Pharmacotherapy for Child and Adolescent Attention-deficit Hyperactivity Disorder

Research in the past 2 decades showed that attention-deficit/hyperactivity disorder (ADHD) is a frequently occurring psychiatric disorder that causes considerable suffering to patients and their families. This article outlines current pharmacologic ADHD treatment options and focuses on their safety profile and efficacy. In addition, it addresses treatment selection, guidelines for monitoring treatment, and recent controversies in the field.

Research in the past 2 decades has demonstrated that attention-deficit/hyperactivity disorder (ADHD) is a frequently occurring psychiatric disorder that causes considerable suffering to patients and their families. ADHD begins in early childhood, and persists through adolescence and into adulthood in 70% of patients. Two large epidemiologic studies in the United States have placed the prevalence of ADHD at 8.7% in children and 4.4% in adults. ADHD affects boys more than girls, although percentages vary across studies. Moreover, the gender ratio among youth presenting for treatment decidedly favors males. However, data from a recent 11-year follow-up study found that girls also have significant morbidity and disability associated with the disorder. Pathognomonic biologic tests are not yet available so a comprehensive clinical assessment, buttressed by use of validated and normed rating scales, and structured diagnostic interviews, remains the gold standard diagnostic approach. The search for biologic markers has recently produced interesting findings, suggesting that such tests could be available in the near future. For instance, data show that ADHD is a highly heritable condition for which potentially responsible candidate genes have been identified and characteristic neuroanatomic as well as neurophysiologic findings have been confirmed. Furthermore, current diagnostic criteria yield similar prevalence rates across the United States and Europe, and the condition is found in most other parts of the world. These data suggest there is a strong neurobiologic contribution to ADHD and support the use of medication treatments. The present paper outlines current pharmacologic ADHD treatment options and focuses on their safety profile and efficacy. In addition, treatment selection, guidelines for monitoring treatment, and recent controversies in the field are addressed.

Assessment and treatment principles

A thorough differential diagnostic evaluation is essential, as children can present with hyperactivity, inattention, and behavioral dysregulation (ie, core symptoms of ADHD) as a result of a variety of other reasons, such as environmental stressors and other psychiatric or medical problems. Exposing children who do not have ADHD to treatment would not be expected to alleviate their condition, and could potentially worsen their symptoms. Although a comprehensive outline of assessment procedures and nonpharmacologic treatments can be consulted elsewhere, a few basic principles are noted here.

Diagnosis

Diagnostic and statistical manual of mental disorders fourth edition (text revision) (DSM-IV) provides diagnostic criteria that are used worldwide (although DSM-IV is not recognized in many countries). For patients to meet ADHD criteria, they must have either (1) 6 or more from a list of 9 symptoms of inattention for at least 6 months, to a degree that is maladaptive or (2) 6 or more of a list of 9 symptoms of hyperactivity/impulsivity for at least 6 months, to a degree that produces impairment in social, school, or occupational functioning. Furthermore, some symptoms that cause impairment should have been present before 7 years of age and some impairment from the symptoms must be present in 2 or more settings (eg, at school/work and at home). In addition, symptoms cannot be better accounted for by another mental disorder (although they may coexist with those of another mental disorder; ie, comorbidity).

Diagnostic Workup

ADHD is diagnosed from comprehensive psychiatric/medical histories and relevant physical and mental status examinations. All other assessments and/or tests that may be used support these primary methods. If a patient has a current or past medical problem, a thorough medical history is mandatory and consultation with specialists may be recommended. In addition to meeting with the patient, evaluators should also conduct an in-person interview of the caretakers and seek information from teachers either in person, by phone, or via completion of rating scales. Psychological testing is not essential but can be helpful, especially if learning disorders are also present. Because patients with ADHD often have co-occurring psychiatric disorders, the presence of comorbidity should be investigated as treatment necessitates taking this into account.

Discussing Treatment Options, Medications, and Monitoring with Patients and Caretakers

Successful treatment of ADHD disorders demands significant caretaker commitment, and is best approached using a chronic care model. Few parents have had the experience of giving medication to their child on a daily basis, as is required when youth with ADHD are treated pharmacologically. For most children, prior medication use would have been limited to antibiotics or other type of acute somatic treatment. In addition to dealing with concerns regarding medication use, it is important for the clinician to instruct the family that ADHD treatment requires frequent monitoring, and to engage in a frank and realistic discussion regarding what medication can and cannot accomplish. Medical screening must be undertaken, and families should be advised regarding potential adverse effects. Medication is often highly effective in treating current symptoms of ADHD. Although the long-term effect on future functioning has not been adequately determined, most patients who are treated with medication for a long period of time continue to demonstrate positive effects of treatment. However, although medications can help to improve family or peer relations acutely and potentially in the future, they cannot necessarily repair relationships or circumstances that may have been damaged or adversely affected as a result of past symptoms. A strong therapeutic alliance should be developed with both the patient and caretakers to foster a clear understanding of the condition, its potential impairments, and the reasons for pursuing medication treatment. Better understanding these issues is presumed to improve adherence to treatment. Adherence to treatment is of considerable importance, because although medication for ADHD is highly effective, many patients discontinue treatment very early on. As a general rule (recognizing that all rules have exceptions), although medication often offers the best option for acute treatment of core ADHD symptoms, a variety of evidence-based psychosocial modalities, such as summer treatment programs, teacher training, and behavioral parent training can be also be used effectively. These can be offered alone or in conjunction with medications, and in some circumstances, combined medication and behavior therapy has been demonstrated to offer advantages. Occasionally, patients are maintained in psychosocial treatment alone because of family preference, suboptimal response to pharmacotherapy, or unacceptable side effects. For these reasons, it is important that all available pharmacologic, nonpharmacologic, and educational options be discussed with the family at the outset of treatment.

Monitoring Tools

Several rating scales have been developed to aid in assessing the effectiveness of ADHD treatment. Some of these can also be used to improve the accuracy of the diagnostic process but should not be considered diagnostic instruments when used alone. Rating scales are available in multiple informant formats (ie, for parents, teachers, and adolescents), and in various lengths (eg, long or abbreviated formats). For instance, there are ultra brief paper and pencil scales that take less than 3 minutes to complete and have been amply validated, as well as a variety of computer-based formats. Box 1 shows the most commonly used assessment tools. These instruments offer the opportunity to quantify data that are otherwise subjective, primarily by comparing ratings for the index patient against data derived from a large group of individuals of the same age and gender (ie, normative database). Ratings should be obtained from multiple sources before treatment is initiated and periodically thereafter to assess outcomes. Resulting scores assist the clinician in establishing when maximum symptom reduction is reached via a systematic and data-driven input process. There has been considerable recent interest in the development of scales to assess the effect of treatment on functional status, and not just symptoms. However, there is not yet an accepted gold standard method available. A comprehensive review of assessment tools is available elsewhere.

Box 1

Name Main Features and Web Site
Conners Scales Available in parent, teacher, adolescent versions Long, short, and abbreviated (10 item) forms www.mhs.com
ADHD Rating Scale-IV Based on the DSM-IV 18 symptoms, school and home versions available www.guilford.com
Brown ADD Scale Available in parent, teacher, and adolescent self-report versions. Assesses executive functions www.psychcorp.pearsonassessments.com
SKAMP Brief 10-item version for teacher or observer www.adhd.net
SNAP-IV Public domain scales www.adhd.net/snap-iv-form.pdf
CBCL Not ADHD specific but one of the oldest and most studied scales. Multiple informant versions www.aseba.org

Most commonly used ADHD rating scales

Psychopharmacology of ADHD

A brief review of the pathophysiology of ADHD is helpful in understanding the potential remedial role that pharmacologic agents can play. The behavioral and cognitive impairments that ADHD patients experience can be viewed from a unifying neuropsychological perspective as originating in deficits in executive functions. These functions encompass high-level tasks such as organizing, prioritizing, focusing, sustaining effort, managing frustration, using working memory, and monitoring and selfregulating. The neuronal substrates for these functions are located in the prefrontal cortex (PFC) and its various diverse connections, including the striatum, thalamus, cerebellum and many other regions. Dopamine (DA) and noradrenaline (NA) are 2 neurotransmitters that are essential to PFC function, and small changes in these neurotransmitters can have marked effects. Too much or too little catecholaminergic presence can result in PFC dysfunction. DA and NA seem to exert actions at the cortical level that are both synergistic and unique. NA is often believed to strengthen attention to stimuli via enhanced network connections, sometimes referred to as increasing signal; DA is also involved in attention to stimuli but also seems to weaken unnecessary connections or decrease noise. All US Food and Drug Administration (FDA)-approved agents are believed to potentiate catecholamine transmission in the PFC, which helps to explain why they are effective in improving ADHD symptoms. The American Academy of Child and Adolescent Psychiatry (AACAP) recommends that the initial psychopharmacologic treatment of ADHD be with an FDA-approved agent. These belong either to the stimulant or nonstimulant categories, as described later. Agents that have not been approved by the FDA are briefly discussed here as well because some have a fairly developed evidence base and can provide alternative options for patients who either do not benefit from or do not tolerate FDA-approved treatments.

Psychopharmacology of ADHD

A brief review of the pathophysiology of ADHD is helpful in understanding the potential remedial role that pharmacologic agents can play. The behavioral and cognitive impairments that ADHD patients experience can be viewed from a unifying neuropsychological perspective as originating in deficits in executive functions. These functions encompass high-level tasks such as organizing, prioritizing, focusing, sustaining effort, managing frustration, using working memory, and monitoring and selfregulating. The neuronal substrates for these functions are located in the prefrontal cortex (PFC) and its various diverse connections, including the striatum, thalamus, cerebellum and many other regions. Dopamine (DA) and noradrenaline (NA) are 2 neurotransmitters that are essential to PFC function, and small changes in these neurotransmitters can have marked effects. Too much or too little catecholaminergic presence can result in PFC dysfunction. DA and NA seem to exert actions at the cortical level that are both synergistic and unique. NA is often believed to strengthen attention to stimuli via enhanced network connections, sometimes referred to as increasing signal; DA is also involved in attention to stimuli but also seems to weaken unnecessary connections or decrease noise. All US Food and Drug Administration (FDA)-approved agents are believed to potentiate catecholamine transmission in the PFC, which helps to explain why they are effective in improving ADHD symptoms. The American Academy of Child and Adolescent Psychiatry (AACAP) recommends that the initial psychopharmacologic treatment of ADHD be with an FDA-approved agent. These belong either to the stimulant or nonstimulant categories, as described later. Agents that have not been approved by the FDA are briefly discussed here as well because some have a fairly developed evidence base and can provide alternative options for patients who either do not benefit from or do not tolerate FDA-approved treatments.

FDA-approved stimulant agents

These include 2 types of agents: amphetamine (AMP) and methylphenidate (MPH). In 1937, Charles Bradley published a classic paper describing a “spectacular” improvement in the school performance of behaviorally disordered children who were treated with dl-amphetamine (Benzedrine). This marked the beginning of modern child psychopharmacology and documented that AMP was a potentially effective treatment for the condition that subsequently became known as ADHD. MPH (Ritalin) followed in the 1950s, with reports by Knobel and colleagues, and others. Stimulants are amongst the most well-researched psychotropics. Their high degree of efficacy has been demonstrated in multiple randomized controlled studies in which they improved the core ADHD symptoms of hyperactivity, impulsivity, and inattention. In addition, stimulants also improve academic productivity or task completion, family interactions, aggression, school disruption, peer interactions, antisocial behaviors, and may even decrease the risk for subsequent comorbid psychiatric disorders and academic failure. Despite the significant and desirable improvements in behavioral and cognitive symptoms, evidence for long-term improvement in academic achievement has been elusive. If patients with ADHD experience acute medication improvements in several skills that are necessary for learning, why has this not resulted in verifiable enhancement of academic long-term outcomes? This apparent contradiction can be partially explained by recognizing a variety of methodological shortcomings. For instance, studies have varied greatly in the types of pharmaceutical formulations used, dose ranges (some perhaps suboptimal), and times of medication administration. Perhaps duration of treatment was not sufficient enough to demonstrate change or patients did not adhere to treatment as prescribed. These issues may have interfered with the power to demonstrate effectiveness in long-term academic function, an outcome measure that is very complex and multidetermined. It is also possible that for such improvement to occur, medication alone may be insufficient, and more comprehensive wraparound modalities may be necessary. A final feasible explanation is that the nature of ADHD symptoms and impairments change with time, and it is possible that stimulant treatment is less well suited to some of the long-term deficits in organization and selfregulation that are seen in older individuals with ADHD.

Several preparations of AMP and MPH are available in the United States, in both generic and branded formulations. The different formulations of each of the 2 drug classes are similar in therapeutic and safety profiles but differ in route of administration and/or mechanism of delivery, which determine the specific formulation’s kinetic profile and the resultant short or long duration of action. In the past few years, the understanding of ADHD changed from a condition that manifests only during school hours to one that can potentially impair the patient’s functioning in all settings throughout the day. For this reason, short-acting immediate-release formulations (IR), despite their high degree of efficacy, present certain challenges because of the need for repeated administration over the course of the day. Longer-acting extended release preparations (ie, ER, LA, SR, XR) may improve compliance by reducing the number of times the patient must take the medication and protect confidentiality by obviating the need for administration during the school day. As reviewed later, a variety of technologies have been used to prolong duration of action.

AMP and MPH are equally efficacious at the group level when dosed comparably, with a response rate of 65% to 75%. However, individual patients can show a preferential response to either AMP or MPH. Thus, the overall stimulant response rate increases to as much as 85% if the 2 classes of medications are tried. Unfortunately, there is no current method to determine which patient will respond better to which type of stimulant. A child’s response to an appropriate dose of stimulant can usually be observed within 30 to 90 minutes of administration. Side effects, if any, tend to be mild, short-lived, and amenable to dose or timing adjustments. The most frequently occurring adverse effects are decreased appetite and insomnia, but other changes in affective function and mood regulation can be observed, particularly when the drug effects wear off. Occasionally, more severe adverse effects can occur, the most worrisome of which is the potential risk for catastrophic cardiovascular events, which is discussed in detail later. Other serious side effects of stimulants, such as psychosis, obsessive ruminations, and movement disorders, are infrequent and usually abate if the medication dose is lowered or stopped. Box 2 shows stimulant side effects and contraindications. Box 3 enumerates black-boxed warnings.

Box 2

  • Side effects

    • Common

      • Insomnia

      • Anorexia

      • Headache

      • Weight loss

      • New onset tics

      • Irritability

    • Less frequent

      • Nausea

      • Abdominal pain

      • Palpitations

      • Dizziness

      • Drowsiness

      • Changes in pulse

    • Rare

      • Allergic reactions

      • Fever

      • Arthralgia

      • Psychosis

      • Depression

      • Sudden death (specifically in preexisting cardiac conditions)

  • Contraindications

    • Advanced arteriosclerosis

    • Symptomatic cardiovascular disease

    • Moderate to severe hypertension

    • Hyperthyroidism

    • Known hypersensitivity or idiosyncrasy to sympathomimetic amines

    • Tics/Tourette syndrome

    • Glaucoma

    • Agitated states

    • History of drug abuse

    • During or within 14 days after the administration of monoamine oxidase inhibitors (MAOI)

Stimulant side effects and contraindications (similar for all preparations but the wording in the package insert may vary from product to product)
Box 3

  • MPH

    • Drug dependence. Should be given cautiously to patients with a history of drug dependence or alcoholism. Frank psychotic episodes can occur. Careful supervision is required during withdrawal.

  • AMP

    • Misuse may cause sudden death/serious cardiovascular adverse events. High potential for abuse. Administration for prolonged periods of time may lead to drug dependence.

Stimulant black-boxed warnings (similar for all preparations but the wording in the package insert may vary from product to product)

Despite recent concerns addressed later in this review, when used according to clinical guidelines, stimulants have enjoyed an unparalleled track record of more than 7 decades of demonstrated efficacy and a relatively low incidence of side effects. Because these agents work quickly, safely, and effectively, there is probably no other mental health condition for which patients, and more frequently their parents, offer the treating clinician more laudatory comments for a job well done. And yet, for reasons not well understood, despite high response rates and level of tolerability, most patients discontinue their medication within a year. The apparent disconnect between the perception of physicians that stimulants have a high degree of efficacy and tolerability and the relatively poor long-term adherence observed in patients is an important focus of research.

Amphetamine (AMP) Preparations

There are 2 kinds of AMP agents: dextroamphetamine (d-AMP) and mixed amphetamine salts (MAS), a racemic AMP formulation bound to a mixture of salts. AMP is believed to work by enhancing DA and NA neurotransmission, both by blocking reuptake and facilitating release of neurotransmitter. Existing AMP preparations are classified into short- and long-acting, and prodrug formulations. The main features are shown in Table 1 .

Table 1
AMP preparations main features
Name/Formulation Duration Dose Forms Starting Dose Maximum Dose (May Increase as per MD Judgment)
Short Acting (only these FDA-approved for children aged 3–5-y)
Adderall (mixed AMP salts) 5, 7.5, 10, 12.5, 15, 20, 30 mg tablets 3–5 y: 2.5 mg every day >6y: 5 mg every day 40 mg
DextroStat (d-AMP) 5, 10 mg tablets 3–5 y: 2.5 mg every Day >6 y: 5 mg every day 40 mg
ProCentra (d-AMP) 5 mL/5 mg solution Same as DextroStat 40 mg
Long Acting
Dexedrine spansule (d-AMP slow release) 5, 10, 15 mg capsule 5–10 mg every day 40 mg
Adderall XR (mixed AMP salts XR) 5, 10, 15, 20, 25, 30 mg capsule 10 mg every day 30 mg; contents can be sprinkled
Prodrug
Vyvanse (LDX) 20, 30, 40, 50, 60, 70 mg capsule 20 mg every day 70 mg; contents can be dissolved in water

Short-acting AMP formulations (about 6 hours duration)

These include generic d-AMP, branded d-AMP (Dextrostat), branded d-AMP solution (ProCentra), generic mixed amphetamine salts or MAS (50% d-AMP plus 50% dl-AMP) and branded MAS (Adderall). Different enantiomer combinations were developed because although d-AMP is more potent, some patients respond to one enantiomer but not the other. AMP has been widely used for decades with excellent safety and efficacy. Short-acting AMP is the only FDA-approved medication for use in children as young as 3 years old. Side effects are shown in Box 2 .

Long-acting AMP formulations (about 8 to 10 hours duration)

These comprise branded d-AMP spansules (Dexedrine), generic mixed amphetamine salts extended release (MAS XR), and branded MAS XR (Adderall XR). Dexedrine spansules are capsules that contain 2 types of beads: d-AMP IR beads that account for the initial action plus other beads covered by a polymer substance resulting in a delayed release of d-AMP. The efficacy and safety profile of the spansule is comparable with that of d-AMP IR. MAS XR are capsules containing Microtrol technology beads. Half of these beads contain MAS IR and the other half are coated with a substance designed to release MAS IR once the beads reach a higher pH environment, usually in the intestine. The efficacy of extended release MAS has been well established in short controlled studies as well as in open label studies up to a 24-month period. The side effect profile is outlined in Box 2 .

Prodrug formulation

Lisdexamfetamine (LDX) or Vyvanse (brand name) is the only agent in this category. LDX is a therapeutically inactive molecule that, after ingestion, is hydrolyzed by endogenous enzymes to l-lysine, a naturally occurring essential amino acid, and active d-amphetamine, which is responsible for its therapeutic effect. Conversion of LDX to d-amphetamine and l-lysine occurs mostly in the blood. Thus, its long duration of action, measured up to 13 hours in school-aged children in controlled research in a laboratory classroom, is perhaps the result of a postabsorption systemic biologic conversion, in contrast to other stimulants that rely on preabsorption delayed release mechanisms. The efficacy of LDX has been documented in short- and long-term studies and the medication has been generally well tolerated. The adverse effect profile is shown in Box 2 . There may be an advantage for LDX with regard to abuse potential. Research showed that, at an equivalent amount of amphetamine base taken orally, LDX 100 mg had attenuated responses on measures of abuse liability compared with immediate-release d-amphetamine 40 mg. LDX is highly soluble and the capsule can be opened to dissolve its contents in water.

Methylphenidate (MPH) Preparations

There are oral and transdermal formulations available in the United States. Similar to AMP, oral preparations can be subclassified according to duration of action into short- or immediate-release, intermediate, and long-acting formulations. Table 2 shows their main features.

Oct 3, 2017 | Posted by in PEDIATRICS | Comments Off on Pharmacotherapy for Child and Adolescent Attention-deficit Hyperactivity Disorder

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