Biederman J, Spencer T.
disorder (ADHD) as a noradrenergic disorder.
1999 Nov 1;46(9):1234-42
"This review revisits the thesis that a dysregulation
of the central noradrenergic networks may underlie the pathophysiology of ADHD.
We review the pertinent neurobiological and pharmacological literature on ADHD.
The noradrenergic system has been intimately associated with the modulation of
higher cortical functions including attention, alertness, vigilance and executive
function. Noradrenergic activation is known to profoundly affect the performance
of attention, especially the maintenance of arousal, a cognitive function known
to be deficient in ADHD. Data from family, adoption, twin, and segregation analysis
strongly support a genetic hypothesis for this disorder. Although molecular genetic
studies of ADHD are relatively new and far from definitive, several replicated
reports have found associations between ADHD with DAT and D4 receptor genes. Brain
imaging studies fit well with the idea that dysfunction in fronto-subcortical
pathways occurs in ADHD with its underlying dysregulation of noradrenergic function.
A wealth of pharmacological data (within and without the stimulant literature)
provides strong evidence for selective clinical activity in ADHD for drugs with
noradrenergic and dopaminergic pharmacological profiles. Available research provides
compelling theoretic, basic biologic and clinical support for the notion that
ADHD is a brain disorder of likely genetic etiology with etiologic and pathophysiologic
heterogeneity. Neurobiological and pharmacological data provide compelling support
for a noradrenergic hypothesis of ADHD and suggest that drugs with noradrenergic
activity may play an important role in the therapeutics of this disorder."
JM, Newcorn JH, Koda VH, Pick L, McKay KE, Knott P.
mechanisms in ADHD children with and without reading disabilities: a replication
J Am Acad Child Adolesc Psychiatry 1997 Dec;36(12):1688-97
To examine noradrenergic (NA) function in children with attention-deficit hyperactivity
disorder (ADHD) by replicating and expanding upon a previous finding that ADHD
children with and without reading disabilities (RD) differ in plasma levels of
the NA metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG). METHOD: Plasma levels
of MHPG were compared in ADHD children who were subdivided on the basis of the
presence or absence of RD. Subsequently, this replication sample was combined
with a previously studied sample to further explore the relationship between plasma
MHPG levels and measures of cognitive function in children with ADHD. RESULTS:
Plasma levels of MHPG were significantly lower in ADHD children without RD, compared
with those with RD, replicating a published finding. Analyses in the combined
sample indicated that, among children with ADHD, plasma MHPG levels were inversely
associated with measures of academic achievement and verbal processing, but not
parent or teacher ratings of behavior or continuous performance test measures
of attention and impulsivity. CONCLUSIONS: These data indicate that children with
ADHD are not homogeneous with regard to NA function and that neurochemical variation
is closely associated with differences in clinical characteristics of the children."
WO, Sinclair E, Glaser R, Horwitz E, Javaid J, Bylund DB.
and dopamine metabolites and educational variables in boys with attention deficit
disorder and hyperactivity.
J Child Neurol 1987 Jan;2(1):50-6
present study evaluated the biochemical measures of urinary homovanillic acid
(HVA) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) in relation to functioning on
selected psychoeducational tests in a group of boys with attention deficit disorder
and hyperactivity. The Wechsler Intelligence Scale for Children-Revised (WISC-R),
the Wide Range Achievement Test (WRAT), and the Peabody Picture Vocabulary Test
were administered to 28 hyperactive and 23 control subjects. The findings suggest
subtle differences in psychoeducational test performance in relation to specific
levels of homovanillic acid and MHPG." [Abstract]
SR, Maas JW, Javors MA, Rogeness GA, Baker J.
in attention-deficit hyperactivity disorder with and without comorbid anxiety.
Am Acad Child Adolesc Psychiatry 1994 Oct;33(8):1165-73
determine whether there are differences in noradrenergic or adrenergic functioning
in children with attention-deficit hyperactivity disorder (ADHD) with and without
anxiety. METHOD: ADHD children with and without a comorbid overanxious (ANX) disorder
were compared to each other and to normal controls in terms of 2-hour urinary
excretion of norepinephrine (NE), epinephrine (EPI), and their metabolites. All
subjects performed a fixed series of mentally stressful tasks during the collection
period. RESULTS: Children with ADHD, regardless of comorbid anxiety, excreted
more normetanephrine (NMN), the chief extracellular metabolite of NE, than controls,
as well as more vanillylmandelic acid. Children with ADHD alone had lower NE/NMN
and EPI/metanephrine ratios compared to controls. Children with ADHD/ANX excreted
more EPI than ADHD children without anxiety. CONCLUSIONS: Children with ADHD may
have a higher tonic activity of the noradrenergic system than controls, while
children with comorbid ADHD/ANX may be differentiated from those with ADHD alone
by higher adrenergic activity." [Abstract]
GL, Ornitz EM, Hariharan M.
Urinary catecholamine excretion and behavioral
differences in ADHD and normal boys.
J Child Adolesc Psychopharmacol
"Urinary catecholamine excretion was assessed in
15 boys with attention-deficit/hyperactivity disorder (ADHD) and 16 normal controls
during a defined physical and mental task. Dihydroxyphenylalanine, dopamine, norepinephrine
(NE), epinephrine (EPI), 3,4-dihydroxyphenylacetic acid, and 3,4-dihydroxyphenylglycol
(DOPEG) concentrations were assayed by high-pressure liquid chromatography with
electrochemical detection. The urinary concentration of DOPEG, an NE metabolite
that has not been previously measured in ADHD, was significantly lower in the
ADHD subjects than in the normal controls. There was also a trend for lower urinary
EPI levels in the hyperactive boys. Stepwise multiple regression analyses demonstrated
that DOPEG and EPI each contributed significantly to the variance in the behavioral
symptoms within the full sample. The results are consistent with previous reports
of abnormal metabolism of norepinephrine and epinephrine in ADHD. These neurochemical
findings may be due to differences between ADHD and normal boys in neuronal (central
or peripheral) or nonneuronal (e.g., adrenal, renal) activity. The results are
also consistent with prior findings in normal children of an inverse relationship
between EPI excretion and inattentive, restless behaviors. Together, these findings
suggest caution in ascribing metabolite changes to ADHD or to ADHD-like behaviors
that may be seen in normal children." [Abstract]
SB, Nemet D, Swanson JM, Regino R, Trampush J, Ziegler MG, Cooper DM.
Response to Exercise in Children with Attention Deficit Hyperactivity Disorder.
Res 2003 Mar 5; [epub ahead of print]
"The objective of this study was
to examine differences in catecholamine (CA) response to exercise between children
who had received a diagnosis of attention-deficit/hyperactivity disorder (ADHD)
and age- and sex-matched controls. On the basis of the notion of a CA dysfunction
in ADHD, we reasoned that the normal robust increase in circulating CA seen in
response to exercise would be blunted in children with ADHD. To test this, we
recruited 10 treatment-naive children with newly diagnosed ADHD and 8 age-matched
controls (all male) and measured CA response to an exercise test in which the
work was scaled to each subject's physical capability. After exercise, epinephrine
and norepinephrine increased in both control and ADHD subjects (p = 0.006 and
p = 0.002, respectively), but the responses were substantially blunted in the
ADHD group (p = 0.018) even though the work performed did not differ from controls.
Circulating dopamine increased significantly in the control subjects (p < 0.016),
but no increase was noted in the subjects with ADHD. Finally, a significant attenuation
in the lactate response to exercise was found in ADHD (between groups, p <
0.005). Our data suggest that CA excretion after exercise challenges in children
with ADHD is deficient. This deficiency can be detected using a minimally invasive,
nonpharmacologic challenge." [Abstract]
GM, Dover MA, Yang BP, Holahan JM, Shaywitz SE, Marchione KE, Hall LM, Fletcher
JM, Shaywitz BA.
Adrenomedullary function during cognitive testing
in attention-deficit/hyperactivity disorder.
J Am Acad Child
Adolesc Psychiatry 2000 May;39(5):635-43
"OBJECTIVE: Reported correlations
between epinephrine (EPI) excretion and classroom performance, the cognition-enhancing
effects of EPI infusion, increased EPI excretion with stimulants, and reports
of decreased EPI excretion in attention-deficit/hyperactivity disorder (ADHD)
suggest that sympathoadrenomedullary function might be altered in ADHD. This hypothesis
was tested by examining sympathetic and adrenomedullary functioning during cognitive
testing in boys with diagnosed ADHD. METHOD: Urinary excretion of EPI and norepinephrine
during a 3-hour cognitive test battery was assessed in 7- to 13-year-old boys.
Excretion rates (nanograms per hour per square meter of body surface area) were
determined in 200 individuals with ADHD (diagnosed according to DSM-IV criteria),
with or without co-occurring oppositional defiant/conduct disorder or learning
disorder. A non-ADHD contrast group (n = 51) with similar comorbidity was also
studied. RESULTS: Substantially lower (mean +/- SE) urinary EPI excretion was
observed in the ADHD-inattentive subtype (n = 71) compared with the control group
(200 +/- 22 versus 278 +/- 24 ng/hr/m2; F = 5.99, p = .015, critical alpha = .017).
No diagnostic group differences were seen for norepinephrine excretion. Correlational
analysis of both parent- and teacher-rated behaviors revealed that inattention
factors consistently negatively predicted urinary EPI excretion. CONCLUSIONS:
The data extend findings of lower adrenomedullary activity during cognitive challenge
in individuals with ADHD and suggest that the alteration is associated with inattentive
NL, Shaywitz SE, Shaywitz BA, Marchione K, Fleischman SJ, Jones TW, Tamborlane
Blunted catecholamine responses after glucose ingestion in children
with attention deficit disorder.
Pediatr Res 1995 Oct;38(4):539-42
simple sugars has been suggested as having adverse behavioral and cognitive effects
in children with attention deficit disorder (ADD), but a physiologic mechanism
has not been established. To address this issue, metabolic, hormonal, and cognitive
responses to a standard oral glucose load (1.75 g/kg) were compared in 17 children
with ADD and 11 control children. Baseline and oral glucose-stimulated plasma
glucose and insulin levels were similar in both groups, including the nadir glucose
level 3-5 h after oral glucose (3.5 +/- 0.2 mmol/L in ADD and 3.3 +/- 0.2 mmol/L
in control children). The late glucose fall stimulated a rise in plasma epinephrine
that was nearly 50% lower in ADD than in control children (1212 +/- 202 pmol/L
versus 2228 +/- 436 pmol/L, p < 0.02). Plasma norepinephrine levels were also
lower in ADD than in control children, whereas growth hormone and glucagon concentrations
did not differ between the groups. Matching test scores were lower and reaction
times faster in ADD than in control children before and after oral glucose, and
both groups showed a deterioration on the continuous performance test in association
with the late fall in glucose and rise in epinephrine. These data suggest that
children with ADD have a general impairment of sympathetic activation involving
adrenomedullary as well as well as central catecholamine regulation." [Abstract]
Matsuishi T, Yamashita Y.
and neurotransmitter studies in patients with learning disabilities]
To Hattatsu 1999 May;31(3):245-8
"To clarify the pathophysiology of learning
disability (LD), we measured the urinary levels of 3-methoxy-4-hydroxyphenyl glycol
(MHPG), and phenylethylamine (PEA) in urine samples collected in a 24 hour period.
Findings were compared with those obtained in age-matched controls and diseased
controls including patients with attention deficit-hyperactivity disorder (ADHD),
infantile autism, and mental retardation. The mean urinary level of MHPG in LD
(n = 6) were not significantly different from those in ADHD (n = 16), mental retardation
(n = 4), infantile autism (n = 5), and the controls (n = 6), while the mean urinary
levels of PEA were significantly lower in LD (n = 6, 91 +/- 17.3 micrograms/mg)
and in ADHD (n = 5, 65 +/- 53.6 micrograms/mg) as compared to age-matched controls
(n = 3, 340 +/- 264.5 micrograms/mg) ANOVA, (p < 0.05). PEA is considered to
play an important role for the pathogenesis of LD and ADHD." [Abstract]
GB, Bornstein RA, Douglass AB, Van Muyden JC, Ashton S, Bazylewich TL.
excretion of MHPG and normetanephrine in attention deficit hyperactivity disorder.
Chem Neuropathol 1993 Jan-Feb;18(1-2):173-8
(expressed per gram of creatinine) of the norepinephrine metabolites 3-methoxy-4-hydroxyphenylethylene
glycol (MHPG) and normetanephrine (NME) was measured in children with attention
deficit hyperactivity disorder (ADHD) and in normal subjects matched for age and
education. In contrast to findings with Tourette syndrome patients, in the ADHD
patients there was no significant difference in excretion of MHPG and NME from
control values." [Abstract]
TJ, Biederman J, Wilens TE, Faraone SV.
Novel treatments for attention-deficit/hyperactivity
disorder in children.
J Clin Psychiatry 2002;63 Suppl 12:16-22
medications for children with attention-deficit/hyperactivity disorder (ADHD)
would be effective, well tolerated, and long acting and not cause mood swings
or worsen comorbid conditions. Current medications work on brain dopamine and/or
norepinephrine systems, which are thought to be involved in ADHD. The medication
class with the most evidence of efficacy in ADHD is stimulants, but they may be
abused, are effective for only 4 to 12 hours, and may cause mood swings or increase
tic severity. In recent years, alternative treatments have been explored. Tricyclic
antidepressants have efficacy comparable to that of stimulants but may cause constipation,
dry mouth, tremors, blood pressure changes, and potentially serious side effects
including cardiac conduction and repolarization delays. Monoamine oxidase inhibitors
may improve ADHD symptoms but are associated with severe dietary restrictions.
Serotonin reuptake inhibitors have little or no effect in ADHD but may improve
comorbid depression. Bupropion, although less effective than stimulants, may improve
both ADHD symptoms and comorbid depression. Antihypertensive agents may improve
impulsivity, hyperactivity, and comorbid tics but cause sedation or rebound hypertension.
Atomoxetine, which is being developed for ADHD, reduces symptoms of ADHD without
exacerbating comorbid conditions and is associated with only minor side effects,
including subtle changes in blood pressure and heart rate. Before prescribing
a treatment, physicians should consider the appropriateness and effectiveness
of any medication for children with ADHD, who may be less tolerant of side effects
and less able to monitor and express concerns about their well-being than adults."
FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin
SM, Gehlert DR, Perry KW.
Atomoxetine increases extracellular levels
of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism
for efficacy in attention deficit/hyperactivity disorder.
"The selective norepinephrine (NE) transporter
inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown
to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD). We investigated
the mechanism of action of atomoxetine in ADHD by evaluating the interaction of
atomoxetine with monoamine transporters, the effects on extracellular levels of
monoamines, and the expression of the neuronal activity marker Fos in brain regions.
Atomoxetine inhibited binding of radioligands to clonal cell lines transfected
with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation
constants (K(i)) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity
for NE transporters. In microdialysis studies, atomoxetine increased extracellular
(EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HT(EX)
levels. Atomoxetine also increased DA(EX) concentrations in PFC 3-fold, but did
not alter DA(EX) in striatum or nucleus accumbens. In contrast, the psychostimulant
methylphenidate, which is used in ADHD therapy, increased NE(EX) and DA(EX) equally
in PFC, but also increased DA(EX) in the striatum and nucleus accumbens to the
same level. The expression of the neuronal activity marker Fos was increased 3.7-fold
in PFC by atomoxetine administration, but was not increased in the striatum or
nucleus accumbens, consistent with the regional distribution of increased DA(EX).
We hypothesize that the atomoxetine-induced increase of catecholamines in PFC,
a region involved in attention and memory, mediates the therapeutic effects of
atomoxetine in ADHD. In contrast to methylphenidate, atomoxetine did not increase
DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug
abuse liabilities." [Abstract]
Neurotransmission of cognition, part 3. Mechanism of action of
selective NRIs: both dopamine and norepinephrine increase in prefrontal cortex.
Clin Psychiatry. 2003 Mar; 64(3): 230-1.
"ISSUE: Selective norepinephrine
reuptake inhibitors exploit the fact that dopamine transporters are absent in
prefrontal cortex, so dopamine has to hitchhike a ride on the norepinephrine transporter
in order to be inactivated. Thus, blocking norepinephrine transporters leads to
an increase in both dopamine and norepinephrine levels in prefrontal cortex as
well as improvement in cognition in attention-deficit/hyperactivity disorder."
JF, Kratochvil CJ.
Safety profile of atomoxetine in the treatment
of children and adolescents with ADHD.
J Clin Psychiatry
2002;63 Suppl 12:50-5
"Atomoxetine is a selective norepinephrine reuptake
inhibitor that is being developed for the treatment of attention-deficit/hyperactivity
disorder (ADHD). Atomoxetine will be the first nonstimulant medication approved
by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD. Throughout
the testing phases, more than 2000 children and adolescents have been exposed
to atomoxetine in clinical trials, with both the number of exposures and the length
of exposure time increasing. Serious adverse events have not been clearly associated
with the drug, and there have been few discontinuations due to adverse events.
The most common drug-related event reported in trials has been decreased appetite
and an initial period of weight loss followed by an apparently normal rate of
weight gain. These events tend to appear early in the course of treatment with
atomoxetine and then decline. Atomoxetine has also been associated with mild increases
in blood pressure and pulse that plateau during treatment and resolve upon discontinuation.
There have been no effects seen on the QT interval, and the cytochrome P450 2D6
metabolism of patients seems to have little effect on safety or tolerability of
the drug. This article will review the data from completed and ongoing clinical
trials available at the time the New Drug Application was submitted to the FDA.
Described are serious adverse events, discontinuations, and treatment-emergent
adverse events. Specifically, cardiac effects and effects on weight, height, and
metabolism that are related to treatment of ADHD with atomoxetine in children
and adolescents are discussed." [Abstract]
D, Adler L, Spencer T, Reimherr FW, West SA, Allen AJ, Kelsey D, Wernicke J, Dietrich
A, Milton D.
Atomoxetine in adults with ADHD: two randomized, placebo-controlled
Biol Psychiatry 2003 Jan 15;53(2):112-20
disorder (ADHD) has been less studied in adults than in children, and the treatment
studies reported to date have been small, single-center trials. To assess the
efficacy of atomoxetine, a new and highly selective inhibitor of the norepinephrine
transporter, we conducted two large, multicenter treatment trials.Two identical
studies using randomized, double-blind, placebo-controlled designs and a 10-week
treatment period were conducted in adults with DSM-IV-defined ADHD as assessed
by clinical history and confirmed by a structured interview (study I, n = 280;
study II, n = 256). The primary outcome measure was a comparison of atomoxetine
and placebo using repeated measures mixed model analysis of postbaseline values
of the Conners' Adult ADHD Rating Scale.In each study, atomoxetine was statistically
superior to placebo in reducing both inattentive and hyperactive and impulsive
symptoms as assessed by primary and secondary measures. Discontinuations for adverse
events among atomoxetine patients were under 10% in both studies.Atomoxetine appears
to be an efficacious treatment for adult ADHD. Its lack of abuse potential may
be an advantage for many patients." [Abstract]
T, Heiligenstein JH, Biederman J, Faries DE, Kratochvil CJ, Conners CK, Potter
Results from 2 proof-of-concept, placebo-controlled studies of
atomoxetine in children with attention-deficit/hyperactivity disorder.
Clin Psychiatry 2002 Dec;63(12):1140-7
"BACKGROUND: Atomoxetine is a nonstimulant
drug being studied for the treatment of attention-deficit/hyperactivity disorder
(ADHD). Atomoxetine is a highly specific inhibitor of the presynaptic norepinephrine
transporter with minimal affinity for other noradrenergic receptors or other neurotransmitter
transporters or receptors. Results of 2 proof-of-concept studies are reported
that tested the hypothesis that a selective inhibitor of presynaptic norepinephrine
uptake would be effective for the treatment of ADHD in school-aged children. METHOD:
Two identical 12-week, stratified, randomized, double-blind, placebo-controlled
trials were conducted in children who met DSM-IV criteria for ADHD. The primary
efficacy outcome measure was the mean change from baseline to endpoint in the
Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD RS) total score. Secondary
efficacy measures included the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S)
and the Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S). RESULTS:
A total of 291 patients were randomized in the 2 trials combined (Study 1, N =
147; Study 2, N = 144). Stimulant-naive patients were randomized to atomoxetine,
placebo, or methylphenidate. Patients with prior stimulant exposure were randomized
to atomoxetine or placebo. Atomoxetine significantly reduced ADHD RS total scores
compared with placebo in each study (p <.001). Changes in the CGI-ADHD-S (Study
1: p =.003; Study 2: p =.001) and CPRS-ADHD Index (Study 1: p =.023; Study 2:
p <.001) also showed atomoxetine to be statistically significantly superior
to placebo in reducing ADHD symptoms. Atomoxetine was found to be well tolerated
in this population of pediatric patients. CONCLUSION: Two studies of atomoxetine
early in its development confirmed that atomoxetine, a specific and selective
inhibitor of noradrenergic uptake, was effective for the treatment of children
with ADHD. In addition, atomoxetine was found to be well tolerated." [Abstract]
J, Heiligenstein JH, Faries DE, Galil N, Dittmann R, Emslie GJ, Kratochvil CJ,
Laws HF, Schuh KJ; Atomoxetine ADHD Study Group.
Efficacy of atomoxetine
versus placebo in school-age girls with attention-deficit/hyperactivity disorder.
"OBJECTIVE: The efficacy of atomoxetine was assessed
in school-age girls with attention-deficit/hyperactivity disorder (ADHD). Atomoxetine
is a potent inhibitor of the presynaptic norepinephrine transporter with minimal
affinity for other noradrenergic receptors or for other neurotransmitter transporters
or receptors. METHODS: A total of 291 children who were 7 to 13 years of age and
met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria
for ADHD participated in 1 of 2 combined, double-blind, placebo-controlled, multisite,
identical clinical trials. This intent-to-treat subset analysis examined the effects
of atomoxetine versus placebo in 51 girls who were randomized to atomoxetine (n
= 30) or placebo (n = 21) for 9 weeks. ADHD symptoms were assessed using parent-
and investigator-rated scales. RESULTS: Atomoxetine was superior to placebo on
the following measures: the Attention-Deficit Hyperactivity Disorder Rating Scale-IV-Parent
Version: Investigator Administered and Scored Total Score; the Inattentive and
Hyperactive/Impulsive subscales of the Attention-Deficit Hyperactivity Disorder
Rating Scale-IV-Parent Version: Investigator Administered and Scored Total Score;
the ADHD Index subscale of the Conners' Parent Rating Scale-Revised: Short Form;
and the Clinical Global Impressions of Severity of ADHD. Statistically significant
efficacy was seen 1 week after randomization and remained so for the duration
of the study. One patient from each of the atomoxetine and placebo groups discontinued
the study as a result of an adverse event. CONCLUSION: Atomoxetine was found to
be effective and well tolerated for the treatment of ADHD in school-age girls."
D, Faries D, Wernicke J, Kelsey D, Kendrick K, Sallee FR, Spencer T; Atomoxetine
ADHD Study Group.
Atomoxetine in the treatment of children and adolescents
with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled,
Pediatrics 2001 Nov;108(5):E83
Atomoxetine is an investigational, nonstimulant pharmacotherapy being studied
as potential treatment for attention-deficit/hyperactivity disorder (ADHD). It
is thought to act via blockade of the presynaptic norepinephrine transporter in
the brain. We assessed the efficacy of 3 doses of atomoxetine compared with placebo
in children and adolescents with ADHD. METHODS: A total of 297 children and adolescents
who were 8 to 18 years of age and had ADHD as defined by the Diagnostic and Statistical
Manual of Mental Disorders, 4th edition, were randomized to placebo or atomoxetine
dosed on a weight-adjusted basis at 0.5 mg/kg/day, 1.2 mg/kg/day, or 1.8 mg/kg/day
for an 8-week period. ADHD symptoms, affective symptoms, and social and family
functioning were assessed using parent and investigator rating scales. RESULTS:
Approximately 71% of children enrolled were male, approximately 67% met criteria
for mixed subtype (both inattentive and hyperactive/impulsive symptoms), and the
only common psychiatric comorbidity was oppositional defiant disorder (approximately
38% of the sample). At baseline, symptom severity was rated as moderate to severe
for most children. At endpoint, atomoxetine 1.2 mg/kg/day and 1.8 mg/kg/day were
consistently associated with superior outcomes in ADHD symptoms compared with
placebo and were not different from each other. The dose of 0.5 mg/kg/day was
associated with intermediate efficacy between placebo and the 2 higher doses,
suggesting a graded dose-response. Social and family functioning also were improved
in the atomoxetine groups compared with placebo with statistically significant
improvements in measures of children's ability to meet psychosocial role expectations
and parental impact. Discontinuations as a result of adverse events were <5%
for all groups. CONCLUSION: Among children and adolescents aged 8 to 18, atomoxetine
was superior to placebo in reducing ADHD symptoms and in improving social and
family functioning symptoms. Atomoxetine was associated with a graded dose-response,
and 1.2 mg/kg/day seems to be as effective as 1.8 mg/kg/day and is likely to be
the appropriate initial target dose for most patients. Treatment with atomoxetine
was safe and well tolerated." [Abstract]
CJ, Heiligenstein JH, Dittmann R, Spencer TJ, Biederman J, Wernicke J, Newcorn
JH, Casat C, Milton D, Michelson D.
Atomoxetine and methylphenidate
treatment in children with ADHD: a prospective, randomized, open-label trial.
J Am Acad Child Adolesc Psychiatry 2002 Jul;41(7):776-84
assess the comparability of atomoxetine, a new therapy for attention-deficit/hyperactivity
disorder (ADHD) and methylphenidate. (Atomoxetine was originally called tomoxetine.
The name was recently changed in order to avoid any potential confusion with tamoxifen
that might lead to errors in dispensing drug.) METHOD: Children with ADHD were
randomized to open-label atomoxetine or methylphenidate for 10 weeks. Response
was assessed with the ADHD-IV Rating Scale. RESULTS: Two hundred twenty-eight
patients were randomized (atomoxetine n = 184, methylphenidate n = 44). Both drugs
were associated with marked improvement in inattentive and hyperactive-impulsive
symptom clusters as assessed by parents and investigators. No statistically significant
differences between treatment groups were observed on the primary outcome measure
(investigator-rated ADHD-IV Rating Scale total score: atomoxetine baseline: 39.4
[8.5], endpoint: 20.0 [13.9]; methylphenidate baseline: 37.6 [9.7], endpoint:
19.8 (16.6); p = .66). Safety and tolerability were also similar between the 2
drugs. Discontinuations due to adverse events were 10/184 (5.4%) for atomoxetine
and 5/44 (11.4%) for methylphenidate; p = .175. CONCLUSION: These data provide
preliminary evidence that atomoxetine is associated with therapeutic effects comparable
to those of methylphenidate." [Abstract]
D, Allen AJ, Busner J, Casat C, Dunn D, Kratochvil C, Newcorn J, Sallee FR, Sangal
RB, Saylor K, West S, Kelsey D, Wernicke J, Trapp NJ, Harder D.
atomoxetine treatment for children and adolescents with attention deficit hyperactivity
disorder: a randomized, placebo-controlled study.
Am J Psychiatry
"OBJECTIVE: The authors assessed the efficacy
of once-daily atomoxetine administration in the treatment of children and adolescents
with attention deficit hyperactivity disorder (ADHD). METHOD: In a double-blind
study, children and adolescents with ADHD (N=171, age range=6-16 years) were randomly
assigned to receive 6 weeks of treatment with either atomoxetine (administered
once daily) or placebo. RESULTS: Outcomes among atomoxetine-treated patients were
superior to those of the placebo treatment group as assessed by investigator,
parent, and teacher ratings. The treatment effect size (0.71) was similar to those
observed in previous atomoxetine studies that used twice-daily dosing. Parent
diary ratings suggested that drug-specific effects were sustained late in the
day. Discontinuations due to adverse events were low (less than 3%) for both treatment
groups, and no serious safety concerns were observed. CONCLUSIONS: Once-daily
administration of atomoxetine is an effective treatment for children and adolescents
with ADHD." [Abstract]
Overtoom CC, Verbaten MN, Kemner C, Kenemans JL,
van Engeland H, Buitelaar JK, van der Molen MW, van der Gugten J, Westenberg H,
Maes RA, Koelega HS.
Effects of methylphenidate, desipramine, and
L-dopa on attention and inhibition in children with Attention Deficit Hyperactivity
Behav Brain Res. 2003 Oct 17; 145(1-2): 7-15.
objective of this study was to investigate the effects of methylphenidate (MPH)
on attention and inhibition in children with Attention Deficit Hyperactivity Disorder
(ADHD) and to establish what the relative contributions of the noradrenergic and
dopaminergic systems to this effect were. In addition to MPH, two other drugs
were administered in order to affect both transmitter systems more selectively,
L-dopa (dopamine (DA) agonist) and desipramine (DMI) (noradrenaline (NA) re-uptake
inhibitor). Sixteen children with ADHD performed a stop-task, a laboratory task
that measures the ability to inhibit an ongoing action, in a double-blind randomized
within-subjects design. Each child received an acute clinical dose of MPH, DMI,
L-dopa, and placebo; measures of performance and plasma were determined. The results
indicated that inhibition performance was improved under DMI but not under MPH
or L-dopa. The response-time to the stop-signal was marginally shortened after
intake of DMI. MPH decreased omission and choice-errors and caused faster reaction
times to the trials without the stop-tone. No effects of L-dopa whatsoever were
noted. Prolactin levels were increased and 5-HIAA levels were lowered under DMI
relative to placebo. It is suggested that the effects of MPH on attention are
due to a combination of noradrenergic and dopaminergic mechanisms. The improved
inhibition under DMI could be serotonergically mediated." [Abstract]
Aston-Jones G, Rajkowski J, Cohen J.
of locus coeruleus in attention and behavioral flexibility.
Psychiatry 1999 Nov 1;46(9):1309-20
"Previous findings have implicated
the noradrenergic locus coeruleus (LC) system in functions along the dimension
of arousal or attention. It has remained uncertain what role this system has in
attention, or what mechanisms may be involved. We review our recent work examining
activity of LC neurons in monkeys performing a visual discrimination task that
requires focused attention. Results indicate that LC cells exhibit phasic or tonic
modes of activity, that closely correspond to good or poor performance on this
task, respectively. A computational model was used to simulate these results.
This model predicts that alterations in electrotonic coupling among LC cells may
produce the different modes of activity and corresponding differences in performance.
This model also indicates that the phasic mode of LC activity may promote focused
or selective attention, whereas the tonic mode may produce a state of high behavioral
flexibility or scanning attentiveness. The implications of these results for clinical
disorders such as attention-deficit hyperactivity disorder, stress disorders,
and emotional and affective disorders are discussed." [Abstract]
CW, Waterhouse BD.
The locus coeruleus-noradrenergic system: modulation
of behavioral state and state-dependent cognitive processes.
Res Brain Res Rev. 2003 Apr;42(1):33-84.
"Through a widespread efferent
projection system, the locus coeruleus-noradrenergic system supplies norepinephrine
throughout the central nervous system. Initial studies provided critical insight
into the basic organization and properties of this system. More recent work identifies
a complicated array of behavioral and electrophysiological actions that have in
common the facilitation of processing of relevant, or salient, information. This
involves two basic levels of action. First, the system contributes to the initiation
and maintenance of behavioral and forebrain neuronal activity states appropriate
for the collection of sensory information (e.g. waking). Second, within the waking
state, this system modulates the collection and processing of salient sensory
information through a diversity of concentration-dependent actions within cortical
and subcortical sensory, attention, and memory circuits. Norepinephrine-dependent
modulation of long-term alterations in synaptic strength, gene transcription and
other processes suggest a potentially critical role of this neurotransmitter system
in experience-dependent alterations in neural function and behavior. The ability
of a given stimulus to increase locus coeruleus discharge activity appears independent
of affective valence (appetitive vs. aversive). Combined, these observations suggest
that the locus coeruleus-noradrenergic system is a critical component of the neural
architecture supporting interaction with, and navigation through, a complex world.
These observations further suggest that dysregulation of locus coeruleus-noradrenergic
neurotransmission may contribute to cognitive and/or arousal dysfunction associated
with a variety of psychiatric disorders, including attention-deficit hyperactivity
disorder, sleep and arousal disorders, as well as certain affective disorders,
including post-traumatic stress disorder. Independent of an etiological role in
these disorders, the locus coeruleus-noradrenergic system represents an appropriate
target for pharmacological treatment of specific attention, memory and/or arousal
dysfunction associated with a variety of behavioral/cognitive disorders."
CM, Wilson MH, MacMillan LB, Kobilka BK, Limbird LE.
alpha 2A-adrenergic receptor mice unveil unique therapeutic benefits of partial
Proc Natl Acad Sci U S A 2002 Sep 17;99(19):12471-6
manipulation of the alpha(2A)-adrenergic receptor (alpha(2A)-AR) in mice has revealed
the role of this subtype in numerous responses, including agonist-induced hypotension
and sedation. Unexpectedly, alpha(2)-agonist treatment of mice heterozygous for
the alpha(2A)-AR (alpha(2A)-AR(+/-)) lowers blood pressure without sedation, indicating
that more than 50% of alpha(2A)-AR must be activated to evoke sedation. We postulated
that partial activation of alpha(2A)-AR in wild-type alpha(2A)-AR(+/+) animals
could be achieved with partial agonists, agents with variable ability to couple
receptor occupancy to effector activation, and might elicit one versus another
pharmacological response. In vitro assays reveal that moxonidine is a partial
agonist at alpha(2A)-AR. Although moxonidine was developed to preferentially interact
with imidazoline binding sites, it requires the alpha(2A)-AR to lower blood pressure
because we observe no hypotensive response to moxonidine in alpha(2A)-AR-null
(alpha(2A)-AR(-/-)) mice. Moreover, we observe that moxonidine lowers blood pressure
without sedation in wild-type mice, consistent with the above hypothesis regarding
partial agonists. Our findings suggest that weak partial agonists can evoke response-selective
pathways and might be exploited successfully to achieve alpha(2A)-AR pharmacotherapy
where concomitant sedation is undesirable, i.e., in treatment of depression or
attention deficit hyperactivity disorder, in suppression of epileptogenesis, or
enhancement of cognition. Furthermore, rigorous physiological and behavioral assessment
of mice heterozygous for particular receptors provides a general strategy for
elucidation of pathways that might be selectively activated by partial agonists,
thus achieving response-specific therapy." [Abstract]
JS, Kessler LE, Borja CM, Kobilka BK, Limbird LE, Arnsten AF.
of the alpha2A-adrenoceptor impairs working memory performance and annuls cognitive
enhancement by guanfacine.
J Neurosci 2002 Oct 1;22(19):8771-7
strengthens the working memory, behavioral inhibition, and attentional functions
of the prefrontal cortex through actions at postsynaptic alpha2-adrenoceptors
(alpha2-AR). The alpha2-AR agonist guanfacine enhances prefrontal cortical functions
in rats, monkeys, and human beings and ameliorates prefrontal cortical deficits
in patients with attention deficit hyperactivity disorder. The present study examined
the subtype of alpha2-AR underlying these beneficial effects. Because there are
no selective alpha2A-AR, alpha2B-AR, or alpha2C-AR agonists or antagonists, genetically
altered mice were used to identify the molecular target of the action of guanfacine.
Mice with a point mutation of the alpha2A-AR, which serves as a functional knock-out,
were compared with wild-type animals and with previously published studies of
alpha2C-AR knock-out mice (Tanila et al., 1999). Mice were adapted to handling
on a T maze and trained on either a spatial delayed alternation task that is sensitive
to prefrontal cortical damage or a spatial discrimination control task with similar
motor and motivational demands but no dependence on prefrontal cortex. The effects
of guanfacine on performance of the delayed alternation task were assessed in
additional groups of wild-type versus alpha2A-AR mutant mice. We observed that
functional loss of the alpha2A-AR subtype, unlike knock-out of the alpha2C-AR
subtype, weakened performance of the prefrontal cortical task without affecting
learning and resulted in loss of the beneficial response to guanfacine. These
data demonstrate the importance of alpha2A-AR subtype stimulation for the cognitive
functions of the prefrontal cortex and identify the molecular substrate for guanfacine
and novel therapeutic interventions." [Abstract]
FB, Russo J.
Comparing guanfacine and dextroamphetamine for the treatment
of adult attention-deficit/hyperactivity disorder.
Psychopharmacol 2001 Apr;21(2):223-8
"The objective of this study was
to compare the efficacy of the alpha-2a agonist guanfacine with that of dextroamphetamine
for the treatment of adult attention-deficit/hyperactivity disorder (ADHD). Seventeen
adult outpatients who met DSM-IV criteria for ADHD participated in a double-blind,
placebo-controlled, crossover study comparing drug effects on ADHD symptoms. Measures
of change included the DSM-IV ADHD Behavior Checklist for Adults and the Copeland
Symptom Checklist for Adult Attention Deficit Disorders. Cognitive measures of
attention included the Stroop and Controlled Oral Word Association Test using
the letters "C," "F," and "L" (COWAT, CFL version).
For each trial, the drug was administered daily and titered up to optimal doses
of maximum efficacy but with a minimum of side effects, and then data were collected.
Both drugs significantly reduced ADHD symptoms on the DSM-IV Adult Behavior Checklist
for Adults over placebo (p < 0.05). The Stroop Color subscale showed significant
improvement for both drugs (p < 0.05), but the Color-Word measures showed significant
improvement for guanfacine only (p < 0.01). The average dose of guanfacine
was 1.10 (SD = 0.60), and the most common side effect of guanfacine was fatigue.
No subjects discontinued drug trials. This preliminary study indicates that guanfacine
may be a well-tolerated treatment option for adult ADHD." [Abstract]
WO, Bylund DB, Hodges K, Glaser R, Ray-Prenger C, Oetting G.
alpha 2-adrenergic receptor binding and the effects of d-amphetamine in boys with
attention deficit hyperactivity disorder.
"Presynaptic inhibitory alpha-adrenergic receptors are
involved in regulating the release of norepinephrine (NE) through a negative feedback
mechanism mediated by NE. Increased alpha2-adrenergic receptor activity suggests
decrease NE release and activity, while decreased alpha2-adrenergic activity suggests
increase NE release and activity. A large body of evidence suggests the involvement
of a disturbance in NE activity in the pathophysiology of attention deficit hyperactivity
disorder (ADHD) in childhood. Platelet alpha2-adrenergic receptor binding was
compared in 23 boys aged 7-12 with the diagnosis of ADHD and 11 normal controls.
The ADHD boys tended to have lower levels of alpha2-binding than controls. The
administration of d-amphetamine in a double-blind placebo-controlled crossover
design did not have any effect on alpha2-receptor binding in ADHD boys. Nonresponders
to d-amphetamine had the lowest alpha2-receptor binding compared to responders
and controls. These findings suggest a normal alpha2-adrenergic activity in ADHD
boys responders to d-amphetamine and a possible increase in NE release in ADHD
boys nonresponders to d-amphetamine due to decreased alpha2-adrenergic receptors."
Elia J, Borcherding BG, Potter WZ, Mefford IN, Rapoport
JL, Keysor CS.
Stimulant drug treatment of hyperactivity: biochemical
Clin Pharmacol Ther 1990 Jul;48(1):57-66
compare the effects of the stimulant drugs dextroamphetamine and methylphenidate
on urinary and plasma monoamines and metabolites within the same clinical sample,
thirty-one children with attention-deficit disorder with hyperactivity were treated
with dextroamphetamine (up to 1.5 mg/kg/day), methylphenidate (up to 3.0 mg/kg/day),
and placebo in an 11-week double-blind crossover trial. As expected, both drugs
showed striking clinical efficacy, and within a subsample of the group, earlier
findings were confirmed, that dextroamphetamine but not methylphenidate lowered
urinary and plasma 3-methoxy-4-hydroxyphenylglycol and whole body norepinephrine
turnover, and that urinary and plasma concentration of homovanillic acid was unaltered
by either drug. Methylphenidate but not dextroamphetamine increased plasma norepinephrine.
Urinary epinephrine and metanephrine were increased with both drugs, but this
increase did not correlate significantly with clinical improvement." [Abstract]
WO, Javaid J, Dekirmenjian H, Chapel JL, Davis JM.
Effects of d-amphetamine
on urinary metabolites of dopamine and norepinephrine in hyperactive boys.
J Psychiatry 1982 Apr;139(4):485-8
"The authors measured the urinary metabolites
3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in 21 hyperactive
boys and 12 matched healthy boys. The hyperactive boys excreted lower amounts
of MHPG than control boys. Hyperactive drug responders excreted lower amounts
of HVA than control boys and hyperactive nonresponders. Drug responders with normal
MHPG excreted low amounts of HVA and those with normal HVA excreted low amounts
of MHPG. d-Amphetamine decreased MHPG in all drug responders and HVA in drug responders
with normal HVA levels, although it tended to increase HVA in those with low HVA
levels. The authors discuss their data in terms of the possible involvement of
norepinephrine and dopamine in the etiology of hyperactivity in children."
WO, Javaid J, Davis JM, Bylund DB.
Urinary MHPG and HVA excretion
in boys with attention deficit disorder and hyperactivity treated with d-amphetamine.
Psychiatry 1983 Jun;18(6):707-14
"The authors examined the excretion of
3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in nine hyperactive
and nine control boys admitted to a clinical research center. The hyperactives
excreted lower 24 hr MHPG and HVA levels than controls. d-Amphetamine 0.5 mg/kg
body weight daily for 2 weeks decreased MHPG and increased HVA. These data replicate
the authors' previous findings on MHPG and HVA and on the effect of d-amphetamine
in hyperactive children. The data suggest the involvement of norepinephrine and
dopamine in the etiology of hyperactivity. It further suggests d-amphetamine may
achieve its clinical effects in hyperactivity by inhibiting NE and potentiating
DA activity." [Abstract]
M, Zametkin AJ, Rapoport JL, Ismond DR, Weingartner H, Lane E, Oliver J, Linnoila
M, Potter WZ.
Treatment of childhood hyperactivity with desipramine:
plasma drug concentration, cardiovascular effects, plasma and urinary catecholamine
levels, and clinical response.
Clin Pharmacol Ther 1986
"Twenty-nine boys with attention deficit disorder/hyperactivity
were randomly assigned to receive desipramine (DMI; n = 17) or placebo (n = 12)
for 14 days in a noncrossover, double-blind study. There was immediate behavioral
improvement with DMI at day 3 that was sustained for 2 weeks; behavioral improvement
did not correlate with plasma concentrations of DMI, hydroxy-DMI, or their sum
at either days 3 or 14. There were no untoward side effects; there was a drug-induced
increase in pulse and diastolic blood pressure. During drug therapy, the urinary
excretion of norepinephrine, vanillymandelic acid, and 3-methoxy-4-hydroxyphenylglycol
(MHPG) was decreased at both days 3 and 14. The plasma MHPG level was decreased
at days 3 and 14 and (standing) plasma NE levels increased at day 14. The decreases
in both urinary and plasma MHPG levels showed significant correlations with behavioral
improvement during the second week. These data corroborate previous findings on
sympathomimetic effects of tricyclic antidepressants in children and support a
noradrenergic mechanism in the mediation of drug effects on attention deficit
M, Rapoport JL, Potter WZ, Oliver J, Keysor CS, Murphy DL.
and dextroamphetamine treatment of childhood hyperactivity. Clinical and biochemical
Arch Gen Psychiatry 1989 Mar;46(3):205-12
boys (mean age, 9 +/- 2 years) with attention deficit disorder with hyperactivity
received three weeks each of dextroamphetamine sulfate (0.5 mg/kg/d), fenfluramine
hydrochloride (0.6 mg/kg/d increased to 2.0 mg/kg/d), and placebo in a double-blind,
random-order, crossover design. Half the boys also met criteria for conduct disorder.
Dextroamphetamine produced immediate and marked improvement in disruptive, overactive
behaviors. Fenfluramine had no effect on any behavioral measure at either the
low or high dosage. Both drugs decreased levels of urinary norepinephrine, 3-methoxy-4-hydroxyphenylglycol
(MHPG), and vanillylmandelic acid. Fenfluramine, however, also produced a significant
decrease in plasma MHPG levels and a larger decrease in urinary norepinephrine
levels. It reduced urinary epinephrine levels as well, an effect opposite to that
of dextroamphetamine. These findings suggest that different mechanisms of action
are involved in the ability of the two drugs to reduce levels of MHPG and vanillylmandelic
acid. Fenfluramine increased plasma prolactin levels and decreased platelet serotonin
levels. Despite the structural similarity of the two drugs, some common overall
effects on catecholamine metabolism, and similar effects on weight, fenfluramine
had none of the motor activity or therapeutic effects of dextroamphetamine."
AJ, Hamburger SD.
The effect of methylphenidate on urinary catecholamine
excretion in hyperactivity: a partial replication.
Psychiatry 1988 Feb 15;23(4):350-6
"Children with attention deficit disorder
with hyperactivity were treated with methylphenidate HCl (0.74 +/- 0.2 mg/kg/day)
for 2 weeks in an open trial to assess changes in the urinary excretion of catecholamines
and behavior. The purpose of this study was to confirm earlier work that methylphenidate
has a distinctly different effect on urinary 3-methoxy-4-hydroxyphenylglycol (MHPG)
excretion as compared to earlier studies with dextroamphetamine. Results confirmed
the earlier finding that methylphenidate does not significantly change urinary
MHPG excretion. No significant relationship was found between behavioral change
and any of the urinary catecholamines or metabolites measured." [Abstract]
AJ, Karoum F, Linnoila M, Rapoport JL, Brown GL, Chuang LW, Wyatt RJ.
urinary catecholamines, and indoleamines in hyperactivity. A comparison of methylphenidate
Arch Gen Psychiatry 1985 Mar;42(3):251-5
with attention deficit disorder with hyperactivity were given either methylphenidate
hydrochloride or dextroamphetamine sulfate to compare the effects on urinary excretion
of catecholamines, indoleamines, and phenylethylamine (PEA). Methylphenidate's
effects were distinctly different from those of dextroamphetamine. After methylphenidate
administration, both norepinephrine (NE) and normetanephrine (NMN) concentrations
were significantly elevated, and there was a 22% increase in excretion of 3-methoxy-4-hydroxyphenylglycol
(MHPG). In contrast, after dextroamphetamine treatment, MHPG excretion was significantly
reduced and NE and NMN values were unchanged. Excretion of dopamine and metabolites
was unchanged by either drug. Urinary PEA excretion was not significantly changed
after methylphenidate treatment, but increased 1,600% in response to dextroamphetamine.
Methylphenidate treatment did not significantly alter serotonin or 5-hydroxyindoleacetic
acid excretion. Effects of dextroamphetamine were not tested." [Abstract]
B, Vered Y, Yoran-Hegesh R, Graff E, Averbuch E, Vinokurow S, Weizman A, Mester
The influence of three months of methylphenidate treatment on
platelet-poor plasma biogenic amine levels in boys with attention deficit hyperactivity
Hum Psychopharmacol 2001 Jun;16(4):333-337
deficit hyperactivity disorder (ADHD) is related to dysregulation in the activity
of brain monoamines. The aim of the present study was to assess the impact of
three months' methylphenidate (MPH) treatment on platelet-poor plasma (PPP) norepinephrine
(NE), dopa and serotonin (5-HT) levels as well as on ADHD symptomatology. Three
months of MPH treatment in 16 ADHD boys, aged 11.4 +/- 1.6 years, resulted in
a significant reduction in PPP NE levels (p < 0.05). A tendency towards a reduction
of PPP 5-HT and dopa levels was detected (p < 0.1 for both). The decrease in
PPP biogenic amine levels after three months of MPH treatment was accompanied
by a significant reduction in all psychometric characteristics of ADHD. This result
indicates the possible role of overactivity of the noradrenergic system in the
pathophysiology of ADHD and suggests that the MPH therapeutic action may be related
to stimulant-induced inhibitory effect on the noradrenergic system." [Abstract]
KA, Keating GM.
Extended-release methylphenidate (Ritalin LA).
2002;62(15):2251-9; discussion 2260-1
"An extended-release formulation
of methylphenidate (Ritalin LA), a CNS stimulant that inhibits dopamine and noradrenaline
(norepinephrine) reuptake into presynaptic neurons, has been developed for use
in patients with attention deficit/hyperactivity disorder (ADHD). In children
with ADHD and healthy male adults, extended-release methylphenidate 20mg was rapidly
absorbed and demonstrated two distinct peak plasma concentrations approximately
4 hours apart. The absorption pharmacokinetics of extended-release methylphenidate
20mg, which closely mimics those of immediate-release methylphenidate 10mg given
in two doses 4 hours apart, permits once-daily administration. In a 2-week randomised,
double-blind, placebo-controlled trial in 134 evaluable children aged 6 to 12
years with ADHD, symptoms improved to a significantly greater extent with extended-release
methylphenidate 10 to 40mg once daily than with placebo. Extended-release methylphenidate
improved both inattention and hyperactivity symptoms and was effective in children
with combined- (inattentive and hyperactive/impulsive) type or predominantly inattentive-type
ADHD. In clinical trials, the safety and tolerability profiles of extended-release
methylphenidate were consistent with that of the immediate-release formulation."
GA, Wasserstein J.
Attention deficit/hyperactivity disorder as a
right hemisphere syndrome. Selective literature review and detailed neuropsychological
Ann N Y Acad Sci 2001 Jun;931:172-95
studies of ADHD implicate well-defined neuroanatomical networks and neurochemical
pathways in its pathophysiological basis. Considerable attention has focused on
the role of anterior and superior frontal regions and portions of the basal ganglia,
including the caudate nucleus and globus pallidus. This paper reviews a growing
literature suggesting differential involvement of right hemisphere mechanisms
specialized for behavioral regulation and attention. Supportive data are drawn
from neuropsychology, neuroanatomy, and neurochemistry. In addition, three cases
are presented that illustrate the complex role of right hemisphere dysfunction
in adult manifestations of ADHD. We suggest that the pleomorphic presentations
of ADHD can be understood in terms of a spectrum of disturbances in overlapping
neural regions, especially involving frontal and parietal areas of the right hemisphere
and their connections to subcortical structures (including the striatum, limbic
system and diencephalic nuclei)." [Abstract]
SR, McCracken JT, Maas JW.
Catecholamines in attention-deficit hyperactivity
disorder: current perspectives.
J Am Acad Child Adolesc
Psychiatry 1996 Mar;35(3):264-72
"OBJECTIVE: To provide an update on the
"catecholamine hypothesis" of attention-deficit hyperactivity disorder
(ADHD). METHOD: Recent work examining the measurement of the norepinephrine, epinephrine,
and dopamine systems in ADHD and normal subjects is reviewed and discussed in
the context of recent neuroimaging and animal studies. RESULTS: While data clearly
indicate a role for all three of the above neurotransmitters in ADHD, a hypothesis
suggesting "too much" or "too little" of a single neurotransmitter
will no longer suffice. The central norepinephrine system may be dysregulated
in ADHD, such that this system does not efficiently "prime" the cortical
posterior attention system to external stimuli. Effective mental processing of
information involves an anterior "executive" attention system which
may depend on dopaminergic input. The peripheral epinephrine system may be a critical
factor in the response of individuals with ADHD to stimulant medication. CONCLUSION:
A multistage hypothesis is presented which emphasizes the interaction of norepinephrine,
epinephrine, and dopamine in modulation of attention and impulse control."
Castellanos FX, Elia J, Kruesi MJ, Gulotta CS, Mefford
IN, Potter WZ, Ritchie GF, Rapoport JL.
Cerebrospinal fluid monoamine
metabolites in boys with attention-deficit hyperactivity disorder.
Res 1994 Jun;52(3):305-16
"Cerebrospinal fluid (CSF), plasma, and urinary
monoamine metabolites were determined for 29 boys, aged 6-12, with attention-deficit
hyperactivity disorder (ADHD). Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA),
homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), the metabolites
of serotonin, dopamine, and norepinephrine, respectively, correlated significantly
with behavioral measures of aggression and impulsivity/hyperactivity. However,
these correlations were in the unexpected direction; for example, CSF 5-HIAA correlated
positively with the Brown-Goodwin Lifetime History of Aggression Scale. HVA in
CSF was positively correlated with several measures of hyperactivity. The replicability
of these findings, as well as possible socioenvironmental effects, and the predictive
value of CSF monoamines in prepubertal hyperactivity are the subjects of ongoing
Oades RD, Daniels R, Rascher W.
neuropeptide-Y levels, monoamine metabolism, electrolyte excretion and drinking
behavior in children with attention-deficit hyperactivity disorder.
Psychiatry Res 1998 Aug 17;80(2):177-86
"Against a background of (a) increased
drinking behavior in children with attention-deficit hyperactivity disorder (ADHD);
(b) the parallel between some behaviors associated with ADHD and hypertension;
(c) the use of the spontaneously hypertensive rat as a model for ADHD; and (d)
similarities in the changes of neuropeptide Y (NPY) and catecholamine in studies
of hypertension and drinking, NPY, catecholamines and electrolyte balance were
compared in the plasma and urine of healthy children and those with ADHD. Drinking
was monitored during 3 h of neuropsychological tests over 2 days in 14 ADHD and
nine healthy children. Patients drank four times as much water and showed twice
the levels of NPY found in controls. In controls there were positive and in patients
there were negative relationships for NPY with drinking and restless behavior.
Patients' plasma levels of norepinephrine (NE) and epinephrine were slightly elevated,
but urinary levels of NE and the serotonin metabolite were markedly increased.
Urinary excretion rates for sodium (not potassium), phosphate and especially calcium
were decreased in patients even after covarying for less urine production in the
ADHD group. NPY levels were inversely related to calcium excretion and drinking
was inversely related to circulating sodium. Increases of drinking and circulating
NPY in ADHD children and decreased electrolyte excretion may reflect a common
disturbance in metabolic homeostasis." [Abstract]
Dopamine may be 'hyper' with respect to noradrenaline metabolism,
but 'hypo' with respect to serotonin metabolism in children with attention-deficit
Behav Brain Res 2002 Mar 10;130(1-2):97-102
Hechtman (J Psychiat Neurosci 1994;19:193) argued for a role for frontal dopamine
(DA) and noradrenaline (NA) in ADHD, where Oades (Prog Neurobiol 1987;29:365)
has described lateralised functional impairments. Mechanisms (e.g. via alpha-2
sites) for stimulating low NA activity in ADHD children (J Am Acad Child Adolesc
Psychiatry 1997;36:1688) in order to promote interactions with mesocortical DA
have been discussed (J Psychopharmacology 1997;11:151; Psychiatr Res 1994;52:305).
We described with indicators of overall transmitter metabolism (monoamines, metabolites
in 24 h urine samples (Behav Brain Res 1997;88:95)) significantly lower utilisation
ratios (MHPG/NA) in ADHD children with respect to healthy controls. Interestingly,
a comparison of between catecholamine levels (DA/NA) showed a correlation with
the conditioned blocking measure of selective attention recorded at the time of
collection. This measure was negatively associated with blocking in controls.
These results are consistent with reports of lower DOPEG and increased DOPAC in
ADHD urine (J Child Adolesc Psychopharmacol 1996;6:63) and indicate that the relatively
hyperactive DA versus NA systems may have functional consequences. Serotonin:
the relevance for ADHD of an association of impulsivity with low serotonin (5-HT)
metabolism (Behav Brain Sci 1986;9:319) has long been played down. Yet, some symptoms
have been related to CSF measures of the metabolite 5-HIAA, and in particular
the HVA/5-HIAA ratio has been reported to correlate with ratings of activity (Psychiatr
Res 1994;52:305). We find that while urinary measures of 5-HIAA are somewhat higher,
the ratio HVA/5-HIAA is markedly lower in ADHD children versus controls. In these
ADHD children 5-HIAA levels were negatively related to d-prime measures in a continuous
performance task (CPTax), and the HVA/5-HIAA was negatively associated with conditioned
blocking. These results suggest a relatively low DA versus 5-HT activity may have
functional consequences, albeit in a subgroup of ADHD. This is consistent with
drug-induced prolactin changes reported by Verbaten et al. (Eur Child Adolesc
Psychiatry 1999;8:30)." [Abstract]
EV, Larionov NP, Popkova EV, Briazgunov IP.
[Metabolism of catecholamines
in children with attention deficit syndrome with hyperactivity]
Med Khim 2000 Sep-Oct;46(5):455-61
"The aim of research was to study catecholamine
excretion peculiarities of the children with attention deficit hyperactivity disorder
(ADHD). 25 children at the age of 7-9 years took part in this research. High-pressure
liquid chromatography (HPLC) was used for measuring the content of catecholamine.
The content of catecholamine was defined in the morning samples of urine. The
examination showed, that ADHD children had the basal level of epinephrine and
norepinephrine more than the normal control in 3.9 and 5.4 times. After cognitive
tests the content of norepinephrine reduced in the ADHD group in 2.1 times in
the comparison with normal control. On the contrary content of epinephrine increased
in 2.8 times. CONCLUSION: Simpatico-adrenal system hyperactivity (especially it's
adrenals component) characterized ADHD children." [Abstract]
Hypodopaminergic and hypernoradrenergic activity in prefrontal
cortex slices of an animal model for attention-deficit hyperactivity disorder--the
spontaneously hypertensive rat.
Behav Brain Res 2002 Mar
"Evidence supports dysfunction of dopaminergic and noradrenergic
systems in patients with attention-deficit hyperactivity disorder (ADHD). Noradrenergic
and dopaminergic systems exert distinct modulatory actions on the transfer of
information through neural circuits that connect functionally distinct cortical
areas with separate striatal regions and remain segregated in parallel striato-pallidal-thalamic
and striato-substantia nigra pars reticulata-thalamic pathways. Prefrontal cortex
performance is maximal at moderate stimulation of postsynaptic dopaminergic and
noradrenergic receptors, and is reduced by either higher or lower levels of receptor
stimulation. Spontaneously hypertensive rats (SHR) are generally considered to
be a suitable genetic model for ADHD, since they display hyperactivity, impulsivity,
poor stability of performance, impaired ability to withhold responses and poorly
sustained attention, when compared with their normotensive Wistar-Kyoto (WKY)
control rats. Evidence suggests that terminals of mesocortical, mesolimbic and
nigrostriatal dopaminergic neurons of SHR release less dopamine in response to
electrical stimulation and/or depolarization as a result of exposure to high extracellular
K+ concentrations, than WKY. Vesicular storage of dopamine was suggested to be
impaired in SHR, causing leakage of dopamine into the cytoplasm and increased
d-amphetamine-induced transporter-mediated release. While electrically stimulated
release of dopamine appears to be decreased in prefrontal cortex of SHR suggesting
hypodopaminergic function, autoreceptor-mediated inhibition of norepinephrine
release appears to be impaired in SHR, suggesting that noradrenergic function
may be poorly regulated in the prefrontal cortex of the SHR. These findings are
consistent with the hypothesis that the behavioral disturbances of ADHD are the
result of an imbalance between noradrenergic and dopaminergic systems in the prefrontal
cortex, with inhibitory dopaminergic activity being decreased and noradrenergic
activity increased relative to controls." [Abstract]