Attention-deficit/hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD) are among the most common and most studied medical conditions of childhood. Recent advances in neuroimaging have illuminated key pathways involved in the pathophysiology of ADHD. Molecular genetics studies are common, wim centers around the world pooling data in order to understand the relative contributions of genes and environment in the pathophysiology of these disorders across the lifespan.
While this exciting work increases optimism about the behavioral and pharmacologic treatment of these conditions, obstacles remain. Perhaps the greatest obstacle to the successful treatment of ADHD, ODD, and CD is careful diagnosis. Despite the fact that they represent three of the most common pediatric psychiatric disorders encountered by pediatricians, family practitioners, and psychiatrists, they are often not diagnosed, misdiagnosed, or not treated. These conditions create significant morbidity in patients of all ages, from early childhood to adulthood. Impairment in school and work performance, peer relations, and family environment are common. Once diagnosed, ADHD, ODD, and CD can be treated with combination pharmacological and psychosocial interventions.
This article reviews what is known about the pharmacologic treatment of ADHD, for which there is abundant literature, and what little is known about the pharmacologic treatment of ODD and CD in the context of advances in pharmacology, neurobiology, and genetics.
DIAGNOSIS AND EPIDEMIOLOGY OFADHD
Attention-deficit/hyperactivity disorder is defined in the DSM-IV as a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and more severe than typically observed in others of the same developmental age.1 Symptoms of ADHD were described in the scientific literature as far back as 1900 when George Still described children who suffered from symptoms of inattention, hyperactivity, and impulsivity. In the 103 years since, the validity of the diagnosis has been hotly debated. The diagnostic terminology has changed multiple times, with varying degrees of emphasis placed on hyperactivity, then inattention, and combinations of both.2
Currently, the DSM-TV defines three subtypes: predominantly inattentive type, predominantly hyperactive-impulsive type, and combined type, although the literature suggests that other subtypes with comorbid CD-ODD, anxiety, or both might also exist.3,4 In addition to specific symptoms of inattention and/or hyperactivity/impulsivity, the diagnosis requires these symptoms to cause impairment in two or more settings (school, peers, and/or home).
Like other DSM-IV disorders, ADHD is a categorical diagnosis, although there is some discussion regarding the disorder being better conceptualized as existing along continua of inattention, hyperactivity, and impulsivity.5 There are 39 different validated rating scales to help clinicians make the diagnosis. These scales typically include the 18 items of ADHD, of which 9 address inattentive behavior, 6 address hyperactivity, and 3 address impulsivity. Common scales include the Conners' ADHD Checklist,6 the Brown Adult ADHD Scale,7 and the Swanson, Nolan and Pelham Questionnaire (SNAP).8
In addition to clinical assessment, neuropsychological testing can be used as an adjunct to diagnosis. Although neuropsychological measures are not diagnostic of ADHD, they can guide treatment plans by evidencing the presence or absence of a learning disorder, or mental retardation.
Finally, many clinicians have recognized the value of assessing family members of ADHD subjects. It is not uncommon for more than one family member to suffer from ADHD or a related psychiatric medical condition, such as depression, anxiety disorders, substance use disorders, or bipolar affective disorder.9
The prevalence of ADHD is between 3% and 7% of school-aged children,1 with the prevalence in boys being 3-fold to 6-fold higher than in girls.10 It is unclear what the rates of ADHD are in adults, but it is estimated that between 20% and 70% of children who suffer from ADHD will continue to be symptomatic as adults. In addition to impairment in academic and social situations, ADHD has been associated with higher numbers of visits to the emergency department, more injuries, more traffic violations, and higher rates of alcohol and drug abuse.11" 13 One study estimated that health care costs of ADHD were more than double those of a comparison non- ADHD cohort for a 9-year period.14
NEUROBIOLOGY AND GENETICS OF ADHD
The genetics and neurobiology of ADHD have been studied in detail in recent years. Research in neuroimaging, neuropharmacology, and neurophysiology all point to dopamine and norepinephrine pathways.15 Because of the dopamine hypothesis of ADHD, we now have pathways to target (eg, mesolimbic dopamine pathways) and candidate genes to explore (eg, dopamine genes).
More is known about the anatomy and neurobiology of ADHD as structural and functional imaging advance. It is thought that the core impairment is a dysfunction of the frontal-subcortical pathways and an associated disturbance in behavioral inhibition.16 Because the frontal and subcortical regions have a preponderance of innervation from catecholaminergic pathways, disturbances in norepinephrine and dopamine transmission may be involved in the pathophysiology of ADHD. Stimulants may act on catecholeminergic pathways to increase the inhibitory influence of the frontal cortex on subcortical structures.17 Thus, norepinephrine and dopamine pathways are the pharmacologic targets in ADHD.
The monoamine hypothesis of ADHD is further strengthened by multiple single-gene-association studies that relate different alleles of the dopamine system as playing a role in vulnerability for ADHD.5 Multiple studies have indicated that the 10 repeat alleles of the dopamine transporter gene (DAT) on chromosome 5 and the greater than 6 repeat alleles of the dopamine four receptor (DRD4) on chromosome 11 are risk factors associated with ADHD. Twin and family studies indicate marked genetic contributions to the development of ADHD. In fact, on average, multiple twin studies report heritability estimates for ADHD between 60% and 92%. Nonetheless, the majority of twin studies indicate that ADHD is best conceptualized as a disorder that is influenced by multiple genetic and environmental factors.
DIAGNOSIS AND EPIDEMIOLOGY OF ODD AND CD
The essential feature of ODD is a recurrent pattern of negativistic, defiant, disobethent, and hostile behavior toward authority figures, which is of sufficient severity to cause impairment. Conduct disorder is characterized by a persistent pattern of behavior in which the basic rights of others and major age-appropriate societal norms or rules are violated.1 While the disruptive disorders are often considered together, there is evidence that the two disorders are distinct entities and can be separated from each other and from ADHD.J8
The prevalence of ODD is between 2% and 15%, and the prevalence of CD is between 1 .5% and 3.4% (although some reports are as high as 16%); however, these diagnoses may account for 30% to 50% of referrals in some clinics.19 There is a higher prevalence of both ODD and CD in boys than in girls.18
MECHANISM OF THE IMPAIRMENT IN ODDANDCD
While the specific neurobiology of the aggressive disruptive disorders are unknown, there have been reports of abnormalities in a number of neurotransmitter systems, including noradrenergic and dopaminergic, and cholinergic systems. Recently, serotonin has been implicated in aggressive youth with a decrease both peripherally and in spinal fluid metabolites.20 In a recent study, published in Science the low-activity genotype of the monamine oxidase A gene was related to violence in maltreated boys.21 The study indicates that boys with this genotype were twice as likely to have conduct disorder than maltreated boys who had the high-activity genotype. The monamine oxidase A gene is responsible for encoding an enzyme that metabolizes the catecholamines. The presumption is that the high-activity enzyme clears the synapse of dopamine, norepinephrine, and serotonin more efficiently and thus allows for more effective neuronal functioning.
The same genetic variant has been identified to make mice more aggressive (through knock-out studies) and was reported in 1993 to be associated with extreme violence in a single Dutch pedigree.22 Although ODD and CD are clearly examples of multifactorial illnesses, influenced by a complex interplay between multiple genetic and environmental factors, it is clear that the monoamines play a role in the etiology and possibly the treatment of these symptom domains.
COMORBIDITY OF ADHD
Perhaps the most important factor in the treatment of ADHD and the related disruptive disorders is an appreciation of the marked comorbidity both within these disorders and between them and other disorders. A recent review of the literature on the topic revealed significant comorbidity rates within ADHD of ODD (35%), CD (50%), mood disorder (15% to 75%), and anxiety disorders (25%).23 In addition, high rates of substance use and tic disorders have been seen in ADHD populations.
TREATMENT OF ADHD ALONE General Prindples
The first general rule for the treatment of ADHD is to ensure that the diagnosis is correct. Careful consideration of all choices in the differential diagnosis can make a critical difference. Conduct disorder and ODD are often mistaken for ADHD. Specific learning disabilities such as a reading disorder, mathematics disorder, or disorder of written expression that can masquerade as attentional problems should be considered. Autistic spectrum disorders should be considered, as these patients often have impulsivity and inattention. Substance abuse should be considered, especially in the adolescent with a recent onset of attentional problems, conduct problems, or both. Also, a mood or anxiety disorder can present as attentional problems in children.
Second, despite good behavioral interventions available for ADHD, a recent report from the Multimodal Treatment Study of Children With ADHD suggests that the approach to ADHD that appears most efficacious is pharmacotherapy, with combination behavioral treatment in cases with comorbidity.4 A key finding in the study is that medication is much more effective when prescribed following the careful algorithm developed by study designers as compared to "community practices." See the Table for a brief review of medication approaches to the treatment of ADHD.
More than 200 controlled medication trials have been conducted in more than 6000 Children, adolescents, and adults with ADHD, establishing ADHD as one of the most frequently studied of all medical conditions.24 By 1996, of 190 trials investigated, 155 studied stimulants, 21 studied antidepressants, 12 studied neuroleptics, and 2 studied antihypertensives. The vast majority of those studies were conducted with school-aged children (N = 171), but there were 6 studies conducted with adolescents, 7 with adults, and 7 with preschoolers.26
Stimulants are by far the most common pharmacotherapy for treatment of ADHD, with methylphenidate (MPH) formulations accounting for 62% of stimulant prescriptions. Dextroamphetamine (DEX) formulations are prescribed 23% of the time, with amphetamine 12%, and pemoline 3%.25
Psychostimulants are available in multiple commercial forms including MPH (Ritalin), DEX (Dexidrine), and D,L-amphetamine ([AMP] Adderall). Short-term response rates are approximately 70% for a trial of a single stimulant.26 Stimulants are thought to increase dopamine and norepinephrine in the synaptic cleft either by inhibition of reuptake into the presynaptic terminal, thus inhibiting their destruction by monoamine oxidase, or by increased retrograde release of the catecholamines into the synaptic cleft (in the case of amphetamines). The result is an increase in vigilance, a decrease in impulsivity, and improved performance on working memory tasks.
Side effects of stimulants are usually mild and include appetite suppression, stomach ache, jitters, headache, exacerbation of motor tics, and sleep disturbance. These are typically self-limited or can be solved with minor changes in the dosing regimen. There have been reported cases of mood disturbance or, very rarely, a toxic psychosis with psychostimulant medication.27 Stimulants are generally safe and effective and have a favorable therapeutic profile. There are concerns about the possibility of linear growth suppression with stimulant medication. While the concerns about linear growth are not likely to be substantiated, there may be a small decrement in the rate of weight acquisition in children treated with psychostimulants when compared to their behaviorallytreated counterparts.27
Starting doses for stimulants typically are 5 mg for MPH and 2.5 mg of DEX or mixed amphetamine salts (AMP?) for the immediate-release preparations given three times a day. The dose can then be titrated over several weeks to achieve maximal symptomatic control to a maximum daily dose of 60 mg for MPH and 40 mg for AMP. According to the American Academy of Child and Adolescent Psychiatry Practice Parameters, children weighing less than 25 kg (55 lbs) should not receive single doses of more than 15 mg of MPH or 10 mg of AMP.
Treatment Options for ADHD
Treatment Options for ADHD
Recently, a number of long-acting preparations of these medications have become available to allow for once-daily dosing. These medications include longacting forms of methylphenidate (Ritalin SR, Concerta, Metadate ER), DEX (spansules), and mixed amphetamine salts (Adderall XR). The onCe-a-day dosing can be very useful in children who are reluctant to take medications, especially at school, and for many can ameliorate the rebound symptoms that at times develop when shorter-acting compounds wear off during the day. The long-acting forms differ in their pharmacology (mixed amphetamine salts with Adderall XR, versus DEX, versus methylphenidate) and in their delivery systems (spansules, versus capsules, versus osmotic pumps). There are studies that support the use of each.
In clinical applications, a child who tails to respond to one preparation may improve on one of the others. In children who have not been previously treated with a stimulant, many clinicians have success beginning with a long- acting form of the medication. In some instances however, it may be useful to begin with an immediate-release tablet and then switch to a long-acting formulation once optimal titration has been achieved. Both options are reasonable for most patients, although in the very young, the immediate-release preparations may offer advantages because of greater flexibility in titration.
ALTERNATIVETREATMENTS for ADHDALONE
The traditional alternative treatment to psychostimulants in patients with ADHD is treatment with tricyclic antidepressants (TCAs), most often Imipramine, clomipramine, desipramine, or amitriptyline. Of these, desipramine is an effective agent in both adults and pediatric patients with ADHD.28·29 Nortriptyline is also effective and safe in children with ADHD, with added benefits in oppositionality and anxiety symptoms.30
The TCAs are efficacious for the treatment of the impulsivity and hyperactivity of ADHD, but less efficacious than psychostimulants for inattention.31 The TCAs were considered a primary treatment of ADHD for many years, however, following case reports of sudden cardiac death in three children, they have fallen from favor in many clinics in the United States. Wilens et al. reviewed the cardiac risk factors associated with TCA treatment of ADHD and concluded that, 'TCA treatment in children and adolescents, like that in adults, is associated with uncertain, but probably minor clinical significance."28 Other potential side effects including dry mouth, constipation, tachycardia, headaches, and weight gain, as well as the need for blood levels and electrocardiographic (ECG) monitoring have limited their use. For the patient who cannot tolerate or is nonresponsive to stimulants, however, TCAs can be a viable alternative.
Recent data suggest that bupropion SR may be a reasonable alternative or second-line agent for ADHD, especially in adolescents in whom either antidepressant properties may be desired or substance abuse makes prescription of psychostimulants less desirable. Bupropion SR is likely a norepinephrine and dopamine reuptake inhibitor with rninimal effect on the serotonergic system. Barrickman et al. demonstrated the efificacy of buproprion in the treatment of ADHD.32 Wilens et al. have demonstrated the efficacy of buproprion SR in adolescents and adults.33 We also found that bupropion SR to be effective in stimulant-responsive adolescents with ADHD.
There is still limited evidence of the efficacy of venlafaxine XR, although since venlafaxine has both noradrenergic and serotonergic properties, there is a theoretical basis to be hopeful for its use in the treatment of ADHD. A small open-label series in adolescents demonstrated some efficacy; however, there was evidence that behavioral activation may have worsened the symptoms in some participants.34
While selective serotonin reuptake inhibitors (SSRIs) are often helpful in treating many conditions that are comorbid with ADHD, there is no evidence that they are useful in the treatment of ADHD alone. In fact, there is the possibility of making the impulsivity and hyperactivity of ADHD worse with SSRI administration, as the restlessness and agitation frequently seen with activating SSRIs may aggravate these symptoms in the ADHD patient.
Clonidine (Catapres) is an agonist of ot2-adrenergic autoreceptor and is used widely to treat ADHD. It is especially useful in the population of ADHD patients who are over-aroused or who need help managing sleep as a side effect of stimulant medication. It may also be useful in ADHD patients who have experienced an exacerbation of tics while on stimulant therapy. While clonidine has less effect on attention, it may be used to reduce the dose of stimulant needed, to help with severe impulsivity and aggressiveness, or to improve the ability to fall asleep.35
The adverse effects of Clonidine include significant bradycardia and hypotension that require monitoring of pulse and blood pressure. Also of concern is rebound hypertension and tachycardia that may be associated if Clonidine is discontinued abruptly, or that may occur even shortly prior to the next dose. Baseline blood pressure and pulse along with a baseline ECG should be obtained prior to initiation of Clonidine. Thus, in the child with a pre-existing cardiac condition or in a family where adherence to the medical regimen may be difficult, another choice might be preferred.
Guanfacine (Tenex) has a mechanism of action similar to Clonidine but may be less sedative. Fewer studies exist with guanfacine but there is evidence for its effectiveness in ADHD alone and in patients with ADHD and tics.36 However, neither Clonidine nor guanfacine have any FDA approval for psychiatric uses.
Magnesium pemoline (Cylert), which was once commonly prescribed as an alternative to MPH and DEX, is no longer recommended as a first-line or even second-line treatment because of liver toxicity. The package insert for pemoline reports 15 cases of acute hepatic failure since 1975, with 12 cases resulting in death or the need for liver transplantation. Current recommendations include using pemoline only after other medications have been tried and after obtaining detailed and informed consent.37
Studies in animals and humans have shown that the administration of nicotine can improve attention, learning, and memory even in nonsmokers. This has led to the study of using nicotinic agonists for the treatment of ADHD. At least one study has shown that the use of a novel nicotinic agonist may be potentially useful in the treatment of ADHD, and the development of this class of drug is in progress.38
TREATMENT OF ODD AND CD WITH AND WITHOUT ADHD
As mentioned, the disruptive behavior disorders ODD and CD frequently co-occur with ADHD, and much of the research has been done in patients with multiple diagnoses. Currently, there is no single medication that specifically targets aggression, although many classes of agents are beneficial in treating aggressive behavior associated with a variety of conditions.
A meta-analysis of the use of stimulants to treat aggression in children with ADHD showed improvements in aggressive behavior that were comparable to improvements in the core symptoms of ADHD, although this effect was somewhat diminished in children with comorbid CD.39 Stimulants can also be used in conjunction with nonpharmacologic treatments such as behavioral modification therapy.40 If stimulants alone fail to decrease the aggressive behavior to a manageable level, the addition of clonidine to the regimen can be efficacious.41 The next line of therapy for the child with comorbid ADHD with or without ODD/CD has classically been to treat with antidepressants, lithium carbonate, carbamazepine, or propranolol. Carbamazepine and propranolol show particular promise in the treatment of aggression; however, their efficacy has not been clearly established, and the American Academy of Child and Adolescent Psychiatry and others recommend further study before making a firm recommendation for their use.42-43
The use ofantipsychoti.es, particularly the newer atypical agents, has increased for the treatment of severe disruptive behavior and aggression. Data from controlled studies that endorse this use in nonpsychotic children have begun to support this practice, including a recent double-blind study of risperidone in a sample of 118 children with severe disruptive behavior and subaverage intelligence.44 Risperidone was associated with significant reductions in conduct problems and was well tolerated. The American Academy of Child and Adolescent Psychiatry cautions that the risks of neuroleptics may outweigh their usefulness in the treatment of aggression in ODD and CD. Before proceeding to this class of medications, clinicians should strongly consider nonpharmacologic treatments such as behavioral modification, psychotherapy, or other psychosocial interventions.
With recent reports supporting the use of atypical antipsychotics to diminish aggressive behavior in children with mental retardation and autism, it will be doubly important that clinicians weigh the risks and benefits of prescribing these medications in this vulnerable population.44,45
ADHD WITH COMORBlD ANXIETY OR MOOD DISORDERS
In contrast to comorbid ADHD and aggression, the model for treatment of comorbid ADHD and anxiety or mood disorders is to treat the ADHD but watch closely for potential exacerbation of the anxiety or mood symptoms. Debate about which condition to treat first continues, but given the rapid onset of response to stimulants in children with ADHD, we recommend treating the ADHD first and monitoring the affective or anxious symptoms closely. If the child is also anxious, the addition of an SSRI is often useful. In certain cases, psychostimulants induce anxiety or depression in susceptible patients, and in such cases, discontinuing the stimulant and starting an antidepressant is advisable.24 The combination of an SSRI along with psychostimulants is safe and effective in this population.46
Another option is treatment with an antidepressant with norepinephrine and dopamine activity, such as bupropion SR. Bupropion SR has been shown to be effective in treating both attentional symptoms and depressive symptoms in an open-label trial of adolescents with comorbid ADHD and depression.47
ADHDWITH COMORBID SUBSTANCE ABUSE
One of the current concerns about the treatment of ADHD in the adolescent population is the known association with substance abuse, although some have argued that this association is mediated entirely through the association with CD.48 Yet while there is abuse potential, particularly with psychostimulant medications, Biederman et al. reported successful treatment of ADHD with psychostimulants actually reduced the risk of substance use.49 For the patient who already has a history of substance abuse, one alternative treatment is bupropion SR, which is effective in adolescents with comorbid ADHD, substance abuse, and CD, and has little potential for abuse.50
Attention-deficit/hyperactivity disorder, CD, and ODD are common psychiatric medical conditions. They occur by themselves, but more often as comorbid conditions. These conditions are influenced by both genetic and environmental factors. Attention-deficit/hyperactivity disorder may be among the most treatable of all medical conditions. Recent advances in the behavioral and pharmacotherapy of ODD and CD have improved the prognosis for many who suffer from these disorders as well. Successful treatment of all three conditions requires an appreciation of the neurotransmitter systems involved in their pathophysiology and selection of medications to address the core areas of dysfunction.
While treating attentional problems, special care must be given to the conditions frequently comorbid with ADHD. We suggest that treatment of comorbid ADHD and aggression include treatment of the attentional problems first with subsequent treatment of any remaining aggressive symptoms. In contrast, in treatment of comorbid ADHD and anxiety or mood disorders, the clinician should take a cautious view and treat first with a stimulant, but observe closely for exacerbation or onset of acute anxiety or sadness.
Whether treating ADHD alone or comorbid conditions, it is important to realize that behavioral and cognitive behavioral therapies are key components of treatment. Although we have focused on the neurobiology, genetics, and pharmacology, the behavioral and pharmacotherapies are equally important to the management of ADHD.
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Treatment Options for ADHD
Treatment Options for ADHD