12-month efficacy and safety of OROS® MPH in children and adolescents with attention-deficit/hyperactivity disorder switched from MPH

PURPOSE: The aim of this study was to evaluate long-term clinical treatment with OROS methylphenidate (MPH) (Concerta) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) who had been previously treated with immediate release (IR) MPH. METHODS: Subjects aged 6-16 years (n=105) who were stable on IR MPH (10-60 mg/day) were switched to 18, 36 or 54 mg OROS MPH once daily for 21 days, depending on prestudy MPH dose. Subjects who benefited from OROS MPH could continue in a 12-month extension period. ADHD symptoms and treatment response were assessed by parents/caregivers and investigators. RESULTS: Out of 105 enrolled children, 101 completed the 21-day treatment phase. In all, 89 parents/caregivers (88.1%) wanted their child to continue with the study treatment into the extension phase, and 56 children (63 %) completed the 1-year trial. The parent/caregiver global assessment of satisfaction ranged from 49 to 69% during the extension phase, and 49 to 71% of investigators rated the treatment as adequate. Efficacy and satisfaction were found more commonly in patients in the older age group (10-16 years), those on a higher dose (36 mg or 54 mg) and with the predominantly inattentive ADHD subtype. OROS MPH was well tolerated. CONCLUSIONS: Children and adolescents can effectively and safely be switched from IR MPH to OROS MPH with improved symptom control and compliance.     

The effect of methylphenidate on Internet video game play in children with attention-deficit/hyperactivity disorder

Objective

A number of studies about attention-deficit/hyperactivity disorder (ADHD) and Internet video game play have examined the prefrontal cortex and dopaminergic system. Stimulants such as methylphenidate (MPH), given to treat ADHD, and video game play have been found to increase synaptic dopamine. We hypothesized that MPH treatment would reduce Internet use in subjects with co-occurring ADHD and Internet video game addictions.

Methods

Sixty-two children (52 males and 10 females), drug-naive, diagnosed with ADHD, and Internet video game players, participated in this study. At the beginning of the study and after 8 weeks of treatment with Concerta (OROS methylphenidate HCl, Seoul, Korea), participants were assessed with Young's Internet Addiction Scale, Korean version (YIAS-K), Korean DuPaul's ADHD Rating Scale, and the Visual Continuous Performance Test. Their Internet usage time was also recorded.

Results

After 8 weeks of treatment, the YIAS-K scores and Internet usage times were significantly reduced. The changes in the YIAS-K scores between the baseline and 8-week assessments were positively correlated with the changes in total and inattention scores from the Korean DuPaul's ADHD Rating Scale, as well as omission errors from the Visual Continuous Performance Test. There was also a significant difference in the number of omission errors among non-Internet-addicted, mildly Internet addicted, and severely Internet addicted participants.

Discussion

We suggest that Internet video game playing might be a means of self-medication for children with ADHD. In addition, we cautiously suggest that MPH might be evaluated as a potential treatment of Internet addiction.     

Memory functions in children with attention deficit/hyperactivity disorder--the effects of methylphenidate on them

The memory functions or capacities in attention-deficit/hyperactivity disorder (AD/HD) are still not clear, though it has been pointed that the working memory in AD/HD could be impaired due to difficulties of motor inhibition or self-regulation. We examined the Auditory Verbal Learning Test (AVLT) and the Rey-Osterrieth Complex Figure Test (RCFT) in addition to the memory tasks of ordinary intelligence tests (WISC-III and K-ABC) in children with AD/HD. Whether these results could be improved by methylphenidate administration or not was also evaluated. Over the half cases had normal results without medication. Some cases in whom methylphenidate were clinically effective showed improved memory functions, especially in the auditory long-term memory, after methylphenidate administration. In conclusion, memory capacities seem normal in AD/HD. Methylphenidate does not have an effect on the memory capacities, but may improve the strategies in which the short-term memory can be effectively transferred to the long-term memory.     

Rebound effects with long-acting amphetamine or methylphenidate stimulant medication preparations among adolescent male drivers with attention-deficit/hyperactivity disorder

This study investigated whether OROS methylphenidate (OROS MPH, Concerta) or extended-release mixed amphetamine salts (se-AMPH ER, Adderall XR) were associated with worsening of driving performance, or drug rebound, relative to placebo 16-17 hours post-ingestion. Nineteen male adolescent drivers aged 17-19 with attention-deficit/hyperactivity disorder (ADHD) were compared on a virtual reality driving simulator and an on-road drive after taking 72 mg of OROS MPH, 30 mg of se-AMPH ER, or placebo. Medication was taken at 08:00 in a randomized, double-blind, placebo-controlled, crossover study. Participants drove a simulator at 17:00, 20:00, 23:00, and 01:00, and drove their own cars over a 16-mile road course at 24:00. The main outcome measures were composite scores of driving performance. Neither OROS MPH nor se-AMPH ER was associated with significant worsening of simulator performance relative to placebo 17 hours post-ingestion in group comparisons. However, inattentive on-road driving errors were significantly more common on se-AMPH ER relative to placebo at midnight (p = 0.04), suggesting possible rebound. During both late simulator and on-road testing, driving performance variance was approximately 300% greater during the se-AMPH ER compared to the OROS MPH condition.     

An open-label, randomized, active-controlled equivalent trial of osmotic release oral system methylphenidate in children with attention-deficit/hyperactivity disorder in Taiwan

This study examined the efficacy and safety of osmotic release oral system methylphenidate (OROS MPH) as compared with immediate-release MPH (IR MPH) in children with attention-deficit/hyperactivity disorder (ADHD) in Taiwan. Sixty-four children with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) ADHD, ages 6-15 years, were randomized to OROS MPH once daily (n = 32) and IR MPH three times daily (n = 32) in an open, randomized, active-controlled equivalent 28-day trial. The main outcome measures included the Conner's Teacher Rating Scale -Revised: Short Form and Conner's Parent Rating Scale-Revised: Short Form, and other measures of social adjustment and side effects. Results showed significant reductions in the core ADHD symptoms, which did not differ between the two treatment groups. Compared to the IR MPH group, the OROS MPH group showed a significantly greater slope of reductions in ADHD symptoms and decline in the severity of problems at school, and with peers and parents over time. There was no difference in rates of side effect profile between the two groups. Our findings suggest that OROS MPH is superior over IR MPH in the greater magnitude of improvement over study period without increased side effects in the Chinese population.     

Effect of osmotic-release oral system methylphenidate on different domains of attention and executive functioning in children with attention-deficit-hyperactivity disorder

Aim This study investigated whether components of attention and executive functioning improve when children with attention‐deficit–hyperactivity disorder (ADHD) are treated with osmotic‐release oral system (OROS) methylphenidate. Method Thirty children (24 males, six females; mean age 8y 6mo, SD 1y 11mo; range 6y 5mo –12y 6mo) with ADHD combined type participated in a double‐blind, placebo‐controlled crossover trial with the child’s clinically most effective dose as identified with a systematic open‐label titration procedure. After 1 week on each treatment (placebo and OROS methylphenidate), a neuropsychological battery that assessed sustained attention, selective attention, attentional control, response inhibition, and working memory was administered. This battery included the Gordon Diagnostic System, seven subtests of the Test of Everyday Attention for Children, and two tests of working memory. Results Performance on two of three tests of response inhibition improved on OROS methylphenidate compared with placebo (p<0.01). Performance on one of two tasks assessing attentional control and one of five measures assessing sustained attention demonstrated clear improvement. There was no improvement on the two tasks assessing selective attention or the two tasks assessing working memory. Interpretation When OROS methylphenidate was used to treat children with ADHD at the clinically most effective dose, general improvement was noted on tasks requiring response inhibition; response to treatment in other domains was either variable or not demonstrated.     

Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies

BACKGROUND: The duration of action of the immediate-release formulation of methylphenidate hydrochloride is short (3 to 4 hours), and 3 times daily dosing is thought to maximize effectiveness across a 12-hour day. The initial sustained-release formulations of methylphenidate had reduced efficacy compared with immediate-release methylphenidate and were not well accepted. Tachyphylaxis was hypothesized to account for the reduced effects, and an ascending drug delivery pattern was proposed to overcome this acute tolerance. METHODS: Children with attention-deficit/hyperactivity disorder were evaluated in a laboratory school to characterize onset and duration of the effect of a variety of methylphenidate regimens. In a proof-of-concept study, an experimental ascending profile was established by an initial bolus followed by small increasing doses of immediate-release methylphenidate in capsules administered every 30 minutes for 8 hours. Two proof-of-product studies of a new oral once-a-day formulation to deliver methylphenidate by an osmotic pump process based on OROS (ALZA Corp, Mountain View, Calif) technology (hereafter referred to "OROS-methylphenidate") were conducted: a pharmacokinetic study and a pharmacodynamic study. RESULTS: The experimental ascending profile matched the effect of the standard regimen of methylphenidate, 3 times daily. In the pharmacokinetic study, OROS-methylphenidate treatment produced a rapid rise followed by increasing plasma concentrations that peaked 7 to 9 hours after administration. In the pharmacodynamic study, OROS-methylphenidate treatment matched the 3 times daily dosing of methylphenidate for onset and duration of efficacy. CONCLUSIONS: These studies demonstrate the translation of a basic science finding (acute tolerance to clinical doses of methylphenidate) into clinical application (the selection of a new drug delivery pattern for methylphenidate). This approach produced a new product (OROS-methylphenidate or Concerta), which proved to have the predicted rapid onset (with 1-2 hours) and long duration of efficacy (10-12 hours) after a single administration in the morning.     

注意缺陷/多动障碍工作记忆的bold-功能磁共振成像研究

目的应用bold-功能磁共振成像(bold-fMRI)技术来研究注意缺陷/多动障碍(AD/HD)患者的工作记忆。并探讨使用哌醋甲酯1个月治疗前后AD/HD患者的脑部激活的改变情况。方法利用倒数n刺激模式(n-back)对7例AD/HD(注意缺陷为主型)和7名正常人进行blod-fMRI检查,对照研究AD/HD患者在工作记忆时涉及的各脑区的激活情况。结果AD/HD组治疗后的1-back任务较治疗前1-back任务在右额下回和右额中回激活明显,二者有显著性差异(P<0.05);AD/HD组在治疗后的2-back任务较治疗前2-back任务在左额下回和左顶叶后下部激活明显(P<0.05)。正常组的1-back任务与患者组治疗前的1-back任务比较没有显著性差异,正常组的2-back任务与患者组治疗前2-back任务比较在左额下回和左顶叶后下部激活明显(P<0.05)。结论AD/HD障碍患者存在执行功能方面的缺陷,AD/HD患者的语义性工作记忆缺损可能与前额叶和顶叶的功能缺陷有关。     

The metaphor and sarcasm scenario test: a new instrument to help differentiate high functioning pervasive developmental disorder from attention deficit/hyperactivity disorder

It is sometimes difficult to discriminate high functioning pervasive developmental disorders (HFPDD) from attention deficit/hyperactivity disorders (AD/HD) in young children because of the behavioral similarities between the two. For adequate diagnosis, understanding fundamental differences in their social cognitive abilities might become significant. In order to detect the differences in social cognitive abilities between AD/HD and HFPDD, a new test, the Metaphor and Sarcasm Scenario Test (MSST) was developed. One hundred and ninety-nine normal school children (the control group), 29 AD/HD children and 54 HFPDD children were involved. The results showed that the inability to understand a sarcastic situation was specific to children with HFPDD, both children with AD/HD and HFPDD could not equally understand metaphor. The correlation between the comprehension of sarcasm and success in the theory of mind task was remarkably high but not for comprehension of metaphor. In conclusion, the MSST has the potential to discriminate HFPDD from AD/HD in young children.     

Quetiapine addition in methylphenidate treatment-resistant adolescents with comorbid ADHD, conduct/oppositional-defiant disorder, and aggression: a prospective, open-label study

OBJECTIVE: This study investigated the safety and efficacy of adding the atypical antipsychotic quetiapine to ongoing OROS methylphenidate treatment for adolescents with comorbid ADHD and severe aggression that were incompletely responsive to methylphenidate monotherapy. METHOD: Participants aged 12-16 years were enrolled in a prospective, open-label trial consisting of 3 weeks of OROS methylphenidate monotherapy titrated to 54 mg/day, followed by 9 weeks of combination treatment with quetiapine and methylphenidate. Twenty-four out of thirty participants failed to meet criteria for significant improvement (Clinical Global Improvement-Severity [CGI-S] and Rating of Aggression Against People and Property [RAAPP] scale scores of 1 or 2 and ADHD-Rating Scale: Investigator Administered and Scored [ADHD-RS-I] score less than 50% of baseline score) with methylphenidate treatment alone and received combined treatment. RESULTS: Investigator and parent ratings of ADHD symptoms, aggression, and global functioning improved significantly during both methylphenidate monotherapy treatment and during combined methylphenidate-quetiapine treatment. At the conclusion of combined treatment, 42% of the sample met all criteria for clinically significant improvement and 79% showed minimal aggression. Mild and transient sedation was reported by about half the cases. Weight loss (0.9 kg) during methylphenidate treatment was offset by weight gain (1.2 kg) during combination treatment. CONCLUSION: Quetiapine addition to methylphenidate was effective in reducing ADHD and aggression in individuals who did not respond sufficiently (based on CGI-S, RAAPP, and ADHD-RS-I criteria for significant improvement) to OROS methylphenidate alone at a 54-mg/day dose.