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Dysregulation of the central noradrenergic
network has long been hypothesized to underlie the pathophysiology of
attention-deficit/hyperactivity disorder (ADHD) (Arnsten etal., 1996).
This hypothesis is derived largely from pharmacological data documenting
that drugs which selectively modulate noradrenergic function show efficacy
in treating ADHD. However, a noradrenergic hypothesis of ADHD is compelling
in its own right because the noradrenergic system has been intimately
associated with the modulation of higher cortical functions including
attention, alertness, and vigilance. As recently reviewed by Solanto (1998),
preclinical and clinical research has implicated the noradrenergic effects
of stimulants in enhancing capacities such as delayed responding, working
memory, and attention. Furthermore, executive function and noradrenergic
activation are known to profoundly affect the performance of attention,
especially the maintenance of arousal, and the ability to sustain attention
on a subject, particularly a boring one.
Current
neuropsychological, genetic, imaging, and pharmacological data emerging
in ADHD research provide compelling support for a noradrenergic hypothesis
of ADHD (Arnsten etal., 1996). Figure
1 Attention
and vigilance depend on adequate modulation by catecholamine neurotransmitters
of prefrontal, cingulate, and parietal cortices, thalamus, striatum, and
hippocampus. These brain networks all have a high density of catecholamine
terminals.
Perhaps the most compelling evidence
for a noradrenergic hypothesis for ADHD derives from psychopharmacological
data (Spencer etal., 1996). Preclinical studies have shown that stimulants
block the reuptake of dopamine and norepinephrine into the presynaptic
neuron and increase the release of these monoamines into the extraneuronal
space. Early animal studies used 6-hydroxydopamine to lesion dopamine
pathways in developing rats. Because these lesions created hyperactivity,
they were thought to provide an animal model of ADHD. Although not entirely
sufficient, changes in dopaminergic and noradrenergic function appear
necessary for the clinical efficacy of the stimulants. Also, the maximal
therapeutic effects of stimulants occur during the absorption phase of
the kinetic curve, within 2 hours after ingestion. The absorption phase
parallels the acute release of neurotransmitters into synaptic clefts,
providing support for the hypothesis that alteration of monoaminergic
transmission in critical brain regions may be the pharmacological basis
for the effects of stimulants in ADHD. A plausible model is that these
medications increase the inhibitory influences of frontal cortical activity
on subcortical structures through dopaminergic and noradrenergic pathways
(Zametkin and Rapoport, 1987). Indeed, Kuzcenski recently found that low
doses of methylphenidate preferentially release norepinephrine. In contrast,
effects on serotonin metabolism appear minimally related to the clinical
efficacy of the stimulants.
Evidence for noradrenergic actions
also comes from studies of antidepressant compounds used to treat ADHD.
While the tertiary amines (imipramine and amitriptyline) are more selective
for the serotonin transporter than for the norepinephrine transporter,
the secondary amines (desipramine, nortriptyline, and protriptyline) are
more selective for the norepinephrine transporter. It is assumed that
the activity of the tricyclic antidepressants (TCAs) in ADHD stems from
their actions on catecholamine reuptake, particularly that of norepinephrine.
Advantages of this class of drugs include their relatively long half-lives
(approximately 12 hours), obviating the need to administer medication
during school hours and lowering the potential for drug abuse or side
effects, and their potentially positive effects on mood and anxiety symptoms.
Of 33 studies (21 controlled and 12
open) evaluating TCAs in hyperactive children, adolescents (n = 1,139),
and adults (n = 78), 30 reported positive effects on ADHD symptoms. Imipramine
and desipramine are the most studied TCAs; there are a handful of studies
on the others. The largest controlled study of a TCA in hyperactive children
found favorable results with desipramine (DMI) in 62 clinically referred
children with ADHD, most of whom had previously failed to respond to psychostimulant
treatment (Biederman etal., 1989). The study was a randomized, placebo-controlled,
parallel-design, 6-week clinical trial. Clinically and statistically significant
differences in behavioral improvement were found for DMI over placebo,
at an average daily dose of 5 mg/kg. Specifically, 68% of DMI-treated
patients were considered very much or much improved, compared with only
10% of placebo patients (p < .001). Although the presence of comorbidity
increased the likelihood of a placebo response, neither comorbidity with
conduct disorder, depression, or anxiety nor a family history of ADHD
yielded differential responses to DMI treatment. In addition, DMI-treated
patients showed a substantial reduction in depressive symptoms compared
with placebo-treated patients.
In a similarly designed controlled
clinical trial in 41 adults with ADHD, DMI, at an average daily dose of
150 mg (average serum level of 113 ng/mL), was statistically and clinically
more effective than placebo. Sixty-eight percent of DMI-treated patients
responded compared with none of the placebo-treated patients (p < .0001).
Moreover, the average severity of ADHD symptoms at the end of the study
was reduced to below the level required to meet diagnostic criteria. Importantly,
while the full DMI dose was achieved at week 2, clinical response improved
further over the following 4 weeks, indicating a latency of response.
Response was independent of dose, serum DMI level, gender, or lifetime
psychiatric comorbidity with anxiety or depressive disorders (Wilens etal.,
1995).
In a prospective, placebo-controlled
discontinuation trial, we recently demonstrated the efficacy of nortriptyline
in doses of up to 2 mg/kg daily in 35 school-age youths with ADHD. In
that study, 80% of youths responded by week 6 in the open phase. During
the discontinuation phase, subjects randomly assigned to placebo lost
the anti-ADHD effect compared with those receiving nortriptyline, who
maintained a robust anti-ADHD effect. There was again a lag in response
to medication and also a lag in loss of response after medication discontinuation.
Although the full dose was achieved by week 2, the full effect evolved
slowly over the ensuing 4 weeks. ADHD youths receiving nortriptyline also
were found to have modest but statistically significant reductions in
oppositionality and anxiety. Nortriptyline was well tolerated, with some
weight gain. Weight gain is frequently considered to be a desirable side
effect in this population. In contrast, a systematic study in 14 treatment-refractory
ADHD youths receiving protriptyline (mean dose of 30 mg) reported less
favorable results. We found that only 45% of ADHD youths responded or
could tolerate protriptyline because of its adverse effects (Wilens etal.,
1995).
The potential benefits of TCAs in
the treatment of ADHD have been clouded by concerns about their safety
stemming from reports of sudden unexplained death in 4 children with ADHD
treated with DMI (Biederman etal., 1989), although the causal link between
DMI and these deaths remains uncertain. A rather extensive body of literature
evaluating cardiovascular parameters in TCA-exposed youths consistently
identified mostly minor, asymptomatic, but statistically significant increases
in heart rate and electrocardiographic measures of cardiac conduction
times associated with TCA treatment. A recent report estimated that the
magnitude of DMI-associated risk of sudden death in children may not be
much larger than the baseline risk of sudden death in this age group.
However, because of this uncertainty, prudence mandates that until more
is known, TCAs should be used as second-line treatment for ADHD and only
after carefully weighing the risks and benefits of treating or not treating
an affected child.
Bupropion hydrochloride is a novel-structured
antidepressant of the aminoketone class related to the phenylisopropylamines
but pharmacologically distinct from known antidepressants. Bupropion appears
to possess both indirect dopamine agonist and noradrenergic effects. Bupropion
has been shown to be effective for ADHD in children in a controlled multisite
study (n = 72) and in a comparison with methylphenidate (n = 15). In an
open study of adults with ADHD, sustained improvement was documented at
1 year at an average of 360 mg for 6 to 8 weeks. In a placebo-controlled
6-week trial of sustained-release bupropion (up to 200 mg b.i.d.) in adults
with ADHD,sustained-release bupropion was well tolerated and effective.
Of 38 completers, 76% improved (>30% reduction of symptoms) compared
with 37% receiving placebo (p = .012). While bupropion has been associated
with a slightly increased risk (0.4%) for drug-induced seizures relative
to other antidepressants, this risk has been linked to high doses, a previous
history of seizures, and eating disorders.
Although a small number of studies
suggested that monoamine oxidase inhibitors (MAOIs) may be effective in
treating juvenile and adult ADHD, their potential for hypertensive crisis
associated with the irreversible MAOIs (e.g., phenelzine, tranylcypromine),
due to dietary transgressions (tyramine-containing foods, i.e., most cheeses)
and drug interactions (pressor amines, most cold medicines, amphetamines),
seriously limits their use. This "cheese effect" may be obviated
with the reversible MAOIs (e.g., moclobemide) that have shown promise
in one open trial, although they are not yet available in the United States.
Promising results have been associated
with the experimental noradrenergic-specific compound, tomoxetine. One
controlled clinical trial in adults documented efficacy and good tolerability.
These initial encouraging results, coupled with extensive safety data
in adults, fueled efforts at testing this compound in the treatment of
pediatric ADHD. An initial open study documented clinical benefits with
excellent tolerability, including a safe cardiovascular profile.
Drugs that mimic norepinephrine at
the a2-receptor are also used in the treatment of ADHD. Despite its wide
use in children with ADHD, there have been very few studies (n = 4 studies
[2 controlled]; n = 122 children) supporting the efficacy of clonidine.
Treatment with clonidine appears to have mostly a behavioral effect in
disinhibited and agitated youths, with limited impact on cognition. Several
cases of sudden death have been reported in children treated with clonidine
plus methylphenidate, raising concerns about the safety of this combination.
Limited literature exists for guanfacine, a more selective a2A-receptor
agonist with fewer side effects. There are 3 small open studies of guanfacine
in children and adolescents with ADHD. In these studies, beneficial effects
on hyperactive behaviors and attentional abilities were reported. In addition,
in a controlled study in normal adults, guanfacine, but not clonidine,
improved planning and spatial working memory. In another controlled study
in adults with ADHD, guanfacine was reported to improve ADHD symptoms
(K. Fletcher, personal communication, 2000). Most recently, a controlled
trial in children with ADHD and tics has shown that guanfacine can improve
ADHD symptoms and reduce tics (L. Scahill, personal communication, 2000).
Thus a variety of noradrenergic agents can improve ADHD symptoms.
In contrast, serotonergic antidepressants
are less effective in the treatment of ADHD. While a single, small, open
study suggested that fluoxetine may be beneficial in the treatment of
children with ADHD, the usefulness of selective serotonin reuptake inhibitors
in the treatment of core ADHD symptoms is not supported by clinical experience
(NIMH, 1996). Similarly uncertain is the usefulness of the mixed serotonergic/noradrenergic
atypical antidepressant venlafaxine in the treatment of ADHD. While a
77% response rate was reported in completers in open studies of adults
with ADHD, 21% dropped out because of side effects (n = 4 open studies;
n = 61 adults). In addition, a single open study of venlafaxine in 16
children with ADHD found a 50% response rate in completers with a 25%
rate of dropout due to side effects, most prominently increased hyperactivity.
In summary, although there is no single
pathophysiological profile of ADHD, data implicate dysfunction in the
fronto-subcortical pathways that control attention and motor behavior.
Moreover, the effectiveness of stimulants, along with animal models of
hyperactivity, point to catecholamine dysregulation as at least one source
of brain dysfunction in persons with ADHD. There is a great need for more
research on the role of norepinephrine in ADHD. As most existing research
on stimulants has focused on dopamine, it will be important for basic
research to examine norepinephrine mechanisms altered by stimulants and
other medications. There is also a need for genetic studies to include
the norepinephrine transporter, norepinephrine synthetic enzymes, and
norepinephrine receptors in ADHD families. Despite their chemical differences,
the various compounds with documented anti-ADHD activity share a common
noradrenergic/dopaminergic activity. In this regard, it is notable that
both noradrenaline as well as dopamine are potent agonists at the D4
receptor, a gene that has been implicated in the etiology of this disorder
(Lanau etal., 1997). It is hoped that advances in the understanding of
the underlying neurobiology of ADHD will lead to the development of a
new generation of safe and effective treatments for this disorder. Such
developments have the promise of revolutionizing the field and improving
the quality of life of the millions of affected patients and their families
worldwide.
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