Attention Deficit Hyperactivity Disorder (ADHD)

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Background

Attention deficit hyperactivity disorder (ADHD) is a developmental condition of inattention and distractibility, with or without accompanying hyperactivity. There are 3 basic forms of ADHD described in the Diagnostic and Statistical Manual, Fifth Edition (DSM-5) of the American Psychiatric Association: inattentive; hyperactive-impulsive; and combined.[1]

Diagnostic criteria (DSM-5)

According to DSM-5, the 3 types of attention deficit/hyperactivity disorder (ADHD) are (1) predominantly inattentive, (2) predominantly hyperactive/impulsive, and (3) combined. The specific criteria for attention-deficit/hyperactivity disorder are as follows:[1]

Inattentive

This must include at least 6 of the following symptoms of inattention that must have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:

Hyperactivity/impulsivity

This must include at least 6 of the following symptoms of hyperactivity-impulsivity that must have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:

Other

In addition, attention-deficit/hyperactivity disorder is specified by the severity based on social or occupational functional impairment: mild (minor impairment), moderate (impairment between “mild” and “severe”), severe (symptoms in excess of those required to meet diagnosis; marked impairment).

Case study

The parents of a 7-year-old boy take him to the family practitioner because they have become increasingly concerned about his behavior not only in school but also a home. In the first grade, he has been bored, disruptive, fighting with classmates, and rude to his teacher. At home he cannot sit still and meals have been very unpleasant. The lad himself wonders why he is there. The parents have 2 older daughters who say their brother is a “pain” and spoiled. There were no pregnancy or birth problems and the child is on no medications. He has had all his scheduled shots.

The doctor decides more information is required before any treatment is indicated. She wants careful observations of the child both at home and in school. She wishes to talk with his teacher and suggests psychological testing. She also wants some time to see the patient alone. Careful investigation and thorough observations must be done before any intervention. Both the physician and the parents are concerned about overuse of medications and the value for behavioral interventions.

Pathophysiology

The pathology of ADHD is not clear. Psychostimulants (which facilitate dopamine release) and noradrenergic tricyclics used to treat this condition have led to speculation that certain brain areas related to attention are deficient in neural transmission. PET scan imaging indicates that methylphenidate acts to increase dopamine.[2] The neurotransmitters dopamine and norepinephrine have been associated with ADHD.

The underlying brain regions predominantly thought to be involved are frontal and prefrontal; the parietal lobe and cerebellum may also be involved. In one functional MRI study, children with ADHD who performed response-inhibition tasks were reported to have differing activation in frontostriatal areas compared with healthy controls. A 2010 study again indicated the presence of frontostriatal malfunctioning in the etiology of ADHD.[3] Although ADHD has been associated with structural and functional alterations in the frontostriatal circuitry, recent studies have further demonstrated changes just outside that region and more specifically in the cerebellum and the parietal lobes.[4] Another study using proton magnetic spectroscopy demonstrated right prefrontal neurochemical changes in adolescents with ADHD.[5]

Work by Sobel et al has demonstrated deformations in the basal ganglia nuclei (caudate, putamen, globus pallidus) in children with ADHD. The more prominent the deformations, the greater the severity of symptoms. Furthermore, Sobel et al have shown that stimulants may normalize the deformations.[6]

Adults with ADHD also have been reported to have deficits in anterior cingulate activation while performing similar tasks.

In a longitudinal analysis, Shaw et al used 389 neuroanatomic MRI images to compare 193 typically developing children with varying levels of symptoms of hyperactivity and impulsivity (measured with the Conners' Parent Rating Scale) with 197 children with ADHD (using 337 imaging scans).[7] Children with higher levels of hyperactivity/impulsivity had a slower rate of cortical thinning. This was most notable in prefrontal cortical regions, bilaterally in the middle frontal/premotor gyri, extending down the medial prefrontal wall to the anterior cingulate. It was also noted in the orbitofrontal cortex and the right inferior frontal gyrus. Slower cortical thinning during adolescence is characteristic of ADHD and provides neurobiological evidence for dimensionality.

A PET scan study by Volkow et al revealed that in adults with ADHD, depressed dopamine activity in caudate and preliminary evidence in limbic regions was associated with inattention and enhanced reinforcing responses to intravenous methylphenidate. This concludes that dopamine dysfunction may be involved with symptoms of inattention but may also contribute to substance abuse comorbidity.[8]

Individuals with ADHD have inhibition impairment, which is difficulty stopping their responses.[9]

According to a study of young children, there is evidence of early brain structural chages in pre-schoolers with ADHD. Researchers used high resolution anatomical (MPRAGE) images and cognitive and behavioral measures in a cohort of 90 medication-naïve preschoolers, aged 4–5 years (52 with ADHD, 38 controls; 64.4% boys). Results show reductions in bilateral frontal, parietal, and temporal lobe gray matter volumes in children with ADHD relative to typically developing children. The largest effect sizes were noted for right frontal and left temporal lobe volumes. Examination of frontal lobe sub-regions revelated that the largest between group effect sizes were evident in the left orbitofrontal cortex, left primary motor cortex (M1), and left supplementary motor complex (SMC). ADHD-related reductions in specific sub-regions (left prefrontal, left premotor, left frontal eye field, left M1, and right SMC) were significantly correlated with symptom severity, such that higher ratings of hyperactive/impulsive symptoms were associated with reduced cortical volumes.[10]

Epidemiology

Frequency

In 2016, an estimated 6.1 million US children aged 2–17 years (9.4%) were diagnosed with ADHD. Of these children, 5.4 million currently had ADHD, which was 89.4% of children ever diagnosed with ADHD and 8.4% of all U.S. children 2–17 years of age. Almost two-thirds of children with current ADHD (62.0%) were taking medication and slightly less than half (46.7%) had received behavioral treatment for ADHD in the past year; nearly one fourth (23.0%) had received neither treatment.[11]

According to a study by CDC researchers, more than 1 in 10 (11%) US school-aged children (4–17 years) had received an ADHD diagnosis by a health care provider by 2011, as reported by parents. A history of ADHD diagnosis by a health care provider increased by 42% between 2003 and 2011.[12]

A study by Akinbami and colleagues showed the following key findings:[13]

In Great Britain, incidence is reported to be less than 1%. The differences between the US and British reported frequencies may be cultural ("environmental expectations") and due to the heterogeneity of ADHD (ie, the many etiological paths to get to inattention/distractibility/hyperactivity). Furthermore, the International Classification of Diseases, 10th Revision (ICD-10) criteria for ADHD used in Great Britain may be considered stricter than the DSM-5 criteria. However, other studies suggest that the worldwide prevalence of ADHD is between 8% and 12%.

Mortality/Morbidity

No clear correlation with mortality exists in ADHD. However, studies suggest that childhood ADHD is a risk factor for subsequent conduct and substance abuse problems, which can carry significant mortality and morbidity.

ADHD may lead to difficulties with academics or employment and social difficulties that can profoundly affect normal development. However, exact morbidity has not been established.

Sex

In children, ADHD is 3–5 times more common in boys than in girls. Some studies report an incidence ratio of as high as 5:1. The predominantly inattentive type of ADHD is found more commonly in girls than in boys.

In adults, the sex ratio is closer to even.

Age

In DSM-IV, the age of onset criteria was "some hyperactive-impulsive or inattentive symptoms that caused impairment were present before age 7 years."  This reflected the view that ADHD emerged relatively early in development and interfered with a child's functioning at a relatively young age. In DSM-5 this has been revised to "several inattentive or hyperactive-impulsive symptoms were present prior to 12 years."  Thus, symptoms can now appear up to 5 years later.  And, there is no longer the requirement that the symptoms create impairment by age 12, just that they are present. After childhood, symptoms may persist into adolescence and adulthood, or they may ameliorate or disappear.

The percentages in each group are not well established, but at least an estimated 15–20% of children with ADHD maintain the full diagnosis into adulthood. As many as 65% of these children will have ADHD or some residual symptoms of ADHD as adults.

The prevalence rate in adults has been estimated at 2–7%. The prevalence rate of ADHD in the adult general population is 4–5%.[14]

Physical

No physical findings have been well correlated with ADHD.

Mental Status Examination may note the following:

ADHD is associated with a number of other clinical diagnoses. Researchers from the CDC, the University of Florida-Jacksonville, and the University of Oklahoma Health Sciences Center found that more than half of children with ADHD also had another mental disorder, and these children were more likely to have other problems, such as struggling with friendships and getting into trouble in school or with the police.[15] Studies have demonstrated that many individuals have both ADHD and antisocial personality disorder (ASD).[16] These individual are at higher risk for self-injurious behaviors. ADHD is also linked to addictive behavior. The more severe the symptoms of ADHD, the greater the use of tobacco, alcohol, and marijuana.[17] Some individuals have both ADHD and an autism spectrum disorder.[18]  

Symptoms of ADHD and bipolar disorder may be directly correlated. Patients with ADHD should be assessed for possible underlying or coexisting bipolar disorder, and vice versa.[19]

Causes

Genetics

Parents and siblings of children with ADHD are 2-8 times more likely to develop ADHD than the general population, suggesting that ADHD is a highly familial disease.

A study noted that ADHD had a 0.8 degree of inheritability and 80% of phenotypic variance could be attributed to genetics.[20]

Concordance of ADHD in monozygotic twins is greater than in dizygotic twins, suggesting some contribution of genetics. Studies estimate the mean heritability of ADHD to be 76%, indicating that ADHD is one of the most heritable psychiatric disorders.

The involved genes or chromosomes are not definitively known. Vulnerability to ADHD may be due to many genes of small effect. For example, several genes that code for dopamine receptors or serotonin products, including DRD4, DRD5, DAT, DBH, 5-HTT, and 5-HTR1B, have been moderately associated with ADHD.

ADHD risk is significantly increased in the presence of 1 risk allele in genes DRD2 (OR=7,5), 5-HTT (OR=2,7), and DAT1 (OR=1,6). ADHD risk is significantly increased at homozygotes for risk alleles in genes DRD2 (OR=54,8), 5-HTT (OR=6,7), and DAT1 (OR=6,6).[21] Another study implicated the following gene coding for ADHD: DRD4, DRD5, SLC6A3, SNAP-25, and HTR1B.[22]

Studies of cognitive deficits reveal another facet to the genetic contributions to ADHD.[23]

Environment

Hypotheses exist that include in utero exposures to toxic substances, food additives or colorings, or allergic causes. However, diet, especially sugar, is not a cause of ADHD.

How much of a role family environment has in the pathogenesis of ADHD is unclear, but it certainly may exacerbate symptoms.

According to one study, exposure to second-hand smoke in the home is associated with a higher frequency of mental disorder among children. Researchers undertook a cross-sectional study of 2357 children representative of the Spanish population aged 4-12 years in 2011-2012. Results showed that children exposed to ≥1 h/day of second-hand smoke had a multivariate odds ratio for ADHD of 3.14 compared to an odds ratio of 2.18 for children not habitually exposed to second-hand smoke.[24]

Personality factors

Although there remains much evidence for the genetic etiology of ADHD, one study indicated that the contribution of personality aspects in combination with genetics may be significant. Specifically, the presence of high neuroticism and low conscientiousness in conjunction with genetic vulnerability may constitute a risk factor in the expression of ADHD.[25]

Approach Considerations

The diagnosis requires the symptoms of ADHD to be present both in school and at home. Furthermore, all patients must have a full psychiatric evaluation and physical examination. Here is a cautionary note underscoring the need for a full assessment for late-onset ADHD in adolescents and young adults.

Adolescents and young adults without childhood ADHD often present to clinics seeking stimulant medication for late-onset ADHD symptoms and there is, indeed, a valid diagnosis of late-onset ADHD in many cases. However, diagnosis based on the traditional parameters for ADHD may be incomplete in their ability to make the proper determination. Researchers have found that a more thorough psychiatric history is called for.

In one study, researchers administered 8 assessments to 239 individuals without childhood ADHD. Assessments included parent, teacher, and self-reports of ADHD symptoms, impairment, substance use, and other mental disorders, with consideration of symptom context and timing. Results show that of the individuals who initially screened positive on symptom checklists, 95% were excluded from late-onset ADHD diagnosis. The most common reason for diagnostic exclusion was symptoms or impairment occurring exclusively in the context of heavy substance use. These findings suggest that clinicians should consider alternative causes of symptoms and carefully assess impairment, psychiatric history, and substance use.[26]

Laboratory Studies

The diagnosis of attention deficit hyperactivity disorder (ADHD) is based on clinical evaluation. No laboratory-based medical tests are available to confirm the diagnosis.

Basic laboratory studies that may help confirm diagnosis and aid in treatment are as follows:

Imaging Studies

Brain imaging, such as functional MRI or single photon emission computed tomography (SPECT) scans have been useful for research, but no clinical indication exists for these procedures because the diagnosis is clinical.

However, in the largest imaging study of ADHD conducted to date, investigators found that five regions of the brain were slightly smaller in children with ADHD compared to children without the disorder. The study included 1713 individuals with ADHD and 1529 unaffected controls. Participants ranged in age from 4 years to 63 years (median age, 14 years). Researchers used MRI scans to assess the differences in the subcortical structures and intracranial volume of patients' brains. Patients with ADHD were found to have reductions in the volumes of the accumbens, the amygdala, the caudate, the hippocampus, and the putamen, as well as reductions in intracranial volume. Effect sizes were highest in most subgroups of children (< 15 years) versus adults (>21 years).[27]

Other Tests

The Conners Parent-Teacher Rating Scale is a questionnaire that can be given to both the parents and the child's teachers.

Barkley Home Situations Questionnaire may be useful.

The Wender Utah Rating Scale may be helpful in diagnosing ADHD in adults. In 2017, a new machine-learning algorithm was used to build a screening scale from responses to 6 questions in the World Health Organization (WHO) Adult Attention-Deficit/Hyperactivity Disorder Self-Report Scale (ASRS) using optimal integer scoring rules. The new measure is short, easily scored, and detects the vast majority of general population cases.[28]

The Continuous Performance Tests (CPTs) are computer-based tasks that often are used to test attention and may be used in conjunction with clinical information to make a diagnosis. A currently popular example is the Test of Variable Attention (TOVA). While these tests can be supportive of the diagnosis in a full clinical evaluation, they have low sensitivity and specificity and should not be the sole basis for diagnosis.

Vision and hearing should be checked.

Medical Care

The therapeutic approach to ADHD has been shifting. In some cases, environmental restructuring and behavioral therapy alone has been effective. Developments in behavioral parent training (BPT) and behavioral classroom management (BCM) have also proven useful. Furthermore, behavioral psychotherapy often is successful when used in conjunction with an effective medication regimen. The medications of choice are stimulants, and for adults with ADHD stimulants represent the best first-line therapeutic option.[29] For related areas of functioning, such as social skills and academic performance, medications combined with behavioral treatments may be indicated. Pharmacotherapy includes the following:

Stimulants (methylphenidate, dextroamphetamine)

Regarding medication for ADHD, stimulants are the first-line therapy and probably the most effective treatment.

All stimulants have similar efficacy but differ by dosing, duration of action, and adverse effect profiles in individual patients. Care should be made to start at the lowest dose and titrate up for clinical efficacy or to intolerance.

Targeted symptoms include impulsivity, distractibility, poor task adherence, hyperactivity, and lack of attention.

Some stimulants come in sustained-release preparations, which may decrease the number of total daily doses. Otherwise, dosing should be spaced every 4-6 hours.

Care should be taken to not dose too close to bedtime because stimulants may cause significant insomnia.

Other common adverse effects include appetite suppression and weight loss, headaches, and mood effects (depression, irritability).

Stimulants may exacerbate tics in children with underlying tic disorders.

Whether growth might be affected while a child is taking stimulants remains unclear. Drug holidays (during summer or on weekends) may or may not be recommended to allow periods of normal growth. The decision is based on the child's growth rate chart and behavior and cognition off medication.

There has been a long concern that the use of stimulate therapy leads to substance abuse. Recent studies have demonstrated that stimulant therapy does not increase the risk of future substance use or abuse.[30] Furthermore, 112 people with ADHD were observed for a period of 10 years. At the time of the follow-up assessment, 82 (73%) had been treated previously with stimulants and 25 (22%) were undergoing stimulant treatment. No statistically significant associations were noticed between stimulant treatment and alcohol, drug, or nicotine use disorders. The findings revealed no evidence that stimulant treatment increases or decreases the risk for subsequent substance use disorders in children and adolescents with ADHD when they reach young adulthood.[31]

Stimulant medications do enhance mental executive functions for those with ADHD.[32]

Other medications

Atomoxetine (Strattera) has become a second-line and, in some cases, first-line treatment in children and adults with ADHD because of its efficacy and classification as a nonstimulant. However, studies have reported that the overall effect of atomoxetine has not been as extensive as that reported of stimulants.

Recent data suggest that bupropion or venlafaxine may be effective. Dosages are similar to those used to treat depression.

Tricyclic antidepressants (imipramine, desipramine, nortriptyline) have been found effective in numerous studies in children with ADHD; however, because of potential adverse effects, they are rarely used for this purpose. If these agents are used, obtain a baseline ECG because these agents can affect cardiac conduction. A few reports have described sudden death in boys taking desipramine, but the exact cause of death was unclear and may have been unrelated to desipramine use.

Clonidine and guanfacine have been used with mixed reports of efficacy. Sudden deaths have been reported in children taking clonidine with methylphenidate at bedtime. Again, the etiology of these deaths is unclear, and this remains a controversial topic. In September 2010, the FDA approved clonidine extended-release (Kapvay) for ADHD as adjunctive therapy to stimulants or as monotherapy.

Modafinil (Provigil) has recent placebo-controlled data supporting its efficacy in children with ADHD. This medication may currently be used as a third- or fourth-line treatment.

Magnesium pemoline (Cylert) had been used in the 1990s, but concerns of rare, potentially fatal hepatotoxicity have made it a rarely used medication.

Blader et al evaluated the ability of divalproex to reduce aggressive behavior in children with ADHD and a disruptive disorder. Children with persistent aggressive behavior that was underresponsive to psychostimulant therapy were randomly assigned to receive divalproex or placebo in addition to stimulant therapy for 8 weeks. A higher proportion of improved behavior was observed in the divalproex group (8 of 14 [57%]) compared with placebo (2 of 13 [15%]). A larger trial is needed to further study the use of divalproex to ameliorate aggressive behavior in patients with ADHD.[33]

Behavioral psychotherapy

Behavioral psychotherapy often is effective when used in combination with an effective medication regimen. Behavioral therapy or modification programs can help diminish uncertain expectations and increase organization.

Working with parents and schools to ensure environments conducive to focus and attention is necessary.

For adults with ADHD, working to establish ways of decreasing distractions and improving organizational skills may be helpful.

Cognitive therapy for adults with ADHD

Metacognitive therapy involves the principles and techniques of cognitive and behavioral therapies to enhance time management. In doing so, these have made adult patients with ADHD better able to counter the anxiety and depressive symptoms they experience in task performance. Metacognitive therapy has proven to be more effective than supportive interventions and represents a viable therapeutic approach.[34]

Psychosocial interventions

A number of psychosocial treatments are effective. These include behavioral parent training (BPT) and behavioral classroom management (BCM).[35] These are best used in conjunction with psychopharmacological approaches.

Emerging evidence shows that nonpharmacological treatments should be considered the first treatment for children with ADHD. For preschoolers, intervention is best with parental training. For school-aged children, interventions of group training for parents and classroom behavioral approaches might be enough. Severe cases benefit from medication and behavioral interventions.[36]

Nonpharmacological interventions

Concern about medications to treat ADHD has increased interest in alternative treatments. Researchers conducted a systematic review and meta-analysis of randomized controlled trials of dietary and psychological treatments for ADHD and found that free fatty acid supplementation produced small but significant reductions in symptoms. A larger effect was observed with artificial food color exclusion, but this was seen in individuals selected for food sensitivities. Further studies are needed to assess behavioral interventions, neurofeedback, cognitive training, and restricted elimination diets.[37]

Diet

For decades, speculation and folklore have suggested that foods containing preservatives or food coloring or foods high in simple sugars may exacerbate ADHD. Many controlled studies have examined this question. To date, no adequate data set has confirmed the speculation.

Activity

In one study of the effect of physical activity on children's attention, researchers found that intense exercise has a beneficial effect on children with ADHD. It can improve their attention and may help their school performance. In the study, 28 volunteers (14 with ADHD and 14 without symptoms) engaged in intense physical activity promoted by a relay race, which required a 5-minute run without a rest interval. After 5 minutes of rest, the volunteers accessed a computer game to accomplish the tasks in the shortest time. The groups of volunteers with ADHD who performed exercise  showed improved performance for the tasks that require attention with a difference of 30.52% compared with the volunteers with ADHD who did not perform the exercise.[38]

Medication Summary

Although health care providers, parents, and teachers have hoped for effective therapies and methods that do not involve medications for children with attention deficit hyperactivity disorder (ADHD), evidence to date supports that the specific symptoms of ADHD are poorly treated without medication. Perhaps the mildest cases of ADHD can be treated with moderate success with environmental restructuring and behavioral therapy, but other than these limited situations, pharmacotherapy often is needed.

Compliance issues with medications for ADHD in children and adults is common.[39] Therefore, the use of long-acting medications at once-a-day dosing to treat ADHD has been shown to have advances over the shorter acting drugs. They have led to higher rates of remission. Their use has been marked to better adherence and they have been demonstrated to be less stigmatizing.[40] Another benefit of the long-acting medications is time of effectiveness (ie, full-day coverage).[41]

In 2015, the FDA approved a once-daily extended-release oral liquid for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children aged 6 years and older.[42]  In the same year, the FDA approved a chewable tablet form of extended-release methylphenidate, to be sold as QuilliChew ER, for treatment of ADHD in patients aged 6 years or older. The tablet comes in strengths of 20, 30, and 40 mg and are scored so they can be split easily. The product is to be taken once daily in the morning.[43]  In June 2017, the FDA approved 2 new ADHD medications, Cotempla XR-ODT and Mydayis. Cotempla XR-ODT is approved for the treatment of ADHD in children and adolescents aged 6-17 years. It is an oral disintegrating tablet form of extended-release methylphenidate, given once every morning, and is available as an 8.6 mg, 17.3 mg, and 25.9 mg tablet.[44] Mydayis is also approved for the treatment of ADHD in adolescents and adults aged 13 years or older. It is an extended-release capsule of mixed amphetamine salts, administered each morning. It is available as a 12.5 mg, 25 mg, 37.5mg, and 50 mg capsule.

The first bedtime methylphenidate (Jornay PM) was approved by the FDA in 2018. It is indicated for ADHD patients aged 6 years or older. It is administered at 8 PM, although the administration time may be adjusted between 6:30 PM and 9:30 PM to optimize tolerability and efficacy the next morning and throughout the day. The capsule contains 2 functional film coatings that act synergistically to achieve a unique pharmacokinetic profile. The first layer delays the initial release of drug for up to 10 hours, and the second layer helps to control the rate of release of the active pharmaceutical ingredient throughout the day. Compared with placebo, Jornay PM achieved significant improvements in ADHD symptoms as measured by the ADHD rating scale IV (p = 0.002) and the parent rating of evening and morning behavior (revised) scale (p < 0.001).[45]

ADHD has been associated with traffic accidents. Chang et al demonstrated that not only are persons with ADHD involved in more accidents but patients who adhere to their medication have reduced rates of such accidents.[46] The association between ADHD and accidents was estimated with Cox proportional hazards regression. The authors conclude that this should lead to increased awareness about the association between serious traffic accidents and ADHD medication.

No link between current or new use of ADHD medications and an increased risk of serious cardiovascular events in healthy young and middle-aged adults has been found.[47]  However, it is recommended to avoid use of CNS stimulants with patients who have cardiac structural abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems.[44, 48]

The FDA has warned that methylphenidate may rarely cause prolonged and painful erections, known as priapism. Because priapism may cause permanent damage to the penis, patients taking methylphenidate who develop an erection lasting longer than 4 hours should seek immediate medical attention.[49]

Prescription Practices

Webb JR et al report a high prevalence of stimulant use among medical students when compared with a larger, general population. More than 83% of students who took stimulants used them to stay awake, specifically for cognitive performance enhancement. The study suggests that this could impact attitudes towards prescribing such medications to patients with ADHD.[50]

Numerous studies have shown a link between patients with ADHD and criminal activity. Lichtenstein and colleagues found that patients receiving ADHD medication had a significant decline in criminal activity. They found a significant reduction of 32% in the criminality rate for men (adjusted hazard ratio, 0.68; 95% confidence interval [CI], 0.63-0.73) and 41% for women (hazard ratio, 0.59; 95% CI, 0.50-0.70) during medicated periods compared with nonmedication periods.[51]

Methylphenidate (Ritalin, Metadate CD, Methylin ER, Ritalin SR, Cotempla XR-ODT, Jornay PM)

Clinical Context:  Methylphenidate is the drug of choice approved by FDA for ADHD in children aged 6 years or older. It is the most commonly used drug. Methylphenidate is available in sustained-release forms. It is also available as a delayed-release bedtime dosage form.

Dexmethylphenidate (Focalin, Focalin XR)

Clinical Context:  Dexmethylphenidate contains the more pharmacologically active d-enantiomer of racemic methylphenidate. It blocks norepinephrine and dopamine reuptake into presynaptic neurons and increases the release of these monamines into extraneuronal spaces. To allow once-daily dosing, each extended-release (XR) capsule contains half the dose as immediate-release capsules and half as enteric-coated, delayed-release capsules.

Dextroamphetamine and amphetamine mixtures (Adderall, Mydayis)

Clinical Context:  Dextroamphetamine and amphetamine mixtures produce CNS and respiratory stimulation. The CNS effect may occur in the cerebral cortex and reticular activating system. This combination may have direct effects on both alpha- and beta-receptor sites in the peripheral system, as well as release stores of norepinephrine in adrenergic nerve terminals.

The mixture contains various salts of amphetamine and dextroamphetamine. It is available as 5-, 7.5-, 10-, 12.5-, 15-, 20-, and 30-mg scored tablets. The extended release form is also available as 12.5 mg, 25 mg, 37.5mg, and 50 mg capsules.

Dextroamphetamine (Dexedrine)

Clinical Context:  Dextroamphetamine is commonly used first or in case of methylphenidate failure. It is approved by the FDA for use in children aged 3 years or older. It is available in sustained-release forms, which may allow for daily dosing.

Lisdexamfetamine (Vyvanse)

Clinical Context:  Lisdexamfetamine is an inactive prodrug of dextroamphetamine. It elicits CNS stimulant activity. Lisdexamfetamine blocks norepinephrine and dopamine reuptake in presynaptic neurons and increases release of these monoamines in extraneuronal spaces. It is indicated for initial and maintenance treatment of ADHD for children aged 6-17 years and adults.

Amphetamine (Dyanavel XR, Evekeo)

Clinical Context:  Noncatecholamine, sympathomimetic amine that elicits CNS stimulant activity. The precise mechanism by which amphetamines produce mental and behavioral effects are unclear. Available as short-acting tablets (Evekeo) that need 2-3 doses/day in children aged 3 years or older. It is also available as a long-acting, once daily oral suspension (Dyanavel XR) or extended release oral disintegrating tablets (Adzenys XR-ODT) for patients aged 6 years or older.

Class Summary

These agents are known to treat ADHD effectively.

Atomoxetine (Strattera)

Clinical Context:  Atomoxetine elicits selective inhibition of the presynaptic norepinephrine transporter. It is used to improve symptoms of ADHD.

Class Summary

Selective norepinephrine reuptake inhibitors have been shown to be effective in the treatment of ADHD.

Bupropion (Wellbutrin)

Clinical Context:  Bupropion inhibits neuronal dopamine reuptake in addition to being a weak blocker of serotonin and norepinephrine reuptake. It is also available in sustained-release preparations (Wellbutrin SR).

Venlafaxine (Effexor)

Clinical Context:  Venlafaxine may inhibit neuronal serotonin and norepinephrine reuptake. In addition, venlafaxine causes beta-receptor down-regulation. It is available in sustained-release preparations (Effexor XR).

Class Summary

Recent studies support efficacy of venlafaxine and bupropion in ADHD. They may have a slower onset of action than stimulants but potentially fewer adverse effects.

Imipramine (Tofranil)

Clinical Context:  Imipramine inhibits the reuptake of norepinephrine or serotonin (5-hydroxytryptamine, 5-HT) at presynaptic neurons. It may be useful in pediatric ADHD.

Class Summary

See article entitled Depression. Patients may require lower doses for ADHD. They may have a quicker onset of action.

Guanfacine (Intuniv)

Clinical Context:  Guanfacine has a similar mechanism of action to clonidine but has a longer half-life and may be less sedative. The extended-release formulation (Intuniv) is indicated for children with ADHD aged 6-17 years as monotherapy or as adjunctive therapy to stimulant medications.

Clonidine (Kapvay)

Clinical Context:  Clonidine is a central alpha2 agonist. Its mechanism of action for ADHD is unknown. It is indicated for ADHD as adjunctive therapy to stimulants or as monotherapy. It is available as an extended-release tablet.

Class Summary

Centrally acting antihypertensives clonidine and guanfacine have been used to treat children with ADHD. Inhibition of norepinephrine release in the brain may be the mechanism of action.

Further Outpatient Care

Regular follow-up is needed long-term for patients with attention deficit hyperactivity disorder (ADHD). Like diabetes or hypertension, ADHD is not an illness for which one can hand the patient a prescription for pills and assume recovery is automatic with the medication.

Further Inpatient Care

Psychiatric hospitalization is indicated if the person becomes suicidal or homicidal.

Prognosis

Childhood ADHD may confer a higher risk of diagnosis with conduct disorders and substance abuse into adolescence and adulthood. These may be primary coexisting disorders or disorders secondary to untreated or undertreated ADHD.

Klein and colleagues looked at 135 male youths with ADHD free of a conduct disorder and another group of 135 males without ADHD in a 33-year longitudinal study. The youths with ADHD did not have increased anxiety or mood disorders in adulthood, but they did have more divorces; higher rates of antisocial personality disorder, substance use disorders, and ongoing ADHD; and worse educational, occupational, economic, and social outcomes. The authors concluded that beginning in adolescence, ADHD predicts significant disadvantages that last well into adulthood. Extended monitoring and treatment of ADHD remains an important aspect of care.[52]

Most children with ADHD have relatively good psychiatric outcomes once they reach adulthood.

At least 15-20% continue to have full ADHD as adults, and as many as 65% may continue to have problematic symptoms of ADHD that interfere with full realization of academic or work potential.

ADHD can be comorbid with the following conditions:

When evaluating a patient with any of these disorders, special care should also be made to evaluate for ADHD thoroughly. ADHD, like bipolar disorder, is readily treatable.

ADHD is a heterogeneic disorder that carries significant comorbidity. Symptoms consistent with ADHD can present as other disorders, or these signs and symptoms could be a precursor in childhood to later disorders such as bipolar disorder or schizophrenia.

The diagnosis of ADHD in young children results in the risk of depression and suicidal behavior adolescence. The depression and suicide attempt risk occur 5-13 years following the diagnosis. Being female, having been exposed to maternal depression, and having other symptoms leads to an even higher risk for depression and suicidal behavior.[53]

Patient Education

The educational requirements of these patients and their family members are high. Family members include parents and siblings of children, spouses and children of adults, and grown children of elderly patients. Encouragement of medication use, education on time structuring and behavioral control, social skill training, and frequent cognitive redirecting is needed.

For patient education resources, see the Mental Health and Behavior Center, as well as Attention Deficit Hyperactivity Disorder.

In addition there is http://www.webmd.com/add-adhd/default.htm

Some useful Web sites are as follows:

What is attention deficit hyperactivity disorder (ADHD)?What are the DSM-5 diagnostic criteria for predominantly inattentive attention deficit/hyperactivity disorder (ADHD)?What are the DSM-5 diagnostic criteria for predominantly hyperactive/impulsive attention deficit/hyperactivity disorder (ADHD)?What are the DSM-5 diagnostic criteria for attention deficit/hyperactivity disorder (ADHD), regardless of type?What is an example of a case study of a child with attention deficit/hyperactivity disorder (ADHD)?What is the pathology of attention deficit/hyperactivity disorder (ADHD)?Which regions of the brain are involved in attention deficit/hyperactivity disorder (ADHD)?What is the incidence of attention deficit/hyperactivity disorder (ADHD) in children in the US?What is the global incidence of attention deficit/hyperactivity disorder (ADHD)?What are the mortality and morbidity risks associated with attention deficit/hyperactivity disorder (ADHD)?How does the prevalence of attention deficit/hyperactivity disorder (ADHD) vary between females or males?What is the prevalence of attention deficit/hyperactivity disorder (ADHD) among different age groups?What findings of a Mental Status Examination are consistent with a diagnosis of attention deficit hyperactivity disorder (ADHD)?What are the common psychiatric comorbid disorders of attention deficit hyperactivity disorder (ADHD)?What is the role of genetics in the etiology of attention deficit hyperactivity disorder (ADHD)?Which genes are linked to attention deficit hyperactivity disorder (ADHD)?What is the role of dietary factors in the etiology of attention deficit hyperactivity disorder (ADHD)?What is the role of environmental factors in the pathogenesis of attention deficit hyperactivity disorder (ADHD)?What is the role of personality factors in the etiology of attention deficit hyperactivity disorder (ADHD)?What are the differential diagnoses for Attention Deficit Hyperactivity Disorder (ADHD)?What are the requirements to confirm a diagnosis of attention deficit hyperactivity disorder (ADHD)?What is the role of lab testing in the diagnosis of attention deficit hyperactivity disorder (ADHD)?What is the role of imaging studies in the diagnosis of attention deficit hyperactivity disorder (ADHD)?What is the role of psychometric testing in the diagnosis of attention deficit hyperactivity disorder (ADHD)?What are the treatment options for attention deficit hyperactivity disorder (ADHD)?What is the first-line medication for attention deficit hyperactivity disorder (ADHD)?What are the common adverse effects of stimulants used to treat attention deficit hyperactivity disorder (ADHD)?What is the increased risk for substance abuse with stimulant therapy for attention deficit hyperactivity disorder (ADHD)?How effective is atomoxetine (Strattera) in the treatment of attention deficit hyperactivity disorder (ADHD)?Which antidepressants are effective in treating attention deficit hyperactivity disorder (ADHD)?How effective are clonidine and guanfacine in treating attention deficit hyperactivity disorder (ADHD)?How effective is modafinil (Provigil) in treating attention deficit hyperactivity disorder (ADHD)?What are possible adverse effects of magnesium pemoline (Cylert) in the treatment of attention deficit hyperactivity disorder (ADHD)?How effective is divalproex in treating comorbid attention deficit hyperactivity disorder (ADHD) and disruptive behavior disorder?How effective is behavioral therapy for attention deficit hyperactivity disorder (ADHD)?How effective is metacognitive therapy (MCT) for attention deficit hyperactivity disorder (ADHD)?What psychosocial interventions are effective in treating attention deficit hyperactivity disorder (ADHD) in children?What nonpharmacological interventions are available for treatment of attention deficit hyperactivity disorder (ADHD)?How does diet exacerbate attention deficit hyperactivity disorder (ADHD)?How does physical activity affect children with attention deficit hyperactivity disorder (ADHD)?What is the efficacy of nonpharmacologic treatment of attention deficit hyperactivity disorder (ADHD)?What are the benefits of long-acting medications in treating attention deficit hyperactivity disorder (ADHD)?Which long-acting medications are FDA-approved for treatment of attention deficit hyperactivity disorder (ADHD)?Does medication adherence reduce the risk of attention deficit hyperactivity disorder (ADHD) -associated traffic accidents?What are the cardiovascular adverse effects of attention deficit hyperactivity disorder (ADHD) medications?What are possible adverse effects of methylphenidate therapy for attention deficit hyperactivity disorder (ADHD)?How are stimulant medications for attention deficit hyperactivity disorder (ADHD) misused?What is the risk of criminal activity for patients receiving medication for attention deficit hyperactivity disorder?Which medications in the drug class Stimulants are used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD)?Which medications in the drug class Psychiatry Agents, Other are used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD)?Which medications in the drug class Atypical antidepressants are used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD)?Which medications in the drug class Tricyclic antidepressants are used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD)?Which medications in the drug class Alpha2 agonists, central-acting are used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD)?What follow-up is required for patients with attention deficit hyperactivity disorder (ADHD)?When is psychiatric hospitalization necessary for attention deficit hyperactivity disorder (ADHD)?What risks increase with attention deficit hyperactivity disorder (ADHD) during adolescence and adulthood?What comorbidities are associated with attention deficit hyperactivity disorder (ADHD)?What education resources are available to patients with attention deficit hyperactivity disorder (ADHD) and their family members?

Author

Stephen Soreff, MD, President of Education Initiatives, Nottingham, NH; Faculty, Boston University, Boston, MA and Daniel Webster College, Nashua, NH

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Glen L Xiong, MD, Associate Clinical Professor, Department of Psychiatry and Behavioral Sciences, Department of Internal Medicine, University of California, Davis, School of Medicine; Medical Director, Sacramento County Mental Health Treatment Center

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Doctor On Demand<br/>Received income in an amount equal to or greater than $250 from: Blue Cross Blue Shield Federal Employee Program<br/>Received royalty from Lippincott Williams & Wilkins for book editor; Received grant/research funds from National Alliance for Research in Schizophrenia and Depression for independent contractor; Received consulting fee from Blue Cross Blue Shield Association for consulting. for: Received book royalty from American Psychiatric Publishing Inc.

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