Decreased Risk of Influenza in Child and Adolescent Patients with Attention?-Deficit Hyperactivity Disorder Following Methylphenidate Treatment: A Nationwide Cohort Study in Taiwan.
ABSTRACT: BackgroundYoung individuals with attention?-deficit hyperactivity disorder (ADHD) may have an elevated risk of influenza because of the difficulty in complying with the behavioral procedures that help protect against influenza. Moreover, the effects of sufficient methylphenidate treatment on influenza have received little attention.ObjectiveThis study evaluated the association between ADHD medication usage and influenza and assessed the effect of duration of ADHD treatment on the risk of influenza using a nationwide population-based database.MethodsThis study investigated methylphenidate usage and the risk of influenza among children and adolescents with ADHD. We identified 5259 young individuals aged less than 18 years who were diagnosed as having ADHD between 1996 and 2013 from the National Health Insurance Research Database of Taiwan, and we tested whether methylphenidate use affects influenza risk using Cox proportional hazard models.ResultsAfter controlling for confounding factors, the results indicated that influenza risk significantly reduced in the group of ADHD patients who were prescribed methylphenidate for 90 days and more (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.52–0.75, p<0.001), demonstrating a 38% reduction in the risk of influenza in this group. However, this was not observed in the group of ADHD patients who used methylphenidate for 1–90 days (HR: 0.69, 95% CI: 0.89–1.05, p=0.12).ConclusionThe lower incidence of influenza observed in the group prescribed with methylphenidate for a longer period highlights the importance of compliance to medication and psychoeducation with regard to ADHD management.
Project description:BACKGROUND:The prescription use of the stimulants methylphenidate and amphetamine for the treatment of attention deficit-hyperactivity disorder (ADHD) has been increasing. In 2007, the Food and Drug Administration mandated changes to drug labels for stimulants on the basis of findings of new-onset psychosis. Whether the risk of psychosis in adolescents and young adults with ADHD differs among various stimulants has not been extensively studied. METHODS:We used data from two commercial insurance claims databases to assess patients 13 to 25 years of age who had received a diagnosis of ADHD and who started taking methylphenidate or amphetamine between January 1, 2004, and September 30, 2015. The outcome was a new diagnosis of psychosis for which an antipsychotic medication was prescribed during the first 60 days after the date of the onset of psychosis. To estimate hazard ratios for psychosis, we used propensity scores to match patients who received methylphenidate with patients who received amphetamine in each database, compared the incidence of psychosis between the two stimulant groups, and then pooled the results across the two databases. RESULTS:We assessed 337,919 adolescents and young adults who received a prescription for a stimulant for ADHD. The study population consisted of 221,846 patients with 143,286 person-years of follow up; 110,923 patients taking methylphenidate were matched with 110,923 patients taking amphetamines. There were 343 episodes of psychosis (with an episode defined as a new diagnosis code for psychosis and a prescription for an antipsychotic medication) in the matched populations (2.4 per 1000 person-years): 106 episodes (0.10%) in the methylphenidate group and 237 episodes (0.21%) in the amphetamine group (hazard ratio with amphetamine use, 1.65; 95% confidence interval, 1.31 to 2.09). CONCLUSIONS:Among adolescents and young adults with ADHD who were receiving prescription stimulants, new-onset psychosis occurred in approximately 1 in 660 patients. Amphetamine use was associated with a greater risk of psychosis than methylphenidate. (Funded by the National Institute of Mental Health and others.).
Project description:Attention Deficit Hyperactivity Disorder (ADHD) and educational achievement are negatively associated in children. Here we test the hypothesis that there is a direct causal effect of ADHD on educational achievement. The causal effect is tested in a genetically sensitive design to exclude the possibility of confounding by a third factor (e.g. genetic pleiotropy) and by comparing educational achievement and secondary school career in children with ADHD who take or do not take methylphenidate. Data on ADHD symptoms, educational achievement and methylphenidate usage were available in a primary school sample of ~10,000 12-year-old twins from the Netherlands Twin Register. A substantial group also had longitudinal data at ages 7-12 years. ADHD symptoms were cross-sectionally and longitudinally, associated with lower educational achievement at age 12. More ADHD symptoms predicted a lower-level future secondary school career at age 14-16. In both the cross-sectional and longitudinal analyses, testing the direct causal effect of ADHD on educational achievement, while controlling for genetic and environmental factors, revealed an association between ADHD symptoms and educational achievement independent of genetic and environmental pleiotropy. These findings were confirmed in MZ twin intra-pair differences models, twins with more ADHD symptoms scored lower on educational achievement than their co-twins. Furthermore, children with ADHD medication, scored significantly higher on the educational achievement test than children with ADHD who did not use medication. Taken together, the results are consistent with a direct causal effect of ADHD on educational achievement.
Project description:Methylphenidate is the psychostimulant medication most commonly prescribed to treat attention deficit hyperactivity disorder (ADHD). Recent trends in the high usage of methylphenidate for both therapeutic and nontherapeutic purposes prompted us to investigate the long-term effects of exposure to the drug on neuronal adaptation. We compared the effects of chronic methylphenidate or cocaine (15 mg/kg, 14 days for both) exposure in mice on dendritic spine morphology and DeltaFosB expression in medium-sized spiny neurons (MSN) from ventral and dorsal striatum. Chronic methylphenidate increased the density of dendritic spines in MSN-D1 (MSN-expressing dopamine D1 receptors) from the core and shell of nucleus accumbens (NAcc) as well as MSN-D2 (MSN-expressing dopamine D2 receptors) from the shell of NAcc. In contrast, cocaine increased the density of spines in both populations of MSN from all regions of striatum. In general, the effect of methylphenidate on the increase of shorter spines (class 2) was less than that of cocaine. Interestingly, the methylphenidate-induced increase in the density of relatively longer spines (class 3) in the shell of NAcc was bigger than that induced by cocaine. Furthermore, methylphenidate exposure increased expression of DeltaFosB only in MSN-D1 from all areas of striatum, and surprisingly, the increase was greater than that induced by cocaine. Thus, our results show differential effects of methylphenidate and cocaine on neuronal adaptation in specific types of MSN in reward-related brain regions.
Project description:BACKGROUND:There is a clinical concern that prescribing methylphenidate, the most common pharmacological treatment for attention-deficit hyperactivity disorder (ADHD), might increase the risk of psychotic events, particularly in young people with a history of psychosis. We aimed to determine whether the risk of psychotic events increases immediately after initiation of methylphenidate treatment or, in the longer term, 1 year after treatment initiation in adolescents and young adults with and without a previously diagnosed psychotic disorder. METHODS:In this cohort study, we used population-based observational data from the Swedish Prescribed Drug Register, the National Patient Register, and the Total Population Register, three population-based registers containing data on all individuals in Sweden, to attain data on sex, birth, death, migration, medication use, and psychotic events for all eligible participants. We screened individuals on these registers to identify those receiving methylphenidate treatment, and who were aged 12-30 years at the start of treatment, for their inclusion in the study. We used a within-individual design to compare the incidence of psychotic events in these individuals during the 12-week periods immediately before and after methylphenidate initiation. Longer term risk was assessed by comparing the incidence of psychotic events 12 weeks before methylphenidate initiation and during a 12-week period one calendar year before the initiation of methylphenidate with the incidence of these events during the 12-week period one calendar year after methylphenidate initiation. We estimated the incidence rate ratios (IRR) and 95% CIs of psychotic events after the initation of methylphenidate treatment, relative to the events before treatment, which were defined as any hospital visit (inpatient admission or outpatient attendance, based on data from the National Patient Register) because of psychosis, using the International Classification of Diseases version 10 definition. Analyses were stratified by whether the individual had a history of psychosis. FINDINGS:We searched the Swedish Prescribed Drug Register to find eligible individuals who had received methylphenidate between Jan 1, 2007 and June 30, 2012. 61 814 individuals were screened, of whom 23 898 (38·7%) individuals were assessed and 37 916 (61·3%) were excluded from the study because they were outside of the age criteria at the start of treatment, they had immigrated, emigrated, or died during the study period, or because they were administered other ADHD medications. The median age at methylphenidate initiation was 17 years, and a history of psychosis was reported in 479 (2·0%) participants. The IRR of psychotic events in the 12-week period after initiation of methylphenidate treatment relative to that in the 12-week period before treatment start was 1·04 (95% CI 0·80-1·34) in adolescents and young adults without a history of psychosis and 0·95 (0·69-1·30) among those with a history of psychosis. INTERPRETATION:Contrary to clinical concerns, we found no evidence that initiation of methylphenidate treatment increases the risk of psychotic events in adolescents and young adults, including in those individuals with a history of psychosis. Our study should reassure clinicians considering initiating methylphenidate treatment for ADHD in adolescents and young adults, and it challenges the widely held view in clinical practice that methylphenidate should be avoided, or its use restricted, in individuals with a history of psychosis. FUNDING:Swedish Research Council, National Institute of Mental Health, UK National Institute of Health Research Nottingham Biomedical Research Centre.
Project description:Psychostimulant medication, most commonly the catecholamine agonist methylphenidate, is the most effective treatment for attention-deficit/hyperactivity disorder (ADHD). However, relatively little is known on the mechanisms of action. Acute effects on brain function can elucidate underlying neurocognitive effects. We tested methylphenidate effects relative to placebo in functional magnetic resonance imaging (fMRI) during three disorder-relevant tasks in medication-naïve ADHD adolescents. In addition, we conducted a systematic review and meta-analysis of the fMRI findings of acute stimulant effects on ADHD brain function.The fMRI study compared 20 adolescents with ADHD under either placebo or methylphenidate in a randomized controlled trial while performing stop, working memory, and time discrimination tasks. The meta-analysis was conducted searching PubMed, ScienceDirect, Web of Knowledge, Google Scholar, and Scopus databases. Peak coordinates of clusters of significant effects of stimulant medication relative to placebo or off medication were extracted for each study.The fMRI analysis showed that methylphenidate significantly enhanced activation in bilateral inferior frontal cortex (IFC)/insula during inhibition and time discrimination but had no effect on working memory networks. The meta-analysis, including 14 fMRI datasets and 212 children with ADHD, showed that stimulants most consistently enhanced right IFC/insula activation, which also remained for a subgroup analysis of methylphenidate effects alone. A more lenient threshold also revealed increased putamen activation.Psychostimulants most consistently increase right IFC/insula activation, which are key areas of cognitive control and also the most replicated neurocognitive dysfunction in ADHD. These neurocognitive effects may underlie their positive clinical effects.
Project description:Attention-deficit/hyperactivity disorder (ADHD) is often comorbid with cocaine abuse. Controversy exists regarding long-term consequences of ADHD medications on cocaine abuse liability. Whereas childhood methylphenidate treatment may be preventative, methylphenidate in teens appears to further increase later cocaine abuse risk. In rodents, adolescent methylphenidate treatment further increases adult cocaine self-administration in the Spontaneously Hypertensive Rat (SHR) model of ADHD, whereas adolescent atomoxetine treatment does not. Effects of ADHD medications on cocaine cue reactivity, a critical component of addiction, are unknown.To investigate this, SHR, Wistar-Kyoto (inbred control) and Wistar (outbred control) rats received therapeutically relevant doses of methylphenidate (1.5 mg/kg, oral) and atomoxetine (0.3 mg/kg, intraperitoneal), or respective vehicles from post-natal day 28-55. Cocaine seeking, reflecting cue reactivity, was measured in adulthood during self-administration maintenance and cue-induced reinstatement tests conducted under a second-order schedule.Compared to control strains, SHR earned more cocaine infusions, emitted more cocaine-seeking responses during maintenance and reinstatement testing, and required more sessions to reach the extinction criterion. Compared to vehicle, adolescent methylphenidate, but not atomoxetine, further increased cocaine intake during maintenance testing in SHR. Adolescent atomoxetine, but not methylphenidate, decreased cocaine seeking during reinstatement testing in SHR. Neither medication had effects on cocaine intake or cue reactivity in control strains.The SHR successfully model ADHD and cocaine abuse comorbidity and show differential effects of adolescent ADHD medications on cocaine intake and cue reactivity during adulthood. Thus, SHR have heuristic value for assessing neurobiology underlying the ADHD phenotype and for evaluating pharmacotherapeutics for ADHD.
Project description:Attention-deficit/hyperactivity disorder (ADHD) diagnosis is based on reported symptoms, which carries the potential risk of over- or under-diagnosis. A biological marker that helps to objectively define the disorder, providing information about its pathophysiology, is needed. A promising marker of cognitive states in humans is pupil size, which reflects the activity of an 'arousal' network, related to the norepinephrine system. We monitored pupil size from ADHD and control subjects, during a visuo-spatial working memory task. A sub group of ADHD children performed the task twice, with and without methylphenidate, a norepinephrine-dopamine reuptake inhibitor. Off-medication patients showed a decreased pupil diameter during the task. This difference was no longer present when patients were on-medication. Pupil size correlated with the subjects' performance and reaction time variability, two vastly studied indicators of attention. Furthermore, this effect was modulated by medication. Through pupil size, we provide evidence of an involvement of the noradrenergic system during an attentional task. Our results suggest that pupil size could serve as a biomarker in ADHD.
Project description:OBJECTIVE:To examine whether sluggish cognitive tempo (SCT) symptomatology moderates dose response to methylphenidate and whether the impact of SCT on medication response is distinct from attention-deficit/hyperactivity disorder (ADHD) subtype effects. METHODS:Stimulant-naive children with ADHD predominantly inattentive type (ADHD-I; n = 126) or ADHD combined type (ADHD-C; n = 45) aged 7-11 years were recruited from the community from September 2006 to June 2013 to participate in a prospective, randomized, double-blind, 4-week crossover trial of long-acting methylphenidate. ADHD diagnosis and subtype were established according to DSM-IV criteria using a structured interview and teacher ADHD symptom ratings. SCT symptoms were assessed using a teacher-rated scale with 2 factors (Sluggish/Sleepy and Daydreamy). Primary outcomes included (1) categorization of children as methylphenidate responders, methylphenidate nonresponders, or placebo responders by 2 blinded physicians and (2) parent and teacher ratings of child behavior on the Vanderbilt ADHD Diagnostic Rating Scales while subjects were on treatment with placebo or 1 of 3 methylphenidate dosages (low, medium, high). RESULTS:Increased SCT Sluggish/Sleepy factor scores were associated with being a methylphenidate nonresponder or placebo responder rather than a methylphenidate responder (P = .04). Sluggish/Sleepy factor scores were also linked to diminished methylphenidate dose response for parent- and teacher-rated inattention symptoms (Sluggish/Sleepy factor × dose P = .004). SCT Daydreamy symptoms and ADHD subtype (ADHD-I vs ADHD-C) were not associated with methylphenidate responder status and did not moderate methylphenidate dose response for inattention symptoms. CONCLUSIONS:SCT Sluggish/Sleepy symptoms, but not SCT Daydreamy symptoms or ADHD subtype, predicted methylphenidate nonresponse. This novel finding, if replicated, may have important implications for assessing SCT as part of ADHD care. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01727414.
Project description:Children with autism spectrum disorder (ASD) have a considerable use of psychotropics. Leveraging nationwide registry data, we aimed to describe the use of psychotropics among children and adolescents with ASD in Denmark. Use of melatonin and attention-deficit/hyperactivity disorder (ADHD) medication increased from 2010 to 2017, while there were limited changes in use of antidepressants and antipsychotics. Thirty percent of the identified children used psychotropics in 2017 most commonly ADHD medication (17%) and melatonin (13%). Methylphenidate, sertraline and risperidone were most often prescribed. Most children filled more than one prescription and, across drug classes, at least 38% received treatment two years after treatment initiation. Use of psychotropics followed psychiatric comorbidities. Comorbidities did not affect age at treatment initiation. Use of psychotropics varied according to age and sex with limited use in the youngest children. In summary, psychotropic drug use has increased in children with ASD mainly due to an increase in the use of ADHD medication and melatonin. In accordance with previous studies, use seems to follow comorbidities. The long treatment duration underlines the need to investigate long-term effects of psychotropic drug use in children with ASD.
Project description:There are persistent concerns of long-term effects of stimulant ADHD medication on the development of substance abuse.Using Swedish national registers, we studied all individuals born between 1960 and 1998 and diagnosed with ADHD (26,249 men and 12,504 women). We investigated the association between stimulant ADHD medication in 2006 and substance abuse during 2009. Substance abuse was indexed by substance-related death, crime, or hospital visits.ADHD medication was not associated with increased rate of substance abuse. Actually, the rate during 2009 was 31% lower among those prescribed ADHD medication in 2006, even after controlling for medication in 2009 and other covariates (hazard ratio: 0.69; 95% confidence interval: 0.57-0.84). Also, the longer the duration of medication, the lower the rate of substance abuse. Similar risk reductions were suggested among children and when investigating the association between stimulant ADHD medication and concomitant short-term abuse.We found no indication of increased risks of substance abuse among individuals prescribed stimulant ADHD medication; if anything, the data suggested a long-term protective effect on substance abuse. Although stimulant ADHD medication does not seem to increase the risk for substance abuse, clinicians should remain alert to the potential problem of stimulant misuse and diversion in ADHD patients.