCLUSIONS A moderate dose of caffeine exacerbates hyperthermia-induced hyperventilation and reductions in the cerebral blood flow index during exercise in the heat with severe hyperthermia.
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Placebo Effect of Caffeine on Maximal Strength and Strength Endurance in Healthy Recreationally Trained Women Habituated to Caffeine.
Filip-Stachnik, A, Krzysztofik, M, Kaszuba, M, Leońska-Duniec, A, Czarny, W, Del Coso, J, Wilk, M
Nutrients. 2020;(12)
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BACKGROUND By using deceptive experimental designs, several investigations have observed that trained individuals may increase their performance when told they were given caffeine, when in fact they received a placebo (i.e., the placebo effect of caffeine). However, most of these investigations on the placebo effect of caffeine used individuals with low caffeine consumption or did not report habitual caffeine consumption, especially in studies analyzing resistance-based exercise. Hence, it is unknown if habitual caffeine consumers benefit from the placebo effect of caffeine on exercise performance. Thus, the aim of the present study was to analyze the placebo effect of caffeine on maximal strength and strength-endurance performance during the bench press exercise (BP) in women with mild-moderate daily consumption of caffeine. METHODS Thirteen resistance-trained women (BP one-repetition maximum (1RM) = 40.0 ± 9.7 kg) habituated to caffeine (4.1 ± 1.7 mg/kg/day) completed a deceptive randomized experimental design with two experimental trials. On one occasion, participants were told that they would receive 6 mg/kg of caffeine but received a placebo (PLAC), and on other occasions, participants did not receive any substance and were told that this was a control situation (CONT). In each experimental trial, participants underwent a 1RM BP test and a strength-endurance test consisting of performing the maximal number of repetitions at 50% of their 1RM. RESULTS In comparison to CONT, PLAC did not enhance 1RM (40.0 ± 10.5 kg vs. 41.0 ± 9.5 kg, respectively; p = 0.10), nor did it enhance the number of repetitions (32.2 ± 5.1 vs. 31.8 ± 4.5; p = 0.66) or mean power (130 ± 34 vs. 121 ± 26; p = 0.08) in the strength-endurance test. CONCLUSION Informing participants that they were given caffeine, when in fact they received a placebo, did not modify any performance variable measured in this investigation. Thus, the use of the placebo effect of caffeine seemed an ineffective strategy to enhance muscle strength and strength endurance during the BP exercise in women with mild-moderate consumption of caffeine.
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Effects of caffeine supplementation on physical performance and mood dimensions in elite and trained-recreational athletes.
Jodra, P, Lago-Rodríguez, A, Sánchez-Oliver, AJ, López-Samanes, A, Pérez-López, A, Veiga-Herreros, P, San Juan, AF, Domínguez, R
Journal of the International Society of Sports Nutrition. 2020;(1):2
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BACKGROUND Caffeine supplementation (CAFF) has an established ergogenic effect on physical performance and the psychological response to exercise. However, few studies have compared the response to CAFF intake among athletes of different competition level. This study compares the acute effects of CAFF on anaerobic performance, mood and perceived effort in elite and moderately-trained recreational athletes. METHODS Participants for this randomized, controlled, crossover study were 8 elite athletes (in the senior boxing national team) and 10 trained-recreational athletes. Under two experimental conditions, CAFF supplementation (6 mg/kg) or placebo (PLAC), the athletes completed a Wingate test. Subjective exertion during the test was recorded as the rating of perceived exertion (RPE) both at the general level (RPEgeneral) and at the levels muscular (RPEmuscular) and cardiorespiratory (RPEcardio). Before the Wingate test, participants completed the questionnaires Profiles of Moods States (POMS) and Subjective Vitality Scale (SVS). RESULTS In response to CAFF intake, improvements were noted in Wpeak (11.22 ± 0.65 vs 10.70 ± 0.84; p = 0.003; [Formula: see text] =0.44), Wavg (8.75 ± 0.55 vs 8.41 0.46; p = 0.001; [Formula: see text] =0.53) and time taken to reach Wpeak (7.56 ± 1.58 vs 9.11 ± 1.53; p < 0.001; [Formula: see text] =0.57) both in the elite and trained-recreational athletes. However, only the elite athletes showed significant increases in tension (+ 325%), vigor (+ 31%) and SVS (+ 28%) scores after the intake of CAFF compared to levels recorded under the condition PLAC (p < 0.05). Similarly, levels of vigor after consuming CAFF were significantly higher in the elite than the trained-recreational athletes (+ 5.8%). CONCLUSIONS CAFF supplementation improved anaerobic performance in both the elite and recreational athletes. However, the ergogenic effect of CAFF on several mood dimensions and subjective vitality was greater in the elite athletes.
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Caffeine improves various aspects of athletic performance in adolescents independent of their 163 C > A CYP1A2 genotypes.
Spineli, H, Pinto, MP, Dos Santos, BP, Lima-Silva, AE, Bertuzzi, R, Gitaí, DLG, de Araujo, GG
Scandinavian journal of medicine & science in sports. 2020;(10):1869-1877
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PURPOSE The purpose of this study was to investigate whether variations in 163 C > A CYP1A2 genotypes (rs 762 551) (AA, AC, and CC) modify the ergogenic effects of caffeine (CAF) on strength, power, muscular endurance, agility, and endurance in adolescent athletes. METHODS One hundred adolescents (age = 15 ± 2 years) were recruited. Participants ingested CAF (6 mg.kg-1 ) or placebo (PLA, 300 mg of cellulose) 1 hour before performing a sequence of physical tests: handgrip strength, vertical jumps, agility test, sit-ups, push-ups, and the Yo-Yo intermittent recovery test level 1 (Yo-Yo IR1). RESULTS Compared to PLA, CAF enhanced (P < .05) sit-up (CAF = 37 ± 9; PLA = 35 ± 8 repetitions) and push-up repetitions (CAF = 26 ± 11; PLA = 24 ± 11 repetitions), and increased distance covered in Yo-Yo IR1 test (CAF = 1010.4 ± 378.9; PLA = 903.2 ± 325.7 m). There was no influence of CAF on handgrip strength (CAF = 35.1 ± 8.9; PLA = 33.7 ± 8.7 kgf), countermovement jump height (CAF = 49.3 ± 12.6; PLA = 47.9 ± 13.8 cm), spike jump height (CAF = 54.2 ± 13.6; PLA = 52.9 ± 14.5 cm), and time in agility test (CAF = 15.8 ± 1.1; PLA = 15.9 ± 1.3 s, P > .05). When present, the ergogenic effect of CAF was not dependent of genotype. CONCLUSION CAF improves muscular endurance and aerobic performance in adolescent athletes, regardless of their 163 C > A CYP1A2 genotype.
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Effects of Discontinuing Methylphenidate on Strengths and Difficulties, Quality of Life and Parenting Stress.
Matthijssen, AM, Dietrich, A, Bierens, M, Kleine Deters, R, van de Loo-Neus, GHH, van den Hoofdakker, BJ, Buitelaar, JK, Hoekstra, PJ
Journal of child and adolescent psychopharmacology. 2020;(3):159-165
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Objectives: To study the effects of discontinuation of long-term methylphenidate use on secondary outcome measures of strengths and difficulties, quality of life (QoL), and parenting stress. Methods: Ninety-four children and adolescents aged 8 to 18 years who had used methylphenidate for over 2 years were randomly assigned to double-blind continuation of treatment for 7 weeks (36 or 54 mg extended release methylphenidate) or to gradual withdrawal over 3 to 4 weeks placebo. We used mixed models for repeated measures to investigate effects on parent, teacher, and child ratings of hyperactivity/inattention and comorbid symptoms with the Strengths and Difficulties Questionnaire (SDQ), investigator- and teacher-rated oppositional symptoms (Conners Teacher Rating Scale-Revised: short form [CTRS-R:S]), and parent-rated aggression with the Retrospective Modified Overt Aggression Scale. QoL was assessed with the Revised Questionnaire for Children and Adolescents to record health-related quality of life and parenting stress with the Nijmegen Parental Stress Index. Results: Hyperactivity/inattention scores from the parent- and teacher-rated SDQ (difference in mean change over time of respectively: -1.1 [95% confidence interval, CI, -2.0 to -0.3]; p = 0.01; -2.9 [95% CI -2.9 to -0.7; p = 0.01]) and oppositional scores of the teacher-rated CTRS-R:S (difference in mean change -1.9 95% CI [-3.1 to -0.6; p < 0.01]) deteriorated to a significantly larger extent in the discontinuation group than in the continuation group. We did not find effects on other symptom domains, aggression, QoL, and parenting stress after discontinuation of methylphenidate. Conclusion: Our study suggests beneficial effects of long-term methylphenidate use beyond 2 years for oppositional behaviors in the school environment. Similarly, beneficial effects were found on hyperactivity-inattention symptoms as rated by parent and teacher scales, confirming our primary study on investigator ratings of attention-deficit/hyperactivity disorder. However, discontinuation of methylphenidate did not appear to have impact on other comorbid problems or aspects of the child's or parental functioning.
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Methylphenidate and galantamine in patients with vascular cognitive impairment-the proof-of-principle study STREAM-VCI.
Leijenaar, JF, Groeneveld, GJ, Klaassen, ES, Leeuwis, AE, Scheltens, P, Weinstein, HC, van Gerven, JMA, Barkhof, F, van der Flier, WM, Prins, ND
Alzheimer's research & therapy. 2020;(1):10
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BACKGROUND To date, no symptomatic treatment is available for patients with vascular cognitive impairment (VCI). In the proof-of-principle study Symptomatic Treatment of Vascular Cognitive Impairment (STREAM-VCI), we investigated whether a single dose of a monoaminergic drug (methylphenidate) improves executive functioning and whether a single dose of a cholinergic drug (galantamine) improves memory in VCI patients. METHODS STREAM-VCI is a single-center, double-blind, three-way crossover trial. We included 30 VCI patients (Mini-Mental State Examination (MMSE) ≥ 16 and Clinical Dementia Rating score 0.5-1.0) with cerebrovascular pathology on MRI. All patients received single doses of methylphenidate (10 mg), galantamine (16 mg), and placebo in random order on three separate study visits. We used the NeuroCart®, a computerized test battery, to assess drug-sensitive cognitive effects. Predefined main outcomes, measured directly after a single dose of a study drug, were (i) change in performance on the adaptive tracker for executive functioning and (ii) performance on the Visual Verbal Learning Test-15 (VVLT-15) for memory, compared to placebo. We performed mixed model analysis of variance. RESULTS The study population had a mean age of 67 ± 8 years and MMSE 26 ± 3, and 9 (30%) were female. Methylphenidate improved performance on the adaptive tracker more than placebo (mean difference 1.40%; 95% confidence interval [CI] 0.56-2.25; p = 0.002). In addition, methylphenidate led to better memory performance on the VVLT-15 compared to placebo (mean difference in recalled words 0.59; 95% CI 0.03-1.15; p = 0.04). Galantamine did not improve performance on the adaptive tracker and led to worse performance on delayed recall of the VVLT-15 (mean difference - 0.84; 95% CI - 1.65, - 0.03; p = 0.04). Methylphenidate was well tolerated while galantamine produced gastrointestinal side effects in a considerable number of patients. CONCLUSIONS In this proof-of-principle study, methylphenidate is well tolerated and improves executive functioning and immediate recall in patients with VCI. Galantamine did not improve memory or executive dysfunction. Results might be influenced by the considerable amount of side effects seen. TRIAL REGISTRATION http://www.clinicaltrials.gov. Registration number: NCT02098824. Registration date: March 28, 2014.