Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention or impulsivity or both, and hyperactivity, which affect children, adolescents, and adults. In some countries, methylphenidate is the first option to treat adults with moderate or severe ADHD. However, evidence on the efficacy and adverse events of immediate-release (IR) methylphenidate in the treatment of ADHD in adults is limited and controversial. OBJECTIVES: To evaluate the efficacy and harms (adverse events) of IR methylphenidate for treating ADHD in adults. SEARCH METHODS: In January 2020, we searched CENTRAL, MEDLINE, Embase, eight additional databases and three trial registers. We also searched internal reports on the European Medicines Agency and the US Food and Drug Administration websites. We checked citations of included trials to identify additional trials not captured by the electronic searches. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing IR methylphenidate, at any dose, with placebo or other pharmacological interventions (including extended-release formulations of methylphenidate) for ADHD in adults. Primary outcomes comprised changes in the symptoms of ADHD (efficacy) and harms. Secondary outcomes included changes in the clinical impression of severity and improvement, level of functioning, depression, anxiety and quality of life. Outcomes could have been rated by investigators or participants. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently on the characteristics of the trials, participants, interventions; outcomes and financial conflict of interests. We resolved disagreements by discussion or consulting a third review author. We obtained additional, unpublished information from the authors of one included trial that had reported efficacy data in a graph. We calculated mean differences (MDs) or standardized MDs (SMDs) with 95% confidence intervals (CIs) for continuous data reported on the same or different scales, respectively. We summarized dichotomous variables as risk ratios (RRs) with 95% CI. MAIN RESULTS: We included 10 trials published between 2001 and 2016 involving 497 adults with ADHD. Three trials were conducted in Europe and one in Argentina; the remaining trials did not report their location. The RCTs compared IR methylphenidate with placebo, an osmotic-release oral system (OROS) of methylphenidate (an extended-release formulation), an extended-release formulation of bupropion, lithium, and Pycnogenol® (maritime pine bark extract). Participants comprised outpatients, inpatients in addiction treatment, and adults willing to attend an intensive outpatient program for cocaine dependence. The duration of the follow-up ranged from 6 to 18 weeks. IR methylphenidate versus placebo We found very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce symptoms of ADHD when measured with investigator-rated scales (MD -20.70, 95% CI -23.97 to -17.43; 1 trial, 146 participants; end scores; Adult ADHD Investigator Symptom Report Scale (AISRS), scored from 0 to 54), but the evidence is uncertain. The effect of IR methylphenidate on ADHD symptoms when measured with participant-rated scales was moderate, but the certainty of the evidence is very low (SMD -0.59, 95% CI -1.25 to 0.06; I2 = 69%; 2 trials, 138 participants; end scores). There is very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce the clinical impression of the severity of ADHD symptoms (MD -0.57, 95% CI -0.85 to -0.28; 2 trials, 139 participants; I2 = 0%; change and end scores; Clinical Global Impression (CGI)-Severity scale (scored from 1 (very much improved) to 7 (very much worse))). There is low-certainty evidence that, compared with placebo, IR methylphenidate may slightly impact the clinical impression of an improvement in symptoms of ADHD (MD -0.94, 95% CI -1.37 to -0.51; 1 trial, 49 participants; end scores; CGI-Improvement scale (scored from 1 (very much improved) to 7 (very much worse))). There is no clear evidence of an effect on anxiety (MD -0.20, 95% CI -4.84 to 4.44; 1 trial, 19 participants; change scores; Hamilton Anxiety Scale (HAM-A; scored from 0 to 56); very low-certainty evidence) or depression (MD 2.80, 95% CI -0.09 to 5.69; 1 trial, 19 participants; change scores; Hamilton Depression Scale (HAM-D; scored from 0 to 52); very low-certainty evidence) in analyses comparing IR methylphenidate with placebo. IR methylphenidate versus lithium Compared with lithium, it is uncertain whether IR methylphenidate increases or decreases symptoms of ADHD (MD 0.60, 95% CI -3.11 to 4.31; 1 trial, 46 participants; end scores; Conners' Adult ADHD Rating Scale (scored from 0 to 198); very low-certainty evidence); anxiety (MD -0.80, 95% CI -4.49 to 2.89; 1 trial, 46 participants; end scores; HAM-A; very low-certainty evidence); or depression (MD -1.20, 95% CI -3.81 to 1.41, 1 trial, 46 participants; end scores; HAM-D scale; very low-certainty evidence). None of the included trials assessed participant-rated changes in symptoms of ADHD, or clinical impression of severity or improvement in participants treated with IR methylphenidate compared with lithium. Adverse events were poorly assessed and reported. We rated all trials at high risk of bias due to selective outcome reporting of harms and masking of outcome assessors (failure to blind outcome assessor to measure adverse events). Overall, four trials with 203 participants who received IR methylphenidate and 141 participants who received placebo described the occurrence of harms. The use of IR methylphenidate in these trials increased the risk of gastrointestinal complications (RR 1.96, 95% CI 1.13 to 2.95) and loss of appetite (RR 1.77, 95% CI 1.06 to 2.96). Cardiovascular adverse events were reported inconsistently, preventing a comprehensive analysis. One trial comparing IR methylphenidate to lithium reported five and nine adverse events, respectively. We considered four trials to have notable concerns of vested interests influencing the evidence, and authors from two trials omitted information related to the sources of funding and conflicts of interest. AUTHORS' CONCLUSIONS: We found no certain evidence that IR methylphenidate compared with placebo or lithium can reduce symptoms of ADHD in adults (low- and very low-certainty evidence). Adults treated with IR methylphenidate are at increased risk of gastrointestinal and metabolic-related harms compared with placebo. Clinicians should consider whether it is appropriate to prescribe IR methylphenidate, given its limited efficacy and increased risk of harms. Future RCTs should explore the long-term efficacy and risks of IR methylphenidate, and the influence of conflicts of interest on reported effects.

Stimulants cocktail: Methylphenidate plus caffeine impairs memory and cognition and alters mitochondrial and oxidative status.

Methylphenidate (MPH) is a psychostimulant widely misused to increase wakefulness by drivers and students. Also, MPH can be found in dietary supplements in a clandestine manner aiming to burst performance of physical exercise practitioners. The abusive use of high doses of caffeine (CAF) in these contexts is equally already known. Here, we demonstrate the behavioral, oxidative and mitochondrial effects after acute exposure to high doses of MPH (80 mg/L) and CAF (150 mg/L), alone or associated (80 mg/L + 150 mg/L, respectively). We used zebrafish as animal model due to its high translational relevance. We evaluated the behavioral effects using the Novel Tank Test (NTT), Social Preference Test (SPT) and Y-maze Task and analyzed biomarkers of oxidative stress and activity of mitochondrial respiratory chain complexes. MPH alone induced antisocial behavior. MPH inhibited lipid peroxidation. The association of MPH + CAF presented memory impairment and anxiogenic behavior. In oxidative status, it inhibited lipid peroxidation, increased protein carbonylation and mitochondrial complex II, III and IV activity. Our results demonstrate that MPH and CAF alone negatively impact the typical behavioral of zebrafish. When associated, changes in cognition, memory, oxidative and mitochondrial status are more relevant.

Natural Products as Modulators of CES1 Activity.

Carboxylesterase (CES) 1 is the predominant esterase expressed in the human liver and is capable of catalyzing the hydrolysis of a wide range of therapeutic agents, toxins, and endogenous compounds. Accumulating studies have demonstrated associations between the expression and activity of CES1 and the pharmacokinetics and/or pharmacodynamics of CES1 substrate medications (e.g., methylphenidate, clopidogrel, oseltamivir). Therefore, any perturbation of CES1 by coingested xenobiotics could potentially compromise treatment. Natural products are known to alter drug disposition by modulating cytochrome P450 and UDP-glucuronosyltransferase enzymes, but this issue is less thoroughly explored with CES1. We report the results of a systematic literature search and discuss natural products as potential modulators of CES1 activity. The majority of research reports reviewed were in vitro investigations that require further confirmation through clinical study. Cannabis products (Δ 9-tetrahydrocannabinol, cannabidiol, cannabinol); supplements from various plant sources containing naringenin, quercetin, luteolin, oleanolic acid, and asiatic acid; and certain traditional medicines (danshen and zhizhuwan) appear to pose the highest inhibition potential. In addition, ursolic acid, gambogic acid, and glycyrrhetic acid, if delivered intravenously, may attain high enough systemic concentrations to significantly inhibit CES1. The provision of a translational interpretation of in vitro assessments of natural product actions and interactions is limited by the dearth of basic pharmacokinetic data of the natural compounds exhibiting potent in vitro influences on CES1 activity. This is a major impediment to assigning even potential clinical significance. The modulatory effects on CES1 expression after chronic exposure to natural products warrants further investigation. SIGNIFICANCE STATEMENT: Modulation of CES1 activity by natural products may alter the course of treatment and clinical outcome. In this review, we have summarized the natural products that can potentially interact with CES1 substrate medications. We have also noted the limitations of existing reports and outlined challenges and future directions in this field.

Intrinsic connections between thalamic sub-regions and the lateral prefrontal cortex are differentially impacted by acute methylphenidate.

BACKGROUND: The thalamus is a major target of dopaminergic projections and is densely connected with the prefrontal cortex. A better understanding of how dopamine changes thalamo-cortical communication may shed light on how dopamine supports cognitive function. Methylphenidate has been shown to facilitate cognitive processing and reduce connectivity between the thalamus and lateral prefrontal cortex. AIMS: The thalamus is a heterogeneous structure, and the present study sought to clarify how the intrinsic connections of thalamic sub-regions are differentially impacted by acute dopamine transporter blockade. METHODS: Sixty healthy volunteers were orally administered either 20 mg of methylphenidate (N = 29) or placebo (N = 31) in a double-blind, randomized, between-subject design. Multi-echo fMRI was used to assess intrinsic functional connectivity of sub-regions of the thalamus during a resting state scan. An N-back working-memory paradigm provided a measure of cognitive performance. RESULTS: Acute methylphenidate significantly reduced connectivity of the lateral prefrontal cortex with the motor and somatosensory sub-regions of the thalamus and reduced connectivity with the parietal and visual sub-regions at a trend level. Connectivity with the premotor, prefrontal, and temporal sub-regions was not impacted. The intrinsic connectivity between the thalamus and the lateral prefrontal cortex was not associated with working-memory performance. CONCLUSIONS: Methylphenidate decreases functional connections between the lateral prefrontal cortex and thalamus broadly, while sparing intrinsic connectivity with thalamic sub-regions involved with working-memory and language related processes. Collectively, our results suggest that the dopamine transporter regulates functional connections between the prefrontal cortex and non-cognitive areas of the thalamus.

The efficacy of zinc augmentation in children with attention deficit hyperactivity disorder under treatment with methylphenidate: A randomized controlled trial.

INTRODUCTION: Regarding to the role of the zinc in the metabolism of the central nervous system and the correlation of zinc supplementation in the treatment of any Attention deficit hyperactivity disorder (ADHD) symptoms, this study was conducted to evaluate the complementary effects of this nutrient. METHOD: This was a double-blind randomized clinical trial study and 60 children with ADHD who were treated with methylphenidate were chosen by random allocation and were divided in the two groups: 30 for the case and 30 for the control group. The treatment in case group was augmented with zinc. Duration of study was six weeks. RESULT: Forty eight (80%) of participants were boy and 12 (20%) were girl. The mean age of patients was 9.6 ± 1.70 years. There was no significant difference between the two groups after the intervention in terms of total score, hyperactivity and impulsivity subscales during variance analysis, but there was a significant difference between the mean of inattention score. CONCLUSION: Augmentation with zinc can enhance the improvement of inattention.

Brief and extended abstinence from chronic oral methylphenidate treatment produces reversible behavioral and physiological effects.

Methylphenidate (MP) is a commonly prescribed psychostimulant to individuals with Attention Deficit Hyperactivity Disorder, and is often used illicitly among healthy individuals with intermittent breaks to coincide with breaks from school. This study examined how intermittent abstinence periods impact the physiological and behavioral effects of chronic oral MP self-administration in rats, and whether these effects persist following prolonged abstinence from the drug. Rats were treated orally with water, low-dose (LD), or high-dose (HD) MP, beginning at PND 28. This daily access continued for three consecutive weeks followed by a 1-week abstinence; after three repeats of this cycle, there was a 5-week abstinence period. Throughout the study, we examined body weight, food intake, locomotor activity, and anxiety- and depressive-like behaviors. During the treatment phase, HD MP decreased body weight, food intake, and depressive- and anxiety-like behaviors, while it increased locomotor activity. During intermittent abstinence, the effects of MP on locomotor activity were eliminated. During prolonged abstinence, most of the effects of HD MP were ameliorated to control levels, with the exception of weight loss and anxiolytic effects. These findings suggest that intermittent exposure to chronic MP causes physiological and behavioral effects that are mostly reversible following prolonged abstinence.

Personalized at-home neurofeedback compared with long-acting methylphenidate in an european non-inferiority randomized trial in children with ADHD.

BACKGROUND: Neurofeedback (NF) has gained increasing interest among non-pharmacological treatments for Attention Deficit Hyperactivity Disorder (ADHD). NF training aims to enhance self-regulation of brain activities. The goal of the NEWROFEED study is to assess the efficacy of a new personalized NF training device, using two different protocols according to each child's electroencephalographic pattern, and designed for use at home. This study is a non-inferiority trial comparing NF to methylphenidate. METHODS: The study is a prospective, multicentre, randomized, reference drug-controlled trial. One hundred seventy-nine children with ADHD, aged 7 to 13 years will be recruited in 13 clinical centres from 5 European countries. Subjects will be randomized to two groups: NF group (Neurofeedback Training Group) and MPH group (Methylphenidate group). Outcome measures include clinicians, parents and teachers' assessments, attention measures and quantitative EEG (qEEG). Patients undergo eight visits over a three-month period: pre-inclusion visit, inclusion visit, 4 "discovery" (NF group) or titration visits (MPH group), an intermediate and a final visit. Patients will be randomized to either the MPH or NF group. Children in the NF group will undergo either an SMR or a Theta/Beta training protocol according to their baselineTheta/Beta Ratio obtained from the qEEG. DISCUSSION: This is the first non-inferiority study between a personalized NF device and pharmacological treatment. Innovative aspects of Mensia Koala™ include the personalization of the training protocol according to initial qEEG characteristics (SMR or Theta/Beta training protocols) and an improved accessibility of NF due to the opportunity to train at home with monitoring by the clinician through a dedicated web portal. TRIAL REGISTRATION: NCT02778360 . Date registration (retrospectively registered): 5-12-2016. Registered May 19, 2016.

"Eat, pray, love. Ritalin": A qualitative investigation into the perceived barriers and enablers to parents of children with ADHD undertaking a mindful parenting intervention.

BACKGROUND AND PURPOSE: There is growing interest in how mindful parenting interventions (MPI) may support families of children with attention deficit hyperactivity disorder (ADHD). The aim of this study was to explore the potential barriers and enablers to parents' participation in a MPI from the perspectives of parents of children with ADHD and healthcare providers. MATERIALS AND METHODS: Thirteen parents of children with ADHD attended focus groups, and seven healthcare providers participated in semi-structured phone interviews. Transcripts of the focus groups and interviews were analysed using inductive thematic analysis. RESULTS: Three overarching themes related to potential barriers and enablers were identified: parent motivation and capacity to engage in a MPI, the need for multimodal and personalised delivery, and considerations for real-world program implementation. CONCLUSION: Parents of children with ADHD appear to require flexible, multimodal MPIs that consider parents' emotional experiences, priorities, and personal struggles.

Treatment for Gulf War Illness (GWI) with KPAX002 (methylphenidate hydrochloride + GWI nutrient formula) in subjects meeting the Kansas case definition: A prospective, open-label trial.

This study tested the safety, tolerability, and efficacy of KPAX002-a combination of methylphenidate hydrochloride plus a micronutrient formula designed to support mitochondrial function-as a treatment for Gulf War Illness (GWI). This open-label trial enrolled 17 subjects meeting the Kansas case definition for GWI. Of the 17 subjects enrolled, 15 qualified for the Intent-to-Treat (ITT) population with 10 subjects completing the trial per protocol. All analyses were on the ITT population. At 12 weeks, subjects taking KPAX002 experienced a mean 25% reduction in their overall GWI symptoms severity as measured by the GWI Symptoms Assessment Tool (SAT) (p < 0.001). Visual analog scale scores were also significantly reduced for fatigue (p = 0.019), cognitive symptoms (p = 0.006), sleep problems (p = 0.026), and pain (p = 0.05). Twelve weeks of KPAX002 administration resulted in a significant improvement in GWI symptoms with an acceptable side effect profile. A larger randomized, double-blinded, placebo-controlled trial is necessary to determine if the observed benefit can be replicated.

Crocus sativus L. Versus Methylphenidate in Treatment of Children with Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind Pilot Study.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders of childhood and adolescence. About 30% of patients do not respond to stimulants or cannot tolerate their side effects. Thus, alternative medication, like herbal medicine, should be considered. The aim of this trial is to compare the safety and efficacy of Crocus sativus (saffron) versus methylphenidate in improving symptoms of children with ADHD. METHODS: In a 6-week randomized double-blind study, 54 patients (children 6-17 years old) with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD were randomly assigned to receive either 20-30 mg/d (20 mg/d for <30 kg and 30 mg/d for >30 kg) methylphenidate (MPH) or 20-30 mg/d saffron capsules depending on weight (20 mg/d for <30 kg and 30 mg/d for >30 kg). Symptoms were assessed using the Teacher and Parent Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) at baseline and weeks 3 and 6. RESULTS: Fifty patients completed the trial. General linear model repeated measures showed no significant difference between the two groups on Parent and Teacher Rating Scale scores (F = 0.749, df = 1.317, p = 0.425, and F = 0.249, df = 1.410, p = 0.701, respectively). Changes in Teacher and Parent ADHD Rating Scale scores from baseline to the study end were not significantly different between the saffron group and the MPH group (p = 0.731 and p = 0.883, respectively). The frequency of adverse effects was similar between saffron and MPH groups. CONCLUSION: Short-term therapy with saffron capsule showed the same efficacy compared with methylphenidate. Nevertheless, larger controlled studies with longer treatment periods are necessary for future studies.

A randomized comparison of long acting methylphenidate and cognitive behavioral therapy in the treatment of binge eating disorder.

Cognitive behavioral therapy (CBT) is a well-established treatment for binge eating disorder (BED); however, this treatment is underutilized, highlighting the need for additional treatment alternatives. Dopamine neurotransmission has been associated with dysregulated eating, and pharmaceutical agents targeting the dopamine system are associated with decreased binge eating and weight. The primary objective of the current investigation was to evaluate the efficacy of psychostimulant medication versus current best practices in the treatment of BED symptoms, in a randomized trial of methylphenidate versus CBT for BED. The secondary objective was to evaluate the ability of impulsivity to predict treatment outcomes. Female outpatients with BED were randomized to receive methylphenidate (n = 22) or CBT (n = 27) for 12 weeks. The primary outcome was objective binge episode frequency; secondary outcomes included subjective binge episode frequency, body mass index (BMI), BED symptoms, and quality of life. Results showed that both treatments had a significant impact on primary and secondary outcomes. Methylphenidate and CBT were associated with decreases in subjective and objective binge episodes; methylphenidate was associated with greater decreases in BMI. Two impulsivity traits predicted clinical outcomes. Results provide preliminary support for the therapeutic benefit of methylphenidate in BED treatment, and prognostic utility of impulsivity in this context.

Does L-Methylfolate Supplement Methylphenidate Pharmacotherapy in Attention-Deficit/Hyperactivity Disorder?: Evidence of Lack of Benefit From a Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

PURPOSE/BACKGROUND: Interventions for attention-deficit/hyperactivity disorder (ADHD) may be inadequate for some patients. There is evidence that supplementation with L-methylfolate augments antidepressant agent effects and thus might also augment ADHD treatment effects by a common catecholaminergic mechanism. METHODS: Forty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of ADHD participated in a randomized, double-blind, placebo-controlled, 12-week trial of 15 mg of L-methylfolate in combination with osmotic-release oral system methylphenidate. Osmotic-release oral system methylphenidate was dose optimized over the first 6 weeks. We evaluated the effects on ADHD symptoms, self-report on the Behavior Rating Inventory of Executive Function of executive function, methylphenidate dosing, neuropsychological test measures, the Adult ADHD Self-report scale, emotional dysregulation, social adjustment, and work productivity, as well as moderating effects of body mass index, autoantibodies to folate receptors, and select genetic polymorphisms. RESULTS: L-Methylfolate was well tolerated, with no significant effect over placebo except improvement from abnormal measures on the mean adaptive dimension of the ASR scale (χ = 4.36, P = 0.04). Methylphenidate dosing was significantly higher in individuals on L-methylfolate over time (χ = 7.35, P = 0.007). Exploratory analyses suggested that variation in a guanosine triphosphate cyclohydrolase gene predicted association with higher doses of methylphenidate (P < 0.001). CONCLUSIONS: L-Methylfolate was associated with no change in efficacy on measures relevant to neuropsychiatric function in adults with ADHD, other than suggestion of reduced efficacy of methylphenidate. Further investigation would be required to confirm this effect and its mechanism and the genotype prediction of effects on dosing.

Chronic Methylphenidate Alters Tonic and Phasic Glutamate Signaling in the Frontal Cortex of a Freely-Moving Rat Model of ADHD.

Glutamate dysfunction has been implicated in a number of substance of abuse studies, including cocaine and methamphetamine. Moreover, in attention-deficit/hyperactivity disorder (ADHD), it has been discovered that when the initiation of stimulant treatment occurs during adolescence, there is an increased risk of developing a substance use disorder later in life. The spontaneously hypertensive rat (SHR) serves as a phenotype for ADHD and studies have found increased cocaine self-administration in adult SHRs when treated with the stimulant methylphenidate (MPH) during adolescence. For this reason, we wanted to examine glutamate signaling in the pre-limbic frontal cortex, a region implicated in ADHD and drug addiction, in the SHR and its progenitor control strain, the Wistar Kyoto (WKY). We chronically implanted glutamate-selective microelectrode arrays (MEAs) into 8-week-old animals and treated with MPH (2 mg/kg, s.c.) for 11 days while measuring tonic and phasic extracellular glutamate concentrations. We observed that intermediate treatment with a clinically relevant dose of MPH increased tonic glutamate levels in the SHR but not the WKY compared to vehicle controls. After chronic treatment, both the SHR and WKY exhibited increased tonic glutamate levels; however, only the SHR was found to have decreased amplitudes of phasic glutamate signaling following chronic MPH administration. The findings from this study suggest that the MPH effects on extracellular glutamate levels in the SHR may potentiate the response for drug abuse later in life. Additionally, these data illuminate a pathway for investigating novel therapies for the treatment of ADHD and suggest that possibly targeting the group II metabotropic glutamate receptors may be a useful therapeutic avenue for adolescents diagnosed with ADHD.

A Randomized Controlled Trial to Examine the Posttreatment Efficacy of Neurofeedback, Behavior Therapy, and Pharmacology on ADHD Measures.

OBJECTIVE: To examine the efficacy of neurofeedback (NF), behavior therapy (BT), and pharmacology (PH) on the improvement of ADHD-related symptoms. METHOD: Fifty-nine children with ADHD ( M = 8.80 years, SD = 1.92 years) were randomly assigned to one of the three treatments in a pre/post assessment design. Mother- and teacher-rated ADHD scales and children were assessed using The Integrated Visual and Auditory Continuous Performance Test (IVA/CPT). RESULTS: The three treatments were effective on the IVA/CPT, but with different trends. BT and especially NF achieved improvement on response control and attention, and PH mainly in visual attention. On the rating scales, BT improved all measures, and NF and PH had a minor but interesting influence. CONCLUSION: From a global perspective, behavior therapy had the most extensive results, but PH had the greatest capacity to improve overall attention. NF was able to improve both control response and inattention. Clinical implications are discussed.

Early monitoring of fatty acid profile in children with attention deficit and/or hyperactivity disorder under treatment with omega-3 polyunsaturated fatty acids.

BACKGROUND: Cognitive effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) might make them helpful in attention deficit/hyperactivity disorder (ADHD). However, the results derived from supplementation studies in children depend on the respective combinations and the study period. We aimed to investigate the serum fatty acid profile, attention scores and the tolerability in a group of ADHD children after receiving methylphenidate (MPH) and ω-3 PUFAs for 1 month. METHODS: A combination of MPH (1 mg/kg/day) and eicosapentaenoic (EPA, 70 mg/day) + docosahexaenoic acids (DHA, 250 mg/day) was administered to 40 ADHD children (7-15 years). An analysis of serum fatty acids by gas chromatography and an assessment of attention by using the Magallanes Scale of Visual Attention (MSVA) were carried out before and after 1 month of treatment. RESULTS: Our data revealed significant decreases of several ω-6 PUFAs, like arachidonic acid (P<0.0259). EPA and DHA concentrations increased by 27% and 3% respectively, and the ω-6/ω-3 index slightly decreased. The quality of attention significantly increased (P<0.026) and an improvement of ADHD core symptoms was reported both by parents and by teachers. No severe side effects occurred. CONCLUSIONS: Results demonstrate that the combination of MPH and EPA+DHA at the tested doses has positive clinical effects and an adequate safety profile. Therefore, our study suggests that ω-3 PUFAs may represent a feasible and a safe adjuvant therapy in children with ADHD and might enhance the effects of MPH. Further long-term follow-up studies are required to confirm these initial findings.

Single Institute Experience With Methylphenidate and American Ginseng in Cancer-Related Fatigue.

BACKGROUND: Single therapy with methylphenidate or American ginseng contributes to the reduction in cancer-related fatigue (CRF) with different pharmacologic mechanisms and is relatively safe. However, the safety and efficacy of treating CRF with methylphenidate and AG combination therapy is unknown. AIM: The primary objective was to assess the clinical safety and the change in fatigue with numerical rating scale (NRS) on the Edmonton Symptom Assessment Scale (ESAS) after intervention with methylphenidate and AG combination therapy. METHODS: We reviewed the electronic medical records of 857 patients seen in our Palliative Medicine outpatient clinic between February 1, 2015, and December 31, 2015. Fatigue was assessed by NRS on ESAS. Toxicity was reviewed on clinician's documents. RESULTS: We identified 28 patients who were prescribed a combination of methylphenidate (10-40 mg/d) and AG (2000 mg/d). Ten patients did not comply with the combination therapy. Three patients had stage 2 adverse effects. Fifteen patients completed prescribed combination therapy per instructions. The mean time interval between pre- and postintervention follow-up was 30.5 days (standard deviation [SD]: 7.78). There was a significant reduction in the fatigue score (mean score 6.93-4.13) from the pre- to postscore records (mean: -2.8; SD: 1.61; P < .0002* [*refers to statistically significant]). Sixty percent of patients reported significant reduction in fatigue (cutoff value: ≥3; reduction in fatigue score from baseline: 80% ≥2, 60% ≥3, and 46.7% ≥4). CONCLUSION: In our retrospective medical record review, the combination treatment of methylphenidate and AG had no discernible associated toxicities and showed potential clinical benefit in CRF.

The age-dependent effects of a single-dose methylphenidate challenge on cerebral perfusion in patients with attention-deficit/hyperactivity disorder.

Methylphenidate (MPH) is a stimulant drug and an effective treatment for attention-deficit/hyperactivity disorder (ADHD) in both children and adults. Pre-clinical studies suggest that the response to stimulants is dependent on age, which may reflect the ontogeny of the dopamine (DA) system, which continues to develop throughout childhood and adolescence. Therefore, the aim of this study was to investigate the modulating effect of age on the cerebral blood flow (CBF) response to MPH in stimulant treatment-naive children and adults with ADHD. Ninety-eight stimulant treatment-naive male pediatric (10-12 years) and adult (23-40 years) patients with ADHD were included in this study. The CBF response to an acute challenge with MPH (0.5 mg/kg) was measured using arterial spin labeling (ASL) pharmacological magnetic resonance imaging, as a proxy for DA function. Region-of-interest (ROI) analyses were carried out for the striatum, thalamus and medial prefrontal cortex and in addition voxel-wise analyses were conducted. An acute challenge with MPH decreased CBF in both children and adults in cortical areas, although to a greater extent in adults. In contrast, ROI analyses showed that MPH decreased thalamic CBF only in children, but not adults. Our findings highlight the importance of taking the developmental perspective into account when studying the effects of stimulants in ADHD patients.

Efficacy of Polyunsaturated Fatty Acids (PUFA) in the Treatment of Attention Deficit Hyperactivity Disorder.

OBJECTIVE: We aimed to investigate the efficacy of polyunsaturated fatty acids (PUFAs) as an adjuvant treatment in patients with ADHD receiving methylphenidate as well as its side effects. METHOD: This randomized clinical trial was conducted on 40 ADHD patients aged between 6 and 12 years. Both treatment and placebo groups received methylphenidate. Treatment arm also received omega-6 once daily. The Parent ADHD Rating Scale was used to evaluate disease improvement. RESULTS: The Parent ADHD Rating Scale scores of the two groups were similar at baseline. Although total score and scores of three categories decreased significantly in both groups, total score and scores of inattention, hyperactivity, and impulsivity were not significantly different between the groups. CONCLUSION: The results did not support the efficacy of PUFA in the treatment of ADHD, and adding PUFAs to the therapeutic regimen of ADHD is not recommended at the moment.

A randomized controlled trial into the effects of neurofeedback, methylphenidate, and physical activity on EEG power spectra in children with ADHD.

BACKGROUND: The clinical and neurophysiological effects of neurofeedback (NF) as treatment for children with ADHD are still unclear. This randomized controlled trial (RCT) examined electroencephalogram (EEG) power spectra before and after NF compared to methylphenidate (MPH) treatment and physical activity (PA) - as semi-active control group - during resting and active (effortful) task conditions to determine whether NF can induce sustained alterations in brain function. METHODS: Using a multicentre three-way parallel group RCT design, 112 children with a DSM-IV diagnosis of ADHD, aged between 7 and 13 years, were initially included. NF training consisted of 30 sessions of theta/beta training at Cz over a 10-week period. PA training was a semi-active control group, matched in frequency and duration. Methylphenidate was titrated using a double-blind placebo controlled procedure in 6 weeks, followed by a stable dose for 4 weeks. EEG power spectra measures during eyes open (EO), eyes closed (EC) and task (effortful) conditions were available for 81 children at pre- and postintervention (n = 29 NF, n = 25 MPH, n = 27 PA). CLINICAL TRIALS REGISTRATION: Train Your Brain? Exercise and Neurofeedback Intervention for ADHD, https://clinicaltrials.gov/show/;NCT01363544, Ref. No. NCT01363544. RESULTS: Both NF and MPH resulted in comparable reductions in theta power from pre- to postintervention during the EO condition compared to PA (ηp (2)  = .08 and .12). For NF, greater reductions in theta were related to greater reductions in ADHD symptoms. During the task condition, only MPH showed reductions in theta and alpha power compared to PA (ηp (2)  = .10 and .12). CONCLUSIONS: This study provides evidence for specific neurophysiological effects after theta/beta NF and MPH treatment in children with ADHD. However, for NF these effects did not generalize to an active task condition, potentially explaining reduced behavioural effects of NF in the classroom.