Psychopharmacology: concepts and opinions about the use of stimulant medications

May combine two claims.

Two major changes in clinical practice occurred in the USA over the past decade: a dramatic revival of amphetamine starting in 1998 and widespread acceptance of second-generation controlled-release formulations of methylphenidate and amphetamine starting in 2000.

“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.”

May combine two claims.

Atomoxetine had lower efficacy than Adderall XR® or Concerta® and never displaced standard stimulant treatments.

“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).”

• cites Wigal et al., 2005Not checked yet

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• cites Newcorn et al., 2007Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Two CR formulations of MPH developed in the USA have been approved for use in Europe (Concerta® and Metadate CD®/Equasym®), and other dual-beaded formulations were developed for use in Europe (Medikinet XL®).

“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®).”

May combine two claims.

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) and by a factor of 3.83 for the USA (from 4.66 to 17.83) over the same period.

“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).”

May combine two claims.

In the 36-month follow-up of MTA, increased substance use in the ADHD group compared to non-ADHD classmate controls was documented, but this emergence of early substance use was not significantly reduced by treatment with stimulant medication.

“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.”

• cites Molina et al., 2007Not checked yet

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May combine two claims.

By 2007, the annual supply in the USA was about 17 DDD, sufficient to treat about 5 million individuals per day.

“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.”

May combine two claims.

Both primary stimulant medications now in use qualified for pediatric exclusivity, and Johnson & Johnson received an extension for Concerta® and Shire Pharmaceutical for Adderall XR®.

“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®).”

May combine two claims.

Availability 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.

“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).”

• cites Bramble, 2003Not checked yet

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May combine two claims.

Stimulant medication use rose sharply worldwide over the past decade, with the biggest increases in the USA.

“The world wide prevalence of stimulant medications has increased dramatically over the past decade, with the largest increases in the USA where prior use was already high.”

• Also stated in: § Key points · plain

  “The overall rate of prescription of stimulant medication has increased worldwide and has continued to increase in the USA, even reaching asymptote for children with ADHD by 2000, due to increases for adults and adolescents and possibly increased diversion for non-medical use.”

May combine two claims.

The sample of 20 cases and 25 controls in Volkow et al. (2007) took several years to identify and test, but this was needed to rule out prior treatment and comorbid effects and to examine sex and gender factors.

“For example, the sample of n = 20 cases and n = 25 controls evaluated by Volkow et al. (2007) required several years to identify and test, but this was necessary to exclude the effects of prior treatment and comorbid factors and to evaluate the effects of sex and gender factors.”

• cites Volkow et al. (2007)Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The overall prescription rate for stimulant medication has risen worldwide and continued to rise in the USA, even plateauing for children with ADHD by 2000, driven by increases for adults and adolescents and possibly by more diversion for non-medical use.

“The overall rate of prescription of stimulant medication has increased worldwide and has continued to increase in the USA, even reaching asymptote for children with ADHD by 2000, due to increases for adults and adolescents and possibly increased diversion for non-medical use.”

May combine two claims.

Proof-of-product trials were bigger and costlier than proof-of-concept trials and employed the laboratory school model.

“Proof-of-product studies were somewhat larger and more expensive and used the laboratory school paradigm (for Concerta® see Pelham et al., 2001 and Swanson et al., 2003, and for Adderall XR® see McCracken et al., 2003).”

• cites Pelham et al., 2001Not checked yet

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• cites Swanson et al., 2003Not checked yet

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• cites McCracken et al., 2003Not checked yet

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May combine two claims.

The steady linear growth in stimulant use seen for decades is ongoing, and partly reflects self-treatment through non-medical use among adolescents and adults.

“The current literature suggests that the regular (linear) increases observed for decades are continuing, and that at least in part this is due to self-treatment via non-medical use of stimulant medications in adolescents and adults.”

May combine two claims.

During the last ten years, clinical practice experienced a return of amphetamine and a move from immediate-release to controlled-release forms of methylphenidate and amphetamine.

“Dramatic changes have occurred over the past decade, with the revival of AMP and the shift from IR formulation to CR formulations of MPH and AMP (see figure 1).”

• Also stated in: § Key points · plain

  “Principles from clinical pharmacology were applied in the 1990s to develop second-generation controlled-release formulations that by 2000 replaced immediate-release formulations of methylphenidate and amphetamine for treatment of children with ADHD.”

May combine two claims.

In this area, acquisitions included Alza by Johnson & Johnson (Concerta®), Richwood by Shire (Adderall®), Medeva by UCB (Metadate CD®), and Celgene's drug by Novartis (Focalin®).

“In the narrow area that is addressed here, this occurred with Concerta® (Alza was acquired by Johnson & Johnson), Adderall® (Richwood was acquired by Shire), Metadate CD® (Medeva was acquired by UCB), and Focalin® (the drug developed by Celgene was acquired by Novartis).”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Industry-sponsored stimulant studies have grown over the past decade because of approval trials for new formulations and promotion and marketing studies.

“Industry-sponsored studies of stimulants have increased over the past decade, due to clinical trials for approval of new formulations and studies for promotion and marketing, which may have generated concern about the influence of commercial firms on clinical use.”

Probably not a substantial claim: may not pass S3 (load-bearing).

One non-stimulant was approved for use in Europe (Strattera®).

“One of the non-stimulants was approved for use in Europe (Strattera®).”

Probably not a substantial claim: may not pass S4 (based).

For new stimulants approved between 1998 and 2008, advertising and marketing seemed to highlight minor differences among CR formulations rather than the shared PK/PD properties of all approved stimulants.

“In the example of new stimulants that were developed and approved between 1998 and 2008, advertising and marketing appear to emphasize small differences to distinguish the variety of CR formulation rather than fundamental PK/PD properties of the stimulant medications that characterize all of the new stimulant drugs approved for use in the treatment of ADHD.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Clinical pharmacology principles were used in the 1990s to create second-generation controlled-release formulations that by 2000 replaced immediate-release methylphenidate and amphetamine for treating children with ADHD.

“Principles from clinical pharmacology were applied in the 1990s to develop second-generation controlled-release formulations that by 2000 replaced immediate-release formulations of methylphenidate and amphetamine for treatment of children with ADHD.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

PET brain imaging in stimulant-naïve adults recently yielded findings that challenge the established theory that abnormally high dopamine transporter density in the striatum is a neural correlate of ADHD.

“Applications of positron emission tomography brain imaging to evaluate stimulant naïve adults recently produced new findings that challenge established theory that a neural correlate of ADHD was abnormally high dopamine transporter density in the striatum.”

May combine two claims.

PK studies in adults and children revealed a 6-hour PK half-life of a single dose of IR amphetamine and an ascending drug delivery profile associated with the BID regime of Adderall® with doses given 4 hours apart.

“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.”

• cites Tulloch et al., 2002Not checked yet

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• cites Greenhill et al., 2003Not checked yet

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May combine two claims.

A study by Swanson et al. (1998) confirmed equal efficacy (maximum effect after an acute dose) and different PD half-lives for Adderall® (6 hours) and Ritalin® (4 hours).

“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).”

• cites Swanson et al., 1998Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Swanson et al. (1993) review of reviews suggested short-term reduction in ADHD symptoms and associated features of opposition and aggression should be expected, while long-term benefits, absence of side effects, paradoxical response, and large effect on higher-order processes should not be expected.

“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).”

• cites Swanson et al. (1993)Not checked yet

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May combine two claims.

First-generation controlled-release formulations of amphetamine and methylphenidate available in the 1980s were considered to have lower efficacy than multiple-dose regimes of immediate-release formulations and were not widely adopted.

“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.”

May combine two claims.

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.

“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.”

• AssumptionRests on an assumption: The selected literature review is representative of the broader literature on stimulant medications.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The initial behavioral and cognitive effects of methylphenidate were described by Conners and Eisenberg in 1963, and later by many investigators.

“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”

• cites Conners and Eisenberg (1963)Not checked yet

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May combine two claims.

Both major changes in clinical practice were stimulated by small studies based on principles of clinical pharmacology; the latter was based on PK/PD modeling and the hypothesis that smooth ascending PK profiles for once-a-day CR formulations would counteract acute tolerance and maintain full efficacy across the day.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Conners (2002) concluded that stimulant effects are consistent over time despite changes in diagnosis, assessment instrument, and research methodology.

“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, assessment instrument, and research methodology’ (p. S29).”

• cites Conners (2002)Not checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The consensus opinion was that stimulant drugs required bolus doses and a PK profile with peaks and valleys to produce and maintain clinical efficacy, implying an inherent limitation on controlled-release formulations.

“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.”

May combine two claims.

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.

“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.”

May combine two claims.

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 standard BID IR methylphenidate, but a first-order smooth (ascending) PK profile without a bolus could achieve full efficacy of the bolus dose regime.

“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.”

• cites Swanson et al., 1999Not checked yet

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May combine two claims.

MPH has a much longer brain PK half-life than cocaine, resulting in persistence of high brain levels of MPH and prolonged high exposure after peak concentration.

“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.”

• cites Volkow et al., 1995Not checked yet

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May combine two claims.

The 'pediatric exclusivity rule' provided an extension of the life of patents, introducing a lucrative financial incentive to conduct clinical trials 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.”

May combine two claims.

The current literature does not support two of the most fervent expectations-the absence of stimulant-related growth suppression and the presence of protection from substance use-that had been used for over a decade as part of the rationale and justification for childhood treatment with stimulant medication.

“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”

Probably not a substantial claim: may not pass S3 (load-bearing).

The years of undertreatment may have been partially due to the unavailability of stimulant medications, which were voluntarily withdrawn from the UK market in 1980.

“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.”

Classified as probably not a substantial claim.

One of the greatest concerns about long-term stimulant use in childhood has been the possibility of increased risk for drug abuse.

“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).”

• cites Volkow & Swanson, 2003Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

A primary source for non-medical use is apparently from prescriptions for medical use diverted by sale or other means.

“A primary source for non-medical use is apparently from prescriptions for medical use diverted by sale or other means.”

May combine two claims.

The MTA was initiated in 1993 to evaluate long-term effects of treatments using an RCT to contrast MedMgt, Beh, and Comb.

“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).”

• cites MTANot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Overmeyer and Taylor (1999) speculated that there was under-recognition and under-treatment of even HKD in the UK compared to the USA, even though ADHD cases with HKD may be more responsive to stimulant medication than ADHD cases without HKD.

“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).”

• cites Overmeyer and Taylor, 1999Not checked yet

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• cites Santosh et al, 2005Not checked yet

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• cites Taylor et al, 2004Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The clinical significance of the growth suppression finding has been questioned by some.

“The clinical significance of this finding has been questioned by some (see Faraone et al., 2008).”

• cites Faraone et al., 2008Not checked yet

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May combine two claims.

In 1990 there was a glaring lack of evidence documenting long-term benefits of stimulant medication despite extensive evidence of short-term efficacy.

“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.”

May combine two claims.

Early follow-up studies suggested clinical effectiveness could be maintained for years, but controlled studies had not been conducted to provide solid evidence of long-term benefit.

“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.”

• cites Satterfield et al., 2007Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Dramatic increases in the early 1990s were attributed to correction of prior under-recognition and under-treatment of ADHD.

“Dramatic increases in the early 1990s were attributed to correction of prior under-recognition and under-treatment of ADHD.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

Studies comparing drugs or formulations with slightly different drug delivery profiles are complex and may be considered unfair by design, although perhaps unfairly.

“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).”

• cites Pelham et al., 1999Not checked yet

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• cites Swanson et al., 2004Not checked yet

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• cites Adesman, 2004Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

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.

“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’.”

• cites Taylor (1979)Not checked yet

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Classified as probably not a substantial claim.

Over the past decade, the opposite was suggested, with claims that childhood treatment with stimulant medication decreased risk.

“However, over the past decade, the opposite was suggested, with claims that childhood treatment with stimulant medication decreased risk (see Wilens et al., 2003).”

• cites Wilens et al., 2003Not checked yet

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May combine two claims.

Over the past decade, the linear increase in supply and prescriptions for stimulants has continued, fueled recently by an increase in use by adolescents and adults.

“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.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

The recent findings from PET studies are not universally accepted, so references to old and long-accepted theories still permeate the literature.

“The recent findings from these studies are not universally accepted, so references to the old and long-accepted theories still permeate the literature.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

This age-specific increase in groups seeking treatment should increase concern about diversion from medical to non-medical use.

“This age-specific increase in groups seeking treatment should increased concern about diversion from medical to non-medical use.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

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.

“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.”

May combine two claims.

Before the mid-1990s, the pharmaceutical industry provided little support for studies of stimulant medications, and there was little marketing of approved stimulant medications then available.

“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®).”

Probably not a substantial claim: may not pass S3 (load-bearing).

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 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.”

May combine two claims.

Public criticism about potential conflicts of interest may reduce future funding for all types of pharmaceutical company-supported studies, which FDAMA encourages and which are usually too costly for NIH funding.

“However, public criticism of potential conflict of interest may inhibit the future funding for all types of studies supported by pharmaceutical companies, which are encouraged under the FDAMA (see Public Law 105-55, 1997) and are usually too expensive for NIH funding.”

• cites Public Law 105-55, 1997Not checked yet

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May combine two claims.

Large, costly clinical trials were required for ADHD treatment approval and assessed effects in home and school settings.

“These were followed by large and very expensive clinical trials to evaluate effects in the home and school settings that were necessary to gain approval for use in the treatment of ADHD.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Pharmaceutical industry influence on clinical research has been widely discussed recently.

“The influence of the pharmaceutical industry on clinical research has been a topic of much discussion recently, as exemplified by a commentary of the Editor of the Journal of the American Medical Association (see DeAngelis & Fontanarosa, 2008).”

• cites DeAngelis & Fontanarosa, 2008Not checked yet

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Probably not a substantial claim: may not pass S2 (checkable).

Multiple assessments, such as household surveys, prescription records, and supply estimates, are needed to establish national patterns of stimulant medication use.

“From personal experience and participation in the current debate about the medical and non-medical use of stimulant drugs (Volkow & Swanson, 2007; Swanson & Volkow, 2008b), it seems necessary to utilize multiple assessments (e.g., household surveys, prescription records, estimates of supply, etc.) to establish national patterns of use of stimulant medication.”

• cites Volkow & Swanson, 2007Not checked yet

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• cites Swanson & Volkow, 2008bNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The linear rise in stimulant use that has lasted for decades has not slowed, but logically it must eventually plateau if treatment is limited to a fraction of the population.

“The linear increase that has persisted for decades has not abated, but logically this must reach an asymptote in the future if treatment is to be restricted to only a percentage of the population.”

May combine two claims.

This expanded approved treatment options but also boosted marketing and advertising.

“This increased the approved alternatives for treatment, but it also increased the marketing efforts and advertising.”

May combine two claims.

Small drug companies can follow hunches and test innovative theories without pilot data or standard scientific or financial review.

“From personal experience, it seems that this segment of the pharmaceutical industry can act on hunches (as demonstrated by the revival of Adderall® by Richwood Pharmaceuticals) and conduct studies of innovative theories (as demonstrated by the drug development program of Alza Pharmaceuticals) without pilot data or the usual scrutiny of scientific or financial review committees.”

Classified as probably not a substantial claim.

Stimulant medication might cause long-term growth-related adverse effects.

“potential side effects (i.e., possible long-term growth-related side effects)”

Probably not a substantial claim: may not pass S3 (load-bearing).

Chronic stimulant treatment may lead to adaptation, such as down-regulated DA turnover and increased DAT density.

“Ludolph et al. (2008) proposed that adaptation to chronic treatment with stimulants (e.g., down-regulated DA turnover and increased DAT density) may occur.”

• cites Ludolph et al. (2008)Not checked yet

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May combine two claims.

In clinical trials, sponsoring companies may lead design and analysis, and investigators may act as little more than hired hands who supply patients and collect data per company protocol.

“One issue is about some practices in clinical trials, when the sponsoring company may take the lead in the design and analysis of the study, and investigators may be ‘little more than hired hands, supplying patients and collecting data according to the company protocol’ (Angell, 2008).”

• cites Angell, 2008Not checked yet

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Probably not a substantial claim: may not pass S2 (checkable).

Advanced statistical methods are needed to test assumptions about mediators and moderators and hypotheses about selection bias and subtypes based on outcome trajectories.

“Sophisticated statistical procedures are necessary to test assumptions about mediators and moderators as well as hypotheses about selection bias and subtypes based on outcome trajectories over time (Swanson et al., 2007).”

• cites Swanson et al., 2007Not checked yet

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May combine two claims.

Those studies identified acute tolerance and recommended ascending drug delivery profiles, which in theory overcome acute tolerance and sustain full efficacy throughout the day for controlled-release MPH and AMP.

“These studies implicated acute tolerance as a factor and recommended ascending drug delivery profiles, which theoretically act to overcome acute tolerance and maintain full efficacy across the day for controlled-release MPH (for Concerta® see Swanson et al., 1999) and AMP (for Adderall XR® see Tulloch et al., 2002 and Greenhill et al., 2003).”

• cites Swanson et al., 1999Not checked yet

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• cites Tulloch et al., 2002Not checked yet

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• cites Greenhill et al., 2003Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Clinical trials needed for FDA approval and for marketing new products demand very large investments.

“However, very large investments are required by the types of clinical trials needed for the FDA approval process, as well as for marketing new products.”