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DISEASE MANAGEMENT
Central Stimulant Treatment of Childhood Attention Deficit Hyperactivity Disorder
eNS Drugs 1997 Apr: 7 (4): 264-272 1172-7047/97/0004-0264/504.50/0
© Adis InternatJonalumited. All rights reserved.
Issues and Recommendations from a US Perspective
Daniel J. Safer Departments of Psychiatry and Pediatrics, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA
Contents Summary ..................... . 1. OveNiew of the Use of Stimulants in Children . 2. Attention Deficit Hyperactivity Disorder (ADHD)
2.1 Diagnosis.................... 2.2 General Treatment Considerations .....
3. Stimulant Treatment for Typical Cases of ADHD 3.1 Counselling for Stimulant Treatment 3.2 Available Stimulants . . . . . 3.3 Dosage Adjustments . . . . . . . . . 3.4 Frequency of Administration .... 3.5 Monitoring of Continued Stimulant Treatment 3.6 Follow-Up Visits . . . . . . . . . . . . . . . . . 3.7 Duration ofTreatment ............ . 3.8 Treatment Failure ............... .
4. Stimulant Treatment for Atypical Cases of ADHD 4.1 Severity of Illness .... 4.2 Comorbid Conditions . 4.3 Other Disorders . . . . .
5. Adverse Effects of Stimulants 6. Drug Interactions with Stimulants . 7. Conclusions ............ .
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Summary The use of eNS stimulants for the treatment of attention deficit hyperactivity disorder (ADHD) in children has steadily increased in most areas of the world over the last 30 years. In mid-1995, at least 1.5 million US children were receiving methylphenidate or dexamphetamine (dextroamphetamine). However, in other countries these agents are not used as widely.
Specific stimulant-induced benefits for children with ADHD include: improved school grades, more completed classroom work, fewer reprimands for disruptive behaviour, improved handwriting, and improved behaviour at home and in social situtions. Stimulants benefit at least 75% of children with ADHD and are remark-
Stimulants in ADHD 265
ably well tolerated, having few (for the most part minor and temporary) adverse effects.
However, the benefits of stimulants that are obvious in most patients with ADHD during a brief clinical trial are primarily symptomatic. Although the behavioural benefits of stimulants are generally present during each period of treatment for as long as the ADHD condition exists (and children with ADHD are now often staying on stimulant medication into their mid-teens), the treatment has not been shown to change the long term outcome of the disorder.
Before prescribing stimulants, paediatric physicians need to perform a careful diagnostic assessment for ADHD using multiple sources of information, including detailed ratings of the child's behaviour from his/her teachers and from a parent. If at baseline, the child's academic and behavioural adjustment in the classroom is good, stimulant medication would be inappropriate. However, if the child's pattern of ADHD has consistently and seriously interfered with his/her classroom and home adjustment, stimulant treatment should be actively considered. Should stimulant therapy be initiated, knowledgeable medical follow-up is required.
1. Overview of the Use of Stimulants in Children
CNS stimulants are the foremost prescribed and the most researched drug treatment for behavioural disorders in childrenJll Since the late 1960s, the rate of stimulant treatment for children in the US has steadily increased. Between 1990 and 1995, it increased 2.5-fold. By mid-1995, approximately 2.8% of all 5 to 18 year olds in the US (totalling 1.5 million) were receiving the most commonly prescribed stimulant, methylphenidate.[2-41
Stimulant medication for children is almost exclusively prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). When effective, the medication serves to lessen developmental ADHD patterns of undue restlessness, impUlsiveness and inattentiveness. In the US in 1995, approximately 90% of the prescriptions for the 2 major stimulants [methylphenidate and dexamphetamine (dextroamphetamine)] were written for the treatment of ADHD in children, and between 30 and 60% of all US children between the ages of 5 and 14 years exhibiting the predominantly hyperactive/impulsive features of ADHD were receiving one of these stimulant medications)4,51
Although the ADHD pattern appears to be similar across cultures, [6] stimulant treatment is a predominant treatment for the disorder only in the US and
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Canada. This is largely because of legal barriers imposed by governments, and cultural differences.
Adults have been treated with stimulant medication for a number of disorders, including depression in the geriatric years, ADHD symptoms lingering into adulthood, augmentation of standard antidepressant medications, and organic disorders of the brain. A discussion of stimulant treatment for adults is dealt with elsewhereJ7.81
2. Attention Deficit Hyperactivity Disorder (ADHD)
2.1 Diagnosis
Before initiating stimulant medication treatment, a careful diagnostic assessment needs to be made. This primarily involves obtaining a detailed developmental, social-behavioural and medical history from the child's parent(s). Detailed information concerning the child's academic and classroom behaviour from his/her major subject teachers should also be obtained. Table I outlines the common findings in children with ADHD.
Teacher ratings of classroom behaviour are profoundly helpful, particularly if obtained over a period of years. Standardised teacher ratings, such as the Conners Abbreviated Teacher's Rating Scale (CATRS),[91 the Iowa Conners Teacher's Rating
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Table I. Important evaluative and historic findings common to children with attention deficit hyperactivity disorder (ADHD)
105 to 10 pOints below their peers
Visual-motor defect> 1 year below age norms
Sizeable academic deficit relative to age and 10 norms
Pre-school patterns of inattentiveness, restlessness, temper outbursts and destructiveness to toys
Family history of ADHD or related disorders
Social and emotional immaturity
Serious and continued school maladjustment beginning in the early elementary school years
Abbreviation: 10 = intelligence quotient.
Scale (see table 11)[10] and the ADD-H Comprehensive Teacher's Rating Scale (ACTeRS)[11] are quite reliable, far more than are parent ratings and vastly more reliable than are observations of the child's behaviour during a visit to the physician.[12] If the child's teacher ratings are unremarkable, then stimulant treatment is not necessary.
The pertinent medical/psychiatric/educational material is reviewed by the physician with an eye to the diagnostic pattern of ADHD as defined in DSM-IV[13] (see table III). The physician should question that the problem is developmental if the child's deviant behaviour began after the age of 7 years. Alate onset should also raise questions about the diagnosis. Although children do not have to meet all the DSM-IV criteria for ADHD to benefit from stimulant treatment, they have to exhibit major problems in attention and/or behaviour to do so (see section 4.2).
Whereas the use of the DSM-IV category ADHD overshadows the ICD-1O[14] category hyperkinetic disorders, it should be noted that they overlap profoundly. Both are characterised by similar descriptions of attention, hyperactivity and impulsivity. Their major differences are that the ICD-IO category places greater stress on pervasiveness (present in more that one environmental setting) and relatively less stress on inattentiveness as a predominant feature.
2.2 General Treatment Considerations
Before initiating treatment, it is important to establish the degree of the child's maladjustment.
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Safer
If the child's ADHD problems are associated with school suspensions, frequent misconduct referrals to the principal's office, the consideration of a grade retention, falling grades and expulsion, then the need to consider stimulant medication - over slower, more labour intensive alternative treatments - is heightened. Essentially, in cases of severe ADHD, stimulants are advised as the first line of treatment.
Multi-modal treatment, usually consisting of remedial education, behavioural counselling and stimulant medication, may be indicated if the child has notable problems in the educational, social and behavioural spheres. However, the major measure of any therapy is its positive outcome. Thus, if the child with ADHD was referred because of school problems and is now performing well academically and behaviourally while receiving stimulant medication alone, one would be understandably reluctant to recommend additional treatment.
3. Stimulant Treatment for Typical Cases of ADHD
3.1 Counselling for Stimulant Treatment
When discussing medication treatment with the parents of an child with ADHD, it is important to stress:
Table II. Items from the Iowa Conners Teacher's Rating Scale[10] (the child's behaviour is rated according to the descriptions in the column headings)
Classroom behaviour Description --~~~---------------not at all just a pretty very
1. Fidgeting
2. Hums and makes other odd noises
3. Inattentive, easily distracted
4. Fails to finish things he/she starts (short attention span)
5. Ouarrelsome
6. Temper outbursts (explosive and unpredictable behaviour)
little much much
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Stimulants in ADHD
Table III. Major features of attention deficit hyperactivity disorder (ADHD) according to DSM_IVI13Ia
Inattentive Short attention span
Makes careless mistakes
Does not listen well
Fails to finish school work
Poor at organisation
Poorly prepared in school
Easily distracted
Forgetful
Avoids prolonged tasks
Hyperactive
Fidgets often
Leaves seat unexcused
Excessive motion
Unable to play quietly
Talks excessively
Into everything
Impulsive Responds prematurely when questioned
Difficulty waiting his/her turn
Interrupts and intrudes often
a DSM-IV requires 6 inattentive and/or 6 hyperactive/impulsive features for the diagnosis of ADHD.
• the biological, frequently genetic, nature of the disorder
• the prominent symptomatic benefits that commonly result from stimulant treatment
• the very impressive safety record of methylphenidate and dexamphetamine
• the fact that stimulants are not habit forming for children with ADHD)IS) At the same time, it is important to make clear
that stimulant treatment has not been shown to change the long term academic and behavioural outcome of ADHD)16)
If a parent chooses not to use medication to treat ADHD in their child, the parent should be advised to seek conjoint counselling with a psychologist who is experienced in behavioural therapy. If the child refuses to take the medication, an evaluated, time-limited trial without it should be instituted, on the condition that a medication trial will follow pending a failure of the medication-free effort.
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267
3.2 Available Stimulants
Between 84 and 98% of all medications prescribed for ADHD are of the stimulant typeP·4) Three stimulants have been approved for the treatment of ADHD in the US. These are methylphenidate, dexamphetamine and pemoline. Prescribing details concerning these medications are presented on table IV.
Dexamphetamine is as clinically effective as methylphenidate for ADHD,[17) but because it is an amphetamine and can cause more appetite suppression, it is used less frequently than methylphenidate in the US. Pemoline is not a stimulant drug of first choice because it can cause an elevation of liver enzyme levels and, very rarely, irreversible hepatotoxicity (see section 5).
Methamphetamine is a long acting stimulant in tablet form that is commercially available in the US, and, although not researched for ADHD, has been suggested for occasional use to treat this disorder by several major investigators)18)
3.3 Dosage Adjustments
It is customary to initiate stimulant medication with low dosages (e.g. methylphenidate 10 to 20 mg/day depending upon age), increasing gradually until teacher ratings show a substantial (usually 50%) improvement from baseline. This procedure can be initiated entirely with a parent administering the morning dose. If methylphenidate tablets are prescribed, the before-school dose can be steadily increased every 2 days or so until the desired effect is achieved, adverse effects become a problem, or if 40 or 60mg is administered with no subsequent classroom benefit. If the morning medication is beneficial at a given dose, according to school reports, then a noon dose (often at half the morning level) can be administered by the school nurse.
In at least 75% of patients, a beneficial response to stimulant treatment is achieved within a week if the dosage is titrated appropriately. [I 9) The child becomes less restless, less impulsive and more attentive. In the process, he/she will complete more classroom work, achieve better grades, be far less
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Table IV. Stimulants used in the US for the treatment of attention deficit hyperactivity disorder
Drug Tablet or Plasma Duration of Total daily Customary doses capsule size half·life clinical effect dose range
Usual onset of action
(mg) (h)114,151 (h)
Methylphenidate 5,10and 2·3 3·4 20
20 sustained 2·3 4116,171
release
Dexamphetamine 5 and 10 5·11 3·4 (dextroamphetamine)
5,10 and 15 5-11 4[16,171
'Spansules'
Pemoline 18.75,37.5 and 5-8 6-7 75
18.75 chewable 5-8 6-7
Abbreviations: bid = twice daily; qam = once daily in the morning.
disruptive of the class routine, and, because of his/her improved visual-motor coordination, exhibit better handwriting. The degree of improvement can be quantified by comparing off-medication to on-medication teacher ratings.
During the first 3 months of treatment, the initial successful dosage may need to be increased somewhat to achieve an optimum effect. For the next few years thereafter, dosage increases are usually not necessary. Thus, in effect, tolerance to the core beneficial effects of stimulant medication does not develop. Dosage increases do, however, become necessary as the child becomes heavier. Should a child who had a good response to stimulant medication no longer show a benefit in later years, it is wise to ascertain if he/she is indeed swallowing the tablet or if appropriate dosage increases relative to increased body size have been made pOl
3,4 Frequency of Administration
Although most children with ADHD receive methylphenidate or dexamphetamine tablets twice daily on school days (before school and around noon), this arrangement is not very satisfactory for parents who find it particularly difficult to deal with their child's undue restlessness and impulsive behaviour at home. Under these circumstances, a lower afterschool (i.e. at 1530h) and/or non-school day medication arrangement may need to be added. Stimu-
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(mg)
10·90
20·80
5·45
5-45
37.5-112.5
37.5-112.5
(h)
0.5
0.5
1 after 3-10 days use
1 after 3-10 days use
10mg bid
20mg bid
5mg bid
10mg bid
75mg qam
37.5mgqam
lant medication can also be continued during summer school and summer day camp periods.
For parents who generally prefer that their child is only medicated during school hours, there still might be occasions when a 4-hour medicationinduced respite from the behavioural expressions of ADHD might be useful. These occasions include: visits to relatives, car rides with other children, attendance in church, and days when the range of activities may be limited, e.g. rainy days.
3,5 Monitoring of Continued Stimulant Treatment
It is preferable that teacher ratings of the classroom behaviour of children with ADHD be regularly sent to and reviewed by the prescribing physician so that the effect of the medication on the target features of ADHD can be effectively monitored. Teacher comments, which are commonly added to the rating scale form, are also reviewed at this time.
As mentioned in section 2.1, the most commonly used teacher rating scale for the evaluation of ADHD is the CATRS.[9] The Iowa Conners Teacher's Rating Scale[lO] has an advantage in that it separates aggressive from restless/inattentive behaviours (table II). The ACTeRS has an advantage in that it separates misconduct, inattentiveness and restlessness) 1 I] Rating scales should fit on only one
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Stimulants in ADHD
page for the convenience of teachers, and the descriptors should be easily understood. If this is not the case, the response rate will be low.
Monitoring drug effects is more complicated in secondary, as compared with elementary, school. This is because of multiple teachers doing the rating and because non-adherence to the medication regimen increases with age. If the adolescent is 'cheeking' the tablet, the prescribing physician should discuss this problem with all those primarily involved and negotiate a treatment contract. If need be, the administering nurse should watch the child swallow the tablet with water and check his/her open mouth subsequently.
3.6 Follow-Up Visits
The frequency of medication follow-up visits to the prescribing physician will in part depend on how well the child is progressing. If the child is doing well, 3 to 4 physician visits per year is a reasonable frequency. During each visit, it is best to interview the parent and the child together about school reports, the child's general adjustment, and adverse effects. The child should be weighed periodically, but cardiovascular monitoring is not routinely warranted. Furthermore, blood stimulant concentrations need not be obtained.
On rare occasions, a parent or relative may use the child's stimulant medication for their own bodyweight control or for purposes of abuse. Thus, if requests for stimulant medication prescriptions are excessive, these possibilities should be investigated.
3.7 Duration of Treatment
It is often useful to briefly stop stimulant treatment once a year for a few days or more to determine if the medication is still necessary. The duration of this cessation should be brief because the child may fail an entire marking period if the medication assessment is delayed while the child remains off the medication.
Commonly, many children with ADHD become less restless in their teens (12 or 13 years for girls and 14 and 15 years for boYS),l211 However, the inattentiveness of children with ADHD generally
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269
persists throughout their high school years.l211 As a result, stimulant treatment may be quite helpful then, even if it does not alter the long term academic outcome. Conduct problems which commonly coexist with ADHD in boys may intensify during the secondary school period. In these cases also, stimulant medication may be useful for its beneficial effects on classroom behaviour, even if it does not ultimately decrease delinquency in adulthood.
3.8 Treatment Failure
If treatment with one stimulant fails (and the diagnosis is not ambiguous), the clinician should try an alternative stimulant before switching to a non-stimulant.[221 This is because stimulants are far safer and generally more effective than alternative medications for ADHD,l231
Initially, the physician should increase the morning dose to determine if a higher dose will be effective. In adolescents, the morning dose of methylphenidate can be increased to 60mg and that of dexamphetamine to 30mg. High doses of stimulants have been reported to result in improvement in over 90% of children with ADHD whose response to standard doses was inadequateP21 Generally, paediatric or psychiatric specialists are more experienced and comfortable prescribing stimulants at these doses.
4. Stimulant Treatment for Atypical Cases of ADHD
4.1 Severity of Illness
Usually, children with the most prominent ADHD features respond more dramatically to stimulant medication. Thus, after the administration of a stimulant medication, children aged 8 years generally exhibit a greater degree of change than do their 15-year-old counterparts. Four- to 5-year-old children who are severely affected by ADHD can be given stimulants and they do almost as well on average as those of primary school ageP41 Response to treatment has not been found to be gender dependent.[ 171
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4,2 Comorbid Conditions
Children with ADHD and coexisting conduct disorders, learning disabilities and/or mild mental retardation usually have a very satisfactory response to stimulant medication,[25,26] In contrast, those who have coexisting anxiety tend to do somewhat less well on average than do others without this comorbid disorder, although findings at present are conflicting, [27]
In children with both ADHD and a tic disorder, stimulant medication improves their ADHD pattern, but, in about 40% of cases, the medication exacerbates the tic movements,[28] Psychotic and autistic children with ADHD occasionally exhibit a decrease in restlessness following the administration of stimulants, but the drug may also intensify their thought disorder,[24] Children with ADHD who have a prominent degree of mental retardation (i.e, an IQ less than 45) seldom benefit from stimulant treatment,[25] although some with fragile X syndrome may be an exceptionP9]
4,3 Other Disorders
Children with learning disabilities who are inattentive but not hyperactive usually respond to stimulant treatment, as evidenced by improved attentionPO] The dosage required for this effect is usually below the average dosage required to treat the typical pattern of ADHD,
About 25% of children with conduct disorder whose misbehaviour began in childhood but who are not clearly hyperactive respond with behavioural improvement in the classroom when given stimulant medicationPl] The dosage required in these cases is often substantial.
5. Adverse Effects of Stimulants
Non-specific headaches, mild abdominal discomfort, an increased vulnerability to crying, pallor, and a decrease in spontaneous movement occur in 10 to 20% of children during the initial phase of stimulant treatment.[32] These effects seldom last more than 3 to 6 weeks, but if present it is usually wise to decrease the dose of the stimulant until the
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Safer
child adjusts to the medication, Subsequently, the dose can be increased, if need be, to attain the desired clinical effect; alternatively, another stimulant can be tried,
A mild increase in heart rate and blood pressure often occurs with methylphenidate, but only during the first few months of treatment.
In about one-half of children treated with stimulants, a mild dose-dependent appetite suppression occurs,[32] most notably during the first 6 months, and most commonly with dexamphetamine, If the stimulant medication is administered at 0800h and again at 1200h, an appetite rebound generally occurs in the evening, at which time an increased amount of food can be offered.
Motor tics (particularly blepharospasm) can occur in a small number of genetically predisposed children who receive stimulant treatment. These movements generally decrease over time,[28] but if prominent may require a dose decrease or in some instances the cessation of treatment. Tics do not persist after the stimulant medication is stopped,
Insomnia can develop in the following circumstances: • if stimulants are administered late in the after
noon or in the evening • if the child is particularly sensitive to stimulants • if long acting stimulants are administered in the
afternoon, The standard remedy for this drug-induced in
somnia is to alter the timing of administration, Visual hallucinations are a quite rare medication
adverse effect;[33] they cease after a significant dose reduction,
A mild 1- to 2-hour increase in the child's activity level after the behavioural effects of the medication cease (usually occurring around 1600h to 1800h) is not unusuaI.!34] This is not very problematic for most parents, but if it is, a small afterschool dose of the stimulant should lessen the rebound effect.
Increases in liver enzymes have been reported to occur in up to 2% of children with ADHD who are treated with pemoline, [35,36] Therefore, periodic liver function blood tests during treatment are
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Stimulants in ADHD
needed to reassure both the doctor and the parents that hepatic changes are not present. If abnormal findings develop, the drug should be discontinued immediately.
Life-threatening or irreversible adverse effects have not been reported to occur in children with ADHD who are treated with methylphenidate or dexamphetamine. Ultimate height and bodyweight are not altered by the stimulant-induced appetite suppression that can occur,[37] and these drugs do not increase the risk of substance abuse.f24]
6. Drug Interactions with Stimulants
Children receiving tricyclic antidepressants should be given stimulants cautiously because these drugs increase the blood concentrations of the other. Combining stimulants with monoamine oxidase inhibitors should be avoided, and combining stimulants with certain selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors can result in an increase in the adverse effects of these antidepressants. Stimulants do not increase the likelihood of seizures, but may delay the absorption of certain anticonvulsants, such as phenobarbital (phenobarbitone) and phenytoin.f38,39]
7. Conclusions
ADHD is now recognised worldwide as a major childhood psychiatric disorder, and stimulant medication is recognised by both specialists (medical as well as non-medical) and parents as a useful symptomatic treatment. In the US, recent survey reports indicated that 85 to 92% of parents whose children had ADHD and were receiving methylphenidate were satisfied with the results of the treatment.[40,41]
Some concern has been expressed in the popular press that stimulant treatment is inappropriately prescribed.f42] This remains to be scientifically demonstrated. In 2 naturalistic classroom studies, at least 75% of school children who were receiving stimulants had teacher ratings indicating substantial on-medication behavioural benefits compared with off-medication ratings.f43,44]
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271
Although there are some points of disagreement amongst the experts, stimulant treatment is not viewed as a controversial treatment within the US scientific community. It has been the most well researched treatment in child psychopharmacology and is one of the most well researched subjects in child mental health,fl] With thousands of scientific articles on the topic, a solid consensus amongst the experts in the US and elsewhere - including the great majority of research psychologists - has developed. [15,24,27,31,45]
References I. Jensen PS, Vitiello B, Laughren TP. Design and methodology
issues for clinical treatment trials in children and adolescents, Psychopharmacol Bull 1994; 30: 3-8
2. Williams L, Lerner M, Swanson J. Prevalence of office visits for ADD. NIMH Conference on Gender Differences in ADHD: 1994 Nov II; Bethesda (MD)
3. Zito JM, Riddle MA, Safer OJ, et al. Pharmacoepidemiology of youth with treatments for mental disorders [abstract]. Psychopharmacol Bull 1995; 31: 540
4. Safer DJ, Zito JM, Fine EM. Increased methylphenidate usage for attention deficit disorder in the 1990s. Pediatrics 1996; 98: 1084-8
5. Wolraich ML, Hannah IN, Pinnock TY, et al. Comparison of diagnostic criteria for attention-deficit hyperactivity disorder in a county-wide sample. J Am Acad Child Adolesc Psychiatry 1996; 35: 319-24
6. Taylor E. Cultural differences in hyperactivity. Adv Develop Behav Pediatr 1987; 8: 125-50
7. Chiarello RJ, Cole JO. The use of psychostimulants in general psychiatry. Arch Gen Psychiatry 1987; 44: 286-95
8. Holmes VE Medical use of psychostimulants. Int J Psychiatry Med 1995; 25: 1-19
9. Conners CK. Rating scales for use in drug studies with children. Psychopharmacol Bull (Spec Issue: Psychopharmacology in Children) 1973: 60
10. Loney J, Milich R. Hyperactivity, inattentiveness and aggression in clinical practice. In: Wolraich M, Routh DK, editors. Advances in behavioral pediatrics, vol. 3. Greenwich (CT): JAI Press, 1981: 123
II, Ullman RK, Sleator EK, Sprague RL. Introduction to the use of ACTeRS, Psychopharmacol Bull 1985; 21: 915-20
12. Sleator EK, Ullman RK. Can the physician diagnose hyperactivity in the office? Pediatrics 1981; 67: 13-7
13. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Press, 1994
14. World Health Organization. The ICD-IO classification of mental and behavioural disorders. Geneva: World Health Organization, 1993: 155-7
15. Barkley RA. Hyperactive children: a handbook for diagnosis and treatment. New York: Guilford Press, 1990
16. Jacobvitz D, Sroufe A, Stewart M, et al. Treatment of attentional and hyperactivity problems in children with sympathomimetic drugs. J Am Acad Child Adolesc Psychiatry 1990; 29: 677-88
eNS Drugs 1997 Apr; 7 (4)
272
17. EliaJ. Drug treatment for hyperactive children. Drugs 1993; 46: 863-71
18. Cantwell D, Wender P. ADD throughout life: new clinical insights. 1994 Oct 17; Montifiore Medical Center, New York City
19. Barkley R. A review of stimulant drug research with hyperactive children. J Child Psychol Psychiatry 1977; 18: 137-65
20. Safer OJ, Allen RP. Absence of tolerance to the behavioral effects of methylphenidate in hyperactive/inattentive children. J Pediatr 1989; 115: 1003-8
21. Fischer M, Barkley RA, Edelbrock CS. The adolescent outcome of hyperactive children diagnosed by research criteria. J Consult Clin Psychol 1990; 58: 580-8
22. Elia J, Borcherding BG, Rapoport JL, et al. Methylphenidate and dextroamphetamine treatments of hyperactivity: are there true non-responders? Psychiatry Res 1991; 36: 141-55
23. Riddle MA, Geller B, Ryan N. Another sudden death in a child treated with desipramine. J Am Acad Child Adoles Psychiatry 1993; 32: 792-7
24. Weiss G, Hechtman LT. Hyperactive children grown up. 2nd ed. New York: Guilford Press, 1993: 31-4, 136-41
25. Aman MG, Marks RE, Turbott SH. Clinical effects of methylphenidate and thioridazine in intellectually subaverage children. J Am Acad Child Adolesc Psychiatry 1991; 30: 246-56
26. Kaplan SL, Busner J, Kupiez S, et al. Effects of methylphenidate on adolescents with aggressive conduct disorder and ADDH. J Am Acad Child Adolesc Psychiatry 1990; 29: 719-23
27. Tannock R, Ickowicz A, Schachar R. Differential effects of methylphenidate on working memory in ADHD children with and without comorbid anxiety. J Am Acad Child Adolesc Psychiatry 1995; 34: 886-96
28. Gadow KD, Sverd J, Sporafkin J, et al. Efficacy of methylphenidate for attention-deficit hyperactivity disorder in children with tic disorder. Arch Gen Psychiatry 1995; 52: 444-55
29. Hagerman RJ, Murphy MA, Wittenberg MD. A controlled trial of stimulant medication with fragile x syndrome. Am J Med Genet 1988; 30: 377-92
30. Dequiros GB, Kinsboume M, Palmer RL, et al. Attention deficit disorder in children: three clinical variants. J Dev Behav Pediatr 1994; 15: 311-9
31. Taylor E, Schachar R, Thorley G, et al. Which boys respond to stimulant medication? Psychol Med 1987; 17: 121-43
© Adis International Umited. All rights reserved.
Safer
32. Ahmann PA, Waltonen SJ, Olson KA, et al. Placebo-controlled evaluations of Ritalin side effects. Pediatrics 1993; 91: 1101-6
33. Lucas AR, Weiss M. Methylphenidate hallucinosis. JAMA 1971; 217: 1979-81
34. Rapoport JL, Buchsbaum MS, Weingartner H. Dextroamphetamine: cognitive and behavioral effects in normal and hyperactive boys and normal men. Arch Gen Psychiatry 1980; 37: 933-43
35. Pratt DS, Dubois RS. Hepatotoxicity due to pemoline (Cylert). J Pediatr Gastroenterol Nutr 1990; 10: 239-41
36. Nehra A, Mullick F, Ishak KG, et al. Pemoline-associated hepatic injury. Gastroenterology 1990; 99: 1517-9
37. Gittelman R, Mannuzza S. Hyperactive boys almost grown up: III. Methylphenidate effects on ultimate height. Arch Gen Psychiatry 1988; 45: 1131-4
38. Greenhill LL. Attention-deficit hyperactivity disorder: the stimulants. Child Adolesc Clin N Am 1995; 4: 123-68
39. Physician's Desk Reference. 50th ed. Omadell (NJ): Medical Economics Co., 1996: 848
40. Gadow KD. Pharmacology of behavior disorders. Clin Pediatr (Phila) 1983; 22: 48-53
41. Virginia Departments of Education, Health Professions, Mental Health, Mental Retardation and Substance Abuse Services. Final report on effects of the use of methylphenidate. House document no. 28. Richmond (VA), 1991: B3
42. Safer DJ, Krager JM. Effect of a media blitz and a threatened law suit on stimulant treatment. JAMA 1991; 268: 1004-7
43. Sleator E, von Neumann A, Sprague R. Hyperactive children: a continuous long-term, follow-up. JAM A 1974; 229: 316-7
44. Safer DJ, Krager JM. Hyperactivity and inattentiveness: school assessment of stimulant treatment. Clin Pediatr (Phila) 1989; 28: 216-21
45. Werry JS, Aman MG, editors. Practitioner's guide to psychotropic drugs for children and adolescents. New York: Plenum, 1993
Correspondence and reprints: Dr Daniel J Safer, 7702 Dunmanway, Dundalk, MD 21222, USA.
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