[Effect of Rehmanniae Radix Praeparata on energy metabolism in prefrontal cortex of rats with attention deficit hyperactivity disorder based on "static Yin and dynamic Yang" theory].

The present study investigated the effect of Rehmanniae Radix Praeparata(RRP) on the energy metabolism of prefrontal cortex(PFC) of spontaneously hypertensive rats with attention deficit hyperactivity disorder(ADHD) based on the "static Yin and dynamic Yang" theory.Thirty spontaneously hypertensive male rats aged 3 weeks were randomly divided into a model group, a methylphenidate(MPH) group(2 mg·kg~(-1)), and an RRP group(2.4 g·kg~(-1)).Wistar-Kyoto(WKY) male rats of the same age were assigned to the normal group.Rats were treated with corresponding drugs twice per day, and those in the model group and the normal group received the same volume of 0.9% sodium carboxymethyl cellulose(CMC-Na) solution by gavage.The open-field test was performed to evaluate the spontaneous and impulsive behaviors of rats before treatment and on the 4~(th) week after treatment.Four weeks after treatment, PFC was isolated and mitochondria were prepared.The content of adenosine triphosphate(ATP), adenosine diphosphate(ADP), and adenosine monophosphate(AMP) in the PFC was determined by high-performance liquid chromatography(HPLC), and energy charge(EC) was calculated.The parameters related to mitochondrial respiratory function were measured by the Clark oxygen electrode, specifically, state 3 respiration(ST3), state 4 respiration(ST4), and respiratory control rate(RCR).Enzymatic activities of succinate dehydrogenase(SDH), cytochrome C oxidase(COX), Na~+-K~+-ATPase, and Ca~(2+)-Mg~(2+)-ATPase were measured by chemical colorimetry.Mitochondrial permeability transition pore(mPTP) opening was measured by spectrophotometry.Protein expression of glucose transporter 1(GLUT1) and GLUT3 in PFC was tested by Western blot.Compared with the results in the model group, RRP could significantly reduce the total distance of movement, vertical times, and distance in the central area in the open field test(P<0.05 or P<0.01), increase the content of ATP and EC, decrease the content of AMP(P<0.05), elevate ST3 and RCR(P<0.05), potentiate activities of SDH, COX, Na~+-K~+-ATPase, and Ca~(2+)-Mg~(2+)-ATPase(P<0.05 or P<0.01), inhibit the opening of mPTP, and increase the expression levels of GLUT1 and GLUT3 proteins(P<0.05).It was inferred that RRP could inhibit hyperacti-vity and impulsivity by improving the energy metabolism disorder in PFC of ADHD rats, and its mechanism may be related to the improvement of mitochondrial respiratory function, potentiation of Na~+-K~+-ATPase, Ca~(2+)-Mg~(2+)-ATPase, and mitochondrial respiratory enzymes, inhibition of the opening of mPTP, and up-regulation of the expression of glucose transporter proteins.This study initially reveals the biological connotation of the "static Yin and dynamic Yang" theory in ADHD.

Editorial: Accumulating Evidence for the Benefit of Micronutrients for Children With Attention-Deficit/Hyperactivity Disorder.

The first paper indicating that a central nervous system stimulant (amphetamine) could be beneficial for children with attention-deficit/hyperactivity disorder (ADHD)-like behavioral symptoms appeared in 1937.1 Over the subsequent 80 years, a range of additional stimulant (methylphenidate) and nonstimulant (atomoxetine, clonidine, guanfacine, and, most recently, viloxazine) drugs have been approved to treat children and adolescents with ADHD. These drug treatments have been the subject of a large number of randomized controlled trails (RCTs). A network meta-analysis found that using clinician ratings, amphetamine, methylphenidate, and atomoxetine were all significantly superior to a placebo.2 These findings suggest that in the short-term at least, these treatments are effective-data are sparse on the efficacy of longer-term drug treatment. However, there are longstanding worries about the use of such drug treatments with children. In particular there are concerns over possible adverse impact on growth. There are also less tangible, but important, concerns of parents as the whether it is appropriate to subject their children to the modification of behavior by drugs.3 For these reasons, there is an urgent need to develop nonpharmacological treatments for children and adolescents with ADHD. One such nonpharmacological treatment is dietary supplementation with micronutrients. In this issue of the Journal, Johnstone et al.4 present a study of micronutrients showing that, under the stringent conditions of an RCT, micronutrients substantially benefit the well-being of young people with ADHD and irritability (risk ratio [RR] = 2.97; 97.5% CI = 1.50-5.90).

Effect of Iron Supplementation in Children with Attention-Deficit/Hyperactivity Disorder and Iron Deficiency: A Randomized Controlled Trial.

OBJECTIVES: To determine the effectiveness of combined iron supplementation and methylphenidate treatment on attention-deficit/hyperactivity disorder (ADHD) symptoms in children/adolescents with ADHD and iron deficiency compared with methylphenidate alone. METHODS: In total, 116 children/adolescents with ADHD were screened for iron deficiency. Participants who exhibited iron deficiency were randomized into 2 groups (ferrous supplementation vs placebo). Vanderbilt ADHD rating scales were completed by parents and teachers at prestudy and poststudy periods. Student's t tests were used to determine improvements of Vanderbilt scores between the groups. RESULTS: Among 116 children who participated in this study, 44.8% (52/116) met the criteria for iron deficiency. Of the total 52 participants with iron deficiency, 26 were randomized to the ferrous group and 26 to the placebo group. Most participants in each group had been prescribed short-acting methylphenidate twice daily in the morning and at noon. After a 12-week study period, total parents' Vanderbilt ADHD symptom scores showed a significant improvement between the groups (mean decrement = -3.96 ± 6.79 vs 0 ± 6.54, p = 0.037). However, teachers' Vanderbilt ADHD symptom scores showed no difference between the groups. CONCLUSION: Children with ADHD and iron deficiency being on methylphenidate and iron supplementation had shown improvement of ADHD symptoms that were reported by parents.

Personalized at-home neurofeedback compared to long-acting methylphenidate in children with ADHD: NEWROFEED, a European randomized noninferiority trial.

BACKGROUND: Neurofeedback is considered a promising intervention for the treatment of attention-deficit hyperactivity disorder (ADHD). NEWROFEED is a prospective, multicentre, randomized (3:2), reference drug-controlled trial in children with ADHD aged between 7 and 13 years. The main objective of NEWROFEED was to demonstrate the noninferiority of personalized at-home neurofeedback (NF) training versus methylphenidate in the treatment of children with ADHD. METHODS: The NF group (n = 111) underwent eight visits and two treatment phases of 16 to 20 at-home sessions with down-training of the theta/beta ratio (TBR) for children with high TBR and enhancing the sensorimotor rhythm (SMR) for the others. The control group (n = 67) received optimally titrated long-acting methylphenidate. The primary endpoint was the change between baseline and endpoint in the Clinician ADHD-RS-IV total score in the per-protocol population (90 NF/59 controls). TRIAL REGISTRATION: US National Institute of Health, ClinicalTrials.gov #NCT02778360. RESULTS: Our study failed to demonstrate noninferiority of NF versus methylphenidate (mean between-group difference 8.09 90% CI [8.09; 10.56]). However, both treatment groups showed significant pre-post improvements in core ADHD symptoms and in a broader range of problems. Reduction in the Clinician ADHD-RS-IV total score between baseline and final visit (D90) was 26.7% (SMD = 0.89) in the NF and 46.9% (SMD = 2.03) in the control group. NF effects increased whereas those of methylphenidate were stable between intermediate and final visit. CONCLUSIONS: Based on clinicians' reports, the effects of at-home NF were inferior to those of methylphenidate as a stand-alone treatment.

Effect of methylphenidate at different doses on new bone formation with rapid maxillary expansion: A micro-CT and histomorphometric study in rats.

OBJECTIVES: This study aimed to evaluate the effect of systemically administered methylphenidate hydrochloride (MPH) on new bone formation in premaxillary suture after rapid maxillary expansion (RME). SETTING AND SAMPLE POPULATION: Thirty-three Wistar rats were divided into four groups: Group 1 (high dose, 30/60 mg/kg MPH), Group 2 (low dose, 4/10 mg/kg MPH), Group 3 (positive control) and Group 4 (negative control). METHODS: RME was applied on the 70th day of the study. A 5-day RME period was followed by a 12-day retention period. The experiment was terminated on the 87th day. Micro-CT for radiological evaluation, haematoxylin-eosin and Masson's trichrome staining methods were used for histomorphometric evaluation. RESULTS: Among experimental groups with RME, the lowest number of osteoblasts and capillaries in Group 1 (P < .05). New bone formation, fibrous callus formation, distal osteotomy line, proximal osteotomy union and cortex remodelling were observed to be lower in Group 1 and Group 2 than Group 3 (P < .05). There was a statistically significant difference between Group 4 and each of the other groups (P = .000) in the evaluation of the results for bone mineral density, bone volume, bone volume percentage, trabecular thickness and trabecular number. CONCLUSIONS: MPH reduces cellular activity for new bone formation in suture in RME groups. Before performing rapid maxillary expansion in patients using MPH, the use of the drug should be postponed after a multidisciplinary decision process or clinical doses should be lowered.

Effects of methylphenidate on sensory and sensorimotor gating of initially psychostimulant-naïve adult ADHD patients.

Deficient information processing in ADHD theoretically results in sensory overload, which in turn may underlie its symptoms. If this sensory overload is caused by deficient filtering of environmental stimuli, then one would expect finding deficits in P50 gating and prepulse inhibition of the startle reflex (PPI). Previous reports on these measures in ADHD have shown inconsistent findings, which may have been caused by either medication use or comorbidity (e.g. ASD). The primary aim of this study was therefore to explore P50 suppression and PPI in adult, psychostimulant-naïve patients with ADHD without major comorbidity, and to examine the effects of 6 weeks treatment with methylphenidate (MPH) on these measures. A total of 42 initially psychostimulant-naive, adult ADHD patients without major comorbidity and 42 matched healthy controls, were assessed for their P50 gating, PPI, and habituation/sensitization abilities at baseline and after 6 weeks of treatment with methylphenidate. Although six weeks of treatment with MPH significantly reduced symptomatology as well as improved daily life functioning in our patients, it neither significantly affected PPI, P50 suppression nor sensitization, but habituation unexpectedly decreased. The absence of PPI and P50 suppression deficits in our patients in the psychostimulant-naïve state indicates no gating deficits. In turn, this suggests that the difficulties to inhibit distraction of attention by irrelevant stimuli that many patients with (adult) ADHD report, have a different origin than the theoretical causes of sensory overload frequently reported in studies on patients with schizophrenia.

Effects of curcumin nanoparticle on the histological changes and apoptotic factors expression in testis tissue after methylphenidate administration in rats.

The present article sought to evaluate the impact of curcumin-loaded superparamagnetic iron oxide (Fe3O4) nanoparticles (NPs) on the histological variables and apoptotic agents in adult male rats after 3-weeks of methylphenidate (MPH) oral administration (20 mg/kg) versus vehicle therapy on the testis. Twenty-four male rats have been categorized randomly into four groups, in which Group 1 has been chosen as the controls, and Group 2 has been a vehicle and taken the sesame oil as curcumin carrier. Moreover, Group 3 has been taken MPH (20 mg/kg by gavage for 21 consecutive days). Group 4 received MPH plus Curcumin nanoparticles (5.4 mg/100 g) for twenty-one consecutive days. Then, testis histology, apoptosis as well as stereology have been examined. According to the examinations, curcumin nanoparticles are significantly capable of improving the sperms and stereological variables; for example, round spermatid and Leydig cells by enhancing the level of the serum testosterone in comparison with the MPH and vehicle groups. Besides, it was found that the gene expression in inflammation pathways and apoptosis genes largely diminished in the treatment group by curcumin nanoparticles in comparison with the MPH and vehicle groups, also we observed considerable differences for the weight of testes between the examined groups. Therefore, Curcumin effectively inhibited the testis damages and MPH-induced apoptosis, indicating possible protecting features of the Curcumin nanoparticles in opposition to MPH.

Methylphenidate and Rosmarinus officinalis improves cognition and regulates inflammation and synaptic gene expression in AlCl3-induced neurotoxicity mouse model.

Methylphenidate (MPH), a psychotropic medication is commonly used for children with attention deficit hyperactivity disorder (ADHD). In this study we elucidated the neuroprotective and anti-inflammatory effects of MPH and Rosmarinus officinalis (rosemary) extract, an ancient aromatic herb with several applications in traditional medicine. Briefly, six groups of mice (n = 8 each group), were specified for the study and behavioral analysis was performed to analyze spatial memory followed by histological assessment and gene expression analysis of synaptic (Syn I, II and III) and inflammatory markers (IL-6, TNFα and GFAP) via qRT-PCR, in an AlCl3-induced mouse model for neurotoxicity. The behavioral analysis demonstrated significant cognitive decline, memory defects and altered gene expression in AlCl3-treated group. Rosemary extract significantly decreased the expression of inflammatory and synaptic markers to the similar levels as that of MPH. The present findings suggested the neuroprotective potential of Rosmarinus officinalis extract. However, further characterization of its anti-inflammatory and neuroprotective properties and MPH is required to strategize future treatments for several neurological and neurodegenerative disorders, including Alzheimer's disease.

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.

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.

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.

Effects of neurofeedback versus methylphenidate for the treatment of ADHD: systematic review and meta-analysis of head-to-head trials.

BACKGROUND: The comparative efficacy and tolerability of methylphenidate (MPH) and neurofeedback (NF) in individuals with attention-deficit/hyperactivity disorder (ADHD) remains uncertain. This study aimed to fill this gap by means of a systematic review/meta-analysis. METHODS: PubMed, OVID, ERIC, Web of Science, ClinialTrials.gov and a set of Chinese databases were searched until 22 August 2018. Standardised mean differences (SMD) were pooled using comprehensive meta-analysis software. RESULTS: 18 randomised controlled trials (RCTs) were included (778 individuals with ADHD in the NF arm and 757 in the MPH group, respectively; 13 studies in Chinese, five in English). At the study first endpoint, MPH was significantly more efficacious than NF on ADHD core symptoms (ADHD symptoms combined: SMD=-0.578, 95% CI (-1.063 to -0.092)) and on two neuropsychological parameters (inattention:-0.959 (-1.711 to -0.208); inhibition:-0.469 (-0.872 to -0.066)). Dropouts were significantly lower in NF versus MPH (OR=0.412, 0.186 to 0.913). Results were robust to sensitivity analyses, with two important exceptions: removing Chinese studies and non-funded studies, no differences emerged between MPH and NF, although the number of studies was small. At the study follow-up, MPH was superior to NF in some outcomes, but results were inconsistent across raters. CONCLUSIONS: Due to the risk of bias of included studies, the results of the sensitivity analysis excluding Chinese and non-funded studies, and the mixed findings on at the follow-up endpoint, further high quality studies are needed to assess the comparative efficacy and acceptability of NF and MPH in individuals with ADHD. TRIAL REGISTRATION NUMBER: CRD42018090256.

Methylphenidate's effects on thalamic metabolism and functional connectivity in cannabis abusers and healthy controls.

Methylphenidate (MPH) is a first line treatment for ADHD and is also misused as a purported cognitive enhancer, yet its effects on brain function are still poorly understood. Recent functional magnetic resonance imaging (fMRI) studies showed that MPH altered cortico-striatal resting functional connectivity (RFC). Here we investigated the effects of MPH in thalamic connectivity since the thalamus modulates striato-cortical signaling. We hypothesized that MPH would increase thalamic connectivity and metabolism, and that this response would be blunted in cannabis abusers. For this purpose, we measured RFC in seven thalamic nuclei using fMRI and brain glucose metabolism using positron emission tomography (PET) and 18F-fluorodeoxyglucose (FDG) in sixteen healthy controls and thirteen participants with cannabis use disorder (CUD) twice after placebo and after MPH (0.5 mg/kg, iv). MPH significantly increased thalamo-cerebellar connectivity and cerebellar metabolism to the same extent in both groups. Group comparisons revealed that in CUD compared to controls, metabolism in nucleus accumbens was lower for the placebo and MPH measures, that MPH-induced increases in thalamic metabolism were blunted, and that enhanced negative connectivity between thalamus and accumbens in CUD was normalized by MPH (reducing negative connectivity). Our findings identify the thalamus as a target of MPH, which increased its metabolism and connectivity. The reduced metabolism in nucleus accumbens and the disrupted thalamo-accumbens connectivity (enhanced negative connectivity) in CUD is consistent with impaired reactivity of the brain reward's circuit. MPH's normalization of thalamo-accumbens connectivity (reduced negative connectivity) brings forth its potential therapeutic value in CUD, which merits investigation.

A comparative study on the neurophysiological mechanisms underlying effects of methylphenidate and neurofeedback on inhibitory control in attention deficit hyperactivity disorder.

In Attention Deficit Hyperactivity Disorder (AD(H)D), treatments using methylphenidate (MPH) and behavioral interventions like neurofeedback (NF) reflect major therapeutic options. These treatments also ameliorate executive dysfunctions in AD(H)D. However, the mechanisms underlying effects of MPH and NF on executive functions in AD(H)D (e.g. the ability to inhibit prepotent responses) are far from understood. It is particularly unclear whether these interventions affect similar or dissociable neural mechanisms and associated functional neuroanatomical structures. This, however, is important when aiming to further improve these treatments. We compared the neurophysiological mechanisms of MPH and theta/beta NF treatments on inhibitory control on the basis of EEG recordings and source localization analyses. The data show that MPH and theta/beta NF both increase the ability to inhibit pre-potent responses to a similar extent. However, the data suggest that MPH and NF target different neurophysiological mechanisms, especially when it comes to functional neuroanatomical structures associated with these effects. Both treatments seem to affect neurophysiological correlates of a 'braking function' in medial frontal areas. However, in case of the NF intervention, inferior parietal areas are also involved. This likely reflects the updating and stabilisation of efficient internal representations in order to initiate appropriate actions. No effects were seen in correlates of perceptual and attentional selection processes. Notably, reliable effects were only obtained after accounting for intra-individual variability in the neurophysiological data, which may also explain the diversity of findings in studies on treatment effects in AD(H)D, especially concerning neurofeedback.

[Regulatory effect of Shudihuang on expressions of BDNF/TrkB and NRG-3 in prefrontal cortex and striatum of ADHD model rats].

To observe the effect of Shudihuang on behaviors and expression of BDNF/TrkB and NRG-3 in prefrontal cortex and striatum of attention deficit hyperactivity disorder (ADHD) model rats. Thirty 4-week-old spontaneous hypertension rats (SHR) were randomly divided into model group, methylphenidate hydrochloride (MPH, 2 mg·kg⁻¹·d⁻¹) and Shudihuang group (2.4 g·kg⁻¹·d⁻¹). Another 10 Wistar-Kyoto (WKY) rats were selected as normal control group. The 0.5% CMC-Na solution was administered to model group and WKY rats (2 mL·kg⁻¹·d⁻¹). All of the rats were treated for 4 weeks. The open field test was performed at the 14th and 28th days after gavage, in order to evaluate the spontaneous and impulsive behaviors. Subsequently, gene and protein expressions of BDNF/TrkB and NRG-3 were tested by RT-qPCR and Western blot. Compared with model group, MPH and Shudihuang groups showed significant reduction in total distance, mean velocity and central distance in the open field test (P<0.05), and Shudihuang group displayed a shorter central distance than MPH group (P<0.05). RT-qPCR and Western blot analysis indicated that expressions of BDNF/TrkB and NRG-3 were lower in prefrontal cortex and striatum of SHR compared with WKY rats. Four weeks later after administration, both Shudihuang and MPH significantly elevated mRNA and protein expressions of BDNF/TrkB and NRG-3 (P<0.05).In conclusion, neurodevelopmental disorder mediated by BDNF/TrkB and NRG-3 was closely related with SHR rats' behaviors. Shudihuang may ameliorate the spontaneous and impulsive behaviors by up-regulating the expressions of BDNF/TrkB and NRG-3 and improving growth and maturation of neurons in SHR.

Reward-enhancing effect of methylphenidate is abolished in dopamine transporter knockout mice: A model of attention-deficit/hyperactivity disorder.

AIM: Attention-deficit/hyperactivity disorder is a heterogeneous neurobiological disorder that is characterized by inattention, impulsivity, and an increase in motor activity. Although methylphenidate has been used as a medication for decades, unknown is whether methylphenidate treatment can cause drug dependence in patients with attention-deficit/hyperactivity disorder. This study investigated the reward-enhancing effects of methylphenidate using intracranial self-stimulation in an animal model of attention-deficit/hyperactivity disorder, dopamine transporter knockout mice. METHODS: For the intracranial self-stimulation procedures, the mice were trained to nosepoke to receive direct electrical stimulation via an electrode that was implanted in the lateral hypothalamus. After the acquisition of nosepoke responding for intracranial self-stimulation, the effects of methylphenidate on intracranial self-stimulation were investigated. RESULTS: In the progressive-ratio procedure, dopamine transporter knockout mice exhibited an increase in intracranial self-stimulation compared with wild-type mice. Treatment with 5 and 10 mg/kg methylphenidate increased intracranial self-stimulation responding in wild-type mice. Methylphenidate at the same doses did not affect intracranial self-stimulation responding in dopamine transporter knockout mice. We then investigated the effects of high-dose methylphenidate (60 mg/kg) in a rate-frequency procedure. High-dose methylphenidate significantly decreased intracranial self-stimulation responding in both wild-type and dopamine transporter knockout mice. CONCLUSIONS: These results suggest that low-dose methylphenidate alters the reward system (ie, increases intracranial self-stimulation responding) in wild-type mice via dopamine transporter inhibition, whereas dopamine transporter knockout mice do not exhibit such alterations. High-dose methylphenidate appears to suppress intracranial self-stimulation responding not through dopamine transporter inhibition but rather through other mechanisms. These results support the possibility that methylphenidate treatment for attention-deficit/hyperactivity disorder does not increase the risk of drug dependence, in attention-deficit/hyperactivity disorder patients with dopamine transporter dysfunction.

Lisdexamfetamine Dimesylate: A Review in Paediatric ADHD.

Lisdexamfetamine dimesylate (lisdexamfetamine; Elvanse®; Tyvense®), an orally-active dexamfetamine prodrug, is indicated in the EU for the treatment of attention-deficit hyperactivity disorder (ADHD) in children aged ≥ 6 years (including adolescents) when the response to previous methylphenidate (MPH) treatment is clinically inadequate. The original approval of the drug was based on the results of phase III trials in children and adolescents with ADHD who had an inadequate response to previous pharmacotherapy (e.g. MPH) or were treatment naïve. In these studies, short-term treatment with flexibly-dosed lisdexamfetamine demonstrated greater efficacy than atomoxetine, based on a prospective comparison, and osmotic-release oral system (OROS)-MPH, based on a post hoc comparison. Improvements in ADHD symptoms were accompanied by improvements in health-related quality of life and functioning that were maintained as long as treatment with lisdexamfetamine was continued in a long-term extension of one of these trials. In subsequent phase IV head-to-head studies in adolescents with ADHD and an inadequate response to previous pharmacotherapy, lisdexamfetamine demonstrated greater efficacy than OROS-MPH when both medications were force-titrated, but not when they were flexibly-titrated. Lisdexamfetamine was generally well tolerated, with an adverse event profile (e.g. decreased appetite, headache, weight reduction, insomnia and irritability) typical of that reported for other stimulants. Thus, lisdexamfetamine provides an alternative option for the treatment of children and/or adolescents with ADHD who have not responded adequately to previous ADHD pharmacotherapies.

Risk of suicide attempts in adolescents and young adults with attention-deficit hyperactivity disorder: a nationwide longitudinal study.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) increases the risk of suicidal behaviours through psychiatric comorbidities; however, a significant direct association has not been observed between ADHD and suicide attempts. Aims To evaluate the risk of suicide attempt in adolescents and young adults with ADHD. METHOD: Using a nationwide, population-based insurance claims database, this longitudinal cohort study enrolled 20 574 adolescents and young adults with ADHD and 61 722 age- and gender-matched controls between 2001 and 2009. Any suicide attempt was identified from enrolment to 31 December 2011. The association between ADHD medications and the likelihood of suicide attempt was assessed. RESULTS: ADHD was an independent risk factor for any suicide attempt (hazard ratio = 3.84, 95% CI = 3.19-4.62) and repeated suicide attempts (hazard ratio = 6.52, 95% CI = 4.46-9.53). Subgroup analyses of men, women, adolescents and young adults demonstrated the same trend. Methylphenidate or atomoxetine treatment did not increase the risk of suicide attempt or repeated suicide attempts. Long-term methylphenidate treatment was associated with a significantly decreased risk of repeated suicide attempts in men (hazard ratio = 0.46, 95% CI = 0.22-0.97). CONCLUSION: ADHD was a risk factor for suicide attempt and a stronger predictor of repeated suicide attempts, independent of comorbidities. Further investigation is warranted to explore the mechanism underlying the association between ADHD and suicidal behaviours. Declaration of interest None.

[Doping for the brain]. / Doping für das Gehirn.

The enhancement of physical and cognitive abilities (i. e. concentration, vigilance, memory) has always been desirable for humans. The term pharmacological neuroenhancement refers to the use of legal or nonprescription psychoactive substances by healthy subjects with the intention of cognitive enhancement. To give the most prominent example, caffeine serves worldwide as a natural stimulant. Brain doping, however, specifies the use of illegal substances or prescription drugs beyond approval with the purpose of cognitive enhancement. Only amphetamines, methylphenidate and modafinil have significant effects on attentiveness, concentration and alertness, whereas other substances, such as anti-dementia drugs or anti-depressants failed to demonstrate cognitive enhancement in healthy subjects.

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.