AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The term attention deficit is misleading. In general, the current predominating theories suggest that persons with ADHD actually have difficulty regulating their attention; inhibiting their attention to nonrelevant stimuli, and/or focusing too intensely on specific stimuli to the exclusion of what is relevant. In one sense, rather than too little attention, many persons with ADHD pay too much attention to too many things, leading them to have little focus.

Three basic forms of ADHD, attention deficit disorder (ADD), are described in the Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association (APA). They are (1) attentional; (2) hyperactive; and (3) combined, most frequently a combination of attentional and hyperactive forms.

The major neurologic functions disturbed by the neurotransmitter imbalance of ADHD fall into the category of executive function. The 6 major tasks of executive function that are most commonly distorted with ADHD are (1) shifting from one mindset or strategy to another (ie, flexibility), (2) organization (eg, anticipating both needs and problems), (3) planning (eg, goal setting), (4) working memory (ie, receiving, storing, then retrieving information within short-term memory), (5) separating affect from cognition (ie, detaching one's emotions from one's reason), and (6) inhibiting and regulating verbal and motoric action (eg, jumping to conclusions too quickly, difficulty waiting in line in an appropriate fashion).

Contrary to some media accounts, attention disorders are not new. In the early 1900s, diagnosis emphasized the hyperactivity component. Today, hyperactivity, impulsivity, and inattention are the areas of focus. However, reports have alluded to disorders involving hyperactivity, impulsivity, and inattention in conjunction with distractibility and inappropriate arousal patterns throughout medical history. What is new is the enhanced awareness of ADHD secondary to rapidly accumulating research findings and its addition to the DSM in 1980.

Pathophysiology

Findings from neuropsychological studies suggest that the frontal cortex and the circuits linking them to the basal ganglia are critical for executive function and, therefore, to attention and exercise inhibition. Many findings support this view, including those described below.

First, MRIs of the right mesial prefrontal cortex in persons with ADHD strongly support decreased activation (low arousal) during tasks that require inhibition of a planned motor response and timing of a motor response to a sensory cue.

Second, MRIs in persons with ADHD also strongly support weakened activity in the right inferior prefrontal cortex and left caudate during a task that involves timing of a motor response to a sensory cue.

Third, the catecholamines are the main neurotransmitters with frontal-lobe function.

Fourth, dopaminergic and noradrenergic neurotransmission appear to be the main targets for medications used to treat ADHD.

Fifth, executive functions are major tasks of the frontal lobes.

Sixth, a 10-year study by National Institute of Mental Health (NIMH) demonstrated that the brains of children and adolescents with ADHD are 3-4% smaller than those of children without the disorder, and that pharmacologic treatment is not the cause. The more severe patients' ADHD symptoms, as rated by parents and clinicians, the smaller their frontal lobes, temporal gray matter, caudate nucleus, and cerebellum were.

Frequency

United States

The prevalence of ADHD in children appears to be 3-7%. ADHD is associated with significant psychiatric comorbidity. Approximately 50-60% of individuals with this disorder meet DSM criteria for at least 1 of the possible coexisting conditions, which include learning disorders, restless-legs syndrome, ophthalmic convergence insufficiency, depression, anxiety disorder, antisocial personality disorder, substance abuse disorder, conduct disorder, and obsessive-compulsive behavior. The risk of a person having ADHD if his or her family member has ADHD or one of the disorders commonly associated with ADHD is significant.

International

The prevalence of ADHD in children in countries such as Germany, New Zealand, and Canada are approximately 5-10%.

Mortality/Morbidity

The morbidity for ADHD varies greatly. This range is a function of many factors, including the specific area of deficit, the patient's environmental response to and interaction with the deficits, the therapy provided, and the presence of coexistent conditions.

Sex

ADHD is more frequently diagnosed in boys than in girls. Most estimates of the male-to-female ratio range between 3:1 and 4:1 in clinic populations. However, many community-based samples produce a ratio of 2:1. Recognition of ADHD has improved over the last decade, and the male-to-female ratio has been decreasing; this may be the result of the increased recognition of inattentive ADHD.

Age

Data concerning the likelihood that a child with ADHD will also have the disorder as an adult are conflicting. As definitions of ADHD subtypes improve, some subtypes will likely be found that cause more adult dysfunction than others.

• Approximately 30-80% of children with ADHD have the disorder as adults. Most experts believe that the rate is well above 50%.
• Hyperactive symptoms may decrease with age because of developmental trends toward self-control. However, persons with ADHD developmentally mature later than the average population. Inattentive symptoms do not appear to have a similar developmental advantage and tend to remain constant into adulthood.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The DSM criteria, in conjunction with a thorough clinical interview regarding daily functioning, are important in the diagnosis of attention deficit hyperactivity disorder (ADHD). Of note, some of the DSM criteria are being revised to reflect state-of-the-art knowledge, including data regarding ADHD in girls and women. The clinician should also gather information that helps to identify any coexistent conditions. 

• History of present illness: All of the following DSM-IV criteria for ADHD must be present:
• • Either the criteria for inattention or the criteria for hyperactivity/impulsivity must be met.
  • • Inattention: At least 6 of the 9 symptoms of inattention listed below must have persisted for at least 6 months to a degree that is maladaptive and inconsistent with the patient's developmental level.
    • 1. Often does not give close attention to details or makes careless mistakes in schoolwork, work, or other activities
      2. Often has difficulty sustaining attention in tasks or play activities
      3. Often does not seem to listen when spoken to directly
      4. Often does not follow through with instructions and does not finish schoolwork, chores, or duties in the workplace (not because of oppositional behavior or failure to understand instructions)
      5. Often has difficulties with organizing tasks and activities
      6. Often avoids, dislikes, or is reluctant to engage in homework that requires sustained mental effort
      7. Often loses things necessary for tasks or activities (eg, school assignments, pencils, books, tools, toys)
      8. Often is easily distracted by extraneous stimuli
      9. Often is forgetful in daily activities
    • Hyperactivity/impulsivity: At least 6 of the 9 symptoms of hyperactivity and impulsivity listed below have persisted for at least 6 months to a degree that is maladaptive and inconsistent with the patient's developmental level.
    • 1. Often fidgets with hands or feet or squirms in seat
      2. Often leaves seat in classroom or in other situations in which remaining seated is expected
      3. Often runs around or climbs excessively in situations in which this behavior is inappropriate (adolescents or adults may be limited to subjective feelings of restlessness)
      4. Often has difficulty playing or engaging in leisure activities quietly
      5. Often on the go or often acts as if driven by a motor
      6. Often talks excessively
      7. Often blurts out answers to questions before questions are completed
      8. Often has difficulty waiting turns
      9. Often interrupts or intrudes on others (eg, butts into conversations or games)
  • The onset occurs no later than the age of 7 years.
  • Symptoms must be present in 2 or more situations (eg, school, work, home).
  • The disturbance causes clinically significant distress or impairment in social, academic, or occupational function.
  • Behavior does not occur exclusively during the course of pervasive developmental disorder, premenstrual dysphoric disorder, schizophrenia, or other psychotic disorder. No mood, anxiety dissociative, or personality disorder accounts for the behavior.
• Past medical history
• • Screen for the following medications or supplements that may have negative interactions with ADHD-related medications:
  • • Anticonvulsant agents
    • Antihypertensive agents
    • Caffeine-containing drugs
    • Pseudoephedrine
    • Ephedra
    • Monoamine oxidase inhibitors (MAOIs)
    • All medications known to be metabolized by means of the cytochrome P450 (CYP) 2D6 hepatic pathway (see the discussion about atomoxetine in the Medication section).
  • Screening for medical concerns that may have negative interactions with ADHD medications (Drugs of concern are shown in parentheses.)
  • • Major arterial disease (stimulants)
    • Narrow-angle glaucoma (stimulants, imipramine, desipramine)
    • Heart disease (clonidine, desipramine, guanfacine, imipramine, stimulants)
    • Heart palpitations (stimulants)
    • Hepatic disease (atomoxetine)
    • Hypertension (stimulants, atomoxetine, bupropion)
    • Orthostasis (atomoxetine, bupropion, stimulants)
    • Pregnancy (all)
    • Renal disease (bupropion, clonidine)
    • Seizure disorder (bupropion, desipramine, imipramine)
    • Urinary retention or hesitancy (atomoxetine, bupropion, stimulants)
  • Approximately 30-50% of people with ADHD have other significant psychiatric comorbidities. Consider screening patients for the following:
  • • Anxiety disorders
    • Bipolar disorder
    • Conduct disorder
    • Depression
    • Dissociative disorders
    • Eating disorder
    • Generalized anxiety disorder
    • Learning disability
    • Mood disorder
    • Obsessive-compulsive disorder
    • Oppositional defiant disorder
    • Panic disorder with or without agoraphobia
    • Pervasive developmental disorder including Asperger disorder
    • Posttraumatic stress disorder (PTSD)
    • Psychotic disorders
    • Social phobia
    • Sleep disorder
    • Substance-related disorders
    • Thought disorder
    • Tourette syndrome or other tic disorders
    • Somatic comorbidity (No somatic comorbidities are significantly associated with ADHD.)
• Family history: Inquire about a family history of ADHD and of the coexistent conditions listed under History of present illness.
• Social history: Inquire about the following:
• • Home and family interactions consistent with ADHD
  • • Disorganization of personal space is the norm.
    • Anger or rage reactions are prevalent.
    • The child usually seems most awake in the late evening.
    • Awakening the child for school causes major problems.
    • The child is often unable to complete what appear to be developmentally appropriate chores.
    • Homework organization and completion are often a problem.
  • Problems with the legal system
  • • Arrests
    • Traffic tickets
    • Motor vehicle accidents
  • School performance
  • • Report cards
    • Reprimands or notes sent home
    • Homework completion and/or turning homework in on time
    • Extracurricular activities
  • Family dysfunction
  • • Drug abuse, alcohol abuse, or both
    • Physical abuse
    • Sexual abuse
    • Recent death
    • Severe chronic illness
    • Severe financial problems
  • Social skills
  • • Friendships
    • Group cohesion
    • Strengths and interests
• Pregnancy, potential for pregnancy, or safe-sex practices
• • Previous intercourse
  • Birth control
  • Condom use
• Work performance
• • Type of work
  • Promptness
  • Overall work performance
• Abuse of substances by patient or his or her friends (if the patient is an adolescent)
• • Alcohol
  • Caffeine
  • Marijuana
  • Other illicit drugs
  • Snorting stimulants
  • Prescription medications
  • Tobacco (eg, cigarettes, chewing tobacco, snuff)

Physical

A focused physical examination is recommended if none has been performed within the last year. Although a child or adolescent with ADHD may exhibit few symptoms in a clinical setting, careful observation of his or her behavior is important.

• Vital signs
• • Height
  • Weight
  • Blood pressure
  • Pulse
• General appearance
• • Fidgeting
  • Impulse control
  • State of arousal
• Mental status examination
• • Affect
  • Cognition
  • Speech patterns
  • Thought patterns

Causes

At present, genetic loading appears to be the primary and perhaps only cause of ADHD. However, many environmental factors have been correlated with ADHD, and future research may prove these to be etiologic factors. Morbidity, as evidenced by signs and symptoms in people with ADHD, may be strongly correlated with the patient's home and school environments.

• Genetic causes
• • Family, twin, adoption, and segregation analysis, as well as molecular genetic studies, show that ADHD has a substantial genetic component. Molecular genetic studies have revealed several genes that appear to be associated with ADHD because of their effect on dopamine receptors, dopamine transport, and dopamine beta-hydroxylase.
  • Research by the NIHM has shown that variants of the gene for catecho-O-methyltransferase (COMT) are associated with different levels of prefrontal dopamine activity. COMT metabolizes dopamine.
  • People with the val/val variant metabolize dopamine rapidly. Because fast metabolism of a substrate decreases the amount of substrate that is biologically available, these people have reduced prefrontal dopamine activity. This reduction, in turn, impairs prefrontal information processing.
  • Individuals with the val/met variant have fairly efficient prefrontal function.
  • Patients with the met/met variant have the most efficient prefrontal function. In fact, this variant results in an enzyme that is 3-4 times weaker than the product of the val/val variant.
• Environmental causes: Problems with pregnancy and/or delivery, heavy marijuana use beginning in early adolescence, marital or family dysfunction, and low social class have all been associated with ADHD. However, many people with ADHD have no such associations.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Dissociative disorder
Mood disorder
Panic disorder with or without agoraphobia
Post-traumatic stress disorder (PTSD)
Psychotic disorders
Social phobia
Substance-related disorders
Tourette syndrome or other tic disorders

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Liver function tests
• • Liver function tests (LFTs) may be indicated if the patient has a history of hepatic dysfunction.
  • Amphetamines, methylphenidate, atomoxetine, and tricyclic antidepressants are metabolized hepatically and excreted mainly in the urine.
  • A cause-and-effect relationship has been established between the use of atomoxetine and reversible hepatic failure. However, no evidence suggests that baseline LFT results assist care with atomoxetine in any way.
  • Consider checking LFTs if a patient who is taking atomoxetine presents with signs of hepatitis including early signs, such as nausea, vomiting, diarrhea, and muscle aches lasting longer than 5 days.
• Determination of CBC counts
• • A coincident relationship has been reported, but no cause-and-effect relationship has been established between use of methylphenidate and blood dyscrasias.
  • A few clinical authorities recommend periodic determination of the CBC counts, but their necessity is not generally endorsed, even for patients receiving long-term treatment.
• Drug screening
• • Consider periodic random drug screening by means of urine testing (witnessed) or serum testing (if witnessing of urine testing is not possible) in all patients with a history of chemical abuse or suspected chemical abuse.
  • Any suspected substances should be investigated.

Imaging Studies

• Evidence suggests that MRI and positron emission tomography (PET) may be useful as future diagnostic methods.
• At present, no laboratory studies, imaging studies, or procedures help with the diagnosis of attention deficit hyperactivity disorder (ADHD), unless the patient's history suggests that other pathology must be ruled out.

Other Tests

• Psychometric and educational testing is often important for the diagnosis of ADHD. The patient's initial history may indicate a need for additional tests, as follows.
• • Examine children by using the Conners' Parent and Teacher Rating Scale and examine adolescents according to the Brown Attention Deficit Disorder Scale (BADDS) for Adolescents and Adults.
  • Assess impulsivity and inattention by using timed computer tests such as the Conners Continuous Performance Test (CPT), the Integrated Visual and Auditory (IVA) CPT, or both.
  • Assess girls by using the Nadeau/Quinn/Littman ADHD Self-Rating Scale for Girls.
  • Assess the patient's executive function by using various neuropsychologic tests.
  • Several well-validated intelligence-quotient (IQ) tests are available.
  • • The Wechsler tests are the standards.
    • Many believe that untimed tests are most appropriate for persons with ADHD.
    • A large discrepancy between the patient's IQ and other measures, such as visual or auditory abilities or an ability to work with numbers, is not uncommon, particularly in older children and adolescents.
  • Many people in whom ADHD is not diagnosed until later years have IQs well above average but a function, such as short-term memory, that is at or below average.
  • Perform a learning-disability (LD) evaluation (IQ versus achievement).
• Baseline ECG to access the QT interval may be indicated before a tricyclic antidepressant is prescribed.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The 2 major components in the medical care of children with attention deficit hyperactivity disorder (ADHD) are behavioral and pharmaceutical therapies. The pharmaceutical component is covered in Medication. In addition, the eMedicine article on adult Attention-Deficit/Hyperactivity Disorder provides extensive tables about the nonstimulant medications.

Most components of behavioral care take place outside of the primary care physician's office. Common components are briefly described below to assist in referral and consultation. Not all components are necessary for every child.

• School or education interventions
• • The age of the child at initial diagnosis and the severity of the symptoms of ADHD likely affect the extent to which the child benefits from working with education specialists.
  • Consultants initially involved with diagnosis and evaluation can also be important in promoting the development of study skills.
  • Teachers have an important function. Their periodic feedback about the child's school performance through the use of standardized scales, narrative descriptions, and telephone follow-up is generally an indispensable component of ongoing care.
• Psychotherapeutics
• • For adolescents, ADHD coaching, participating in a support group, or both can help normalize the disorder and assist them in obtaining well-focused peer feedback and general information.
  • Counselors such as psychologists, behavioral developmental pediatricians, clinical social workers, and advanced practice nurses who are well familiarized with ADHD can be invaluable to affected children and their families.
  • Behavioral modification and family therapy are usually necessary for optimal care.

Consultations

The timing of consultations depends on the physician's degree of knowledge and experience with the evaluation and treatment of ADD/ADHD. Several possible scenarios are described below.

• No consultation is necessary: In this scenario, the patient is well known and perhaps has family members with ADD/ADHD whose condition is stabilized with medications without problems with coexistent conditions and if the patient has a clear history consistent with ADD/ADHD without coexistent conditions.
• Refer the patient to an ADD/ADHD specialist or clinic referral and/or a psychiatrist or a behavioral developmental pediatrician: In this scenario, the patient may or may not be well known, and he or she may have family members with ADD/ADHD whose condition is stabilized by medications without problems with coexistent conditions. However, the patient must be questioned about ADD/ADHD or coexistent conditions.
• Refer the patient to an ADD/ADHD specialist and clinic, to a psychotherapist, and/or to a psychiatrist or a behavioral developmental pediatrician: In this scenario, the patient may or may not be well known; he or she has no family history of ADD/ADHD; and he or she may or may not have a family history of a mood disorder, an anxiety disorder, or ADD/ADHD. The patient must be questioned about ADD/ADHD or coexistent conditions.
• Refer the patient to an ADD/ADHD specialist and clinic and/or to a psychiatrist or a behavioral developmental pediatrician: In this scenario, the patient may or may not be well known and perhaps has other family members with ADD/ADHD whose condition is stabilized by medications without problems with coexistent conditions; however, ADD/ADHD cannot be diagnosed and/or coexistent conditions cannot be ruled out with confidence.
• Consider a brief consultation with or referral to an ADD/ADHD specialist or a psychiatrist or behavioral developmental pediatrician: In this scenario, the patient may or may not be well known to the practitioner, and his or her condition has been stabilized by medications without problems with identified coexistent conditions. However, the medication either no longer works or has started to cause adverse effects, and the medication cannot be adjusted with confidence.
• Refer the patient as soon as possible to a specialist or specialty clinic for drug rehabilitation: In this scenario, a patient is being evaluated and is not taking psychostimulants, or he or she is being reevaluated for current psychostimulants and chemical abuse is noted. If the patient is taking psychostimulants and if the medications are being taken properly, a consultation call to decide whether the stimulants should be continued may be more appropriate than simply stopping them.

Diet

No special diet clearly affects ADHD. Until this situation changes, a healthy diet with minimal, if any, caffeine should be emphasized.

Activity

No evidence-based studies have been conducted to elucidate the potential role of physical activity in children with ADHD. Because regular physical activity is important in patients with some of the common coexistent conditions (eg, depression, anxiety) and in improving concentration, it may be an important component of therapy.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The 2 major components in the medical care of children with attention deficit hyperactivity disorder (ADHD) are behavioral and pharmaceutical therapies. The behavioral component is covered in the Treatment section above. In addition, the eMedicine article on adult Attention-Deficit/Hyperactivity Disorder provides extensive tables about the nonstimulant medications.

Pediatric dosing of stimulant medications

Dosing of stimulant medications vary among ADHD centers throughout the American medical community. The Table below is derived from the stimulant trial protocol of The Affinity Center, Inc, a center for the evaluation and treatment of ADHD and mood disorders in Cincinnati, Ohio.

Pediatric Dosing of Stimulant Medications

Note.—In general, when the terms methylphenidate, Dexedrine, and Ritalin are used without abbreviations for extended-release preparations (eg, continuous release [CR], sustained release [SR], osmotic-release oral system [OROS]), a short-acting, immediate-release (IR) preparation is implied.

^*Maximum pediatric dose suggested by the US Food and Drug Administration (FDA). Although some children benefit greatly from doses greater than these, benefit from use of either the lowest and highest ends of the dose range is uncommon.

†The methylphenidate patch contains a different total methylphenidate dose than the name implies because it is designed to last 12 hours (eg, 10-mg patch [patch size 12.5 cm²] delivers about 10 mg over 9 h [estimated delivery rate is 1.1 mg/h for this particular patch]). Delivery rate varies depending on patch size.

‡Many patients describe their experience with methylphenidate sustained-release (SR) preparations as erratic and uncomfortable.

Dose conversions

Conversions for psychostimulants are always approximations, especially when one is converting between stimulants, such as methylphenidate and dextroamphetamine. Different forms of the same drug have slightly different pharmacokinetics, and patients often have different responses to them. FDA-recommended conversions between short- and long-acting preparations of the same drug are based on attempts to match serum-concentration curves and not clinical-performance curves.

In clinical practice, ratios for converting among medications vary by ADHD manifestations, adverse effects, comorbidities, and the patients' metabolism. Common approximations are described below. Individual patients vary; therefore, close follow-up, and possibly titration, is initially necessary.

For methylphenidate LA, CD, or ER preparations, convert by using a ratio of 2:1 with immediate-release methylphenidate. For example, Ritalin 10 mg q4h is converted to Ritalin LA 20 mg q8h. For a few patients, effects last only 5-6 hours with the long-acting preparations although effects last 3.5-4 hours with the IR form. However, a short effect from one 8-hour preparation does not always mean another 8-hour has the same problem.

For XR mixed amphetamine salts (MAS), convert using a ratio of 2:1 with IR MAS. The half-life of MAS widely varies among individuals. Some patients do better with a lower second dose and, thus, may benefit from an IR and XR morning combination.

Dexedrine Spansule seems to have the greatest interpatient variance when converting the IR form to the CR form. The IR-to-CR ratio for equivalent clinical effects appears to vary from 1:1 to about 1:1.5; however, this conversion has not been well studied. For example, Dextrostat 10 mg q4h is converted to Dexedrine CR 10-15 mg q8h.

Methylphenidate OROS tablets are converted in an 18:5 ratio with methylphenidate. For example, Ritalin 10 mg q4h is converted to Concerta 36 mg. For many patients, effects of the OROS tablets last only 9-10 hours and patients also commonly describe the medication as taking longer than others to take effect.

Methylphenidate OROS tablets are converted in an 18:10 ratio with methylphenidate LA, CD, or ER. For example, Ritalin LA 10 mg q8h is converted to Concerta 18 mg.

Methylphenidate transdermal patch is converted in a 1:1 ratio with methylphenidate IR and a 1:2 ratio with the long-acting preparations, although the FDA suggests starting with the lowest dose patch and working up.

Lisdexamfetamine dosing conversion be compared with dextroamphetamine immediate-release (Dexedrine IR). The lisdexamfetamine prescribing information describes lisdexamfetamine dimesylate 100 mg as an equivalent oral dose to d-amphetamine sulfate immediate-release 40 mg.  

Categories of medications

Psychostimulants are effective in patients with ADHD. In addition, they have been available for many decades, allowing for a strong appreciation of their lack of major adverse effects when used at therapeutic doses.

Atomoxetine (Strattera), a nonstimulant selective norepinephrine reuptake inhibitor (SNRI), has been effective in many people with ADHD. This relatively new medication has the advantages of qd-to-bid dosing and unscheduled status with the Drug Enforcement Agency (DEA). However, cases of reversible hepatic failure have been directly attributed to atomoxetine, and an evaluation of other long-term adverse effects has been limited to data from a few years.

Patients may significantly benefit more from stimulants than from atomoxetine, but they have untenable adverse effects with several stimulant products and doses. In the experience of numerous subspecialists, these patients may benefit from a combination of atomoxetine and a stimulant. For many patients, atomoxetine appears to augment the effects of the stimulant, allowing for clinical efficacy with a low dose and decreasing the likelihood of adverse effects.

Antidepressants and alpha-agonists have an important role in some individuals with ADHD. Most have well-known adverse-effect profiles. Unlike stimulants, antidepressants or alpha-agonists can cause cardiac adverse effects, and this possibly must be kept in mind.

Modafinil (Provigil, Sparlon), a medication used to treat excessive daytime sleepiness, improves core symptoms in many children with ADHD. In early studies in children, common adverse affects occurring at rates higher than those of placebo were insomnia (24%) and anorexia (14%).

In August 2006, Cephalon, the manufacturer of modafinil (Sparlon), received a nonapprovable letter from the FDA for the treatment of ADHD. Cephalon has decided that it will not pursue further development of Sparlon for ADHD. Modafinil is still available as Provigil, which does have FDA approval to improve wakefulness for adults with narcolepsy, sleep apnea, or shift-work sleep disorders. To view information from a media briefing describing the FDA decision, see Cephalon Media Briefing.

Transcripts of the FDA Psychopharmacologic Drugs Advisory Committee minutes that describe the rashes observed in clinical trials with modafinil are available. For more information see FDA Psychopharmacologic Drugs Advisory Committee minutes from March 23, 2006 that discuss modafinil for ADHD.

Drug Category: Central alpha agonists

Central alpha agonists can be helpful in treating hyperactivity, tics, or both. They have a long history of pediatric use for this indication. Rare cases of sudden death have been reported in a few children who were given clonidine with concurrent methylphenidate. Reports also describe fatal ventricular fibrillation in patients in whom treatment with clonidine was abruptly stopped rather than slowly tapered, as is appropriate. Details of these cases do not substantiate a cause-and-effect association, only concurrence. Therefore, the FDA has not stated whether these drugs should be used simultaneously. Nevertheless, a prudent approach is to avoid using these drugs together in any patient with a first-degree relative who died from a sudden cardiac cause. Also prudent is obtaining an ECG in any patient who may benefit from this combination but who has a history of arrhythmia. Most experts continue to use clonidine with any of the stimulants when clinically indicated.

Drug Name	Clonidine (Catapres)
Description	Stimulates alpha2-adrenoreceptors in brainstem, activating an inhibitory neuron, which reduces sympathetic outflow. Result is decreased vasomotor tone and HR.
Pediatric Dose	0.025-0.05 mg PO hs or divided bid initially; slowly increase prn to desired effect (often 0.05-0.1 mg bid/tid)
Contraindications	Documented hypersensitivity
Interactions	TCAs inhibit hypotensive effects; coadministration with beta-blockers may potentiate bradycardia; TCAs may enhance hypertensive response associated with abrupt clonidine withdrawal; narcotic analgesics enhance hypotensive effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Cerebrovascular disease; coronary insufficiency; sinus-node dysfunction; renal impairment; abrupt withdrawal may cause severe cardiac arrhythmias

Drug Category: SNRIs

These are used as an alternative to stimulants.

Drug Category: Antidepressants

Many patients have reported clinically significant improvement with the use of some antidepressants. Although antidepressants are beneficial when added to a stimulant or SNRI in certain clinical situations, a psychostimulant or SNRI is still the medication of choice for most persons with ADHD because of its safety profile and superior efficacy.

Drug Name	Bupropion (Wellbutrin)
Description	Inhibits neuronal dopamine reuptake. Weak blocker of serotonin and norepinephrine reuptake.
Pediatric Dose	37.5-300 mg/d PO divided bid; not to exceed 200 mg/dose at least 8 h apart to avoid increasing seizure threshold
Contraindications	Documented hypersensitivity; seizure disorder; anorexia nervosa; concurrent MAOIs
Interactions	Carbamazepine, cimetidine, phenytoin, and phenobarbital may decrease effects; toxicity increases with concurrent levodopa and MAOIs
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Renal or hepatic insufficiency (decrease dose); doses >450 mg/d significantly decreases seizure threshold

Drug Name	Desipramine (Norpramin)
Description	May increase synaptic concentration of norepinephrine in CNS by inhibiting reuptake by presynaptic neuronal membrane. May have effects in the desensitization of adenyl cyclase and downregulation of beta-adrenergic and serotonin receptors. Adjust dose to response and serum level.
Pediatric Dose	10-25 mg PO qd; may gradually increase to 2-5 mg/kg/d as tolerated; can be divided bid/tid prn to improve tolerance of adverse effects
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; recent postmyocardial infarction; current MAOIs or fluoxetine or administration in previous 2 wk
Interactions	Decreases antihypertensive effects of clonidine but increases effects of sympathomimetics and benzodiazepines; effects increase with phenytoin, carbamazepine, and barbiturates; levels may increase with concurrent stimulants
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Associated with sudden death, do not use unless safer antidepressants have been tried with adequate doses and treatment duration (unwise to prescribe without consulting a tertiary-care mental health professional); cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, and hyperthyroidism (in patients receiving thyroid replacement) may occur

Drug Category: Psychostimulants

Psychostimulants stimulate the areas of decreased activation to a higher state of arousal. The spectrums of therapeutic efficacy and adverse effects of all the FDA-scheduled category II psychostimulants for ADHD are similar. For any individual, therapeutic efficacy may vary greatly among drugs, preparations, or formulations (generic vs brand name).

The most common adverse effects are anorexia, sleep disturbances, mild anxiety, and rebound (eg, posttherapeutic agitation, anger, lethargy). Most individuals who take psychostimulants for ADHD develop tolerance for the adverse effects within a few weeks. Although adverse-effect profiles, akin to therapeutic profiles, are similar for all psychostimulants, patients have their own positive and negative responses, which vary among the drugs.

Individuals with certain current or latent coexistent psychiatric disorders (eg, psychosis, bipolar disorder, some disorders of anxiety or depression) are particularly vulnerable to adverse effects due to stimulants if they do not receive concurrent medication, psychological counseling, or both for the coexistent condition.

The following chart contains FDA-approved dosing information and FDA-stated contraindications. Of note, many experts question the FDA's maximums for most stimulant medications (see the Table above for ranges). Experts also question several comorbidities thought to be contraindications because evidence suggests that tics may be as likely to improve with stimulants as worsen with them. Furthermore, BP improves in some individuals with hypertension receiving stimulants, whereas others simply need a slight increase in their dose of antihypertensive. Last, though the FDA lists glaucoma as a contraindication, the specific concern is only narrow-angle glaucoma.

Drug Name	Methylphenidate transdermal patch (Daytrana)
Description	CNS stimulant. Therapeutic action for ADHD not known but thought to block norepinephrine and dopamine reuptake into presynaptic neuron and to increase release of these monoamines into extraneuronal space. Racemic mixture composed of the d- and l-enantiomers. The d-enantiomer is more pharmacologically active than the l-enantiomer. Transdermal administration exhibits minimal first-pass effect compared with oral administration; consequently, lower dose of transdermal methylphenidate (on mg/kg basis) compared with oral dose of methylphenidate may still produce higher d-methylphenidate level. Available in 4 dosage strengths. Different-sized patches contain different amounts of methylphenidate and deliver different amounts over 9-h dose period. Respective patch sizes, methylphenidate content per patch, and dose delivered over 9 h are 12.5, 18.75, 25, and 37.5 cm2; 27.5, 41.3, 55, and 82.5 mg; and 10, 15, 20, and 30 mg. Onset of desired effect occurs approximately 2 h after application and persists 3-4 h after removal.
Adult Dose	Not established
Pediatric Dose	<6 years: Not established 6-12 years: Initiate with lowest dose (10 mg [12.5 cm2]); if maximal response not observed, may titrate upward incrementally in 1-wk intervals Apply patch to skin on hip every am and remove after 9 h; alternate placement every am between hips; may decrease or increase duration patch is worn according to adverse effects or clinical needs; not to exceed 30 mg/d
Contraindications	Documented hypersensitivity; verbal tics or Tourette syndrome; glaucoma; anxiety, tension, or agitation; current MAOIs or within last 14 d
Interactions	May decrease effectiveness of antihypertensive drugs; coadministration with vasopressors may increase blood pressure; concurrent MAOIs or use in previous 14 d may increase risk of hypertensive crisis; may inhibit metabolism of coumarin anticoagulants, anticonvulsants (eg, phenobarbital, phenytoin, primidone), some TCAs (eg, imipramine, clomipramine, desipramine), and SSRIs; downward dosage adjustment of aforementioned medications may be required
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Apply to dry, clean skin; do not cut patch (active ingredient will be released too quickly); may cause insomnia, blurred vision, skin irritation, allergic skin rash, nausea, anorexia, and slower weight gain and height growth; because of additive risk of sudden death, caution in persons with known structural cardiac abnormalities; may exacerbate psychosis, seizures, or hypertension; tolerance and psychological dependence may occur; avoid exposing patch to direct heat sources (eg, heating pad, electric blanket), heat increases drug release by 2-fold

Drug Name	Lisdexamfetamine (Vyvanse)
Description	Inactive prodrug of dextroamphetamine. Elicits CNS stimulant activity. Blocks norepinephrine and dopamine reuptake in presynaptic neurons and increases release of these monoamines in extraneuronal space. Indicated for attention-deficit/hyperactivity disorder (ADHD).
Adult Dose	Not established
Pediatric Dose	<6 years: Not established 6-12 years: 30 mg PO every am; if needed may increase by 20-mg/d increments at weekly intervals; not to exceed 70 mg/d >12 years: Not established Swallow cap whole or dissolve contents in glass of water and drink immediately
Contraindications	Documented hypersensitivity; advanced arteriosclerosis; symptomatic cardiovascular disease; moderate-to-severe hypertension; hyperthyroidism; glaucoma
Interactions	Reduces effects of guanethidine and bretylium; toxicity of phenytoin, tricyclic antidepressants, warfarin, primidone, phenobarbital, meperidine, and vasopressors may increase when administered concurrently; MAOIs increase toxicity of dextroamphetamine
Pregnancy	C - Safety for use during pregnancy has not been established
Precautions	Caution in dementia, seizures, hypertension, structural cardiac abnormalities, or other cardiovascular disease; increased risk for sudden death associated with use in patients with serious heart conditions; sudden death, stroke, and MI have also been reported in adults receiving stimulant drugs at usual doses; may exacerbate preexisting psychiatric disorders and increase potential for emergence of treatment-related psychotic or manic symptoms; may increase risk of temporary growth suppression

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Follow-up varies and depends on the patient's profile, the physician's experience, and the access to healthcare providers.
• After the patient's condition is stabilized, a follow-up frequency of every 6-12 weeks is often appropriate for the first year.
• After that, patients whose condition is stable may do best with visits every 4 months to assess their medications.
• Psychotherapy may need to be continued for months to years.

In/Out Patient Meds

• See Medication.
• See the Table.

Complications

• Coexisting neuropsychiatric disorders and learning disorders can complicate the diagnosis and treatment of ADHD (see History).

Prognosis

• The prognosis for patients with ADHD is excellent if the following conditions are present:
• • The patient has no major comorbidity.
  • Medication management takes into account minor comorbidities and the great range of individual responses.
  • Patients and caregivers receive appropriate education about ADHD and ADHD management.
  • Adherence to therapy continues.
  • Any and all coexisting learning disabilities are diagnosed, and remediation is scheduled and undertaken.
  • Any and all coexisting emotional problems are investigated and treated appropriately by a primary care physician or the patient is referred to a mental health professional.

Patient Education

• Provide information about the pathophysiology in lay terms.
• Provide information about complementary therapeutic approaches to medication (eg, involvement of education specialists, counseling or coaching, school accommodations, parent training).
• Provide clinical medication information.
• Include appropriate follow-up parameters.
• Attend to administrative issues related to medication (eg, prescription writing and safety, compliance with state laws).
• Provide emergency information.
• Seek school accommodations.
• Provide contact information for local and national support organizations.
• Provide literature or written resources (eg, books, periodicals).
• For excellent patient education resources, visit eMedicine's Mental Health and Behavior Center. Also, see eMedicine's patient education article Attention-Deficit/Hyperactivity Disorder.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Methylphenidate and the amphetamines all are schedule II controlled substances (C-II); therefore, prescriptions for these drugs must follow strict federal and state guidelines.
• Any psychostimulants that legal authorities find (eg, while writing a speeding ticket to a patient) can cause suspicion.
• • Therefore, if patients must carry their medication away from home, the drugs should be kept in the original container from the pharmacy.
  • In some states, having the medication in any container is acceptable as long as the pills are accompanied by a physician's order on a prescription form or letterhead that states that the patient is under the physician's care and takes the medication as directed by a physician.
• Many clinicians ask all patients receiving C-II drugs to sign an agreement stating that they will use only 1 pharmacy, that they will never share the medication, and that they will never use more than the prescribed amount.
• Although the rate of stimulant abuse in ADHD specialty centers is remarkably low, it is not zero.
• • Warn adolescent patients about the potentially fatal outcomes of intravenous psychostimulant abuse.
  • In addition, snorting crushed psychostimulants (observed in many adolescent environments) is potentially addictive and fatal; therefore, warn patients about the dangers of snorting drugs.
  • Adderall (because it is sticky and has coloring that can be noted) and Concerta (because of the consistency of the preparation) are less likely to be abused by means of snorting, though no studies of this practice have been conducted.
  • Consider reminding adolescent patients with ADHD that if any of their medication knowingly leaves their hands and is used as an intravenous psychostimulant or snorted as a crushed psychostimulant, the fate of the abuser is partially his or her responsibility.
• Federal and state laws grant special educational accommodations for patients with ADHD and learning disabilities. Become familiar with these laws.

Special Concerns

• In the International Classification of Disease, Ninth Revision (ICD-9), ADD/ADHD is coded as follows:
• • 314.00 - All ADD/ADHD without hyperactivity (eg, inattentive type)
  • 314.01 - All ADD/ADHD with hyperactivity (eg, predominantly inattentive type with hyperactivity and hyperactive type)
  • 314.9 - Nonspecific (ie, other prominent symptoms of ADD/ADHD that do not meet the above criteria)
• ADHD is a controversial diagnosis for several reasons. Many well-meaning individuals have spoken out against making children behave according to a norm or take medications for the sake of improving their grades. These individuals have expressed concern about addiction or medication of children. This concern is valid; however, the following issues must also be considered:
• • Improved school performance is often linked to improved social skills and heightened self-esteem.
  • Stimulants used to treat ADHD do not cause addiction. Although tolerance usually develops for the stimulant-associated effects of anorexia, insomnia, or mild euphoria, tolerance does not develop to the neurotransmission augmentation of ADHD-related neurochemistry.
  • The use of psychostimulants in children should be scrutinized carefully. Fortunately, methylphenidate (historically the major medication for ADHD) has been available for more than 40 years. Although no placebo-controlled prospective studies have been performed, experience has shown it to be one of the safest pharmaceuticals used in children.
  • Data from a recent analysis of all available studies of the possible effect of stimulant treatment for ADHD on future substance abuse support the safety of stimulant treatment. Conducting a meta-analysis, researchers from the Massachusetts General Hospital found that medication treatment for children with ADHD reduced the risk of future substance abuse by almost 2-fold.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• APA. Diagnostic and Statistical Manual of Mental Disorders. 4^th ed. Washington, DC: American Psychiatric Association Press; 1994:78-85.
• Brown TE. Brown ADD Scales. San Antonio, TX: Psychological Corp; 1996:5-6.
• Elia J, Ambrosini PJ, Rapoport JL. Treatment of attention-deficit-hyperactivity disorder. N Engl J Med. Mar 11 1999;340(10):780-8. [Medline].
• Hunt RD, Paguin A, Payton K. An update on assessment and treatment of complex attention-deficit hyperactivity disorder. Pediatr Ann. Mar 2001;30(3):162-72. [Medline].
• Johnson TM. Evaluating the hyperactive child in your office: is it ADHD?. Am Fam Physician. Jul 1997;56(1):155-60, 168-70. [Medline].
• Nadeau KG, Littman E, Quinn P. Understanding Girls With AD/HD. Springfield, MD: Advantage Books; 2000.
• Ramchandani P, Joughin C, Zwi M. Attention deficit hyperactivity disorder in children. Clin Evid. Jun 2002;262-71. [Medline].
• Rappley MD. Clinical practice. Attention deficit-hyperactivity disorder. N Engl J Med. Jan 13 2005;352(2):165-73. [Medline].
• Reeves G, Schweitzer J. Pharmacological management of attention-deficit hyperactivity disorder. Expert Opin Pharmacother. Jun 2004;5(6):1313-20. [Medline].
• Spencer TJ, Biederman J, Wilen T. Pharmacotherapy of ADHD with antidepressants. In: Barkley RS, ed. Attention Deficit HyperactivityDisorder: A Handbook for Diagnosis and Treatment. 2^nd ed. New York, NY: Guilford Press; 1998:552-63.
• Wilens TE. Straight Talk about Psychiatric Medications for Kids. New York, NY: Guilford Press; 2002.
• Wolraich ML, ed. The Classification of Child and Adolescent Mental Diagnoses in Primary Care: Diagnostic and Statistical Manual for Primary Care (DSM-PC) Child. Elk Grove, IL: American Academy of Pediatrics; 1996.

Article Last Updated: Dec 18, 2006