NIH Public Access
`g Author Manuscript
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`0' 'HEPs
`Published in final edited form as:
`J Child Psychol Psychiatry. 2009 January ; 50(1 -2): 180 -193. doi:10.1111 /j.1469- 7610.2008.02062.x.
`
`_.t- _,, aIkLb e n P\'lk: 2 (J i (} January
`
`Psychopharmacology: concepts and opinions about the use of
`stimulant medications
`
`James M. Swanson and Nora D. Volkow
`
`This `perspective piece' on the topic of psychopharmacology was requested to be opinion -
`driven and conceptual in nature, rather than a systematic review or a state -of- the -science article.
`Recently we (Volkow & Swanson, 2008a) adopted a broad approach to address multiple classes
`of psychotropic medication used to treat children (stimulants, anti -depressants, and anti -
`psychotics). We provided examples from traditional clinical pharmacology to discuss their
`pharamacokinetic (PK) and pharmacodynamic (PD) properties, as well as examples from
`modern positron emission tomography (PET) brain imaging to characterize the time course of
`drug effects at the primary cellular sites of action in the brain (transporters, enzymes, and
`receptors). Rather than repeat this broad approach here, we will provide a narrow, opinion -
`driven, and conceptual review of one of these classes - stimulant medication - that has been
`used primarily for the treatment of children with attention deficit hyperactivity disorder
`(ADHD) and hyperkinetic disorder (HKD) and recently has shown dramatic increases (see
`Swanson & Volkow, 2008) for the treatment of adolescents and adults. To narrow the scope
`further, we will focus on established concepts that have been challenged in the literature over
`the past decade (from 1998 to 2008). As requested, we will focus on personal experiences in
`research related to these concepts to highlight the historical context and some changes in
`clinical psychopharmacology over the past decade.
`
`The literature on effects of the stimulant medications amphetamine (AMP) and
`methylphenidate (MPH) for the treatment of ADHD and HKD is enormous and increasing.
`However, the fundamental clinical effects of AMP were well described initially by Bradley
`(1937, 1950) over a half century ago and later by many investigators (including by Weiss,
`Werry, Minde, Douglas, & Sykes, 1968 in this journal), and the fundamental behavioral and
`cognitive effects of MPH were described initially by Conners and Eisenberg (1963) over 40
`years ago and later by many investigators including by Taylor et al. (1977) and in this journal
`by Douglas et al. (1986).
`
`Many reviews have been published to summarize the plethora of studies that followed,
`including influential early reviews in this journal (see Barkley, 1977) and from the European
`perspective by Taylor (1979) and in this journal by Bramble (2003). All seem to reach about
`the same basic conclusions about the effects of AMP and MPH that were reported in these
`initial studies. Fifteen years ago these were summarized by Swanson et al. (1993) in a `review
`of reviews' that suggested what should be expected (e.g., short -term reduction in symptoms
`of ADHD and associated features of opposition and aggression) and what should not be
`expected (long -term benefits, absence of side effects, paradoxical response, large effect on
`higher -order processes). Almost a decade later, this was reinforced by Conners (2002), who
`concluded that the `effects of stimulants are consistent over time despite changes in diagnosis,
`
`Correspondence to: James M. Swanson, Child Development Center Irvine, The Child Development Center, 19722 Mac -Arthur Boulevard,
`Irvine, California 92612; United States; Email address: E -mail: jmswanson @uci.edu.
`Conflict of interest statement: James M. Swanson has received honoraria for lectures from J & J Jassen- Ortho, Inc., UCB Pharma Ltd
`and Convention Likage Inc., and consulting fees from NV Organon.
`
`EXHIBIT
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`DATE:
`DEBRA STEVENS,
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`assessment instrument, and research methodology' (p. S29). So, what new concepts and
`controversial questions will be addressed here?
`
`Over the past decade there have been some major changes in how the stimulants are used in
`clinical practice, as well as some major controversies about the fundamental pharmacological
`and neurochemical processes underlying the action of stimulant medications. For our opinion -
`driven article we selected five controversial questions to address: (1) How has clinical
`pharmacology been used to direct major changes in clinical practice? (2) How have new
`findings from PET imaging studies changed the understanding of the neural effects of stimulant
`medications and the brain -basis for ADHD? (3) How have long-term outcomes in large -scale
`clinical trials changed the rationale for treatment with stimulant medications? (4) How has the
`continued increase in use of stimulants for treatment altered concern about misuse of stimulant
`medication? (5) How has industry- sponsored research altered the clinical practice of treatment
`of individuals with stimulant medication?
`
`After addressing these five concepts, we will update expectations about the use of stimulant
`medications in 2008, discuss the impact of current expectations of the rationale for and clinical
`practice of using stimulant medications in the treatment of ADHD and HKD, and offer some
`conclusions based on personal experiences in these areas of research on psychopharmacology.
`
`Controversial concepts and questions
`1. How has clinical pharmacology been used to direct major changes in clinical practice?
`Changes have occurred in clinical practice since the beginning. The initial clinical practice
`described by Bradley in 1937 was based on the use of the racemic formulation of AMP
`(Benzedrine)), which was marketed by Smith, Kline andTrench in 1936, but by 1950 this
`shifted to the use of the pure d- isomer of AMP (Dexedrine ®) that could be used at lower doses,
`which was marketed in 1949. By the 1970s, clinical practice had shifted again to the use of a
`different drug, MPH (Ritalin ®), which was developed by CIBA pharmaceutical and received
`FDA approval in 1960. In 1994, there was an attempt to revive of use of AMP, but this was
`not successful initially. Richwood Pharmaceuticals tried to market a formulation of AMP
`developed by Rexar Pharmaceuticals and approved for appetite control in 1960 (Obetrol ®, a
`racemic 75:25 mixture of the d -AMP and 1 -AMP optical isomers), with a new name
`(Adderall ®). One of the claims was that Adderall® was a unique alternative and long- acting
`stimulant that could be given once a day and thus avoid in- school dosing (see full page
`advertisement in the Journal of the American Academy of Child and Adolescent Psychiatry,
`November, 1994). The evidence for this was apparently based on `some physician's testimony
`as to special benefit in a segment of ADHD patients' (see FDA Minutes of Meeting, NDA 11-
`522, 1995), which was challenged by the FDA. An earlier FDA review (see Federal Register,
`1973) found insufficient evidence of efficacy and safety of this drug despite the approval before
`modern guidelines were in place. However, after negotiation with the FDA, Richwood
`Pharmaceutical received re- approval in 1996 to market Adderall® for the treatment of ADHD,
`even though there were no controlled trials of the effects on children with ADHD.
`
`This called for clinical pharmacological studies to document under double -blind conditions
`the PK and PD effects of Adderall®. Richwood Pharmaceuticals funded the first controlled
`studies, which utilized the laboratory school paradigm and surrogate measures of response to
`compare the duration of action of immediate release (IR) formulations of AMP (Adderall ®)
`and MPH (Ritalin ®) in small groups of children with ADHD. One of these studies confirmed
`the claim of equal efficacy (maximum effect after an acute dose) and different PD half -lives
`for Adderall® (6 hours) and Ritalin® (4 hours) (Swanson et al., 1998). The other with just 21
`children confirmed equivalence of efficacy of comparable multiple dose regimes for IR
`formulations with different PD half -lives (i.e., BID Adderall® and TID Ritalin® regimes)
`
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`(Pelham et al., 1999). Additional controlled research in naturalistic settings of the home and
`school confirmed these laboratory studies. As shown in Figure 1 a, there was a dramatic increase
`in prescriptions for IR AMP starting in 1998 that by 2000 remarkably equaled the number of
`prescriptions for IR MPH. In 2000, Richwood Pharmaceuticals was acquired by Shire
`Pharmaceuticals, which had a larger sales force and increased the marketing of Adderall ®.
`
`The second major change in clinical practice was a shift from IR to controlled release (CR)
`formulations. One common limitation of Adderall® and Ritalin® was the relatively short
`duration of action of these IR formulations that required multiple doses to maintain full efficacy
`across the day. In the 1980s, first- generation CR formulations of AMP (Dexedrine
`Spansules ®) and MPH (Ritalin SR ®) were available, but they were considered to have lower
`efficacy than multiple -dose regimes of the IR formulations and thus were not widely adopted
`in clinical practice. The consensus opinion was that the stimulant drugs required bolus doses
`and a PK profile with peaks and valleys to produce and maintain clinical efficacy, which
`implied an inherent limitation on CR formulations.
`
`This also called for studies based on principles and techniques from clinical pharmacology. In
`a series of small studies funded by Alza Pharmaceuticals, Swanson et al. (1999) tested the
`bolus -dose assumption using the `sipping study' methodology in a small proof of concept study
`to consider another possible explanation for reduced efficacy of CR formulations - acute
`tolerance to stimulant medication. A laboratory school study of 29 children with ADHD
`showed that a zero -order smooth (flat) drug delivery profile was insufficient to maintain
`efficacy across the day compared to the standard BID regime of IR MPH, but that a first -order
`smooth (ascending) PK profile without a bolus could achieve the full efficacy of the bolus dose
`regime. PK/PD modeling (see Levy, 1994; Park et al., 1998) suggested that acute tolerance to
`MPH could account for this pattern of PD effects. This discovery led to the design of a new
`commercial product (Concerta ®) based on the osmotic release oral system (OROSR), which
`was modified to achieve the proposed optimum first -order (ascending) drug delivery profile.
`Concerta® was tested in proof of product studies in the laboratory classroom to document onset
`and duration of efficacy (see Pelham et al., 2002; Swanson et al., 2003). This was followed by
`typical multi -site clinical trials with much larger groups of subjects (see Swanson et al., 2000;
`Wolraich et al., 2001) considered necessary for submission to the FDA in order to document
`efficacy and safety and gain approval, which was granted in 2000. As shown in Figure lb,
`Concerta® had almost immediate acceptance in clinical practice when it was introduced and
`marketed in 2000. Prescriptions for CR MPH starting increasing then, and by 2002 the use of
`CR MPH virtually replaced IR MPH in clinical practice. In 2002, Alza Pharmaceuticals was
`acquired by Johnson & Johnson, which had a larger sales force and increased the marketing
`of Concerta®.
`
`To maintain competitiveness in the rapidly increasing market for stimulant drugs, Shire
`Pharmaceutical initiated a drug development program for CR AMP to match the predominant
`clinical regime of IR AMP (i.e., BID doses of Adderall ®) and achieve full efficacy across the
`day with once -a -day administration. PK studies in adults (see Tulloch et al., 2002) and children
`(see Greenhill et al., 2003) were conducted to guide this development, which revealed a 6 -hour
`PK half -life of a single dose of IR AMP and an ascending drug delivery profile associated with
`the BID regime of Adderall® with the doses given 4 hours apart. A dual -beaded drug delivery
`system was designed to match this ascending drug delivery profile, which was developed as a
`CR formulation called Adderall XR ®. Proof -of- product PK/PD studies confirmed efficacy and
`duration of action (see McCracken et al., 2003). Upon approval granted by the FDA in 2002,
`Adderall XR® also gained almost immediate acceptance in clinical practice, as reflected by
`the rapid increase in prescriptions shown in Figure lb.
`
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`In summary, two major changes in clinical practice occurred over the past decade in the USA
`(see Figure 1): the dramatic revival of AMP starting in 1998 and widespread acceptance of
`second -generation CR formulations of MPH and AMP starting in 2000. Both of these changes
`were stimulated by small studies based on principles of clinical pharmacology, with the latter
`based on PK/PD modeling and the hypothesis that predicted that smooth ascending PK profiles
`for once -a -day CR formulations would counteract acute tolerance and maintain full efficacy
`across the day.
`
`2. How have new findings from PET imaging changed the understanding of brain -basis for
`ADHD and the neural effects of stimulant medications?
`One of the first biochemical theories of ADHD was based on speculation about the
`neurochemical effects of the stimulants that produced rapid reduction of symptoms. Wender
`(1971) proposed the catecholamine deficit theory based in part on the belief that stimulants
`were catecholamine agonists that produced enhancement of NE and DA signals in the brain
`(see Solanto, 1998 for the history and early elaborations of this biochemical theory).
`
`One question about the neural mechanism of action of MPH revolved around its similarity to
`cocaine in site and primary mechanism of action, blockade of dopamine transporters (DAT)
`in the striatum, but without similar euphoric effects. The early studies by Volkow et al.
`(1995) clarified this by using PET imaging with radiolabeled MPH to document the PK
`properties of the drug in the human brain. MPH had a much longer brain PK half -life than
`cocaine, which resulted in persistence of high brain levels of MPH and thus prolonged high
`exposure after the peak concentration was achieved. Apparently this produced acute tolerance
`to the brain levels of MPH that initially produced euphoric effects after intravenous dosing.
`However, questions remained about oral doses of MPH, which historically had been considered
`to produce a weak stimulant effect, which was assumed to be because rapid peripheral
`metabolism prevented high brain concentrations of the drug. Volkow et al. (1998, 2002)
`performed PET studies to estimate the neural effects of oral MPH doses on occupancy of DAT,
`and documented that on the average 80% of transporters in the striatum were blocked in adults
`by oral dose less than 1.0 mg /kg. This level of DAT blockade by an oral dose in the clinical
`range was as great as for intravenous doses of MPH or cocaine. This supported the hypothesis
`that differences in the euphoric effects of these two drugs were due to differences in their brain
`PK properties (and the presence of acute tolerance related to the extended presence of high
`concentrations of MPH in the brain), rather than to low concentrations of MPH at the neural
`site of action.
`
`PET methods have also been used to investigate possible biological markers for ADHD. An
`exceedingly influential study by Dougherty et al. (1999) was based on the use of Single Photon
`Emission Computed Tomography (SPECT), a low resolution alternative to PET, and a new
`radioligand (iodine -23- labeled altropane) to estimate the density of DAT in the basal ganglia
`of the brain. A study of 6 adults with ADHD suggested that DAT density was 70% higher than
`expected by historical norms for the SPECT -altropane method. Some studies by another group
`have partially replicated the effect in sub -groups of ADHD subjects with different SPECT
`methods (see Krause et al., 2000). This theory was appealing since high DAT density could
`account for an ADHD -related DA deficit (i.e., this would produce an increased reuptake of
`DA released into the synapse), as well as the beneficial response to MPH (i.e., the blockade of
`DAT would reduce DA uptake and act to correct the DA deficit).
`
`The hypothesis of high DAT density as a brain -basis of ADHD was accepted for over a decade,
`and is now typically cited as one of the primary biological bases of ADHD. To test this
`hypothesis, Volkow et al. (2007a) evaluated a larger sample (20 stimulant -naïve adults with
`ADHD and 25 controls matches for sex and ethnicity) and a more sensitive method of
`estimating DAT density (using PET rather than SPECT and radiolabeled cocaine rather than
`
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`altropane as the ligand). Surprisingly, this study was unable to document lower DAT density
`in the caudate nucleus or in any basal ganglia region, and in fact observed a trend in the opposite
`direction. As shown in Figure 2, some of the other subsequent studies (see Volkow et al.,
`2007 for specific references) using PET methods with higher resolution and larger samples of
`ADHD and control subjects have also reported failure to replicate the fmding of dramatically
`increased DAT density associated with ADHD.
`
`Based on this selected literature review, we believe that modern PET studies have confirmed
`the DA- agonist theory of stimulant drugs and have challenged the DAT -density theory of the
`brain -basis of ADHD. The recent findings from these studies are not universally accepted, so
`references to the old and long- accepted theories still permeate the literature.
`
`3. How have long -term outcomes in large -scale clinical trials changed the rationale for
`treatment with stimulant medications?
`Despite extensive and accumulating evidence of short-term efficacy of stimulant medication,
`in 1990 there was a glaring lack of evidence documenting long -term benefits. Several early
`follow -up studies in the literature suggested that clinical effectiveness could be maintained for
`years (see Satterfield et al., 2007 for a review), but controlled studies had not been conducted
`to provide solid evidence of long -term benefit. The Multimodal Treatment study of ADHD
`(MTA) was initiated in 1993 to evaluate the long -term effects of treatments using the `gold
`standard' for evidence -based medicine -a randomized clinical trial (RCT) - to contrast the
`long -term effects of state -of -the -art pharmacological treatment (MedMgt), psychosocial
`treatment (Beh), and the combination of these two treatment modalities (Comb). As with most
`RCTs, relative rather than absolute effects were evaluated by comparing outcomes of these
`treatments to each other, and (in lieu of a no- treatment control group) to treatment -as -usual in
`the community (CC). After a 14 -month treatment -by- protocol phase, the MTA became an
`observational follow -up that is still in progress. Elsewhere, the MTA Group has provided
`summaries and detailed accounts of the main findings, interpretations, and qualifications from
`the 14- month, 24- month, and 36 -month assessments of outcomes (see Arnold et al., 2008;
`Swanson et al., 2008a, 2008b), so only a brief summary will be presented here. Despite initial
`evidence of long -term relative benefits over the first two years of treatment, when the definition
`of long -term was extended to 3 years, the secondary analyses of the MTA follow -up were not
`able to document any long -term relative benefits of prior or current treatment with stimulant
`medication. However, post -hoc analyses of growth in MTA revised the once -discredited (see
`Spencer et al., 1996) hypothesis of stimulant -related growth suppression. By the third year of
`the study when the participants were between the ages of 10 and 12 years of age, an accumulated
`reduction in height gain of about 2 cm and a reduction in weight gain by about 2 kg was observed
`in the newly treated subgroups compared to the subgroup of cases never treated with stimulant
`medication. The clinical significance of this finding has been questioned by some (see Faraone
`et al., 2008).
`
`One of the greatest concerns about the long -term clinical use of stimulant medication in
`childhood has been the possibility that this might increase the risk for drug abuse (see Volkow
`& Swanson, 2003). However, over the past decade, the opposite was suggested, with claims
`that childhood treatment with stimulant medication decreased risk (see Wilens et al., 2003). In
`the 36 -month follow -up of the MTA, this hypothesis was evaluated (see Molina et al., 2007).
`Increased substance use in the ADHD group compared to a non -ADHD classmate control group
`was documented, but this emergence of early substance use in the ADHD group was not
`significantly reduced by treatment with stimulant medication. Also, récent publications of long-
`term follow -up of cohorts that were included in the Wilens et al. (2003) review suggest that
`by adulthood there was no evidence of the long -term effects of childhood treatment with
`
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`stimulants - beneficial or harmful - on later substance use or abuse (see Volkow & Swanson,
`2008e).
`
`In summary, it is surprising and disappointing that the current literature does not support two
`of the most fervent expectations - the absence of stimulant- related growth suppression
`(Spencer et al., 1996) and the presence of protection from substance use (Wilens et al., 2003)
`- that had been used for over a decade as part of the rationale and justification for the use of
`childhood treatment with stimulant medication.
`
`4. How has the continued increase in use of stimulants for treatment altered concern about
`misuse of stimulant medication?
`Three decades ago, Taylor (1979) observed that despite similarities of prevalence of ADHD
`in different countries, stimulant medications ...are used in treatment with frighteningly
`different frequency in different places'. Overmeyer and Taylor (1999) speculated that there
`was under -recognition and under -treatment of even HKD (the severe form of ADHD) in the
`UK compared to the USA, even though ADHD cases with HKD may be more responsive to
`stimulant medication that ADHD cases that do not meet the criteria for HKD (see Santosh et
`al, 2005; Taylor et al, 2004). The years of undertreatment may have been partially due to the
`unavailability of stimulant medications, which were voluntarily with -drawn from the UK
`market in 1980. Availability was changed in 1995 when MPH was re- licensed in the UK, and
`over the next 5 years there was a dramatic 10 -fold increase in prescriptions from about 20,000
`to nearly 200,000 (see Bramble, 2003). However, Jick et al. (2004) pointed out that a large
`UK -USA difference remained over the period from 1999 to 2001: the percentage of the 5- to
`14- year -old children treated in the UK estimated from the General Practice Research Database
`(0.5 %) was about 20 -fold lower than that estimated by a health maintenance organization from
`the west coast of the USA (9.3 %).
`
`Estimates of national supplies of stimulants provide another way to characterize cross -national
`differences and to extend the comparison through 2005. The UN provides annual reports of
`supply of stimulant drugs (along with other drugs with abuse potential) by countries, stated in
`terms of defined daily dose (DDD) per 1,000 in the population, with DDD = 30 mg for MPH
`and 15 mg for AMP. The UK was not listed in these reports before 1996, but reports since
`1996 provide data for a UK -USA comparison of the national supplies of stimulants. As shown
`in Figure 3, the combined MPH -AMP DDD estimate increased by a factor of 3.17 for the UK
`(from 0.42 in 1996 to 1.33 in 2005), but increased by an even greater factor of 3.83 for the
`USA over the same time period (from 4.66 to 17.83).
`
`How has the continued increase in the USA been used or misused? In the 1980s through the
`2000s, the use of stimulants showed regular linear increases (Safer & Krager, 1988; Zito et al.,
`2003). Dramatic increases in the early 1990s were attributed to correction of prior under -
`recognition and under -treatment of ADHD. A survey of use of stimulants in children in the
`USA suggested a leveling off of the number of children treated with stimulants by 2002 to
`about 2.2 million (4.8% of 6-12- year -olds, 3.2% of 13 -19- year -olds, and .3% of children under
`the age of 6 year (see Zuvekas et al., 2006). However, findings from subjective survey method
`should be confirmed by more objective methods, such as by inspection of the trend in UN
`estimates of the national supply. Swanson and Volkow (2008) noted that the national supply
`in the USA continued to increase linearly after 2002 (see Figure 4a). By 2007, the annual supply
`(stated in terms of UN estimate of DDD) was about 17, which for the population of the USA
`is sufficient to treat about 5 million individuals per day. However, the supply estimates do not
`provide age -specific trends. Since 2000, prescription records have been provided separately
`for age groups. While the total increase in prescriptions remained linear from 2000 to 2007
`and reached about 30 million by 2007 (see Swanson & Volkow, 2008b and Figure 4a), there
`was no increase over this time period in prescriptions for the 0 -5, 6 -10, or 10 -14 age groups
`
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`(confirming the report provided by Zuvekas et al., 2006). However, in the 15-19,20-24, and
`over -25 age groups, the increase in prescriptions did not asymptote, but rather continued to
`increase linearly (see Figure 4b).
`
`Of course, the recent increases in prescriptions for adolescents and adults may just reflect a
`correction of prior under- recognition and under- treatment of those age groups. However,
`another contributing factor should be considered: when stimulants are prescribed for adolescent
`and adults who are seeking treatment for themselves, there may be a higher rate of diversion
`for non -medical use than for children whose parents are seeking treatment for them. For
`example, in a series of publications based on school -based surveys, McCabe et al. (2004,
`2006) reported that about 8% of non -ADHD students in middle school, high school, and college
`engaged in nonmedical use of stimulants. Others have confirmed this pattern in adults as well
`as in children (see Wilens et al., 2008 for a review). A primary source for non -medical use is
`apparently from prescriptions for medical use diverted by sale or other means.
`
`Increased diversion may be related to the provocative suggestion that stimulant medications
`may be `cognitive enhancers' for the general population (Sahakian & Morein- Zamir, 2007).
`This commentary was presented to stimulate discussion, and it generated pro and con points
`of view on a special website (see http: / /www.nature.com). In an Internet survey of adults (18
`to 49 years of age), Novak et al. (2007) found that in a majority of the participants the primary
`motivation given for non -medical use was to increase productivity (i.e., for cognitive
`enhancement). In a survey of college students, Teter et al. (2006) also found that diversion in
`a majority of cases was for cognitive enhancement.
`
`In summary, over the past decade, the linear increase in supply and prescriptions for stimulants
`has continued, fueled recently by an increase in use of stimulants by adolescents and adults.
`This age -specific increase in groups seeking treatment should increased concern about
`diversion from medical to non -medical use.
`
`5. How has industry- sponsored research altered the clinical practice of treatment of
`individuals with stimulant medication?
`Before the mid- 1990s, the pharmaceutical industry provided little support for studies of the
`stimulant medications, and there was little marketing of the approved stimulant medications
`then available - MPH (Ritalin ®), AMP (Dexedrine® and Obetrol ®), and pemoline (Cylert®).
`Apparently, this was partially due to a general lack of incentives to conduct research with
`children (see DeVaugh -Geiss et al., 2006). This state of affairs required the acceptance of the
`practice of conducting clinical trials and gaining approval for a new drug for use in adults and
`then prescribing it `off label' to treat children. This changed in the USA in 1997, when the US
`Congress enacted Public Law 105 -115, the Food and Drug Modernization Act (FDAMA).
`Also in 1997, the European Medicines Agency (EMEA) organized a round table
`(http: // emea.europa.eu/ pdfs/ human/paediatrics /1796704en.pdf) to discuss pediatric
`medicines, and by 2007 new Pediatric Regulations in the Europe Union were approved to
`facilitate the development and availability of new medicines for children.
`
`The FDAMA provided provisions to encourage the evaluation of new drugs in children. The
``pediatric exclusivity rule' provided an extension of the life of patents, which introduced a
`lucrative financial incentive to conduct clinical trials in children. The FDA website
`(http: / /www.fda.gov /cder /pediatric /index.htm) provides a list of manufacturers who have been
`granted patent extension based on the Pediatric Exclusivity provision. Both of the primary
`stimulant medications now in use qualified, and Johnson & Johnson (or its subsidiary, McNeil
`Consumer Health Care) received an extension of the patent for its CR formulation of MPH
`(Concerta ®) and Shire Pharmaceutical received an extension for its patent of its CR formulation
`of AMP (Adderall XR ®).
`
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`In addition to the drug development programs that led to Concerta® and Adderall XR® (see
`section 1 above), several others have been initiated. This has resulted in additional new CR
`formulations of stimulant medication commerical products that have been approved for the
`treatment of ADHD (see Table 1). Studies that compare drugs or formulations with slightly
`different drug delivery profiles are complex (see Pelham et al., 1999;Swanson et al., 2004),
`and may be considered unfair by design (see Adesman, 2004), although perhaps unfairly (see
`Swanson, 2004).
`
`Two non -stimulants have been evaluated as alternative pharmacological treatments for ADHD.
`First, the anti- depressant atomoxetine (Strattera ®) was developed by Lilly Pharmaceuticals
`with claims of specific targeting of the norepinephrine transporter, but it had lower efficacy
`than Adderall XR® (see Wigal et al., 2005) or Concerta® (see Newcorn et al., 2007), and it
`never displaced the standard treatments with stimulants (see Figure 1). Second, the narcolepsy
`drug modafinil was evaluated by Cephalon Pharmaceuticals for use in the treatment of ADHD.
`Based on multiple clinical trials that documented clear efficacy with an effect size only slightly
`lower than the stimulants (see Biederman et al., 2005;Greenhill et al., 2006;Swanson et al.,
`2007), a submission was made for FDA approval. However, the presence of dermatological
`side effects resulted in a decision of non -approval, this led to the and eventual withdrawal of
`the application (see http: / /www.FDA.gov).
`
`Two of the CR formulations of MPH developed in the USA have been approved for use in
`Europe (Concerta® and Metadate CD ®, which is labeled Equasym ®), and other dual- beaded
`formulations were developed for use in Europe (Medikinet XL ®). One of the non -stimulants
`was approved for use in Europe (Strattera ®). Guidelines for the pharmacological treatment of
`ADHD and HKD have been published (e.g., NICE Clinical Guideline 72, 2008 see
`www.nice.org.uk) and discussed in detail (see Taylor et al., 2004) elsewhere, and since these
`guidelines are widely available they need not be repeated here.
`
`Based on this highly selected review of the literature, it is our opinion that the primary
`pharmaceutical treatments of ADHD and HKD have not changed in any fundamental way since
`the initial studies of Bradley (1937, 1950) and Conners and Eisenberg (1963). The primary
`treatment is still with the stimulant medications (AMP and MPH). The primary difference is
`that stimulants are now delivered in once -a -day CR formulations rather than multiple daily
`doses of IR formulations.
`
`Revised concepts and answers to controversial questions
`We have presented some concepts about stimul