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, 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.