Invited reviewThe use of stimulant medications for non-core aspects of ADHD and in other disorders
Introduction
The psychotropic effects of naturally occurring stimulants such as those found in tobacco, coca leaves and coffee have been recognized by the Chinese and other indigenous cultures for several thousand years. Their use in the west was associated first with the importation of coffee and tobacco in the 16th century. Around the beginning of twentieth century cocaine became popular as a therapeutic and recreational agent, and along with opium and alcohol, was a popular ingredient in many American patented medicines. In the 1920s synthetic stimulants started to appear with discovery first of amphetamine and then a range of substituted amphetamine derivatives. These new drugs were demonstrated to be effective in changing a broad range of human behaviors. This led to an avalanche of questions not only about the science behind these medications, but also the ethics of using stimulant medications in the day to day world, and in clinical practice. Indeed since this time the amphetamines and amphetamine derivatives have moved from being considered a panacea for a broad range of disorders and freely available without prescription, into a highly restricted class of Controlled Drug with much more limited and narrower clinical indications.
Much of the early exploration of the therapeutic use of stimulants in clinical practice took place at the same time as a rapidly evolving scientific methodology. The focus shifted from simply asking “what helps whom?” to “what helps whom, when and why?” and “are there costs as well as benefits?” Answering these questions for the stimulants has never been easy. It is known that at therapeutic doses the clinical effects of these medications include but are not limited to; improvements in executive functioning, attention and concentration, reductions in overactivity, impulsivity, fatigue and excessive somnolence, improvements in mood and energy levels and reductions in apathy and intellectual blunting (Greenhill et al., 2001, Santosh and Taylor, 2000). Together these symptoms occur across a range of disorders extending beyond the traditional indications of ADHD and narcolepsy. These include; affective disorders and schizophrenia, chronic fatigue and the consequences of various vascular and organic brain pathologies amongst others. It is also clear that the neurobiological mechanisms of action of stimulants are rather complex (Heal et al., 2013). It is now generally accepted that mechanisms of action differ between the different drugs and that they involve direct effects on both dopamine and noradrenaline as well as downstream impacts on a broader range of neurotransmitters. Whilst it has traditionally been assumed that the main effects are a result of altered neurotransmission in the cortico-striatal loops, recent studies suggest that whilst these regions are important, there may also be a broader impact on other brain regions and functions (Coghill et al., 2007, Cubillo et al., 2014).
This selective review will focus mainly on the non ADHD indications of amphetamine and methylphenidate based stimulants that are used to treat ADHD and will not discuss stimulants used legally as a part of day to day life e.g. nicotine and caffeine or illegally for recreational purposes e.g. cocaine and methamphetamine. We will not discuss pemoline as it is now only very rarely used in clinical practice due to potentially serious adverse effects. We have, however, included information regarding modafinil, which whilst not strictly a stimulant, has similar therapeutic indications to the included stimulants. Whilst the main focus is on non ADHD indications we will start each section with a brief review of the treatment of non-core aspects of ADHD and ADHD comorbid with other disorders.
Section snippets
Methylphenidate
Methylphenidate is considered to exert its primary effect by blocking the reuptake transporters in dopaminergic and noradrenergic systems (Volkow et al., 2002).
Dexamphetamine and other amphetamine preparations
The amphetamines differ from methylphenidate in that their pharmacological effects are predominantly mediated by releasing monoamines although this is complemented by reuptake inhibition (the primary mechanism of action of methylphenidate) and inhibition of monoamine oxidase (Heal et al., 2013). Dexamphetamine is available in several European countries and Australia, Adderall (a mixed enantiomers/mixed salts amphetamine preparation) is available in North America. Lisdexamfetamine, an
Lisdexamfetamine
Lisdexamfetamine is a therapeutically inactive amphetamine prodrug which, after oral ingestion is hydrolyzed on the surface of red blood cells to l-lysine and d–amphetamine. As a consequence, lisdexamfetamine has an extended duration of action with maximum plasma concentration of dexamphetamine achieved in 3.5–3.7 h (Boellner et al., 2010), and clinical effects that persist up to at least 13 h in children and 14 h in adults. The fact that this extended duration of action is a consequence of
Modafinil
Modafinil was approved in the US for use in narcolepsy, shift-work sleep disorder and obstructive sleep apnea with residual excessive sleepiness despite optimal use of continuous positive airway pressure (a treatment for sleep apnoea) (Kumar, 2008). Its pharmacological action seems to be somewhat similar to the stimulants though the mechanism of action is not fully understood (Gerrard and Malcolm, 2007). Modafinil has been shown to improve a range of cognitive functions including spatial span,
Discussion
Psychostimulants have a clear and very well defined role in the management of ADHD where they rank amongst the most effective treatments in medicine. Whilst the psychostimulants also seem likely to be equally effective and safe treatments for ADHD symptoms in those whose ADHD is complicated by another comorbid disorder relatively few studies have looked carefully at these populations. It is likely that this, at least in part, reflects a reluctance on the part of the pharmaceutical companies,
Support
No support was received for the preparation of this manuscript.
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