A Calming Influence: An Analysis of ADHD Treatments

Brought to you through an educational grant from the Pediatrics Division of McNeil

Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

• Describe the epidemiology of attention-deficit/hyperactivity disorder (ADHD) and variations in diagnosis and treatment of this condition across different ages, ethnicities, and socioeconomic groups.
• Recognize core symptoms of ADHD and describe common comorbid conditions, including disruptive behavior disorders, mood disorders, anxiety disorders, and learning disabilities.
• Differentiate treatment options for ADHD with regard to effectiveness, tolerability, safety, monitoring parameters, and potential for drug interactions.
• Compare the advantages and disadvantages of stimulant and nonstimulant product formulations with regard to pharmacokinetic differences, abuse potential, adherence, and ease of administration.
• Provide counseling to patients, family members, and caregivers to promote adherence and the safe and effective use of medications to manage ADHD.

This educational lesson will be available to pharmacists on-line at www.pharmacytimes.com.

For full disclosure information, send an e-mail request to: arybovic@ascendmedia.com.

The diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD) can be both anxiety-provoking and alleviating, given one's perspective. For the child and the parent, they can mean newly found success in school and more enjoyable family and social interactions. For both parents and health care providers, they are associated with concern about the long-term outcome and safety of treatment.

Recent FDA advisory committee meetings regarding ADHD medications have heightened concerns. In February 2006, the FDA called a panel to discuss ways to study whether ADHD medications increase the risks of adverse cardiovascular outcomes, including sudden unexplained death. These risks as well as psychiatric adverse effects?including hallucinations, aggression, and suicide?were discussed in another advisory panel meeting in March 2006.^1,2 In October 2005, the FDA had recommended and approved a medication guide to accompany prescriptions for atomoxetine, warning of increased suicidal thinking and hepatotoxicity.³ In the same month, the FDA had removed pemoline from the market because of an unacceptable risk of hepatotoxicity.⁴

These warnings serve to help increase awareness and enhance monitoring by patients and health care providers so as to detect those at risk and to help prevent adverse outcomes. As the most accessible health care professionals, pharmacists are in a prime position to provide background information to clinicians and parents on the data behind the warnings. Doing so can help minimize the risks of treatment and promote appropriate pharmacotherapy.

This article reviews the diagnosis, epidemiology, and clinical course of ADHD in addition to the effectiveness and tolerability of treatment options, including diverse drug-product formulations. Answers to commonly asked questions are included to help pharmacists counsel about the warnings and discuss the benefits and risks of treatments. Side-effect management strategies and recommended health screening to prevent adverse outcomes will be discussed.

Diagnostic Considerations

Pharmacists should encourage a thorough diagnostic evaluation by an experienced clinician whenever symptoms of poor attention or hyperactivity and impulsivity cause impaired functioning for a child socially or academically.⁵ Symptoms typically are present by the time the child enters school and must be present by age 7 in at least 2 settings for 6 months to meet diagnostic criteria.⁶ Symptomatic behaviors are grouped into 2 categories: inattention and hyperactivity/impulsivity. Whether an individual has primarily inattentive symptoms, hyperactive/ impulsive symptoms, or both, the diagnosis is still ADHD. Examples of functionally impairing ADHD symptoms include making careless mistakes, losing items necessary for tasks, the inability to sit still and focus, and interrupting or intruding on others?all of which make social and academic success unattainable.^5,6

Symptoms of inattention or hyperactivity/impulsivity can be associated with conditions other than ADHD. For example, 70% to 90% of children and 30% to 60% of adolescents who meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for bipolar disorder also meet criteria for ADHD.^7,8 It is possible to have both conditions concurrently.⁸ An experienced child psychiatrist or psychologist is most qualified to detect and differentiate ADHD from such disorders as bipolar disorder or substanceinduced behavioral and cognitive dysfunction.⁵ Several other conditions?including oppositional defiant disorder, conduct disorder, anxiety disorder, mood disorder, learning disability, and Tourette's syndrome?can co-occur with ADHD and must be considered before drug selection.^8-10

For example, stimulants can worsen bipolar disorder and anxiety disorders and sometimes worsen tics associated with Tourette's syndrome.^6,8 Methylphenidate does not routinely worsen tics. A study comparing the effects of methylphenidate, clonidine, or placebo in 136 children with ADHD and Tourette's disorder showed that the worsening of tics was no greater in the methylphenidate group, compared with the clonidine or placebo group.¹¹ Disruptive behavior disorders such as conduct disorder have been shown to improve significantly when coexisting ADHD is treated with stimulant medication.^9,10 Clinicians typically need 2 or 3 visits with a child or teen, as well as assessments from multiple informants (child, parents, teachers, caregivers), before a diagnosis of ADHD and comorbid conditions can be confirmed.^5,9,10

Although brain studies show no definitive pathologic marker for ADHD, the prefrontal cortex (which regulates attention), basal ganglia, and the caudate nucleus (which regulates movements and impulsivity) consistently are reported as abnormal?typically smaller.⁶ In addition, individuals with ADHD are twice as likely to display a defective 7-repeat allele of the dopamine 4 receptor gene. Polymorphisms in dopamine and norepinephrine presynaptic transport proteins exist in persons with ADHD, causing dysregulation of dopaminergic and noradrenergic control of attention, hyperactivity, and impulsivity.^5,6,9 Considerable data gathered from neuroimaging studies, the long-term developmental course of ADHD, international studies, and familial aggregation studies (genetic and environmental) have demonstrated that ADHD is a legitimate brain disorder and a valid clinical diagnosis.^5,9

Epidemiology

ADHD occurs in 3% to 10% of children aged 6 to 12 years worldwide.¹² Four boys are diagnosed for every girl with ADHD in the United States. This difference is likely due to higher rates of disruptive behavior disorders?such as oppositional defiant disorder and conduct disorder?in boys, compared with girls, driving referrals for assessment.^5,12

ADHD is perceived by many to be an American disorder. Studies show, however, that?when consistent diagnostic criteria and evaluation methods are used to objectively assess samples of school-age children from countries in Europe, Latin America, Africa, and Asia?the prevalence of ADHD is similar in these countries to prevalence rates in the United States.^9,13 Published differences in the rates of ADHD across cultures and continents are likely a reflection of differences in social tolerance, perceptions of normal and deviant behavior, and parental expectations.¹³

Within the United States, significant differences are noted in ADHD diagnoses, stimulant usage, and health care visits according to race/ethnicity, region, and type of insurance, according to the results of several studies.^9,14 For example, children from southern and midwestern states are more likely to be diagnosed with ADHD and to receive prescriptions for stimulant, compared with children in the West and Northeast.^14,15 Children without insurance have lower levels of care for ADHD, relative to children with insurance. Hispanic-American and African-American children are less likely to be diagnosed with ADHD by parent report and are less likely to receive prescriptions for ADHD medications than are white American children.^14,15

An estimated 60% to 80% of children with ADHD continue to have significant symptoms in adolescence, and approximately one third to one half of these individuals will have functionally impairing symptoms in adulthood.⁵ The presence of comorbid conditions?particularly bipolar disorder, oppositional defiant disorder, and conduct disorder?increase the likelihood of ADHD chronicity.^5,9 Adult ADHD occurs in 2% to 5% of the population. The same DSM-IV-TR diagnostic criteria for children (forgetfulness, losing items, disorganization, poor impulse control) apply to adolescents and adults. Adolescents and adults, however, typically do not display obvious motor overactivity.^5,6,16 As the demand for life planning increases with age, adolescents and adults display more procrastination, overreactions to frustration, poor motivation, difficulty with time management, and occupational and interpersonal relationship problems.¹⁶

Prescribing for ADHD

During the past 10 years, prescriptions for medications to treat ADHD have increased significantly in all age groups, including preschoolers.^17,18 A landmark study examined psychotropic prescribing for 2200 children, aged 2 to 4 years, enrolled in separate health plans (Medicaid, HMO) in 3 different regions of the United States from 1990 to 1995. In 1995, the investigators found that 1.2% were receiving stimulants (a 3-fold increase), 1.1% were receiving antidepressants (a 2-fold increase), and 0.32% were receiving clonidine (a 28-fold increase), compared with 1990.¹⁷ Scrutiny of psychotropic medication use in preschoolers is needed, because ADHD is difficult to diagnose in very young children, and most medications are not FDA-approved for children less than 6 years old.

Considering all age groups, children and adolescents receive the most prescriptions for medications to treat ADHD. As of March 2006, ~1 million prescriptions were dispensed monthly for adults, and 2 million prescriptions were dispensed monthly for children and adolescents in the United States. From January to June 2005, methylphenidate (MPH) was the most prescribed product (47%); amphetamine products, including mixed amphetamine salts, were second (33.4%); and atomoxetine was the third (16.4%) most prescribed product.¹⁸

Nonpharmacologic Interventions

Behavioral interventions?such as positive rewards for good behavior (contingency management), structured limit setting, and breaking up tasks into short (15-20-minute) manageable segments?are all useful components of an effective multimodal treatment plan for ADHD. Contingency management has the most evidence of effectiveness.¹⁹ Table 1 reviews behavioral interventions recommended by the American Academy of Pediatrics. Controlled clinical trials have shown that psychosocial and behavioral interventions are less effective than stimulant medication; however, parent and teacher satisfaction ratings with these nonpharmacologic interventions are high. Controversy persists regarding the comparative benefits of behavioral therapy versus medication.^19,20

Dietary-manipulation and complementary-medicine approaches have been studied as treatments for ADHD.Avoiding artificial food additives has been found ineffective for ADHD in the majority of individuals, although these strategies may be useful for a small group of children with true sensitivities to food additives. Megavitamin therapy should be discouraged, because studies show no benefit and a risk of liver dysfunction. Avoiding sugar and aspartame also has been found ineffective in well-designed controlled clinical trials.²¹

Limited evidence shows improvement in attentional symptoms when omega-3 fatty acids are added to a healthy diet.²¹ Ensuring a healthy, balanced diet and maintaining a predictable routine with a regular sleep schedule can help prevent behavioral symptoms triggered by an unpredictable, chaotic lifestyle. Children act out behaviorally in response to stressors in their environment.^5,22

Comparing ADHD Medications

Methylphenidate/Dexmethylphenidate

Methylphenidate (MPH) is the most well-studied and most-prescribed stimulant with the most available product formulations, including the newly released transdermal patch^12,20,23 (Table 2). MPH was demonstrated to be more effective than behavioral interventions and community care in the landmark Multimodal Treatment Study of Children with Attention- Deficit/Hyperactivity Disorder (MTA) study.^12,19,20,23 This controlled study randomly assigned 579 children (80% boys, 20% girls) 7 to 10 years old with DSM-IV-diagnosed ADHD, combined type, to MPH immediate-release 3 times a day, behavioral therapy, combination MPH and behavioral therapy, or community care over 14 months. The behavioral interventions included parent training, contingency management, and ADHD summer camp. Community care was naturalistic, with no investigator intervention; many received prescriptions for stimulant medication.

The results of this study showed that MPH was generally well-tolerated, and efficacy was maintained for 14 months in a structured clinical follow-up setting with regular contact with a clinician and coordinated care with teachers and parents. No tolerance developed to the therapeutic effects of MPH.^5,10,18,20 A subsequent study in MPH responders aged 7 to 12 years showed that it maintained effectiveness without dose escalation for 2 years. The average effective dose was 35 mg per day.²⁴

MPH is available in short-acting, intermediate-acting, and long-acting once-daily preparations (Table 2). Short-acting preparations are the least-expensive effective option when dosed 2 or 3 times a day. Intermediate-acting agents are used infrequently because of their unpredictable absorption and variable duration of action.^12,23 Once-daily preparations?including modified-release MPH (Metadate CD), once-daily extended release MPH (Ritalin LA), and osmotically released oral system (OROS) MPH (Concerta)?have gained popularity because they eliminate in-school dosing and provide all-day symptom coverage. OROS MPH has an advantage of less abuse potential, because it cannot be crushed and snorted.

A retrospective analysis comparing immediate-release (IR) MPH use patterns with OROS MPH use patterns in 5939 patients over 34 months found that OROS MPH use was associated with longer treatment periods, increased patient adherence, and fewer emergency room visits for injury.²⁵ All extended-release, once-daily preparations have the potential for increased insomnia, compared with IR preparations, given that drug levels persist into the late-afternoon and evening hours.^12,26 It is unknown whether the cardiovascular adverse effects are more problematic with extended-release preparations because of persistent blood drug levels over 8 to 12 hours; more study is needed.

The MPH transdermal system is a multipolymeric adhesive patch available in 10-, 15-, 20-, and 30-mg dosage strengths.²⁰ In a small laboratory classroom study, this system was found to produce blood levels and behavioral effects comparable with those of matched-dose IR MPH given 3 times a day. The patch is a useful option for children who are unable to swallow medicine, and wearing the patch for 9 hours provides a full day of symptom coverage. A new patch should be applied every morning to a clean, dry, hairless area. Side effects are similar to those with oral MPH, except for irritation at the patch site. Easy removal of the patch can be an advantage if side effects occur, and it is a disadvantage in oppositional youth who defiantly remove their patch.²⁰

Dexmethylphenidate is the dextrorotary isomer of d,l MPH that has demonstrated comparable therapeutic effects in controlled trials. One study showed that an average titrated dose of 18.25 mg of dexmethylphenidate was comparable with an average titrated dose of 32.14 mg/day of d,l MPH in 192 children aged 6 to 17 years. Dexmethylphenidate is twice as potent as d,l MPH, and the conversion is 5 mg of d,l MPH to 2.5 mg of dexmethylphenidate.^12,27 No clinical advantage has been demonstrated for dexmethylphenidate over d,l MPH. Several premarketing studies showed that it produces less headache and more gastrointestinal upset, compared with MPH, but postmarketing studies show comparable tolerability.^26-28 Dexmethylphenidate is available in an extended-release capsule with a duration of action of approximately 12 hours (Table 2).¹²

Dextroamphetamine/Mixed Amphetamine Salts

Dextroamphetamine and mixed amphetamine salts are comparable in efficacy with MPH but are twice as potent, so dosing should begin with half the initial dose of MPH (2.5 mg instead of 5 mg; Table 3). The evidence does not show that mixed amphetamine salts are superior to dextroamphetamine; however, some clinicians prefer them.^12,23 The duration of effect with the IR amphetamine products is longer than that with IR MPH. Nevertheless, multiple daily doses are required for many patients. Mixed amphetamine salts are available in an extended-release capsule that provides 12 hours of symptom control.^12,23

Atomoxetine

Atomoxetine, a selective norepinephrine reuptake inhibitor, is the first nonstimulant approved by the FDA for the treatment of ADHD.^12,29 In contrast to stimulants, it has no abuse potential, and it is not a controlled substance. Several placebo-controlled clinical trials demonstrated its effectiveness for ADHD. Several trials, however, showed that symptoms of inattention and hyperactivity/ impulsivity were still in the clinically significant range of ADHD at the end of the trial.^12,29 Atomoxetine has a longer onset of therapeutic benefit (2-4 weeks), compared with stimulants (within an hour of an effective dose). Possible adverse effects are similar to those with stimulants, except for a greater risk of sedation and sexual side effects^12,29 (Tables 4 and 5). The hepatotoxicity warning in the medication guide is based on 2 males (1 adult, 1 child) who developed liver injury during atomoxetine therapy that resolved upon discontinuation of treatment.^3,12

Bupropion

Bupropion has a safer cardiovascular profile, compared with tricyclic antidepressants (TCAs), and is generally better tolerated. It has not been studied as extensively for ADHD, and it is not FDA-approved for this indication.^5,12 There have been 2 placebo-controlled trials and one small trial (n = 15) showing comparable efficacy with MPH. Children or adolescents with uncontrolled seizures or eating disorders should not receive bupropion.^6,11 It is available in IR, slow-release, and extended-release product formulations.^5,11

Tricyclic Antidepressants

Although not approved by the FDA for ADHD, TCAs are as effective as stimulants for behavioral symptoms of ADHD, as shown in controlled clinical trials, but they are less effective for inattention, and they are not well-tolerated long term.^5,6 Sudden death has been reported in 7 children, and arrhythmias are the suspected cause. Electrocardiograph monitoring is required before and during TCA therapy to assess the patient for adverse cardiac effects. Anticholinergic side effects can interfere with cardiovascular recovery after exercise, and children or adults may not tolerate the sedation, dizziness, constipation, and weight gain caused by TCAs.^5,6

Clonidine/Guanfacine

Clonidine and guanfacine are alpha-adrenergic agonists that may be useful as adjunctive treatments to stimulants for behavioral management, tic disorders, or insomnia. Guanfacine is 10 times less potent, causes less sedation, and has a longer half-life than clonidine, so it may be dosed once or twice a day, compared with 3 or 4 times a day with clonidine. Several reports of guanfacine-induced mania are known.¹² An extended-release product formulation is under investigation for ADHD.¹² Note that neither clonidine nor guanfacine is FDA-approved for ADHD.

Modafinil

Modafinil is a Class IV controlled substance that differs from stimulants and atomoxetine in that it does not inhibit the reuptake of norepinephrine or dopamine.¹² It stimulates specific hypothalamic centers to promote wakefulness and attention to tasks. It is FDA-approved to treat narcolepsy, shift-work sleep disorder, and sleep apnea (adjunctively), but it is not FDA-approved for ADHD. Controlled clinical trials with patients with ADHD show superior efficacy versus placebo and good tolerability at doses of 340 to 425 mg/day. Headache, jitteriness, insomnia, decreased appetite, and cardiovascular and psychiatric adverse events have been reported with modafinil.^2,12,30

Other Psychotropic Medications

Selective serotonin reuptake inhibitors are ineffective for ADHD, although they may be coadministered with stimulants to treat anxiety, depression, or obsessive-compulsive disorder.⁶ Atypical antipsychotics?including risperidone, quetiapine, olanzapine, ziprasidone, and aripiprazole?are not effective treatments for the core symptoms of ADHD, although they have been used short term (1-3 months) to control violent, aggressive behavior associated with ADHD and comorbid diagnoses, particularly conduct disorder or bipolar disorder.⁶

Common Questions Regarding Pharmacologic Treatment

What Medical Screening Is Necessary Prior to Starting Medication?

Before initiating medication, 3 to 6 target outcomes or goals of therapy should be identified that are realistic and measurable. For example, a child with an inability to complete homework assignments should have as a goal to complete his or her assignments. Several validated rating scales (eg, Conners' Rating Scale) and behavioral checklists are available for parents, teachers, and siblings to measure ADHD symptoms before and after treatment initiation.³¹ Videotapes can be useful tools to objectively assess symptoms prior to and during ongoing medication therapy.⁶

A careful medical history should be gathered to determine whether there is a significant family history of cardiac or cardiovascular disease, seizures, eating disorders, bipolar disorder, psychosis, or liver dysfunction that could increase the child's risk for adverse drug events. Baseline weight, height, blood pressure, pulse, somatic complaints, and sleeping habits and eating habits should all be documented for at least a week prior to starting medication in order to better differentiate medication adverse effects from the child's preexisting conditions.^1-3,6,8 Potential adverse effects, prevention, and management strategies should be thoroughly discussed with parents, caregivers, and children prior to medication initiation (Table 5).

Which Medications Cause Which Type of Psychiatric Adverse Effects?

Hundreds of postmarketing reports of 4 broad categories of psychiatric adverse events have been associated with stimulants, atomoxetine, and modafinil therapy for ADHD. These categories include (1) psychosis or mania, (2) aggression or violent behavior, (3) suicidal ideation or behavior, and (4) miscellaneous psychiatric adverse events such as severe anxiety or panic attacks.^1,2,12 The first 2 categories have been reported with all of the above agents. Atomoxetine is the only agent with a labeled warning about increased suicidality. The warning is based on analysis of 12 trials involving 2200 patients (1357 receiving atomoxetine, 851 receiving placebo). The average risk of suicidal thinking was 4 per 1000 patients treated, compared with none in the placebo group. One patient attempted suicide. Prescreening for psychiatric illness and careful monitoring after medication initiation are essential, particularly in the first weeks to months of treatment.^1-3,12

What Are the Facts About Cardiovascular Safety?

Stimulants and atomoxetine are rarely associated with sudden unexplained death or other cardiac and cardiovascular side effects. All have been associated with small increases in blood pressure and pulse, deemed clinically insignificant during clinical trials. For example, atomoxetine-treated children experienced an increase of 1.5 mm Hg in systolic and diastolic blood pressure. In a separate trial, children receiving OROS MPH over 1 year experienced a 3.3-and a 1.5-mm Hg mean increase in systolic and diastolic blood pressure, respectively, while their pulse increased an average of 3.9 beats per minute. The increase in pulse and blood pressure is dose-related.^1-3,12

Pediatric sudden unexplained death is the most serious adverse event associated with drug treatment for ADHD.The FDA compiled cases from 1992 through February 2005 and found 13 cases in 3.8 million exposures to amphetamine and dextroamphetamine, for a rate of 0.3 cases per 100,000 exposed. There were 11 cases in 7.1 million exposures to MPH, for a rate of 0.2 per 100,000 exposed. Three cases of sudden unexplained death were reported in 601,246 cases exposed to atomoxetine, for a rate of 0.5 cases per 100,000 exposed. The extent of under-reporting is unknown. The estimated 1-year reporting rates of sudden unexplained death per 100,000 children exposed for 2005, from highest to lowest, are atomoxetine 1.5, amphetamine 0.7, and MPH 0.2. Undiscovered structural abnormalities of the heart (thin myocardial wall, valve problems, etc) were implicated in at least 5 of the cases of sudden unexplained death associated with amphetamine administration for ADHD.^1-3

The estimated rate of unexplained death from cardiac causes in children and young adults aged 1 through 30 years is 1.3 to 8.5 per 100,000 patient-years.³² These data support the FDA's conclusion that the rate of unexplained death in pediatric patients treated with stimulants is no greater than the number of deaths that would be expected to occur in this population without treatment with stimulants. The extent of underreporting is unknown in both groups of treated and nontreated individuals.

The risks of ADHD medication for individuals with structural abnormalities of the heart outweigh the benefits. An echocardiogram is needed to detect structural cardiac abnormalities.^1,2,12 If health screening reveals a positive family history of heart disease or if a parent requests it, an echocardiogram should be done to rule out structural cardiac abnormalities. The patient's pulse and blood pressure should be monitored at least monthly, and the child or parent should report any new physical symptoms, including fatigue, rapid or slow heartbeat, and shortness of breath.^1,2,12

What Is the Risk of Substance Abuse?

Individuals with ADHD have a 2 to 7 times greater risk for substance abuse, compared with those without ADHD.^5,9,33 If conduct disorder or a mood disorder also is present, the risk of substance abuse increases. Fortunately, effective pharmacologic treatment has been shown to decrease alcohol and substance abuse and to assist individuals with participation in substance abuse recovery.^5,9,33

How Does Long-term Use of ADHD Medication Affect Growth?

Longitudinal studies with stimulants including MPH and amphetamines have documented a decrease in growth velocity and weight in children treated continuously (7 days a week) over 2 to 3 years without evidence of growth rebound during this period of development.^34,35 One study in children aged 7 to 10 years treated with MPH continuously over 3 years (to age 10-13) showed a temporary slowing in growth rate, on average a total of 2 cm less growth in height and 2.7 kg less in weight.³⁶ It is unknown whether growth rebound occurs during periods off stimulant medication or in subsequent years, although several studies suggest growth rebound occurs off stimulant or growth effects attenuate over time.^34,35

Summary

Effectiveness of ADHD Treatments

The first-line treatment options for ADHD include behavioral therapy or stimulant medications (MPH, dexmethylphenidate, dextroamphetamine, mixed amphetamine salts), behavioral therapy, or both. Behavioral interventions alone may be sufficient for mild, subthreshold cases (with fewer and less-severe symptoms). When symptoms meet DSM-IV-TR criteria, are moderate-to-severe, and cause functional impairment in more than one setting, stimulant therapy should be initiated following a thorough baseline symptom assessment and a medical workup to ensure the safety of the medication. Stimulants are comparable in efficacy, according to the results of clinical trials, but there is wide interindividual variation in response. For example, if MPH or dexmethylphenidate is ineffective, dextroamphetamine or mixed amphetamine salts may be effective, and vice versa.²³

Atomoxetine may be considered firstline for those with an active substance abuse disorder, because it has no abuse potential and is not a controlled substance. Yet, it is less effective than stimulants and therefore rates secondline status for most patients.5,12,29 Bupropion has not been as well-studied as stimulants or atomoxetine, and available literature warrants secondline status. Bupropion is a good option for stimulant nonresponders or for those with ADHD and depression, or if smoking cessation is desired.5,12 TCAs are effective, but they are considered third-line agents because of their suboptimal tolerability, the risk of cardiovascular toxicity, and toxicity in overdose.^5,6,12

Clonidine and guanfacine should be thought of as fourth-line agents or adjuncts to more-established treatments due to the lack of their established effectiveness for ADHD as monotherapy.^5,12 Atypical antipsychotics - including risperidone, quetiapine, olanzapine, ziprasidone, and aripiprazole - are appropriate when used short term (1-3 months) to control violent, aggressive behavior associated with ADHD and comorbid diagnoses, particularly conduct disorder or bipolar disorder.⁶

Safety Information

ADHD medications, primarily stimulants, have been used safely and effectively to treat children since the 1950s. Only in the past 10 to 15 years, however, have medications been prescribed routinely into adolescence and adulthood. The substantial increase in the number of people taking stimulants for longer periods of time is bound to increase reports of psychiatric adverse events and cardiovascular toxicity. The FDA has concluded that the rate of sudden unexplained death does not appear to be greater in patients with ADHD medication than in the general population. Yet, because these medications are known to increase blood pressure and pulse, careful baseline screening and monitoring are needed.^1-3,12

For a list of references, send a stamped, selfaddressed envelope to: References Department, Attn. A. Rybovic, Pharmacy Times, Ascend Media Healthcare, 103 College Road East, Princeton, NJ 08540; or send an email request to: arybovic@ascendmedia.com

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