Neuropsychol Rev (2007) 17:61–72 DOI 10.1007/s11065-006-9017-3

ORIGINAL PAPER

Pharmacologic Treatment of Attention-Deficit/Hyperactivity Disorder: Efficacy, Safety and Mechanisms of Action Steven R. Pliszka

Received: 30 November 2006 / Accepted: 30 November 2006 / Published online: 23 January 2007 C Springer Science+Business Media, LLC 2007


Abstract Studies examining the efficacy, safety and mechanisms of action of agents for the treatment of attentiondeficit/hyperactivity disorder (ADHD) are reviewed, with an emphasis on newer agents such as the long acting stimulants and atomoxetine. Recent studies of medications are characterized by large, rigorously diagnosed samples of children, adolescents and adults with ADHD, use of standardized rating scales and extensive safety data. These studies confirm a robust treatment effect for the Food and Drug Administration approved agents ranging from 0.7 to 1.5. The most common short term side effects to the most commonly used agents include insomnia, loss of appetite, and headaches. Despite public controversy and labeling changes to warn of extremely rare cardiovascular and psychiatric side effects, the evidence does not support the hypothesis that medication for ADHD increases risk for sudden death, mania or psychosis. A wide variety of neuroimaging techniques including electrocephalogram (EEG) power, event related potentials (ERP), functional magnetic resonance imaging (fMRI), and positron emission tomography (PET) are beginning to examine the mechanisms of action of medications for ADHD, and implicating the catecholamines and prefrontal and anterior cingulate cortices as prime sites of actions for these agents.

Introduction The pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD) is one of the most thoroughly researched topics in the mental health arena. The use of amphetamine in children with disruptive behavior disorders was first described by Bradley (1937) seven decades ago, thus the treatment of ADHD (albeit referred to by many different names) predates the use of antibiotics. The negative impact of symptoms of ADHD on many different aspects of patient and family life is well established (Barkley, 2006); fortunately, a wide array of pharmacological agents is now available for the treatment of ADHD. Advances in functional magnetic resonance imaging (fMRI), electroencephalogram (EEG) techniques, event related potentials (ERP), and radionucleotide imaging have begun to examine the mechanisms of action of these agents, particularly the stimulants. This article will examine the efficacy and safety of pharmacological agents for ADHD, with an emphasis on the more recently developed medications. Recent neuroimaging studies examining the action of methylphenidate in normal volunteers and patients with ADHD will then be reviewed. Stimulants

Keywords ADHD . Psychopharmacology . Magnetic resonance imaging . PET

S. R. Pliszka (
) Division of Child and Adolescent Psychiatry, Department of Psychiatry, 7703 Floyd Curl Drive MC 7792, San Antonio, TX 78229-3900, USA e-mail: [email protected]

Stimulants have consistently shown robust behavioral efficacy in hundreds of randomized controlled trials (RCT) conducted since the 1960’s. By 1993, Swanson’s “Review of reviews” reported over 3,000 citations and 250 reviews of stimulant treatment (Swanson et al., 1993). Robust shortterm stimulant-related improvements in ADHD symptoms were found in 161 studies encompassing 5 preschool, 140 school age, 7 adolescent and 9 adult RCTs (Spencer et al., 1996). Improvement was noted for 65–75% of the 5,899 patients assigned to stimulant treatment versus only 4–30% Springer

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of those assigned to placebo for methylphenidate (MPH) (n = 133 trials), dextroamphetamine (DEX) (n = 22 trials), and pemoline (n = 6 trials). This body of data has continued to grow since then with the introduction of the short acting mixed salts of amphetamine (MSA) (Pliszka, Browne, Olvera, & Wynne, 2000). MPH has both a dextro (d) and levo (l) isomer; the d-MPH isomer alone shows efficacy equal to that of the d, 1-MPH form, with some evidence that the d-isomer administered alone has a slightly longer duration of action than d,l.-MPH (Weiss, Wasdell, & Patin, 2004). Short acting stimulants rarely have a duration of action longer than six hours, requiring multiple doses per day. In recent years, long acting forms have been developed for d,l MPH (Concerta, Daytrana Transdermal System, Metadate CD, Ritalin LA), MSA (Adderall XR) and d-MPH (Focalin XR). Studies documenting the efficacy of these agents relative to placebo are listed in Table 1. All of these studies are characterized by large samples, rigorous diagnostic criteria for ADHD, use of standardized rating scales for assessing symptoms of ADHD, and double blind, controlled designs. Results showed long acting agents to have a response rate similar to that shown by short acting stimulants in the earlier studies. Side effects of stimulants As noted in Table 1, the most common stimulant side effects are headache, insomnia and loss of appetite. Despite many years of use, there continues to be some controversy regarding stimulant safety. Many of the short term studies in Table 1 were followed by longer term open label studies lasting 1–2 years (Wilens et al., 2005; McGough et al., 2005). No serious adverse events were reported and laboratory and electrocardiogram (ECG) findings were unremarkable (Findling et al., 2005). In 2005, Health Canada briefly suspended the sale of Adderall XR due to concerns regarding a small number of cases of sudden death in both children and adolescents. A review by the U.S. Food and Drug Administration (FDA) Villalaba (2006) estimated the rate of sudden death in stimulant-treated ADHD children for the exposure period January 1, 1992 to December 31, 2004 to be 0.2/100,000 patient years for MPH, and 0.3/100,000 patient-years for amphetamine (the differences between the agents not clinically meaningful). Thus the sudden death rate for children on ADHD medications does not exceed the base rate of sudden death in the general population. No evidence currently indicates a need for routine cardiac evaluation (i.e., ECG) before starting stimulant treatment in otherwise healthy individuals. However, these findings suggest that ADHD medications should be used cautiously in children and adolescents with pre-existing heart disease. These cases should be referred for a pediatric cardiology consultation for possible EKG and/or echocardiogram. The FDA Springer

also reviewed post-marketing safety data for stimulants for reports of mania/psychotic symptoms, aggression, and suicidality (Gelperin, 2006). Such reports have many limitations, as information about dosage, comorbid diagnoses, and concomitant medications is often not available. Nonetheless, for each of the stimulants, there occurred very rare events of psychotic symptoms, specifically involving visual and tactile hallucinations of insects. Symptoms of aggression and suicidality (but no completed suicides) were also reported. The FDA ordered changes to stimulant medication labeling to more prominently discuss these risks. While such labeling changes encourage families and clinicians to more closely monitor patients for these rare events, the new label does not require a change in the clinical use of stimulant medications. Whether stimulants affect the growth of children with ADHD has been controversial for many years. Recently, two major reviews (Poulton, 2005; Faraone, Biederman, Morley, & Spencer, 2006) examined all of the available data and concluded that stimulant treatment may be associated with a reduction in expected height gain, at least in the first 1–3 years of treatment. The Multi-modality Treatment of ADHD study showed reduced growth in ADHD patients after 2 years of stimulant treatment compared with those patients who received no medication (MTA Cooperative Group, 2004) and these differences persisted at 36 months (MTA Cooperative Group, 2006). Interestingly, the children with ADHD in the MTA study were taller and heavier than average at the start of the study; those treated continuously with medication tended to approach the mean of the population for height and weight by year three of follow up. Charach et al. (2006) found higher doses of stimulant correlated with reduced gains in height and weight. The effect did not become significant until the dose in MPH equivalents was >2.5 mg/kg/day for four years. In a review by Poulton (2005) concern was raised that children with ADHD treated with stimulants might show a reduced height gain of about 1 cm/year and more long term studies were recommended. However, two recent 1–3 years follow up studies did not show an impact on growth (Pliszka, Matthews, Braslow, & Watson, 2006c; Spencer et al., 2006a). Children with ADHD treated with stimulants should have height and weight measured at least semi-annually. Children whose height or weight percentile drops across two major lines (5th, 10th, 25th, 50th, 75th, 90th, and 95th) should be considered for treatment with a non stimulant. Drug holidays appear to eliminate any growth effects of stimulants (Pliszka et al., 2006c) and should be considered if the child’s ADHD symptoms do not cause severe impairment on weekends and during the summer. Atomoxetine Atomoxetine is a noradrenergic reuptake inhibitor that is superior to placebo in the treatment of ADHD in children,

Concerta

Metadate CD

Ritalin LA

Focalin XR

Concerta

Adderall XR 278 adolescents aged 10–17 years

Adderall XR 223 adults

Concerta

Daytrana

OROS-MPH

MPH

MPH

d-MPH

OROS-MPH

MSA

MSA

ORPS MPH

MPH transdermal system (MTS)

270 children aged 6–12

220 adolescents

141 adults

97 children aged 6–17 years

134 children aged 6–12

321 children aged 6–16 years

282 children aged 6–12 years

Adderall XR 509 children, aged 6–12 years

MSA

N, age group

Brand Decreased appetite-22% Headache-14% Insomina-16% Abdominal pain-14% Moodiness-9%

Safety

Response rates: Placebo- 27% 10 mg-52% 20 mg 66% 30 mg 71% 40 mg 64% Significant improvement of ADHD symptoms relative to baseline

66% response to MPH, 39% to placebo

Response rates: d-MPH-67% Placebo-13%

Teacher ratings significantly improved over placebo

Response rates: MPH-64% Placebo-27%

Insomnia-33% Decreased appetite-32% Headache-30% Nervousness-26%

Decreased appetite- 36% Headache-16% Weight loss-9% Insomnia-12;

Small but clinically insignificant effects on blood pressure

Decreased appetite and insomnia

Headache-15% Decreased appetite-10% Abdominal pain-10% Insomnia-7%

Response rates: OROS MPH: 47% Decreased appetite, headache and MPH-47% insomnia Placebo-17%

AM and PM teacher and behavior rating scales improved relative to placebo

Efficacy data

5-week DBPC parallel groups, 4 dose levels of MTS

Response rate: MPH MTS-72% Placebo-24%

Decreased appetite-25% Insomnia 10% Nausea-10% Decreased weight-10% Tic-5% Moodiness-5%

Open titration to Response rates: OROS MPH-52% Headache-7% efficacious dose of Placebo-31% Decreased appetite-2% 37% of subjects required 72 mg of Insomnia-4% (Only MPH OROS MPH, then OROS MPH a day responders in study) randomized for two weeks to OROS MPH or placebo

4 week, DBPC parallel group, placebo vs 4 doses of MSA

4 weeks, DBPC parallel groups

6 weeks, DBPC parallel groups

7 week, DBPC parallel groups

2 week DBPC parallel groups

3 week DBPC parallel groups

MPH responders randomized to placebo MPH or OPOS MPH

4 week, DBPC parallel groups

Design

Summary of recent studies of the use of stimulants in the treatment of ADHD

Generic name

Table 1

(Findling & Lopez, 2005)

(Wilens et al., 2006)

(Biederman et al., 2005; Weisler et al., 2006)

(Spencer et al., 2006b)

(Biederman et al., 2006)

(Greenhill et al., 2006b)

Package Insert

(Greenhill, Findling, & Swanson, 2002)

(Wolraich et al., 2001)

(Biederman, Lopez, Boellner, & Chandler, 2002)

Author

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Springer

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adolescents, and adults (Michelson et al., 2003; Michelson et al., 2001; Michelson et al., 2002; Swensen, Michelsen, Buesching, & Faries, 2001). Given its pharmacokinetic halflife of 5 hours, it is generally dosed twice a day. Atomoxetine may also reduce tics (Allen et al., 2005) and be effective in children with ADHD who have comorbid anxiety (Sumner et al., 2005). The FDA has issued warnings regarding rare side effects of hepatotoxicity and suicidal ideation (Food and Drug Administration, 2005). Modafinil Modafinil showed efficacy in the treatment of ADHD in two double-blind, placebo-controlled trials (Greenhill et al., 2006a; Swanson et al., 2006) but the FDA declined to approve it for clinical use. There was one case of suspected Stevens Johnson syndrome among the hundreds of children who participated in the clinical trials, so the sponsor declined to pursue further development of modafinil as a treatment for ADHD. Other agents A number of agents have historically been used off-label for the treatment of ADHD. Controlled studies have shown that tricyclic antidepressants are superior to placebo in ADHD treatment, although the effect size is less than that of stimulants (Daly & Wilens, 1998). Bupropion is an antidepressant with effects primarily on the norepinephrine and dopamine systems that also shows modest efficacy in the treatment of ADHD (Conners et al., 1996). These antidepressant medications are used much less frequently today because of the availability of atomoxetine and multiple stimulant formulations. Nonetheless, they remain reasonable second-line agents. The alpha-agonist clonidine has long been used for treating ADHD. Connor, Fletcher, & Swanson (1999) performed a meta-analysis of 11 studies which suggested clonidine possessed efficacy in the treatment of ADHD, although no definitive studies have been performed. The closely related alpha-2A agonist guanfacine was superior to placebo in reducing ADHD symptoms in children with comorbid ADHD and tics (Scahill et al., 2001), although it did not improve executive functioning in healthy adult volunteers (Muller et al., 2005). The most common current use for the alpha-agonists is in combination with stimulants to optimally treat ADHD symptoms and tics, in those with this comorbidity (Tourette’s Syndrome Study Group, 2002). Medication algorithm for ADHD The Texas Children’s Medication Algorithm Project (CMAP) has recently updated its guidelines for ADHD treatment (Pliszka et al., 2006a). Fig. 1 lays out the recSpringer

ommended stages of pharmacologic treatment for ADHD. The algorithm recommends stimulants as the first stage of ADHD treatment due to their large effect size and superiority to non-stimulants in comparative trials (Biederman, Wigal, Spencer, McGough, & Mays, 2006; Wigal et al., 2005). It is also recommended that if one stimulant class (MPH or amphetamine) fails, then the alternative class should be tried. Atomoxetine may also be combined in low doses with a stimulant. Clinical experience suggests this is helpful for symptoms late in the day or at bedtime when administering a stimulant may induce insomnia. Buproprion or a tricyclic antidepressant should be tried if the FDA-approved agents are unsatisfactory, and alpha-agonists should be used for ADHD alone only as medication of last resort. Treatment of comorbidity The Texas CMAP algorithm discusses the pharmacologic treatment of ADHD with major depressive disorder (MDD), anxiety disorder, tics disorder, and severe aggression (Pliszka et al., 2006a). Treatment of comorbid MDD is complicated by the association of antidepressant treatment with increased suicidal ideation (4% on antidepressant vs. 2% on placebo) in children and adolescents with depression (Hammad, Laughren, & Racoosin, 2006). CMAP recommends that the patient with both ADHD and MDD be assessed for the severity of the two disorders, and that the most severe disorder be treated first. Thus, a child whose ADHD is causing greater impairment should be treated via the ADHD CMAP algorithm. If the ADHD and MDD symptoms simultaneously resolve with ADHD treatment, no further pharmacologic intervention is needed. If the MDD symptoms persist despite resolution of the ADHD symptoms, then treatment of depression should be added; either an antidepressant or a psychosocial intervention. In contrast, if the MDD symptoms are more severe (pervasive depression, weight loss, loss of functioning) than the ADHD symptoms, treatment for MDD should be initiated (usually a serotonin reuptake inhibitor). If the ADHD symptoms persist after remission of the depression, than an ADHD treatment should be added. Since atomoxetine has been shown to be effective in the treatment of both anxiety and ADHD (Sumner et al., 2005), it may be considered for first line use for children with ADHD and comorbid anxiety. Serotonin reuptake inhibitors are commonly added to stimulants for this subgroup of patients, although data showing the efficacy of this approach are lacking (Abikoff et al., 2005). Children with tic disorders can be treated safely with stimulants without increasing tics (Gadow, Sverd, Sprafkin, Nolan, & Grossman, 1999) and the CMAP algorithm suggests beginning at Stage 1 with stimulant medications for this subgroup. If stimulants worsen tics, then the clinician

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Diagnostic Assessment and Family Consultation Regarding Treatment Alternatives Any stage(s) can be skipped depending on the clinical picture.

Stage 0

Stage 1

Non-Medication Treatment Alternatives

Methylphenidate or Amphetamine Response

Partial Response or Nonresponse

Stage 2

Partial Response (if MSA or DEX used in Stage 1)

Stimulant not used in Stage 1

Stage 1A (Optional) AMP formulation not used in Stage 1

Response

Continuation

Partial Response or Nonresponse Response

Partial Response or Nonresponse

Stage 3

Partial Response (if MSA or DEX used in Stage 2)

Stage 2A (Optional) AMP formulation not used in Stage 2

Response Continuation

Partial Response or Nonresponse

Atomoxetine Response

Partial Response

Partial Response or Nonresponse

Stage 4

to stimulant or atomoxetine

Bupropion or TCA

Stage 3A (Optional) Combine stimulant and atomoxetine

Response Continuation

Partial Response or Nonresponse Response Continuation

Partial Response or Nonresponse

Stage 5

Agent not used in Stage 4 Response Continuation Partial Response or Nonresponse

Stage 6

Alpha Agonist

Clinical Consultation

AMP = Amphetamine DEX = Dextroamphetamine MSA = Mixed salts amphetamine TCA = Tricyclic antidepressant

Maintenance

Fig. 1 Algorithm for the psychopharmacological treatment of ADHD

should utilize a non-stimulant medication such as atomoxetine (Allen et al., 2005). Some children with ADHD and comorbid tics respond only to stimulants in terms of their ADHD, yet the stimulant worsens their tics. In such cases, alpha-agonist medication should be added to the stimulant

to reduce both classes of symptoms (Tourette’s Syndrome Study Group, 2002). Severe aggressive behavior occurs in substantial numbers of children with ADHD, particularly in those with comorbid oppositional defiant, conduct disorder, or bipolar Springer

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disorder (Jensen et al., 2005). Stimulant or atomoxetine treatment of children with ADHD often reduces comorbid oppositional or aggressive behavior (Connor, Glatt, Lopez, Jackson, & Melloni, 2002; Newcorn, Spencer, Biederman, Milton, & Michelson, 2005). Thus, aggressive and conduct disorders symptoms will resolve in the comorbid child when the ADHD is robustly treated (Klein et al., 1997). If treatment of ADHD is not sufficient to eliminate the aggressive behavior, then a behavioral treatment should be added to the ADHD treatment. It is prudent to address any psychosocial or parent management problems contributing to the aggression (Pappadopulos et al., 2003; Schur et al., 2003). If the aggressive behavior is not resolved with such an approach, and the aggressive behavior is dangerous to the patient or others, than a second generation antipsychotic should be added to the stimulant (Pliszka et al., 2006a). The efficacy of second generation antipsychotic monotherapy in treating aggression is increasingly well established by controlled trials (Snyder et al., 2002). A recent study by Aman et al. (2004) randomized a group of aggressive children with ADHD to risperidone or placebo; one-half of these children were also already being treated with a stimulant for their ADHD and remained on it during the double-blind trial testing risperidone or placebo. No significant increases in side effects were seen in the combined risperidone-stimulant group, although both groups had similar reductions in aggression. Second generation antipsychotics should be used with caution, however, as children exposed to them chronically are at long term risk of weight gain, diabetes, and metabolic syndrome (Correll & Carlson, 2006). Neurobiological mechanisms of action of ADHD treatments Radio-labeled ligands can be used to study cerebral blood flow, or they can be designed to bind to areas of interest in the brain, particularly the dopamine transporter (Spencer et al., 2005) or dopamine receptors (Volkow, Wang, Fowler, & Ding, 2005). Methylphenidate itself can be labeled with carbon-11 to determine its distribution in the brain (Volkow et al., 2005). A typical therapeutic dose of 0.5 mg/kg of MPH will lead to the blockade of about 60% of the dopamine transporters in the striatum (Volkow et al., 1998). Another approach to examine the effects of MPH in the brain is to image subjects with positron emission tomography (PET) using 11C-raclopride, which binds to dopamine-2 receptors. Volkow et al. (2001) performed PET using this ligand in healthy men on both placebo and 60 mg of MPH. On MPH, more dopamine was released, leading to a decline in raclopride binding relative to placebo. MPH (and amphetamine) also have affinity for the norepinephrine transporter as well, but since the raclopride does not bind to it, studies of this sort cannot elucidate the effect of MPH on norepinephrine. Nonetheless, Volkow et al. (2001) established that MPH Springer

acutely increases the amount of dopamine in the synaptic cleft. Next, Volkow et al. (2004) examined the effect of MPH on dopamine release in two different situations: while subjects passively viewed pictures and again while performing a difficult mathematics task. Relative to placebo, MPH produced much greater reduction in raclopride binding (dopamine release was increased) during the mathematics tasks than in the passive condition. Thus it appears that the dopamine release is associated with tasks requiring executive functions or response to a stimuli signaling reward. MPH can block reuptake of dopamine only when it is being released in significant amounts. This may explain why the effects of MPH (and other stimulants) are most pronounced in the classroom or other structured settings where cognitively stressful activities occur. Recently, Rosa-Neto et al. (2005) performed a PET raclopride study with nine adolescents with ADHD; the subjects were scanned both on placebo and again on a therapeutic dose of MPH. MPH induced a decrease in raclopride binding relative to placebo. The magnitude of the decrease in raclopride binding correlated well with MPHinduced improvements on cognitive testing. Another approach that is becoming more fruitful in assessing stimulant action in the brain is the direct study of the binding of ligands to the dopamine transporter (Spencer et al., 2005). Several ligands, including 123I-Altropane, 123I-IPT and 99Tc-TRODAT-1, and 123I-citalopram are available which bind to the dopamine transporter and give a measure of its binding potential. Typically, Single Positron Emission Tomography (SPECT) is used to assess the amount of ligand binding to the receptor, although Altropane can be use with PET (Spencer et al., 2005). The PET ligand PE2I can also be used to image the dopamine transporter (Jucaite, Fernell, Halldin, Forssberg, & Farde, 2005). In seven studies reviewed by Spencer et al. (2005), five showed the dopamine transporter binding to be increased in subjects with ADHD relative to controls, while two studies showed no difference between the ADHD and control groups. Some early studies have begun to examine the effect of MPH on dopamine transporter binding. Krause et al. (2003) obtained SPECT using TRPDAT-1 in a small number of adults with ADHD both at baseline and again after a dose of MPH. They found the dopamine transporter binding potential to be reduced with treatment, but the SPECT was done 90 minutes after the MPH dose when the medication is expected to be binding to the transporter. Thus it cannot be concluded that MPH down regulated the transporter (Spencer et al., 2005). Vles et al. (2003) also found that dopamine transporter binding potential was reduced after three months of MPH treatment in six boys with ADHD, but the timing of SPECT in relation to the last MPH dose was not reported. When MPH treatment was withdrawn from five children with ADHD, dopamine transporter binding potential immediately increased to pretreatment values,

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suggesting that MPH does not induce any long term down regulation of the transporter (Feron et al., 2005). Cerebral blow flood can be assessed by either SPECT (2001) or PET (Matochik et al., 1993; Matochik et al., 1994) but this technique has not been as fruitful as might be expected, either as a diagnostic tool or to assess stimulant effects in the brain. In the largest study to date, Kim et al. (2001) assessed 32 boys with ADHD using 99 Tc HMPAO SPECT at baseline and after a trial of MPH. The subjects were rigorously screened to insure the absence of psychiatric comorbidity or learning disabilities. Significant cerebral blow flow increases after MPH were found in bilateral prefrontal cortex, caudate, and thalamus of subjects who were MPH responders. Unfortunately, studies performed since then have not had the power to allow firm conclusions to be made about the effects of MPH on cerebral blood flow. Ten adult subjects had cerebral blood flow assessed by PET before and after a three week MPH trial. MPH induced increases in blood flow in cerebellar vermis, but decreases in precentral gyri, left caudate nucleus, and right claustrum (Schweitzer et al., 2003). In contrast, Szobot et al. (2003) found decreased left parietal blood flow on MPH relative to placebo in a relatively large (n = 36) study of children and adolescents with ADHD; the same group also found that MPH withdrawal led to increases in blood flow as assessed by SPECT in the motor, premotor, and anterior cingulate cortex (Langleben et al., 2002). Reviewing these data, Castellanos (2002) questioned the utility of SPECT/PET cerebral blood flow studies, suggesting that fMRI and assessment of catecholamine transporter would be more likely to lead to further understanding of the mechanisms of pharmacological treatments for ADHD. In view of this, the American Psychiatric Association recommended against the use of SPECT for the diagnosis or monitoring of treatment for ADHD or other psychiatric disorders (http://www.psych.org/psych pract/clin issues/populations/ children/SPECT.pdf). EEG and ERP measures have also been used to study the response of children with ADHD to medication. In this line of work, EEG activity is examined within specific frequency bands. The complex EEG waveform is decomposed via Fournier analysis into component frequency bands: delta (13 Hz). The beta band is associated with mental alertness; most studies have shown that children with ADHD show decreased beta and increased amounts of the other frequencies, particularly in the frontal area (Barry, Clarke, & Johnstone, 2003; Loo & Barkley, 2005). While there is a subgroup of children who show an excess of beta (Clarke, Barry, McCarthy, & Selikowitz, 2001), they do not appear to be clinically distinguishable from those with decreased beta. Children with ADHD also show decreased theta/beta and theta/alpha ratios relative to controls; stimulant

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treatment of ADHD can increase these ratios, “normalizing” the EEG (Clarke, Barry, Bond, McCarthy, & Selikowitz, 2002). This would also suggest that stimulants might act by increasing cortical arousal, consistent with the blood flow studies of Kim et al. (2001) noted above. Clarke et al. (2002) compared 20 children with ADHD who responded well to MPH to 20 children who had responded well to dextroamphetamine using EEG power. Theta/beta ratios in the frontal, central, and posterior leads were higher for the MPH responders than the dextroamphetamine responders, MPH responders had greater theta/alpha ratios in the frontal leads. Loo et al. (2004), found similar results, adding that MPH non responders tended to show decreased beta while on medication. Increased beta also correlated with improvements in ADHD symptoms on parent behavior rating scales. It is important to note, however, that these results represent group averages. At the level of the individual patient, EEG does not predict stimulant response above the rate predicted by the clinical diagnostic information (Loo and Barkley, 2005). Nonetheless, while not yet appropriate for standard clinical practice, examination of EEG power may help elucidate patterns of medication response that are not yet distinguishable on clinical measures. Loo et al. (2003) compared the MPH response of children with ADHD who were homozygous for the 10-repeat allele of the dopamine transporter with those who were heterozygous for the 9-repeat allele. The 10-R homozygotes showed increased beta power and increased beta/theta ratios on MPH relative to placebo, while children with ADHD who were 9-repeat allele carriers showed the opposite pattern. In the future, use of EEG in conjunction with genetic and functional MRI may allow a more comprehensive picture of the neurophysiology of stimulant effects. In ERP, the subject performs a repetitive cognitive task and EEG is obtained during each trial. The EEG is then averaged over many trials, canceling out random brain activity and producing a waveform which represents the brain’s response to each class of stimuli in the task. In studies of ADHD, oddball auditory ERP tasks and inhibitory tasks such as the continuous performance test (CPT) have been most utilized (Barry, Johnstone, & Clarke, 2003). In the auditory oddball task, the subject must detect rare tones among a long string of common tones. Healthy controls produce a larger P300 wave to the oddball tones than to the common tones, but this difference is markedly reduced in children with ADHD (Barry et al., 2003). The meaning of this difference in the P300 is debated. The P300, which in these tasks is most prominent over the parietal areas, possibly reflects activity related to evaluation of the stimuli but may also represent the amount of mental capacity that is invested in the task (Kok, 1997). In most treatment studies of oddball tasks using ERP, MPH enhances the P300 response to the rare stimuli (Klorman, 1991). Thus it is tempting to conclude that MPH increases the allocation of mental resources to a task, but Springer

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further studies have not borne this out. Jonkman et al. (2000) obtained ERP on healthy controls and children with ADHD while they performed a decision task, which was presented in both easy and hard conditions. Irrelevant probes appeared at various times in the task. Consistent with other studies, children with ADHD had a reduced P300, particularly in the hard condition. In the easy condition, the P300 to the probe was higher in both groups relative to the hard condition. This is because in the hard condition, attentional capacity must be reallocated from the probes to the main task. Since the groups did not differ on the P300 to the probe, this indicated that the groups were not different in total attentional capacity. Since the P300 was smaller to the difficult task stimuli in the ADHD children, it was concluded that they did not allocate those attentional resources as efficiently as controls. ADHD subjects then performed the task on placebo and again on MPH. Relative to placebo, MPH increased P300 to task stimuli in both the easy and hard conditions, and did not affect P300 to the probe stimuli. The lack of an effect on the probe means that MPH did not increase overall attentional capacity, but the equal effect of MPH on P300 in both the easy and hard tasks also means that the stimulant was not excreting its effect by changing the allocation of resources. Thus the effect of MPH on P300 in this type of task is unclear. Since ADHD (particularly the combined type) has been conceptualized as a disorder of inhibitory control (Barkley, 1997), more clear results have emerged from studies using tasks assessing this cognitive domain. On the CPT, the child must respond to target stimuli and avoid responding to other stimuli, in the Go/No Go task the child responds to a Go stimuli the majority of the time but must refrain from responding when the No Go stimuli are presented. No-Go or stop signals on an inhibitory task are associated with a right lateralized N200 which may signal the triggering of the prefrontal inhibitory processes (Kok, 1986); this N200 has been shown to be reduced in children with ADHD (Pliszka, Liotti, & Woldorff, 2000). When on MPH, the N200 to No Go stimuli of children with ADHD no longer showed any differences from controls (Broyd et al., 2005). No Go stimuli of inhibitory tasks also elicit a frontocentral P300 (to be distinguished from the parietal P300 discussed above) which is thought to be generated by the anterior cingulate (Schmajuk, Liotti, Busse, & Woldorff, 2006). Seventeen boys with ADHD performed the CPT while ERP was obtained at baseline and then one week later after a 10 mg dose of MPH (Seifert, Scheuerpflug, Zillessen, Fallgatter, & Warnke, 2003). A group of healthy controls was also studied. P300 to the No Go stimuli was greater than that to the Go stimuli, the No Go P300 of children with ADHD was significantly increased after treatment with MPH. Thus there is some evidence that MPH improves the functioning of prefrontal and anterior cingulate mechanisms involved in inhibition. Springer

Functional MRI (fMRI), which is non invasive and involves no nuclear radiation, is an expanding research tool. Using primarily measures of inhibitory control, comparisons of ADHD children to controls during fMRI have shown differences in fronto-striatal activity (Bush, Valera, & Seidman, 2005), particularly in the right prefrontal cortex (Rubia, Smith, Brammer, Toone, & Taylor, 2005) and anterior cingulate (Bush et al., 1999; Pliszka et al., 2006b). Studies of stimulant effects on the brain using fMRI have been limited to date, but are increasing. Initially, Vaidya et al. (1998) showed that MPH, relative to placebo, increased frontal activation in both children with ADHD and controls. Striatal activation was increased on MPH relative to placebo in children with ADHD but controls showed the opposite pattern, even though both groups improved in cognitive task performance. In a small heterogeneous group of adolescents with ADHD and reading disorders, MPH increased activity in the left ventral basal ganglia relative to placebo, but had no effect on task performance (Shafritz, Marchione, Gore, Shaywitz, & Shaywitz, 2004). Adults with ADHD showed increased activation of the anterior cingulate on MPH relative to placebo while performing a difficult interference task (Bush, 2005). Larger scales treatment studies with children, adolescents, and adults remain to be done. Future directions Today there is a wide array of effective agents for the treatment of ADHD. Stimulants are the most effective agents available, but atomoxetine is a valuable agent, particularly for those who do not respond to stimulants or who have comorbid anxiety or depressive disorders. Older agents such as bupropion and tricyclic antidepressants now have a lesser role, although alpha agonists have a valuable role in treating comorbid tics. Neuroimaging studies will soon begin to unlock the mechanisms of actions of these agents and genetic studies may identify subtypes that are clinically indistinguishable but respond preferentially to certain agents. In general, understanding of the pathophysiology of ADHD will hopefully lead to the development of new and more effective agents.

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