Örebro University
School of Medical Sciences
Degree project, 15 ECTS
January 2021
A comparative study of methylphenidate
and lisdexamphetamine in adult ADHD –
a systematic literature review
Version 2
Author: Michelle Karlsson Bok
Supervisor: Mussie Msghina, MD, PhD, Assoc. Professor
Abstract
Attention deficit hyperactivity disorder (ADHD) affects not only children as it was initially assumed but continues into adulthood in 50% of the cases. ADHD is a major cause of cognitive disability in children, increases risks for criminal behavior, unemployment and is generally associated with low quality of life. The treatment of ADHD is primarily with the so-called central stimulants, which increase norepinephrine and dopamine transmission in the brain. These medications are classed as narcotics, and currently there are no clinically
available predictors of efficacy, so trial and error attempts are made until one finds optimal treatment. During the trial time, risk for additional suffering and adverse events increase. The main aim of the study was to compare methylphenidate (MPH) and lisdexamphetamine (LDX) in the treatment of adult ADHD. A second aim was to investigate predictors for treatment outcome that can be used for precision medicine. This study was a systematic review of the existing litterateur by searching two databases, PubMed and Cochrane Library. Inclusion criteria were adults with ADHD, treated with MPH or LDX for at least 6 weeks, in a randomized placebo-controlled design. The results indicate that both LDX and MPH are highly effective, with similar efficacy, but that LDX may be associated with less adverse events in adults and hence a better choice. Possible predictors of treatment response found were severity of illness, dosage of drug and level of education. These findings, including major weaknesses and limitations, will be discussed in what follows.
Abbreviation list
ADHD – Attention Deficit Hyperactivity Disorder ADD – Attention Deficit Disorder
DSM – Diagnostic and Statistical Manual of Mental Disorders
ESSENCE – Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical
Examinations
ASD – Autism Spectrum Disorder ODD – Oppositional Defiant Disorder MPH – Methylphenidate
AMP – Amphetamine LDX – Lisdexamphetamine
PICO – Population, Intervention, Control, Outcome
ICD – International Statistical Classification of Diseases and Related Health Problems AISRS – Adult ADHD Investigator Symptom Rating Scale
ADHD-RS – ADHD Rating Scale ASRS – Adult ADHD Self-Report Scale CGI – Clinician Global Impression AIM-A – ADHD Impact Module – Adult CAARS – Conners’ Adult ADHD Rating Scales
WRAADDS – Wender-Reimherr Adult Attention Deficit Disorder Scale GAF – Global Assessment of Functioning
Table of contents 1. Introduction 2. Method 2.1 Primary aim
2.1.1 Inclusion and exclusion criteria 2.1.1.1 Population
2.1.1.2 Intervention 2.1.1.3 Control 2.1.1.4 Outcome
2.1.2 Search strategy and databases 2.2 Secondary aim
2.2.1 Inclusion and exclusion criteria 2.2.1.1 Population
2.2.1.2 Intervention 2.2.1.3 Control 2.2.1.4 Outcome
2.2.1.5 Additional inclusion and exclusion criteria 2.2.2 Search strategy and databases
2.3 Ethical considerations 3. Results
3.1 Primary aim
3.1.1 Primary outcome: ADHD Symptoms 3.1.1.1 ADHD-RS, AISRS and ASRS 3.1.1.2 Clinical Global Impression (CGI) 3.1.1.3 ADHD Impact Module (AIM-A)
3.1.1.4 Conners’ Adult ADHD Rating Scale (CAARS)
3.1.1.5 Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) 3.1.2 Secondary outcome: Adverse events
3.2 Secondary aim 4. Discussion 4.1 Primary aim 4.2 Secondary aim 4.3 Limitations 5. Conclusion
1. Introduction
Attention deficit hyperactivity disorder, ADHD, has an estimated prevalence of roughly 2,5% among adults [1] and is associated with impulsivity, hyperactivity and difficulty with
concentration [2]. There are three different subtypes of ADHD, the hyperactive-impulsive subtype, the inattentive subtype (ADD) and the combined subtype. Both require six out of nine symptoms for diagnosis according to DSM-V, symptom duration of at least six months, symptom debut before the age of 12 and symptom manifestation in two or more settings that affect social or professional functioning [3]. For the third subtype, the combined subtype, criteria for both hyperactive-impulsive subtype and inattentive subtype have to be met [3]. The hyperactive-impulsive subtype is characterized by hyperactivity and impulsive behavior, for instance difficulty with waiting, being still and regularly interrupting [3]. The inattentive subtype is associated with difficulties with concentration and organization, whereas the combined subtype has features from both the hyperactive-impulsive and the inattentive subtype [3]. The ADHD diagnosis is usually made during childhood [2] and even though ADHD in the past has been considered a diagnosis that primarily affects children and declines in intensity as the individual grows older [4], there are numerous studies that indicate that the affected individuals continue to meet the criteria for diagnosis well into adulthood [1].
The etiology of ADHD is not fully understood but is assumed to be of a multifactorial background with both genetic and environmental components contributing. Environmental factors that have been associated with ADHD are pre- and postnatal factors such as low birth weight, premature birth, low Apgar score, maternal epilepsy, maternal smoking during pregnancy and lead poisoning [5, 6]. There are also studies showing genetic associations and a new ADHD diagnosis is more common among relatives to individuals with an already confirmed diagnosis [7, 8]. ADHD is included in the ESSENCE concept which stands for
Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations, along
with other disorders like autism spectrum disorder (ASD) and intellectual disability. Since individuals with ADHD often display symptoms of ASD as well [9] there are theories of a common genetic background between the two [10]. Additionally, ADHD is associated with a higher risk of developing other neuropsychiatric disorders such as bipolar disorder,
depression, anxiety and oppositional defiant disorder (ODD) [8, 11, 12, 13, 14]. Besides these comorbidities, ADHD is also associated with worse performance in school, not finishing
college and a lower quality of life [8,11,13,15].
Individuals with ADHD have difficulty with impulsivity control and increased risk of antisocial behavior [8, 11, 12, 14], which could be the reason for frequent visits to the
emergency room [12], increased risk of criminality [13], including driving felony [16], use of narcotics [8, 11, 12] and alcohol [8, 11, 12]. Individuals with untreated ADHD, also perform worse on tests that measure vigilance, they make more mistakes and have longer reaction time [17]. They also perform worse on various other tests that measure behavioral flexibility, attention and integration of sensory information [17]. Executive functions, such as motor response inhibition, working memory and planning have also been shown to be suboptimal [18].
The pathophysiology of ADHD, similar to the etiology, is unknown and more studies are needed to understand this. However, there are studies that have tried to identify different mechanisms that contribute to the disorder. One theory behind impulsivity and hyperactivity is delay aversion where the individual has a reluctance of waiting and therefor acts impulsive [19]. Further, studies have shown that individuals with ADHD have less total volume of gray matter in the brain, including several structures like caudatus nucleus [20, 21, 22], lentiform nucleus [17] as well as putamen and amygdala [21]. The reduced volume of gray matter in the brain is probably a contributing factor to the difficulties an individual with ADHD experiences. Additionally, there are studies that indicate further pathophysiological
mechanisms like dysfunction of the anterior cingulate cortex [23], hypoactivation in, among other areas, ventromedial prefrontal cortex, insula and putamen [22] along with delayed maturing of cortical structures [24]. Furthermore, a gene encoding for a dopamine-transporter has been associated with ADHD [25], the dopamine receptor D2 has been associated with hyperactivity in mice [26], polymorphisms in the norepinephrine transporter has been associated with ADHD [27] and blockade of norepinephrine alpha 2a receptor can induce ADHD-like symptoms in monkeys [28]. Since central stimulants affects the dopamine and norepinephrine systems in the brain, these could be the reason behind successful treatment of ADHD.
ADHD is treated with both psychosocial interventions such as behavioral therapy and medications such as central stimulants [29]. Treatment with central stimulants, such as methylphenidate (MPH) and amphetamine (AMP), has been associated with more normal
volumes of gray matter in the brain [20], increased activity in structures such as ventromedial prefrontal cortex and insula [22] and a protective effect on later drug-use [30] in individuals with ADHD. Both MPH and AMP acts by increasing levels of extracellular norepinephrine and dopamine in the brain by blocking re-uptake and degradation [31,32], and therefor the monoamines available in the synapse increase [33]. Additionally, AMP also induces monoamine release [34] and increases extracellular serotonin in the brain [31]. The raise of extracellular dopamine, following MPH treatment, has been shown to increase interest, excitement and motivation for mathematical tasks [35]. It has been shown that treatment with MPH gives individuals with ADHD better performance on tests that measure vigilance, divided attention, focused attention and flexibility compared to before treatment [17]. Similar results, such as improved sustained attention, is also seen with AMP treatment [36]. Not only does the individual perform better on tests but improvements of symptoms such as
hyperactivity and inattention are also associated with central stimulant treatment [36, 37, 38, 39, 40].
Even if treatment with central stimulants have proven effective in many cases with decrease of symptoms, there are also negative side-effects. MPH is associated with increased anxiety and depression [39] and both MPH and AMP is associated with decreased appetite, sleep problems as well as cardiovascular events such as increased blood pressure and heart rate [39, 41]. Because of this, it is important to give the right medication to the right patient. Studies have shown that some individuals do not respond to one of the two, MPH or AMP [42], indicating differences between individuals that may suggest giving different stimulants to different patients. Therefor it is of value to evaluate and compare the efficacy of the two and to find predictors that can foresee the treatment effect to facilitate the treatment of ADHD.
Which meditation is the better choice when treating adult ADHD, methylphenidate or lisdexamphetamine? Are there any predictors that can anticipate treatment efficacy of methylphenidate and lisdexamphetamine?
2. Method 2.1 Primary aim
The main aim of this systematic review was to compare the effects and side-effects of MPH and the AMP-derivate lisdexamphetamine (LDX) in adults with ADHD.
2.1.1 Inclusion- and exclusion criteria
The inclusion criteria has been based on PICO; Population, Intervention, Control and Outcome.
2.1.1.1 Population
The population were adults (≥18 years), men and women, with a confirmed diagnosis of ADHD according to either DSM-III, DSM-IV, DSM-V or ICD-10. The study population had to exceed 15 included participants. Articles which studied children and adolescences (<18 years) were excluded in this study as well as studies with a smaller study population than 16 participants. Studies that investigated healthy participants, or any other diagnosis than ADHD, as well as studies using other diagnostic criteria than DSM-III, DSM-IV, DSM-V or ICD-10 were not included in this study. Having co-morbidities or other medication were not an obstacle for participating in this study. No consideration has been taken to subtype of ADHD.
2.1.1.2 Intervention
Treatment with MPH or LDX for at least six weeks during double-blind conditions were the wanted intervention. Cross-over studies with less than six-week intervals as well as open-label studies and single-blind studies was not included in this study. Articles with additional interventions such as MPH or LDX in combination with psychotherapy or nicotine patches were excluded. No consideration has been taken to administration form, dosage or intensity of treatment when reviewing and choosing articles for this study.
2.1.1.3 Control
Studies having placebo as control or having a head-to-head comparison between MPH or LDX were included. Having other drugs as or no control were an exclusion criteria. Studies examining different dosages of MPH or LDX without placebo as control were not included.
2.1.1.4 Outcome
The primary outcome was symptoms of ADHD measured with AISRS, ASRS, ADHD-RS, CGI, AIM-A, GAF, CAARS or WRAADDS. Adult ADHD Investigator Symptom Rating Scale (AISRS) or the ADHD Rating Scale (ADHD-RS) are clinician rated and measures symptoms of ADHD with 18 questions referring to the 18 symptoms in the DSM-IV criteria. Adult ADHD Self-Report Scale (ASRS) is the self-reported version of the
AISRS/ADHD-RS. Clinical Global Impression (CGI) scale is clinician rated and measures severity of disease and treatment response. It measures severity of illness (CGI-S), global improvement (CGI-I) and efficacy index (CGI-E). ADHD Impact Module – Adult (AIM-A) is self-reported and measures quality of life, daily functioning and symptoms. Conners' Adult ADHD Rating Scales (CAARS) exists both in self-reported versions (CAARS:S-S) and in observer rated versions (CAARS:O-SV) and measures ADHD symptoms. Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) measures ADHD symptoms. Secondary outcome were adverse events, either self-reported or objective.
2.1.2 Search strategy and databases
Two databases were searched, PubMed and Cochrane Library. The search in PubMed
consisted of three blocks, one for ADHD, one for MPH and one for LDX. These three blocks were combined with boolean operators to get a full cover search (see appendix 1). This search resulted in 4891 results. To limit the search further, additional filters for “Randomized
Controlled Trial”, “Humans”, “English” and “Adults: 19+ years” were used, that resulted in 261 results. Title and abstract were reviewed and 103 studies were excluded for not meeting the inclusion criteria for the population, 69 studies for the type of intervention, six studies for the type of control, 41 studies for the outcome measures and five studies due to other reasons. The 37 articles remaining were reviewed in full text. Eight articles were excluded for having an additional intervention such as nicotine patch or psychotherapy combined with MPH or LDX, four articles for lack of double-blinding during six-weeks of intervention, one article for lack of placebo control, two articles for being cross-over studies during less than six-week intervals, four studies for not diagnosing ADHD according to DSM-III, IV, V or ICD-10, one article for not defining the participants age and one article for having a shorter intervention than six weeks (see appendix 2). This resulted in 16 articles chosen to be included in this study from PubMed (see figure 1).
The search in Cochrane consisted of four blocks, one for ADHD, one for MPH, one for LDX and one for adults (≥18 years). These were combined with boolean operators for a full cover search (see appendix 3). No additional filters were used. This search resulted in 379 results. After 234 doublets and six review articles had been removed, 139 results remained and these titles and abstracts were reviewed. Out of these, 42 abstracts were excluded for not meeting the inclusion criteria for the population, 31 abstracts for intervention, eight abstracts for control, 21 abstracts for outcome and five abstracts for other reasons. Out of the 32 abstracts
remaining, 29 only existed as an abstract or conference poster and were not included in this study. Three articles were reviewed in full text but all were excluded due to having an intervention period of less than six weeks (see appendix 2). Thus, no additional articles were included from Cochrane Library (see figure 2).
Figure 1. Flowchart over the excluded and included articles from PubMed
Figure 2. Flowchart over the excluded and included articles from Cochrane Library
The included articles were assessed for bias according to SBU:s “Bedömning av
randomiserade studier (effekt av att tilldelas en intervention)” (see appendix 4) and included
studies were all rated as having moderate to high risk of bias. It is difficult to make studies of central stimulants fully blinded since participants will subjectively perceive the effects of the active treatment and the observers will likely identify if a participant is given active treatment or placebo-based treatment by participants psychiatric evaluation and behavior. This bias is inevitable and therefor all studies were included.
2.2 Secondary aim
The secondary aim of this systematic review was to identify biomarkers that can be used to predict efficacy of pharmacological treatment with MPH and LDX.
2.2.1 Inclusion- and exclusion criteria
The inclusion criteria have been roughly based on PICO; Population, Intervention, Control and Outcome.
2.2.1.1 Population
The population were adults (≥18 years), men and women, with a confirmed diagnosis of ADHD according to either DSM-III, DSM-IV, DSM-V or ICD-10. The study population had to exceed 15 included participants. Articles which studied children and adolescences (≤18 years) were excluded in this study as well as studies with a smaller study population than 16 participants. Studies that investigated healthy participants, or any other diagnosis than ADHD, as well as studies using other diagnostic criteria than DSM-III, DSM-IV, DSM-V or ICD-10 were not included in this study. Having co-morbidities or having other medication were not an obstacle for participating in this study.
2.2.1.2 Intervention
Treatment with MPH or LDX during any amount of time. No consideration has been taken to administration form, dosage or intensity of treatment when reviewing and choosing articles for this study. Open-label studies were included.
2.2.1.3 Control
Desirable control when reviewing articles were placebo but studies without control have also been included.
2.2.1.4 Outcome
The primary outcome was symptoms of ADHD measured with AISRS, ASRS, ADHD-RS, CGI, AIM-A, GAF, CAARS or WRAADDS.
2.2.1.5 Additional inclusion criteria
Additional inclusion criteria were examination of some sort of predictor, such as age, sex, time since diagnosis or subtype of ADHD, for treatment response.
2.2.2 Search strategy and databases
Two databases, PubMed and Cochrane Library were searched. For the PubMed search, four search blocks were used, one for ADHD, one for MPH, one for LDX and one for biomarkers. These were combined with boolean operators for a full cover search (see appendix 5).
Additional filters were used to limit the search further; “Randomized Controlled Trial”, “Humans”, “English” and “Adults: 19+ years” which resulted in 77 results. Title and abstract of these articles was reviewed and 42 studies was excluded for not meeting the inclusion criteria for the population, two studies for intervention, two studies for outcome and three studies due to other reasons. The 28 articles remaining were reviewed in full text. 16 articles were excluded for not having examined a predictor and three studies were excluded for not diagnosing ADHD according to DSM III, IV, V or ICD-10 (see appendix 6). Hence, nine studies from PubMed was included in this study (see figure 3).
Figure 3. Flowchart over the excluded and included articles from PubMed
The search in Cochrane consisted of five blocks, one for ADHD, one for MPH, one for LDX, one for biomarkers and one for adults (≥18 years). These were combined with boolean
operators for a full cover search (see appendix 7). No additional filters were used. This search resulted in zero results, hence no articles from Cochrane Library were included in this study.
2.3 Ethical considerations
Since this is a literature study no patient data or confidentiality information have been included or processed. Hence, no ethical considerations or permission was needed.
3. Results 3.1 Primary aim
Table 1. Included studies matching the inclusion criteria.
Author Name of study Drug Bias assassement Population Intervention Control Outcome Results Adverse events
Armstrong, RB., Ascher S., Goodman DW., Ma YW., Rostain AL., Starr HL. [43] Randomized, 6-Week, Placebo-Controlled Study of Treatment for Adult
Attention-Deficit/Hyperactivity Disorder:
Individualized Dosing of Osmotic-Release Oral System (OROS)
Methylphenidate With a Goal of Symptom Remission
MPH. Moderate risk of bias. 357 adults (18-65 years) with ADHD confirmed with DSM-IV. Subjects was randomized to MPH (n=178) or to placebo for 6 weeks (n=179). Placebo. Change in ADHD symptoms evaluated with AISRS, CGI, ASRS and AIM-A.
Subjects in the MPH group had a greater change from baseline (-17.1) than the placebo group (-11.7) in total AISRS score. Treatment difference were significantly better for the MPH group with LS mean difference -5.0 (p<.001). A significantly greater percentage of the MPH group did go into remission (AISRS score < 18) compared to the placebo group (45% vs 30.8%; p=.0008). Greater improvements were also revealed on CGI-I (p<.001), CGI-S (p<.001), AIM-A (p ≤.028) and ASRS (p<.001) in the MPH group compared to the placebo group.
72.4% in the MPH group experienced adverse events compared to 49.7% in the placebo group. The most frequent adverse events (>1/10)
were headache, dry mouth, decreased appetite and initial insomnia. Other common adverse events (>1/100) were
insomnia, anxiety, irritability, jitteriness, palpitations, upper respiratory tract infection and nausea. Eight subjects in the MPH group discontinued due to adverse events such as increased blood pressure, headache, gastroenteritis, tremor, anxiety, insomnia, oral pain and hypertension. Babinski DE., Humphery H., Pelham WE., Waschbusch DA., Waxmonsky JG. [44] Parent-Reported Improvements in Family Functioning in a Randomized Controlled Trial of Lisdexamfetamine for Treatment of Parental Attention-Deficit/Hyperactivity Disorder
LDX. Moderate risk of bias. 30 patients diagnosed with ADHD assessed with DSM-IV.
8 week double-blind phase where patients were randomized to either LDX (n=10) or placebo (n=10). Placebo. Symptoms of ADHD were measured with ADHD-RS.
Compared to the placebo group the LDX group were associated with significant reductions in ADHD symptoms on the ADHD-RS (p=.003).
Five parents dropped out due to adverse events during the titration phase. Arndt S,. Bever-Stille KA., Gaffney GR., Holman TL., Kuperman S., Lund BC., et al. [45] Bupropion SR vs. Methylphenidate vs. Placebo for Attention Deficit Hyperactivity Disorder in Adults
MPH. Moderate risk of bias. 30 adults (18–60 years old) with confirmed ADHD according to DSM-IV. Subjects were randomized to either bupropion (n=11), MPH (n=8) or placebo (n=11) for 7 weeks. Placebo. ADHD symptoms were assessed with CGI-S and ADHD-RS.
CGI response rate for MPH was 50% vs 27% for placebo, however this greater response was not significant (p=.14). There was a significant improvement in ADHD-RS in both the MPH group and the placebo group compared to baseline (p<.05).
75% of the MPH group reported at least one adverse event compared to the placebo group where 67% reported at least one adverse event. Two patients dropped out due to adverse events in the MPH group. The most commonly reported adverse events (>1/10)
in the MPH group was decreased appetite, insomnia, tremor, sweating, and jitteriness.
Baer L., Biederman J., Bourgeois M., Faraone SV., Fried R., Godfrey KM., et al. [46] The effects of lisdexamfetamine dimesylate on driving behaviors in young adults with ADHD assessed with the Manchester driving behavior questionnaire
LDX. High risk of bias. 75 patients (18-26 years) with confirmed diagnosis of ADHD according to DSM IV. Randomized, double-blind, placebo-controlled study of LDX during 6-weeks. 35 participants were randomized to receive LDX and 34 to receive placebo.
Placebo CGI-I and ADHD-RS were used to evaluate overall severity and change in severity of ADHD symptoms.
In the LDX group there was a 65% response rate (CGI ≤ 2
and at least 30% reduction in baseline ADHD-RS score) compared to the placebo group where the response rate was 27% (p=.001).
LDX was associated with decreased appetite, mucosal dryness and jitteriness compared to placebo (p<.05). LDX was also associated with statistically significant increases in pulse and QT interval. One patient in the LDX group discontinued due to affective dullness. Arngrim T., Carter K., Chen CW., Ginsberg Y., Huss M., Kumar V., et al. [47] Methylphenidate Hydrochloride Modified-Release in Adults with Attention Deficit Hyperactivity Disorder: A Randomized Double-Blind PlaceboControlled Trial
MPH. Moderate risk of bias. 725 adult patients (18–60 years) with ADHD according to DSM-IV. Randomized, double-blind study of MPH during 9-weeks. The patients were randomized to different dosages of MPH (n=544) or placebo (n=181). Placebo. ADHD-RS was used to evaluate the symptoms of ADHD and the change from baseline. Secondary outcomes were measured with CGI-I, CGI-S, CAARS-O:S and ASRS.
75% of all patients treated with MPH had >30% improvement in ADHD-RS compared to placebo. Responders in the MPH groups were 75.8% (p=.0011), 80.5% (p=.0001) and 81.0% (p=.0001) compared to placebo where only 58.4% responded to treatment. Improvement from baseline in ADHD-RS was significantly larger in all MPH groups compared to placebo (p<.0001). Improvements on the CGI-I (p<.0009), CGI-S (p<.0001), CAARS-O:S (p<.0014) and ASRS (p<.0001) were significantly greater compared to placebo.
Adverse events such as headache, decreased appetite, dry mouth and nausea were more likely to occur in the MPH groups (>1/10) than in the placebo group. During phase 1 2.2% of the patients dropped due to adverse events such as anxiety and decreased appetite in the MPH groups. There was no signs of any cardiovascular adverse events.
Aleardi M., Biederman J., Doyle R., Faraone S., Herzig K., Mick E., et al. [48] A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder
MPH. High risk of bias. 146 patients (19-60 years) with ADHD according to DSM-IV. Double-blind, randomized study of MPH during 6 weeks where patients received either MPH (n=104) or placebo (n=42). Placebo. Change in symptoms and severity during the study measured with CGI and AISRS.
There were a significant reduction in symptoms on the ADHD-RS in the MPH group compared to placebo (p<.0001). 68% in the MPH group responded (much/very much improved on the CGI together with >30% reduction in symptoms on AISRS) compared to only 17% in the placebo group (p<.0001). Even GAF was improved during treatment with MPH (p<.01).
Decreased appetite, dry mouth and mild moodiness in the MPH group reached statistical significance (p=.01, p=.001 and p=.001 respectively) compared to placebo. Increases in heart rate, but not blood pressure, was associated with MPH treatment (p<.001). Additionally, the ECG ventricular rate (p<.001) and the OTc interval (p<.01) increased in the MPH group compared to placebo. Adler LA., Dauphin M., Deas P., Dirks B., Raychaudhuri Self-Reported quality of life in adults with attention-deficit/hyperactivity disorder and
LDX. High risk of bias. 161 adults (18-55 years) with ADHD according to DSM-IV. Randomized trial of LDX during 10 weeks where patients were treated with either
Placebo. Symptoms were measured with ADHD-RS, AIM-A and CGI-S.
At the end of the study the LS mean change in ADHD-RS total score were -10.3 for placebo and -21.4 for LDX (p<.0001). All patients were
Adverse events was reported by 58.8% in the placebo group and 78.5% in the LDX group. Common adverse events (>1/10) were decreased
A., Saylor K., et al. [49] executive function impairment treated with lisdexamfetamine dimesylate: a randomized, double-blind, multicenter, placebo-controlled, parallel-group study LDX (n=80) or placebo (n=81). ”moderately-severely ill” on the CGI-S at baseline, however at week 10 22.7% of the placebo group and 51.9% of the LDX group were rated not at all or borderline mentally ill. LDX was associated with larger improvement on the AIM-A scales compared to placebo (p ≤.0302).
appetite, dry mouth, jitteriness, headache, insomnia, initial insomnia, irritability and decreased weight. Discontinuitation due to adverse evense were 2.5% in the placebo group and 6.3% in the LDX group. No meaningful cardiovascular adverse event were observed. Biederman J., Doyle R., Hammerness P., Kotarski M., Mick E., Spencer T., et al. [50] A Randomized, 3-Phase, 34-Week, Double-Blind, Long-Term Efficacy Study of Osmotic- Release Oral System-Methylphenidate in Adults With Attention-Deficit/Hyperactivity Disorder
MPH. High risk of bias. 227 adult patients (19-60 years) with an diagnosis of ADHD based on DSM-IV. Double-blind, randomized, placebo-controlled study of MPH during 6 weeks. 112 participants were randomized to MPH and 115 to placebo.
Placebo. Severity and change in severity of ADHD were assessed with CGI scale. Symptoms of ADHD were assessed with AISRS.
In the MPH group there was a greater significant
improvement in AISRS score compared to the placebo group (p<.0001). The MPH group was also more likely to respond (CGI-I≤2 and AISRS improvement >30%) to treatment than the placebo group (62% vs 37%; p<.001).
Significantly more subjects in the MPH group discontinued due to adverse events (11% vs 3%; p=.01). Common (>1/10) adverse events which were statistically significant were decreased appetite, insomnia, jitteriness and mucosal dryness. Less common (>1/100) but statistically significant were neurological symptoms. No significant difference was seen between the MPH group and the placebo group in cardiovascular parameters. Berwaerts J., Casas M., Dejonckheere J., Ginsberg Y., Heger S., Kooij SJJ., et al. [51]
Efficacy and safety of prolonged-release OROS
methylphenidate in adults with attention deficit/hyperactivity disorder: A 13-week, randomized, double-blind, placebo-controlled, fixed- dose study
MPH. Moderate risk of bias. 279 adults (18-65 years) with ADHD according to DSM-IV. Double-blind, randomized study where participants received MPH or placebo during 13 weeks. 189 participants were assigned to receive MPH and 92 participants to receive placebo. Placebo. ADHD symptoms were measured with O, CAARS-O:SV and CAARS-S:S. Severity of ADHD was assessed with CGI-S and CGI-C. AIM-A was used to assess quality of life. Improvement in CAARS-O:SV was seen in all groups. The only statistically significant improvement was seen in the MPH group with the highest dose of MPH compared to placebo (p=.0024). A significant decrease in CAARS-S:S score was also observed in both MPH groups compared to placebo (p<.05). In the MPH group with highest dose of MPH there was also a significant greater
improvement in CGI-S score compared to placebo (p=.0018). Significant improvement in AIM-A was also observed in both MPH groups compared to placebo (p<.0001).
The most common reason for discontinuation in the MPH groups was adverse events. At least one treatment associated adverse event was experienced by 91.3% in the MPH group with higher dose, 86.5% in the MPH group with lower dose and 78.4% in the placebo group. Common adverse events (>1/10) were headache, decreased appetite, dry mouth, nausea, insomnia,
nasopharyngitis and decreased weight. In the MPH group with lower dose of MPH, 15 participants discontinued due to adverse events and in the MPH group with higher dose of MPH 19 participants discontinued due to adverse events. Adverse events affecting the
cardiovascular system were reported by 21 (23.6%) and 33 (35.9%) subjects in the two MPH groups compared to 3 subjects (3.1%) in the placebo group. The most common cardiovascular adverse events with MPH were tachycardia, palpitations and increased heart rate. Participants in the MPH groups were more likely to receive hypertension during the study compared with placebo (14.5% and 18.9% vs 7.4%). One participant in the MPH group with higher dose reported abnormal ECG. Kashimoto Y., Koh T., Matsumura T., Saito Y., Takahashi N., Tominaga Y. [52] A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of osmotic-controlled release oral delivery system methylphenidate HCl in adults with
attention-deficit/hyperactivity disorder in Japan
MPH. Moderate risk of bias. 284 adults (18-65 years) with ADHD according to DSM-IV. Randomized, double-blind study of MPH compared to placebo during 8 weeks, including 4 weeks of titration and 4 weeks of efficacy assessement.143 participants were randomized to receive MPH and 141 to placebo. Placebo. Change in DSM-IV symptom from baseline to end of treatment. Symptoms of ADHD, measured with CAARS-O:SV and CAARS-S:SV as well as CGI-S and CGI-C.
The LS mean change in DSM-IV Total ADHD Symptom subscale score of the CAARS-O:SV was -12.5 in the MPH group and -7.9 in the placebo group (p=.0001). A significantly greater change was seen in the MPH group compared to the placebo group in the CAARS-O:SV total score (p=.0002). Improvement on CGI-S and CGI-C score were also significantly larger in the MPH group compared to the placebo group (p=.0001).
More participants in the MPH group, compared to the placebo group, experienced adverse events (81,8% vs 53,9%). The most common (>1/10) adverse events in the MPH group were decreased appetite, palpitations, nasopharyngitis, nausea, thirst and insomnia . Less common (>1/100) adverse events were headache, weight decrease and tachycardia. Drop outs due to adverse events occurred among 6 participants in the MPH group (4.2%) and one participant in the placebo group (0.7%). Aleardi M., Biederman J., Dougherty M., Doyle R., Dunkel S., Hammerness P., et al. [53] A Randomized, Placebo-Controlled Trial of OROS Methylphenidate in Adults with Attention-Deficit/Hyperactivity Disorder
MPH. Moderate risk of bias. 149 adults (19-60 years) meeting full diagnostic criteria for DSM-IV. Double-blind, randomized study of MPH during 6 weeks. 72 participants were randomized to MPH and 77 to placebo. Placebo. Severity of ADHD was measured with CGI scale. Symptoms of ADHD were assessed with AISRS. Decrease in symptoms on AISRS was significantly larger for the MPH group compared to the placebo group (p<.001). More participants in the MPH group, 66% compared to 39% in the placebo group, responded to treatment (CGI ≤2 and 30% reduction in AISRS; p=.002). More participants in the MPH group had 30% and 50% reductions in AISRS scored compared to placebo (p<.001).
The most common (>1/10) adverse events which reached statistical significance were decreased appetite, mucosal dryness, gastrointestinal adverse events, jitteriness, insomnia and cardiovascular complaints. MPH was associated with statistically significant increases heart rate (p<.001), blood pressure (SBP p=.02 and DBP p<.001) and decrease of QT interval (p=.001). Less common
(>1/100) but still significant adverse events reported were depression, dizziness and anxiety. 14% in the MPH group dropped out due to adverse events compared to 4% in the placebo group. Biederman J., Faraone SV., Mick E., Spencer T., Surman C. [54] Is Response to OROS-Methylphenidate Treatment Moderated by Treatment with Antidepressants or Psychiatric Comorbidity? A Secondary Analysis from a Large Double Blind Study of Adults with ADHD
MPH. Moderate risk of bias. 227 adults (19-60 years) with DSM-IV ADHD. Double-blind, randomized study of MPH during 6 weeks. 112 participants were randomized to MPH and 115 to placebo.
Placebo. Severity and change in severity were measured with CGI scale. The AISRS was also used to assess symptoms.
Compared to the placebo group, the MPH group was associated with a significant improvement on CGI (p<.001) and on AISRS (p=.0003).
The MPH group reported more psychiatric adverse effects such as jitteriness, irritability, anxiety and self-harm compared to placebo (p<.001).
Chronis-Tuscano A., Colon CJ., Efron LA., Jiles CD., Jones HA., Pian J., et al. [55]
Efficacy of Osmotic-Release Oral System (OROS) Methylphenidate for Mothers With Attention-Deficit/Hyperactivity Disorder (ADHD): Preliminary Report of Effects on ADHD Symptoms and Parenting
MPH. High risk of bias. 23 adults with ADHD according to DSM-IV. Double blind, randomized study of MPH during 7 weeks. Participants were randomized to either MPH (n=9) or placebo (n=11). Placebo. ADHD symptoms were assessed by CAARS and CGI scale.
Participants in the MPH groups had significant improvements CAARS (p<.05) and CGI (p<.0001) compared to placebo.
Participants reported few adverse events. There was no significant adverse events during this study except for weight loss in the MPH group compared to placebo. Alm B., Ammer R., Fischer R., Ose C., Philipsen A., Retz W., et al. [56] Multiscale assassement of treatment efficacy in adults with ADHD: a randomized placebo-controlled, multi-centre study with extended-release methylphenidate
MPH. High risk of bias. 162 patients (≥18 years) with ADHD according to DSM-IV. Double-blind, randomized study of MPH during 8 weeks, including 2 weeks titration period and 6 weeks mantainence period. 84 participants received MPH and 78 participants received placebo. Placebo. Primary outcome was measured with WRADDS. ADHD-RS and CAARS-S:L were also used to evaluate ADHD symptoms. Severity and change of severity was measured with CGI scale.
In the MPH group there was a decline in WRADDS score compared to the placebo group (-13.8 vs -6.2). The difference between the MPH group and the placebo group at week 8 was 6.8 points and statistically significant (p=.0003). There was also a difference between the two groups in ADHD-DC symptom score (p<.01). The MPH group did also have a greater improvement in CAARS-S:L (p=.008) compared to placebo. 50% of the MPH group responded
Three patients in the MPH groups dropped out due to adverse events. 55 patients in the MPH group reported adverse events compared to 32 patients in the placebo group (p=.003).The most common (>1/10) adverse events in the MPH group were decreased appetite, dry mouth, excessive thirst, headache, palpitations, dizziness, gastric problems and nausea. No statistically significant change in blood pressure was observed at the end of the study.
(30% reduction in WRAADDS score) to treatment compared to 18% in the placebo group. 50% of the MPH group had a ”very much” or ”much” improvement in CGI compared to 24.4% in the placebo group (p=.0001). Alfonso A., Augustus JN., Babinski DE., Bernstein m., Crum KI., Humphrey HH., et al. [57] Does pharmacological treatment of ADHD in adults enhance parenting performance? Results of a double-blind randomized trial
LDX. Moderate risk of bias. 22 adults who were diagnosed with ADHD according to DSM-IV. Study of LDX durgin 8 weeks. Double-blind study where the participants were randomized to either placebo (n=10) or their optimal dose of LDX (n=9). Placebo. ADHD-RS and CGI were used to assess symptoms of ADHD.
A significant reduction on the ADHD-RS (p<.01) and CGI (p<.01) was seen in the LDX group compared to placebo. 80% of the LDX group compared to 30% of the placebo group were rated as ”much” and ”very much” improved on the CGI-I (p<.05).
Decrease of appetite, dry mouth, headache and insomnia were the most common adverse events during the titration phase. However none of these reached statistical significance. Five subjets dropped out due to adverse events such as jitteriness and headache in the LDX. No significant cardiovascular adverse events were observed.
Adler LA., Silbe S., Starr HL., Zimmerman B. [58]
Efficacy and Safety of OROS Methylphenidate in Adults With Attention-Deficit/Hyperactivity Disorder: A Randomized, Placebo-Controlled, Double-Blind, Parallel Group, Dose-Escalation Study
MPH. High risk of bias. 226 adults (18-65 years) with ADHD according to DSM-IV. Participants were randomly assigned to either MPH (n=110) or placebo (n=116) for 7 weeks. Placebo. Change in ADHD symptoms measured with AISRS and CGI-I.
Larger improvement on AISRS in the MPH group was observed compared to the placebo group (LS mean -10.6 and -6.8 respectively; p=.012). Likewise a significantly greater improvement was seen on the CGI-I (p=.008). 36.9% of the MPH group responded (≥30%
change in AISRS compared to baseline and a score ≤2 on the CGI-I) compared to 20.9% of the placebo group (p=.009).
84.5% in the MPH group reported adverse events compared to 63.8% in the placebo group. 14.5% in the MPH group and 5.2% in the placebo group discontinued due to adverse events such as irritability, increased blood pressure, anxiety and depressed mood. The most common adverse events (>1/10) were decreased appetite, headache, dry mouth, anxiety, nausea and increased blood pressure.
16 articles were included in this study, 12 evaluating MPH effects and four evaluating LDX effects. Number of participants included in this study were 3123 of which 31 participants dropped before randomization or were treated with other drugs. Out of the 3092 participants remaining 1568 participants received MPH, 134 participants received LDX and 1390 participants received placebo. 17.6% (n=276) dropped from MPH treatment, 5.2% (n=7) dropped from the LDX treatment and 15.8% (n=219) dropped from the placebo treatment.
3.1.1 Primary outcome: ADHD symptoms 3.1.1.1 ADHD-RS, AISRS and ASRS
Seven articles, four with LDX and three with MPH, examined symptoms of ADHD with ADHD-RS. All studies examining LDX, Babinski et al [44], Baer et al [46], Adler et al [49] and Alfonso et al [57], found significant reductions on ADHD-RS in participants when treated with LDX compared to placebo (p=.003, p=.001, p<.0001 and p=.012 respectively).
When examining MPH effects, Arndt et al [45], found significant reductions on ADHD-RS in the MPH group after treatment compared to baseline, but no significance compared to the placebo group. Arngrim et al [47] and Alm et al [56], found significant improvements on ADHD-RS in the MPH group compared to the placebo group (p<.0001 and p<.01
respectively).
Six articles, all examining MPH, used AISRS for assessment of ADHD symptoms. All studies, Armstrong et al [43], Aleardi et al [48], Biederman et al [50], Aleardi et al [53], Biederman et al [54] and Adler et al [58], found significant improvements on AISRS in the group treated with MPH compared to placebo (p<.001, p<.0001, p<.0001, p<.001, p=.0003 and p=.012 respectively).
Two articles, both examining MPH, used ASRS to measure ADHD symptoms. Both studies, Armstrong et al [43] and Arngrim et al [47] found statistically significant larger
improvements on ASRS in the participants treated with MPH compared to placebo (p<.001 and p<.0001).
15 studies used CGI to assess ADHD severity and treatment response, three examining LDX and 12 examining MPH. Baer et al [46] and Alfonso et al [57] found significant
improvements in the subjects treated with LDX compared to placebo on the CGI scales (p=.001 and p<.01 respectively). Adler et al [49] found a greater improvement (51.9% vs 22.7%) on the CGI scales in the LDX group compared to the placebo group, however no p-value was reported.
Armstrong et al [43], Arngrim et al [47], Aleardi et al [48], Biederman et al [50], Kashimoto et al [52], Aleardi et al [53], Biederman et al [54], Chronis-Tuscano et al [55], Alm et al [56] and Adler et al [58] found a statistically significant improvement on the CGI scales in the group treated with MPH compared to placebo (p<.001, p<.0009, p<.0001, p<.001, p=.0001, p=.002, p<.001, p<.0001, p=.0001 and p=.008 respectively). Berwarts et al [51] found a significant improvement in one of the groups treated with MPH, the higher dose, compared to placebo (p=.0018) but not in the MPH group with lower dose. Arndt et al [45] did not find a significant CGI improvement in the MPH group compared to the placebo group (p=.14).
3.1.1.3 ADHD Impact Module – Adult (AIM-A)
Three articles used AIM-A to evaluate daily functioning and quality of life, two studies of MPH and one of LDX. Adler et al [49] reported a significant improvement on AIM-A in the LDX group compared to the placebo group (p≤.0302).
Examining MPH, Armstrong et al [43] and Berwaerts et al [51] found a significantly larger improvement on AIM-A in the participants treated with MPH compared to placebo (p≤.028 and p<.0001 respectively).
3.1.1.4 Conners' Adult ADHD Rating Scale (CAARS)
Five studies used CAARS to evaluate ADHD symptoms, all examining MPH. They all, Arngrim et al [47], Berwaerts et al [51], Kashimoto et al [52], Chronis-Tuscano et al [55] and Alm et al [56], found statistically significant improvements on CAARS in the participants treated with MPH compared to placebo (p<.0014, p<.05, p=.0002, p<.05 and p=.008).
One article, studying MPH, used WRAADDS to examine ADHD symptoms. Alm et al [56] found significant improvements on WRAADDS in the group treated with MPH compared to the group treated with placebo (p=.0003).
3.1.2 Secondary outcome: Adverse events
In the studies examining LDX, Baer et al [46] reported significant adverse events to be decreased appetite, mucosal dryness, jitteriness, increases in pulse and QT interval (p<.05) in the group treated with LDX. Even Adler et al [49] reported adverse events such as decreased appetite, dry mouth and jitteriness, however this study did not find any significant
cardiovascular adverse events. Other commonly reported (>1/10) adverse events in this study were insomnia, irritability and decreased appetite. Alfonso et al [58] did report similar
adverse events but these did not reach statistical significance.
In the studies examining MPH, commonly reported (>1/10 in either of the studies) adverse events such as headache, dry mouth, decreased appetite, insomnia, jitteriness, tremor,
sweating, nausea, nasopharyngitis, decreased weight, palpitations, thirst and gastric problems were reported by Armstrong et al [43], Arndt et al [45], Biederman et al [50], Berwearts et al [51], Kashimoto et al [52], Alm et al [56] and Adler et al [58]. Neither of these reached statistical significance or no p-value was reported. Aleardi et al [48] reported adverse events such as decreased appetite, dry mouth and mild moodiness that were statistically significant (p≤.01). Aleardi et al [53] reported statistically significant adverse events to be decreased appetite, mucosal dryness, gastrointestinal problems, jitteriness, insomnia, cardiovascular complaints, depression, dizziness and anxiety (p<.05). Biederman et al [54] also found adverse events which reached significance such as jitteriness, irritability, anxiety and self-harm (p<.001). Chronis-Tuscano et al [55] reported decreased weight as an adverse event which reached statistical significance (p<.05).
Among the MPH studies, cardiovascular adverse events such as increased blood pressure, heart rate and QT interval were reported by Armstrong et al [43], Berwaerts et al [51] and Adler et al [58] but did not reach statistical significance or no p-value was reported. Arngrim et al [47], Adler et al [49], Biederman et al [50] and Alm et al [56] did not find any
significant cardiovascular adverse events. Aleardi et al [48] did find significant increases in heart rate and QTc interval (p<.001 and p<.01 respectively), but not in blood pressure, in the participants treated with MPH. Aleardi et al [53] found significant increases in heart rate
(p<.001), blood pressure (p≤.02) and decrease of QT interval (p=.001) among the participants treated with MPH.
3.2 Secondary aim
For all included studies, see table 2.
Table 2. Included studies matching the inclusion criteria.
Author Drug Name of study PICO Results
Adeyi B., Babcock T., Brams M., Weisler RH. [59]
LDX Relationship of ADHD symptoms and global illness severity in adults treated with
lisdexamfetamine dimesylate
Adults (18-55 years) with ADHD according to DSM-IV. Placebo-controlled, withdrawal study of LDX. Treatment response was measured with CGI and ADHD-RS.
Subjects who relapsed had a higher score of CGI at the end of intervention compared to those who did not. Dejonckheere J., Kooij SJJ., Philipsen A., Rösler M., Schäuble B., van Agthoven M., et al. [60]
MPH Predictors and impact of non-adherence in adults with attention-deficit/hyperactivity disorder receiving OROS methylphenidate: results from a randomized, placebo-controlled trial
Adults with ADHD according to DSM-IV. Placebo-controlled, dose-response study of MPH. Treatment efficacy was assessed with CAARS and adherence to treatment was evaluated. Predictors for non-adherence evaluated were sex, treatment group, time since diagnosis, family history of ADHD, education, baseline CAARS and DUSI score.
Adherence were larger in the placebo group compared to the MPH group (p<.04), among men (p<.09), in subjects with long time since diagnosis (p=.007), in participants with lower education (completed high school vs university; p=.0284) and in subjects with lower DUSI scores (p=.0252). Significant predictors of CAARS outcome were baseline score of CAARS (p<.0001), study time point (p<.0001), and adherence in the study (p<.0001). A greater improvement in CAARS score was seen in subjects with a family history of ADHD (p=.0104) and with shorter time since diagnosis (p=.0072)
Adeyi B., Adler LA., Babcock T., Dirks B., Ginsberg L., Katic A., et al. [61]
LDX Long-term treatment outcomes with lisdexamfetamine dimesylate for adults with attention-deficit/hyperactivity disorder stratified by baseline severity
Adult participants with ADHD according to DSM-IV. Open-label study during 12 months. ADHD symptoms were measured with ADHD-RS and CGI.
The improvements on ADHD-RS were larger for the subjects with CGI-S score 5 and ≥6 compared to subjects with score 4 when treated with LDX. Subjects with ≥6 also had greater improvement than subjects with score 5 when treated with LDX. This result were similar in both subtypes,inattentive and
hyperactivity/impusivity. There was also a greater response to LDX treatment with higher dose. Faraone SV., Glatt SJ.,
Goodman D., Kollins SH., Spencer TJ. [62]
LDX Dose response effects of lisdexamfetamine dimesylate treatment in adults with ADHD: an exploratory study
Adults (18-55 years) with DSM-IV confirmed ADHD. Double-blind, placebo-controlled study of LDX during 4 weeks. ADHD symptoms were evaluated with ADHD-RS and CGI.
Baseline ADHD-RS score was a significant positive predictor for ADHD-RS score at the end of the study (p<.001) while LDX dose was a significant negative predictor for ADHD-RS at the end of the study (p<.001). Previous treatment for ADHD did not significantly affect ADHD-RS at the end of the study. Larger improvements on ADHD-RS Inattentive subscale were associated with higher baseline score (p<.001) and higher dose of LDX (p<.001). Larger improvements on the ADHD-RS Hyperactivity/Impulsivity were seen with higher baseline score (p<.001) but not with a increase in LDX dose (p=.417).
Carson KM., Dupaul GJ., O’Dell SM., Rossi JS., Swentosky A., Verdi G., et al. [63]
LDX Double-Blind, Placebo-Controlled, Crossover Study of the Efficacy and Safety of
Lisdexamfetamine
Collage students (18-23 years) with ADHD according to DSM-IV. Double-blind, placebo-controlled study of LDX during
Greater improvements on CAARS were associated with increased dose of LDX.
Dimesylate in College Students With ADHD
5 weeks. ADHD symptoms were assessed with CAARS. Buitelaar JK., Casas
M., Dejonckheere J., Kooij S., Ramos-Quiroga A., Schäuble B., et al. [64]
MPH Predictors of treatment outcome in adults with ADHD treated with OROS® methylphenidate
Adults (18-65 years) with ADHD according to DSM-IV. Double-blind, placebo-controlled study of MPH during 5 weeks followed by an open-label study during 7 weeks. ADHD symptoms were measured with CAARS:O-SV and CAARS:S-S. To predict treatment outcome, age, gender, history of mood/anxiety disorders, history of drug/alcohol abuse, country, education employment, baseline score of CAARS score and treatment group were assessed.
Greater improvements on CAARS were associated with higher age (p=.0358), male gender (p=.0056), lower educational level (p=.0079), larger baseline CAARS:O-SV score (p<.0001) after treatment with MPH during the double-blind phase. No significant association was seen between country, history of mod/anxiety disorders, history of drug/alcohol abuse or employment during the double-blind phase. In the open-label phase greater
improvements was observed among subjects with higher CAARS:O-SV score at the end of phase 1 (p<.0001) and among employed subjects (p=.0467). No significant association was seen during the open-label phase. Greater self-reported symptom improvements (with CAARS:S-S) was associated with male gender (p=.0114), lower educational level (p=.0322), higher CAARS:S-S score at baseline (p<.0001) and higher dose of MPH (p<.0001) when treated with MPH during the double-blind phase. No other significant associations were made. During the open-label phase, the only predictor of greater improvement of CAARS:S-S score that reached statistical significance was higher baseline score of CAARS:S-S. Brams M., Gao J., Gasior M., Giblin J., Wigal T., et al. [65] LDX Effects of open-label lisdexamfetamine dimesylate on self-reported quality of life in adults with ADHD
Adults (18-55 years) with ADHD according to DSM-IV. Open-label study of LDX during 4 weeks, followed by a double-blind, placebo-controlled study during 2 weeks. ADHD-RS, AIM-A and CGI were used to measure outcome. Age and gender were analyzed as predictors.
No significant differences were seen on AIM-A improvements between the two age or gender groups.
Adeyi B., Babcock T., Dirks B., Scheckner B. [66]
LDX Efficacy of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder previously treated with amphetamines: analyses from a randomized, double-blind, multicenter, placebo-controlled titration study
Adults (18-55 years) with a confirmed ADHD diagnosis according to DSM-IV. Double-blind, placebo-controlled study of LDX during 4 weeks. ADHD symptoms were measured with ADHD-RS and CGI. Predictor of outcome were previously treatment with amphetamines (AMPH).
No significant association were observed between participants previously treated with AMPH and participants not treated with AMPH when given LDX on ADHD-RS or CGI score.
Adler LA., Biederman J., Goodman DW., Kollins SH., Krishnan S., Weisler RH., et al. [67]
LDX Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Lisdexamfetamine Dimesylate in Adults With Attention-Deficit/Hyperactivity Disorder
Adults (18-55 years) with ADHD according to DSM-IV. Double-blind, randomized, study of LDX in different dosages during 4 weeks. ADHD symptoms were measured with ADHD-RS and CGI.
Increased dose of LDX was not associated with significant greater improvement on ADHD-RS. However, increased dose of LDX was associated with greater improvement on CGI (p<.01).
Nine studies were included in this article, all from PubMed, seven examining LDX and two examining MPH. Two studies examined CGI score as a predictor for LDX treatment
response. Both, Adeyi et al [59] and Adeyi et al [60] did report an association between higher CGI score at baseline and better treatment response.
One study examined predictors for adherence during treatment with MPH, Dejonckheere et al [60], which in turn were a predictor for treatment response measured with CAARS (p<.001). Adherence were significantly better among subjects with long time since diagnosis (p=.007), with lower education level (p=.0284) and with lower Drug Use Screening Inventory (DUSI) score (p=.0252). Other predictors of improvement on CAARS according to the same study were higher baseline CAARS score (p<.0001), study time point (p<.0001), family history of ADHD (p=.0104) and shorter time since diagnosis (p=.0072). Accordingly, another study of MPH, Buitelaar et al [64], reported association of greater improvement on CAARS and lower educational level and greater baseline CAARS score. The same study also reported male gender, higher age, employment and higher dose of MPH to be predictors for greater treatment response measured with CAARS. However, gender and age were according to Dejonckheere et al [60] and Brams et al [65] not a predictor for treatment response with MPH when measured with CAARS or LDX when measured with AIM-A respectively. When examining LDX and predictor for treatment response measured with CAARS, Carson et al [63], did present a higher dose of LDX as a predictor for greater improvements.
A higher dose of LDX was also a predictor for better treatment response according to Adeyi et al [61], Faraone et al [62] and Adler et al [67] when measuring CGI, ADHD-RS Inattentive subscale and CGI respectively. Faraone et al [62] also reported higher baseline score of ADHD-RS as a predictor for greater improvement. However, Adler et al [67] and Faraone et al [62] did not find a significant greater treatment response with increased dose of LDX on the ADHD-RS and ADHD-RS Hyperactivity/Impulsivity subscale respectively.
When examining other predictors such as country, history of mood/anxiety disorders, history of drug/alcohol abuse, by Buitelaar et al [64], no association with treatment response of MPH was observed. Furthermore, Faraone et al [62] and Adeyi et al [66] did not find any
association between previous treatment and current treatment response of LDX.
4. Discussion
ADHD accommodates functional impairments and suffering for the affected individuals in many ways, such as increased risk of worse performance in school and lower educational
level [9, 12, 14, 16], of criminality and justice involvement [13] and accidents [14]. However, it does not only affect the individual, since for example special school support,
unemployment, imprisonment and healthcare are consequences that affect the society and economy. Since it is also diagnosed in childhood [2], and thereafter is lifelong, it brings a lot of consequences and suffering for both the individual and society during many years
compared to other diseases which have a later debut or is curable.
The primary drugs for treatment of ADHD are strong, classified drugs which bring worry in the society and since no predictor of treatment efficacy is available, trial and error attempts to find individualized treatment are made. During the trial period there can be unnecessary suffering for both the individual and the society for months/years since adverse events such as cardiovascular and psychiatric consequences can derive from treatment with stimulants [39, 41]. Additionally, long-term adverse events when adults are given stimulants are also not sufficiently examined since age is a risk factor for several adverse events including
cardiovascular problems.
4.1 Primary aim
When using ADHD-RS, practically all studies, no matter the drug examined, did present significant improvements when treated with stimulants compared to placebo. This
strengthens the evidence that both MPH and LDX are effective in reducing symptoms and treating ADHD. All studies using the AISRS and ASRS accordingly presented significant improvements on the scales after treatment with MPH. However, no studies examining LDX used these scales but since ADHD-RS, AISRS and ASRS all measure ADHD symptoms, it can be assumed that subjects treated with LDX would also exhibit similar improvements on AISRS and ASRS. The conclusion is therefor that there was no significant difference between the efficacy of MPH and LDX in the treatment of ADHD.
When using CGI to assess ADHD severity and treatment response the majority (2/3) of studies examining LDX found significant improvements. Hence, it is likely that LDX does improve CGI score and therefor severity of ADHD and treatment response. However, since only three studies examining LDX used this scale and not all could show significant
improvements, it is possible that the results may not be representative for the whole ADHD population. On the other hand, the majority of studies examining MPH showed significant improvements on the CGI-scale when compared to placebo. Since a greater amount of studies
examining MPH used CGI, the conclusion that MPH is effective in improving ADHD severity is presumably more accurate, than for LDX, for the whole population. Though, one study failed to present significant improvements but this could be the result of a small study population with only 30 participants, eight receiving MPH and 11 receiving placebo.
Only three studies did use AIM-A to evaluate daily functioning and quality of life, all studies did present significant improvements when treated with central stimulants compared to placebo. Since only one study examined LDX and two studies examined MPH, it seems likely that the efficacy of LDX and MPH are comparable but further studies are needed to make more accurate conclusions.
When using CAARS and WRAADDS to examine ADHD symptoms all studies presented significant improvements when subjects were treated with MPH. This indicates that MPH is effective in treating ADHD symptoms but however, since all these studies only examined MPH, therefor no conclusion regarding LDX or comparison can be made.
Since a greater amount of studies about MPH and more participants receiving MPH than LDX it is possible that this affects the results. MPH has been a valid drug for treating ADHD longer time than LDX which can contribute to there being more studies including MPH. In the outcome measures where MPH and LDX is represented by a similar amount of studies, results aim towards similar efficacy between LDX and MPH. Nonetheless, further studies are required in the area.
Adverse events were reported among the majority (3/4) of studies examining LDX and these were similar between the three. However not all studies did provide significant results which brings limitations regarding the conclusions that can be made. It is likely that LDX treatment is associated with adverse events such as decreased appetite, mucosal dryness, jitteriness, cardiovascular consequences and insomnia but it is possible that this does not represent the whole ADHD population and further studies are needed in the area. More studies examining MPH did report significant adverse events and because of this it is more likely that the adverse events reported are truthful than in the LDX studies. Many studies did report similar adverse events but not p-value were accounted for, however since these studies are
independent of each other and did report similar adverse events this also advocates that MPH treatment are associated with adverse events. When examining more serious cardiovascular
adverse events many studies did report findings that did not reach statistical significance or no p-value were accounted for, while a few studies did find significant results. Though these results are divided, it is not possible to conclude whether or not MPH is associated with cardiovascular adverse events. However, since these are serious side effects it is much needed with further studies to provide more information about the safety of MPH.
A similar amount of subjects dropped from the MPH and placebo treatments compared to the LDX treatment which had less subjects dropping. This likely indicates that treatment with MPH does give more unwanted effects and adverse events than does MPH which could indicate that LDX is a better alternative when choosing treatment for ADHD among adults. However, there are divided results and uneven number of studies and further studies need to be made before any conclusions can be made.
4.2 Secondary aim
Biomarkers are broadly used in many health care areas such as oncology, endocrinology and in treatment of autoimmune diseases. The use of biomarkers have been very important to the development of precision medicine where each individual can get customized treatment for best possible outcome. However, in psychiatry no biomarkers or predictors are identified which entails a standardized treatment to all patients no matter the severity or traits of the disease. Discoveries of predictors for treatment of ADHD can be one important step towards precise medicine with individualized treatment. In contrast to the studies included in the primary aim, there are more studies included examining LDX in the secondary aim. Previous studies of children have shown that genetics affect the treatment effect [68, 69] such as variants of the dopamine transporter gene [70]. Since genetics does not change during life it can be assumed that these also applies for adults but no genetic predictors were found in this study, likely because of the exclusion of articles containing children.
When examining CGI score at baseline as a predictor for LDX treatment response two of two studies did present significant associations which indicates that severity of illness could be a predictor of treatment response. Accordingly, additional studies examining MPH did report association between higher baseline CAARS score and greater improvement, this also indicates that severity of illness and ADHD symptoms affect treatment response of MPH as well.
One study examined adherence to treatment and since the same study did present significant association between adherence and greater improvements on CAARS it can be seen as a predictor for treatment response of MPH. Hence, predictors for adherence such as long time since diagnosis, lower educational level and long time since diagnosis are also predictors for treatment response. However, only lower educational level was reported by one other study which only gives this predictor more validity than the others.
Male gender did in one study reach statistical significance which suggest that it could be a possible predictor for greater treatment response of MPH. On the other hand, one other study did find signs of similar results, but these failed to reach statistical significance. Therefor, no reliable conclusions can be drawn. Much in the same way, since only one study reported age and employment as predictors no conclusion can be drawn on wether these are predictors of MPH treatment response or not.
Increased dosages of LDX were reported as predictor of increased treatment response by three studies which does indicate some association between the two. However, two studies did not present any significant associations which makes it difficult to include or dismiss dose of LDX as a predictor for treatment response.
4.3 Limitations
This study was made during limited amount of time which have affected the method. It would have been optimal to make a meta-analysis of the results to further strengthen the study scientifically and statistically. Additional search methods would also have been used if more time were available to make sure a full cover search were made to cover all significant, previous studies. Studies of children examining genetic predictors would also have been included since genetics does not change over time. Furthermore, since all studies have been included no matter the risk of bias there is a risk of bias in this study. However, since it is practically impossible to make studies of central stimulants double-blinded this risk of bias is inevitable. Additional limitations of this study is that a lot of the reported adverse events did not account for a p-value which brings insecurities regarding the validity of these reports. However, since many studies reported similar adverse events it advocates for validity.
5. Conclusions
the society. Today there is no precise medicine being practiced when treating ADHD since no predictors are distinguished and no clear guidelines which medicine is the better choice. This study does find some evidence that LDX is a better alternative when treating adult ADHD since MPH is unitary associated with adverse events. Predictors of treatment response are likely severity of illness at baseline, dosage of drug and low education level, among others. However, further studies are needed to give more validity to the results presented by this study.
