Long-Acting Methylphenidate Formulations in the Treatment of Attention-Deficit/Hyperactivity Disorder

A Systematic Review of Head-to-Head Studies

David Coghill; Tobias Banaschewski; Alessandro Zuddas; Antonio Pelaz; Antonella Gagliano; Manfred Doepfner

BMC Psychiatry. 2013;13(237)

Abstract

Background The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed.

The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection.

Methods A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included.

Results Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study.

Conclusions Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation. No formulation is clearly superior to another; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment. For patients achieving suboptimal symptom control, switching long-acting MPH formulations may be beneficial. When switching formulations, it is usually appropriate to titrate the immediate-release component of the formulation; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components. Further studies are necessary to provide guidance in clinical practice, particularly in the treatment of adults and pre-school children and the impact of comorbidities and symptom severity on treatment response.

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Table 1. Summary of long-acting methylphenidate (MPH) formulations
MPH formulation	Synonyms	Product availability	Modified-release technology	Immediate-release: extended-release ratio (%)	Duration of action^a
Biphentin®[10]	MPH ER	Canada	Multilayer-release (MLR) bead formulation	40:60	Not stated: biphasic delivery profile
Concerta®[12]	Concerta extended release; Concerta® LP; methylphenidate hydrochloride; OROS MPH	Africa^b, Asia^c, Australia, Europe^d, New Zealand, North America^e, South America^f	OROS® (Osmotic Release Oral System)	22:78	12 hours
Daytrana®[13]	MPH transdermal system; MethyPatch; MTS	USA	Transdermal patch	Continuous delivery	9 hours
Equasym XL®[11]	Equasym Depot®; Equasym Retard®, Equasym XR®, Quasym LP®; Metadate CD®; Metadate ER®	Europe^g, South Korea, USA	Diffucaps®	30:70	8 hours
Focalin XR®[7]	D-MPH-ER	Switzerland, USA^h	SODAS® (Spheroidal Oral Drug Absorption System)	50:50	Not stated: two distinct peaks approximately 4 hours apart
Medikinet® retard [9]	Medikinet®; Medikinet® CR; Medikinet® EM; Medikinet® MR; Medikinet® XL	Europeⁱ, Israel, Korea, South America^j	Modified-release capsules	50:50	8 hours
Ritalin LA®[6]	Ritalin LP®; Miacalcic	France, Chile, USA^h	SODAS® (Spheroidal Oral Drug Absorption System)	50:50	Not stated: two distinct peaks approximately 4 hours apart
Ritalin SR®[5]	n/a	Canada, USA^h	Wax matrix	Continuous release	8 hours

^aDuration of action as stated in the prescribing information.
^bBotswana, Brazil, Egypt, Namibia, Nicaragua, South Africa.
^cBahrain, China, Hong Kong, Indonesia, Israel, Japan, Jordan, Republic of Korea, Kuwait, Lebanon, Malaysia, Oman, Philippines, Qatar, Saudi Arabia, Singapore, Taiwan Province of China, United Arab Emirates, Yemen.
^dAustria, Belgium, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Iceland, Ireland, Latvia, Lichtenstein, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, UK.
^eBahamas, Barbados, Canada, Cayman Islands, Dominican Republic, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Trinidad and Tobago, USA.
^fArgentina, Aruba, Bolivia, Chile, Columbia, Costa Rica, Ecuador, Panama, Paraguay, Peru, Uruguay, Venezuela.
^gDenmark, Finland, France, Germany, Ireland, the Netherlands, Norway, Sweden, Switzerland, UK.
hInformation obtained from Thomson Cortellis^TM.
ⁱAustria, Belgium, Cyprus, Denmark, Estonia, Finland, France, Germany, Ireland, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, UK.
^jArgentina, El Salvador, Guatemala, Honduras.

Table 2. Summary of articles identified in the literature search that compare ≥2 long-acting MPH formulations
Author, year	Long-acting MPH formulation and dosing^a	Sample size Age range	Diagnosis	Comorbid conditions	Outcome measures
Pharmacokinetic studies
Gonzalez et al., 2002 [20]	Concerta® (18, 36, 54 mg)	n = 36	Not applicable	Not stated	PK parameters for 24 hours post-dose, including bioequivalence
Gonzalez et al., 2002 [20]	Equasym XL® (20, 40, 60 mg)	21–40 years	Not applicable	Not stated
Haessler et al., 2008 [26]	Ritalin LA® (40 mg)	n = 28	Not applicable	Not stated	PK parameters for 24 hours post-dose, including bioequivalence
Haessler et al., 2008 [26]	Medikinet® retard (40 mg)	18–30 years	Not applicable	Not stated
Markowitz et al., 2003 [22]	Concerta® (18 mg)	n = 20	Not applicable	Not stated	PK parameters for 24 hours post-dose, including bioequivalence
Markowitz et al., 2003 [22]	Ritalin LA® (20 mg)	21–34 years	Not applicable	Not stated
Modi et al., 2000 [23]	Concerta® (18 mg)	n = 36	Not applicable	Not stated	PK parameters for 30 hours post-dose
Modi et al., 2000 [23]	Ritalin SR® (20 mg)	18–41 years	Not applicable	Not stated	PK parameters for 30 hours post-dose
Pierce et al., 2010 [24]	Concerta® (18, 27, 36, 54 mg)	n = 71	ADHD according to DSM-IV-TR criteria	Possibly ODD	PK properties of d,l-MPH after single, multiple, fixed and escalating doses of Concerta® and Daytrana®
Pierce et al., 2010 [24]	Daytrana® (10, 15, 20, 30 mg/9 hours)	6–17 years	ADHD according to DSM-IV-TR criteria	Possibly ODD
Reiz et al., 2008 [25]	Concerta® (18 mg)	n = 24	Not applicable	Not stated	PK parameters for 24 hours post-dose, including bioequivalence
Reiz et al., 2008 [25]	Biphentin® (20 mg)	19–25 years	Not applicable	Not stated
Schutz et al., 2009 [28]	Equasym XL® (20 mg)	n = 14	Not applicable	Not stated	PK parameters for 24 hours post-dose, including bioequivalence
Schutz et al., 2009 [28]	Medikinet® retard (20 mg)	22–43 years	Not applicable	Not stated
Spencer et al., 2010 [21]	Concerta® (36 mg)	n = 21	Not applicable	Not stated	PET imaging
Spencer et al., 2010 [21]	Equasym XL® (40 mg)	18–55 years	Not applicable	Not stated	PET imaging
Tuerck et al., 2007 [27]	Focalin XR® (20 mg)	n = 25	Not applicable	Not stated	PK parameters for 24 hours post-dose, including bioequivalence
Tuerck et al., 2007 [27]	Ritalin LA® (40 mg)	19–45 years	Not applicable	Not stated
Laboratory school studies
Lopez et al., 2003 [31]	Concerta® (18, 36 mg)	n = 36	ADHD according to C-DISC criteria	Not stated	SKAMP-Attention; SKAMP-Deportment; SKAMP-Combined; Math-Attempted; Math-Correct
Lopez et al., 2003 [31]	Ritalin LA® (20 mg)	6–12 years	ADHD according to C-DISC criteria	Not stated
Muniz et al., 2008 [33]	Concerta® (36, 54 mg)	n = 84	Combined-type ADHD (89%); Inattentive-type ADHD (11%) according to DSM-IV criteria, established by C-DISC	Not stated	SKAMP-Combined; SKAMP-Attention; SKAMP-Deportment; Math-Attempted; Math-Correct; CPRS
Muniz et al., 2008 [33]	Focalin XR® (20, 30 mg)	6–12 years		Not stated
Schulz et al., 2010 [38]	Ritalin LA® (20 mg)	n = 147	Combined-type ADHD (55%); Inattentive-type ADHD (37%); Hyperactive/impulsive-type ADHD according to DSM-IV criteria, confirmed by K-SADS	Disturbance in social behaviour (n = 4), initial insomnia (n = 2), ODD (n = 2), dysphemia (n = 1), encopresis (n = 1)	SKAMP-Combined; Math-Attempted; Math-Correct; NCBRF-TIQ
Schulz et al., 2010 [38]	Medikinet® retard (20 mg)	6–14 years			SKAMP-Combined; Math-Attempted; Math-Correct; NCBRF-TIQ
Silva et al., 2005 [32]	Concerta® (18 mg)	n = 54	Combined inattentive/hyperactive-type ADHD (70%); Inattentive-type ADHD (28%); Hyperactive/impulsive-type ADHD (2%) according to DSM-IV criteria	Not stated	SKAMP-Attempted; SKAMP-Deportment; SKAMP-Combined; Math-Attempted; Math-Correct
Silva et al., 2005 [32]	Ritalin LA® (20 mg)	6–12 years		Not stated
Silva et al., 2008 [18]	Concerta® (36, 54 mg) Focalin XR® (20, 30 mg)	n = 82 6–12 years	Combined-type ADHD (94%); Inattentive-type (6%) according to DSM-IV criteria	Not stated	SKAMP-Attention; SKAMP-Deportment; SKAMP-Combined; Math-Attempted; Math-Correct; CPRS
Sonuga-Barke et al., 2004 [34]	Concerta® (18, 36, 54 mg) Equasym XL® (20, 40, 60 mg)	n = 184 6–12 years	Combined-type (82%); Inattentive-type (13%); Hyperactive/impulsive-type (5%) according to DSM-IV criteria and confirmed by DISC	Comorbid condition (25%), including anxiety and ODD	Placebo-adjusted SKAMP-Combined
Post-hoc study of COMACS [37]
Sonuga-Barke et al., 2007 [35]	Concerta® (18, 36, 54 mg) Equasym XL® (20, 40, 60 mg)	n = 184 6–12 years	Females: Combined-type (77%); Inattentive-type (15%); Hyperactive/impulsive-type (8%). Males: Combined-type (84%); Inattentive-type (12.4%); Hyperactive/impulsive-type (4%)	Comorbid condition (25%), including anxiety and ODD	SKAMP-Combined; PERMP
Post-hoc study of COMACS [37]	Concerta® (18, 36, 54 mg) Equasym XL® (20, 40, 60 mg)	n = 184 6–12 years		Comorbid condition (25%), including anxiety and ODD	SKAMP-Combined; PERMP
Sonuga-Barke et al., 2008 [36]	Concerta® (18, 36, 54 mg)	n = 184	Combined-type (82%); Inattentive-type (13%); Hyperactive/impulsive-type (5%) according to DSM-IV criteria, confirmed by DISC	Comorbid condition (25%), including anxiety and ODD	GMM analysis
Sonuga-Barke et al., 2008 [36]	Equasym XL® (20, 40, 60 mg)	6–12 years
Post-hoc study of COMACS [37]	Equasym XL® (20, 40, 60 mg)	6–12 years
Swanson et al., 2004 [37]	Concerta® (18, 36, 54 mg)	n = 184	Combined-type (82%); Inattentive-type (13%); Hyperactive/impulsive-type (5%) according to DSM-IV criteria, confirmed by DISC	Comorbid condition (25%), including anxiety and ODD	SKAMP-Attention; SKAMP-Deportment; PERMP
Swanson et al., 2004 [37]	Equasym XL® (20, 40, 60 mg)	6–12 years
COMACS study	Equasym XL® (20, 40, 60 mg)	6–12 years
Randomized controlled trials
Doepfner et al., 2011 [42]	Concerta® (18, 36 mg)	n = 113	Combined-type ADHD according to DSM-IV, confirmed by interview (DCL-ADHD)	ODD or conduct disorder (36%)	SKAMP-D; DAYAS; FBB-ADHD
Doepfner et al., 2011 [42]	Medikinet® retard (10, 20, 30 mg)	6–16 years		ODD or conduct disorder (36%)	SKAMP-D; DAYAS; FBB-ADHD
Findling et al., 2008 [43]	Concerta® (18, 27, 36, 54 mg)	n = 282	Combined-type ADHD (71–86%); Inattentive-type ADHD (11–26%); Hyperactive/impulsive-type ADHD (1–2%) according to DSM-IV-TR criteria	Possibly ODD	ADHD-RS-IV mean total score; CTRS-R; CPRS-R; CGI–S; CGI–I; PGA; MPH plasma concentrations at 7.5, 9 and 10 hours post-dose
Findling et al., 2008 [43]	Daytrana® (10, 15, 20, 30 mg)	6–12 years		Possibly ODD
Switching studies
Arnold et al., 2010 [46]	Concerta® (18, 27, 36, 45, 54 mg)	n = 171	Combined-type ADHD (77%); Inattentive-type ADHD (21%); Hyperactive/impulsive -type ADHD (2%) according to DSM-IV-TR criteria	Possibly ODD	ADHD-RS-IV mean total scores; CGI–I; PGA, CPRS-R; CGI–S
	Ritalin LA® (10, 20, 30, 40, 50 mg)	6–12 years
	Equasym XL® (10, 15, 20, 30, 40, 50 mg)
	Daytrana® (10, 15, 20, 30 mg)
Bukstein et al., 2009 [47]	Concerta® (18, 27, 36, 45, 54 mg)	n = 171	See Arnold et al., 2010 [46]	Possibly ODD	AIM-C; MSS
	Ritalin LA® (10, 20, 30, 40, 50 mg)	6–12 years
	Equasym XL® (10, 15, 20, 30, 40, 50 mg)
	Daytrana® (10, 15, 20, 30 mg)
Dirksen et al., 2002 [48]	Equasym XL® (20, 40, 60 mg)	n = 308	ADHD according to DSM-IV criteria (diagnostic code 314.01)	Not stated	CGI–I; CGI–S; CGI-Efficacy Index
	Concerta® (18, 36, 54, 72 mg)	6–17 years
	Other long-acting MPH (excluding Concerta®; dose not stated)	6–17 years
Observational studies
Doepfner et al., 2011 [49]	Equasym XL® (10–120 mg)	n = 822	Disturbance of activity/attention (F90.0; 55%); hyperkinetic conduct disorder (F90.1; 36%); other hyperkinetic disorders (F90.8; 8%) according to ICD-10 criteria	Not stated	CGI–S; CGI–I; FBB-ADHD; DAYAS; SDQ-P
Doepfner et al., 2011 [49]	Other long-acting MPH (most commonly Medikinet® retard; approximately 0.85 mg/kg/day)	6–17 years
OBSEER study		6–17 years
Doepfner et al., 2011 [50]	Equasym XL® (10–120 mg)	n = 782	For total study sample (n = 822) see Doepfner et al., 2011 [49]	Not stated	FBB-ADHD; CGI–S; DAYAS; KINDL
Doepfner et al., 2011 [50]	Other long-acting MPH (mean [SD] 29.2 [11.28] mg)	6–17 years
Post-hoc study of OBSEER [49]	Other long-acting MPH (mean [SD] 29.2 [11.28] mg)	6–17 years
Rothenberger et al., 2011 [51]	See Doepfner et al., 2011 [49]	n = 822 6–17 years	See Doepfner et al., 2011 [49]	Not stated	KINDL; SAMS
Post-hoc study of OBSEER [49]	See Doepfner et al., 2011 [49]	n = 822 6–17 years	See Doepfner et al., 2011 [49]	Not stated	KINDL; SAMS
Meta-analyses
Faraone et al., 2006 [55]	Equasym XL®; Ritalin LA®;	n = 29 articles			Effect size expressed as SMD
Faraone et al., 2006 [55]	Concerta®; Daytrana®	Children and adolescents			Effect size expressed as SMD
Faraone and Buitelaar, 2010 [56]	Equasym XL®; Ritalin LA®;	n = 23 articles			Effect size expressed as SMD
Faraone and Buitelaar, 2010 [56]	Concerta®; Daytrana®	Children and adolescents			Effect size expressed as SMD
Faraone and Glatt, 2010 [57]	Concerta®;	n = 18 articles			Effect size expressed as SMD
Faraone and Glatt, 2010 [57]	Focalin XR®	Adults			Effect size expressed as SMD
Peterson et al., 2008 [58]	Concerta®;	n = 22 articles			Ratio of relative risks
Peterson et al., 2008 [58]	Focalin XR®	Adults			Ratio of relative risks
Systematic reviews
Banaschewski et al., 2006 [52]	Concerta®; Ritalin LA®; Equasym XL®; Medikinet® retard	Not stated			Effect size expressed as SMD
Brams et al., 2008 [53]	Concerta®; Daytrana®; Focalin XR®; Equasym XL®; Ritalin LA®	n = 18 articles			SKAMP, CADS-T, IOWA Conners' Rating Scale, ADHD-RS-IV, PERMP, CGIS-T
Brams et al., 2008 [53]	Concerta®; Daytrana®; Focalin XR®; Equasym XL®; Ritalin LA®	Children and adolescents
Brams et al., 2010 [19]	Concerta®; Focalin XR®; Equasym XL®; Ritalin LA®	n = 15 articles			PERMP
Brams et al., 2010 [19]	Concerta®; Focalin XR®; Equasym XL®; Ritalin LA®	Children, adolescents and adults			PERMP
Swanson et al., 2002 [54]	Concerta®; Equasym XL®; Ritalin LA®	Not stated			SKAMP, 10-Minute Math Test, PK measures, effect size

ADHD, attention deficit hyperactivity disorder; ADHD-RS-IV, ADHD Rating Scale-version IV; AIM-C, ADHD Impact Module-Children; C-DISC, Diagnostic Interview Schedule for Children 1997; CADS-T, Conners' ADHD/DSM-IV Scale for teachers; CGI-I, Clinical Global Impressions-Improvement; CGI-S, Clinical Global Impressions-Severity of Illness; CGIS-T, Conners' Global Index Scale for teachers; CPRS, Conners' Parent Rating Scale; CTRS-R, Conner's Teacher Rating Scale-Revised; DAYAS, Day Profile of ADHD Symptoms; DCL, Diagnostic Checklist for ADHD; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition, Text Revision; FBB-ADHD, Fremdbeurteilungsbogen für Aufmerksamkeitsdefizit-Hyperaktivitätsstörung (German symptom checklist for attention deficit hyperactivity disorder); GMM, Growth Mixture Modelling; ICD-10, International Classification of Diseases, version 10; KINDL, Kinder Lebensqualitatsfragebogen; IOWA, Inattention/Overactivity With Aggression; K-SADS, Kiddie Schedule for Affective Disorders and Schizophrenia; MPH, methylphenidate; MSS, Medication Satisfaction Survey; NCBRF-TIQ, Nisonger Child Behaviour Rating Form; ODD, oppositional defiant disorder; PERMP, permanent product measure of performance; PET, Positron Emission Tomography; PGA, Parent Global Assessment; PK, pharmacokinetic; SAMS; Satisfaction with Medication Scale; SD, Standard deviation; SDQ-P, Strengths and Difficulties Questionnaire for Parents; SKAMP, Swanson, Kotkin, Agler, M-Flynn and Pelham Rating Scale; SKAMP-D, German version of Swanson, Kotkin, Agler, M-Flynn and Pelham Rating Scale; SMD, Standard Mean Difference. aLong-acting stimulants other than methylphenidate have not been included.

Table 3. Pharmacokinetic parameters across the day for head-to-head pharmacokinetic studies (presented for single-dose comparison only)
	C_max, ng/mL			T_max, hours			AUC, ng • h/mL
	C_max0–4	C_max4–10	C_max	T_max0–4	T_max4–10	T_max	AUC_0–4	AUC_4–10	AUC_0–∞
Gonzalez et al., 2002 [20] (fasted state)
Concerta®	–	–	–	–	–	–	6.28	–	36.43
(18 mg)							(2.65)		(13.50)
Equasym XL®	–	–	–	–	–	–	10.01	–	39.74
(20 mg)							(3.06)		(11.75)
Concerta®	–	–	–	–	–	–	11.88	–	94.05
(36 mg)							(5.86)		(44.51)
Equasym XL®	–	–	–	–	–	–	20.36	–	98.49
(2 × 20 mg)							(8.74)		(52.05)
Concerta®	–	–	–	–	–	–	18.81	–	143.38
(54 mg)							(7.18)		(64.83)
Equasym XL®	–	–	–	–	–	–	32.01	–	145.34
(3 × 20 mg)							(13.09)		(65.21)
Haessler et al., 2008 [26] (fed state)
Ritalin LA®	11.8	12.8	13.3	–	–	–	33.5	57.8	126.8
(40 mg)	(3.95)	(4.13)	(4.04)				(11.07)	(16.91)	(34.5)
Medikinet® retard	16.5	18.3	19.6	–	–	–	42.4	68.0	141.5
(40 mg)	(6.69)	(5.66)	(5.95)				(16.54)	(19.47)	(38.3)
Haessler et al., 2008 [26] (fasted state)
Ritalin LA®	10.0	14.5	14.5	–	–	–	27.6	57.1	114.1
(40 mg)	(3.51)	(3.02)	(3.02)				(8.89)	(14.36)	(30.8)
Medikinet® retard	16.5	14.7	17.1	–	–	–	44.9	49.3	115.7
(40 mg)	(4.62)	(4.45)	(4.88)				(14.77)	(18.47)	(37.2)
Markowitz et al., 2003 [22] (fasted state)
Concerta®	3.4	–	5.9	3.3	–	6.0	9.3	–	66.9
(18 mg)	(44)^a		(37)^a	(36)^a		(28)^a	(51)^a		(49)^a
Ritalin LA®	7.0	–	9.9	2.1	–	5.5	18.5	–	78.7
(20 mg)	(47)^a		(41)^a	(48)^a		(15)^a	(44)^a		(54)^a
Modi et al., 2000 [23] (fasted state)
Concerta®	–	–	3.75	–	–	6.7	–	–	42.0
(18 mg)			(1.0)			(1.8)			(14)
Ritalin SR®	–	–	4.84	–	–	3.7	–	–	46.7
(20 mg)			(1.6)			(1.6)			(16)
Pierce et al., 2010 [24] (fasted state; age 6–12 years)
Concerta®	–	–	7.80	–	–	6.02	–	–	94.2
(18 mg)			(3.35)			(4.0–10.0)^b			(43.8)
Daytrana®	–	–	9.30	–	–	10.0	–	–	99.2
(10 mg/9 hours)			(3.60)			(8.0–12.0)^b			(42.9)
Pierce et al., 2010 [24] (fasted state; age 13–17 years)
Concerta®	–	–	4.95	–	–	8.0	–	–	60.1
(18 mg)			(1.42)			(1.0–10.0)^b			(16.3)
Daytrana®	–	–	4.15	–	–	10.0	–	–	48.7
(10 mg/9 hours)			(2.59)			(6.0–12.0)^b			(21.9)
Reiz et al., 2008 [25] (fed state)
Concerta®	3.33	4.09	4.13	2.51	5.86	4.96	8.77	26.29	48.21
(18 mg)	(1.03)	(1.01)^c	(1.01)	(1.15)	(1.61)^c	(2.56)	(3.37)	(5.57)^c	(9.79)
Biphentin®	4.8	4.73	5.07	2.26	6.02	3.71	12.35	28.57	54.01
(20 mg)	(1.39)	(1.09)^c	(1.32)	(0.64)	(1.26)^c	(2.03)	(3.78)	(6.68)^c	(13.11)
Schutz et al., 2009 [28] (fed state)
Equasym XL®	3.82	–	4.05	3.24	–	3.99	9.66	–	37.35
(20 mg)	(0.96)		(0.96)	(1.13)		(1.88)	(3.24)		(10.92)
Medikinet® retard	4.83	–	5.26	2.82	–	4.06	11.72	–	39.90
(20 mg)	(1.87)		(2.11)	(1.00)		(1.65)	(4.64)		(13.77)
Tuerck et al., 2007 [27] (fasted state)
Focalin XR®	13.7	14.9	15.5	1.5	6.5	5.8	36.3	59.1	119
(20 mg)	(4.6)	(4.0)	(4.3)	(1.0–2.0)^b	(4.5–7.0)^b	(1.0–7.0)^b	(10.6)	(16.0)	(40.7)
Ritalin LA®	13.2	16.3	16.4	2.0	6.5	6.5	35.0	60.9	122
(40 mg)	(3.0)	(4.5)	(4.4)	(1.5–4.5)^b	(4.0–8.0)^b	(2.0–7.0)^b	(8.7)	(15.0)	(36.3)

Data are shown as mean (standard deviation) unless stated otherwise.
AUC, area under the curve; C_max , maximum plasma methylphenidate concentration; T_max , time to maximum plasma methylphenidate concentration.
^aPercentage coefficient of variation; bmedian (range); c4–12 hours post-dose.
N.B. Spencer et al., 2010 [21] did not present the values listed; therefore this reference was not included in the table.

Authors and Disclosures

David Coghill^1,*,†, Tobias Banaschewski^2,†, Alessandro Zuddas³, Antonio Pelaz⁴, Antonella Gagliano^5,† and Manfred Doepfner^6,†

¹ Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
² Department of Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany
³ Department of Biomedical Sciences, University of Cagliari, Cagliari, Sardinia, Italy
⁴ Department of Child and Adolescent Psychiatry, Hospital Clinico Universitario San Carlos, Madrid, Spain
⁵ Department of Pediatric Science, University of Messina, Policlinico Universitario G. Martino, Messina, Italy
⁶ Department of Child and Adolescent Psychiatry, University of Cologne, Cologne, Germany

Competing interests
A Gagliano received conference attendance support and speaker's fees from Lilly, Novartis and Shire. She is or has been involved in clinical trials conducted by Lilly and Shire. The present work is unrelated to the above grants and relationships.
A Pelaz served in an advisory role for Lilly, and has received conference attendance support or received speaker's fees from Bristol-Myers Squibb, Janssen, Juste, Lilly, Otsuka, Rubio and Shire. He has been involved in clinical trials conducted by Janssen and Rubio. The present work is unrelated to the above grants and relationships.
T Banaschewski served in an advisory or consultancy role for Bristol-Myers Squibb, Develco Pharma, Lilly, Medice, Novartis, Shire and Vifor Pharma. He received conference attendance support, conference support or received speaker's fees from Lilly, Janssen McNeil, Medice, Novartis and Shire. He is or has been involved in clinical trials conducted by Lilly and Shire. The present work is unrelated to the above grants and relationships.
D Coghill served in an advisory or consultancy role for Flynn Pharma, Otsuka, Lilly, Janssen, Medice, Pfizer, Schering-Plough, Shire and Vifor. He received conference attendance support, conference support or received speaker's fees from Flynn Pharma, Lilly, Janssen, Medice, Novartis and Shire. He is or has been involved in clinical trials conducted by Lilly and Shire and has received research funding from Lilly, Janssen, Shire and Vifor. The present work is unrelated to the above grants and relationships.
M Doepfner served in an advisory or consultancy role for Lilly, Medice, Novartis, Shire and Vifor Pharma. He received conference attendance support, conference support or received speaker's fee from Lilly, Medice, Novartis and Shire. M Doepfner is or has been involved in clinical trials conducted by Lilly and Vifor. The present work is unrelated to the above grants and relationships.
A Zuddas served in an advisory or consultancy role for Astra-Zeneca, Bristol-Myers Sqibb/Osuka, Lilly, Lundbeck, Shire and Vifor Pharma. He received conference attendance support and conference support or received speaker's fees from Lilly and Shire. He is/has been involved in clinical trials conducted by Lilly, Shire and Vifor. The present work is unrelated to the above grants and relationships.
The systematic review was funded by Shire AG. Shire AG provided funding to Caudex Medical, Oxford, UK, for support with writing and editing this manuscript.

*Correspondence
d.r.coghill@dundee.ac.uk
† Equal contributors