What is the aim of this review?
We reviewed the evidence about the effects of treating adults with ADHD with a stimulant drug called immediate-release (IR) methylphenidate.
Key messages
Compared with placebo (a dummy pill), IR methylphenidate may promote a small reduction in the symptoms of ADHD and may increase the doctor’s perception of an improvement in symptoms. IR methylphenidate increased the risk of adverse effects such as loss of appetite, dry mouth, nausea and stomach aches.
Compared with lithium (a drug to treat overactivity and excitement), IR methylphenidate may promote few or no changes in the symptoms of ADHD, anxiety and depression.
These results are uncertain, and we do not know if we can trust them.
What was studied in this review?
ADHD is a mental-health impairment. The problem is diagnosed in adults who show signs of inattention (e.g. trouble concentrating), hyperactivity (e.g. unable to sit still) and impulsivity (e.g. doing things without thinking).
We looked for trials comparing IR methylphenidate, at any dose, with other drugs (including extended-release formulations of methylphenidate where the drug is released slowly over time) or placebo, to treat ADHD in adults. We wanted to know the effect of IR methylphenidate on the symptoms of ADHD and if people had adverse events. We also wanted to know if people treated with the drug or their doctors perceived changes in their symptoms (getting worse or better), mental health (depression, anxiety) or quality of life.
What are the main results of the review?
We found 10 trials, involving 497 adults. Three trials were carried out in Europe and one in Argentina; the remaining trials did not report their location. Six trials compared IR methylphenidate with placebo. In the other trials, IR methylphenidate was compared to an extended-release form of bupropion (an antidepressant), lithium, an extended-release form of methylphenidate named osmotic-release oral system (OROS), and Pycnogenol® (a medicine derived from the bark of a pine tree). People were treated for 6 to 18 weeks. Participants were mainly outpatients; some participants were inpatients for addiction treatment, or individuals willing to attend an intensive outpatient program for cocaine dependence.
IR methylphenidate versus placebo
One trial with 146 participants reported that IR methylphenidate may reduce symptoms of ADHD when judged by the doctors. When participants judge their own symptoms, there may be a moderate positive effect. We are however uncertain about these results and they may change with the addition of more data. IR methylphenidate appears to have little or no effect in reducing symptoms of anxiety and depression. We have concerns about the methods and conflicts of interest presented by this trial and the other nine trials that were evaluated.
IR methylphenidate versus lithium
IR methylphenidate may have little or no effect on symptoms of ADHD (judged by the doctors), or anxiety and depression, but the results are uncertain. None of the included trials assessed changes in symptoms of ADHD rated by participants, or the clinical impression of severity or improvement in participants treated with IR methylphenidate compared with lithium.
Adverse events
Adverse events (side effects) were poorly assessed and reported in all trials. Overall, four trials with 203 participants who received IR methylphenidate and 141 participants who received placebo described the occurrence of harms. The use of IR methylphenidate reported in these trials increased the risk of digestive complications and loss of appetite. Harm to the heart and circulation was reported, but in a limited and inconsistent manner. One trial comparing IR methylphenidate to lithium reported five and nine adverse events, respectively.
We considered almost all trials to have notable concerns related to their sources of funding and conflicts of interest.
How up-to-date is this review?
The evidence is current to 3 January 2020.
We found no certain evidence that IR methylphenidate compared with placebo or lithium can reduce symptoms of ADHD in adults (low- and very low-certainty evidence). Adults treated with IR methylphenidate are at increased risk of gastrointestinal and metabolic-related harms compared with placebo. 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.
Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention or impulsivity or both, and hyperactivity, which affect children, adolescents, and adults. In some countries, methylphenidate is the first option to treat adults with moderate or severe ADHD. However, evidence on the efficacy and adverse events of immediate-release (IR) methylphenidate in the treatment of ADHD in adults is limited and controversial.
To evaluate the efficacy and harms (adverse events) of IR methylphenidate for treating ADHD in adults.
In January 2020, we searched CENTRAL, MEDLINE, Embase, eight additional databases and three trial registers. We also searched internal reports on the European Medicines Agency and the US Food and Drug Administration websites. We checked citations of included trials to identify additional trials not captured by the electronic searches.
Randomized controlled trials (RCTs) comparing IR methylphenidate, at any dose, with placebo or other pharmacological interventions (including extended-release formulations of methylphenidate) for ADHD in adults. Primary outcomes comprised changes in the symptoms of ADHD (efficacy) and harms. Secondary outcomes included changes in the clinical impression of severity and improvement, level of functioning, depression, anxiety and quality of life. Outcomes could have been rated by investigators or participants.
Two review authors extracted data independently on the characteristics of the trials, participants, interventions; outcomes and financial conflict of interests. We resolved disagreements by discussion or consulting a third review author. We obtained additional, unpublished information from the authors of one included trial that had reported efficacy data in a graph. We calculated mean differences (MDs) or standardized MDs (SMDs) with 95% confidence intervals (CIs) for continuous data reported on the same or different scales, respectively. We summarized dichotomous variables as risk ratios (RRs) with 95% CI.
We included 10 trials published between 2001 and 2016 involving 497 adults with ADHD. Three trials were conducted in Europe and one in Argentina; the remaining trials did not report their location. The RCTs compared IR methylphenidate with placebo, an osmotic-release oral system (OROS) of methylphenidate (an extended-release formulation), an extended-release formulation of bupropion, lithium, and Pycnogenol® (maritime pine bark extract). Participants comprised outpatients, inpatients in addiction treatment, and adults willing to attend an intensive outpatient program for cocaine dependence. The duration of the follow-up ranged from 6 to 18 weeks.
IR methylphenidate versus placebo
We found very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce symptoms of ADHD when measured with investigator-rated scales (MD −20.70, 95% CI −23.97 to −17.43; 1 trial, 146 participants; end scores; Adult ADHD Investigator Symptom Report Scale (AISRS), scored from 0 to 54), but the evidence is uncertain. The effect of IR methylphenidate on ADHD symptoms when measured with participant-rated scales was moderate, but the certainty of the evidence is very low (SMD −0.59, 95% CI −1.25 to 0.06; I2 = 69%; 2 trials, 138 participants; end scores).
There is very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce the clinical impression of the severity of ADHD symptoms (MD −0.57, 95% CI −0.85 to −0.28; 2 trials, 139 participants; I2 = 0%; change and end scores; Clinical Global Impression (CGI)-Severity scale (scored from 1 (very much improved) to 7 (very much worse))). There is low-certainty evidence that, compared with placebo, IR methylphenidate may slightly impact the clinical impression of an improvement in symptoms of ADHD (MD −0.94, 95% CI −1.37 to −0.51; 1 trial, 49 participants; end scores; CGI-Improvement scale (scored from 1 (very much improved) to 7 (very much worse))). There is no clear evidence of an effect on anxiety (MD −0.20, 95% CI −4.84 to 4.44; 1 trial, 19 participants; change scores; Hamilton Anxiety Scale (HAM-A; scored from 0 to 56); very low-certainty evidence) or depression (MD 2.80, 95% CI −0.09 to 5.69; 1 trial, 19 participants; change scores; Hamilton Depression Scale (HAM-D; scored from 0 to 52); very low-certainty evidence) in analyses comparing IR methylphenidate with placebo.
IR methylphenidate versus lithium
Compared with lithium, it is uncertain whether IR methylphenidate increases or decreases symptoms of ADHD (MD 0.60, 95% CI −3.11 to 4.31; 1 trial, 46 participants; end scores; Conners’ Adult ADHD Rating Scale (scored from 0 to 198); very low-certainty evidence); anxiety (MD −0.80, 95% CI −4.49 to 2.89; 1 trial, 46 participants; end scores; HAM-A; very low-certainty evidence); or depression (MD −1.20, 95% CI −3.81 to 1.41, 1 trial, 46 participants; end scores; HAM-D scale; very low-certainty evidence). None of the included trials assessed participant-rated changes in symptoms of ADHD, or clinical impression of severity or improvement in participants treated with IR methylphenidate compared with lithium.
Adverse events were poorly assessed and reported. We rated all trials at high risk of bias due to selective outcome reporting of harms and masking of outcome assessors (failure to blind outcome assessor to measure adverse events). Overall, four trials with 203 participants who received IR methylphenidate and 141 participants who received placebo described the occurrence of harms. The use of IR methylphenidate in these trials increased the risk of gastrointestinal complications (RR 1.96, 95% CI 1.13 to 2.95) and loss of appetite (RR 1.77, 95% CI 1.06 to 2.96). Cardiovascular adverse events were reported inconsistently, preventing a comprehensive analysis. One trial comparing IR methylphenidate to lithium reported five and nine adverse events, respectively.
We considered four trials to have notable concerns of vested interests influencing the evidence, and authors from two trials omitted information related to the sources of funding and conflicts of interest.