Methylphenidate normalizes resting-state brain dysfunction in boys with attention deficit hyperactivity disorder.
ABSTRACT: We used resting-state functional magnetic resonance imaging (RS-fMRI) to investigate the acute effects of methylphenidate hydrochloride (MPH) on spontaneous brain activity in children with attention deficit hyperactivity disorder (ADHD). In all, 23 boys with ADHD were scanned twice, under either 10?mg dose of MPH or placebo, in a randomized, cross-over, counterbalanced placebo-controlled design. 32 Matched healthy controls were scanned once for comparison. Seven of the 23 ADHD boys participated in a follow-up 8-week MPH treatment. A regional homogeneity (ReHo) method was applied to characterize the local synchronization of spontaneous brain activity. ADHD boys under placebo compared with controls showed decreased ReHo in bilateral dorsolateral prefrontal cortices and increased ReHo in bilateral sensorimotor and parieto-visual cortices. Relative to placebo, MPH upregulated ReHo in bilateral ventral prefrontal cortices and cerebellar vermis, and downregulated ReHo in right parietal and visual areas that overlapped with the abnormally enhanced activities. When under MPH, ReHo differences between patients and controls were no longer observed. The preliminary prediction analysis revealed that the decreased ReHo in right parietal cortex after the acute MPH was positively correlated with the decreased symptom scores after the 8-week MPH treatment in the seven patients. We show that an acute dose of MPH normalized all fronto-parieto-cerebellar dysfunctions in boys with ADHD during the resting state. Preliminary findings furthermore suggest the potential of RS-fMRI as a prognostic imaging tool to identify response to MPH treatment.
Project description:Children with attention-deficit/hyperactivity disorder (ADHD) have deficits in performance monitoring often improved with the indirect catecholamine agonist methylphenidate (MPH). We used functional magnetic resonance imaging to investigate the effects of single-dose MPH on activation of error processing brain areas in medication-naive boys with ADHD during a stop task that elicits 50% error rates.Twelve medication-naive boys with ADHD were scanned twice, under either a single clinical dose of MPH or placebo, in a randomized, double-blind design while they performed an individually adjusted tracking stop task, designed to elicit 50% failures. Brain activation was compared within patients under either drug condition. To test for potential normalization effects of MPH, brain activation in ADHD patients under either drug condition was compared with that of 13 healthy age-matched boys.During failed inhibition, boys with ADHD under placebo relative to control subjects showed reduced brain activation in performance monitoring areas of dorsomedial and left ventrolateral prefrontal cortices, thalamus, cingulate, and parietal regions. MPH, relative to placebo, upregulated activation in these brain regions within patients and normalized all activation differences between patients and control subjects. During successful inhibition, MPH normalized reduced activation observed in patients under placebo compared with control subjects in parietotemporal and cerebellar regions.MPH normalized brain dysfunction in medication-naive ADHD boys relative to control subjects in typical brain areas of performance monitoring, comprising left ventrolateral and dorsomedial frontal and parietal cortices. This could underlie the amelioration of MPH of attention and academic performance in ADHD.
Project description:Youth with attention deficit hyperactivity disorder (ADHD) have deficits in interference inhibition, which can be improved with the indirect catecholamine agonist methylphenidate (MPH). Functional magnetic resonance imaging was used to investigate the effects of a single dose of MPH on brain activation during interference inhibition in medication-naïve ADHD boys. Medication-naïve boys with ADHD were scanned twice, in a randomized, double-blind design, under either a single clinical dose of MPH or placebo, while performing a Simon task that measures interference inhibition and controls for the oddball effect of low-frequency appearance of incongruent trials. Brain activation was compared within patients under either drug condition. To test for potential normalization effects of MPH, brain activation in ADHD patients under either drug condition was compared with that of healthy age-matched comparison boys. During incongruent trials compared with congruent-oddball trials, boys with ADHD under placebo relative to controls showed reduced brain activation in typical areas of interference inhibition, including right inferior prefrontal cortex, left striatum and thalamus, mid-cingulate/supplementary motor area, and left superior temporal lobe. MPH relative to placebo upregulated brain activation in right inferior prefrontal and premotor cortices. Under the MPH condition, patients relative to controls no longer showed the reduced activation in right inferior prefrontal and striato-thalamic regions. Effect size comparison, furthermore, showed that these normalization effects were significant. MPH significantly normalized the fronto-striatal underfunctioning in ADHD patients relative to controls during interference inhibition, but did not affect medial frontal or temporal dysfunction. MPH therefore appears to have a region-specific upregulation effect on fronto-striatal activation.
Project description:To evaluate the efficacy and safety of osmotic-release methylphenidate (OROS-MPH) compared with placebo for attention-deficit/hyperactivity disorder (ADHD), and the impact on substance treatment outcomes in adolescents concurrently receiving cognitive-behavioral therapy (CBT) for substance use disorders (SUD).This was a 16-week, randomized, controlled, multi-site trial of OROS-MPH + CBT versus placebo + CBT in 303 adolescents (aged 13 through 18 years) meeting DSM-IV diagnostic criteria for ADHD and SUD. Primary outcome measures included the following: for ADHD, clinician-administered ADHD Rating Scale (ADHD-RS), adolescent informant; for substance use, adolescent-reported days of use in the past 28 days. Secondary outcome measures included parent ADHD-RS and weekly urine drug screens (UDS).There were no group differences on reduction in ADHD-RS scores (OROS-MPH: -19.2, 95% confidence interval [CI], -17.1 to -21.2; placebo, -21.2, 95% CI, -19.1 to -23.2) or reduction in days of substance use (OROS-MPH: -5.7 days, 95% CI, 4.0-7.4; placebo: -5.2 days, 95% CI, 3.5-7.0). Some secondary outcomes favored OROS-MPH, including lower parent ADHD-RS scores at 8 (mean difference = 4.4, 95% CI, 0.8-7.9) and 16 weeks (mean difference =6.9; 95% CI, 2.9-10.9) and more negative UDS in OROS-MPH (mean = 3.8) compared with placebo (mean = 2.8; p = .04).OROS-MPH did not show greater efficacy than placebo for ADHD or on reduction in substance use in adolescents concurrently receiving individual CBT for co-occurring SUD. However, OROS-MPH was relatively well tolerated and was associated with modestly greater clinical improvement on some secondary ADHD and substance outcome measures. Clinical Trial Registration Information-Attention Deficit Hyperactivity Disorder (ADHD) in Adolescents with Substance Use Disorders (SUD); http://www.clinicaltrials.gov; NCT00264797.
Project description:Methylphenidate (MPH) is one of the most commonly used stimulants for the treatment of attention deficit hyperactivity disorder (ADHD). Although several studies have evaluated the effects of MPH on human brain activation during specific cognitive tasks using functional magnetic resonance imaging (fMRI), few studies have focused on spontaneous brain activity. In the current study, we investigated the effect of MPH on the intra-regional synchronization of spontaneous brain activity during the resting state in 18 normal adult males. A handedness questionnaire and the Wechsler Adult Intelligence Scale were applied before medication, and a resting-state fMRI scan was obtained 1 h after medication (20 mg MPH or placebo, order counterbalanced between participants). We demonstrated that: (1) there were no significant differences in the performance of behavioral tasks between the MPH and placebo groups; (2) the left middle and superior temporal gyri had stronger MPHrelated regional homogeneity (ReHo); and (3) the left lingual gyrus had weaker MPH-related ReHo. Our findings showed that the ReHo in some brain areas changes with MPH compared to placebo in normal adults, even though there are no behavioral differences. This method can be applied to patients with mental illness who may be treated with MPH, and be used to compare the difference between patients taking MPH and normal participants, to help reveal the mechanism of how MPH works.
Project description:Psychostimulants remain first-line treatment options for the management of attention-deficit/hyperactivity disorder (ADHD). A multilayer extended-release bead methylphenidate capsule (provisional name Aptensio XR™, MPH-MLR) with unique release properties is being investigated for the treatment of ADHD.The aim of this study was to assess the efficacy (primary) and safety and tolerability (secondary) of MPH-MLR compared with placebo in children and adolescents aged 6-18 years with ADHD.This study was a parallel, double-blind, multicenter, placebo-controlled, forced-dose, phase III study in which patients were randomized to placebo or MPH-MLR 10, 15, 20, or 40 mg given once daily. There were four study phases: (1) 4-week screening/baseline; (2) 1-week, double-blind treatment (DBP); (3) 11-week, open-label, dose-optimization period; and (4) 30-day follow-up call. During the open-label dose-optimization period all patients started with MPH-MLR 10 mg, unless the investigator deemed it necessary to begin at a higher dose, and were titrated to an optimized dose (10, 15, 20, 30, 40, 50, 60 mg; all given once daily) based on response and adverse events (AEs). The primary endpoint was the change from baseline to end of DBP in ADHD Rating Scale, 4th Edition (ADHD-RS-IV) total score. Secondary endpoints included changes in ADHD-RS-IV subscales and Clinical Global Impression-Improvement Scale (CGI-I) at the end of the DBP. The primary analysis was an analysis of covariance including terms for treatment, site, and baseline ADHD-RS-IV total score.A total of 221 patients completed the DBP. The primary endpoint had a statistically significant difference among treatments (p = 0.0046) and sites (p = 0.0018), and baseline covariate made a significant contribution (p < 0.0001). As the MPH-MLR dose increased, the ADHD-RS-IV total score improved; the 20 and 40 mg doses were statistically different (p = 0.0145 and p = 0.0011, respectively) from placebo. Females responded differently than did males (p = 0.0238); there was a significant difference among treatments for males but not for females, partly because only one-third of subjects were female and partly because some females who received placebo had considerable improvement during the DBP. Similarly, the ADHD-RS-IV subscales and CGI-I scores at the end of the DBP also showed more improvement as the dose of MPH-MLR increased. During the open-label phase, ADHD-RS-IV total scores improved (mean change from baseline -22.5) and correlated as the dose of MPH-MLR increased; CGI-I scores also improved. No unexpected AEs were noted.Dose-related improvements in ADHD-RS-IV scores that exceeded those of placebo were observed in patients treated with MPH-MLR. No new safety signals were noted.
Project description:Regional homogeneity (ReHo) and the amplitude of low-frequency fluctuation (ALFF) are two approaches to depicting different regional characteristics of resting-state functional magnetic resonance imaging (RS-fMRI) data. Whether they can complementarily reveal brain regional functional abnormalities in attention-deficit/hyperactivity disorder (ADHD) remains unknown. In this study, we applied ReHo and ALFF to 23 medication-naïve boys diagnosed with ADHD and 25 age-matched healthy male controls using whole-brain voxel-wise analysis. Correlation analyses were conducted in the ADHD group to investigate the relationship between the regional spontaneous brain activity measured by the two approaches and the clinical symptoms of ADHD. We found that the ReHo method showed widely-distributed differences between the two groups in the fronto-cingulo-occipito-cerebellar circuitry, while the ALFF method showed a difference only in the right occipital area. When a larger smoothing kernel and a more lenient threshold were used for ALFF, more overlapped regions were found between ALFF and ReHo, and ALFF even found some new regions with group differences. The ADHD symptom scores were correlated with the ReHo values in the right cerebellum, dorsal anterior cingulate cortex and left lingual gyrus in the ADHD group, while no correlation was detected between ALFF and ADHD symptoms. In conclusion, ReHo may be more sensitive to regional abnormalities, at least in boys with ADHD, than ALFF. And ALFF may be complementary to ReHo in measuring local spontaneous activity. Combination of the two may yield a more comprehensive pathophy-siological framework for ADHD.
Project description:High smoking rates in adults with attention-deficit/hyperactivity disorder (ADHD) and nicotine's amelioration of ADHD suggest that effective ADHD treatment might facilitate abstinence in smokers with ADHD. The present study evaluated if using osmotic-release oral system methylphenidate (OROS-MPH) to treat ADHD enhances response to smoking cessation treatment in smokers with ADHD.A randomized, double-blind, placebo-controlled, 11-week trial with a 1-month follow-up was conducted at 6 clinical sites between December 2005 and January 2008. Adults (aged 18-55 years) meeting DSM-IV criteria for ADHD and interested in quitting smoking were randomly assigned to OROS-MPH titrated to 72 mg/d (n = 127) or placebo (n = 128). All participants received brief weekly individual smoking cessation counseling for 11 weeks and 21 mg/d nicotine patches starting on the smoking quit day (day 27) through study week 11. Outcome measures included prolonged smoking abstinence and DSM-IV ADHD Rating Scale (ADHD-RS) score.Of 255 randomly assigned participants, 204 (80%) completed the trial. Prolonged abstinence rates, 43.3% and 42.2%, for the OROS-MPH and placebo groups, respectively, did not differ significantly (OR = 1.1; 95% CI, 0.63-1.79; P = .81). Relative to placebo, OROS-MPH evidenced a greater reduction in DSM-IV ADHD-RS score (P < .0001) and in cigarettes per day during the post-quit phase (P = .016). Relative to placebo, OROS-MPH increased blood pressure and heart rate to a statistically, but not clinically, significant degree (P < .05); medication discontinuation did not differ significantly between treatments.Treatment for ADHD did not improve smoking cessation success; OROS-MPH, relative to placebo, effectively treated ADHD and was safe and generally well tolerated in this healthy sample of adult ADHD smokers.clinical trials.gov Identifier: NCT00253747.
Project description:Many papers have shown results from the multi-site dataset of resting-state fMRI (rs-fMRI) in attention deficit hyperactivity disorder (ADHD), a data-sharing project named ADHD-200. However, few studies have illustrated that to what extent the pooled findings were consistent across cohorts. The present study analyzed three voxel-wise whole-brain metrics, i.e., amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and degree centrality (DC) based on the pooled dataset as well as individual cohort of ADHD-200. In addition to the conventional frequency band of 0.01-0.08 Hz, sub-frequency bands of 0-0.01, 0.01-0.027, 0.027-0.073, 0.073-0.198, and 0.198-0.25 Hz, were assessed. While the pooled dataset showed abnormal activity in some brain regions, e.g., the bilateral sensorimotor cortices, bilateral cerebellum, and the bilateral lingual gyrus, these results were highly inconsistent across cohorts, even across the three cohorts from the same research center. The standardized effect size was rather small. These findings suggested a high heterogeneity of spontaneous brain activity in ADHD. Future studies based on multi-site large-sample dataset should be performed on pooled data and single cohort data, respectively and the effect size must be shown.
Project description:There are limited head-to-head data comparing the efficacy of long-acting amfetamine- and methylphenidate-based psychostimulants as treatments for individuals with attention-deficit hyperactivity disorder (ADHD). This post hoc analysis provides the first parallel-group comparison of the effect of lisdexamfetamine dimesylate (lisdexamfetamine) and osmotic-release oral system methylphenidate (OROS-MPH) on symptoms of ADHD in children and adolescents.This was a post hoc analysis of a randomized, double-blind, parallel-group, dose-optimized, placebo-controlled, phase III study.The phase III study was carried out in 48 centres across ten European countries.The phase III study enrolled children and adolescents (aged 6-17 years) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for a primary diagnosis of ADHD and who had a baseline ADHD Rating Scale IV (ADHD-RS-IV) total score of 28 or higher.Eligible patients were randomized (1:1:1) to receive a once-daily, optimized dose of lisdexamfetamine (30, 50 or 70 mg/day), placebo or OROS-MPH (18, 36 or 54 mg/day) for 7 weeks.In this post hoc analysis, efficacy was assessed using the ADHD-RS-IV and Clinical Global Impressions-Improvement (CGI-I) scale. Responders were defined as those achieving at least a 30% reduction from baseline in ADHD-RS-IV total score and a CGI-I score of 1 (very much improved) or 2 (much improved). The proportion of patients achieving an ADHD-RS-IV total score less than or equal to the mean for their age (based on normative data) was also determined. Endpoint was the last on-treatment visit with a valid assessment. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs.Of the 336 patients randomized, 332 were included in the safety population, 317 were included in the full analysis set and 196 completed the study. The mean (standard deviation) ADHD-RS-IV total score at baseline was 40.7 (7.31) for lisdexamfetamine, 41.0 (7.14) for placebo and 40.5 (6.72) for OROS-MPH. The least-squares (LS) mean change (standard error) in ADHD-RS-IV total score from baseline to endpoint was -24.3 (1.16) for lisdexamfetamine, -5.7 (1.13) for placebo and -18.7 (1.14) for OROS-MPH. The difference between lisdexamfetamine and OROS-MPH in LS mean change (95% confidence interval [CI]) in ADHD-RS-IV total score from baseline to endpoint was statistically significant in favour of lisdexamfetamine (-5.6 [-8.4 to -2.7]; p < 0.001). The difference between lisdexamfetamine and OROS-MPH in the percentage of patients (95% CI) with a CGI-I score of 1 or 2 at endpoint was 17.4 (5.0-29.8; p < 0.05; number needed to treat [NNT] 6), and the difference in the percentage of patients (95% CI) achieving at least a 30% reduction in ADHD-RS-IV total score and a CGI-I score of 1 or 2 was 18.3 (5.4-31.3; p < 0.05; NNT 6). The difference between lisdexamfetamine and OROS-MPH in the percentage of patients (95% CI) with an ADHD-RS-IV total score less than or equal to the mean for their age at endpoint was 14.0 (0.6-27.4; p = 0.050). The overall frequency of TEAEs and the frequencies of decreased appetite, insomnia, decreased weight, nausea and anorexia TEAEs were greater in patients treated with lisdexamfetamine than in those treated with OROS-MPH, whereas headache and nasopharyngitis were more frequently reported in patients receiving OROS-MPH.This post hoc analysis showed that, at the doses tested, patients treated with lisdexamfetamine showed statistically significantly greater improvement in symptoms of ADHD than those receiving OROS-MPH, as assessed using the ADHD-RS-IV and CGI-I. The safety profiles of lisdexamfetamine and OROS-MPH were consistent with the known effects of stimulant medications.
Project description:BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral psychiatric disorder that afflicts children, with a reported prevalence of 2.4% to 19.8% worldwide. Stimulants (methylphenidate [MPH] and amphetamine) are considered first-line ADHD pharmacotherapy. MPH is a catecholamine reuptake inhibitor, whereas amphetamines have additional presynaptic activity. Although MPH and amphetamine can effectively manage ADHD symptoms in most pediatric patients, many still fail to respond optimally to either. After administration, the prodrug stimulant lisdexamfetamine dimesylate (LDX) is converted to l-lysine and therapeutically active d-amphetamine in the blood. The objective of this study was to evaluate the clinical efficacy of LDX in children with ADHD who remained symptomatic (ie, nonremitters; ADHD Rating Scale IV [ADHD-RS-IV] total score > 18) on MPH therapy prior to enrollment in a 4-week placebo-controlled LDX trial, compared with the overall population. METHODS:In this post hoc analysis of data from a multicenter, randomized, double-blind, forced-dose titration study, we evaluated the clinical efficacy of LDX in children aged 6-12 years with and without prior MPH treatment at screening. ADHD symptoms were assessed using the ADHD-RS-IV scale, Conners' Parent Rating Scale-Revised short form (CPRS-R), and Clinical Global Impressions-Improvement scale, at screening, baseline, and endpoint. ADHD-RS-IV total and CPRS-R ADHD Index scores were summarized as mean (SD). Clinical response for the subgroup analysis was defined as a ? 30% reduction from baseline in ADHD-RS-IV score and a CGI-I score of 1 or 2. Dunnett test was used to compare change from baseline in all groups. Number needed to treat to achieve one clinical responder or one symptomatic remitter was calculated as the reciprocal of the difference in their proportions on active treatment and placebo at endpoint. RESULTS:Of 290 randomized participants enrolled, 28 received MPH therapy at screening, of which 26 remained symptomatic (ADHD-RS-IV > 18). ADHD-RS-IV total scores, changes from baseline, clinical responsiveness, and rates of symptomatic remission in this subgroup were comparable to the overall population. The safety and tolerability profiles for LDX were comparable to other stimulants currently available. CONCLUSION:In this analysis, children with significant clinical ADHD symptoms despite MPH treatment improved during treatment with LDX and experienced similar improvements in their symptoms as the overall study population. TRIAL REGISTRATION:ClinicalTrials.gov: NCT00556296.