Timothy E. Wilens, M.D.
Attention-deficit/ hyperactivity disorder (ADHD) is the most common neurobehavioral disorder practitioners treat in children. Epidemiologic studies indicate that ADHD is prevalent throughout the world with general consensus that from 4 to 5% of youth and up to 2% of adults have the disorder. Although previously thought to remit in early adolescence, ADHD is now seen as a chronic condition continuing into adulthood in approximately half of childhood cases. Whereas the overt hyperactive-impulsive symptoms diminish over time, the bulk of attentional problems persist.
The diagnosis of ADHD is made by careful clinical history applying the DSM-IV criteria now available in a user-friendly primary care version (DSMPC). Youth with ADHD are characterized by a considerable degree of inattentiveness, distractibility, impulsivity, and often hyperactivity that is inappropriate for the developmental stage of the child. Children with predominately inattention may have more difficulties in school and in completing homework, whereas children with excessive hyperactive or impulsive symptoms may perform acceptably academically but have difficulties at home or in situations of less guidance and structure. Adolescents and adults tend to present with prominent attentional difficulties affecting work, schooling, and relationships as well as manifesting residua of impulsivity (intrusiveness, impatience) and hyperactivity (fidgetiness, restlessness). DSM-IV recognizes three subtypes of ADHD (% occurrence): a combined subtype (40-70% of cases), a predominantly inattentive subtype (20-50%), and a predominantly hyperactive-impulsive subtype (<15%). Although not diagnostic, rating scales, checklists, and neuropsychological tests may be helpful in providing evidence for the disorder and accompanying co-occurring conditions. Youth with ADHD are at risk for co-occurring psychiatric disorders (disruptive, mood, and anxiety) as well as learning disabilities. ADHD and its associated conditions also are a significant risk for higher rates and earlier ages of onset of cigarette smoking and alcohol and drug abuse.
While its precise neural and pathophysiological substrate remains unknown, an emerging literature suggests the presence of abnormalities in frontal networks or frontal-striatal dysfunction. Dopaminergic dysfunction in particular, and norepinephrine indirectly, appear to be important in the underlying neurochemistry of ADHD. Data from family-genetic, twin, and adoption studies as well as segregation analysis suggest a genetic origin for some forms of the disorder. Molecular genetic studies have implicated the dopamine D2, D4 receptors and the dopamine transporter as candidate genes.
Treatment
The management of ADHD includes consideration of two major areas: nonpharmacological (educational remediation, individual and family psychotherapy) and pharmacotherapy. ADHD support groups (i.e. CHADD) are an invaluable and inexpensive manner for families to learn about ADHD and resources available for their children or themselves.
Specialized educational planning based on the child's difficulties is necessary in a majority of cases. Educational adjustments should be considered in ADHD youth with difficulties in behavioral or academic performance. Increased structure, predictable routine, learning aids, resource room time, and checked homework are among typical educational considerations in these youth. Similar modifications in the home environment should be undertaken to optimize the child's ability to complete homework. Frequent parental communication with the school about the child's progress is essential.
Medications remain a mainstay of treatment of ADHD with recent multisite studies supporting that medication management of ADHD is the most important variable in outcome in context to multimodal treatment. The stimulants, antihypertensives, and antidepressants comprise the available agents for ADHD.
Stimulants. The psychostimulants are considered first line agents for ADHD, based in part on their extensive efficacy and safety data. Stimulants are sympathomimetic drugs which increase intrasynaptic catecholamines (mainly dopamine) by inhibiting the presynaptic reuptake mechanism and releasing presynaptic catecholamines. The most commonly used compounds in this class include methylphenidate (Ritalin), dextro-amphetamine (Dexedrine), amphetamine compounds (Adderall), and magnesium pemoline (Cylert). Methylphenidate and D-amphetamine are both short acting compounds, with an onset of action within 30 to 60 minutes and a peak clinical effect usually seen between 1 and 2 hours after administration lasting 2 to 5 hours. The amphetamine compounds (Adderall) and sustained release preparations of methylphenidate and dextroamphetamine are intermediate acting compounds with an onset of action within 60 minutes and a peak clinical effect usually seen between 1 and 3 hours after administration maintained for up to 8 hours.
Despite the findings on efficacy of the stimulants, studies have also reported consistently that typically one-third of ADHD individuals do not respond or cannot tolerate this class of agents. Based on marginally different mechanisms of action, some patients who lack a satisfactory response or manifest adverse effects to one stimulant, may respond favorably to another. Stimulants should be initiated at the lowest available dosing once daily and increased every three to four days until a response is noted or adverse effects emerge. Typically, parameters for upward daily dosing of the stimulants are 1 mg/kg/day for the amphetamines, 2 mg/kg/day for methylphenidate, and 3 mg/kg/day for pemoline.
Predictable short-term adverse effects include reduced appetite, insomnia, edginess, and GI upset. Pemoline may rarely cause hepatitis; hence, patient education about the symptoms of early hepatic dysfunction and infrequent liver function tests are advised. There are a number of controversial issues related to chronic stimulant use. Although stimulants may produce anorexia and weight loss, their effect on ultimate height is less certain. Recent reports present the possibility that growth delays previously ascribed to stimulants may actually represent maturational delays to ADHD itself. Stimulants may precipitate or exacerbate tic symptoms in ADHD children with recent work suggesting that up to one-third of children with tics may have worsening of their tics with stimulant exposure. There is a paucity of data supporting the contention that ADHD children abuse their medication; however, data suggests that diversion of stimulants to non-ADHD youth is a concern. The literature indicates that pharmacological treatment of ADHD youth reduces the risk for later substance abuse.
Antidepressants. The antidepressants are generally considered second line drugs of choice for ADHD. The tricyclic antidepressants (TCAs)-imipramine, desipramine, and nortriptyline-block the re-uptake of neurotransmitters including norepinephrine. TCAs are effective in controlling abnormal behaviors and improving cognitive impairments associated with ADHD across the lifespan, but less so than the majority of stimulants. The TCAs are particularly useful in stimulant failures, or when oppositionality, anxiety, tics, or depressive symptoms co-occur within ADHD. Dosing of the TCAs are doses starting with 25 mg daily and titrated upward slowly to a maximum of 5 mg/kg/day (2 mg/kg/day for nortriptyline). Although immediate relief can be seen, a lag of two to four weeks to maximal effect is common. Typical adverse effects include dry mouth, constipation, sedation, and weight gain. As minor increases in heart rate and the ECG intervals are predictable with TCAs, ECG monitoring at baseline and at therapeutic dose is suggested, but not mandatory.
Bupropion (Wellbutrin, Zyban) is an antidepressant with indirect dopamine and noradrenergic effects. Bupropion has been shown effective for ADHD in controlled trials of children and adults. Given its utility in reducing cigarette smoking, improving mood, lack of monitoring results, and paucity of adverse effects, bupropion is often used as an initial agent for complex ADHD patients with substance abuse or an unstable mood disorder. Based on anecdotal reports of anti-ADHD effectiveness at low doses in a minority of patients, it is recommended that the treatment be initiated at 37.5 mg and titrated upward every three to four days up to 300 mg in younger children and 450 mg in older children or adults. Adverse events include activation, irritability, insomnia and rarely seizures.
Antihypertensives. The antihypertensives clonidine (Catapres) and guanfacine (Tenex) are used to treat the hyperactive-impulsive symptoms of ADHD. Clonidine is a relatively short-acting compound with usual daily dose ranges from 0.05 to 0.4 mg. Guanfacine is longer acting and less potent than clonidine with usual daily dose ranges from 0.5 to 3 mg. The antihypertensives have been used for the treatment of ADHD as well as associated tics, aggression, and sleep disturbances, particularly in younger children. Although sedation is more commonly seen with clonidine, both agents may cause depression and rebound hypertension. Recent reports have implicated the combination of clonidine plus methylphenidate in the deaths of four children; however, many mitigating and extenuating circumstances were operative making these cases uninterpretable. Cardiovascular monitoring (vital signs, ECG) remains optional.
Combined pharmacological approaches can be used for the treatment of comorbid ADHD, as augmentation strategies for patients with insufficient response to a single agent, pharmacokinetic synergism, and for the management of treatment emergent adverse effects. Examples include the use of an antidepressant plus a stimulant for ADHD and comorbid depression (fluoxetine [Prozac] plus methylphenidate), the use of clonidine to ameliorate stimulant-induced insomnia, and the use of a mood stabilizer plus an anti-ADHD agent to treat ADHD comorbid with bipolar disorder.
In summary, there is increasing recognition that ADHD is a heterogenous disorder that persists in a number of cases into adult years. Emerging findings support a genetic and neurobiological basis for ADHD with catecholaminergic dysfunction as a central finding. The literature supports the effectiveness of pharmacotherapy not only for the core behavioral symptoms of ADHD but also for improving linked impairments such as cognition, substance abuse, social and family functioning. Similarities between juveniles and adults in characteristics, biology, and pharmacological responsivity of ADHD supports the continuity of the disorder across the lifespan.
Attention-deficit/ hyperactivity disorder (ADHD) is the most common neurobehavioral disorder practitioners treat in children. Epidemiologic studies indicate that ADHD is prevalent throughout the world with general consensus that from 4 to 5% of youth and up to 2% of adults have the disorder. Although previously thought to remit in early adolescence, ADHD is now seen as a chronic condition continuing into adulthood in approximately half of childhood cases. Whereas the overt hyperactive-impulsive symptoms diminish over time, the bulk of attentional problems persist.
The diagnosis of ADHD is made by careful clinical history applying the DSM-IV criteria now available in a user-friendly primary care version (DSMPC). Youth with ADHD are characterized by a considerable degree of inattentiveness, distractibility, impulsivity, and often hyperactivity that is inappropriate for the developmental stage of the child. Children with predominately inattention may have more difficulties in school and in completing homework, whereas children with excessive hyperactive or impulsive symptoms may perform acceptably academically but have difficulties at home or in situations of less guidance and structure. Adolescents and adults tend to present with prominent attentional difficulties affecting work, schooling, and relationships as well as manifesting residua of impulsivity (intrusiveness, impatience) and hyperactivity (fidgetiness, restlessness). DSM-IV recognizes three subtypes of ADHD (% occurrence): a combined subtype (40-70% of cases), a predominantly inattentive subtype (20-50%), and a predominantly hyperactive-impulsive subtype (<15%). Although not diagnostic, rating scales, checklists, and neuropsychological tests may be helpful in providing evidence for the disorder and accompanying co-occurring conditions. Youth with ADHD are at risk for co-occurring psychiatric disorders (disruptive, mood, and anxiety) as well as learning disabilities. ADHD and its associated conditions also are a significant risk for higher rates and earlier ages of onset of cigarette smoking and alcohol and drug abuse.
While its precise neural and pathophysiological substrate remains unknown, an emerging literature suggests the presence of abnormalities in frontal networks or frontal-striatal dysfunction. Dopaminergic dysfunction in particular, and norepinephrine indirectly, appear to be important in the underlying neurochemistry of ADHD. Data from family-genetic, twin, and adoption studies as well as segregation analysis suggest a genetic origin for some forms of the disorder. Molecular genetic studies have implicated the dopamine D2, D4 receptors and the dopamine transporter as candidate genes.
Treatment
The management of ADHD includes consideration of two major areas: nonpharmacological (educational remediation, individual and family psychotherapy) and pharmacotherapy. ADHD support groups (i.e. CHADD) are an invaluable and inexpensive manner for families to learn about ADHD and resources available for their children or themselves.
Specialized educational planning based on the child's difficulties is necessary in a majority of cases. Educational adjustments should be considered in ADHD youth with difficulties in behavioral or academic performance. Increased structure, predictable routine, learning aids, resource room time, and checked homework are among typical educational considerations in these youth. Similar modifications in the home environment should be undertaken to optimize the child's ability to complete homework. Frequent parental communication with the school about the child's progress is essential.
Medications remain a mainstay of treatment of ADHD with recent multisite studies supporting that medication management of ADHD is the most important variable in outcome in context to multimodal treatment. The stimulants, antihypertensives, and antidepressants comprise the available agents for ADHD.
Stimulants. The psychostimulants are considered first line agents for ADHD, based in part on their extensive efficacy and safety data. Stimulants are sympathomimetic drugs which increase intrasynaptic catecholamines (mainly dopamine) by inhibiting the presynaptic reuptake mechanism and releasing presynaptic catecholamines. The most commonly used compounds in this class include methylphenidate (Ritalin), dextro-amphetamine (Dexedrine), amphetamine compounds (Adderall), and magnesium pemoline (Cylert). Methylphenidate and D-amphetamine are both short acting compounds, with an onset of action within 30 to 60 minutes and a peak clinical effect usually seen between 1 and 2 hours after administration lasting 2 to 5 hours. The amphetamine compounds (Adderall) and sustained release preparations of methylphenidate and dextroamphetamine are intermediate acting compounds with an onset of action within 60 minutes and a peak clinical effect usually seen between 1 and 3 hours after administration maintained for up to 8 hours.
Despite the findings on efficacy of the stimulants, studies have also reported consistently that typically one-third of ADHD individuals do not respond or cannot tolerate this class of agents. Based on marginally different mechanisms of action, some patients who lack a satisfactory response or manifest adverse effects to one stimulant, may respond favorably to another. Stimulants should be initiated at the lowest available dosing once daily and increased every three to four days until a response is noted or adverse effects emerge. Typically, parameters for upward daily dosing of the stimulants are 1 mg/kg/day for the amphetamines, 2 mg/kg/day for methylphenidate, and 3 mg/kg/day for pemoline.
Predictable short-term adverse effects include reduced appetite, insomnia, edginess, and GI upset. Pemoline may rarely cause hepatitis; hence, patient education about the symptoms of early hepatic dysfunction and infrequent liver function tests are advised. There are a number of controversial issues related to chronic stimulant use. Although stimulants may produce anorexia and weight loss, their effect on ultimate height is less certain. Recent reports present the possibility that growth delays previously ascribed to stimulants may actually represent maturational delays to ADHD itself. Stimulants may precipitate or exacerbate tic symptoms in ADHD children with recent work suggesting that up to one-third of children with tics may have worsening of their tics with stimulant exposure. There is a paucity of data supporting the contention that ADHD children abuse their medication; however, data suggests that diversion of stimulants to non-ADHD youth is a concern. The literature indicates that pharmacological treatment of ADHD youth reduces the risk for later substance abuse.
Antidepressants. The antidepressants are generally considered second line drugs of choice for ADHD. The tricyclic antidepressants (TCAs)-imipramine, desipramine, and nortriptyline-block the re-uptake of neurotransmitters including norepinephrine. TCAs are effective in controlling abnormal behaviors and improving cognitive impairments associated with ADHD across the lifespan, but less so than the majority of stimulants. The TCAs are particularly useful in stimulant failures, or when oppositionality, anxiety, tics, or depressive symptoms co-occur within ADHD. Dosing of the TCAs are doses starting with 25 mg daily and titrated upward slowly to a maximum of 5 mg/kg/day (2 mg/kg/day for nortriptyline). Although immediate relief can be seen, a lag of two to four weeks to maximal effect is common. Typical adverse effects include dry mouth, constipation, sedation, and weight gain. As minor increases in heart rate and the ECG intervals are predictable with TCAs, ECG monitoring at baseline and at therapeutic dose is suggested, but not mandatory.
Bupropion (Wellbutrin, Zyban) is an antidepressant with indirect dopamine and noradrenergic effects. Bupropion has been shown effective for ADHD in controlled trials of children and adults. Given its utility in reducing cigarette smoking, improving mood, lack of monitoring results, and paucity of adverse effects, bupropion is often used as an initial agent for complex ADHD patients with substance abuse or an unstable mood disorder. Based on anecdotal reports of anti-ADHD effectiveness at low doses in a minority of patients, it is recommended that the treatment be initiated at 37.5 mg and titrated upward every three to four days up to 300 mg in younger children and 450 mg in older children or adults. Adverse events include activation, irritability, insomnia and rarely seizures.
Antihypertensives. The antihypertensives clonidine (Catapres) and guanfacine (Tenex) are used to treat the hyperactive-impulsive symptoms of ADHD. Clonidine is a relatively short-acting compound with usual daily dose ranges from 0.05 to 0.4 mg. Guanfacine is longer acting and less potent than clonidine with usual daily dose ranges from 0.5 to 3 mg. The antihypertensives have been used for the treatment of ADHD as well as associated tics, aggression, and sleep disturbances, particularly in younger children. Although sedation is more commonly seen with clonidine, both agents may cause depression and rebound hypertension. Recent reports have implicated the combination of clonidine plus methylphenidate in the deaths of four children; however, many mitigating and extenuating circumstances were operative making these cases uninterpretable. Cardiovascular monitoring (vital signs, ECG) remains optional.
Combined pharmacological approaches can be used for the treatment of comorbid ADHD, as augmentation strategies for patients with insufficient response to a single agent, pharmacokinetic synergism, and for the management of treatment emergent adverse effects. Examples include the use of an antidepressant plus a stimulant for ADHD and comorbid depression (fluoxetine [Prozac] plus methylphenidate), the use of clonidine to ameliorate stimulant-induced insomnia, and the use of a mood stabilizer plus an anti-ADHD agent to treat ADHD comorbid with bipolar disorder.
In summary, there is increasing recognition that ADHD is a heterogenous disorder that persists in a number of cases into adult years. Emerging findings support a genetic and neurobiological basis for ADHD with catecholaminergic dysfunction as a central finding. The literature supports the effectiveness of pharmacotherapy not only for the core behavioral symptoms of ADHD but also for improving linked impairments such as cognition, substance abuse, social and family functioning. Similarities between juveniles and adults in characteristics, biology, and pharmacological responsivity of ADHD supports the continuity of the disorder across the lifespan.
