Expert: Ivan Goldberg, M.D. - 3/29/2010

Question
How come the pamphlet inside Ritalin box says that long term use of methylphenidate is unknown. Does this mean there have never been reports on side effects after many years of use on humans? Thank you

Answer
Hi, Trevor . . .

Medications are usually approved on the basis of short term (generally 8-16 week) studies of their safety and effectiveness. There are no requirements that manufacturers conduct long-term studies. Below are abstracts of reports of some long-term studies involving methylphenidate.

Best regards . . .

Ivan
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Toxicol Lett. 2010 Mar 1;193(1):4-8. Epub 2009 Dec 22.
Prospective follow-up studies found no chromosomal mutagenicity of methylphenidate therapy in ADHD affected children.
Walitza S, Kämpf K, Oli RG, Warnke A, Gerlach M, Stopper H.

Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland.
Five to ten percent of all children suffer from attention-deficit/hyperactivity disorder (ADHD), which is often treated with the central nervous stimulant methylphenidate (MPH). In 2005 controversy arose due to a report of enhanced cytogenetic effects in 12 children after 3 months of MPH treatment. Since then, several prospective studies have been performed and published, which are summarized here. A table comparing the micronucleus frequencies, a marker investigated in all of these studies, is presented. An induction of cytogenetic effects by MPH was only reported in one, the 2005 study by El-Zein et al., while all other studies, with now altogether 110 MPH-exposed individuals, showed no elevation. To address the question of long-term use of MPH, we published the data of 30 chronically treated children and also saw no difference compared to untreated children. Here, we report as new follow-up data that an additional 12 months time point in a small group of 12 children who had begun MPH therapy within our published study also did not reveal elevated cytogenetic damage. Furthermore, a previously unpublished analysis of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG; a non-invasive biomarker for DNA-base oxidation and its repair) in 11 children before and after 3 months of MPH exposure yielded no significant difference. Since gene mutations may not necessarily manifest as chromosomal aberrations, micronuclei or SCEs, we discuss the available data from animal models, which also do not reveal a mutagenic potential of MPH. Although the only two available epidemiological studies do not report elevated risk for MPH exposure, the results are not conclusive yet, and further monitoring of exposed populations is suggested. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

PMID: 20026394 [PubMed - indexed for MEDLINE]
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2.
Clin Ther. 2009 Aug;31(8):1844-55.
Long-term tolerability of the methylphenidate transdermal system in pediatric attention-deficit/hyperactivity disorder: a multicenter, prospective, 12-month, open-label, uncontrolled, phase III extension of four clinical trials.
Findling RL, Wigal SB, Bukstein OG, Boellner SW, Abikoff HB, Turnbow JM, Civil R.

University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio 44106, USA. robert.findling@UHhospitals.org
BACKGROUND: Short-term treatment with the meth-ylphenidate transdermal system (MTS) has been well tolerated in several clinical trials in children with attention-deficit/hyperactivity disorder (ADHD). However, the effects of long-term use have not been systematically evaluated. OBJECTIVES: The primary objective of this study was to assess the 12-month tolerability of MTS in children with ADHD. Effectiveness was a secondary objective. METHODS: This Phase III study was a multicenter, 12-month, open-label, flexible-dose extension of 4 previous trials. In those studies, children aged 6 to 12 years with a diagnosis of ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria) received MTS, osmotic-release oral system methylphenidate, or placebo. At entry into the present study, the children either continued to receive their optimal dose of MTS (10, 15, 20, or 30 mg per 9-hour patch wear time) or underwent dose titration over 4 weeks to an optimal MTS dose, which was continued for the remainder of the study. Tolerability was evaluated based on adverse events (AEs), physical examinations, vital signs, electrocardiograms, laboratory tests, the Children's Sleep Habits Questionnaire, and the occurrence of application-site reactions. RESULTS: Of 327 enrolled subjects, 326 received treatment and 157 completed the study. The majority of enrolled subjects were male (64.8%) and white (73.7%), with a mean (SD) age of 9.2 (1.9) years. Two hundred sixty-five (81.3%) of the 326 subjects who received MTS reported AEs. AEs led to study discontinuation in 29 subjects (8.9%). The majority (98.3%) of treatment-emergent AEs were of mild or moderate severity. The most common AEs were decreased appetite (24.8%), headache (16.6%), upper respiratory tract infection (12.3%), cough (11.7%), pyrexia (10.1%), and decreased weight (10.1%). Of the 1118 AEs, 40.8% were considered possibly or probably related to study treatment. Three serious AEs (facial contusion, ankle fracture, and syncope) occurred and were considered unrelated to study treatment. Based on data collected across all study visits, application-site reactions generally consisted of mild erythema associated with mild discomfort at the patch site. Application-site reactions accounted for 22 (6.7%) study discontinuations. CONCLUSIONS: Slightly less than half (48.0%) of subjects completed this 12-month, open-label extension study of MTS. Most AEs were mild to moderate in severity and, with the exception of application-site reactions, were typical of those previously observed with methylphenidate. ClinicalTrials.gov identifier: NCT00151957.

PMID: 19808143 [PubMed - indexed for MEDLINE]
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3.
Expert Opin Drug Saf. 2009 Nov;8(6):655-68.
Safety of stimulant treatment in attention deficit hyperactivity disorder: Part I.
Merkel RL Jr, Kuchibhatla A.

University of Virginia, Department of Psychiatry and Neurobehavioral Sciences, Charlottesville, 22908, USA. rlm3u@virginia.edu
BACKGROUND: The safety profile of newer stimulant products is of interest. Because most studies focus on school-age children, there is also an increased interest in the treatment of other populations. Concern continues for the risk of substance abuse in the use of stimulants. OBJECTIVE: The purpose of this paper is to review published data on the safety and tolerability of the newer forms of stimulants, treatment in special populations, and the risks of substance abuse and dependence in the treatment of attention deficit hyperactivity disorder. METHODS: Literature obtained through Medline and Pubmed from 1995 were reviewed as well as key articles referenced in the literature. CONCLUSIONS: The use of the newer stimulant agents shows a safety profile of frequent, but usually mild side effects. They are generally safe in special populations. The risk of developing long-term substance abuse with attention deficit hyperactivity disorder, without co-morbidities, is small and may decrease with proper treatment. More research is needed.

PMID: 19785509 [PubMed - indexed for MEDLINE]
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4.
Pediatrics. 2009 Jul;124(1):e75-80.
Cardiac safety of methylphenidate versus amphetamine salts in the treatment of ADHD.
Winterstein AG, Gerhard T, Shuster J, Saidi A.

aepartment of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA. almut@ufl.edu
OBJECTIVES: Safety concerns about central nervous system stimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD) include adverse cardiac effects. This study aimed to compare the risk for cardiac events in users of methylphenidate and amphetamine salts. METHODS: A retrospective cohort design using claims data from the Florida Medicaid fee-for-service program representing a total of 2131953 children and adolescents was used. The analysis included all beneficiaries who were between 3 and 20 years of age, enrolled between July 1994 and June 2004, had at least 1 physician diagnosis of ADHD and were newly started on methylphenidate or amphetamine salts. Each month of follow-up was classified according to stimulant use into current use or former use. We defined cardiac events as first emergency department (ED) visit for cardiac disease or symptoms. Risk between current users of methylphenidate versus amphetamine salts and former users of drugs in these categories was compared by using a time-dependent Cox proportional hazard model that adjusted for differences in gender; race; age; year of the index date; disability; congenital anomalies; history of circulatory disease; history of hospital admission; and use of antidepressants, antipsychotics, and bronchodilators. RESULTS: A total of 456 youth visited the ED for cardiac reasons during 52783 years of follow-up. After adjustment for differences in covariates, the risk for cardiac ED visits was similar among current users of methylphenidate or amphetamines. Periods of former use had a similar risk between youth with an exposure history to methylphenidate or amphetamine. CONCLUSION: Exposure to methylphenidate and amphetamines salts showed similar risk for cardiac ED visits. Additional population-based studies that address manifestation of serious heart disease, especially after long-term use, dosage comparisons, and interactions with preexisting cardiac risk factors are needed to inform psychiatric treatment decisions.

PMID: 19564272 [PubMed - indexed for MEDLINE]
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5.
J Atten Disord. 2009 Mar;12(5):449-59.
Long-term effectiveness and safety of dexmethylphenidate extended-release capsules in adult ADHD.
Adler LA, Spencer T, McGough JJ, Jiang H, Muniz R.

New York University School of Medicine, New York, NY 10016, USA. lenard.adler@med.nyu.edu
OBJECTIVE: This study evaluates dexmethylphenidate extended release (d-MPH-ER) in adults with ADHD. METHOD: Following a 5-week, randomized, controlled, fixed-dose study of d-MPH-ER 20 to 40 mg/d, 170 adults entered a 6-month open-label extension (OLE) to assess long-term safety, with flexible dosing of 20 to 40 mg/d. Exploratory effectiveness outcomes included change from Week 5 on ADHD Rating Scale (ADHD-RS) and proportion of responders on Clinical Global Impressions-Improvement (CGI-I) scale. RESULTS: 103 patients completed OLE, and effectiveness was evaluable in 102 patients. d-MPH-ER was well tolerated; the most common adverse events (>15%) were headache, insomnia, and decreased appetite. Mean improvements in ADHD-RS score were -10.2 for patients switched from placebo to d-MPH-ER (n = 20) and -8.4 for those maintained on d-MPH-ER (n = 82). Respective CGI-I responder rates were 95.0% and 95.1%. CONCLUSION: Once-daily d-MPH-ER 20 to 40 mg is safe and effective for long-term treatment of adult ADHD.

PMID: 19218542 [PubMed - indexed for MEDLINE]
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6.
J Psychopharmacol. 2009 Mar;23(2):194-205. Epub 2008 May 30.
Safety of therapeutic methylphenidate in adults: a systematic review of the evidence.
Godfrey J.

Westhaven and Portland CMHT, Westhaven, Weymouth, Dorset, UK. jonathan.godfrey@dorset-pct.nhs.uk
Attention deficit hyperactivity disorder (ADHD) often persists into adulthood. Stimulant drugs, including methylphenidate, have showed efficacy in trials for ADHD in adults. Adult psychiatrists are likely to encounter increasing numbers of adult patients who may benefit from methylphenidate. A systematic review of the literature was made to examine the evidence on the safety of methylphenidate, when used therapeutically in adults. Twenty-six placebo-controlled trials were found, in which 811 adults received methylphenidate for ADHD and other conditions. In the short term, methylphenidate was well tolerated and no serious side effects were observed. There is little information on the long-term safety of methylphenidate in adults, although the number of serious adverse effects reported to regulatory authorities has, so far, been low. Methylphenidate is associated with a modest rise in blood pressure and heart rate. Surveys of stimulant use in US universities show that misuse of prescribed medication, for recreation or to enhance study, is fairly common although the level of harm that arises from this practice is unclear.

PMID: 18515459 [PubMed - indexed for MEDLINE]
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7.
Child Adolesc Psychiatr Clin N Am. 2008 Apr;17(2):459-74, xi.
Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function.
Vitiello B.

Child and Adolescent Treatment and Preventive Intervention Research Branch, Division of Services and Intervention Research, National Institute of Mental Health, Room 7147, 6001 Executive Boulevard, Bethesda, MD 20892-9633, USA. bvitiell@mail.nih.gov
The effects of stimulant medications and atomoxetine on physical growth and on cardiovascular function are reviewed in light of the most recent data, with attention to clinical implications and research needs. Although these medications have a favorable benefit/risk profile and do not induce clinically significant changes in growth or cardiovascular function in the majority of cases, careful patient monitoring is needed to identify individuals at risk for negative outcomes. More research is needed to elucidate the mechanism of growth suppression to estimate better the risk for rare but life-threatening events and test the effectiveness of monitoring procedures.

PMID: 18295156 [PubMed - indexed for MEDLINE]
PMCID: PMC2408826
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8.
J Neural Transm. 2008;115(2):335-9. Epub 2008 Feb 8.
No increase in long-term risk for nicotine use disorders after treatment with methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD): evidence from a non-randomised retrospective study.
Huss M, Poustka F, Lehmkuhl G, Lehmkuhl U.

Head of Department for Child and Adolescent Psychiatry, Johannes Gutenberg-University, Mainz, Germany. michael.huss@ukmainz.de
OBJECTIVE: To evaluate long-term effects of methylphenidate (MPH) treatment in ADHD children on the development of nicotine use disorders (SUD-N). METHODS: Multisite retrospective non-randomised longitudinal study with 215 ADHD children (diagnosis at 9.2 years of age; reassessment for SUD-N at 21.9 years of age) strictly parallel allocated to MPH treated (n = 106) and drug naive (n = 109) children. RESULTS: There was no difference between the groups with respect to frequency (84% MPH; 89% non-MPH; chi(2) = 1.6; p = 0.21) and age of onset for first cigarette smoking (log rank 1.68; p = 0.19). Continuous smoking was reached by 51% (MPH) and 61% (non-MPH) of the patients. Survival analyses revealed a small and nominally significant delay in age of onset for continuous smoking in the MPH-group (log rank = 3.85; p = 0.049). Nicotine dependency was reached by 20% (MPH) and 27% (non-MPH). Age of onset does not differ between groups (log rank = 2.24; p = 0.13). DISCUSSION: Limited evidence due to the non-randomised nature of the study is given that MPH does not induce SUD-N. The data suggests there may be a beneficial effect of MPH on delay of onset for continuous nicotine consumption in ADHD patients.

PMID: 18253808 [PubMed - indexed for MEDLINE]
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9.
J Am Acad Child Adolesc Psychiatry. 2007 Dec;46(12):1633-41.
Long-term effects of methylphenidate on neural networks associated with executive attention in children with ADHD: results from a longitudinal functional MRI study.
Konrad K, Neufang S, Fink GR, Herpertz-Dahlmann B.

Child Neuropsychology Section, Department of Child and Adolescent Psychiatry, University Hospital Aachen, Germany. kkonrad@ukaachen.de
OBJECTIVE: Little is known about the long-term effects of stimulants on the functional organization of the developing brain. Nonacute effects of stimulants on neural activity related to three aspects of attention (alerting, reorienting, and executive control) were examined in children with attention-deficit/hyperactivity disorder (ADHD) using a longitudinal functional magnetic resonance imaging approach. METHOD: Nine boys with ADHD were scanned while drug naïve (t1) and after 1 year of methylphenidate treatment (t2). Eleven matched controls were also investigated twice. ADHD children stopped medication 1 week before t2. RESULTS: Although all of the children showed stable alerting and reorienting performance from t1 to t2, normal controls significantly improved their executive control performance at t2, whereas children with ADHD did not. Neurally, controls showed a larger increase in neural activity from t1 to t2 in regions critical to task performance (i.e., in the temporoparietal junction during reorienting of attention and in the anterior cingulate cortex during executive control) compared to the patient group. However, only children with ADHD showed a decrease in neural activity in the insula and putamen during reorienting, indicating a reduction in compensatory brain activation over time. CONCLUSIONS: These data suggest that 1 year of MPH treatment may be beneficial, albeit insufficient, to show enduring normalization of neural correlates of attention.

PMID: 18030085 [PubMed - indexed for MEDLINE]
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10.
J Emerg Med. 2010 Jan;38(1):18-21. Epub 2007 Nov 19.
Acute myocardial infarction related to methylphenidate for adult attention deficit disorder.
Thompson J, Thompson JR.

Division of Cardiovascular Services, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Adult Attention Deficit Disorder is increasingly diagnosed and treated. Psychostimulant medications, such as methylphenidate, are commonly prescribed for this condition, but the long-term safety of such medications in an adult population is unknown at present. Because these medications are closely related to amphetamines, it is expected that toxic side effects would be similar. We present the case of a 27-year-old man who suffered an acute myocardial infarction due to coronary vasospasm related to use of methylphenidate complicated by concomitant use of pseudoephedrine. Copyright 2010 Elsevier Inc. All rights reserved.

PMID: 18024065 [PubMed - in process]
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11.
Environ Health Perspect. 2007 Jun;115(6):936-40. Epub 2007 Feb 21.
Does methylphenidate cause a cytogenetic effect in children with attention deficit hyperactivity disorder?
Walitza S, Werner B, Romanos M, Warnke A, Gerlach M, Stopper H.

Department of Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany.
BACKGROUND AND OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is the most common psychiatric disorder in children and adolescents (6-12% affected). Treatment with methylphenidate (MPH) in the United States has increased to a current prescription rate of > 5 million per year. However, a 2005 study by El-Zein and co-workers [Cancer Lett 230:284-291] reporting a 3-fold increase in genomic damage in all 12 analyzed children after 3 months of therapy with MPH resulted in much concern about potential carcinogenic effects. Here we provide new information concerning the cytogenetic effect of MPH in children. DESIGN, PARTICIPANTS, AND METHODS: In a prospective study, we analyzed the genomic damage in children with ADHD (initial sample size 38 children) before and 1 (30 children), 3 (21 children), and 6 (8 children) months after initiation of MPH therapy. In addition, we investigated a group of 9 children receiving chronic MPH therapy. Patients were recruited within a study of our Clinical Research Group on ADHD in the Department of Child and Adolescent Psychiatry and Psychotherapy of the University of Würzburg. Assessment and treatment of patients were performed during inpatient or outpatient health care. The measure for genomic damage was the frequency of micronuclei, a subset of chromosomal aberrations, in peripheral lymphocytes. RESULTS: MPH treatment resulted in no significant alteration in the micronucleus frequency. CONCLUSIONS: Because the findings published in 2005 by El-Zein and co-workers could not be replicated, the concern regarding a potential increase in the risk of developing cancer later in life after long-term MPH treatment is not supported.

PMID: 17589603 [PubMed - indexed for MEDLINE]
PMCID: PMC1892117
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12.
J Clin Psychopharmacol. 2006 Oct;26(5):516-8.
Naturalistic long-term use of methylphenidate in bipolar disorder.
Lydon E, El-Mallakh RS.

Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Antidepressant use seems to be problematic in bipolar disorder. The dopaminergic agent, bupropion, seems to be equally effective to serotoninergic agents but with greater safety. Methylphenidate is a stimulant medication that is sometimes used as an antidepressant in bipolar adults and is frequently used in children with comorbid bipolar and attention-deficit disorder. There are no data available for the safety of long-term methylphenidate in adults. A retrospective chart review of bipolar patients who received methylphenidate while attending a bipolar clinic was conducted. Data regarding side effects and symptoms were collected. Sixteen charts were reviewed. The mean duration of methylphenidate treatment was 14 months (+/-SD, +/-17.5 months; range, 1-60 months). Five had comorbid attention-deficit disorder, the remainder received the methylphenidate for depression. The mean dose was 16.3 mg/d (+/-SD, +/-8.7 mg/d; range, 5-40 mg/d). Several mild to moderate side effects were reported. Two patients (12.5%) discontinued methylphenidate because of adverse side effects. When available (44% of the sample), general assessment of function increased from (+/-SD) 48.3 +/- 9.9 to 69.3 +/- 10.6 (P = 0.006). Methylphenidate seems to be safe in the naturalistic setting. Controlled studies are needed to confirm its efficacy and safety in bipolar depression.

PMID: 16974196 [PubMed - indexed for MEDLINE]
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13.
J Am Acad Child Adolesc Psychiatry. 2006 May;45(5):527-37.
Does prolonged therapy with a long-acting stimulant suppress growth in children with ADHD?
Spencer TJ, Faraone SV, Biederman J, Lerner M, Cooper KM, Zimmerman B; Concerta Study Group.

Massachusetts General Hospital, Boston, 02114, USA. spencer@helix.mgh.harvard.edu
OBJECTIVE: To investigate whether prolonged therapy with a long-acting stimulant affects growth in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: One hundred seventy-eight children ages 6 to 13 years received OROS methylphenidate (OROS MPH, CONCERTA) for at least 21 months. Height and weight were measured monthly during the first year and every 3 months thereafter. RESULTS: At baseline, subjects were approximately the expected height for their age and somewhat heavier than expected. Subjects gained height steadily throughout the study and were on average 0.23 cm less than expected at month 21. Weight did not increase and BMI decreased slightly in the first 4 months. Thereafter, weight Z score and BMI Z score remained relatively constant and children were on average 1.23 kg less than expected at month 21. Previous stimulant therapy tended to be associated with a smaller decrease in Z score during the study compared with no previous stimulant therapy. Drug holidays did not significantly affect growth. CONCLUSIONS: The effects of prolonged OROS MPH therapy on growth were clinically insignificant and limited to slight decreases in weight during the first months of therapy. Drug holidays did not reduce any impact on growth and are thus of questionable utility for limiting potential effects of treatment on growth.

PMID: 16670649 [PubMed - indexed for MEDLINE]
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14.
J Am Acad Child Adolesc Psychiatry. 2006 May;45(5):520-6.
Comparative effects of methylphenidate and mixed salts amphetamine on height and weight in children with attention-deficit/hyperactivity disorder.
Pliszka SR, Matthews TL, Braslow KJ, Watson MA.

Department of Psychiatry, University of Texas of Health Science Center at San Antonio, 78229, USA. oliszka@uthscsa.edu
Comment in:

J Am Acad Child Adolesc Psychiatry. 2007 Mar;46(3):305; author reply 305-6; discussion 306.
OBJECTIVE: To determine whether methylphenidate (MPH) and mixed salts amphetamine (MSA) have different effects on growth in children with attention-deficit/hyperactivity disorder. METHOD: Patients treated for at least 1 year with MPH or MSA were identified. A linear regression was performed to determine the effect of stimulant type, patient gender, cumulative stimulant dose, and length of time in treatment on change in Z scores for height. A subset of patients was identified who had 3 years of consistent stimulant treatment on either MSA or MPH. Repeated-measures analyses of variance were performed to examine the effects of time and medication type on Z scores for weight, height, and body mass index. RESULTS: The linear regression showed no effect of stimulant type, drug holidays, or length of time of treatment on change in height Z score. Cumulative dose of stimulant had a small (-0.26) relationship to change in height Z scores. For patients treated for 3 years, there were no effects of stimulant or time on height Z scores. MSA produced more decrease in weight and body mass index Z scores than MPH; all of the subjects were heavier than average at baseline. CONCLUSION: MSA and MPH did not differ in their effects on height. MSA had more of an effect on weight than MPH, although the effect was modest in magnitude and may be of limited clinical significance.

PMID: 16670648 [PubMed - indexed for MEDLINE]
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15.
J Dev Behav Pediatr. 2006 Feb;27(1):1-10.
Long-term stimulant medication treatment of attention-deficit/hyperactivity disorder: results from a population-based study.
Barbaresi WJ, Katusic SK, Colligan RC, Weaver AL, Leibson CL, Jacobsen SJ.

Department of Pediatric and Adolescent Medicine, Division of Developmental and Behavioral Pediatrics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. barbaresi.william@mayo.edu
The purpose of this study was to offer detailed information about stimulant medication treatment provided throughout childhood to 379 children with research-identified attention-deficit hyperactivity disorder (ADHD) in the 1976-1982 Rochester, MN, birth cohort. Subjects were retrospectively followed from birth until a mean of 17.2 years of age. The complete medical record of each subject was reviewed. The history and results of each episode of stimulant treatment were compared by gender, DSM-IV subtype of ADHD, and type of stimulant medication. Overall, 77.8% of subjects were treated with stimulants. Boys were 1.8 times more likely than girls to be treated. The median age at initiation (9.8 years), median duration of treatment (33.8 months), and likelihood of developing at least one side effect (22.3%) were not significantly different by gender. Overall, 73.1% of episodes of stimulant treatment were associated with a favorable response. The likelihood of a favorable response was comparable for boys and girls. Treatment was initiated earlier for children with either ADHD combined type or ADHD hyperactive-impulsive type than for children with ADHD predominantly inattentive type and duration of treatment was longer for ADHD combined type. There was no association between DSM-IV subtype and likelihood of a favorable response or of side effects. Dextroamphetamine and methylphenidate were equally likely to be associated with a favorable response, but dextroamphetamine was more likely to be associated with side effects. These results demonstrate that the effectiveness of stimulant medication treatment of ADHD provided throughout childhood is comparable to the efficacy of stimulant treatment demonstrated in clinical trials.

PMID: 16511362 [PubMed - indexed for MEDLINE]
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16.
J Am Acad Child Adolesc Psychiatry. 2005 Oct;44(10):1015-23.
ADHD treatment with once-daily OROS methylphenidate: final results from a long-term open-label study.
Wilens T, McBurnett K, Stein M, Lerner M, Spencer T, Wolraich M.

Massachusetts General Hospital, Pediatric Psychopharmacology, Boston, MA 02114, USA. twilens@partners.org
Erratum in:

J Am Acad Child Adolesc Psychiatry. 2006 May;45(5):632.
OBJECTIVE: Few studies have assessed effectiveness and tolerability of stimulants when used for prolonged periods in children with attention-deficit/hyperactivity disorder (ADHD). This article presents final results from an open-label, multisite study of a once-daily formulation of methylphenidate (MPH), OROS MPH. METHOD: Subjects received OROS MPH (18-54 mg initially, with adjustments based on clinical condition) for up to 24 months. Multiple measures of ADHD symptoms, vital signs, weight, height, and laboratory results were assessed throughout the study period. RESULTS: A total of 407 children enrolled in the open-label study and 229 completed the trial. Effectiveness of OROS MPH therapy was maintained throughout the study as indicated by parent and investigator assessments. There was a 26% increase in mean daily dose over the study period, with the majority of the increase occurring during year 1. In general, treatment was well tolerated, with 31 (7.6%) of subjects discontinuing because of adverse events. Minimal effects on growth in height and weight were observed during the study. No clinically significant effects on vital signs or laboratory test parameters were observed. CONCLUSIONS:: Sustained effectiveness of OROS MPH was maintained for up to 24 months with minimal effects on growth, tics, vital signs, or laboratory test values.

PMID: 16175106 [PubMed - indexed for MEDLINE]
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17.
Psychol Med. 2004 Aug;34(6):973-82.
Efficacy and safety of methylphenidate in 45 adults with attention-deficit/hyperactivity disorder. A randomized placebo-controlled double-blind cross-over trial.
Kooij JJ, Burger H, Boonstra AM, Van der Linden PD, Kalma LE, Buitelaar JK.

Parnassia, Psycho-medical Centre, Department of Adult ADHD, The Hague, The Netherlands. s.kooij@parnassia.nl
BACKGROUND: Data on the efficacy and safety of methylphenidate in adults with attention deficit/ hyperactivity disorder (ADHD) are lacking in Europe. This study was undertaken to report on the efficacy and safety of methylphenidate in an adult out-patient population with ADHD, and to compare results with US data. METHOD: A double-blind randomized cross-over trial comparing methylphenidate and placebo in 45 adults with ADHD with childhood onset was performed in a dose-titration design. Methylphenidate was titrated from 0.5 mg/kg per day in week 1 up to 1.0 mg/kg per day in week 3. RESULTS: Response rates using methylphenidate varied between 38 and 51%, and using placebo between 7 and 18% (p<0.05), depending on outcome measure used. Although the overall percentage of subjects having any side effect on both methylphenidate and placebo was rather high, side effects on methylphenidate over and above those on placebo were few and mild. CONCLUSIONS: Methylphenidate proves to be an effective and well tolerated treatment for symptoms of ADHD in adults in the short term. Future research should study the long-term response and clarify the impact of gender, co-morbidity, socio-economic status and IQ on response rates in adults with ADHD.

PMID: 15554568 [PubMed - indexed for MEDLINE]
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18.
Paediatr Drugs. 2003;5(12):787-94.
Long-term use of stimulants in children with attention deficit hyperactivity disorder: safety, efficacy, and long-term outcome.
Hechtman L, Greenfield B.

Division of Child Psychiatry, McGill University, Montreal Children's Hospital, Montreal, Quebec, Canada. lhechtman@hotmail.com
Comment in:

J Sch Nurs. 2004 Jun;20(3):182-3.
The purpose of this review is to summarize existing data on the long-term safety and efficacy of stimulant treatment, and how long-term stimulant treatment of children with attention deficit hyperactivity disorder (ADHD) affects their outcome. Existing controlled studies of children with ADHD treated and untreated with stimulants, as well as long-term prospective follow-up studies, are reviewed. Children with ADHD treated with stimulants for as long as 2 years continue to benefit from the treatment, with improvements observed in ADHD symptoms, comorbid oppositional defiant disorder, and academic and social functioning, with no significant problems of tolerance or adverse effects. Long-term, prospective follow-up studies into adulthood show that stimulant treatment in childhood has slight benefits regarding social skills and self-esteem. Long-term adverse effects from stimulant treatment in childhood regarding adult height or future substance abuse have not been supported by existing studies.

PMID: 14658920 [PubMed - indexed for MEDLINE]
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19.
J Atten Disord. 2002;6 Suppl 1:S45-56.
Longer term effects of stimulant treatments for Attention-Deficit/Hyperactivity Disorder.
Jensen P.

Center for the Advancement of Children's Mental Health, Columbia University, New York, NY 10032, USA. pj131@columbia.edu
Of pharmacological options available for Attention-Deficit/Hyperactivity Disorder (ADHD), stimulant medications are the most studied, the most commonly used, the most effective, and the first-line choice for treatment. Evidence of the short-term efficacy of methylphenidate (MPH) and other stimulants as well as behavioral treatments in the management of symptoms of ADHD is abundant This paper reviews therapeutic trials with a duration or follow-up period of 12 months or more and evaluates the longer term outcomes of available treatments for ADHD. The trials were reported by Ialongo et al. (1993), Horn et al. (1991), Schachar, Tannock, Cunningham, and Corkum (1997), Gillberg et al. (1997), Hechtman and Abikoff (1995), and the National Institute of Mental Health (MTA Cooperative Group, 1999a, 1999b).

PMID: 12685518 [PubMed - indexed for MEDLINE]
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20.
J Atten Disord. 2002;6 Suppl 1:S17-30.
Forty years of methylphenidate treatment in Attention-Deficit/ Hyperactivity Disorder.
Conners CK.

Duke University Medical Center ADHD Program, Durham, NC 27705, USA. ckconners1@direcway.com
This paper reviews approximately 40 years of stimulant drug treatment of children with behavior and learning problems. These patients generally fall under the rubric of Attention-Deficit/Hyperactivity Disorder (ADHD), with core symptoms of hyperactivity, impulsivity, and inattention being the most studied and most robust of the targets for stimulant treatment. In addition, the drug effects on other targets, such as cognitive and academic function, are included. The largest selection of studies involves methylphenidate. Both qualitative studies and meta-analytic studies from major reviews are examined. Variations in the methodology of the reviews are described and some of the discrepancies in interpretation examined. Despite wide variations in subject selection, types of trials, degree of methodological rigor, and the decade in which the studies took place, the evidence is remarkably consistent The overall results suggest significant clinical impact upon the core features of ADHD. More studies of long-term effects and special populations such as older adolescents and adults will be necessary, though existing evidence strongly supports similar findings as for the younger patients with a diagnosis of ADHD.

PMID: 12685516 [PubMed - indexed for MEDLINE]
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21.
Toxicology. 1995 Nov 30;103(2):77-84.
Experimental studies on the long-term effects of methylphenidate hydrochloride.
Dunnick JK, Hailey JR.

National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Toxicology and carcinogenesis studies of methylphenidate hydrochloride, a drug used in the treatment of attention-deficient disorders, were performed in F344 rats and B6C3F1 mice. In these studies, methylphenidate hydrochloride was administered for 2 years at doses of 0, 100, 500 or 1000 ppm in the feed to rats and at doses of 0, 50, 250, 500 ppm to mice in groups that consisted of 50 animals/dose/sex/species. The average amount of methylphenidate consumed per day was estimated to be 4-47 mg/kg/day for rats and 5-67 mg/kg/day for mice. Survival was similar in dosed and control groups. An increase in benign tumors of the liver and increased liver weights were observed in male and female mice at the high dose. An increase in hepatoblastomas was also seen in high dose male mice. Methylphenidate was not mutagenic in the Salmonella assay system, and it is hypothesized that this tumorigenic effect might be due to nongenotoxic effects of the chemical such as an increase in cell proliferation. Increased incidences of neoplasms were not seen in rats. However, there was a notable decrease in mammary gland fibroadenomas in female rats and a marginal decrease in benign pheochromocytomas in male rats. Epidemiology studies of methylphenidate have found no evidence of a carcinogenic effect in humans and like our findings in rats, report a less than expected rate of cancers in patients taking methylphenidate.

PMID: 8545847 [PubMed - indexed for MEDLINE]
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22.
Pediatrics. 1979 Jun;63(6):847-50.
The effects of stimulant medication on the growth of hyperkinetic children.
Croche AF, Lipman RS, Overall JE, Hung W.

This article reviews the literature on possible growth-suppressing effects of stimulant medications in the long-term treatment of children with the hyperkinetic behavior syndrome. The evidence clearly indicates a temporary retardation in the rate of growth in weight and suggests a temporary slowing of growth in stature, but no effect on adult stature or weight. This temporary effect on growth is present during the first few years of treatment and seems related to drug dosage and to the presence or absence of drug holidays. These conclusions related specifically to treatment during the prepubertal period; little is known of the growth-related effects of treatment extending through pubescence.

PMID: 450520 [PubMed - indexed for MEDLINE]
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