Neurostimulants:
méthylphénidate,
dextroamphétamine and non-stimulants, atomoxetine, etc
| 1: Curr Opin Pharmacol. 2005 Feb;5(1):87-93. |
|
Stimulants: use and abuse in the treatment of attention
deficit hyperactivity disorder.
Fone KC, Nutt DJ.
Institute of Neuroscience, School of Biomedical Science, Queen's Medical Centre,
University of Nottingham, Nottingham NG7 2UH, UK.
Attention deficit hyperactivity disorder (ADHD) is the most prevalent childhood
developmental disorder and is also of unclear neurobiological aetiology. However,
recent advances in molecular genetics and brain imaging implicate dopaminergic
hypofunction in the frontal lobes and basal ganglia in ADHD. Psychostimulants
(e.g. methylphenidate and amphetamine, which are potent inhibitors of the
dopamine transporter) are the first choice medication for ADHD and have a good
acute efficacy and safety profile when used for this disorder. Whether long-term
psychostimulant administration to adolescents alters neural development and
behaviour or increases the risk of substance abuse is less certain. The precise
molecular mechanism of action of psychostimulants is beginning to be established.
Furthermore, preclinical studies have begun to use lower clinically relevant
doses and oral administration of psychostimulants to determine their long-term
effect on development, behaviour and neurochemistry, which is an important
public health issue associated with chronic medication of adolescents with ADHD.
PMID: 15661631 [PubMed - in process]
|
2: Exp Clin Psychopharmacol.
2004 Feb;12(1):57-64. |
|
Effect of methylphenidate on time perception in children with
attention-deficit/hyperactivity disorder.
Baldwin RL, Chelonis JJ, Flake RA, Edwards MC, Feild CR, Meaux JB, Paule MG.
Department of Pediatrics, University of Arkansas for Medical Sciences--Arkansas
Children's Hospital, Little Rock, AR 72202, USA. baldwinronaldL@uams.edu
The effects of methylphenidate (MPH) on performance of a time-production task
were studied in 17 children with attention-deficit/hyperactivity disorder who
participated in 1 test session on and 1 off MPH. Participants held a response
lever down for at least 10 but no longer than 14 s. Administration of MPH had no
effect on the number of correct responses or on the mean duration of lever holds.
MPH administration significantly decreased timing response variability,
increased holds of 10- to 11-s duration, and decreased lever holds of extremely
short durations. These results indicate that administration of MPH resulted in
more precise timing performance without changing the mean duration of lever
holds, suggesting an enhancement in working memory.
PMID: 14769100 [PubMed - in process]
|
3: J Am Acad Child Adolesc Psychiatry. 2004 Mar;43(3):260-8. |
|
Methylphenidate improves visual-spatial memory in children with
attention-deficit/hyperactivity disorder.
Bedard AC, Martinussen R, Ickowicz A, Tannock R.
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
OBJECTIVE: To investigate the effect of methylphenidate (MPH) on visual-spatial
memory, as measured by subtests of the Cambridge Neuropsychological Testing
Automated Battery (CANTAB), in children with attention-deficit/hyperactivity
disorder (ADHD). Visual-spatial memory is a core component of working memory
that has been shown to be impaired in ADHD, irrespective of comorbid reading and/or
language problems. METHOD: A clinic-referred sample of school-age children with
a confirmed DSM-IV diagnosis of ADHD (n = 26) completed tests of visual-spatial
memory, planning ability, and recognition memory in an acute, randomized,
placebo-controlled, crossover trial with three single fixed doses of MPH. MPH
effects on right-handed and left-handed motor control were also assessed.
RESULTS: MPH significantly improved performance on a self-ordered, updating
visual-spatial working memory task and on maintenance of visual-spatial
information but had no effects on measures of visual-spatial planning ability or
recognition memory. Also, MPH significantly improved left-handed motor control.
CONCLUSIONS: Beneficial effects of MPH on visual-spatial processing in ADHD are
selective and restricted to visual-spatial memory.
|
4:
J Am Acad Child Adolesc Psychiatry. 2004 Feb;43(2):191-8.
|
|
Differential effects
of methylphenidate on attentional functions in children with attention-deficit/hyperactivity
disorder.
Konrad K, Gunther T, Hanisch C, Herpertz-Dahlmann B.
Techinical University of Aachen, Germany. kerstin.konrad@kjp.rwth-aachen.de
OBJECTIVE: To examine the effects of methylphenidate on different attentional
functions and behavior in children with attention-deficit/hyperactivity disorder
(ADHD). METHOD: A total of 60 ADHD children aged between 8 and 12 years
completed a randomized, double-blind, placebo-controlled, within-subject
crossover trial with two doses of methylphenidate (0.25 and 0.5 mg/kg body
weight) and placebo. A comprehensive neuropsychological test battery was applied,
including tests of alertness and sustained, focused, and divided attention as
well as two executive tests, the stop-signal paradigm and a visual set-shifting
task. RESULTS: A linear improvement was identified for both medication
conditions in the alertness and focused and sustained attention task, but no
significant improvement was found for divided attention. Quadratic trends were
found for both executive tasks. Responders defined by behavior ratings did not
differ from nonresponders. CONCLUSIONS: Results indicate that attentional
functions are influenced differentially by methylphenidate: intensity-dimension
functions are best influenced by higher doses, executive functions by moderate
doses, and selectivity-dimension functions by variable doses. In addition,
divergent results from behavior rating scales and from attentional paradigms
emphasize that clinicians have to decide what constitutes an appropriate
clinical response. A more comprehensive assessment of attention may help to find
an individually optimal dose for the treatment of attentional dysfunctions.
PMID: 14726726 [PubMed - indexed for MEDLINE]
|
5:
CNS Drugs. 2004;18(4):243-50 |
|
Pharmacokinetic
considerations in the treatment of attention-deficit hyperactivity disorder with
methylphenidate.
Wolraich ML, Doffing MA.
University of Oklahoma Health Sciences Center, Child Study Center, Oklahoma
City, Oklahoma, USA.
Methylphenidate is commonly used for the treatment of attention-deficit
hyperactivity disorder (ADHD). Its efficacy in improving the core symptoms of
ADHD, as well as some of the aggressive and oppositional behaviours, is well
documented, based on a large volume of research. Methylphenidate has a wide
margin of safety and relatively mild adverse effects, most commonly appetite
suppression and insomnia.Methylphenidate is a rapidly absorbed medication that,
in its d-isomer form, readily penetrates the CNS, particularly the striatum. It
appears to function by blocking the reuptake of dopamine.Both the plasma
concentrations and behavioural effects of methylphenidate demonstrate a time to
maximum of between 1 and 3 hours, with the maximum behavioural effects occurring
when the plasma concentrations are increasing. Because of the rapid onset of
action, the effects of methylphenidate can be dramatic but usually last only
about 4 hours with the immediate-release formulation. The behavioural responses
of individuals are also highly variable, so that it is necessary to start
treatment at a low dosage and increase up to a maximally effective dosage (usually
starting at 10-15 mg/day with increases of 10-15mg at weekly intervals to a
maximum dosage of 60 mg/day, irrespective of formulation). Because of the
variability in behavioural responses, assessment of plasma concentrations is not
clinically useful nor does weight help in deciding an appropriate dosage. The
difficulties in administering methylphenidate multiple times a day, particularly
during the school day, have been alleviated in the past few years by the
development of extended-release preparations with varying behavioural effects
lasting 8-12 hours. The 8-hour preparations (Metadate((R)) CD and Ritalin((R))
LA) utilise a microbead technology, while the 12-hour preparation
(Concerta((R))) utilises an osmotic pump system. All extended-release
formulations effectively control the symptoms of ADHD. While pharmacokinetic
differences appear to exist between some of these new formulations, there are
currently no clinical data available to demonstrate clinical efficacy
differences between them.
PMID: 15015904 [PubMed - in process]
6: Arq Neuropsiquiatr. 2004
Jun;62(2B):399-402. Epub 2004 Jul 20.
The effect of methylphenidate on oppositional defiant disorder
comorbid with attention deficit/hyperactivity disorder.
Serra-Pinheiro MA, Mattos P, Souza I, Pastura G, Gomes F.
Grupo de Estudos do Deficit de Atencao, Federal University of Rio de Janeiro.
totasp@hotmail.com
OBJECTIVE: To assess the effect of methylphenidate on the diagnosis of
oppositional-defiant disorder (ODD) comorbid with attention-deficit
hyperactivity disorder (ADHD). METHOD: We conducted an open-label study in which
10 children and adolescents with a dual diagnosis of ODD and ADHD were assessed
for their ODD symptoms and treated with methylphenidate. At least one month
after ADHD symptoms were under control, ODD symptoms were reevaluated with the
Parent form of the Children Interview for Psychiatric Syndromes (P-ChIPS).
RESULTS: Nine of the 10 patients no longer fulfilled diagnostic criteria for ODD
after they were treated with methylphenidate for ADHD. CONCLUSION:
Methylphenidate seems to be an effective treatment for ODD, as well as for ADHD
itself. The implications for the treatment of patients with ODD not comorbid
with ADHD needs further investigation.
PMID: 15273834 [PubMed - in process]
|
7:
Journal
of the American Academy of Child & Adolescent Psychiatry. 43(5):559-567, May
2004. |
|
Stimulant Treatment Over Five Years: Adherence,
Effectiveness, and Adverse Effects.
Charach, Alice M.D.; Ickowicz, Abel M.D.; Schachar,
Russell M.D.
Abstract:
Objective: To evaluate the impact of adherence and medication status on
effectiveness and adverse effects of stimulant use in children with
attention-deficit/hyperactivity disorder (ADHD) over 5 years.
Method: Seventy-nine of 91 participants in a 12-month
randomized controlled trial of methylphenidate and parent groups enrolled in a
follow-up study. Adherence to stimulants, treatment response, and adverse
effects were evaluated annually for 5 years. Changes in teacher-reported
symptoms and parent-reported adverse effects were compared at 2, 3, 4, and 5
years for 3 groups: adherents, nonadherents on medication, or nonadherents off
medication. Controlling for age, gender, and baseline severity, adherence status
and medication status were evaluated as correlates of teacher-reported ADHD
symptom scores at each year using multiple regression analyses.
Results: At 2 years, adherents (n = 41) showed greater
improvement in teacher-reported symptoms than those off medication (n = 16) and
equivalent response to nonadherents on stimulants (n = 16) (p = .02). At 5 years,
adherents (n = 16) showed greater improvement in teacher-reported symptoms than
nonadherents on stimulants (n = 15) and those off medication (n = 14) (p = .04).
At year 2 medication status ([beta] = 4.67 [0.40-8.95, p = .033]) and at year 5
adherence status ([beta] = 7.23 [3.01-11.44, p = .001]) correlated with higher
teacher-reported symptom scores. Clinically significant adverse effects were
present for 5 years, most commonly loss of appetite.
Conclusions: Psychostimulants improve ADHD symptoms for up to
5 years, but adverse effects persist.
Copyright 2004 (C) American Academy of Child and Adolescent Psychiatry
8:-
Arch Gen Psychiatry. 2003;60:204-211
Development of a New Once-a-Day Formulation of
Methylphenidate for the Treatment of
Attention-deficit/Hyperactivity Disorder.
Proof-of-Concept and
Proof-of-Product Studies.
James Swanson,
PhD; Suneel Gupta, PhD; Andrew Lam, PhD; Ira Shoulson, MD; Marc Lerner, MD;
Nishit Modi, PhD; Elizabeth Lindemulder, PhD; Sharon Wigal, PhD
.
http://archpsyc.ama-assn.org/cgi/content/abstract/60/2/204
| 9:
Expert Opin Emerg Drugs.
2002 Oct;7(2):269-76. |
|
New drugs for treatment of attention-deficit/hyperactivity disorder.
Chung B,
Suzuki AR,
McGough JJ.
300 UCLA Medical Plaza, Suite 1414, Los Angeles, CA 90095, USA.
Attention-deficit/hyperactivity disorder (ADHD) is one of the longest recognised
and most common neuropsychiatric disorders of childhood. Recent research
indicates that ADHD is most often a lifelong condition associated with
significant impairment in multiple domains of functioning. ADHD is a clinical
diagnosis made on the basis of history and clinical examination. Current
molecular, neuroimaging and neuropsychological studies have greatly elucidated
our understanding of the basic science of ADHD. The underlying pathophysiology
of ADHD has been theorised to be dysregulation of inhibitory noradrenergic
frontocortical activity on dopaminergic striatal structures. Pharmacotherapy is
recognised as the most effective component of ADHD treatment, although some role
exists for proper educational placement, parent management training and social
skills development. Methylphenidate and amphetamine are the current standards in
ADHD medication treatment. Other medication classes such as tricyclic
antidepressants and certain antihypertensives are also used in off-label therapy.
Anticipated improvements in new ADHD medications include the development of
extended release delivery systems, improved tolerability, alternative mechanisms
of action and enhanced efficacy in treatment refractory cases.
PMID: 15989550 [PubMed - in process]
-
-
- Identification
of the human cytochromes P450 responsible for atomoxetine
metabolism.
Ring BJ,
Gillespie JS,
Eckstein JA,
Wrighton SA.
Department of Drug Disposition, Lilly Research Laboratories,
Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
ring_barbara_j@lilly.com
Studies were performed to determine the human enzymes
responsible for the biotransformation of atomoxetine to its
major metabolite, 4-hydroxyatomoxetine, and to a minor
metabolite, N-desmethylatomoxetine. Utilizing human liver
microsomes containing a full complement of cytochrome P450
(P450) enzymes, average K(m) and CL(int) values of 2.3
microM and 103 microl/min/mg, respectively, were obtained
for 4-hydroxyatomoxetine formation. Microsomal samples
deficient in CYP2D6 exhibited average apparent K(m) and CL(int)
values of 149 microM and 0.2 microl/min/mg, respectively. In
a human liver bank characterized for P450 content, formation
of 4-hydroxyatomoxetine correlated only to CYP2D6 activity.
Of nine expressed P450s examined, 4-hydroxyatomoxetine was
formed at a rate 475-fold greater by CYP2D6 compared with
the other P450s. These results demonstrate that CYP2D6 is
the enzyme primarily responsible for the formation of
4-hydroxyatomoxetine. Multiple P450s were found to be
capable of forming 4-hydroxyatomoxetine when CYP2D6 was not
expressed. However, the efficiency at which these enzymes
perform this biotransformation is reduced compared with
CYP2D6. The formation of the minor metabolite
N-desmethylatomoxetine exhibited average K(m) and CL(int)
values of 83 microM and 0.8 microl/min/mg, respectively.
Utilizing studies similar to those outlined above, CYP2C19
was identified as the primary enzyme responsible for the
biotransformation of atomoxetine to N-desmethylatomoxetine.
In summary, CYP2D6 was found to be the primary P450
responsible for the formation of the major oxidative
metabolite of atomoxetine, 4-hydroxyatomoxetine. Furthermore,
these studies indicate that in patients with compromised
CYP2D6 activity, multiple low-affinity enzymes will
participate in the formation of 4-hydroxyatomoxetine.
Therefore, coadministration of P450 inhibitors to poor
metabolizers of CYP2D6 substrates wo
uld not be predicted to decrease the clearance of
atomoxetine in these individuals.
PMID: 11854152 [PubMed - indexed for MEDLINE]
|