1. http://www.cesar.umd.edu/cesar/drugs/ritalin.pdf >> pdf
Ritalin2. http://www.ncbi.nlm.nih.gov/pubmed/19445548Paediatr
Drugs.2009;11(3):203-26. doi: 10.2165/00148581-200911030-00005.
Atomoxetine: a review of its use in attention-deficit
hyperactivity disorder in children and adolescents.
Garnock-Jones KP1,Keating GM.
Author information 1Wolters Kluwer Health mid R: Adis, Auckland,
New Zealand, an editorial office of Wolters Kluwer Health,
Philadelphia, Pennsylvania, USA. [email protected]
Abstract
Atomoxetine (Strattera(R)) is a selective norepinephrine
(noradrenaline) reuptake inhibitor that is not classified as a
stimulant, and is indicated for use in patients with
attention-deficit hyperactivity disorder (ADHD). Atomoxetine is
effective and generally well tolerated. It is significantly more
effective than placebo and standard current therapy and does not
differ significantly from or is noninferior to immediate-release
methylphenidate; however, it is significantly less effective than
the extended-release methylphenidate formulation OROS(R)
methylphenidate (hereafter referred to as osmotically released
methylphenidate) and extended-release mixed amfetamine salts.
Atomoxetine can be administered either as a single daily dose or
split into two evenly divided doses, has a negligible risk of abuse
or misuse, and is not a controlled substance in the US. Atomoxetine
is particularly useful for patients at risk of substance abuse, as
well as those who have co-morbid anxiety or tics, or who do not
wish to take a controlled substance. Thus, atomoxetine is a useful
option in the treatment of ADHD in children and adolescents. The
mechanism of action of atomoxetine is unclear, but is thought to be
related to its selective inhibition of presynaptic norepinephrine
reuptake in the prefrontal cortex. Atomoxetine has a high affinity
and selectivity for norepinephrine transporters, but little or no
affinity for various neurotransmitter receptors. Atomoxetine has a
demonstrated ability to selectively inhibit norepinephrine uptake
in humans and animals, and studies have shown that it
preferentially binds to areas of known high distribution of
noradrenergic neurons, such as the fronto-cortical subsystem.
Atomoxetine was generally associated with statistically, but not
clinically, significant increases in both heart rate and blood
pressure in pediatric patients with ADHD. While there was an
initial loss in expected height and weight among atomoxetine
recipients, this eventually returned to normal in the longer term.
Data suggest that atomoxetine is unlikely to have any abuse
potential. Atomoxetine appeared less likely than methylphenidate to
exacerbate disordered sleep in pediatric patients with ADHD.
Atomoxetine is rapidly absorbed, and demonstrates dose-proportional
increases in plasma exposure. It undergoes extensive
biotransformation, which is affected by poor metabolism by
cytochrome P450 (CYP) 2D6 in a small percentage of the population;
these patients have greater exposure to and slower elimination of
atomoxetine than extensive metabolizers. Patients with hepatic
insufficiency show an increase in atomoxetine exposure. CYP2D6
inhibitors, such as paroxetine, are associated with changes in
atomoxetine pharmacokinetics similar to those observed among poor
CYP2D6 metabolizers. Once- or twice-daily atomoxetine was effective
in the short-term treatment of ADHD in children and adolescents, as
observed in several well designed placebo-controlled trials.
Atomoxetine also demonstrated efficacy in the longer term treatment
of these patients. A single morning dose was shown to be effective
into the evening, and discontinuation of atomoxetine was not
associated with symptom rebound. Atomoxetine efficacy did not
appear to differ between children and adolescents. Stimulant-naive
patients also responded well to atomoxetine treatment. Atomoxetine
did not differ significantly from or was noninferior to
immediate-release methylphenidate in children and adolescents with
ADHD with regard to efficacy, and was significantly more effective
than standard current therapy (any combination of medicines
[excluding atomoxetine] and/or behavioral counseling, or no
treatment). However, atomoxetine was significantly less effective
than osmotically released methylphenidate and extended-release
mixed amfetamine salts. The efficacy of atomoxetine did not appear
to be affected by the presence of co-morbid disorders, and symptoms
of the co-morbid disorders were not affected or were improved by
atomoxetine administration. Health-related quality of life (HR-QOL)
appeared to be positively affected by atomoxetine in both short-
and long-term studies; atomoxetine also improved HR-QOL to a
greater extent than standard current therapy. Atomoxetine was
generally well tolerated in children and adolescents with ADHD.
Common adverse events included headache, abdominal pain, decreased
appetite, vomiting, somnolence, and nausea. The majority of adverse
events were mild or moderate; there was a very low incidence of
serious adverse events. Few patients discontinued atomoxetine
treatment because of adverse events. Atomoxetine discontinuation
appeared to be well tolerated, with a low incidence of
discontinuation-emergent adverse events. Atomoxetine appeared
better tolerated among extensive CYP2D6 metabolizers than among
poor metabolizers. Slight differences were evident in the adverse
event profiles of atomoxetine and stimulants, both immediate- and
extended-release. Somnolence appeared more common among atomoxetine
recipients and insomnia appeared more common among stimulant
recipients. A black-box warning for suicidal ideation has been
published in the US prescribing information, based on findings from
a meta-analysis showing that atomoxetine is associated with a
significantly higher incidence of suicidal ideation than placebo.
Rarely, atomoxetine may also be associated with serious liver
injury; postmarketing data show that three patients have had
liver-related adverse events deemed probably related to atomoxetine
treatment. Treatment algorithms involving the initial use of
atomoxetine appear cost effective versus algorithms involving
initial methylphenidate (immediate- or extended-release),
dexamfetamine, tricyclic antidepressants, or no treatment in
stimulant-naive, -failed, and -contraindicated children and
adolescents with ADHD. The incremental cost per quality-adjusted
life-year is below commonly accepted cost-effectiveness thresholds,
as shown in several Markov model analyses conducted from the
perspective of various European countries, with a time horizon of 1
year.
3. http://www.ncbi.nlm.nih.gov/pubmed/18555941Clin Ther.2008
May;30(5):942-57. doi: 10.1016/j.clinthera.2008.05.006.
Evolution of the treatment of attention-deficit/hyperactivity
disorder in children: a review.
Findling RL1.
Author information 1Case Western Reserve University, Ohio, USA.
[email protected]
Abstract
BACKGROUND:
Efficacious and well-tolerated medications are available for the
treatment of attention-deficit/hyperactivity disorder (ADHD).
Stimulants such as methylphenidate (MPH) and amphetamines are the
most widely used medications approved by the US Food and Drug
Administration for the treatment of ADHDin children.
OBJECTIVE:
This article reviews the literature on the development and use
of medications for the treatment of ADHD in children.
METHODS:
A search of MEDLINE was conducted toidentify relevant studies
and critical reviews on the treatment of ADHD in children. The main
criteria for inclusion of a study were that it have a controlled
design, enroll >100 subjects if a clinical trial and >20
subjects if a classroom study, assess symptoms with the most widely
used scales and tests,and be published from 2000 to 2008.A few
older pivotal studies were also included.
RESULTS:
Many studies have reported the long-term efficacy and
tolerability of immediate-release formulations of MPH. The
disadvantages of such formulations include the need for multiple
daily dosing and a potential for abuse. Various extended-release
formulations of MPH have been found effective in controlled studies
enrolling large numbers of children with ADHD. The efficacy and
tolerability of dexmethylphenidate, the active D-isomer of MPH, in
an extended-release formulation have also been reported. An
extended-release formulation of mixed amphetamine salts (MMAS-XR)
that is dosed once daily has been found to be efficacious and well
tolerated. The non-stimulant atomoxetine has been reported to be
well tolerated and efficacious, although it may not be as effective
as stimulants; this formulation is, however, less likely than
stimulants to be associated with abuse and diversion. A recently
approved prodrug stimulant, lisdexamfetamine dimesylate (LDX), was
developed to provide a long duration of effect that is consistent
throughout the day, with a reduced potential for abuse. In a
placebo-controlled study in children with ADHD, less intersubject
variability in T(max), C(max), and AUC from time zero to the last
quantifiable concentration was seen in the 8 subjects who received
LDX (percent coefficient of variation, 15.3, 20.3, and 21.6,
respectively) compared with the 9 subjects who received MAS-XR
(52.8, 44.0, and 42.8).In 2 clinical trials, significantly greater
improvements in teacher and parent ratings of ADHD symptoms were
seen with LDX compared with placebo (P