Elsevier

Neuropharmacology

Volume 87, December 2014, Pages 161-172
Neuropharmacology

Invited review
The use of stimulant medications for non-core aspects of ADHD and in other disorders

https://doi.org/10.1016/j.neuropharm.2014.06.014Get rights and content

Highlights

  • Stimulants appear to improve the emotional lability often associated with ADHD.

  • Stimulants may improve the oppositional and conduct symptoms often seen in ADHD.

  • Stimulants may improve outcomes in those with treatment resistant depression.

  • Stimulants may improve negative symptoms and cognitive performance in schizophrenia.

  • Stimulants may improve outcomes post stroke, head injury, dementia and cancer.

Abstract

Psychostimulants play a central role in the management of ADHD. Here we review the evidence pertaining to the use of methylphenidate, dexamphetamine and related amphetamine salts, the prodrug lisdexamfetamine and modafinil for the management of comorbid ADHD and non-ADHD indications. There is a growing consensus that stimulant medications are helpful at improving the emotional dysregulation and lability, and oppositional and conduct symptoms that are often associated with ADHD. There is some evidence that psychostimulants may improve outcomes in those with treatment resistant depression, reduce negative symptoms and improve cognitive performance in schizophrenia, and that methylphenidate may reduce binge eating in those with bulimia nervosa. In general medicine, whilst the evidence is at times contradictory, psychostimulants have been shown in some studies to be effective treatments for chronic fatigue and narcolepsy, and to improve outcomes post stroke, post head injury, in dementia and various cancers. It seems likely that these effects often result from a combination of, reduction in fatigue, improvements in concentration and cognitive functioning and a lifting of mood which may be a direct or indirect consequence of the medication. Further studies seem warranted and these should focus on efficacy, effectiveness and long term safety.

This article is part of the Special Issue entitled ‘CNS Stimulants’.

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.

References (152)

  • V. Gross-Tsur et al.

    Epilepsy and attention deficit hyperactivity disorder: is methylphenidate safe and effective?

    J. Pediatr.

    (1997)
  • M. Kahbazi et al.

    A randomized, double-blind and placebo-controlled trial of modafinil in children and adolescents with attention deficit and hyperactivity disorder

    Psychiatry Res.

    (2009)
  • S.L. Kaplan et al.

    Effects of methylphenidate on adolescents with aggressive conduct disorder and ADDH: a preliminary report

    J. Am. Acad. Child. Adolesc. Psychiatry

    (1990)
  • J.A. Koneski et al.

    Efficacy and safety of methylphenidate in treating ADHD symptoms in children and adolescents with uncontrolled seizures: a Brazilian sample study and literature review

    Epilepsy Behav.

    (2011)
  • H. Lavretsky et al.

    Methylphenidate augmentation of citalopram in elderly depressed patients

    Am. Journal Geriatric Psychiatry: Official Journal Am. Assoc. Geriatric Psychiatry

    (2001)
  • F.R. Levin et al.

    Treatment of cocaine dependent treatment seekers with adult ADHD: double-blind comparison of methylphenidate and placebo

    Drug. Alcohol Depend.

    (2007)
  • L. Lundt

    Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study

    J. Affect Disord.

    (2004)
  • J.L. Moore et al.

    An evaluation of the effects of methylphenidate on outcomes in adult epilepsy patients

    Epilepsy Behav.

    (2002)
  • L.G. Olson et al.

    A pilot randomized controlled trial of dexamphetamine in patients with chronic fatigue syndrome

    Psychosomatics

    (2003)
  • P.M. Plenger et al.

    Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study

    Arch. Phys. Med. Rehabil.

    (1996)
  • D.J. Posey et al.

    Positive effects of methylphenidate on inattention and hyperactivity in pervasive developmental disorders: an analysis of secondary measures

    Biol. Psychiatry

    (2007)
  • C.H. Adler et al.

    Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease

    Mov. Disord.

    (2003)
  • R.C. Albucher et al.

    Adderall for obsessive-compulsive disorder

    Am. J. Psychiatry

    (2001)
  • T. Banaschewski et al.

    Long-acting medications for the hyperkinetic disorders: a systematic review and European treatment guideline

    Eur. Child. Adolesc. Psychiatry

    (2006)
  • H. Bastuji et al.

    Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (1988)
  • H.N. Bawden et al.

    Treatment of children with Williams syndrome with methylphenidate

    J. Child. Neurol.

    (1997)
  • P.M. Becker et al.

    Effect of modafinil on fatigue, mood, and health-related quality of life in patients with narcolepsy

    Psychopharmacol. Berl.

    (2004)
  • M.L. Berthier

    Poststroke aphasia : epidemiology, pathophysiology and treatment

    Drugs Aging

    (2005)
  • K.M. Beusterien et al.

    Health-related quality of life effects of modafinil for treatment of narcolepsy

    Sleep

    (1999)
  • J. Biederman et al.

    Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in children and adolescents

    J. Pediatr.

    (2008)
  • D. Blockmans et al.

    Does methylphenidate reduce the symptoms of chronic fatigue syndrome?

    Am. J. Med.

    (2006)
  • B. Bolea-Alamanac et al.

    Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology

    J. Psychopharmacol.

    (2014)
  • E. Bruera et al.

    Methylphenidate associated with narcotics for the treatment of cancer pain

    Cancer Treat. Rep.

    (1987)
  • E. Bruera et al.

    Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report

    J. Clin. Oncol.

    (2003)
  • R. Cantello et al.

    Major depression in Parkinson's disease and the mood response to intravenous methylphenidate: possible role of the “hedonic” dopamine synapse

    J. Neurol. Neurosurg. Psychiatry

    (1989)
  • Z. Chang et al.

    Stimulant ADHD medication and risk for substance abuse

    J. Child. Psychol. Psychiatry

    (2013)
  • A.C. Childress et al.

    The effects of lisdexamfetamine dimesylate on emotional lability in children 6 to 12 years of age with ADHD in a double-blind placebo-controlled trial

    J. Atten. Disord.

    (2014)
  • S. Cortese et al.

    Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents

    J. Child. Psychol. Psychiatry

    (2013)
  • A. Cubillo et al.

    Drug-specific laterality effects on frontal lobe activation of atomoxetine and methylphenidate in attention deficit hyperactivity disorder boys during working memory

    Psychol. Med.

    (2014)
  • M.S. Damian et al.

    Modafinil for excessive daytime sleepiness in myotonic dystrophy

    Neurology

    (2001)
  • C. DeBattista et al.

    A prospective trial of modafinil as an adjunctive treatment of major depression

    J. Clinical Psychopharmacology

    (2004)
  • R.W. Dittmann et al.

    Efficacy and safety of lisdexamfetamine dimesylate and atomoxetine in the treatment of attention-deficit/hyperactivity disorder: a head-to-head, randomized, double-blind, phase IIIb study

    CNS Drugs

    (2013)
  • J. Ermer et al.

    An open-label investigation of the pharmacokinetic profiles of lisdexamfetamine dimesylate and venlafaxine extended-release, administered alone and in combination, in healthy adults

    Clin. Drug Investig.

    (2013)
  • W.E. Fann et al.

    Methylphenidate in tardive dyskinesia

    Am. J. Psychiatry

    (1973)
  • P.S. Fastenau et al.

    Neuropsychological status at seizure onset in children: risk factors for early cognitive deficits

    Neurology

    (2009)
  • M. Fava et al.

    A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness

    J. Clin. Psychiatry

    (2005)
  • H. Feldman et al.

    Methylphenidate in children with seizures and attention-deficit disorder

    Am. J. Dis. Child.

    (1989)
  • L. Ferraro et al.

    Modafinil enhances the increase of extracellular serotonin levels induced by the antidepressant drugs fluoxetine and imipramine: a dual probe microdialysis study in awake rat

    Synapse

    (2005)
  • O. Freudenreich et al.

    Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial

    J. Clinical Psychiatry

    (2009)
  • A. Gabriel

    The mixed amphetamine salt extended release (Adderall XR, Max-XR) as an adjunctive to SSRIS or SNRIS in the treatment of adult ADHD patients with comorbid partially responsive generalized anxiety: an open-label study

    Atten. Defic. Hyperact. Disord.

    (2010)
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