MANAGING ADHD
`
`ADHD: TREATMENT AND OUTCOME*
`
`Christopher J. Kratochvil, MD
`
`Chronic diseases and disorders are treated to reduce or eliminate sy mptoms and to
`minimize impairments. Like other chronic health problems, attention deficit hyperactivi(cid:173)
`ty disorder (ADH D) must be approached as a disorder that causes difficulties throughout
`the day, every day. Poor symptom coverage can cause poor outcomes. Thus, the treatment
`goal is to manage patients in such a \\3} as to provide consistent daytime coverage of
`symptoms and associated behaviors.u
`Clinicians are accustomed to asking their pediatric ADHD patients about school
`performance, but it is equally important to inquire about other aspects of functioning
`as \\ell. How are they able to get along \\ith their peers? How are things going with the
`family? These are areas that ha\·e not been addressed adequately when assessing and
`managing children with ADHD. The treatment goals for ADHD are not only to
`improve academic functioning but also to improve outcomes by imprO\·ing function(cid:173)
`ing in nonacademic areas and the quality of relationships outside the classroom(cid:173)
`relieving the frustration, anger, and poor self-image that typically impact more broadl,
`on functioning and interpersonal relationships.' We kno\\ from the clinical e,·idence
`presented in Dr Gephart's re\iew (page Sl60} that negative outcomes, sue 1 a• ·ub(cid:173)
`stance abuse, smoking,' dri\'ing accidents.1 and physical aggression, .. ' increa, dr:imat(cid:173)
`ically in ADHD patients \\ho are untreated.
`
`BEllAVIORAL bi1ER\ENTIOM
`When used concomitantly \\ith pharmacotherapy. beha\"ora mrenentici1h ha\-e been
`proven effecfoe in the treatment of children \\ith ADI-ID. A lou"'·term stud; sponsored by
`the National Institutes of Health looked at well-deli\'ered rha,macotber-ipy. well-delivered
`behavioral therapy, combination therapy of the 2 appro~cL-s. arid l)p1cal community care.9
`Those who received t} pica! community care fared • 11e wor.t. but th~se findings are rewaling.
`They tell us that a systematic way of caring for chikt en \\itb ADHD is still lacking in the
`community and that \\hen children are not n.:.itl'Ci systemaucally. they may not realize the
`greatest potential for benefit.
`The study also demonstrated thdr fo most ADHD symptoms, children in the com(cid:173)
`bined treatment and the medication ma11agem,.J11 groups showed greater unpro\·ement
`than those who were given interisi,·e beha\'ioral treatment \\ithout medication. Howe\'er.
`children who received comb, 1E'd be11a\ioral treatment \\ith medication did not differ
`acutely in core ADHD outcomes compared with children treated with medication alone!
`The intensive behavioral modification strategies used witllin this study-deli\-ered by
`highly trained behaviorists within the controlled and ideal framework of the clinical trial set(cid:173)
`ting- are achieved elsewhere through systematic training of parents and teachers in behav(cid:173)
`ioral therapy techniques. Strategies include environmental modifications, regulatory
`strategies, external aids, and psychosocial support. The goals of these behavioral interventions
`are to improve academic functioning and peer relationships. Behavioral interventions can par(cid:173)
`ticularly play a significant role in the management of children with anxiety or aggressive dis(cid:173)
`orders that are comorbid with ADHD.w Additional evidence is being collected through
`ongoing Multimodal Treatment Study of Children with ADHD (MTA) evaluations to assess
`the long-term benefits of behavioral interventions to improve core ADHD symptoms.2
`
`*Based on a presentation given by Or Kratochvil at a symposium held in conjunction
`with the American Academy of Pediatrics 2003 National Conference and Exhibition.
`
`ADHD TOOLKIT
`To facilitate multimodal, multidis(cid:173)
`ciplinary treatment, the American
`Academy of Pediatrics created a re(cid:173)
`source toolkit for clinicians, available at
`the National Initiative for Children's
`Healthcare Quality Web site:
`www. n i ch q. org/resources/tool kit/.
`This kit includes:
`• Diagnostic checklists for teachers
`and parents
`•Diagnostic tools for clinicians
`•Treatment guidel ines for select(cid:173)
`ing and implementing therapy
`plans, setting treatment goals,
`dosing medication, and manag(cid:173)
`ing side effects
`• Parent information and support
`resources
`• Information and sample forms for
`coding and billing
`
`The important role of pharma(cid:173)
`cotherapy in the treatment of ADHD
`has been well documented in the med(cid:173)
`ical literature and has been established
`conclusi\·ely
`by MTA
`findings.•
`Stimulants have been the cornerstone of
`ADI-ID therapy for decades. A variety of
`nonstimulant
`therapies have also
`demonstrated efficacy.
`
`rotn.A .. "\I TuERAPtES
`\\ lTB l:S FOOD AND DRUG
`AD.UC-.,STRATION I DICATIONS
`The 2 primary
`stimulants,
`amphetamine and methylphenidate
`(MPH). have been used since 193 7
`and 1957, respectively. Historically,
`one limitation of stimulant drugs was
`their short-acting profile. Over the
`past I 0 years, however, long-acting
`stimulant formulations have changed
`the way that many clinicians have
`to manage ADHD.
`been able
`Extended
`release stimulants are
`advantageous because
`they are
`approved for first-line use in children
`and adolescents and have a 7- to 12-
`hour action profile, which varies with
`the formulation. Ho\\ever, they pro(cid:173)
`vide limited coverage in late evenings
`or early mornings, have the potential
`
`5162
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`Vol. 4 (3A) • March 2004
`
`Page 1 of 4
`
`KVK-TECH EXHIBIT 1010
`
`

`

`for abuse and diversion, and have
`been linked with side effects such as
`decreased appetite and trouble falling
`asleep.11 12
`
`DEXTROAMPllETA \f/\'E/
`LFl'OA\IPhFT Ml.\£ (ADDf~ LLXF)
`This long-acting stimulant con(cid:173)
`tains 75% dextro and 25% levo-iso(cid:173)
`mers of amphetamine salts. Its I 0- to
`12-hour action profile is achieved with
`a biphasic delivery system that releases
`50% of the medication beads immedi(cid:173)
`ately and 50% approximately 4 hours
`later. For this reason, it is \·ery impor(cid:173)
`tant to instruct patients not to chew
`these capsules. Clinical im-estigations
`show that this compound is a \'iable
`therapeutic option and may be a clini(cid:173)
`cal consideration, part icularly for
`pat ients taking shorter-acting Adderall.
`The compound has been demonstrated
`to be effective for the treatment of
`ADHD, based on clinician and parent
`reports."
`
`MP_
`Metadate• CD. This 20-mg for(cid:173)
`mulation of MPH uses a bipbasic
`bead delivery system that releases
`30% of MPH (6 mg) immediately
`and 70% ( 14 mg) about 3 hours after
`dosing. The rationale for this formu(cid:173)
`lation is based on the notion that
`tachyphylaxis occurs with stead"
`blood
`levels of st imulant d'"llgs.
`Increasing blood levels with a delayed
`drug burst is intended to provide sus(cid:173)
`tained
`therapeutic benefit. This
`delayed-release medicat ion has a
`duration of action of approximately
`8 hours.••
`Ritalin• LA. This drug uses a
`biphasic bead delivery system that
`releases 50% of the MPH as immedi(cid:173)
`ate-release beads and 50% as extended(cid:173)
`release beads 4 hours later. Studies of
`this formulation show drug efficacy
`and a similar side-effect profile to that
`of MPH.'s
`Concerta '. T his extended-release
`formulation of MPH is designed for a
`10-
`to 12-hour effect, using an
`
`advanced extended-release delivery sys(cid:173)
`tem. This capsule has a short-acting
`drug coating. It also features a laser(cid:173)
`drilled hole at one end, creating an
`osmotic gradient that pulls water in
`and systematically pushes MPH out at
`timed intervals. '6
`
`0PTIMIZl.\'G RESPONSE
`ro Sr'
`"rs
`Extended-release stimulants pro(cid:173)
`vide a longer duration of action than
`short-acting MPH , but immed iate(cid:173)
`release medications can still play a
`role in therapy. Dexmethylphenidate
`(Focalin-), for example, utilizes just I
`isomer of MPH for a 3- to 4-hour
`duration of action. This agent may be
`used in conjunction with a Ionger(cid:173)
`acting drug, dosed m ·eral times per
`day, or perhaps used in some oth'"f
`situation in which it is necei. ary to
`sculpt the dose according to the indi(cid:173)
`\'idual patient.
`Se,·eral factors come into play in
`optimizing the re~ponse to stimu(cid:173)
`lants. First an J toremost, the dose
`must be hi2b enough to ensure full
`efficacv. Second, duration of action is
`an unportant consideration. How
`mut
`time elapses before the drug
`becomes effecti\·e. and when do the
`effects wear off? As discussed by D r
`Gephart, ADHD lasts all day, and
`
`MANAG ING ADI-ID
`
`management should extend beyond
`the school hours.
`Sculpting the dose of the stimu(cid:173)
`lants can be accompl ished in several
`ways (Figure 1).11 For example, if a
`patients needs 16 hours of coverage
`throughout the day, 2 doses of
`Metadate will last about 16 hours.
`Whereas the I 0- to 12-hour coverage
`of other sustained-release stimulants
`may be adequate for some children,
`some may require the addition of a
`short-acting stimulant, such as Focal in
`or MPH, at the end of the day, when
`homework is being done.
`
`0'1srt:\llLANT THERAPY
`A tomoxetine selectively blocks
`the reuptake of norepinephrine. As
`such. its pharmacokinetic profile dif(cid:173)
`fers from that of stimulants, and ato(cid:173)
`moxerine is not a Schedule fl class
`drug. Whereas the stimulants take
`effect
`immediately,
`the onset of
`action of atomoxetine is more grad(cid:173)
`ual, \\ith full therapeutic effect some(cid:173)
`times occurring 4 to 5 weeks after
`initiating therapy. Its mechanism of
`action makes it an unl ikely candidate
`for abuse.1• Duration of efficacy is an
`even stronger advantage, as atomoxe(cid:173)
`tine bas demonstrated symptom con(cid:173)
`throughout the waking day
`trol
`(Figure 2). ' M Still , the medication is
`
`Figure 1. Optimi:ing Response to Stimulants
`
`IR= 4 hours
`
`Metadate CO= 6-8 hours
`
`Ritalin LA = 8 hours
`Concerta/Adderall XR = 10-12 hours
`
`In general, use extended-release formulations
`•
`• Give first dose as early as possible in morning
`Increase dose to ensure maximum benefit
`•
`• Sculpt the dose
`- Give IR 3 limes daily
`- Give Metadate CD or Ritalin LA twice daily
`- Give IR early morning and Concerta/Adderall XR around noon
`- Give Concerta/Adderall XR early and IR around 6 PM
`
`IR = immediate release.
`Data from Greenhill et al."
`
`Advanced Studies in Medicine •
`
`5163
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`Page 2 of 4
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`

`MANAGING ADHD
`
`not a panacea; reported side effects
`include gastrointestinal upset and
`tiredness.
`Atomoxetine appears to have bene(cid:173)
`fits into the evening and next morning,
`with positive impact on evening activi(cid:173)
`ties, including completing homework,
`settling at bedtime, and arguing. "
`Morning symptoms were also signifi(cid:173)
`cant!)
`improved with atomoxetine
`compared with MPH taken 3 times
`daily.'0 These initial findings of benefit
`in the morning and evening warrant
`further investigation, as does the effica(cid:173)
`cy ofatomoxetine compared with stim(cid:173)
`ulant therapy.
`
`0PTIM/Z/VG RESPO/\'SE
`TO ATr ro 7 \'E
`Although once-daily dosing is rec(cid:173)
`ommended for atomoxetine, early clin(cid:173)
`ical trials \~ere of twice-daily dosing.
`Therefore, if patients taking atomoxe(cid:173)
`tine once daily experience tolerability
`problems, atomoxetine may be taken
`twice daily. The recommended starting
`dose is 0.5 mg/kg, given with food. then
`increased to 1.2 mg/kg for 2 weeks. The
`maximum approved dose is 1.4 mg/kg.
`A therapeutic trial of drug efficacy
`should be undertaken for at least 4
`weeks. Consider cross-tapering if the
`
`patient is taking a stimulant. Some
`clinicians have found it useful to use a
`cross-titration (ie, cutting the dose of
`the stimulant in half) for a couple of
`weeks while ascending dose titration of
`atomoxetine. Somnolence associated
`with atomoxetine can be managed by
`dosing the medication following the
`evening meal.
`
`Tl R L ' 0FTIO.\
`St '(
`Several antidepressants have been
`utilized in the treatment of ADHD,
`although none of them are appro\·ed
`by the US Food and Drug Admin(cid:173)
`istration for this indication. The tri(cid:173)
`C)dic antidepressants are sometimes
`used in treatment of ADHD but
`would not be used as a first-line agent
`due to the side-effect profile. "hich
`includes concerns regardin11 card1.ic
`side effects.21 Bupropion has been
`shown to pro\·ide benefit tvr youths as
`well as adults with ADHD. but the e\•i(cid:173)
`dence is weak and w0 ll-controlled trials
`of this medi
`tioL. ha\'e not been pub(cid:173)
`lished. Bup p11. u does have the possi(cid:173)
`bility of mducing
`seizures
`in
`SUSCE'p ible patients.~ It appears that
`monoamine oxidase inhibitors can
`reduce symptoms of ADHD as well,:J~•
`but these drugs are rarely used for this
`
`Figure 2. Stimulants vs Ato ,,,-
`
`• ttrfe Duratl~ of Effect on ADHD Symptoms
`:"," "
`
`MPH (IR), D·AMPH
`
`Mixed AMPH salts (IR)
`
`Combined MPH IR and ER beads
`
`MPH (long acting)
`
`MPH (osmotic release)
`
`Mixed AMPH salts (ER)
`
`School
`
`6 AM 8 AM
`Noon
`0 Preliminary data
`
`Social Home Bedtime
`Self
`6 PM
`
`12 AM
`
`MPH = methylphenidate; IR = immediate release; D-AMPH = dextroamphetamine, ER = extended release.
`AMPH = amphetamine.
`Data from Wilens et al"; Biederman et al'~ Michelson et al"; Kelsey et al."
`
`indication because dietal) restrictions
`are significant and the risk exists for
`cardiac crisis.
`
`CONCLl'SION
`ADHD can be effectively treated
`utilizing stimulant and nonstimulant
`medications. Because ADHD symp(cid:173)
`toms can cause impairment throughout
`the day and over the lifetime, we must
`utilize pharmacologic and behavioral
`treatments that these patients need.
`
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`5 165
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`