Your Family Physician

Introduction

Background

The term attention deficit is misleading. In general, the current predominating theories suggest that persons with attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), 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 (ADD) pay too much attention to too many things, leading them to have little focus.

Three basic forms of ADHD (ADD) are described in the Diagnostic and Statistical Manual IV (DSM-IV) of the American Psychiatric Association (APA).¹ They are (1) attentional; (2) hyperactive/impulsive; and (3) combined, which is most frequently a combination of attentional and hyperactive forms.

The major neurologic functions disturbed by the neurotransmitter imbalance of ADHD (ADD) fall into the category of executive function. The 6 major tasks of executive function that are most commonly distorted with ADHD (ADD) include (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, ADHD (ADD) is 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 (ADD) 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 exercising inhibition. Many findings support this view, including those described below.

Executive functions are major tasks of the frontal lobes. MRI of the right mesial prefrontal cortex in persons with ADHD (ADD) strongly supports decreased activation (low arousal) during tasks that require inhibition of a planned motor response and timing of a motor response to a sensory cue. MRI in persons with ADHD (ADD) also strongly supports 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.

The catecholamines are the main neurotransmitters with frontal-lobe function. Catecholamine controlled dopaminergic and noradrenergic neurotransmission appear to be the main targets for medications used to treat ADHD (ADD).

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

In addition to the role of the neurotransmitters most commonly associated with the frontal lobes and the pathways mentioned above, some investigations have begun exploring a possible role for 5-hydroxytryptamine (5-HT). Although the brain’s motor regions are innervated by 5-HT projections, no connection between 5-HT and ADHD (ADD) motor pathology has yet been identified. However, connections have been made to attention-related processes. Altered 5-HT activity does appear to be at least part of the cause for difficulties with perceptual sensitivity and the appropriate recognition of the relative significance of stimulation.

Frequency

United States

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

International

People with ADHD (ADD) have been identified in every country studied, with comparable frequency.

Mortality/Morbidity

The morbidity for ADHD (ADD) widely varies. 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 (ADD) 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 (ADD) 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 (ADD).

Age

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

• Approximately 30-80% of children with ADHD (ADD) 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 and changes in brain composition (ie, pruning of abundant neural connections) that occur during late adolescence. However, persons with ADHD (ADD) 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-IV criteria, in conjunction with a thorough clinical interview regarding daily functioning, are important in the diagnosis of attention deficit hyperactivity disorder (ADHD), previously termed attention deficit disorder (ADD). Of note, some of the DSM-IV criteria have been revised to reflect state-of-the-art knowledge, including data regarding ADHD (ADD) in girls and women. The clinician should also gather information that helps to identify any coexisting conditions.

• History of present illness: All of the following DSM-IV criteria for ADHD (ADD) 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 fails to 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 often fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions)
      5. Often has difficulty organizing tasks and activities
      6. Often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (eg, schoolwork, homework); often loses things necessary for tasks or activities (eg, school assignments, pencils, books, tools, toys)
      7. Often is easily distracted by extraneous stimuli (eg, toys, school assignments, pencils, books, tools)
      8. Often is forgetful in daily activities
    • Hyperactivity/impulsivity: At least 6 of the 9 symptoms of hyperactivity (symptoms 1-6) and impulsivity (symptoms 7-9) 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 about or climbs excessively in situations in which it is inappropriate (in adolescents and adults, may be limited to subjective feelings of restlessness)
      4. Often has difficulty quietly playing or engaging in leisure activities
      5. Often on the go or often acts as if driven by a motor
      6. Often talks excessively
      7. Often blurts out answers before questions have been completed
      8. Often has difficulty awaiting turn
      9. Often interrupts or intrudes on others (eg, butts into conversations or games)
  • Some hyperactive-impulsive or inattentive symptoms that caused impairment are present before age 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 exclusively occur during the course of pervasive developmental disorder, premenstrual dysphoric disorder, schizophrenia, or other psychotic disorder. No mood disorder, anxiety dissociative disorder, or personality disorder accounts for the behavior.
• Past medical history
  • Screen for the following medications or supplements that may have negative interactions with ADHD (ADD)-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 (ADD) 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 (ADD) have other significant psychiatric comorbidities. Consider screening patients for the following:
    • Anxiety disorders (generalized anxiety disorder [GAD], obsessive-compulsive disorder [OCD], panic disorder, social phobia)
    • Bipolar disorder
    • Communication disorder (receptive, expressive)
    • Conduct disorder (oppositional defiant disorder in children)
    • Depression
    • Dissociative disorders
    • Eating disorder
    • Enuresis/encopresis
    • Learning disability
    • Pervasive developmental disorder including Asperger syndrome
    • Posttraumatic stress disorder (PTSD)
    • Psychotic disorders
    • Sleep disorder (sleep apnea, restless leg syndrome, delayed sleep phase syndrome)
    • Substance-related disorders
    • Thought disorder
    • Tourette syndrome or other tic disorders
    • Somatic comorbidity (No somatic comorbidities are significantly associated with ADHD [ADD].)
• Family history: Inquire about a family history of ADHD (ADD) and of the coexistent conditions listed under History of present illness.
• Social history: Inquire about the following:
  • Home and family interactions consistent with ADHD (ADD)
    • 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.
    • High activity level is noted.
    • Completion of multistep directions is difficult.
    • Losing or forgetting material or conversations is observed.
  • 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
    • Parent(s) with ADHD (ADD)
    • Physical abuse
    • Sexual abuse
    • Recent death of loved one or friend
    • 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 (ADD) may exhibit few symptoms in a clinical setting, careful observation of 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 (ADD). However, many environmental factors have been correlated with ADHD (ADD), and future research may prove these to be etiologic factors. Morbidity, as evidenced by signs and symptoms in people with ADHD (ADD), 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 (ADD) has a substantial genetic component. Molecular genetic studies have revealed several genes that appear to be associated with ADHD (ADD) 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: No environmental causes have been clearly identified. However, problems with pregnancy (including cigarette smoking during pregnancy) and/or delivery, head injuries, toxin exposure, heavy marijuana use beginning in early adolescence, marital or family dysfunction, and low social class have all been associated with ADHD (ADD).

Differential Diagnoses

Anxiety Disorder: Generalized Anxiety	Mood Disorder: Bipolar Disorder
Anxiety Disorder: Obsessive-Compulsive Disorder	Mood Disorder: Depression
Anxiety Disorder: Separation Anxiety and School Refusal	Oppositional Defiant Disorder
Conduct Disorder	Pervasive Developmental Disorder
Eating Disorder: Anorexia	Pervasive Developmental Disorder: Asperger Syndrome
Eating Disorder: Bulimia	Sleep Disorder: Night Terrors
Learning Disorder: Mathematics	Sleep Disorder: Nightmares
Learning Disorder: Reading	Sleep Disorder: Problems Associated With Other Disorders
Learning Disorder: Written Expression

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

Laboratory Studies

Workup in attention deficit hyperactivity disorder (ADHD), previously termed attention deficit disorder (ADD), includes the following:

• 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. Current use is appropriate for research purposes only.
• At present, no laboratory studies, imaging studies, or procedures help with the diagnosis of ADHD (ADD), 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 (ADD). 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.²
• Assess impulsivity and inattention using timed computer tests such as the Conners Continuous Performance Test (CPT), the Integrated Visual and Auditory (IVA) CPT, or both.
• Assess girls using the Nadeau/Quinn/Littman ADHD Self-Rating Scale for Girls.
• Assess the patient's executive function by using various neuropsychologic tests.
• Perform a learning disability evaluation (intelligence quotient [IQ] vs achievement).
• Several well-validated IQ tests are available.
  • The Wechsler tests are the standards.
  • Many believe that untimed tests are most appropriate for persons with ADHD (ADD).
  • 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
• Baseline ECG to access the QT interval may be indicated before a tricyclic antidepressant is prescribed.

Treatment

Medical Care

The 2 major components in the medical care of children with attention deficit hyperactivity disorder (ADHD), previously termed attention deficit disorder (ADD), 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 provider'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 (ADD) 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.
  • Implementation of academic accommodations and adaptations is often necessary
• Psychotherapeutics
  • For adolescents, ADHD (ADD) 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 (ADD) can be invaluable to affected children and their families.
  • Behavioral modification and family therapy are usually necessary for optimal care.
  • Refer parent(s) for evaluation of ADHD (ADD), if suspected.
  • Coexisting conditions must be addressed as part of therapy.

Consultations

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

• No consultation is necessary: In this scenario, the patient is well known and perhaps has a family member with ADHD (ADD) but no coexistent conditions. The patient has a clear history consistent with ADHD (ADD) without coexistent conditions.
• Referral to an ADHD (ADD) specialist, clinic, and/or a psychiatrist or a behavioral developmental pediatrician
  • The patient may or may not be well known and may have a family member with ADHD (ADD) but no coexistent conditions whose condition. However, the clinician feels the patient must be questioned further about ADHD or coexistent conditions.
  • The patient may or may not be well known and may have no family history of ADHD (ADD) but has a concerning family history of a mood or anxiety disorder.
  • The patient may or may not be well known and perhaps has other family members with ADHD (ADD) whose condition is stabilized by medications without problems with coexistent conditions; however, ADHD (ADD) cannot be diagnosed and/or coexistent conditions cannot be ruled out with confidence.
• A brief consultation with or referral to an ADHD (ADD) specialist or a psychiatrist or behavioral developmental pediatrician: In this scenario, the patient may or may not be well known to the practitioner, and the 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.
• Referral 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 is being re-evaluated 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 (ADD). Until this situation changes, a healthy diet with minimal, if any, caffeine should be emphasized. Note that, in children, caffeine is often consumed in the form of chocolate candy, chocolate milk, or "energy" drinks.

Activity

No evidence-based studies have been conducted to elucidate the potential role of physical activity in children with ADHD (ADD). However, anecdotal clinical reports commonly attest to improvements in focus and sleep quality associated with regular physical activity and exercise. In addition, regular physical activity is important in patients with some of the common coexistent conditions (eg, depression, anxiety) and helps improve concentration. Therefore, physical activity is often an important component of therapy.

Medication

The 2 major components in the medical care of children with attention deficit hyperactivity disorder (ADHD), previously termed attention deficit disorder (ADD), 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 (ADD) centers throughout the medical community in the United States. The table below is derived from the stimulant trial protocol of The Affinity Center, Inc, a center for the evaluation and treatment of ADHD (ADD) 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], SR, osmotic-release oral system [OROS]), a short-acting, 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 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-acting and long-acting (LA) 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 (ADD) 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 LA 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 preparation 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 LA preparations, although the FDA suggests starting with the lowest dose patch and working up.

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

Categories of medications

Psychostimulants are effective in patients with ADHD (ADD). 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 (ADD). 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 some may have untenable adverse effects with any stimulant product or dose. 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 clinical 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 (ADD). Most have well-known adverse-effect profiles. Antidepressants and alpha-agonists can cause cardiac adverse effects, and this possibly must be kept in mind.

Modafinil (Provigil), a medication used to treat excessive daytime sleepiness, improves core symptoms in many children with ADHD (ADD). 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 (ADD). Cephalon has decided that it will not pursue further development of Sparlon for ADHD (ADD). 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. Many ADHD (ADD) specialists continue to use modafinil in selected patients without problems. 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.

Central alpha agonists

Central alpha agonists can be helpful in treating hyperactivity, tics, or delayed sleep onset. They have a long history of pediatric use for this indication. Rare cases of sudden death had been reported several years ago in a few children who were given clonidine with concurrent methylphenidate. Reports also described 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.

The FDA has not stated that these drugs should not be simultaneously used. 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 without first getting an ECG. Obtaining an ECG in any patient who may benefit from this combination but who has a history of arrhythmia is also prudent. Most experts continue to use clonidine with any of the stimulants when clinically indicated.

Guanfacine (Tenex)

Stimulates alpha2-adrenoreceptors in brainstem, activating an inhibitory neuron, which reduces sympathetic outflow. Result is decreased vasomotor tone and HR.

Clonidine (Catapres)

Stimulates alpha2-adrenoreceptors in brainstem, activating an inhibitory neuron, which reduces sympathetic outflow. Result is decreased vasomotor tone and HR.

Selective norepinephrine reuptake inhibitors (SNRIs)

These are nonstimulant ADHD (ADD) medications generally used as adjuncts to stimulants.

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 adverse 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.

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 (ADD) because of its safety profile and superior efficacy.

Imipramine (Tofranil)

Inhibits reuptake of norepinephrine or serotonin (5-hydroxytryptamine, 5-HT) at presynaptic neuron.

Bupropion (Wellbutrin)

Inhibits neuronal dopamine reuptake. Weak blocker of serotonin and norepinephrine reuptake.

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.

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 (ADD) are similar. For any individual, therapeutic efficacy may vary greatly among drugs, preparations, or formulations (generic vs brand name).

The most common adverse effects include anorexia, sleep disturbances, mild anxiety, and rebound (eg, post-therapeutic agitation, anger, lethargy). Most individuals who take psychostimulants for ADHD (ADD) 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 the adverse effects of stimulants if they do not receive concurrent medication, psychological counseling, or both for the coexistent condition.

The following 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, blood pressure improves in some individuals with hypertension receiving stimulants, whereas others simply need a slight increase in their dose of antihypertensive. Finally, although the FDA lists glaucoma as a contraindication, the specific concern is only narrow-angle glaucoma.

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-mg or 10-mg scored tab. Dexedrine Spansules (CR) available as 5-mg, 10-mg, or 15-mg Spansules.

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. LA preparations more expensive than short-acting preparations. Concerta (LA) tends to be more expensive than other preparations; 1 cap of Concerta, similar to other stimulants, costs the same whatever dose.

Although clinical difference between generic drug and branded-generics or Ritalin has not been 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.

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-receptor 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-mg, 7.5-mg, 10-mg, 12.5-mg, 15-mg, 20-mg, or 30-mg scored IR tabs and 10-mg, 20-mg, and 30-mg XR caps.

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.

Methylphenidate transdermal patch (Daytrana)

CNS stimulant. Therapeutic action for ADHD (ADD) 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 -enantiomer and l -enantiomer. The d -enantiomer is more pharmacologically active than the l -enantiomer. Transdermal administration exhibits minimal first-pass effect compared with PO administration; consequently, lower dose of transdermal methylphenidate (on mg/kg basis) compared with PO 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.

Lisdexamfetamine (Vyvanse)

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 ADHD in children aged 6 y or older and adults.

Adult

30 mg PO every am; if needed may increase by 10-mg or 20-mg/d increments at weekly intervals; not to exceed 70 g/d

Pediatric

<6 years: Not established
>6 years: Administer as in adults
Swallow cap whole or dissolve contents in glass of water and drink immediately

Follow-up

Further Outpatient Care

• Follow-up for attention deficit hyperactivity disorder (ADHD), previously termed attention deficit disorder (ADD), varies and depends on the patient's profile, the clinician'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 conditions are stable may do best with visits every 4 months to assess their medications.
• Psychotherapy may need to be continued for months to years.

Inpatient & Outpatient Medications

• See Medication.
• See the Table.

Complications

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

Prognosis

• The prognosis for patients with ADHD (ADD) 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 (ADD) and ADHD (ADD) 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 provider 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

Medicolegal Pitfalls

Used in the treatment of attention deficit hyperactivity disorder, previously termed attention deficit disorder (ADD), methylphenidate and the amphetamines are all 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 the prescriber's order on a prescription form or letterhead that states that the patient is under the clinician's care and takes the medication as directed.
• Many clinicians ask all patients receiving C-II drugs to sign an agreement stating that they will use only one 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 (ADD) specialty centers is low, it is not zero, and stimulant misuse on college campuses is a growing concern.
  • Warn adolescent patients about the potentially fatal outcomes of intravenous psychostimulant abuse.
  • Snorting crushed psychostimulants (observed in many adolescent environments) is potentially addictive and fatal; therefore, warn patients about the dangers of snorting drugs.
  • Consider reminding adolescent patients with ADHD (ADD) 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 (ADD) and learning disabilities who have documented negative impact on their ability to learn. Become familiar with these laws.

Special Concerns

• In the International Classification of Disease, Ninth Revision (ICD-9), ADHD (ADD) is coded as follows:
  • 314.00 - All ADHD (ADD) without hyperactivity (eg, inattentive type)
  • 314.01 - All ADHD (ADD) with hyperactivity (eg, predominantly inattentive type with hyperactivity and hyperactive type)
  • 314.9 - Nonspecific (ie, other prominent symptoms of ADHD [ADD] that do not meet the above criteria)
• ADHD (ADD) 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 (ADD) 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 (ADD)-related neurochemistry.
  • The use of psychostimulants in children should be scrutinized carefully. Fortunately, methylphenidate (historically the major medication for ADHD [ADD]) 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 (ADD) 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 (ADD) reduced the risk of future substance abuse by almost 2-fold.

Source : http://emedicine.medscape.com/article/912633