Psychopharmacology
Psychopharmacological treatments of the AD-DBDs can
be traced to 1930s when benzedrine was successfully used to treat a
heterogeneous group of behaviorally disturbed children and adolescents.
Psychostimulants remain the medication of choice for the majority of children
with ADHD. They have been stud-ied in literally hundreds of controlled trials
in all age groups, have documented safety and are now available in extended
re-lease preparations that are easy to use and decrease the potential for
stigma associated with school administration that previously plagued children
and families with ADHD. However, several other currently available medications
have demonstrated efficacy for ADHD and are often used off-label to treat this
condition. They offer useful alternatives for those who are stimulant
nonre-sponders, or for whom stimulants may be contraindicated.
Methylphenidate (MPH), dextroamphetamine (DEX) and
mix-ture of amphetamine salts (MAS) (which is a mixture of several amphetamine
compounds, 75% of which is DEX) have all been shown to be effective in treating
ADHD. Of these, MPH is the most often prescribed and accounts for approximately
60% of stimulant use in the USA. MAS has become a popular alternative to MPH,
and despite slight differences in mechanism of action, profiles of response and
adverse effects, there are no strong data to indicate that any one stimulant
preparation is substantially more effective or better tolerated than any other.
Despite these similarities, there are sometimes differences in individual
re-sponse profiles, which demonstrate that one preparation may be substantially
better than the others for a particular individual.
The stimulants produce significant improvement in
atten-tion, hyperactivity, impulse control and aggressiveness, leading to
better organization of behavior, task completion and self-regulation. There is
fairly robust improvement in social skills, as evidenced by peer ratings, and
parent and teacher ratings of social function. There is also improvement in
academic produc-tivity, although change in actual academic performance has been
more difficult to demonstrate. Although most data with stimu-lants have been
obtained in samples of school-age children with ADHD, there is increasing
recognition that stimulants can be used successfully across the lifespan
(Spencer et al., 2001).
The decision to prescribe psychostimulant
medication is best undertaken following a comprehensive assessment, with full
consideration given to the range of pharmacologic and nonphar-macologic
treatment options which are available. Prior to a trial with any of the
stimulants, baseline data should be obtained, in-cluding general medical
status, and more specific evaluations of height, weight, blood pressure and a
complete blood count.
The past several years have seen a veritable
explosion in the number of stimulant treatment options for individuals with
ADHD. Most of the attention has focused on development of sustained release
preparations, which eliminate the need to take medication several times over
the course of the day, and to pro-vide a more consistent profile of delivery.
This has the added ben-efit of decreasing the need for in-school dosing, and
along with it the potential for stigmatization of children with ADHD and
diversion of medication. Both MPH and MAS are now available in preparations
formulated to last 12 hours. MPH is also available in two new delivery forms
that are each intended to last 8 hours A new immediate-release stimulant
treatment, d-MPH (the active stereoisomer of MPH), has also recently come on
the market.
The decision regarding which stimulant to select is
best determined by considering properties intrinsic to the different
medications – such as duration of activity and adverse effect profile – as well
as the individual circumstances of the patient (e.g., when is peak medication
level needed most, what is the in-dividual’s lifestyle, etc.). Nonresponders to
one medication may respond well to another, since their mechanisms of action
are not identical, and if there is not adequate response to one stimulant
medication, another should be tried.
Increasingly, MPH is given in its long-acting forms
as a first-line approach. The usual starting dose for Concerta (12-hour
formulation) is 18 mg, which is equivalent to 5 mg IR-MPH ad-ministered three
times daily, and may be increased 18 mg at a time. Various forms and strengths
of intermediate-release MPH are also available. Immediate-release (IR) MPH can
be used as a primary therapeutic agent, given in either b.i.d. or t.i.d. dosing
schedules, however, its niche increasingly is to supplement the longer-acting
preparations, either to achieve more rapid onset of effect or to extend
duration of action. When IR-MPH is used as a primary option, the usual starting
dose is 5 mg. The dose is then increased in 5 mg increments. The upper
recommended dose for MPH is 60 mg, although use of higher doses may be required
in certain cases.
MAS and DEX can often be administered in a similar
manner to MPH, and also come in a variety of IR and extended release
formulations. Adderall XR (MAS) is the only amphet-amine preparation formulated
to act for 12 hours. Brand Adderall or generic MAS are also available in a
shorter acting form that lasts approximately 5 to 6 hours. DEX is available in
both a span-sule, with duration of activity comparable to the shorter acting MAS,
and an IR preparation, which lasts approximately 4 hours. A recent study found
that DEX spansule and MAS have com-parable efficacy and duration. DEX and MAS
are more potent than MPH, so the initial starting dose and upper dose limit are
lower. The recommended dosage range for DEX is 2.5 to 40 mg. Although DEX has a
somewhat longer half-life than MPH, a t.i.d. schedule is still often required.
Adverse effects (AE) of stimulants are generally
mild, but occasionally can become problematic. The most commonly ob-served AEs
include headache, abdominal pain, decreased appe-tite (with or without weight
loss) and initial insomnia. There are slight increases in pulse and BP, which
are not very meaningfulat the group level, but can take on greater significance
for par-ticular individuals. Affective changes, including blunted affect,
irritability and mood lability, can also be seen, either at peak dose or when
the dose wears off. Use of longer acting psychostimu-lants tends to minimize
mood lability and other AEs that are of-ten considered to be a reflection of
the on–off effects which are more frequently seen with IR preparations. Motor
or vocal tics can develop. However, there has been a convergence of evidence
that stimulant treatment does not necessarily exacerbate tics, and even some
suggestions that these conditions are relatively independent. There has been
some concern that stimulants can precipitate psychotic symptoms such as
hallucinations, although this is very rare and almost always seen as a
reflection of exces-sive dosing or use in individuals with disorders other than
ADHD (e.g., psychotic disorders).
Atomoxetine is a new medication with highly potent
and selec-tive activity to block the noradrenergic transporter. It is
structur-ally distinct from both the stimulants and the tricyclic
antide-pressants and has been studied extensively in both children and adults.
Atomoxetine was shown to be effective in reducing both inattentive and
hyperactive/impulsive symptoms over a 9-week period in a sample of children and
adolescents. Doses of 0.5 mg/ kg, 1.2 mg/kg and 1.8 mg/kg were studied. All
doses had treat-ment effects that were different from placebo, with treatment
effects seen at the first postmedication treatment visit, but the highest
degree of improvement was found in the 1.2 mg/kg and the 1.8 mg/kg groups. The
medication also produced change in functional measures as well as ADHD
symptoms, with the great-est degree of change in the 1.8 mg/kg group.
Atomoxetine can be administered on either a twice
daily or once daily schedule, even though that its half-life in the
over-whelming majority of individuals is 4 hours. Despite this fact,
therapeutic benefit seems to be maintained over the full day. Ad-verse effects
with atomoxetine have been relatively mild, with decreased appetite and a small
increase in pulse and BP being the two most consistent findings. Because it is
not a stimulant, and because its effects are highly selective for noradrenaline
and not dopamine, atomoxetine is thought not to have abuse potential.
The noradrenergic tricyclic antidepressants,
principally imipra-mine and desipramine, have been the most extensively studied
and, until the mid-1990s, were the most often prescribed non-stimulant
medication for individuals with ADHD. For desip-ramine, doses between 2.5 and 5
mg/kg/day have been recom-mended. In the case of both of these medications,
cardiac side effects are of concern and premedication work-up must include at
least an ECG. Tachycardia and postural hypotension are com-monly seen, but are
not often problematic. Prolongation of the PR and QT intervals may be a greater
source of concern and should be reviewed with a pediatric cardiologist. The
decision to prescribe tricyclics for ADHD children must be made with the
knowledge that several sudden deaths have been reported in children taking
desipramine. Although it has been argued that data do not support the
conclusion and that tricyclics have a high degree of cardiovascular toxicity in
children, proper informed consent should be obtained. It should also be noted
that neither imipramine nor desipramine is FDA approved for the treatment of
ADHD children
Bupropion and venlafaxine have been studied for
their potential utility in the AD-DBDs. Investigations of bupropion in ADHD
have demonstrated the effectiveness of the medication compared with placebo,
but not as effective as stimulants. In contrast to this latter finding, others
have found bupropion to be as effective as methylphenidate.
There are similar but more preliminary data
indicating that venlafaxine might be useful for ADHD. Significant improve-ments
in attention, concentration and other cognitive functions have been reported in
volunteers. Open label studies of adults with ADHD also found venlafaxine to be
effective. The most common side effects reported were nausea and sedation. An
open label study in 8- to 17-year-old subjects found significant reduc-tions in
impulsivity and hyperactivity as rated by parents.
Although there have been no studies using SSRIs in
ADHD and comorbid CD/ODD, these medications are of some interest in light of
recent findings implicating serotonergic mechanisms in aggression and reported
utility of fluoxetine in treating adults with impulsive aggression. At present,
there are no controlled tri-als to support the efficacy of the SSRIs for the
core symptoms of ADHD, and their role in treating comorbid ADHD and CD/ODD is
inferential only.
Since the mid-1980s, there has been considerable
interest in the use of alpha-2-adrenergic agonists in the treatment of ADHD
Ini-tial studies were conducted with clonidine, but the more specific alpha-2
agent guanfacine has recently been the focus of inves-tigation. The alpha-2
agonists are reportedly most effective in treating symptoms of hyperactivity,
impulsivity and aggression in children with ADHD. Effects on attentional
symptoms have been less clear, although a recent study found that guanfacine
treatment was associated with improved ratings and CPT meas-ures of attention
(Scahill et al., 2001). Because of
their role in treating overarousal and aggression, the alpha-2 agonists seem
ideally suited for use in children with comorbid ODD/CD/aggres-sion. They have
been effective in treating ADHD patients who either have diagnosed tic
disorders, or are at increased risk of de-veloping them, such as those children
with a positive family his-tory of tics. This is particularly important, since
as many as 40 to 60% of patients with Tourette’s syndrome seen in psychiatric
set-tings have significant behavior problems. Although the alpha-2 agonists may
be less effective than stimulants in the treatment of ADHD, they may be
particularly useful in individuals whose tics worsen on a stimulant medication.
These agonists have also been used in combination with a stimulant. However,
there have been safety considerations involving this combination. These are
primarily involving the possibility of additive risk of rebound hy-pertension
of alpha-2 agonists with the mild increase in pulse and blood pressure from
stimulants.
Clonidine has a gradual onset of action which may
be related to the time required for receptor down regulation. The usual dose
ranges from 0.05 to 0.3 mg/day, often in a three times a day dosing schedule.
One of the advantages is that it can be used to treat the initial insomnia,
which sometimes results from late afternoon stimulant. Clonidine is available
in both tablet form and a depot skin patch preparation. The latter provides
sus-tained coverage for one week, and may be particularly useful for treating
children with ADHD whose behavior is characterized by a variable pattern of
extreme lability, especially in the early morning, before stimulants and oral
clonidine take effect. Guan-facine comes only in an oral preparation.
Guanfacine tablets are of 1.0 mg strength, so care must be taken not to confuse
the dif-ferent doses for clonidine and guanfacine. Since guanfacine has a
somewhat longer half-life than clonidine, it can often be given in a two or
three times a day dosing schedule.
The most common side effect of the alpha-2
medications is sedation, although this tends to decrease after several weeks.
Dry mouth, nausea and photophobia are among the other adverse effects reported.
At high doses, hypotension and dizziness are also possible. The skin patch
often causes local pruritic derma-titis. Glucose tolerance may decrease,
especially in those at risk for diabetes. It is important carefully to evaluate
cardiovascu-lar function when using the alpha-2 agonists, especially when used
in combination with stimulants treatment as noted earlier. Additionally, there
have been reports of sudden death in three cases treated with the combination
of clonidine and methylphe-nidate, although a review of this situation by the
FDA concluded these unfortunate events were not attributable to the
combina-tion. However, careful monitoring is required. Since clonidine is not
FDA approved for use in ADHD, informed consent should clearly indicate that
this is an “off-label” treatment.
Lithium has been found to be effective in
well-designed stud-ies of aggressive children, impulsive–aggressive adolescents
and young adult delinquents, although there are some questions regarding the
magnitude of effect. Antiepileptic medications have also been used in the
treatment of behavior problems char-acterized by aggressiveness and
impulsivity. Carbamezapine is considered an effective treatment for aggression
in children, but more recent findings have tempered the initial enthusiasm.
Sodium valproate is another antiepileptic shown to be effective in the
treatment of chronic temper outbursts and mood. Although valproate has been
used for the treatment of aggressive patients for over a decade, very few
published reports have used a con-trolled design.
Neuroleptic medications have also been used in the
treat-ment of the AD-DBDs, principally to treat children with severe behavioral
problems characterized by aggression and combative-ness. Although older
neuroleptics such as chlorpromazine, thio-ridazine and halperidol are FDA
approved for the treatment of severe behavior problems in children, they are
infrequently used at present. Recently, there has been more interest in the
atypi-cal neuroleptic risperidone. In a double blind placebo controlled study,
risperidone was found to be superior to placebo in ame-liorating aggression in
youths with conduct disorder (Findling et
al., 2000).
During the course of the last few years, there has
been a re-markable increase in the number of medications that are used in the
treatment of ADHD and CD. It is important to keep in mind that the majority of
the medications are not approved by the FDA for specific use in ADHD and/or CD
and as such their use for these two disorders continues to be “off-label”. Less
than optimal treatment is likely to result in inadequate or partial
improvement, as demonstrated in the community standard group of the multi-modal
treatment study of children with ADHD (i.e., MTA), which is discussed in more
detail below. In order to reduce this variabil-ity in treatment practices,
recently there have been attempts to develop treatment algorithms. The purpose
of such algorithms is to integrate relevant research findings and clinical experience
in the development of medication decision trees. Recently, an expert panel has
reported on the development and implementation of an algorithm for the
treatment of ADHD and its common comorbid conditions (Pliszka et al., 2000a, 2000b).
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