Review of ADHD Pharmacotherapies

Review of ADHD Pharmacotherapies: Advantages,Disadvantages, and Clinical Pearls

JOAN M. DAUGHTON, M.D., AND CHRISTOPHER J. KRATOCHVIL, M.D.

Pharmacotherapy for the treatment of attention-deficit/hyperactivity disorder (ADHD) originally consistedprimarily of stimulant medications in immediate-releasepreparations dosed multiple times per day. Data dem-onstrating the efficacy of these stimulant medications forthe treatment of ADHD and their role in treatingchildren was well established by the 1970s. Multipleformulations of the stimulant medications have subse-quently been developed during the past 40 years.Recent studies, including the NIMH CollaborativeMultisite Multimodal Treatment Study of ChildrenWith Attention-Deficit/Hyperactivity Disorder andthe Preschool ADHD Treatment Study, have helpedto clarify the role of stimulant medications in thetreatment of ADHD.1Y5 Significant data supportingthe use of nonstimulant pharmacotherapy have alsoemerged in the last decade.1 This review summarizesthe recent advances in ADHD treatment, providingadvantages, disadvantages, and clinical pearls for the useof these treatments.

SHORT-ACTING STIMULANT PREPARATIONS

Advantages: The stimulant medications have anextensive database supporting their safety, robustefficacy, and rapid onset of action. Studies of thestimulant medications have consistently shown thatapproximately two of every three patients treated withstimulants respond, with an effect size generally cited ataround 1.0.3 Their absorption is rapid, with clinicaleffects noticeable as early as 30 minutes after ingestion.

Disadvantages: The shorter duration of action limitsconsistent efficacy as well as compliance because thesemedications must be taken two to three times daily.

Helpful Hints:

In medications containing only the methylphenidated-enantiomer (e.g., d-methylphenidate [Focalin]), a50% reduction in dose may be needed compared withmethylphenidate products containing both the d- andl-isomers (methylphenidate [Ritalin]). Adderall con-tains d-amphetamine and l-amphetamine salts in theratio of 3:1; however, no recommendations are madefor converting the dosing of Adderall to a productcontaining only d-amphetamine (d-amphetamine[Dexedrine]).1

One immediate-release methylphenidate product(Methylin) is available as chewable tablets as well asan oral solution, for children who have difficultyswallowing pills or capsules.

Growth should be regularly monitored duringtreatment with stimulants because data from severalstudies suggest that, as a group, consistently med-icated children have a temporary modest slowing ingrowth rate while taking stimulant medication.1Y4,6

Blood pressure and heart rate should be monitoredbefore and during stimulant treatment for everypatient. In addition to an individual and family health

Psychopharmacology Perspectives aims to discuss practical approaches toeveryday issues in pediatric pharmacotherapy. The discussions may address aspectsof clinical care related to psychopharmacology for which we do not have ade-quate applicable controlled trials, and includes discussions that are "off-label"from the perspective of the U.S. Food and Drug Administration. Although wefully appreciate that for virtually all disorders, medication is only one aspect ofcomprehensive care, this column focuses primarily on psychopharmacologicalmanagement. These are not meant to be practice guidelines, but rather examplesof the thought process that may go into pharmacotherapy decision making.

Accepted November 23, 2008.Drs. Daughton and Kratochvil are with the University of Nebraska Medical

Center.Correspondence to Joan Daughton, M.D., 985584 Nebraska Medical Center,

Omaha, NE 68198-5584; e-mail: [email protected]/09/4803-02402009 by the American Academy of Child and

Adolescent Psychiatry.DOI: 10.1097/CHI.0b013e318197748f

Assistant EditorP S Y C H O P H A R M A C O L O G Y P E R S P E C T I V E S Christopher J. Kratochvil, M.D.

240 WWW.JAACAP.COM J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 48:3, MARCH 2009

history, inquiries should be made regarding a historyof severe heart palpitations, fainting, exercise intoler-ance, chest pain, or family history of sudden death. Aphysical examination focused on signs of cardiovas-cular disease should be performed before initiatingtreatment as well.

Consultation with a cardiologist is recommended ifstimulants are considered a clinically necessary in-tervention in patients with cardiomyopathy, seriousheart rhythm abnormalities, or other serious cardiacproblems because sudden death has been reportedin patients with these conditions. The recent jointadvisory of the American Academy of Pediatricsand the American Heart Association recommendsobtaining an electrocardiogram as part of the eval-uation of patients with serious cardiac problems whoare being considered for ADHD pharmacotherapy.6

When to Use:

Short-acting stimulants may be used as initial treat-ment in children weighing less than 16 kg, for whomsufficiently low doses do not exist in a long-actingform.3

A short-acting medication can be useful as anadditional treatment when used in conjunction witha long-acting stimulant. For example, early afternoonis often when a long-acting medications effects arestarting to wear off, and a short-acting medication canbe given to resolve ADHD symptoms during home-work time or other after-school activities that requirefocus and concentration. Similarly, a short-actingmedication can be given upon awakening to helpreduce ADHD symptoms during the morningroutine and allow the long-acting medication to begiven before leaving for school to increase thelikelihood of its duration of action lasting throughoutthe school day.

Inexpensive generic formulations of the immediate-release stimulants are available (Fig. 1).7 Table 1summarizes the short-acting methylphenidate andamphetamine Food and Drug Administration(FDA)Yapproved treatments for ADHD.

LONG-ACTING STIMULANT PREPARATIONS: PULSE,PEARLS, PUMP, PATCH, AND PRODRUG

Table 2 summarizes the long-acting methylpheni-date and amphetamine FDA-approved treatments forADHD.

Advantages: The longer acting stimulants are equallyas efficacious as the short-acting stimulants and providea longer effective response that limits the need formultiple daily doses. This also decreases the stigma ofhaving to receive medications within the school setting.

Disadvantages: Because of their longer duration ofaction, if side effects do emerge, they may extend laterinto the day. Cost is an important consideration whenchoosing a medication, and many of the extended-release medications are more expensive. A cost compar-ison between all FDA-approved ADHD medicationscan be found in Figure 1.

Helpful Hints:

One of the differences between the various long-acting stimulant medications is the duration of action(Table 2), which can be helpful in tailoring treatmentfor each patient.

The long-acting stimulant medications require thesame caution as short-acting stimulants in regard tocardiac as well as growth problems.

When to Use:

The long-acting stimulant preparations are consid-ered first-line treatments for ADHD. Either themethylphenidate or the amphetamine class may beused because they have equal efficacy and similarside-effect profiles.8,9

Pulse

Single-pulse sustained-release methylphenidateproducts include Ritalin SR, Metadate ER, andMethylin ER.

Helpful Hint:

These wax-matrix products must be swallowed wholeto retain the long-acting properties.

Pearls

These bead-filled capsules generally contain half thedose as immediate-release beads and half as enteric-coated delayed-release beads. This mimics the use of twodoses of immediate-release medication dosed 4 hoursapart. Products using this general type of technologyinclude Dexedrine Spansule, Ritalin LA, Focalin XR,Adderall XR, and Metadate CD. Metadate CD isslightly different from the other beaded formulations in

PSYCHOPHARMACOLOGY PERSPECTIVES

WWW.JAACAP.COM 241J . AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 48:3, MARCH 2009

that 30% of the beads are immediately released, and70% are released 3 hours later.

Helpful Hint:

The beaded formulations may be helpful for childrenwho have difficulty swallowing pills because thecapsules may be opened and the beads sprinkled into

applesauce, yogurt, or other soft foods. The beadsshould not be chewed.

Pump

The osmotic-release oral system methylphenidatecapsule (Concerta) uses an osmotic delivery system inwhich the tablet is coated with a 22% immediate-releasemethylphenidate for initial dosing. The long-duration

Fig. 1 Cost comparison of Food and Drug AdministrationYapproved medications for attention-deficit/hyperactivity disorder.

DAUGHTON AND KRATOCHVIL


component is delivered by an osmotic pump (osmotic-release oral system) that gradually releases methylphe-nidate producing an ascending serum concentrationcurve to approximate a three-times-daily dosingschedule.

Helpful Hints:

This capsule should not be opened or chewed. Clinicians should notify parents and youths that thecapsule is passed through the gastrointestinal tractand into the stool intact.

Children with reduced gastrointestinal absorption orintestinal resections may not receive the full benefitfrom this medication because of decreased absorptionor transit time.

Patch

The transdermal delivery system for methylphenidate(Daytrana) contains methylphenidate in a multipoly-meric adhesive layer attached to a transparent backing.Methylphenidate is steadily absorbed after application ofthe patch, but levels do not peak until 7 to 9 hours later,with a noticeable reduction of symptoms by the end ofthe first 2 hours. Mild skin reactions to the patch arecommon, and insomnia is often reported when wornfor more than 9 hours.

Helpful Hints:

The patch may be particularly useful for those whocannot swallow pills and are unable to tolerate the oralform or for those requiring more flexible durationof dosing.

More methylphenidate is bioavailable because thedrug does not go through first-pass metabolism.

Although this methylphenidate preparation is re-commended to be worn for 9 hours, a recent studysuggests that the duration of the effect on ADHDsymptoms is related to the amount of time the patchis worn such that early removal of the patch allows fora controlled duration, ending approximately 2 to3 hours after the patch is removed.

Prodrug

Lisdexamfetamine dimesylate (Vyvanse) is a thera-peutically inactive prodrug in which d-amphetamine ispharmacologically activated after oral ingestion. Thismedication has been shown in two recent studies to bewell tolerated, effective, and long-lasting (10 hours).

TABLE1

FDA-ApprovedShort-ActingStim

ulantADHD

Pharmacotherapies

Medication(Trade

Nam

e)Modeof

Delivery

FDA

Approval

Generic

Available

Preparations

Doses,m

gTypicalStartin

gDose3

Maxim

umDose

PerDay

Durationof

Action,

h

Methylphenidate(Ritalin)

Immediaterelease

Age

Q6Yes

Tablet

5,10,2

05mg

60mg

4Methylphenidate

(Methylin)

Immediaterelease

Age

Q6No

Tablet,chew

able

tablet,solution

5,10,2

0tablets2.5,

5,10

chew

abletablet,

5mg/5mLand

10mg/5mLsolutio

n

5mg

Lesser

of2mg/kg/

dayor

60mg

4

d-Methylphenidate

(Focalin)

Immediaterelease

Ages6Y17

Yes

Tablet

2.5,

5,10

2.5mgb.i.d

.Lesser

of1mg/kg/

dayor

20mg

4

Mixed

amphetam

ine

salts

(Adderall)

Immediaterelease

Age

Q3Yes

Tablet

5,7.5,

10,1

2.5,

15,2

0,30

3Y5y:2.5mgq.d.;

Q6y:5mgq.d.

tob.i.d.

Lesser

of1mg/kg/

dayor

40mg

4

Amphetam

ine

(Dexedrine)

Immediaterelease

Age

Q3Yes

Tablet

52.5mgq.d.

40mg

4

Amphetam

ine

(Dextrostat)

Immediaterelease

Age

Q6Yes

Tablet

5,10

5mgq.d.

tob.i.d.

40mg

4

Note:ADHD

=attention-deficit/hyperactivity

disorder;F

DA=Food

andDrugAdm

inistration;

q.d.

=medicationdelivered

once

perday.



TABLE2

FDA-ApprovedLo

ng-ActingStim

ulantADHD

Pharmacotherapies

Medication(Trade

Nam

e)Modeof

Delivery

FDA

Approval

Generic

Available

Preparations

Doses,m

g

Typical

Startin

gDose3

Maxim

umDose

PerDay

Duration

ofAction

Methylphenidate

(Ritalin

SR)V

pulse

Graduallyreleased

from

wax

matrix

Age

Q6No

Tablet

2010

mg

60mg

Upto

8h

Methylphenidate

(MetadateER)V

pulse

Graduallyreleased

from

wax

matrix

Age

Q6No

Tablet

10,2

010

mg

Lesser

than

2mg/kg/day

or60

mg

7Y8h

Methylphenidate

(Methylin

ER)V

pulse

Graduallyreleased

from

wax

matrix

Age

Q6No

Tablet

10,2

010

mg

60mg

7Y8h

Methylphenidate

(MetadateCD)V

pearls

BeadeddeliverysystemV30%

immediatereleaseand70%

3hlater

Age

Q6No

Capsule(m

aybe

opened

and

sprinkled)

10,20,30,40,50,60

20mg

Lesser

than

2mg/kg/day

or60

mg

8Y9h1

Methylphenidate

(Ritalin

LA)V

pearls



4hlater

Age

Q6No

Capsule(m

aybe

opened

and

sprinkled)

10,2

0,30,4

020

mg

60mg

7Y9h1

d-Methylphenidate

(Focalin

XR)V

pearls



4hlater

Age

Q6No

Capsule

5,10,1

5,20

5mg

Lesser

than

1mg/kg/day

or30

mg

Upto

12h

Methylphenidate

(Concerta)Vpump

OROSdeliverysystemV18%

immediatereleaseoutercoating

and82%

gradually

released

osmotically;d

esignedto

replicatet.i.d.immediaterelease

Age

Q6No

Tablet

18,2

7,36,5

418

mg

Lesser

than

2mg/kg/day

or72

mg

Upto

12h

Methylphenidate

(Daytrana)Vpatch

Patchwornup

to9hperday,

gradually

releasing

methylphenidate

Ages6Y12

No

Transderm

alfilm

10,1

5,20,3

010

mg

Lesser

than

1mg/kg/day

or30

mg

12h

Mixed

amphetam

inesalts

(AdderallX

R)V

pearls



4hlater

Age

Q6No

Capsule(m

aybe

opened

and

sprinkled)

5,10,1

5,20,2

5,30

10mgq.d.

Lesser

than

1.0mg/kg

or30

mg

10h

Amphetam

ine(D

exedrine

Spansule)V

pearls

BeadeddeliverysystemVinitial

dose

released

immediatelyand

remaind

ergradually

released

Age

Q6No

Capsule

5,10,1

55Y10

mgq.d.

tob.i.d.

Lesser

than

1.0mg/kg

or40

mg

10h

Lisdexam

fetamine

(Vyvanse)V

prodrug

Amphetam

inewith

lysine

attached,

activated

ingastrointestinal

tractwhenlysine

iscleaved

Ages6Y12

andadults

No

Capsule

20,30,40,50,60,70

30mgq.d.

Lesser

than

1.0mg/kg

or70

mg

10h

Note:ADHD

=attention-deficit/hyperactivity

disorder;F

DA=Food

andDrugAdm

inistration;

OROS=osmotic-releaseoralsystem

;q.d.=

medicationdelivered

once

perday.

DAUGHTON AND KRATOCHVIL


Helpful Hint: It is hypothesized that this medication may beassociated with diminished risk for abuse because ofits decreased and/or delayed release after intravenous orintranasal administration and delayed blood level spikeafter ingestion, decreasing any immediate effects.

NONSTIMULANT PREPARATIONS

One overall advantage of nonstimulant medications isthe decreased substance abuse liability.

Atomoxetine

Atomoxetine (Strattera) is a nonstimulant approvedby the FDA for the treatment of ADHD (Table 3). Itworks by blocking presynaptic uptake at noradrenergicneurons. Atomoxetine is well absorbed after oral ad-ministration and is metabolized primarily through thecytochrome P450 2D6 (CYP2D6) pathway.

Advantages: Possible advantages of atomoxetine overstimulants include a lower potential for abuse, long-lasting therapeutic effects, and the fact that it is not acontrolled substance.

Disadvantages: The efficacy of atomoxetine seemsto be less than that of the stimulants. In one meta-analysis,8 atomoxetines effect size was 0.62, in com-parison to 0.91 for immediate-release stimulants and0.95 for sustained-release stimulants. Furthermore, theinitial therapeutic effects of atomoxetine are gradual,developing a peak efficacy during 2 to 6 weeks. Ato-moxetine holds a bolded warning for increased poten-tial for suicidal ideation, at a rate of 3.7 cases per 1,000children compared with none in placebo-treated chil-dren. Patients and their families should be educated

about this risk, and patients should be monitored closelyfor suicidality during the first few months of treatmentand during any dose changes. There is another boldedFDA warning stating atomoxetine should be discon-tinued if a patient develops jaundice or laboratory evi-dence of liver injury develops. Although no reports ofliver injury occurred during clinical trials with atomo-xetine, liver injury recurred on rechallenge in onepatient and is likely a rare side effect of the drug.Studies show acute growth effects but limited long-

term effects on growth parameters with atomoxetine.1Y3

Helpful Hints:

Taking atomoxetine with food may help to avoid thecommon side effects of nausea or upset stomach.

Dosing may be started as a split dose or initially givennear bedtime to diminish the effects of tiredness ordrowsiness, which is more apt to be present duringinitiation and titration of the medication.

Doses of atomoxetine should initially be reduced ifadministered with agents that inhibit the cytochromeP450 2D6,(CYP2D6) enzyme, such as paroxetine orfluoxetine, because of the potential for significantincreases in atomoxetine blood levels.

When to Use:

In general, atomoxetine is considered after trials ofmethylphenidate and amphetamine have been inef-fective or poorly tolerated.

Atomoxetine may be first-line treatment in childrenwith a history of substance abuse or dependence andwith significant anxiety symptoms or based on familypreference.

TABLE 3FDA-Approved Nonstimulant ADHD Pharmacotherapy

Medication(Trade Name) Mode of Delivery

FDAApproval Generic

AvailablePreparations Doses, mg

Typical StartingDose3

MaximumDose PerDay

Atomoxetine(Strattera)

Immediate releaseVgenerallydosed q.d. but can bedosed b.i.d.

Age Q6 No Capsule 10, 18, 25, 40,60, 80, 100

TABLE4

NonYF

DA-ApprovedMedications

Usedin

ADHD

Pharmacotherapy

Medication

(Trade

Nam

e)Modeof

Delivery

FDAApproval

Generic

Available

Preparations

Doses,m

gTypicalStartin

gDose3

Maxim

umDose

PerDay

Bupropion

(Wellbutrin/

Zyban)

Immediaterelease

No

Yes

Film

-coatedtablet

75,1

00Lesserthan

3mg/kg

or150mg/day

Lesser

than

6mg/kg

or300mg/day

(nosingledose

9150mg)

Bupropion

SRTypicallydosedb.i.d.;

mim

icsbupropion

giventhree

times

daily

No

Yes

Film

-coatedtablet

100,

150,

200

Lesserthan

3mg/kg

or150mg/day

Lesser

than

6mg/kg

or300mg/day

(nosingledose

9150mg)

Bupropion

XL

Typicallydosedq.d.;

mim

icsbupropion

t.i.d.and

bupropion

SRb.i.d.d

osing

No

Yes

Tablet

150,

300

Lesserthan

3mg/kg

or150mg/day

Lesser

than

6mg/kg

or300mg/day

(nosingledose

9150mg)

Modafinil

(Provigil)

Immediaterelease;

q.d.

dosing

NoV

concerns

ofrash

characteristicof

Stevens-John

son

synd

rome

No

Tablet

100,

200

Unknown

200mg

Guanfacine

(Tenex)

Resultsseen

with

in1wk

Approvabilityletter

received

Yes

Tablet

1,2

See Table 4 for all nonYFDA-approved medications. SeeFigure 2 for a cost comparison for all nonYFDA-approved medications summarized below.

Alpha Agonists (Not FDA Approved for ADHD)

Clonidine (Catapres) and guanfacine (Tenex) arealpha agonists, which seem to stimulate inhibitorypresynaptic autoreceptors in the central nervous systemat lower doses. They have demonstrated use alone orin combination with stimulants.1

Advantages: The alpha agonists may be useful for coresymptoms of ADHD, as well as associated sleep and ticdisorders.

Disadvantages: Their half-lives may necessitate multi-ple daily doses. Because of their antihypertensive proper-ties, use of these medications may lead to hypotensionand orthostasis. There have been several case reports ofunexpected sudden death in children taking the com-bination of clonidine and methylphenidate, although acontrolled study of the combination of these twomedications found no evidence of cardiac toxicity.

Helpful Hints:

Clonidine is available in a patch, allowing once-dailydosing.

An extended-release guanfacine preparation hasrecently received a letter of approvability by the FDA.

When to Use: Their current role in the treatment ofADHD is primarily as adjunctive medication in thosepatients who do not respond to and/or those whocannot tolerate the FDA-approved treatments.

Bupropion (Not FDA Approved for ADHD)

Bupropion (Wellbutrin, Wellbutrin SR, and Well-butrin XL) is an antidepressant that acts via dopamineand norepinephrine.

Advantages: Although its therapeutic effect seems to beless than that of stimulants or atomoxetine, it does havedemonstrated efficacy in the treatment of ADHD.3

Disadvantages: Common side effects include ir-ritability, anorexia, insomnia, and, less commonly,development of tics. The risk for drug-inducedseizures increases 10-fold at dosages greater than450 mg/day.

Helpful Hint:

It is also approved for smoking cessation (Zyban).

When to Use:

This is another medication that is primarily adjunc-tive treatment or after first-line treatments have failed.

Fig. 2 Cost comparison of nonYFood and Drug AdministrationYapproved medications.



It may have a role in patients with co-occurring mooddisorders, substance abuse, or smoking.

NONYFDA-APPROVED STIMULANT

Modafinil (Provigil) is an antinarcoleptic stimulantagent that is believed to produce a wakeful effect byactivating the cortex and may be useful for enhancinggeneral arousal, attention, and motivation.

Advantages: Modafinil demonstrated efficacy in threedouble-blind placebo-controlled studies of ADHD inchildren.

Disadvantages: Commonly reported side effects in-clude insomnia, decreased appetite, and headache. Thismedication was not approved by the FDA for thetreatment of ADHD because, at least in part, of safetyconcerns about a rare but serious rash (e.g., erythemamultiforme) characteristic of Stevens-Johnson syn-drome.1 Lastly, the cost of this medication often li-mits its use.

Helpful Hint:

Studies have shown increased efficacy doses in therange of 340 to 425 mg/day.

When to Use:

This medication, if used at all, should be used withgreat caution because of the risk for Stevens-JohnsonYlike rash.

RESOURCES

Parents and Clinicians

http://www.Chadd.orghttp://www.cdc.gov/ncbddd/adhd/

Parents

http://www.nimh.nih.gov/health/publications/adhd/complete-publication.shtml

http://www.parentsmedguide.com/pmg_adhd.html

Clinicians

http://www.massgeneral.org/schoolpsychiatry/screeningtools_table.asp

DISCUSSION

1. Short-acting stimulant medications may be useful inlower weight children, in conjunction with a long-acting stimulant, and when cost is a limiting factor.

2. Differences between long-acting stimulant prepara-tions that influence treatment planning include du-ration of action, cost, ability for children to swallowpills, and abuse risk.

3. Nonstimulant medications are effective as primary aswell as adjunctive treatments for ADHD.

4. NonYFDA-approved medications can be used effec-tively and safely as adjunctive treatments for ADHDor when first-line treatments have failed.

5. Awareness of the various characteristics of eachmedication that has been studied in the treatment ofADHD allows for optimal care for each individualpatient.

Disclosure: Dr. Kratochvil receives research funding from NIMHGrant 5K23MH06612701A1. He receives grant support from EliLilly, McNeil, Shire, Abbott, Somerset, and Cephalon; is a consultantfor Eli Lilly, AstraZeneca, Abbott, and Pfizer. He is the editor of theBrownUniversity Child & Adolescent Psychopharmacology Update,a member of the REACH Institute Primary Pediatric Psycho-pharmacology Steering Committee, a member of the American Profes-sional Society for ADHD and Related Disorders Board of Directors,and on the CME Outfitters Professional Advisory Board. He receivesstudy drugs for an NIMH-funded study from Eli Lilly. The otherauthor reports no conflicts of interest.

REFERENCES

1. Beiderman J, Spencer TJ. Psychopharmacological interventions. ChildAdolesc Psychiatric Clin N Am. 2008;17:439Y458.

2. American Academy of Pediatrics Committee on Quality Improvementand Subcommittee on Attention-Deficit/Hyperactivity Disorder. Treat-ment of attention deficit/hyperactivity disorder: overview of the evidence.Pediatrics. 2005;115:e749Ye757 (doi:10.1542/peds.2004

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Review of ADHD Pharmacotherapies