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