Published online June 4, 2007
PEDIATRICS Vol. 120 No. 1 July 2007, pp. e120-e128 (doi:10.1542/peds.2006-1402)
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ARTICLE

Hematologic and Blood Biochemistry Monitoring During Methylphenidate Treatment in Children With Attention-Deficit/Hyperactivity Disorder: 2-Year, Open-Label Study Results

Sharon B. Wigal, PhDa, Timothy E. Wilens, MDb, Mark Wolraich, MDc and Marc Lerner, MDa

a Department of Pediatrics, University of California, Irvine, California
b Psychopharmacology Research Unit, Massachusetts General Hospital, Boston, Massachusetts
c Department of Pediatrics, University of Oklahoma, Oklahoma City, Oklahoma


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. Patients receiving methylphenidate for the management of attention-deficit/hyperactivity disorder are recommended to receive periodic hematologic monitoring. The objective of this study was to evaluate the long-term effects of methylphenidate treatment on blood biochemistry and hematologic values.

METHODS. This study involved a detailed analysis of changes in hematologic and blood biochemistry values over the course of a 2-year study of once-daily OROS methylphenidate in otherwise healthy children aged 6 to 13 years with attention-deficit/hyperactivity disorder. Routine hematologic and blood biochemistry assessments were performed at baseline, at 6 and 12 months during study treatment, and at the end of the study.

RESULTS. Of the 407 subjects enrolled in the study, 289 completed year 1, and 229 completed 21 of 24 months. No subject was excluded from entry into the study or discontinued from the study because of abnormalities of any of the blood chemistries evaluated. There were no clinically significant changes from baseline in mean values for hematologic or blood biochemistry parameters. For most values, the mean change in value over the course of the study was <5%.

CONCLUSIONS. These longer-term data suggest that chronic therapy with OROS methylphenidate has no clinically significant impact on laboratory values, challenging the necessity of routine hematologic monitoring in otherwise healthy children with attention-deficit/hyperactivity disorder who are treated with methylphenidate.

Key Words: ADHD • hematologic monitoring • blood biochemistry • methylphenidate • stimulant • Concerta

Abbreviations: ADHD—attention-deficit/hyperactivity disorder • ALT—alanine aminotransferase • AST—aspartate aminotransferase • GGT—{gamma}-glutamyltransferase

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder treated in children.1 The disorder is often chronic, with symptoms and associated impairment persisting into adolescence and adulthood.2,3 Throughout the life span, ADHD is associated with significant functional impairment, including school failure; comorbid psychiatric and developmental conditions; and family, peer, and emotional difficulties.4,5

Because of the chronic nature of the disorder, long-term treatment has been recommended in ADHD treatment guidelines.6,7 A 14-month, long-term, multisite, multimodal treatment study demonstrated that medication management of ADHD is the most important variable in successful treatment outcome.8 Because of their established efficacy, stimulants are considered first-line agents for the treatment of ADHD.6,7,9–13 Methylphenidate is the most commonly prescribed stimulant used to treat ADHD, with extended-release formulations, such as OROS methylphenidate (Concerta, McNeil Pediatrics, Ft Washington, PA), providing ADHD symptom management throughout the day with 1 daily dose.14

Treatment guidelines recommend routine monitoring for children treated with stimulant medications.6,7 Along with the regular assessments of treatment efficacy and the emergence of adverse effects, it has also been recommended that physicians routinely monitor height, weight, blood pressure, and heart rate in patients treated with stimulants.15,16 In addition, routine hematologic monitoring, including periodic complete blood cell count, differential, and platelet counts, is advised during prolonged therapy with both immediate-release and extended-release methylphenidate formulations.17–22 Rare cases of thrombocytopenia and/or easy bruisability, epistaxis, and gingival bleeding; leukopenia; anemia; and eosinophilia have been reported in patients receiving methylphenidate, but a causal relationship with the drug has not been established.23

Despite the recommendations of routine hematologic monitoring in methylphenidate-treated patients, over years of extensive methylphenidate use, no known serious blood biochemistry or hematologic abnormalities have been reported in clinical trials, including those in extended-release methylphenidate formulations.9,24,25 Therefore, the clinical usefulness of routine hematologic or blood biochemistry monitoring is uncertain. Given the costs and discomfort associated with routine hematologic and blood biochemistry assessments, a systematic evaluation of a large sample of children prospectively followed for the development of abnormal laboratory values associated with long-term methylphenidate use is warranted. Such data would provide useful safety information to assess the use of routine blood testing in patients with ADHD treated with methylphenidate.

The current study includes an analysis of blood biochemistry values, including hematology, measured during the course of a long-term, open-label trial of OROS methylphenidate in which children with ADHD received therapy for ≤24 months. Based on the literature, no clinically significant effects on blood biochemistries in general, and on hematologic findings in particular, were hypothesized to occur in this otherwise healthy group of children and young adolescents. This study provides, to our knowledge, the largest data set evaluating the long-term effect of methylphenidate on producing clinically important effects on hematologic and blood biochemistry values.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Subjects and Study Design
Subjects from 14 sites were enrolled in this open-label study for ≤24 months. The full details of the open-label study are reported elsewhere.26 The primary study assessed the long-term safety and efficacy of OROS methylphenidate in children with ADHD.26 Multiple measures of ADHD symptoms, vital signs, weight, height, and laboratory results were assessed throughout the 2-year study period.26 The study involved children, aged 6 to 13 years, who had participated in previous OROS methylphenidate trials.14,27–30 The previous studies included only children who had been receiving methylphenidate either with a positive response or without having experienced a significant adverse event based on parent or physician reports.

The study included otherwise healthy children with ADHD. Therefore, subjects with clinically significant gastrointestinal problems, a history of clinically important electrocardiogram abnormalities or blood pressure measurements, or a coexisting medical condition likely to interfere with the safe administration of methylphenidate as determined by the investigator were excluded. Patients were also excluded if they were currently taking the following medications: sedative/hypnotic agents; anticonvulsant agents; desmopressin; antihistamines containing sedatives; lithium; oral corticosteroids; or monoamine oxidase inhibitors, tricyclic antidepressants, theophylline, or warfarin. Patients were not allowed to take additional doses of methylphenidate or other medications for treatment of ADHD beyond those prescribed in the study.

Although children with psychiatric comorbidities were eligible for inclusion, those with Tourette's syndrome or family history of Tourette's syndrome; an ongoing seizure disorder; bipolar disorder; psychotic disorder; marked anxiety, tension, or agitation; a mood or anxiety disorder requiring drug therapy; drug or alcohol abuse within the 6 months before study entry; or an eating disorder were excluded from study entry. Adolescents with a history of nonresponse to methylphenidate or a hypersensitivity or significant intolerance to methylphenidate also were excluded.

Subjects were initially assigned to 1 of 3 dosing levels of OROS methylphenidate (18, 36, or 54 mg once daily) based on either their dose in the previous study or their methylphenidate dose received before entry to 1 of the OROS methylphenidate studies. OROS methylphenidate dosage could be adjusted upward or downward in 18-mg increments throughout the study to a maximum of 54 mg per day if the investigator deemed it necessary. Subjects could follow their usual dosing pattern, including having their doses reduced, stopping medication on weekends, or taking planned drug holidays.

The prospective trial was terminated by the sponsor with Food and Drug Administration acknowledgment between 21 and 24 months of subject participation for administrative reasons that were unrelated to safety or effectiveness. Because data were available for only a minority of subjects at 24 months (n = 56), the final end point is referred to as 21/24 months.

Each subject's parent(s) or guardian(s) was required to give signed informed consent, and subjects aged ≥7 years were also required to give written assent if they were able to write their name. The consent and assent forms, study protocol, and any advertisements for subjects were reviewed and approved by the institutional review board of participating centers before initiation of the study.

Laboratory Tests
Blood samples were collected from patients before medication exposure, during medication exposure, and at the completion of the study. Because the current study included children who had participated in a previous OROS methylphenidate trial, if <4 weeks had elapsed since completing a previous study, laboratory tests were not performed at baseline. At the 6- and 12-month visits, blood was drawn for hematology and chemistry. Laboratory tests also were performed at the final study visit of the 2-year study. Subjects who withdrew from the study prematurely had their hematologic and blood biochemistry values measured as part of the exit criteria, with laboratory tests to be completed within 2 weeks of study termination.

Patients were not instructed to fast before blood samples were collected. Collection times were random within and across subjects, with most laboratory tests being administered in the late afternoon.

A central clinical laboratory (Covance Inc, Indianapolis, IN) was used to analyze blood samples for determination of the laboratory indices. All of the blood samples were collected, centrifuged, and immediately stored in a temperature-monitored storage device at –20°C. All of the samples were shipped at –20°C to a central laboratory.

The standard hematologic laboratory tests included hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and platelet count. Blood biochemistry analyses included sodium, potassium, chloride, blood urea nitrogen, creatinine, calcium, phosphorus, glucose, total protein, albumin, bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), {gamma}-glutamyltransferase (GGT), and lactate dehydrogenase.

At the central clinical laboratory, flow cytometry assays were used to measure red blood cell count and platelets, and manual microscopy was used to measure red blood cell count morphology. Calculation was used to measure hematocrit. A peroxidase assay was used to measure white blood cell count, neutrophils, lymphocytes, monocytes, and eosinophils. Basophil/lobularity was used to measure basophils. Colorimetric assays were used to measure hemoglobin, albumin, alkaline phosphatase, bilirubin, calcium, creatinine, GGT, phosphorus, and protein. Enzymatic assays were used to measure ALT, AST, glucose, lactate dehydrogenase, and blood urea nitrogen. Ion-selective electrode assays were used to measure electrolytes.

Reference values were defined and standard for all testing, and laboratory values that were out of range were identified and repeated at the investigator's discretion. For this analysis, postbaseline laboratory values were assigned as "clinically significant change" (above or below the reference limits for that laboratory test) or "no clinically significant change" (within reference limits for that laboratory test). All of the clinically important out-of-range laboratory values were followed until they returned to within the reference range, with the investigator treating the patient as medically required at appropriate intervals until such laboratory values stabilized. Patients were to be discontinued from the study if the investigator deemed any clinically significant abnormal laboratory values as possibly attributable to the use of methylphenidate

Analyses
All of the analyses were completed by using the intent-to-treat patient population data from the last observation carried forward. For each parameter, mean and SD values and change from baseline were determined at each time point. In addition, the percentages of patients with low, normal, or high values at each time point were determined. Reference values were standard for all of the sites and followed by the central laboratory, and values outside of these were defined as high or low.

McNemar's Test for Marginal Homogeneity
In epidemiologic studies, outcomes are frequently analyzed as falling above or below a fixed value, but with paired data and a fixed value, McNemar's test of marginal homogeneity may be used to test for equality of the distribution of the outcomes.31 To complete an additionalanalysis of these study data, the percentage of subjects with clinically significant changes in each blood biochemistry parameter at any time point during the study was determined. McNemar's test for marginal homogeneity was used to determine whether the probability of having an abnormal laboratory test value was equal at baseline and at the end of the study.

Safety
Throughout the study, parents were questioned about adverse events at each follow-up visit. No systematic scales were used for the determination of adverse events. The investigator determined whether any clinically significant out-of-range laboratory values that emerged during treatment with OROS methylphenidate were considered to be adverse events.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients
A total of 407 children entered the study, and 289 completed the first year of therapy.26 Of these, 278 enrolled in the second year of treatment, and 229 children received treatment to the 21/24-month end point.26 As reported previously, select baseline characteristics and demographic data for all of the enrolled subjects are provided in Table 1. 26


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  		TABLE 1 Baseline Characteristics and Demographics

 
Dosing
At the start of the study, 47.4% of the subjects were receiving a 36-mg dose of OROS methylphenidate, 28.5% were receiving an 18-mg dose, and 24.1% were receiving a 54-mg dose.26 Throughout the study, the mean daily dose of OROS methylphenidate increased by 26%, from 35.2 mg at baseline to 44.2 mg at end point (month 21/24).26 The mean duration of exposure to study medication at any dose was 471 days.26 As a result of planned medication breaks being permitted during the 2-year study, 163 subjects (40%) reported a period of ≥7 days without medication (90 subjects reported medication breaks of 7–29 days in duration, and 73 subjects reported breaks of >29 days).26

Changes From Baseline in Hematologic and Blood Biochemistry Values
At baseline, 98% of hematologic and blood chemistries values were available, and 88% of these values were available at completion of the study. Mean baseline values for parameters measured and mean change from baseline at the final time point of the study are given in Table 2. There were no clinically significant changes from baseline in mean values for hematologic or blood biochemistry parameters.


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  		TABLE 2 Change From Baseline in Hematologic and Blood Biochemistry Values

 
The percentage change from baseline was <5% for most values and only exceeded 5% for monocytes (change from baseline: –0.57% [9.2%]), basophils (change from baseline: –0.16% [21.3%]), eosinophils (change from baseline: –0.36% [11.6%]), hematocrit (change from baseline: 1.90 mL/dL [5.2%]), serum creatinine (change from baseline: 0.09 mg/dL [18.8%]), total bilirubin (change from baseline: –0.1 mg/dL [21.7%]), serum lactate dehydrogenase (change from baseline: –14.67 U/L [6.7%]), and serum alkaline phosphatase (change from baseline: 26.02 U/L [11.0%]). For most parameters, including all of those where the percentage change from baseline exceeded 5%, the absolute change from baseline was less than or approximately the same as the SD for baseline values.

Changes in hematologic and blood biochemistry values were also analyzed as to whether a clinically significant change occurred at any point during the study. For most parameters, the percentage of patients having clinically significant changes in any value at any time during the study was <10%. The percentage of patients was >10% for 6 values: serum glucose (21.4%; n = 65), hematocrit (20.7%; n = 59), total bilirubin (19.5%; n = 64), neutrophils (19.0%; n = 55), lymphocytes (17.0%; n = 49), and white blood cell count (11.1%; n = 35).

Hematologic and blood biochemistry values also were analyzed according to whether they were lower than the reference range (low), within the reference range (normal), or higher than the reference range (high) at baseline and at the final study time point (Table 3). For most parameters, values remained normal or normalized in ≥95% of patients. The only parameters for which >5% of subjects had changes to values outside of the reference range at end of study were bilirubin (19%; n = 39), hematocrit (14%; n = 28), lymphocytes (8%; n = 17), neutrophils (8%; n = 17), serum glucose (8%; n = 16), serum calcium (7%; n = 15), albumin (7%; n = 14), and serum alkaline phosphatase (6%; n = 13).


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  		TABLE 3 Subjects With Values Within the Reference Range for Each Laboratory Parameter at Baseline and Study End Point

 
Approximately 7% of laboratory study visits were recorded as "retest" or "unscheduled visit." It is not certain whether any or all of these visits were because of investigators requesting follow-up for an out-of-range laboratory value.

McNemar's Test for Marginal Homogeneity
Although all of the patients had laboratory values within the reference ranges at baseline, McNemar's test for marginal homogeneity was used to assess whether the probability of having a value outside reference limits was greater at the last time point in the study compared with at baseline (Table 4). The results indicate that for most parameters, there was no statistically significant change in the probability of abnormal values. The only parameters that yielded statistically significant P values of <.05 were hematocrit (P = .042), red blood cell count (P = .008), serum calcium (P = .041), serum albumin (P = .022), and total bilirubin (P < .001).


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  		TABLE 4 McNemar's Test for Marginal Homogeneity: Baseline Versus Last Time Point

 
Clinical Laboratory Adverse Events
Before enrollment in the 2-year, open-label study, no subjects were excluded from the original controlled clinical trials because of abnormal laboratory findings, and no subjects were dropped from the controlled studies because of clinically significant laboratory findings or adverse events. Likewise, no subjects developed a clinically significant laboratory value during the course of the 2-year open study necessitating discontinuation from the trial.

Over the 2-year period, 3 patients had abnormal hematologic/blood biochemistry laboratory evaluations that were reported as adverse events per the investigators’ discretion. Leukopenia was reported in 1 patient while taking 36 mg of OROS methylphenidate (white blood cell count = 4000/µL at baseline, 2790/µL at 12 months, and 3430/µL at study end point). One patient was reported to have increased creatinine while taking 36 mg of OROS methylphenidate (creatinine = 0.6 mg/dL at baseline, 0.5 mg/dL at 12 months, and 1.2 mg/dL at study end point). Abnormal liver function test results were reported in 1 patient taking 54 mg of OROS methylphenidate (AST = 40.0 U/L at baseline and 53.0 U/L at study end point; ALT = 44.0 U/L at baseline and 51.0 U/L at study end point; GGT = 13.0 U/L at baseline and 26.0 U/L at study end point). In all 3 of the patients, the adverse events were considered mild, continuous, and possibly related to OROS methylphenidate treatment. The subjects with elevated creatinine and liver enzymes were not discontinued from the study and were referred to their primary care physicians. No follow-up was reported by the study investigators, and no other information is available.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The results of these analyses were reassuring in that no subject developed a clinically significant laboratory value during the course of the 2-year open study that necessitated discontinuation from the trial. Moreover, the results of the study indicate that for most hematologic and blood biochemistry parameters, the change in mean value over the course of the study was <5%, and shifts to abnormal values (high or low) were seen in <5% of subjects. These data suggest that routine blood monitoring is unwarranted in otherwise healthy youth with ADHD receiving OROS methylphenidate treatment. The effects of methylphenidate on youth with ADHD with baseline medical conditions (ie, hepatitis, bone marrow suppression, etc) remain unclear.

Our overall findings indicate that most values over the course of the current study were within the reference range, with a small percentage falling outside reference values. This would be expected because reference ranges for laboratory values are set to include 95% of healthy subjects, with 5% of healthy subjects falling outside of the reference range. For most values with subjects within the reference range at baseline, <10% of subjects experienced clinically significant shifts at any time during the study. Of the 5 values that showed a statistically significant change, only hematocrit and total bilirubin showed clinically significant changes in >10% of subjects and shifts to abnormal values over the course of the study in >5% of subjects. For all of the values, the absolute change from baseline to end point was either approximately the same as or less then the SD for the baseline value. These data suggest that although prolonged therapy with OROS methylphenidate may produce statistically significant changes in such laboratory values as hematocrit and bilirubin, it does not produce clinically significant (or important) changes in hematologic or blood biochemistry values overall.

Hematologic and blood biochemistry values differ by age, gender, and race, and such differences are associated with maturation.32,33 For example, in the Bogalusa Heart Study, complete blood cell counts were analyzed from 3018 children and adolescents aged 5 to 17 years and demonstrated that hemoglobin levels, hematocrit, and red blood cell count increased with age (P < .01), and white blood cell count decreased with age (P < .0005).32 Because a naturalistic fluctuation in values is usually seen in children, especially as they age, such variation would be expected throughout the course of a 2-year study. Therefore, the minor fluctuations in laboratory values demonstrated in the current long-term study in children with ADHD were expected, even in this patient population that included mostly white, male subjects.

Over the 24-month treatment period, OROS methylphenidate treatment was safe, with only 3 patients having abnormal hematologic/blood biochemistry laboratory evaluations reported as adverse events. The OROS methylphenidate dosage varied. The patient with leukopenia and the patient with increased creatinine were treated with 36 mg of OROS methylphenidate. The patient with abnormal liver function tests (elevated liver enzymes) was treated with 54 mg of OROS methylphenidate. All 3 of the adverse events were considered mild and continuous by the study investigator, and no subject was withdrawn from the study because of adverse events. Although the subjects with elevated creatinine and liver enzymes were referred to their primary care physicians, no follow-up was reported by the study investigators.

This is the first time that such a detailed analysis of hematologic and blood biochemistry values has been reported for any methylphenidate therapy during long-term treatment in subjects with ADHD; however, several other studies have suggested previously that no consistent changes in such values occur. For example, a 3-week, double-blind, placebo-controlled study of modified- release methylphenidate (Metadate CD) in children with ADHD found no consistent changes in hematology or blood biochemistry values.9 In fact, fewer children in the modified-release methylphenidate group (48 of 158 [30%]) had out-of-range laboratory values that were within reference range at baseline compared with the placebo group (63 of 163 [39%]). The lack of consistent changes was also confirmed in a 3-week, open-label study in which blood biochemistry was assessed at baseline and weekly throughout.24 In the study, only subjects with blood biochemistry values within reference ranges were included, and there were no clinically significant changes in any of the hematology or blood biochemistry values throughout the study.

As was demonstrated in the MTA study, frequent clinician-patient contact and monitoring of treatment outcome is an important part of ensuring optimal efficacy.8 Although periodic monitoring of growth (height and weight) and vital signs (blood pressure and heart rate), as well as adverse events and the efficacy of treatment, seem to be necessary,6,7,15,16 routine hematologic monitoring in methylphenidate-treated patients does not. The absence of clinically significant effects of stimulant therapy with methylphenidate on values of hematologic values or blood biochemistry (as demonstrated for OROS methylphenidate in this long-term study) suggests that routine monitoring of hematologic and blood biochemistry laboratory values in otherwise healthy children may not be necessary. Additional work in medically compromised children is needed to address this question completely.

In clinical practice, routine monitoring of hematologic and blood biochemistry parameters is intended to serve as a screening tool to identify individual patients with an adverse reaction. The current study analyzed changes in hematologic and blood biochemistry parameters as a group means and not as individual changes in the parameters measured. Therefore, additional studies are needed to determine the threshold for clinically important changes and to determine how many patients are likely to have elevations of what magnitude above the determined threshold.

The results of this study need to be tempered against their limitations. Children were screened to be otherwise healthy, and, therefore, this is a selected group that may not be representative of general pediatric and psychiatric practices. However, no youth was excluded because of abnormal values. The generalizability of these data to medically compromised children (ie, those with hepatic, hematologic, or other blood dyscrasias) remains unknown. Exclusion or discontinuation from the clinical trial based on "clinically significant findings" varied by site and by investigator. Also, a number of subjects withdrew from the study before the 21/24-month end point. In addition, no placebo or untreated group of ADHD children was available for comparison purposes to better understand the current fluctuations of values in context to "normal variation."


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Despite these limitations, no safety issues related to hematologic or blood biochemistry values were identified in this long-term study. Although 3 patients had abnormal hematologic/blood biochemistry laboratory evaluations that were reported as adverse events, there seemed to be no clinically significant changes from baseline in mean values for hematologic or blood biochemistry evaluations during the study. These data suggest that prolonged therapy with OROS methylphenidate has no clinically significant impact on hematologic or blood biochemistry values. The current lack of clinically important changes in laboratory test values demonstrated in this 2-year study challenges the necessity of routine hematologic monitoring in children with ADHD who are treated with OROS methylphenidate.


   ACKNOWLEDGMENTS
 
We acknowledge the contributions of the Concerta Study Group and the editorial support of JK Associates, Inc.


   FOOTNOTES
 
Accepted Dec 13, 2006.

Address correspondence to Sharon B. Wigal, PhD, University of California, 19722 MacArthur Blvd, Irvine, CA 92612. E-mail: sbwigal{at}uci.edu

Financial Disclosure: Dr Wigal receives research support from Alza, Celgene, Celltech, Cephalon, Eli Lilly and Company, McNeil Pediatrics, Novartis, and Shire Laboratories, Inc; is a speaker the Alza, Cephalon, McNeil Pediatrics, National Institute on Mental Health, New Rivers, Novartis, Shire Laboratories, Inc, and Sigma-Tau speaker's bureaus; and is also a consultant/on the advisory board for Alza, Cephalon, McNeil Pediatrics, Novartis, and Shire Laboratories, Inc. Dr Wilens receives grant support from Abbott Laboratories, Cephalon, Ortho-McNeil, Eli Lilly and Company, National Institute on Drug Abuse, Neurosearch, and Shire Laboratories Inc; is a speaker for the Ortho-McNeil, Novartis Pharmaceuticals, and Shire Laboratories Inc speaker's bureaus; and is also a consultant for Abbott Laboratories, Cephalon, Janssen, National Institute on Mental Health, Ortho-McNeil, Eli Lilly and Company, National Institute on Drug Abuse, Novartis, Pfizer, and Shire Laboratories, Inc. Dr Wolraich receives research support from Eli Lilly and Company and is a consultant for Eli Lilly and Company and Shire Laboratories, Inc. Dr Lerner receives research support from Alza, Celltech, Cephalon, Eli Lilly and Company, McNeil Pediatrics, Novartis, and Shire Laboratories, Inc; is a speaker for the Alza, Cephalon, Celltech, Eli Lilly and Company, Janssen, McNeil Pediatrics, Novartis, and Shire Laboratories, Inc speaker's bureaus; and is also a consultant for Celltech, Cephalon, McNeil Pediatrics, Novartis, and Shire Laboratories, Inc.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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