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Efficacy, Acceptability, and Tolerability of Lisdexamfetamine, Mixed Amphetamine Salts, Methylphenidate, and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis

Authors:
  • University of Maribor Slovenia

Abstract and Figures

Abstract Objective: Psychostimulants are the first-line treatment in adults with attention-deficit hyperactivity disorder (ADHD). This meta-analysis aimed to evaluate the efficacy, acceptability, and tolerability of lisdexamfetamine (LDX), mixed amphetamine salts (MASs), modafinil (MDF), and methylphenidate (MPH) in comparison with placebo. Data Sources: We systematically searched PubMed/MEDLINE and Clinicaltrials.gov in May 2016, along with CENTRAL and EU Clinical Trials Register in February 2016, for the randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted on adults diagnosed with ADHD. Study Selection and Data Extraction: Substantial comorbidity, substance abuse or dependence, and nonpharmacological interventions represented grounds for exclusion. Published reports were the sole source for data extraction. Improvement in ADHD symptoms was the primary outcome. Random-effects model meta-analysis was applied to calculate the standardized mean difference (SMD) with 95% CIs. Data Synthesis: The search retrieved 701 records, of which 20 studies were eligible for analysis. High effect size (expressed as SMD) in reducing ADHD symptoms was observed for LDX (−0.89; 95% CI = −1.09, −0.70), whereas MASs (−0.64; 95% CI = −0.83, −0.45) and MPH (−0.50; 95% CI = −0.58, −0.41) reduced symptoms moderately compared with placebo. No efficacy was shown for MDF (0.08; 95% CI; −0.18, 0.34). Relevance to Patient Care and Clinical Practice: In this meta-analysis, the efficacy, tolerability, and acceptability of psychostimulants were compared with that for placebo. Five of the included trials have not been evaluated in any of the previously published meta-analyses. Conclusions: The results suggest that LDX has the largest effect size and has a promising potential for treating adults with ADHD.
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Research Report
Introduction
Attention-deficit hyperactivity disorder (ADHD) is a neuro-
developmental disorder characterized by the core symp-
toms of inattention, hyperactivity, and impulsivity.1 Its
worldwide prevalence in children and adolescents is
between 2.5% and 10% and less in adults.2,3 According to
the literature, 30% to 50% of children diagnosed in child-
hood continue to have symptoms into adulthood, which
means that many ADHD cases warrant treatment into adult-
hood with effective pharmacotherapy.4 ADHD is associated
with significantly increased mortality rates as was shown
by the Danish national study, where the authors found that
people diagnosed with ADHD in adulthood had a higher
mortality rate ratio.5
According to the newest British guidelines of British
Association for Psychopharmacology, the management of
ADHD consists of nonpharmacological and pharmacological
795703AOPXXX10.1177/1060028018795703Annals of PharmacotherapyStuhec et al
research-article2018
1Ormoz Psychiatric Hospital, Department of clinical pharmacy, Ormoz,
Slovenia, European Union
2University of Ljubljana, Faculty of Pharmacy, Slovenia, European Union
Corresponding Author:
Matej Stuhec, Department of Clinical Pharmacy, Ormoz Psychiatric
Hospital, Ptujska cesta 33, SI-2270 Ormoz, Slovenia, European Union.
Email: matejstuhec@gmail.com
Efficacy, Acceptability, and Tolerability of
Lisdexamfetamine, Mixed Amphetamine
Salts, Methylphenidate, and Modafinil
in the Treatment of Attention-Deficit
Hyperactivity Disorder in Adults: A
Systematic Review and Meta-analysis
Matej Stuhec, MPharm, PhD1,2, Petar Lukić, MPharm2,
and Igor Locatelli, MPharm, PhD2
Abstract
Objective: Psychostimulants are the first-line treatment in adults with attention-deficit hyperactivity disorder (ADHD).
This meta-analysis aimed to evaluate the efficacy, acceptability, and tolerability of lisdexamfetamine (LDX), mixed
amphetamine salts (MASs), modafinil (MDF), and methylphenidate (MPH) in comparison with placebo. Data Sources: We
systematically searched PubMed/MEDLINE and Clinicaltrials.gov in May 2016, along with CENTRAL and EU Clinical Trials
Register in February 2016, for the randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted
on adults diagnosed with ADHD. Study Selection and Data Extraction: Substantial comorbidity, substance abuse or
dependence, and nonpharmacological interventions represented grounds for exclusion. Published reports were the sole
source for data extraction. Improvement in ADHD symptoms was the primary outcome. Random-effects model meta-
analysis was applied to calculate the standardized mean difference (SMD) with 95% CIs. Data Synthesis: The search
retrieved 701 records, of which 20 studies were eligible for analysis. High effect size (expressed as SMD) in reducing
ADHD symptoms was observed for LDX (−0.89; 95% CI = −1.09, −0.70), whereas MASs (−0.64; 95% CI = −0.83, −0.45)
and MPH (−0.50; 95% CI = −0.58, −0.41) reduced symptoms moderately compared with placebo. No efficacy was shown
for MDF (0.08; 95% CI; −0.18, 0.34). Relevance to Patient Care and Clinical Practice: In this meta-analysis, the
efficacy, tolerability, and acceptability of psychostimulants were compared with that for placebo. Five of the included trials
have not been evaluated in any of the previously published meta-analyses. Conclusions: The results suggest that LDX has
the largest effect size and has a promising potential for treating adults with ADHD.
Keywords
ADHD, adults, psychostimulants, efficacy, tolerability, meta-analysis.
2 Annals of Pharmacotherapy 00(0)
options, including stimulants and nonstimulants. Although psy-
chotherapy (eg, cognitive behavioral therapy) is a first-line treat-
ment in children and adolescents with ADHD, pharmacotherapy
is the first-line treatment in adults with ADHD.6 According to
evidence-based pharmacotherapy, the effect sizes calculated
from meta-analyses are one of the most important outcomes,
which are clinically applicable to distinguish drug effective-
ness between 2 different medications. According to the guide-
lines and well-designed meta-analyses, stimulants are the
first-line treatment for ADHD in children, adolescents, and
adults, with their medium to high effect sizes, which have been
already calculated in many meta-analyses.1,6-9
Although large effect sizes of stimulants for ADHD
treatment were calculated in meta-analyses, most medica-
tions have not been studied in older adults (e.g., older than
50 years). Another significant limitation is a lack of meta-
analyses in adults with ADHD with the inclusion of the
newest trials.
According to the published meta-analyses in children
and adolescents, lisdexamfetamine (LDX) was the most
effective treatment strategy for ADHD with its large effect
size represented as standardized mean difference (SMD)
>1.0.1,6-9 However, there are no results on comparative effi-
cacy among different stimulants, including LDX, with the
latest randomized controlled trials (RCTs) until 2015 in
adults. In the literature, there are many different meta-anal-
yses available in adults,10-20 although many of them included
only methylphenidate (MPH) immediate release form and
similar forms of MPH excluding LDX and modafinil
(MDF).11,13,16,17,20 Also, there are only 4 meta-analyses
available that included LDX and compared it with other
stimulants or/and only placebo in adults.10,14,18,19 Meta-
analyses published by Mészáros et al19 and Faraone14
included only 1 RCT with LDX, which had a significant
impact on heterogeneity, and the results should be repli-
cated with the addition of the latest LDX RCTs. Meta-
analyses published by Castells et al10 included only
amphetamines with 7 RCTs, excluding MPH and MDF.
Meta-analyses published by Maneeton et al18 included only
LDX, with its 5 trials excluding MDF. Among these 4 meta-
analyses, the meta-analyses published by Mészáros et al,19
Faraone,14 and Castells et al10 were released in 2012 or
before and, therefore, with small numbers of LDX RCTs
available included in the meta-analysis.
The primary aim was to address efficacy (improvement
in ADHD symptoms, clinical global impression [CGI], and
executive function [EF] deficit), acceptability, and tolera-
bility of psychostimulants used in the treatment of ADHD
in adults using a meta-analysis. Additionally, we aimed to
upgrade previous meta-analyses with most recent RTCs
evaluating the efficacy and safety of LDX, mixed amphet-
amine salts (MASs), and MPH in different forms and to
include MDF in the comparison.
Methods
Eligibility Criteria
In the current systematic review with meta-analysis, we
applied a structured PICOS principle in defining the inclu-
sion/exclusion criteria as advised by the PRISMA guide-
lines.21 Only randomized, double-blind, placebo-controlled,
and parallel-group clinical trials that measured ADHD
symptoms were included in the systematic review. We set
the minimal duration of the studies at 2 weeks and a mini-
mum age of the included participants at 17 years. The diag-
nosis of ADHD had to be established in childhood or newly
discovered in adulthood and again confirmed with a vali-
dated diagnostic instrument before allocation to an inter-
vention group.
Interventions of interest were stimulants of the central
nervous system, MASs, LDX, MPH, and MDF, applied
orally irrespective of the release form, dosing regimen, or
dosing method (fixed or titration). Studies in which one of
the interventions did not include placebo, or a nonpharma-
cological intervention was applied and compared with a
drug, were excluded. Both treatment-naïve patients and
those previously treated for ADHD were included.
Search Strategy
We identified studies by using freely accessible databases:
Cochrane Central Register of Controlled Trials (last search:
May 6, 2016), PubMed/MEDLINE (last search: 1946 to
February 9, 2016), ClinicalTrials.gov (last search: February
9, 2016), and EU Clinical Trials Register (last search: May
6, 2016). We repeated searches several times between
December 17, 2014, and May 6, 2016. The search terms we
used in all our searches were as follows: (attention deficit
disorder with hyperactivity OR ADHD) AND adult AND
(methylphenidate OR dextroamphetamine OR amphet-
amine salts OR lisdexamfetamine OR atomoxetine OR
bupropion OR desipramine OR modafinil OR guanfacine
OR clonidine OR venlafaxine OR reboxetine OR dulox-
etine OR galanthamine) AND (double blind) AND
(Randomized Controlled Trial). Expansion of the search
terms to nonstimulants was aimed to identify any multiple
drug trials involving stimulants and nonstimulants that
may have not otherwise been detected. Moreover, the iden-
tified citations reflect the research activity within this field.
We did not apply restrictions regarding date, language, or
publishing status but excluded conference abstracts that
were not published as journal articles. We searched refer-
ence lists in relevant systematic reviews with meta-analy-
ses as well as those in hard copies of the studies assessed
for eligibility for any records not identified in the elec-
tronic databases. We did not contact study authors to iden-
tify any additional studies.
Stuhec et al 3
Data Extraction and Study Outcomes
Two reviewers (PL and IL) independently carried out data-
base search, reference list inspection, eligibility assessment,
and data collection according to predefined selection crite-
ria. Any disagreements were resolved by discussion or con-
sultation with the third reviewer (MS). Data extraction and
processing were performed in pen and stored electronically.
The data of interest were as follows: first author, publica-
tion year, drug(s) tested, study design, inclusion/exclusion
criteria, number of randomized participants, proportion of
previously treated participants, number of participants in
each study arm, mean age, mean age at initial diagnosis,
proportion of male participants, dosage regimen, mean
daily dose, dosing method (fixed, titration), study duration,
ADHD rating scale, primary outcomes, secondary out-
comes, and safety outcomes.
The outcomes of interest were decided on according to
their clinical relevance and applicability. The primary out-
come was the improvement in ADHD symptoms assessed
with a validated instrument for measuring current symp-
toms. Investigator rating scales were the preferred method
of symptoms assessment. We used self-reported scales
where the clinical scales were not applied or data unavail-
able. Secondary efficacy outcomes were CGI improvement
(CGI-I) and EF deficit improvement assessed with a vali-
dated instrument. The outcome retention in treatment
reflected the acceptability of the intervention and was
defined as a proportion of patients who completed the trial.
The outcome discontinuation as a result of adverse events
was a safety outcome reflecting tolerability of the interven-
tion and was defined as a proportion of the patients who
reported the adverse event as a cause of their dropping out
before the end point.
We collected mean changes (mean difference) from
baseline to end point with their SDs for continuous out-
comes (improvements in ADHD symptoms and EF deficit)
and the number of participants with events against the num-
ber of participants in each study arm for binary outcomes
(CGI, retention in treatment, discontinuation as a result of
an adverse event).
Assessment of the Risk of Bias
Two reviewers (PL and IL) independently assessed the risk
of bias utilizing the Cochrane Collaboration’s tool criteria.22
Differences were resolved through consensus. The tool
addresses 7 specific domains of bias—namely, sequence
generation, allocation concealment, blinding of participants
and personnel, blinding of outcome assessment, incomplete
outcome data, selective outcome reporting, and other
sources of bias. Descriptions of the methods and procedures
reported by the study authors provided support in assigning
the judgment relating to the risk of bias as “low risk,” “high
risk,” or “unclear risk.” The risk of bias was assessed at the
study level, except for the domains incomplete outcome
data and selective outcome reporting where only the pri-
mary outcome (improvement in ADHD symptoms) was
evaluated.
Data Synthesis
Statistical package Review Manager (RevMan) version
5.3 was used to calculate effect measures and data synthe-
sis.22 The treatment effect measure for continuous out-
comes is expressed as the SMD and presented as a point
estimate with 95% CI. Quantitative synthesis was con-
ducted by applying DerSimonian and Laird’s model of
random effects, as suggested by marked heterogeneity
observed in earlier reviews. The inverse variance method
was used for continuous variables (SMD), whereas the
Mantel-Haenszel method was used for binary outcomes
for which the treatment effect measure was expressed as
risk ratio (RR).22
Sensitivity and Subgroup Analysis
The 2 sensitivity analyses replicated the meta-analysis by
exclusion of studies assigned with 1 or more high risk of
bias judgements, and by expression of the treatment effect
in terms of the mean difference where symptom improve-
ment was assessed by an identical instrument. An attempt
was made at finding possible sources of heterogeneity by
performing the following subgroup analyses for primary
efficacy outcome only. The first juxtaposed the effect sizes
of 2 dosing methods—titration and fixed—and the second
compared 3 different release forms of MPH.
Results
The search returned a total of 701 references of which 652
were excluded after study titles and abstracts were screened;
hence, 49 potentially relevant full-text articles were
acquired. Following an eligibility assessment, 20 studies
were included in the systematic review and 19 in the meta-
analysis. Figure 1 shows a detailed flowchart of the study
selection process.
Two studies investigated MASs,23,24 3 LDX,25-27 and
14 MPH,28-41 whereas 1 trial focused on MDF.42 Five of the
included studies have not been found in the preceding rele-
vant meta-analyses.32,33,40-42 Table 1 summarizes the main
characteristics of the studies eligible for the meta-analysis.
A comprehensive summary table of the study reports is
noted in online Appendix 1 (Table S1; available online at
http://journals.sagepub.com/home/aop/supplemental-data).
The primary efficacy outcome was an improvement in
ADHD symptoms. High effect size (expressed as SMD) in
reducing ADHD symptoms was observed for LDX (−0.89;
4 Annals of Pharmacotherapy 00(0)
95% CI = −1.09, −0.70; I2 = 0%), whereas MASs (−0.64;
95% CI = −0.83, −0.45; I2 = 0%) and MPH (−0.50; 95%
CI = −0.58, −0.4; I2 = 21%) reduced symptoms moder-
ately compared with placebo. No efficacy was shown for
MDF (0.08, 95% CI; −0.18, 0.34; 1 study). We excluded 1
study of MPH from the meta-analysis because summary
data could not be obtained.37 Figure 2 shows a forest plot of
study results related to improvement in ADHD symptoms.
An improvement in the CGI was a dichotomized vari-
able defined as grade 2 or lower on the CGI-I scale. In 5
studies, however, this criterion was coupled with a reduc-
tion in scale scores by 30%.25,27,29,30,38 Two studies of
Figure 1. Study selection flowchart.
Stuhec et al 5
MASs, 3 of LDX, and 12 of MPH were combined in this
meta-analysis, whereas 2 studies of MPH did not assess this
outcome.35,41 Compared with placebo, psychostimulants
appear more likely to improve global impression of ADHD
(expressed as RR)—MASs (2.27; 95% CI = 1.71, 3.00;
I2 = 0%), LDX (2.23; 95% CI = 1.76, 2.83; I2 = 0%), and
MPH (1.61; 95% CI = 1.41, 1.84; I2 = 54%)—whereas the
study of MDF did not demonstrate advantage over placebo
(0.93; 95% CI = 0.65, 1.32). Figure 3 shows a forest plot of
study results related to improvement in the CGI.
Only 1 trial per drug (altogether 4 studies) was observed
for evaluation of improvement in EF deficit; thus, the meta-
analysis was not applicable for this secondary outcome.
Stimulants demonstrated advantage over placebo (expressed
as SMD): MASs (−0.65; 95% CI = −0.90, −0.40),23 LDX
(−0.75; 95% CI = −1.08, −0.42),26 and MPH (−0.34; 95%
CI = −0.56, −0.13),32 except for MDF (−0.07; 95%
CI = −0.33, 0.19).42
The probability of retention in treatment (acceptability)
was statistically significantly higher with MASs (1.18; 95%
CI = 1.03, 1.35; I2 = 0%) than with placebo (expressed as
RR), whereas difference was insignificantly favourable for
LDX (1.04: 95% CI = 0.93, 1.15; I2 = 27%) and MPH
(0.97; 95% CI = 0.93, 1.01; I2 = 54%). The study of MDF
showed no advantage over placebo (0.78; 95% CI = 0.65,
0.94, 1 study). Figure 4 shows the corresponding forest plot.
Treatment tolerability was assessed in all eligible studies
(Figure 5). Statistically significantly higher probability
(expressed as RR) of discontinuation caused by treatment-
emergent adverse events compared with placebo was
Table 1. Summary of Study Characteristics.
Author, Year
Study Size (n)
/Nonnaïve
Patients (%)
Mean Age/
Mean initial
Diagnosis
Age (years)
Gender
(Percentage
Male) Rating Scale Used
Dosing
Method Dose Range (mg)
Duration
(weeks)
MAS
Spencer et al, 200823 274/24.1 36.5/31 50.0 ADHD DSM-IV-TR Titration 12.5-75 1×/d 7
Weisler et al, 200624 255/22.0 39.2/33.8 60.1 ADHD DSM-IV-TR Fixed 20-60 1×/d 4
LDX
Adler et al, 200825 420/9.8 or 17.9 35.1/NDA 54.3 ADHD DSM-IV-TR Fixed 30-70 1×/d 4
Adler et al, 201326 161/NDA 34.6/5.4 52.2 ADHD DSM-IV-TR Titration 30-70 1×/d 10
Biederman et al, 201227 69/43.5 22.2/NDA 56.5 ADHD DSM-IV-TR Titration 30-70 1×/d 6
MPH
Adler et al, 200928 229/34.9 39.0/NDA 56.2 AISRS Titration 36-108 1×/d 7
Biederman et al, 200629 149/NDA 35.2/4.8 51.8 AISRS Titration 36-108 1×/d 6
Biederman et al, 201030 227/NDA 35.6/NDA 45.7 AISRS Titration 36-144 1×/d 6
Casas et al, 201331 279/NDA 35.7/31.7 52.3 CAARS-O: SV Fixed 54-72 1×/d 13
Goodman et al, 201732 357/NDA 35.7/NDA 53.8 AISRS Titration 18-72 1×/d 6
Huss et al, 201433 725/13.2 35.4/NDA 54.5 ADHD DSM-IV Fixed 40-80 1×/d 9
Kuperman et al, 200134 37/NDA 32.3/NDA 70.0 UPD ADHD DSM-III Titration Up to 0.9 mg/kg/d
divided into 3×/d
8
Medori et al, 200835 402/NDA 34.0/29.9 54.4 CAARS-O: SV Fixed 18, 36, 72 1×/d 5
Retz et al, 201236 162/33.3 37.4/NDA 46.9 WRAADDS Titration 10-120 divided into
2×/d
6
Rösler et al, 200937 363/37.7 34.5/5.8 49.6 WRAADDS Titration 10-60 divided into
2×/d
24
Spencer et al, 200538 146/8.9 38.0/NDA 58.2 AISRS Titration Up to 1.3 mg/kg/d
divided into 3×/d
6
Spencer et al, 200739 221/36.2 38.7/6.5 57.5 ADHD DSM-IV Fixed 20-40 1×/d 5
Takahashi et al, 201440 284/13.4 33.8/31.9 48.9 CAARS-O: SV Titration 18-72 1×/d 8
Weisler et al, 201241 430/NDA 33.9/21.3 57.1 ADHD DSM-IV Fixed 54 1×/d 6
MDF
Arnold et al, 201442 338/37.0 39.3/NDA 60.0 AISRS Fixed 255-510 1×/d 9
Abbreviations: ADHD, attention-deficit hyperactivity disorder; ADHD DSM-IV, ADHD rating scale based on DSM-IV; ADHD DSM-IV-TR, ADHD
rating scale based on DSM-IV-TR; AISRS, ADHD Adult Investigator Symptom Rating Scale; CAARS-O: SV, Conners’ Adult ADHD Rating Scale,
observer (clinician) report, screening form; DSM-III, Diagnostic and Statistical Manual of Mental Disorders, Third Edition; DSM-IV, Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; LDX,
lisdexamfetamine; MASs, mixed amphetamine salts; MDF, modafinil; MPH, methylphenidate; NDA, no data available; UPD ADHD DSM-III, ADHD
rating scale based on DSM-III Rating Scale updated to DSM-IV; WRAADDS, Wender-Reimherr Adult-Attention-Deficit-Disorder Scale.
6 Annals of Pharmacotherapy 00(0)
observed for MASs (3.36; 95% CI = 1.48, 7.63; I2 = 0%),
MPH (2.63; 95% CI = 1.90, 3.64; I2 = 0%), and MDF
(3.21; 95% CI = 1.45, 7.09, 1 study); however, for LDX, a
borderline significance was observed (2.91; 95% CI =
0.98, 8.68; I2 = 0%, P = 0.055).
Significant heterogeneity was observed among the stud-
ies of MPH in the assessment of CGI and the retention in
treatment (acceptability). An I2 statistic of 54% was esti-
mated in both outcomes (Figures 3 and 4). Additionally, an
apparent weak overlapping was found in 2 studies,31,38
Figure 2. Mixed amphetamine salts, lisdexamfetamine, methylphenidate, and modafinil compared with placebo in attention-deficit
hyperactivity disorder symptom scale score reduction. Cochrane’s Risk of bias summary shows judgments for each study in each
domain of bias. For studies Biederman et al,29 2006, Biederman et al,30 2010, and Retz et al,36 2012, the end point scores were used
because mean changes from the baseline could not be obtained. (A) Random sequence generation (selection bias); (B) allocation
concealment (selection bias); (C) blinding of participants and personnel (performance bias); (D) blinding of outcome assessment
(detection bias); (E) incomplete outcome data (attrition bias); (F) selective reporting (reporting bias); (G) other bias. Low risk of bias
(plus), high risk of bias (minus), unclear risk of bias (question mark).
Stuhec et al 7
Figure 3. Mixed amphetamine salts, lisdexamfetamine, methylphenidate, and modafinil compared with placebo in illness improvement
on the clinical global impression scale.
8 Annals of Pharmacotherapy 00(0)
Figure 4. Mixed amphetamine salts, lisdexamfetamine, methylphenidate, and modafinil compared with placebo in overall retention in
treatment (acceptability).
Stuhec et al 9
Figure 5. Mixed amphetamine salts, lisdexamfetamine, methylphenidate, and modafinil compared with placebo in discontinuation
caused by treatment-emergent adverse events (tolerability).
10 Annals of Pharmacotherapy 00(0)
which also fell outside the 95% triangular confidence area
in the funnel plot. Although no heterogeneity was observed
for ADHD symptom improvement among the studies of
MPH (Figure 2; I2 = 21%), apparent poor overlapping
occurred in 2 studies and one of them was also an outlier in
the funnel plot.34,38 All funnel plots are presented in online
Appendix 2 (Figures S1 to S4).
A judgment of low risk of bias was assigned to 11 studies,
where a random component was described in the sequence
generation, and an adequate method was used to conceal
allocation. An unclear risk of bias judgment was assigned to
9 studies; 1 report provided insufficient information to per-
mit judgment of low risk or high risk, whereas 8 reports did
not describe or mention the randomization method used.
Blinding was intended in all included studies. However,
high risk of bias was assigned to a study with nonidentical
dosing regimens across the intervention groups together
with a single-blind lead-in phase.34 Low risk of attrition bias
was assigned to 9 studies with the drop-out rate <20% or
between 20% and 30%, provided the mixed-effect model for
repeated measures approach was applied. The discontinua-
tion rate above 30% or per-protocol efficacy analysis sup-
ported the judgment of high risk resulting from incomplete
outcome data in 7 studies.* Unclear risk resulting from the
disparity in data between 2 reports was found in 1 study,
whereas incompletely reported clinical scores were replaced
with self-report scale scores in the other. High risk of bias
was assigned to 4 studies that presented results only graphi-
cally. Because the mean changes were unavailable, we used
end point values where feasible.29,30,36,37 The pharmaceutical
industry funded all eligible studies. The risk of bias assess-
ment across studies is added to the forest plot presented in
Figure 2.
A sensitivity analysis of the primary efficacy outcome
found that exclusion of the studies with the judgment of
high risk of bias did not result, in numerical terms at least,
in marked changes (data not shown). All studies of MASs
and LDX used the same symptom rating scale (ADHD
DSM-IV-TR, Table 1), and therefore, the mean difference
rating score was calculated on the same number of studies
as in the forest plot in Figure 2. Compared with placebo,
significant reduction of ADHD symptom scores was
observed for MASs (−7.69; 95% CI = −9.89, −5.49) and
LDX (−10.4; 95% CI = −12.6, −8.22).
The subgroup analysis was only applicable for studies
of MPH. The studies were split into 3 subgroups according
to the release form—namely, immediate release,34,38
extended release,33,36,37,39 and osmotic controlled oral
delivery system.28-32,35,40,41 No dissimilarity in efficacy
was observed between different release forms of MPH.
However, substantial heterogeneity in effect size within
the subgroups was found. Another analysis split the stud-
ies into 2 subgroups according to the dosing method used.
The 2 dosing methods did not show any advantage of one
over the other.
Discussion
This article included RCTs of the available stimulants
(MPH, MASs, LDX, and MDF). A primary focus was on
how the treatment of interest compares with placebo,
regarding both efficacy and safety. This meta-analysis is the
first where MPH, MASs, LDX, and MDF were examined in
1 study. In addition to previous meta-analyses, our results
bring new data on comparative efficacy, acceptability, and
tolerability.10,11,13-20
Results from our meta-analysis show that LDX is the
most effective treatment strategy, which is in line with pre-
viously published meta-analyses. In the meta-analysis pub-
lished by Castells et al,10 SMD for amphetamines was −0.72
(95% CI = −0.87, −0.57), but all the amphetamines were
combined in 1 group, including LDX and MASs.10 The sec-
ond meta-analysis published by Maneeton et al18 showed a
large effect size for LDX (−0.97; 95% CI = −1.15, −0.78).18
This meta-analysis includes new studies with LDX for
treatment of ADHD in adults. A prodrug form of LDX may
as well influence the monoamine release. However, a direct
comparison with other drugs has to be confirmed in head-
to-head RCTs in the adult population.15 Despite these limi-
tations and a lack of comparative RCTs, these results
demonstrate that LDX is a very effective medication in
ADHD treatment. Interestingly, the effect size for MASs
was much smaller than that for LDX. The effect size for
MPH compared with placebo was also lower than for LDX,
which has been shown in multiple previous meta-analyses
in adults, children, and adolescents. One of the main rea-
sons could be pooling all MPH RCTs into a heterogeneous
group regardless of their release form. This approach has
been seen in previous meta-analyses.1,6 However, more
RCTs, especially of amphetamines and MDF, are necessary
to corroborate these promising findings and arrive at defi-
nite conclusions. Heterogeneity in outcomes among MPH
studies was the highest among all the stimulants (I2 = 21%).
Larger heterogeneity in the MPH group could be related to
different MPH release forms.
In the meta-analysis of CGI-I score, all medications,
except MDF (1 trial), showed a higher probability of global
improvement compared with placebo. The RR values indi-
cate an apparent advantage of LDX and MASs over MPH.
The heterogeneity in all groups might not be relevant (under
30%), except for MPH (I2 = 54%). It could be in part
explained by a different definition of treatment improve-
ment among the MPH studies (CGI-I 2 alone or coupled
with various cut-off scores). Another possible cause is that
*References 23, 27, 28, 31, 37, 38, 42
Stuhec et al 11
the improvement may not have been observed because of
the short duration of some RCTs. In 2 larger studies, a sub-
stantial discontinuation could be a likely contributor to a
marked heterogeneity. Therefore, interpretation of these
results requires extra caution.
Only 1 trial of each drug evaluated improvement in EF
deficit. EF plays an essential role in an adult’s life, and its
deficit is believed to be closely related to attention deficit
and ADHD-related quality of life.43 The largest effect size
in EF improvement was produced by LDX followed by
MASs, MPH, and MDF. Given the importance of EF in
adult life, further trials are essential to determine the effi-
cacy of stimulant use in adult ADHD.
In addtion to drug efficacy assessment, acceptability and
tolerability are also critical to successful treatment. Except
for MASs, amphetamines did not demonstrate a signifi-
cantly higher acceptability (retention in treatment) than pla-
cebo and was significantly lower for MDF. Insignificant
results along with marked heterogeneity may lead to flawed
interpretation of acceptability. The total RR in the meta-
analysis of discontinuation caused by adverse events was
higher than placebo for all stimulants; however, it was bor-
deline statistically significant for LDX. Incidence among
the studies, however, did not exceed 20%. There were some
differences in RRs between different dosing methods (fixed
vs titration); nevertheless, it is not essential for clinical
practice because titration to the optimal dose is advised
according to ADHD treatment guidelines.38 It should also
be noted that some of the adverse effects occur over a lon-
ger period, meaning that positive results need to be treated
with extra caution because the trials were of short
duration.44
The quality and risk of bias assessment were an impor-
tant part of this meta-analysis. The majority of trials were
attributed at least 1 high risk of bias judgment (11/20).
Although the risk of bias was significant in many RCTs, a
sensitivity analysis did not find changes in the outcomes.
The findings should be observed together with the limita-
tions of this meta-analysis. Only stimulants were included,
and therefore, comparison of the efficacy with nonstimu-
lants (e.g., atomoxetine) was not possible. For such a com-
parison, additional meta-analyses are needed. The second
relevant limitation was that treatment-naïve patients were
not exclusively eligible, which means that some patients had
already been treated with different medications. This
approach increased the number of eligible RCTs for the
meta-analysis and provided results that more closely reflect
real clinical practice. Another important limitation concerns
comorbidity. Comorbidity of ADHD with psychiatric disor-
ders is substantial.6 Many RCTs included some comorbidity,
which might have led to a higher heterogeneity of the results.
However, such results better simulate real clinical practice
because ADHD is often treated simultaneously with
other mental conditions (e.g., anxiety disorders, depressive
symptoms).6 Additional limitation could originate from
ADHD subtype of the included patients that was reported in
only 10 trial reports. Even fewer, 7 trial reports considered
ADHD subscale scores as secondary outcomes. However,
results were reported in a manner that did not allow data
extraction. We, therefore, decided to analyze the ADHD
total scores only. Study duration is a significant limitation as
well. In real clinical practice, ADHD is often treated at least
for 1 year, or often longer; hence, these results could not be
extrapolated to chronic treatment. Long-term effects are par-
ticularly problematic with LDX because the available data
on this are scarce. Another significant limitation is heteroge-
neity, which was high in MPH, possibly connected with a
different formulation of MPH (immediate vs modified
release). When analyzing withdrawal resulting from adverse
events and all-cause treatment discontinuation, it is impor-
tant to consider that heterogeneity may be inevitable because
of study design and protocol requirements. Some trials can
have an open-label follow-on phase allowing patients to
drop out later on in the study.9 We did not contact authors of
any of the included studies to seek original trial protocols or
unreported data, or to clarify ambiguities. Finally, the indi-
rect network meta-analysis allows multiple pairwise com-
parisons between the drugs, which can overcome the
principal limitation of the standard meta-analysis—that is,
comparison of single drug with placebo.
Despite significant limitations, our findings have several
clinical implications and represent a considerable update to
previous meta-analyses, particularly with most recent RCTs
that have not previously been included. With the most
recent RCTs included, the results lend themselves to broader
implication, including the updates to the ADHD treatment
guidelines. Despite the importance of this and other meta-
analyses, other factors also need to be taken into account
when planning treatment with drugs, such as well-designed
clinical trials, treatment guidelines, drug tolerability, drug-
drug interactions, and numerous others. Because only a
minority of adults with ADHD receive adequate pharmaco-
logical treatment,45,46 the results of this study could also
support evidence-based decision regarding the pharmaco-
logical treatment option for patients with ADHD.
Conclusions
These results suggest that LDX has the largest effect size
and has a promising potential for treating adults with
ADHD. MASs have a larger effect size on EF improvement
than MPH. Five of the included trials were not evaluated in
any of the published meta-analyses, and therefore, this
research is a necessary addition to the previous assessments
of stimulants in the treatment of ADHD. Given that the
results of this meta-analysis did not find any favorable
effect for MDF, several new RCTs of MDF are warranted to
examine its value in the treatment of ADHD.
12 Annals of Pharmacotherapy 00(0)
Authors’ Note
Some results of this article were also presented as a poster at the
European College of Neuropsychopharmacology (ECNP) Congress
in Vienna in September 2016.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
Supplemental Material
Supplemental material is available for this article online.
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... Attention-deficit/hyperactivity disorder is mitigated by pharmacological medications that increase concentrations or residence time of dopamine and norepinephrine in the synapse. According to evidence-based guidelines and meta-analyses of pharmacological management of ADHD, stimulants are considered the first-line treatment in both children (Faraone and Buitelaar, 2010;Chan et al., 2016;Catalá-López et al., 2017;Wolraich et al., 2019) and adults (Rostain, 2008;Cunill et al., 2016;De Crescenzo et al., 2017;Stuhec et al., 2019), while non-stimulants remain second-line option treatments (Bolea-Alamañac et al., 2014;Chan et al., 2016;Caye et al., 2019). ...
... In two meta-analyses, both AMPH and MPH showed comparable efficacy in adults (Faraone and Glatt, 2009) and children (Catalá-López et al., 2017) with ADHD. Other meta-analyses revealed amphetamine as having greater efficacy than methylphenidate and non-stimulants in children (Faraone and Buitelaar, 2010;Stuhec et al., 2015;Joseph et al., 2017) and adults (De Crescenzo et al., 2017;Stuhec et al., 2019) with ADHD. A reduction of adult ADHD symptoms was observed in lisdexamfetamine, whereas mixed amphetamine salts and methylphenidate reduced symptoms moderately compared to placebo (Stuhec et al., 2019). ...
... Other meta-analyses revealed amphetamine as having greater efficacy than methylphenidate and non-stimulants in children (Faraone and Buitelaar, 2010;Stuhec et al., 2015;Joseph et al., 2017) and adults (De Crescenzo et al., 2017;Stuhec et al., 2019) with ADHD. A reduction of adult ADHD symptoms was observed in lisdexamfetamine, whereas mixed amphetamine salts and methylphenidate reduced symptoms moderately compared to placebo (Stuhec et al., 2019). In children and adolescents with ADHD, efficacy in reduction of ADHD symptoms compared to placebo is small for bupropion, modest for atomoxetine and methylphenidate, and high efficacy for lisdexamfetamine (Stuhec et al., 2015). ...
Article
Full-text available
For decades, psychostimulants have been the gold standard pharmaceutical treatment for attention-deficit/hyperactivity disorder (ADHD). In the United States, an astounding 9% of all boys and 4% of girls will be prescribed stimulant drugs at some point during their childhood. Recent meta-analyses have revealed that individuals with ADHD have reduced brain volume loss later in life (>60 y.o.) compared to the normal aging brain, which suggests that either ADHD or its treatment may be neuroprotective. Crucially, these neuroprotective effects were significant in brain regions (e.g., hippocampus, amygdala) where severe volume loss is linked to cognitive impairment and Alzheimer’s disease. Historically, the ADHD diagnosis and its pharmacotherapy came about nearly simultaneously, making it difficult to evaluate their effects in isolation. Certain evidence suggests that psychostimulants may normalize structural brain changes typically observed in the ADHD brain. If ADHD itself is neuroprotective, perhaps exercising the brain, then psychostimulants may not be recommended across the lifespan. Alternatively, if stimulant drugs are neuroprotective, then this class of medications may warrant further investigation for their therapeutic effects. Here, we take a bottom-up holistic approach to review the psychopharmacology of ADHD in the context of recent models of attention. We suggest that future studies are greatly needed to better appreciate the interactions amongst an ADHD diagnosis, stimulant treatment across the lifespan, and structure-function alterations in the aging brain.
... Furthermore, MPH leads to monoamine oxidase activity inhibition, while MASs do not (Robinson 1985;Faraone 2018). Functionally, a recent metaanalysis suggested that with respect to ADHD symptoms, MPH and MASs have similar effect sizes (Stuhec et al. 2019). ...
... Given that our sample was heterogeneous with respect to ADHD symptoms, we expected MPH to have a more pronounced effect on CRT performance than MASs. Following Stuhec et al. (2019), we also tested whether this differential effect is moderated by the extent of ADHD symptoms. ...
Article
Full-text available
RationaleMethylphenidate (MPH) and mixed D,L-amphetamine salts (MASs; Adderall) were previously found to have unreliable effects on judgment and decision processes.Objective We predicted that MPH and MASs have a specific effect of reducing heuristic responses, which should lead to increased performance on the cognitive reflection test (CRT). The CRT is considered to be a testbed for heuristic versus deliberative response modes.Methods We recruited a sample of 15,361 individuals using the Prolific Academic crowdsourcing platform. From this initial pool, our final sample consisted of 294 participants (125 MPH users and 169 MASs users) who conformed to the study criteria and completed the experimental tasks. Tasks were performed on days where participants were either medicated or not, allowing to assess the effect of medication status.ResultsThere was a strong positive effect of taking MPH on CRT scores (Cohen’s d = 0.40) which was not qualified by frequency of MPH usage, ADHD symptoms, and demographic factors. There was also a somewhat weaker effect for MASs (Cohen’s d = 0.07). No effects of MPH and MASs were recorded for risk-taking and numeracy.Conclusions The results indicate that MPH enhances decision-making in tasks where heuristic responses typically bias it.
... Methylphenidate and atomoxetine are medications approved by the Food and Drug Administration and widely used in Taiwan (Gau et al. 2006(Gau et al. , 2007 and all over the world. The efficacy of these two medications on behavioral symptoms and social functions has been well-established in children and adults with ADHD in western countries (Spencer et al. 2000;Stuhec et al. 2019) and Taiwan (Gau et al. 2006(Gau et al. , 2007. However, their comparative effects on executive functions remain to be studied . ...
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Objectives: This study aimed to compare the efficacy of methylphenidate and atomoxetine on improving executive functions among children with attention-deficit/hyperactivity disorder (ADHD). Methods: This was an open-label, head-to-head, 3-month, randomized clinical trial with two-arm parallel-treatment groups: osmotic-release oral system methylphenidate (OROS-MPH; n = 79) and atomoxetine once daily (n = 78). Three major domains of executive functions were assessed, including response selection/inhibition, flexibility, and planning/working memory. The neuropsychological measures included the Conners' continuous performance test and the Cambridge Neuropsychological Test Automated Battery. Results: We found that both treatment groups showed improvement in executive functions (p-value <0.05 for the major indices of each domain). In addition, OROS-MPH was associated with a greater magnitude of improvement in the response selection/inhibition; the slope for detectability improvement in the Conners' continuous performance test was 0.06 for atomoxetine and 0.15 for OROS-MPH (p-value <0.01); the slope in rapid visual information processing was 2.22 for atomoxetine and 3.45 for OROS-MPH (p-value <0.05). Conclusion: Both OROS-MPH and atomoxetine improved various domains of executive functions in children with ADHD. There is greater improvement in response selection/inhibition among patients treated with OROS-MPH than those with atomoxetine. This trial was registered with ClinicalTrials.gov (no. NCT00916786).
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Objective Describe symptoms associated with ADHD/treatment-related adverse side effects among adults with ADHD in the US and assess their impact on quality of life (QoL) and work productivity. Methods An online survey among adults receiving ADHD medications in the US was conducted to collect information relating to symptoms associated with ADHD/treatment-related adverse side effects. Participants were recruited from the panel of a well-established market research firm, Dynata, from July 26 to July 30, 2021 and were included in the study if they met the eligibility criteria and were willing to participate in the survey. Correlations between symptoms and key outcomes (QoL/employment/work impairment) were estimated using linear regression analyses. Results Of 585 participants, 95.2% experienced ≥1 symptom associated with ADHD/treatment-related adverse side effects in the past month (average =5.8 symptoms). The number of symptoms was significantly correlated with reduced QoL, reduced probability of being employed, and increased work/activity impairment. Among subgroups with insomnia/other sleep disturbances and emotional impulsivity/mood lability, 50.4% and 44.7% reported their symptoms had ‘a lot’ or ‘extremely’ negative impact on their overall well-being, respectively. Conclusions Symptoms associated with ADHD/treatment-related adverse side effects are common and have substantial impact on QoL and work productivity of adults with ADHD. Although the survey focused on events experienced in the month preceding the survey date to alleviate potential recall bias, findings should be considered in light of this potential bias.
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Attention-deficit/hyperactivity disorder (ADHD) significantly worsens quality of life and long-term functional outcomes in adults. Individual impairments in adults with ADHD can be further contextualized within considerable costs to society at large. Food and Drug Administration (FDA) approved stimulants and nonstimulant medications can significantly improve ADHD symptoms in adults. In the past 2 decades, the United States FDA has expanded approval of pharmacotherapeutic options for adult ADHD. However, limitations still persist in available psychotropics for certain patient populations such as those with comorbid substance use or cardiovascular illness. Clinicians therefore must appreciate several ongoing investigations into medications with unique mechanisms of action. This article reviews the current FDA approved and emerging medication options while providing guidelines for pharmacologic management of adult ADHD.
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Since the landmark MTA (Multimodal Treatment of ADHD) trial unequivocally demonstrated the efficacy of methylphenidate, catecholaminergic drugs, especially stimulants, have been the therapeutic mainstay in treatment of Attention-Deficit Hyperactivity Disorder (ADHD). We review the new drugs which have entered the ADHD formulary. The lessons learned from drug-candidates that have succeeded in clinical trials together with those that have not have also been considered. What emerges confirms and consolidates the hypothesis that clinically effective ADHD drugs indirectly or directly increase catecholaminergic neurotransmission in the prefrontal cortex (PFC). Attempts to enhance catecholaminergic signalling through modulatory neurotransmitter systems or cognitive-enhancing drugs have all failed. New drugs approved for ADHD are catecholaminergic reuptake inhibitors and releasing agents, or selective noradrenaline reuptake inhibitors. Triple reuptake inhibitors with preferential effects on dopamine have not been successful. The substantial number of failures probably accounts for a continued focus on developing novel catecholaminergic and noradrenergic drugs, and a dearth of drug-candidates with novel mechanisms entering clinical development. However, substantial improvements in ADHD pharmacotherapy have been achieved by the almost exclusive use of once-daily medications and prodrugs, e.g. lisdexamfetamine and Azstarys®, which improve compliance, deliver greater efficacy and reduce risks for diversion and abuse.
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Attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a higher prevalence rate in people with intellectual disability compared with their peers without such disability. The classic presentation is that of inattention and/or hyperactivity and impulsivity, but these symptoms can manifest differently in people with intellectual disability. Despite a higher prevalence, the rate of diagnosis and treatment of ADHD in intellectual disability remains low. This article discusses the clinical presentation of ADHD in people with intellectual disability and the relationship between ADHD and other comorbid conditions, such as autism and bipolar disorder. Pharmacological and non-pharmacological interventions are discussed from a practical and a clinical point of view.
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Since the 1950s the psychopharmacotherapy has become an essential factor in the treatment of mental diseases. This article describes the development since the turn of the century with three focal points: 1) newly available substances in Germany are presented and classified, 2) developments and discussions over the years are presented including changes in everyday clinical practice and 3) a perspective on currently emerging developments is given. Even though no real innovations occurred, the tolerability of psychopharmacotherapy has clearly increased. Many aspects of psychopharmacotherapy are now critically discussed; however, due to the lack of alternatives the currently available substances are still the treatment of first choice in many situations. Some strategies that currently appear to be promising still need to be investigated in methodically sophisticated randomized controlled clinical trials and prove their applicability in routine clinical practice.
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Objective To assess treatment patterns in adults with attention-deficit/hyperactivity disorder (ADHD) and associated healthcare costs in a real-world US setting. Methods Claims data from the IBM® MarketScan® Commercial Subset (Q1/2014-Q4/2018) was used to identify adults diagnosed with ADHD who newly initiated on ADHD treatment (index date). Treatment sequences were defined using an algorithm; for each sequence, the regimen comprised all ADHD-related agents observed within 30 days of the first agent during the 12-month study period. Treatment changes included discontinuation, switch, add-on, and drop. Treatment characteristics were described for the first treatment regimen observed. Total adjusted annual healthcare costs were compared between patients with no treatment change and patients with 1, 2, and ≥3 treatment changes. Results Among 122,881 adults with ADHD, the majority initiated a stimulant (95.1%) as their first treatment regimen observed; 9.3% of patients initiated combination therapy of ≥2 ADHD-related agents, and 34.9% of patients had psychotherapy. After an average first treatment regimen duration of 7.1 months, 50.2% of patients experienced a treatment change (22.5% discontinued, 17.5% switched, 5.3% had an add-on, and 4.6% had a treatment drop). Among those who discontinued, 44.8% did so within the first month of initiation. Mean annual healthcare costs were higher among patients with at least 1 treatment change compared to those with no treatment changes; excess costs increased with each additional treatment change. Conclusions Treatment changes were commonly observed and were associated with excess healthcare cost, emphasizing the unmet treatment needs of adults with ADHD in the US.
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Rationale: The factors underlying the variability in the results of randomized, placebo-controlled clinical trials (RPCCT) assessing pharmacological interventions for adults with attention deficit hyperactivity disorder (ADHD) are not fully understood. Methods: A systematic review and meta-analysis of RPCCT comparing pharmacological treatment and placebo in adults with ADHD was carried out. The study outcomes were all-cause treatment discontinuation, efficacy on ADHD symptoms, and safety. Patient-, intervention-, and study design-related covariates were collected. Meta-regression methods were applied. Results: Forty-four studies involving 9952 patients were included. All-cause treatment discontinuation was slightly higher with pharmacological treatment than with placebo (odds ratio (OR) = 1.18; 95 % confidence interval (CI) 1.02, 1.36; p = 0.003). A better outcome on all-cause treatment discontinuation was observed in studies that provided concomitant psychotherapy when compared to those that did not (rate of OR (ROR) = 0.68, p = 0.048). Pharmacological treatment was efficacious for reducing ADHD symptoms (standardized mean difference (SMD) = 0.45; 95 % CI 0.37, 0.52; p < 0.00001), with stronger intervention effects found in studies investigating stimulant drugs (difference of SMD (Diff SMD) = 0.18, p = 0.017), in shorter studies (Diff SMD = -0.01, p = 0.044), and when clinician-rated scales were used (Diff SMD = 0.44, p < 0.0001). Pharmacological treatment was associated with more frequent adverse events (AEs) (OR = 2.29; 95 % CI 1.97, 2.66; p = 0.006). Studies with a lead-in phase and with a higher proportion of patients previously treated with stimulants were associated with a better safety outcome (ROR = 0.59, p = 0.017; ROR = 0.98, p = 0.036, respectively). Conclusion: Pharmacological treatment provides mild symptom improvement but is associated with frequent AEs and higher treatment discontinuation than placebo, particularly when no concomitant psychotherapy is administered. Stimulants appear more efficacious than non-stimulant drugs and the former should be preferred over the latter. The efficacy of pharmacological treatment should be monitored over time because it may decrease progressively.
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To estimate prevalence and incidence of attention deficit hyperactivity disorder (ADHD) in children and adolescents in Slovenia using different epidemiological models. Data from the National Institute of Public Health of the Republic of Slovenia for the period 1997-2012 were analyzed. The database includes the annual number of newly diagnosed outpatients with ADHD in Slovenia. The evaluation for ADHD diagnoses was done in accordance with the Tenth Revision of the International Classification of Diseases (ICD-10) outpatient data codes. In model 1, a linear increase was proposed to fit the data in the period from 1997 to 2003 in order to extrapolate the data before 1997. In model 2 and 3, an exponential increase in the annual incidence rate was proposed. The incidence rate of ADHD diagnosis in 1997 was 0.032% and in 2012 it increased to 0.082%. Mean prevalence rate was 750 (95% confidence interval: 660-840) per 100 000 children and adolescents. It was estimated that the prevalence rate in 2020 would be 1% (95% confidence interval: 0.875-1.125), which is 6.3-fold higher than in 1997. ADHD is a common mental health disorder among Slovenian children and adolescents, but it remained underdiagnosed compared with Western countries. Our results indicated a need for improved timely interventions in Slovenia, not only in child and adolescent psychiatry but also in primary settings and adult psychiatry, where ADHD should be more efficiently recognized.
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Background The literature on the prevalence of mental disorders affecting children and adolescents has expanded significantly over the last three decades around the world. Despite the field having matured significantly, there has been no meta-analysis to calculate a worldwide-pooled prevalence and to empirically assess the sources of heterogeneity of estimates.Methods We conducted a systematic review of the literature searching in PubMed, PsycINFO, and EMBASE for prevalence studies of mental disorders investigating probabilistic community samples of children and adolescents with standardized assessments methods that derive diagnoses according to the DSM or ICD. Meta-analytical techniques were used to estimate the prevalence rates of any mental disorder and individual diagnostic groups. A meta-regression analysis was performed to estimate the effect of population and sample characteristics, study methods, assessment procedures, and case definition in determining the heterogeneity of estimates.ResultsWe included 41 studies conducted in 27 countries from every world region. The worldwide-pooled prevalence of mental disorders was 13.4% (CI 95% 11.3–15.9). The worldwide prevalence of any anxiety disorder was 6.5% (CI 95% 4.7–9.1), any depressive disorder was 2.6% (CI 95% 1.7–3.9), attention-deficit hyperactivity disorder was 3.4% (CI 95% 2.6–4.5), and any disruptive disorder was 5.7% (CI 95% 4.0–8.1). Significant heterogeneity was detected for all pooled estimates. The multivariate metaregression analyses indicated that sample representativeness, sample frame, and diagnostic interview were significant moderators of prevalence estimates. Estimates did not vary as a function of geographic location of studies and year of data collection. The multivariate model explained 88.89% of prevalence heterogeneity, but residual heterogeneity was still significant. Additional meta-analysis detected significant pooled difference in prevalence rates according to requirement of funcional impairment for the diagnosis of mental disorders.Conclusions Our findings suggest that mental disorders affect a significant number of children and adolescents worldwide. The pooled prevalence estimates and the identification of sources of heterogeneity have important implications to service, training, and research planning around the world.
Article
Background: There are no data on age-related pharmacotherapy for Attention Deficit Hyperactivity Disorder (ADHD) medication in children and adolescents in the most European countries. The main aim of this paper was to obtain that data for children and adolescents in Slovenia. Method: The number of ADHD drug prescriptions per patient was obtained from the health claims data on prescription drugs of the Health Insurance Institute of Slovenia for the study period (2003-2015). Three age groups were analyzed: 2-5?years, 6-12?years, and 13-17?years. Only immediate-release methylphenidate (IR-MPH), methylphenidate-osmotic release oral delivery system (OROS-MPH), and atomoxetine (ATX) were available and included in this study. Results: Less than 50% of patients in Slovenia were treated with medication. The number of patients treated with MPH in the 6-12 age group remained approximately the same between 2007 and 2015 (604-729 patients). In the 13-17 age group, however that number increased 2-fold between 2003 and 2015, from 288 to 555. The number of patients treated with ATX in the 6-12 age group age group increased from 20 to 163 between 2007 and 2015. The number was similar in the 13-17 age group, increasing from 10 to 165 in the same period. In 2015, 21% of the patients from all age groups in this study were treated with ATX. Conclusions: The number of patients treated for ADHD increased rapidly in all age groups. Patients under the age of six are prescribed medication in Slovenia, which should be avoided.
Article
Objective: To evaluate the efficacy and safety of individualized dosing within the approved dose range for osmotic-release oral system (OROS) methylphenidate hydrochloride in adults with attention-deficit/hyperactivity disorder (ADHD). Methods: A double-blind, 6-week trial was conducted between July 2009 and February 2010 at 35 US sites. Adults with ADHD (DSM-IV diagnostic criteria) and a screening ADHD Investigator Symptom Rating Scale (AISRS) score > 24 were randomly assigned to OROS methylphenidate 18 mg or matching placebo. Treatment dose could be increased at 18 mg increments, up to 72 mg/d, until an optimal dose was achieved. AISRS score changes from baseline to end point (primary outcome) were analyzed using analysis of covariance. Results: At baseline, the intent-to-treat population of 169 OROS methylphenidate and 172 placebo subjects (mean age = 35.8 years) had mean (standard deviation [SD]) AISRS scores of 37.8 (6.94) and 37.0 (7.51), respectively. OROS methylphenidate-treated subjects exhibited a significantly greater mean (SD) AISRS score improvement than placebo subjects (-17.1 [12.44] vs -11.7 [13.30]; P < .001). In general, OROS methylphenidate-treated subjects experienced greater improvements than placebo subjects in secondary measures of symptom frequency, cognitive function, work productivity, and quality-of-life. Little effect of OROS methylphenidate was observed in exploratory sleep assessments. The adverse event pattern was similar to previous reports of stimulants in adults with ADHD. Conclusions: OROS methylphenidate treatment with individualized doses titrated to achieve symptom remission demonstrated greater ADHD symptom reduction than placebo treatment. These data support the overall efficacy of OROS methylphenidate treatment in the management of adults with ADHD and provide new possibilities for additional intervention. Trial registration: ClinicalTrials.gov identifier: NCT00937040.
Article
Introduction: The efficacy and safety of triple-bead mixed amphetamine salts (MAS), an oral, once-daily, enhanced extended-re lease amphetamine formulation designed for a duration of action up to 16 hours, were evaluated in adults with attention-deficit/hyperactivity disorder (ADHD). Method: In this phase 3, 7-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, dose-optimization study of 272 adults with ADHD (DSM-IV-TR criteria), subjects (aged 18 to 55 years) were randomly assigned to triple-bead MAS (starting dose 12.5 mg) or placebo. The primary outcome measure was change in ADHD Rating Scale-IV (ADHD-RS-IV). Secondary outcome measures included Clinical Global Impressions (CGI) scale, Time-Sensitive ADHD Symptom Scale (TASS) (measuring extended duration), Brown Attention-Deficit Disorder Scale (BADDS) (measuring executive function), Adult ADHD Impact Module (AIM-A) (measuring quality of life [QOL]), and ADHD-RS-IV hyperactivity-impulsivity and inattentiveness subscales. Adverse events (AEs), vital signs, electrocardiograms (ECGs), and laboratory data were collected. The trial was conducted from January 2005 to June 2005. Results: Triple-bead MAS resulted in significantly greater improvement versus placebo in mean ADHD-RS-IV total score change (p < .0001), CGI-Improvement (p < .0001), TASS total score at 13-16 hours postdose (p = .002), BADDS total score (p < .0001), all AIM-A domains (p <= .01), and ADHD-RS-IV subscales (p <= .01), demonstrating extended duration of efficacy and improvements in executive function and QOL. The most common treatment-emergent AEs included insomnia, dry mouth, decreased appetite and weight, and headache. Most treatment-emergent AEs were mild or moderate in severity. Conclusions: Triple-bead MAS was significantly more effective than placebo in treating adult ADHD. The extended duration of action up to 16 hours and significant improvements in executive function and QOL address unique treatment needs of adults with ADHD. Treatment-emergent AEs with triple-bead MAS were consistent with amphetamine treatment.
Article
Attention-Deficit/Hyperactivity Disorder (ADHD) can persist into adulthood with a continuation of the pattern of childhood psychopathology, cognition and functioning. Adult comorbidities include substance use disorders, antisocial personality disorder, anxiety, and depression. Studies have shown that as in children, methylphenidate treatment for adults can lead to a robust, dose-dependent improvement in ADHD symptoms. Future research is needed to evaluate the safety and efficacy of long-term treatment with methylphenidate (MPH).
Article
Introduction Pharmacotherapy is essential for the treatment of children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD). There are only two metaanalyzes available in the literature where bupropion (BUP) was also included and compared to atomoxetine (ATX) and methylphenidate (MPH) in the treatment of ADHD in youths. Objectives There is a lack of comparative effectiveness research among ADHD medications in terms of efficacy, where BUP is compared with ATX, lisdexamfetamine (LDX) and MPH. Aim The main aim of this work was to compare the efficacy of these drugs in children and adolescents using a metaanalysis. Methods A literature search was conducted to identify double-blind, placebo-controlled, noncrossover studies of ADHD. A systematic electronic literature search of PubMed (1975–April 2014) and clinicaltrials.gov with full text (1981–April 2014) was conducted. Drug efficacy was calculated based on the standardized mean difference (SMD). Treatment score was the primary endpoint. Results 28 articles and 27 trials met inclusion criteria and were sufficient for inclusion in the metaanalysis. BUP 0.32 (95% CI, -0.05, 0.69) showed small efficacy, ATX 0.68 (95% CI, 0.59, 0.76), and MPH 0.75 (95% CI, 0.52, 0.98) showed modest efficacy in reducing ADHD symptoms and LDX showed high efficacy 1.28 (95% CL, 0.71, 1.84). Conclusions The results suggest that LDX has the best efficacy and has promising potential for treating children and adolescents with ADHD. Effect sizes should not be the only evidence for clinicians when choosing ADHD medication. More research is needed for a better clinical evaluation of BUP.
Article
Attention deficit hyperactivity disorder (ADHD) is a common mental disorder associated with factors that are likely to increase mortality, such as oppositional defiant disorder or conduct disorder, criminality, accidents, and substance misuse. However, whether ADHD itself is associated with increased mortality remains unknown. We aimed to assess ADHD-related mortality in a large cohort of Danish individuals. By use of the Danish national registers, we followed up 1·92 million individuals, including 32 061 with ADHD, from their first birthday through to 2013. We estimated mortality rate ratios (MRRs), adjusted for calendar year, age, sex, family history of psychiatric disorders, maternal and paternal age, and parental educational and employment status, by Poisson regression, to compare individuals with and without ADHD. During follow-up (24·9 million person-years), 5580 cohort members died. The mortality rate per 10 000 person-years was 5·85 among individuals with ADHD compared with 2·21 in those without (corresponding to a fully adjusted MRR of 2·07, 95% CI 1·70-2·50; p<0·0001). Accidents were the most common cause of death. Compared with individuals without ADHD, the fully adjusted MRR for individuals diagnosed with ADHD at ages younger than 6 years was 1·86 (95% CI 0·93-3·27), and it was 1·58 (1·21-2·03) for those aged 6-17 years, and 4·25 (3·05-5·78) for those aged 18 years or older. After exclusion of individuals with oppositional defiant disorder, conduct disorder, and substance use disorder, ADHD remained associated with increased mortality (fully adjusted MRR 1·50, 1·11-1·98), and was higher in girls and women (2·85, 1·56-4·71) than in boys and men (1·27, 0·89-1·76). ADHD was associated with significantly increased mortality rates. People diagnosed with ADHD in adulthood had a higher MRR than did those diagnosed in childhood and adolescence. Comorbid oppositional defiant disorder, conduct disorder, and substance use disorder increased the MRR even further. However, when adjusted for these comorbidities, ADHD remained associated with excess mortality, with higher MRRs in girls and women with ADHD than in boys and men with ADHD. The excess mortality in ADHD was mainly driven by deaths from unnatural causes, especially accidents. This study was supported by a grant from the Lundbeck Foundation. Copyright © 2015 Elsevier Ltd. All rights reserved.