Stimulant drugs

European Child & Adolescent Psychiatry 9: I/27ÐI/43 Steinkopff Verlag 2000 Abstract Stimulants are a key ele-
the risk of peer ridicule and added adult colepsy, resistant depression and partial greater than a year show a clear persist- effective in the reduction of hyperactiv- preferably in realistic practice settings, Clinical Lecturer in Child & Adolescent Department of Child & Adolescent Psychiatry Institute of PsychiatryDe Crespigny Park, Denmark Hill Key words Stimulants Ð pharma-
Department of Child & Adolescent Psychiatry Institute of PsychiatryDe Crespigny Park, Denmark Hill (11) and to a consensus that their chief value was in the treat- ment of the disorders of attention and activity. Their use has The centrally acting sympathomimetic stimulants were intro- increased with increasing recognition of these disorders.
duced into medicine in the 1930s. A chance observation that Besides central stimulation, their actions include appetite they were beneÞcial for children with a variety of mental dis- reduction, sympathetic nervous system activity and the pro- turbances led rapidly to a controlled trial of benzedrine duction of stereotyped repetitive behaviours. This article will European Child & Adolescent Psychiatry, Vol. 9, Suppl. 1 (2000) Steinkopff Verlag 2000 focus mostly on their use in the reduction of hyperactivity; scription for proÞt or abuse. The evidence does not indicate other possible clinical indications will be considered later.
any corresponding increase in abuse of methylphenidate.
Treatment with a stimulant is a key element in the therapy Rather, prescriptions rise because more children (especially of Attention DeÞcit Hyperactivity Disorder (ADHD). When girls) are being diagnosed and treated with stimulants, they are medication is indicated, a stimulant is usually the Þrst choice.
treated for longer, and more adults are being treated (27).
More is known about stimulant use in children than about any There is an increased frequency of clinical recognition of other class of psychotropic drugs. Today, there are four ADHD in many countries, resulting from heightened public marketed immediate-release stimulant medications: methyl- awareness, and (in the US) changes in educational law and pol- phenidate, dextroamphetamine, Adderall and pemoline. No icy that oblige public schools to identify students with ADHD new type of psycho-stimulant has entered the market for more (86). Undertreatment and overtreatment, underdiagnosis and than 20 years. Recently, the d-isomer of methylphenidate has overdiagnosis are all real phenomena; but alarmist or exag- been studied with a view to launching it as a separate medica- gerated reports can also do signiÞcant harm by discouraging tion. Research into methylphenidate delivery, via dermal parents from seeking treatment for suffering children, or other- patch, and pulse release systems is also underway.
wise increasing the stigma and blame borne by families (41).
Studies of the short-term effects of stimulants on the symp- toms of ADHD constitute the largest body of treatment litera-ture on any childhood onset psychiatric disorder. Stimulantshave proved to be effective: improvement has been noted in 65 % to 75 % of patients assigned to stimulant treatment versusonly 4 % to 30 % of those assigned to placebo for methyl- Research in pharmacokinetics now focuses on speciÞc effects phenidate, dexamphetamine and pemoline trials (83).
of stereoisomers and whether tolerance and sensitisation existat the doses used by children with ADHD. There has been noreport of behavioural sensitisation to stimulants (which wouldbe shown by progressive augmentation of stimulant induced behaviours), or of tolerance, in children receiving stimulantson a long-term basis. Stimulants show rapid absorption, low Psychostimulants have been used since the 1930s to attenuate plasma protein binding and rapid extracellular and hepatic hyperactivity and improve cognitive performance (6, 11).
metabolism (62). Each dose of the stimulant medication has a Behavioural therapies are also available. In Europe, where the short duration of action with little carry-over of effects. Mul- prescription of stimulants has been restricted by custom (93, tiple doses are often needed to sustain an effect over the school 107) and by law (25), clinical guidelines recommend an initial day. The effects of methylphenidate and dexamphetamine on rigorous trial of multiple psychosocial interventions such as behaviour appear within 30 minutes, reach a peak within one behaviour modiÞcation, cognitive therapy, family therapy and to three hours and are gone by Þve hours (87). Long-term teacher consultation. In North America, where the prescription tolerance is rare and continual increases in dose are not needed of stimulants has been accepted for decades (85, 107), and to maintain clinical beneÞt (74). The drugsÕ very short elimi- some restrictions have been relaxed, clinical guidelines nation half-lives make stimulants highly eligible for crossover recommend an initial rigorous pharmacological trial.
designs (87) because pharmacokinetic carryover of active drug There are correspondingly large differences between coun- tries in rates of diagnosis and treatment. Large scale surveys This roller-coaster time response complicates dosing suggest that in 1995, 2.8 % of US youth between the ages of schedules. Doses at school are often necessary, in spite of the Þve to 18 years were being prescribed stimulants (27, 73).
risk of peer ridicule and added adult supervision requirements.
Commercial information from pharmaceutical companies sug- Some children seem to have intense wear-off effects (rebound) gests that more than 90 % of the world sales of methyl- in the late afternoon. Controlled studies using actometers and phenidate are accounted for by the US. Stimulant prescription analogue classrooms have not been able to conÞrm this as a is much lower in Western Europe Ð perhaps 15 to 30 times less group phenomenon, but it is encountered clinically in individ- common in the UK and Germany and very much lower still in The absorption of sustained-release methylphenidate is Media reports indicate that the US public has become slower and produces a smaller peak concentration than an increasingly concerned about an apparently dramatic rise in equivalent dose of standard methylphenidate. This pattern of the use of stimulant medication. The increase has also raised absorption does not necessarily translate into good behav- concerns at the US drug enforcement administration (30). It is, ioural control; and the relatively slow rise and ßat curves of however, unlikely that the increase in prescription is due to an plasma levels could mean that slow-release methylphenidate increase in drug diversion to illegal purposes, or due to pre- is more prone to tachyphylaxis (a decrease in the potency of a given dose with repeated administration). Sustained-release suggested that the serotonin effect on hyperactivity is localized formulations of methylphenidate, dexamphetamine, and downstream of dopaminergic neurotransmission and that nor- pemoline have effects on laboratory tasks of attention up to adrenergic neurotransmission was unlikely to play an impor- tant role in improving overactivity of DAT-KO mice. By con-trast, agents that increased serotonergic neurotransmissionwere all observed to reduce hyperactivity in the DAT-KO mice. The high dopaminergic tone probably determines thepotency of the serotonergic inhibitory effect.
The mechanism by which psychostimulants act to reduce Taken together, these data indicate that the primary calm- hyperactivity is not yet known in detail. Frontal-striatal func- ing effect of psychostimulants in DAT-KO mice is mediated tion, as assessed by functional MRI, is affected by methyl- by the 5-HT system. They suggest the importance of a relative phenidate. Methylphenidate improves response inhibition and balance of the 5-HT and dopaminergic systems for normal frontal activation in both children with ADHD and healthy motor activity, so that alterations in any of the parameters that controls, but increases striatal activity in ADHD children, control this delicate homeostatic situation might underlie while decreasing it in the healthy controls (98). In normal hyperactive states. It should however be emphasized that these healthy adults, methylphenidate has recently been shown to Þndings may not necessarily be replicable in human subjects.
have beneÞcial effects on working memory, with the improve- Serotonergic drugs, such as SSRIs, have not shown much ments in working memory performance being related to reduc- promise in the past in the treatment of childhood ADHD. The tions in rCBF in the dorsolateral prefrontal cortex and poste- mice in question seem to have had a different neurochemical milieu from that occurring naturally in children with ADHD.
Methylphenidate enhances stimulus discrimination Other animal models, such as the spontaneously hypertensive processes and processes that mediate the regulation of effort over time (80). In humans, stimulants appear to exert rate-dependent effects on activity levels, and to enhance the motoroutput, rather than the stimulus evaluation stages of informa-tion processing. These effects may involve stimulation of Use of stimulants in ADHD: the evidence basepre-synaptic inhibitory autoreceptors, resulting in reducedactivity in dopaminergic and noradrenergic pathways (81).
For over 50 years ADHD has been treated with stimulant Increasing intrasynaptic dopamine has been hypothesised to medications such as methylphenidate and amphetamines. The enhance executive control processes, and overcome deÞcits in research is so large and well established that the short-term inhibitory control and working memory reported in children effect of methylphenidate no longer requires detailed review.
with ADHD (15). Perhaps the most important regulator of There is no doubt that it is more effective than placebo, in the dopaminergic function is the dopamine transporter (DAT).
short term, for schoolchildren with ADHD. (For a useful This is located on the plasma membrane of dopaminergic neu- bibliography, the reader may consult the National Institute of rons, where it controls the concentration of dopamine by rap- Mental Health Database of Treatment of ADHD on the NIMH idly removing the transmitter from the extracellular space and localising it into the cytoplasm (1). Methylphenidate probably Several groups and organisations have recently attempted acts, at least in part, through inhibition of DAT.
to develop authoritative statements about practice based on the The animal model of DAT-knockout mice could therefore scientiÞc literature. The McMaster University ÔEvidence Base be useful as an analogue to ADHD. Mice that lack the gene for Treatment of ADHDÕ (55), the (UK) Royal College of Psy- encoding the plasma membrane dopamine transporter (DAT) chiatrists Research Unit ÔFocus on the Use of Stimulants in have elevated dopaminergic tone and are hyperactive. This Children with ADHD Ð Primary Evidence-Base BrieÞngÕ (42), activity is exacerbated by exposure to a novel environment.
the National Institutes of Health Consensus Development They are also impaired in spatial cognitive function, and show Conference Statement (November 16Ð18, 1998) on ÔDiagno- a decrease in locomotion in response to stimulants.
sis and Treatment of Attention DeÞcit Hyperactivity DisorderÕ Psychostimulants preferentially inhibit the DAT, but they (http://www.nlm. nih.gov/pubs/cbm/adhd.html), the ÔPractice also block the action of other monoamine transporters (1, 10, ParametersÕ of the American Academy of Child and Adoles- 91). A string of elegantly designed experiments, using numer- cent Psychiatry, the ÔAssessment of attention deÞcit/hyperac- ous agonists and antagonists of dopamine, serotonin and tivity disorder therapyÕ of the Canadian Coordinating Office norepinephrine in DAT-knockout (DAT-KO) mice, has for Health Technology Association (http://www.ccohta.ca), demonstrated that serotonergic neurotransmission can modu- and the ÔGuidelinesÕ of a European professional consensus late hyperactivity without producing concurrent changes in development group (95) are noteworthy examples. In general, extracellular striatal dopamine concentrations ( 22). They also they have all agreed on broad conclusions such as the beneÞ- European Child & Adolescent Psychiatry, Vol. 9, Suppl. 1 (2000) Steinkopff Verlag 2000 cial short-term effects, but all emphasize that many details of have probably carried out these procedures perfectly satisfac- practice cannot yet be based on scientiÞc evidence. Meta- tory; but mechanical methods of meta-analysis may exclude analyses still have to be taken with a great deal of caution: they them and so lose the majority of the evidence base. Similarly, attempt to integrate studies that have used very different many studies use large numbers of heterogeneous outcome methods, and decision rules about which studies to include can measures Ð which may be a strength for the purposes of the lead to small and potentially biased selections from the large particular study but lead to their being excluded from meta- analyses. Investigators, reviewers and editors all need toensure that modern standards of reporting are maintained.
Nevertheless, and in spite of all the reservations that can be Effects of stimulants on children with ADHD raised, the unanimity of so many studies about the short-termeffects of stimulants is compelling. The methodological short- The efficacy of stimulant drugs in ADHD has been evaluated comings of one study are not the same as those of others, so with scores of published studies involving thousands of sub- no serious reviewer has challenged the Þndings of the superi- jects (107). Several formal meta-analyses have been available ority of stimulants to placebo in the short term (85).
for more than a decade (43, 96). There is also a publishedÔreview of reviewsÕ (85) and a recent systematic review (83).
They have established a consensus about stimulant medica- tions. They reduce the symptoms of ADHD. About 75 % ofpatients have clinically meaningful beneÞts and, despite some The exact indications for stimulants are still being debated.
common and transient adverse effects, the medications have a The effect is present at all levels of severity and there is little evidence about the appropriate threshold of severity above Short-term trials have reported improvements in the most which the beneÞts of psycho-stimulant therapy outweigh the salient and impairing behavioural symptoms of ADHD, risk. A positive response to stimulants is not diagnostic for including overt aggression, while the medication is being ADHD, because stimulant medications improve behaviour taken. Individual children show different patterns of improve- and attention in children with other disorders Ð and even in ment with few children showing across-the-board gains. Chil- normal children (70). There have been suggestions that hyper- dren receiving stimulants may still have more behavioural kinetic disorder Ð the combination of cross-situational and severe hyperactivity with marked inattention, in the absence Stimulants produce signiÞcant improvements in daily class of emotional disorder Ð predicts greater positive response to performance, but long-term academic learning has not yet methylphenidate (61). This was not conÞrmed by the recent, been shown to beneÞt. In the classroom, stimulants decrease large-scale and well-conducted MTA trial (described below): interrupting, Þdgeting, Þnger tapping and increase Ôon-taskÕ response seemed to be quantitatively similar in most groups of behaviour. At home stimulants improve parent-child interac- children with ADHD that were studied Ð boys and girls, tions, Ôon-taskÕ behaviours, and compliance. In social settings, anxious and non-anxious. The last word has not yet been said: stimulants ameliorate peer-nomination rankings of social the lack of placebo or non-treatment conditions in the MTA standing, improve problem solving during games with peers trial made it unsuitable for deÞnitive conclusions about the (104), and increase attention during baseball (72). Stimulants factors that determine treatment response. It seems, however, decrease response variability and impulsive responding on that no clinical prediction of who will respond is as effective cognitive tasks (90), increase the accuracy of performance, and improve short-term memory, reaction time, computation, The Royal College of Physicians report emphasized that most cases in research investigations and trials have been Studies of the time course of actions show a different selected on stringent criteria. The bulk of research evidence for pattern of improvement for behavioural and for attentional clinical practice is therefore derived from cases meeting strict symptoms with behaviour affected more than attention. Stim- ADHD criteria in school age children with normal intelligence ulant drugs show a large effect size for behavioural measures who are free of major comorbidity. We know little about how (usually quoted greater than 0.8 SD, e.g. by Elia et al. (18) and far the lessons can be generalized to children in a broader Thurber & Walker (96)), and moderate effect sizes (0.6 to 0.8 group of ADHD, or to those with comorbid conditions or low IQ. There is however a modest amount of information Ð not Reservations can still be made about the details of any one wholly satisfactory but a guide to practitioners Ð about stimu- trial. Most of the reports lack description of methodological lant use in preschool children, and in children with tics, autism, aspects that could increase their likelihood of bias. For learning difficulties, and epilepsy (see below).
instance, most articles do not describe the methods of rando-mization and concealment of allocation. Many of the studies existence of hazards from medication needs to be reckonedinto treatment choices as well, and family preferences are Truly long-term trials do not exist. Even if the methodological important. Psychological intervention is less powerful than problems were to be overcome, it would be ethically difficult medication, but it is still effective Ð and not all children will to run placebo-controlled trials over the whole span from childhood to adulthood when treatments of proven efficacy are ț The combination of both treatments is clearly superior to available. Nevertheless, several controlled evaluations have behavioural treatment alone. It follows that children with now been made over periods of time greater than a year (5, 25, suboptimal responses to behavioural treatment should be 36, 57, 77). Collectively these studies show a clear persistence offered medication as well; unfortunately, in many Euro- of medication effects over time. Gillberg et al. (25) reported pean practices this is not done, or done only after a delay of greater effects at home whilst Schachar et al. (77) and the MTA Cooperative Group (58) show larger improvements at school.
ț The combination of both treatments offers a few advantages The mean total methylphenidate daily doses range between over medication alone: peer relationships become more 30Ð37.5 mg per day. Family-initiated treatment discontinua- satisfactory, parents are more satisÞed with treatment, the tion occurred particularly in children with persistent stimulant dose of medication needed is reduced, and an ÔexcellentÕ related adverse events (77) or in those who were assigned to therapeutic response is more likely. However, in most out- come measures the effect of combined therapy is similar tothat of medication alone. Our inference is that, when med-ication has been the Þrst choice and is effective, the addi- tion of cognitive/behavioural therapy need not be routinebut should be targeted to achieve specific outcomes in Most guidelines recommend combinations of pharmacologi- cal and psychosocial treatments for ADHD, on the basis thatmultiple areas of impairment require multiple modalities oftreatment. The best strategy is not yet established by the trials: clinicians should carefully consider the nature and severity ofthe child's speciÞc impairments and suggest empirically vali- In the six to 15 year age group, all reviewers agree that the ben- dated intervention tailored to the individualÕs problems, the eÞts of stimulant medication in modifying the core symptoms need to maximize compliance, the availability of the inter- outweigh the short-term adverse effects. Pre-treatment base- line assessment of adverse effects is routinely recommended.
A few studies do compare the different pharmacological Many of the problems associated with stimulant use appear to treatments, with each other or with non-pharmacological be relatively mild, short-lived and responsive to dosing or tim- treatments. The small group of studies comparing different ing adjustments. Clinical recommendations are given below.
stimulants suggests that they are more effective than placebo Several researchers have emphasized that many of the sup- but similar to each other. More rigorous studies are needed to posed adverse effects of methylphenidate, such as insomnia establish the relative effectiveness of stimulants and tricyclic and tics, have not in fact been supported by group comparisons antidepressants, bupropion, SSRIs and clonidine.
between stimulants and placebo. These designs can, however, The best current evidence about the comparison between be very insensitive means of detecting severe adverse effects stimulants and behaviour therapy comes from a large, recent which may be infrequent, and therefore not yielding signiÞcant multicentre treatment assessment (MTA) conducted by the group differences, but still important. Long-term surveillance National Institute for Mental Health in the USA. This is a and systematic reporting in large series are required. Unfortu- landmark study, in its careful planning and execution and the nately, data are inadequate on the long-term effects and sever- large numbers of subjects involved. Subjects with ADHD were ity of adverse effects of medication. Timing (e.g. in preschool randomized to a closely monitored programme of stimulant children, in adulthood and around puberty) is an important medication, intensive behavioural treatment, the combination element to be considered in future studies.
of both, or routine treatment in the community. The conclu-sions include: ț A carefully crafted programme of treatment with methyl- phenidate is more effective in the reduction of hyperactiv- There are no universally recognized dosage guidelines and ity symptoms than an intensive programme of behavioural blood tests do not contribute. Research has not yet focussed and cognitive intervention. This does not mean that sharply on some of the pressing practical questions Ð such as methylphenidate is always the treatment of Þrst choice. The choosing the safest dose of dexamphetamine at which to start European Child & Adolescent Psychiatry, Vol. 9, Suppl. 1 (2000) Steinkopff Verlag 2000 treatment (e.g. for pre-school children), deciding whether to Gender should not in itself inßuence the decision to pre- administer a stimulant two or three times a day or more, choos- scribe, but the age of the child and the pattern of problems may ing to increase, decrease or keep the stimulant dose the same, well do so. If hyperactivity is present only in one situation, e.g.
and deciding whether to stop stimulants at the Þrst sign of tics.
only at school or only at home, then stresses in that situation The US National Institute of Mental Health multi-modality should be sought and alleviated as the Þrst line of management.
treatment study of ADHD devised a rigorous algorithm for With school speciÞc problems, speciÞc learning disabilities pharmacological treatment (28) that reßected consensus views should be sought carefully, through psychometric assessment.
and clinical practice across several centres in North America.
If present, then adjustment of educational techniques and This Ôcarefully craftedÕ medication was much superior to com- expectations should be given a try before anti-hyperactivity munity treatment, even though the latter usually included treatments. If hyperactive behaviour is conÞned to the home methylphenidate. It is not necessarily directly applicable to situation, then the possibility of adverse parenting inßuences routine practice, but the principle of careful and frequent mon- should be considered, leading to a parent training approach.
itoring of response and adjustment of dosage is likely to Children with predominant inattention, without significant hyperactivity or impulsivity, may still beneÞt from and toler-ate lower doses of stimulants. In pervasive and severe cases, amulti-modal treatment approach will be needed. Medicationshould be initiated as a trial with proper monitoring of thetarget symptoms deÞned for the individual child.
After careful reading of the trials and systematic reviews, wehave not found it possible to produce unchallengeable guides to practice that would be appropriate everywhere. Clinicaljudgement is still required to make a thorough clinical assess- Preschoolers with ADHD Medication is rarely the treatment ment and an individual treatment plan.
of Þrst choice in preschool children. There are few studies of We can however emphasize the extent of the professional drug treatment in this population in part because, in some consensus that has been achieved among specialists. The Þrst countries, methylphenidate is not licensed for use by children conclusion is that stimulants should be made available for less than six years of age. Spencer et al. (83), however, children with severe disorders of activity and attention. Not all reviewed Þve controlled studies of stimulants with pre-school- clinics yet provide this; in some countries the treatment is used ers and concluded that young children responded less well to so rarely as to be exceptional; we have to regard this as being stimulant therapy than school-age children. These studies unsustainable by the evidence base. Some common assump- showed considerable variability across outcome measures and tions about stimulants have turned out to be unfounded and between subjects. A recent, carefully designed trial has how- need to be corrected. For example, stimulants have a wide vari- ever found substantial improvement in ADHD core behaviours ety of helpful social effects in addition to improving the core in pre-school subjects (effect size approximately 0.8 SD), but symptoms of inattention, overactivity and impulsivity (and the little improvement in compliance with parental instructions effects are highly variable between individuals). The treatment often remains effective for years. The effect is not dependentupon the supposed cause of the disorder: it should be seen as symptomatic and may still help even if there is associated psy- treatment of adolescents with cognitive or behavioural symp- chosocial disadvantage. A further conclusion is that stimulants toms of ADHD, but the rate of response may be lower than for should not always be given. The most powerful therapy is not children of elementary school age. Non-compliance with medication is a greater problem in treatment of adolescents The diagnosis of ADHD is a major selection criterion for due to the increased prevalence of stimulant related dyspho- treatment. We recommend a cautious approach in which fur- ria. The risk of misuse of stimulants is increased in adoles- ther selection criteria are used; a decision tree is provided by cents; giving or selling medication to peers is more common Taylor et al. (95). Either the core problems need to be severe, than abuse by the patient themselves. The drug interactions so that the clinician considers that drug treatment is required that could result from undisclosed substance misuse should be at once or that other treatments will not help unless the core symptoms have been controlled with medication; or a trial ofpsychological interventions should be made Þrst (for up to Stimulants in adults There are relatively few treatment stud- three months) and stimulant medication reserved for those ies targeting this group. Although adult ADHD is a concept whose initial response is not satisfactory.
which has gained in recognition and popularity in recent years as a discrete diagnostic entity and a legitimate focus for ther- higher potential for abuse by the patientÕs peers and family apeutic efforts, it remains contentious. Controlled studies of (33). Dexamphetamine dose is usually one half the dose of treatment with stimulants show response rates varying methylphenidate. Up to 25 % respond positively to one of the between 25 and 78 %, with a mean response rate of 54 %, drugs but not the other. Therefore, if one stimulant is insuffi- lower than that found for children and adolescents. Some stud- ciently effective, another should usually be tried before using ies have reported that side-effects and other considerations result in few adults, even the responders, maintaining them- Long-acting and slow release preparations. Long-acting selves on methylphenidate therapy. The uncertainty of the preparations are appealing for children for whom the standard diagnosis and the prospect of a long-term prescription with a formulations act brießy, those who experience severe rebound stimulant medication can create a dilemma for physicians. A or for whom administering medication every four hours is review of papers abstracted in MEDLINE shows that antide- inconvenient, stigmatising or impossible. The most commonly pressants such as desipramine seem as effective as stimulants, used and systematically studied long-acting proprietary stim- in adults, and conclude that certain antidepressants and stim- ulants are Ritalin-SR (sustained release methylphenidate), ulants may offer a safe Þrst-line treatment for adults with Dexedrine Spansule, Adderall (a mixture of amphetamine and ADHD (38). Pemoline has been shown to have only moderate dextroamphetamine salts) and Cylert (pemoline). These are efficacy, low tolerability in high doses, and concerns about licensed in the USA, but not in many (including most Euro- hepatic dysfunction. It is therefore considered only as a sec- ond-line medication for treating ADHD in adults (108).
The few studies available on long-acting stimulant use, involve small samples ranging from 15 to 30 participants andthe lack of more and larger treatment trials is notable. Theliterature suggests that slow release methylphenidate is an effective treatment for ADHD in the short term, but that itsonset of action may be delayed and that it may be less potent Methylphenidate is usually the Þrst choice, but dexampheta- than the standard preparation. It is particularly useful in the mine may be preferred if the child has epilepsy. A starting dose management of children who cannot take medication at of methylphenidate is 5 mg twice daily, with the dose being school, or those who suffer marked Ôon/offÕ effects of standard adjusted in the light of response. Dose is usually not calculated stimulant preparations. The sustained release preparation is based on body weight but rather based on individual response.
only available as a 20 mg tablet, which is not scored, so that However, the usual range for methylphenidate is 0.3Ð0.7 mg the doses must be prescribed in multiples of 20.
per kg per dose rounded to the nearest 2.5 or 5 mg. The dose The advice for those receiving slow-release preparation may need to rise as high as 15 mg of methylphenidate three methylphenidate as the Þrst trial stimulant medication is to times a day, before response is seen. If higher doses are neces- commence with a single tablet daily. Those who are taking sary, it is advised that a specialist be consulted. The maximum standard methylphenidate, or other stimulants, should receive usually recommended is 60 mg per day. Weight-adjusted guide- an equal dose of the sustained-release preparation rounding up lines, which suggest that doses of 0.3 mg per kilogram show to the nearest multiple of 20. The families should be informed optimal effects, have not been supported by studies of dose- from the outset that their child may need an increased dose of response curves for children with ADHD (71).
the sustained-release drug or an additional dose of standard Another possible strategy is to start with a morning dose methylphenidate if the sustained preparation has a delayed only and assess drug effects by comparing morning and after- onset or too short a duration of action. It is important to remind noon school performance (using a drug-free baseline measure children and parents that the medication should not be chewed to ensure that other factors are not responsible for any differ- or the sustained-release drug will rapidly be absorbed, in a ences). Apart from target symptoms, monitoring should manner similar to standard methylphenidate. Given concerns include recording BP and pulse (at each adjustment of dose, about the impact of sustained-release methylphenidate on then every six months); height, weight and appetite (six weight loss, rating food intake over the course of the day and monthly) with maintenance of a growth chart; and a rating of weight is recommended. It may have a slower onset of action.
tics, depression, irritability, lack of spontaneity, withdrawal, As with the regular formulation there is considerable variabil- rebound behaviour and excessive perseveration (at every ity in response and children should be carefully monitored in visit). Rarely leucopenia, thrombocytopenia, gastrointestinal symptoms or hair loss have been observed in clinical practice.
Sustained-release methylphenidate is dispensed in a wax Dexamphetamine is sometimes said to have a longer dura- matrix preparation from which it is slowly absorbed and one tion of action than methylphenidate, permitting less frequent 20 mg slow-release tablet is expected to approximate to 10 mg doses, but its disadvantages include greater risk of growth standard methylphenidate twice daily (4). Available evidence retardation, appetite suppression, compulsive behaviours and suggests that sustained-release methylphenidate is signifi- European Child & Adolescent Psychiatry, Vol. 9, Suppl. 1 (2000) Steinkopff Verlag 2000 cantly better than placebo for the treatment of ADHD (19, 63, quently Ð we suggest monthly. However, this precaution is not 65, 105). However, it is possible that it is less potent than stan- sufficient Ð indeed, it is not known to be useful. The onset of dard methylphenidate and, thus, children may require a higher hepatitis is unpredictable. Patients should be alerted to notify dose than they would if given the standard preparation (19, the clinician immediately if nausea, vomiting, lethargy, 29). Some studies have concluded that the two drugs were malaise or jaundice appear or if abdominal discomfort persists equally effective, and that the improved compliance expected with slow-release formulation was advantageous (29, 105). Bycontrast, Pelham et al. (65), using a double blind, placebo-controlled, cross-over design, compared standard methyl-phenidate with sustained-release methylphenidate in ADHD, and reported that 70 % of those children for whom continueddrug treatment was necessary, were Þnally recommended stan- Stimulant related adverse events occur early in treatment for dard methylphenidate. The remainder were thought to respond children with ADHD and appear to be mild, short-lived and equally to either formulation. Pelham et al. (63) compared responsive to dose or timing adjustments. Severe adverse sustained-release and standard methylphenidate with slow- events occur in 4Ð10 % of children treated, with delayed sleep release dexamphetamine and pemoline and concluded that all onset and reduced appetite, stomachache and headache being four drugs were superior to placebo. When individual the most frequently cited. Mild disturbances, for example, of responses were examined, 14 out of 15 children who had been sleep and appetite are more common. Some children experi- continued on medication were recommended a long-acting ence motor tics while on stimulants but it is not clear whether drug. Fitzpatrick et al. (19), in a double-blind, placebo-con- this results from stimulants or from the development of a pre- trolled, cross-over trial of standard methylphenidate, sus- existing diathesis. Two groups report that sleep and appetite tained-release methylphenidate and the two combined, con- problems are similar between sustained-release and standard cluded that all three regimes seemed similar in efficacy methylphenidate (19, 105), while PelhamÕs group reported although there was a non-signiÞcant trend favouring the com- that although other adverse effects were similar between dif- bined treatment for every clinical measure.
ferent drug conditions, sleep and appetite problems were more Adderall is a mixture of dextroamphetamine sulphate, prominent with the longer-acting drugs (63). Hepatotoxicity dextroamphetamine saccharate, amphetamine sulphate and has been reported for children treated with pemoline on a amphetamine aspartate salts. It is functionally more potent long-term basis (8, 111). Occasionally children have been than methylphenidate and has a longer half-life (66). For doses reported to display cognitive impairments or perseverative of Adderall greater than 5 mg, signiÞcant time course effects behaviours but these usually respond to a decrease in dose. In are seen. Rapid improvements on teacher ratings and math per- rodent models, very high doses of stimulants have inßuenced formance are observed by 1.5 hours after administration, and the growth of hepatic tumours (16), though this has never been these effects dissipate by the end of the day (87). The timing demonstrated in children. Rarely children receiving high doses of peak effects and the duration of action increase with dose.
of stimulants have shown psychotic reactions or hallucinosis.
It has also been shown that single-dose treatments of Adderall Despite the Consensus Development Conference report cau- are as effective as two daily doses of methylphenidate and tioning that high doses of stimulants may cause CNS damage, therefore increase the possibility of managing treatment with- cardiovascular damage and hypertension, these effects have out involving the school in medication administration (52).
been reported only in children taking much higher doses than The differences in time-response patterns of Adderall and therapeutically recommended. For example, the dose-related, methylphenidate may help tailor treatment to meet speciÞc psychotomimetic effects of dexamphetamine in normal indi- clinical needs of different children with ADHD.
viduals require single oral doses 30 times that used in children Magnesium pemoline has the least abuse potential of the Ð 300 mg single dose dexamphetamine versus 10 mg in a child stimulants. It may be given once a day although absorption and (3) resembling conditions formed in severe overdose but not metabolism vary widely and some children need two daily in standard practice. No consistent reports of behavioural doses. It shows effects within the Þrst one to two hours after a rebound, motor tics, compulsive picking of nose and skin, dose, lasting for seven to eight hours after ingestion. The dose dose-related emotional or cognitive constriction, or dose- of pemoline is roughly 1.5 times the total daily dose of related growth delays have been found in controlled studies methylphenidate (starting at 37.5 mg per day; maximum Þnal (83, 84). They should therefore be seen as untoward events dose of 112.5 mg per day). At current dose recommendations, rather than an expected part of the package of actions.
chorioathetoid movements, insomnia, chemical hepatitis and Adverse effects seem to be similar for all stimulants and even very rarely fulminant liver failure have been reported, increase with the dose. They are often transient; decreasing the leading to it being unlicensed in many countries. Liver dose eliminates or reduces common side-effects such as enzymes should be assessed before treatment and subse- irritability, headaches, abdominal pain and loss of appetite.
Persistent or severe side-effects may require a change of drug.
Increased excitability, activity, talkativeness, irritability andinsomnia may all be troublesome four hours or more after a Co-morbid symptoms may alter the response to stimulants in dose. Management strategies include increased structure after school, a dose of medication later in the afternoon (oftensmaller than the morning and midday doses), use of long- ADHD with chronic tic disorders Some children with ADHD acting formulations and the addition of clonidine. Persistent develop transient, usually subtle, tics when one of the stimu- stimulant-related dysphoria may decrease with lowering the lant medications is initiated. Stimulants should be used with dose, but may also require switching to a different stimulant caution when there is a patient or family history of tics. If or to an antidepressant. Growth retardation (decrease in ADHD symptoms cause functional impairment and other expected weight and height gain) resulting from stimulant use medications are ineffective or have unacceptable side-effects is infrequent; it can usually be managed by using drug-free and if parents are capable of close monitoring, a stimulant may periods of a few weeks to allow for catch-up growth. There is be used even with a history of tics. If tics appear or worsen, the little evidence that stimulants produce a decrease in the seizure usual response is to observe for a few days or a few weeks but threshold or that addiction results from the prescription of if tics remain problematic, dose reduction or a different med- ication may be tried. Children with TouretteÕs disorder have Stimulants are contraindicated in schizophrenia, severe shown either worsening (78) or improving frequency patterns depression, hyperthyroidism, cardiac arrhythmias, angina (21). Clinical judgement is required to balance the relative pectoris, glaucoma and when the drug has previously caused impairment from tics and from ADHD symptoms and consid- hypersensitivity. Caution is needed in the presence of hyper- ering efficacy and safety of stimulants versus other medication tension, tics, epilepsy, pervasive developmental disorders, or psychosocial treatments. In the short term, many experience severe mental retardation, drug or alcohol dependence and improvement in ADHD symptoms with acceptable effects on family history of TouretteÕs syndrome.
tics (13). Methylphenidate appears to be better tolerated thandexamphetamine (13). The safety over the longer term is notclear. In prepubertal children, long-term treatment withmethylphenidate, with mandatory careful clinical monitoring, has been described as relatively safe and effective for the man-agement of ADHD behaviours in many (but not all) children Even when the child is well regulated in school, stimulants with mild to moderate tic disorder (21). The few studies avail- cannot easily be used to cover very important home routines able suggest that clonidine is as effective in children with such as getting ready for school, doing homework and com- TouretteÕs syndrome plus ADHD, as in children with ADHD plying with bedtime schedules. Late mornings in school are without tics. Tricyclic antidepressants such as imipramine not covered by a very early dose (leading to the need for a appear to have an advantage, as they improve ADHD symp- second dose), and multiple doses are often required during the school day. Stimulants given after 4 pm (to cover homework)can result in insomnia. Administering the medication in school ADHD with anxiety disorder The MTA study suggests that generates a variety of problems including irregular supervision children with co-morbid anxiety respond as well as those with- by busy school personnel, poor record keeping of schedule II out anxiety, but the issue remains controversial. Anxiety dis- drugs, thefts, and the risk of peer ridicule for the child with orders have been reported to show an increased placebo ADHD. Combination administration of immediate release and response rate (17, 68, 69), a greater incidence of adverse sustained release stimulant pills though very popular in prac- effects, and less improvement on cognitive tests (89) during tice has been tested in only one controlled study and found to randomised controlled methylphenidate trials. Careful moni- be no more effective that sustained-release tablets alone (19).
toring is therefore called for. A recent study reports that care- The reasons why children may come off stimulants may be ful titration of the dose of the stimulant results in equal because of the troublesome side-effects like anorexia, weight response rates in both ADHD with anxiety, and ADHD with- loss, headaches, insomnia and tics, which affect a small minor- out anxiety (14). Another study reports that anxiety could actu- ity of the children; also the warnings on the packet, of high ally be a result of intermediate- to long-term stimulant med- abuse potential, of drugs such as Adderall or dexamphetamine, ication use, and/or a potential marker for a poor response to lead to drug drop-out, poor compliance or failure of parents to intermediate- to long-term stimulant treatment (100). Patients initiate the treatment. Stimulants may show differences in with ADHD and co-morbid anxiety disorder or depression response across settings and domains in the same child (64), may respond better to TCAs than to stimulants. Buspirone is and make reliable predictions of drug response very difficult.
an appropriate choice in this population. European Child & Adolescent Psychiatry, Vol. 9, Suppl. 1 (2000) Steinkopff Verlag 2000 ADHD with mental retardation Patients with ADHD and mild the dopamine transporter in the striatal area of the brain, but at degrees of intellectual retardation may beneÞt from and toler- a rate far slower than intravenous cocaine (101); which may ate stimulant medication. Children with an IQ of less than 45 explain why methylphenidate is abused less often than are less likely to have a clinically signiÞcant positive response cocaine. Although methylphenidate does appear in the emer- and are at greater risk for adverse effects.
gency room mentions and the Drug Abuse Warning Network,its mention-rate is only 1/40 of cocaineÕs (27). Since 1990, in the United States of America, there has been a Þvefold increase behaviour is often reduced during the drug treatment of in the emergency room mentions of methylphenidate in the children with ADHD (see above). The combination of methyl- Drug Abuse Warning Network and a tenfold increase among phenidate and behaviour modiÞcation is often advocated to children 10 to 14 years of age, who are just as likely to report enhance clinical outcome for children with ADHD and other abuse of methylphenidate as of cocaine (55). Adolescent treat- disruptive disorders, and supported by some small-scale stud- ment centres have uniformly reported an increase in abuse of ies (e.g.: 44, 45). Methylphenidate enhances the impact of methylphenidate although few adolescents report this drug as behaviour modiÞcation more often than vice versa; but some children who do not respond well to medication may never- On the other hand, Biederman et al. (9) have reported that theless be helped by a behaviour therapy approach. Conduct treatment with stimulants may actually have a beneÞcial effect disorder is heterogeneous and non-hyperactive forms of con- by decreasing the rate of drug abuse in this population.
duct disorder are not usually responsive to stimulant treatment.
However, the numbers in this study are very small and needreplication.
ADHD and other neurological disorders When inattentive- In conclusion, childhood ADHD is associated with an ness, impulsiveness and overactivity are present as a result of increased risk of drug abuse and cigarette smoking, but the a known syndrome affecting the brain, then stimulants are balance of evidence does not suggest that psycho-stimulants often effective. Fetal alcohol syndrome, for example, is not a increase the risk of abuse. There are, however, only very lim- contraindication. Similarly, a series of double-blind, placebo- ited published data on the extent of illicit use, and the absence controlled case studies evaluated the effect of methylphenidate of published data from Europe may camoußage a problem that on four children with Williams syndrome. Two of them might be growing as methylphenidate becomes more widely responded favourably in terms of decreased impulsivity, prescribed. It is therefore imperative that clinicians prescrib- decreased irritability, and lower activity as well as well as ing stimulants should monitor the use of the drug properly, improved ability to pay attention (7). The effect of the med- making sure that it is not being abused by the childÕs family, ication is symptomatic and is not dependent upon underlying peers or those dispensing medication at school.
aetiology (92). Recently, Havens and McCaskill (35) havedemonstrated that ADHD symptoms in children with congen-ital Acquired Immune DeÞciency Syndrome (AIDS) respondto stimulants, though they may have more side-effects.
with epilepsy and ADHD have shown that it is more effective As a rule, it is recommended that the order of monotherapy is than placebo and no more likely to produce an increase in Þt stimulants (methylphenidate or dexamphetamine). When frequency (32). These relatively small trials are reassuring, but refractory to stimulants, after a re-assessment, depending on cannot necessarily be generalized to children with poorly con- the individual needs of the case, imipramine, nortriptyline, trolled epilepsy. We still prefer dexamphetamine as the drug clonidine or carbamazepine are used. Only methylphenidate of Þrst choice for the subgroup of children who are at particu- and dexamphetamine should be used in most generic mental lar risk of developing status epilepticus. Good information health and paediatric services; the other drugs are unlicensed about Þt frequency over long periods is essential.
for this indication in most countries and should be reserved forspecialist centres. It is recommended that if one stimulant is ADHD with drug dependence The drug regulatorsÕ concern insufficiently effective, another should be tried before using about increased methylphenidate production has been stated as follows: children with ADHD are at increased risk for drug useand abuse in adolescence; adolescents with ADHD are beingtreated in increasing numbers with methylphenidate; methyl-phenidate may become increasingly abused, diverted, or serve Stimulant co-pharmacy and combined pharmacotherapy as a gateway to other illicit drugs. Oral methylphenidate how-ever, is not likely to induce euphoria in the same way as Co- pharmacy implies the use of two or more medications to cocaine. When given orally, [C11]methylphenidate occupies treat different disorders (e.g. SSRI and antipsychotic medica- tion to treat depression in schizophrenia), while combined Methylphenidate and antidepressants Although used safely pharmacotherapy implies the use of more than one medication in some contexts, in clinical practice, the combination of to treat a disorder (e.g. methylphenidate and clonidine to treat imipramine and methylphenidate has occasionally been ADHD). Stimulant prescription as part of co-pharmacy is less associated with confusion, affective lability, aggression and controversial than combined pharmacotherapy, in the major- agitation (31). It is postulated that methylphenidate can increase plasma levels of imipramine unpredictably, demand-ing caution in the use of the combination. Methylphenidate Combining clonidine with methylphenidate should not be administered together with monoamine oxidase has been concern about the use of clonidine in combination with stimulant medication (86). This concern has been basedon the cases of four children who died suddenly. The evidence Stimulants and neuroleptics Dopamine blocking agents may derived from these cases is hard to interpret because of special seem an illogical combination with stimulants; but there is circumstances and inadequate detail (109). Recommendations some trial evidence for an increased benefit for methyl- are conßicting: Swanson, Conner and Cantwell (88) believe phenidate plus thioridazine over methylphenidate alone Ð that the use of the combination is ill advised until controlled especially in behaviour as seen at home rather than at school studies can be conducted to evaluate efficacy and side effects.
(26). This must be set against the known toxicity of neurolep- Most practitioners appear to be taking the line of cautious use tic drugs, and cautious practice will only use the combination rather than a complete ban, and including ECG monitoring in in rare and extreme circumstances. In principle, the advent of atypical neuroleptics with fewer hazards may have altered the Clonidine is not a stimulant but works through alpha ratio of risk to beneÞt. Risperidone, for example, is coming adrenergic mechanisms. Limited effectiveness of clonidine as into frequent use before trials have been completed, on the a single therapy has been shown in the treatment of ADHD and basis of a reputation for fewer extrapyramidal hazards. It is not in TouretteÕs disorder (40, 48). It is considered in ADHD free of adverse effects, sedation and weight gain being promi- particularly when tics, features of pervasive developmental nent; and it antagonizes some of the actions of methyl- disorder, or insomnia are part of the clinical presentation, but phenidate (such as those mediated by D2 receptors). In our its value is restricted because of relatively small effect and the view, the combination of stimulants and neuroleptics Ð like other forms of polypharmacy Ð should only be embarked on Clonidine is initiated at a dose of 25 to 50 mcg at bedtime by a specialist service; and that in those exceptional cases and the dose is titrated gradually over several weeks up to 150 where it is to be used, then an atypical neuroleptic should be to 300 mcg per day in three to four divided doses. Pulse and blood pressure should be monitored for bradycardia andhypotension. Clonidine has a gradual onset of therapeuticaction in part because of the slow dose penetration to minimiseside-effects and perhaps due to the time required for receptor down regulation. SigniÞcant clinical response is not seen foras long as a month and maximal effect may be delayed for ADHD is by far the commonest indication, but there are other another several months. When discontinuing clonidine, the circumstances in which stimulants may be considered.
dose should be tapered rather than stopped suddenly to avoida withdrawal syndrome consisting of increased motor rest- Narcolepsy is usually a lifelong disorder, in which daytime lessness, headaches, agitation, elevated blood pressure, pulse sleepiness is a common, and sometimes a distressing, com- rate and possible exacerbation of tics reported in patients with plaint and is often associated with cataplexy (20). When cata- symptoms of TouretteÕs disorder and ADHD. Erratic compli- plexy is not present, then a careful workup is needed to dis- ance with medication increases the risk of adverse cardiovas- tinguish narcolepsy from the other causes of excessive daytime cular events. Families should be cautioned about this and sleepiness such as insufficient nocturnal sleep, sleep apnoea, clonidine should not be prescribed if it cannot be administered drugs, and idiopathic CNS hypersomnia. Dextroamphetamine, reliably. Depression could occur as a side effect, especially in pemoline, methylphenidate, methamphetamine, and clomi- patients with a history of depressive symptoms in themselves pramine are all considered useful; modaÞnil has also been or their families. Glucose tolerance may decrease, especially shown effective in double-blind trials against placebo (97).
in those at risk for diabetes. When combining clonidine with Antidepressant therapy Ð to activate central adrenergic sys- additional medications or if dosing of medication is inconsis- tems Ð is sometimes used for the relief of the other symptoms tent an alternative strategy might be to substitute dexamphet- (sleep paralysis, and hypnagogic hallucinations) that may be amine for methylphenidate or guanfacine for clonidine.
accompanied by abnormal rapid eye movement sleep. Selegi-line (54) and tranylcypromine (24) have also been advocated.
European Child & Adolescent Psychiatry, Vol. 9, Suppl. 1 (2000) Steinkopff Verlag 2000 The disorder is often unrecognized in childhood but is ropsychological ratings. Plenger et al. (1996) reported similar worth considering when falling asleep in class is misconstrued Þndings. Speech et al. (1993), by contrast, did not Þnd that as inattentiveness or rudeness (110). Stimulant medications methylphenidate was any more helpful than placebo on cog- should be considered, but are not always indicated. Education, nitive performance in people who had suffered injury to the emotional and academic support, and careful follow-up over brain. Whyte et al. (1997) used a double-blind placebo com- time are always indicated and may be sufficient therapy.
parison to examine the effects of methylphenidate on various Lifestyle changes (including Ònap therapyÓ) are helpful to at facets of attentional function after brain injury: methyl- phenidate produced a signiÞcant improvement in the speed ofmental processing Ð but not in orienting to distractions, most Depression is more often a result of abusing stimulant drugs aspects of sustained attention, or measures of motor speed. All than a target for therapy with them (46). Nevertheless, the trials are rather small; the results taken together suggest methylphenidate has been advocated as an antidepressant ther- that methylphenidate may have some value in selected cases apy in some circumstances, for example, when other antide- after brain injury, but that it is primarily useful for symptoms pressants fail (60). The evidence base for this use is not strong that can be attributed to slowed mental processing.
(76). It cannot be said that a rigorous evaluation has been Comparable results have been found in children. In a small made, but some expert clinicians recommend it (103). The series of cases (n = 10), children whose behavioural and evidence is best for some special situations: the palliation of cognitive sequelae to traumatic brain injury (TBI) warranted affective symptoms in terminal illness (Macleod 1998), and psychiatric help were treated with methylphenidate. In two of the combination of depression and lack of energy that may the cases, it was used to stimulate minimally responsive appear during the course of AIDS (Wagner et al. 1997) and patients, while the rest had cognitive and behavioural prob- other chronic medical disorders (Masand et al. 1996). For lems. Methylphenidate improved cognitive function, behav- fatigue symptoms in multiple sclerosis, on the other hand, the iour and arousal as measured by parental and teacher reports, stimulant pemoline was less effective than amantadine in a evaluation by the rehabilitation team, and/or neuropsychome- tric testing (39). A small-scale controlled trial by Mahalick andcolleagues (51) has indicated a substantial superiority of Counteracting fatigue is more often considered an abuse than methylphenidate to placebo in treating attentional disorders a use; but dextroamphetamine has been found more effective secondary to brain injury. In a case series, methylphenidate has than placebo in sustaining the performance of helicopter pilots recently been reported to improve attentional problems in during long-prolonged operations (12). This, should not, how- children with AIDS-related dementia (35).
ever, be taken as a general recommendation! It is only underextreme circumstances such as combat that the effect on Bulemia nervosa The symptomatology of bulemics who have fatigue will be helpful. A more common experience is the a comorbid cluster B disorder resembles that of patients with deleterious effect of stimulant abuse on the ability to react effi- ADHD in many ways, especially in high levels of impulsivity.
ciently. Logan (1996) collated histories of drivers killed or A pilot study of methylphenidate in two patients with bulemia arrested while under the inßuence of methamphetamine: their and cluster B personality disorder, who had not previously typical driving behaviours included drifting out of the lane of responded to adequate trials of psychotherapy and SSRIs, travel, erratic driving, weaving, speeding, drifting off the road, showed signiÞcant improvement in binging and purging (79).
It has been suggested that methylphenidate should be studiedin this disorder.
Cognitive impairment in ADHD is so often helped by stimu-lants that clinicians will sometimes consider its use in other Conduct disorder As described above, there is little doubt that types of cognitive impairment. So far the evidence does not in unselected series of children with conduct disorder many support it in most circumstances. A pilot trial of sustained- will show comorbid ADHD and many will respond to a stim- release methylphenidate for intellectual blunting in HIV- ulant. It is not, however, shown that children with conduct infected drug abusers did not show superiority over placebo disorder who are free of ADHD will beneÞt at all. Taylor et al.
(van Dyck et al. 1997). Negative symptoms in AlzheimerÕs (92) reported a short-term predictive study within a group of disease and other types of dementia were somewhat lessened boys who showed a wide range of oppositional and hyperac- by methylphenidate in one pilot trial by Galynker et al. (1997), tive symptomatology. The response in symptoms of conduct but the effect size was quite small. However, Gualtieri and disorder was predicted by the degree of hyperactive behaviour, Evans (1988) did Þnd somewhat more promising results in 15 not by the degree of oppositionality. The implication was that patients after traumatic brain injury. Methylphenidate was nonhyperactive boys with good attention but with conduct given in a double-blind, placebo-controlled cross-over design, disorder are unlikely to beneÞt from stimulants.
and there was a modest improvement in behavioural and neu- Use of stimulants during sports by people with ADHD CNS care; costs during the Þrst year of treatment (which are those stimulants used in the management of ADHD are not permit- presented here) are likely to be higher than those in subsequent ted for use in competition by the International Olympic Com- years; potential savings such as a reduced need for behavioural mittee (IOC) and this could pose a problem for the physicians therapy following drug treatment are not accounted for.
of patients with ADHD. On the one hand, attention, concen- Another economic analysis by the Canadian coordinating tration, Þne motor co-ordination and balance are improved office for health technology assessment (CCOHTA) is avail- after methylphenidate administration even in people without able at website: http://www.ccohta.ca. The study used incre- ADHD; on the other, the therapeutic beneÞts are not available mental cost-effectiveness analysis to evaluate alternative to the athlete with ADHD who wishes to compete under IOC approaches to the therapy of attention deÞcit and hyperactivity rules (37). Cessation of therapy 24 hours before competition disorder. Three global approaches were examined in relation- is usually adequate to allow drug clearance, avoiding a posi- ship to non-treatment: pharmaceutical therapy, behavioural tive result on drug testing. Research is essential to study therapy; and the combination of drug and behaviour therapy.
whether stimulants provide an unfair advantage, and to iden- Within the pharmaceutical therapy group, three individual tify the disadvantages that the symptoms of ADHD impose on medications (methylphenidate, dexamphetamine and pemo- affected athletes, before clear guidelines can be given on this line) were considered. Because pemoline is associated with rare but potentially fatal hepatic failure and therefore not con-sidered a therapeutic option by many clinicians, the analysiswas also performed after excluding the strategy. The results ofthe pemoline-exclusive analysis showed that methylphenidate was dominant over both dexamphetamine and non-pharma-ceutical strategies. Methylphenidate cost $ 83 Canadian dol- Economic analyses are just beginning to appear. One comes lars for each point difference in the Conners teacher rating from the Wessex Health AuthorityÕs evaluation unit (available scale or approximately $ 500 Canadian dollars for a clinically on website: http://www.epi.bris.ac.uk/rd/publicat/dec/dec78.
signiÞcant response. Results were generally robust in sensi- htm). This notes that the drug itself is relatively inexpensive, tivity analysis. When medications were given only on school costing about £ 200 per year for a typical course. Including days, the combination therapy became viable, if less cost- costs of out patient clinics increases the cost of treatment to effective, and dexamphetamine was no longer strictly domi- something closer to £ 700 for the Þrst year of full treatment.
nated. When pemoline was included in the analysis at the Other costs (for instance, in lost work for outpatient atten- lower dose used in the literature, the results were similar to dances or if a parent must administer the medicine at school) those for the pemoline-exclusive analysis. Pemoline at the higher dose in the literature became a viable option but was a Their method of quantifying beneÞts is based on estimates little less cost-effective than methylphenidate, with a cost of of quality of life improvements, assuming that effects seen at $ 106 Canadian dollars per point improvement in ConnersÕ four to six months will persist to a year and that all follow up Teacher Rating Scale, and about $ 640 Canadian dollars per would be carried out in secondary care with an average of Þve clinically signiÞcant improvement. Pharmaceutical therapies out patient appointments in the Þrst year. These calculations were more attractive than psychological behavioural therapies therefore represent maximum costs faced by commissioners in under all conditions Ð but the effectiveness of psychological districts where follow-up is entirely hospital based. Costs therapy may have been underestimated by the selection strat- would obviously be less in clinics with less frequent follow- egy which included only a very small number of the investi- up. On this basis, the most plausible estimate gave a cost per gations in the literature and a very small number (less than 20!) Quality Adjusted Life Year of between £ 7,400 and £ 9,200 (depending on how the severity of the disorder before treat-ment is modelled) Ð which compares favourably with mostaccepted medical and surgical interventions. A wide-rangingsensitivity analysis showed that the cost utility estimates were These estimates may well have underestimated beneÞts Decades of research about the use of stimulants have estab- and overestimated costs. The QALY is not a very sensitive tool lished that they are an effective and cost-effective therapy for for the types of changes seen on methylphenidate. The effects children with ADHD. The evidence is exceptionally strong in of methylphenidate on child-teacher relations, peer relations, children of school age and for periods of up to 18 months of self esteem, aggression and anti-social behaviour, and beneÞts therapy; longer-term therapy is based on clinical experience to parents, teachers and siblings were not taken into account.
and consensus. Other indications do not yet have a sound basis Costs may be reduced if follow-up is based largely in primary in trial evidence. Their actions at a psychological level of European Child & Adolescent Psychiatry, Vol. 9, Suppl. 1 (2000) Steinkopff Verlag 2000 analysis have been well described and continue to be a useful the MTA trial from NIMH (cited above) in which details of tool for analysing the nature of the cognitive and behavioural administration seem to have a major effect on the response achieved. Further research, preferably in realistic practice Major gaps in knowledge remain, and some of them hinder settings, can therefore be expected. Different forms of com- clinicians in reaching sound management policies. The bination with psychological interventions need systematic pharmacokinetics, pharmacogenetics and pharmacodynamics comparison. We also need to know much more about the of their effects are known only in sketchy (and sometimes effects in groups of children outside the core of school-aged speculative) outline. Ethical and practical difficulties of children with typical ADHD: preschool children, adults, those research on children have limited the progress made, and with partial syndromes (such as inattentiveness) and those recent advances in minimally intrusive investigations, and in with comorbid disorders call for much more speciÞc investi- therapeutic use in adults, should remedy the deÞcit. Research gation. The research Þeld is active and moving quickly and to establish good regimes of administration has also been lack- clinicians need to familiarise themselves with a changing ing. The importance of this has recently been highlighted by 8. Berkovitch M, Pope E, Phillips J, Koren 15. Douglas VI, Barr RG, Amin K, OÕNeill mitter transporters: recent progress.
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