Treatment of ADHD: A Developmental Approach

Attention deficit hyperactivity disorder (ADHD) is very common. In the United States, between 6% and 10% of children and adolescents are affected, as are 4% of adults.¹ Children in other countries also have ADHD, although rates of comorbid disorders may vary from those found in the United States.²

The pediatrician is often the first physician many families contact when they suspect their child has ADHD. Also, the pediatrician is often responsible for overseeing treatment of ADHD over many years. Often, this involves changing formulations, strengths, or types of medication and providing non-medical interventions for a child as he or she matures. Thus, it is vital that pediatricians have a good understanding of the symptoms and treatment of ADHD at all stages of a child's development.

Here I discuss the diagnosis and treatment of ADHD in toddlers, in school-aged children, and in adolescents. I discuss an age-specific differential diagnosis, describe appropriate treatment options (including some off-label and soon-to-be-approved agents), and address common management issues for patients and their families. Case vignettes illustrate some of the typical issues likely to be seen in patients of each age group when they first present for an ADHD evaluation.

APPROACH TO THE CHILD WITH SUSPECTED ADHD: GENERAL GUIDELINES

Both the American Academy of Child and Adolescent Psychiatry (AACAP) and the American Academy of Pediatrics (AAP) have published treatment guidelines within the last 10 years regarding the diagnosis, treatment, and long-term management of ADHD. Both sets of guidelines came out before the FDA approval of atomoxetine; consequently, neither includes that medication as a treatment option.

The AACAP guidelines, which were published first, provide several recommendations for the general assessment of youth with ADHD.³ They recommend a thorough assessment that includes a developmental, medical, psychiatric, and family history.

The AAP guidelines were published in 2001.⁴ These guidelines also call for a complete assessment, followed by the least restrictive and invasive interventions with ongoing evaluation of treatment, education plans, and support for the family and child. The AAP guidelines offer 5 general recommendations:

•Treat ADHD as a chronic condition.

•To maximize functioning, identify target outcomes for each patient.

•Treat with a stimulant and/or behavior therapy.

•If treatment is not effective or the target outcome cannot be achieved, reevaluate both the diagnosis and therapy.

•See children with ADHD every 3 to 6 months for ongoing monitoring and assessment, including achievement of both target outcomes and growth parameters.

A third set of recommendations--and the one most recently revised--is the Texas Children's Medical Algorithm.⁵ The updated guidelines incorporate changes in treatment recommendations, including the use of atomoxetine and the treatment of ADHD in patients with comorbid psychiatric diagnoses.

It is important to review the core set of ADHD symptoms listed in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), which appears in Table 1 on page 9 of this issue.⁶ Look for symptom onset before age 7 years, presence in more than one setting (school, home, peers), and functional impairment. The mental status examination should include evaluation of speech and language skills, tests for hearing impairment, and an estimation of cognitive ability.⁶ In addition, screen for lead toxicity and possible abuse. Referrals to rule out comorbid medical disorders and assessment for other psychiatric disorders as primary or a comorbid cause of symptoms should be completed before therapy is initiated.

Treatment is usually multimodal and can include parent training, psychotherapy, educational interventions, and pharmacotherapy.

TODDLERS

JT, a 4-year-old African American boy, is brought in for evaluation by his mother after combined type ADHD had been diagnosed in his older sister. The sister's symptoms had been stabilized with a stimulant.

The mother reports that the boy was about to be expelled from preschool because he refused to hold the teacher's hand and would run into busy streets. The mother could not go to the grocery store without another adult, because her son would escape from the grocery cart and run away if she turned to remove an item from the shelf. She was afraid to sleep at night because he would try to leave the house. She worried that her son would be injured or killed because he could not stay or sit still and did not follow any rules.

As any busy pediatrician knows, all toddlers suffer from a deficit of attention and an excess of energy. Attention spans and the ability to sit still increase with age. How do you decide which toddler is just a normal 3-year-old, and which is seriously out of control and in need of treatment for ADHD?

The first step is a thorough history of the child's developmental trajectory--including speech, gross and fine motor milestones, birth trauma, and family history. Perform a neurologic examination, and assess vision and hearing. For a disruptive toddler, referral to a local child-screening center for a more complete speech and language assessment and cognitive assessment is crucial.

Diagnosis. The differential diagnosis of ADHD in toddlers includes:

•Speech and language disorders.

•Hearing or vision impairment.

•Mental retardation, including fragile X syndrome.

•Fetal alcohol syndrome.

•Pervasive developmental disorder (PDD).

•Lead toxicity.

•Physical or sexual abuse.

•Other neurodevelopmental disorders, such as neurofibromatosis, that are highly comorbid with ADHD.

In addition, several psychiatric disorders can present with symptoms that overlap with those of ADHD. These include adjustment disorders, separation anxiety, obsessive-compulsive disorder, reactive attachment disorder (seen in children who have been in foster care and are adopted at a more advanced age after severe deprivation), and depression.

Assessment. Laboratory testing for lead poisoning and genetic disorders (such as fragile X syndrome or neurofibromatosis) is performed if indicated by the history and physical examination findings.

If the comprehensive assessment determines that a child has speech and language deficits, PDD, or mental retardation, address those issues first, before adding specific therapies for ADHD. Interventions for children with mental retardation, PDD, or speech and language delays include speech therapy, physical and occupational therapy (if needed), and a structured special education preschool with interventions geared toward helping the child reach appropriate speech and academic milestones with same-age peers.

Treatment. If the toddler does not have a developmental delay or another psychiatric disorder, the next step is to design an intervention tailored to his or her specific needs and those of the family. Most experts who treat toddlers with ADHD recommend beginning with parent training and a structured preschool or daycare setting to modify the child's environment. Should those therapies fail to minimize symptoms, the next step is pharmacologic intervention.

Dextroamphetamine is the only medication that is FDA-approved for the treatment of ADHD in children aged 3 to 5 years. However, more controlled data exist on the non- FDA-approved medication, methylphenidate--which has been used in multiple controlled trials and in one large National Institute of Mental Health (NIMH) multi-site trial in this age group.^7-9 The trials involved preschoolers aged 3 to 5 years. Trials lasted from 3 to 8 weeks and compared at least 1 dose of methylphenidate with placebo. In all trials, methylphenidate was superior to placebo in reducing ADHD symptoms. Results of the NIMH trial have not yet been reported.

There are no published trials of the treatment of preschool ADHD with atomoxetine.

Most experts recommend starting with the unapproved methylphenidate, then trying dextroamphetamine or mixed amphetamine salts. Because most preschoolers cannot swallow pills, the best choices are chewable tablets or liquid formulations (some methylphenidate formulations). The long-acting beaded formulations of any of these stimulants (Adderall XR, Metadate CD, Ritalin LA, and Focalin XR), which can be sprinkled on food and do not need to be swallowed whole, can also be tried.

Most guidelines recommend using short-acting agents for initial titration followed by a long-acting agent for maintenance. Start toddlers at half the starting dose for school-aged children, and then titrate up every 7 days, with close monitoring of side effects and growth patterns. Most guidelines also recommend monthly visits after the initial titration period. Because preschoolers with ADHD who require pharmacotherapy are usually symptomatic in all settings (home, school or day care, and social), the guidelines recommend 7-days-per-week treatment.

SCHOOL-AGED CHILDREN

At the request of his second grade teacher, LB--a 7-year-old European American boy--presented for treatment of his ADHD. In kindergarten, he had struggled with sitting during story time and talked all the time. By first grade, LB was still routinely getting out of his seat to sharpen pencils, was trapped in a tree, and was not invited for playdates. No one wanted him on the soccer team because he would not pass the ball to teammates. He lost his Game Boy and rarely completed or turned in his homework. Homework time was impossible and his parents were frustrated when they tried to get him to complete his homework assignments.

When the behaviors persisted in second grade, the parents brought him in for an assessment.

School-aged children with ADHD present for evaluation at one of two different points; the timing depends on the ADHD subtype. The two presentations have different differential diagnoses and medical workups. I will discuss these issues separately here. The treatment options are similar, however, and these are discussed together.

Combined type ADHD. The vignette above describes a typical first or second grader with classic combined type ADHD who presents with symptoms in all settings and who has serious impairment in school functioning. Children with combined type ADHD usually have had symptoms since kindergarten or preschool; however, the family often does not seek help until late in the first-grade year--after the teacher finally becomes overwhelmed and calls the parents with an ADHD academic or behavioral crisis.

Typically, in September and October, the child's ADHD symptoms are usually chalked up to the need to adjust to school; disruptive behavior in November and December is often overlooked by the teacher as being caused by the excitement of the upcoming holidays; and it is likely to be ignored a third time in January, when it is attributed to readjustment after the winter break. Then in February, the ADHD behavior that has been present for the entire school year is suddenly seen as a big problem. The child and parent(s) are referred to you with a diagnosis by the teacher of ADHD who recommends that the parents ask for a prescription for a stimulant.

Teachers are often good at recognizing signs and symptoms of ADHD. However, the classroom Connors scale or Vanderbilt scales do not replace a thorough office assessment.

The differential diagnosis for combined type ADHD includes other disruptive behavior disorders, such as:

•Oppositional defiant disorder.

•Conduct disorder.

•Bipolar disorder.

•Post-traumatic stress disorder.

•Tourette syndrome (if the patient has any tics). Include the following in the history taking:

•Family history of mood and disruptive behavioral disorders.

•Response to prior medications trials (if every stimulant trial makes the child worse, the diagnosis is probably not ADHD).

•Assessment for cardinal symptoms of bipolar disorder. (Although symptoms of bipolar disorder and ADHD do overlap, certain symptoms are characteristic of bipolar disorder and can help differentiate between the diagnoses in your office [Table 1].)

Inattentive type ADHD. Primary inattentive type ADHD tends to predominate in girls. Affected children typically present in third or fourth grade because of deteriorating school performance and problems with daydreaming/staring, talking too much, and not caring about schoolwork. Impairment often begins to appear when schoolwork starts to involve more than the simple memorization and work sheets of early elementary school. Homework, book reports, and long-term projects become more difficult and require sequential planning, understanding, and a capacity to synthesize material.

Children with inattentive type ADHD frequently do not exhibit many of the hyperactive symptoms of ADHD. The differential diagnosis for this type of ADHD includes:

•Absence epilepsy.

•Mixed language disorders.

•Learning disabilities.

•Anxiety disorders.

•Mood disorders, especially major depression.

•Adjustment disorders.

•Post-traumatic stress disorder.

Developmental language disorders are frequently missed and are not screened for in children who are struggling in school but who have no speech delay or articulation problems. One of the easiest office screens for language problems is to ask a child to tell you the plot of the last movie he or she saw. A third or fourth grader should be able to give a good plot summary, identify the movie's key message or theme, and note favorite scenes and characters. If a child who is a native speaker and of normal intelligence cannot do this, a formal speech and language assessment is needed.

Anxiety disorders and depression are characterized by thoughts, feelings, and worries that preoccupy much of a patient's time and that interfere with schoolwork. Some children with obsessive-compulsive disorder spend hours doing homework, reading and rereading all their assignments, and writing and rewriting. In a similar manner, they may also struggle to finish tests. These children are frequently referred for evaluation for ADHD; however, a careful assessment reveals that they cannot pay attention because their worries interfere with completion of homework and listening to the teacher.

Therapy. In a patient who has a language disorder, epilepsy, or a primary psychiatric disorder other than ADHD, treatment begins by targeting that disorder. In children whose primary diagnosis is ADHD, both behavioral therapy and ADHD medications are standard components of the treatment plan. Other interventions include seating in the front of the classroom, extra time on tests, writing down homework assignments, and use of a laptop or keyboard in the classroom. Because of the increasing academic demands of later elementary school, children may need help organizing projects and with other tasks that require executive functioning skills.

All FDA-approved ADHD medications are available for use in school-aged patients. These include atomoxetine, methylphenidate in multiple formulations, and mixed amphetamine salts--all as first-line therapy. Second-line treatments include transdermal methylphenidate patches, bupropion, and tricyclic antidepressants.

Transdermal methylphenidate is listed as a second-line agent because of the high rates of rash associated with active drug patches in registration trials (24% to 30% among participants who received active drug patches, compared with 3% to 6% among those who received placebo patches).¹⁰

The FDA was concerned that a rash from the patch would translate to an allergy to methylphenidate in oral as well as transdermal forms. To address the concern about sensitization, the labeling on transdermal methylphenidate states that it is not a first-line agent and that its use should be limited to those children who cannot swallow oral medications.

Third-line agents are the a-agonists clonidine and guanfacine, which help more with hyperactivity than inattention. These agents tend to be more useful in children with comorbid tics and in those who cannot tolerate stimulants or atomoxetine because of severe anorexia, insomnia, or rebound ADHD symptoms.

A recent multi-site study by researchers in Cincinnati, Pittsburgh, Rochester, and Buffalo compared treatment of ADHD in 4 groups of patients.¹¹ One group received placebo, 1 received clonidine, 1 received methylphenidate, and 1 received a combination of methylphenidate and clonidine. Preliminary results demonstrated that combination therapy and clonidine monotherapy were safe and effective.

Atomoxetine monotherapy has been shown to be more effective than stimulants in children with comorbid anxiety disorders.¹²

An application for modafinil--an agent currently indicated for the treatment of narcolepsy in adults--has been submitted to the FDA as a new agent for the treatment of pediatric ADHD. Two studies of this agent showed positive results.^13,14 However, in March 2006, an FDA review revealed 49 rashes in 933 children and adolescents exposed to modafinil; these included 22 allergic rashes, 1 case of Stevens-Johnson syndrome, and 1 case of erythema multiforme. Because of the high rate of occurrence of systemic rashes, the FDA asked for additional safety data before approving the medication for the treatment of pediatric ADHD.

Adverse effects of pharmacotherapy. Although rashes are the biggest concern with the 2 newest forms of ADHD medication (ie, the transdermal patch and modafinil), the most common side effects in preschool and school-aged patients are anorexia, weight loss, and insomnia. Effective management of these side effects allows patients to continue treatment that is otherwise successful.

If loss of appetite and weight loss are problems, try decreasing the dosage to see if the child's appetite improves. If anorexia persists, the best approach is to have the patient pack in calorie-dense food, especially at the beginning and end of the day. Parents should make sure the child has a high-calorie breakfast, such as peanut butter on toast, pizza, sausage, chocolate milk, or even Pediasure. I also recommend an after-school snack and a bedtime snack, in addition to dinner. Such a regimen can keep the calorie intake high enough to allow the child to continue along appropriate growth trajectories. For children who are picky eaters but who like chocolate, Nutella (a chocolate, milk, and hazelnut spread for bread) is a calorie-dense snack that they are likely to eat.

Other easy changes that can help increase caloric intake include providing chocolate milk boxes instead of juice boxes for lunch and using whole milk rather than skim or 1% milk. Letting parents know that the average school-aged child needs only 2 chicken nuggets to meet his daily protein requirement allays worries about food intake. If they are worried about balance in the diet, suggest a chewable multivitamin.

Children with ADHD frequently have difficulty settling down for the evening, and bedtime struggles may increase with stimulant treatment. Most studies recommend sleep hygiene as the first step in treating insomnia. This includes no caffeinated beverages and no television, radio, phone, computer or game systems, food, or reading in the bedroom. Sleep is easier if children have an established bedtime routine and no distractions in the room where they sleep. If a child is still struggling, try a shorter-acting stimulant, melatonin 1 hour before bed, or clonidine for sleep initiation.

ADOLESCENTS

SH, a 16-year-old Hispanic girl, presented before her senior year of high school because of ongoing academic struggles. She had trouble staying organized and focused in school and during driver's education classes. She frequently was too busy talking to focus on the teacher and had lost several assignment books and 2 cell phones. Long-term projects were especially difficult, and she frequently stayed up late the night before projects were due. SH was a solid C student in private school, despite having a high IQ and no learning disabilities. Her teachers reported that she just seemed "not to care" about academics as much as her social life.

Adolescents with ADHD present a variety of diagnostic and therapeutic challenges. Many have been identified long before high school as having ADHD; often, they need modified treatment regimens and to be monitored for side effects, academic performance, social functioning, and comorbid disorders. However, some teenagers present for the first time in ADHD clinics. These teenagers tend to have the inattentive sub-type of ADHD rather than combined or hyperactive sub-types, which are identified and treated in the school-aged child because of the motor/hyperactivity symptoms.

Teens with ADHD of mild to moderate severity may initially present in high school, because the supports of elementary and middle school (close monitoring of homework, organized schedules, and small number of teachers) disappear. In high school, teens have many different teachers who all give a lot of homework--especially papers and projects that require long-term planning and good organizational skills. Note-taking and studying to master material become necessary. Consequently, adolescents with ADHD may have a rapid drop in grades in the unstructured but academically demanding high school environment.

For adolescents, the differential diagnosis includes mood disorders (both depression and bipolar), anxiety disorders, learning disabilities, adjustment disorders, substance abuse, and psychotic disorders (including schizophrenia). Any adolescent who presents for an ADHD evaluation with a marked change in academic performance should be assessed for this differential. A toxicology screen is also indicated for substance abuse. Ask about a family history of ADHD and/or mood, anxiety, substance use or abuse, or psychotic disorders that commonly coexist with ADHD.

Therapy. Teenagers with ADHD need treatment in several areas, including educational support, coverage with medication for long hours, and planning for drivers' licenses and the transition to college or work. Educational support is key for adolescents with ADHD. Interventions may include asking the school system for a 504 plan or a full individual education plan (IEP) if the teen needs more services than preferential seating and extra time on tests (including SATs). Teenagers with ADHD may need an academic coach or tutor to help with organizational skills, note-taking, study skills, and test-taking strategies. Most schools do not teach these crucial academic tools; teens with ADHD have difficulties in these executive functioning areas and need extra help.

Medication needs to cover a much longer period of the day than for children in elementary school. The high school day usually begins by 7:30 am and ends at 2:30 pm; this is often followed by afterschool activities or sports and 4 hours of homework until 11:00 pm or midnight. None of the long-acting stimulants (with effects from 8 to 12 hours) last for a typical high school day of academics and activities (Table 2).

Several options exist to add long-day coverage for adolescents with ADHD. One option is to use atomoxetine, the non-stimulant medication that can be dosed either once daily or twice daily for 24-hour coverage of ADHD symptoms. Other options that allow the teen to experience a longer duration of action are to:

•Add a short-acting stimulant in the afterschool hours to cover for homework.

•Split the long-acting stimulant to twice a day, with half the dose at 7 am and half at noon.

•Use the methylphenidate (Daytrana) patch, and leave it on for 12 hours. The medication effects will persist for another 3 hours after patch removal. According to the FDA's Web site, the original trials with Daytrana that involved a 12-hour application of the patch showed high rates of loss of appetite and insomnia (because the effects of the medication lasted for 15 hours).

•Give both a stimulant and atomoxetine. The stimulant provides the focus needed for the school day, and the atomoxetine provides 24-hour coverage for driving and homework. One report of co-administration of a stimulant and atomoxetine showed that the medications could safely be given together; ADHD symptoms were reduced most effectively with a full dose of stimulant and 0.5 mg/kg/d of atomoxetine.¹⁵

Patients with comorbid mood or anxiety disorders may need treatment with an SSRI or bupropion for the mood and anxiety symptoms if monotherapy with atomoxetine is not successful. For teens with bipolar disorder, therapy should first be directed toward stabilizing the mood disorder; the ADHD medication is added in slowly and at low doses to determine whether it increases cycling. Because many ADHD medications can impair sleep, and because lack of sleep can trigger a manic episode, it is crucial to monitor sleep patterns in your patient with bipolar disorder and ADHD.

Two other areas of adolescent concern are more likely to be problematic in adolescents with ADHD:

•Substance abuse, including alcohol and cigarettes.

•Driving a car.

Five and 10-year follow-up studies have showed that by adolescence to young adulthood, boys and girls with ADHD had higher rates of smoking, alcohol abuse, and substance use than those without ADHD (Table 3).^16,17 Those with ADHD had an earlier onset of these behaviors.

We know from the same group of researchers that pharmacotherapy of ADHD reduces the risk of substance abuse problems in adolescents with ADHD to levels almost as low as those in non-ADHD peers. Among those persons with treated ADHD, 25% had substance abuse problems; this rate was 75% in those with untreated ADHD. In contrast, the rate was 18% in persons without ADHD.¹⁸

Driving is also a significant concern for teenagers and young adults with ADHD. Several studies note higher rates of accidents, speeding tickets, and moving violations with ADHD.^19,20 Treatment with stimulants--especially the longer-acting ones--leads to improved driving performance on driving simulators, including in the evening hours.²¹

These studies show that treating your adolescent ADHD patient with medication at a time when the teenager frequently wants to stop taking those pills can reduce the risk of both substance abuse and driving problems. For many patients with ADHD, your treatment allows them to successfully complete high school and to make the transition to college or to work in another location.

This is also frequently the time when adolescents make their last visit to you. For college-bound ADHD patients, it is particularly helpful to make a connection with the treating clinician in the college student health center. If you obtain permission from your adolescent patient and his family, you can write a letter for the student's file at college along the following lines . . . "I have treated my patient since age 7 for ADHD combined type with stimulant XR. He is currently taking 40 mg daily; side effects on this dosage include insomnia and mild loss of appetite. I have given him a 30-day supply of stimulant medication and ask that you continue his treatment while he is in college. Please contact me with any questions. Dr X."

This letter allows your patient to continue treatment while in college with a confirmed diagnosis from you. The patient need not go without treatment and fail his first semester away from home. Teenagers find this letter of treatment very helpful, particularly since college freshmen who present to the student health center for a stimulant prescription the week before midterms may not be believed or seen in a timely fashion.

When your adolescent patient is transitioning to a job, a similar letter to the physician who is taking over the care is helpful.

References:

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