Rossella Medori, J. Antoni Ramos-Quiroga, Miguel Casas, J.J.S. Kooij, Asko Niemelä, Götz-Erik Trott, Emma Lee, and Jan K.

Transcription

1 A Randomized, Placebo-Controlled Trial of Three Fixed Dosages of Prolonged-Release OROS Methylphenidate in Adults with Attention-Deficit/Hyperactivity Disorder Rossella Medori, J. Antoni Ramos-Quiroga, Miguel Casas, J.J.S. Kooij, Asko Niemelä, Götz-Erik Trott, Emma Lee, and Jan K. Buitelaar Background: There is increasing recognition of attention-deficit/hyperactivity disorder (ADHD) in adults and the need to evaluate efficacy and safety of methylphenidate treatment in these patients. Methods: In this double-blind trial, 401 adults with ADHD (218 men; years) were randomly assigned to receive prolonged-releas osmotic release oral system (OROS) methylphenidate (18 mg, 36 mg, or 72 mg/day) or placebo for 5 weeks. Primary outcome was change total score on Conners Adult ADHD Rating Scale (CAARS: investigator-rated) at end point compared with baseline. Adverse events, vita signs, and laboratory parameters were assessed. Results: Treatment with 18-mg, 36-mg, and 72-mg/day prolonged-release methylphenidate, compared with placebo, was associated with significantly larger improvement in CAARS total symptom score from baseline to end point than placebo: mean 10.6 change (p.01), 11.5 (p.01), and 13.7 (p.001) versus 7.6, respectively. Responders 30% ( decrease) were 50.5%, 48.5%, and 59.6% versus 27.4% (p.001). Other efficacy measures also showed improvements. Incidence of adverse events was 75%, 76%, and 82% in 18-mg, 36-mg, an 72-mg/day groups, respectively, and 66% in placebo; most frequent included decreased appetite (25% methylphenidate; 7% placebo) and headache (21% methylphenidate; 18% placebo). In methylphenidate-treated patients, 4.3% discontinued due to adverse event; one serious adverse event was possibly related to study drug. Blood pressure and pulse increased at week 1 and then remained stable through week Conclusions: Prolonged-release methylphenidate is an effective treatment of ADHD in adults, with a safety profile consistent with methylphenidate use in pediatrics. Key Words: ADHD, adult, methylphenidate, prolonged release, The prolonged-release (PR) osmotic release oral system randomized trial, stimulant (OROS) formulation of methylphenidate is designed to deliver methylphenidate in a controlled manner for approximately 12 Attention-deficit/hyperactivity disorder (ADHD) is one of hours, thereby allowing coverage of symptoms over a full day. the most common psychiatric disorders in children characterized by developmentally inappropriate inattention, hyistration, was shown to be an effective and safe treatment of This long-acting formulation, designed for once-a-day adminperactivity, and impulsiveness. The disorder persists into adulthood ADHD in children and adolescents 14 ( 16). Several controlled in between 15% and 65% of the patients, depending on definition of studies with immediate-release (IR) formulations suggest persistence (1). The prevalence of ADHD among adults is estimatedmethylphenidate to be an appropriate treatment of ADHD in to be 4.4% in the United States 2,3) ( and 3.4% (range 1.2% 7.3%) in adults (17 20). 10 countries in the Americas, Europe, and Middle East 4). Methylphenidate is one of the most frequently prescribed and studiedadults with ADHD using a flexible dose approach in which ( Two controlled studies evaluated PR methylphenidate in stimulant medications for treatment of ADHD in children 5). ( In medication was titrated to optimal response 21,22). ( In both children and adolescents, the use of stimulants including methyl-studiesphenidate has been associated with cardiovascular effects 6 11). ( treatment of adults with ADHD, with a safety profile consistent PR methylphenidate was found to be an effective With the increasing recognition of ADHD in adults 12,13), ( there is with use of IR methylphenidate in children and adults 14 19). ( In a need to evaluate the efficacy and safety of methylphenidate in the addition to the studies with PR methylphenidate, a multilayer treatment of ADHD in this population. extended-release formulation of methylphenidate was shown to be an effective treatment of ADHD in adults using a flexible dose approach (23). Another 5-week study assessed three fixed doses (20 mg, 30 mg, and 40 mg/day) of extended-release dexmethylphenidate in adults with ADHD and showed active treatment was more efficacious than placebo 24). ( From Janssen-Cilag EMEA (RM), Neuss, Germany; Department of Psychiatry (JAR-Q, MC), Hospital Universitari Vall d Hebron and Department of Psychiatry and Legal Medicine (JAR-Q, MC), Universitat Autònoma de Barcelona, Barcelona, Spain; Psycho-Medical Programs (JJSK), Program Adult ADHD, Den Haag, The Netherlands; Department of Psychiatry (AN), Oulu University Hospital, Oulu, Finland; (G-ET) Aschaffenburg, Germany; Janssen Belgium (EL), Beerse, Belgium; and Department of Psychiatry (JKB), University Medical Center, St Radboud, and Karakter Child and Adolescent Psychiatry University Center (JKB), Nijmegen, The Netherlands. Address reprint requests to Rossella Medori, M.D., Janssen-Cilag EMEA, Reiffeisenstrasse 8, Neuss, Germany; rmedori@jacde.jnj.com. Received July 30, 2007; revised November 2, 2007; accepted November 3, We report a large, 5-week, double-blind, placebo-controlled trial designed to evaluate the short-term efficacy and safety of three fixed dosages (18 mg, 36 mg, and 72 mg/day) of PR methylphenidate in adult patients with ADHD. Selection of dosages reflected the range of dosages of PR methylphenidate (CONCERTA) approved for use for treating ADHD in children and adolescents in various countries, so as to assess the efficacy and safety of fixed dosages of PR methylphenidate used with children in the treatment of ADHD in adults /08/$34.00 doi: /j.biopsych BIOL PSYCHIATRY 2008;63: Society of Biological Psychiatry

2 982 BIOL PSYCHIATRY 2008;63: R. Medori et al. Methods and Materials Patients The trial included adult men and women with a diagnosis of ADHD according to the criteria of the Diagnostic and Statistical Manual of Mental Diseases, Fourth Edition (DSM-IV) (25) and confirmed by the Conners Adult ADHD Diagnostic Interview for DSM-IV (CAADID) (26). Other requirements for inclusion were age 18 to 65 years; chronic course of ADHD symptomatology from childhood to adulthood with some symptoms present before age 7 years, as determined by investigators following the CAADID interview; and CAARS total score of 24 at screening (26). The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I/P) was used to evaluate the presence of other comorbidities and exclude other symptoms (27). Attentiondeficit/hyperactivity disorder was not diagnosed if symptoms were better accounted for by another psychiatric disorder (e.g., mood, anxiety, psychotic, personality disorder). Patients were excluded if the investigator judged they (or their child) had a history of poor response or intolerance to methylphenidate; they had been diagnosed with any current clinically unstable psychiatric condition (e.g., acute mood disorder, bipolar disorder, acute obsessive-compulsive disorder), as determined by the investigator; or they had been diagnosed with substance use disorder (abuse/dependence) according to DSM-IV criteria within the last 6 months. Other exclusion criteria included family history of schizophrenia or affective psychosis; serious illnesses (e.g., hepatic or renal insufficiency or significant cardiac, gastrointestinal, psychiatric, or metabolic disturbances); hyperthyroidism, myocardial infarction, or stroke within 6 months of screening; and history of seizures, glaucoma, or uncontrolled hypertension. Procedure This double-blind, randomized, placebo-controlled, parallelgroup, fixed-dose trial was conducted at 51 investigator sites in 13 European countries from April 2005 to June The research protocol was approved by the ethics committees at each site, and all participants gave written informed consent. Eligible patients were randomized into one of four treatment groups to receive oral dosages of 18 mg, 36 mg, or 72 mg methylphenidate or placebo once daily. Patients receiving 18 mg or 36 mg/day methylphenidate or placebo received the treatment dose for 5 weeks. Patients in the 72-mg methylphenidate group were titrated from a starting dose of 36 mg/day for 4 days to 54 mg/day for 3 days, after which 72 mg/day was administered for 4 weeks. Randomization was based on a computer-generated randomization and stratification scheme prepared before the study. Randomization was balanced by using permuted blocks of treatments, stratified by study center, and implemented via an interactive voice response system. The trial included a washout period of up to 4 weeks during which current therapy was tapered to discontinuation. Patients on a stable dosage of antidepressant therapy for at least 3 months prior to screening were allowed to continue at the same daily dose during the study, with the exception of monoamine oxidase inhibitors, which were tapered to discontinuation with a minimum washout period of 2 weeks. Baseline procedures included administration of efficacy measures, clinical laboratory tests (hematology, biochemistry), vital signs (supine and standing blood pressure, pulse), and physical examination. Patients were instructed to take their medication in the morning, beginning the day after baseline assessments. Their medication compliance was checked by having them return all used and unused blister containers to the study center. Procedures were performed after patients took their morning medication and at various times during the day, depending on when they visited the site. At the end of weeks 1 and 3, efficacy measures were administered, vital signs measured, and adverse events monitored. At the end of week 5, or at early withdrawal, efficacy and safety procedures performed at baseline were repeated. Eligible patients continued in a 7-week open-label extension that assessed the safety of methylphenidate in a flexible dose regimen of 18 mg to 90 mg/day. This report covers the 5-week double-blind phase. Assessment The Conners Adult ADHD Rating Scales (CAARS) for which psychometric data have been reported are considered appropriate for measuring symptoms in adults with ADHD and have been used in clinical trials of adult ADHD (23,26,28). This study used both Observer (CAARS:O-SV) and Self (CAARS:S-S) forms. The CAARS Observer form comprises 18 investigator-rated items corresponding to the 18 DSM-IV ADHD symptoms and provides a total score referred to as the CAARS total ADHD Symptom Score and two subscales. The CAARS Self form is a 26-item, self-report, four-point rating scale that measures symptoms based on the DSM-IV criteria for ADHD providing total score, ADHD index, and four subscales. Investigators who performed ratings for CAARS assessments successfully completed a formal training and qualification program. The primary efficacy measure was the change in CAARS:O-SV total score at end point compared with baseline. Secondary end points included changes in CAARS:O-SV total and subscale scores at weeks 1, 3, and 5, and changes from start to the end of treatment in the following: 1) CAARS:S-S total and subscale scores; 2) Clinical Global Impression Severity of Illness subscale (CGI-S) used to rate the severity of a patient s illness on a 7-point scale (29); and 3) Sheehan s Disability Scale (SDS) designed to measure impairment on work, social and home life, or family responsibilities with a self-administered 10-point visual analog scale for three items. A trained and certified clinician administered these tests in each patient s native language. Safety evaluations included monitoring of adverse events, clinical laboratory tests, vital signs, and physical examination. Statistical Analysis A sample size of 94 patients per group was calculated to provide 90% power to detect a mean difference of six units between an active-dose group and placebo in change from baseline for the primary end point, based on a two-sample, two-tailed, t test with alpha.016 and standard deviation of 11. Adjusting for a rate of 6% for patients without baseline or postbaseline efficacy assessments, the required number of patients was 100 per treatment group and 400 total. Efficacy analyses included patients who received at least one dose of medication and had at least one postbaseline efficacy measurement. Primary end point was change in CAARS:O-SV total score from baseline to last postrandomization assessment. Change from baseline at each visit and end point (last observation carried forward [LOCF]) was analyzed using analysis of covariance that included treatment, sex, and country as factors and baseline scores as a covariate. Treatment effects were estimated based on least squares means of the difference. Dunnett s procedure was used to adjust for multiple comparisons of the three PR methylphenidate dosages versus placebo at end point. Pairwise comparisons between each of the methylphenidate dosing groups were performed using analysis of covariance

3 R. Medori et al. BIOL PSYCHIATRY 2008;63: that included treatment, sex, and country as factors and baseline scores as a covariate. Responders were predefined as showing 30% reduction of CAARS:O-SV total score from baseline at end point and were analyzed using the Cochran-Mantel-Haenszel test, controlling for country. Sidak correction was used to adjust for multiple comparisons of the three PR methylphenidate dosages versus placebo in the responder analysis. Patients with 50% improvement in CAARS:O-SV total score were also analyzed. Clinical Global Impression Severity of Illness subscale was analyzed with analysis of variance on ranked changes from baseline, with treatment, sex, and country as factors at each assessment time point and end point, and CAARS:S-S and SDS comparisons of change from baseline to end point were analyzed using analysis of covariance, with treatment, sex, and country as factors and baseline score as covariate, with comparisons of the three PR methylphenidate dosages versus placebo adjusted using Dunnett s procedure. All statistical analyses were performed using SAS (Version 8.02; SAS Institute, Cary, North Carolina). Results A total of 448 patients were screened and 402 patients were randomized into placebo or one of the three PR methylphenidate groups. Overall, 365 (91%) of randomized patients completed the 5-week double-blind study period: 94.1%, 90.2%, and 86.3% in the 18-mg, 36-mg, and 72-mg/day PR methylphenidate groups, respectively, and 93.8% in the placebo group. (SD) duration of exposure was 33.9 (6.53) days in the four groups. (SD; range) daily dosage was.24 mg/kg (.048 mg/kg;.1.4 mg/kg ),.50 mg/kg (.112 mg/kg;.3.8 mg/kg ), and.96 mg/kg (.198 mg/kg; mg/kg ) in the 18-mg, 36-mg, and 72-mg/day PR methylphenidate groups, respectively. The statistical analysis of efficacy included 394 patients, and safety assessment included 401 patients who received at least one dose of trial medication. Baseline demographic and clinical characteristics were similar across placebo and the three PR methylphenidate groups (Table 1). Overall, median age was 34 years, 54% were men, and 98% were Caucasian. Median age at diagnosis of Table 1. Baseline Demographic and Clinical Characteristics of Randomized Patients PR Methylphenidate Treatment Demographic Placebo (n 96) 18 mg/day (n 101) 36 mg/day 72 mg/day Total (n 401) Age in years, mean (95% CI) 34.5 (32.5;36.4) 34.2 (32.1;36.3) 33.8 (31.7;35.8) 33.6 (31.5;35.6) 34.0 (33.0;35.0) Gender, male, n (%) 59 (61.5) 58 (57.4) 46 (45.1) 55 (53.9) 218 (54.4) Race, n (%) White 94 (97.9) 100 (99.0) 98 (96.1) 99 (97.1) 391 (97.5) Other a 2 (2.1) 1 (1.0) 4 (3.9) 3 (2.9) 10 (2.5) ADHD History Age at diagnosis, mean (95% CI) 31.4 (28.8;33.9) 30.5 (27.7;33.2) 29.2 (26.3;31.9) 28.9 (26.1;31.5) 29.9 (28.6;31.2) Childhood ADHD subtype b, n (%) Combined type 68 (70.8) 72 (71.3) 80 (78.4) 79 (77.5) 299 (74.6) Predominantly inattentive 21 (21.9) 23 (22.8) 16 (15.7) 19 (18.6) 79 (19.7) Predominantly hyperactive-impulsive 5 (5.2) 5 (5.0) 6 (5.9) 3 (2.9) 19 (4.7) Not otherwise specified 2 (2.1) (.5) Adult ADHD subtype b, n (%) Combined type 67 (69.8) 64 (63.4) 76 (74.5) 77 (75.5) 284 (70.8) Predominantly inattentive 24 (25.0) 32 (31.7) 19 (18.6) 22 (21.6) 97 (24.2) Predominantly hyperactive-impulsive 2 (2.1) 4 (4.0) 7 (6.9) 3 (2.9) 16 (4.0) Not otherwise specified 3 (3.1) 1 (1.0) (1.0) Psychiatric comorbidity, n (%) Alcohol/substance use disorders Currently active c 0 1 (1.0) 1 (1.0) 1 (1.0) 3 (.7) History and not active 12 (12.5) 12 (11.9) 15 (14.7) 15 (14.7) 54 (13.5) Mood and anxiety disorders d Currently active 10 (10.4) 10 (9.9) 11 (10.8) 17 (16.7) 48 (12.0) History and not active 25 (26.0) 27 (26.7) 36 (35.3) 32 (31.4) 120 (29.9) Efficacy Measures e, mean (95% CI) CAARS:O-SV (n 95) (n 99) (n 101) (n 99) Total score 37.2 (35.8;38.6) 35.6 (34.2;37.0) 37.3 (35.9;38.6) 36.6 (35.2;37.8) CAARS:S-S (n 93) (n 95) (n 99) (n 95) Total score 51.1 (49.0;53.2) 48.5 (46.0;50.9) 51.2 (49.0;53.4) 50.6 (48.2;53.0) CGI-S (n 95) (n 99) (n 101) (n 99) Total score 4.9 (4.7;5.0) 4.9 (4.7;5.0) 5.0 (4.8;5.1) 4.9 (4.7;5.1) ADHD, attention-deficit/hyperactivity disorder; CAADID, Conners Adult ADHD Diagnostic Interview for DSM-IV; CAARS:O-SV, Conners Adult ADHD Rating Scale: Investigator rated; CAARS:S-S, Conners Adult ADHD Self Report Short Version; CGI-S, Clinical Global Impression Severity, investigator rated; CI, confidence interval; PR, prolonged-release; SDS, Sheehan s Disability Scale, self-report. a Other is defined as Black or African heritage, Hispanic, and Other. b CAADID responses. c Patients were excluded if diagnosed within the last 6 months; information was obtained after screening for three patients. d Patients were excluded if symptoms better accounted for by another psychiatric disorder than ADHD. e Possible range of scores on each measure: CAARS:O-SV: 0 54; CAARS:S-S: 0 78; CGI-S: 1 7; SDS: SDS excluded since visual analog raw scores are not considered appropriate for group comparisons.

4 984 BIOL PSYCHIATRY 2008;63: R. Medori et al. ADHD was 32 years, with the majority (71%) diagnosed with ADHD combined subtype. Currently active and stable psychiatric comorbidities in the study population included mood and anxiety disorders in 12% of patients and personality disorders in 1% of patients. baseline scores of efficacy measures were comparable across the treatment groups (Table 1). Efficacy (SD) change from baseline to end point in CAARS:O-SV total score with LOCF was 10.6 (10.34), 11.5 (9.97), and 13.7 (11.11) in 18-mg, 36-mg, and 72-mg PR methylphenidate groups, respectively, versus 7.6 (9.93) in placebo (Table 2). The decrease (improvement) in CAARS:O-SV total score from baseline to end point was significantly larger in the three PR methylphenidate groups versus placebo (p-values.015). Statistical significance was not reached between any of the three PR methylphenidate treatment groups. Interactions and main effects of country and gender were not significant (p-values.06). The effect sizes 1 for the 18-mg, 36-mg, and 72-mg PR methylphenidate groups were.38,.43, and.62, respectively. There were significantly more responders ( 30% reduction in CAARS:O-SV total score) in the PR methylphenidate groups compared with placebo: 50.5%, 48.5%, and 59.6% in 18-mg, 36-mg, and 72-mg groups, respectively, versus 27.4% of placebotreated patients; p.001. Patients with 50% improvement in CAARS:O-SV total score was 22.2%, 24.8%, and 31.3% in 18-mg, 36-mg, and 72-mg groups, respectively, versus 13.7% of placebotreated patients, p.01. The largest improvement in CAARS: O-SV total and subscale scores occurred after week 1 for all groups, with additional improvement through week 5 (Table 3). On CAARS:S-S (total score, ADHD index, four subscales), CGI-S, and SDS efficacy measures, significant improvements occurred in mean change from baseline to end point in the three PR methylphenidate groups compared with placebo (Table 2). Adverse Events Adverse events are summarized by preferred term (Medical Dictionary for Regulatory Activities 2 ) in Table 4 for the 401 patients who received at least one dose of trial medication. More patients in the PR methylphenidate groups (75% 82%) compared with placebo (66%) reported a treatment-emergent adverse event, and more events were considered at least possibly related to trial medication in the PR methylphenidate groups (52% 69%) than in placebo group (43%). The highest percentage of adverse events was reported in the 72-mg group. The most frequently reported adverse events ( 10% treated with PR methylphenidate) were decreased appetite, headache, insomnia, nausea, and dry mouth, with decreased appetite and dry mouth exhibiting dose-relatedness. Psychiatric-related adverse events (e.g., irritability, anxiety, nervousness) occurred more frequently in methylphenidate-treated patients, particularly at the highest dose. Tachycardia (5.6%) and palpitations (3.9%) were reported in the three PR methylphenidate groups but not in placebo. Decreased weight was reported as an adverse event in 22 (7.2%) patients 1 Defined as the treatment difference between the PR methylphenidate group and placebo in least square means divided by the square root of the mean square error, based on a mixed model with random intercept and an unstructured covariance matrix. 2 MedDRA the Medical Dictionary for Regulatory Activities terminology is the international medical terminology developed under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). treated with PR methylphenidate. decrease in weight from baseline at end point was.9, 1.1, and 1.9 kg in the 18-mg, 36-mg, and 72-mg groups, respectively (p-values.001), versus.4 kg in placebo. Most adverse events were mild or moderate in all treatment groups, with only four patients reporting a serious adverse event in the 18-mg and 72-mg PR methylphenidate groups. In the 18-mg group, a cerebrovascular accident was reported in a 59-year-old man who temporarily stopped treatment and recovered in 16 days, and anxiety disorder was reported in a 43-yearold woman who continued treatment and recovered in 4 days. In the 72-mg group, a 34-year-old woman recovered from a migraine attack after 2 days without stopping treatment, and a 21-year-old man was reported with the onset of a depressive disorder after a breakdown of his relationship; he continued study treatment, received additional counseling, and recovered in 4 weeks. The investigators considered depression possibly related and the other three events as not related or doubtfully related to the trial medication. Thirteen (4.3%) patients treated with PR methylphenidate permanently discontinued trial medication due to one or more adverse events, with 1, 4, and 8 patients in the 18-mg, 36-mg, and 72-mg groups, respectively. Most frequently reported adverse events leading to discontinuation were anxiety (four patients), irritability and nervousness (both reported by three patients), and tremor, insomnia, and restlessness (all reported by two patients). Patients recovered from all of the adverse events, except for one report of aggression and delusion of reference in the 36-mg group, tinnitus in the 72-mg group, and hypertension in the placebo group. The investigators considered hypertension and delusion of reference as very likely related and the other two events as doubtfully or possibly related to the trial medication, and delusion of reference was reported resolved after 1 week. Cardiovascular-Related Effects As shown in Table 5, PR methylphenidate was associated with statistically significant increases in blood pressure, but these were limited to week 1 (systolic and diastolic) in the 72-mg group and week 3 (diastolic) in the 36-mg group. In all groups, change from baseline in blood pressure occurred at week 1, with only slight further increases or decreases from week 1 through week 5. Clinically relevant criteria for systolic ( 140 mm Hg) and/or diastolic ( 90 mm Hg) blood pressure were met by a percentage of patients at baseline ( 38%) and at least one time point during treatment ( 43%) in PR methylphenidate and placebo groups. Pulse showed statistically significant increases at the three time points in the three PR methylphenidate groups and at week 3 for placebo. In all groups, increase from baseline in pulse occurred at week 1, with only slight further increases or decreases from week 1 through week 5. There were no clinically notable changes in laboratory values over time. Discussion In this large 5-week, double-blind, randomized, placebocontrolled trial, three fixed doses of PR methylphenidate, 18 mg, 36 mg, and 72 mg/day, were an effective treatment of ADHD in adults, as indicated by changes in primary and secondary measures versus placebo. Over 5 weeks of treatment, PR methylphenidate was statistically superior to placebo at 18 mg, 36 mg, and 72 mg/day with effect sizes of.38,.43, and.62, respectively. Efficacy of the medication was apparent in the first week of

5 Table 2. Efficacy Outcomes by Change From Baseline to Double-Blind End Point Efficacy Measure Placebo Change 95% CI Prolonged-Release (PR) Methylphenidate Treatment 18 mg/day 36 mg/day 72 mg/day CAARS:O-SV (n 95) (n 99) (n 101) (n 99) Total score ; ; ; ; Subscale Inattentive ; ; ; ; Hyperactive/Impulsive ; ; ; ; CAARS:S-S (n 91) (n 93) (n 95) (n 92) Total score ; ; ; ; Subscale Inattention/Memory problems ; ; ; ; Hyperactivity/Restlessness ; ; ; ; Impulsivity/Emotional Lability ; ; ; ; Problems with Self-Concept ; ; ; ; ADHD index ; ; ; ; CGI-S (n 93) (n 97) (n 100) (n 98) Total score.5.69; ; ; ; SDS (n 74) (n 76) (n 79) (n 75) Total score ; ; ; ; All analyses were intention to treat with last observation carried forward values for CAARS: O-SV (administered at baseline and weeks 1, 3, and 5) and actual values for other efficacy measures (administered at baseline and week 5). p value for comparison between each dose group and placebo using two-tailed t test. ADHD, attention-deficit/hyperactivity disorder; CAARS:O-SV, Conners Adult ADHD Rating Scale: Investigator rated; CAARS:S-S, Conners Adult ADHD Self Report Short Version; CGI-S, Clinical Global Impression Severity, investigator rated; CI, confidence interval; PR, prolonged release; SDS, Sheehan s Disability Scale, self-report. R. Medori et al. BIOL PSYCHIATRY 2008;63:

6 986 BIOL PSYCHIATRY 2008;63: R. Medori et al. Table 3. Change From Baseline to Treatment Weeks 1, 3, and 5 in CAARS:O-SV Total and Subscale Scores Efficacy Measure Treatment Week Placebo (n 95) Change 95% CI Prolonged-Release (PR) Methylphenidate Treatment 18 mg/day (n 99) 36 mg/day (n 101) 72 mg/day (n 99) CAARS:O-SV Total score Week ; ; ; ; Week ; ; ; ; Week ; ; ; ; Inattentive subscale Week ; ; ; ; Week ; ; ; ; Week ; ; ; ; Hyperactive/Impulsive subscale Week ; ; ; ; Week ; ; ; ; Week ; ; ; ; All analyses were intention to treat with observed values. p value for comparison between each dose group and placebo using two-tailed t test. CAARS:O-SV, Conners Adult ADHD Rating Scale: Investigator rated; CI, confidence interval; PR, prolonged release. treatment and appeared dose-dependent. Adverse events (e.g., decreased appetite, headache, insomnia, nausea, dry mouth), including psychiatric-related (e.g., irritability, anxiety) and cardiovascular-related events (e.g., tachycardia and palpitations), occurred more frequently in PR methylphenidate than placebo groups; some adverse events appeared dose-related (e.g., decreased appetite, dry mouth); adverse events seldom led to discontinuation of medication; and adverse events were rarely serious. For cardiovascular parameters, PR methylphenidate was associated with statistically significant increases in blood pressure, but these were small and occurred primarily at week 1 with only slight further increases or decreases from week 1 through week 5. Clinical relevant criteria for hypertension (systolic 140 mm Hg and diastolic 90 mm Hg blood pressure) were met by a similar percentage of patients in all treatment groups. Pulse showed statistically significant increases at the three time points in all PR methylphenidate groups but was similar to placebo in Table 4. Summary of Adverse Events PR Methylphenidate Treatment Adverse Event, n (%) Placebo (n 96) 18 mg/day (n 101) 36 mg/day 72 mg/day All MPH (n 305) Any serious adverse event 0 2 (2.0) 0 2 (2.0) 4 (1.3) Discontinued due to adverse event 1 (1.0) 1 (1.0) 4 (3.9) 8 (7.8) 13 (4.3) Any adverse event 63 (65.6) 76 (75.2) 77 (75.5) 84 (82.4) 237 (77.7) Possibly related to trial medication a 41 (42.7) 52 (51.5) 60 (58.8) 70 (68.6) 182 (59.7) Adverse event 3% total b Decreased appetite 7 (7.3) 20 (19.8) 22 (21.6) 35 (34.3) 77 (25.2) Headache 17 (17.7) 26 (25.7) 21 (20.6) 17 (16.7) 64 (21.0) Insomnia 7 (7.3) 12 (11.9) 12 (11.8) 17 (16.7) 41 (13.4) Nausea 4 (4.2) 8 (7.9) 16 (15.7) 15 (14.7) 39 (12.8) Dry mouth 2 (2.1) 8 (7.9) 7 (6.9) 21 (20.6) 36 (11.8) Dizziness 7 (7.3) 6 (5.9) 10 (9.8) 9 (8.8) 25 (8.2) Weight decreased 5 (5.2) 3 (3.0) 8 (7.8) 11 (10.8) 22 (7.2) Nasopharyngitis 9 (9.4) 7 (6.9) 8 (7.8) 4 (3.9) 19 (6.2) Tachycardia 0 4 (4.0) 5 (4.9) 8 (7.8) 17 (5.6) Irritability 1 (1.0) 4 (4.0) 4 (3.9) 9 (8.8) 17 (5.6) Anxiety 1 (1.0) 3 (3.0) 5 (4.9) 8 (7.8) 16 (5.2) Hyperhidrosis 1 (1.0) 5 (5.0) 3 (2.9) 8 (7.8) 16 (5.2) Fatigue 6 (6.3) 4 (4.0) 4 (3.9) 6 (5.9) 14 (4.6) Depressed mood 1 (1.0) 6 (5.9) 3 (2.9) 5 (4.9) 14 (4.6) Palpitations 0 2 (2.0) 5 (4.9) 5 (4.9) 12 (3.9) Nervousness 1 (1.0) 0 3 (2.9) 8 (7.8) 11 (3.6) Initial insomnia 2 (2.1) 3 (3.0) 2 (2.0) 5 (4.9) 10 (3.3) All MPH, combined 18-mg, 36-mg, and 72-mg/day PR methylphenidate treatment groups; PR, prolonged release. a Includes trial medication relationship of possibly, probably, and very likely. b Summarized by preferred term according to Medical Dictionary for Regulatory Activities (MedDRA).

7 R. Medori et al. BIOL PSYCHIATRY 2008;63: Table 5. Summary of Cardiovascular-Related Measurements Measurement a Placebo (n 96) 18 mg/day (n 101) PR Methylphenidate Treatment 36 mg/day 72 mg/day Baseline, mean (range) Systolic blood pressure (mm Hg) (98 170) (82 150) (80 162) (90 173) Diastolic blood pressure (mm Hg) 82.1 (60 120) 80.7 (50 110) 79.1 (40 112) 79.8 (60 120) Pulse (bpm) 77.2 (52 113) 78.6 (55 103) 79.1 (53 123) 77.4 (57 109) Change from Baseline (range) Systolic blood pressure (mm Hg) Week 1.8 (90 170).8 (94-160).2 (90 168) 4.0 b (90 189) Week (90 170).6 ( ).6 (90 160).1 (97 155) Week (90 182).1 (88-160).4 ( ) 2.2 (85 170) Diastolic blood pressure (mm Hg) Week (52 128).1 (50 111) 1.9 (50 110) 2.0 b (44 114) Week 3.7 (58 104).3 (60 110) 2.3 b (60 110) 1.9 (52 103) Week (60 117).8 (60 108) 1.7 (50 120) 1.6 (50 104) Pulse (bpm) Week (54 128) 2.9 b (49 112) 5.3 b (59 123) 8.1 b (64 147) Week b (58 107) 2.7 b (60 112) 5.7 b (60 136) 10.6 b (56 122) Week (55 115) 3.9 b (60 123) 5.2 b (60 116) 9.8 b (58 160) Met Clinically Relevant Criteria, n (%) Systolic blood pressure ( 140 mm Hg) Baseline 15 (15.8) 14 (13.9) 20 (19.8) 14 (13.9) Week 1 17 (18.1) 14 (14.3) 9 (8.9) 22 (22.2) Week 3 18 (19.6) 13 (13.5) 15 (16.5) 18 (18.9) Week 5 17 (19.3) 12 (13.0) 14 (15.9) 18 (21.2) Diastolic blood pressure ( 90 mm Hg) Baseline 24 (25.3) 25 (24.8) 19 (18.8) 19 (18.8) Week 1 21 (22.3) 19 (19.4) 22 (21.8) 26 (26.3) Week 3 22 (23.9) 17 (17.7) 22 (24.2) 23 (24.2) Week 5 14 (15.9) 13 (14.1) 17 (19.3) 23 (27.1) Pulse ( 90 bpm) Baseline 3 (3.2) 2 (2.0) 8 (7.9) 1 (1.0) Week 1 4 (4.3) 5 (5.1) 9 (8.9) 12 (12.1) Week 3 6 (6.6) 5 (5.3) 9 (10.0) 17 (17.9) Week 5 5 (5.7) 10 (10.9) 9 (10.2) 12 (14.1) bpm, beats per minute; PR, prolonged release. Range is the minimum and maximum of actual values. a Measured while patient standing. b Statistically significant change at.05 level versus baseline (two-tailed paired t test). the 18-mg group and larger in 36-mg and 72-mg groups. As with blood pressure, increase in pulse occurred primarily at week 1, with only slight further increases or decreases from week 1 through week 5. Biederman et al. (21) evaluated PR methylphenidate in adults with a flexible dose approach in which medication was titrated to optimal response (e.g., dose was increased by 36 mg/day only for subjects who failed to attain an a priori definition of improvement) up to a maximum daily dose of 1.3 mg/kg over a 6-week treatment period. Other differences from the present study included efficacy measures (Clinical Global Impression-Improvement [CGI-I] and Adult ADHD Investigator System Report Scale [AISRS]) (30). daily dose of methylphenidate at week 6 was 80.9 mg ( 31.8 mg). In both studies, treatment with PR methylphenidate was associated with clinically and statistically significant reductions in DSM-IV symptoms of inattention and hyperactivity/impulsivity relative to patients treated with placebo. Given the reported information, we were able to compute a common metric, the numbers needed to treat (NNT); namely, the number of patients that should be treated to improve one additional patient compared with use of the comparator, where a smaller number is associated with more effective treatment. Using a similar definition of clinical response ( 30% decrease in the main outcome measure), the NNT for the present study are 4.3 (18 mg), 4.7 (36 mg), and 3.1 (72 mg), and 3.4 for the Biederman et al. (21) study. Attention-deficit/hyperactivity disorder is not as well understood in adults as in children, and in turn, there is more concern about the validity of the diagnosis in adults. The diagnosis is still questioned in Europe where this trial was completed, but there is increasing literature on the recognition and need for treatment of ADHD in adults (12,31), reflecting growing evidence that symptoms persist beyond childhood and symptoms in adults show the same responsiveness to methylphenidate treatment as seen in children (20,32). A recent systematic European review of the efficacy of prolonged-release stimulants (methylphenidate, dexamphetamine) and atomoxetine for treatment of ADHD in children, adolescents, and adults includes the recommendation for their use in adults, with the observation that psychotherapeutic interventions also have an important role (33). The safety profile in the present study was consistent with Biederman et al. (21) and reflects a large sample of patients who received PR methylphenidate (305 and 67 patients, respectively). In both studies, the most frequently reported adverse events with

8 988 BIOL PSYCHIATRY 2008;63: R. Medori et al. PR methylphenidate treatment included decreased appetite, headache, insomnia, nausea, and dry mouth. Our study suggested that adverse events such as decreased appetite and dry mouth may increase with higher doses. The same trend was observed for the incidence of adverse events belonging to the following body systems: psychiatric disorders, gastrointestinal disorders, metabolism and nutrition disorders, and cardiac disorders. In the present study, as in Biederman et al. (21), adverse events did not generally lead to discontinuations of PR methylphenidate, and adverse events were rarely serious. In both studies, treatment was associated with small but statistically significant increases in blood pressure and heart rate and with weight loss. The U.S. Food and Drug Administration (FDA) directed manufacturers of all drug products approved for treatment of ADHD to develop patient medication guides to alert patients to possible cardiovascular risks and risks of adverse psychiatric symptoms associated with these medicines (6). In this study, patients were not enrolled if they had serious illnesses (e.g., significant cardiac, vascular, pulmonary disturbances) or were diagnosed with any clinically unstable psychiatric condition (e.g., acute mood disorder, bipolar disorder, acute obsessivecompulsive disorder). Biederman et al. (21) excluded patients with significant chronic medical conditions. In the three PR methylphenidate (18-mg, 36-mg, 72-mg) groups, there were reports of tachycardia (4%, 4.9%, 7.8%) and palpitations (2%, 4.9%, 4.9%) suggestive of a dose-response relationship; these events did not require an intervention and were not serious. There were small increases in blood pressure (.1,.4, 2.2 mm Hg for standing systolic and.7, 1.7, 1.6 mm Hg for diastolic at week 5) and statistically significant increases in pulse at 5 weeks of treatment (3.9, 5.2, 9.8 beats per minute [bpm]). Blood pressure and pulse increases occurred primarily at week 1, with slight further increases or decreases from week 1 through week 5. In Biederman et al. (21), cardiovascular complaints were reported in 9% of the PR methylphenidate group, although no event was characterized as tachycardia or palpitation or as serious. Biederman et al. (21) reported changes in blood pressure and pulse at week 6 and there were increases in blood pressure (2.2 and 1.6 mmhg for systolic and diastolic) and pulse (4.5 bpm). Further research will need to evaluate possible cardiovascular risks associated with long-term PR methylphenidate treatment, including changes in blood pressure and pulse changes. In the present study, reports of psychiatric symptoms (e.g., irritability, anxiety, nervousness) were suggestive of a doseresponse relation, with incidence 9% in any treatment group. One report of depressive disorder was considered serious and possibly related to treatment; the patient continued treatment with no report of recovery. The overall incidence of psychiatric adverse events in Biederman et al. (21) appeared similar to those reported in this study. There are limitations to the present study that include 1) a relatively short 5-week treatment period did not address longterm treatment; 2) sample size was not of the magnitude required to evaluate the possibility of rare adverse events; 3) lack of ethnical/racial diversity; 4) efficacy measures did not cover the full range of effectiveness measures (psychologic, educational, social); and 5) efficacy measures were administered once on designated days and they would not detect fluctuations in clinical symptoms over the course of the day, limiting comparisons between PR and IR formulations of methylphenidate. The potential benefits of the PR methylphenidate delivery, including improved compliance with a once-daily administration and possible reduced risk of abuse with the formulation, have been discussed (21). The present study evaluated three fixed doses up to 72 mg/day, the maximal dose FDA has approved in adolescents. Although not designed for direct comparisons between dosages, this study indicates a clinical benefit of treatment with PR methylphenidate for ADHD in adults at fixed daily doses of 18 mg and 36 mg and that these benefits were more pronounced with a daily dose of 72 mg. If weight-base dosing is considered appropriate for this medication, then higher doses would need to be studied in adults. This study was supported by Janssen Pharmaceutica N.V., Belgium. The trial is registered at ClinicalTrials.gov (NCT ; CR002479): A Study of the Effectiveness and Safety of Prolonged-Release Methylphenidate Hydrochloride in Adult Patients With Attention Deficit/Hyperactivity Disorder We thank the investigators, their study teams, and patients for participating in the study. Joachim Dejonckheere of SGS Life Sciences analyzed the data. We also acknowledge Bradford Challis, Ph.D., and Susan Glasser, Ph.D., of Johnson & Johnson Pharmaceutical Research & Development, L.L.C., for their contribution to the preparation of the manuscript. Drs. Rossella Medori and Emma Lee are employees of Janssen, and the other authors were investigators in the clinical study. Dr. Ramos-Quiroga reports having received lecture and consulting fees from Janssen-Cilag and Laboratorios Rubió and research funding from Janssen-Cilag. Dr. Casas reports having received lecture and consulting fees from Janssen-Cilag and Laboratorios Rubió and research funding from Janssen-Cilag. Dr. Kooij reports having been a consultant, member of advisory board, and/or speaker for Janssen Cilag BV and Eli Lilly. Dr. Buitelaar reports having been a consultant, member of advisory board, and/or speaker for Janssen Cilag BV, Eli Lilly, Bristol-Myer Squibb, UBC, Shire, Medice. Dr. Niemelä reports having received lecture fees from Janssen-Cilagand. Dr. Trott reports no applicable financial interests or potential conflicts of interest. Supplementary material is available online. 1. Faraone SV, Biederman J, Mick E (2005): The age-dependent decline of attention deficit hyperactivity disorder: A meta-analysis of follow-up studies. Psychol Med 35: Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, et al. (2006): The prevalence and correlates of adult ADHD in the United States: Results from the National Comorbidity Survey Replication. Am J Psychiatry 163: Kessler RC, Adler LA, Barkley R, Biederman J, Conners CK, Faraone SV, et al. (2005): Patterns and predictors of attention-deficit/hyperactivity disorder persistence into adulthood: Results from the national comorbidity survey replication. Biol Psychiatry 57: Fayyad J, De Graaf R, Kessler R, Alonso J, Angermeyer M, Demyttenaere K, et al. (2007): Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. Br J Psychiatry 190: Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Arnold V, Beitchman J, et al. (2001): Summary of the practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. JAm Acad Child Adolesc Psychiatry 40: U.S. Food and Drug Administration (2007): FDA Directs ADHD Drug Manufacturers to Notify Patients about Cardiovascular Adverse Events and Psychiatric Adverse Events. Rockville, MD: National Press Office. Press P Anders T, Sharfstein S (2006): ADHD drugs and cardiovascular risk. N Engl J Med 354: ; author reply

9 R. Medori et al. BIOL PSYCHIATRY 2008;63: Nissen SE (2006): ADHD drugs and cardiovascular risk. N Engl J Med 354: Okie S (2006): ADHD in adults. N Engl J Med 354: Rappley MD, Moore JW, Dokken D (2006): ADHD drugs and cardiovascular risk. N Engl J Med 354: ; author reply Wojnowski L (2006): ADHD drugs and cardiovascular risk. N Engl J Med 354: ; author reply Asherson P, Chen W, Craddock B, Taylor E (2007): Adult attention-deficit hyperactivity disorder: Recognition and treatment in general adult psychiatry. Br J Psychiatry 190: Asherson P (2005): Clinical assessment and treatment of attention deficit hyperactivity disorder in adults. Expert Rev Neurother 5: Wolraich ML, Greenhill LL, Pelham W, Swanson J, Wilens T, Palumbo D, et al. (2001): Randomized, controlled trial of oros methylphenidate once a day in children with attention-deficit/hyperactivity disorder. Pediatrics 108: Swanson J, Gupta S, Lam A, Shoulson I, Lerner M, Modi N, et al. (2003): Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: Proof-of-concept and proof-of-product studies. Arch Gen Psychiatry 60: Pelham WE, Gnagy EM, Burrows-Maclean L, Williams A, Fabiano GA, Morrisey SM, et al. (2001): Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings. Pediatrics 107:E Bouffard R, Hechtman L, Minde K, Iaboni-Kassab F (2003): The efficacy of 2 different dosages of methylphenidate in treating adults with attention-deficit hyperactivity disorder. Can J Psychiatry 48: Faraone SV, Spencer T, Aleardi M, Pagano C, Biederman J (2004): Metaanalysis of the efficacy of methylphenidate for treating adult attentiondeficit/hyperactivity disorder. J Clin Psychopharmacol 24: Spencer T, Biederman J, Wilens T, Doyle R, Surman C, Prince J, et al. (2005): A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 57: Kooij JJ, Burger H, Boonstra AM, Van der Linden PD, Kalma LE, Buitelaar JK (2004): Efficacy and safety of methylphenidate in 45 adults with attention-deficit/hyperactivity disorder. A randomized placebo-controlled double-blind cross-over trial. Psychol Med 34: Biederman J, Mick E, Surman C, Doyle R, Hammerness P, Harpold T, et al. (2006): A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 59: Reimherr FW, Williams ED, Strong RE, Mestas R, Soni P, Marchant BK (2007): A double-blind, placebo-controlled, crossover study of osmotic release oral system methylphenidate in adults with ADHD with assessment of oppositional and emotional dimensions of the disorder. J Clin Psychiatry 68: Jain U, Hechtman L, Weiss M, Ahmed TS, Reiz JL, Donnelly GA, et al. (2007): Efficacy of a novel biphasic controlled-release methylphenidate formula in adults with attention-deficit/hyperactivity disorder: Results of a double-blind, placebo-controlled crossover study. J Clin Psychiatry 68: Spencer TJ, Adler LA, McGough JJ, Muniz R, Jiang H, Pestreich L (2007): Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 61: American Psychiatric Association (2000): Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. Washington, DC: The American Psychiatric Association. 26. Conners C, Erhardt D, Sparrow E (1999): Conners Adult ADHD Rating Scales (CAARS): Technical Manual. North Tonawanda, NY: Multi-Health Systems. 27. First M, Spitzer R, Gibbon M, Williams G (1994): Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (SCID-P), Version 2. New York: New York State Psychiatric Institute, Biometrics Research. 28. Michelson D, Adler L, Spencer T, Reimherr FW, West SA, Allen AJ, et al. (2003): Atomoxetine in adults with ADHD: Two randomized, placebocontrolled studies. Biol Psychiatry 53: National Institute of Mental Health (NIMH) (1985): CGI (Clinical Global Impression Scale) NIMH. Psychopharmacol Bull 21: Spencer T, Adler L (2004): Diagnostic approaches to adult attentiondeficit/hyperactivity disorder. Prim Psychiatry 11: Nutt DJ, Fone K, Asherson P, Bramble D, Hill P, Matthews K, et al. (2007): Evidence-based guidelines for management of attention-deficit/hyperactivity disorder in adolescents in transition to adult services and in adults: Recommendations from the British Association for Psychopharmacology. J Psychopharmacol 21: Kooij JJ, Buitelaar JK, van den Oord EJ, Furer JW, Rijnders CA, Hodiamont PP (2005): Internal and external validity of attention-deficit hyperactivity disorder in a population-based sample of adults. Psychol Med 35: Banaschewski T, Coghill D, Santosh P, Zuddas A, Asherson P, Buitelaar J, et al. (2006): Long-acting medications for the hyperkinetic disorders. A systematic review and European treatment guideline. Eur Child Adolesc Psychiatry 15: