Psychostimulants & Non-ADHD Uses

Invited review

The use of stimulant medications for non-core aspects of ADHDand in other disorders

Eugenia Sinita a, David Coghill b, *a Department of Research and Development, National Centre of Mental Health, Clinical Psychiatric Hospital, Chisinau, Republic of Moldovab Division of Neuroscience, University of Dundee, Dundee, UK

a r t i c l e i n f o

Article history:Available online 18 June 2014

Keywords:ADHDMethylphenidateDexamphetamineLisdexamfetamineAmphetamineModanilDepressionFatigueSchizophreniaNarcolepsyCancer

a b s t r a c t

Psychostimulants play a central role in the management of ADHD. Here we review the evidence per-taining to the use of methylphenidate, dexamphetamine and related amphetamine salts, the prodruglisdexamfetamine and modanil for the management of comorbid ADHD and non-ADHD indications.There is a growing consensus that stimulant medications are helpful at improving the emotional dys-regulation 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 resistantdepression, reduce negative symptoms and improve cognitive performance in schizophrenia, and thatmethylphenidate may reduce binge eating in those with bulimia nervosa. In general medicine, whilst theevidence is at times contradictory, psychostimulants have been shown in some studies to be effectivetreatments for chronic fatigue and narcolepsy, and to improve outcomes post stroke, post head injury, indementia 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 moodwhich may be a direct or indirect consequence of the medication. Further studies seem warranted andthese should focus on efcacy, effectiveness and long term safety.

This article is part of the Special Issue entitled CNS Stimulants. 2014 Published by Elsevier Ltd.

1. Introduction

The psychotropic effects of naturally occurring stimulants suchas those found in tobacco, coca leaves and coffee have beenrecognized by the Chinese and other indigenous cultures for severalthousand years. Their use in the west was associated rst with theimportation of coffee and tobacco in the 16th century. Around thebeginning of twentieth century cocaine became popular as a ther-apeutic and recreational agent, and along with opium and alcohol,was a popular ingredient in many American patented medicines. Inthe 1920s synthetic stimulants started to appear with discoveryrst of amphetamine and then a range of substituted amphetaminederivatives. These new drugs were demonstrated to be effective inchanging a broad range of human behaviors. This led to anavalanche of questions not only about the science behind thesemedications, but also the ethics of using stimulant medications inthe day to day world, and in clinical practice. Indeed since this timethe amphetamines and amphetamine derivatives havemoved from

being considered a panacea for a broad range of disorders andfreely availablewithout prescription, into a highly restricted class ofControlled Drug with much more limited and narrower clinicalindications.

Much of the early exploration of the therapeutic use of stimu-lants in clinical practice took place at the same time as a rapidlyevolving scientic methodology. The focus shifted from simplyasking what helps whom? to what helps whom, when andwhy? and are there costs as well as benets? Answering thesequestions for the stimulants has never been easy. It is known that attherapeutic doses the clinical effects of these medications includebut are not limited to; improvements in executive functioning,attention and concentration, reductions in overactivity, impulsivity,fatigue and excessive somnolence, improvements in mood andenergy levels and reductions in apathy and intellectual blunting(Greenhill et al., 2001; Santosh and Taylor, 2000). Together thesesymptoms occur across a range of disorders extending beyond thetraditional indications of ADHD and narcolepsy. These include; af-fective disorders and schizophrenia, chronic fatigue and the con-sequences of various vascular and organic brain pathologiesamongst others. It is also clear that the neurobiological mechanisms* Corresponding author.

E-mail address: [email protected] (D. Coghill).

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Neuropharmacology

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http://dx.doi.org/10.1016/j.neuropharm.2014.06.0140028-3908/ 2014 Published by Elsevier Ltd.

Neuropharmacology 87 (2014) 161e172

of action of stimulants are rather complex (Heal et al., 2013). It isnow generally accepted that mechanisms of action differ betweenthe different drugs and that they involve direct effects on bothdopamine and noradrenaline as well as downstream impacts on abroader range of neurotransmitters. Whilst it has traditionally beenassumed that the main effects are a result of altered neurotrans-mission in the cortico-striatal loops, recent studies suggest thatwhilst these regions are important, there may also be a broaderimpact on other brain regions and functions (Coghill et al., 2007;Cubillo et al., 2014).

This selective review will focus mainly on the non ADHD in-dications of amphetamine and methylphenidate based stimulantsthat are used to treat ADHD and will not discuss stimulants usedlegally as a part of day to day life e.g. nicotine and caffeine or ille-gally for recreational purposes e.g. cocaine and methamphetamine.We will not discuss pemoline as it is now only very rarely used inclinical practice due to potentially serious adverse effects. We have,however, included information regarding modanil, which whilstnot strictly a stimulant, has similar therapeutic indications to theincluded stimulants. Whilst the main focus is on non ADHD in-dications we will start each section with a brief review of thetreatment of non-core aspects of ADHD and ADHD comorbid withother disorders.

2. Methylphenidate

Methylphenidate is considered to exert its primary effect byblocking the reuptake transporters in dopaminergic and norad-renergic systems (Volkow et al., 2002).

2.1. ADHD and developmental disorders

Many studies have clearly demonstrated that methylphenidateis a safe and effective treatment for those with uncomplicatedADHD (Banaschewski et al., 2006; Bolea-Alamanac et al., 2014; Nuttet al., 2007). Whilst there have been far fewer studies investigatingthe efcacy and safety of methylphenidate in those with ADHD andco-existing disorders, most studies that have looked at thisconclude that methylphenidate remains effective at reducingADHD symptoms in the presence of either neurological or mentalhealth comorbidities.

Oppositional and aggressive behaviors are the most commoncomorbidities associated with ADHD, and studies suggest thatmethylphenidate treatment can reduce aggression and antisocialbehavior as measured with Adolescent Antisocial Behavior check-list (Kaplan et al., 1990). A large 24 week multicenter double blindplacebo controlled trial involving a study group of 363 subjects,supported the effects of methylphenidate on emotional dysregu-lation and mood lability as measured by the Emotional Dysregu-lation Scale and Emotional Lability Scale (Rosler et al., 2010). In thissame study methylphenidate also reduced obsessive e compulsivesymptoms as well as core ADHD symptoms. Around 30e40% ofthose with autism also suffer from ADHD. An initial study of tenpatients suggested that children with autism and ADHD treatedwith methylphenidate showed some improvement in their ADHDsymptoms, with the greatest improvements being on hyperactivitysymptoms. Importantly therewas noworsening in stereotypies andrepetitive behaviors (Quintana et al., 1995). A larger study con-ducted by the Research Units in Pediatric PsychopharmacologyAutism Network also found benets for methylphenidate in thereduction of ADHD symptoms (RUPPAN, 2005). Whilst methyl-phenidate clearly separated from placebo in this study, the effectsize of around 0.5, and response rate of 49% were considerablylower than those typically seen for uncomplicated ADHD. In a studyof sixty six children with autism, Aspergers and PDD (pervasive

developmental disorder) not otherwise specied, those receivingmethylphenidate showed general improvement in ADHD symp-toms, however there were no improvements in stereotypies andrepetitive behaviors (Posey et al., 2007) A further reanalysis of datafrom this study suggested positive effects on social communicationand self-regulation although these may well have been secondaryto improvements in ADHD (Jahromi et al., 2009). In addition to thepositive effects there were some additional adverse effects notnormally seenwith any frequency in pure ADHD. These included;irritability, lethargy, sadness, dullness, social withdrawal and, inthis study, stereotyped behaviors. Eighteen percent of study sub-jects withdrew due to adverse events, while others seemed tobenet from treatment. Even though the results are promising, theauthors suggested that methylphenidate should not be recom-mended as a treatment for core features of autism unlessconcomitant ADHD symptoms are present.

Compared in a threeweek randomized double blind study to theantipsychotic thioridazine, methylphenidate was reported by bothparents and teachers, to be better at improving behavior in childrenwith intellectual impairment (Aman et al., 1991). A subsequentlarge double blind placebo controlled trial involving 122 subjectsconrmed that intellectual disability did not inuence methyl-phenidate efcacy in children and adolescents with severe ADHDand autism (Simonoff et al., 2013). Methylphenidate was superiorto placebo on both parent and teacher rated Conners' ADHD index.Overall, 40% of study subjects on active drug, compared to 7%receiving placebo, were considered to improve or much improveaccording to the Clinical Global Impressions (CGI) Improvementscale. In a small placebo controlled study of four children sufferingWilliam's syndrome, a genetic syndrome for which many sufferersmeet diagnostic criteria for ADHD, the ndings for methylpheni-date were generally positive: irritability, impulsivity and activitylevels decreased, while ability to focus attention was improved(Bawden et al., 1997).

The presence of tics/Tourette's was for many years listed as acontraindication for treatment with stimulants. This however is notsupported by the evidence from clinical studies. Initial evidencefrom both high quality studies and studies with methodologicallimitations also shows that psychostimulants do not contribute tonew onset of tics (Roessner et al., 2006). In ADHD associated withchronic multiple tic disorder methylphenidate improved generalADHD symptoms without modifying tics (Gadow et al., 1999).Further controlled trials, and a meta-analysis that included ninedouble blind, randomized, placebo-controlled trials concluded thatthere is no evidence that methylphenidate worsens tic severity inthe short term (Bloch et al., 2009). However it should be noted thatthese ndings represent the mean impact across the group and, assuggested by a recent Cochrane group systematic review(Pringsheim and Steeves, 2011), psychostimulants may exacerbatetics in individual cases. Recent European clinical guidelines on thepharmacological treatment of Tourette syndrome and other ticdisorders support the use of stimulants in those with ADHD andtics/Tourette's but call for clinicians to be cautious and monitorcarefully (Roessner et al., 2011).

ADHD is often complicated by substance misuse. In generalthere is no evidence to suggest safety issues whenmethylphenidateis co-administered with nicotine, alcohol or opiates. However co-administration of methylphenidate and cocaine may result inserious adverse events and should generally be avoided. There arehowever several published reports of small controlled studies inindividuals who abuse cocaine. A study involving 12 young patientssuffering ADHD and cocaine addiction, found that methylphenidateadministered for 12 weeks reduced ADHD symptoms, cocaine use(toxicological measures performed weekly) and cravings (Levinet al., 1998). A subsequent more recent 14 week double-blind

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placebo controlled study of adults with ADHD and comorbidcocaine addiction also demonstrated positive results with extendedrelease methylphenidate being associated with a lowering ofcocaine use despite there being no clinically signicant reduction inADHD symptoms (Levin et al., 2007).

ADHD patients have incidence rates of unprovoked seizures andepilepsy up to two to three times greater than those without ADHD(Fastenau et al., 2009). Among children with epilepsy, ADHD is themost frequent psychopathological comorbidity. In ADHD patientswithout epilepsy, the incidence of seizures does not differ amongthose allocated to methylphenidate, atomoxetine or placebo(Wernicke et al., 2007). Studies also suggest no change in brainelectric activity and no increased risk of seizures in children withADHD with pre-existing electroencephalographic abnormalities oractive seizures who are receiving methylphenidate treatment(Gucuyener et al., 2003). Whilst the summary of product charac-teristics for methylphenidate warns against the use of methyl-phenidate in children whose seizures are not well controlled thereis little evidence to support this proposal. Several studies haveinvestigated methylphenidate in those with ADHD and a coexistingseizure disorder. In patients with well-controlled epilepsy or withinfrequent seizures, methylphenidate was demonstrated to be safeand effective and associated with a low seizure risk (Feldman et al.,1989; Gross-Tsur et al., 1997; Koneski and Casella, 2010; Koneskiet al., 2011).

2.2. Affective disorders

The potential role of methylphenidate in treating patients withdepression has been investigated. Whilst not particularly relevanttoday, an early study of methylphenidate was demonstrated toincrease plasma concentration of the tricyclic antidepressantsimipramine and desmethylimipramine in 7 depressed patients, andthis was hypothesized as having played a role in clinical improve-ment (Wharton et al., 1971). Three cases where depression wassuccessfully treated with methylphenidate monotherapy in elderlypatients who had either been unable to tolerate tricyclic antide-pressants, or had a medical illness that contraindicated tricyclictherapy have been reported (Katon and Raskind, 1980). These au-thors suggested that methylphenidate should be explored as a safeantidepressant agent in this population. In depressed patientssuffering from a general medical condition and hospitalized ineither a medical or surgical unit, methylphenidate resulted in amoderate or marked improvement in 16 out of 29 patients within 2days of the maximum dose being reached (Rosenberg et al., 1991).Later a series of cases of methylphenidate as an add-on to selectiveserotonin reuptake inhibitors (SSRI) therapy was reported (Stollet al., 1996). The authors found clinical improvement, and evenremission, was achieved faster, was more durable and sustainable,and was not anyhow inuenced by presence or absence of ADHDsymptoms (Stoll et al., 1996). Methylphenidate augmentation ofescitalopram treatment in elderly patients with depression also ledto accelerated antidepressant response by week 3 of treatment(Lavretsky and Kumar, 2001). Eight out of 10 patients receivingopen label study medication had signicantly improved by week 8.In the same study 4 out of 7 patients treated with modanilaugmentation started to improve during the rst week of treat-ment, thus meeting criteria for rapid response.

Despite these positive ndings a large multi-center controlledtrial, that included 145 subjects suffering major depressive disor-der, who had failed between one and three previous antidepressanttherapies, found that methylphenidate augmentation of antide-pressant monotherapy for ve weeks resulted in no improvementsas reported by the Montgomery e Asberg Depression Scale(MADRS) and CGI (Ravindran et al., 2008). However fatigue and

apathy were signicantly improved. These contrasting ndings,across different studies, may be explained by the more advancedmethodology of this last trial. This allowed the researchers todifferentiate a more pure antidepressant effect from the reductionof negative symptoms such as fatigue or apathy. It is possibletherefore that the antidepressant effects previously reportedwere also a consequence of activation and increased alertness,rather than a true lifting of low mood. However if this reduction infatigue and apathy is associated with improved functioning andquality of life it should not be ignored.

2.3. Effects in elderly individuals

Several studies have focused on the elderly. The prole ofmethylphenidate effects on cognition in healthy elderly volunteersmay be different from that in healthy young people. Using VisualAnalogue Scales, digit span from Wechsler Adult Intelligence Scaleand tests from Cambridge Neuropsychological Test AutomatedBattery (CANTAB), Turner et al. (2003) found no positive effects ofmethylphenidate on measures of ageerelated cognitive declinesuch as working memory, sustained attention and response inhi-bition. However, as noted above, there is a body of evidenceshowing that methylphenidate in elderly individuals may be usedas a treatment for depression and apathy symptoms. One particularbenet here is the speed of action whereby clinically signicanteffects can be obtained almost immediately. In a randomizedcontrolled trial methylphenidate at a dose of 20 mg/day waseffective in apathetic elderly patients and resulted in improve-ments in their general functioning and affect (Katon and Raskind,1980). In a study using the Hamilton Rating Scale for Depressionto measure outcome in achieved in 11 patients 70 years and older,positive outcomes were reported for methylphenidate adminis-tered as an add-on to SSRIs with rapid onset and clinically signi-cant improvements achieved in 2e3 weeks (Lavretsky et al., 2003).Cantello et al. (1989) reported that, in Parkinson disease with co-morbid major depression, methylphenidate did not provoke anyeuphoric effect. The authors suggested that this could be explainedby the degeneration of dopaminergic neurons in tegmental area.They proposed that this may be important for understanding boththe neurobiology of depression in Parkinson disease, and themechanism of action of methylphenidate. However it is wellrecognized that, in therapeutic doses, methylphenidate does notusually result in euphoria or a drug induced high so this expla-nation may be less signicant than originally thought. In anotherstudy of depressed Parkinson's patients, fatigue did respond tomethylphenidate and patients signicantly improved as measuredby Fatigue Severity Scale and Multidimensional Fatigue Inventory(Mendonca et al., 2007).

2.4. Schizophrenia

Methylphenidate did not reduce tardive dyskinesia in a placebocontrolled study involving 17 patients previously treated withtypical antipsychotics (Fann et al., 1973). In 1976 Janowsky andDavis showed that compared to dexamphetamine, levamphet-amine and levodopa, methylphenidate were the most powerfulinducers of acute psychotic symptoms when given to actively illschizophrenic patients (Janowsky and Davis, 1976). Whilst there islittle evidence to guide decision making the advice on managingschizophrenia in the context of ADHD, which has remained stableover the past decade, is to observe cautionwhen prescribing ADHDdrugs to children and adolescents or adults with a past history ofpsychotic episodes or a family history of psychosis (Greenhill et al.,2002). Where psychotic symptoms do occur with therapeutic dosesof ADHD drugs, they are most likely to be a symptom of a psychotic

E. Sinita, D. Coghill / Neuropharmacology 87 (2014) 161e172 163

disorder, but rarely may represent an adverse drug reaction (Ross,2006). Transient dose reduction or discontinuation of the ADHDdrug is generally the best approach. If the psychotic symptomsresolve, a re-challenge with a different class of ADHD drug may beappropriate. If not, another diagnosis and treatment with neuro-leptics should be reconsidered. It is important however toacknowledge the impact that untreated ADHD may have on anindividual's life and their ability to comply with treatment recom-mendations (Cortese et al., 2013). We were unable to identify anystudies that investigated the effects of methylphenidate on nega-tive symptoms in schizophrenia.

2.5. Eating disorders

A case report described clinical improvements associated withmethylphenidate in a case of bulimia nervosa comorbid with ADHD(Schweickert et al., 1997). Another study built on the hypothesisthat certain types of bulimia nervosa may be associated with co-morbid cluster B personality disorders, (i.e. borderline, narcissistic,histrionic and antisocial behavior patterns and are characterized bydramatic, erratic and emotional behaviors). The authors proposedthat these cases, which are often non-responsive to psychotherapyor antidepressants, resemble ADHD in their impulsivity and maytherefore respond to methylphenidate. The authors reported ontwo patients with bulimia and personality disorder both reducedtheir binging and purging behaviors when started on methylphe-nidate (Sokol et al., 1999). Whilst this is obviously very preliminaryevidence and of low quality it is maybe surprising that furtherstudies have not been conducted.

2.6. Narcolepsy

Whilst narcolepsy is a recognized (although in the UK unli-censed) indication for methylphenidate the supporting evidence,whilst positive, is sparse. Methylphenidate does however seem tokeep narcoleptic patients awake. We only identied one random-ized controlled trial, a comparison study that included pemoline,protryptiline and methylphenidate, but no placebo. Methylpheni-date was given in doses up to 60 mg/day, across divided doses, andwas found to be an efcient waking agent (Mitler et al., 1986). It isbelieved that the stimulants function by facilitating catechol-aminergic systems important for wakefulness (Jouvet, 1969).

2.7. Chronic fatigue

A double-blind placebo-controlled randomized study withcrossover design demonstrated a clear superiority of 20 mgmethylphenidate in reducing fatigue symptoms and concentrationdifculties in 64 patients with chronic fatigue syndrome. Seventeenpercent of patients demonstrated clinically signicant improve-ment of fatigue, and 22% showed improvements in concentration asmeasured by the Checklist Individual Strength and a VisualAnalogue Scale (Blockmans et al., 2006).

2.8. Vascular and organic brain pathology

Methylphenidate has been used in a range of clinical situa-tions following either vascular or organic brain insults. Methyl-phenidate given alongside physiotherapy during the rst threeweeks after a vascular accident improved depressive symptomsand motor functioning (Grade et al., 1998). Lazarus et al. (1992)found similar results with 80% of elderly stroke patients withdepression obtaining full or partial response, as measured byHamilton Depression Rating Scale following treatment withmethylphenidate. A retrospective chart review of 25 post stroke

patients reported very rapid improvements in depressivesymptoms within the rst 48 h of methylphenidate treatment(Lingam et al., 1988).

Compared to both the SSRI antidepressant sertraline and pla-cebo in a double-blind parallel group study of 30 patients withtraumatic brain injury, methylphenidate was superior with respectto improvements in depression, and did not interfere with thenatural neurocognitive recovery (Lee et al., 2005). In the same studywhilst sertraline was effective as an antidepressant, those taking itdid not show the same improvements in cognition seen with pla-cebo and methylphenidate. Methylphenidate has also been shownto reduce anger and temper outbursts in patients after brain injury(Mooney and Haas, 1993). In this study methylphenidate alsoimproved memory and general psychopathology symptomsfollowing 6 weeks of treatment. Another 90 day study of in-dividuals with medium and mediumesevere brain injury foundthat, compared to those receiving placebo, patients receivingmethylphenidate signicantly improved on day 30, as measured bythe Disability Rating Scale. They also improved on memory, atten-tion and vigilance assessments although these improvements werenot sustained and at the end of the study no differences wereobserved between the groups (Plenger et al., 1996). In anotherstudy of individuals with brain injury methylphenidate was foundto reduce the incidence of seizures in those patients whose seizureswere a consequence of trauma (Wroblewski et al., 1992). Howeverthis effect seemed to be blocked by the coeadministration oftricyclic antidepressants. Contrary to these positive results meth-ylphenidate did not result in improvements on a battery ofneurobiological assessments including those measuring attention,learning and cognitive processing speed in a double blind placebocontrolled study of 12 patients with chronic closed head injury,14e108 months post-injury (Speech et al., 1993).

Whilst methylphenidate also seems to have a positive effect ondepression and negative symptoms in patients with dementia(Alzheimer's and vascular) it may be that this is due to the impacton the negative symptoms rather than a true antidepressant effect(Galynker et al., 1997). In the frontal variant of frontotemporal de-mentia, methylphenidatewhen given a single dose of 40mg did notmodify cognition, but did inuence decision making by reducingrisk e taking behaviors (Rahman et al., 2006).

2.9. Epilepsy (non ADHD)

In adult patients with epilepsy methylphenidate was adminis-tered in a non-randomized open label study as add-on to basicantiepileptic therapy for 3 months (Moore et al., 2002). Quality oflife, measured using a disorder specic measure, cognition,measured using the Microcog assessment of cognitive functioning,and fatigue measured using visual analogue scales, all improved instudy subjects. Safety was suggested by lack of negative inuenceupon seizure control, and less than 10% modication of antiepi-leptic drugs plasma concentrations.

2.10. Oncology

Several studies have investigated the potential benets ofmethylphenidate in patients with cancer. An early study reportedthat methylphenidate administered to oncology patients receivingnarcotic analgesia, increased pain relief whilst decreasing sedation(Bruera et al., 1987). An uncontrolled study of methylphenidate addon to morphine analgesic therapy in cancer patients also suggestedthat methylphenidate allowed an increase in mean equivalentdoses of the analgesic whilst reducing sedation, and with 12 out of14 patients reporting clinical improvements. Another study showedthat methylphenidate could counteract daytime sedation caused by


opioid analgesia, and improve night sleep in oncology patients(Wilwerding et al., 1995).

In a one year open label study of methylphenidate used to treat30 depressed cancer patients, ten subjects showed markedimprovement and 13 moderate improvement. Response was usu-ally achieved within days and few side effects were reported.Eleven of these patients were treated for a year without evidence oftolerance or abuse (Fernandez et al., 1987). In another study ofthirty patients with malignant glioma, despite neurocognitivedeterioration, methylphenidate increased stamina, motivation andoverall functioning (Meyers et al., 1998). Fatigue symptoms, as re-ported by the Functional Assessment for Chronic Illness Therapy eFatigue, also improved in 31 advanced cancer patients as a result of7 day treatment with methylphenidate (methylphenidate admin-istered every 2 h, maximum daily dose 20 mg) (Bruera et al., 2003).This study reported improvement in general wellbeing, depression,drowsiness, appetite, pain and nausea. Interestingly all 31 patientscontinued the treatment after the study was nished. Similar re-sults were reported in an open label study of methylphenidate usein 11 advanced cancer patients where only one patient dis-continued treatment because of adverse events (Sarhill et al., 2001).An open-label phase II study led to the conclusion that a 10mg doseof methylphenidate in advanced cancer patients frequentlyimproved depression, anorexia, fatigue, attention and reducedsedation (Homsi et al., 2001), although some patients required anincreased dose for optimal effects. Hypoactive delirium, that wasnot explained by either a metabolic or drug-induced cause,improved in 13 out of 14 patients with advanced cancer treatedwith methylphenidate (one patient died before reaching the ther-apeutic dose) (Gagnon et al., 2005). Children, who survivedlymphoblastic leukemia and malignant brain tumors, but whodeveloped learning and attention problems, improved on methyl-phenidate treatment in a controlled trial as measured by teachersand parents Conners' Rating Scales and Social Skills Rating. Seventynine percent of them continued best therapy after the studynished (Mulhern et al., 2004).

We found one published negative studywheremethylphenidateadministered as prophylactic agent to oncologic patients under-going radiotherapy showed no improvement in either fatigue orquality of life (Butler et al., 2007). The results of the treatmentshowed that methylphenidate was not more effective than placeboon Functional Assessment of Cancer Therapy with brain and fatiguesubscales, and also on Center for Epidemiologic Studies Scale andMini Mental State Examination during 12 weeks of treatment thatsixty eight patients received after their brain radiation therapy.

3. Dexamphetamine and other amphetamine preparations

The amphetamines differ from methylphenidate in that theirpharmacological effects are predominantly mediated by releasingmonoamines although this is complemented by reuptake inhibition(the primary mechanism of action of methylphenidate) and inhibi-tion of monoamine oxidase (Heal et al., 2013). Dexamphetamine isavailable in several European countries and Australia, Adderall(a mixed enantiomers/mixed salts amphetamine preparation) isavailable in North America. Lisdexamfetamine, an amphetamineprodrug, is available inNorthAmerica,Mexico,Brazil, someEuropeanCountries and Australia. Compared to methylphenidate there hasbeen much less study into the use of amphetamines in non-ADHDpatients although studies of lisdexamfetamine are starting to appear.

3.1. ADHD

Ninety eight adults with ADHD, half of whom had a past historyof depression or anxiety, were randomly assigned to receive

psychotherapy and dexamphetamine, antidepressant paroxetine,both or placebo, in a 20 week trial. Those receiving both activemedications together showed a greater rate of adverse eventswith no added improvements on Hamilton Rating Scales of Anxietyand Depression, compared to those receiving each active drugseparately (Weiss and Hechtman, 2006). The presence of a lifetimeinternalizing disorder attenuated the response to dexamphetamine.


Whilst the have beenmany studies indicating that amphetamineabuse is associated with high levels of depression, few studies haveinvestigated amphetamines, used in therapeutic doses, as anadjunct treatment for depression. A small placebo controlled ran-domized trial of dexamphetamine in men with depression and fa-tigue in the context of HIV reported that 8/11 (73%) of those treatedwith dexamphetamine reported signicant improvements in bothmood and energy levels compared to 3/12 (25%) of those treatedwith placebo (Wagner and Rabkin, 2000). Interestingly despite alack of clinical trial data, both in absolute terms andwhen comparedto methylphenidate, the Maudsley Prescribing Guidelines mentiondexamphetamine 20 mg/day treatment as monotherapy for un-complicated depression, as adjunctive treatment in severe depres-sion, monotherapy in advanced cancer and in depression secondaryto general illness and HIV (Patra, 2012).

An interesting case study published in 2001 describes a patientwho had been suffering from obsessive e compulsive symptomsand tics from early childhood who had not responded to variousSSRI treatments, even at high doses, or to the deep brain stimulationof the anterior internal capsule. This patient experienced suddenand dramatic improvement in affective symptoms and no change inhis tics, after he took Adderall (a mixed enantiomers/mixed saltsamphetamine preparation) prescribed to his son, (Albucher andCurtis, 2001). An open-label trial of Adderall administered to thir-ty two adult patients with ADHD and a comorbid general anxietydisorder, who had failed to respond to 8 week long SSRI treatment,found that anxiety symptoms measured by the CGI severity sub-scale and the Hamilton Anxiety Scale improved after 12 weekstreatment with Adderall as an add-on to SSRIs (Gabriel, 2010).Statistically signicant differences were also found for the AdultADHD Self-report Scale, and Sheehan's Disability Scale.

3.3. Schizophrenia

In an open-label case series with 6months follow up (2 years for2 study subjects) it was shown that stimulants, such as Adderall,could be safe and efcacious in case of ADHD comorbid withchildhood-onset schizophrenia (Tossell et al., 2004).

3.4. Chronic fatigue

In a six week parallel-design placebo controlled randomizedstudy, 9/10 patients suffering from chronic fatigue syndrometreated with dexamphetamine made clinically signicant im-provements on the Fatigue Severity Scale compared to four out often on placebo (Olson et al., 2003). The authors suggest that whenthe cause of the fatigue is a focal dysfunction on neural pathways,dexamphetamine might have an impact in adaptation of previouslyunused pathways as well as the development of new pathways toreplace those damaged.

3.5. Vascular and organic brain pathology

Whilst amphetamines have been reported to have a directimpact on post-stroke recovery that is correlated with both


neuronal and synaptic growth during the recovery phases (Khokaret al., 2003) a recent review concluded that the current evidencewhich consists of case e studies, open-label and comparisonstudies remain insufcient to make rm conclusions (Walker-Batson, 2013). Berthier (2005) reviewed the literature and re-ported that amphetamines can result in long lasting improvementsin sub-acute aphasia (language comprehension and formulationdisturbance caused by specic regional brain dysfunction) in poststroke patients. All twenty-ve post-stroke patients administeredamphetamine, L-dopa, both or L-dopa combined with physio-therapy, improved clinically, on the Fugl-Meyer score and Barthel'sindex, regardless of which therapy was given (Sonde and Lokk,2007) making clear conclusions difcult to draw. Compared toplacebo amphetamine combined with physiotherapy did not resultin any additional improvements in post-stroke recovery in elderlypatients who suffered a sub-acute stroke (Sonde et al., 2001). Astudy of dexamphetamine vs placebo administered for 4 days to 10hemiplegic patients after ischemic infarction did not show anysignicant differences in study and control groups at the end of 10sessions, but signicant effect of dexamphetamine was observedafter the treatment was discontinued and at the 12 months follow-up visit (Walker-Batson et al., 1995). A prospective trial ofdexamphetamine and 10 sessions of aphasia treatment in 21 post-stroke patients who had suffered non-hemorrhagic infarctionfound that treatment with dexamphetamine was signicantlybetter than placebo, as measured by the Fugl-Meyer Motor Scale(Walker-Batson et al., 2001).

4. Lisdexamfetamine

Lisdexamfetamine is a therapeutically inactive amphetamineprodrug which, after oral ingestion is hydrolyzed on the surface ofred blood cells to L-lysine and Deamphetamine. As a consequence,lisdexamfetamine has an extended duration of action withmaximum plasma concentration of dexamphetamine achieved in3.5e3.7 h (Boellner et al., 2010), and clinical effects that persist upto at least 13 h in children and 14 h in adults. The fact that thisextended duration of action is a consequence of rate limitingbiotransformation distinguishes lisdexamfetamine from other thelong acting stimulants that depend on a range of physical deliverytechnologies. Since lisdexamfetamine is not bio-transformed intoits active compounds any more rapidly if inhaled or injected, therisks of drug abuse are considerably reduced. Lisdexamfetamine isat least as effective a treatment of ADHD as are the long actingmethylphenidate compounds and the non-stimulant atomoxetinewith recent European studies suggesting it may even be moreefcacious (Coghill et al., 2013; Dittmann et al., 2013). In the USlisdexamfetamine was approved by the FDA for children withADHD in 2007, and for adults in 2008. Lisdexamfetamine is alsoapproved for the management of ADHD in children and adults inCanada, Brazil and Australia and for children who are not optimallytreated with methylphenidate in the UK and several other Euro-pean countries.

4.1. ADHD- comorbidities and non-core symptoms

In children lisdexamfetamine was shown to be effective inimproving emotional lability as well as core ADHD symptoms(Childress et al., 2014). The study demonstrated that the reductionof affective symptoms was not dependent on initial emotionallability intensity, and decreased in both groups of patients (ADHDwith not prominent and prominent emotional lability at baseline)versus placebo. No worsening in emotional expression in childrenwith ADHD treated with lisdexamfetamine for 7 weeks wasobserved in an open-label trial with Emotion and Expression Scale

for Children used as primary outcome measure (Katic et al., 2012).Lisdexamfetamine improved reading rate but not accuracy on theGray Oral Reading Test - 4 in a modied laboratory school studyinvolving 26 children aged 6e12 (Wigal et al., 2012). Lisdexamfet-amine did not improve smoking cessation rates or concomitantnicotine dependence in adults with ADHD in a small study of 32subjects (Kollins et al., 2014).


In a study that aimed to analyze the response to the stimulant inescitalopram non-remitters, adults with Major Depressive Disorderwho failed to respond to an 8 week trial of escitalopram, wereadministered lisdexamfetamine or placebo for the period of 6weeks. The primary endpoint assessment was the Montgomery eAsberg Depression Rating Scale (MADRS) (Trivedi et al., 2013). Theresults were positive with reduced depressive symptoms and anadjusted effect size of 0.3 for lisdexamfetamine. An exploratoryopen-label pharmacokinetic study of concomitant administrationof lisdexamfetamine and venlafaxine extended release revealed noalteration of exposure to either lisdexamfetamine or venlafaxinewith combined treatment. However increased blood pressure andpulse in the combined group suggests a need formore rigorous vitalsigns monitoring when these medications are given together(Ermer et al., 2013).

An interesting study of lisdexamfetamine in 45 adult patientswith stable bipolar I/II disorder and comorbid ADHD found thatlisdexamfetamine administered as add-on to the participants usualmedications for four weeks had a benecial impact on not onlymajor metabolic parameters and body weight decrease, but also onthe Self-Report Scale, MADRS and CGI scores (McIntyre et al., 2013).No subjects were discontinued due to destabilization of the bipolardisorder.

4.3. Schizophrenia

Lisdexamfetamine was administered in a 10 week open labelstudy followed by a 4 week randomized placebo controlled with-drawal, as adjunctive therapy to outpatients treated with atypicalantipsychotics with clinically stable schizophrenia and predomi-nant negative symptoms (Lasser et al., 2013). At week 10 more thana half of participants signicantly improved on both modied Scalefor the Assessment of Negative Symptoms (minimum of 20%reduction), and Positive and Negative Syndrome Scale. Abrupt lis-dexamfetamine discontinuation did not however result in anyworsening of positive or negative symptoms.

4.4. Chronic fatigue syndrome

In adult patients with chronic fatigue syndrome, lisdexamfet-amine was signicantly better than placebo in improving fatiguesymptoms, pain and global functioning, but did not show anybenets for emotional control, initiative, working memory, plan-ning/organizing and task monitoring included in subscales of theadult version of the Behavior Rating Inventory of Executive Func-tion (BRIEF)(Young, 2013).

4.5. Multiple sclerosis

The hypothesis that lisdexamfetamine may improve cognitionin multiple sclerosis patients was supported in a recent phase IIdouble e blind placebo controlled study with sixty three ran-domized patients (Morrow et al., 2013). Patients treated with lis-dexamfetamine signicantly improved on Symbol Digit ModalitiesTest and CVLT2. Although there was no improvement observed on


other measured outcomes, including other cognitive assessments,depression and fatigue evaluation e lisdexamfetamine was shownto improve cognition and mental speed.

5. Modanil

Modanil was approved in the US for use in narcolepsy, shift-work sleep disorder and obstructive sleep apnea with residualexcessive sleepiness despite optimal use of continuous positiveairway pressure (a treatment for sleep apnoea) (Kumar, 2008). Itspharmacological action seems to be somewhat similar to thestimulants though the mechanism of action is not fully understood(Gerrard and Malcolm, 2007). Modanil has been shown toimprove a range of cognitive functions including spatial span,working memory, rapid visual information processing and atten-tional set-shifting in healthy volunteers as well as in patient groupsincluding ADHD and schizophrenia (Saavedra-Velez et al., 2009;Turner et al., 2004a).

5.1. ADHD

Modanil has been shown to improve cognitive functioning inadults with ADHD. In a study involving 20 subjects, in a similar wayto its effects on healthy individuals improvements were seen ontests of memory span, visual memory, spatial planning, and motorinhibition (Turner et al., 2004a). These improvements in accuracywere accompanied by slower response latencies suggesting thatmodanil may increase the ability to reect on problems as wellas reducing impulsive responding. Modanil was superior to pla-cebo at improving symptoms on both the Teacher and Parent ADHDRating Scale-IV scores in 6 week double blind placebo controlledtrial of 46 children and adolescents with ADHD, whowere assessedas out-patients using Teacher and Parent ADHD-IV Rating Scale asprimary outcome (Kahbazi et al., 2009). In another, much larger,study involving 638 children and adolescents with ADHD, mod-afanil was again superior to placebo on the ADHD-IV Rating Scale,CGI and Conner's Parent Rating Scale e Revised, especially in thosewith either inattentive or combined subtypes of ADHD (Biedermanand Pliszka, 2008). Overall the efcacy of modanil in those withADHD is comparable to that seen with the stimulants. The usualclinical dose is around 200 mg/day (Taylor and Russo, 2000). Sig-nicant adverse effects in clinical trials, including a case of Stevens-Johnson syndrome, a life-threatening skin condition, in which celldeath causes the epidermis to separate from the dermis, led to theapplication for licensing being withdrawn.


In a very small trial all 7 patients receiving modanil as an add-on to antidepressant treatment achieved full or partial remissionwithin a very short period of 1e2 weeks (Menza et al., 2000). Re-sidual fatigue and tiredness responded the fastest. Another study ofmodanil in major depression reported signicant changes in re-action time on the Stroop Interference Test, but not depressionsymptoms, anxiety scales or other aspects of cognition (measuredusing Hamilton Depression Rating Scale, Beck Depression In-ventory, CGI, Visual Analog Scale Fatigue) (DeBattista et al., 2004).An open-label trial in patients with major depression investigatedthe effects of modanil, administered from the beginning oftreatment, as an add-on to paroxetine and uoxetine (Ferraro et al.,2005). Following a period of at least 4 weeks with no antidepres-sant therapy patients receivedmodanil titrated to 200mg/day andeither paroxetine or uoxetine for 6 weeks. Clinically signicantimprovement was noted from the rst week of treatment, andremained stable throughout the study period. Fifty eight percent of

the patients achieved remission according to change in HamiltonRating Scale for Depression (HAM-D) scores. These results could beexplained at least in part by the fact that, in rodents, modanil hasbeen shown to increase extracellular serotonin levels in the dorsalraphe nucleus and prefrontal cortex when administered simulta-neously with antidepressants (Ferraro et al., 2005). Further positiveresults were seen in a large 12 week study of modanil adminis-tered to 245 patients with major depression suffering excessivesleepiness and fatigue. Seventy percent of the 194 patients whonished the study had CGI Improvement scores of 1 and 2 (verymuch improved andmuch improved) (Thase et al., 2006). Modanilwas also found to be effective in a large 8 week randomizedplacebo-controlled trial of subjects with major depressionwho hada partial response to SSRI treatment. At the nal visit, modanilsignicantly improved patients' overall clinical condition comparedwith placebo on the basis of CGI-I scores. There were trends towardgreater mean reductions in the Epworth Sleepiness Scale and the17-item HAM-D, and MADRS scores versus placebo. Whilst mod-anil signicantly reduced scores for worst fatigue at nal visitthere were no signicant differences between modanil and pla-cebo for fatigue as rated at the nal assessment (Fava et al., 2005).Fatigue, depression and excessive sleepiness were reported asresponding tomodanil in patients with seasonal affective disorderin an open-label pilot study involving 11 patients (Lundt, 2004).Notwithstanding several limitations in study design (open labeltreatment was given at one site), a stable change in symptoms ofdepression and improved sleepiness rating scales suggests thepotential for modanil in this group of patients.

5.3. Schizophrenia

A neuroimaging study investigating the effects of modanil oncognition in schizophrenia patients found that only those patientswith suboptimal baseline cognitive functioning showed increasedactivity in dorsolateral prefrontal cortex and that this was associ-ated with improvements in clinical functioning (Hunter et al.,2006). Spence et al. (2005) also found increased activity of theanterior cingulate cortex during a working memory task in a studyof modanil in 17 patients with schizophrenia. However only asubset of these patients showed improved cognitive performance.A further study suggested that modanil may improve short termmemory, attention and set shifting in patients with schizophreniaand that it appears to be associated with only a small risk ofinducing an acute exacerbation of psychosis (5 out of 83 patients onactive treatment compared to 3 of 70 patients in control group)(Turner et al., 2004b). An eight week long double blind exible doseplacebo controlled study of modanil administered as an add-on inpatients previously stabilized on clozapine revealed no signicantbenets in terms of reduction in negative symptoms, improvedcognitive functioning or correction of clozapine related sedationand sleepiness (Freudenreich et al., 2009). There are several casereports that provide inconsistent evidence regarding modanilefcacy in reducing sedation caused by antipsychotic treatment,with some reporting psychosis relapse and others clinicalimprovement (Makela et al., 2003). It seems that individual patientcharacteristics in the population, which may include cognitivefunctioning, genetic polymorphism and current/previous antipsy-chotic therapy may inuence the way that patients with schizo-phrenia respond to modanil (Morein-Zamir et al., 2007).

5.4. Substance abuse

Several studies have investigated the impact of modanil onsubstance misuse. Compared to placebo, modanil increased theduration of cocaine abstinence in individuals suffering from


Brent Sheardown

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conrmed dependence in a large double-blind placebo-controlledstudy of 210 patients (Dackis et al., 2012). Smoked cocaine self-administration was reduced by modanil in frequent users, asshown by a study of 8 non-treatment-seeking cocainee dependentindividuals (Hart et al., 2008). The same study also reported areduction in subjective effect-ratings and cardiovascular measures.However in a larger double blind placebo controlled studyinvolving 210 subjects, modanil was not superior to placebo inreducing the number of non-use days for cocaine, but did signi-cantly reduce craving and maximum number of consecutive non-use days (Anderson et al., 2009). Post-hoc analysis of this datashowed that the active treatment group had better results inreducing levels of alcohol dependence and reducing their cocaineintake. The effective dose was proved to be 200 mg.

5.5. Narcolepsy

Early evidence supported modanil as an effective wake pro-moting agent in those with sleep disorders: more than 80% ofsubjects with idiopathic hypersomnia and 70% of subjects withnarcolepsy reported signicant reduction in sleep attacks anddrowsiness (Bastuji and Jouvet, 1988). The rst large multi-centerdouble blind randomized controlled trial of modanil in narco-lepsy involved 283 subjects and supported the efcacy of modanilas a wake-promoting agent on all three primary outcomes: Sub-jective Sleepiness, SleepMultiple Latency Test and theMaintenanceof Wakefulness Test as well as on the CGI (US Modanil in Narco-lepsy Multicenter USMNMSG, 1998). Quality of life improved inpatients with narcolepsy treated with modanil, and this was re-ected in increased vitality, social functioning and performingvarious activities (Beusterien et al., 1999). This study that included481 subjects showed that improvement in Health-Related Qualityof Life was achieved on a 400 mg dose of modanil. Similar resultswere reported in a later study of 151 outpatients receiving mod-anil for a total duration of 6 weeks for whom fatigue decreasedsignicantly (Becker et al., 2004).

5.6. Fatigue

A small study of 7 patients suffering chronic fatigue syndromewithout any detected comorbidity highlighted that modanilmight not be benecial for these patients as neither clinicalsymptoms nor neuropsychological performance improved withdoses of either 200 or 400 mg (Randall et al., 2005). Modanil alsodid not separate from placebo in a randomized placebo-controlledcrossover trial in post-polio patients suffering chronic fatigue(Vasconcelos et al., 2007). However both fatigue and excessivedaytime sleepiness were noted to be reduced in a series of patientswith primary biliary cirrhosis treated with modanil at minimum100 mg/day for two months in an open-label trial (Jones andNewton, 2007).

5.7. Organic brain pathology

Modanil reduced symptoms of fatigue and excessive somno-lence in patients with multiple sclerosis in a single blind phase 2placebo-controlled study that used Fatigue Severity Rating as pri-mary outcome (Rammohan et al., 2002). Both 200 mg and 400 mgdoses were reported as being safe in these patients, with clinicaleffects similar for both doses. Attention, motor function, motorexcitability, dexterity improved in patients with multiple sclerosisreceiving modanil treatment with concomitant trans-cranialmagnetic stimulation during the 8 week trial (Lange et al., 2009).Whilst a later trial involving 155 patients suffering multiple scle-rosis found no evidence of safety concerns after 5 weeks of

treatment it also failed to demonstrate any clear benets formodanil over placebo (Stankoff et al., 2005). Modanil has alsobeen reported as positive in a 14-day double blind placebocontrolled trial of 40 patients with myotonic dystrophy in whom itreduced fatigue and daytime somnolence, increased vigilance, andimproved quality of life (MacDonald et al., 2002). These resultssupport those obtained in an earlier open label trial which alsoshowed a signicant reduction in excessive daytime sleepiness(Damian et al., 2001). Patients with Parkinson's disease alsodemonstrated amoderate response tomodanil with 35% afrmingsome improvement on active treatment but not on placebo (Adleret al., 2003; Happe et al., 2001). A later small study of thirteenParkinson's patients also reported positive results with a reductionin excessive daytime sleepiness with modanil without signicantimprovement of fatigue symptoms (Tyne et al., 2010). Modanilimproved spasticity in a very small study of ten patients withspastic cerebral palsy (Hurst and Lajara-Nanson, 2002). In patientswith amyotrophic lateral sclerosis modanil resulted in clinicalimprovements in 76% compared to a 14% response rate to placebowith no serious adverse events reported in this randomized trial(Rabkin et al., 2009). Excessive daytime sleepiness in traumaticbrain injury was also reduced by modanil treatment (Kaiser et al.,2010).

5.8. Oncology

In a study based on one-year retrospective chart review of pa-tients treated for between 42 and 183 days (mean: 138 days), withopioid analgesics for pain control and modanil to reduce opioid-induced sedation, there was a signicant improvement in theEpworth Sleepiness Scale (Webster et al., 2003). Even though thestudy included 11 patients only, and was underpowered to conductfurther analyses, the authors concluded that modanil treatmentmay allow the continuation of pain relief despite the signicantadverse effects of the opioid medications, such as excessive sleep-iness. Potential modanil related adverse events such as arterialhypertension and anxiety, were mentioned by the authors, but notinvestigated as a part of the study. Enhancement of variouscognitive skills by modanil was reported in a study involving 82breast cancer survivors suffering persistent fatigue and cognitivedecline following chemotherapy (Kohli et al., 2009). Fatigue, gen-eral activity, mood, walking ability and social interactions alsoseemed to improve with modanil for many breast cancer survi-vors who were experiencing persistent adverse effects almost twoyears after completing treatment. Ten out of 20 patients withadvanced lung cancer chose to continuemodanil treatment after apilot trial that demonstrated efcacy in resolving cancer e relatedfatigue (Spathis et al., 2009).

6. Discussion

Psychostimulants have a clear and very well dened role in themanagement of ADHD where they rank amongst the most effectivetreatments in medicine. Whilst the psychostimulants also seemlikely to be equally effective and safe treatments for ADHD symp-toms in those whose ADHD is complicated by another comorbiddisorder relatively few studies have looked carefully at these pop-ulations. It is likely that this, at least in part, reects a reluctance onthe part of the pharmaceutical companies, who have funded manyof the recent studies, to conduct these non-core studies. There doeshowever seem to be a growing consensus that stimulant medica-tions are helpful at improving the emotional dysregulation andlability that is often associated with ADHD as well as improvingoppositional and perhaps some conduct disorder symptoms aswell. A detailed discussion of the relationship between the medical


use of stimulants and substance misuse is beyond the scope of thispaper. This however remains a controversial topic and current ev-idence is, to a degree, contradictory. Initial meta- analyses sug-gested that treating ADHD with methylphenidate reduces the riskof later substance misuse (Wilens et al., 2003) and this is supportedby a recently published Swedish study using data from nationalregisters (Chang et al., 2013). However another recent meta-analysis found comparable outcomes between children with andwithout medication treatment history for any substance use andabuse or dependence outcome across all of the substances inves-tigated (Humphreys et al., 2013). Current studies do not howeversupport the notion that treatment of ADHD with stimulant medi-cations results in an increase in substance misuse.

Whilst far fewer studies have investigated the potential use ofstimulant medications for non-ADHD indications there data tosupport potential uses in both psychiatric and non-psychiatricmedical conditions. Unfortunately many of the available data arefrom studies conducted quite some time ago, at a time when trialswere less regulated, less expensive and unfortunately not always asrigorously conducted. There are also far more studies investigatingthe use of methylphenidate compared to the amphetaminesalthough new research is emerging and there are several studiesinvestigating the use of lisdexamfetamine, a relatively newamphetamine prodrug, in non ADHD disorders. When looked attogether there are some data to support the use of stimulantmedications in a range of clinical indications but as is often the casewhere data are sparse there are many contradictions that precluderm evidence based conclusions.

Within psychiatry initial evidence suggested that methylphe-nidate, dexamphetamine and lisdexamfetamine may improveoutcomes in those with treatment resistant depression (Katon andRaskind, 1980; Rosenberg et al., 1991; Stoll et al., 1996; Trivedi et al.,2013; Wagner and Rabkin, 2000) although evidence from a largewell designed trial suggest that these effects may relate more to areduction in fatigue and apathy rather than a true antidepressanteffect (Ravindran et al., 2008). Studies with modanil have alsobeen positive and have suggested that when used in combinationwith an SSRI antidepressant it may result in a shortened time toresponse (Ferraro et al., 2005; Menza et al., 2000). Whilst there hasbeen an understandable caution around the use of stimulantmedications in those with psychosis, recent studies have suggestedthat both lisdexamfetamine and modanil may help in the reduc-tion of negative symptoms in schizophrenia and improve cognitiveperformance in some patients although not all studies agree(Freudenreich et al., 2009). It is unfortunate that the early sugges-tions that methylphenidate may reduce binge eating in those withbulimia nervosa (Schweickert et al., 1997; Sokol et al., 1999) havenot been followed up as there is evidence to suggest that impulsive,as well as compulsive, behaviors may play a part in binge eating(Robbins et al., 2012).

In general medicine the nding that stimulants are effectivetreatments for fatigue, whilst not surprising, are important as thepotential therapeutic indications are broader than just for thosewith chronic fatigue and narcolepsy and include post stroke pa-tients, post head injury and those with dementia. For post strokepatients the ndings seemmore positive for methylphenidate thanfor the amphetamines. Zorowitz et al. (2005) reported the ndingsof a large Post-stroke Rehabilitation Recovery Project that included1161 patients. Their aims were to explore how often stimulantswere used in patients recovery, which of them were administered,and what was the effect. No signicant difference in outcomes(length of stay, motor recovery, cognitive recovery, dischargedestination) were observed on stimulant treatment compared toother approaches (including physical, occupational and speechlanguage pathology therapy, antidepressants, antipsychotics and

opioid analgesic medications) (Gassaway et al., 2005). As in thosewith depression and schizophrenia it seems likely that for thosewith organic brain pathologies positive ndings may reect acombination of reduction in fatigue, improvements in concentra-tion and other cognitive functions and a lifting of mood which maybe a direct or indirect consequence of the medication. Similar im-provements in those with cancer are also very encouraging andperhaps deserve more research and clinical attention (Bruera et al.,1987; Kohli et al., 2009; Meyers et al., 1998; Spathis et al., 2009). Inparticular benets in pain control could be transferred to otherconditions where chronic pain is a major problem. It must beacknowledged that the evidence base for many of these claims isrelatively sparse and it was slightly surprising to us that even fornarcolepsy and chronic fatigue the evidence base is not stronger.Most studies are relatively old and neither particularly large norwell designed.

Before concluding it is important to mention safety issues.Safety data for the stimulants when used to manage non-ADHDconditions is sparse and long term data is lacking. Whilst theshort term safety of the stimulants when used to treat ADHD hasbeen well described (Graham and Coghill, 2008) the regulatoryagencies have, over the past few years, quite rightly, voiced someconcern about the lack of good quality, long term safety data for thestimulant medications. In Europe Committee for Medicinal Prod-ucts for Human Use (CHMP) concluded that a study of the long termeffects of methylphenidatewas needed, and in particular more dataon the effects of methylphenidate on growth, sexual development,neurological system, psychiatric states and cardiovascular system(Graham et al., 2011). In response to these concerns the ADDUCE(Attention Decit Hyperactivity Disorder Drugs Use Chronic Ef-fects) research team was formed from a consortium of experts inthe elds of ADHD, drug safety, neuropsychopharmacology andcardiovascular research. Both retrospective studies focusing onalready collected data and prospective studies of new cohorts areongoing with the rst publications starting to appear (Murray et al.,2013). As many of the non-ADHD indications for stimulants are alsochronic conditions that often require longer term treatment theselonger term safety data will be also be important in this context.

In conclusion whilst there is no doubt that the main clinicalindication for the stimulant medications will continue to be for themanagement of ADHD these medications have the potential to beeffective, often as an adjunctive treatment, in a range of otherpsychiatric and medical conditions where, if used more regularly,they may improve patient outcomes. As always further study isrequired to assess both efcacy and safety in these conditions.

Support

No support was received for the preparation of this manuscript.

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