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Chapter: Essentials of Psychiatry: Childhood Disorders: Attention-deficit and Disruptive Behavior Disorders

Psychopharmacology - Attention-deficit and Disruptive Behavior Disorders

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.



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.


Tricyclic Antidepressants


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


Other Antidepressants


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.


Sertonin Reuptake Inhibitors


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.


Alpha-2-adrenergic Agonists


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.


Other Agents


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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