Extended‐release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults

Abstract

Background

Attention deficit hyperactivity disorder (ADHD) is a psychiatric diagnosis increasingly used in adults. The recommended first‐line pharmacological treatment is central nervous system (CNS) stimulants, such as methylphenidate, but uncertainty remains about its benefits and harms.

Objectives

To assess the beneficial and harmful effects of extended‐release formulations of methylphenidate in adults diagnosed with ADHD.

Search methods

We searched CENTRAL, MEDLINE, Embase, nine other databases and four clinical trial registries up to February 2021. We searched 12 drug regulatory databases for clinical trial data up to 13 May 2020. In addition, we cross‐referenced all available trial identifiers, handsearched reference lists, searched pharmaceutical company databases, and contacted trial authors.

Selection criteria

Randomised, double‐blind, parallel‐group trials comparing extended‐release methylphenidate formulations at any dose versus placebo and other ADHD medications in adults diagnosed with ADHD.

Data collection and analysis

Two review authors independently extracted data. We assessed dichotomous outcomes as risk ratios (RRs), and rating scales and continuous outcomes as mean differences (MDs) or standardised mean differences (SMDs). We used the Cochrane risk of bias tool to assess risks of bias, and GRADE to assess the certainty of the evidence. We meta‐analysed the data using a random‐effects model. We assessed three design characteristics that may impair the trial results' 'generalisability'; exclusion of participants with psychiatric comorbidity; responder selection based on previous experience with CNS stimulants; and risk of withdrawal effects. Our prespecified primary outcomes were functional outcomes, self‐rated ADHD symptoms, and serious adverse events. Our secondary outcomes included quality of life, ADHD symptoms rated by investigators and by peers such as family members, cardiovascular variables, severe psychiatric adverse events, and other adverse events.

Main results

We included 24 trials (5066 participants), of which 21 reported outcome data for this review. We also identified one ongoing study. We included documents from six drug regulatory agencies covering eight trials. Twenty‐one trials had an outpatient setting and three were conducted in prisons. They were primarily conducted in North America and Europe. The median participant age was 36 years. Twelve trials (76% of participants) were industry‐sponsored, four (14% of participants) were publicly funded with industry involvement, seven (10% of participants) were publicly funded, and one had unclear funding. The median trial duration was eight weeks. One trial was rated at overall unclear risk of bias and 20 trials were rated at overall high risk of bias, primarily due to unclear blinding of participants and investigators, attrition bias, and selective outcome reporting. All trials were impaired in at least one of the three design characteristics related to 'generalisability'; for example, they excluded participants with psychiatric comorbidity such as depression or anxiety, or included participants only with a previous positive response to methylphenidate, or similar drugs. This may limit the trials’ usefulness for clinical practice, as they may overestimate the benefits and underestimate the harms.

Extended‐release methylphenidate versus placebo (up to 26 weeks)

For the primary outcomes, we found very low‐certainty evidence that methylphenidate had no effect on ‘days missed at work’ at 13‐week follow‐up (mean difference (MD) −0.15 days, 95% confidence interval (CI) −2.11 to 1.81; 1 trial, 409 participants) or serious adverse events (risk ratio (RR) 1.43, CI 95% CI 0.85 to 2.43; 14 trials, 4078 participants), whereas methylphenidate improved self‐rated ADHD symptoms (small‐to‐moderate effect; SMD −0.37, 95% CI −0.43 to −0.30; 16 trials, 3799 participants). For secondary outcomes, we found very low‐certainty evidence that methylphenidate improved self‐rated quality of life (small effect; SMD −0.15, 95% CI −0.25 to −0.05; 6 trials, 1888 participants), investigator‐rated ADHD symptoms (small‐to‐moderate effect; SMD −0.42, 95% CI −0.49 to −0.36; 18 trials, 4183 participants), ADHD symptoms rated by peers such as family members (small‐to‐moderate effect; SMD −0.31, 95% CI −0.48 to −0.14; 3 trials, 1005 participants), and increased the risk of experiencing any adverse event (RR 1.27, 95% CI 1.19 to 1.37; 14 trials, 4214 participants). We rated the certainty of the evidence as ‘very low’ for all outcomes, primarily due to high risk of bias and 'indirectness of the evidence'. One trial (419 participants) had follow‐up at 52 weeks and two trials (314 participants) included active comparators, hence long‐term and comparative evidence is limited.

Authors' conclusions

We found very low‐certainty evidence that extended‐release methylphenidate compared to placebo improved ADHD symptoms (small‐to‐moderate effects) measured on rating scales reported by participants, investigators, and peers such as family members. Methylphenidate had no effect on 'days missed at work' or serious adverse events, the effect on quality of life was small, and it increased the risk of several adverse effects. We rated the certainty of the evidence as ‘very low’ for all outcomes, due to high risk of bias, short trial durations, and limitations to the generalisability of the results. The benefits and harms of extended‐release methylphenidate therefore remain uncertain.

Plain language summary

Extended‐release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults

Review question

This review investigated the positive and negative effects of methylphenidate and compared them to placebo or to other medications in adults diagnosed with attention deficit hyperactivity disorder (ADHD). We particularly focused on effects on daily functioning, such as the number of days a person is absent from work, and the effects on ADHD symptoms and quality of life assessed by the patients themselves, and also by a doctor or a researcher.

Background

ADHD is a psychiatric diagnosis characterised by difficulties with concentration, hyperactivity, and impulsive behaviour that often affects social life, the ability to do well at work, and to maintain personal relationships. Increasingly more adults are diagnosed with ADHD and receive drugs. Treatment of ADHD should consist of a range of different approaches, including psychotherapy, social interventions, other types of non‐medical treatments, and pharmacological drugs. Methylphenidate and amphetamine are the recommended first‐choice ADHD drugs. Methylphenidate is a drug that increases the activity of the central nervous system (CNS). This review focuses on methylphenidate given as a pill that you only need to take once or twice a day, a so‐called 'extended‐release formulation'. Methylphenidate has been tested in many clinical trials in adults with ADHD, but the overall positive and negative effects seem uncertain, because of concerns about how these trials were designed and how the results were reported. Methylphenidate is also used in children and adolescents with ADHD.

Study characteristics

The search is current to February 2021. We found 24 studies (5066 participants) diagnosed with ADHD and we also identified one ongoing study. In each study the participants were divided into two groups; one group received extended‐release methylphenidate and the other received placebo, also known as a 'sugar pill'. Two trials also included another ADHD drug as a third group. The median age (i.e. the middle age from a list of all ages arranged in order from youngest to eldest) of the participants was 36 years old. The studies were primarily conducted in Europe and North America in outpatients, which means that the participants were not hospitalised during the trials. The studies lasted around eight weeks. Half of the trials were sponsored by the companies that also sell the drugs, which may have affected the way these trials were designed.

Key results

Compared with placebo, methylphenidate as an extended‐release pill reduced the severity of ADHD symptoms when rated by the participants, investigators, as well as family members or spouses. Methylphenidate did not reduce the number of days missed at work, and the effect on quality of life rated by the participants was small. The trials did not find an increased risk of serious harms but methylphenidate increased the overall risk of experiencing any harm. 

Quality of the evidence

We rated our certainty in the evidence as ‘very low’, which means that it is still uncertain whether methylphenidate’s positive effects outweigh the negative effects. All studies were at high risk of being affected by different sources of bias in the way they were designed and conducted, which could affect (bias) the results. Consequently, methylphenidate’s reported positive and negative effects in the trials are not reliable, and could change importantly if new trials are conducted. There is also limited knowledge about the long‐term effects of methylphenidate, which is often taken for years, since most trials lasted around eight weeks, and only one trial lasted for 52 weeks.

We identified several problems with the trials; for example, participants having other psychiatric diagnoses as well as ADHD were often not allowed to participate, although people with ADHD often have multiple psychiatric diagnoses, like anxiety and depression. This limits the trials' usefulness for important groups of adults with ADHD. Also, often only people who had previously taken methylphenidate, or similar drugs, with good results were allowed to participate. This means that the studies could underestimate the severity and the number of people who experience problems taking the drugs. To get more reliable estimates of methylphenidate's positive and negative effects, it therefore seems necessary to conduct new clinical trials, free from the problems highlighted in this review.

Summary of findings

Summary of findings 1. Extended‐release methylphenidate compared to placebo for ADHD.

Extended‐release methylphenidate compared to placebo for ADHD
Patient or population: adults diagnosed with ADHD Setting: outpatient setting Intervention: extended‐release methylphenidate Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with extended‐release methylphenidate
Functional outcome:days missed at work/ school/ training   Time of assessment: 13 weeks	The mean number of days missed at work, school or training in the control group was 2.4	The mean number of days missed at work, school or training was 0.15 days fewer (2.11 fewer to 1.81 more)	‐	409 (1 RCT)	⊕⊝⊝⊝ Very lowa,b	‐
ADHD symptoms (self‐rated)   Time of assessment: median 8 weeks (range 2 ‐ 26)	‐	The mean ADHD score in the intervention groups was 0.37 SDlower (0.43 lower to 0.30 lower)	‐	3799 (16 RCTs)	⊕⊝⊝⊝ Very lowa,b	An SMD of 0.37 may be considered a small‐to‐moderate effect size
Serious adverse events   Time of assessment: median 8 weeks (range 4 ‐ 52)	Study population		RR1.43 (0.85 to 2.43)	4078 (14 RCTs)	⊕⊝⊝⊝ Very lowa,b	‐
	12 per 1000	17 per 1000 (10 to 30)
Quality of life (self‐rated)   Time of assessment: median 6 weeks (range 4 ‐ 52)	‐	The mean quality of life score in the intervention groups was 0.15 SD lower (0.25 lower to 0.05 lower)	‐	1888 (6 RCTs)	⊕⊝⊝⊝ Very lowa,b	An SMD of 0.15 may be considered a small effect size
ADHD symptoms (investigator‐rated)   Time of assessment: median 8 weeks (range 2 ‐ 26)	‐	The mean investigator‐rated ADHD score in the intervention groups was 0.42 SD lower (0.49 lower to 0.36 lower)	‐	4183 (18 RCTs)	⊕⊝⊝⊝ Very lowa,b	An SMD of 0.42 may be considered a small‐to‐moderate effect size
ADHD symptoms (peer‐rated)   Time of assessment: median 7.5 weeks (range 6 ‐ 9)	‐	The mean peer‐rated ADHD score in the intervention groups was 0.31 SD lower (0.48 lower to 0.14 lower)	‐	1005 (3 RCTs)	⊕⊝⊝⊝ Very lowa,b	An SMD of 0.31 may be considered a small‐to‐moderate effect size
Adverse events (proportion experiencing any adverse event)   Time of assessment: median 8 weeks (range 4 ‐ 52)	Study population		RR1.27 (1.19 to 1.37)	4214 (14 RCTs)	⊕⊝⊝⊝ Very lowa,b	‐
	641 per 1000	814 per 1000 (763 to 878)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ADHD: Attention deficit hyperactivity disorder; CI: Confidence interval; RCT: Randomised controlled trial; RR: Risk ratio; SD: Standard deviation; SMD: Standardised mean difference.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect

^aWe downgraded two levels due to risk bias; primarily due to blinding issues caused by methylphenidate's effects, high attrition (dropout) rates, and selective reporting of the included trials.
^bWe downgraded two levels due to indirectness; 19 of 21 trials had limited generalisability due to strict inclusion of allowed psychiatric comorbidity; 19 of 21 trials used an 'enriched design' thereby excluding potential participants with previous poor response to methylphenidate; and 16 of 21 trials were at risk of being confounded by withdrawal effects since participants were asked to stop concurring CNS stimulant use prior to randomisation. In addition, 18 of 21 trials had a short follow‐up between 2 to 13 weeks.

Background

Description of the condition

The diagnosis of attention deficit hyperactivity disorder (ADHD) for adults is described in the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5; APA 2013) and in the International Classification of Disorders (ICD‐11; WHO 2019a). Individuals diagnosed with ADHD are characterised by having problems with concentration, hyperactivity, and impulsivity, with substantial impact on a person’s private, social, and professional life. The diagnostic criteria for ADHD have changed over time (Lange 2010; Doernberg 2016). The DSM‐5 criteria require the presence of five or more symptoms of inattention or hyperactivity/impulsivity for at least six months. The symptoms should affect two or more domains of social, academic, and work/school functioning, and they should have been present before the age of 12 years (APA 2013). The DSM‐5 criteria operate with three diagnostic subtypes: 'combined presentation', 'predominantly inattentive presentation', and 'predominantly hyperactive/impulsive presentation' (APA 2013). The ICD‐11 criteria are similar to the DSM system but do not define an age cut‐off for symptom occurrence, although they state that most experience symptoms prior to the age of 12. The ICD‐11 criteria define five subtypes, including three subtypes identical to those in DSM‐5, and two more, entitled 'other specified presentation' and 'unspecified presentation' (WHO 2019a).

A systematic review of epidemiological studies reported a pooled prevalence of adult ADHD of 2.5% (Simon 2009), with the most recent World Health Organization (WHO) Mental Health Survey reporting a prevalence of 2.8% (range 0.6% to 7.3%) across 10 countries (Fayyad 2017). The prevalence of adult ADHD was higher in males than in females (odds ratio (OR) 1.6, 95% confidence interval (CI) 1.3 to 1.9) (Fayyad 2017). According to the US National Epidemiologic Survey on Alcohol and Related Conditions, women diagnosed with ADHD exhibit less hyperactive behaviour compared to men, but a similar level of 'risky behaviour', and higher levels of anxiety (Cortese 2018b).

The youngest children in a school class have a higher risk of getting a diagnosis of ADHD than the oldest (Elder 2010; Evans 2010; Morrow 2012; Sayal 2017; Layton 2018; Root 2019). A recent systematic review of 334 studies concluded that ADHD is overdiagnosed in children and adolescents (Kazda 2021). Interestingly, follow‐up epidemiological studies have reported that between 5% and 22% of those diagnosed in childhood fulfil the diagnostic ADHD criteria in adulthood only (Faraone 2006; Moffitt 2015; Agnew‐Blais 2016; Caye 2016). Adults with ADHD also often have psychiatric comorbidities (Kessler 2006; Jacob 2007; Sobanski 2007a; Cumyn 2009; Grosz‐Lesch 2013; Philipsen 2014), such as depression, anxiety or substance abuse disorders. For these reasons, the diagnosis of adult ADHD and its categorisation as a 'neurodevelopmental disorder', the treatment modalities, the impact of socioeconomic factors, and the natural course of the symptoms for those diagnosed are debated (Barkley 2002; Timimi 2004; Coghill 2004; Marcovitch 2004; Bailly 2005; Asherson 2010; Moncrieff 2010; Moncrieff 2011; MHRA 2010; MEB 2016).

Description of the intervention

Methylphenidate is a central nervous system (CNS) stimulant related to amphetamine. It inhibits dopamine and noradrenergic reuptake transporters, thus increasing the synaptic concentration of these neurotransmitters (Challman 2000; Iversen 2006). Methylphenidate can be administered as immediate‐release or extended‐release oral tablet formulations. The extended‐release formulations use different coatings and release mechanisms to ensure a prolonged release of methylphenidate (Coghill 2013; Maldonado 2013), and are prescribed more frequently than immediate‐release formulations (Treceño 2012; Beau‐Lejdstrom 2016). The UK National Institute for Health and Care Excellence (NICE) state in their ADHD treatment guideline that pharmacological treatment, such as CNS stimulants, should be used as part of a multimodal approach consisting also of social and psychological interventions (NICE 2018).

Several extended‐release methylphenidate formulations have been approved for ADHD in adults. The US Food and Drug Administration (FDA) approved the first drug for this indication in 2005 with the authorisation of Novartis’s dex‐methylphenidate (FDA 2007). The German Bundesinstitut für Arzneimittel und Medicinprodukte (BfArM), was the first European drug regulator to approve a formulation for the indication in adults in 2011, with the approval of Medice’s extended‐release formulation (BfArM 2011). Methylphenidate has been the most prescribed CNS stimulant for ADHD, but in some countries, e.g. in the USA, amphetamines are now more widely prescribed for use in adult ADHD (Safer 2016; Piper 2018).

In the USA, methylphenidate is classified as a 'schedule II controlled substance', meaning that it is authorised for medical use but that it has a "high potential for abuse which may lead to severe psychological or physical dependence" (US DEA 2021). The most recent systematic review on diversion and misuse of prescription stimulants, such as methylphenidate, found that it is a "significant public health concern" (Faraone 2020a).

How the intervention might work

Methylphenidate has central and peripheral stimulatory effects. The drug's central effects are primarily due to increased synaptic concentrations of dopamine and norepinephrine, which are suggested to have behavioural and cognitive effects in adults with ADHD (Foquest 2019, p 22), but the exact mode of therapeutic action is unknown (FDA 2017, p 20). The main hypothesis underlying CNS stimulant use for ADHD is that these neurotransmitters activate specific brain regions related to attention and inhibition control (Cortese 2020). A systematic review of single‐dose methylphenidate studies in healthy adults reported on improvements in several cognitive domains (Linssen 2014). Methylphenidate is also used as a cognitive enhancement drug (i.e. 'study drug') by students and adults (Sussman 2006; Wilens 2008; Franke 2013). A systematic review of methylphenidate's impact on maths and reading skills in children found only small‐to‐moderate effects (Kortekaas‐Rijlaarsdam 2019), and a systematic review of observational studies on methylphenidate's impact on academic achievements (e.g. school tests, failure to pass a class, grades) reported that the evidence on methylphenidate's benefits is uncertain (De Faria 2021).

Methylphenidate's peripheral stimulatory effects include increases in heart rate and blood pressure (Mick 2013). Observational studies of CNS stimulant use in children and in adults have reported an increased risk of cardiovascular events (Holick 2009; Schelleman 2012; Dalsgaard 2014; Shin 2016) or no increased risk (Cooper 2011; Habel 2011). The FDA Prescriber Information warns about the risk of serious cardiovascular events (FDA 2017, section 5.1).

The published literature on observational studies assessing the effects of methylphenidate on various functional outcomes have reported ambiguous results. Studies using a before‐after medication design have reported on beneficial methylphenidate effects on outcomes such as serious traffic accidents (Chang 2014) and criminal behaviour (Lichtenstein 2012). In contrast to these studies, long‐term observational follow‐up studies from the Multimodal Treatment of ADHD (MTA) study in children (MTA 1999) have not found beneficial effects on outcomes such as hospital admissions, delinquency, or academic performance for those treated with methylphenidate compared to no treatment after three to eight years of follow‐up (Jensen 2007; Molina 2007 Molina 2009). At 16 years of follow‐up, the subgroup of those consistently taking methylphenidate was on average 5 cm shorter than the subgroup with the lowest methylphenidate intake (Swanson 2017). A systematic review (Krinzinger 2019) assessing the risk of psychiatric harms of methylphenidate from long‐term treatment assessed in various study designs reported that the evidence base is weak and that more studies are needed. Generally, confounding and bias are inadequately addressed in observational research in psychiatry (Munkholm 2020) and one should be cautious about drawing inference from such uncontrolled study designs.

Why it is important to do this review

In the UK, NICE recommends methylphenidate as the first‐line drug for ADHD in adults (NICE 2018, section 1.7.11). The prescription rate of ADHD drugs in the UK for adults between 25 and 45 years of age rose 16‐fold from 3.4 per 10,000 in 2000 to 53 per 10,000 in 2015 (Renoux 2016). Across 14 countries, the annual average increase in ADHD medication use was 18% between 2001 and 2015 (Raman 2018).

The World Health Organization (WHO) has twice rejected applications to include methylphenidate on the WHO Model list of Essential Medicines. The first application was submitted by faculty at the Icahn School of Medicine in 2018 (Moscibrodzki 2018). The second application by Faraone 2020b focused on methylphenidate for children and adolescents, and was additionally signed by ADHD key opinion leaders. In both rejections, the WHO argued that there were uncertainties about the benefits and harms, and that the quality of the evidence was low (WHO 2019b; p 441; Storebø 2021; WHO 2021a; WHO 2021b). In the first rejection, the WHO also highlighted that a Cochrane Review of immediate‐release methylphenidate for ADHD in adults (Epstein 2014) was retracted in 2016, since the review authors were unable to respond to criticism of the methodological limitations of the included trials (Epstein 2016; Boesen 2017a). The review on immediate‐release methylphenidate was updated by a new author team (Cândido 2021).

Previous systematic reviews have assessed methylphenidate compared to placebo (Faraone 2004; Peterson 2008; Koesters 2009; Meszaros 2009; Faraone 2010; Castells 2011; McDonagh 2011; Castells 2013; McDonagh 2015; Cunill 2016; Cortese 2018, Elliott 2020). The most recent of these reviews have reported on small to moderate effects of methylphenidate with a high degree of uncertainty about the quality of the evidence (McDonagh 2015; Cunill 2016; Cortese 2018; Elliott 2020). Important limitations to these reviews were their reliance on mostly published literature and a focus on ADHD symptom scales, which might not be the most patient‐relevant outcomes. A systematic review (Schatz 2015) of patient preference studies included three surveys of adult ADHD patients (Mühlbacher 2009; Mühlbacher 2010; Glenngård 2013), all of which ranked work and school performance and social contacts as most important.

Due to substantial selective reporting (McDonagh 2011), and a dearth of assessed patient‐reported outcomes in previous reviews, the benefits and harms of methylphenidate for adult ADHD remain uncertain. This uncertainty was particularly emphasised in the sister review on immediate‐release methylphenidate for adult ADHD (Cândido 2021).

Objectives

To assess the beneficial and harmful effects of extended‐release formulations of methylphenidate in adults diagnosed with ADHD.

Methods

Criteria for considering studies for this review

Types of studies

Double‐blind, parallel‐group, randomised controlled trials (RCTs).

Types of participants

Adults diagnosed with ADHD according to DSM (APA 1987; APA 2000; APA 2013) or ICD (WHO 1992; WHO 2019a) criteria. Adults had to be diagnosed according to the criteria of ADHD in childhood, before the introduction of the ADHD diagnosis in adolescence and adulthood with the DSM‐5 (APA 2013) and ICD‐11 (WHO 2019a).

Types of interventions

Methylphenidate in any extended‐release formulation, at any dose, compared with placebo or an active control, or both. We permitted co‐interventions, such as cognitive behavioural therapy and pharmaceutical interventions, provided they were delivered to both groups.

Types of outcome measures

Primary outcomes

1. Functional outcomes (functional capacity), such as academic and job adherence, measured as days of lost work or study activities (Philipsen 2008).

2. Self‐rated ADHD symptoms, measured on validated rating scales such as the Connors' Adult ADHD Rating Scale (Conners 1999).

3. Serious adverse events, defined according to the International Council for Harmonisation (ICH) guideline (ICH 2003).

Secondary outcomes

1. Quality of life, measured on validated scales such as the Quality of Life Enjoyment and Satisfaction Questionnaire‐Short Form (Mick 2008).

2. Investigator‐rated (trialist, physician, other healthcare professional) ADHD symptoms, measured on a validated rating scale.

3. Peer‐rated (spouse, family or friends) ADHD symptoms, measured on a validated rating scale.

4. Severe psychiatric adverse events, i.e. any psychiatric adverse event classified as 'severe' or 'serious', or any psychiatric event leading to dose reduction or to dropout.

5. Cardiovascular variables (i.e. blood pressure and heart rate).

6. Adverse events other than serious adverse events.

We used data with the longest possible follow‐up within three outcome periods: short‐term (up to six months); medium‐term (up to 12 months); and long‐term (more than 12 months).

Search methods for identification of studies

We ran the first searches in October 2017. We ran top‐up searches of all databases in March 2019 and February 2021, apart from the Database of Abstracts of Reviews of Effects (DARE), which was last published in April 2015. We searched the databases and trial registries listed below using the strategies in Appendix 1. We did not limit the searches by publication date or language.

Electronic searches

We searched the following electronic sources.

1. Cochrane Central Register of Controlled Trials (CENTRAL; Issue 2, 2021), in the Cochrane Library, which includes the Cochrane Developmental, Psychosocial and Learning Problems Specialised Register (searched 16 February 2021).

2. MEDLINE Ovid (1946 to February Week 1 2021).

3. MEDLINE In‐Process & Other Non‐Indexed Citations Ovid (1946 to 12 February 2021).

4. MEDLINE Epub Ahead of Print Ovid (12 February 2021).

5. Embase Ovid (1974 to 12 February 2021)

6. APA PsycINFO Ovid (1806 to February Week 2 2021).

7. Cochrane Database of Systematic Reviews (CDSR; Issue 2, 2021), part of the Cochrane Library (searched 16 February 2021).

8. Database of Abstracts of Reviews of Effects (DARE; Issue 2, 2015, final issue), part of the Cochrane Library (searched 3 October 2017).

9. CINAHL Plus EBSCOhost (Cumulative Index to Nursing and Allied Health Literature; 1937 to 16 February 2021).

10. Conference Proceedings Citation Index ‐ Science Web of Science (CPCI‐S; 1990 to 16 February 2021).

11. LILACS (Latin American and Caribbean Health Science Information database; lilacs.bvsalud.org/en/; searched 16 February 2021).

12. ClinicalTrials.gov (clinicaltrials.gov; searched 16 February 2021).

13. EU Clinical Trials Register (clinicaltrialsregister.eu; searched 16 February 2021).

14. ISRCTN Registry (www.isrctn.com; searched 16 February 2021).

15. WHO International Clinical Trials Registry Platform (apps.who.int/trialsearch; attempted access 16 February 2021 but site unresponsive because of high traffic generated by the pandemic)

Searching other resources

Drug regulatory agency databases

We searched the following 12 drug regulatory agencies for publicly‐available trial data up to 12 May 2020. To our knowledge, there have been no new methylphenidate formulations approved for adult use since that date, so we did not update these searches. Some agencies host multiple databases; full details of these and descriptions of the searches are reported in Appendix 2.

1. The US Food and Drug Administration (FDA; www.accessdata.fda.gov/scripts/cder/daf)

2. The European Medicines Agency (EMA; www.ema.europa.eu/en/medicines)

3. The Heads of Medicines Agencies (HMA; mri.cts-mrp.eu/Human/)

4. Health Canada (Drug Product Database; Summary Basis of Decision; Clinical Study Reports)

5. The Australian Therapeutic Goods Administration (TGA; Australian Register of Therapeutic Goods; Public Assessment Reports)

6. The German Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM; www.pharmnet-bund.de/)

7. The Dutch Medicines Evaluation Board (MEB; www.geneesmiddeleninformatiebank.nl/en)

8. The British Medicines and Healthcare products Regulatory Agency (MHRA; products.mhra.gov.uk/)

9. The French Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM; archiveansm.integra.fr/Mediatheque/Publications/Rapports-Syntheses-Rapports-publics-d-evaluation)

10. The Irish Health Product Regulatory Authority (HPRA; hpra.ie/homepage/medicines/medicines-information/find-a-medicine)

11. SwissMedic (www.swissmedic.ch/swissmedic/en/home/humanarzneimittel/authorisations/swisspar.html)

12. The Japanese Pharmaceuticals and Medical Devices Agency (PMDA; www.pmda.go.jp/english/review-services/reviews/approved-information/drugs/0003.html)

Pharmaceutical company databases

We also searched methylphenidate manufacturer websites and databases for clinical trials. See Appendix 2 for details.

1. Yale University Open Data Access (YODA; yoda.yale.edu/), which contains trials sponsored by Johnson & Johnson, including Janssen.

2. Novartis’ database (www.novctrd.com/).

3. Purdue Pharma’s website (www.purduepharma.com/healthcare-professionals/clinical-trials/).

4. Medice’s website (www.medice.de/the-company).

Author correspondence

We contacted all corresponding authors for each included trial. We wrote to all authors or contact people up to three times. If we did not receive an answer the first time, we searched Google to identify other email addresses. We approached some authors already at the protocol stage.

Searching other systematic reviews and guidelines

We searched national clinical ADHD guidelines (Sundhedsstyrelsen 2017; NICE 2018) and recently‐published systematic reviews of ADHD medications (Cortese 2018; Elliott 2020).

Cross‐referencing of trial identifiers

Finally, we cross‐referenced trial registry identifiers, grant funding numbers, and searched the reference lists of included published reports and documents to find additional information.

Data collection and analysis

Selection of studies

Two review authors (KB and ASP) independently screened titles and abstracts for eligibility, using Covidence. We compared full‐text reports of potentially eligible studies against the inclusion criteria (Criteria for considering studies for this review), resolving disagreements by discussion with a third review author (KJ). We listed the reasons for exclusion of full‐text reports in the PRISMA diagram (Moher 2009), and they may be seen in Characteristics of excluded studies.

Data extraction and management

Two review authors (KB and ASP) independently extracted study data on methodology, population characteristics and outcomes using a prespecified data extraction sheet, and compared the data. We resolved disagreements by discussion with a third review author (KJ). One review author (KB) entered the data into Review Manager 5 (Review Manager 2020), and a second review author (ASP) double‐checked them for accuracy.

Assessment of risk of bias in included studies

Two review authors (KB and ASP) independently assessed each trial for risks of bias using the original Cochrane risk of bias tool (Higgins 2011). Consensus was sought, and disagreements were resolved through discussion with a third review author (KJ). The risk of bias tool consists of seven domains, with each domain given a rating of low, unclear or high risk of bias.

1. Random sequence generation (selection bias): Was the sequence generated adequately (e.g. computer‐generated) or inadequately (e.g. using the day of study enrolment) to allocate participants?

2. Allocation sequence concealment (selection bias): Was the implementation of the randomisation sequence adequate (e.g. central allocation by a third party) or inadequate (e.g. open allocation or using non‐opaque envelopes)?

3. Blinding of participants and personnel (performance bias): Methylphenidate’s effects may compromise blinding of participants and investigators. We rated the trials at unclear risk of bias, unless the blinding was tested and confirmed. We applied the same method to trials that added active components to the placebo pill, e.g. folic acid in Levin 1998a and Levin 1998b, to mimic adverse effects like stomach‐ache and decreased appetite.

4. Blinding of outcome assessment (detection bias): We applied the same method for this domain as described above for blinding of participants and personnel.

5. Incomplete outcome data (attrition bias): We based our assessment on four variables:

   1. dropout rates in each arm;

   2. dropout rates in each arm due to adverse events;

   3. the statistical method used to account for missing data ‐ acceptable methods would include multiple imputations, whereas improper methods would include completers’ analysis and last observation carried forward (LOCF) (Lachin 2016);

   4. other aberrations, such as analyses including more participants than actually completed the trials. There is no dropout level that eliminates the risk of bias, unless it is zero, and we did not define a lower threshold to guide our assessments.

6. Selective outcome reporting (reporting bias): We rated a trial at high risk of bias if it prespecified one of our primary or secondary outcomes in a trial registry, protocol, or published report, but did not report it. We categorised as reporting bias any adverse event‐reporting threshold (i.e. that a certain percentage of participants must experience an adverse event before it is reported).

7. Other potential sources of bias: Was the study free of other sources of bias, such as baseline differences?

Overall risk of bias assessment for individual trials

We made an overall risk of bias assessment for each trial, based on the individual domain ratings, as recommended in the Cochrane Handbook (Higgins 2011). We considered all bias domains as critical for the overall risk of bias, so if one or more domains were rated as high risk we rated the trial as having an overall high risk of bias.

Specific limitations to the generalisability (external validity)

We assessed three study design characteristics related to the generalisability of ADHD drug trials. We depicted these three design characteristics as additional items within the Cochrane risk of bias tool, and rated them being at high, low or unclear risk of limiting the external validity of each trial. These design characteristics should not be mistaken for additional risk of bias domains (which describe internal validity). Rather, they informed our assessment of 'indirectness' when we graded the certainty of the evidence (see Data synthesis). 

1. Psychiatric comorbidity

Adults with an ADHD diagnosis are often also diagnosed with other psychiatric diagnoses, such as depression, anxiety or substance abuse (Kessler 2006, Jacob 2007, Sobanski 2007a, Cumyn 2009, Grosz‐Lesch 2013, Philipsen 2014). The exclusion of participants with psychiatric comorbidity may reduce the trials’ generalisability (Surman 2010). It has also been suggested that such exclusions could lead to an overestimation of the treatment effect (Pliszka 1989; Sobanski 2007b, MHRA 2010).

1. Low risk: Participants diagnosed with other psychiatric diagnoses than ADHD were not excluded, unless methylphenidate was contraindicated (e.g. bipolar affective disorder or suicidality).

2. Unclear risk: There was no description, or an unclear one, whether participants with psychiatric comorbidity were allowed.

3. High risk: Participants with psychiatric comorbidities other than ADHD or other psychiatric symptoms, were excluded from participation in the trial.

2. Responder selection ('enriched design')

Some patients do not benefit from or tolerate methylphenidate, and are referred to as "non‐responders" (Elia 1991; De Sonneville 1994; Cho 2007). It is ethically unacceptable to include participants who are known to experience harm or not to benefit from the intervention. However, the exclusion of such participants will lead to an overestimation of benefits and an underestimation of harms compared to a treatment‐naïve population, especially if only participants known to benefit from the drug are included. Selecting participants based on previous exposure to the drug is called an 'enriched design' (FDA 2019).

1. Low risk: Participants were treatment‐naïve.

2. Unclear risk: There was no description, or an unclear one, of exclusion criteria or of previous stimulant use.

3. High risk: Previous exposure to methylphenidate or other stimulants was allowed, or 'non‐responders' (or similar) were excluded before randomisation, or both.

3. Withdrawal effects

Discontinuation of psychotropic drugs can cause acute and protracted withdrawal symptoms (Lerner 2019). The literature pertaining specifically to methylphenidate withdrawal is scarce, but evidence related to other CNS stimulants, most commonly cocaine, amphetamine, and methamphetamine, suggests that withdrawal symptoms may persist for weeks or months (Lago 1994; Baker 2004; Cruickshank 2009; Phillips 2014). Due to methylphenidate's status as a Schedule‐II drug (US DEA 2021), FDA's Prescriber Information on methylphenidate products warns that chronic use can lead to dependence and tolerance (FDA 2017). It seems plausible that if participants take CNS stimulants upon enrolment in a methylphenidate trial and stop treatment before randomisation, they might experience withdrawal effects. If the taper period (often called a “washout”) is not of sufficient duration, withdrawal or rebound symptoms may occur during the trial (Cox 2008, Récalt 2019). To our knowledge, there are no published guidelines on how to taper methylphenidate. Consensus documents (Kooij 2010; Kooij 2019) and British (NICE 2018, section 1.10, 'Review of medication and discontinuation') and German (DGPPN 2021) national ADHD guidelines contain no guidance on how to taper methylphenidate. A systematic review of CNS stimulant discontinuation in children and adolescents with ADHD did not identify any concrete guidance (Lohr 2021). To assess the risk of withdrawal effects, we therefore made an individual trial‐by‐trial assessment of whether the stated washout periods were of sufficient duration to avoid withdrawal effects.
 

1. Low risk: Participants were treatment‐naïve, or the stimulant‐free period before randomisation was of such duration that the risk of withdrawal effects was considered minimal.

2. Unclear risk: There was no description, or an unclear one, of the participants’ treatment status, or it was uncertain if the stimulant‐free period prior to randomisation was sufficient to avoid withdrawal effects.

3. High risk: Stimulants were stopped before randomisation, with a washout phase of insufficient duration, or without a washout.

Measures of treatment effect

Dichotomous data

We summarised dichotomous data as risk ratios (RRs) with corresponding 95% confidence intervals (95% CIs).

Continuous data

For continuous data and rating scales, we extracted mean change or endpoint (preferred) data and the corresponding standard deviations (SDs) or standard errors (SEs), in order to calculate a mean difference (MD). If the outcome was reported on different scales, we used a standardised mean difference (SMD) with a 95% CI.

Unit of analysis issues

Cross‐over trials

We excluded cross‐over trials due to the risk of carry‐over stimulant effects and the likely loss of blinding. In a trial of immediate‐release methylphenidate (Gualtieri 1985), all eight participants were able to correctly guess their allocation, probably due to the adverse events.

Studies with multiple time points

We split up outcome periods into short‐term (up to six months), medium‐term (up to 12 months), and long‐term (more than 12 months). If a trial reported multiple sets of study data within the same predefined outcome period, we extracted data with the longest follow‐up time.

Studies with multiple treatment groups

In studies with multiple methylphenidate groups and a single comparator arm, we pooled the groups to make a single, pair‐wise comparison (Higgins 2021).

Dealing with missing data

A drug class review from 2011 reported that a considerable amount of data were missing in ADHD drug trials (McDonagh 2011). As well as searching for unpublished and regulatory data, as described elsewhere, we took the following precautions.

1. We highlighted unreported trial outcomes in the ‘selective outcome reporting’ bias domain of the risk of bias tables.

2. We imputed missing standard deviations (SDs) based on trials using the same scale and of similar size.

3. We extracted and meta‐analysed the overall dropout rates. We used the full population sizes rather than restricted populations, e.g. per‐protocol populations or ‘safety‐populations’.

4. We highlighted each trial's statistical method for dealing with missing data, such as last observation carried forward (LOCF), in the ‘attrition bias’ domain of the risk of bias tables.

5. We preferred analyses based on imputed rather than completer's data, and made it clear if we made such a choice.

Assessment of heterogeneity

We assessed clinical heterogeneity related to differences in the trial populations, interventions or settings. We assessed methodological heterogeneity using the Cochrane risk of bias tool and the three domains related to the trials’ generalisability (psychiatric comorbidity, responder selection, and withdrawal effects; see Assessment of risk of bias in included studies). We assessed statistical heterogeneity using the I² statistic and Chi² test (Deeks 2021), and explored reasons for heterogeneity through subgroup (see: Subgroup analysis and investigation of heterogeneity) and sensitivity analyses (see: Sensitivity analysis) when the I² statistic was greater than 50%.

Assessment of reporting biases

We describe elsewhere in detail how we assessed outcome reporting bias (Assessment of risk of bias in included studies). 

We assessed publication bias and other small‐study effects using funnel plots, with estimated effect sizes plotted against their standard error (Egger 1997), provided 10 or more studies reported a given outcome (Page 2021).

Data synthesis

We summarised data using random‐effects meta‐analyses with inverse‐variance weighting due to anticipated clinical, methodological and statistical heterogeneity (McDonagh 2011; Storebø 2015). We considered all studies eligible for meta‐analysis regardless of their risk of bias assessment and methylphenidate dosage, as there is no established dose‐response relationship (NICE 2008; Huss 2017).

Subgroup analysis and investigation of heterogeneity

We prespecified subgroup analyses when the I² was greater than 50%.

1. Psychiatric comorbidity: trials that excluded participants with psychiatric comorbidity versus trials that did not.

2. Responder selection: trials with responder selection ('enriched design') versus trials without responder selection.

3. Withdrawal effects: trials with a high risk of withdrawal effects versus trials with a low risk of withdrawal effects.

4. Conflicts of interest: industry‐sponsored trials versus other trials.

Sensitivity analysis

We also prespecified sensitivity analyses when the I² was greater than 50%.

1. Restricting the analyses to trials with low risk of attrition bias according to our bias assessment.

Summary of findings and assessment of the certainty of the evidence

We created a summary of findings table for our three primary outcomes and four of our secondary outcomes comparing extended‐release methylphenidate with placebo. Rather than including all individual adverse events in the summary of findings table, we chose the ‘proportion of participants experiencing adverse event’ as an overall outcome for harms in the table. We chose to include short‐term data only, due to the scarcity of medium‐ and long‐term follow‐up. We used GradePro GDT to construct the table.

Using the GRADE approach, two review authors (KB and ASP) independently assessed the certainty of evidence for each outcome included in the table. They assigned ratings of 'high', 'moderate', 'low', or 'very low' certainty according to the presence of the following five elements; 'study limitations' (i.e. risk of bias), 'inconsistency' (i.e. statistical heterogeneity), 'indirectness' (i.e. low generalisability), imprecision (i.e. wide confidence intervals), and 'publication bias' (Schünemann 2013).

Results

Description of studies

Results of the search

We ran searches in October 2017, March 2019 and February 2021 of databases and trial registries, which returned a total of 11,104 records; 6182 duplicates were removed in EndNote/Covidence, leaving 4922 records. We found 68 records by searching drug regulatory agency databases and pharmaceutical company databases (May 2020), corresponding with trial authors (continuously from 2016 to 2021), and by cross‐referencing all documents, giving a total of 4990 records to be screened. We excluded 4648 of these records and assessed 342 reports in full text. We excluded 144 full‐text reports, leaving 198 reports for inclusion. We therefore included 189 reports, drug regulatory documents, trial registry entries, and other documents, describing 24 randomised, placebo‐controlled trials; 2 reports describing one ongoing trial; and 7 reports awaiting classification (Figure 1). We listed the reasons for exclusion of full‐text records in the Characteristics of excluded studies.

1.

Flow diagram.
BfArM= Bundesinstitut für Arzneimittel und Medizinprodukte, FDA= US Food and Drug Administration, MEB= Medicines Evaluation Board, MHRA= Medicines and Healthcare products Regulatory Agency, TGA= Therapeutic Goods Administration, YODA= Yale University Open Data Access.

Three trials appeared in trial registries only (Combine Substudy 2005; College Study 2009; Methacan 2017), while the remaining 22 trials also appeared in published reports. We included regulatory documents from 11 drug applications reporting data from eight trials: four OROS methylphenidate applications reported data from three pivotal trials (Medori 2005; Adler 2006; Casas 2008); three long‐acting methylphenidate applications reported data from one trial (Huss 2010); two controlled‐release methylphenidate applications reported data from one trial (Weiss 2014); one dex‐methylphenidate extended‐release application reported data from one trial (Spencer 2003a); and one extended‐release methylphenidate application reported data from two trials (Rösler 2004; Retz 2008). We have assessed these drug applications further in a separate research project (Boesen 2021a; Leufkens 2021). See the appendices for more information on clinical trial registries, pharmaceutical company databases, cross‐referenced records, and other resources (Appendix 3), drug regulatory documents (Appendix 4), and author correspondence (Appendix 5). We have made our full dataset available (see Contributions of authors).

Included studies

We included 24 randomised, parallel‐group, placebo‐controlled trials of extended‐release methylphenidate (5066 participants), conducted between 1998 and 2019 (Table 1). All 24 trials compared extended‐release methylphenidate with placebo, and two trials also included active comparators, bupropion (Levin 1998a) and atomoxetine (Weisler 2009) respectively.

Twenty‐one trials reported outcome data for our review, and three did not: the Combine Substudy 2005 appears to be unpublished; the College Study 2009 was apparently never conducted; and Asherson 2016 reported group‐level data including participants younger and older than 18 years of age, which made the data ineligible for our review. The COMPAS study (Compas 2007 GPT/Compas 2007 CM) used a factorial study design with four arms testing two comparisons (methylphenidate versus placebo; group psychotherapy versus clinical management). To allow pairwise comparisons we split up the trial into two: methylphenidate versus placebo for those receiving group psychotherapy (Compas 2007 GPT) and methylphenidate versus placebo for those receiving clinical management (Compas 2007 CM).

Key trial characteristics

The median sample size was 224 (range 20 to 725) and the median trial length was eight weeks (range 2 to 52 weeks). The trials assessed six different extended‐release methylphenidate formulations; osmotic‐controlled release oral delivery system (OROS) (14 trials), sustained‐release (SR) (4 trials), extended‐release (ER) (3 trials), long‐acting (LA) (1 trial), controlled‐release (CR) (1 trial), and dex‐methylphenidate extended‐release (1 trial). Fourteen trials used a dose‐titration design, five trials used a fixed‐dose design and included multiple methylphenidate groups, three trials used a fixed‐dose design with one methylphenidate group, and for two trials there was missing information. Twelve trials (3836 participants; 76% of total population) were industry‐sponsored, four trials (708; 14% of population) were publicly‐funded with industry involvement, seven trials (502; 10% of population) were publicly‐funded, and in one trial (20 participants) funding was unclear. See also Table 1 below.

Table 1. Key trial characteristics

Trial	Formulation	Dose design (fixed/titration)	Study start date to study end date	Sponsor	Sponsor categorisation	Number of participants	Duration in weeks	Other comments
Levin 1998a	Sustained‐release methylphenidate	Titration (40 mg to 80 mg)	February 1998 ‐October 2004	National Institute on Drug Abuse (NIDA)	Publicly funded	98	10	Number of participants includes the bupropion group
Levin 1998b	Sustained‐release methylphenidate	Titration (40 mg to 60 mg)	April 1998 ‐ March 2004	National Institute on Drug Abuse (NIDA)	Publicly funded	106	13	‐
Levin 2001	Sustained‐release methylphenidate	Fixed (20 mg)	Not reported	Not reported	Not reported	20	4	‐
Biederman 2003	Osmotic Controlled‐release Oral Delivery System (OROS) methylphenidate	Titration (36 mg to 1.3 mg/kg, max 144 mg)	June 2003 –August 2007	McNeil/Janssen	Industry trial	227	6	‐
Spencer 2003a	Dex‐methylphenidate extended release	Fixed (20 mg to 30 mg to 40 mg)	April 2003 ‐September 2003	Novartis	Industry trial	221	5	‐
Chronis‐Tuscano 2004	OROS methylphenidate	Titration (36 mg to 90 mg)	December 2004 ‐December 2006	University of Maryland and McNeil	Publicly funded, with industry involvement	20	2	According to clinicaltrials.gov, the sponsor was the University of Maryland and McNeil was a collaborator. According to the published report, the trial was “supported by” McNeil.
Rösler 2004	Extended‐release methylphenidate	Titration (10 mg to 60 mg)	November 2004 ‐May 2006	Medice	Industry trial	359	24	‐
Combine Substudy 2005	Sustained‐release methylphenidate	No data	December 2005 ‐April 2007 (estimated)	National Institute on Alcohol Abuse and Alcoholism (NIAAA)	Publicly funded	No data	12	‐
Medori 2005	OROS methylphenidate	Fixed (18 mg to 36 mg to 72 mg)	April 2005 ‐August 2006	Janssen	Industry trial	402	5	‐
Winhusen 2005	OROS methylphenidate	Titration (18 mg to 72 mg)	November 2005 ‐March 2008	National Institute on Drug Abuse (NIDA)	Publicly funded, with industry involvement	255	11	Janssen was listed as collaborator on clinicaltrials.gov.
Adler 2006	OROS methylphenidate	Titration (36 mg to 108 mg)	April 2006 ‐December 2006	McNeil	Industry trial	229	7	‐
Konstenius 2006	OROS methylphenidate	Titration (18 mg to 72 mg)	February 2006 ‐June 2007	Addiction Centre Stockholm	Publicly funded	24	12	‐
Compas 2007 (Compas 2007 CM; Compas 2007 GPT)	Extended‐release methylphenidate	Titration (10 mg to 60 mg, or up to 1.3 mg/kg)	April 2007 ‐August 2011	German Federal Ministry of Education and Research	Publicly funded, with industry involvement	433	52	Medice’s medical director was involved in designing the trial and collecting data according to the published reports.
Ginsberg 2007	OROS methylphenidate	Fixed (72 mg)	May 2007 ‐ April 2010	Karolinska University Hospital	Publicly funded	30	5	‐
Konstenius 2007	OROS methylphenidate	Titration (18 mg to 180 mg)	April 2007 ‐September 2011	Addiction Centre Stockholm	Publicly funded	54	24	‐
Casas 2008	OROS methylphenidate	Fixed (54 mg to 72 mg)	February 2008 ‐ April 2009	Janssen	Industry trial	279	13	‐
Retz 2008	Extended‐release methylphenidate	Titration (40 mg to 120 mg)	September 2008 ‐ January 2010	Medice	Industry trial	162	8	‐
College Study 2009	OROS methylphenidate	No data	No data	University of Pittsburgh	Publicly funded, with industry involvement	No data	8	Study was seemingly never conducted. Ortho‐McNeil‐Janssen was listed as collaborator on clinicaltrials.gov.
Goodman 2009	OROS methylphenidate	Titration (18 mg to 72 mg)	July 2009 ‐February 2010	Janssen	Industry trial	357	6	‐
Weisler 2009	OROS methylphenidate	Fixed (54 mg)	May 2009 ‐January 2010	Janssen	Industry trial	216	6	Number of participants includes the atomoxetine group, but not the bavisant groups
Huss 2010	Long‐acting methylphenidate	Fixed (40 mg to 60 mg to 80 mg)	November 2010 ‐ August 2012	Novartis	Industry trial	725	9	‐
Takahashi 2011	OROS methylphenidate	Titration (18 mg to 72 mg)	March 2011 ‐ April 2012	Janssen	Industry trial	284	8	‐
Weiss 2014	Controlled‐release methylphenidate	Fixed (25 mg to 45 mg to 70 mg to 100 mg)	October 2014 ‐January 2015	Purdue	Industry trial	375	4	‐
Asherson 2016	OROS methylphenidate	Titration (18 mg to 72 mg)	May 2016 ‐July 2019	King’s College London	Publicly funded	190	8	Number of participants includes those aged 18 years and older only

Setting and participants

Twenty‐one trials had an outpatient setting and three trials were conducted in prison (Ginsberg 2007; Konstenius 2007; Asherson 2016). The industry trials were homogeneous by setting, population and trial design. The five publicly‐funded trials that reported outcome data for this review either included participants with a comorbid substance abuse diagnosis (Levin 1998a; Levin 1998b; Konstenius 2006), or were conducted in prison with inmates (Ginsberg 2007), or both (Konstenius 2007). We summarise trial setting and participant characteristics in Table 2 below.

Table 2. Key trial settings and participant characteristics

Trial ID	Location, number of sites	Mean age in years	% of male	Required co‐diagnosis	Other trial characteristics
Levin 1998a	USA, 5 sites	39	57	Opiate dependence	All participants were maintained on a methadone program during the trial. Assessed substance use outcomes as well
Levin 1998b	USA, 2 sites	37	83	Cocaine dependence	Assessed substance use outcomes as well
Levin 2001	USA, 1 site	37	63	No	None
Biederman 2003	USA, 1 site	36	55	No	None
Spencer 2003a	USA, 18 sites	39	57	No	None
Chronis‐Tuscano 2004	USA, 1 site	40	0	No	All participants were mothers who had daughters also diagnosed with attention deficit hyperactivity disorder
Rösler 2004	Germany, 28 sites	35	50	No	None
Combine Substudy 2005	USA, 1 site	No data	No data	Alcohol dependence	None
Medori 2005	13 European countries, 48 sites	34	54	No	None
Winhusen 2005	USA, 6 sites	38	57	No	All participants received a transdermal nicotine patch as part of a smoking cessation programme. Assessed smoking‐related outcomes as well
Adler 2006	USA, 27 sites	39	56	No	None
Konstenius 2006	Sweden, 1 site	37	79	Amphetamine dependency	Assessed substance use outcomes as well
Compas 2007 (Compas 2007 CM; Compas 2007 GPT)	Germany, 7 sites	35	50	No	Factorial study design (methylphenidate versus placebo; group psychotherapy versus clinical management)
Ginsberg 2007	Sweden, 1 site	34	100	No	Conducted in a prison setting with male inmates
Konstenius 2007	Sweden, 1 site	42	100	Amphetamine dependence	Conducted in prison setting with male inmates; first 2 weeks of trial in prison before release, and remaining 22 weeks outside prison. Assessed substance use outcomes as well
Casas 2008	11 European countries, 42 sites	36	52	No	None
Retz 2008	Germany, 11 sites	37	47	No	None
College Study 2009	USA, 1 site	No data	No data	No	Study not conducted
Goodman 2009	USA, 35 sites	36	53	No	None
Weisler 2009	USA, 37 sites	33	62	No	None
Huss 2010	9 countries (Belgium, Sweden, Denmark, Germany, Norway, Columbia, South Africa, USA, Singapore), 67 sites	35	55	No	None
Takahashi 2011	Japan, 39 sites	34	49	No	None
Weiss 2014	USA and Canada, 38 sites	36	47	No	None
Asherson 2016	UK, 3 sites	No data	100	No	Conducted in a prison setting with male inmates

Excluded studies

We excluded 144 reports after full‐text reading (Figure 1). Fifty‐seven reported on an ineligible study design (e.g. no blinding, or no control group); 33 reported on an ineligible intervention (e.g. immediate‐release methylphenidate); 22 were duplicates; 16 included ineligible patient populations (e.g. children with ADHD or adults diagnosed with psychiatric diagnoses other than ADHD); and 16 were irrelevant (e.g. not reporting in clinical trials).

We report, in detail, 38 full‐text reports, falling into four categories:

1. extended‐release methylphenidate trials using a cross‐over design (9 reports);

2. non‐blind or industry‐sponsored open‐label extension phases of already‐included trials (9 reports);

3. immediate‐release methylphenidate trials (we only list trials not already included in the immediate‐release methylphenidate reviews by Cândido 2021 or Epstein 2014, or when it was difficult to determine the used formulation) (9 reports);

4. trials with other design issues, such as randomisation to an intervention in which both groups received methylphenidate (11 reports).

See Characteristics of excluded studies tables for details.

Studies awaiting classification

We were unable to retrieve seven records from our systematic searches. All seven were conference proceedings, and probably not reporting on trials of relevance to this review. See details in Characteristics of studies awaiting classification.

Ongoing studies

We identified one French publicly‐funded study (Methacan 2017), which is scheduled to be completed in May 2022. It includes adults diagnosed with ADHD and comorbid cannabis dependence.

Risk of bias in included studies

We assessed the risks of bias for the 21 studies reporting outcome data (Figure 2). See the individual assessments in the Characteristics of included studies tables. We did not assess the risk of bias for the three trials (College Study 2009; Combine Substudy 2005; Asherson 2016) from which we had no data, or from the ongoing trial (Methacan 2017).

2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Fifteen studies described adequate methods for randomisation and allocation concealment and were rated at low risk of selection bias, while six studies reported insufficient information and were rated at unclear risk (Levin 1998a; Levin 1998b; Levin 2001; Spencer 2003a; Chronis‐Tuscano 2004; Rösler 2004).

Blinding

We rated all 21 trials at unclear risk of bias for blinding of participants and personnel and blinding of investigators. Thirteen trials used a dose titration schedule and eight trials used a fixed‐dose trial design (Levin 2001; Spencer 2003a; Medori 2005; Ginsberg 2007; Casas 2008; Weisler 2009; Huss 2010; Weiss 2014). One trial (Konstenius 2007) reported testing for unblinding. The trial used a dose titration design and tested whether the participants could guess their allocation during the titration phase. They reported that 48% of the participants in each group correctly guessed their allocation, 11% and 26% were wrong, and 41% and 26% were uncertain. Thus, the blinding was less than perfect. The remaining trials did not report whether or not they tested for unblinding.

Incomplete outcome data

We rated four trials at low risk of attrition bias. Two of these trials had no dropouts, Chronis‐Tuscano 2004 lasted two weeks only and Ginsberg 2007 was conducted in a prison setting, and two industry‐sponsored trials had low dropout rates (Retz 2008; 5% for methylphenidate, 4% for placebo) and (Takahashi 2011; 6% and 4%), respectively). We judged the remaining 17 trials to be at high risk of attrition bias, as the total dropout rates ranged from 10% to 63% in the methylphenidate groups and 6% to 55% in the placebo groups. Some trials had similar dropout rates between the groups, but most trials had more dropouts in either the methylphenidate or the placebo group; see our meta‐analysis (Analysis 3.1). Eleven of these trials stated that they conducted intention‐to‐treat analyses by using the last observation forward (LOCF). Fifteen trials also reported dropouts due to adverse events, generally favouring placebo (see meta‐analysis Analysis 3.2). We noted aberrations in two trials (Casas 2008; Huss 2010); the combination of high dropout rates and the use of the LOCF method meant that more participants were categorised as 'responders', i.e. benefiting from the drug, than the actual number of participants completing the trials in the high‐dose groups.

3.1. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 1: Dropout (overall)

3.2. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 2: Dropout (due to adverse events)

Selective reporting

We rated two trials as having a low risk of reporting bias (Compas 2007 CM/Compas 2007 GPT; Ginsberg 2007), two trials as having unclear risk (Medori 2005; Casas 2008), and all other trials as having a high risk. Harms were particularly poorly reported. Nineteen trials reported on adverse events to various degrees, but we had access to the full lists without reporting thresholds for two trials only, Compas 2007 (Compas 2007 GPT/Compas 2007 CM) and Ginsberg 2007. Adverse events reporting thresholds were prevalent also in drug regulatory documents, and thresholds varied for different documents describing the same trials.

Other potential sources of bias

We rated one trial (Retz 2008) at high risk of other bias due to baseline differences in gender distribution and self‐rated symptom severity. We rated one trial at unclear risk of other bias (Spencer 2003a), since it was noted in the FDA review that an audit of trial sites had found a miscoding of a participant's reasons for dropping out, which meant we could not judge the overall impact. We rated the remaining trials at low risk of other bias.

Overall risk of bias assessment

We rated 20 studies at an overall 'high risk' of bias and one trial (Ginsberg 2007) at an overall 'unclear risk' of bias. We rated the blinding domains as 'unclear risk' for all trials, and we identified substantial biases in the attrition and reporting bias domains.

Generalisability (external validity) assessment

We considered all 21 trials to have at least one design characteristic rated at high risk of limiting the external validity (Figure 2). We rated 14 trials (3539 participants, 70% of total population) at high risk regarding all three design characteristics, 9 of which were industry trials. See the individual assessments in the Characteristics of included studies tables.

Restrictive inclusion criteria

We rated one trial at low risk (Konstenius 2007), one at unclear risk (Ginsberg 2007), and 19 trials at high risk due to restrictions of allowed psychiatric comorbidity. The limited external validity of these trials was acknowledged in several reports (Chronis‐Tuscano 2004; Adler 2006; Compas 2007 GPT/Compas 2007 CM; Casas 2008; Huss 2010; Takahashi 2011).

Responder selection ('enriched design')

We considered two trials to be at unclear risk (Levin 2001; Biederman 2003) and 19 trials to be at high risk; 16 of these trials described how participants were excluded based on previous treatment response; for example, due to a “history of poor response” (Spencer 2003a), were “known non‐responders” (Casas 2008) or “non‐responsive” (Ginsberg 2007). Three trials reported how many of the participants had previously been exposed to methylphenidate (Chronis‐Tuscano 2004; Rösler 2004; Retz 2008).

Withdrawal effects

We rated one trial (Goodman 2009) at low risk since the inclusion criteria stipulated stimulant treatment was not allowed within five years of enrolment. We rated four trials at unclear risk, either due to a lack of information (Levin 2001; Biederman 2003; Weisler 2009) or because of a washout phase of six months (Compas 2007 GPT/Compas 2007 CM). We rated 16 trials at high risk due to washout or CNS stimulant‐free periods between one week (Levin 1998b), one to two weeks (Adler 2006; Weiss 2014), one to four weeks (Spencer 2003a; Huss 2010; Takahashi 2011), two weeks (Levin 1998a; Rösler 2004; Konstenius 2006; Ginsberg 2007; Konstenius 2007; Casas 2008; Retz 2008) and one month (Medori 2005; Winhusen 2005), respectively. Chronis‐Tuscano 2004 did not specify the washout period, but the trial was designed in a way that exposed all participants to the methylphenidate before randomisation.

Effects of interventions

See: Table 1

Extended‐release methylphenidate versus placebo

Twenty‐one trials reported outcome data for this comparison. All 21 trials reported short‐term outcome data between two and 26 weeks of follow‐up, and one trial also reported outcome data at 52 weeks of follow‐up (Compas 2007 CM/Compas 2007 GPT). Due to large dropout rates at 52 weeks, we analysed the symptom‐rating scale data using both the 'completers’ and 'last mean carried forward' datasets, as reported by the authors. No trials with a continuous randomised, placebo‐controlled phase reported long‐term follow‐up of more than 52 weeks.

Primary outcomes

Functional outcomes

Short‐term follow‐up (up to six months)

One trial (two comparisons; Compas 2007 CM/Compas 2007 GPT) reported a mean difference (MD) of −0.15 days (95% CI −2.11 to 1.81; I² = 68%; 1 trial, 409 participants; very low‐certainty evidence) missed at work/school/training at 13 weeks of follow‐up (Analysis 1.1), and −0.42 days (95% CI −2.48 to 1.64; I² = 39%; 1 trial, 2 comparisons, 329 participants; very low‐certainty evidence) between 13 and 26 weeks (Analysis 1.2).

1.1. Analysis.

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 1: Days missed at work/school/training (week 13)

1.2. Analysis.

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 2: Days missed at work/school/training (weeks 13‐26)

Three trials specified functional outcomes we could not analyse: College Study 2009 defined Grade Points Average (i.e. final grades for college students) but the trial was not conducted. Konstenius 2007 defined “relapse to crime” (e.g. readmission to prison) and Asherson 2016 prespecified “number of adjudications for antisocial behaviour” and “positive incentive and earned privileges” in prison, but the outcomes were not reported.

Medium‐term follow‐up (at 52 weeks)

The MD was 0.71 days (95% CI −1.61 to 3.03; I² = 0%; 1 trial, 2 comparisons, 292 participants; very low‐certainty evidence) missed from work/school/training in favour of placebo between weeks 26 and 52 using completers' data (Analysis 1.3). We asked the corresponding author for baseline to week 52 data, but did not receive the information.

1.3. Analysis.

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 3: Days missed at work/school/training (weeks 26‐52)

Self‐rated ADHD symptom severity

Short‐term follow‐up (between 2 and 26 weeks)

Sixteen trials (10 reporting endpoint values, six change scores) showed a small‐to‐moderate SMD −0.37 (95% CI −0.43 to −0.30; I² = 0%; 16 trials, 17 comparisons, 3799 participants; very low‐certainty evidence) in favour of methylphenidate (Analysis 1.4). The funnel plot was symmetrical (Figure 3). Ginsberg 2007 was a small study (30 participants) conducted in a prison setting. The trial reported an SMD of 1.6, which we considered to be an outlier and removed it from the meta‐analysis. The overall result did not change. 

1.4. Analysis.

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 4: ADHD symptoms (self‐rated) (short‐term)

3.

Funnel plot. Extended‐release methylphenidate versus placebo: ADHD symptoms (self‐rated).

The MD was −3 points (95% CI −4.34 to −1.76; I² = 13%; 6 trials, 7 comparisons, 1189 participants) on the most commonly‐used DSM‐IV Total ADHD 18‐item scale (range 0 to 54 points) (Analysis 1.5).

1.5. Analysis.

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 5: ADHD symptoms (self‐rated) [subgroup MD] (short‐term)

Medium‐term follow‐up (at 52 weeks)

The MD was −1.59 points (95% CI −4.26 to 1.09; I² = 20%; 1 trial, 2 comparisons, 234 participants; very low‐certainty evidence) on the DSM‐IV Total ADHD scale (range 0 to 54), using completers’ data (Analysis 1.6). The MD was −2.23 points (95% CI −3.50 to −0.95; I² = 2%; 1 trial, 2 comparisons, 419 participants; very low‐certainty evidence) on the ADHD Index (range 0 to 36) using the last mean carried forward data (Analysis 1.7).

1.6. Analysis.

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 6: ADHD symptoms (self‐rated) (medium‐term)

1.7. Analysis.

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 7: ADHD symptoms (self‐rated) [LMCF data] (medium‐term)

Serious adverse events

Short‐ and medium‐term follow‐up (between 5 and 52 weeks)

There was no evidence of a difference between the groups on this outcome (RR 1.43, 95% CI 0.85 to 2.43; I² = 0%; 14 trials, 15 comparisons, 4078 participants; very low‐certainty evidence) (Analysis 1.8). The funnel plot was symmetrical (Figure 4). See Appendix 6 for the full list of events.

1.8. Analysis.

Comparison 1: Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term), Outcome 8: Serious adverse events

4.

Funnel plot of comparison: 1 Extended‐release methylphenidate versus placebo ‐ primary outcomes (short and medium term), outcome: 1.8 Serious adverse events.

Secondary outcomes

Quality of life

Short‐term follow‐up (between 4 and 26 weeks)

Six trials (3 reporting endpoint values, 3 change scores) showed a small SMD of −0.15 (95% −0.25 to −0.05; I² = 0%; 6 trials, 7 comparisons, 1888 participants; very low‐certainty evidence), favouring methylphenidate (Analysis 2.1). Two studies did not report prespecified quality‐of‐life outcomes (Biederman 2003; Adler 2006), one trial did not report data for adults aged 18 years and older separately (Asherson 2016), and one trial reported subscales only but not a total score (Goodman 2009).

2.1. Analysis.

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 1: Quality of life (self‐rated) (short‐term)

The MD was −0.9 points (95% CI −2.17 to 0.31; I² = 0%; 4 trials, 5 comparisons, 1234 participants) on the most commonly‐used scale, Q‐LES‐QSF (range 14 to 70 points) (Analysis 2.2). The minimal important difference on this scale has been estimated to be 3 points (Mick 2008).

2.2. Analysis.

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 2: Quality of life (self‐rated) [subgroup MD] (short‐term)

Medium‐term follow‐up (at 52 weeks)

The MD was −0.66 points (95% CI −2.97 to 1.64; I² = 36%; 1 trial, 2 comparisons, 419 participants; very low‐certainty evidence; Analysis 2.3).

2.3. Analysis.

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 3: Quality of life (self‐rated) (medium‐term)

Investigator‐rated ADHD symptom severity

Short‐term follow‐up (between 2 and 26 weeks)

Eighteen trials (15 reporting endpoint values, 3 change scores) showed a small‐to‐moderate SMD of −0.42 (95% CI −0.49 to −0.36; I² = 0%; 18 trials, 19 comparisons, 4183 participants; very low‐certainty evidence), favouring methylphenidate (Analysis 2.4). The funnel plot was symmetrical around the large trials (Figure 5). As with self‐rated symptoms (Analysis 1.4), we removed Ginsberg 2007 from this analysis. The trial reported an SMD of 2.1, which seemed to be an outlier. Had we retained Ginsberg 2007, the funnel plot would be symmetrical also around the smaller trials, but it does not affect our result.

2.4. Analysis.

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 4: ADHD symptoms (investigator rated) (short‐term)

5.

Funnel plot of comparison: 2 Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short‐ and medium‐term), outcome: 2.4 ADHD symptoms (investigator‐rated) (short‐term).

The MD was −4.74 points (95% CI −5.65 to −3.84; I² = 15%; 11 trials, 12 comparisons, 3121 participants) on the most commonly‐used rating scale, DSM‐IV Total ADHD 18‐item (range 0 to 54 points) (Analysis 2.5).

2.5. Analysis.

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 5: ADHD symptoms (investigator‐rated) [subgroup MD] (short‐term)

Medium‐term follow‐up (at 52 weeks)

The MD was −1.29 points (95% CI −3.38 to 0.80; I²= 0%; 1 trial, 2 comparisons, 243 participants; very low‐certainty evidence) on the DSM‐IV Total ADHD rating scale (range 0 to 54) using completers' data (Analysis 2.6). The MD was −2.18 points (95% CI −3.55 to −0.80; I² = 15%; 1 trial, 2 comparisons, 419 participants; very low‐certainty evidence) on the ADHD Index (range 0 to 36) using the last mean carried forward data (Analysis 2.7).

2.6. Analysis.

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 6: ADHD symptoms (investigator‐rated) (medium‐term)

2.7. Analysis.

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 7: ADHD symptoms (investigator‐rated) [LMCF data] (medium‐term)

Peer‐rated ADHD symptom severity

Short‐term follow‐up (between 4 and 9 weeks)

Three trials reported on this outcome. The raters were called "subject‐designated raters" (Goodman 2009), "assessments made by friend, family members or colleague" (Huss 2010), and "consistent observer" (Weiss 2014). They found a small‐to‐moderate SMD of −0.31 (95% CI −0.48 to −0.14, I² = 18%; 1005 participants; very low‐certainty evidence), favouring methylphenidate (Analysis 2.8).

2.8. Analysis.

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 8: ADHD symptoms (peer‐rated) (short‐term)

Severe psychiatric adverse events

Short‐term follow‐up (up to six months)

The components of this outcome were inconsistently reported. We did not perform a meta‐analysis, due to scarcity and heterogeneity of data, but all available data are presented in Appendix 7.

Cardiovascular parameters

Short‐ and medium‐term follow‐up (between 5 and 52 weeks)

Eleven trials (5 reporting endpoint values, 6 change scores) showed a difference in pulse of 4.64 beats per minute (95% CI 3.13 to 6.15; I² = 65%; 11 trials, 12 comparisons, 2558 participants; very low‐certainty evidence), higher for methylphenidate (Analysis 2.9). There was no difference for systolic blood pressure (Analysis 2.10), whereas 10 trials (5 reporting endpoint values, 5 change scores) showed a difference in diastolic blood pressure of 1.24 mm Hg (95% CI 0.04 to 2.44; I² = 60%; 10 trials, 11 comparisons, 2276 participants; very low‐certainty evidence) higher for methylphenidate (Analysis 2.11). We noted that Konstenius 2007 did not report data on diastolic blood pressure from the placebo group (and it was not included in the analysis), but the methylphenidate group data were the same before and after treatment, down to the decimal place.

2.9. Analysis.

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 9: Cardiovascular: pulse (beats per minute)

2.10. Analysis.

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 10: Cardiovascular: systolic blood pressure

2.11. Analysis.

Comparison 2: Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term), Outcome 11: Cardiovascular: diastolic blood pressure

Adverse events

Short‐ and medium‐term follow‐up (between 2 and 52 weeks)

For overall dropout, there was no evidence of a difference between the groups (RR 1.01, 95% CI 0.84 to 1.21; I² = 59%; 21 trials, 22 comparisons, 4769 participants; very low‐certainty evidence; Analysis 3.1). For dropouts due to adverse events, the RR was 2.36 (95% CI 1.62 to 3.43; I² = 16%; 15 trials, 3963 participants; very low‐certainty evidence), favouring placebo (Analysis 3.2). For participants experiencing any adverse event, the RR was 1.27 (95% CI 1.19 to 1.37; I² = 69%; 14 trials, 15 comparisons, 4214 participants; very low‐certainty evidence), favouring placebo (Analysis 3.3). For number of adverse events, three trials (951 participants) reported on 2183 events in 586 participants on methylphenidate and 1216 events in 365 participants on placebo (see full dataset; Contributions of authors). For participants experiencing any psychiatric adverse event, the RR was 1.83 (95% CI 1.43 to 2.34; I² = 68%; 8 trials, 9 comparisons, 2737 participants, very low‐certainty evidence), favouring placebo (Analysis 3.4); note, only one study (Biederman 2003) reported the exact criteria for this outcome. Weight was −1.78 kg (CI 95% CI −2.36 to −1.20, I² = 81%; 10 trials, 11 comparisons, 2302 participants; very low‐certainty evidence), lower for those on methylphenidate (Analysis 3.5).

3.3. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 3: Adverse events (proportion experiencing any adverse event)

3.4. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 4: Psychiatric adverse events (proportion of participants)

3.5. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 5: Weight (change in kilograms)

We estimated the RR for 12 specific adverse effects (see Table 3, and Analysis 3.6 to Analysis 3.17 for further detail). Ten events occurred more frequently for those on methylphenidate, with RRs ranging from 1.35 (95% CI 1.18 to 1.54) for headache to 5.52 (95% CI 2.77 to 10.99) for feeling jittery. Two events, depression and irritability, did not occur more frequently for those on methylphenidate. We rated the certainty of the evidence as very low for all effect estimates.

3.6. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 6: Adverse event: decreased appetite

3.17. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 17: Adverse event: aggression

Table 3. Adverse events table

Adverse event	Number of trials (participants)	Risk ratio (95% Confidence Interval)	I2	Analysis
Decreased appetite	16 trials, 17 comparisons (4491 participants)	4.08 (3.34 to 4.98)	0%	Analysis 3.6
Dry mouth	16 trials, 17 comparisons (4491 participants)	3.36 (2.61 to 4.34)	16%	Analysis 3.7
Headache	16 trials, 17 comparisons (4238 participants)	1.35 (1.18 to 1.54)	0%	Analysis 3.8
Palpitations	15 trials, 16 comparisons (4274 participants)	3.67 (2.42 to 5.57)	12%	Analysis 3.9
Insomnia	16 trials, 17 comparisons (4435 participants)	1.97 (1.51 to 2.57)	5%	Analysis 3.10
Sexual dysfunction	9 trials, 10 comparisons (3057 participants)	2.66 (1.31 to 5.39)	0%	Analysis 3.11
Anxiety	13 trials, 14 comparisons (3829 participants)	2.23 (1.40 to 3.57)	28%	Analysis 3.12
Depression	9 trials, 10 comparisons (2791 participants)	1.47 (0.87 to 2.49)	39%	Analysis 3.13
Irritability	11 trials, 12 comparisons (3377 participants)	1.39 (1.00 to 1.93)	0%	Analysis 3.14
Feeling jittery	7 trials (2254 participants)	5.52 (2.77 to 10.99)	0%	Analysis 3.15
Agitation	10 trials, 11 comparisons (3166 participants)	2.16 (1.25 to 3.71)	9%	Analysis 3.16
Aggression	4 trials, 5 comparisons (1319 participants)	2.10 (1.32 to 3.33)	0%	Analysis 3.17

Subgroup and sensitivity analyses

Six outcomes met our predefined threshold for conducting subgroup and sensitivity analyses, i.e. I² above 50%. We considered it inappropriate to analyse four of these outcomes, due to probable selective reporting: pulse was reported by 11 trials (Analysis 2.9); diastolic blood pressure by 10 trials (Analysis 2.11); participants experiencing psychiatric adverse events by eight trials (Analysis 3.4); and body weight by 10 trials (Analysis 3.5). We analysed two outcomes: 'overall dropout rate' (I² = 59%) (Analysis 3.1) and 'participants experiencing any adverse event' (I² = 69%) (Analysis 3.3).

Overall dropout rate

The four subgroup analyses did not show any differences for 'psychiatric comorbidity' (Analysis 4.1), 'responder selection' (Analysis 4.2, 'withdrawal effects' (Analysis 4.3), or 'conflicts of interest' (Analysis 4.4). We did not conduct the sensitivity analysis based on attrition bias.

4.1. Analysis.

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 1: Overall dropout rate: psychiatric comorbidity (subgroup analysis)

4.2. Analysis.

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 2: Overall dropout rate: 'enriched design' (subgroup analysis)

4.3. Analysis.

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 3: Overall dropout rate: withdrawal effects (subgroup analysis)

4.4. Analysis.

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 4: Overall dropout rate: funding (subgroup analysis)

Participants experiencing any adverse events

There were no differences in the two subgroup analyses for psychiatric comorbidity (Analysis 4.5) and 'withdrawal effects' (Analysis 4.6), whereas the subgroup analysis of 'conflicts of interest' showed a higher proportion of participants experiencing adverse events in industry‐funded trials compared to publicly‐funded trials with industry involvement (Analysis 4.7). We did not conduct the 'responder selection' subgroup analysis, since all trials were classified at high risk of being enriched. The sensitivity analysis based on attrition bias showed no evidence of a difference (Analysis 4.8).

4.5. Analysis.

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 5: Proportion experiencing any adverse event: psychiatric comorbidity (subgroup analysis)

4.6. Analysis.

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 6: Proportion experiencing any adverse event: withdrawal effects (subgroup analysis)

4.7. Analysis.

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 7: Proportion experiencing any adverse event: funding (subgroup analysis)

4.8. Analysis.

Comparison 4: Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses, Outcome 8: Proportion experiencing any adverse event: dropout rates (sensitivity analysis)

Extended‐release methylphenidate versus atomoxetine

Weisler 2009 compared OROS methylphenidate 54 mg per day (68 participants) and atomoxetine 80 mg per day (74 participants) at six‐week follow‐up. The trial also included a placebo comparison (these results are reported above).

Primary outcomes

Functional outcomes

There were no data for this outcome.

Self‐rated ADHD symptom severity

There was no difference between OROS methylphenidate and atomoxetine for this outcome (MD −0.66, 95% CI −6.36 to 5.04; 1 trial, 142 participants; very low‐certainty evidence; Analysis 5.1) when assessed with the CAARS:DSM IV total ADHD scale (range 0 to 54 points).

5.1. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 1: ADHD symptoms (self‐rated)

Serious adverse events

There was no difference between OROS methylphenidate and atomoxetine (RR 3.26, 95% CI 0.14 to 78.72; 1 trial, 142 participants; very low‐certainty evidence; Analysis 5.2).

5.2. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 2: Serious adverse events

Secondary outcomes

There were differences favouring atomoxetine on two outcomes: initial insomnia (RR 5.44, 95% CI 1.65 to 17.98; 1 trial, 142 participants; very low‐certainty; Analysis 5.3) and weight change (MD −0.91 kg, 95% CI −1.49 to −0.33; 1 trial, 142 participants; very low‐certainty evidence; Analysis 5.4).

5.3. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 3: Adverse event: initial insomnia

5.4. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 4: Weight

There were no differences for the other secondary outcomes of investigator‐rated ADHD symptoms (Analysis 5.5), overall dropout rates (Analysis 5.6), proportion of participants experiencing adverse events (Analysis 5.7), dropouts due to adverse events (Analysis 5.8), headache (Analysis 5.9), decreased appetite (Analysis 5.10), irritability (Analysis 5.11), dry mouth (Analysis 5.12), decreased libido (Analysis 5.13), feeling jittery (Analysis 5.14), or palpitations (Analysis 5.15).

5.5. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 5: ADHD symptoms (investigator‐rated)

5.6. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 6: Overall dropout

5.7. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 7: Adverse events (AE): proportion experiencing any AE

5.8. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 8: Adverse events (leading to dropout)

5.9. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 9: Adverse event: headache

5.10. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 10: Adverse event: decreased appetite

5.11. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 11: Adverse event: irritability

5.12. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 12: Adverse event: dry mouth

5.13. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 13: Adverse event: decreased libido

5.14. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 14: Adverse event: feeling jittery

5.15. Analysis.

Comparison 5: Extended‐release methylphenidate versus atomoxetine, Outcome 15: Adverse events: palpitations

Extended‐release methylphenidate versus bupropion

Levin 1998a compared sustained‐release methylphenidate (32 participants) and bupropion 400 mg per day (33 participants) at 10‐week follow‐up.

Primary outcomes

Functional outcomes

There were no data for this outcome.

Self‐rated ADHD symptom severity

There was no difference between SR methylphenidate and bupropion for self‐rated ADHD symptom severity (MD 3.46, 95% CI −1.40 to 8.32; 1 trial, 65 participants; very low‐certainty evidence), assessed with the Adult ADHD Rating Scale (range 0 to 54 points) (Analysis 6.1).

6.1. Analysis.

Comparison 6: Extended‐release methylphenidate versus bupropion, Outcome 1: ADHD symptoms (self‐rated)

Serious adverse events

There were no data for this outcome.

Secondary outcomes

There were no reported differences between the groups for overall dropout rates (Analysis 6.2), or dropouts due to adverse events (Analysis 6.3); 1 trial, 65 participants.

6.2. Analysis.

Comparison 6: Extended‐release methylphenidate versus bupropion, Outcome 2: Overall dropout

6.3. Analysis.

Comparison 6: Extended‐release methylphenidate versus bupropion, Outcome 3: Dropouts due to adverse events

Certainty of the evidence

We rated the certainty of the evidence for all outcomes and for all comparisons as very low. We downgraded our certainty in the evidence in two domains; 'risk of bias' and 'indirectness'. We judged 20 of the 21 trials that reported outcome data to be at high risk of bias overall, and one trial (Ginsberg 2007) at unclear risk of bias overall. Several trial design characteristics contributed to the downgrading in the 'indirectness' domain, such as short trial duration, exclusion of participants with psychiatric comorbidity, responder selection ('enriched design'), and withdrawal effects. See also (Assessment of risk of bias in included studies).

Discussion

Summary of main results

We included 24 clinical trials (5066 participants) using six different extended‐release methylphenidate formulations for adults with ADHD. Twenty‐one trials reported data for this review, of which 12 were sponsored by industry.

We found very low‐certainty evidence that the reported beneficial effects of methylphenidate over placebo assessed with symptom‐rating scales by the participants, investigators, or peers such as family members, were small to moderate. The effect on quality of life was small, and there was no effect on 'days missed at work'. In comparing the two groups, we found no increase in the risk of serious adverse events or overall dropout among those receiving methylphenidate, whereas the risk of experiencing any adverse event, dropping out due to an adverse event, and the risk of experiencing any psychiatric adverse event were higher in the methylphenidate group. The relative risk for 10 of the 12 assessed adverse events were higher in the methylphenidate group than placebo, including headache, dry mouth, palpitations and psychiatric adverse events such as anxiety, agitation and feeling jittery, whereas there was no increased risk for two events, depression and irritability. We considered 20 out of 21 trials to be at high risk of bias, particularly due to an uncertainty related to the blinding of participants and investigators, high attrition rates, and selective outcome reporting. Eighteen of the trials had a follow‐up between 2 and 13 weeks, two trials at 24 weeks, and one trial at 52 weeks. The evidence is therefore mainly applicable to short‐term treatment, with long‐term effects largely unknown. Finally, we identified important limitations about the generalisability of the results.

Two trials, Levin 1998a and Weisler 2009, reported on comparisons of extended‐release methylphenidate versus other ADHD medications, bupropion and atomoxetine. The trials had modest sample sizes (98 and 216 participants) and the direct comparative evidence is therefore sparse. There were no differences between the drugs on most reported outcomes, and no conclusions can be drawn. We also note with concern that we did not identify trials comparing immediate‐release with extended‐release methylphenidate, nor different extended‐release formulations compared with each other. We are currently raising the issue related to the lack of direct comparisons in ADHD drug authorisations (Boesen 2021b; Boesen 2021c).

Overall completeness and applicability of evidence

We searched drug regulatory agency databases, and included more than 1100 pages of regulatory documents from drug approval reviews, public assessment reports, and other documents. Despite these efforts, our results are limited by selective reporting. Important patient‐relevant outcomes were not reported in a number of the included trials: 14 of 21 trials reported on serious adverse events, 10 reported on cardiovascular variables; six of 10 trials reported on prespecified quality‐of‐life outcomes (of which, only one study, Takahashi 2011, appeared in a journal publication; the other results were obtained from regulatory documents), and only one trial reported a functional outcome. Additionally, only seven of our 23 attempts to contact authors were fruitful in obtaining more information or more outcome data from the clinical trials (Appendix 5).

The rates of important psychiatric harms are uncertain. In the British drug regulator's OROS methylphenidate public assessment report (British Medicines and Healthcare products Regulatory Agency; MHRA), we noted that “psychosis/mania” was reported to occur in 3% of participants on methylphenidate versus 1% in the placebo group during the double‐blind placebo‐controlled phase (MHRA 2010, p 63). This estimate, based on three pivotal trials (Medori 2005; Adler 2006; Casas 2008), is 30 times higher than the 0.1% risk of “new psychotic or symptoms” according to the FDA’s Prescribing Information (FDA 2017, section 5.2). We also noted large differences across trials that were not explained by obvious trial differences. For example, Rösler 2004 reported that 11% of participants on methylphenidate experienced "reduced libido", compared to 1% in the pooled analysis of Medori 2005, Adler 2006, and Casas 2008 (MHRA 2010, p 61). The Dutch drug regulatory agency (Dutch Medicines Evaluation Board; MEB) noted in their public assessment report of long‐acting methylphenidate (which they did not approve for market authorisation) that the strict exclusion criteria probably reduced the incidence of reported harms in the trials:

“Psychiatric AEs were common (i.e. total of 43%, including insomnia 11%, anxiety 7%, irritability 7%, and restlessness 7%) and some were serious. Since these events were more common in patients with a psychiatric history and since elaborate psychiatric exclusion criteria were implemented in the study, which prevented inclusion of patients with more serious psychiatric comorbidity, it is concluded that the rate of psychiatric AEs would have been even higher without these exclusions” (MEB 2016, p 36).

In terms of applicability, there is, as far as we know, limited empirical evidence on minimal important differences in rating scales used in ADHD drug trials. It is therefore uncertain whether the reported effects are clinically relevant. For the quality‐of‐life scale, Quality of Life Enjoyment and Satisfaction Questionnaire‐Short Form (range 14 to 70 points), the minimal important difference is estimated to be three points (Mick 2008); however, we found a difference between methylphenidate and placebo of only one point (Analysis 2.2). The lack of direct comparisons between methylphenidate and other ADHD drugs also limits the clinical applicability of the evidence.

Quality of the evidence

We rated the overall certainty of the evidence as 'very low' due to high risk of bias and limitations in the external validity. This means that further research is likely to change the effect estimates. The statistical heterogeneity was low for most effect estimates, which was unsurprising, since most participants were enrolled in homogeneous, industry‐sponsored trials.

A major limitation to the evidence is the limited generalisability due to several problematic trial design characteristics; exclusion of participants with psychiatric comorbidity, responder selection based on previous treatment response, potential withdrawal effects, short trial durations, and a lack of patient‐relevant outcomes. In MHRA's public assessment report on OROS methylphenidate, they noted, “Current psychiatric morbidity and a history of psychiatric morbidity appeared to reduce the effect size (excluding the 72mg dose in study 3013). No obvious pattern of differences was seen in whether the adult was MPH naïve or not” (MHRA 2010, p 51). However, in order to properly address the impact of such study designs we would need access to Clinical Study Reports and individual patient data. Ideally, new and less biased trials should be conducted.

Potential biases in the review process

There are several biases and limitations in the review. An important limitation may be the omission of potentially relevant data. As stated above, we included a large amount of regulatory data, but we were also denied access to clinical data. In 2016, we asked Medice, the Marketing Authorisation Holder of Medikinet in Europe, for access to trial data from their two pivotal trials (Rösler 2004 and Retz 2008). Medice’s medical director declined our request, with the argument that Cochrane Reviews are “full of errors and biased” and then cited an article by Banaschewski 2016, which criticised a Cochrane Review of methylphenidate for children and adolescents with ADHD (Storebø 2015). In 2019, we asked the German drug regulatory agency, Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) about access to the same trial data. The German regulator consulted with Medice, which again declined the request. We recently raised this rejection with the Heads of Medicines Agencies (Boesen 2021d; Boesen 2021e), which is a European umbrella organisation consisting of the heads of the European national drug regulatory agencies. This rejection of access to Clinical Study Reports conflicts with the European Medicines Agency's transparency policies 0043 (EMA 2018) and 0070 (EMA 2019) that grant access to data from centrally‐authorised drugs (Gøtzsche 2011; CURIA 2020; Dyer 2020).

The composite outcome of 'severe psychiatric adverse event' was not well‐suited to estimate psychiatric harms, and one should always be careful with composite outcomes. It was also a limitation that we did not specify which adverse events to assess at protocol stage. For future reviews of psychiatric drugs, we recommend prespecifying individual harms, preferably in collaboration with patients. It would also be preferable to pool adverse events according to their Medical Dictionary for Regulatory Activities (MedDRA) terms, rather than analysing individual events. Miscoding and splitting up events into separate terms may dilute potential signals of harms and make the analyses unreliable (Maund 2014). Ideally, our high‐level outcomes of harm (i.e. aggregate outcomes such as 'dropout due to adverse events'), should be defined at the protocol stage also, see Differences between protocol and review.

We did not prespecify a hierarchy for extracting data from multiple resources. Such an approach is recommended in complex reviews to avoid selectively reporting available results (Mayo‐Wilson 2017; Mayo‐Wilson 2018). We included the data that were judged as most complete and in best accordance with our specified criteria (see 'Dealing with missing data’). To be as transparent as possible, we share the full dataset (see link in Contributions of authors). Separate efforts would be required to systematically assess potential differences (Mayo‐Wilson 2017a; Jørgensen 2020; Paludan‐Müller 2021).

In most included trials, participants were allowed (to varying degrees) to continue psychopharmacological treatments, such as antidepressants and anxiolytics. How these drugs affected the reported outcomes is not known. We would probably need detailed information at an individual participant level to perform reliable subgroup analyses based on treatment status. We decided not to go into this question in detail in the current review. However, it seems to be an important research question that needs to be addressed, provided there are sufficiently granulated data.

To our knowledge, this is the first review to systematically assess external validity issues in trials of methylphenidate for ADHD in adults. It should be highlighted that our attempt to operationalise these design characteristics is open for discussion. We hope our review may increase the focus on external validity issues, which may be as pertinent from a clinical point of view as the standard risk of bias assessment when assessing the benefits and harms of drugs like methylphenidate.

Agreements and disagreements with other studies or reviews

Our results for adverse effects, cardiovascular effects, and weight changes correspond with previous systematic reviews of ADHD mediations for children and adolescents (Storebø 2015; Liang 2018; Catalá‐López 2017; Storebø 2018) and for adults (Mick 2013). Our quality assessment also agrees with Cochrane Reviews on methylphenidate for ADHD in children and adolescents (Storebø 2015; Storebø 2018), immediate‐release methylphenidate for adults (Cândido 2021), and amphetamines for ADHD in children and adolescents (Punja 2016) and adults (Castells 2018). However, it is difficult to compare our results directly with non‐Cochrane Reviews on methylphenidate for adult ADHD (Faraone 2004; Peterson 2008; Koesters 2009; Meszaros 2009; Faraone 2010; Castells 2011; Castells 2013; Cunill 2016; Cortese 2018). These reviews used different methodologies and included different drugs and trials. One of the most recent systematic reviews (Cortese 2018) reported similar effects on ADHD symptom scales, dropout rates due to adverse events, and overall dropout rates for methylphenidate. However, the review did not assess functional outcomes, quality of life or individual adverse events, and the review authors rated the certainty of the evidence for some of the outcomes as ‘moderate’ (clinician‐rated ADHD symptoms) or ‘high’ (dropout due to adverse events), whereas we rated the certainty of the evidence as ‘very low’ for all outcomes. The most recent systematic review by Elliott 2020 identified clinical trial limitations, such as external validity issues, short trial duration, and a lack of patient‐reported outcomes, similar to our own findings. The updated sister review to this review on immediate‐release methylphenidate for adult ADHD (Cândido 2021) concluded, “Clinicians should consider whether it is appropriate to prescribe IR methylphenidate, given its limited efficacy and increased risk of harms. Future RCTs should explore the long‐term efficacy and risks of IR methylphenidate, and the influence of conflicts of interest on reported effects”.

Authors' conclusions

Implications for practice.

Clinical guidelines and consensus documents, such as the European Consensus Statement (Kooij 2019), the World Federation of ADHD International Consensus Statement (Faraone 2021), and the NICE ADHD guideline (NICE 2018), should reflect the ‘very low’ certainty of the evidence. The evidence to support methylphenidate as a pharmacological treatment for ADHD in adults is weak, and treatment beyond 52 weeks is unsupported by randomised trials. Furthermore, there is inadequate direct comparative evidence to guide clinical practice about extended‐release methylphenidate against other ADHD medications. In practice, each patient should make a shared decision with their family and with their physician, and decide whether or not the reported benefits outweigh the harms for them.

Implications for research.

It seems necessary to conduct new clinical trials of extended‐release methylphenidate, to allow more reliable assessments of methylphenidate’s benefits and harms in adults with ADHD. These trials should be free from the methodological limitations highlighted in this review: Such new trials should last longer, preferably for years rather than weeks; the trial participants should be stimulant‐naïve to avoid withdrawal effects and to avoid selection bias of participants who already tolerate the drug; the trial inclusion criteria should be broad and allow inclusion of participants with relevant psychiatric comorbidities; and finally such trials should be designed to address clinically relevant outcomes, like patient‐reported quality of life and functional capacity, such as the ability to maintain social and work‐related activities. In this regard, it will be important to conduct a systematic survey of patients, peers, and healthcare professionals, a so‐called 'Core Outcome Set' study (COMET 2021), to define which outcomes to measure in ADHD drug trials. This was recently done for clinical trials in depression (Chevance 2020). Some also argue that the blinding issue in CNS stimulant trials should be resolved through the use of 'active placebos' (Storebø 2015), but other design issues may be more pertinent, and also more feasible, to address in new trials.

History

Protocol first published: Issue 11, 2017

Appendices

Appendix 1. Search strategies (databases)

Cochrane Central Register of Controlled Trials (CENTRAL)

Searched 3 October 2017 [1477 records]
Searched 12 March 2019 [114 new records]
Searched 16 February 2021 [147 new records]

#1[mh "attention deficit and disruptive behavior disorders"]
#2[mh "attention deficit disorder with hyperactivity"]
#3[mh "conduct disorder"]
#4ADHD or ADHS or ADDH or AD next HD or HKD or TDAH
#5((attention* or behav*) near/3 (defic* or dysfunc* or disorder*))
#6((disrupt* near/3 disorder*) or (disrupt* near/3 behav*) or (defian* near/3 disorder*) or (defian* near/3 behav*))
#7(impulsiv* or inattentiv* or inattention*)
#8[mh hyperkinesis]
#9(hyperkin* or hyper‐kin* or hkd)
#10(minimal near/3 brain near/3 (disorder* or dysfunct* or damage*))
#11(hyperactiv* or hyper‐activ*)
#12{or #1‐#11}
#13[mh methylphenidate]
#14(Adaphen* or Aptensio* or Aradix* or Attenade* or Biphentin* or Calocain* or Centedrin* or Concerta* or Conmet* or Daytrana* or Dexmethylphenidat* or Difumenil* or D‐methylphenidat* or Equasym* or Fenilidato* or Focalin* or Matoride* or Medicebran* or Medikid* or Medikinet* or Meridil* or Metadate* or Methylphenidylacetat* or methyl NEXT phenidylacetat* or Methylofenidan* or Methylin* or Methypatch or methylphenidat* or Metilfenidato* or Phenidylate or Phenidyl hydrochlorid* or Phenidylhydrochlorid* or Quillivant* or Richter Works or Riphenidat* or Ritalin* or Ritrocel* or Rubifen* or Tsentedrin*)
#15#13 or #14
#16    #12 and #15 in Trials    
#17    #12 and #15 with Publication Year from 2017 to 2019, in Trials   
#18    #12 and #15 with Publication Year from 2019 to 2021, in Trials    

MEDLINE Ovid

Searched 3 October 2017 [1467 records]
Searched 12 March 2019 [97 new records]
Searched 15 February 2021 [99 new records]

1 "attention deficit and disruptive behavior disorders"/
2 attention deficit disorder with hyperactivity/
3 conduct disorder/
4 ADHD.tw,kf.
5 ADHS.tw,kf.
6 ADDH.tw,kf.
7 ("AD/HD" or hkd).tw,kf.
8 TDAH.tw,kf.
9 ((attention$ or behav$) adj3 (defic$ or dysfunc$ or disorder$)).tw,kf. (49848)
10 ((disrupt$ adj3 disorder$) or (disrupt$ adj3 behav$) or (defian$ adj3 disorder$) or (defian$ adj3 behav$)).tw,kf
11 (impulsiv$ or inattentiv$ or inattention$).tw,kf.
12 hyperkinesis/
13 (hyperkin$ or hyper‐kin$).tw,kf. (4266)
14 (minimal adj3 brain adj3 (disorder$ or dysfunct$ or damage$)).tw,kf.
15 (hyperactiv$ or hyper‐activ$).tw,kf.
16 or/1‐15
17 exp Methylphenidate/
18 Adaphen$.mp.
19 Aptensio$.mp.
20 Aradix$.mp.
21 Attenade$.mp.
22 Biphentin$.mp.
23 Calocain$.mp.
24 Centedrin$.mp.
25 Concerta$.mp.
26 Conmet$.mp.
27 Daytrana$.mp.
28 Dexmethylphenidat$.mp.
29 Difumenil$.mp.
30 D‐methylphenidat$.mp.
31 Equasym$.mp.
32 Fenilidato$.mp.
33 Focalin$.mp.
34 Matoride$.mp.
35 Medicebran$.mp.
36 Medikid$.mp.
37 Medikinet$.mp.
38 Meridil$.mp.
39 Metadate$.mp.
40 (Methylphenidylacetat$ or methyl phenidylacetat$).mp.
41 Methylofenidan$.mp.
42 Methylin$.mp.
43 Methypatch.mp.
45 Metilfenidato$.mp.
44 methylphenidat$.mp.
46 Novo‐Methylphenidat$.mp.
47 Phenidylate.mp.
48 (Phenidyl hydrochlorid$ or Phenidylhydrochlorid$).mp.
49 Quillivant$.mp.
50 Richter Works.mp.
51 Riphenidat$.mp.
52 Ritalin$.mp.
53 Ritrocel$.mp.
54 Rubifen$.mp.
55 Tsentedrin$.mp.
56 or/17‐55
57 16 and 56
58 randomized controlled trial.pt.
59 controlled clinical trial.pt.
60 randomized.ab.~
61 placebo.ab.
62 clinical trials as topic.sh.
63 randomly.ab.
64 trial.ti.
65 or/58‐64
66 exp animals/ not humans.sh.
67 65 not 66
68 57 and 67
69 (201710* or 201711* or 201712* or 2018* or 2019* ).dt,ez,da,ed.70  68 and 69
71  (201902* or 201903* or 201904* or 201905* or 201906* or 201907* or 201908* or 201909* or 201910* or 201911* or 201912* or 2020* or 2021*).dt,ez,da,ed. 
72     68 and 70 

MEDLINE In_Process and Other Non‐indexed Citations OVID

Searched 3 October 2017 [126 records]
Searched 13 March 2019 [66 new records]
Searched 15 February 2021 [53 new records]

1 ADHD.tw,kf.
2 ADHS.tw,kf.
3 ADDH.tw,kf.
4 ("AD/HD" or hkd).tw,kf.
5 TDAH.tw,kf.
6 ((attention$ or behav$) adj3 (defic$ or dysfunc$ or disorder$)).tw,kf.
7 ((disrupt$ adj3 disorder$) or (disrupt$ adj3 behav$) or (defian$ adj3 disorder$) or (defian$ adj3 behav$)).tw,kf.
8 (impulsiv$ or inattentiv$ or inattention$).tw,kf.
9 (hyperkin$ or hyper‐kin$).tw,kf.
10 (minimal adj3 brain adj3 (disorder$ or dysfunct$ or damage$)).tw,kf.
11 (hyperactiv$ or hyper‐activ$).tw,kf.
12 or/1‐11
13 Adaphen$.mp.
14 Aptensio$.mp.
15 Aradix$.mp.
16 Attenade$.mp.
17 Biphentin$.mp.
18 Calocain$.mp.
19 Centedrin$.mp.
20 Concerta$.mp.
21 Conmet$.mp.
22 Daytrana$.mp.
23 Dexmethylphenidat$.mp.
24 Difumenil$.mp.
25 D‐methylphenidat$.mp.
26 Equasym$.mp.
27 Fenilidato$.mp.
28 Focalin$.mp.
29 Matoride$.mp.
30 Medicebran$.mp.
31 Medikid$.mp.
32 Medikinet$.mp.
33 Meridil$.mp.
34 Metadate$.mp.
35 (Methylphenidylacetat$ or methyl phenidylacetat$).mp.
36 Methylofenidan$.mp.
37 Methylin$.mp.
38 Methypatch.mp.
39 methylphenidat$.mp.
40 Metilfenidato$.mp.
41 Novo‐Methylphenidat$.mp.
42 Phenidylate.mp.
43 (Phenidyl hydrochlorid$ or Phenidylhydrochlorid$).mp.
44 Quillivant$.mp.
45 Richter Works.mp.
46 Riphenidat$.mp.
47 Ritalin$.mp.
48 Ritrocel$.mp.
49 Rubifen$.mp.
50 Tsentedrin$.mp.
51 or/13‐50
52 random$.tw,kf.
53 placebo.ab.
54 trial.ti.
55 RCT.tw,kf.
56 or/52‐55
57 12 and 51 and 56

MEDLINE E‐Pub Ahead of Print (OVID)

Searched 3 October 2017 [27 records]
Searched 13 March 2019 [13 new records]
Searched 15 February 2021 [22 new records]

1 ADHD.tw,kf.
2 ADHS.tw,kf.
3 ADDH.tw,kf.
4 ("AD/HD" or hkd).tw,kf.
5 TDAH.tw,kf.
6 ((attention$ or behav$) adj3 (defic$ or dysfunc$ or disorder$)).tw,kf.
7 ((disrupt$ adj3 disorder$) or (disrupt$ adj3 behav$) or (defian$ adj3 disorder$) or (defian$ adj3 behav$)).tw,kf.
8 (impulsiv$ or inattentiv$ or inattention$).tw,kf.
9 (hyperkin$ or hyper‐kin$).tw,kf
10 (minimal adj3 brain adj3 (disorder$ or dysfunct$ or damage$)).tw,kf.
11 (hyperactiv$ or hyper‐activ$).tw,kf.
12 or/1‐11
13 Adaphen$.mp.
14 Aptensio$.mp.
15 Aradix$.mp.
16 Attenade$.mp.
17 Biphentin$.mp.
18 Calocain$.mp.
19 Centedrin$.mp.
20 Concerta$.mp.
21 Conmet$.mp.
22 Daytrana$.mp.
23 Dexmethylphenidat$.mp.
24 Difumenil$.mp.
25 D‐methylphenidat$.mp.
26 Equasym$.mp.
27 Fenilidato$.mp.
28 Focalin$.mp.
29 Matoride$.mp.
30 Medicebran$.mp.
31 Medikid$.mp.
32 Medikinet$.mp.
33 Meridil$.mp.
34 Metadate$.mp.
35 (Methylphenidylacetat$ or methyl phenidylacetat$).mp.
36 Methylofenidan$.mp.
37 Methylin$.mp.
38 Methypatch.mp.
39 methylphenidat$.mp.
40 Metilfenidato$.mp.
41 Novo‐Methylphenidat$.mp.
42 Phenidylate.mp.
43 (Phenidyl hydrochlorid$ or Phenidylhydrochlorid$).mp.
44 Quillivant$.mp.
45 Richter Works.mp.
46 Riphenidat$.mp.
47 Ritalin$.mp.
48 Ritrocel$.mp.
49 Rubifen$.mp.
50 Tsentedrin$.mp.
51 or/13‐50
52 random$.tw,kf.
53 placebo.ab.
54 trial.ti.
55 RCT.tw,kf.
56 or/52‐55
57 12 and 51 and 56

Embase Ovid strategy up to 2019

Searched 2 October 2017 [2687 records]
Searched 15 March 2019 [187 new records]

1 attention deficit disorder/
2 hyperactivity/
3 conduct disorder/
4 ADHD.tw,kw.
5 ADDH.tw,kw.
6 ADHS.tw,kw.
7 ("AD/HD" or HKD).tw,kw.
8 TDAH.tw,kw.
9 ((attention$ or behav$) adj3 (defic$ or dysfunc$ or disorder$)).tw,kw.
10 ((disrupt$ adj3 disorder$) or (disrupt$ adj3 behav$) or (defian$ adj3 disorder$) or (defian$ adj3 behav$)).tw,kw.
11 (impulsiv$ or inattentiv$ or inattention$).tw,kw.
12 hyperkinesis/
13 (hyperkin$ or hyper‐kin$ or hkd).tw,kw.
14 (minimal adj3 brain adj3 (disorder$ or dysfunct$ or damage$)).tw.
15 (hyperactiv$ or hyper‐activ$).tw.
16 or/1‐15
17 methylphenidate/
18 (Adaphen$ or Aptensio$ or Aradix$ or Attenade$ or Biphentin$).mp.
19 methylphenidate/
20 (Adaphen$ or Aptensio$ or Aradix$ or Attenade$ or Biphentin$ or Calocain$ or Centedrin$ or Concerta$ or Conmet$ or Daytrana$ or Dexmethylphenidat$ or Difumenil$ or D‐methylphenidat$ or Equasym$ or Fenilidato$ or Focalin$ or Matoride$ or Medicebran$ or Medikid$ or Medikinet$ or Meridil$ or Metadate$ or Methylphenidylacetat$ or methyl phenidylacetat$ or Methylofenidan$ or Methylin$ or Methypatch or methylphenidat$ or Metilfenidato$ or Phenidylate or Phenidyl hydrochlorid$ or Phenidylhydrochlorid$ or Quillivant$ or Ritcher Works or Riphenidat$ or Ritalin$ or Ritrocel$ or Rubifen$ or Tsentedrin$).mp.
21 19 or 20
22 16 and 21
23 limit 22 to "therapy (best balance of sensitivity and specificity)"
24 remove duplicates from 23
25 limit 24 to yr="2017 ‐Current"

Embase Ovid Strategy 2021 

Searched 15 February 2021 [271 new records]
1     attention deficit disorder/ 
2     hyperactivity/ 
3     conduct disorder/ 
4     ADHD.tw,kw. 
5     ADDH.tw,kw. 
6     ADHS.tw,kw. 
7     ("AD/HD" or HKD).tw,kw. 
8     TDAH.tw,kw. 
9     ((attention$ or behav$) adj3 (defic$ or dysfunc$ or disorder$)).tw,kw.
10     ((disrupt$ adj3 disorder$) or (disrupt$ adj3 behav$) or (defian$ adj3 disorder$) or (defian$ adj3 behav$)).tw,kw.
11     (impulsiv$ or inattentiv$ or inattention$).tw,kw. 
12     hyperkinesis/ 
13     (hyperkin$ or hyper‐kin$ or hkd).tw,kw. 
14     (minimal adj3 brain adj3 (disorder$ or dysfunct$ or damage$)).tw,kw. 
15     (hyperactiv$ or hyper‐activ$).tw,kw. 
16     or/1‐15 
17     methylphenidate/ 
18     (Adaphen$ or Aptensio$ or Aradix$ or Attenade$ or Biphentin$).mp. 
19     methylphenidate/ 
20     (Adaphen$ or Aptensio$ or Aradix$ or Attenade$ or Biphentin$ or Calocain$ or Centedrin$ or Concerta$ or Conmet$ or Daytrana$ or Dexmethylphenidat$ or Difumenil$ or D‐methylphenidat$ or Equasym$ or Fenilidato$ or Focalin$ or Matoride$ or Medicebran$ or Medikid$ or Medikinet$ or Meridil$ or Metadate$ or Methylphenidylacetat$ or methyl phenidylacetat$ or Methylofenidan$ or Methylin$ or Methypatch or methylphenidat$ or Metilfenidato$ or Phenidylate or Phenidyl hydrochlorid$ or Phenidylhydrochlorid$ or Quillivant$ or Ritcher Works or Riphenidat$ or Ritalin$ or Ritrocel$ or Rubifen$ or Tsentedrin$).mp. 
21     19 or 20 
22     16 and 21 (
23     Randomized controlled trial/ 
24     Controlled clinical study/ 
25     random$.ti,ab. 
26     randomization/
27     intermethod comparison/ 
28     placebo.ti,ab. 
29     (compare or compared or comparison).ti.
30     ((evaluated or evaluate or evaluating or assessed or assess) and (compare or compared or comparing or comparison)).ab. 
31     (open adj label).ti,ab. 
32     ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab. 
33     double blind procedure/ 
34     parallel group$1.ti,ab. 
35     (crossover or cross over).ti,ab.
36     ((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab. (
37     (assigned or allocated).ti,ab. 
38     (controlled adj7 (study or design or trial)).ti,ab.
39     (volunteer or volunteers).ti,ab. 
40     human experiment/
41     trial.ti. 
42     or/23‐41 
43     (random$ adj sampl$ adj7 ("cross section$" or questionnaire$1 or survey$ or database$1)).ti,ab. not (comparative study/ or controlled study/ or randomi?ed controlled.ti,ab. or randomly assigned.ti,ab.) 
44     Cross‐sectional study/ not (randomized controlled trial/ or controlled clinical study/ or controlled study/ or randomi?ed controlled.ti,ab. or control group$1.ti,ab.) 
45     (((case adj control$) and random$) not randomi?ed controlled).ti,ab. 
46     (Systematic review not (trial or study)).ti. 
47     (nonrandom$ not random$).ti,ab. 
48     "Random field$".ti,ab. 
49     (random cluster adj3 sampl$).ti,ab. 
50     (review.ab. and review.pt.) not trial.ti. 
51     "we searched".ab. and (review.ti. or review.pt.)
52     "update review".ab. 
53     (databases adj4 searched).ab. 
54     (rat or rats or mouse or mice or swine or porcine or murine or sheep or lambs or pigs or piglets or rabbit or rabbits or cat or cats or dog or dogs or cattle or bovine or monkey or monkeys or trout or marmoset$1).ti. and animal experiment/ 
55     Animal experiment/ not (human experiment/ or human/) 
56     or/43‐55 
57     42 not 56
58     22 and 57 
59     limit 58 to yr="2019 ‐Current" 

PsycINFO Ovid

Searched 3 October 2017 [1339 records]
Searched 13 March 2019 [74 new records]
Searched 15 February 2021 [136 new records]

1 exp attention deficit disorder/
2 exp Behavior Problems/
3 adhd.tw.
4 addh.tw.
5 adhs.tw.
6 "ad/hd".tw.
7 TDAH.tw.
8 ((attention$ or behav$) adj3 (defic$ or dysfunc$ or disorder$)).tw.
9 ((disrupt$ adj3 disorder$) or (disrupt$ adj3 behav$) or (defian$ adj3 disorder$) or (defian$ adj3 behav$)).tw.
10 Impulsiveness/
11 (impulsiv$ or inattentiv$ or inattention$).tw.
12 hyperkinesis/
13 (hyperkin$ or hyper‐kin$ or hkd).tw.
14 (minimal adj3 brain$ adj3 (damag$ or disorder$ or dysfunc$)).tw.
15 (hyperactiv$ or hyper‐activ$).tw.
16 or/1‐15
17 methylphenidate/
18 (Adaphen$ or Aptensio$ or Aradix$ or Attenade$ or Biphentin$ or Calocain$ or Centedrin$ or Concerta$ or Conmet$ or Daytrana$ or Dexmethylphenidat$ or Difumenil$ or D‐methylphenidat$ or Equasym$ or Fenilidato$ or Focalin$ or Matoride$ or Medicebran$ or Medikid$ or Medikinet$ or Meridil$ or Metadate$ or Methylphenidylacetat$ or methyl phenidylacetat$ or Methylofenidan$ or Methylin$ or Methypatch or methylphenidat$ or Metilfenidato$ or Phenidylate or Phenidyl hydrochlorid$ or Phenidylhydrochlorid$ or Quillivant$ or Richter Works or Riphenidat$ or Ritalin$ or Ritrocel$ or Rubifen$ or Tsentedrin$).tw,id.
19 17 or 18
20 16 and 19
21 clinical trials/
22 random sampling/
23 placebo/
24 Experiment controls/ (836)
25 ((clinic$ or control$) adj (study or trial$ or experiment$)).tw.
26 ((compar$ or control$ or experiment$ or treat$) adj3 (subjects or group$)).tw.
27 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
28 (randomiz$ or randomis$).tw.
29 randomly.tw.
30 exp program evaluation/
31 exp treatment outcomes/
32 exp treatment effectiveness evaluation/
33 ((effectiveness or evaluat$) adj3 (stud$ or research$)).tw.
34     or/21‐33
35 20 and 34
36 limit 35 to up=20190301‐20210208

Cochrane Database of Systematic Reviews (CDSR), in the Cochrane Library

Searched 3 October 2017 [10 records]
Searched 12 March 2019 [5 new records]
Searched 16 February 2021 [1 new record]

#1[mh "attention deficit and disruptive behavior disorders"]
#2[mh "attention deficit disorder with hyperactivity"]
#3(ADHD or ADHS or ADDH or AD next HD or HKD or TDAH):ti,ab,kw
#4((attention* or behav*) near/3 (defic* or dysfunc* or disorder*)):ti,ab,kw
#5(impulsiv* or inattentiv* or inattention*):ti,ab,kw
#6(hyperactiv* or hyper next activ*):ti,ab,kw
#7{or #1‐#6}
#8[mh methylphenidate]
#9(Adaphen* or Aptensio* or Aradix* or Attenade* or Biphentin* or Calocain* or Centedrin* or Concerta* or Conmet* or Daytrana* or Dexmethylphenidat* or Difumenil* or D‐methylphenidat* or Equasym* or Fenilidato* or Focalin* or Matoride* or Medicebran* or Medikid* or Medikinet* or Meridil* or Metadate* or Methylphenidylacetat* or methyl next phenidylacetat* or Methylofenidan* or Methylin* or Methypatch or methylphenidat* or Metilfenidato* or Phenidylate or Phenidyl hydrochlorid* or Phenidylhydrochlorid* or Quillivant* or Richter Works or Riphenidat* or Ritalin* or Ritrocel* or Rubifen* or Tsentedrin*):ti,ab,kw
#10#8 or #9
#11#7 and #10 in Cochrane Reviews, Cochrane Protocols
#12#7 AND #10 with Cochrane Library publication date Between Nov 2017 and Mar 2019, in Cochrane Reviews, Cochrane Protocols    
#13 #7 AND #10 with Cochrane Library publication date Between Mar 2019 and Feb 2021, in Cochrane Reviews, Cochrane Protocols

Database of Abstracts of Reviews of Effects (DARE), in the Cochrane Library

Searched 3 October 2017 [23 records]
Not searched after 2017 as database no longer maintained.

#1[mh "attention deficit and disruptive behavior disorders"]
#2[mh "attention deficit disorder with hyperactivity"]
#3[mh "conduct disorder"]
#4ADHD or ADHS or ADDH or "AD next HD" or HKD or TDAH
#5((attention* or behav*) near/3 (defic* or dysfunc* or disorder*))
#6((disrupt* near/3 disorder*) or (disrupt* near/3 behav*) or (defian* near/3 disorder*) or (defian* near/3 behav*))
#7(impulsiv* or inattentiv* or inattention*)
#8[mh hyperkinesis]
#9(hyperkin* or hyper‐kin* or hkd)
#10(minimal near/3 brain near/3 (disorder* or dysfunct* or damage*))
#11(hyperactiv* or hyper‐activ*)
#12{or #1‐#11}
#13[mh methylphenidate]
#14(Adaphen* or Aptensio* or Aradix* or Attenade* or Biphentin* or Calocain* or Centedrin* or Concerta* or Conmet* or Daytrana* or Dexmethylphenidat* or Difumenil* or D‐methylphenidat* or Equasym* or Fenilidato* or Focalin* or Matoride* or Medicebran* or Medikid* or Medikinet* or Meridil* or Metadate* or Methylphenidylacetat* or methyl phenidylacetat* or Methylofenidan* or Methylin* or Methypatch or methylphenidat* or Metilfenidato* or Phenidylate or Phenidyl hydrochlorid* or Phenidylhydrochlorid* or Quillivant* or Ritcher Works or Riphenidat* or Ritalin* or Ritrocel* or Rubifen* or Tsentedrin*)
#15#13 or #14
#16#12 and #15 in Other Reviews

CINAHL Plus EBSCOhost

Searched 4 October 2017 [634 records]
Searched 15 March 2019 [119 new records]
Searched 16 February 2021 [98 new records]

S1(MH "Attention Deficit Hyperactivity Disorder")
S2ADHD
S3ADDH
S4ADDH
S5ADHS
S6"AD/HD" or HKD OR TDAH
S7((attention* or behav*) n3 (defic* or dysfunc* or disorder*))
S8((disrupt* N3 disorder*) or (disrupt* N3 behav*) or (defian* N3 disorder*) or (defian* N3 behav*))
S9(impulsiv* or inattentiv* or inattention*
S10(MH "Hyperkinesis")
S11hyperkin* or hyper‐kin*)
S12(minimal N3 brain N3 (disorder* or dysfunct* or damage*))
S13hyperactiv* or hyper‐activ*
S14S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13
S15(MH "Methylphenidate")
S16(Adaphen* or Aptensio* or Aradix* or Attenade* or Biphentin* or Calocain* or Centedrin* or Concerta* or Conmet* or Daytrana* or Dexmethylphenidat* or Difumenil* or D‐methylphenidat* or Equasym* or Fenilidato* or Focalin* or Matoride* or Medicebran* or Medikid* or Medikinet* or Meridil* or Metadate* or Methylphenidylacetat* or methyl phenidylacetat* or Methylofenidan* or Methylin* or Methypatch or methylphenidat* or Metilfenidato* or Phenidylate or Phenidyl hydrochlorid* or Phenidylhydrochlorid* or Quillivant* or Richter Works or Riphenidat* or Ritalin* or Ritrocel* or Rubifen* or Tsentedrin*)
S17S15 OR S16
S18S14 AND S17
S19(MH "Clinical Trials+")
S20MH random assignment
S21(MH "Meta Analysis")
S22(MH "Crossover Design")
S23(MH "Quantitative Studies")
S24PT randomized controlled trial
S25PT Clinical trial
S26(clinical trial*) or (control* N2 trial*)
S27("follow‐up study" or "follow‐up research")
S28(prospectiv* study or prospectiv* research)
S29(MH "Program Evaluation")
S30(MH "Treatment Outcomes")
S31TI(single N2 mask* or single N2 blind*) OR AB(single N2 mask* or single N2 blind*)S32TI((doubl* N2 mask*) or(doubl* N2 blind*)) OR AB((doubl* N2 mask*) or (doubl* N2 blind*))
S33TI ((tripl* N2 mask*) or (tripl* N2 blind*)) or ((trebl* N2 mask*) or (trebl* N2 blind*)) OR AB((tripl* N2 mask*) or (tripl* N2 blind*)) or ((trebl* N2 mask*) or (trebl* N2 blind*)
S34(MH "Evaluation Research+")
S35TI (evaluat* N2 study or evaluat* N2 research) OR AB (evaluat* N2 study or evaluat* N2 research)
S36TI(random* OR RCT) OR AB(random* OR RCT)
S37S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 OR S35 OR S36
S38S18 AND 37

Conference Proceedings Citation Index ‐ Science Web of Science Clarivate

Searched 4 October 2017 [166 records]
Searched 15 March 2019 [5 new records]
Searched 16 February 2021 [4 new records]

# 10 #9 AND #8
Indexes=CPCI‐S Timespan=All years
# 9 TS=(random* OR control* OR RCT* OR placebo* OR blind* or "systematic review" OR "meta analys*s")
Indexes=CPCI‐S Timespan=All years
# 8 #7 AND #6
Indexes=CPCI‐S Timespan=All years
# 7 TS= (Adaphen* or Aptensio* or Aradix* or Attenade* or Biphentin* or Calocain* or Centedrin* or Concerta* or Conmet* or Daytrana* or Dexmethylphenidat* or Difumenil* or "D‐methylphenidat*" or Equasym* or Fenilidato* or Focalin* or Matoride* or Medicebran* or Medikid* or Medikinet* or Meridil* or Metadate* or Methylphenidylacetat* or "methyl phenidylacetat*" or Methylofenidan* or Methylin* or Methypatch or methylphenidat* or Metilfenidato* or Phenidylate or "Phenidyl hydrochlorid*" or Phenidylhydrochlorid* or Quillivant* or "Richter Works" or Riphenidat* or Ritalin* or Ritrocel* or Rubifen* or Tsentedrin*)
Indexes=CPCI‐S Timespan=All years
# 6#5 OR #4 OR #3 OR #2 OR #1
Indexes=CPCI‐S Timespan=All years
# 5 TS=(minimal near/3 brain near/3 (disorder* or dysfunct* or damage*))
Indexes=CPCI‐S Timespan=All years
# 4 TS=(impulsiv* or inattentiv* or inattention* OR hyperkin* or "hyper‐kin*" OR hyperactiv* OR "hyper‐activ*")
Indexes=CPCI‐S Timespan=All years
# 3 TS=((disrupt* near/3 disorder*) or (disrupt* near/3 behav*) or (defian* near/3 disorder*) or (defian* near/3 behav*))
Indexes=CPCI‐S Timespan=All years
# 2 TS=((attention* or behav*) near/3 (defic* or dysfunc* or disorder*))
Indexes=CPCI‐S Timespan=All years
# 1 TS=(ADHD or ADHS or ADDH or "AD HD" or HKD or TDAH)
Indexes=CPCI‐S Timespan=All years

LILACS (Latin American and Caribbean Health Science Information)

Searched 4 October 2017 [19 records]
Searched 15 March 2019 [no new records]
Searched 16 February 2021 [no new records]

(mh:("attention deficit and disruptive behavior disorders" OR "attention deficit disorder with hyperactivity" OR "conduct disorder" OR hyperkinesis)) OR (tw:(adhd OR adhs OR addh OR "AD/HD" OR hkd OR tdah )) OR (tw:("ATTENTION DEFICIT*" OR impulsiv* OR inattentiv* OR inattention* OR hyperactiv* OR hyper‐activ*)) AND (mh:((adaphen* OR aptensio* OR aradix* OR attenade* OR biphentin* OR calocain* OR centedrin* OR concerta* OR conmet* OR daytrana* OR dexmethylphenidat* OR difumenil* OR d‐methylphenidat* OR equasym* OR fenilidato* OR focalin* OR matoride* OR medicebran* OR medikid* OR medikinet* OR meridil* OR metadate* OR methylphenidylacetat* OR methyl phenidylacetat* OR methylofenidan* OR methylin* OR methypatch OR methylphenidat* OR metilfenidato* OR phenidylate OR phenidylhydrochlorid* OR phenidylhydrochlorid* OR quillivant* OR richter works OR riphenidat* OR ritalin* OR ritrocel* OR rubifen* OR tsentedrin*))) AND (instance:"regional") AND ( db:("LILACS") AND type_of_study:("clinical_trials" OR "systematic_reviews"))

ClinicalTrials.gov clinicaltrials.gov/

Searched 4 October 2017 [48]
Searched 15 March 2019 Limited by First posted from 10/05/2017 to 03/15/2019 [4 new records]
Searched 16 February 2021 Limited by First posted from 03/15/2019  to 02/16/2021[22 new records]

LONG ACTING OR DELAYED OR EXTENDED OR PROLONGED OR RELEASE | ADHD OR "ATTENTION DEFICIT" OR HYPERACTIVE | Methylphenidate | Adult

EU Clinical Trials Register www.clinicaltrialsregister.eu/ctr‐search/

Searched 4 October 2017 [28 records]
Searched 15 March 2019 [2 new records]
Searched 16 February 2021 [1 new record]

methylphenidate AND ADHD AND Age Range = ADULT

ISRCTN www.isrctn.com/

Searched 4 October [5 records]
Searched 15 March 2019 [ no new records]
Searched 16 February 2021 [ no new records]

Condition: Attention Deficit Hyperactivity Disorder Interventions: methylphenidate Participant age range: Adult

WHO ICTRP www.who.int/ictrp/en/

Searched 4 October [38 records]
Searched 15 MARCH 2019 limited by date of registration between 05/10/2017 AND 15/03/2019 [5 new records] 
Attempted access 16 March 2021 limited by date of registration between 15/03/2019 AND 16/02/2021 but website unresponsive because of heavy traffic generated by pandemic.

CONDITION ADHD OR "ATTENTION DEFICIT" OR HYPERACTIV*

INTERVENTION methylphenidate AND extended OR methylphenidate AND prolonged OR methylphenidate AND release OR methylphenidate AND Long

Appendix 2. Search strategy (regulatory and pharmaceutical company databases)

Drug regulatory agencies

We included drug regulatory documents that contained data from clinical trials according to our inclusion criteria (Criteria for considering studies for this review). We did not include regulatory documents related to generic drugs or applications that did not include clinical trial data or only reported pharmacokinetic studies or studies in healthy adults.

We searched 12 drug regulatory agency databases (eTable 1). The European Medicines Agency has not approved any methylphenidate formulation, so we also searched the Heads of Medicines Agencies' (HMA) MR Index of approved drugs to identify which National Competent Authorities have approved the drugs in Europe. HMA’s MR Index is a European database of approved pharmaceutical drugs in the European Union across the different National Competent Authorities. The HMA MR Index database is not exhaustive, so we also handsearched all known European drug regulatory agencies' websites and databases of regulatory documents. See overview in eTable 1.

We describe each search string and detailed results in the Excel datafile available from osf.io/39wzk/?view_only=a1d2c58b069c4e99b8c836107e99fcad.

eTable 1. Overview of searched drug regulatory agency databases and websites

Regulatory agency (country)	Database	Content	Link
FDA (USA)	Drugs@FDA	Drug Approval Packages	www.accessdata.fda.gov/scripts/cder/daf
EMA (EU)	EMA Medicines	Public Assessment Reports	www.ema.europa.eu/en/medicines
Heads of Medicines Agencies (EU)	MR Index	Overview of approved drugs in the EU and links to various regulatory documents	mri.cts-mrp.eu/Human
Health Canada	Public Release of Clinical Information (PRCI)	Clinical Study Reports	clinical-information.canada.ca/search/ci-rc
Health Canada	Drug Product Database	Product Monographs	www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html
Health Canada	Drug and Health product Register	Summary Basis of Decision Letters	hpr-rps.hres.ca/reg-content/summary-basis-decision.php
TGA (AU)	Australian Register of Therapeutic Goods	Prescribing Information	www.tga.gov.au/artg
TGA (AU)	AusPAR database	Public Assessment Reports	www.tga.gov.au/ws-auspar-index
BfArM (DE)	Pharmnet‐Bund	Public Assessment Reports, CSR synopses	PharmNet.bund.de
MEB (NL)	The Medicines Data Bank	Public Assessment Reports, CSR synopses	www.geneesmiddeleninformatiebank.nl/en
MHRA (UK)	Products database	SmPC, Public Assessment Reports	products.mhra.gov.uk
ANSM (FR)	Rapports publics d'évaluation	Public Assessment Reports	archiveansm.integra.fr/Mediatheque/Publications/Rapports-Syntheses-Rapports-publics-d-evaluation
HPRA (IE)	Find a medicine	Public Assessment Reports, SmPC, PIL	www.hpra.ie/homepage/medicines/medicines-information/find-a-medicine
SwissMedic	SwissPAR database	Public Assessment Reports	www.swissmedic.ch/swissmedic/de/home/humanarzneimittel/authorisations/swisspar.html
PMDA (JN)	Review Reports database	Public Assessment Reports	www.pmda.go.jp/english/review-services/reviews/approved-information/drugs/0001.html
ANSM: Agence Nationale de Sécurité du Médicament et des Produits de Santé; AU: Australia; BfArM: Bundesinstitut für Arzneimittel und Medizinproducte [ Federal Institute for Drugs and Medical Devices]; DE: Deutschland (Germany); EMA: European Medicines Agency; FDA: US Food and Drug Administration; FR: France; HPRA: Health Products Regulatory Authority; IE: Ireland; JN: Japan; MEB: Medicines Evaluation Board; MHRA: Medicines and Healthcare products Regulatory Agency; NL: Netherlands; PIL: Patient Information Leaflet; PMDA: Pharmaceuticals and Medical Devices Agency; SmPC: Summary of Product Characteristics; TGA: Therapeutic Goods Administration; UK: United Kingdom.

Pharmaceutical company databases

We searched the websites and clinical trial databases of the marketing authorisation holders of extended‐release methylphenidate formulations approved for use in adults: Novartis (Ritalin LA, Ritalin SR and Focalin XL), Janssen (Concerta), Medice (Medikinet) and Purdue (Foquest/Adhansia).

Yale University Open Data Access (YODA)

The YODA database (yoda.yale.edu) contains clinical trial results from Johnson & Johnson sponsored trials, which Janssen is a part of. We assessed trials with the tag 'methylphenidate'. You may also request full clinical study reports from the YODA database. We did not do this for the current version of review but it might be relevant for potential review updates.

Novartis

Clinical Trial Results Database, available at www.novctrd.com. We used the keyword 'ADHD'.

Medice

We searched Medice’s website, www.medice.de/the-company, but they do not seem to have a publicly available database of clinical trial data. We contacted the company’s medical director but our request to access the data was declined, see also Potential biases in the review process.

Purdue

Purdue has a website dedicated to sharing clinical trial results, www.purduepharma.com/healthcare-professionals/clinical-trials. The data are not publicly available and you have to file a formal request to get access. We decided not to request access to data for this version of the review. They might be relevant for a future update.

Appendix 3. Results from trial registries, company databases and other resources

eTable 2. ClinicalTrials.gov

NCT ID	Related trial	Data available	Document type
NCT00061087a	Levin 1998a	No	N/A
NCT00136734a	Levin 1998b	No	N/A
NCT00181571a	Biederman 2003	No	N/A
NCT00318981a	Chronis‐Tuscano 2004	No	N/A
NCT00619840	Rösler 2004	No	N/A
NCT00261872	Combine Substudy 2005	No	N/A
NCT00246220	Medori 2005	Yes	Clinical study report synopsis (German extension study)a,b
NCT00253747	Winhusen 2005	Yes	Data on website
NCT00326391	Adler 2006	Yes	Clinical study report synopsisa
NCT00482313	Ginsberg 2007	No	N/A
NCT00714688	Casas 2008	Yes	Data on website
NCT00730249	Retz 2008	No	N/A
NCT00931398	College Study 2009	No	N/A
NCT00937040	Goodman 2009	Yes	Data on website
NCT00880217a	Weisler 2009	No	N/A
NCT01259492	Huss 2010	Yes	Data on website
NCT01323192a	Takahashi 2011	Yes	Data on website
NCT02139124a	Weiss 2014	Yes	Data on website
NCT03481959a	Methacan 2017	No	N/A
CSR: Clinical Study Report; EUCTR: EU Clinical Trials Register; ID: identifier; NCT: National Clinical Trial; N/A: not applicable; YODA: Yale University Open Data Access.

Footnotes
^aIdentified via cross‐referencing.
^bThe synopsis is about a German extension phase of the study.
 

eTable 3. EU Clinical Trials Register

Identifier	Related trial	Data available	Document type
2004­000730­37	Medori 2005	Yes	Clinical Study Report synopsis
2006‐000222‐31a	Compas 2007 CM/ Compas 2007 GPT	No	N/A
2006‐002249‐35	Konstenius 2007	No	N/A
2006‐002553‐80a	Ginsberg 2007	No	N/A
2007‐002111‐82	Casas 2008	Yes	Document not includedb
2008‐000942‐29a	Retz 2008	Yes	Document not includedc
2010‐021533‐31	Huss 2010	Yes	Clinical trial report (53 pages)
2015‐004271‐78	Asherson 2016	Yes	Clinical Study Report
2017‐000386‐77	Methacan 2017	No	N/A
EUCTR: EU Clinical Trials Register; N/A: not applicable; YODA: Yale University Open Data Access.

Foonotes

^aIdentified via cross‐referencing.
^bPDF‐file of data from ClinicalTrials.gov.
^cEarlier version of the included synopsis from BfArM.
 

eTable 4. ISRCTN

Identifier	Related trial	Data available	Document type
ISRCTN81602628	Konstenius 2006	No	N/A
ISRCTN54096201	Compas 2007 CM/Compas 2007 GPT	No	N/A
ISRCTN77940178	Konstenius 2007	No	N/A
ISRCTN16827947a	Asherson 2016	No	N/A
N/A: not applicable

Footnote

^aIdentified via cross referencing.

eTable 5. Pharmaceutical company databases

Database	Identifier	Trial	Available data
Novartis	CRIT124E2302	Spencer 2003a	Clinical study report synopsis
Novartis	CRIT124D2302	Huss 2010	Document not includeda
Novartis	CRIT124D2302E1	Huss 2010	Document not includedb
YODAc	NCT00246220	Medori 2005	Document not includeda
YODA	NCT00326391	Adler 2006	Clinical study report synopsisd
YODA	NCT00714688	Casas 2008	Clinical study report synopsis
YODA	NCT00937040	Goodman 2009	Clinical study report synopsisd
YODA	NCT01323192	Takahashi 2011	Clinical study report synopsisd
NCT: National Clinical Trial; YODA: Yale University Open Data Access.

Footnotes

For YODA, we counted the trial entries and available documents as separate records in our flowchart. For Novartis, we only counted the included documents in our flowchart.

^aIdentical to document from EU Clinical Trials Register, therefore not included.
^bSimilar to the document from BfArM (but without the amendments), therefore not included.
^cThe Yale University Open Data Access (YODA) declined two of our requests. The Weisler 2009 trial was sponsored by Janssen and compared bavisant, a histamine antagonist, with placebo, OROS methylphenidate and atomoxetine. Our request was declined because bavisant has been out‐licensed to another company. Chronis‐Tuscano 2004 lists McNeil as sponsor in the published report, and as collaborator and sponsor in the Clinicaltrials.Gov entry. We were not granted access to data with the argument that Johnson & Johnson is not the data holder.
^dMade available upon our request.

eTable 6. National guidelines and other systematic reviews

One author (KB) handsearched two national guidelines (Sundhedsstyrelsen 2017; NICE 2018), as prespecified in our protocol (Boesen 2017b), and the two most recently published systematic reviews (Cortese 2018; Elliott 2020). It yielded three additional records, and three references were not obtainable.

Sundhedsstyrelsens Nationale Kliniske Retningsline (2017)

We assessed the file ‘PICO 3 – MPH versus placebo’. Exact references to publications were not reported in the file (available from www.sst.dk/-/media/Udgivelser/2015/NKR-ADHD-voksne/PICO-3---MPH-vs,-d-,-placebo-PDF.ashx?la=da&hash=844986F014AF8E03BA2845BBF62FDEB42CC15FD9):

Carpentier (not included, cross‐over)
Gualtieri 1985 (not included, immediate‐release (IR) methylphenidate (MPH))
Spencer 1995 (not included, IR MPH)
Kuperman 2001 (not included, IR MPH)
Schubiner 2002 (not included, IR MPH)
Tennenbaum 2002 (not included, cross‐over)
Bouffard 2003 (not included, cross‐over)
Kooij 2004 (not included, cross‐over)
Spencer 2005 (not included, cross‐over)
Biederman 2006 (already included)
Levin 2006 (already included)
Jain 2007 (not included, cross‐over)
Levin 2007 (already included)
Reimherr 2007 (not included, cross‐over)
Spencer 2007 (already included)
Medori 2008 (already included)
Adler 2009 (already included)
Rösler 2009 (already included)
Biederman 2010 (already included)
Konstenius 2010 (already included)
Rösler 2010 (already included)
Winhusen 2010 (already included)
Ginsberg 2012 (already included)
Ginsberg 2012a (already included)
Retz 2012 (already included)
Weisler 2012 (already included)
Casas 2013 (already included)
Konstenius 2013 (already included)
Rösler 2013 (already included, Medori 2005 publication)
Huss 2014 (already included)

We identified no additional references.

NICE guideline (2018)

We assessed the ‘Evidence Review’, appendix D, on ‘Pharmacological efficacy and sequencing’. On page 39, the list of randomised controlled trials (RCTs) in adults appear (section 1.1.3.5), of which 12 used extended release methylphenidate. Available from www.nice.org.uk/guidance/ng87/evidence/c-pharmacological-efficacy-and-sequencing-pdf-4783686303.

Ref 21: Adler et al 2009, Journal of Clinical Psychopharmacology (already included)
Ref 90: Biederman et al 2006, Biological Psychiatry (already included)
Ref 91: Biederman et al 2010, Journal of Clinical Psychopharmacology (already included)
Ref 117: Bron et al 2014, Neuropsychopharmacology (not included; cross‐over)
Ref 140: Casas et al 2013, World Journal of Biological Psychiatry (already included)
Ref 162: Chronis‐Tuscano et al 2008, Journal of Clinical Psychiatry (already included)
Ref 282: Ginsberg et al 2012, British Journal of Psychiatry (already included)
Ref 287: Goodman et al 2017, Journal of Clinical Psychiatry (already included)
Ref 446: Medori et al 2008, Biological Psychiatry (already included)
Ref 524: Retz et al 2012, World Journal of Biological Psychiatry (already included)
Ref 533: Rosler et al 2009, European Archives of Psychiatry and Clinical Neuroscience (already included)
Ref 594: Spencer et al 2007, Biological Psychiatry (already included) (on page 32, it mistakenly says ref 593 which is an IR‐MPH trial).

We identified no additional references.

Cortese systematic review (2018)

Fifty‐one studies with adult ADHD were included (Cortese 2018). We handsearched all 133 included studies listed in the Supplement, Appendix 8, ‘Studies/citations retained for the network meta‐analysis’ (page 237), because they were not categorised according to intervention. Studies that seemed relevant (adult ADHD; extended‐release methylphenidate) or studies we were unable to exclude solely based on the information provided in Supplement appear here.

Ref 6: Adler 2009 (already included, we did not include the Adler 2011 publication since this is an open label extension, which is listed in our excluded list)
Ref 15: Bedard 2015 (not included; children and adolescents)
Ref 18: Biederman 2006 (already included, all references)
Ref 23: Biel 2016 (not included, immediate release (IR))
Ref 25: Bron 2014 (not included, cross‐over study)
Ref 27: Casas 2013 (already included, all references)
Ref 32: CRIT124 (information not provided in list; study with adolescents, not included)
Ref 45: Ginsberg study (already included, all references)
Ref 46: Goodman study (already included, all references)
Ref 55: Huss study (already included, all references)
Ref 63: Kooij 2004 (not included, cross‐over)
Ref 70: Medori 2008 (already included, three references included, two not obtainable)
Ref 77: NCT01069523 (not included, children)
Ref 82: COMPAS study (already included, all references)
Ref 85: Reimherr 2007 (not included, cross‐over)
Ref 86: Rösler 2009 (already included, all references)
Ref 92: Schrantee (not included, IR methylphenidate)
Ref 98: Spencer 1995 (not included, IR methylphenidate)
Ref 103: Spencer 2005 (not included, IR methylphenidate)
Ref 105: Spencer 2003 (already included, one reference not obtainable)
Ref 112: Takahashi 2012 (already included, all references)
Ref 120: Weisler 2012 (already included, all references)
Ref 122: Wender 2011 (not included, IR methylphenidate)
Ref 132: Winhusen (already included, all references)

We identified six additional references (three included, three unobtainable).

Elliot systematic review (2020)

We assessed the studies listed in Elliott 2020, table 1. Studies with relevant interventions (MPH, MPH SR, MPH LA, and OROS MPH) and a parallel group design are listed here.

Matochik 1994 (not included, formulation not specified but we assume it was immediate release (IR))
Levin 2001 (already included, all references)
Biederman 2006 (already included, all references)
Levin 2006 (already included, all references)
Levin 2007 (already included, all references)
Spencer 2007 (already included, all references)
Medori 2008 (already included, all references)
Adler 2009 (already included, all references)
Rösler 2009 (already included, all references)
Biederman 2010 (already included, all references)
Konstenius 2010 (already included, all references)
Philipsen 2010 (already included, all references)
Winhusen 2010 (already included, all references)
Ginsberg 2012 (already included, all references)
Retz 2012 (already included, all references)
Weisler 2012 (already included, all references)
Casas 2013 (already included, all references)
Huss 2014 (already included, all references)
Konstenius 2014 (already included, all references)
Takahashi 2014 (already included, all references)
Schrantee 2016 (not included, IR)
Goodman 2017 (already included, all references)

We identified no additional references.

eTable 7. Cross referenced records

Type of record	Records	Related trial(s)
Publications	11	Levin 1998a (1), Compas 2007 CM/Compas 2007 GPT (2), Ginsberg 2007 (1), Huss 2010 (4), Medori 2005 (3)
ClinicalTrials.gova	10	Levin 1998a entry; Levin 1998b entry; Biederman 2003 entry; Chronis‐Tuscano 2004 entry; Medori 2005 CSR synopsisb; Adler 2006 CSR Synopsis; Weisler 2009 entry; Takahashi 2011 entry; Weiss 2014 entry; Methacan 2017 entry
EU Clinical Trials Registera	6	Medori 2005 CSR synopsis; Compas 2007 CM/Compas 2007 CM entry, Ginsberg 2007 entry, Retz 2008 entry, Huss 2010 Clinical Trial Report; Asherson 2016 Synopsis
ISRCTNa	1	Asherson 2016 entry
NiH RePORTERa	2	Levin 1998a (1), Levin 1998b (1)
Total records	30

 Footnotes

CSR = Clinical Study Report; NiH = National Institute of Health Research Portfolio Online Reporting Tools

^aTrial entries or separately linked documents.
^bGerman extension study.

Appendix 4. Results from drug regulatory agencies

Drug regulatory databases

See the full search results in the additional datafile available on OSF (osf.io/39wzk/?view_only=a1d2c58b069c4e99b8c836107e99fcad).

eTable 8. Drug regulatory documents

Agency	Documenttype	Drug (trade name)	Related trial(s)
BfArM	Public Assessment Report (English)	Extended‐release methylphenidate (Medikinet®)	Rösler 2004 and Retz 2008
BfArM	Public Assessment Report (German)	Extended‐release methylphenidate (Medikinet®)	Rösler 2004 and Retz 2008
BfArM	CSR synopsisc	Extended‐release methylphenidate (Medikinet®)	Retz 2008
BfArM	CSR synopsis	OROS methylphenidate (Concerta®)	Medori 2005
BfArM	Clinical Trial Report	ER methylphenidate (Medikinet®)	Compas 2007 CM/Compas 2007 GPT
BfArM	CSR synopsis	OROS methylphenidate (Concerta®)	Casas 2008
BfArM	CSR synopsis + (part of) Clinical Trial Reporte	LA methylphenidate (Ritalin LA®)	Huss 2010
BfArM	Clinical trial report (extension study)	LA methylphenidate (Ritalin LA®)	Huss 2010
FDA	Drug Approval Package	OROS methylphenidate (Concerta®)	Medori 2005 and Adler 2006
FDA	Drug Approval Package	Controlled‐release methylphenidate (Adhansia®)	Weiss 2014
FDA	Drug Approval Package	Dex‐methylphenidate (Focalin XR®)	Spencer 2003a
Health Canada	Product Monograph	Controlled‐release methylphenidate (Foquest®)	Weiss 2014
Health Canada	Product Monograph	OROS methylphenidate (Concerta®)	Medori 2005
MEB	Public Assessment report	Long‐acting methylphenidate (Ritalin LA/XL®)	Huss 2010
MHRA	Public Assessment Report	Long‐acting methylphenidate (Ritalin XL®)	Huss 2010
MHRA	Public Assessment Report	OROS methylphenidate (Concerta®)	Medori 2005, Adler 2006 and Casas 2008
TGA	Prescribing Information	Extended‐release methylphenidate (Ritalin LA®)	Huss 2010
TGA	Prescribing Information	OROS methylphenidate (Concerta®)	Medori 2005, Adler 2006, and Casas 2008b
BfArM: Bundesinstitut für Arzneimittel und Medizinprodukte [Federal Institute for Drugs and Medical Devices]; CSR: Clinical Study Report; ER: extended release; FDA: US Food and Drug Adminsitration; ID: identifier; LA: long acting; MEB: Medicines Evaluation Board; MHRA: Medicines and Healthcare products Regulatory Agency; MPH: methylphenidate; OROS: Osmotic controlled‐Release Oral delivery System ; TGA: Therapeutic Goods Administration; XL: prolonged release

Footnotes:
^aThis was a BfArM Public Assessment Report of Medikinet in German. We did not find this record in our systematic search of the BfArM database, but as a reference in an Arzneitelegramm (www.arznei-telegramm.de/html/2011_10/1110085_01.html).
^bOnly harms data from Casas 2008 were included.
^cAlmost identical to document from EUCTR.
^eOne collated document, consisting of one CSR Synopsis and a part Clinical Trial Report (the full report was found on EUCTR).

Appendix 5. Author correspondence

We contacted all corresponding authors. Seven of the correspondences were fruitful; three correspondences yielded additional information, and four correspondences yielded a total of nine additional records for inclusion in the review.

eTable 9. Overview of author correspondence

Trial	Corresponding author	Sponsorship	Outcome and summary of correspondence
Levin 1998a and Levin 1998b	Frances Levin	Publicly funded	Negative. No reply after three emails.
Levin 2001	Edward Levin	Publicly funded	Negative. No reply after three emails.
Biederman 2003	Joseph Biederman	Janssen	Negative. Author reply: “Sorry. The sponsor has the data”.
Spencer 2003a	Thomas Spencer	Novartis	Negative. No reply after three emails.
Chronis‐Tuscano 2004	Andrea Chronis‐Tuscano	Publicly funded with industry‐involvement	Negative. No reply after three emails.
Rösler 2004	Michael Rösler	Medice	Negative. No reply after three emails.
Combine Substudy 2005	Raymond Anton	Publicly funded	Negative. Corresponding author referred us to the NIH database but informed us that there would be no data of interest. We contacted the NIH data manager about the content. We did not receive a reply after three emails.
Medori 2005	Rossella Medori	Janssen	Negative. No reply after three emails.
Winhusen 2005	Theresa Winhusen	Publicly funded with industry‐involvement	Positive. One record (trial protocol) and corresponding author also referred us to the trial database.
Adler 2006	Lenard Adler	Janssen	Negative. Author reply: “You need to contact the study sponsor”.
Konstenius 2006 and Konstenius 2007	Maija Konstenius	Publicly funded	Negative. Replied to our first email but did not respond to our follow‐up emails where we specified our request.
Compas 2007 CM/ Compas 2007 GPT	Alexandra Philipsen	Publicly funded with industry‐involvement	Positive. One record (documents describing adverse events and serious adverse events), and corresponding author also referred us to the BfArM website where the full trial report was available.
Ginsberg 2007	Ylva Ginsberg	Publicly funded	Positive. Two records (doctoral thesis, one published article).
Casas 2008	Miguel Casas	Janssen	Negative. Author reply: “We have not the raw data as it was a Janssen's study”.
Retz 2008	Wolfgang Retz	Medice	Negative. No reply after three emails.
College Study 2009	Oscar Bukstein	Publicly funded with industry‐involvement	Positive. Auhor reply: “I apologize; the project funding was withdrawn before we got started. I forgot to take this off clinicaltrials.gov Oscar Bukstein” Our response: “Thank you indeed for the quick reply. Can you tell me why the funding was withdrawn, it seemed like a very important study?” Author reply: “We thought so too. Investigator‐initiated pharma sponsored study. The bosses thought it was too close to end of patent.”
Goodman 2009	H Lynn Starr (medical director)	Janssen	Positive. We were contacted by Janssen's Therapeutic Area Head, who informed us to request data at YODA.
Weisler 2009	Ella Daly	Janssen	Positive. One record (conference proceeding) and referred to YODA database for further information.
Huss 2010	Michael Huss	Novartis	Negative. The author replied to our first email, but not to our second email in which we we specified the data we were interested in. Author reply: “Thank you for contacting me on this behalf. However, I was a bit irritated since we did not have OROS‐methlyphenidate but MPH‐LA in our study”. In the email, we had by mistake written 'OROS MPH' and not 'MPH LA'.
Takahashi 2011	Nagahide Takahashi	Janssen	Negative. No reply after three emails.
Weiss 2014	Margaret Weiss	Purdue	Positive. Four records (conference posters), sent from Adlon Therapeutics.
Asherson 2016	Philip Asherson	Publicly funded	Negative. Replied to our first email but did not reply to subsequent emails where we asked for the protocol and potential interim data.
Methacan 2017	Elodie Soler	Publicly funded	Negative. No reply after three emails.
BfArM: Bundesinstitut für Arzneimittel und Medizinprodukte [Federal Institute for Drugs and Medical Devices]; LA: long acting; MPH: methylphenidate; NIH: National Institutes of Health; OROS: osmotic‐controlled release oral delivery system; YODA: Yale University Open Data Accesss.

Appendix 6. Serious adverse events

eTable 10. Specification of serious adverse events

Study	Methylphenidate			Placebo
	Number of participants	Number of serious adverse events	Type of event(s) (number of events)	Number of participants	Number of serious adverse events	Type of event(s) (number of events)
Biederman 2003	109	0	None	114	0	None
Spencer 2003ab	165	2 events in 2 participants	Ulcerative colitis and hypovolemic shock, high fever and loss of consciousness	53	0	None
Medori 2005c	305	4 events in 4 participants	Cerebrovascular accident, anxiety disorder, migraine attack, depressive disorder	96	0	None
Winhusen 2005	127	2	Car accident, worsening of depression leading to hospitalisation	128	0	None
Adler 2006d	110	0	None	116	0	None
Compas 2007 CM/ Compas 2007 GPTe	205	19 events in 15 participants	Depression (1), suicidal ideation (1), aggression (1), tension (1), somnambulism (1), alcohol poisoning (1), appendix disorder (1), ocular hypertension (1), retinal detachment (1), cholecystectomy (1), rehabilitation therapy (1), adenomyosis (1), haermorrhagic ovarian cyst (1), transient ischaemic attack (1), pneumonia (1), pregnancy (2), chest pain (1), tachycardia (1).	209	12 events in 9 participants	Depression (1), suicidal ideation (1), road traffic accident (2), epicondylitis (1), fall (1), abdominal discomfort (1), gastrointestinal pain (1), ovarian cyst (1), syncope (1), salpingitis (1), vertigo (1), arthroscopy (1).
Ginsberg 2007	15	0	None	15	0	None
Konstenius 2007f	27	0	None	Not reported	Not reported	Not reported
Casas 2008g	181	7 events in 5 participants	Abdominal pain + nausea, ruptured ovarian cyst, suicidal ideation and subsequent suicide attempt, concussion, inter‐vertebral disc protrusion (1 each)	97	2 events in 2 participants	Cholecystitis (1), joint injury (1)
Retz 2008	84	1	Rupture of the acromioclavicular joint	78	2	Appendicitis, postoperative pain
Goodman 2009	174	0	None	175	1 event in 1 participant	Suicidal ideation
Weisler 2009 h	68	1	Convulsion	73	1	Pericarditis
Huss 2010i	542	4 events in 4 participants	Goiter, infected bites, loss of consciousness, ovarian cyst rupture	180	6 events in 2 participants	Sudden hearing loss and vertigo, eye infection, syncope, agitation and depression
Takahashi 2011	143	2	Psychotic disorder, tension pneumothorax	141	0	None
Weiss 2014j	297	16 events in 12 participants	Diarrhoea (1), feeling jittery (1), cellulitis (1), muscle strain (1), osteoarthritis (1), uterine cancer (1), headache (1), anxiety (1), emotional disorder (1), insomnia (3), mood altered (1), psychotic disorder (1), calculus urinary (1), nephrolithiasis (1).	78	2 events in 2 participants	Headache (2)

Footnotes

^aThe 15 trials reporting serious adverse events for at least one group.
^bReported in FDA (Food and Drug Administration) Medical Review, p 19. The three other events occurred in extension phase.
^c'Aggression and delusion of reference' was not listed as a serious adverse event.
^d'Abnormal thinking" was not listed as a serious adverse event.
^eReported for the two methylphenidate and placebo groups together at 52 weeks follow‐up.
^fReported in conference proceeding, but not for placebo group.
^gData according to ClinicalTrials.gov.
^hThe pericarditis event in the placebo group occurred after study completion, but it was not reported when exactly. In comparison, the aneurism event in Huss 2010 (see below), was not included since it occurred after study completion.
ⁱWe noted that one death (in the methylphenidate group) due to aortic dissection rupture 21 days after study completion was not reported as a serious adverse event (Huss 2010; Huss et al. 2014, p 56).
^jThere were important differences between reported serious adverse events in Health Canada’s Product Information, FDA’s Medical Review and on ClinicalTrials.gov. We used the ClinialTrials.gov results.

Appendix 7. Severe psychiatric adverse events

eTable 11. Serious adverse events or severe psychiatric adverse events

Study	Serious psychiatric adverse events and severe psychiatric adverse events
	Methylphenidate (number of participants)	Placebo (number of participants)	Comments
Levin 1998a	Not reported	Not reported	Adverse effects were collected according to severity (mild/moderate/severe) (Levin 2006, p 145), but they were not reported in the paper.
Levin 1998b	Not reported	Not reported	Adverse effects were collected according to severity (mild/moderate/severe) (Levin 2007, p 26), but they were not reported in the paper.
Levin 2001	Not reported	Not reported	‐
Biederman 2003	No SAEs. Severe adverse events not described	No SAEs. Severe adverse events not described	‐
Spencer 2003a	No SAEs. Overall rate of "severe adverse events" of 8.5%; ('insomnia' was reported by 2 participants)	No SAEs. Rate of "severe adverse events" of 5.7%; events not specified for the placebo participants	Only "severe adverse events" occurring in more than one participant was reported (Spencer 2007, p 1384)
Chronis‐Tuscano 2004	Not reported	Not reported	‐
Rösler 2004	Not reported	Not reported	Akathisia and dyskinesia were mentioned as "neurological abnormalities", but not detailed (Rösler 2009, p 125)
Medori 2005	2 SAEs: 'depression' and 'anxiety'. 3% of participants experienced psychosis/mania (combined Medori 2005, Adler 2006, Casas 2008); three of these events were highlighted as "severe" ('thinking abnormal', 'delusion of reference', 'abnormal behaviour) but uncertain whether this list was exhustive.	0 SAEs, "severe adverse events" not systematically reported. 1% of participants (combined Medori 2005, Adler 2006, Casas 2008) experienced placebo/mania, but not further specified.	Not reported systematically. The data was reported under "Psychosis/mania" in the MHRA Public Assessment Report (MHRA 2010, p 63)
Winhusen 2005	1 SAE ('worsening of depression'). Severe adverse events not described.	No SAEs. Severe adverse events not described.	‐
Adler 2006	0 SAEs. "severe" adverse events included: 'abnormal thinking', 'irritability', 'anxiety', 'initial insomnia' and 'asthenia'. Frequency not reported.	0 SAEs. 2 "severe adverse events" included 'somnolence' and 'affect lability'. Frequency not reported.	A total of 8 participants experienced severe adverse events on methylphenidate, and 4 on placebo. Reported in Adler 2009, p 244.
Konstenius 2006	SAEs not reported. No severe adverse events.	SAEs not reported. No severe adverse events.	"Reported Aes were mild and reversible", (Konstenius 2010, p 132). We therefore assume that no severe events occurred.
Compas 2007 CM/ Compas 2007 GPT	5 SAEs: 'depression' (1), 'suicidal ideation' (1), 'aggression' (1),' tension' (1), 'somnambulism' (1). Severe adverse events not described	2 SAEs: 'depression' (1), 'suicidal ideation' (1). Severe adverse events not described	Reported in document sent by corresponding author (Philipsen 2020, personal communication)
Ginsberg 2007	No SAEs. Severe adverse events not described	No SAEs. Severe adverse events not described. 'Intrusive thoughts' (1) listed as event but severity not described	'Instrusive thoughts' [Tvångstanker] listed in adverse event table in Ginsberg & Lindefors, 2013 p. 24. The severity of events were described as, "The severity of AEs was usually rated as mild to moderate and not a reason for discontinuation" (Ginsberg thesis 2012, p 53).
Konstenius 2007	No SAEs. Severe adverse events not described.	SAEs not reported. No reporting of severe adverse events. 'Hearing voices' (1) and 'agitation' listed as events, but severity not described.	Konstenius 2014, p 446
Casas 2008	2 SAEs in one participant: 1 'suicide ideation' and 1 'suicide attempt'. Severe adverse events not specified	No SAEs of interest. Severe adverse events not specified	The total number of participants experiencing a severe adverse event was reported in the YODA CSR synopsis on p. 23: 23 participants on MPH and 10 participants on placebo. Events not specified.
Retz 2008	No relevant SAEs. "No severe adverse events related to study medication".	No relevant SAEs. "No severe adverse events related to study medication".	Retz 2012, p 57.
Goodman 2009	0 SAEs. 3 participants with "severe adverse events": 'anxiety' (1), 'restlessness' (1), and 'nervousness and jitter' (1).	1 SAE: 'suicidal ideation'. 1 participant with severe adverse event: 'insomnia'.	Severe adverse events reported in Goodman 2017, p 111.
Weisler 2009	No SAEs. Severe adverse events not described. 'Suicidal ideation' (1) listed as event but not described further.	No SAEs. Severe adverse events not described. 'Suicidal ideation' (1) listed as event but not described further.	The suicidal events were captured using the Columbia Suicide Severity Rating Scale (Weisler 2012, p 430).
Huss 2010	0 SAEs. Severe adverse events not described	2 SAEs: 'depression' and 'agitation' (unclear if one or two participants). Severe adverse events not described	‐
Takahashi 2011	1 SAE ('psychotic disorder'). 9 answered 'yes' to questions regarding suicidal ideations (6 according to the CSR synopsis). Severe adverse events not described.	0 SAEs. 9 participants answered 'yes' to having suicidal ideation (2.9%, corresponding to 4 participants). Severe adverse events not described.	The suicidal events were captured using the Columbia Suicide Severity Rating Scale (YODA CSR synopsis, p 16).
Weiss 2014	8 SAEs: 'Anxiety' (1), 'emotional disorder' (1), 'insomnia' (3), 'mood altered' (1), 'psychotic disorder' (1), 'feeling jittery' (1). Severe adverse events not described. Suicidal ideation (100mg group) (1).	0 SAEs. Severe adverse events not described. Suicidal behaviour (1).	Data comes from the ClinicalTrial.gov entry. Note that in FDA's Clinical Review, the SAEs are called "significant adverse events" (FDA Clinical Review, p. 35 of 57). The suicide events are described in Weiss 2020, p 7.
CSR: Clinical Study Report. FDA: US Food and Drug Administration. MHRA: Medicines and Healthcare product Regulatory Agency. P: Page. SAE: Serious adverse events. YODA: Yale Open access DAtabase.

eTable 12. Dose reductions due to psychiatric adverse events

Study	Dose reductions due to psychiatric adverse events
	Methylphenidate (number of participants)	Placebo (number of participants)	Comments
Levin 1998a	3 participants, but the adverse events were not reported	0	Reasons for dose reduction were not described
Levin 1998b	3 participants ('insomnia', 'depressed', and 'clenched jaws')	1 participant ('sedation')	‐
Levin 2001	Fixed dose	Fixed dose	‐
Biederman 2003	Not reported	Not reported	‐
Spencer 2003a	Fixed dose	Fixed dose	‐
Chronis‐Tuscano 2004	Not reported	Not reported	‐
Rösler 2004	Not reported	Not reported	‐
Medori 2005	Fixed dose	Fixed dose	‐
Winhusen 2005	Not reported	Not reported	‐
Adler 2006	3 participants experienced 'anxiety'	Not reported	Only events leading to dose reduction in 2% of participants or more were reported. Adler 2009, p 244.
Konstenius 2006	Not reported	Not reported	'Nervousness' (1), but not described if it occurred in the methylphenidate or placebo arm.
Compas 2007 CM/ Compas 2007 GPT	Not reported	Not reported	‐
Ginsberg 2007	Fixed dose	Fixed dose	‐
Konstenius 2007	'Feeling edgy' (1)	'Suicidal ideation' (1)	The event in the placebo group led to "study medication discontinuation".
Casas 2008	Fixed dose	Fixed dose	‐
Retz 2008	19 total dose reductions. Reasons for reduction not described.	2 total dose reductions. Reasons for reduction not described.	Retz 2012, p 53
Goodman 2009	Not reported	Not reported	‐
Weisler 2009	Dose reduction was not allowed	Dose reduction was not allowed	‐
Huss 2010	Fixed dose	Fixed dose	‐
Takahashi 2011	Not reported	Not reported	‐
Weiss 2014	Fixed dose	Fixed dose	‐
P: Page.

eTable 13. Dropouts due to psychiatric adverse events

Study	Dropouts (due to psychiatric adverse events)
	Methylphenidate (number of participants)	Placebo (number of participants)	Comments
Levin 1998a	'Psychomotor agitation' (1)	No dropouts	We did not count the 'fatigue' event in the placebo group as a psychiatric event.
Levin 1998b	'Persistent insomnia' (1) and 2 participants were "removed from the protocol because of worsening of pre‐existing mood lability [and] anxiety".	3 participants were "removed from the protocol because of worsening of pre‐existing depression".	it is unclear what the 'removal from the protocol' entails (Levin 2007, p 22 (3.1. 'participant flow'). In the flowchart, respectively 3 participant on methylphenidate and 2 on placebo were listed as dropout due to "psychiatric", but events not described further.
Levin 2001	Not reported	Not reported	None
Biederman 2003	6 AEs leading to drop out: 'jitteriness' (1), 'irritability' (3), 'depression' (1), 'anxiety' (1)	One dropout ('irritability') but it was not described in which trial it occurred (the publication reported from two trials, one with immediate and one with extended‐release methylphenidate)	Described in Biederman 2007 p 5, which reported data from the trial's interim analysis
Spencer 2003a	'Insomnia' (3), 'jittery' (2), 'anxiety' (2)	'Insomnia' (1)	Adverse events leading to drop out in more than two participants reported (FDA's Focalin labelling, p 12 of 21). The 'insomnia' event in the placebo group was described in Spencer 2007, calculated from 1.9%
Chronis‐Tuscano 2004	No dropouts	No dropouts	None
Rösler 2004	Not reported	Not reported	None
Medori 2005	11 participants experiencing 12 events: 'anxiety' (4), 'irritability' (3), 'nervousness' (3), 'restlessness' (2), 'insomnia' (2)	No events	Reasons for dropouts only reported for events experienced by two participants or more. We also included 'insomnia' although it is classified as a nervous system disorder in the table (MHRA 2010, p 59)
Winhusen 2005	No dropouts due to adverse events	No dropouts due to adverse events	None
Adler 2006	5 participants and 7 events: 'anxiety' (3), 'agitation', 'mood altered', 'panic attack', 'thinking abnormal' (1 each)	3 participants and 3 events: 'depressed mood' (2), 'depression' (1)	FDA Medical Review, p 103 of 456
Konstenius 2006	Not reported	Not reported	None
Compas 2007 CM/ Compas 2007 GPT	Not reported	Not reported	Only the number of participants who stopped MPH or placebo due to adverse events were reported (Philipsen 2015, Figure 1). Unclear if they dropped out of the study and type of adverse events not reported
Ginsberg 2007	No dropouts	No dropouts	None
Konstenius 2007	Not reported	Not reported	None
Casas 2008	'Insomnia' (5)	Not reported	Only the most common reason for dropout ('insomnia'), was reported in Casas 2013, p 275.
Retz 2008	Not reported	Not reported	None
Goodman 2009	2 participants: 'anxiety' (1), 'anxiety and insomnia' (1)	1 participant: 'suicidal ideation' (corresponding to the serious adverse event)	Goodman 2016, p 107
Weisler 2009	Not reported	Not reported	None
Huss 2010	47 reported participants: 'anxiety' (9), 'agitation' (5),' depressed mood' (5), 'depression' (5), 'insomnia' (5), 'irritability' (4), 'restlessness' (4), 'aggression' (2), 'apathy' (2), 'disturbance in attention' (2), 'impulse‐control disorder' (2), 'panic attack' (2)	4 reported participants: 'anxiety' (1), 'agitation' (1), 'depression' (1), 'panic attack' (1)	"Adverse event leading to dropout" reporting threshold: 0.4% (Clinical Trial Report, p 40) and 2% in Huss et al 2012
Takahashi 2011	Not reported	Not reported	None
Weiss 2014	'Anxiety' (2), 'insomnia' (2), 'affect lability' (1), 'emotional disorder' (1), 'irritability' (1)	'Irritability' (2)	FDA Clinical Review, table 13, p 35 of 57
AE: Adverse events. FDA: US Food and Drug Administration. P: page.

Data and analyses

Comparison 1. Extended‐release methylphenidate versus placebo ‐ primary outcomes (short‐ and medium‐term).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Days missed at work/school/training (week 13)	2	409	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐2.11, 1.81]
1.2 Days missed at work/school/training (weeks 13‐26)	2	327	Mean Difference (IV, Random, 95% CI)	‐0.42 [‐2.48, 1.64]
1.3 Days missed at work/school/training (weeks 26‐52)	2	292	Mean Difference (IV, Random, 95% CI)	0.71 [‐1.61, 3.03]
1.4 ADHD symptoms (self‐rated) (short‐term)	17	3799	Std. Mean Difference (IV, Random, 95% CI)	‐0.37 [‐0.43, ‐0.30]
1.5 ADHD symptoms (self‐rated) [subgroup MD] (short‐term)	17		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.5.1 DSM‐IV Total ADHD (18 items, 0‐54 points)	7	1189	Mean Difference (IV, Random, 95% CI)	‐3.05 [‐4.34, ‐1.76]
1.5.2 ASRS (18 items, 0‐72 points)	2	953	Mean Difference (IV, Random, 95% CI)	‐6.25 [‐8.25, ‐4.25]
1.5.3 CAARS: short version (26 items, 0‐78 points)	5	1451	Mean Difference (IV, Random, 95% CI)	‐5.21 [‐7.14, ‐3.29]
1.5.4 CAARS: long version (66 items, 0‐90 points)	1	162	Mean Difference (IV, Random, 95% CI)	‐28.40 [‐48.28, ‐8.52]
1.5.5 CAARS: unspecified subscale	2	44	Mean Difference (IV, Random, 95% CI)	‐8.23 [‐17.79, 1.32]
1.6 ADHD symptoms (self‐rated) (medium‐term)	2	234	Mean Difference (IV, Random, 95% CI)	‐1.59 [‐4.26, 1.09]
1.7 ADHD symptoms (self‐rated) [LMCF data] (medium‐term)	2	419	Mean Difference (IV, Random, 95% CI)	‐2.23 [‐3.50, ‐0.95]
1.8 Serious adverse events	14	4078	Risk Ratio (IV, Random, 95% CI)	1.43 [0.85, 2.43]

Comparison 2. Extended‐release methylphenidate versus placebo ‐ secondary outcomes (short and medium term).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Quality of life (self‐rated) (short‐term)	7	1888	Std. Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.25, ‐0.05]
2.2 Quality of life (self‐rated) [subgroup MD] (short‐term)	7		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.2.1 Q‐LES‐QSF (14‐70 points)	5	1234	Mean Difference (IV, Random, 95% CI)	‐0.93 [‐2.17, 0.31]
2.2.2 AIM‐A total score	1	279	Mean Difference (IV, Random, 95% CI)	‐0.50 [‐0.99, ‐0.00]
2.2.3 AAQOL	1	375	Mean Difference (IV, Random, 95% CI)	‐6.10 [‐10.67, ‐1.53]
2.3 Quality of life (self‐rated) (medium‐term)	2	419	Mean Difference (IV, Random, 95% CI)	‐0.66 [‐2.97, 1.64]
2.4 ADHD symptoms (investigator rated) (short‐term)	19	4183	Std. Mean Difference (IV, Random, 95% CI)	‐0.42 [‐0.49, ‐0.36]
2.5 ADHD symptoms (investigator‐rated) [subgroup MD] (short‐term)	19		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.5.1 DSM‐IV Total ADHD (18 items, 0‐54 points)	12	3121	Mean Difference (IV, Random, 95% CI)	‐4.74 [‐5.65, ‐3.84]
2.5.2 DSM‐5 Total ADHD (18 items, 0‐54 points)	1	375	Mean Difference (IV, Random, 95% CI)	‐4.38 [‐7.37, ‐1.39]
2.5.3 WRAADDS (28 items, 0‐56 points)	2	521	Mean Difference (IV, Random, 95% CI)	‐6.06 [‐8.48, ‐3.63]
2.5.4 CGI (range 0‐7)	2	36	Mean Difference (IV, Random, 95% CI)	0.09 [‐0.67, 0.86]
2.5.5 TAADS (7 items, 0‐28 points)	1	106	Mean Difference (IV, Random, 95% CI)	‐3.50 [‐7.85, 0.85]
2.5.6 CAARS: unspecified scale	1	24	Mean Difference (IV, Random, 95% CI)	0.10 [‐10.21, 10.41]
2.6 ADHD symptoms (investigator‐rated) (medium‐term)	2	243	Mean Difference (IV, Random, 95% CI)	‐1.29 [‐3.38, 0.80]
2.7 ADHD symptoms (investigator‐rated) [LMCF data] (medium‐term)	2	419	Mean Difference (IV, Random, 95% CI)	‐2.18 [‐3.55, ‐0.80]
2.8 ADHD symptoms (peer‐rated) (short‐term)	3	1005	Std. Mean Difference (IV, Random, 95% CI)	‐0.31 [‐0.48, ‐0.14]
2.9 Cardiovascular: pulse (beats per minute)	11	2558	Mean Difference (IV, Random, 95% CI)	4.64 [3.13, 6.15]
2.10 Cardiovascular: systolic blood pressure	10	2276	Mean Difference (IV, Random, 95% CI)	1.11 [‐0.06, 2.27]
2.11 Cardiovascular: diastolic blood pressure	10	2276	Mean Difference (IV, Random, 95% CI)	1.24 [0.04, 2.44]

Comparison 3. Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Dropout (overall)	22	4769	Risk Ratio (IV, Random, 95% CI)	1.01 [0.84, 1.21]
3.2 Dropout (due to adverse events)	15	3963	Risk Ratio (IV, Random, 95% CI)	2.36 [1.62, 3.43]
3.3 Adverse events (proportion experiencing any adverse event)	14	4214	Risk Ratio (IV, Random, 95% CI)	1.27 [1.19, 1.37]
3.4 Psychiatric adverse events (proportion of participants)	7	2737	Risk Ratio (IV, Random, 95% CI)	1.83 [1.43, 2.34]
3.5 Weight (change in kilograms)	10	2302	Mean Difference (IV, Random, 95% CI)	‐1.78 [‐2.36, ‐1.20]
3.6 Adverse event: decreased appetite	16	4491	Risk Ratio (IV, Random, 95% CI)	4.08 [3.34, 4.98]
3.7 Adverse event: dry mouth	16	4491	Risk Ratio (IV, Random, 95% CI)	3.36 [2.61, 4.34]
3.8 Adverse event: headache	16	4238	Risk Ratio (IV, Random, 95% CI)	1.35 [1.18, 1.54]
3.9 Adverse event: palpitations	15	4265	Risk Ratio (IV, Random, 95% CI)	3.67 [2.42, 5.57]
3.10 Adverse event: insomnia	16	4435	Risk Ratio (IV, Random, 95% CI)	1.97 [1.51, 2.57]
3.11 Adverse event: sexual dysfunction	7	3057	Risk Ratio (IV, Random, 95% CI)	2.66 [1.31, 5.39]
3.12 Adverse event: anxiety	13	3829	Risk Ratio (IV, Random, 95% CI)	2.23 [1.40, 3.57]
3.13 Adverse event: depression	7	2791	Risk Ratio (IV, Random, 95% CI)	1.47 [0.87, 2.49]
3.14 Adverse event: irritability	11	3377	Risk Ratio (IV, Random, 95% CI)	1.39 [1.00, 1.93]
3.15 Adverse event: feeling jittery	7	2254	Risk Ratio (IV, Random, 95% CI)	5.52 [2.77, 10.99]
3.16 Adverse event: agitation	8	3166	Risk Ratio (IV, Random, 95% CI)	2.16 [1.25, 3.71]
3.17 Adverse event: aggression	2	1319	Risk Ratio (IV, Random, 95% CI)	2.10 [1.32, 3.33]

3.7. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 7: Adverse event: dry mouth

3.8. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 8: Adverse event: headache

3.9. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 9: Adverse event: palpitations

3.10. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 10: Adverse event: insomnia

3.11. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 11: Adverse event: sexual dysfunction

3.12. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 12: Adverse event: anxiety

3.13. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 13: Adverse event: depression

3.14. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 14: Adverse event: irritability

3.15. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 15: Adverse event: feeling jittery

3.16. Analysis.

Comparison 3: Extended‐release methylphenidate versus placebo ‐ secondary outcomes: adverse events (short‐ and medium‐term), Outcome 16: Adverse event: agitation

Comparison 4. Extended‐release methylphenidate versus placebo: subgroup and sensitivity analyses.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Overall dropout rate: psychiatric comorbidity (subgroup analysis)	22	4769	Risk Ratio (IV, Random, 95% CI)	1.01 [0.84, 1.21]
4.1.1 Low risk	1	54	Risk Ratio (IV, Random, 95% CI)	0.74 [0.53, 1.03]
4.1.2 Unclear risk	1	30	Risk Ratio (IV, Random, 95% CI)	Not estimable
4.1.3 High risk	20	4685	Risk Ratio (IV, Random, 95% CI)	1.04 [0.86, 1.25]
4.2 Overall dropout rate: 'enriched design' (subgroup analysis)	22	4769	Risk Ratio (IV, Random, 95% CI)	1.01 [0.84, 1.21]
4.2.1 Unclear risk	2	247	Risk Ratio (IV, Random, 95% CI)	1.02 [0.26, 3.98]
4.2.2 High risk	20	4522	Risk Ratio (IV, Random, 95% CI)	0.99 [0.83, 1.19]
4.3 Overall dropout rate: withdrawal effects (subgroup analysis)	22	4769	Risk Ratio (IV, Random, 95% CI)	1.01 [0.84, 1.21]
4.3.1 Low risk	1	357	Risk Ratio (IV, Random, 95% CI)	0.91 [0.61, 1.34]
4.3.2 Unclear risk	5	822	Risk Ratio (IV, Random, 95% CI)	0.90 [0.62, 1.30]
4.3.3 High risk	16	3590	Risk Ratio (IV, Random, 95% CI)	1.07 [0.85, 1.34]
4.4 Overall dropout rate: funding (subgroup analysis)	22	4769	Risk Ratio (IV, Random, 95% CI)	1.01 [0.84, 1.21]
4.4.1 Industry funded	13	3782	Risk Ratio (IV, Random, 95% CI)	1.14 [0.88, 1.47]
4.4.2 Publicly funded with industry involvement	3	688	Risk Ratio (IV, Random, 95% CI)	0.73 [0.59, 0.91]
4.4.3 Publicly funded	5	279	Risk Ratio (IV, Random, 95% CI)	0.99 [0.70, 1.40]
4.4.4 Unclear funding	1	20	Risk Ratio (IV, Random, 95% CI)	0.33 [0.04, 2.69]
4.5 Proportion experiencing any adverse event: psychiatric comorbidity (subgroup analysis)	14	4214	Risk Ratio (IV, Random, 95% CI)	1.27 [1.19, 1.37]
4.5.1 High	13	4184	Risk Ratio (IV, Random, 95% CI)	1.26 [1.18, 1.36]
4.5.2 Unclear	1	30	Risk Ratio (IV, Random, 95% CI)	2.40 [1.12, 5.13]
4.6 Proportion experiencing any adverse event: withdrawal effects (subgroup analysis)	14	4214	Risk Ratio (IV, Random, 95% CI)	1.27 [1.19, 1.37]
4.6.1 High	11	3310	Risk Ratio (IV, Random, 95% CI)	1.28 [1.18, 1.38]
4.6.2 Unclear	2	555	Risk Ratio (IV, Random, 95% CI)	1.21 [0.95, 1.53]
4.6.3 Low	1	349	Risk Ratio (IV, Random, 95% CI)	1.46 [1.22, 1.74]
4.7 Proportion experiencing any adverse event: funding (subgroup analysis)	14	4214	Risk Ratio (IV, Random, 95% CI)	1.27 [1.19, 1.37]
4.7.1 Industry funded	12	3545	Risk Ratio (IV, Random, 95% CI)	1.32 [1.23, 1.41]
4.7.2 Publicly funded with industry involvement	2	669	Risk Ratio (IV, Random, 95% CI)	1.09 [1.05, 1.14]
4.8 Proportion experiencing any adverse event: dropout rates (sensitivity analysis)	14	4214	Risk Ratio (IV, Random, 95% CI)	1.27 [1.19, 1.37]
4.8.1 High	10	3363	Risk Ratio (IV, Random, 95% CI)	1.21 [1.14, 1.29]
4.8.2 Unclear	1	375	Risk Ratio (IV, Random, 95% CI)	1.46 [1.12, 1.89]
4.8.3 Low	3	476	Risk Ratio (IV, Random, 95% CI)	1.56 [1.35, 1.81]

Comparison 5. Extended‐release methylphenidate versus atomoxetine.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 ADHD symptoms (self‐rated)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.2 Serious adverse events	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.3 Adverse event: initial insomnia	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.4 Weight	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.5 ADHD symptoms (investigator‐rated)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.6 Overall dropout	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.7 Adverse events (AE): proportion experiencing any AE	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.8 Adverse events (leading to dropout)	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.9 Adverse event: headache	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.10 Adverse event: decreased appetite	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.11 Adverse event: irritability	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.12 Adverse event: dry mouth	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.13 Adverse event: decreased libido	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.14 Adverse event: feeling jittery	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.15 Adverse events: palpitations	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected

Comparison 6. Extended‐release methylphenidate versus bupropion.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 ADHD symptoms (self‐rated)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
6.2 Overall dropout	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
6.3 Dropouts due to adverse events	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected

Characteristics of studies

Characteristics of included studies [ordered by year]

Levin 1998a.

Study characteristics
Methods	Trial ID(s): NCT00061087, R01DA011444 (NIH RePORTER ID), NIDA‐011444‐1 (grant ID), 4184R (NYSPI Institutional Review Board ID) Trial registry entry: clinicaltrials.gov/show/NCT00061087, NIH RePORTER entry Sponsor: New York State Psychiatric Institute Funding/industry involvement: National Institute of Drug Abuse (NIDA) grants R01 DA00144, KO2 00465 and K02 DA00288 Location: USA No. sites: 5 Start to completion: February 1998 to March 2004 Duration: 10 weeks Sample size: 65
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse disorder: DSM‐IV: opiate dependency Mean age (range): 39 (inclusion criteria 18 ‐ 60) years Male participants (%): 57
Interventions	Trial arms methylphenidate sustained‐release (n = 32) bupropion sustained‐release (n = 33) placebo (n = 33) Type of methylphenidate: methylphenidate sustained‐release (SR) Dosage range: 40 mg to 80 mg Fixed or titrated: titrated Administrations per day: 2 Co‐intervention(s): weekly cognitive behavioural therapy + methadone treatment programme
Outcomes	Reported outcomes of relevance for the review are listed here. Missing outcomes are listed in the 'selective reporting' risk of bias domain Adult ADHD Rating Scale (AARS) (self‐rated, 18 items, 0 ‐ 54 points) Wender–Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) (investigator rated, 7 items, range not reported) Dropouts due to adverse events
Notes	Declared conflicts of interest: "Dr. Levin is a consultant for Eli Lily and Company, Shire Pharmaceuticals Group, and Ortho‐McNeil Pharmaceutical Inc. Also she has investigator‐initiated grants with Eli Lily and Company and UCB Pharma Inc" (Levin 2006)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote "Randomization was stratified by site, and by the amount of recent cocaine use (no use, low use as defined as <10 days/month and $200/month spent, and high use as defined as ≥ 10 days/month and $200/month spent). Within each site, patients were stratified by gender and ethnicity" (Levin, 2006).
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quotes "double‐blind, placebo‐controlled, randomized, three‐arm trial" (Levin, 2006). "Folic acid in the form of a 1mg tablet was added to all placebo capsules in an attempt to improve the blind" (Levin, 2006). Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quotes "double‐blind, placebo‐controlled, randomized, three‐arm trial" (Levin 2006). "Folic acid in the form of a 1mg tablet was added to all placebo capsules in an attempt to improve the blind" (Levin 2006). Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 11 of 32 (34%) and placebo 8 of 33 (24%) 18 out of the 115 participants entered the study but did not complete the 2‐week placebo lead‐in (p 141) Dropouts due to adverse events: methylphenidate 1 of 11, placebo 2 of 8. Statistical method to account for missing data: generalized estimation equation model (assumes missing data is random)
Selective reporting (reporting bias)	High risk	Comments Adverse event reporting threshold: No threshold, but no systematic reporting of events Serious adverse events not reported (we assume none occurred, but it was not described) The WRAADS outcome was not reported, "no treatment effects" (Levin 2006, p 144) Blood pressure and pulse (Levin 2006, p. 139) not reported
Other bias	Low risk	None found
Psychiatric comorbidity (External validity)	High risk	Quote "Participants were excluded if they (1) met DSM‐IV criteria for current psychiatric disorders (other than ADHD or substance abuse) which required psychiatric intervention or had a history of an eating disorder" (Levin 2006)
Responder selection (External validity)	High risk	Quote "Patients with known sensitivity to MPH or BPR" (CT.gov)
Withdrawal effects (External validity)	High risk	Quote "Participants were excluded if they […] were taking any prescription psychotropic medications other than methadone" (Levin 2006) Comments Following 2 weeks of placebo lead‐in, participants were randomised into one of the three arms 18 of the 115 participants entered the study but did not complete the placebo lead‐in phase Current cocaine substance abuse was prevalent: methylphenidate group (64%) and placebo (41%)

Levin 1998b.

Study characteristics
Methods	Trial ID(s): NCT00136734, 3236‐NIDA‐011755‐1 (grant ID), 1R01DA011755‐01 (NIH RePORTER number) Trial registry entry: clinicaltrials.gov/show/NCT00136734; NIH RePORT entry Sponsor: New York State Psychiatric Institute Funding/industry involvement: National Institute on Drug Abuse (NIDA) grants: K23 DA16743, K23 DA00429, K02 DA00288, RO1 DA11755, and K02 DA00465 Location: USA No. sites: 2 Start to completion: April 1998 to March 2004 Duration: 13 weeks Sample size: 106 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse disorder: DSM‐IV: cocaine dependence Mean age (range): 37 (23 ‐ 52) years Male participants (%): 83
Interventions	Trial arms methylphenidate sustained‐release (SR) (n = 53) placebo (n = 53) Type of methylphenidate: methylphenidate sustained‐release (SR) Dosage range: 40 mg to 60 mg Fixed or titrated: titrated Administrations per day: 2 Co‐intervention(s): weekly cognitive behavioural therapy
Outcomes	Relevant outcomes for the review are listed here Adult ADHD Rating Scale (AARS) (self‐rated, 18 items, 0 ‐ 54 points) Targeted Adult Attention Deficit Disorder Scale (TAADS) (investigator rated, 7 items, 0 ‐ 28 points) Dropouts due to adverse events
Notes	Declared conflicts of interest: "Dr. Levin is a consultant for Eli Lily and Company, Shire Pharmaceuticals Group, AstraZeneca, Cephalon/Alkermes and OrthoMcNeil Pharmaceutical Inc. Also she has research support from Eli Lily and Company, UCB Pharma Inc, Shire Pharmaceuticals Group, AstraZeneca and OrthoMcNeil Pharmaceutical Inc" (Levin 2007)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote "Participants were randomized into either the MPH or PBO group" (quote, Levin 2007)
Allocation concealment (selection bias)	Unclear risk	Comment: not described
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quotes "This study was a double‐blind, placebo‐controlled, randomized trial" (quote, Levin 2007) "Folic acid in the form of a 1 mg tablet was added to all placebo capsules in an attempt to improve the double‐blind" (quote, Levin 2007) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quotes "This study was a double‐blind, placebo‐controlled, randomized trial" (quote, Levin 2007) "Folic acid in the form of a 1 mg tablet was added to all placebo capsules in an attempt to improve the double‐blind" (quote, Levin 2007) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 30 of 53 (57%), placebo 29 of 53 (55%) Dropouts due to adverse events: 1 of 30 and 1 of 29 respectively. We note that most dropouts were labelled "not interested" (Levin, 2007) Statistical method to account for missing data: General estimation equation method
Selective reporting (reporting bias)	High risk	Comments Adverse event reporting threshold: no specific threshold, but no systematic reporting Serious adverse events not described. We anticipate that no SAEs occurred, but it is not reported AARS end point values not reported, there was "no significant difference between the groups" (quote, Levin 2007) Cardiovascular parameters not reported, although they were stated to be measured (Levin 2007, p 21)
Other bias	Low risk	Comment: None found
Psychiatric comorbidity (External validity)	High risk	Quote "Participants were excluded if they (1) met DSM‐ IV criteria for current psychiatric disorders (other than ADHD or substance abuse) which required psychiatric intervention" (Levin, 2007)
Responder selection (External validity)	High risk	Quotes "Known sensitivity to MPH" (Levin 2007). "[Inclusion criteria] Meets DSM‐IV criteria for cocaine dependence" (CT.gov)" "Following the PBO lead‐in phase, participants were randomized into either the MPH or PBO group" (Levin 2007) Comment 18 participants dropped out after entering the trial but before being randomised (figure 1)
Withdrawal effects (External validity)	High risk	Quote "[Inclusion criteria] Meets DSM‐IV criteria for cocaine dependence" (CT.gov) Comment The study contained a 1‐week placebo lead‐in before being randomised to active drug or placebo

Levin 2001.

Study characteristics
Methods	Trial ID(s): not registered Trial registry entry: not registered (we named the trial after year of publication) Sponsor: not reported Funding/industry involvement: not reported Location: USA No. sites: 1 site Start to completion: not reported Duration: 4 weeks Sample size: 20 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse disorder: no Mean age (range): 37 (19 to 56) years Male participants (%): 63
Interventions	Trial arms methylphenidate sustained‐release (SR) + placebo patch (n = 10) placebo + placebo patch (n = 10) methylphenidate sustained‐release (SR) + nicotine patch (not included in review) placebo + nicotine patch (not included in review) Type of methylphenidate: methylphenidate sustained‐release (MPH SR) Dosage range: 20 mg Fixed or titrated: fixed Administrations per day: 1 Co‐intervention(s): not described
Outcomes	Reported outcome of relevance for the review is listed here. Missing outcomes are listed in the 'selective reporting' risk of bias domain Clinical Global Impression‐Severity (CGI‐S) scale (0 ‐ 7 point Likert scale, 0 = no symptoms to 7 = most symptoms)
Notes	Declared conflicts of interest: not reported in Levin 2001
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote "The treatments were given in a randomized, double‐blind fashion with a placebo patch and pill" (Levin 2001).
Allocation concealment (selection bias)	Unclear risk	Quote. "The treatments were given in a randomized, double‐blind fashion with a placebo patch and pill" (Levin 2001).
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote "The treatments were given in a randomized, double‐blind fashion with a placebo patch and pill, whereby neither the participants nor the experimenters who worked with the participants were informed as to the treatment condition" (Levin 2001). Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quotes: "The treatments were given in a randomized, double‐blind fashion with a placebo patch and pill, whereby neither the participants nor the experimenters who worked with the participants were informed as to the treatment condition" (Levin 2001). "ADHD symptoms were assessed by a clinician blind to treatment in a structured interview using the CGI scale" (Levin 2001). Comment: Blinding was stated, but the effectiveness of the blinding technique was not tested.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 1 of 10 (10%), placebo 3 of 10 (30%). Adverse events leading to dropouts: not reported Statistical method used to account for missing data: not reported
Selective reporting (reporting bias)	High risk	Comments Adverse events not reported Serious adverse events not reported
Other bias	Low risk	Comment None identified
Psychiatric comorbidity (External validity)	High risk	Quotes "Participants with diagnoses of major depressive disorder or generalized anxiety disorder were excluded" (Levin 2001) "All Ham‐D scores of participants were 9 or lower" (Levin 2001).
Responder selection (External validity)	Unclear risk	Quote: "None of the participants were on methylphenidate or other stimulant medication before the study" (Levin 2001). Comment It is unclear if the participants were stimulant naïve or not.
Withdrawal effects (External validity)	Unclear risk	Quote "None of the participants were on methylphenidate or other stimulant medication before the study" (Levin 2001). Comment Washout not described, and uncertain if the participants had to stop current medication and whether they were stimulant naïve or not

Biederman 2003.

Study characteristics
Methods	Trial ID(s): NCT00181571, 2003‐p‐000037 (protocol) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00181571 Sponsor: Massachusetts General Hospital Funding/industry involvement: Ortho‐McNeil Janssen ("Clinical trials were supported with financial support from Ortho‐McNeil Janssen" (Biederman 2010), and on ClinicalTrials.Gov the company is listed as collaborator) Location: USA No. sites: 1 site Start to completion: June 2003 to August 2007 Duration: 6 weeks Sample size: 227 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse diagnosis: no Mean age (range): 36 (19 ‐ 60) years Male participants (%): 55
Interventions	Trial arms Osmotic‐controlled release oral delivery system (OROS) methylphenidate (n = 112) Placebo (n = 115) Type of methylphenidate: OROS methylphenidate Dosagerange: 36 mg to 144 mg Fixed or titrated: titrated Administrations per day: 1 Co‐intervention(s): not reported
Outcomes	Relevant outcomes for the review are listed here Adult ADHD Investigator System Report Scale (AISRS) (investigator‐rated, 18 items, 0 ‐ 54 points) Cardiovascular variables Harms
Notes	Declared conflicts of interest: "Dr Joseph Biederman is currently receiving research sup‐ port from the following sources: Alza, AstraZeneca, Bristol‐ Myers Squibb, Eli Lilly & Company, Janssen Pharmaceuticals Inc, McNeil, Merck, Organon, Otsuka, Shire, National Institutes of Mental Health and NICHD. In 2009, Dr Joseph Biederman received a speaker’s fee from the following sources: Fundacion Areces, Medice Pharmaceuticals, and the Spanish Child Psychiatry Association. In previous years, Dr Joseph Biederman received research support, consultation fees, or speaker’s fees for/from the following additional sources: Abbott, AstraZeneca, Celltech, Cephalon, Eli Lilly & Company, Esai, Forest, Glaxo, Gliatech, Janssen, McNeil, NARSAD, NIDA, New River, Novartis, Noven, Neurosearch, Pfizer, Pharmacia, The Prechter Foundation, Shire, The Stanley Foundation, UCB Pharma, Inc, and Wyeth. Dr Eric Mick receives research support from the following sources: Ortho‐McNeil Janssen Scientific Affairs, Pfizer, Shire Pharmaceuticals; and has been an advisory board member for Shire Pharmaceuticals. Dr Surman has received research support from Abbott, Alza, Cephalon, Elminda, Eli Lilly, the Hilda and Preston Davis Foundation, McNeil, Merck, New River, National Institutes of Health, Organon, Pfizer, Shire, and Takeda; has been a speaker for Janssen‐Ortho, McNeil, Novartis, and Shire; and has been a consultant/advisor for McNeil, Shire and Takeda. He has also been a speaker for the MGH Academy and Reed Medical Education, which produces programs that are funded by several pharmaceutical companies. Dr Robert Doyle has received speaker honoraria from Shire, Novartis, McNeil, Neuroscience Educational Institute, Continuing Medical Education Outfitters, PriMed, APA, and AACAP. Dr Hammerness has participated, as an investigator, in research studies funded by the following companies: Abbott, Bristol‐Myers Squibb, Cephalon, Eli Lilly, Glaxo‐SmithKline, Johnson & Johnson, McNeil, Merck, New River, Organon, Pfizer, Shire, and Takeda. In the past 2 years, Dr Hammerness has received research funds or participated in CME activities/professional talks supported by the following companies: Abbott, Eli Lilly, Forest, McNeil, Shire. Dr Hammerness has also received research funds from Elminda Ltd and has participated in speaker training with Shire. Dr Hammerness has also received honoraria from Reed Medical Education (a company working as a logistics collaborator for the MGH Psychia‐ try Academy); education programs supported through grants from pharmaceutical companies along with participant tuition. Ms Meghan Kotarski reports no competing interests. Dr Thomas Spencer has received research support from the following sources: Shire Laboratories Inc, Cephalon, Eli Lilly & Company, Glaxo‐ Smith Kline, Janssen, McNeil Pharmaceutical, Novartis Pharmaceuticals, Pfizer, and NIMH. Dr Thomas Spencer has been a speaker for the following speaker’s bureaus: Shire Laboratories, Inc, Eli Lilly & Company, Glaxo‐Smith Kline, Janssen, McNeil Pharmaceutical, and Novartis Pharmaceuticals. Dr Thomas Spencer has been on the advisory board for the following pharmaceutical companies: Shire Laboratories Inc, Cephalon, Eli Lilly & Company, Glaxo‐Smith Kline, Janssen, McNeil Pharmaceutical, Novartis Pharmaceuticals, and Pfizer" (Biederman 2010)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "All study subject randomizations and study medications were administered by the research pharmacy at the Massachusetts General Hospital" (Biederman 2010).
Allocation concealment (selection bias)	Low risk	Quote "All study subject randomizations and study medications were administered by the research pharmacy at the Massachusetts General Hospital, and all doses of OROS‐ MPH and placebo were delivered in identically appearing tablets" (Biederman 2010)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quotes "Physician raters and subjects were equally blind to treatment assignment" (Biederman, 2010) "All study subject randomizations and study medications were administered by the research pharmacy at the Massachusetts General Hospital, and all doses of OROS‐ MPH and placebo were delivered in identically appearing tablets" (Biederman, 2010) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quotes "Physician raters and subjects were equally blind to treatment assignment" (Biederman 2010) "All study subject randomizations and study medications were administered by the research pharmacy at the Massachusetts General Hospital, and all doses of OROS‐ MPH and placebo were delivered in identically appearing tablets" (Biederman 2010) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 26 of 112 (23%), placebo 17 of 115 (15%) Dropouts due to adverse events: methylphenidate 12 of 26, placebo 3 of 17 Statistical method to account for missing data: mixed effects model repeated measures (Biederman 2010), general estimating equations with last observation carried forward (Biederman 2006)
Selective reporting (reporting bias)	High risk	Comments Adverse event reporting threshold: No explicit threshold, only events reported at two or more visits were tabulated Several adverse events seemed to be categories rather than actual events, e.g. "cardiovascular", "neurological" and "musculoskeletal" (See Biederman 2010, table 1) Cardiovascular parameters and weight only reported in interim paper and not full study The Q‐LES‐QSF outcome was not reported
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	High risk	Quotes "Any clinically unstable psychiatric conditions including the following: acute psychosis, acute panic, acute OCD, acute mania, acute suicidality, bipolar disorder, acute substance use disorders (alcohol or drugs, sociopathy, criminality, or delinquency" (CT.gov) "[Exclusion criteria] Other clinically unstable psychiatric conditions (ie, bipolar disorder, psychosis, suicidality), drug or alcohol abuse or dependence within the 6 months preceding the study" (Biederman 2010)
Responder selection (External validity)	Unclear risk	Quote "Subjects with current adequate treatment for ADHD or a history of a previous adequate trial of Concerta" (were excluded) Comment It is unclear whether this means the participants were stimulant naïve
Withdrawal effects (External validity)	Unclear risk	Quote "[Exclusion criteria] Subjects with current adequate treatment for ADHD or a history of a previous adequate trial of Concerta" (CT.gov) Comments Current and previous stimulant use was not reported We were unsure how to interpret "adequate trial" and rated the domain as unclear

Spencer 2003a.

Study characteristics
Methods	Trial ID(s): CRIT124E2302 (protocol), 2302 (US Food and Drug Administration Drug Approval Package) Trial registry entry: not registered Sponsor: Novartis Funding/industry involvement: industry trial Location: USA No. sites: 18 Start to completion: April 2003 to September 2003 Duration: 5 weeks Sample size: 221
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse diagnosis: no Mean age (range): 39 years (We noted the age range was 18 ‐ 60, but they included participants up to 62 years of age) Male participants (%): 58
Interventions	Trial arms Dex‐methylphenidate extended‐release 20 mg (n = 58) Dex‐methylphenidate extended‐release 30 mg (n = 55) Dex‐methylphenidate extended‐release 40 mg (n = 55) Placebo (n = 53) Type of methylphenidate: dex‐methylphenidate extended‐release Dosage range: 20 mg to 40 mg Fixed or titrated: fixed Administrations per day: 1 Co‐intervention(s): "Patients receiving any psychological or behavioral therapies for ADHD were also excluded" (FDA review p 41)
Outcomes	Relevant outcomes for the review are listed here Conners' Adult ADHD Ratings Scales‐Self‐Report: Short Version (CAARS‐S:S) (self‐rated, 26 items, 0 ‐ 78 points) DSM‐IV Adult ADHD Rating Scale (investigator‐rated, 18 items, 0 ‐ 54 points) Quality of Life Enjoyment and Satisfaction Questionnaire (Q‐LES‐Q) (self‐rated, 14 domains, 14 ‐ 70 points) Cardiovascular variables Harms
Notes	Declared conflicts of interest: Conflicts of interests were not reported in Spencer 2007 or the open‐label extension by Adler 2009. The first and second authors declared the following interests in Adler 2006 trial: "Dr Adler receives grant/research support from the following pharmaceutical companies: Abbott Laboratories, Cortex Pharmaceuticals, Bristol‐Myers Squibb, Merck & Co, Novartis Pharmaceuticals, Pfizer, Eli Lilly, Shire, Ortho McNeil/Janssen/ Johnson and Johnson, New River Pharmaceuticals, Cephalon, and the National Institute of Drug Abuse. He is on the speaker’s bureau for Eli Lilly and Shire. He serves on the advisory board and as a consultant for the following pharmaceutical companies: Abbott Laboratories, Cortex Pharmaceuticals, Novartis Pharmaceuticals, Pfizer, Eli Lilly, Shire, Ortho McNeil/Janssen/ Johnson and Johnson, New River Pharmaceuticals, Cephalon, Merck & Co, Organon, Sanofi‐Aventis Pharmaceuticals, and Psychogenics. Dr Spencer receives research support from the following sources: Shire Laboratories Inc, Cephalon, Eli Lilly and Company, GlaxoSmithKline, Janssen, McNeil Pharmaceutical, Pfizer, Novartis Pharmaceuticals, and the National Institute of Mental Health. He is a speaker for the following speaker’s bureaus: Shire Laboratories Inc, Eli Lilly and Company, GlaxoSmithKline, Janssen, McNeil Pharmaceutical, and Novartis Pharmaceuticals. He is on the advisory boards of the following pharmaceutical companies: Shire Laboratories Inc, Cephalon, Eli Lilly and Company, GlaxoSmithKline, McNeil Pharmaceutical, Pfizer, Janssen, and Novartis Pharmaceutical" (Adler 2006).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote "Subjects were equally randomised to each of the four treatment arm" (Spencer 2007)
Allocation concealment (selection bias)	Unclear risk	Comment Not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote "Matching placebo control. All capsules of study drug were identical in appearance" (CSR Synopsis) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote "Matching placebo control. All capsules of study drug were identical in appearance" (CSR Synopsis) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 27 of 168 (16%), placebo 10 of 53 (19%) Three participants were excluded after randomisation Dropouts due to adverse events: methylphenidate 18 (10,7%), placebo 4 participants (7,5%) Statistical method to account for missing data: Last observation carried forward on ITT population for primary and secondary outcomes (Spencer 2007, p. 1382)
Selective reporting (reporting bias)	High risk	Comments Adverse event reporting thresholds: Published report (five most frequent adverse events, 12.1%), FDA Medical Review (0.6% for Focalin XL), CSR Synopsis (14 adverse events reported, no stated threshold), FDA Prescriber Information (dose‐dependent events, 5%) "Severe adverse events", only those occurring in two or more participants were reported (Spencer 2007, p. 1384) 'Dropouts due to adverse events' reported for events experienced by two or more participants (FDA Labelling, p. 12)
Other bias	Unclear risk	Comments The FDA audit of trial sites discovered a case of miscoded reasons for withdrawal. The participant experienced multiple psychiatric adverse events before dropping out, but was coded as "withdrew consent" (FDA Admin and Correspondence, p. 14 of 41) The FDA concluded (p. 16 of 41), "no underreporting of adverse events was noted". We judge the extent of miscoding and possible impact on the overall results is unclear
Psychiatric comorbidity (External validity)	High risk	Quotes "Patients with a history of alcohol or substance abuse within the last 6 months were excluded, as were patients with any psychiatric or medical comorbidity that may have interfered with study participation or assessments or for which MPH treatment may have posed a risk" (Spencer 2007) "Patients receiving any psychological or behavioral therapies for ADHD were also excluded" (FDA review p. 41)
Responder selection (External validity)	High risk	Quote "Patients were also excluded if the investigator judged that they had a history of poor response or intolerance to stimulants (e.g., MPH, d‐MPH, amphetamine salts, or dextroamphetamine salts)" (Spencer 2007) Comments Previous exposure to ADHD medication: methylphenidate 54 of 168 (32%) and placebo 26 of 53 (49%) (CSR Synopsis, p. 3) Previous exposure to stimulants: methylphenidate arm 46 of 164 (28%), placebo 15 of 55 (27%) (Spencer 2007, table 1)
Withdrawal effects (External validity)	High risk	Quotes "Patients were also excluded if the investigator judged that they had a history of poor response or intolerance to stimulants (e.g., MPH, d‐MPH, amphetamine salts, or dextroamphetamine salts)" (Spencer 2007) "Patients were required to discontinue all psychotropic drugs within 1 to 4 weeks prior to the screening visit" (Spencer 2007) Comments Previous exposure to ADHD medication: methylphenidate 54 of 168 (32%) and placebo 26 of 53 (49%) (Clinical Study Report synopsis, p. 3) and exposure to stimulants: methylphenidate 46 of 164 (28%) and placebo 15 of 55 (27%) (Spencer 2007, table 1) It was not reported how many participants who were in current treatment and had to stop treatment before randomisation

Chronis‐Tuscano 2004.

Study characteristics
Methods	Trial ID(s): NCT00318981, IIS‐2003‐023 (protocol ID) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00318981 Sponsor: University of Maryland (see ClinicalTrials.Gov) Funding/industry involvement: McNeil listed as sponsor in article and as a collaborator on ClinicalTrials.Gov. Location: USA No. sites: 1 Start to completion: December 2004 to December 2006 Duration: 2 weeks Sample size: 20 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse disorder: no Mean age (range): 40 years (not reported) Male participants (%): 0
Interventions	Trial arms OROS methylphenidate (n = 9) Placebo (n =11) Type of methylphenidate: OROS methylphenidate Dosage range: 36 mg to 90 mg Fixed or titrated: titrated Administrations per day: not reported Co‐intervention(s): "Psychosocial interventions should be suspended during the study"
Outcomes	Relevant outcomes for the review are listed here CAARS: unspecified (says ADHD Index, but range does not match the ADHD Index subscale) Clinical Global Improvement ‐ Severity (CGI‐S) (range 7 ("extremely ill") to 0 ("normal") There were no results reported from the double‐blind phase
Notes	Declared conflicts of interest: "Dr. Chronis‐Tuscano has received grant/ research support from the National Institute of Mental Health (NIMH) (R34 MH073567‐01A1). Dr. Stein has been a consultant for Novartis; has received grant/research support from Novartis, Pfizer, NIMH, and Eli Lilly; and has been a member of the speakers or advisory boards for McNeil and Novartis. Dr. Conlon has been a member of the speakers or advisory boards for McNeil Pediatrics, Eli Lilly, Novartis, and Shire. Dr. Robb has been a consultant for Lundbeck, Otsuka, and Eli Lilly; has received grant/research support from Pfizer, Janssen, Forest, Bristol‐Myers Squibb, GlaxoSmithKline, Supernus, and NIMH; has received honoraria from the American Academy of Child and Adolescent Psychiatry; and has been a member of the speakers or advisory boards for McNeil Pediatrics, Eli Lilly, Abbott, and Bristol‐Myers Squibb. Drs. Jones, Jiles, and Efron and Mss. Seymour, Rooney, Wagner, and Pian report no financial affiliations or other relationships relevant to the subject of this article" (Chronis‐Tuscano 2008)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote "During Phase 2, mothers were randomly assigned to placebo or their maximally effective dose" (Chronis‐Tuscano 2008)
Allocation concealment (selection bias)	Unclear risk	Quote "During Phase 2, mothers were randomly assigned to placebo or their maximally effective dose" (Chronis Tuscano 2008) Comment The procedure between phase 1 and 2 was not described and we were unable to rate the risk of bias
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quotes "Study physicians, research staff, and participants were blind to medication dose throughout the study" "Also, it is often difficult to maintain participant blind in discontinuation studies such as this, given that participants who have previously experienced drug effects are more likely to be aware if they are being actively medicated or not (Chronis‐Tuscano p. 1946) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quotes "Study physicians, research staff, and participants were blind to medication dose throughout the study" (Chronis‐Tuscano 2004) "Also, it is often difficult to maintain participant blind in discontinuation studies such as this, given that participants who have previously experienced drug effects are more likely to be aware if they are being actively medicated or not (Chronis‐Tuscano p. 1946) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment No dropouts
Selective reporting (reporting bias)	High risk	Comment Adverse events, serious adverse events, blood pressure, pulse, and weight were not reported for the randomised phase (phase 2)
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	High risk	Quotes "Mothers were excluded on the basis of any current Axis I disorder other than ADHD, Beck Depression Inventory‐II scores consistently above 16 (N = 5), severe tics or Tourette’s syndrome" "As such, our exclusion of participants with current comorbid disorders may limit the generalizability of these findings to real‐world clinical settings" (Chronis‐Tuscano p. 1946)
Responder selection (External validity)	High risk	Comments The 2‐week placebo‐controlled phase was preceded by a 5‐week titration phase for all participants, meaning that all participants were exposed to methylphenidate before randomisation Previous exposure to stimulants was not reported
Withdrawal effects (External validity)	High risk	Quote "It was expected that those randomly assigned to placebo would experience worsening of symptoms and parenting behavior from week 5 to 7, while those randomly assigned to their maximally effective dose would not evidence change" (Chronis‐Tuscano p. 1944) Comment The trial consisted of 2 phases. In phase 1, all participants were titrated to highest tolerated methylphenidate dose afterwards they were randomised to placebo or continued methylphenidate. Washout between phase I and 2 was not reported

Rösler 2004.

Study characteristics
Methods	Trial ID(s): NCT00619840, 6520‐9979‐06 (protocol), EMMA (trial acronym) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00619840 Sponsor: Medice Funding/industry involvement: industry trial Location: Germany No. sites: 28 Start to completion: November 2004 to May 2006 Duration: 24 weeks Sample size: 359 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse disorder: no Mean age (range): 35 (18 +) years Male participants (%): 50
Interventions	Trial arms Extended‐release (ER) methylphenidate (n = 241) Placebo (n = 118) Type of methylphenidate: extended‐release methylphenidate Dosagerange: 10 mg to 60 mg Fixed or titrated: titrated Administrations per day: 2 Co‐intervention(s): disease management sessions (7 sessions)
Outcomes	Relevant outcomes for the review are listed here Conners' Adult ADHD Rating Scales‐Self‐Report (CAARS‐S): DSM‐IV Total ADHD (self‐rated, items 18, 0 ‐ 54 points) Wender‐Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) (investigator rated, 28 items, 0 ‐ 56 points) Cardiovascular variables Harms
Notes	Declared conflicts of interest: not reported in the primary publication. In Rösler 2010 they reported: "M. Rösler is speaker and member of the advisory board from Lilly Germany, Janssen‐Cilag, Shire and Medice. He has received research support from Medice. He has grants from the German Federal Ministery of Education and Research. W. Retz has no financial interests in the connection with this manuscript. R. Fischer is the Medical Director of the study sponsor. C. Ose has received honoraria from Medice. B. Alm has no financial interests in connection with this study. J. Deckert has received honoraria from Medice and Janssen‐Cilag. A. Philipsen is member of the advisory board of Medice and Janssen‐Cilag. She has received research support from Medice. S. Herpertz has no financial interests in connection with this study. R. Ammer is member of the general management of the study sponsor Medice"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote "The participants (mean number 13 participants/study centre) were randomized to MPH ER or placebo at a ratio of 2:1" (Rösler 2009)
Allocation concealment (selection bias)	Unclear risk	Quote "The participants (mean number 13 participants/study centre) were randomized to MPH ER or placebo at a ratio of 2:1" (Rösler 2009)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote "placebo‐controlled" Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote "placebo‐controlled" Comment: Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote "Another field of limitations is the large drop‐out rate in combination with the use of LOCF as imputation method", and, "This may lead to concerns regarding the robustness of the conclusions drawn from the data" (Rösler 2009) Comments Dropout rates: methylphenidate 58 of 241 (24%), placebo 52 of 118 (43%) Dropouts due to adverse events methylphenidate 31 of 52, placebo 10 of 52 Statistical method used to account for missing data: Last observation carried forward
Selective reporting (reporting bias)	High risk	Comments Adverse event reporting threshold: Published report (4%, no threshold stated but for events occurring more frequently in the methylphenidate group this was the lower bar) The adverse events list does not contain the "neurological abnormalities" mentioned in the text Serious adverse events not reported
Other bias	Low risk	Comments None found
Psychiatric comorbidity (External validity)	High risk	Quotes "Individuals with low intelligence (IQ < 85), schizophrenia, bipolar disorder, acute depressive episode, acute anxiety disorders and other unstable psychiatric conditions were excluded, as were subjects with any serious medical illness" (Rösler 2009) "Alcohol, medication or drug dependency in the past 6 months or manifest drug abuse" (CT.gov)
Responder selection (External validity)	High risk	Quotes "The proportion of individuals who had received earlier stimulant treatment was equal (38.2 vs. 38.3%) in both groups" (Rösler 2009) "[exclusion criteria] Treatment with psychostimulants in the past 2 weeks" (CT.gov)
Withdrawal effects (External validity)	High risk	Quotes "[exclusion if] Treatment with psychostimulants in the past 2 weeks" (CT.gov) "Individuals treated with any psychopharmacological drug in addition to study medication were not included. A wash‐ out period of at least 2 weeks was necessary for any psychopharmacological drug before study inclusion" (Rösler 2009) "The proportion of individuals who had received earlier stimulant treatment was equal (38.2 vs. 38.3%) in both groups" (Rösler 2009)

Combine Substudy 2005.

Study characteristics
Methods	Trial ID(s): NCT00261872, 06‐AA‐0004 (protocol ID) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00261872 Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA) Funding/industry involvement: not reported Location: not reported No. sites: not reported Start to completion: December 2005 to April 2007 (estimated) Duration: 12 weeks Sample size: not reported
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse disorder: DSM‐IV: alcohol dependency Mean age (range): no data (21 ‐ 65 years) Male participants (%): not reported
Interventions	Trial arms Sustained‐release methylphenidate Placebo Type of methylphenidate: Described as "slow released" methylphenidate, which we assume is the SR formulation Dosage range: not reported Fixed or titrated: not reported Administrations per day: not reported Co‐intervention(s): naltrexone + behavioural therapy
Outcomes	Relevant outcomes for the review are listed here CAARS undefined rating scale We have no data from this study
Notes	Declared conflicts of interest: conflicts were not declared in the publication that reported on the main Combine study (Anton 2006)

Medori 2005.

Study characteristics
Methods	Trial ID(s): NCT00246220, 2004‐000730‐37 (EUCTR), CR002479 (protocol ID), 42603ATT3002 (FDA review), Study 4 (Aus Product Information), Study 5 (Health Canada Drug Monograph), LAMDA (trial name) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00246220, www.clinicaltrialsregister.eu/ctr-search/trial/2004-000730-37 Sponsor: Janssen Funding/ industry involvement: industry trial Location: 13 European countries (Great Britain, Germany, Denmark, Norway, Sweden, Finland, Czech Republic, Greece, France, The Netherlands, Spain, Portugal, and Switzerland) No. sites: 48 sites Start to completion: April 2005 to August 2006 Duration: 5 weeks Sample size: 402 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse disorder: no Mean age (range): 34 (18 ‐ 63) years Male participants (%): 54
Interventions	Trial arms OROS methylphenidate 18 mg (n = 101) OROS methylphenidate 36 mg (n = 102) OROS methylphenidate 72 mg (n = 103) Placebo (n = 96) Type of methylphenidate: OROS methylphenidate Dosage: 18 mg to 72 mg Fixed or titrated: fixed Administrations per day: 1 Co‐intervention(s): not reported
Outcomes	Relevant outcomes for the review are listed here Conners' Adult ADHD Rating Scales‐Self‐Report: Short Version (CAARS‐S:S) (self‐rated, 26 items, 0 ‐ 78 points) Conners' Adult ADHD Rating Scales‐Observer (CAARS‐O): DSV‐IV Total Symptoms (investigator rated, 18 items, 0 ‐ 54 points) Quality of Life Enjoyment and Satisfaction Questionnaire (Q‐LES‐QSF) (self‐rated, 14 items, 14 ‐ 70 points) Cardiovascular variables Harms
Notes	Declared conflicts of interest: "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" (Medori 2008)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "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" (Medori 2008)
Allocation concealment (selection bias)	Low risk	Quote "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" (Medori 2008)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote "placebo‐controlled" (Medori 2008) Comment: Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote "placebo‐controlled" (Medori 2008) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 31 of 306 (10%) and placebo 6 of 96 (6%). Dropouts due to adverse events: methylphenidate 12 of 31 and placebo 0 of 6. (Supplementary 2) Statistical method to account for missing data: Last observation carried forward and actual values for the secondary outcomes (Medori 2008)
Selective reporting (reporting bias)	Unclear risk	Comments Adverse event reporting threshold: CSR Synopsis (5%), published report (3%), FDA Medical Review and Health Canada Drug Monograph (2%), Australian Prescribing Information (1%, combined Medori, Adler, Casas) There were discrepancies between the adverse event reporting in the MHRA Public Assessment Report between tables on pages 60 and 62 for the outcomes of depression and aggression We do not know the actual adverse event reporting threshold for the trial of the pooled reporting in the Australian 'Prescribing Information', therefore we rated as unclear
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	High risk	Quote "Any clinically unstable psychiatric condition including, but not limited to the following: acute mood disorder, bipolar disorder, acute obsessive­compulsive disorder (OCD), anti­social personality disorder, borderline personality disorder. Subjects with a family history of schizophrenia or family history of affective psychosis. Autism or Asperger's syndrome. Subjects with presence of motor tics, history of Tourette's syndrome or family history of Tourette's syndrome. A diagnosis of substance use disorder (abuse/dependence) according to DSM­IV criteria within 6 months prior to screening evaluation (nicotine and caffeine dependence are not exclusionary). Episodic abuse in the past is not an exclusion criterion. Current eating disorder (e.g. bulimia, anorexia nervosa) or history of an eating disorder" (EUCTR)
Responder selection (External validity)	High risk	Quotes "Known to be a non­responder to methylphenidate, or subject has a child known to be a non­responder to methylphenidate" (EUCTR) "Has been treated with any methylphenidate­containing medication within 1 month of screening visit. One month is considered a reasonable time for patients treated with methylphenidate to return to a disease status baseline" (EUCTR). "Known allergy or hypersensitivity to methylphenidate, or components of PR OROS methylphenidate" (EUCTR). "The majority of subjects were stimulant naïve with 13% having been on prior stimulants" (FDA Medical Review, p. 87 of 456).
Withdrawal effects (External validity)	High risk	Quotes "[exclusion criteria] Has been treated with any methylphenidate­containing medication within 1 month of screening visit. One month is considered a reasonable time for patients treated with methylphenidate to return to a disease status baseline" (EUCTR) "The majority of subjects were stimulant naïve with 13% having been on prior stimulants" (FDA Medical Review, p. 87 of 456)

Winhusen 2005.

Study characteristics
Methods	Trial ID(s): NCT00253747, NIDA CTN‐0029 (protocol ID), 5U10DA013732 (NIDA grant number) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00253747 Sponsor: University of Cincinnati Funding/industry involvement: NIDA grants (5U10DA013732), Janssen was listed as collaborator on ClinicalTrials.Gov Location: USA No. sites: 6 Start to completion: November 2005 to March 2008 Duration: 11 weeks Sample size: 255 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse diagnosis: no Mean age (range): 38 (18 ‐ 55) years Male participants (%): 57%
Interventions	Trial arms OROS methylphenidate (n = 127) placebo (n = 128) Type of methylphenidate: OROS methylphenidate Dosagerange: 18 mg to 72 mg Fixed or titrated: titrated Administrations per day: 1 Co‐intervention(s): nicotine patch + smoking cessation counselling (weekly)
Outcomes	Relevant outcomes for the review are listed here ADHD DSM‐IV Total score (investigator rated, 18 items, range 0 to 54) Cardiovascular variables Harms
Notes	Declared conflicts of interest: "Dr Adler is a consultant for Abbott Laboratories, Cortex Pharmaceuticals, Novartis Pharmaceuticals, Pfizer, Shire, Eli Lilly, Ortho McNeil/Janssen/Johnson and Johnson, New River Pharmaceuticals, Cephalon, Merck, Organon, Sanofi‐Aventis Pharmaceuticals, Psychogenics, Mindsite, Major League Baseball, and Psychogenics; has received grant/research support from Abbott Laboratories, Cortex Pharmaceuticals, Bristol‐Myers Squibb, Merck and Co, Novartis Pharmaceuticals, Pfizer, Shire, Eli Lilly, Ortho McNeil/ Janssen/Johnson and Johnson, New River Pharmaceuticals, Cephalon, and the National Institute of Drug Abuse; is a member of the speakers/advisory boards for Abbott Laboratories, Cortex Pharmaceuticals, Novartis Pharmaceuticals, Pfizer, Shire, Eli Lilly, Ortho McNeil/Janssen/Johnson and Johnson, New River Pharmaceuticals, Cephalon, Merck, Organon, Sanofi‐Aventis Pharmaceuticals, Eli Lilly, and Shire; and has received royalty payments (as inventor) from NYU for license of adult ADHD scales and training materials. Dr Weiss is a consultant for Titan Pharmaceuticals and has received grant/research support from Eli Lilly. Drs Winhusen, Somoza, Brigham, Liu, Green, Covey, Croghan, and Leimberger and Mr Lewis and Ms Dorer have no personal affiliations or financial relationships with any commercial interest to disclose relative to the article" (Winhusen 2010)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Randomization of participants to OROS‐MPH or matching placebo was in a 1:1 ratio, stratified by site, and completed by computer at a centralized location" (Winhusen 2010)
Allocation concealment (selection bias)	Low risk	Quote "Randomization of participants to OROS‐MPH or matching placebo was in a 1:1 ratio, stratified by site, and completed by computer at a centralized location" (Winhusen 2010)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote "matching placebo". Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote "matching placebo" Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate (24/127) 19%; placebo (27/128), 21% Dropout due to adverse events: methylphenidate (0/24) and placebo (0/27) Statistical method used to account or missing data: General Estimation Equation (GEE) model for ADHD symptom rating. This assumes that data are missing at random We also observed a low number of baseline/completers for the investigator‐rated ADHD symptoms reported on CT.gov: 38 for methylphenidate and 42 for placebo
Selective reporting (reporting bias)	High risk	Comment Adverse event reporting thresholds: Published report (5%), CT.gov (3%)
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	High risk	Quote "Candidates were excluded if they were a significant suicidal/homicidal risk; had used tobacco products other than cigarettes in the past week; had a positive urine screen for an illicit drug; or met DSM‐IV criteria for current abuse or dependence for any psychoactive substance other than nicotine, current major depression, any current anxiety disorder except specific phobias, antisocial personality disorder, or a lifetime diagnosis of bipolar disorder or psychosis" (Winhusen 2010)
Responder selection (External validity)	High risk	Quote "Individuals were also excluded if they had been treated for ADHD with psychomotor stimulants […] within the last 30 days" (Winhusen) 2. "If they had a known allergy to OROS‐MPH, or if they had been non‐responders to a reasonable course of MPH treatment" (Winhusen 2010)
Withdrawal effects (External validity)	High risk	Quote "Individuals were also excluded if they had been treated for ADHD with psychomotor stimulants or had used smoking cessation counseling programs or medications within the last 30 days" (Winhusen 2010)

Adler 2006.

Study characteristics
Methods	Trial ID(s): NCT00326391, CR011560 (protocol), 02‐159 (FDA and the Medicines and Healthcare products Regulatory Agency (MHRA) reviews), Study 5 (Austrialia Prescriber Information) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00326391 Sponsor: McNeil (according to clinicaltrials.gov), Johnson & Johnson (according to the CSR synopsis and the trial publication) Funding/industry involvement: industry trial Location: USA No. sites: 27 sites Start to completion: April 2006 to December 2006 Duration: 7 weeks Sample size: 229 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse diagnosis: no Mean age (range): 39 (18 ‐ 65) years Male participants (%): 56
Interventions	Trial arms OROS methylphenidate (n = 113) placebo (n = 116) Type of methylphenidate: osmotic‐controlled release oral delivery system (OROS) methylphenidate Dosagerange: 36 mg to 108 mg Fixed or titrated: titrated Administrations per day: 1 Co‐intervention(s): not reported
Outcomes	Relevant outcomes for the review are listed here Conners' Adult ADHD Ratings Scales‐Self‐Report: Short version (CAARS‐S:S) (self‐rated, 26 items, 0‐78 points) Adult ADHD Investigator Symptom Report Scale (AISRS) (investigator rated, 18 items, 0‐54 points) Cardiovascular variables Harms
Notes	Declared conflicts of interest: "Dr Adler receives grant/research support from the following pharmaceutical companies: Abbott Laboratories, Cortex Pharmaceuticals, Bristol‐Myers Squibb, Merck & Co, Novartis Pharmaceuticals, Pfizer, Eli Lilly, Shire, Ortho McNeil/Janssen/ Johnson and Johnson, New River Pharmaceuticals, Cephalon, and the National Institute of Drug Abuse. He is on the speaker’s bureau for Eli Lilly and Shire. He serves on the advisory board and as a consultant for the following pharmaceutical companies: Abbott Laboratories, Cortex Pharmaceuticals, Novartis Pharmaceuticals, Pfizer, Eli Lilly, Shire, Ortho McNeil/Janssen/Johnson and Johnson, New River Pharmaceuticals, Cephalon, Merck & Co, Organon, Sanofi‐Aventis Pharmaceuticals, and Psychogenics. Dr Spencer receives research support from the following sources: Shire Laboratories Inc, Cephalon, Eli Lilly and Company, GlaxoSmithKline, Janssen, McNeil Pharmaceutical, Pfizer, Novartis Pharmaceuticals, and the National Institute of Mental Health. He is a speaker for the following speaker’s bureaus: Shire Laboratories Inc, Eli Lilly and Company, GlaxoSmithKline, Janssen, McNeil Pharmaceutical, and Novartis Pharmaceuticals. He is on the advisory boards of the following pharmaceutical companies: Shire Laboratories Inc, Cephalon, Eli Lilly and Company, GlaxoSmithKline, McNeil Pharmaceutical, Pfizer, Janssen, and Novartis Pharmaceutical. Drs Starr, Silber, Palumbo, and Orman, and Ms Zimmerman, are all employees of Johnson and Johnson. Dr Starr also owns stock in Johnson and Johnson" (Adler 2009).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Subjects were randomized using a computer‐generated randomization schedule stratified by investigator site with a block size of 4" (Adler 2009)
Allocation concealment (selection bias)	Low risk	Quote "To randomize subjects, a qualified study staff used an interactive voice recognition system and entered the subject’s date of birth, sex, and responses to selected eligibility questions. The system first verified that each subject randomized was unique and then, following the randomization schedule, identified the unique kit number of the dosing package that the study staff was to dispense to the subject at the baseline visit" (Adler 2009)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote "Each investigator received an allotment of double‐blind medication before the study started, and each subject received overencapsulated tablets that appeared identical to the treatment of all other subjects at the beginning of the study" (Adler 2009) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote "Each investigator received an allotment of double‐blind medication before the study started, and each subject received overencapsulated tablets that appeared identical to the treatment of all other subjects at the beginning of the study" (Adler 2009) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 42 of 113 (37%), placebo 26 of 116 (22%) Dropouts due to adverse events: methylphenidate 16 of 42, placebo 6 of 26 Statistical method used to account for missing data: Last observation carried forward
Selective reporting (reporting bias)	High risk	Comments Adverse event reporting threshold: Published paper (5%), CSR synopsis (no threshold but it only mentioned "the most commonly" adverse events), FDA Medical Review (1%) The quality of life outcome Q‐LES‐Q‐SF was mentioned in the CSR synopses (obtained from YODA and CT.gov), but not reported. For the quality of life outcome, AIM‐A, only one ('work/home/school') out of six domains was reported in the MHRA 2010 report (p. 46) and in the FDA review (p. 246), but the AIM‐A overall quality of life score was not reported, like for Casas 2008 There were discrepancies between the adverse event reporting in the MHRA Public Assessment Report between tables on page 60 and 62 for the outcomes of depression and aggression
Other bias	Low risk	Comments None found
Psychiatric comorbidity (External validity)	High risk	Quotes "Subjects with symptoms of marked anxiety, tension, agitation, or a HAM‐A score of 21 or greater or with symptoms of moderate severity of depression ratings using a HAM‐D score of 17 or higher were excluded" (Adler 2009). "The patients who met the DSM‐ IV criteria for depressive or anxiety disorders were excluded from the study, even if their HAM scores did not reach these cutoffs" (Adler 2009) "Patients with comorbid psychiatric diagnosis per DSM‐IV criteria of bipolar disorder, cyclothymic disorder, schizophrenia, pervasive developmental disorder, severe obsessive‐compulsive disorders, or any other diagnosis that in the judgment of the investigator could have deemed the subject to be inappropriate for the study were excluded" (Adler 2009) "Subjects with a history of drug or alcohol abuse within the past 6 months" (Adler 2009) "Subjects with moderated depression, marked anxiety, suicidal ideation, or drug or alcohol dependence were also excluded from the study. Therefore, these data may not generalize to adult patients who are not otherwise healthy" (Adler 2009, p. 246)
Responder selection (External validity)	High risk	Quotes "Known nonresponders to methylphenidate were also excluded, as were subjects with a history of allergy to methylphenidate" (Adler 2009) "Most subjects (93.0%) were not taking ADHD medication at baseline; 35,4% had previously taken medications for ADHD" (Adler 2009)
Withdrawal effects (External validity)	High risk	Quotes "Subjects being treated for ADHD at screening were washed out from all ADHD medication for 7 to 14 days before beginning the study" (Adler 2009) "Most subjects (93.0%) were not taking ADHD medication at baseline; 35.4% had previously taken medications for ADHD" (Adler 2009) Baseline measures were recorded after the 1‐2 weeks of washout, including ADHD symptoms (FDA Review, p. 91 of 456)

Konstenius 2006.

Study characteristics
Methods	Trial ID(s): ISRCTN81602628 Trial registry entry: www.isrctn.com/ISRCTN81602628 Sponsor: Addiction Centre Stockholm, Sweden Funding/industry involvement: no Location: Sweden No. sites: 1 Start to completion: February 2006 to June 2007 Duration: 12 weeks Sample size: 24
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse diagnosis: DSM‐IV: amphetamine dependence Mean age (range): 37 (18 ‐ 65) years Male participants (%): 79
Interventions	Trial arms OROS methylphenidate (n = 12) Placebo (n = 12) Type of methylphenidate: OROS methylphenidate Dosage range: 18 mg to 72 mg Fixed or titrated: titrated Administrations per day: 1 Co‐intervention(s): skills training programme (weekly)
Outcomes	Relevant outcomes for the review are listed here Conners' Adult ADHD Rating Scales‐Self‐Report (CAARS‐S) (self‐rated, unspecified) Conners' Adult ADHD Rating Scales‐Observer (CAARS‐O) (investigator‐rated unspecified)
Notes	Conflicts of interest: "There are no conflicts of interest to declare" (Konstenius 2010)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Twenty‐four participants were randomized to either PL or MPH by the Karolinska University Hospital Pharmacy, using the Trombul software" (Konstenius 2010)
Allocation concealment (selection bias)	Low risk	Quote "Twenty‐four participants were randomized to either PL or MPH by the Karolinska University Hospital Pharmacy, using the Trombul software" (Konstenius 2010)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote "This study was a double‐blind, placebo controlled, randomized trial" (Konstenius 2010) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote "This study was a double‐blind, placebo controlled, randomized trial" (Konstenius 2010) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 5 of 12 (42%), placebo 2 of 12 (17%) Dropouts due to adverse events: not reported Statistical method used to account for missing data: Last observation carried forward (as reported in table 1, although in the method's section it says they used completer's population)
Selective reporting (reporting bias)	High risk	Comments Adverse event reporting threshold: No specific threshold, but non‐systematic reporting of type and frequency SAEs were not reported. It seems that no SAEs occurred, but it was not directly reported
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	High risk	Quote "Exclusion criteria included: (1) current or past DSM IV diagnosis of any other substance dependence except nicotine, (2) history of any major psychiatric disorder (e.g., schizophrenia and major depression) or any current psychiatric condition requiring medication" (Konstenius 2010)
Responder selection (External validity)	High risk	Quotes "Known hypersensitivity for methylphenidate" (Konstenius 2010) "[Inclusion criteria] Amphetamine (amph) dependence according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM‐IV)" (ISRCTN)
Withdrawal effects (External validity)	High risk	Quotes "Amphetemine (amph) dependence according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM‐IV)" (ISRCTN) "Participants are required to stay abstinent of any substance for minimum two weeks prior the inclusion" (ISRCTN)

Ginsberg 2007.

Study characteristics
Methods	Trial ID(s): NCT00482313, 2006‐002553‐80 (EUCTR), ADHD Norrtälje 2006 (protocol ID), 6104/2009‐305 F27&28 (Project ID) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00482313 Sponsor: Karolinska University Hospital Funding/industry involvement: no Location: Sweden No. sites: 1 Start to completion: May 2007 to April 2010 Duration: 5 weeks Sample size: 30 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse diagnosis: no Mean age (range): 34 (21 ‐ 61) years Male participants (%): 100
Interventions	Trial arms OROS methylphenidate (n = 15) placebo (n = 15) Type of methylphenidate: OROS methylphenidate Dosagerange: 72 mg Fixed or titrated: fixed Administrations per day: 1 Co‐intervention(s): personal psychosocial treatment (not ADHD‐specific, on a daily level)
Outcomes	Relevant outcomes for the review are listed here Adult ADHD Self‐Report Scale (ASRS) (self‐rated, 18 items, 0 ‐ 72 points) Conners' Adult ADHD Rating Scales‐Observer (CAARS‐O) (investigator‐rated, 18 items, 0 ‐ 54 points) Cardiovascular variables Harms
Notes	Declared conflicts of interest: not reported in the primary publication (Ginsberg 2015). In the 3‐year follow‐up study they reported: "This was an investigator‐initiated study funded by the Swedish Ministry of Health and Social Affairs and the Stockholm County Council, Sweden. Dr Ginsberg has served as an investigator, consultant and/or speaker for Novartis, Eli Lilly, HB Pharma, and Shire. Dr Larsson has served as a speaker for Eli Lilly and received a research grant from Shire. Dr Långström received one speaker's honorarium from Lundbeck in 2013, and Dr Lindefors has no conflicts to declare" (Ginsberg 2015)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "The pharmacy laboratory assigned participants to the two study groups using a random number table prior to preparing and dispensing the study drug according to the study protocol" (Ginsberg 2012)
Allocation concealment (selection bias)	Low risk	Quote "The random number table was stored in the pharmacy department and was concealed from study staff and participants until completion of the study" (Ginsberg 2012)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quotes "The placebo and methylphenidate capsules and packaging were identical in appearance and were coded with a unique randomisation number" (Ginsberg 2012) "Both study staff and participants were masked to assignment during the RCT" (Ginsberg 2012) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quotes "The placebo and methylphenidate capsules and packaging were identical in appearance and were coded with a unique randomisation number" (Ginsberg 2012) "Both study staff and participants were masked to assignment during the RCT" (Ginsberg 2012) "In most cases, the same specifically trained and masked assessor performed the evaluations [...]." (Ginsberg 2012) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comments Dropout rates: methylphenidate 0 of 15 (0%), placebo 0 of 15 (0%) Dropouts due to adverse events: none. Statistical method to account for missing data: Last observation carried forward. It is not clear why they would use LOCF when there were no dropouts
Selective reporting (reporting bias)	Low risk	Comments Adverse event reporting threshold: Yearly report (in Swedish) (full reporting), published paper (non‐systematic reporting). The QOLI outcome was not measured during the double‐blind phase and therefore does not count as selective outcome reporting
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	Unclear risk	Quotes "[exclusion criteria] Any clinically unstable psychiatric condition including, but not limited to, acute mood disorder, bipolar disorder, acute OCD. A diagnosis of substance use disorder (abuse/dependence) according to DSM‐IV criteria within 3 months prior to screening evaluation for the study." (CT.gov) "Participants with comorbid disorders such as autism‐spectrum disorder, anxiety and depression could take part if they were considered to be stable at baseline. Previous drug‐ elicited episodes of psychosis were not a cause for exclusion, other than chronic psychoses" (Ginsberg 2012) "In contrast to most previous treatment studies of adult ADHD, we did not exclude participants with current treatment for comorbid disorders, unless the concurrent treatment interfered with the activity of methylphenidate. This allowed us to extend the external validity of the results to a broader ADHD population" (Ginsberg 2012, p. 72) Comment We rate this domain as unclear. The exclusion criteria listed on CT.gov/EUCTR seem strict whereas from the article they appear less restrictive.
Responder selection (External validity)	High risk	Quotes "Participants were excluded if they were known to be non‐responsive or intolerant to methylphenidate" (Ginsberg 2012) "Five inmates had previously been treated with methylphenidate", corresponding to 17% of population "None of the inmates were known to be non‐responsive or intolerant to methylphenidate" (Ginsberg 2012)
Withdrawal effects (External validity)	High risk	Quotes 18 of 30 participants had a primary amphetamine substance abuse diagnosis (Ginsberg 2012, supplement) "The screening visit took place up to 2 weeks before randomisation to enable medications excluded from the study to be tapered off prior to the baseline visit" "Five inmates had previously been treated with methylphenidate" (Ginsberg 2012) "Participants were excluded if they showed evidence of substance misuse up to 3 months before baseline, assessed in urine samples" (Ginsberg 2012)

Konstenius 2007.

Study characteristics
Methods	Trial ID(s): 2006‐002249‐35, ISRCTN77940178, MKJF001(protocol ID) Trial registry entry: www.clinicaltrialsregister.eu/ctr-search/trial/2006-002249-35/SE, www.isrctn.com/ISRCTN77940178 Sponsor: Addiction Centre Stockholm, National Psychiatric Services Coordination Taskgroup Funding/industry involvement: no Location: Sweden No. sites: 1 Start to completion: April 2007 to September 2011 Duration: 24 weeks Sample size: 54
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse diagnosis: DSM‐IV: amphetamine dependence Mean age (range): 42 (18 ‐ 65) years Male participants (%): 100 Other trial characteristics: Only criminal offenders were included. Treatment started 2 weeks before release from prison and continued for 22 weeks after release
Interventions	Trial arms OROS methylphenidate (n = 27) Placebo (n = 27) Type of methylphenidate: OROS methylphenidate Dosage range: 18 mg to 180 mg Fixed or titrated: titrated Administrations per day: 1 Co‐intervention(s): cognitive behavioural therapy (first 12 weeks), meeting with psychologist/coach (weeks 13 ‐ 24, every 14 days)
Outcomes	Relevant outcomes for the review are listed here Conners' Adult ADHD Rating Scales (CAARS): DSM‐IV Total ADHD (self‐rated, 18 items, 0 ‐ 54 points) Harms
Notes	Declared conflicts of interest: "The authors declare no conflicts of interest" (Konstenius 2013)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "The randomization list was generated by an independent pharmacist using the computer‐based program design by Trombult Programing. Between March 2007 and February 2011, 54 subject numbers were randomized into two parallel groups (MPH or identical placebo) with the block size 2" (Konstenius 2014)
Allocation concealment (selection bias)	Low risk	Quote "The randomization code was retained by the Karolinska Pharmacy and disclosed after the end of the trial. No interim analysis was performed" (Konstenius 2014)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quotes "MPH or identical placebo" (Konstenius 2014) "Block randomization was used because of the length of the trial and the nature of the medication effect, and was unknown to the principle investigator and the study staff" (Konstenius 2014) "Although efforts were made to maintain blinding, 48% of the participants receiving MPH and 48% of the placebo group identified their medication correctly during the titration phase or after reaching the maximum dose. However, many of the participants in both treatment groups remained uncertain (41% MPH, 26% placebo) or were wrong (11% MPH, 26% placebo) about which treatment arm they were allocated to" (Konstenius 2014)
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quotes "MPH or identical placebo" (Konstenius 2014) "Block randomization was used because of the length of the trial and the nature of the medication effect, and was unknown to the principle investigator and the study staff" (Konstenius 2014) Comment Blinding was stated, but the effectiveness of the blinding technique on the investigators was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 17 of 27 (63%), placebo 23 of 27 (85%) Reasons for dropouts: not reported for respectively (14/17) and (19/23) of the participants. They were labelled as "dropouts" only. Statistical method to account for missing data: Last observation carried forward
Selective reporting (reporting bias)	High risk	Comments Serious adverse events not reported for the placebo group Blood pressure, pulse, and weight values not reported for the placebo group The "relapse to crime" outcome was not reported The CGI‐Improvement and CGI‐Severity were not reported
Other bias	Low risk	Comment None found.
Psychiatric comorbidity (External validity)	Low risk	Quote "The study exclusion criteria were: (i) DSM‐IV diagnosis of any other substance dependence except nicotine, currently or during the 12 months prior to incarceration, (ii) a major psychiatric disorder (e.g. schizophrenia, severe depression)" (Konstenius 2014) Comment These criteria seemed less strict than those for Konstenius 2006 and we rated it low.
Responder selection (External validity)	High risk	Quotes "Known hypersensitivity to methylphenidate" (ISRCTN) "Those who meet the Diagnostic and Statistical Manual of Mental Disorders ‐ Fourth Edition (DSM‐IV) criteria for amphetamine addiction" (ISRCTN)
Withdrawal effects (External validity)	High risk	Quotes "Those who meet the Diagnostic and Statistical Manual of Mental Disorders ‐ Fourth Edition (DSM‐IV) criteria for amphetamine addiction" (ISRCTN) "All participants met the diagnostic criteria for amphetamine dependence during the last 12 months prior to the current incarceration, and had used amphetamines on a minimum of 12 occasions during the last 12 weeks preceding the incarceration" (Konstenius 2014) "All participants had i.v. amphetamine use" ( #4078) "Patients were required to abstain from any illicit substances during the 2 weeks preceding the inclusion" (Konstenius 2014)

Compas 2007 CM.

Study characteristics
Methods	See description for Compas 2007 GPT
Participants
Interventions
Outcomes
Notes

Compas 2007 GPT.

Study characteristics
Methods	Trial ID(s): 2006‐000222‐31 (EUCTR), ISRCTN54096201, 70170 (protocol ID) Trial registry entry: www.clinicaltrialsregister.eu/ctr-search/trial/2006-000222-31/DE, www.isrctn.com/ISRCTN54096201 Sponsor: Universitätsklinikum Freiburg Funding/industry involvement: German Federal Ministry of Education and Research (01GV0605 and 01GV0606). The Marketing Authorisation Holder, Medice, was involved in the study design and outcome collection Location: Germany No. sites: 7 sites Start to completion: April 2007 to August 2011 Duration: 52 weeks Sample size: 433 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse diagnosis: no Mean age (range): 35 (18 ‐ 58) years Male participants (%): 53 (for group psychotherapy comparison), 47 (for clinical management comparison)
Interventions	Trial arms Extended‐release (ER) methylphenidate + clinical management (n = 110) Placebo + clinical management (n = 107) Extended‐release (ER) methylphenidate + group psychotherapy (n = 107) Placebo + group psychotherapy (n = 109) Type of methylphenidate: extended‐release methylphenidate Dosagerange: 10 mg to 60 mg or up to 1.3 mg/kg Fixed or titrated: titrated Administrations per day: 2 Co‐intervention(s): group psychotherapy (weekly until week 12, monthly afterwards) or clinical management, non‐specific counselling in individual sessions (weekly until week 12, afterwards monthly)
Outcomes	Relevant outcomes for the review are listed here Absence from work/education/training Conners' Adult ADHD Rating Scales (CAARS): DSM‐IV Total ADHD (self‐rated, 18 items, 0 ‐ 54 points) Conners' Adult ADHD Rating Scales‐Observer: Long Version (CAARS‐O:L): DSM‐IV ADHD Symptoms Total (investigator rated, 18 items, 0 – 54 points). Quality of Life Enjoyment and Satisfaction Questionnaire (Q‐LES‐QSF) (self‐rated, 14 items, 14 ‐ 70 points) Harms
Notes	Declared conflicts of interest: "Dr Philipsen reported serving on advisory boards, giving lectures, performing phase 3 studies, or receiving travel grants within the last 3 years from Eli Lilly and Co, Janssen‐Cilag, MEDICE Arzneimittel Pütter GmbH and Co KG, Novartis, and Shire; and has authored books and articles on psychotherapy published by Elsevier, Hogrefe, Schattauer, Kohlhammer, and Karger. Dr Matthies reported receiving a speaker’s fee from Janssen‐Cilag; and involvement in clinical trials conducted by Janssen‐Cilag and Eli Lilly and Co. Dr Colla reported serving on advisory boards, receiving speaker’s honoraria, or performing phase 3 studies within the last 3 years with Shire, Eli Lilly and Co, and Novartis. Dr Jacob reported receiving speaker’s honoraria from MEDICE; serving as an advisory board member of Eli Lilly and Co; performing phase 3 studies at MEDICE, Novartis, Janssen‐Cilag, Eli Lilly and Co; and performing an investigator‐initiated trial with Eli Lilly and Co. Dr Sobanski reported receiving speaker’s honoraria from MEDICE, Eli Lilly and Co, and Novartis; serving as an advisory board member of MEDICE, Shire, and Eli Lilly and Co; and performing phase 3 studies and investigator‐initiated trials with MEDICE, Novartis, Janssen‐Cilag, and Eli Lilly and Co. Dr Alm reported receiving speaker’s honoraria from MEDICE; serving on the advisory board of Eli Lilly and Co; performing phase 3 studies at MEDICE, Novartis, Janssen‐Cilag, Eli Lilly and Co; and performing an investigator‐initiated trial with Eli Lilly and Co. Dr Roesler reported serving as an advisory board member of MEDICE, Eli Lilly and Co, and Janssen‐Cilag; serving as a member of the speakers bureau of MEDICE, Eli Lilly and Co, Shire, and Novartis; and performing clinical studies for MEDICE. Dr Retz reported receiving speaker’s honoraria from and serving as an advisory board member of MEDICE, Shire, and Novartis; and performing clinical trials for BMBF, Novartis, Vifor, and MEDICE. Dr Kis reported receiving speaker’s honoraria from MEDICE, Servier, and Eli Lilly and Co; and serving as an advisory board member of MEDICE, Novartis, and Servier. Dr Huss reported serving as an advisory board member of Eli Lilly and Co, Engelhardt Arzneimittel, Janssen‐Cilag, MEDICE, Novartis, Shire, and Steiner Arzneimittel within the past 5 years; serving as consultant to Engelhardt Arzneimittel, MEDICE, and Steiner Arzneimittel; receiving honoraria from Eli Lilly and Co, Engelhard Arzneimittel, Janssen‐Cilag, MEDICE, Novartis, and Shire; and receiving unrestricted grants for investigator‐initiated trials from Eli Lilly and Co, MEDICE, Engelhard Arzneimittel, and Steiner Arzneimittel. Mr Schlander reported receiving research support from sick funds, physicians’ associations, health technology agencies, industry associations, and biopharmaceutical enterprises, including Janssen (Johnson & Johnson) and Shire, all under unrestricted educational grant policy. Dr Tebartz van Elst reported serving on advisory boards, giving lectures, or receiving travel grants within the last 3 years from Eli Lilly and Co, Janssen‐ Cilag, Novartis, Shire, UCB, GlaxoSmithKline, Servier, Janssen‐Cilag, and Cyberonics. No other disclosures were reported" (Philipsen 2015). Furthermore: "Roland Fischer, MD, MEDICE Arzneimittel Pütter GmbH and Co KG, Iserlohn, Germany, gave advice on preparing the study protocol and assisted in managing serious adverse events; he received no compensation" (Philipsen 2015).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Computer‐based generation of randomization lists, prepacking, and shipment of medication were implemented by Medice Arzneimittel Pütter GmbH & Co. KG with a 1:1:1:1 treatment ratio, stratified by center and using blocks of variable length which were not communicated, to guarantee concealment" (Philipsen 2014)
Allocation concealment (selection bias)	Low risk	Quote "Central randomization via fax is performed, using block randomization with variable block length. This guarantees concealment of randomization" (Philipsen 2010)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quotes "Matching placebo" (BfArM submission) "For patients and therapists, the study is open with respect to the assignment to the two treatment conditions psychotherapy and clinical management. Blinding is restricted to medical treatment (methylphenidate, placebo) and observer ratings of symptoms of ADHD (CAARS‐O‐L) and clinical global impression. Raters are not informed on the treatment allocation and are not involved in the trial except of interviewing the subjects" (Philipsen 2010) "Blinding was restricted to medication and to observer ratings of ADHD and CGI. We did not systematically assess whether blinding was effective in patients. However, because patients who received methylphenidate and those who received placebo both reported high numbers of AEs, with minimal effects to vital signs and weight, we believe the blinding was effective" (Philipsen 2015) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quotes "Matching placebo" (BfArM submission) "For patients and therapists, the study is open with respect to the assignment to the two treatment conditions psychotherapy and clinical management. Blinding is restricted to medical treatment (methylphenidate, placebo) and observer ratings of symptoms of ADHD (CAARS‐O‐L) and clinical global impression. Raters are not informed on the treatment allocation and are not involved in the trial except of interviewing the subjects" (Philipsen 2010) "Blinding was restricted to medication and to observer ratings of ADHD and CGI. We did not systematically assess whether blinding was effective in patients. However, because patients who received methylphenidate and those who received placebo both reported high numbers of AEs, with minimal effects to vital signs and weight, we believe the blinding was effective" (Philipsen 2015) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates (week 13): methylphenidate 20 of 217 (9%); placebo 34 of 216 (16%) Dropout rates (week 52): methylphenidate 72 of 217 (33%); placebo 102 of 216 (47%) Dropouts due to adverse events: not clearly reported Statistical method to account for missing data: last mean carried forward
Selective reporting (reporting bias)	Low risk	Comments Adverse event reporting threshold: Author correspondence (all results), published reports (all results, Kis et al., 2020) EUCTR (not reported), BfArM database (5%) Serious adverse events: not reported in published report, on EUCTR or in BfArM database; obtained from author correspondence Absence from work/school/education reported as baseline ‐13 weeks, w13 ‐ w26 and w26 ‐ w52 (BfArM document), but not baseline ‐ 52 weeks.
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	High risk	Quotes "Schizophrenia, bipolar disorder, borderline personality disorder, antisocial personality disorder, suicidal or self‐injurious behaviour, autism, motor tics, Tourette’s syndrome" (BfArM submission) "Substance abuse/dependence within 6 months prior to screening. Episodic abuse is not an exclusion criterion. Positive drug screening" (BfArM submission) "ADHD must be the predominant clinical feature in patients (major co‐morbid conditions are excluded). Also patients with co‐morbid conditions that clearly demand alternative treatment regimes or interfere with study medication are not included" (Philipsen 2010) "Our findings may not be generalizable to routine care settings in which comorbidities are not excluded and patients may have more psychosocial impairments or difficulties meeting the time and effort requirements for this trial" (Philipsen 2015)
Responder selection (External validity)	High risk	Quotes "Known methylphenidate intolerance" (BfArM submission) Comments Participants excluded at screening: MPH intolerance (n = 1, 1.2%) (Philipsen 2014) Particpants previously treated with a stimulant: 18% (Table 6, Philipsen 2014) Previous stimulant treatment: 90 of 419 (21%) (Table 1, Philipsen 2015)
Withdrawal effects (External validity)	Unclear risk	Quotes Exclusion criteria: "Treatment with stimulants or ADHD‐specific psychotherapy within 6 months prior the screening" (BfArM submission) [excluded at pre‐screening]: Current MPH treatment (n=39, 4.1%) (Philipsen 2010)

Casas 2008.

Study characteristics
Methods	Trial ID(s): NCT00714688, 2007‐002111‐82 (EUCTR), 42603ATT3013 (protocol ID), 3013 (Regulatory reviews), LAMDA II (trial name) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00714688, www.clinicaltrialsregister.eu/ctr-search/trial/2007-002111-82/FR Sponsor: Janssen Funding/industry involvement: industry trial Location: 11 European countries (Norway, France, Sweden, Denmark, the Netherlands, Spain, Belgium, United Kingdom, Finland, Germany, and Switzerland) No. sites: 42 sites Start to completion: February 2008 to April 2009 Duration: 13 weeks Sample size: 279 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV‐TR Concomitant substance abuse diagnosis: no Mean age (range): 36 (18 ‐ 64) years Male participants (%): 52
Interventions	Trial arms OROS methylphenidate 54 mg (n = 90) OROS methylphenidate 72 mg (n = 92) Placebo (n = 97) Type of methylphenidate: OROS methylphenidate Dosage range: 54 mg to 72 mg Fixed or titrated: fixed Administrations per day: 1 Co‐intervention(s): not reported
Outcomes	Relevant outcomes for the review are listed here Conners' Adult ADHD Rating Scales‐Self‐Report: Short Version (CAARS‐S:S) (self‐rated, 26 items, 0‐78 points) Conners' Adult ADHD Ratings Scales‐Observer (CAARS‐O): DSM‐IV Total ADHD (investigator rated, 18 items, 0‐54 points) ADHD Impact Module–Adult (AIM‐A): overall quality of life (unspecified) Cardiovascular variables Harms
Notes	Declared conflicts of interest: "M. Casas has, in the past 3 years, been a consultant, a member of an advisory board and/or a speaker for Janssen–Cilag, Eli Lilly, Shire and Rubió. He has received research grants from Janssen–Cilag, Rubió and Eli Lilly. M. Rösler is a consultant for Janssen–Cilag, Medice, Lilly and Shire, and is a member of the speaker’s bureau of Janssen–Cilag, Medice and Shire. J.J.S. Kooij has been a speaker for Janssen–Cilag BV and Eli Lilly and has received research grants from Janssen– Cilag BV and Shire. Y. Ginsberg has served as a consultant and speaker for Janssen–Cilag and Novartis and as a speaker for Lundbeck. She is a principal investigator for the LAMDA‐I and LAMDA‐II studies, funded by Janssen–Cilag. J.A. Ramos‐Quiroga has, in the past 3 years, been a consultant, a member of an advisory board and/or a speaker for Janssen–Cilag, Eli Lilly, Shire and Rubió. He has received research grants from Jans‐ sen–Cilag, Rubió, Eli Lilly and Alicia Koplowitz Foundation. S. Heger is a former employee of Janssen–Cilag EMEA, and has since acted as a speaker and consultant for the company. J. Berwaerts is an employee of Johnson & Johnson Pharmaceutical Research & Development. J. Dejonkheere is a consultant working on behalf of SGS–Life Science Services, a company employed by Janssen–Cilag EMEA to provide statistical analysis. B. Schäuble and E. van der Vorst are employees of Janssen–Cilag EMEA" (Casas 2013)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Randomization was based on a computer‐generated scheme prepared by the sponsor, balanced by using permuted blocks of treatments and stratified by study centre. Based on this scheme, study drug was packaged for each subject. Medication kit numbers were pre‐printed on drug labels and assigned as subjects were randomly assigned to treatment. Treatment codes were obtained from a central interactive voice response system giving a medication kit number for the drug to which the subject had been assigned" (Casas 2013)
Allocation concealment (selection bias)	Low risk	Quote "Randomization was based on a computer‐generated scheme prepared by the sponsor, balanced by using permuted blocks of treatments and stratified by study centre. Based on this scheme, study drug was packaged for each subject. Medication kit numbers were pre‐printed on drug labels and assigned as subjects were randomly assigned to treatment. Treatment codes were obtained from a central interactive voice response system giving a medication kit number for the drug to which the subject had been assigned" (Casas 2013)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote "matching placebo. Placebo and PR OROS MPH were over‐encapsulated to look identical" (CSR Synopsis) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote "matching placebo. Placebo and PR OROS MPH were over‐encapsulated to look identical" (CSR Synopsis) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 72 of 182 (40%), placebo 29 of 97 (30%) Dropouts due to adverse events: methylphenidate 34 of 72, placebo 2 of 29 Statistical method used to account for missing data: Last observation carried forward (Casas, p. 270) While only 55 participants (59.8%) allocated to 72 mg OROS MPH completed the study, 64.1% were considered to be "responders" (Casas 2013, p. 272). This was also noticed in the MHRA 2010 Review, p. 45, "The most appropriate method for handling missing data is to consider those that drop out as treatment failures. As noted earlier there is an incredibly high dropout rate in this study, with 30% of patients not completing in the placebo group, and 40% in the active group. It is clear from the data presented that in this trial the applicant has not treated missing as failure, as more patients appear to have responded than actually finished the trial in the 72 mg/day group". We made a similar observation for Huss 2010
Selective reporting (reporting bias)	Unclear risk	Comments Adverse event reporting threshold: Published report (5%), CT.gov (5%), CSR synopsis (10%), AUS PI and MHRA PAR (1% combined Medori, Adler, Casas) There were discrepancies between the adverse event reporting in the MHRA Public Assessment Report between tables on page 60 and 62 for the outcomes of depression and aggression We do not know the actual adverse event reporting threshold for the trial in the pooled reporting in the Australian Prescribing Information, therefore we rated as unclear Overall AIMA‐Quality of life outcome was reported in CSR synopsis, whereas in published report and MHRA report (MHRA 2010, p. 47) the six domains but no overall score was reported
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	High risk	Quotes "any clinically unstable psychiatric condition; family history of schizophrenia or affective psychosis; autism, Asperger’s syndrome, eating disorder, motor tics or history (including family history) of Tourette’s syndrome; substance use disorder (not including caffeine or nicotine dependence)" (Casas 2013) "In addition, as with many clinical trials in individuals with ADHD, the exclusion of subjects with clinically relevant comorbidities may mean that the patient cohort does not reflect the typical real‐world ADHD population" (Casas 2013, p. 279)
Responder selection (External validity)	High risk	Quotes "Known to be a non­responder to methylphenidate, or subject has a child known to be a non­responder to methylphenidate" (EUCTR) "Has been treated with any methylphenidate­containing medication within 1 month of screening visit. One month is considered a reasonable time for patients treated with methylphenidate to return to a disease status baseline" (EUCTR). "Participation in and premature withdrawal from 42603ATT3002 or 42603ATT3004 study" (EUCTR), which is the MEDORI trial "Known allergy or hypersensitivity to methylphenidate, or components of PR OROS methylphenidate" (EUCTR). "8.6% [of the participants] stopped methylphenidate prior to randomisation" (MHRA PAR, p. 41)
Withdrawal effects (External validity)	High risk	Quotes "After up to 2 weeks’ screening to enable safe tapering and discontinuation of disallowed medications (4 weeks for monoamine oxidase inhibitors), eligible subjects were randomly allocated (1:1:1) to OROS MPH 54 or 72 mg/day, or matching placebo" (Casas 2013) "Concomitant medications to be discontinued during the screening period were α2 adrenergic receptor agonists, antipsychotics, theophylline, coumarin anticoagulants or anticonvulsants, any ADHD treatment, monoamine oxidase inhibitors, herbal and over‐the‐counter stimulant diet preparations or drugs containing stimulants" (Casas 2013). "[Exclusion criteria] Has been treated with any methylphenidate­containing medication within 1 month of screening visit. One month is considered a reasonable time for patients treated with methylphenidate to return to a disease status baseline" (EUCTR) "8.6% stopped methylphenidate prior to randomisation" (MHRA PAR, p. 41)

Retz 2008.

Study characteristics
Methods	Trial ID(s): NCT00730249, 2008‐000942‐29 (EUCTR), 6520‐0650‐13 (protocol ID), QUMEA (trial name) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00730249, www.clinicaltrialsregister.eu/ctr-search/trial/2008-000942-29/DE Sponsor: Medice Funding/industry involvement: industry trial Location: Germany No. trial sites: 11 sites Start to completion: September 2008 to January 2010 Duration: 8 weeks Sample size: 162 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse diagnosis: no Mean age (range): 37 (18+) years Male participants (%): 47
Interventions	Trial arms Extended‐release (ER) methylphenidate (n = 84) Placebo (n = 78) Type of methylphenidate: extended‐release methylphenidate Dosagerange: 40 mg to 120 mg Fixed or titrated: titrated Administrations per day: 2 Co‐intervention(s): disease management sessions (6 sessions)
Outcomes	Relevant outcomes for the review are listed here Conners' Adult ADHD Rating Scales‐Self‐Report: Long version (CAARS‐S:L) (self‐rated, 66 items, 0 ‐ 90 points) Wender‐Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) (investigator‐rated, 7 domains, 28 items; range = 0 ‐ 56) Cardiovascular variables Harms
Notes	Declared conflicts of interest: "WR has received honoraria and travel grants from Novartis, AstraZeneca, Medice and Flynn Pharma and is on the advisory board of Shire. MR has received honoraria, travel grants, and paid consultancy from Lilly, Janssen‐Cilag, Shire and Medice and is on the advisory board of Lilly and Shire. CO has received honoraria from Medice. AS currently serves as trial statistician is on a data safety and monitoring the advisory board for Boehringer Ingelheim KG. BA is on the advisory board of Lilly. AP has received honoraria and travel grants from Janssen‐Cilag, Medice, Lilly, Novartis and is on the advisory board of Janssen‐Cilag, Lilly and Shir. RF is the Medical Director of Medice. RA is member of the general management of Medice and sponsor of the trial" (Retz 2012)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Randomisation was performed by Medice’s Galenic Department which included the generation of the randomisation list and the preparation of emergency envelopes. We used block randomisation with a block size of 4. The block size was not mentioned in the investigational plan or the consent given to patients" (Retz 2012)
Allocation concealment (selection bias)	Low risk	Quote "Randomisation was performed by Medice’s Galenic Department which included the generation of the randomisation list and the preparation of emergency envelopes. We used block randomisation with a block size of 4. The block size was not mentioned in the investigational plan or the consent given to patients" (Retz 2012)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote "double‐blind, placebo‐controlled" (Retz 2012) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote "double‐blind, placebo‐controlled" Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comments Dropout rates: methylphenidate 4 of 84 (5%), placebo 3 of 78 (4%) Dropouts due to adverse events: methylphenidate 3 of 4, placebo 1 of 3 Statistical method to account for missing data: LOCF (primary outcome), not clear for secondary outcomes
Selective reporting (reporting bias)	High risk	Comments Adverse event reporting threshold: Published paper (only 12 events reported and they had to occur statistically significant more often in either arm, 17% level for MPH) Adverse events leading to dropout and dose reductions not reported
Other bias	High risk	Comment We noted baseline differences between the groups: there were more women in the MPH ER group than the placebo group (61% vs 44%) and a higher baseline CAARS‐Self rating (126 points vs 114 points), although the sample size was 162 participants
Psychiatric comorbidity (External validity)	High risk	Quotes "Individuals with low intelligence (IQ <85), dementia, schizophrenia, bipolar disorder, current major depression, acute anxiety disorders and other unstable psychiatric conditions were excluded, as were subjects with any serious medical illness" (Retz 2012) "Also subjects with drug or alcohol dependence during the 6 months before screening [...] were not included" (Retz 2012)
Responder selection (External validity)	High risk	Comment Previous ADHD treatment: 29.8% in the MPH ER group and 37.2% in the placebo group (Retz 2012)
Withdrawal effects (External validity)	High risk	Quotes "Treatment with psychostimulants in the past two weeks before screening" (CT.gov) "A wash‐out period of at least 2 weeks was necessary for any psychopharmacological drug before study inclusion" (Retz 2012) Comment Previous stimulant treatment: 29.8% in the MPH ER group and 37.2% in the placebo group (Retz 2012)

College Study 2009.

Study characteristics
Methods	Trial ID(s): NCT00931398, ConcertaATT4100 (other study ID) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00931398 (registered 2 July 2009) Sponsor: University of Pittsburg Funding/industry involvement: Ortho‐McNeil‐Janssen was involved in the study (listed on ClinicalTrials.Gov as collaborator) Location: USA No. sites: 1 Start to completion: "Study was not initiated due to lack of funding by the sponsor" according to ClinicalTrials.Gov entry Duration: 8 weeks Sample size: not reported
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse diagnosis: no Mean age (range): not reported (range 18 to 25 years) Male participants (%): not reported
Interventions	Trial arms OROS methylphenidate Placebo Type of methylphenidate: OROS methylphenidate Dosagerange: 18 mg to 72 mg Fixed or titrated: not reported Administrations per day: not reported Co‐intervention(s): not reported
Outcomes	Relevant outcomes for the review are listed here The study was not conducted. GPA (Grades point average) CAARS: DVM IV Total ADHD
Notes	Declared conflicts of interest: There are no publications or published protocols

Goodman 2009.

Study characteristics
Methods	Trial ID(s): NCT00937040, CONCERTA­ATT­3014 (other study ID), CR015058 (protocol ID) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00937040 Sponsor: Ortho‐McNeil Janssen Funding/industry involvement: industry trial Location: USA No. sites: 35 sites Start to completion: July 2009 to February 2010 Duration: 6 weeks Sample size: 357
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse diagnosis: no Mean age (range): 36 (18 ‐ 65) years Male participants (%): 54
Interventions	Trial arms OROS methylphenidate (n = 178) Placebo (n = 179) Type of methylphenidate: OROS methylphenidate Dosagerange: 18 mg to 72 mg Fixed or titrated: titrated Administrations per day: 1 Co‐intervention(s): not reported
Outcomes	Relevant outcomes for the review are listed here Adult Self‐Report‐Scale (ASRS) (self‐rated, 18 items, 0 ‐ 72 points) Adult ADHD Investigator System Report Scale (AISRS) (investigator‐rated, 18 items, 0 ‐ 54 points) Significant Other's Rating of Adult ADHD Rating Scale IV (peer‐rated, 18 items, 0 ‐ 54 points) Harms
Notes	Declared conflicts of interest: "Dr Goodman discloses the following financial considerations: consultant and/or reports associated with WebMD, Medscape, Temple University, American Professional Society of ADHD and Related Disorders, Neuroscience Education Institute, Children and Adults with ADHD Association, Shire, McNeil, Cephalon, Teva, Lundbeck, Janssen US and Canada, OptumInsight (Ingenix Pharmaceutical Services), Sunovion, Thomson Reuters, GuidePoint Global, Otsuka, Med‐IQ, Novartis, Ironshore Pharmaceuticals, Neos Therapeutics, Rhodes Pharmaceuticals, Avacat, Major League Baseball, National Football League, American Physician Institute for Advanced Professional Studies, LLC, Healthequity Corporation, Prescriber’s Letter, Consumer Reports, and Pontifax. Dr Rostain is an employee of the University of Pennsylvania; has been on the scientific advisory boards of Pearson and Alcobra; has been a consultant to the State University of New York (SUNY) at Albany; has received grant/research support from the Agency for Healthcare Research and Quality and the National Institute of Mental Health; has made educational presentations/received honoraria from WebMD, MedScape, and the National Association for Continuing Education; and has received royalties from Routledge/Taylor Francis Group. Dr Armstrong discloses the following financial considerations relating to Johnson & Johnson: stockholder, stock options holder, and pension. Dr Ma is an employee of Johnson & Johnson Consumer, Inc, and is a Johnson & Johnson stockholder. Dr Ascher is an employee of Janssen Pharmaceutical Development, LLC, and is a stockholder of Johnson & Johnson as well as a holder of stock options. Dr Starr is an employee of Janssen Scientific Affairs, LLC, and is a Johnson & Johnson stockholder" (Goodman 2016).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Subjects were randomly assigned by an interactive voice response system to 18 mg/d of OROS methylphenidate or matching placebo" (Goodman 2016)
Allocation concealment (selection bias)	Low risk	Quote "Subjects were randomly assigned by an interactive voice response system to 18 mg/d of OROS methylphenidate or matching placebo" (Goodman 2016)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quotes "OROS methylphenidate or matching placebo" (Goodman 2016). "Treatment dose could be increased at each of 3 subsequent weekly visits to 36 mg, 54 mg, and 72 mg (maximum) until the subject reached an AISRS score < 18 or a limit of tolerability" (Goodman 2016). "After the investigator completed the AISRS and CGI‐I assessments at each DAP visit, the investigator determined the subject’s daily dose. The dose was maintained or adjusted up or down by 18‐mg steps, but the adjusted daily dose was not allowed by protocol to go below 18 mg/d or above 72 mg/d. At Visit 5, no dose increase was allowed" (CSR synopsis). Comment Blinding was stated, but the effectiveness of the blinding technique was not tested.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quotes "OROS methylphenidate or matching placebo" (Goodman 2016) "Treatment dose could be increased at each of 3 subsequent weekly visits to 36 mg, 54 mg, and 72 mg (maximum) until the subject reached an AISRS score < 18 or a limit of tolerability" (Goodman 2016) "After the investigator completed the AISRS and CGI‐I assessments at each DAP visit, the investigator determined the subject’s daily dose. The dose was maintained or adjusted up or down by 18‐mg steps, but the adjusted daily dose was not allowed by protocol to go below 18 mg/d or above 72 mg/d. At Visit 5, no dose increase was allowed" (CSR synopsis) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 37 of 178 (21%), placebo 41 of 179 (23%). Dropouts due to adverse events: methylphenidate 8 of 37, placebo 5 of 41 Statistical method used to account for missing data: Last observation carried forward
Selective reporting (reporting bias)	High risk	Comments Adverse event reporting thresholds: CT.gov (5% for methylphenidate arm), published paper (5%), clinical study report synopsis (not systematically reported) Cardiovascular variables and weight were measured but not reported (CSR synopsis, p. 6) AIM‐A overall quality of life score not reported (like in Casas 2008), only subscales (Goodman 2016)
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	High risk	Quote "History of diagnosis of substance or alcohol dependence or admission/hospitalization for rehabilitation for dependence. Current neurologic or psychiatric diagnosis that would make patient inappropriate for participation. Anxiety assessments of moderate or severe. Depression assessments of moderate or severe" (CT.gov)
Responder selection (External validity)	High risk	Quotes "Known allergies, hypersensitivity, or intolerance to OROS MPH" (CT.gov) "Subjects who were unable to tolerate 18 mg daily were discontinued from the study" (CSR synopsis)
Withdrawal effects (External validity)	Low risk	Quotes "Subjects excluded were those with [...] a history of stimulants or atomoxetine use within 5 years or other ADHD medications within 30 days and those for whom, in the investigator’s opinion, methylphenidate posed an unacceptable risk through a potential drug interaction or a concurrent medical, neurologic, or psychiatric illness" (Goodman 2016) "None of the subjects was currently taking medication for ADHD" (Goodman 2016)

Weisler 2009.

Study characteristics
Methods	Trial ID(s): NCT00880217, 31001074ATT2001 (protocol ID), CR015964 (other study ID) Trial registry entry: clinicaltrials.gov/ct2/show/NCT00880217 Sponsor: Janssen Funding/industry involvement: industry trial Location: USA No. trial sites: 37 sites Start to completion: May 2009 to January 2010 Duration: 6 weeks Sample size: 216 (for the methylphenidate, atomoxetine and placebo arms)
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV‐TR Concomitant substance abuse diagnosis: no Mean age (range): 33 (18 ‐ 55) Male participants (%): 62
Interventions	Trial arms OROS methylphenidate 54 mg/day (n = 68) atomoxetine 80 mg/day (n = 74) placebo (n = 74) bavisant 1 mg/day (not included) bavisant 3 mg/day (not included) bavisant 10 mg/day (not included) Type of methylphenidate: OROS methylphenidate Dosagerange: 54 mg Fixed or titrated: fixed Administrations per day: 1 Co‐intervention(s): not reported
Outcomes	Relevant outcomes for the review are listed here Conners' Adult ADHD Rating Scales (CAARS): DSM‐IV Total ADHD (self‐rated, 18 items, 0 ‐ 54 points) Attention Deficit Hyperactivity Rating Scale (ADHD RS), Investigator‐Administered and Scored Version (investigator‐rated, 18 items, 0 ‐ 54 points) Harms
Notes	Declared conflicts of interest: "Richard Weisler was the principal investigator for the study and received no compensation for time spent in the preparation of this manuscript. Dr Weisler has been a consultant to, on the speaker’s bureaus of, and received research support from Johnson & Johnson or an operating company (McNeil Pharmaceutical, Janssen). He owns Johnson & Johnson stock in mutual funds or in managed accounts with no direct control. Richard Weisler, MD, in his career, has also been a consultant to, on the speaker’s bureaus of, and/or received research support from the following: Abbott, speaker’s bureau, consultant, received research support; Agency for Toxic Substances and Disease Registry, consultant; Astra Zeneca, speaker’s bureau, consultant, received research support; Biovail, speaker’s bureau, consultant, received research support; Bristol‐Myers Squibb, speaker’s bureau, consultant, received research support, stockholder has held or holds stock; Burroughs Wellcome, speaker’s bureau, received research support; Cenerx, received research support; Centers of Disease Control and Prevention, consultant; Cephalon, speaker’s bureau, consultant, received research support; Ciba Geigy, speaker’s bureau, received research support; CoMentis, received research support; Corcept, consultant, Cortex, stockholder has held or holds stock; Dainippon Sumitomo Pharma America, received research support; Eisai, received research support; Eli Lilly, speaker’s bureau, consultant, received research support; Forest, speaker’s bureau, consultant, received research support; GlaxoSmithKline, speaker’s bureau, consultant, received research support; Lundbeck, received research support; Medicinova, received research support; Medscape Advisory Board, consultant; Merck, received research support, stockholder has held or holds stock; National Institute of Mental Health, consultant, received research support; Neurochem, received research support; New River Pharmaceuticals, received research support; Novartis, speaker’s bureau, received research support; Organon, speaker’s bureau, consultant, received research support; Otsuka America Pharma, consultant; Pfizer, speaker’s bureau, consultant, received research support, stockholder has held or holds stock; Pharmacia, consultant, received research support; Repligen, received research support; Saegis, received research support; Sandoz, received research support; Sanofi, speaker’s bureau, consultant, received research support; Sanofi‐ Synthelabo, speaker’s bureau, consultant, received research support; Schwabe/Ingenix, received research support; Sepracor, received research support; Shire, speaker’s bureau, consultant, received research support; Solvay, speaker’s bureau, consultant; Sunovion, speaker’s bureau, consultant, received research support; Synaptic, received research support; Takeda, received research support; TAP, received research support; Transcept Pharma, consultant, received research support; TransTech, consultant; UCB Pharma, received research support; Validus, speaker’s bureau, consultant; Vela, received research support; and Wyeth, speaker’s bureau, consultant, received research support. Gahan Pandina, Ella Daly, Kimberly Cooper and Cristi‐ ana Gassmann‐Mayer are employees of Janssen Research & Development, LLC, and own stock in Johnson & Johnson. All authors met International Committee of Medical Journal Editors (ICMJE) criteria and all those who fulfilled those criteria are listed as authors. Bradford Challis, an employee of Janssen Research & Development, LLC, contributed to writing of the initial draft with author guidance, copy editing and incorporating author comments. The study is registered at ClinicalTrials.gov: NCT00880217" (Weisler 2012)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quotes "Participants were randomly assigned equally to one of six treatment groups" (Weisler 2012) "The randomization scheme was based on a computer‐generated schedule, balanced by using permuted blocks of treatments, stratified by centre and implemented using an interactive voice response system" (Weisler 2012)
Allocation concealment (selection bias)	Low risk	Quote "The randomization scheme was based on a computer‐generated schedule, balanced by using permuted blocks of treatments, stratified by centre and implemented using an interactive voice response system" (Weisler 2012)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote "The blinding of the study medication was achieved by over‐encapsulation, with all study drugs provided as opaque hard‐gelatin capsules that were identical in shape, size, and appearance" (Weisler 2012) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote "The blinding of the study medication was achieved by over‐encapsulation, with all study drugs provided as opaque hard‐gelatin capsules that were identical in shape, size, and appearance" (Weisler 2012) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 13 of 68 (19%), placebo 11 of 74 (15%) Dropouts due to adverse events: methylphenidate 6 of 13, placebo 2 of 11. Statistical method to account for missing data: mixed effects model, but unclear how it was used
Selective reporting (reporting bias)	High risk	Comments Adverse event reporting threshold: Published report (5%, except cardiovascular events with 2%) Cardiovascular variables measured but not reported
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	High risk	Quotes "[Exclusion criteria] Patients with any current Axis I psychiatric disorder" (CT.gov) "The main exclusion criteria were any current Axis I psychiatric condition including major depressive disorder, bipolar disorder, schizophrenia, generalized anxiety disorder, obsessive‐compulsive disorder, post‐traumatic stress disorder, borderline personality disorder, or eating disorder" (Weisler 2012)
Responder selection (External validity)	High risk	Quotes "Demonstrated history of non‐response to treatment with a psychostimulant medication or to treatment with atomoxetine or methylphenidate" (Weisler 2012) "The percentage of participants who took psychotropic medication in the 3 months prior to study treatment ranged from 7% to 14% among the treatment groups" (Weisler 2012)
Withdrawal effects (External validity)	Unclear risk	Quote "The percentage of participants who took psychotropic medication in the 3 months prior to study treatment ranged from 7% to 14% among the treatment groups" (Weisler 2012) Comment Previous stimulant use and wash‐out of current stimulants were not reported

Huss 2010.

Study characteristics
Methods	Trial ID(s): NCT01259492, 2010‐021533‐31 (EUCTR), CRIT124D2302 (protocol), D2302 (regulatory reviews) Trial registry entry: clinicaltrials.gov/ct2/show/NCT01259492, www.clinicaltrialsregister.eu/ctr-search/trial/2010-021533-31/DE Sponsor: Novartis Funding/industry involvement: industry trial Location: Belgium, Columbia, Denmark, Germany, Norway, Singapore, South Africa, Sweden and USA No. sites: 67 sites Start to completion: November 2010 to August 2012 Duration: 9 weeks Sample size: 725 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV Concomitant substance abuse diagnosis: no Mean age (range): 35 (18 ‐ 60) Male participants (%): 55
Interventions	Trial arms: Long‐acting (LA) methylphenidate 40 mg (n = 181) Long‐acting (LA) methylphenidate 60 mg (n = 182) Long‐acting (LA) methylphenidate 80 mg (n = 181) Placebo (n = 181) Type of methylphenidate: Long‐acting (LA) methylphenidate Dosage: 40 mg to 80 mg Fixed or titrated: fixed Administrations per day: 1 Co‐intervention(s): "Any psychological or behavioral therapies for the treatment of ADHD were discontinued at least 1 month prior to the screening visit. Patients who initiated these therapies within 3 months prior to screening visit for reasons other than ADHD were excluded from the trial." (Huss 2014)
Outcomes	Relevant outcomes for the review are listed here Adult Self‐Report Scale (ASRS) (self‐rated, 18 items, 0 ‐ 72 points) ADHD DSM‐IV RS (investigator rated, 18 items, 0 ‐ 54 points) Conners' Adult ADHD Rating Scale‐Observer ratings (CAARS‐O) ("assessments made by a friend, family member or colleague", 26 items, 0 ‐ 78 points) Harms
Notes	Declared conflicts of interest: "Michael Huss has served as an advisory board member for Eli Lilly, Engelhardt Arzneimittel, Janssen‐Cilag, Medice, Novartis, Shire, and Steiner Arzneimittel, and as a consultant for Engelhardt Arzneimittel, Medice, and Steiner Arzneimittel. He received honoraria from Eli Lilly, Engelhardt Arzneimittel, Janssen‐Cilag, Medice, Novartis, and Shire. He has received unrestricted grants for investigator‐initiated trials from Eli Lilly, Medice, Engelhardt Arzneimittel, and Steiner Arzneimittel. Ylva Ginsberg has served as a consultant and speaker for Janssen‐Cilag and Novartis and as a speaker for Lundbeck. She has also been a principal investigator of two international multicenter trials initiated by Janssen‐Cilag, and she was the coordinating investigator of a MPH trial conducted in adult prison inmates with ADHD, funded by the Swedish Ministry of Health and Social Affairs. Torbjorn Tvedten has received speaker fees from Novartis and Lundbeck. Torben Arngrim has been involved in clinical trials conducted by Janssen‐Cilag and Novartis. He has received speaker fees from Janssen‐Cilag, Novartis, Eli Lilly, and HB Pharma, and has served as an advisory board member for Novartis and Shire. Alexandra Philipsen has received speaker fees and/or travel grants from Eli Lilly, Janssen‐Cilag, Medice, Novartis, and Shire, and has been involved in clinical trials conducted by Eli Lilly, Janssen‐Cilag, Medice, and Novartis. She has served as an advisory board member for Eli Lilly, Janssen‐Cilag, Medice, Novartis, and Shire. She is the co‐ordinating investigator of a multicenter trial on the treatment of adult ADHD (Current Controlled Trials ISRCTN54096201, funded by the Federal Ministry of Education and Research 01GV0606). Katherine Carter is an employee of Novartis Pharmaceutical Corporation. Chien‐ Wei Chen is an employee of Novartis Pharmaceutical Corporation. Vinod Kumar is an employee of Novartis Pharmaceutical Corporation" (Huss 2014)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Patients were randomized to one of the treatment arms using a validated Interactive Voice/Web Response System (IVRS/ IWRS). A unique, confidential randomization number was assigned to each patient and IVRS/ IWRS allocated medication accordingly, as assigned, throughout the respective treatment periods. An unbiased, confidential patient randomization list was produced by the IVRS/ IWRS provider using a validated system that automated the random assignment of patient numbers to randomization numbers. A separate medication randomization list was produced under the responsibility of Novartis Drug Supply Management using a validated system that automated the random assignment of medication numbers to medication packs containing each of the study drugs" (Huss 2014)
Allocation concealment (selection bias)	Low risk	Quote "Patients were randomized to one of the treatment arms using a validated Interactive Voice/Web Response System (IVRS/ IWRS). A unique, confidential randomization number was assigned to each patient and IVRS/ IWRS allocated medication accordingly, as assigned, throughout the respective treatment periods. An unbiased, confidential patient randomization list was produced by the IVRS/ IWRS provider using a validated system that automated the random assignment of patient numbers to randomization numbers. A separate medication randomization list was produced under the responsibility of Novartis Drug Supply Management using a validated system that automated the random assignment of medication numbers to medication packs containing each of the study drugs" (Huss 2014)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote "All sites and personnel for clinical, medical, statistical, data management and monitoring were blinded, and randomization data were kept strictly confidential until the time of un‐blinding after the conclusion of the study. The identity of the treatments has been concealed by the use of study drugs that are all identical in packaging, labeling, schedule of administration, appearance, taste, and odor, in line with Consort guidelines" Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quotes "All sites and personnel for clinical, medical, statistical, data management and monitoring were blinded, and randomization data were kept strictly confidential until the time of un‐blinding after the conclusion of the study. The identity of the treatments has been concealed by the use of study drugs that are all identical in packaging, labeling, schedule of administration, appearance, taste, and odor, in line with Consort guidelines" (Huss 2014) "Patients whose symptoms were not adequately controlled on study medication were discontinued from the study and treated at the discretion of the investigator" (Huss 2014) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 113 of 544 (21%), placebo 28 of 181 (16% Dropouts due to adverse events: methylphenidate 61 of 113 (11%) and placebo 4 of 28 (2%) (CTR, p. 40) Statistical method to account for missing data: Last observation carried forward On the DSM IV RS outcome, there were more 'responders' than actual completers for two of the three methylphenidate arms. For the 60 mg group, there were 141 of 182 (77%) 'completers' but 80,5% were categorised as 'responders'. For the 80 mg group, there were 138 of 181 (76%) 'completers' versus 81% 'responders' (Huss 2014, p. 53). A similar observation was made for Casas 2008. In MEB's drug assessment report, they commented on problems with one trial site, "All data for the 22 patients randomized at one site were removed from the efficacy analysis due to serious non‐compliance with International Conference On Harmonization (ICH)‐GCP at the site. The results in the excluded site were similar to the rest of the study" (MEB 2016, p. 24).
Selective reporting (reporting bias)	High risk	Comments Adverse event reporting threshold: Published report (5%), CT.gov (2%, data was pooled from the 3 phases), Novartis trial report (5%, although the report also reported adverse events adjusted for exposure time with a threshold of 1 event per 100 patient weeks) Blood pressure and pulse from phase 1 was not reported Reporting threshold for adverse events leading to dropout: published report (2%), Clinical Trial Report (0.4% corresponding to two participants) CTR, p. 40
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	High risk	Quotes "Any psychiatric condition that requires medication or may interfere with study participation" (Clinical trial report) "A limitation of the study is the limited external validity, as the protocol did not allow the inclusion of patients with psychiatric co‐morbidities" (Huss 2014, p. 61)
Responder selection (External validity)	High risk	Quotes "Additionally, patients with either hypersensitivity or history of poor response or intolerance to stimulants as per the investigator’s judgment were excluded from this study" (Huss 2014) "13.3% of the patients had received stimulants previously, most frequently used treatments were MPH/ methylphenidate (9.1%), mixed amphetamine salts (2.5%), and lisdexamfetamine dismesylate (1.1%)" (Huss 2014)
Withdrawal effects (External validity)	High risk	Quotes "Any therapies for ADHD, as well as all psychotropic medications were required to be discontinued 1–4 weeks prior to randomization" (Huss 2014) "In patients receiving any psychotropic medications the minimum discontinuation period varied according to drug class as follows: 1 week prior to the screening visit for stimulants including MPH, antidepressants other than fluoxetine, antipsychotics, anticonvulsants for non‐ epilepsy uses, mood stabilizing medications such as lithium, and herbal preparations with psychotropic potential" (Huss 2014) "13.3% of the patients had received stimulants previously, most frequently used treatments were MPH/ methylphenidate (9.1%), mixed amphetamine salts (2.5%), and lisdexamfetamine dismesylate (1.1%)" (Huss 2014)

Takahashi 2011.

Study characteristics
Methods	Trial ID(s): NCT01323192, JNS001‐JPN‐A01 (other study ID), CR017755 (protocol ID) Trial registry entry: clinicaltrials.gov/ct2/show/NCT01323192 Sponsor: Janssen Funding/industry involvement: industry trial Location: Japan No. sites: 39 sites Start to completion: March 2011 to April 2012 Duration: 8 weeks Sample size: 284
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐IV‐TR Concomitant substance abuse diagnosis: no Mean age (range): 34 (18 ‐ 59) years Male participants (%): 49
Interventions	Trial arms OROS methylphenidate (n = 143) Placebo (n = 141) Type of methylphenidate: OROS methylphenidate Dosagerange: 18 mg to 72 mg Fixed or titrated: titrated Administrations per day: 1 Co‐intervention(s): not reported
Outcomes	Relevant outcomes for the review are listed here Conners' Adult ADHD Rating Scales (CAARS): DSM‐IV Total ADHD (self‐rated, 18 items, 0 ‐ 54 points) Conners' Adult ADHD Rating Scales (CAARS): DSM‐IV Total ADHD symptoms (investigator rated, 18 items, 0 ‐ 54 points) Quality of Life Enjoyment and Satisfaction Questionnaire (Q‐LES‐QSF) (self‐rated, 14 items, 14 ‐ 70 points) Cardiovascular variables Harms
Notes	Declared conflicts of interest: "NT, TK, YT, YS, YK and TM are employees of Janssen Pharmaceutical KK, Japan. This study was supported by Janssen Pharmaceutical KK, Japan. Editorial support was provided by Allison Michaelis, PhD, of Medergy and was funded by Janssen Global Services, LLC" (Takahashi 2014)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Patients were randomly assigned to receive OROS MPH or placebo based on a computer‐generated randomization schedule prepared before the study by the sponsor or under the supervision of the sponsor. The randomization was balanced by using randomly permuted blocks of treatment and was stratified by study centre. Study drug code numbers were preprinted on the study drug labels and were assigned to patients as they qualified for the study and were randomly assigned to treatment" (Takahashi 2014)
Allocation concealment (selection bias)	Low risk	Quote "To maintain the study blind, the study drug container had a multipart label containing the protocol number, medication kit number, code number and other information on each part. It was impossible to identify the study drug by using the label information" (Takahashi 2014)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote "The study drugs were identical in appearance and were packaged in identical containers. Data that may potentially unblind the treatment assignment (e.g., study agent serum concentrations) were to be handled with special care to ensure that the integrity of the blind was maintained and the potential for bias was minimized. This could include making special provisions, such as segregating the data in question from view by the investigators, clinical team, or others as appropriate until the time of data‐base lock and unblinding" (Takahashi 2014) Comments The pills had different colours according to their strength (yellow, grey, white) (CSR Synopsis) Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote "The study drugs were identical in appearance and were packaged in identical containers. Data that may potentially unblind the treatment assignment (e.g., study agent serum concentrations) were to be handled with special care to ensure that the integrity of the blind was maintained and the potential for bias was minimized. This could include making special provisions, such as segregating the data in question from view by the investigators, clinical team, or others as appropriate until the time of data‐ base lock and unblinding" (Takahashi 2014) Comments The pills had different colours according to their strength (yellow, grey, white) (CSR Synopsis) Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comments Dropout rates: methylphenidate 9 of 143 (6%), placebo 6 of 141 (4%) Dropouts due to adverse events: methylphenidate 6 of 9, placebo 1 of 6 Statistical method used to account for missing data: Last observation carried forward (for efficacy analyses)
Selective reporting (reporting bias)	High risk	Comments Adverse event reporting threshold: Published paper (5%), Clinical Study Report synopsis (5%), CT.gov (2%) No systematic reporting of adverse events from the post‐study visit Blood pressure and weight not reported (CSR synopsis)
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	High risk	Quotes "Exclusion criteria included diagnosis of bipolar I disorder, schizophrenia, schizoaffective disorder, severe obsessive compulsive disorder, pervasive developmental disorder (e.g., autistic disorder or Asperger’s disorder) or suicidality" (Takahashi 2014) "Patients with confirmed cancer or other serious illnesses (e.g., hepatic or renal insufficiency or significant cardiac, gastrointestinal, psychiatric, or metabolic disturbances) were also excluded" (Takahashi 2014) "Third, ADHD is more likely to be complicated with other psychiatric illness, such as anxiety disorders. We excluded these patients in this study, and the efficacy of OROS MPH for these patients should be tested in the future" (Takahashi, p. 498)
Responder selection (External validity)	High risk	Quotes "Patients were excluded from the study if they were a non‐responder to MPH and/or had a history of hypersensitivity or intolerance to MPH" (Takahashi 2014) "It could be considered that excluding non‐responders to MPH from this study may have had a positive bias on patient selection. However, no patient was excluded from the study due to this exclusion criterion, so it is unlikely that this exclusion had an effect on the overall results" (Takahashi 2014, p. 498) "14.7% (OROS MPH) and 12.1% (placebo) received one or more psychotropic agents for ADHD within 3 months prior to screening" (Takahashi 2014)
Withdrawal effects (External validity)	High risk	Quotes "Washout up to 4 weeks of ADHD medication" (Takahashi 2014), CT.gov and CSR Synopsis says 1 ‐ 2 weeks. "Within 3 months prior to screening, 14.7% subjects in the JNS001 group and 12.1% subjects in the placebo group received 1 or more psychotropic agents for ADHD. The most commonly used psychotropic agents for ADHD were atomoxetine hydrochloride and pemoline" (CSR Synopsis)

Weiss 2014.

Study characteristics
Methods	Trial ID(s): NCT02139124, 063‐010 (protocol ID) Trial registry entry: clinicaltrials.gov/ct2/show/NCT02139124 Sponsor: Purdue Funding/industry involvement: industry trial Location: Canada and USA No. sites: 38 sites Start to completion: October 2014 to January 2015 Duration: 4 weeks Sample size: 375 participants
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐5 Concomitant substance abuse diagnosis: no Mean age (range): 36 (18 ‐ 72) Male participants (%): 47
Interventions	Trial arms Controlled‐release (CR) methylphenidate 25 mg (n = 77) Controlled‐release (CR) methylphenidate 45 mg (n = 73) Controlled‐release (CR) methylphenidate 70 mg (n = 73) Controlled‐release (CR) methylphenidate 100 mg (n = 74) Placebo (n = 78) Type of methylphenidate: Controlled‐release (CR) methylphenidate Dosage range: 25 mg to 100 mg Fixed or titrated: fixed Administrations per day: not reported Co‐intervention(s): not reported
Outcomes	Relevant outcomes for the review are listed here ADHD‐5‐RS Total Score (investigator‐rated, 18 items, 0 ‐ 54 points) CAARS:Self‐rated short version (26 items, 0 ‐ 78 points) CAARS:Observer rated (26 items, 0 ‐ 78 points)* Adult ADHD Quality of Life (AaQOL) (4 domains; Life Productivity, Psychological Health, Life Outlook, Relationships, total score 100)** Harms *Described as rated by "consistent observer" and "completed the CAARS at home" in Weiss 2020, but it is unclear who specifically rated the symptoms **As reported in the poster on quality of life
Notes	Declared conflicts of interest: "The author(s) declared the following potential conflicts of interest with respect to the research, analyses, authorship and/or publication of this article: M.D.W. has received consultant fees or received honoraria from Janssen, Purdue Pharma (Canada), Purdue Pharma L.P., Shire, Rhodes, Mundipharma, NLS Pharma, and Akili. A.C.C. has received research support from Akili, Alcobra, Arbor, Forest, Ironshore, KemPharm, Lilly, Lundbeck, Medgenics, Neos, Neurovance, NextWave, NLS, Noven, Otsuka, Pearson, Pfizer, Purdue Pharma (Canada), Rhodes Pharmaceuticals L.P., Shire, Sunovion, Supernus, Theravance, and Tris; been a consultant for and received honoraria from Kempharm, Ironshore, Neos, Pfizer, Rhodes Pharmaceuticals L.P., Shire, Sunovion, Supernus and Tris; received travel support from Ironshore, NextWave, Pfizer, and Shire; has received writing assistance on projects from Arbor, Ironshore, Neos, NextWave, Pfizer, Rhodes Pharmaceuticals L.P., Shire and Tris; received payment for lectures from Arbor, Neos, Pfizer, Shire and Tris; and has been an advisory board member for Arbor, Ironshore, Neos, Neurovance, NextWave, Noven, Pfizer, Purdue Pharma L.P. and Rhodes Pharmaceuticals L.P. G.A.E.D. is an employee of Purdue Pharma (Canada)." (Weiss 2020) "The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Purdue Pharma (Canada)." (Weiss 2020).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Eligible participants were randomized by an integrated web response system in a 1:1:1:1:1 ratio " (Weiss 2020)
Allocation concealment (selection bias)	Low risk	Comment "Eligible participants were randomized by an integrated web response system in a 1:1:1:1:1 ratio " (Weiss 2020)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quotes "placebo‐controlled" (CT.gov) "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)" (CT.gov) "matching placebo) (Weiss 2020) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quotes "placebo‐controlled" (CT.gov) "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)" (CT.gov) "matching placebo" (Weiss 2020) Comment Blinding was stated, but the effectiveness of the blinding technique was not tested
Incomplete outcome data (attrition bias) All outcomes	High risk	Comments Dropout rates: methylphenidate 33 of 297 (11%), placebo 9 of 78 (12%) Dropouts due to adverse events: methylphenidate 8 of 33, placebo 2 of 9 Statistical method to account for missing data: not reported.
Selective reporting (reporting bias)	High risk	Comments Serious adverse events (SAE) uncertainties. Health Canada Monograph: reported only one of those SAEs (uterine cancer) appearing on CT.gov; CT.gov: 16 events in 12 participants; FDA Clinical Review: 12 participants are reported (but events not specified); Published article (Weiss, 2020) and CPA Poster: one SAE (uterine cancer) Adverse event reporting threshold: CT.gov (0%), Health Canada Product Monograph (1%), FDA Clinical Review (2%), published article (5%) Pulse, systolic and diastolic values not reported (Weiss 2020)
Other bias	Low risk	Comment None found
Psychiatric comorbidity (External validity)	High risk	Quotes "Having a primary diagnosis of schizophrenia, schizoaffective disorder, primary affective disorder, schizotypal personality, major depression, bipolar disorder, generalized anxiety, borderline personality disorder, antisocial personality or another unstable psychiatric condition requiring treatment, as assessed by the structured interview conducted at Visit 1" (CT.gov). "Participants were excluded from the study if they had a psychiatric comorbidity that required treatment (as judged by the investigator)" (Weiss, 2020)
Responder selection (External validity)	High risk	Quotes "Known to be non‐responsive to methylphenidate treatment. Non‐response is defined as methylphenidate use at various doses for a phase of at least four weeks at each dose with little or no clinical benefit" (CT.gov). "history of allergy to stimulants or serious adverse reactions to MPH or were known to have a poor response to MPH treatment" (Weiss, 2020)
Withdrawal effects (External validity)	High risk	Quotes "Subjects who meet eligibility requirements will undergo ADHD medication washout, if applicable" (CT.gov) "Following screening (up to 14 days) participants were washed out of any previous psychotropic medication for at least 7 days" (Weiss, 2020) "Eligible participants included those with a post‐washout baseline ADHD DSM‐5 rating scale score ≥24 (Dupaul et al., 2016), who were either treatment naïve or dissatisfied with their current ADHD pharmacotherapy (310 participants [82.7%] were treatment naïve and 65 participants [17.3%] had previously received an ADHD medication that was discontinued at or prior to Visit 1)" (Weiss, 2020)

Asherson 2016.

Study characteristics
Methods	Trial ID(s): 2015‐004271‐78 (EUCTR), ISRCTN16827947, CIAOII (other study ID) Trial registry entry: www.clinicaltrialsregister.eu/ctr-search/trial/2015-004271-78/GB; www.isrctn.com/ISRCTN16827947 Sponsor: King's College, London Funding/industry involvement: National Institute of Health (NIH) Efficacy and Mechanism Evaluation (EME) grant Location: United Kingdom No. sites: 3 sites Start to completion: May 2016 to July 2019 Duration: 8 weeks Sample size: 190 participants (18 years and older) (In the CSR it was reported how many were older/younger than 18 years of age)
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐5 Concomitant substance abuse diagnosis: no Mean age (range): not reported (inclusion criteria: 16 ‐ 25 years) Male participants (%): 100 Other trial characteristics: prison inmates only
Interventions	Trial arms OROS methylphenidate Placebo Type of methylphenidate: OROS methylphenidate Dosagerange: 18 mg to 72 mg Fixed or titrated: titrated Administrations per day: 1 or 2 Co‐intervention(s): not reported
Outcomes	Relevant outcomes for the review are listed here Number of adjudications for antisocial behaviour and rule‐breaking in prison Number of positive incentive and earned privileges (IEPs) for positive engagement in education, occupational and rehabilitation programmes recorded in the prison CAARS: ADHD Rating scale (investigator‐rated, unspecified rating scale) CORE Outcome Measure (quality of life outcome) Harms
Notes	Declared conflicts of interest: "King’s College London departmental research support account received payments for work by PA: consultancy to Shire, Eli Lilly and Novartis; educational/research awards from Shire, Lilly, Novartis, Vifor Pharma, GW Pharmaceuticals and QbTech; speaker at events sponsored by Shire, Lilly, Novartis, Flynn Pharma and Medicen. PA received personal honoraria for speaking at events sponsored by Shire, Flynn Pharma and Medicen. SY has received honoraria for consultation and/or educational talks in the last 5 years from Janssen, HB Pharma and/or Shire. She is author of the ADHD Child Evaluation (ACE) and ACE+ for adults and lead author of R&R2 for ADHD Youths and Adults. In the last 3 years, SL has received personal fees from Janssen, Otsuka and Sunovion and research support from Janssen, all in connection with schizophrenia meetings and trials. JS has worked with several pharmaceutical companies to seek to identify new or improved medications, but they do not have a relationship to the study reported here. This has included research grant support and consultancy payments to King’s College London and travelling and/or accommodation and/or conference expenses (including, in the past 3 years, from Martindale, Indivior, MundiPharma, Camurus/Braeburn). The other authors declare that they have no competing interests." (Asherson 2019).

ADHD: attention deficit hyperactivity disorder; ADHD‐5‐RS: ADHD Rating Scale based on the diagnostic DSM‐5 criteria; CR: controlled‐release; CSR: Clinical Study Report; CT: ClinicalTrials.gov; DSM: Diagnostic and Statistical Manual of Mental Disorders; 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; DSM‐IV RS: ADHD Rating Scale based on the diagnostic DSM‐IV criteria; DSM‐5: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; EUCTR: European Union Clinical Trials Register; FDA: US Food and Drug Administration; ICD: International Classification of Diseases; LA: long acting; MHRA: Medicines and Healthcare product Regulatory Agency; MPH: methylphenidate; No.: number; OROS: Osmotic‐controlled Release Oral delivery System; SR: sustained release.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Adler 2011	Ineligible study design (open‐label, no control group); extension phase of the included Adler 2006
Ang 2015	Ineligible population (participants were diagnosed with methamphetamine use disorder and then a subgroup also had an ADHD diagnosis). This is a conference proceeding related to Ling 2014, which is the full trial report. The proportion of those diagnosed with ADHD is shown in Table 1.
Biehl 2016	Ineligible intervention (immediate‐release methylphenidate), otherwise eligible RCT design. Not included in immediate‐release methylphenidate reviews
Bink 2014	Ineligible study design (no randomisation to methylphenidate). Participants were randomised to neurofeedback or not, whereas both groups received treatment as usual, including stimulant treatment.
Bouziane 2019	Ineligible intervention (immediate‐release methylphenidate). Publication related to Schrantee 2016; included in the Cochrane Review on immediate‐release methylphenidate (Cândido 2021). Wrote to corresponding author who clarified the formulation
Buitelaar 2009	Ineligible study design (open‐label, no control group); extension phase of Medori 2005
EUCTR 2005‐004037‐18	Ineligible study design (open‐label, no control group); extension phase of Medori 2005
EUCTR 2008‐006242‐26	Ineligible intervention (immediate‐release methylphenidate), otherwise eligible study design. Trial registry for Biehl 2016
EUCTR 2010‐023654‐37	Ineligible intervention (immediate‐release methylphenidate). Trial registry for Schrantee 2016 trial, included in the Cochrane Review on immediate‐release methylphenidate for adult ADHD (Cândido 2021). Wrote to corresponding author who clarified the formulation
EUCTR 2011‐000210‐19	Ineligible study design (open‐label, no control group); extension phase of Huss 2010
EUCTR 2012‐000517‐37	Ineligible study design (open‐label, no control group). All participants received OROS methylphenidate; pilot study preceding the included Asherson 2016 trial
EUCTR 2014‐001488‐11	Ineligible study design (cross‐over) and also uncertainty whether immediate‐ or extended‐release formulation. Otherwise seemingly eligible design
EUCTR 2017‐000368‐14	Ineligible study design (blind for researchers, but not for prescribers and participants). Comparison of OROS methylphenidate and lisdexamfetamine on symptomatology and functional capacity
Geissler 2020	Ineligible study design (no blinding of methylphenidate treatment). Participants were randomised to group psychotherapy + open‐label extended‐release methylphenidate or to clinical management without methylphenidate; AIMAC trial (3 reports excluded: Geissler 2020; Häge 2018; Jans 2013)
Häge 2018	Ineligible study design (no blinding of methylphenidate treatment). Participants were randomised to group psychotherapy + open‐label extended‐release methylphenidate or to clinical management without methylphenidate; AIMAC trial (3 reports excluded: Geissler 2020; Häge 2018; Jans 2013)
Imhof 2009	Ineligible study design (open‐label, no control group); extension phase to Medori 2005
ISRCTN52392534	Ineligible study design (cross‐over trial). Trial registry for Bron 2014, RCT comparing OROS methylphenidate versus placebo in adult ADHD
ISRCTN77828247	Ineligible study design (cross‐over). Trial testing controlled‐release methylphenidate (tradename Biphentin) and placebo on driving skills. There are uncertainties about the trial design, but without the cross‐over design it might have been eligible
Jans 2013	Ineligible study design (no blinding of methylphenidate treatment). Participants were randomised to group psychotherapy + open‐label extended‐release methylphenidate or to clinical management without methylphenidate; AIMAC trial (three reports excluded: Geissler 2020; Häge 2018; Jans 2013)
Levin 2002	Ineligible intervention (bupropion, and also no control group). In the manuscript they compare bupropion results with methylphenidate (uncertain which formulation). However, the methylphenidate data were collected in non‐randomised fashion without a control group
Marchant 2010	Ineligible study design (open‐label, no control group); extension phase of the cross‐over RCT Reimherr 2007, testing OROS methylphenidate versus placebo in adult ADHD
NCT00307684	Ineligible study design (open‐label, no control group); extension phase of Medori 2005
NCT01338818	Ineligible study design (open‐label, no control group); extension phase of Huss 2010
NCT02675400	Ineligible study design (open‐label, no blinding for intervention). Randomisation of fathers with ADHD to open‐label methylphenidate (formulation not specified) or to amphetamine. Publicly funded
NCT04507204	Ineligible study design (open‐label, no blinding for intervention). Randomisation to either open‐label controlled‐release methylphenidate (Purdue's formulation) or to open‐label OROS methylphenidate (Janssen's formulation). Sponsored by Purdue
Olsen 2012	Ineligible study design (cross‐over). RCT testing transdermal methylphenidate (Daytrana) and placebo in adult ADHD. Without the cross‐over design it might have been eligible
Reimherr 2010	Ineligible study design (cross‐over). Post‐hoc publication related to Reimherr 2007, which tested OROS methylphenidate and placebo in adult ADHD
Reimherr 2013	Ineligible study design (cross‐over). RCT comparing transdermal methylphenidate (Daytrana) and placebo. Same trial as Olsen 2012
Reimherr 2015	Ineligible study design (cross‐over). Post‐hoc publication related to Reimherr 2007, which tested OROS methylphenidate and placebo in adult ADHD
Schaeuble 2010	Ineligible study design (open‐label, no control group); extension phase of Adler 2006
Schrantee 2016a	Ineligible intervention (immediate‐release methylphenidate). Publication related to Schrantee 2016; included in the Cohrane Review on immediate‐release methylphenidate (Cândido 2021). Wrote to corresponding author who clarified the formulation
Schrantee 2016b	Ineligible intervention (immediate‐release methylphenidate). Publication related to Schrantee 2016; included in the Cohrane Review on immediate‐release methylphenidate (Cândido 2021). Wrote to corresponding author who clarified the formulation
Surman 2019	Ineligible study design (both groups received methylphenidate). All participants were prescribed OROS methylphenidate and then randomised to receive placebo or L‐methylfolate
Walhovd 2020	Ineligible intervention (immediate‐release methylphenidate). Publication related to Schrantee 2016; included in the Cochrane Review on immediate‐release methylphenidate (Cândido 2021). Wrote to corresponding author who clarified the formulation
Wender 1998	Ineligible intervention (immediate‐release methylphenidate); likely refers to Wender 2011, which was an RCT comparing immediate‐release methylphenidate with placebo in a 2x2 week cross‐over design. Not included in immediate‐release methylphenidate reviews (Epstein 2014; Cândido 2021)
Wender 2001	Ineligible intervention (immediate‐release methylphenidate); likely refers to Wender 2011, which was an RCT comparing immediate‐release methylphenidate with placebo in a 2x2 week cross‐over design. Not included in immediate‐release methylphenidate reviews (Epstein 2014; Cândido 2021)
Williams 2010	Ineligible study design (cross‐over). Post‐hoc publication related to Reimherr 2007, which tested OROS methylphenidate and placebo in adult ADHD
Zinnow 2018	Ineligible study design (both groups received methylphenidate). In Step 2, participants were randomised to extended‐release methylphenidate + neurofeedback or to extended‐release methylphenidate alone

ADHD: attention deficit hyperactivity disorder; AIMAC: attention deficit hyperactivity disorder (ADHD) in mothers and children; OROS: Osmotic‐Release Oral System; RCT: randomised controlled trial.

Characteristics of studies awaiting classification [ordered by study ID]

Perry 2002.

Methods	Not specified
Participants	Adults with ADHD
Interventions	Bupropion sustained‐release and methylphenidate (formulation not specified)
Outcomes	Not specified
Notes	It may be a conference proceeding for Kuperman 2001, which was a trial comparing bupropion and immediate‐release methylphenidate with placebo (included in the Cândido 2021 review). Perry was a co‐author on that paper

Spencer 2003b.

Methods	Not specified
Participants	Adults with ADHD
Interventions	Methylphenidate, formulation not specified
Outcomes	Not specified
Notes	N/A

Spencer 2004.

Methods	Not specified
Participants	Adults with ADHD
Interventions	Dex‐methylphenidate
Outcomes	Not specified
Notes	It may be a conference proceeding for Spencer 2003a.

Wender 2002.

Methods	Not specified
Participants	Adults with ADHD
Interventions	Methylphenidate, formulation not specified
Outcomes	Not specified
Notes	It may be a conference proceeding for Wender 2011, which was an immediate‐release methylphenidate cross‐over trial versus placebo for 2 x 2 weeks, followed by a 12‐month open‐label extension study.

Wender 2003a.

Methods	Not specified
Participants	Adults with ADHD
Interventions	Methylphenidate, formulation not specified
Outcomes	Not specified
Notes	It may be a conference proceeding related to Wender 2011, which was an immediate‐release methylphenidate cross‐over trial versus placebo for 2 x 2 weeks, followed by a 12‐month open‐label extension study.

Wender 2003b.

Methods	Not specified
Participants	Adults with ADHD
Interventions	Methylphenidate, formulation not specified
Outcomes	Not specified
Notes	It may be a conference proceeding related to Wender 2011, which was an immediate‐release methylphenidate cross‐over trial versus placebo for 2 x 2 weeks, followed by a 12‐month open‐label extension study.

Zhong 2019.

Methods	Not specified
Participants	237 participants; not reported whether all were diagnosed with ADHD, and age not reported
Interventions	OROS methylphenidate and atomoxetine
Outcomes	Not specified
Notes	N/A

ADHD: attention deficit hyperactivity disorder; N/A: not applicable; OROS: Osmotic Controlled‐release Oral Delivery System.

Characteristics of ongoing studies [ordered by study ID]

Methacan 2017.

Study name	METHACAN
Methods	Trial ID(s): 2017‐000386‐77 (EUCTR), NCT03481959, P140313 (protocol), 'Effectiveness of methylphenidate late formula to reduce cannabis use in young cannabis‐related patients and attention deficit disorder hyperactivity (METHACAN)' (trial name) Trial registry entry: www.clinicaltrialsregister.eu/ctr-search/trial/2017-000386-77/FR, clinicaltrials.gov/ct2/show/NCT03481959 Sponsor: Assistance Publique ‐ Hopitaux de Paris Funding/industry involvement: no Location: France No. sites: 2 sites Start to completion: May 2019 ‐ May 2022 (expected) Duration: 12 weeks Sample size: not reported
Participants	Information on exclusion criteria related to psychiatric comorbidity is listed in the risk of bias table ADHD diagnostic system: DSM‐5 Concomitant substance abuse diagnosis: cannabis dependence (not reported if DSM or ICD) Mean age (range): not reported (range 12 ‐ 25 years) Males (%): not reported
Interventions	Trial arms Ritalin LA Placebo Type of methylphenidate: long‐acting methylphenidate Dosagerange: 10 mg to 30 mg Fixed or titrated: not reported Administrations per day: not reported Co‐intervention(s): not reported
Outcomes	Relevant outcomes for the review are listed here ADHD Rating scale IV score (unspecified scale, reported on clinicaltrials.gov) Global Clinical Improvement Scale (7‐point Likert scale, 0 = very much worse, 4 = no change, 7 = very much improved)
Starting date	May 2019
Contact information
Notes	Declared conflicts of interest: no publication available, information from EUCTR and clinicaltrials.gov/ct2/show/NCT03481959

Differences between protocol and review

Searching regulatory databases

We did not update our searches of regulatory databases (last searched May 2020), since ‐ to our knowledge ‐ new methylphenidate formulations have not been approved for adult ADHD after that time.

Eligibility criteria ‐ minimum trial duration

In our protocol (Boesen 2017b) we did not define a minimum trial duration as an inclusion criterion. However, we did not include single‐dose studies. Many single‐dose experiments have been conducted in laboratory settings where the participants are tested with, for instance, cognitive tests or in driving simulators.

Eligibility criteria ‐ trials with more than one phase

Some included trials consisted of several ‘phases’ (e.g. Biederman 2003; Medori 2005; Huss 2010), where the participants were re‐randomised to participate in additional 'phases' depending on their clinical response during the placebo‐controlled trial. We included only the first randomised phase of such trials to avoid participant‐level unit‐of‐analysis errors. There are also several methodological problems related to such study designs that limit their generalisability: the blinding would be difficult to maintain; there would be a risk of exposing those participants re‐randomised to placebo to withdrawal effects; and the trial design would favour those who tolerate the drug, which is responder selection ('enriched design').

Naming the included trials

We named the included studies after the year the study started rather than the year of the first trial publication, which is often common practice. We did not specify this in the protocol. We did this to increase transparency, as there might be many years of difference between when the study was conducted and the trial publication, e.g. the Goodman 2009 trial was conducted between 2009 and 2010, but the trial results were published in a medical journal in 2016.

Counting records

For trial registries, regulatory databases, and pharmaceutical companies, we counted trial entries and separately available documents with data as separate records in our flowchart. We did this to make the counting of references in the review and in the flowchart easier.

Risk of bias ‐ assessing attrition bias

In our protocol (Boesen 2017b), we stated that we would assess whether 'missing data were adequately addressed' and whether dropout rates were 'balanced' between the groups. To avoid making subjective judgements, we instead extracted information on total dropout rates, dropouts due to adverse events and the statistical method to account for missing data, and based our bias assessments on this information.

Risk of bias ‐ assessing selective reporting

In our protocol (Boesen 2017b), we stated that we would use the ORBIT tool (Kirkham 2018), to assess selective outcome reporting. Due to our review's complexity and different data sources (published reports, clinical trial registries, and drug regulatory documents), we tailored our outcome reporting assessment as described in our Assessment of risk of bias in included studies. However, it should be noted that our methodology overlaps with that proposed by Kirkham 2018.

Adverse events – specifying outcomes

In our protocol (Boesen 2017b), we did not specify which specific harms‐related outcomes to assess; neither the individual events nor the high‐level outcomes such as ‘proportion experiencing any event’. We consider the high‐level outcomes to be standard measures of harms and their selection was not ‘data‐driven’, i.e. chosen because of specific results. However, in future reviews and updates, it will be preferable to prespecify the specific harms‐related outcomes at the protocol stage.

Adverse events ‐ data extraction

In our protocol (Boesen 2017b), we did not specify how we would extract individual adverse events. In some trial reports, two or more events were reported that were related to the same type of event. For insomnia, if two or more types of insomnia events (e.g. initial and middle insomnia) were reported, we preferred ‘initial insomnia’. For sexual dysfunction, we chose those events that seemed to describe more general problems related to sexual function.

Adverse events ‐ analyses

We pooled adverse events and serious adverse events from the short‐term and medium‐term periods, as only one trial reported medium‐term data. We wanted to avoid splitting up the analyses, and since we used risk ratios, we considered it a feasible method.

Trial Sequential Analysis

In our protocol (Boesen 2017b), we specified we would run such analyses. However, we judged that this would be uninformative, since 20 of 21 trials were at high risk of bias and had limited generalisability.

Subgroup analyses of symptom rating scales

Mean differences on a rating scale may be more clinically relevant than a unitless standardised mean difference. Therefore, we also reported the mean differences based on the rating scales used in the trials. We grouped scales assessing the same items and using the same range.

Subgroup analyses

We did not conduct two of the six prespecified subgroup analyses (Boesen 2017b):

1. 'Treatment status'; i.e. trials of CNS stimulant‐naïve participants versus trials of previously CNS stimulant treated participants. This analysis was practically the same analysis as our 'withdrawal effects' analysis (called 'washout' in our protocol) and was deemed redundant.

2. 'Publication status'; we did not consider this analysis as feasible. We included data from many different sources including regulatory documents, trial registries, and data sent directly from the investigators, which blurred the distinction between published and non‐published data.

Sensitivity analyses

We did not perform the planned sensitivity analysis based on our risk of bias assessment. There were no trials rated as having an overall low risk of bias.

Contributions of authors

KB: Data extraction, data analysis, writing first draft of final review, revision of draft. Guarantor of review.

ASP: Data extraction, data analysis, revision of draft.

PCG: Data analysis, revision of draft, supervision of project.

KJ: Data analysis, revision of draft, supervision of project.

All authors approved submission and publication of the manuscript.

Data sharing statement

The full dataset is available in Excel format at osf.io/39wzk/?view_only=a1d2c58b069c4e99b8c836107e99fcad.

Sources of support

Internal sources

• Nordic Cochrane Centre, Denmark

  Supported the review authors in the form of salary: KB, ASP and KJ.

External sources

• None, Other

Declarations of interest

Kim Boesen: none known.
Asger Sand Paludan‐Müller: none known.
Peter C Gøtzsche: none known. 
Karsten Juhl Jørgensen: none known. 

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