Short-Term Effects of Lisdexamfetamine Dimesylate on Cardiovascular Parameters in a 4-Week Clinical Trial in Adults With Attention-Deficit/Hyperactivity Disorder
Objective: To evaluate the short-term impact of lisdexamfetamine dimesylate on cardiovascular parameters in adults with attention-deficit/
hyperactivity disorder (ADHD).
Method: Medically healthy adults (18–55 years of age) with DSM-IV-TR–defined ADHD were randomly assigned to placebo or 30, 50, or 70 mg/d of lisdexamfetamine dimesylate for 4 weeks between May and November 2006. Electrocardiograms, systolic and diastolic blood pressure, and pulse were assessed pretreatment and weekly thereafter.
Results: There were no significant differences for mean systolic or diastolic blood pressure in any lisdexamfetamine dimesylate dose group versus placebo. Changes in pulse from baseline to endpoint were 0.0, 2.8, 4.2, and 5.2 bpm in the placebo and lisdexamfetamine dimesylate 30, 50, and 70 mg/d groups, respectively (P < .05, all lisdexamfetamine dimesylate groups vs placebo). Post hoc pulse outliers (pulse ≥ 100 bpm; any 1 event) ranged from 3.3% to 8.5% of subjects in the lisdexamfetamine dimesylate groups, and no subjects in the placebo group were pulse outliers (P < .05 for lisdexamfetamine dimesylate 50 mg vs placebo only). There were no clinically meaningful electrocardiogram abnormalities. Overall, 8.3% (35/420; safety population) of subjects had treatment-
emergent cardiovascular adverse events, and 1.7% (7/420) withdrew from the study because of cardiovascular complaints. Cardiovascular adverse events with lisdexamfetamine dimesylate in these medically healthy adults were generally mild to moderate in severity.
Conclusions: Lisdexamfetamine dimesylate had limited short-term effects on heart rate, blood pressure, and electrocardiogram parameters that were of minimal clinical concern. These findings support the relative safety of lisdexamfetamine dimesylate. However, considering the potential of outliers, it is advisable to monitor cardiovascular parameters in stimulant-treated patients. Interpretation of these findings is limited to patients with no preexisting cardiac conditions who are taking their medication as prescribed.
Trial Registration: clinicaltrials.gov Identifier: NCT00334880
J Clin Psychiatry 2009;70(12):1652–1661
© Copyright 2009 Physicians Postgraduate Press, Inc.
Submitted: May 5, 2009; accepted September 28, 2009
Corresponding author: Lenard A. Adler, MD, Department of Psychiatry, New York University School of Medicine, 530 First Ave #7D, New York, NY 10016 (Lenard.Adler@nyumc.org).
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders worldwide, affecting as many as 8% of children.1,2 Once considered a pediatric condition, prominent ADHD symptoms are now recognized to persist into adolescence and adulthood in approximately half of childhood cases.3,4 Recent data suggest that the prevalence of ADHD in adults is 4.4% in the United States.5
Stimulant treatment is among the established treatments for ADHD in adults.6–12 In clinical practice, the majority of adults who are being treated pharmacologically for ADHD are treated with stimulants.13 Among reported adverse effects (AEs) of stimulants, much attention has been paid to the potential cardiovascular effects of these agents.14,15
The stimulants currently used to treat ADHD are methylphenidate- and amphetamine-based products, sympathy omimetics known to increase blood pressure (BP) and pulse.10,16–19 Stimulants are not recommended for use in patients with preexisting serious structural cardiac abnormalities, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of these agents.20–23 Guidelines for monitoring cardiovascular parameters in children include general recommendations from the American Heart Association (AHA) for careful monitoring of risk factors and concomitant drug therapy in children receiving psychotropic agents.16 These recommendations for screening and monitoring of children and adolescents receiving stimulants and other psychotropic agents (described more fully below) are well accepted. The AHA recently issued recommendations specifically on electrocardiogram (ECG) screening of children being considered for stimulant therapy for ADHD.24 Additionally, a recent guideline from the American Academy of Pediatrics does not recommend routine ECG screening prior to treatment with stimulants, but as an option reserved for cases in which patient or family history or physical examination suggests the potential for cardiac disease.25 While pediatric recommendations are useful, risk factors for cardiovascular disease are different in adults. Currently, medical associations have not issued definitive recommendations for monitoring cardiovascular parameters in adults receiving stimulant medications.
The cardiovascular effects reported in otherwise healthy adults with ADHD receiving stimulants appear modest in magnitude, with changes noted in pulse and BP, but not ECG parameters. Previous studies of long-acting stimulants have noted small but statistically significant effects versus placebo on BP and pulse, and these findings have been interpreted as having limited clinical significance.15,18,19,26 However, there are a limited number of studies that have examined the effects of stimulants on cardiovascular parameters in adults with ADHD.
Lisdexamfetamine dimesylate is a prodrug stimulant that is indicated for the treatment of ADHD in children 6 to 12 years of age and in adults. Lisdexamfetamine dimesylate is a prodrug that is therapeutically inactive. After oral ingestion, lisdexamfetamine dimesylate is converted to l-lysine and active d-amphetamine. While a small amount of lisdexamfetamine dimesylate is hydrolyzed to d-amphetamine in the gastrointestinal tract, it has recently been identified that the conversion of lisdexamfetamine dimesylate into active d-amphetamine occurs primarily in the blood.27,28
Lisdexamfetamine dimesylate reduced symptoms of ADHD in adults with generally good tolerability, with a safety profile consistent with long-acting stimulant use, in a large, randomized, placebo-controlled, multisite clinical trial.29 Given the limited published information on cardiovascular tolerability of stimulants in adults with ADHD, this article focuses on the analyses of vital signs and ECG data that were ascertained as part of this study of lisdexamfetamine dimesylate in medically healthy adults with ADHD. We hypothesized that similar to what has been previously reported in this patient population,18 compared with placebo, lisdexamfetamine dimesylate would be associated with significant increases in heart rate and BP, but not ECG indices.
These analyses of cardiovascular data are from a large, multicenter, randomized, double-blind, placebo-controlled, parallel-group, forced-dose titration study conducted at 48 sites in the United States between May and November 2006.29 Institutional review board approval was obtained for each study site, and all participants provided written informed consent after receiving a complete explanation of the study. This study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice according to the International Conference on Harmonization guidelines.
Subjects eligible for participation in the study were aged 18 to 55 years and satisfied Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for a primary diagnosis of ADHD. Subjects were diagnosed with ADHD via a comprehensive psychiatric evaluation using the Adult ADHD Clinical Diagnostic Scale (version 1.2),30 with moderate-to-severe ADHD symptoms, as indicated by a baseline score of at least 28 on the ADHD Rating Scale (ADHD-RS). The ADHD-RS was administered to subjects by trained raters utilizing adult prompts developed at New York University and Massachusetts General Hospital.30,31
Additional inclusion criteria included a 12-lead ECG with QT/QTcF (Fridericia) intervals < 450 msec for men and < 470 msec for women, a resting heart rate between 40 and 100 beats per minute (bpm), a PR interval < 200 msec, and a QRS interval < 110 msec. ECG measurements were performed at screening and visits 2 to 6. At screening, 3 readings were taken at least 3 minutes apart after the subject rested supine for 10 minutes, ensuring accurate intervals were established to determine eligibility. At subsequent visits, ECG was recorded 1 or more times. Investigators made determinations regarding the clinical significance of ECG abnormalities with consultation of a cardiologist at the discretion of the investigator. Subjects were excluded from the study if they had a history of hypertension; a resting, sitting systolic BP (SBP) > 139 mm Hg or diastolic BP (DBP) > 89 mm Hg; any clinically significant abnormality on ECG; or a known cardiac structural abnormality/condition that might affect cardiac performance. Of note, if a participant had an SBP > 139 mm Hg or DBP > 89 mm Hg, the measurements were repeated twice more at 5-minute intervals, and the average of the measurements was used to determine the subject’s eligibility for the trial.
Other exclusion criteria included any comorbid psychiatric diagnosis with significant symptoms that, in the opinion of the examining physician, would contraindicate treatment with lisdexamfetamine dimesylate or would confound efficacy and safety assessments; history of seizures (other than infantile febrile seizures); and current or recent history (within the last 6 months) of substance abuse (excluding nicotine). In addition, subjects were excluded if they were taking any prohibited medication (excluding ADHD medications, which were discontinued during a washout period) within 30 days of the screening visit. Excluded medications included, in addition to drugs with central nervous system effects, those known to affect BP, such as sympathomimetic and antihypertensive medications.
Study Design and Assessment Measures
The study had 3 phases: screening and washout, baseline, and double-blind treatment. Subjects underwent a screening period to ensure eligibility for participation in the study. Eligible subjects underwent a washout period during which all ADHD medications were discontinued for at least 7 days (28 days if the subject was taking atomoxetine). Following the screening and washout periods, study participants underwent a baseline visit and were randomly assigned to treatment groups to receive placebo or once-daily oral doses of lisdexamfetamine dimesylate 30, 50, or 70 mg during the 4-week double-blind period. Randomization was achieved using a block-randomization schedule with a block size of 7 with a 2:2:2:1 allocation ratio of each of the 3 active doses versus placebo. Subjects randomly assigned to receive 50- or 70-mg/d doses of lisdexamfetamine dimesylate underwent a 1- and 2-week forced titration schedule, respectively. During the 4-week double-blind period, subjects attended weekly clinic visits for evaluation.
Safety assessments were conducted throughout the study and included the recording of AEs, vital signs (ie, SBP, DBP, and pulse), and ECGs, as well as clinical laboratory tests and physical examinations. Assessments of AEs were coded using the Medical Dictionary for Regulatory
Activities, Version 9.1 (MedDRA: Maintenance and Support Service Organization, Reston, Virginia). Vital signs were recorded at all study visits. Blood pressure and pulse were determined after subjects were seated for 5 minutes. Blood pressure measurements were made using the subject’s same arm for the duration of the study and were recorded using a manual or automated procedure (the same method was used throughout the study for individual subjects). Electrocardiograms were recorded 3 times during the screening visit but once per visit thereafter. Recordings were made after the subject rested supine for 10 minutes. Data collected included heart rate and interval parameters of QRS, QT, PR, and R-R.
Data were analyzed using SAS Version 8.0 or higher (SAS Institute Inc., Cary, North Carolina). Efficacy was assessed in the intention-to-treat (ITT) population, defined as all subjects who were randomly assigned to treatment and had both a baseline and at least 1 postrandomization ADHD-RS total score available. Efficacy analyses and data were previously published.29 Safety analyses were performed
on the safety population, defined as all subjects who were enrolled, were randomized, and received the study drug.
For analyses assessing safety, the length of exposure to the study drug was calculated based on the dates of first dispensing and last dose of study medication and then dichotomized by week (ie, 1 week = 1–7 days, 2 weeks = 8–14 days, etc). Vital sign and ECG parameters were summarized by mean and standard deviation (SD). Changes in SBP, DBP, pulse, and ECG parameters from baseline were analyzed for differences among treatment groups using analysis of covariance (with Dunnett’s test) at each postrandomization visit and at endpoint, using the baseline measurement as the covariate. For safety data, endpoint data were defined as the last nonmissing assessment obtained after the baseline visit, resulting in a
A priori (prespecified in the statistical plan) categorical analyses of cardiovascular parameters included analysis of vital signs (SBP, DBP, and pulse) and QT interval corrected using Fridericia method (QTcF). The Fridericia correction was chosen due to its resistance to the confounding effects of abnormally high or low heart rate.32 Blood pressure assessments were categorized as outliers according to the following criteria: for SBP, as ≥ 150 mm Hg from a baseline of < 150 mm Hg; for DBP, as ≥ 95 mm Hg from a baseline of < 95 mm Hg; and for pulse, as ≥ (mean + [2 × SD]) from a baseline of < (mean + [2 × SD]). Categorical analyses of QTcF interval were prespecified by cutoff values of > 450 msec, > 480 msec, or > 500 msec for absolute values and as 30 to 59 msec and ≥ 60 msec change from baseline. These analyses were performed using shift tables for each postrandomization visit and at endpoint. Outlier criteria for QTcF were based on guidances from the US Food and Drug Administration32 and from the European Agency for the Evaluation of Medicinal Products33 and were used to investigate the potential for effects of lisdexamfetamine dimesylate on ventricular repolarization.
Post hoc outlier analyses of cardiovascular parameters (ie, SBP, DBP, pulse) were also performed using outlier criteria defined as SBP ≥ 140 mm Hg and ≥ 10% change in
SBP from baseline to any time point during the study; DBP ≥ 90 mm Hg and ≥ 10% change in DBP from baseline to any time point during the study; or pulse ≥ 100 bpm at any time point during the study. Outlier criteria for BP were based on recommendations from the US Department of Health and Human Services (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) for classification of high BP (ie, 140 mm Hg/90 mm Hg)34 with inclusion of a minimum percentage change (ie, 10%) to account for normal variability of
BP measurement.35,36 Post hoc analyses are presented for outliers meeting criteria at any time point during the study and at a minimum of 2 time points during the study.
Subject Demographics and Disposition
A total of 420 participants (lisdexamfetamine dimesylate 30 mg/d: n = 119; lisdexamfetamine dimesylate 50 mg/d: n = 117; lisdexamfetamine dimesylate 70 mg/d: n = 122; placebo: n = 62) were included in the present analysis and represent the safety population. All 4 treatment groups
in the safety population were well matched at baseline and had no significant differences in baseline demographics, ADHD-RS total scores, or Clinical Global Impressions-Severity of Illness scale37 scores. Baseline demographic characteristics of the participants are presented in Table 1.
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Six subjects received treatment but did not have postrandomization ADHD-RS scores. Therefore, the ITT population consisted of 414 subjects. Of the 420 enrolled subjects, 349 (83%) completed the study; the remaining 71 (17%) discontinued prior to study completion (Figure 1). The rates of discontinuation in the lisdexamfetamine dimesylate treatment groups (13%–20%) were similar to that of the placebo group (16%).29
Concomitant medications used by subjects in this analysis were recorded at baseline, throughout the double-blind treatment period, and at follow-up. Approximately 39% of subjects in the study took concomitant medication, but, per protocol, few of these subjects used medications that would potentially impact cardiovascular parameters. Specifically, 1 subject in the 50 mg/d lisdexamfetamine dimesylate group took pseudoephedrine, 1 subject in the 30 mg/d lisdexamfetamine dimesylate group took albuterol, 1 subject in the 50 mg/d group and 1 subject in the placebo group took atomoxetine, 1 subject in the 50 mg/d group and 1 subject in the placebo group took methylphenidate, and 2 subjects in the 50 mg/d group, 1 in the 70 mg/d group, and 1 in the placebo group took Obetrol (similar to mixed amphetamine salts).
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Cardiovascular Safety Analysis
At baseline, there were no statistically significant differences in least squares (LS) mean SBP or DBP between the groups randomly assigned to receive lisdexamfetamine dimesylate 30, 50, or 70 mg/d versus the placebo group. Treatment with lisdexamfetamine dimesylate was not associated with statistically significant changes in LS
mean SBP or DBP from baseline at endpoint. Furthermore, the SBP and DBP LS mean changes from baseline at endpoint for each lisdexamfetamine dimesylate dose group were not statistically different than those of the group
receiving placebo (Table 2).
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Baseline LS mean (SE) pulse (obtained as part of vital signs assessment) was similar among treatment groups: 70.8 (0.87), 72.4 (0.87), 69.8 (0.86), and 70.9 (1.20) for the 30, 50, and 70 mg/d lisdexamfetamine dimesylate and placebo groups, respectively. Likewise, heart rates (measured by ECG) were similar among treatment groups: 65.4 (0.86), 66.4 (0.87), 65.1 (0.85), and 66.3 (1.20) for the 30, 50, and 70 mg/d lisdexamfetamine dimesylate and placebo groups, respectively. Overall analysis showed statistically significant treatment effects of lisdexamfetamine dimesylate versus placebo for pulse (P < .05) and heart rate (P < .05) at endpoint. All lisdexamfetamine dimesylate dose groups showed increases from baseline in pulse at endpoint, while the placebo group did not. Data for all 4 treatment groups are shown in Table 2. Significant differences in pulse were noted starting at week 2 and persisted through week 4. Significant increases in heart rate (ECG) were seen starting at week 2 and remained similarly elevated through week 4. Mean heart rate changes from baseline at endpoint are described in Table 2 for the 4 treatment groups. Analyses comparing the individual lisdexamfetamine dimesylate dose groups with placebo demonstrated that all the lisdexamfetamine dimesylate groups were associated with significantly increased heart and pulse rates from baseline at endpoint relative to placebo.
Changes in PR interval from baseline to endpoint were statistically different compared with placebo for some dose groups. PR interval LS mean (95% CI) differences were –2.8 (−6.22 to 0.72), −4.4 (−7.87 to −0.94), and −4.9 (−8.38 to −1.47) msec for the 30, 50, and 70 mg/d groups (P < .01 for the 50 and 70 mg/d groups). RR interval LS mean (95% CI) differences were −40.3 (−80.74 to 0.08), −45.6 (−85.95 to −5.32), and −50.6 (–90.84 to –10.38) msec for the 30, 50, and 70 mg/d groups (P < .05 for the 50 and 70 mg/d groups). No significant changes in QRS intervals were associated with lisdexamfetamine dimesylate treatment or any specific lisdexamfetamine dimesylate dose groups at any time point over the course of the study or at endpoint (Table 2). The LS mean QT interval decreased from baseline across both the lisdexamfetamine dimesylate and placebo groups throughout the study. Analysis showed no significant treatment effect overall for lisdexamfetamine dimesylate versus placebo for mean change from baseline of QT interval at any time period throughout the study (ie, weeks 1 through 4 and endpoint). The 3 individual lisdexamfetamine dimesylate treatment groups showed no significant change in QTcF interval from baseline as compared with placebo at endpoint (Table 2) or at any of the 4 visits throughout the study.
A Priori Outlier Analyses
A priori outlier analyses for BP showed 1 event (30 mg/d lisdexamfetamine dimesylate group) and 2 events (70 mg/d lisdexamfetamine dimesylate group) of SBP ≥ 150 mm Hg from a baseline of < 150 mm Hg at any point in the study, along with 1 event (30 mg/d lisdexamfetamine dimesylate group), 5 events (50 mg/d lisdexamfetamine dimesylate group), and 9 events (70 mg/d lisdexamfetamine dimesylate group) of DBP ≥ 95 mm Hg from a baseline of < 95 mm Hg at any point during the study. Four events (placebo group), 31 events (30 mg/d lisdexamfetamine dimesylate group), 43 events (50 mg/d lisdexamfetamine dimesylate group), and 26 events (70 mg/d lisdexamfetamine dimesylate group) met the a priori criteria for pulse rate outliers [change ≥ (mean + 2 × SD)] at any time point during the study.
One subject had a QT interval > 500 msec at baseline visit and subsequent QT intervals either between 451 msec and 480 msec or ≤ 450 msec at weekly postbaseline visits and ≤ 450 msec at endpoint. At baseline, there were 15 QTcF interval readings between 451 msec and 480 msec, 5 in the placebo group and 10 in the 30 mg/d lisdexamfetamine dimesylate group. In all of these cases, subsequent QTcF readings at postbaseline visits were either between 451 msec and 480 msec or ≤ 450 msec. At postbaseline
visits, 2 QTcF readings between 451 msec and 480 msec were observed in subjects receiving placebo, 1 at week 4 and 1 at endpoint. In subjects receiving 30 mg/d lisdexamfetamine dimesylate, 5 QTcF readings between 451 msec and 480 msec were recorded, 1 each at weeks 1 through 4 and at endpoint. In subjects receiving 50 mg/d lisdexamfetamine dimesylate, no postbaseline QTcF readings between 451 msec and 480 msec were recorded; 1 reading was recorded at week 1 in a subject receiving 70 mg/d lisdexamfetamine dimesylate. There were no QTcF interval readings of > 480 msec or > 500 msec across all postbaseline treatment weeks. There were no QTcF changes from baseline of ≥ 60 msec. At endpoint, the numbers of subjects with a QTcF interval change from baseline between 30 msec and 59 msec were 2 (3.2%), 5 (4.2%), 1 (0.9%), and 3 (2.5%) for the placebo, 30, 50, and 70 mg/d lisdexamfetamine dimesylate dose groups, respectively.
Post Hoc Outlier Analyses
A total of 9 subjects met the criteria for SBP outlier,
defined as SBP ≥ 140 mm Hg and ≥ 10% change in SBP from baseline, at least once during the study (Table 3). These outliers—3 from the 30 mg/d group, 2 from the 50 mg/d group, and 4 from the 70 mg/d group—all received treatment with lisdexamfetamine dimesylate, but there was no apparent dose relationship. Eight of the 9 SBP outliers met the criteria at only 1 time point during the study. The remaining subject met the outlier criteria at 2 time points, but the criteria were not sustained through endpoint.
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DBP outlier criteria, DBP ≥ 90 mm Hg and ≥ 10% change in DBP from baseline, were met by 19 subjects (2 in the placebo group, 3 in the 30 mg/d lisdexamfetamine dimesylate group, and 7 each in the 50 mg/d and 70 mg/d lisdexamfetamine dimesylate groups) as described in Table 3. Thirteen of the 17 outliers in the lisdexamfetamine dimesylate treatment group had outlying values at only 1 time point, and of the 4 subjects that were outliers at more than 1 time point, none sustained the criteria through endpoint.
Five subjects met the outlier criteria for both SBP and DBP (30 mg/d lisdexamfetamine dimesylate: n = 2 and 70 mg/d lisdexamfetamine dimesylate: n = 3) at any time point during the study (Table 3). All 5 outliers described above met the criteria at only 1 point in the study, and none met the criteria at endpoint.
In this analysis, 21 subjects (30 mg/d lisdexamfetamine dimesylate: n = 7, 50 mg/d lisdexamfetamine dimesylate: n = 10, and 70 mg/d lisdexamfetamine dimesylate: n = 4) met outlier criteria for pulse, defined as pulse ≥ 100 bpm, at clinic visits at least once during the study (Table 3) (P < .05 vs placebo for lisdexamfetamine dimesylate 50 mg/d; P = NS for 30 mg/d and 70 mg/d). Of the 21 outliers, 17 met the criteria at only 1 point in the study, while 4 met the criteria during at least 2 weekly study visits. Of those with pulse ≥ 100 bpm on more than 1 occasion, 2 had such readings at endpoint: 1 at 30 mg/d and 1 at 50 mg/d.
Cardiovascular Adverse Events
Treatment with lisdexamfetamine dimesylate was not associated with any deaths or serious AEs. There were no cardiovascular-related AEs classified as occurring prerandomization. The cardiovascular-related treatment-emergent adverse events (TEAEs) reported at any time point during the study at an incidence ≥ 2% were increased BP, dyspnea, increased heart rate, palpitations, and tachycardia (Table 4). No cardiovascular-related TEAEs occurred in the group
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The majority of cardiovascular TEAEs were rated as mild or moderate in severity. Of the 6 reported AEs of palpitations, 4 were classified as mild and 2 were classified as moderate in severity. Sinus tachycardia was reported in 1 patient and classified as mild in severity and possibly/probably related to drug treatment. Tachycardia, which was reported in 4 subjects, was classified as mild in severity in 2 subjects, moderate in 1 subject, and severe in 1 subject, and as possibly/probably related to drug treatment in all cases. Six of the 8 dyspnea AEs were classified as mild, with 1 case each being reported as moderate or severe and as possibly/probably related to drug treatment in all but 1 case. Of the reports of dyspnea, 2 were associated with concomitant tachycardia (1 of these was also associated with hypertension) and another with palpitations and left arm discomfort. Of the 10 reported events of elevated BP, 8 were mild and 2 were moderate in severity, and all events were considered possibly/probably related to drug treatment, while all of the increased heart rate TEAEs (n = 7) were mild in severity and deemed possibly/probably related to drug treatment in all cases. Of reports of elevated BP, 1 was associated with concurrent sinus tachycardia and drug discontinuation.
Overall, 7 subjects (1.7%) withdrew from the study because of cardiovascular adverse effects: 1 (0.8%) in the 30 mg/d lisdexamfetamine dimesylate group, 2 (1.7%) in the 50 mg/d lisdexamfetamine dimesylate group, and 4 (3.3%) in the 70 mg/d lisdexamfetamine dimesylate group. These 7 subjects reported a total of 11 cardiovascular TEAEs, which are described in Table 5. With the exception of 1 patient, all TEAEs resolved, with none of the events requiring ongoing treatment. One patient who was discontinued due to elevated BP was successfully treated with an angiotensin receptor antagonist/diuretic combination until study exit. It is not known whether treatment was continued beyond study exit.
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The results of the current analyses of data from medically healthy adults with ADHD partially support our hypothesis of the effect of lisdexamfetamine dimesylate on cardiovascular indices. As hypothesized, lisdexamfetamine dimesylate was associated with predictable but modest increases in pulse and heart rate and with no meaningful effects on other ECG parameters such as PR, RR, and QT intervals. Of note, lisdexamfetamine dimesylate was not associated with statistically significant or clinically meaningful changes in SBP or DBP in this study with the exception of 1 subject, as noted above, who was treated for elevated BP.
Discontinuations related to abnormal cardiovascular measures were generally low (≤ 5%) in studies of stimulant therapy in otherwise healthy patients with ADHD.15,38 As may be expected since BP increases with age, discontinuation rates associated with cardiovascular TEAEs are somewhat higher in studies of adults treated with long-acting stimulants for ADHD, ranging from ~ 2%–5%, and are in line with the findings of the current study.15,19,38,39 These data highlight the limited cardiovascular AEs
associated with lisdexamfetamine dimesylate in medically healthy adults but also underscore the need to assess
baseline cardiovascular status and to monitor for cardiovascular symptoms that may emerge during treatment in this patient population. The importance of this monitoring is supported by a recent epidemiologic report that noted
increasing prevalence of hypertension in all racial/ethnic and gender groups standardized by age.40 In addition, patients may not be aware of their cardiovascular risk factors. It should be stressed that since subjects with a history or evidence of active cardiovascular diseases were excluded in this study of lisdexamfetamine dimesylate, no conclusions regarding its safety in such a population can be drawn.
In a placebo-controlled trial in adults with ADHD, pulse increases ranged from 4.2 to 6.2 bpm for 3 doses (20, 40, and 60 mg/d) of mixed amphetamine salts extended-release (MAS XR) compared with 1.9 bpm for placebo.11 Heart rate increased by 4.5 bpm for all doses (mean [SD] dose = 80.9 [31.8] mg/d) of osmotic-release oral system methylphenidate (OROS-MPH) combined compared with −2.7 bpm for placebo19 in one study that utilized an optimal dosing scheme, and in a recent placebo-controlled trial with fixed doses of OROS-MPH, pulse increases at endpoint were 2.7, 3.9, 5.2, and 9.8 bpm for placebo and 18, 36, and 72 mg/d of OROS-MPH, respectively.41 In a recent placebo-controlled study of OROS-MPH with an expanded dose range (36, 54, 72, 90, 108 mg/d), pulse rate increased by 3.6 bpm for those receiving OROS-MPH versus −1.6 bpm for those receiving placebo.42 In a fixed-dose, placebo-controlled study of
d-methylphenidate extended release (dMPH-ER; 20, 30, 40 mg/d), a small, significant mean increase in pulse (4.4 bpm) was demonstrated for those receiving dMPH-ER, and an apparent dose trend was also noted, with increases ranging from 3.1 to 6.0 bpm.43 When noted in these studies, tachycardia was reported as an AE in 5.6%41 and 2.7%42 of subjects receiving OROS-MPH and 1.2% of subjects receiving dMPH-ER.43 Although not classified as a stimulant, atomoxetine is also associated with cardiovascular effects,44 with increased pulse rates of 6.7,45 3.8,45 and 4.5 bpm46 being reported in three 10-week, placebo-controlled studies. While consistent mean increases in pulse were observed in the current study, with a range across doses of 2.8 to 5.2 bpm, there was a low incidence (1.1%) of tachycardia reported as an AE and a relatively low incidence (5.0%) of pulse rate ≥ 100 bpm at any visit during the study, with < 1% having a pulse rate ≥ 100 bpm at 2 or more visits.
Although the finding that the great majority of subjects in this study experiencing DBP readings categorized as outliers had such readings on only 1 occasion is reassuring in terms of the low occurrence of sustained effects, these findings do suggest that careful observation of adult subjects receiving long-acting stimulants is warranted.
Our data, demonstrating no significant overall effects on BP given the relatively large size of the study, differ somewhat from the existing literature. Stimulants as a group have been reported as being associated with increases of 2 to 4 mm Hg in mean BP.20–23,47,48 Of interest, studies of mixed amphetamine salts and methylphenidate showed statistically significant increases versus placebo or versus baseline of
approximately 1 to 5 mm Hg in mean SBP or mean DBP with treatment.10,18,19 Large studies that focused on short- and long-term cardiovascular effects of MAS XR demonstrated that mean changes in SBP, DBP, and pulse, while not judged to be clinically relevant, were statistically significant.11,15 On the other hand, 2 recent placebo-controlled studies41,42 with OROS-MPH have found small, nonsignificant changes in BP. Medori et al41 found SBP changes at endpoint of 1.1, 0.1, 0.4, and 2.2 mm Hg and DBP changes of −1.8, −0.8, 1.7, and 1.6 mm Hg for placebo, 18, 36, and 72 mg/d of OROS-MPH, respectively. Adler et al42 found a change at endpoint of −1.2 mm Hg in SBP and 0.4 mm Hg in DBP in subjects receiving OROS-MPH. Similarly, changes in SBP (−0.5 mm Hg) and DBP (1.0 mm Hg) in the placebo-controlled trial of dMPH-ER43 were small and not different from placebo. Atomoxetine was associated with small changes in SBP (2.3 and 3.5 mm Hg, respectively) and DBP (2.3 and 1.2 mm Hg, respectively) in two 10-week studies that reported both parameters45 and in DBP (1.7 mm Hg) in a third 10-week study.46
The current findings are consistent with recent studies
in pediatric and adult subjects with ADHD treated with stimulants that showed a relative lack of significant effects of these drugs on ECG parameters.14,15,49 More specifically, the current data, in aggregate with the literature, show consistency in a lack of clinically meaningful effect on atrioventricular (PR) or intraventricular conduction (QRS) or repolarization (QTc). While the lisdexamfetamine dimesylate data are generally reassuring, it is important to note that these studies have generally examined screened and medically healthy adults with ADHD without a history of cardiovascular disease.
Consensus guidelines for monitoring cardiovascular parameters in adults receiving stimulant medications have not yet been developed. However, in the absence of established guidelines, it seems consistent with good clinical practice to monitor BP and pulse (periodically and/or when clinically indicated) throughout treatment as well as to follow relevant labeling recommendations published in package inserts for these medications (see below).20–23,47,48 A history of potential cardiovascular risk symptoms such as syncope, and, in particular, syncope on exertion; dizziness; palpitations; dyspnea; and/or chest discomfort, as well as current use of prescription and nonprescription medications and family history of cardiac disease, should be queried prior to beginning therapy, with this information guiding the choice of further evaluation. For the adult population, in particular, it is also important to consider that major cardiovascular risk factors increase with age.50 As mentioned previously, the incidence of hypertension, in general, is increasing, and, therefore, review of previous BP and pulse readings and assessment of baseline BP and pulse will rule out preexisting hypertension prior to ADHD treatment. Monitoring occurrence of the above-mentioned symptoms at follow-up visits with attention to periods of dose adjustment are sensible as well. Similarly, clinical monitoring is clearly advisable when other medications with potential cardiovascular impacts are added or adjusted by clinicians or if other known cardiovascular risk factors such as increased weight or diabetes develop or worsen during treatment. Aggregate data to date in this patient population support that ECG monitoring is not mandatory but should be considered if indicated by history and physical examination.24,25 Additionally, the reader should keep in mind that all stimulant medications in the United States, including lisdexamfetamine dimesylate, have guidance in the package insert, including sections on contraindications, warnings, precautions, and cardiovascular AEs associated with these agents, that should be reviewed prior to prescribing any stimulant medication.
The current study has several limitations. It was a short-term study with a 4-week, double-blind treatment period with cardiovascular parameters assessed only in the short-term, acute setting. Other studies are needed to evaluate the potential effects of lisdexamfetamine dimesylate on cardiovascular parameters over longer durations of treatment. Also, the cardiovascular measures reported and analyzed were obtained during the collection of safety data for a pivotal clinical trial29 and were not part of a formal cardiovascular study on the effects of psychostimulants. As such, subjectively reported cardiovascular AEs were not systematically assessed with objective measurements. This study, as is generally true, did not limit or assess caffeine intake from food, drink, and nutritional supplements. Another limitation of this study is that it included forced-dose escalation, which might result in overestimation of AEs in the absence of a dose-optimization regimen. In addition, because older adults (> 55 years) and adults with comorbid psychiatric and cardiovascular diseases were systematically screened and excluded from the current study, it may not adequately represent the general adult population with ADHD. For this reason, it may not be appropriate to generalize the results of this study to the broader adult population with ADHD, who may present with cardiovascular comorbidities such as preexisting hypertension or structural cardiac abnormalities. Ideally, large-scale observational studies would avoid the limitations described above as well as those of sampling error associated with the limited patient population and the limited number of subjects enrolled in placebo groups in such short-term efficacy trials. These large-scale trials would provide data from subjects treated in wide clinical use of these agents that are needed to fully assess the clinical impact of cardiovascular effects of stimulants.
Despite these limitations, the secondary analyses from this study supported previous conclusions that lisdexamfetamine dimesylate was generally well tolerated. We found effects on pulse and heart rate and no effect on ECG, similar to that previously reported with long-acting stimulants, but no significant effects on BP in this study. It should be noted that misuse or abuse of any stimulant medication may cause or contribute to sudden death or other serious cardiovascular/medical events.20–23 Thus, lisdexamfetamine dimesylate and other approved stimulants are most safely used as prescribed in their approved product information. Careful attention to cardiovascular history, symptoms, and clinical findings in adults with ADHD prior to and during treatment with stimulants is advisable.
Drug names: albuterol (Proventil and others), atomoxetine (Strattera), d-methylphenidate extended release (Focalin XR), lisdexamfetamine dimesylate (Vyvanse), osmotic-release oral system methylphenidate (Concerta), pseudoephedrine (Semprex, Bromfed, and others).
Author affiliations: Department of Psychiatry, New York University School of Medicine, New York (Dr Adler); Department of Psychiatry, Duke University Medical Center, Durham, North Carolina, and University of North Carolina at Chapel Hill (Dr Weisler); Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (Dr Goodman); and Biostatistics, Shire Development Inc, Wayne, Pennsylvania (Mr Hamdani and Dr Niebler).
Potential conflicts of interest: Dr Adler has received royalty payments as an inventor from New York University; receives or has received grant research support from Abbott, Bristol-Myers Squibb, Cephalon, Cortex, Eli Lilly, Merck, National Institute of Drug Abuse, New River, Novartis, Ortho-McNeil/Janssen/Johnson & Johnson, Pfizer, and Shire; is or has been a speaker for Eli Lilly and Shire; and is or has been on the advisory board and consulted for Abbott, Cephalon, Cortex, Eli Lilly, Merck, Mindsite, New River, Novartis, Organon, Ortho-McNeil/Janssen/Johnson & Johnson, Pfizer, Psychogenics, Sanofi-Aventis, and Shire. Dr Weisler receives or has received research support from Abbott, AstraZeneca, Ayerst, Bioavail, Bristol-Myers Squibb, Burroughs Wellcome, CeNeRx, Cephalon, Ciba-Geigy, CoMentis, Corcept, Dainippon-Sumitomo, Eisai, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson, Lundbeck, McNeil, MediciNova, Merck, National Institute of Mental Health, Neurochem, New River, Novartis, Organon, Parke Davis, Pfizer, Pharmacia, Repligen, Saegis, Sandoz, Sanofi-Synthelabo, Schwabe/Ingenix, Sepracor, Shire, SmithKline Beecham, Solvay, Synaptic, Takeda, TAP, UCB, Upjohn, Vela, and Wyeth; is or has been a speaker for Abbott, AstraZeneca, Bioavail, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest, GlaxoSmithKline, Organon, Pfizer, Sanofi, Shire, Solvay, Validus, and Wyeth Ayerst; is or has been a consultant for Abbott, Ayerst, Biovail, Bristol-Myers Squibb, Centers for Disease Control and Prevention, Corcept, Eli Lilly, Forest, GlaxoSmithKline, Johnson & Johnson, Novartis, Organon, Otsuka America, Pfizer Inc, Sanofi-Synthelabo, Shire, Solvay, Agency for Toxic Substances Disease Registry, Validus, and Wyeth; and is or has been a financial stockholder of Bristol-Myers Squibb, Cortex, Merck, and Pfizer. Dr Goodman receives or has received research support from Cephalon, Eli Lilly, Forest, McNeil, New River, and Shire; receives or has received honoraria from Forest, Eli Lilly, Shire, McNeil, and Wyeth; is or has been a speaker for Forest, McNeil, Shire, and Wyeth; is or has been a consultant for Clinical Global Advisors, Eli Lilly, Forest, McNeil, New River, Novartis, Schering-Plough, Shire, and Thompson Reuters; and receives royalties from MBL Communications, Inc. Mr Hamdani and Dr Niebler are full-time employees of Shire Development.
Funding/support: Supported by funding from Shire Development Inc.
Previous presentation: Data in this manuscript were presented at the 161st Annual Meeting of the American Psychiatric Association; May 3–8, 2008; Washington, DC.
Acknowledgments: Writing and editorial assistance was provided by Barbara Gomez, PhD, and Michael Pucci, PhD. Dr Gomez is a former employee of and Dr Pucci is a current employee of Health Learning Systems, part of CommonHealth. Health Learning Systems was paid by Shire Development Inc. for this assistance. We thank Timothy E. Wilens, MD, of Massachusetts General Hospital, Harvard Medical School,
Boston, Massachusetts, for his review and editing of the manuscript. Dr Wilens receives or has received grant support from Abbott, McNeil, Eli Lilly, NIH (NIDA), Merck, and Shire; has been on the speakers bureaus for Eli Lilly, McNeil, Novartis, and Shire; is or has been a consultant for Abbott, AstraZeneca, McNeil, Eli Lilly, NIH (NIDA), Novartis, Merck, and Shire; and has a published book with Guilford Press, Straight Talk About Psychiatric Medications for Kids.
1. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet. 2005;366(9481):237–248. doi:10.1016/S0140-6736(05)66915-2 PubMed
2. Polanczyk G, de Lima MS, Horta BL, et al. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007;164(6):942–948. doi:10.1176/appi.ajp.164.6.942 PubMed
3. Barkley RA, Fischer M, Edelbrock CS, et al. The adolescent outcome of hyperactive children diagnosed by research criteria, pt 1: an 8-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry. 1990;29(4):546–557. PubMed
4. Barkley RA, Fischer M, Smallish L, et al. The persistence of attention-deficit/hyperactivity disorder into young adulthood as a function of reporting source and definition of disorder. J Abnorm Psychol. 2002;111(2):279–289. doi:10.1037/0021-843X.111.2.279 PubMed
5. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(4):716–723. doi:10.1176/appi.ajp.163.4.716 PubMed
6. Wilens TE, Dodson W. A clinical perspective of attention-deficit/hyperactivity disorder into adulthood. J Clin Psychiatry. 2004;65(10):1301–1313. PubMed
7. Greenhill LL, Pliszka S, Dulcan MK, et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry. 2002;41(suppl 2):26S–49S
8. Weiss MD, Weiss JR. A guide to the treatment of adults with ADHD.
J Clin Psychiatry. 2004;65(suppl 3):27–37. PubMed
9. Spencer T, Wilens T, Biederman J, et al. A double-blind, crossover comparison of methylphenidate and placebo in adults with childhood-onset attention-deficit hyperactivity disorder. Arch Gen Psychiatry. 1995;52(6):434–443. PubMed
10. Spencer T, Biederman J, Wilens T, et al. Efficacy of a mixed amphetamine salts compound in adults with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2001;58(8):775–782. doi:10.1001/archpsyc.58.8.775 PubMed
11. Weisler RH, Biederman J, Spencer TJ, et al. Mixed amphetamine salts extended-release in the treatment of adult ADHD: a randomized,
controlled trial. CNS Spectr. 2006;11(8):625–639. PubMed
12. Fallu A, Richard C, Prinzo R, et al. Does OROS-methylphenidate improve core symptoms and deficits in executive function? results of an open-label trial in adults with attention deficit hyperactivity disorder. Curr Med Res Opin. 2006;22(12):2557–2566. doi:10.1185/030079906X154132 PubMed
13. Faraone SV, Spencer TJ, Montano CB, et al. Attention-deficit/
hyperactivity disorder in adults: a survey of current practice in psychiatry and primary care. Arch Intern Med. 2004;164(11):1221–1226. doi:10.1001/archinte.164.11.1221 PubMed
14. Findling RL, Biederman J, Wilens TE, et al; SLI381.301 and .302 Study Groups. Short- and long-term cardiovascular effects of mixed amphetamine salts extended release in children. J Pediatr. 2005;147(3):348–354. doi:10.1016/j.jpeds.2005.03.014 PubMed
15. Weisler RH, Biederman J, Spencer TJ, et al. Long-term cardiovascular
effects of mixed amphetamine salts extended release in adults with ADHD. CNS Spectr. 2005;10(suppl 20):35–43. PubMed
16. Gutgesell H, Atkins D, Barst R, et al. AHA Scientific Statement: cardiovascular monitoring of children and adolescents receiving psychotropic drugs. J Am Acad Child Adolesc Psychiatry. 1999;38(8):1047–1050. PubMed
17. Nissen SE. ADHD drugs and cardiovascular risk. N Engl J Med. 2006;354(14):1445–1448. doi:10.1056/NEJMp068049 PubMed
18. Wilens TE, Hammerness PG, Biederman J, et al. Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2005;66(2):253–259. PubMed
19. Biederman J, Mick E, Surman C, et al. A randomized, placebo-
controlled trial of OROS methylphenidate in adults with attention-
deficit/hyperactivity disorder. Biol Psychiatry. 2006;59(9):829–835. doi:10.1016/j.biopsych.2005.09.011 PubMed
20. Concerta [package insert]. Titusville, NJ: McNeil Pediatrics; 2009.
21. Focalin XR [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2009.
22. Adderall XR [package insert]. Wayne, PA: Shire US Inc.; 2009.
23. Vyvanse [package insert]. Wayne, PA: Shire US Inc.; 2009.
24. Vetter VL, Elia J, Erickson C, et al; American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee; American Heart Association Council on Cardiovascular Nursing. Cardiovascular monitoring of children and adolescents
with heart disease receiving medications for attention deficit/
hyperactivity disorder [corrected]: a scientific statement from the American Heart Association Council on Cardiovascular Disease in
the Young Congenital Cardiac Defects Committee and the Council
on Cardiovascular Nursing. Circulation. 2008;117(18):2407–2423. doi:10.1161/CIRCULATIONAHA.107.189473 PubMed
25. Perrin JM, Friedman RA, Knilans TK; Black Box Working Group; Section on Cardiology and Cardiac Surgery. Cardiovascular monitoring and stimulant drugs for attention-deficit/hyperactivity disorder. Pediatrics. 2008;122(2):451–453. doi:10.1542/peds.2008-1573 PubMed
26. Pliszka SR. Pharmacologic treatment of attention-deficit/hyperactivity disorder: efficacy, safety and mechanisms of action. Neuropsychol Rev. 2007;17(1):61–72. doi:10.1007/s11065-006-9017-3 PubMed
27. Pennick M. Hydrolytic conversion of lisdexamfetamine dimesylate to the active moiety, d-amphetamine. Poster presented at: 64th Annual Scientific Convention and Meeting of the Society of Biological Psychiatry; May 14–16, 2009; Vancouver, British Columbia, Canada.
28. Pennick M. Absorption of lisdexamfetamine dimesylate and hydrolysis to form the active moiety, d-amphetamine. Poster presented at:
49th Annual Meeting of the New Clinical Drug Evaluation Unit;
June 29–July 2, 2009; Hollywood, FL.
29. Adler LA, Goodman DW, Kollins SH, et al; 303 Study Group. Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008;69(9):1364–1373. doi:10.4088/JCP.v69n0903 PubMed
30. Adler L, Cohen J. Diagnosis and evaluation of adults with
attention-deficit/hyperactivity disorder. Psychiatr Clin North Am. 2004;27(2):187–201. doi:10.1016/j.psc.2003.12.003 PubMed
31. ADHD-RS Initial Evaluation. http://www.askdrjones.com./
wp-content/uploads/patientforms/ADHD%20Screening-Initial%20Eval.pdf. Accessed August 12, 2009.
32. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center
for Biologics Evaluation and Research. Guidance for industry:
E14 clinical evaluation of QT/QTc interval prolongation and
proarrhythmic potential for non-antiarrhythmic drugs.
ICH E14. http://www.fda.gov/cder/guidance/6922fnl.htm.
Accessed March 8, 2007.
33. Moss AJ. Drugs that prolong the QT interval: regulatory and QT measurement issues from the United States and European perspectives.
Ann Noninvasive Electrocardiol. 1999;4(3):255–256. doi:10.1111/j.1542-474X.1999.tb00208.x
34. US Dept Health and Human Services. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JNC 7 Express (for Primary Care). http://www.nhlbi.nih.gov/guidelines/hypertension/jncintro.htm. Accessed December 9, 2008.
35. Mancia G, Ferrari A, Gregorini L, et al. Blood pressure and heart rate variabilities in normotensive and hypertensive human beings. Circ Res. 1983;53(1):96–104. PubMed
36. Marshall TP. Blood pressure variability: the challenge of variation.
Am J Hypertens. 2008;21(1):3–4. doi:10.1038/ajh.2007.20 PubMed
37. Guy W. Clinical global impressions. In: ECDEU Assessment Manual for Psychopharmacology. US Dept Health, Education, and Welfare; Public Health Service, Alcohol, Drug Abuse and Mental Health Administration. Rockville, Md: National Institute of Mental Health, Psychopharmacology Research Branch; 1976:218–222.
38. Spencer T, Biederman J, Wilens T, et al. A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57(5):
456–463. doi:10.1016/j.biopsych.2004.11.043 PubMed
39. Biederman J, Spencer TJ, Wilens TE, et al; SLI381.304 study group. Long-term safety and effectiveness of mixed amphetamine salts
extended release in adults with ADHD. CNS Spectr. 2005;10
(suppl 20):16–25. PubMed
40. Cutler JA, Sorlie PD, Wolz M, et al. Trends in hypertension prevalence, awareness, treatment, and control rates in United States adults between 1988-1994 and 1999-2004. Hypertension. 2008;52(5):818–827. doi:10.1161/HYPERTENSIONAHA.108.113357 PubMed
41. Medori R, Ramos-Quiroga JA, Casas M, et al. A randomized, placebo-controlled trial of three fixed dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2008;63(10):981–989. doi:10.1016/j.biopsych.2007.11.008 PubMed
42. Adler LA, Zimmerman B, Starr HL, et al. Efficacy and safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, double-blind, parallel group, dose-escalation study. J Clin Psychopharmacol. 2009;29(3):239–247. doi:10.1097/JCP.0b013e3181a390ce PubMed
43. Spencer TJ, Adler LA, McGough JJ, et al; Adult ADHD Research Group. Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007;61(12):1380–1387. doi:10.1016/j.biopsych.2006.07.032 PubMed
44. Graham J, Coghill D. Adverse effects of pharmacotherapies for
attention-deficit hyperactivity disorder: epidemiology, prevention
and management. CNS Drugs. 2008;22(3):213–237. doi:10.2165/00023210-200822030-00003 PubMed
45. Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry. 2003;53(2):112–120. doi:10.1016/S0006-3223(02)01671-2 PubMed
46. Adler LA, Spencer T, Brown TE, et al. Once-daily atomoxetine for adult attention-deficit/hyperactivity disorder: a 6-month, double-blind trial.
J Clin Psychopharmacol. 2009;29(1):44–50. doi:10.1097/JCP.0b013e318192e4a0 PubMed
47. Metadate CD [package insert]. Smyrna, GA: UCB, Inc.; 2008.
48. Ritalin [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2009.
49. Wilens TE, Prince JB, Spencer TJ, et al. Stimulants and sudden death: what is a physician to do? Pediatrics. 2006;118(3):1215–1219. doi:10.1542/peds.2006-0942 PubMed
50. Jousilahti P, Vartiainen E, Tuomilehto J, et al. Sex, age, cardiovascular risk factors, and coronary heart disease: a prospective follow-up study of 14,786 middle-aged men and women in Finland. Circulation. 1999;99(9):1165–1172. PubMed