Methylphenidate use and divorce.
CMAJ. 2007 Sep 25;177(7):751; author reply 751
Authors: Schultz BK
PMID: 17893352 [PubMed - indexed for MEDLINE ]
Prevalence of methylphenidate use among Canadian children following parental divorce.
CMAJ. 2007 Jun 5;176(12):1711-4
Ritalin side effects Authors: Strohschein LA
BACKGROUND: Evidence suggests that children living in single-parent or step-parent households are more likely than children in households with 2 biological parents to be prescribed methylphenidate. I conducted a study of prospective data to investigate parental divorce as a predictor of methylphenidate use. METHODS: I used data for children who participated in the National Longitudinal Survey of Children and Youth from 1994 to 2000. The sample was restricted to children who remained in the survey in 2000 and who, at initial interview, lived in a household with 2 biological parents (n = 4784). A generalized estimating equation model was used to compare the odds ratios of methylphenidate use among children whose parents obtained a divorce between 1994 and 2000 relative to children whose parents remained married during this period. RESULTS: Between 1994 and 2000, 633 children (13.2%) experienced the divorce of their parents. The proportion of children who received methylphenidate at any time between 1994 and 2000 was 3.3% among those whose parents remained married and 6.1% among those whose parents divorced during this period. After adjustment for age of the mother and sex and age of the child, I found that methylphenidate use was significantly higher among children whose parents subsequently divorced than among those whose parents remained married (odds ratio 1.82, 95% confidence interval 1.01-3.33). INTERPRETATION: The increased risk of children receiving a prescription for methylphenidate in the period following parental divorce raises questions about the causal links in this association. Future research is needed to replicate these findings and to investigate possible explanations.Ritalin side effects
PMID: 17548384 [PubMed - indexed for MEDLINE Ritalin side effects]
Relative benefits of stimulant therapy with OROS methylphenidate versus mixed amphetamine salts extended release in improving the driving performance of adolescent drivers with attention-deficit/hyperactivity disorder.
Pediatrics. 2006 Sep;118(3):e704-10
Ritalin side effects Authors: Cox DJ, Merkel RL, Moore M, Thorndike F, Muller C, Kovatchev B
OBJECTIVE: Automobile accidents are the leading cause of death among adolescents, and collisions are 2 to 4 times more likely to occur among adolescents with attention-deficit/hyperactivity disorder. Studies have demonstrated that stimulants improve driving performance. This study compared 2 long-acting stimulant medications during daytime and evening driving evaluations. METHODS: Adolescent drivers with attention-deficit/hyperactivity disorder were compared on a driving simulator after taking 72 mg of OROS methylphenidate, 30 mg of mixed amphetamine salts extended release, or placebo in a randomized, double-blind, placebo-controlled, crossover study design. During laboratory testing, adolescents drove a driving simulator at 5:00 pm, 8:00 pm, and 11:00 pm. Driving performance was rated by adolescents and investigators. RESULTS: The study included 35 adolescent drivers with attention-deficit/hyperactivity disorder (19 boys/16 girls). The mean age was 17.8 years. The overall Impaired Driving Score demonstrated that OROS methylphenidate led to better driving performance compared with placebo and mixed amphetamine salts extended release, whereas mixed amphetamine salts extended release demonstrated no statistical improvement over placebo. Specifically, relative to placebo, OROS methylphenidate resulted in less time driving off the road, fewer instances of speeding, less erratic speed control, more time executing left turns, and less inappropriate use of brakes. OROS methylphenidate and mixed amphetamine salts extended release worked equally well for male and female adolescents and equally as well with teenagers who have combined and inattentive subtypes of attention-deficit/hyperactivity disorder. CONCLUSIONS: This study validates the use of stimulants to improve driving performance in adolescents with attention-deficit/hyperactivity disorder. In the study, OROS methylphenidate promoted significantly improved driving performance compared with placebo and mixed amphetamine salts extended release.Ritalin side effects
PMID: 16950962 [PubMed - indexed for MEDLINE Ritalin side effects]
PET study examining pharmacokinetics, detection and likeability, and dopamine transporter receptor occupancy of short- and long-acting oral methylphenidate.
Am J Psychiatry. 2006 Mar;163(3):387-95
Ritalin side effects Authors: Spencer TJ, Biederman J, Ciccone PE, Madras BK, Dougherty DD, Bonab AA, Livni E, Parasrampuria DA, Fischman AJ
OBJECTIVE: The abuse potential of methylphenidate has been related to the drug's capacity to produce a rapid onset of blockade of the presynaptic dopamine transporter in the brain. An oral once-a-day osmotic controlled-release formulation of methylphenidate produces a more gradual rise in plasma methylphenidate concentration, compared with immediate-release methylphenidate. The authors hypothesized that osmotic-release methylphenidate would also produce a slower onset of blockade of the presynaptic dopamine transporter and would be associated with a lower risk for detection and likeability, compared to immediate-release methylphenidate. METHOD: Twelve healthy adults were randomly assigned to receive single doses of immediate-release methylphenidate or osmotic-release methylphenidate. Doses predicted to produce equivalent maximum concentration (C(max)) values were selected (40 mg of immediate-release methylphenidate and 90 mg of osmotic-release methylphenidate). Plasma d-methylphenidate levels and responses to detection/likeability questionnaire items were obtained hourly for 10 hours after administration of methylphenidate on two separate occasions for each subject. Dopamine transporter receptor occupancies were measured at hours 1, 3, 5, and 7 by using a carbon-11-labeled imaging agent (Altropane) and positron emission tomography. RESULTS: Despite similar C(max) values for both formulations, osmotic-release methylphenidate was associated with a longer time to maximum concentration, longer time to maximum CNS dopamine transporter occupancy, and no detection/likeability, compared with immediate-release methylphenidate. CONCLUSIONS: The findings suggest that the abuse potential of oral methylphenidate is strongly influenced by the rate of delivery and not solely by the magnitude of plasma concentration or brain transporter occupancy. These results advance understanding of the underlying central effects of methylphenidate in humans and identify a potentially less abusable methylphenidate formulation.Ritalin side effects
PMID: 16513858 [PubMed - indexed for MEDLINE Ritalin side effects]
Multisite controlled study of OROS methylphenidate in the treatment of adolescents with attention-deficit/hyperactivity disorder.
Arch Pediatr Adolesc Med. 2006 Jan;160(1):82-90
Ritalin side effects Authors: Wilens TE, McBurnett K, Bukstein O, McGough J, Greenhill L, Lerner M, Stein MA, Conners CK, Duby J, Newcorn J, Bailey CE, Kratochvil CJ, Coury D, Casat C, Denisco MJ, Halstead P, Bloom L, Zimmerman BA, Gu J, Cooper KM, Lynch JM
BACKGROUND: Despite the persistence of attention-deficit/hyperactivity disorder (ADHD) into adolescence, little is known about the efficacy and tolerability of stimulant medications in this age group. OBJECTIVE: To report the results of a multisite controlled study among adolescents with ADHD evaluating the efficacy and tolerability of osmotic-release oral system (OROS) methylphenidate. DESIGN: Adolescents (N = 220) having a confirmed Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of ADHD underwent dose titration to identify dosages of OROS methylphenidate that improved symptoms to predefined criteria. Subjects successfully completing the dose titration phase (n = 177) (ie, tolerated and responded to treatment and adhered to the protocol) were randomized to receive 2 weeks' treatment with their individualized dosage of OROS methylphenidate (18, 36, 54, or 72 mg once daily) or placebo. Treatment effectiveness was measured using investigator, parent, and adolescent assessments of ADHD. RESULTS: A significant reduction from baseline in the investigator-rated ADHD Rating Scale, the primary efficacy measure, was found with OROS methylphenidate treatment compared with placebo. Similar findings were noted with parent- and adolescent-report measures. Based on a Clinical Global Impression improvement subscale score of much or very much improved, 52% of subjects in the OROS methylphenidate group improved compared with 31% receiving placebo. Thirty-seven percent of subjects required the maximum dosage of 72 mg/d. The incidence of drug-related adverse events was similar between the 2 study groups. CONCLUSION: In adolescents, once-daily OROS methylphenidate significantly reduced ADHD symptoms and was well tolerated using dosages up to 72 mg/d.Ritalin side effects
PMID: 16389216 [PubMed - indexed for MEDLINE Ritalin side effects]
Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity.
Arch Gen Psychiatry. 2005 Nov;62(11):1266-74
Ritalin side effects Authors:
CONTEXT: Hyperactivity and inattention are common symptoms in children with autistic disorder and related pervasive developmental disorders, but studies of stimulants in these conditions have been inconclusive. OBJECTIVES: To determine the efficacy and safety of methylphenidate hydrochloride in children with pervasive developmental disorders and hyperactivity. DESIGN: Double-blind, placebo-controlled, crossover trial followed by open-label continuation. SETTING: Five academic outpatient clinics. PARTICIPANTS: Seventy-two drug-free children, aged 5 to 14 years, with pervasive developmental disorders accompanied by moderate to severe hyperactivity. INTERVENTIONS: Prior to randomization, subjects entered a 1-week test-dose phase in which each subject received placebo for 1 day followed by increasing doses of methylphenidate (low, medium, and high doses) that were each given for 2 days. The low, medium, and high doses of methylphenidate hydrochloride were based on weight, and they ranged from 7.5 mg/d to 50.0 mg/d in divided doses. Subjects who tolerated the test dose (n = 66) were assigned to receive placebo for 1 week and then 3 methylphenidate doses in random order during a double-blind, crossover phase. Children responding to methylphenidate then entered 8 weeks of open-label treatment at the individually determined best dose. MAIN OUTCOME MEASURES: The primary outcome measure was the teacher-rated hyperactivity subscale of the Aberrant Behavior Checklist. Response was defined as "much improved" or "very much improved" on the Clinical Global Impressions Improvement item coupled with considerable reductions in the parent-rated and/or teacher-rated Aberrant Behavior Checklist hyperactivity subscale score. RESULTS: Methylphenidate was superior to placebo on the primary outcome measure, with effect sizes ranging from 0.20 to 0.54 depending on dose and rater. Thirty-five (49%) of 72 enrolled subjects were classified as methylphenidate responders. Adverse effects led to the discontinuation of study medication in 13 (18%) of 72 subjects. CONCLUSIONS: Methylphenidate was often efficacious in treating hyperactivity associated with pervasive developmental disorders, but the magnitude of response was less than that seen in typically developing children with attention-deficit/hyperactivity disorder. Adverse effects were more frequent.Ritalin side effects
PMID: 16275814 [PubMed - indexed for MEDLINE Ritalin side effects]
Continuity of methylphenidate treatment for attention-deficit/hyperactivity disorder.
Arch Pediatr Adolesc Med. 2005 Jun;159(6):572-8
Ritalin side effects Authors: Marcus SC, Wan GJ, Kemner JE, Olfson M
OBJECTIVE: To compare the continuity of methylphenidate hydrochloride (MPH) therapy among youth Medicaid beneficiaries treated for attention-deficit/hyperactivity disorder with immediate-release (IR) or extended-release (ER) MPH formulations.Method An analysis was conducted of statewide California Medicaid claims (2000-2003) focusing on children and adolescents, ages 6 to 17 years, who started ER-MPH or IR-MPH treatment for attention-deficit/hyperactivity disorder. The study cohorts were limited to youth who had not filled a prescription for MPHs, amphetamines, pemoline, or atomoxetine for 6 months preceding the index prescription and remained eligible for Medicaid benefits for the following 12 months. The study groups were compared with respect to background demographic traits and clinical characteristics. Mean and median duration of MPH treatment episodes were defined to terminate if a gap of 30 or more days occurred from the end of the last prescription supply to the start of the next prescription. Survival time ratios were used to assess treatment duration controlling for group differences in background characteristics. RESULTS: As compared with patients initiating IR-MPH treatment, patients initiating ER-MPH treatment had a significantly longer mean estimated duration of treatment (ER-MPH, 140.3 days [95% confidence interval (CI), 136.3-144.4 days] vs IR-MPH, 103.4 days [95% CI, 101.3-103.4 days]). Similar results were found in analyses stratified by patient age, race/ethnicity, and sex. Controlling for group differences in age, sex, race/ethnicity, coprescribed psychotropic medications, other treated mental disorders, case management, managed care participation, and seasonal effects, ER-MPH treatment initiation was associated with an average 37% longer duration of treatment than IR-MPH treatment (survival time ratio, 1.37 [95% CI, 1.32-1.42]). Among patients treated with ER-MPH, treatment initiation with an osmotic release oral system MPH (Concerta) was associated with significantly longer mean duration (147.2 days [95% CI, 142.6-151.7 days]) than treatment initiation with Metadate CD (controlled delivery) (113.0 days [95% CI, 100.9-125.1 days]) or Ritalin LA (long acting) (101.1 days [95% CI, 91.2-111.0 days]), respectively. CONCLUSIONS: Extended-release MPH formulations were associated with greater continuity of MPH treatment than IR formulations in the study population. Initial selection of an ER formulation may help to prolong continuity of MPH therapy among youth Medicaid beneficiaries with attention-deficit/hyperactivity disorder.Ritalin side effects
PMID: 15939858 [PubMed - indexed for MEDLINE Ritalin side effects]
Attention deficit and hyperactivity disorder, methylphenidate, and epilepsy.
Arch Dis Child. 2005 Jan;90(1):57-9
Ritalin side effects Authors: Tan M, Appleton R
Attention deficit hyperactivity disorder (ADHD) is characterised by inattention, impulsivity, and hyperactivity. The DSM-IV diagnosis of ADHD requires the presence of six of nine items or features that must have been present for at least six months, to have had an onset before 7 years of age, and to have resulted in significant distress or impairment.1 In the general population, the prevalence of ADHD is approximately 5%.2 There is a high co-morbidity of epilepsy and attentional and behavioural problems,3,4 including ADHD, and it has been estimated that at least 20% of patients with epilepsy may present with features of ADHD.5.Ritalin side effects
PMID: 15613514 [PubMed - indexed for MEDLINE Ritalin side effects]
The effects of methylphenidate on neural systems of attention in attention deficit hyperactivity disorder.
Am J Psychiatry. 2004 Nov;161(11):1990-7
Ritalin side effects Authors: Shafritz KM, Marchione KE, Gore JC, Shaywitz SE, Shaywitz BA
OBJECTIVE: Recent studies have suggested that attention deficit hyperactivity disorder (ADHD) is associated with abnormalities in basal ganglia and prefrontal cortical functioning. However, these studies have primarily relied upon cognitive tasks that reflect impulse control rather than attentional mechanisms. METHOD: The authors used functional magnetic resonance imaging to investigate the neural correlates of selective and divided attention in a randomized, double-blind, placebo-controlled pharmacological challenge with methylphenidate in 15 adolescents with ADHD (ages 14-17), eight adolescents with reading disorder (ages 12-17), and four adolescents with both reading disorder and ADHD (ages 14-18) who were scanned during both a methylphenidate and a placebo session. Fourteen healthy comparison subjects (ages 12-20) who were not given methylphenidate served as the primary comparison group. RESULTS: During the divided attention task, unmedicated subjects with ADHD or reading disorder recruited the left ventral basal ganglia significantly less than the healthy comparison subjects. Methylphenidate led to an increase in activation in this region but had no effect on task performance. Subjects with ADHD also recruited the middle temporal gyrus significantly less than the comparison subjects, but methylphenidate did not have a direct effect on activation in this region. CONCLUSIONS: These results suggest that ADHD is associated with abnormal processing in attentional networks, with specific dysfunction in striatal circuitry. Methylphenidate may act to normalize activity within this network.Ritalin side effects
PMID: 15514398 [PubMed - indexed for MEDLINE Ritalin side effects]
Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain.
Am J Psychiatry. 2004 Jul;161(7):1173-80
Ritalin side effects Authors: Volkow ND, Wang GJ, Fowler JS, Telang F, Maynard L, Logan J, Gatley SJ, Pappas N, Wong C, Vaska P, Zhu W, Swanson JM
OBJECTIVE: Methylphenidate is the most commonly prescribed drug for attention deficit hyperactivity disorder (ADHD), yet its therapeutic mechanisms are poorly understood. The objective of this study was to assess if methylphenidate, by increasing dopamine (neurotransmitter involved in motivation) in brain, would enhance the saliency of an academic task, making it more interesting. METHOD: Healthy subjects (N=16) underwent positron emission tomography with [(11)C]raclopride (dopamine D(2) receptor radioligand that competes with endogenous dopamine for binding) to assess the effects of oral methylphenidate (20 mg) on extracellular dopamine in the striatum. The authors compared the effects of methylphenidate during an academic task (solving mathematical problems with monetary reinforcement) and a neutral task (passively viewing cards with no remuneration). In parallel, the effects of methylphenidate on the interest that the academic task elicited were also evaluated. RESULTS: Methylphenidate, when coupled with the mathematical task, significantly increased extracellular dopamine, but this did not occur when coupled with the neutral task. The mathematical task did not increase dopamine when coupled with placebo. Subjective reports about interest and motivation in the mathematical task were greater with methylphenidate than with placebo and were associated with dopamine increases. CONCLUSIONS: The significant association between methylphenidate-induced dopamine increases and the interest and motivation for the task confirms the prediction that methylphenidate enhances the saliency of an event by increasing dopamine. The enhanced interest for the task could increase attention and improve performance and could be one of the mechanisms underlying methylphenidate's therapeutic effects. These findings support educational strategies that make schoolwork more interesting as nonpharmacological interventions to treat ADHD.Ritalin side effects
PMID: 15229048 [PubMed - indexed for MEDLINE Ritalin side effects]
A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (the Comacs Study).
Pediatrics. 2004 Mar;113(3 Pt 1):e206-16
Ritalin side effects Authors: Swanson JM, Wigal SB, Wigal T, Sonuga-Barke E, Greenhill LL, Biederman J, Kollins S, Nguyen AS, DeCory HH, Hirshe Dirksen SJ, Hatch SJ,
OBJECTIVE: The objective of this study was to evaluate differences in the pharmacodynamic (PD) profile of 2 second-generation extended-release (ER) formulations of methylphenidate (MPH): Metadate CD (MCD; methylphenidate HCl, US Pharmacopeia) extended-release capsules, CII, and Concerta (CON; methylphenidate HCl) extended-release tablets, CII. Little empirical information exists to help the clinician compare the PD effects of the available ER formulations on attention and behavior. Previous studies have shown that the near-equal doses of MCD and CON provide equivalent, total exposure to MPH as measured by area under the plasma concentration time curve, yet their pharmacokinetic (PK) plasma concentration versus time profiles are different. We previously offered a theoretical PK/PD account of the similarities and differences among available ER formulations based on the hypothesis that all formulations produce effects related to MPH delivered by 2 processes: 1) an initial bolus dose of immediate-release (IR) MPH that is expected to achieve peak plasma concentration in the early morning and have rapid onset of efficacy within 2 hours of dosing, which for the MCD capsule is delivered by 30% of the total daily dose as uncoated beads and for the CON tablet is delivered by an overcoat of 22% of the total daily dose; and 2) an extended, controlled delivery of ER MPH that is expected to achieve peak plasma concentrations in the afternoon to maintain efficacy for a programmed period of time after the peak of the initial bolus, which for the MCD capsule is delivered by polymer-coated beads and for the CON tablet by an osmotic-release oral system. According to this PK/PD model, clinical superiority is expected at any point in time for the formulation with the highest MPH plasma concentration. METHODS: This was a multisite, double-blind, double-dummy, 3-way crossover study of 2 active treatments (MCD and CON) and placebo (PLA). Children with confirmed diagnoses of attention-deficit/hyperactivity disorder were stratified to receive bioequivalent doses of MCD and CON that were considered to be low (20 mg of MCD and 18 mg of CON), medium (40 mg of MCD and 36 mg of CON), or high (60 mg of MCD and 54 mg of CON), and in a randomized order each of the study treatments was administered once daily in the morning for 1 week. On the seventh day of each treatment week, children attended a laboratory school, where surrogate measures of response were obtained by using teacher ratings of attention and deportment and a record of permanent product of performance on a 10-minute math test at each of the 7 classroom sessions spread across the day at 1.5-hour intervals. Safety was assessed by patient reports of adverse events, parent ratings on a stimulant side-effects scale, and measurement of vital signs. RESULTS: The analyses of variance revealed large, statistically significant main effects for the within-subject factor of treatment for all 3 outcome measures (deportment, attention, and permanent product). The interactions of treatment x session were also highly significant for all 3 outcome measures. Inspection of the PD profiles for the treatment x session interactions suggested 4 patterns of efficacy across the day: 1) PLA > MCD approximately CON (PLA superiority) immediately after dosing; 2) MCD > CON > PLA during the morning (MCD superiority); 3) MCD approximately CON > PLA during the afternoon (PD equivalence of MCD and CON); and 4) CON > MCD approximately PLA in the early evening (CON superiority). The effect of site was significant, because some study centers had low and some high scores for behavior in the lab classroom, but both the low- and high-scoring sites showed similar PD patterns across the day. The interaction of dose x treatment was not significant, indicating that the pattern of treatment effects was consistent across each dose level. There were no statistically significant overall differences among the 3 treatments for the frequency of treatment-emergent adverse events, ratings of side effects, or vital signs. Two additional PK/PD questions were addressed: 1. The a priori hypothesis called for a comparison of the average of sessions (removing session as a factor) during a time period that corresponds to the length of a typical school day (from 1.5 through 7.5 hours after dosing). For the planned contrast of the 2 treatment conditions (MCD versus CON), the difference was significant, confirming the a priori hypothesis of superiority of near-equal daily doses of MCD over CON for this predefined postdosing period. 2. In the design of the study, the dose factor represented the total daily dose, consisting of 2 components: the initial bolus doses of IR MPH, which differ for the near-equal total daily doses of MCD and CON, and the reservoir doses of ER MPH, which were the same for the 2 formulations. To evaluate the moderating effects of the bolus component of dose on outcome, average effect size (ES) was calculated for the efficacy outcomes at the time of expected peak PK concentration times of the initial bolus component for each formulation at the 3 dose levels. The correlation (r) of ES with IR MPH bolus dose was significant for each of the 3 outcome measures (r approximately .9), indicating that the magnitude of effects in the early morning may be attributed to the dose administered by the IR MPH bolus of each formulation. For the 2 dose conditions with equal 12-mg IR MPH boluses (MCD 40 and CON 54), the ESs were large and indistinguishable (eg, deportment ES approximately 0.75 for both). CONCLUSIONS: Once-daily doses of MCD and CON produced statistically significantly different PD effects on surrogate measures of behavior and performance among children with attention-deficit/hyperactivity disorder in the laboratory school setting. As predicted by the PK/PD model, superiority at any point in time was achieved by the formulation with the highest expected plasma MPH concentration.
Ritalin side effects
PMID: 14993578 [PubMed - indexed for MEDLINE Ritalin side effects]
A dose-response study of OROS methylphenidate in children with attention-deficit/hyperactivity disorder.
Pediatrics. 2003 Nov;112(5):e404
Ritalin side effects Authors: Stein MA, Sarampote CS, Waldman ID, Robb AS, Conlon C, Pearl PL, Black DO, Seymour KE, Newcorn JH
OBJECTIVE: OROS methylphenidate HCL (MPH) is a recently developed long-acting stimulant medication used to treat attention-deficit/hyperactivity disorder (ADHD). This study was conducted to examine dosage effects on ADHD symptoms and stimulant side effects and to explore potential moderating effects of ADHD subtype. METHODS: Children with ADHD combined type (ADHD-CT) or predominantly inattentive type (ADHD-PI; n = 47), ages 5 to 16 years, underwent a placebo-controlled, crossover trial using forced titration with weekly switches at 3 dosage levels. Parent and teacher ratings of ADHD symptoms were used to evaluate efficacy. In addition, vital signs and standardized measures of stimulant side effects were obtained weekly. RESULTS: Parent ratings were more sensitive to treatment effects than teacher ratings. ADHD symptoms and Clinical Global Impressions Severity Index ratings at each dose condition differed significantly from placebo and baseline ratings, which did not differ from one another. For those with ADHD-CT, there was a clear linear dose-response relationship, with clinically significant reductions in ADHD Rating Scale-IV scores occurring in two thirds to three fourths of the subjects during either 36- or 54-mg dose conditions. Children with ADHD-PI, conversely, were more likely to respond optimally to lower doses and derived less benefit from higher doses, with 60% displaying significant improvement on the ADHD Rating Scale-IV at 36 mg or lower. Mild stimulant side effects were reported during placebo and at all dosage levels. With the exception of insomnia and decreased appetite, which were more common at higher doses, parent report of side effects was not related to dose. In addition, younger and smaller children were more likely to display sleep difficulties and decreased appetite at the higher dose levels Although pulse rate increased slightly with increasing dose, there were no dose effects on blood pressure. CONCLUSIONS: In children with ADHD-CT, the most common subtype of ADHD, increasing doses of stimulant medication were associated with increased improvement of inattention and hyperactivity symptoms. In children with ADHD-PI, symptom improvement occurred at lower doses and less benefit was derived from higher doses. In both ADHD subtypes, higher doses were associated with parent ratings of increased insomnia and decreased appetite.
Ritalin side effects
PMID: 14595084 [PubMed - indexed for MEDLINE Ritalin side effects]
Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD.
Am J Psychiatry. 2003 Nov;160(11):1909-18
Ritalin side effects Authors: Volkow ND, Swanson JM
OBJECTIVE: Methylphenidate, the most common treatment for attention deficit hyperactivity disorder (ADHD), increases extracellular dopamine in the brain, which is associated with its reinforcing as well as its therapeutic effects. The authors evaluated variables that distinguish these two properties. METHOD: The brain imaging and clinical literatures were analyzed to identify variables that contribute to the abuse liability as well as to the clinical efficacy of methylphenidate. RESULTS: Four variables were identified. 1) Dose--there is a threshold for methylphenidate-induced dopamine increases to be perceived as reinforcing and to produce therapeutic effects. 2) Pharmacokinetics--the reinforcing effects of methylphenidate are associated with rapid changes in serum concentrations and presumably fast dopamine increases (as achieved with intravenous injection or insufflation), whereas the therapeutic effects are associated with slowly ascending serum concentrations and presumably smoothly rising dopamine levels (as achieved with oral administration). 3) Individual differences--sensitivity to methylphenidate varies across individuals and sets a threshold for blood and brain levels required for reinforcing effects (drug liking) and for therapeutic effects (symptom reduction). 4) Context--the effects of methylphenidate are modulated by different settings in abuse (rituals of self-administration and powerful conditioning) and in clinical use (external demands of low activity and focused attention). CONCLUSIONS: Reinforcing effects occur when methylphenidate elicits large and fast dopamine increases that mimic those of phasic dopamine cell firing, whereas therapeutic effects occur when methylphenidate elicits slow, steady-state dopamine increases that mimic those of tonic firing. Thus, the characteristics of clinical use (low doses administered orally and titrated for therapeutic effects) constrain methylphenidate's abuse.
Ritalin side effects
PMID: 14594733 [PubMed - indexed for MEDLINE Ritalin side effects]
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.
Arch Gen Psychiatry. 2003 Feb;60(2):204-11
Ritalin side effects Authors: Swanson J, Gupta S, Lam A, Shoulson I, Lerner M, Modi N, Lindemulder E, Wigal S
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.
Ritalin side effects
PMID: 12578439 [PubMed - indexed for MEDLINE Ritalin side effects]
Effects of methylphenidate on functional magnetic resonance relaxometry of the cerebellar vermis in boys with ADHD.
Am J Psychiatry. 2002 Aug;159(8):1322-8
Ritalin side effects Authors: Anderson CM, Polcari A, Lowen SB, Renshaw PF, Teicher MH
OBJECTIVE: The authors used functional magnetic resonance imaging (fMRI) to test the effects of methylphenidate on steady-state blood volume in the midline vermis of the cerebellum in boys with attention deficit hyperactivity disorder (ADHD). This region was selected as it has been observed to be significantly smaller in children with ADHD. Also, in preclinical studies, the vermis has been shown to modulate forebrain dopamine systems, to influence locomotor activity, and to contain a significant density of dopamine transporters. METHOD: T(2) relaxometry was used to indirectly assess blood volume in the cerebellum (hemispheres and midline vermis) of 10 boys with ADHD who were administered placebo or one of three different doses of methylphenidate continuously for 1 week. T(2) relaxation time values are inversely proportional to local cerebral blood volume. After each week of treatment, and within 1-3 hours of the boys' afternoon dose, testing for drug efficacy was performed by using objective measures of activity. RESULTS: Moderate and high doses of methylphenidate increased T(2) relaxation time in a rate-dependent manner-increasing T(2) relaxation time in the most active children with ADHD and reducing T(2) relaxation time in subjects with ADHD who were not objectively hyperactive. CONCLUSIONS: This preliminary study supports a role for the vermis in ADHD and suggests that further research is needed to clarify the relationship between vermal size, vermal blood flow, stimulant response, and the developmental pathophysiology of ADHD.
Ritalin side effects
PMID: 12153824 [PubMed - indexed for MEDLINE Ritalin side effects]
A double-blind, placebo-controlled study of modified-release methylphenidate in children with attention-deficit/hyperactivity disorder.
Pediatrics. 2002 Mar;109(3):E39
Ritalin side effects Authors: Greenhill LL, Findling RL, Swanson JM,
OBJECTIVE: To compare the efficacy, safety, and tolerability of once-daily administration of modified-release methylphenidate (MPH MR) with placebo in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: The study was a 3-week, double-blind, 32-site, randomized clinical trial comparing MPH MR with placebo. Children were 6 to 16 years of age, had a diagnosis of ADHD, and had not failed a previous trial of stimulant treatment for ADHD. After a 1-week, single-blind, placebo-washout period, participants received a once-daily dose of MPH MR or placebo, which was started with 1 capsule (20 mg) and individually titrated up to a maximum of 3 capsules (60 mg). The primary outcome measure was specified as a reduction in ADHD symptom severity from the teacher version of the 10-item Conners' Global Index. Investigators, teachers, and parents evaluated safety. RESULTS: The study randomized 321 children: 158 to MPH MR and 163 to placebo. Children in the MPH MR group were started on a dose of 20 mg/d and reached a mean dose of 40.7 mg/d (1.28 mg/kg/d) at endpoint. Compared with placebo, MPH MR significantly reduced ADHD symptoms ratings on the teacher version of the 10-item Conners' Global Index, on the parent version of the Conners' Global Index, on the parent assessment of global efficacy, and on investigator assessment of global improvement. The most common adverse events in the MPH MR group were headache, anorexia, abdominal pain, and insomnia. Only anorexia occurred at a rate that was significantly greater than placebo. CONCLUSION: MPH MR administered once daily in the morning is effective and safe in controlling ADHD symptoms throughout the school day.
Ritalin side effects
PMID: 11875167 [PubMed - indexed for MEDLINE Ritalin side effects]
Methylphenidate in the treatment of children with attention-deficit hyperactivity disorder.
CMAJ. 2001 Nov 27;165(11):1505-6
Ritalin side effects Authors: Vitiello B
Ritalin side effects
PMID: 11762576 [PubMed - indexed for MEDLINE Ritalin side effects]
Prescription of methylphenidate to children and youth, 1990-1996.
CMAJ. 2001 Nov 27;165(11):1489-94
Ritalin side effects Authors: Miller AR, Lalonde CE, McGrail KM, Armstrong RW
BACKGROUND: There are concerns about the frequency and appropriateness of psychostimulant drug prescription to children. In order to identify unusual or unexpected patterns of use or prescribing, we reviewed prescription of methylphenidate (Ritalin) to children and adolescents aged 19 years or less in British Columbia between 1990 and 1996. METHODS: We obtained information about patients, physicians and prescriptions from British Columbia's Triplicate Prescription Program database for controlled drugs. Prescription data were available for the period Jan. 1, 1990, to Dec. 31, 1996. Linkage with the BC Linked Health Dataset provided additional demographic and health information. RESULTS: In 1990, 1715 children received at least 1 prescription for methylphenidate (1.9 per 1000 children). By 1996, the number had increased to 10,881 children (11.0 per 1000). Because some children were prescribed methylphenidate in more than 1 year, we also calculated the frequency with which the drug was prescribed to children who had never received it before. This rate increased from 1.0 per 1000 children in 1990 to 4.7 per 1000 in 1995; the rate fell in 1996 to 3.5 per 1000. The number of children receiving methylphenidate varied across health regions of the province, from 12.0 to 35.4 per 1000. Use also varied by socioeconomic status quintile: in the 2 lowest (least privileged) quintiles, 21.6 per 1000 children received methylphenidate, compared with 18.4 per 1000 in the 3 highest quintiles (relative risk 1.2, 95% confidence interval 1.1-1.2). Pediatricians and psychiatrists wrote 23% and 21% of all prescriptions respectively. General practitioners accounted for 56% of all prescriptions and 41% of initial methylphenidate prescriptions. A claim for prior specialist consultation was found in 30% of such cases. Many of the children who received more than 10 prescriptions had seen 4 or more physicians. The average daily dosage prescribed differed little among general practitioners, pediatricians and psychiatrists, unlike the mean interval between successive prescriptions: 89.9 (standard deviation [SD] 68.2), 99.8 (SD 64.1) and 75.9 (SD 70.2) days respectively. Persistence with therapy was more likely when a psychiatrist provided the initial prescription, or with involvement of more than one specialty. INTERPRETATION: Many trends and practices in the prescription of methylphenidate to children in British Columbia are consistent with other settings and accepted standards. Some aspects warrant closer investigation, including regional and socio-economic discrepancies in the distribution of patients, the relative involvement of primary and specialist care providers, continuity of care issues and time intervals between prescriptions.
Ritalin side effects
PMID: 11762572 [PubMed - indexed for MEDLINE Ritalin side effects]
How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? A meta-analysis.
CMAJ. 2001 Nov 27;165(11):1475-88
Ritalin side effects Authors: Schachter HM, Pham B, King J, Langford S, Moher D
BACKGROUND: Numerous small clinical trials have been carried out to study the behaviourally defined efficacy and safety of short-acting methylphenidate compared with placebo for attention-deficit disorder (ADD) in individuals aged 18 years and less. However, no meta-analyses that carefully examined these questions have been done. We reviewed the behavioural evidence from all the randomized controlled trials that compared methylphenidate and placebo, and completed a meta-analysis. METHODS: We searched several electronic sources for articles published between 1981 and 1999: MEDLINE Ritalin side effects, EMBASE, PsychINFO, ERIC, CINAHL, HEALTHSTAR, Biological Abstracts, Current Contents and Dissertation Abstracts. The Cochrane Library Trials Registry and Current Controlled Trials were also consulted. A study was considered eligible for inclusion if it entailed the following: a placebo-controlled randomized trial that involved short-acting methylphenidate and participants aged 18 years or less at the start of the trial who had received any primary diagnosis of ADD that was made in a systematic and reproducible way. RESULTS: We included 62 randomized trials that involved a total of 2897 participants with a primary diagnosis of ADD (e.g., with or without hyperactivity). The median age of trial participants was 8.7 years, and the median "percent male" composition of trials was 88.1%. Most studies used a crossover design. Using the scores from 2 separate indices, this collection of trials exhibited low quality. Interventions lasted, on average, 3 weeks, with no trial lasting longer than 28 weeks. Each primary outcome (hyperactivity index) demonstrated a significant effect of methylphenidate (effect size reported by teacher 0.78, 95% confidence interval [CI] 0.64-0.91; effect size reported by parent 0.54, 95% CI 0.40-0.67). However, these apparent beneficial effects are tempered by a strong indication of publication bias and the lack of robustness of the findings, especially those involving core ADD features. Methylphenidate also has an adverse event profile that requires consideration. For example, clinicians only need to treat 4 children to identify an episode of decreased appetite. INTERPRETATION: Short-acting methylphenidate has a statistically significant clinical effect in the short-term treatment of individuals with a diagnosis of ADD aged 18 years and less. However, the extension of this placebo-controlled effect beyond 4 weeks of treatment has not been demonstrated. Exact knowledge of the extent and definition of the short-term behavioural usefulness of methylphenidate is questioned.
Ritalin side effects
PMID: 11762571 [PubMed - indexed for MEDLINE Ritalin side effects]
Randomized, controlled trial of oros methylphenidate once a day in children with attention-deficit/hyperactivity disorder.
Pediatrics. 2001 Oct;108(4):883-92
Ritalin side effects Authors: Wolraich ML, Greenhill LL, Pelham W, Swanson J, Wilens T, Palumbo D, Atkins M, McBurnett K, Bukstein O, August G
OBJECTIVE: A new once-a-day methylphenidate (MPH) formulation, Concerta (methylphenidate HCl) extended-release tablets (OROS MPH), has been developed. This study was conducted to determine the safety and efficacy of OROS MPH in a multicenter, randomized, clinical trial. METHODS: Children with attention-deficit/hyperactivity disorder (ADHD; n = 282), all subtypes, ages 6 to 12 years, were randomized to placebo (n = 90), immediate-release methylphenidate (IR MPH) 3 times a day (tid; dosed every 4 hours; n = 97), or OROS MPH once a day (qd; n = 95) in a double-blind, 28-day trial. Outcomes in multiple domains were assessed, and data were analyzed using analysis of variance and Kaplan Meier product limit estimates for time to study cessation. The primary time point for analysis was the last available patient visit using last observation carried forward. RESULTS: Children in the OROS and IR MPH groups showed significantly greater reductions in core ADHD symptoms than did children on placebo. This was true both at the end of week 1 and at the end of treatment on the basis of mean teacher and parent IOWA Conners ratings. IR MPH tid and OROS MPH qd did not differ significantly on any direct comparisons. Forty-eight percent of the placebo group discontinued early compared with 14% and 16% in the IR MPH and OROS MPH groups, respectively. CONCLUSIONS: For the treatment of core ADHD symptoms, OROS MPH dosed qd and IR MPH dosed tid were superior to placebo and were not significantly different from each other.attention-deficit/hyperactivity disorder, methylphenidate, OROS, Concerta.
Ritalin side effects Ritalin side effects
PMID: 11581440 [PubMed - indexed for MEDLINE Ritalin side effects]