Abstract
Objective
To review the literature on the safety and efficacy of methylphenidate, OROS-methylphenidate, methylphenidate ER, and dexmethylphenidate in adults with Attention-Deficit/Hyperactivity Disorder (ADHD). To analyze the effects of different doses of methylphenidate, it's various formulations, and methylphenidate on efficacy and safety in this population.
Data Sources
Literature retrieval was performed through Pubmed/MEDLINE (Up to May 2010) using the terms methylphenidate, dexmethylphenidate, and attention-deficit hyperactivity disorder. In addition, reference citations from publications identified were reviewed.
Study Selection and Data Extraction
Double-blinded, placebo-controlled clinical trials, as well as crossover and open-label trials found using the search criteria listed above were included for review. Case reports were not included in this review.
Data Synthesis
Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric condition that is commonly seen in children and adolescents, that persists into adulthood for about 50% of patients. Methylphenidate and dexmethylphenidate are often prescribed to treat the symptoms associated with ADHD. The literature validating the safety and efficacy of methylphenidate and dexmethylphenidate in children and adolescents with ADHD is substantial. However, the literature specifically addressing the safety and efficacy of these medications in the adult population is less extensive and prescribing is often anecdotal based on child and adolescent data. Understanding the literature regarding methylphenidate and dexmethylphenidate and its effects in adults can enhance evidence-based medicine (EBM) and improve treatment outcomes
Conclusion
Methylphenidate and dexmethylphenidate are safe and effective medications to treat the symptoms of ADHD in adults. Based on the literature, increased doses are associated with better treatment response with moderate safety concerns. The different dosage forms available enable individualization of treatment.
Introduction
Attention-deficit hyperactivity disorder (ADHD) affects roughly 4 to 12% of children, depending on the reference, and approximately 4.7% of adults. 1 It is characterized by symptoms of hyperactivity, impulsivity, and inattention. Examples of symptoms in both children and adults can be seen in Table. 1. Patients can either present with predominantly hyperactive/impulsive or inattentive symptoms, or most often a combination of both symptoms. Children, particularly boys, tend to present with predominant hyperactive symptoms that may dissipate as they get older. Meanwhile, girls tend to have more inattentive symptoms, and therefore may be under-diagnosed. While the Diagnostic and Statistical Manual-IV-Text Revision does have criteria for ADHD it is mostly geared towards children and not adults. However, about 50% of children diagnosed with ADHD continue to have symptoms into adulthood and continued treatment may be necessary. 2
Possible Symptoms of ADHD in Childhood and Adulthood. 1
Treatment options for ADHD include pharmacological interventions, behavioral modifications, and the combination of both. Based on guidelines, first line pharmacological options are stimulant medications, methylphenidate (MPH) and amphetamine, in both children and adults.3, 4 There are also non-stimulant options, such as atomoxetine and guanfacine. This article will focus on reviewing the efficacy and safety of MPH in adults.
MPH has been approved by the Food and Drug Administration (FDA) to be used in children as young as 6 years of age and adults with ADHD since 1955. MPH exerts its effects in ADHD by blocking dopamine transport or carrier proteins, and norepinephrine to a much lesser extent. As a result, sympathomimetic activity in the CNS, including the prefrontal cortex, is increased. This leads to improved attention span, increased ability to follow directions or complete tasks, decreased distractibility, and decreased impulsivity and aggression. 5 In the periphery, the effects of MPH are minimal at therapeutic doses, but can cause tachycardia or elevated blood pressure. Other commonly observed adverse effects are anorexia and insomnia. Dexmethylphenidate, the more potent isomer of MPH, is also commercially available for the treatment of ADHD. Using dexmethylphenidate does allow for a lower dose to be used and increases the duration of action by 1-2 hours.
MPH is often prescribed anecdotally to adults with ADHD, as most of the literature validating its efficacy studied the child and adolescent population. However, numerous double-blind and open-label clinical trials have studied MPH, OROS-MPH, MPH ER, and dexmethylphenidate in adults. This article will comprehensively review the efficacy and safety of MPH at different doses and frequencies in adults with ADHD in an attempt to clarify its appropriateness in clinical practice.
Efficacy of Methylphenidate and Dexmethylphenidate in Adults
The efficacy of MPH and dexmethylphenidate in adults has been reviewed in various clinical trials (Table. 2). The study designs, population data, dosing information, efficacy results and additional information that is pertinent to adequate analysis of these clinical trials is encompassed in Table. 2. The following is a summary of the results of the various formulations, as well as any conclusions that can be drawn from this data.
Efficacy and Safety Data of Methylphenidate and Dexmethylphenidate in Adults.6–21
Methylphenidate Immediate-Release Formulation
Six double-blinded, placebo-controlled clinical trials were reviewed that analyzed the efficacy of MPH in adults with Attention Deficit Disorder (ADD) or Attention Deficit/Hyperactivity Disorder (ADHD). 6 – 11 The trial evaluating MPH's efficacy in patients with minimal brain dysfunction (MBD) was not reviewed due to differences in diagnostic criteria which could confound any useful comparisons to other trials.12 Data revealed inconsistent response rates of 38%-78% in patients treated with MPH. However, these rates were superior to the response rates of 4%-19% with placebo, when reviewing each trial individually. 6 – 11 Possible reasons for the variability could be differences in diagnostic criteria of the subjects, inconsistent definitions of response rate, as well as variations of dosing titration schedules and mean doses used in each trial.
It is difficult to determine the effect that dose had on response rate and other efficacy outcomes. Mattes, et al found no significant benefit of MPH on ADD symptomology with “low/moderate” doses. 6 Conflicting data was presented by Wender et al and Bouffard et al which reported response rates of 57% and 63%-73%, respectively, at “low-moderate” doses.7, 9 The range of response rates in the Bouffard et al trial is due to the difference in definition of response, with 63% corresponding to a more conservative designation. Robust treatment responses of 78% were seen at doses up to 1.0 mg/kg/d8 and up to 76% with doses of up to 1.3 mg/kg/d. 11 However, Kooij et al did not show this positive dose-to-effect correlation, with only 38% of MPH subjects responding to doses of up to 1.0 mg/kg/d. 10
Overall, MPH established statistically significant differences in most efficacy outcomes when compared with placebo. Due to the myriad of outcome measures used in these six trials, it is difficult to directly compare the results. However, these differences were more drastic with increased doses of MPH. Scores at endpoint on the Physician's Global Rating Scale (PGRS), Connors Rating Scale, Clinical Global Impression-Severity scale (CGI-S), and the Global Assessment Scale all showed statistically significant superiority for MPH compared with placebo (Table. 2). However, there were differing results on the Global Assessment of Functioning (GAF), with Bouffard et al establishing positive treatment effects and Kooij, et al showing no difference between MPH and placebo.9, 10 The data from the Mattes et al trial displayed that subjects treated with MPH had less psychiatrist rated impulsivity, and MPH was more effective than placebo only in pts with a diagnosis of drug abuse. However, the authors concluded that MPH was not effective for ADD, residual type in adults. 6
Regarding onset of treatment effect, improvement can be seen as early as week 1, at doses of 0.5 mg/kg/d. 8 Similar rapid effect starting at week 2 at doses of up to 1.3 mg/kg/d, with symptom reduction persisting until endpoint.11 MPH subjects in the Wender, et al trial had response rates of 57% at the end of week 2 with low-moderate doses, which may indicate that the early effect is not due to quick titration. 7
OROS-Methylphenidate (OROS-MPH)
Four double-blinded 13 – 16 and two open-label17, 18 clinical trials evaluated the efficacy of OROS-MPH in adults with ADHD (Table. 2). The response rates for subjects taking OROS-MPH ranged from 36.9%-66%, depending on the trial. 13 – 18 . It is important to note that in the trial reporting the response rate of 36.9%, roughly 80% of patients had ADHD, combined type and 20% had inattentive type. 14 Medori et al analyzed the effects of MPH at various doses and found that the 18 mg, 36 mg, and 54 mg doses had responses rates of 50.5%, 48.5%, and 59.6%, respectively, failing to indicate a dose-to-effect relationship. 15 It is interesting to note that in the Reimherr et al trial, researchers found that the mean daily doses of treatment responders was 57 mg, compared to a mean of 75 mg in non-responders, which also does not show a positive dose-to-effect relationship. 16 Since different trials used different outcome measurements, it is hard to determine if the different dosing titration strategies had an effect on symptom reduction.
Biederman et al and Adler et al showed statistically significant decreases on the Adult ADHD Investigator System Report Scale (AISRS) when compared with placebo, with differences at all titration visits in the Adler et al trial.13, 14 When isolating the inattention and impulsivity subscales, MPH subjects had greater reduction of these symptoms than PLA patients (Table. 2).13, 16– 18 OROS-MPH showed statistically significant differences with placebo on all of the following scales: Connors Adult ADHD Rating Scale (CAARS),15, 17 the CGI-S 17 , the CGI-I,14, 16 and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS). 16 See Table. 2 for numerical results and clinical trial information.
Methylphenidate Extended-Release (MPH-ER)
Literature review only yielded one clinical trial that analyzed the effect of MPH-ER in adults.
19
This study was conducted in 28 sites across Germany, with 359 subjects. The mean dose of MPH-ER was 41.2 mg/d, or 0.55 mg/kg/d, which indicates a moderate dose. The response rates in this group were 61%, compared with 42% in the placebo group (
Dexmethylphenidate
The efficacy data in adults with ADHD treated with dexmethylphenidate is confined to one double-blinded, fixed-dose, placebo-controlled, 5 week trial
20
and a 6-month, open label extension phase.
21
The double-blinded trial started all patients at 10 mg/d and then patients were assigned to fixed-dose treatment groups of 20 mg/d, 30 mg/d, 40 mg/d, and placebo. Response rates for these groups are as follows: 47.4%, 37%, 55.6% and 26.4%, respectively. Dexmethylphenidate treated subjects also had statistically significant reductions (
The 6-month, open-label follow-up trial primarily evaluated the safety effects of patients taking dexmethylphenidate for an extended period of time. 21 However, the researchers did perform various effectiveness measures to determine persistent effect.
All patients were initiated on 10 mg/d for the first week, and then flexible dosages of 20 to 40 mg/d were given according to treatment response and tolerability. Specific numerical values are given in Table. 2. In summary, the positive treatment effect of dexmethylphenidate from the double-blinded phase was maintained throughout the 6 months. Worth mentioning, about half of subjects discontinued the open-label phase due to adverse effects.
Safety of Methylphenidate
Following an in-depth review of all clinical data relevant to MPH and its derivatives, a few key adverse effects have shown up repeatedly among these trials. The most common side effects noted were loss of appetite (anorexia), headache, insomnia, and dry mouth. In addition to these, there was a notable degree of weight loss. The cardiovascular implications will also be reviewed and summarized below.
The rates of appetite loss varied greatly among the different trials; as low as 12%, 16 to a high of 41%. 9 Both MPH (22%-41%) and OROS MPH (12%-38%) showed higher occurrences of this side effect when compared to dexmethylphenidate (17.6%-18.2%). The most plausible explanation for this discrepancy is that dexmethylphenidate is the active enantiomer of MPH, making it a more effective drug with less side effects. OROS MPH is merely a reformulation of MPH, so it contains the same active ingredient (MPH), and therefore has a similar rate of appetite loss. An additional formulation of MPH ER showed a similar rate to MPH (38%). It should be noted that only two trials have been done with dexmethylphenidate, as opposed to six each for MPH and OROS MPH.
Headaches appeared in multiple trials with contradictory results. An older trial conducted by Wender et al
7
found a statistically significant higher rate of headache in MPH over placebo. On the other hand, Kooij et al
10
found a higher rate, but no statistical significance (16% vs. 4%,
Insomnia, in itself, is a possible implication of adult ADHD. Out of all the trials reviewed, Reimherr et al
16
was the only trial to show a statistically significant higher rate of OROS MPH over placebo: 22% vs. 7%,
Due to its properties as a CNS stimulant, it was not surprising that dry mouth (eyes and nose) was a common complaint among study participants. Statistical significance over placebo was demonstrated by Spencer et al, 11 Biederman et al 17 and Spencer et al. 20 Higher rates with no statistical comparison were also demonstrated by Medori et al, 15 Adler et al 14 and Rösler et al. 19 Please note the corresponding incidence rates of dry mouth in the various trials in Table. 2. Regardless of formulation, a clearly evident pattern of dry mouth occurred across most trials.
Weight loss has shown to be another side effect of stimulant use, even over short periods of time. Spencer et al8 showed a statistically significant change in weight between MPH and placebo in three weeks of medication use. Spencer et al
11
showed a decrease of 2.4 kg in 6 weeks (
Cardiovascular Implications
Much controversy has arisen regarding the cardiovascular implications of stimulant therapy in adults. Enough data had been shown to warrant the FDA ordering an amendment to MPH information to include a warning for adults regarding the risk of sudden death, stroke, and myocardial infarction. In addition, warnings of hypertension and tachycardia are also included in the package insert.
In general, many of the trials trended towards slightly increased heart rates, with some showing statistical significance. It should be noted that there was very little clinical significance in this data. Trials from Spencer et al, 8 Spencer et al 11 and Rösler et al 19 all showed a significantly higher final heart rate at the end of MPH treatment versus placebo. Trials with OROS MPH showed mean increases in heart rate ranging from 3.6 bpm to 9.8 bpm. It should be noted that Medori et al 2008 showed a dose dependant relationship between higher doses of OROS MPH and heart rate. Dexmethylphenidate showed slightly lower rates of increased heart rate (4.4 bpm and 3.7 bpm).
In contrast, clinical information regarding systolic and diastolic pressures varied significantly amongst trials. Most trials showed no statistically significant increases in systolic pressure; some even showed decreases. 14 , 17, 20 Changes in systolic pressure ranged from -2.9 mmHg 17 to +5 mmHg. 9 Diastolic pressures followed similar trends (-1.4 mmHg 17 to +4 mmHg 17 ), with very little statistical significance. As with the heart rate, these subtle changes in blood pressure were of no clinical significance. Nonetheless, it would behoove prescribers to educate patients of these possible cardiovascular effects.
Abuse Potential
Due to its structural similarity to amphetamine, there is an abuse potential associated with MPH similar to that of cocaine. By acting on dopamine transporters, MPH can show similar effects to cocaine and other stimulants. Kollins et al summarized the possible abuse potential for MPH in both animals and humans. 22 In studies of reinforcement or self-administration, 13/15 trials reported increased rates of abuse with MPH or dexmethylphenidate over placebo. It should be noted that, for the two trials not showing increased reinforcement, the route of administration was oral. Since oral medications take longer to act, it was hypothesized that this may account for the discrepancy. In trials comparing subjective ranking systems, (Profile of Mood States, Addiction Research Center Inventory, Visual Analog Scales, etc.) MPH and dexmethylphenidate showed increased rates as well. 22
Discussion
The efficacy of MPH, OROS-MPH, MPH-ER, and dexmethylphenidate is firmly established based on our review. All efficacy measures proved that these medications significantly improve ADHD symptoms in adults when compared with placebo. There is conflicting evidence regarding whether increasing doses yield greater symptom improvement. Therefore, in clinical practice, each patient should be given individualized care. MPH and dexmethylphenidate have proven to be effective on all ADHD symptoms, including inattentive and hyperactive/impulsive symptoms. It is important for clinicians to understand that treatment effects with MPH and dexmethylphenidate can be seen as early as the first week of treatment. Also, the different formulations of MPH enhance patient care through the capability for individualized dosing regimens.
After a thorough review of all adverse events, a few key side effects reoccur throughout the data. These side effects include headache, insomnia, loss of appetite, weight loss, and dry mouth. It should be noted that no true dose-dependant relationship has been noted for any of these aside from weight loss. Adler et al 21 demonstrated dose-related increases in weight loss with dexmethylphenidate. In addition, Medori et al 15 showed similar results with OROS-MPH at dosages ranging from 18-72 mg. Of primary concern are the cardiovascular implications of MPH use in adults. Although no statistical comparisons were done, a dose-relationship can still be noted between MPH and heart rate. 15 Slight increases in blood pressure, although of little clinical significance, should still be taken into consideration when prescribing. Patients with borderline cardiovascular conditions (hypertension, palpitations, family history, etc.) should be monitored carefully when starting a stimulant medication, such as methylphenidate. As a schedule II substance, it should be noted that a potential risk for abuse does exist. Patients should be educated on this before beginning treatment and should be monitored accordingly. As with many medications, frequency of these adverse events increase as dosages increase; it should be noted that many of these events occur within the first few weeks of use.
Disclosure
This manuscript has been read and approved by all authors. This paper is unique and is not under consideration by any other publication and has not been published elsewhere. The authors and peer reviewers of this paper report no conflicts of interest. The authors confirm that they have permission to reproduce any copyrighted material.