ORIGINAL RESEARCH ARTICLE CNS Drugs 2008; 22 (7): 603-611 1172-7047/08/0007-0603/$48.00/0 © 2008 Adis Data Information BV. All rights reserved. Effect of Switching Drug Formulations from Immediate-Release to Extended-Release OROS Methylphenidate A Chart Review of Spanish Adults with Attention-Deficit Hyperactivity Disorder Josep Antoni Ramos-Quiroga,1,2 Rosa Bosch,1 Xavier Castells,1,3 Sergi Valero,1 Mariana Nogueira,1 Nuria Gómez,1 Silvia Yelmo,1 Marc Ferrer,1,2 Yolanda Martínez1 and Miguel Casas1,2 1 Adult ADHD Program, Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain 2 Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain 3 Clinical Pharmacology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain Abstract Background: The potential advantages of osmotic-release oral system (OROS) methylphenidate (Concerta®) over immediate-release (IR) methylphenidate (Rubifen®) in adults with attention-deficit hyperactivity disorder (ADHD), with respect to medication adherence, effectiveness and tolerability, are yet to be determined. Objective: To compare the adherence, effectiveness and tolerability of OROS methylphenidate versus IR methylphenidate in adults with ADHD. It was hypothesized (after data collection) that adherence and effectiveness would be higher with OROS methylphenidate than with the IR formulation. Study design: A chart review was carried out from April 2004 until April 2005. Setting: Adult ADHD outpatient program in a general hospital in Spain. Patients: Seventy adults with ADHD who met DSM-IV-TR criteria and who did not have any other current major psychiatric disorder. Intervention: Patients were treated with IR methylphenidate three times daily for 3 months and then switched to OROS methylphenidate once daily. Main outcome measure: Effectiveness was assessed by means of the ADHD rating scale-IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale at 3 months (coinciding with treatment switch) and at 6 months. The Simplified Medication Adherence Questionnaire (SMAQ) was used to assess treatment adherence, and was administered at both 3 and 6 months. Results: Seventy adult ADHD patients (mean age ± SD: 30 ± 9.6 years; n = 48 men [68.6%]) were included in this study. The mean baseline ADHD-RS-IV score was 34.6 (SD = 10.9). The mean daily dose of IR methylphenidate was 52.1 mg Ramos-Quiroga et al. 604 (SD = 13.8 mg) administered as three divided doses. After the treatment switch, the mean OROS methylphenidate daily dose was 57.9 mg (SD = 16.5 mg) administered once daily. The switch from IR methylphenidate to OROS methylphenidate was associated with a statistically significant improvement in all items of the SMAQ questionnaire. OROS methylphenidate was more effective than IR methylphenidate (p = 0.0005) in reducing symptoms of ADHD. The percentage of responders was 28.6% with IR methylphenidate and 91.4% with the OROS formulation (p = 0.0005). OROS methylphenidate was preferred by 97% of patients. The most common adverse events for each formulation were dry mouth (30% IR methylphenidate) and mood instability (31% OROS methylphenidate). No patients stopped treatment with methylphenidate because of adverse events. Conclusions: The switch from IR to OROS methylphenidate was associated with an improvement in both adherence and effectiveness. There were no differences between IR and OROS methylphenidate in terms of tolerability. Background Attention-deficit hyperactivity disorder (ADHD) is a chronic, disabling condition that is most commonly diagnosed in childhood but continues on into adulthood for many patients affected in childhood.[1] It has a worldwide prevalence rate of 8–12% in children[2] and 1.2–7.3% in adults.[3] The average prevalence rate in adults is 2–4%.[2,4,5] In adults, ADHD impairs multiple aspects of functioning, such as interpersonal relationships, academic performance and occupational status.[6] Furthermore, it increases the risk of motor vehicle accidents,[7] comorbid substance abuse disorders[8] and legal problems.[6] Stimulants are the gold-standard treatment of ADHD in children[9-11] and have also proven effective for adults in controlled clinical trials.[12-15] Methylphenidate is one of the most commonly prescribed and extensively researched pharmacological treatments of ADHD.[16] However, methylphenidate has a short half-life and requires administration up to three times daily. This administration schedule often leads to limited treatment adherence, resulting in a reduction of stimulant effectiveness. The chronic nature of ADHD, together with the importance of the drug administration schedule, makes adherence a crucial issue for stimulant effectiveness in this 1 disorder. Non-adherence rates have been estimated to be between 20% and 65% in children with ADHD,[17] but are unknown in adults. Adherence is inversely related to the number of tablets or capsules ingested daily, and can therefore be improved by reducing the frequency of dosage.[18,19] During the past several years, different oncedaily drug formulations have become available. Among these new formulations, only the osmoticrelease oral system (OROS) methylphenidate (Concerta®)1 formulation has been introduced in Spain. In children and adolescents with ADHD, the OROS formulation has proven effective,[20-22] has been shown to improve treatment adherence,[22-24] and patients can be effectively and safely switched to this formulation from the immediate-release (IR) formulation.[25] Since the introduction of OROS methylphenidate to the market, many adults treated with the IR formulation were switched to the OROS formulation because it was expected to be at least as effective as the IR formulation but to also have the additional benefit of improving adherence because of its less frequent administration. However, no study has yet been conducted to assess whether this easier administration does improve adherence. The use of trade names is for product identification purposes only and does not imply endorsement. © 2008 Adis Data Information BV. All rights reserved. CNS Drugs 2008; 22 (7) Methylphenidate Formulation Switch in Adult ADHD This study took advantage of the partially standardized clinical protocol (which was in force until April 2005) at the Hospital Universitari Vall d’Hebron, Barcelona, Spain, to investigate whether the switch from IR to OROS methylphenidate increased drug adherence, resulting in improved effectiveness and tolerability. Patient preference was also assessed. Methods Study Design The Adult ADHD Program of the Psychiatry Department of Hospital Universitari Vall d’Hebron, Barcelona, Spain, follows a clinical protocol approved by the Institutional Review Board, and is updated as significant new assessment tools or treatments become available. This specific and partially standardized procedure made it possible to carry out a chart review for those patients who decided to change to OROS methylphenidate from the time it was introduced to the Spanish market in April 2004 until April 2005, when OROS methylphenidate became the first-line treatment for adults with ADHD in this program. Patients Charts were selected only if patients met the following inclusion criteria: DSM-IV diagnosis of ADHD; no other current major psychiatric disorders; no history of previous treatment for ADHD; and having switched from IR methylphenidate to OROS methylphenidate. Seventy patients fulfilled the inclusion criteria and were included in the analysis. The diagnostic and baseline assessment protocol of the Adult ADHD Program is comprised of a psychiatric evaluation, structured diagnostic interviews and a neuropsychological battery of tests. The Conners Adult ADHD Diagnostic Interview for the DSM-IV[26] and the Structured Clinical Interviews I and II for DSM-IV (SCID-I and SCID-II)[27,28] were used to confirm the diagnoses of ADHD in adulthood. All patients were evaluated by an experienced psychiatrist (Drs Ramos-Quiroga, Gómez, Yelmo or © 2008 Adis Data Information BV. All rights reserved. 605 Ferrer) and one of three clinical psychologists (Drs Bosch, Nogueira or Martínez). Treatment The psychopharmacological treatment protocol of the Adult ADHD Program adapted international guidelines[11] to suit the Spanish pharmaceutical market, and established methylphenidate as the drug of choice unless contraindicated. When the OROS methylphenidate formulation was introduced in Spain in 2004, the Adult ADHD Program developed the following two-step methylphenidate treatment. During the first 3 months of treatment, patients were treated with IR methylphenidate (Rubifen®) three times daily. IR methylphenidate was titrated over the first few days of treatment until a target dosage of 1.0 mg/kg/day was reached.[29] In patients who did not tolerate this target dosage, the dosage was lowered to suit the patient. Once stabilized, patients were maintained at a fixed dosage. After 3 months, the patient could be switched to once-daily OROS methylphenidate (Concerta®) in order to simplify the administration schedule. Because the IR methylphenidate formulation is available in 5, 10 and 20 mg doses, and OROS methylphenidate is only available in 18, 36 and 54 mg doses, the following conversion rule was applied: a 15 mg dose of IR methylphenidate was substituted with an 18 mg dose of OROS methylphenidate.[30] However, the dose could be decreased if significant adverse effects were experienced after the switch from the IR formulation to the OROS formulation. These adjustments were based on clinical judgement. The commercially available methylphenidate formulations, manufactured by JanssenCilag (Concerta®) and Rubió Laboratories (Rubifen®), were financed by the Spanish health system. Assessments The follow-up assessment included an evaluation at 3 months after the optimal dose of medication had been established to ensure continuity of effectiveness and adherence. It included the ADHD Rating Scale-IV (ADHD-RS-IV),[31] the Clinical Global CNS Drugs 2008; 22 (7) Ramos-Quiroga et al. 606 Impression-Improvement (CGI-I) scale[32] and the Simplified Medication Adherence Questionnaire (SMAQ).[33] The same follow-up assessment was performed at 6 months. The diagnostic reliability between raters was excellent; a κ of 1.0 was obtained for the ADHD-RS-IV and CGI-I, with a 95% CI of 0.8, 1.0. The SMAQ is a physician-rated questionnaire comprising the following six items: 1. Do you ever forget to take your medicine? 2. Are you careless at times about taking your medicine? 3. Sometimes if you feel worse, do you stop taking your medicine? 4. Thinking about the last week, how many times have you not taken your medicine? 5. Did you not take any of your medicine over the past weekend? 6. Over the past 3 months, how many days have you not taken any medicine at all? Item 6 was used to determine the proportion of noncompliant patients. Those patients who reported taking no methylphenidate tablets for ≥5 days, ≥10 days and ≥20 days over the past 3 months were defined as mildly, moderately and highly noncompliant, respectively. Medication preference was assessed at 6 months. The study physician directly asked patients “In your opinion, which methylphenidate would you prefer to take from now on, IR methylphenidate or OROS methylphenidate?” Treatment responders were defined as patients who showed a ≥30% improvement in their ADHDRS-IV score compared with baseline. Statistical Analysis Changes in both qualitative and quantitative variables from baseline were assessed at 3 and 6 months by means of the McNemar and Wilcoxon tests, respectively. A multiple regression analysis was used to assess the effects of the independent variables on effectiveness. Results are reported with a 95% confidence interval, and p-values were twotailed. All statistical analyses were performed using SPSS v.14 (SPSS Inc., Chicago, IL, USA). © 2008 Adis Data Information BV. All rights reserved. Results Baseline data were collected on 48 male and 22 female patients. No patients withdrew from the study. Mean age was 30 years (SD = 9.6 years) and baseline weight was 71.4 kg (SD = 14.3 kg). The most common disorder subtype was ADHD combined type (65%), followed by predominantly inattentive type (29%) and predominantly hyperactiveimpulsive type (6%). Mean baseline ADHD-RS-IV score was 34.6 (SD = 10.9). The mean daily dose of IR methylphenidate was 52.1 mg (SD = 13.8 mg) administered as three divided doses. After the treatment switch, the mean OROS methylphenidate daily dose was 57.9 mg (SD = 16.5 mg) administered once daily. The administered dose of methylphenidate was higher for the OROS formulation than for the IR formulation because the two formulations do not have equivalent dosages. Medication Adherence As shown in table I, the switch from IR to OROS methylphenidate was associated with an improvement in all items of the SMAQ questionnaire, indicating better adherence to the OROS formulation. Adherence to OROS was superior during working days as well as during the weekend. Moreover, the number of days no medicine was taken at all was 7-fold higher with IR methylphenidate than OROS methylphenidate. In addition, the proportion of mildly, moderately and highly noncompliant patients was 37.1%, 11.4% and 4.7%, respectively, while taking IR methylphenidate, and 2.9%, 0% and 0%, respectively, while receiving the OROS formulation. Thus, although the prescribed dose was only slightly higher with the OROS formulation, because patients were significantly more adherent to this formulation, the adherence was likely to account for more of the difference in the amount of drug taken than the difference in prescribed dose. Effectiveness Not surprisingly, while both methylphenidate formulations were found to be effective in the treatment of adults with ADHD, as assessed by either the CNS Drugs 2008; 22 (7) Methylphenidate Formulation Switch in Adult ADHD 607 Table I. Comparison of medication adherence, effectiveness and satisfaction between immediate-release (IR) methylphenidate and osmotic-release oral system (OROS) methylphenidate in adult attention-deficit hyperactivity disorder (ADHD) Outcome IR methylphenidate (n = 70) OROS methylphenidate (n = 70) p-Value Mean (SD) daily dose [mg] 52.1 (13.8) 57.9 (16.5) 0.0005 Patients reporting at least one missed dose (%) [SMAQ item 1] 91.4 22.9 0.0005 Patients reporting not taking medication at the scheduled time (%) [SMAQ item 2] 45.7 25.7 0.044 Patients reporting not taking medication when feeling worse (%) [SMAQ item 3] 17.1 2.9 0.002 Patients reporting at least one missed dose during the previous week (%) [SMAQ item 4] 88.6 20.0 0.0005 Patients reporting not taking any medicine over the previous weekend (%) [SMAQ item 5] 74.3 20.0 0.0005 Mean (SD) days no medicine was taken over the previous 3 months [SMAQ item 6] 4.66 (6.25) 0.66 (1.56) 0.0005 Mildly noncomplianta (%) 37.1 2.9 NA Moderately noncompliantb (%) 11.4 0 Highly noncompliantc (%) 4.7 0 Adherence to treatment Noncompliance Effectiveness ADHD-RS-IVd [mean (SD)] 25.1 (9.1) 15.1 (7.2) 0.0005 CGI-I (patient rating) [mean (SD)] 2.83 (0.82) 1.57 (0.55) 0.0005 CGI-I (physician rating) [mean (SD)] 2.80 (0.83) 1.57 (0.55) 0.0005 Treatment responders (%)e 28.6 91.4 0.0005 97 NA Preference (%)f a 3 Patients reported taking no methylphenidate for ≥5 days in the previous 3 months. b Patients reported taking no methylphenidate for ≥10 days in the previous 3 months. c Patients reported taking no methylphenidate for ≥20 days in the previous 3 months. d Baseline mean (SD) ADHD-RS-IV was 34.6 (10.9). e Responders were those patients showing a ≥30% improvement in their ADHD-RS-IV score compared with baseline. f Patients preferring each formulation. ADHD-RS-IV = ADHD Rating Scale-IV;[31] CGI-I = Clinical Global Impression-Improvement scale;[32] NA = not applicable; SMAQ = Simplified Medication Adherence Questionnaire.[33] ADHD-RS-IV or the CGI-I, the OROS formulation proved to be more effective than the IR formulation irrespective of the assessment instrument (see table I). Furthermore, nearly all patients (97%) preferred OROS methylphenidate. When controlled for in the multivariate analysis, the methylphenidate dose did not affect the differences found between treatment groups with regard to adherence, preference or effectiveness. Since patients receiving IR methylphenidate were primarily non-adherent (88.6% reported at least one missed dose during the previous week) and patients receiving OROS methylphenidate were mostly adherent (80.0% reported no © 2008 Adis Data Information BV. All rights reserved. missed doses in the previous week), treatment effectiveness could not be adjusted for adherence. Tolerability Both formulations were well tolerated and no patients stopped methylphenidate due to adverse events. The most common adverse events with IR and OROS methylphenidate were headache (21% vs 26%), decreased appetite (24% vs 20%), tachycardia (13% vs 27%), abdominal complaints (18% vs 23%), dry mouth (30% vs 28%), mood instability (20% vs 31%) and insomnia (21% vs 18%). None of these differences were statistically significant. CNS Drugs 2008; 22 (7) Ramos-Quiroga et al. 608 Discussion The switch from IR methylphenidate three times daily to OROS methylphenidate once daily in adults with ADHD was associated with an improvement in treatment adherence and was preferred by most patients. In addition, both methylphenidate formulations were effective for the treatment of adults with ADHD, although the OROS formulation was superior to the IR formulation. These findings raise the question of whether the superior adherence of OROS methylphenidate is due to its greater effectiveness, or whether its superior effectiveness is due to its better adherence. The improved treatment adherence with OROS methylphenidate was shown by an improvement on all items of the SMAQ questionnaire. The mean number of days no medicine was taken over the past 3 months (SMAQ item 6) was 7-fold higher with IR methylphenidate (4.66) than with the OROS formulation (0.66). Frequency of dose and price are two factors that could explain the difference in adherence rates between the two methylphenidate formulations.[19] Because of its once-daily dosage, the OROS formulation is simpler to take, which may partly explain its higher rate of adherence; however, it is more expensive than the IR formulation, which could also potentially affect adherence. Because the Spanish National Health System pays 60% of all pharmaceutical expenses, cost is a variable that likely has relatively limited impact on patient adherence in Spain, relative to that in countries that have a health system policy in which patients must pay for a considerable amount of their medication expenses. Our findings relating to higher adherence, effectiveness and satisfaction with the OROS formulation were similar to those previously reported in children.[22] The greater effectiveness of the OROS formulation compared with the IR formulation is likely explained by its higher adherence (80% of patients taking OROS methylphenidate and 11.4% of patients taking IR methylphenidate reported no missed doses in the previous week). It was not possible to conduct an analysis of formulation effectiveness adjusted for adherence to determine whether the greater effectiveness of the OROS formula© 2008 Adis Data Information BV. All rights reserved. tion was due to greater adherence or to a better pharmacokinetic profile because these two factors are interdependent. Another possible explanation for the difference in effectiveness could have been the difference in dosages between the two formulations; however, this was not the case, as can be seen from the multivariate analysis. Finally, the superior effectiveness of the OROS formulation could also be explained by a time effect, because the IR formulation was always administered prior to the OROS formulation; however, this seems unlikely because of the relatively brief period of time required to achieve a therapeutic effect with methylphenidate. It is striking to note that, in our study, the percentage of responders was 28.6% for IR methylphenidate and 91.4% for the OROS formulation, in contrast to the 75–80% of responders previously reported in several controlled clinical trials for both IR and OROS methylphenidate.[13,14,34] Moreover, although no direct, head-to-head comparisons between IR and OROS methylphenidate exist, one study combining data from two placebo-controlled trials with OROS and IR methylphenidate found no difference in efficacy between these two formulations.[35] However, Biederman et al.[35] found no difference in adherence to treatment. In our study, adherence was notably higher with OROS methylphenidate and, consequently, efficacy was also higher. One explanation could be that, in controlled clinical trials, adherence is a requirement and is comprehensively monitored, and noncompliant patients are frequently withdrawn from the study. This results in high adherence and efficacy, but low external validity because, in real clinical settings, as in this naturalistic study, although patients are advised to follow the recommendations of the physician, they are not withdrawn from medical assistance if they are noncompliant. As in the controlled clinical trials, our study showed that OROS methylphenidate resulted in high adherence and effectiveness. Conversely, unlike results from controlled clinical trials, missed doses were common while taking IR methylphenidate in our study, resulting in a low response rate and low effectiveness. This suggests that the controlled clinical trials have greater exterCNS Drugs 2008; 22 (7) Methylphenidate Formulation Switch in Adult ADHD nal validity with the OROS formulation than with the IR formulation. The lower adherence rates that we found for IR methylphenidate may explain its lower effectiveness in this study compared with those reported in the controlled clinical trials.[13,14,34] It was not surprising that almost all patients preferred the OROS formulation as it was simpler to take, resulting in better adherence, yielding higher methylphenidate intake and thus resulting in higher effectiveness, while having a similar tolerability profile. Finally, our study shows that both methylphenidate formulations were well tolerated, and only dose-related adverse events were observed. Adverse events were mild and no patient discontinued treatment. No patients abused methylphenidate, regardless of the formulation. Although no statistically significant differences in the percentage of patients experiencing adverse events were found between the two methylphenidate formulations, it is notable that reports of tachycardia and mood instability were numerically more common in patients taking OROS methylphenidate. This finding could be interpreted as a consequence of higher adherence to the OROS formulation, resulting in a higher methylphenidate intake and thus more frequent adverse events, but a controlled study should be carried out to confirm this hypothesis. This study had a naturalistic design, and the foundation for reports of preference of medication formulation, medication adherence and response to treatment were obtained in a nonblinded fashion and were thus potentially subject to reporter bias. Therefore, several limitations should be considered when interpreting these results. Firstly, because this was a single-centre study, the external validity is limited and caution must be exercised in generalizing the results. Secondly, the results on adherence must also be considered with caution, since the adherence assessment was based on self-report and not on direct and objective measures such as methylphenidate blood concentrations. However, inaccuracy of patient reports of adherence would be expected to affect the results of both treatment groups in a similar manner. Finally, the fact that drug adminis© 2008 Adis Data Information BV. All rights reserved. 609 tration and clinical assessments were not blinded may have influenced our findings. However, it is unlikely that bias explains the considerable adherence, efficacy and preference differences between the IR and the OROS methylphenidate formulations that were found in this study. Nevertheless, since the main aim of this study was to compare adherence between two methylphenidate formulations that differed in their administration schedules, it was essential to maintain a naturalistic design that kept a three-times-daily and once-daily administration schedule for the IR and OROS formulations, respectively. The use of a double-dummy design would not allow for the assessment of differences in adherence between the two formulations because all patients would have received a three-times-daily administration to allow for blinding. Conclusions Methylphenidate can be effectively and safely switched from an IR formulation to an OROS formulation in adults with ADHD within the clinical setting. This switch is associated with greater medication adherence. Both OROS and IR methylphenidate formulations are effective and well tolerated for the treatment of ADHD in adults, although the OROS formulation appeared to be more effective in this study. It should be noted that OROS and IR methylphenidate are not approved in Spain or in any other European nation for the treatment of ADHD in adults. Additional studies are necessary to clarify if OROS methylphenidate can be considered first-line treatment for ADHD in adults. Acknowledgements This study was presented at the official symposium on ‘Adult ADHD’ at the World Psychiatry Association International Congress, which was held on 12–16 July 2006 in Istanbul, Turkey. This study was supported in part by a nonrestricted grant from the Generalitat de Catalunya (Departament de Salut) and the Fundació La Caixa (PAI-TLP 2006). It has also been supported by a grant from the Spanish Ministry of Education (Fondo de Investigaciones Sanitarias Instituto Carlos III FIS PI04/0524) and a scholarship from the Spanish Ministry of Health awarded to Xavier Castells, MD (ISCIII: 300056). The authors are grateful to Yolanda Santaella, Ira CNS Drugs 2008; 22 (7) Ramos-Quiroga et al. 610 Potashner and Amy Larabel for their support in the preparation of this manuscript. Dr Ramos-Quiroga and Dr Casas have received honoraria for being speakers for and have been on the advisory boards of Laboratorios Rubió and Janssen-Cilag. Dr Marc Ferrer has received honoraria for being a speaker for and has been on the advisory board of Janssen-Cilag. All other authors have no conflicts of interest that are directly relevant to the content of this study. References 1. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet 2005; 366 (9481): 237-48 2. Faraone SV, Biederman J. What is the prevalence of adult ADHD? Results of a population screen of 966 adults. J Atten Disord 2005; 9 (2): 384-91 3. Fayyad J, De Graaf R, Kessler R, et al. Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. Br J Psychiatry 2007 May; 190: 402-9 4. 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Structured clinical interview for DSM-IV axis II personality disorders (SCID-II). Washington, DC: American Psychiatric Press, Inc., 1997 29. Faraone SV, Spencer T, Aleardi M, et al. Meta-analysis of the efficacy of methylphenidate for treating adult attention-deficit/ hyperactivity disorder. J Clin Psychopharmacol 2004; 24 (1): 24-9 30. Concerta® (methylphenidate HCl) extended-release tablets CII [online]. Available from URL: http://www.fda.gov/cder/foi/ label/2007/021121s014lbl.pdf. [Accessed 2007 Nov 12] 31. DuPaul GJ. ADHD rating scale-IV: checklists, norms, and clinical interpretation. New York: Guilford Press, 1998 32. Guy W. Early Clinical Drug Evaluation (ECDEU) assessment manual. Rockville (MD): National Institute of Mental Health, 1976 CNS Drugs 2008; 22 (7) Methylphenidate Formulation Switch in Adult ADHD 33. Knobel H, Alonso J, Casado JL, et al. Validation of a simplified medication adherence questionnaire in a large cohort of HIVinfected patients: the GEEMA Study. Aids 2002; 16 (4): 605-13 34. 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 Jun; 52 (6): 434-43 35. Biederman J, Mick EO, Surman C, et al. Comparative acute efficacy and tolerability of OROS and immediate release for- © 2008 Adis Data Information BV. All rights reserved. 611 mulations of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder. BMC Psychiatry 2007; 7: 49 Correspondence: Dr Josep Antoni Ramos-Quiroga, Servei de Psiquiatria, Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron no. 119-129, Barcelona 08035, Spain. E-mail: jaramos@vhebron.net CNS Drugs 2008; 22 (7)