Coauthor(s): Christine Mayhall, PhD, Consulting Psychologist, The Affinity Center of Cincinnati
Susan Louisa Montauk, MD, is a member of the following medical societies: American Academy of Family Physicians, and Society of Teachers of Family Medicine
Editor(s): Chet Johnson, MD, Medical Director, Child Development Unit, Professor, Department of Pediatrics, University of Kansas Medical Center; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Caroly Pataki, MD, Associate Program Director, Clinical Associate Professor, Department of Psychiatry and Biobehavioral Sciences, Division of Child and Adolescent Psychiatry, Neuropsychiatric Institute and Hospital, UCLA; Carrie Sylvester, MD, MPH, Director of Education in Child and Adolescent Psychiatry, Professor, Departments of Psychiatry and Pediatrics, Northwestern University Medical School; and Murray M Kappelman, MD, Professor, Departments of Pediatrics and Psychiatry, University of Maryland School of Medicine
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:
In the US: 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.
Internationally: 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
History: The DSM criteria, in conjunction with a thorough clinical interview regarding daily functioning, are important in the diagnosis of 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.
Often does not give close attention to details or makes careless mistakes in schoolwork, work, or other activities
Often has difficulty sustaining attention in tasks or play activities
Often does not seem to listen when spoken to directly
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)
Often has difficulties with organizing tasks and activities
Often avoids, dislikes, or is reluctant to engage in homework that requires sustained mental effort
Often loses things necessary for tasks or activities (eg, school assignments, pencils, books, tools, toys)
Often is easily distracted by extraneous stimuli
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.
Often fidgets with hands or feet or squirms in seat
Often leaves seat in classroom or in other situations in which remaining seated is expected
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)
Often has difficulty playing or engaging in leisure activities quietly
Often on the go or often acts as if driven by a motor
Often talks excessively
Often blurts out answers to questions before questions are completed
Often has difficulty waiting turns
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
Anxiety Disorder: Generalized Anxiety
Anxiety Disorder: Obsessive-Compulsive Disorder
Anxiety Disorder: Separation Anxiety and School Refusal
Conduct Disorder
Eating Disorder: Anorexia
Eating Disorder: Bulimia
Learning Disorder: Mathematics
Learning Disorder: Reading
Learning Disorder: Written Expression
Mood Disorder: Bipolar Disorder
Mood Disorder: Depression
Oppositional Defiant Disorder
Pervasive Developmental Disorder
Pervasive Developmental Disorder: Asperger Syndrome
Sleep Disorder: Night Terrors
Sleep Disorder: Nightmares
Sleep Disorder: Problems Associated With Other Disorders
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
{mospagebreak}
Workup
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 complete blood cell 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 CBCs, 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 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.
{mospagebreak}
Treatment
Medical Care: The 2 major components in the medical care of children with 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
The 2 major components in the medical care of children with 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.
Medication Initial Pediatric Dose Pediatric Dosage Range and Maximum Dose* Common Pediatric Dose* Preparations
Methylphenidate IR (Ritalin, Methylin, generic) 2.5-5 mg 0.1-0.8 mg/kg/dose PO qd to 5 times/d
Not to exceed 60 mg/d 0.3-0.5 mg/kg/dose PO tid/qid All preparations available as 5-, 10-, or 20-mg scored tabs
Methylin also available as 2.5-, 5-, or 10-mg chewable tab and 5 mg/5 mL and 10 mg/mL oral solution
Methylphenidate sustained-release (SR) (Ritalin LA, Metadate CD) Convert from IR or use 10 mg 0.2-1.4 mg/kg/dose PO qd/tid
Not to exceed 60 mg/d 0.6-1 mg/kg/dose PO qd/bid 10-, 20-, 30-, or 40-mg (Ritalin LA only); (Metadate also has 50- and 60-mg)
Spansules can be sprinkled
Methylphenidate extended release (ER)‡
(Ritalin SR, Methylin ER, Metadate ER, generic SR) Convert from IR 0.2-1.4 mg/kg/dose PO qd/tid
Not to exceed 60 mg/d 0.6-1 mg/kg/dose PO qd/bid 20-mg Spansules; do not cut, crush, or chew
Methylphenidate OROS tablets (Concerta) Convert from IR or use 18 mg 0.3-2 mg/kg PO qd
Not to exceed 54 mg/d 0.8-1.6 mg/kg PO qd 18-, 36- and 54-mg tabs; do not cut, crush, or chew
Methylphenidate transdermal patch (Daytrana)† Convert from IR or use 10 mg (12.5 cm2 patch) released over 9 h and titrate up prn 0.3-2 mg/kg released over 12 h
Not to exceed one 30-mg patch 10-30 mg released over 9 h 10-, 15-, 20-, 30-mg patches
Dexmethylphenidate IR (Focalin) 2.5-5-mg 0.1-0.5 mg/kg/dose PO qd to qid
Not to exceed 20 mg/d 0.2-0.3 mg/kg/dose PO bid/tid 2.5-, 5-, or 10-mg scored tabs
Dexmethylphenidate extended release (Focalin-XR) 5-10-mg 0.2-1 mg/kg/dose PO qd to bid
Not to exceed 20 mg/d 0.4-0.6 mg/kg/dose PO qd/bid 5-, 10-, or 20-mg scored tabs
Dextroamphetamine (Dexedrine, Dextrostat) 2.5-5 mg 0.1-0.7 mg/kg/dose PO qd/qid
Not to exceed 60 mg/d 0.3-0.5 mg/kg/dose PO qd/tid Dexedrine: 5-mg scored tabs; Dextrostat: 5-, 10-, or 15-mg scored tabs
Dextroamphetamine Spansules (Dexedrine CR) 5 mg 0.1-0.75 mg/kg/dose PO qd/bid
Not to exceed 60 mg/d 0.3-0.6 mg/kg/dose PO qd/bid 5-, 10-, or 15-mg Spansules; do not cut, crush, or chew
Mixed amphetamine salts IR (Adderall, generic) 2.5-5 mg 0.1-0.7 mg/kg/dose PO qd/qid
Not to exceed 40 mg/d 0.3-0.5 mg/kg/dose PO tid/qid 5-, 7.5-, 10-, 12.5-, 15-, 20-, or 30-mg scored tabs
Mixed amphetamine salt XR (Adderall-XR) Convert from IR or use 5-10 mg 0.2-1.4 mg/kg/dose PO qd/tid
Not to exceed 30 mg/d 0.6-1.0 mg/kg/dose PO qd/bid 5-, 10-, 15-, 20-, 25-, or 30-mg Spansules; can be sprinkled
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 United States 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 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 though 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 is highly variable between 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.
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 benefit significantly 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: 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
Dextroamphetamine (Dexedrine, Dexedrine Spansules, Dextrostat) — Increases amount of circulating dopamine and norepinephrine in cerebral cortex by blocking reuptake of norepinephrine or dopamine from synapse. Short-acting brands fairly similar in cost; generic is 50-60% less expensive. Dexedrine available as 5-mg scored tab. Dextrostat available as 5-, 10-, or 15-mg scored tab. Dexedrine Spansules (CR) available as 5-, 10-, or 15-mg Spansules.
Pediatric Dose <3 years: Not recommended by FDA
IR: 2.5-5 mg PO qd up to qid; not to exceed 60 mg/d
ER: 5 mg qd/bid; not to exceed 60 mg/d
Contraindications Documented hypersensitivity; hypertension; MAOI use; advanced arteriosclerosis; hyperthyroidism; narrow-angle glaucoma
Interactions Coadministration with MAOIs may precipitate hypertensive crisis and arrhythmias with anesthetics; may increase toxicity of phenobarbital, propoxyphene, meperidine, TCAs, phenytoin, and norepinephrine
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Angina, narrow-angle glaucoma, cardiovascular disease, Tourette syndrome or other tic disorders, dementia, depression, anxiety disorders, anorexia, sleep disturbances, seizures, and hypertension
Drug Name
Methylphenidate (Concerta, Methylin, Metadate, Ritalin) — Stimulates cerebral cortex and subcortical structures. Generic and branded-generic (Methylin and Metadate regular or ER) formulations 50-60% less expensive than Ritalin. Long-acting preparations more expensive than short-acting preparations. Concerta (long acting) tends to be more expensive than other preparations; 1 capsule of Concerta, similar to other stimulants, costs the same whatever dose. Although clinical difference between generic drug and branded-generics or Ritalin not verified, many patients have enough variability among preparations that they are willing to pay the difference. Many experts observed enough variability that they do not prescribe plain generic products unless patient (or insurance) insists. FDA allows for 20% variability in certain parameters between generics and brands and determines equivalence solely by pharmacokinetics and not data from clinical studies.
Pediatric Dose Initial dose (unless high, short-acting dose known to be acceptable to the patient is being replaced):
IR: 2.5-5 mg PO qd up to qid; not to exceed 60 mg/d
CD, ER, or SR: 10-20 mg qd; not to exceed 60 mg/d
Concerta: 18 mg PO qd; not to exceed 54 mg/d
Contraindications Documented hypersensitivity; narrow-angle glaucoma; Tourette syndrome; motor tics; agitation; tension; severe anxiety
Interactions Reduces effects of guanethidine and bretylium; toxicity of phenytoin, TCAs, warfarin, primidone, and phenobarbital may increase when administered concurrently; MAOIs increase toxicity
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Dementia, depression, anxiety, seizures, arterial disease, anorexia, sleep disturbances, coronary artery disease, and hypertension
Drug Name
Dextroamphetamine and amphetamine mixture (Adderall) — Produce CNS and respiratory stimulation. CNS effect may occur in cerebral cortex and reticular activating system. May have direct effect on alpha- and beta-receptor sites in peripheral system and release stores of norepinephrine in adrenergic nerve terminals. Mixture contains various salts of amphetamine and dextroamphetamine. Available as 5-, 7.5-, 10-, 12.5-, 15-, 20-, or 30-mg scored IR tabs and 10-, 20-, and 30-mg XR capsules.
Pediatric Dose <3 years: Not recommended
3-6 years: 2.5 mg/d PO qd initially; may increase by 2.5 mg qwk
>6 years: 5 mg PO qd or divided bid initially; increase by 5 mg qwk; not to exceed 40 mg/d (IR) or 30 mg/d (XR)
IR pills may be broken up and mixed in applesauce; XR capsules may be opened and contents mixed in applesauce, but beads should not be chewed.
Contraindications Documented hypersensitivity; hypertension; advanced arterial disease; active hyperthyroidism; narrow-angle glaucoma; agitated states; administration of MAOIs within last 14 d
Interactions Coadministration with MAOIs may precipitate hypertensive crisis; anesthetics may precipitate arrhythmias; dextroamphetamine may increase toxicity of phenobarbital, propoxyphene, meperidine, TCAs, phenytoin, and norepinephrine
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Caution in nephritis, hypertension, angina, narrow-angle glaucoma, cardiovascular disease, psychopathic personalities, or history of drug abuse
Drug Name
Dexmethylphenidate (Focalin, Focalin XR) — Contains pharmacologically active d-enantiomer of racemic methylphenidate. Blocks norepinephrine and dopamine reuptake into presynaptic neuron and increases release of these monamines into extraneuronal space.
Pediatric Dose <6 years: Not established
>6 years:
Focalin: 2.5 PO bid initially; may increase in 2.5- to 5-mg increments qwk if warranted; not to exceed 20 mg/d
Focalin XR: (for patient not currently taking dexmethylphenidate or racemic methylphenidate): 5 mg PO qd initially; may increase in 5-mg increments qwk if warranted; not to exceed 20 mg/d
Focalin XR (for patient currently taking dexmethylphenidate [Focalin]): Same total daily dose as Focalin but qd
Focalin XR (for patient currently taking racemic methylphenidate): Switch to half total daily dose and administer qd; not to exceed 20 mg/d
Contraindications Documented hypersensitivity to dexmethylphenidate or methylphenidate; marked anxiety, tension, or agitation; glaucoma; motor tics or Tourette syndrome; coadministration with MAOIs or within 14 d after discontinuation of MAOIs
Interactions Coadministration with MAOIs or within 14 d after discontinuation of MAOIs contraindicated and may result in hypertensive crisis; coadministration with other vasopressors (eg, pseudoephedrine) may increase BP; may counteract effect of antihypertensive drugs; may inhibit metabolism of warfarin, anticonvulsants (eg, phenobarbital, phenytoin, primidone), and TCAs (eg, imipramine, clomipramine, desipramine); serious adverse events reported with concomitant clonidine, though no causality established
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Not intended to treat severe depression or fatigue states; may exacerbate psychosis; may lower seizure threshold in patients with history or EEG abnormalities; may cause visual disturbances and increase BP; caution in history of drug dependence or alcoholism; periodically monitor CBC, differential, and platelet count if therapy prolonged; common adverse effects include nervousness, insomnia, decreased appetite, abdominal pain, and weight loss; XR formulation must be swallowed whole or sprinkled on a spoonful of applesauce (do not crush, chew, or divide)
Drug Name
Methylphenidate transdermal patch (Daytrana) — 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 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
Guanfacine (Tenex) — Stimulates alpha2-adrenoreceptors in brainstem, activating an inhibitory neuron, which reduces sympathetic outflow. Result is decreased vasomotor tone and HR.
Pediatric Dose Not established; limited data suggest 0.25-0.5 mg PO qd; slowly increase prn to desired effect (often 0.5-1 mg qd); sometimes divided bid
Contraindications Documented hypersensitivity
Interactions TCAs inhibit hypotensive effects
Pregnancy B – Usually safe but benefits must outweigh the risks.
Precautions Congestive heart failure; asthma; peptic ulcer disease; regional vascular disease; abrupt (ie, not tapered) discontinuation can lead to reactive hypertension and serious cardiac arrhythmias
Drug Name
Clonidine (Catapres) — 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 Name
Atomoxetine (Strattera) — SNRI that inhibits presynaptic norepinephrine transporter. Also appears to indirectly stimulant dopamine activity in frontal lobes. Many anecdotal reports state that, when stimulants are not well-tolerated at a dose necessary for efficacy (eg, because of anxiety) and atomoxetine is not efficacious enough alone, the combination of atomoxetine and low dose (tolerable) stimulants is often very effective.
About 5-10% of patients are poor metabolizers of the drug and have increased drug exposure, peak serum levels, and half-lives. If intolerable but benign side effects are present at FDA recommended doses, but not at lower dose, efficacy may be observed at the lower dose; therefore consider a low-dose trial. Usually clinically effective qd despite 5-h half-life (24 h in poor metabolizers); unknown if serum levels are correlated with efficacy.
Pediatric Dose <70 kg: 0.5 mg/kg PO qd initially; after 3 d, increase to 1.2 mg/kg PO qd or divided bid (morning and late afternoon); not to exceed 1.4 mg/kg/d or 100 mg/d (whichever is less)
>70 kg: 40 mg PO qd initially; after 3 d, increase to 80 mg/d PO qd or divided bid (morning and late afternoon); may increase after 2-4 wk; not to exceed 100 mg/d
Contraindications Documented hypersensitivity; use of MAOIs within 2 wk of start of therapy (fatal reaction may occur); narrow-angle glaucoma
Interactions CYP2D6 inhibitors (eg, fluoxetine, paroxetine, quinidine) may increase levels; neither induces nor inhibits CYP2D6; coadministration with vasopressors may increase HR and BP; fatal reactions may occur if MAOIs used within 2 wk of start of therapy; may potentiate effect of beta2-adrenergic agonists on cardiovascular system
Pregnancy C – Safety for use during pregnancy has not been established.
Precautions Decrease dose in moderate-to-severe hepatic dysfunction; rare reversible hepatic failure reported (educate about signs of early hepatitis); rare allergic reactions (eg, angioneurotic edema, urticaria, rash) reported; caution in hypertension, tachycardia, or cardiovascular or cerebrovascular disease; may increase BP or HR; may cause urinary hesitancy or orthostatic hypotension; monitor weight; must be taken after meals to avoid nausea and vomiting
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
Imipramine (Tofranil) — Inhibits reuptake of norepinephrine or serotonin (5-hydroxytryptamine, 5-HT) at presynaptic neuron.
Pediatric Dose 10-25 mg/d PO initially, may gradually increase to 2-5 mg/kg/d as tolerated; can divide daily dose bid/tid prn to improve tolerance of adverse effects
Contraindications Documented hypersensitivity; narrow-angle glaucoma; acute recovery phase following myocardial infarction; current MAOI or fluoxetine use or use in the previous 2 wk (avoid)
Interactions Increases toxicity of sympathomimetic agents (eg, isoproterenol, epinephrine) by potentiating effects and inhibiting antihypertensive effects of clonidine; avoid combining with methylphenidate, which inhibits hepatic metabolism of imipramine, prolonging its half-life and potentially causes extremely high, toxic levels
Pregnancy D – Unsafe in pregnancy
Precautions Caution in cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, or in patients receiving thyroid replacement; may impair mental or physical abilities required for potentially hazardous tasks
Drug Name
Bupropion (Wellbutrin) — 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) — 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
{mospagebreak}
