Psychopharmacology: concepts and opinions about the use of stimulant medications.

Our ‘opinion-driven and conceptual review’ of the past decade of research has identified many differences between the prior and current use and understanding of effects of stimulant medications, which are summarized in Table 2. As requested, we will offer some conclusions based on personal experiences in research related to the five concepts considered here. Table 2 Changes in the Use and Understanding of Stimulant Medications From personal experience in developing the second-generation CR formulations that are the mainstay of current clinical treatment, it seems that the advances that led to these formulations were initiated by development programs of small pharmaceutical companies (Alza and Richwood), which invested in proof-of-concept studies directed by fundamental principles of modern PK/PD evaluation (see Park et al., 1998). 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). However, this fundamental principle of acute tolerance is not understood or recognized by all, which is reflected in reviews of the second-generation CR formulations (see the absence of mention of acute tolerance in the reviews by Banaschewski et al., 2006 and Connor & Steingard, 2004) and by some investigators who have participated in the development of new CR formulations without an ascending drug delivery profile (e.g., see Schachar et al., 2008). From personal experience with PET imaging studies of adults, it seems that the most difficult component of this research is not the high cost of the imaging procedure but instead is the recruitment of cases without prior treatment and comorbid conditions and the accumulation of a sufficient number of both cases and controls to allow for evaluation of other important factors that may affect DAT density (such as sex and ethnicity). 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. From personal experience in the analysis of data from the serial follow-ups of the MTA (aMTA Cooperative Group, 2004a, MTA Cooperative Group, 2004b; Swanson et al., 2007a, 2007b), it seems difficult to evaluate long-term effects due to changes in treatment regimes over time. 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). Based on analyses utilizing these statistical methods, the expectation of long-term persistence of the initial relative superiority of state-of-the-art treatment with stimulants over other treatments in the MTA has not been confirmed in the naturalistic follow-up (see Swanson et al., 2008a, 2008b). 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. 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. From personal experience about industry-funded studies (e.g., Swanson et al., 1998, 1999, 2003), it is clear the costs of proof-of-principle or proof-of-concept studies are small compared to the costs of large clinical trials that follow new discoveries and are essential for gaining FDA approval for new and improved commercial products. 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. Strict adherence to gudelines is clearly essential to ensure support for the research required to develop new products, with evaluation of safety and efficacy in children, and to gain approval for use in this age group rather than to rely on off-label prescribing of medications evaluated and approved in adults. Key points 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. Applications of positron emission tomography brain imaging to evaluate stimulant naive adults recently produced new findings that challenge established theory that a neural correlate of ADHD was abnormally high dopamine transporter density in the striatum. The long-term naturalistic follow-up of the Multimodal Treatment study of ADHD suggests that rigorous childhood treatment with stimulant medication produces initial relative benefits over other treatments that may not persist beyond 2 years. 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. 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. Footnotes 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.