Pharmacologic treatment of attention-deficit hyperactivity disorder
http://www.100md.com
《美国医学杂志》
Pediatrics and Human Development, Kalamazoo Center for Medical Studies, Kalamazoo, Michigan, USA
Abstract
Attention-deficit hyperactivity disorder (ADHD) is highly prevalent in children and adolescents. Highly effective pharmacological treatments are available that allow the child and the adolescent to function at his/her full potential. Various preparations of methylphenidate and amphetamines have been used for a long time in the treatment of ADHD. This article reviews these and some of the newer drugs used in the treatment of ADHD, including atomoxetine and bupropion
Keywords: Attention deficit hyperactivity disorder; Methylphenidate; Amphetamines; Atomoxetine; Bupropion
Attention-deficit hyperactivity disorder (ADHD) is noted in 3% to 9% of children and adolescents, three times more commonly in males than females. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10]The precise diagnosis depends on which diagnostic criteria the clinician refers to, and the reader is referred to the classification used by the The International Classification of Diseases, 10th ed (ICD-10)[11] , World Health Organization (1993); the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR, 4th ed., 2000);[12] and the American Academy of Pediatrics' The Classification of Child and Adolescent Mental Diagnoses in Primary Care: Diagnostic and Statistical Manual for Primary Care (DSM-PC): Child and Adolescent Version.[13]
The DSM-IV-TR (2000) presents detailed lists of symptoms and criteria for arriving at a diagnosis; the DSM-PC is used in the United States in primary care offices and is based on the DMR-IV-TR. [12],[13] The ICD-10 is typically used by insurance companies, provides flexibility in the diagnosis, and identifies ADHD as attention-deficit/hyperkinetic disorder.[11] Other ADHD classifications may be used depending on the training and location of the clinician in the world. The approach to ADHD in this article is based on the concept that ADHD is a neurobiological condition that involves the presence of attention span dysfunction along with variable degrees of hyperactivity and impulsivity. table1 lists criteria for good and poor outcomes in youth with ADHD.
Children and adolescents who have problems with attention and self-control may develop considerable impairments in academic skills, social skills attainment, and emotional/psychological stability. If the youth cannot focus sufficiently in school to learn basic information for success as a student, adolescent growth and development may be impaired, complicating the ability to succeed in adult life as well. Such individuals may not mature appropriately in various important dimensions-intellectual, social, and emotional. table2 provides a list of conditions that must be considered when a diagnosis of ADHD arises. A careful assessment is necessary to be sure the core ADHD symptoms are not due to other mental health disorders. Also, comorbid conditions may be present and the youth can present with both ADHD and additional diagnosis table3. Psychiatric disorders may be found in 44% of youth having ADHD; 32% have at least two psychiatric disorders, and 11% have three or more.[14],[15]
Evaluation
ADHD diagnosis is based on careful assessments of the functioning of the child or the adolescent in various environments as school, home, and work (if appropriate).[7],[8],[16] Information is also helpful regarding peer relations, family mental health history, family conflict history, and history of psychological trauma in the adolescent. There is no definitive test(s) for ADHD, but a comprehensive evaluation is helpful, include behavioral, psychological, and neurological testing. The assessment should look at presenting problems of the child or the adolescent, differential diagnoses, and potential co-morbid disorders. [1],[2],[3]A careful physical examination is also important along with selective laboratory tests based on findings from the medical history and examination. Records from other providers and teachers can also be very useful in the evaluation process. The youth should be screened for depression, anxiety disorders, and other mental health conditions. The clinician should work with appropriate consultants in psychology, psychiatry, neurology and other fields, depending on the presenting findings.
Psychological management
Various psychological treatments are available to the trained clinician to improve ADHD in the adolescent, as outlined in table4. [17],[18],[19]There is very little research support for the efficacy of these psychological treatments except for Cognitive Behavioral Therapy.[2] In the United States, most ADHD youths are treated with medication. It is the recommendation of this author that youths receiving a diagnosis of ADHD receive management involving both psychological and psychopharmacological interventions if possible. Critics of an approach only using medication as treatment note that drugs result in positive changes in only a few functional areas, side effects may be considerable in some youth placed on medications, and at least 25% of ADHD youth do not improve with psychopharmacology.[17],[19] The rest of this article now focuses on the use of medication to improve ADHD in youth.
Psychopharmacologic management
There is over 60 years of research noting that medication can ameliorate ADHD symptoms in children, adolescents, and adults.[1]-[3], [20],[21],[22],[23],[24],[25]The beneficial role of psychopharmacology is due to its effects on the central nervous system noradrenergic and dopaminergic pathways. table5 lists the medications that have been proven to benefit ADHD: stimulants, antidepressants, alpha[2] agonists, and norepinephrine reuptake inhibitors. Principles of ADHD psychopharmacology are listed in table6.
Stimulant Medication
Hundreds of research studies on patients with ADHD have noted the beneficial effects of stimulant medication (methylphenidate, amphetamine, and pemoline table5. [1],[2],[3],[20] Since the late 1930s, it has been seen that stimulants improve attention span impairment, and sometimes, hyperactivity and impulsivity. [1],[2],[3],[20] Approximately 75% or more of those with ADHD note some benefit, and the use of medication has become a standard part of management for these patients by many clinicians. The most comprehensive study today was arranged by the National Institute of Mental Health (NIHM) in the United States; this research was named the NIMH Collaborative Multisite Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (or the MTA study). [4],[5],[6] , [26] It involved almost 600 children aged 7-9 years of age and documented the efficacy of methylphenidate (MPH) for these children above that of psychological therapies; the second best management strategy was the combination of MPH plus cognitive behavioral therapy.[5],[26] This discussion now considers methylphenidate (MPH), amphetamine, and pemoline.
Methylphenidate
Methylphenidate (MPH) is the stimulant most commonly prescribed for patients with ADHD since its production started in 1957. [1],[2],[3]Its beneficial effect on attention span dysfunction is based on selective binding of the presynaptic dopamine transporter in the CNS striatal and prefrontal areas, leading to rise in extracellular dopamine; it also causes a blockade of the CNS norepinephrine transporter in the norepinephrine system.[27] MPH (Ritalin and generic form as well) is taken orally with peak pharmacologic action in 1-2 hours, disappearing in 4 hours, requiring another dose if attention span benefit is desired. Beneficial effects of stimulant medication may include enhanced concentration, reduced hyperarousal, reduced impulsivity, reduced motor restlessness (ie., less gross/fine motor movement and/or work performance), and less aggressive and/or antisocial behavior.
A common method of prescription is to have the youth take MPH in the early morning, noon, and, if necessary, late afternoon. [1],[2],[3]The youth and clinician can decide together the schedule that works best for the patient. A low dose (as 2.5 to 5 mg) can be started at first, with gradual titration upwards, finding the optimal dose for each individual patient. The dosage range is 0.3 to 2.0 mg/kg/day with single doses usually not exceeding 20 mg and daily doses not exceeding 60-80 mg. There is no correlation between weight of the youth and optimal MPH dose, and plasma levels of MPH are not useful. A number of tools are used to verify effectiveness, such as patient/family interviews, parent ratings, school grades or reports, and others. Reasons for failure of MPH to be effective are listed in table7.
Stimulant Side-effects
Stimulant (including MPH) side-effects are listed in table8, some of which are transient, and can be reduced if the patient starts with a low dose and slowly increases the dosage to maximize benefit with reduced side effects. [1],[2],[3]Contraindications to MPH and stimulants include drug dependence, uncontrolled hypertension, glaucoma, symptomatic cardiovascular disorder, psychosis, and hyperthyroidism; stimulants should not be combined with monoamine oxidase inhibitors, because this mixture may lead to a hypertensive crisis. Mixing a stimulant with a tricyclic antidepressant may lead to sudden death from cardiac arrhythmia in rare cases.[28],[29] MPH can interfere with the metabolism of some anticonvulsant drugs, such as ethosuximide, phenytoin, and phenobarbital. Stimulant effectiveness can be reduced by mixing stimulants with antihistamine drugs.
Nausea or emesis that may occur on stimulants often improves if the medication is taken with meals. If the cardiovascular system is normal, the mild rise in heart rate and blood pressure noted with stimulants is not a problem. Dizziness occurs in some patients, worse with short-acting stimulants versus long-acting types (see below under MPH preparations); if this occurs, look for dehydration or blood pressure changes and treat as necessary. Headaches may develop while taking stimulants, sometimes related to peaking MPH plasma levels, and sometimes related to drug withdrawal; sometimes a different stimulant relieves the headache. There is no indication that the use of stimulant medication increases the risk of substance abuse in youth.
The phenomenon of delayed growth in children or growing adolescents on stimulants remains controversial and seems to be, in part, related to appetite suppression with decreased nutrition; it appears to be a transient effect, though more research in this area is on-going. [1],[2],[3]Youth on stimulants who are not growing properly need careful supervision. If the appetite is blunted while on stimulants, a number of measures can be taken, including taking food when the stimulant wears off (as in the evening), using high-caloric foods, taking the patient off stimulants when not in school (such as during vacation or on weekends), and trying other stimulants or anti-ADHD medications.
Tolerance may develop in some youth on high stimulant dose and does not indicate any type of addiction; management involves lowering the stimulant dose or trying a different anti-ADHD drug. Rebound can develop in which increased ADHD symptoms (as rage episodes and irritability) develop as the stimulant effect wears off, such as late morning or late afternoon for short-acting MPH or late afternoon for the long-acting MPH. MPH may interfere with sleep and the addition of other medications causing sedation may be beneficial, such as bupropion, tricyclic antidepressants, alpha[2] agonists (as clonidine), mirtazepine, trazodone, or melatonin.
ADHD is found in 50% to 75% of patients with Tourette Syndrome (TS) and TS may be officially diagnosed in some children or adolescents after starting stimulant drugs. Research does not suggest that stimulant medications cause TS and the presence of tics is a relative and not absolute contraindication to stimulant medication. Youths with both ADHD and TS may be given both stimulant medications (if effective) and anti-tic medication (such as risperidone, haloperidol, or pimozide). If the tics are worsened by the stimulant drugs, other anti-ADHD medications may be tried that do not typically worsen tics; these include alpha[2] agonists (as clonidine or guanfacine) or atomoxetine. Bupropion may improve ADHD but worsens tics.
MPH Preparations
Ritalin and genetic MPH have been very popular until recently, when a number of longer acting MPH products came to be developed. Ritalin-SR is a longer-acting version of Ritalin, delivering 7 mg of MPH over several hours. However, its absorption is erratic in half or more of patients and it is produced only in a 20 mg form. Pharmaceutical companies have developed a variety of alternative MPH preparations over the past decade and these are listed in table9. There are no unbiased studies available at this time to help a clinician and patient decide which of these products are superior; and patients must simply find out which product is best for them. [1],[2],[3]If a patient has difficulty swallowing pills, some of the longer-acting products can be opened and added to food; these products include Ritalin LA and Metadate CD; longer-acting amphetamine products that can be opened and added to food include Dexedrine Spansule, and Adderall XR. [Table - 10] shows the comparison of the relative duration of action of these compounds. The reader is referred to recent articles reviewing these newer MPH preparations.[2],[9],[10],[23]
Amphetamine Products
A well-known alternative to MPH is dextroamphetamine (Dexedrine, Dextrostat) and it can be used if MPH is not acceptable or helpful to the patient with ADHD; however, the potential adverse effects of MPH are the same as MPH table8. [1],[2],[3]The beneficial effects of amphetamine on ADHD date back to 1937. Dextroamphetamine is effective for 3 to 6 hours and its mechanism of action includes norepinephrine reuptake inhibition and selective binding to the dopamine transporter with increased dopamine release; weak effects on the serotonin system are also noted. Amphetamine products that are available are listed in [Table - 11]. Dextroamphetamine is taken 1 to 3 times a day with gradual titration to 0.15 to 0.5 mg/kg/day, up to 40 to 50 mg a day. A generic version is also available. Dexedrine Spansule is given once a day and produces anti-ADHD effects for 8 to 10 hours. Amphetamines may induce more depression than MPH and the abuse potential of amphetamine is well-known. Amphetamine and MPH are not combined. Adderall and Adderall XR are long-acting amphetamine products that last up to 10 and 12 hours respectively.
Pemoline
Pemoline (magnesium pemoline; Cylert) is a stimulant medication taken once daily with a dosage range of 0.5 to 3.0 mg/kg/day, with a maximum dose of 112.5 to 131.25 mg per day. A movement disorder can be noted in some patients on this medication. Chemical hepatitis develops in approximately 3% after several months. In the United States, the Federal Drug Administration (Washington, DC) has given a "black box" warning for pemoline because of rare irreversible liver failure that may occur. Patients should be informed of this side-effect and have their liver function tests closely monitored. Unfortunately, even close monitoring cannot prevent death from liver failure. Because of this problem, pemoline is now uncommonly used as an anti-ADHD drug in the United States. Its production in the U.S. has been stopped.
NON-STIMULANT MEDICATIONS
Alpha2 Agonists
Clonidine
Clonidine (Catapres) is a presynaptic, central-acting alpha2-adrenergic agonist that is used by some clinicians to manage ADHD symptoms, though it may take weeks to months to achieve full benefit. [1],[2],[3] Clonidine is used as an alternative or adjunctive medication to MPH; it is often given with MPH and works because its sedative properties off-set the insomnic effect of MPH. Clonidine is also used to manage Tourette Syndrome, post-traumatic stress disorder, and severe aggressiveness with conduct disorder or oppositional defiant disorder.
[Table - 12] lists potential adverse effects of clonidine and its daily dose ranges from 0.05 to 0.4 mg/day; depending on its use, clonidine is provided 2 to 4 times a day or only at bedtime. Gradual build-up and withdrawal when stopping are recommended. Rapid withdrawal may lead to rebound hypertension. When prescribing this drug, some baseline data (blood pressure, pulse, blood sugar, electrocardiogram [EKG]); should be considered this data should be followed on a regular basis, including a repeat EKG every 6 months. Tolerance and liver function test activation is also reported. A few deaths have been reported in children and adolescents taking both MPH and clonidine. Clonidine is also available as a patch lasting 3 to 7 days; this patch may prevent sedation and/or elevated blood pressure seen with the pill form. As with any patch, dermatitis may occur at the site of the patch application; changing the patch site and local application of hydrocortisone usually resolves the local dermatitis.
Guanfacine
Guanfacine (Tenex) is an alpha2 A-adrenergic agonist related to clonidine and also not proven to benefit the attention span problems of ADHD. Its use may result in less blood pressure problems and sedation than seen with clonidine. Adverse reactions are similar to clonidine, but there may be more agitation and headaches. Its daily dosage range is 0.5 mg to 4.0 mg.
Antidepressants
Tricyclic Antidepressants
Research studies reveal that tricyclic antidepressants (TCAs) can be of help to patients with ADHD and is usually listed as an alternative to stimulant medications if stimulants are not of help or are contraindicated. [Table - 13] lists other indications for the use of TCAs. [1],[2],[3]These medications include imipramine (Tofranil, others) 50-200 mg/day, desipramine (Norpramin, Desipramine) 50-200 mg/day, amitriptyline (Elavil) 50-200 mg/day, and nortriptyline (Pamelor) 20-100 mg/day. Mechanism of action includes blockage of norepinephrine and serotonin reuptake and down regulation of beta-adrenergic receptors.
[Table - 14] lists adverse effects of TCAs, including those that are anticholinergic. Youth placed on TCAs should be monitored on a periodic basis, with evaluations noting vital signs, complete blood counts, serum levels of TCAs, and EKGs; management plans are noted in the literature.[29] Plasma TCAs levels correlate with toxity, but not with the level of benefit. TCAs tend to cause less rebound effect than stimulants, and tolerance may develop with TCAs. Sedation can be severe and is worse with imipramine than with desipramine or notriptyline. TCA-induced tremor can be helped with careful reduction in TCA dose or adding propranolol (10-40 mg per day), though this may lead to depression in some patients.
If agitation develops as a result of the TCA, its dose should be lowered or a benzodiazepine medication could be added. Mania may develop if a TCA is added to someone with latent bipolar disorder; also, psychosis may develop if a TCA is added to someone with latent schizophrenia. Rare cases of death are noted in children or adolescents with TCAs, especially desipramine. Nausea, emesis, fatigue, or worsening behavior may develop if the TCA is stopped too abruptly; this is called the discontinuation syndrome. Care must be taken when adding other medications to TCAs. For example, toxic TCA levels may occur when combining TCAs with selective serotonin reuptake inhibitors. The combination of MPH and a TCA may lead to rising TCA levels as well. Respiratory depression and death may develop after combining alcohol and TCAs.
Bupropion
Bupropion (Wellbutrin) is an antidepressant medication with noradrenergic/dopaminergic effects to improve depression, reduce irritability, and ameliorate attention dysfunction.[1],[2],[3] Venlafaxine (Effexor) is an atypical antidepressant that is also used by some clinicians for ADHD. Bupropion is given in a daily dosage range of 50-300 mg (3.0 to 6.0 mg/kg/day) as Wellbutrin, 100-150 mg twice daily as Wellbutrin-SR, and once a day as Wellbutrin XL (150 mg or 300 mg). In an alternative formulation of bupropion (Zyban), it is used to manage tobacco addiction. [Table - 15] lists side effects of bupropion, including seizure activity-0.1% under 300 mg a day and 0.4% over 300 mg a day. Bupropion is contraindicated if youths have epilepsy or eating disorders (such as bulimia nervosa ). Risks for seizures are reduced if bupropion is not taken under 8 hours apart, medication is slowly titrated upward in dose, SR formulation is used, and high doses of the regular formulation are not used. Drug-to-drug interactions are minimal with bupropion and it does not lead to cardiac conduction delays.
Atomoxetine
Atomoxetine (Strattera) is a nonstimulant currently listed by the United States' Federal Drug Administration as an alternative anti-ADHD drug and is used in those not wishing to take a stimulant or where stimulant or other medications are not effective. [1],[2],[3],[9],[30] Its actions include the blockade of the presynaptic norepinephrine transporter in the prefrontal cortex. It is started at 0.5 mg/kg/day and gradually raised to 1.0 to 1.4 mg/kg/day to a maximum of 100 mg per day given once or twice a day. [Table - 16] lists potential adverse effects, including drug-to-drug interactions involving selective serotonin reactive inhibitors and others metabolized by cytochrome P450 2D6. Atomoxetine has a low affinity for various receptors, such as alpha1-adrenergic, alpha]adrenergic, serotonergic, cholinergic, and histaminic. There is no increase in drug addiction, drug diversion, cardiovascular complications, or tics. [Table - 17] lists treatment options used by some clinicians but not proven to be of benefit for children, adolescents, or adults with ADHD.
References
1. Greydanus DE, Sloane MA, Rappley MD. Psychopharmacology of ADHD in adolescents. Adolesc Med 2002; 13: 599-624.
2. Greydanus DE, Pratt HD, Sloane MA et al. Attention-deficit/hyperactivity disorder in Children and adolescents: Interventions for a complex costly clinical conundrum. Pediatr Clin North Am 2003; 50: 1049-1092.
3. Greydanus DE. Psychopharmacology of ADHD in adolescents: Quo vadis Psychiatr Times 2003; 20: 5-9.
4. National Institute of Mental Health (NIMH). Attention Deficit Hyperactivity Disorder. NIMH, NIH Publication No. 01-4589, 2001. Available at: http://www.nimh.nih.gov/publicat/helpchild.cfm.
5. National Institute of Mental Health. NIMH Research on Treatment for Attention Deficit Hyperactivity Disorder (ADHD): The Multimodal Treatment Study-Questions and Answers. Washington, DC: NIMH, 2000. Available at: http://www.nimh.nih.gov/events/mtaqa.cfm
6. National Institute of Health (NIH). Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder . NIH Consensus Statement Online 1998: Nov 16-18; [cited year, month, day]; 16(2): 1-37.
7. Pratt HD. Neurodevelopmental Issues in the assessment and treatment of deficits in attention, cognition, and learning during adolescence. Adolesc Med 2002; 13(3): 579-598.(Greydanus Donald E)
Abstract
Attention-deficit hyperactivity disorder (ADHD) is highly prevalent in children and adolescents. Highly effective pharmacological treatments are available that allow the child and the adolescent to function at his/her full potential. Various preparations of methylphenidate and amphetamines have been used for a long time in the treatment of ADHD. This article reviews these and some of the newer drugs used in the treatment of ADHD, including atomoxetine and bupropion
Keywords: Attention deficit hyperactivity disorder; Methylphenidate; Amphetamines; Atomoxetine; Bupropion
Attention-deficit hyperactivity disorder (ADHD) is noted in 3% to 9% of children and adolescents, three times more commonly in males than females. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10]The precise diagnosis depends on which diagnostic criteria the clinician refers to, and the reader is referred to the classification used by the The International Classification of Diseases, 10th ed (ICD-10)[11] , World Health Organization (1993); the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR, 4th ed., 2000);[12] and the American Academy of Pediatrics' The Classification of Child and Adolescent Mental Diagnoses in Primary Care: Diagnostic and Statistical Manual for Primary Care (DSM-PC): Child and Adolescent Version.[13]
The DSM-IV-TR (2000) presents detailed lists of symptoms and criteria for arriving at a diagnosis; the DSM-PC is used in the United States in primary care offices and is based on the DMR-IV-TR. [12],[13] The ICD-10 is typically used by insurance companies, provides flexibility in the diagnosis, and identifies ADHD as attention-deficit/hyperkinetic disorder.[11] Other ADHD classifications may be used depending on the training and location of the clinician in the world. The approach to ADHD in this article is based on the concept that ADHD is a neurobiological condition that involves the presence of attention span dysfunction along with variable degrees of hyperactivity and impulsivity. table1 lists criteria for good and poor outcomes in youth with ADHD.
Children and adolescents who have problems with attention and self-control may develop considerable impairments in academic skills, social skills attainment, and emotional/psychological stability. If the youth cannot focus sufficiently in school to learn basic information for success as a student, adolescent growth and development may be impaired, complicating the ability to succeed in adult life as well. Such individuals may not mature appropriately in various important dimensions-intellectual, social, and emotional. table2 provides a list of conditions that must be considered when a diagnosis of ADHD arises. A careful assessment is necessary to be sure the core ADHD symptoms are not due to other mental health disorders. Also, comorbid conditions may be present and the youth can present with both ADHD and additional diagnosis table3. Psychiatric disorders may be found in 44% of youth having ADHD; 32% have at least two psychiatric disorders, and 11% have three or more.[14],[15]
Evaluation
ADHD diagnosis is based on careful assessments of the functioning of the child or the adolescent in various environments as school, home, and work (if appropriate).[7],[8],[16] Information is also helpful regarding peer relations, family mental health history, family conflict history, and history of psychological trauma in the adolescent. There is no definitive test(s) for ADHD, but a comprehensive evaluation is helpful, include behavioral, psychological, and neurological testing. The assessment should look at presenting problems of the child or the adolescent, differential diagnoses, and potential co-morbid disorders. [1],[2],[3]A careful physical examination is also important along with selective laboratory tests based on findings from the medical history and examination. Records from other providers and teachers can also be very useful in the evaluation process. The youth should be screened for depression, anxiety disorders, and other mental health conditions. The clinician should work with appropriate consultants in psychology, psychiatry, neurology and other fields, depending on the presenting findings.
Psychological management
Various psychological treatments are available to the trained clinician to improve ADHD in the adolescent, as outlined in table4. [17],[18],[19]There is very little research support for the efficacy of these psychological treatments except for Cognitive Behavioral Therapy.[2] In the United States, most ADHD youths are treated with medication. It is the recommendation of this author that youths receiving a diagnosis of ADHD receive management involving both psychological and psychopharmacological interventions if possible. Critics of an approach only using medication as treatment note that drugs result in positive changes in only a few functional areas, side effects may be considerable in some youth placed on medications, and at least 25% of ADHD youth do not improve with psychopharmacology.[17],[19] The rest of this article now focuses on the use of medication to improve ADHD in youth.
Psychopharmacologic management
There is over 60 years of research noting that medication can ameliorate ADHD symptoms in children, adolescents, and adults.[1]-[3], [20],[21],[22],[23],[24],[25]The beneficial role of psychopharmacology is due to its effects on the central nervous system noradrenergic and dopaminergic pathways. table5 lists the medications that have been proven to benefit ADHD: stimulants, antidepressants, alpha[2] agonists, and norepinephrine reuptake inhibitors. Principles of ADHD psychopharmacology are listed in table6.
Stimulant Medication
Hundreds of research studies on patients with ADHD have noted the beneficial effects of stimulant medication (methylphenidate, amphetamine, and pemoline table5. [1],[2],[3],[20] Since the late 1930s, it has been seen that stimulants improve attention span impairment, and sometimes, hyperactivity and impulsivity. [1],[2],[3],[20] Approximately 75% or more of those with ADHD note some benefit, and the use of medication has become a standard part of management for these patients by many clinicians. The most comprehensive study today was arranged by the National Institute of Mental Health (NIHM) in the United States; this research was named the NIMH Collaborative Multisite Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (or the MTA study). [4],[5],[6] , [26] It involved almost 600 children aged 7-9 years of age and documented the efficacy of methylphenidate (MPH) for these children above that of psychological therapies; the second best management strategy was the combination of MPH plus cognitive behavioral therapy.[5],[26] This discussion now considers methylphenidate (MPH), amphetamine, and pemoline.
Methylphenidate
Methylphenidate (MPH) is the stimulant most commonly prescribed for patients with ADHD since its production started in 1957. [1],[2],[3]Its beneficial effect on attention span dysfunction is based on selective binding of the presynaptic dopamine transporter in the CNS striatal and prefrontal areas, leading to rise in extracellular dopamine; it also causes a blockade of the CNS norepinephrine transporter in the norepinephrine system.[27] MPH (Ritalin and generic form as well) is taken orally with peak pharmacologic action in 1-2 hours, disappearing in 4 hours, requiring another dose if attention span benefit is desired. Beneficial effects of stimulant medication may include enhanced concentration, reduced hyperarousal, reduced impulsivity, reduced motor restlessness (ie., less gross/fine motor movement and/or work performance), and less aggressive and/or antisocial behavior.
A common method of prescription is to have the youth take MPH in the early morning, noon, and, if necessary, late afternoon. [1],[2],[3]The youth and clinician can decide together the schedule that works best for the patient. A low dose (as 2.5 to 5 mg) can be started at first, with gradual titration upwards, finding the optimal dose for each individual patient. The dosage range is 0.3 to 2.0 mg/kg/day with single doses usually not exceeding 20 mg and daily doses not exceeding 60-80 mg. There is no correlation between weight of the youth and optimal MPH dose, and plasma levels of MPH are not useful. A number of tools are used to verify effectiveness, such as patient/family interviews, parent ratings, school grades or reports, and others. Reasons for failure of MPH to be effective are listed in table7.
Stimulant Side-effects
Stimulant (including MPH) side-effects are listed in table8, some of which are transient, and can be reduced if the patient starts with a low dose and slowly increases the dosage to maximize benefit with reduced side effects. [1],[2],[3]Contraindications to MPH and stimulants include drug dependence, uncontrolled hypertension, glaucoma, symptomatic cardiovascular disorder, psychosis, and hyperthyroidism; stimulants should not be combined with monoamine oxidase inhibitors, because this mixture may lead to a hypertensive crisis. Mixing a stimulant with a tricyclic antidepressant may lead to sudden death from cardiac arrhythmia in rare cases.[28],[29] MPH can interfere with the metabolism of some anticonvulsant drugs, such as ethosuximide, phenytoin, and phenobarbital. Stimulant effectiveness can be reduced by mixing stimulants with antihistamine drugs.
Nausea or emesis that may occur on stimulants often improves if the medication is taken with meals. If the cardiovascular system is normal, the mild rise in heart rate and blood pressure noted with stimulants is not a problem. Dizziness occurs in some patients, worse with short-acting stimulants versus long-acting types (see below under MPH preparations); if this occurs, look for dehydration or blood pressure changes and treat as necessary. Headaches may develop while taking stimulants, sometimes related to peaking MPH plasma levels, and sometimes related to drug withdrawal; sometimes a different stimulant relieves the headache. There is no indication that the use of stimulant medication increases the risk of substance abuse in youth.
The phenomenon of delayed growth in children or growing adolescents on stimulants remains controversial and seems to be, in part, related to appetite suppression with decreased nutrition; it appears to be a transient effect, though more research in this area is on-going. [1],[2],[3]Youth on stimulants who are not growing properly need careful supervision. If the appetite is blunted while on stimulants, a number of measures can be taken, including taking food when the stimulant wears off (as in the evening), using high-caloric foods, taking the patient off stimulants when not in school (such as during vacation or on weekends), and trying other stimulants or anti-ADHD medications.
Tolerance may develop in some youth on high stimulant dose and does not indicate any type of addiction; management involves lowering the stimulant dose or trying a different anti-ADHD drug. Rebound can develop in which increased ADHD symptoms (as rage episodes and irritability) develop as the stimulant effect wears off, such as late morning or late afternoon for short-acting MPH or late afternoon for the long-acting MPH. MPH may interfere with sleep and the addition of other medications causing sedation may be beneficial, such as bupropion, tricyclic antidepressants, alpha[2] agonists (as clonidine), mirtazepine, trazodone, or melatonin.
ADHD is found in 50% to 75% of patients with Tourette Syndrome (TS) and TS may be officially diagnosed in some children or adolescents after starting stimulant drugs. Research does not suggest that stimulant medications cause TS and the presence of tics is a relative and not absolute contraindication to stimulant medication. Youths with both ADHD and TS may be given both stimulant medications (if effective) and anti-tic medication (such as risperidone, haloperidol, or pimozide). If the tics are worsened by the stimulant drugs, other anti-ADHD medications may be tried that do not typically worsen tics; these include alpha[2] agonists (as clonidine or guanfacine) or atomoxetine. Bupropion may improve ADHD but worsens tics.
MPH Preparations
Ritalin and genetic MPH have been very popular until recently, when a number of longer acting MPH products came to be developed. Ritalin-SR is a longer-acting version of Ritalin, delivering 7 mg of MPH over several hours. However, its absorption is erratic in half or more of patients and it is produced only in a 20 mg form. Pharmaceutical companies have developed a variety of alternative MPH preparations over the past decade and these are listed in table9. There are no unbiased studies available at this time to help a clinician and patient decide which of these products are superior; and patients must simply find out which product is best for them. [1],[2],[3]If a patient has difficulty swallowing pills, some of the longer-acting products can be opened and added to food; these products include Ritalin LA and Metadate CD; longer-acting amphetamine products that can be opened and added to food include Dexedrine Spansule, and Adderall XR. [Table - 10] shows the comparison of the relative duration of action of these compounds. The reader is referred to recent articles reviewing these newer MPH preparations.[2],[9],[10],[23]
Amphetamine Products
A well-known alternative to MPH is dextroamphetamine (Dexedrine, Dextrostat) and it can be used if MPH is not acceptable or helpful to the patient with ADHD; however, the potential adverse effects of MPH are the same as MPH table8. [1],[2],[3]The beneficial effects of amphetamine on ADHD date back to 1937. Dextroamphetamine is effective for 3 to 6 hours and its mechanism of action includes norepinephrine reuptake inhibition and selective binding to the dopamine transporter with increased dopamine release; weak effects on the serotonin system are also noted. Amphetamine products that are available are listed in [Table - 11]. Dextroamphetamine is taken 1 to 3 times a day with gradual titration to 0.15 to 0.5 mg/kg/day, up to 40 to 50 mg a day. A generic version is also available. Dexedrine Spansule is given once a day and produces anti-ADHD effects for 8 to 10 hours. Amphetamines may induce more depression than MPH and the abuse potential of amphetamine is well-known. Amphetamine and MPH are not combined. Adderall and Adderall XR are long-acting amphetamine products that last up to 10 and 12 hours respectively.
Pemoline
Pemoline (magnesium pemoline; Cylert) is a stimulant medication taken once daily with a dosage range of 0.5 to 3.0 mg/kg/day, with a maximum dose of 112.5 to 131.25 mg per day. A movement disorder can be noted in some patients on this medication. Chemical hepatitis develops in approximately 3% after several months. In the United States, the Federal Drug Administration (Washington, DC) has given a "black box" warning for pemoline because of rare irreversible liver failure that may occur. Patients should be informed of this side-effect and have their liver function tests closely monitored. Unfortunately, even close monitoring cannot prevent death from liver failure. Because of this problem, pemoline is now uncommonly used as an anti-ADHD drug in the United States. Its production in the U.S. has been stopped.
NON-STIMULANT MEDICATIONS
Alpha2 Agonists
Clonidine
Clonidine (Catapres) is a presynaptic, central-acting alpha2-adrenergic agonist that is used by some clinicians to manage ADHD symptoms, though it may take weeks to months to achieve full benefit. [1],[2],[3] Clonidine is used as an alternative or adjunctive medication to MPH; it is often given with MPH and works because its sedative properties off-set the insomnic effect of MPH. Clonidine is also used to manage Tourette Syndrome, post-traumatic stress disorder, and severe aggressiveness with conduct disorder or oppositional defiant disorder.
[Table - 12] lists potential adverse effects of clonidine and its daily dose ranges from 0.05 to 0.4 mg/day; depending on its use, clonidine is provided 2 to 4 times a day or only at bedtime. Gradual build-up and withdrawal when stopping are recommended. Rapid withdrawal may lead to rebound hypertension. When prescribing this drug, some baseline data (blood pressure, pulse, blood sugar, electrocardiogram [EKG]); should be considered this data should be followed on a regular basis, including a repeat EKG every 6 months. Tolerance and liver function test activation is also reported. A few deaths have been reported in children and adolescents taking both MPH and clonidine. Clonidine is also available as a patch lasting 3 to 7 days; this patch may prevent sedation and/or elevated blood pressure seen with the pill form. As with any patch, dermatitis may occur at the site of the patch application; changing the patch site and local application of hydrocortisone usually resolves the local dermatitis.
Guanfacine
Guanfacine (Tenex) is an alpha2 A-adrenergic agonist related to clonidine and also not proven to benefit the attention span problems of ADHD. Its use may result in less blood pressure problems and sedation than seen with clonidine. Adverse reactions are similar to clonidine, but there may be more agitation and headaches. Its daily dosage range is 0.5 mg to 4.0 mg.
Antidepressants
Tricyclic Antidepressants
Research studies reveal that tricyclic antidepressants (TCAs) can be of help to patients with ADHD and is usually listed as an alternative to stimulant medications if stimulants are not of help or are contraindicated. [Table - 13] lists other indications for the use of TCAs. [1],[2],[3]These medications include imipramine (Tofranil, others) 50-200 mg/day, desipramine (Norpramin, Desipramine) 50-200 mg/day, amitriptyline (Elavil) 50-200 mg/day, and nortriptyline (Pamelor) 20-100 mg/day. Mechanism of action includes blockage of norepinephrine and serotonin reuptake and down regulation of beta-adrenergic receptors.
[Table - 14] lists adverse effects of TCAs, including those that are anticholinergic. Youth placed on TCAs should be monitored on a periodic basis, with evaluations noting vital signs, complete blood counts, serum levels of TCAs, and EKGs; management plans are noted in the literature.[29] Plasma TCAs levels correlate with toxity, but not with the level of benefit. TCAs tend to cause less rebound effect than stimulants, and tolerance may develop with TCAs. Sedation can be severe and is worse with imipramine than with desipramine or notriptyline. TCA-induced tremor can be helped with careful reduction in TCA dose or adding propranolol (10-40 mg per day), though this may lead to depression in some patients.
If agitation develops as a result of the TCA, its dose should be lowered or a benzodiazepine medication could be added. Mania may develop if a TCA is added to someone with latent bipolar disorder; also, psychosis may develop if a TCA is added to someone with latent schizophrenia. Rare cases of death are noted in children or adolescents with TCAs, especially desipramine. Nausea, emesis, fatigue, or worsening behavior may develop if the TCA is stopped too abruptly; this is called the discontinuation syndrome. Care must be taken when adding other medications to TCAs. For example, toxic TCA levels may occur when combining TCAs with selective serotonin reuptake inhibitors. The combination of MPH and a TCA may lead to rising TCA levels as well. Respiratory depression and death may develop after combining alcohol and TCAs.
Bupropion
Bupropion (Wellbutrin) is an antidepressant medication with noradrenergic/dopaminergic effects to improve depression, reduce irritability, and ameliorate attention dysfunction.[1],[2],[3] Venlafaxine (Effexor) is an atypical antidepressant that is also used by some clinicians for ADHD. Bupropion is given in a daily dosage range of 50-300 mg (3.0 to 6.0 mg/kg/day) as Wellbutrin, 100-150 mg twice daily as Wellbutrin-SR, and once a day as Wellbutrin XL (150 mg or 300 mg). In an alternative formulation of bupropion (Zyban), it is used to manage tobacco addiction. [Table - 15] lists side effects of bupropion, including seizure activity-0.1% under 300 mg a day and 0.4% over 300 mg a day. Bupropion is contraindicated if youths have epilepsy or eating disorders (such as bulimia nervosa ). Risks for seizures are reduced if bupropion is not taken under 8 hours apart, medication is slowly titrated upward in dose, SR formulation is used, and high doses of the regular formulation are not used. Drug-to-drug interactions are minimal with bupropion and it does not lead to cardiac conduction delays.
Atomoxetine
Atomoxetine (Strattera) is a nonstimulant currently listed by the United States' Federal Drug Administration as an alternative anti-ADHD drug and is used in those not wishing to take a stimulant or where stimulant or other medications are not effective. [1],[2],[3],[9],[30] Its actions include the blockade of the presynaptic norepinephrine transporter in the prefrontal cortex. It is started at 0.5 mg/kg/day and gradually raised to 1.0 to 1.4 mg/kg/day to a maximum of 100 mg per day given once or twice a day. [Table - 16] lists potential adverse effects, including drug-to-drug interactions involving selective serotonin reactive inhibitors and others metabolized by cytochrome P450 2D6. Atomoxetine has a low affinity for various receptors, such as alpha1-adrenergic, alpha]adrenergic, serotonergic, cholinergic, and histaminic. There is no increase in drug addiction, drug diversion, cardiovascular complications, or tics. [Table - 17] lists treatment options used by some clinicians but not proven to be of benefit for children, adolescents, or adults with ADHD.
References
1. Greydanus DE, Sloane MA, Rappley MD. Psychopharmacology of ADHD in adolescents. Adolesc Med 2002; 13: 599-624.
2. Greydanus DE, Pratt HD, Sloane MA et al. Attention-deficit/hyperactivity disorder in Children and adolescents: Interventions for a complex costly clinical conundrum. Pediatr Clin North Am 2003; 50: 1049-1092.
3. Greydanus DE. Psychopharmacology of ADHD in adolescents: Quo vadis Psychiatr Times 2003; 20: 5-9.
4. National Institute of Mental Health (NIMH). Attention Deficit Hyperactivity Disorder. NIMH, NIH Publication No. 01-4589, 2001. Available at: http://www.nimh.nih.gov/publicat/helpchild.cfm.
5. National Institute of Mental Health. NIMH Research on Treatment for Attention Deficit Hyperactivity Disorder (ADHD): The Multimodal Treatment Study-Questions and Answers. Washington, DC: NIMH, 2000. Available at: http://www.nimh.nih.gov/events/mtaqa.cfm
6. National Institute of Health (NIH). Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder . NIH Consensus Statement Online 1998: Nov 16-18; [cited year, month, day]; 16(2): 1-37.
7. Pratt HD. Neurodevelopmental Issues in the assessment and treatment of deficits in attention, cognition, and learning during adolescence. Adolesc Med 2002; 13(3): 579-598.(Greydanus Donald E)