Minimal Brain Dysfunction

Current Therapeutic Concepts

Minimal Brain Dysfunction

Robert W. Piepho, Dick R. Gourley and John W. Hi" This paper discusses the treatment of minimal brain dysfunction (MBD), a cognitive/ behavioral disorder of unknown etiology in children. Drug therapy is the single most effective treatment for MBD, although individualized remedial education, psychotherapy and family counseling are also indicated. The centrally acting sympathomimetics, methylphenidate and dextroamphetamine-the drugs of choice in the treatment of MBD-are

effective in about three-fourths of affected children for the improvement of behavioral symptoms. The cognitive disability associated with MBD rarely will be totally alleviated by drug therapy. When methylphenidate or dextroamphetamine is not effective, magnesium pemoline or an antipsychotic agent such as chlorpromazine or thioridazine may be indicated. Tricyclic antidepressants (imipramine, etc.) have been used, but they are

not as effective as psychostimulants and they may produce more serious side effects. Antianxiety agents, anticonvulsants and miscellaneous drugs have been tried in MBD therapy but generally are of little or no value. The actions, interactions, dosage and side effects of the various drugs, particularly methylphenidate and dextroamphetamine, are discussed in detail.

"Minimal brain dysfunction" (MBD) is one of many terms that has been used to describe a cognitive/behavioral disorder of childhood. Other synonyms for this disorder include: postencephalitic behavior disorder, hyperkinesis, hyperactivity, hyperkinetic syndrome, minimal brain damage and minimal cerebral dysfunction (MCD). In this article "MBD" wi" be used to describe this syndrome since it is the least objectionable term and implies no specific etiology, no pathognomonic signs and no particular similarity in cause, course of the disease or treatment. 1,2 MBD was first described in the 1920s, when its occurrence-was noted as a sequela to von Economo's encephalitis. Recognition of the disorder has increased over the past 50 years, and MBD is now recognized as a disorder of considerable clinical importance. Although the diagnostic criteria are not always uniform, a fairly consistent prevalence rate for this disorder is usually noted among studies, i. e., 5-10 percent. It is at least twice as common in males as in females. In clinics that are involved with treatment of psychiatrica"y disturbed children of primary school age, a diagnosis of MBD is noted in approximately 50 percent of cases referred. 1

more severe cases of MBD. Most pathological studies have attempted to correlate prenatal or perinatal events with MBD. In a 1974 study by Hart and coworkers,3 15 percent of children defined as scholastic underachievers were found to have perinatal complications that could have affected the central nervous system. Other studies have found a slightly higher incidence of prenatal or perinatal CNS insult, but there still is not a conclusive link between medical history and the presence of MBD. Thus, the clinical practitioner should observe children with potentially dangerous CNS insult of a prenatal or perinatal nature as they grow to school age. However, many other cases of MBD wi" be noted in the absence of any positive medical history. 4 Lesions or abnormalities that have been postulated to be responsible for the symptomatology of MBD include brain damage, biochemical disorders, minor congenital physical anomalies, low CNS arousal level, genetic disorders or a biological variation that is unmasked by exposure to universal compulsory education.5

The clinical delineation of MBD is not an easy diagnosis; many sets of symptomatology have been described in the scientific literature, but it is impossible to define a checklist of symptoms for a cerebral disorder manifested in a heterogenous group of school-age children. The actual diagnosis of MBD is usually made on the basis of medical and sociopsychological history. The historical material generally is obtained from the child's family members, teachers and counselors, since examination of the child is often of little use. In one study, approximately 75 percent of children referred for MBD displayed no hyperactive behavior in the physician's office, indicating that the hyperactive child who is usually disruptive in the classroom setting wi" not manifest this behavior in the one-

to-one setting. Although there is no critical diagnostic test for MBD, it is important to attempt to rule out other syndromes such as borderline schizophrenia or reactive difficulties. The schizophrenic child usually wi" appear more fearful, wi" have pronounced phobic symptomatology and wi" avoid social contact while exhibiting undue preoccupation with violent or sexual matters. The child with social or reactive difficulties usually can be defined on the basis of recent disruption in the familial environment, but psychoenvironmental trauma of this type still does not totally rule out the concomitant presence of MBD.1 Over 100 clinical manifestations have been attributed to MBD in various descriptions found in the neuropsychiatric literature. Some of the more commonly noted clinical symptoms are discussed in this article. The two major areas of dysfunction in MBD are the areas of behavior and perception / cognition. The most common behavioral alterations in MBD are an increased level of motor activity (hence, the term "hyperkinetic syndrome"), impaired coordination, short attention span, excessive impulsivity, interpersonal problems of a differential nature in dealing with children vis-a-vis adults (children wi" find the MBD child "bossy and aggressive," while adults wi" describe the child as "unmanageable and disobedient") and a low threshold for loss of emotional control. The most common perceptual/cognitive difficulties include problems with spatial orientation, left-right orientation, difficulty in auditory and visual memory, and difficulty in transferring information from one sensory modality to another. Thus, many MBD victims exhibit learning difficulties in spite of normal intelligence and a reasonably healthy family background . The reason for their scholastic underachievement (usua"y noted in reading, spelling or arithmetic) generally can be attributed to either the behavioral problems with attention span or the cognitive

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Journal of the American Pharmaceutical Association

Pathogenesis The actual causative factors in MBD have remained a mystery since its initial definition in the 1920s. The words "minimal brain dysfunction," imply a disordered function in the brain, and this dysfunction is considered "minimal," although many practitioners would disagree with this latter term in the

Robert W. Piepho, PhD, is Associate Professor and Vice Chairman, and Dick R. Gourley, PharmD, is Associate Professor and Chairman, Department of Clinical Education and Services, University of Nebraska College of Pharmacy, University of Nebraska Medical Center. John W. Hili, PhD, is Director of Learning Disabilities, University of Nebraska Medical Center, Omaha, Nebraska 68105.

Diagnostic and Clinical Findings

Minimal Brain Dysfunction

deficits in processing of didactic information. Two-thirds of nonretarded adolescent underachievers have been shown to have had typical manifestations of MBD in their early childhood, re-emphasizing the importance of early rec
The treatment of children with MBD must be tailored to the needs of each individual case. Since the pathogenesis of the disorder is not defined, therapy must be symptomatic and is empirical. The four main approaches in the treatment of the disease are: (1) education of the family with appropriate counseling, (2) remedial education for the affected child, (3) psychotherapy for the child and (4) pharmacotherapy. Education of family members is extremely important for their understanding of the problem and for their cooperation in helping the child comply with the medication regimen. Specialized remedial education for the child is essential, so that the child can erase his academic deficits and attain the academic level of his peers. Psychotherapy is indicated so the child can learn to cope with his family and friends once he is in a recuperative phase. The child is often accustomed to censure from his teachers and parents and abuse from his peers, resulting in the formation of many psychological scars. These scars must be ameliorated with adequate psychotherapy, since most of the medications currently used for MBD can relieve the immediate symptoms but cannot aid the child in coping with the indirect consequences of his former behavior on other individuals. 1 Pharmacotherapy

Many pharmacotherapeutic approaches have been taken in the treatment of MBD, and the use of medications in affected children has proved to be the most effective single treatment of the disorder. Drugs that have been used include amphetamine and amphetamine-like compounds, antipsychotic agents, tricyclic antidepressants, anti-anxiety agents and sedatives, anticonvulsants, caffeine, deanol, antihistamines, lithium salts, penicillamine and calcium disodium edetate. Centrally Acting Sympathomimetics. The

primary agents utilized in the treatment of MBD are methylphenidate, dextroamphetamine and magnesium pemoline. This therapeutic approach was used as early as 1937 but did not become popular until the late 1960s. 7 Dextroamphetamine was initially used in 1937 and continued as the agent of choice until the late 1960s, when methylphenidate usage increased in association with reports of a lower incidence of side effects with the latter drug. It now appears that these reports of greater safety with methylphenidate are of questionable clinical significance. 6 There also are studies attesting to the greater clinical efficacy of methylphenidate 8 over dextroamphetamine by some authorities who prefer use of the former drug, while proponents of dextroamphetamine indicate that, used appropriately, it has comparable clinical efficacy at a lower cost. 9 Methylphenidate is the primary agent for the pharmacotherapy of MBD. It is given orally in doses of 0.3-1.5 mg/kg twice daily after meals (in the morning and mid-day, to avoid the potential iatrogenic insomnia that can ensue from the drug) . A study with single-dose methodology for methylphenidate revealed that a morning dose of 20 mg had similar clinical efficacy to a multiple dosage form of dextroamphetamine. 10 However, 15 percent of the children did not retain a therapeutic response for the entire school day. In addition, children will often experience decreased blood levels in the "play" hours after school and social conflicts may develop. Our current approach with methylphenidate therapy is to use a "twice daily" dosing pattern with morning and mid-day dosing times; this approach has provided good control in our patients with a minimum of problematic side effects. Methylphenidate is of value in MBD therapy, since it appears to reduce hyperactivity and restlessness, prevent distraction, and increase attention span. These effects aid in making the child more available for the learning environment; hence a secondary but. important effect of the drug is to increase learning ability. Motor ability and coordination also are enhanced by the drug. 11 The use of methylphenidate in children with MBD also can cause certain undesirable side effects. Suppression of growth has been reported with both weight and height decrements being noted; 12 however, when medication was discontinued over vacations, a spurt in growth returned the treated children to control levels. 13 A more recent study of 100 patients has revealed "no stunting of

growth from the long-term use of methylphenidate, dextroamphetamine or imipramine/desipramine in children."14 Our current treatment approach is to allow the child to remain drug-free, if pragmatically possible, over weekends and vacations to prevent any transient growth decrement and to allow for continual re-evaluation of the need for pharmacotherapy. Cardiovascular side effects, usually either increased diastolic blood pressure or tachycardia, have been reported. Insomnia and anorexia (resulting in weight loss) have been reported, but may occur less commonly than with other amphetamine derivatives. Methylphenidate is also reported to inhibit hepatic drug metabolism and the half-life of several substances, e.g., ethyl biscoumacetate and desipramine, may be prolonged, resulting in potential toxicity. It is particularly important to consider potential interactions with the anticonvulsant drugs, as these drugs often are used concurrently in the child with MBD. There have been several reports of ataxia in patients on phenytoin / methylphenidate combination regimens. 11 Dextroamphetamine is used similarly to methylphenidate in the treatment of MBD. Although some studies indicate similar clinical efficacy, 9 most of the clinical literature surveyed is indicative of an approximately 10-15 percent higher symptom improvement rate with methylphenidate. 8,11 The use of dextroamphetamine in MBD, rather than the use of levoamphetamine or racemic amphetamine mixtures, is based on the established superiority of dextroamphetamine in various clinical trials. 15-17 The usual dosing pattern for dextroamphetamine is 5-20 mg twice daily after meals, morning and midday, or the sustained-release dosage forms that are available cem be used in a single morning dose. Our preference is to use the five mg tablets, as they allow for greater latitude in dosage adjustment and evaluation of clinical response on a time course basis. The time course of dextroamphetamine action in the MBD child is only slightly shorter than that of methylphenidate, with a peak effect noted one-two hours after dosing and a duration of action of four-six hours. Dosage is generally titrated from an initial dose of five mg bid. up to an effective level by increasing the dose by five mg per dose every two-three days until either the symptoms are ameliorated or side effects are noted. Side effects reported with dextroamphetamine are similar to those of methylphenidate, and usually decrease a few weeks

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Journal of the American Pharmaceutical Association

after initiation of therapy. Persistence of insomnia may be treated with a mild hypnotic agent such as diphenhydramine (25 mg) or can occasiona!ly be alleviated by taking the child off dextroamphetamine ~nd initiating . therapy with methylphenidate. When this type of change in stimulant therapy is attempted, a 24-hour period shoul9 elapse prior to initiation of therapy with the new stimulant drug. 9 The potential abu~e of psychostimulant drugs by children previously treated with these agents h~s been a concern of many health professionals. However, at present there are studies which indicate that abuse of drugs in later life is not a sequela to amphetamine ther~py in childhood. 6,18 Magnesium pemoline also has been used in children with MBD. This drug is a CNS stimulant with psychostimulant effects similar to those of dextroamphetamine. It has been shown to po?sess similar beneficial actions as well as similar side effeqts, with insomnia and anorexia being the most prevalent. Magnesium pemoline does not produce as rapid a clinical response as dextroamphetamine, but after eight weeks of treatment with either drug, a similar clinical response can be anticipated. Magnesium pemoline may be considered as an alterllative for patients who cannot tolerate either of the stimulants previously discussed. 19 Antipsychotic Agents. A variety of other agents have been used to treat cases of MBD that are unresponsive to or inappropriate for psychostimulant therapy. Several antipsychotic drugs have been employed, including chlorpromazine, thioridazine, haloperidol and reserpine. Chlorpromazi!le has been reported to be significantly more effectivE? than placebo in the treatment of hyperactivity; in some studies, jt has shown equivalent efficacy to that of dextroamphetamine (which generally is effective in approximately 70 percent of cases) . However, the psychostimulants have a broader spectrum of action in MBD; in one study, chlorpromazine controlled hyperactivity but failed to produce significant attentional improvem~nt. 20 Studies with thioridazin~ have provided results es?entially similar to those described for chlorpromazine. 2o A report of the effect of haloperidol on cognitive behavior in children with hyperactivity indicated that methylphenidate and low-dose haloperidol (0.025 mg/kg) both facilitated cognitive performance, while high-dose haloperidol (0.05 mg/kg) appeared to cause a slight deterioration of performance. 21 Reserpine has been responsible for improvement in 34

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percent of children with M BD; this limited success rate negates its use in this disorder. 8 Thus, the antipsychotic agents occasionally may be useful in the therapy of MBD, but they are capable of depressing the higher CNS functions of attention and, more importantly, cognition. These latter concerns, coupled with the multiple autonomic and extrapyramidal side effects associated with the antipsychotic agents, preclude their use ~s primary agents. They can be viewed as an alternate choice of therapy only in patients who are poor candidates for psychostimulant therapy. Tricyclic Antidepressants. Many reports have inq!cated that the tricyclic antidepressants, 'generally imipramine, may be beneficial in the t~eatment of children with MBD. These studies were undertaken because tricyclic antidepressants are nonscheduled drugs (in contrast to the psychostimulants) and qecause of the possibility of single-dose th~r~py dUE1 to the!r long half-life. Although most studies have indicated their superiority over' placeb9, the tricyclic antidepressants ar~ not a? effective as the psychostimulants. Further drawbacks to their use include the development of tolerance in some children and the numerous deleterious side effects. 1 Side 'effects may be somewhat limited by the maximum daily dose approved by FDA (five mg/kg/ day) , but autonomic effects, weight loss, gastrointestinal irritation, fine tremors, hyperirritability and mood alterations must be conti!,"!ually evaluat~d. In addition, the !llore severe effects on the CNS, e.g., seizures, and on the cardiovascular system must be monitored, although these effects usually do not occur if the practitioner adher~s to the FDA recommendation. Thus, ?Ithough the tricyclic antidepressants are beneficial in the child with MBD, th~ir use at present is experimental, and precautions must be taken if they are prescribed. 6 Antianxiety Agents and Sedatives. These agents hav~ not undergone extensive clinical trials in t~e treatment of MBD, but the ayailable data indicate that they are of little use. The bEmzodiazepines appear to be of no value in therapy;22 phenobarbital has been reported to worsen the child's behavior. 6,23 The' use of these agents should be avoided in children with MBD. Anticonvulsants. Although there have been initial enthusiastic reports regarding the use of allticonvulsant drugs in the therapy of MBD, these agents appear to be of no value. They have been used prima.rily in children with behavioral disturbances who are seizure-free, but still have abnormal EEG trac-

ings. In these cases, they have been shown to have no effect in alleviating either the behavioral or cognitive symptoms, and their use in MBD is not recommended unless concomitant seizure activity is present. 6,23 Miscellaneous Agents. Many other agents have been used in an attempt to treat MBD. Most of these drugs have not been of benefit, but were merely part of the search for a more desirable therapeutic approach to MBP than the use of scheduled drugs. One of the most interesting drugs tried was caffeine. An initial report by Schnackenberg in 197324 reported that a cup of coffee ' for breakfast and lunch was essentially as effective as methylphenidate. The promise of this initial study was followed up rapidly because of the potential decrease in side effects associated with a course of therapy with coffee rather than the sched~Ied stimulants. However, a: subsequent study with pure caffeine and a larger patient population compared the effects of caffeine to those of the psychostimulants in a double-blind crossover design. Caffeine was found to be equal to placebo and not as effective as either methylphenidate or dextroamphetamine. 25 Further studies are needed to clarify the potential use of coffee or caffeine in MBD, but at present it must be concluded that "coffee therapy" is of questionable value. Antihistamines such as diphenhydramine have not proved adequate for therapy.26 Published research with lithium salts indicates that lithium is "inadequate for treating hyperactive children. "27 Deanol, a reputed acetylcholine precursor, has been avgilable for over a decgde for use in pediatric psychopharmacology. However, its efficacy in MBD is questionable. In one study, in vyhich it was given in large doses (250-500 mg/ day) over a threemonth period, it compared favorably with methylphenidate on a number of behavioral measures. 'However, this stLldy was far from conclusive anq further studies are needed to document the role of deanol in therapy of MBD.28 There are several indications that chronic Iqw-Ievellead exposure can result in subtle CNS damage Cind hyperactivity. In a recent stUdy, 13 hyperkinetic children with blood and ~rinary lead levels that were elevated in a "nontoxic" range were treated with the lead chelating agents, penicillamine or calcium disodium edetate. Six of the children had positive medical histories of perinatal or developmental CNS insult and did not respond, while the other seven MBD children,

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Minimal Brain Dysfunction

who had unremarkable histories and a potential lead-induced hyperactivity, showed marked improvement. The authors concluded that lead may play an important role in the etiology of MBD, and measurements of blood and urinary lead levels may become a part of the standard workup in cases of MBD with no previous history of CNS insult. 29 Therapeutic Considerations

Table 1. Daily doses of drugs useful in therapy of MBD Psychostimulants Methylphenidate Dextroamphetamine

5-120 mg 2.5-60 mg

Phenothiazines Chlorpromazine Thioridazine

10-1000 mg 20-600 mg

Tricyclic Antidepressants Imipramine Desipramine

25-200 mg 25-200 mg

Miscellaneous Agents * Caffeine Deanol

100-200 mg 250-500 mg

From the previous discussion of pharmacotherapy, the psychostimulants (methylphenidate or dextroamphetamine) are the drugs of choice in MBD. When these drugs are not effective, magnesium pemoline, chlorpromazine or thioridazine are the secondary agents to consider, followed by tricyclic antidepressants. If none of these agents is successful, deanol or caffeine might be attempted to achieve a response. Appropriate. doses for commonly used agents are given in Table 1 (at right) . It should be remembered that the child and his family will need supportive counseling to ensure compliance with the medication regimen as well as to ensure therapeutic success. Counseling, remedial education and psychotherapy may all be indicated in addition to pharmacotherapy. The pharmacist can play an important role in the assurance of total therapy for the MBD patient. A question is often raised by parents regarding the duration of therapy. This is a difficult inquiry to answer because duration of therapy is empirical, based on the re-

sponse of the child during drug-free periods such as weekends and vacations. A number of children with MBD will continue to show characteristics of the disorder into adult life, and therapy of some type may be needed for the remainder of the patient's life. Some clinicians have treated patients into the fourth decade of life and, interestingly, these patients do not appear to have become tolerant to the effects of the psychostimulant drugs or dependent upon the psychological attraction of their euphoric actions. 1 The prognosis for the MBD child is questionable. It generally is assumed that MBD is a benign psychiatric disorder that is outgrown by puberty or in early adolescence; however, MBD has been causally linked to

References

11 . Fischer, K. C., and Wilson, W. P. : Methylphenidate and the hyperkinetic state, Dis. Nerv. Syst. 32: 695-698 (Oct.)

* Agents in this group are of questionable value in treatment ofMBD.

1971 . 1. Wender, P. H. : The minimal brain dysfunction syndrome, Ann. Rev. Med. 26: 45-62, 1975. 2. Schmitt, B. D.: The minimal brain dysfunction myth, Am. J. Dis. Child. 129: 1313-1318 (Nov.) 1975. 3. Hart, Z., Rennick , P. M., Klinge, V., et al.: A pediatric neurologist's contribution to evaluations of school underachievers, Am. J. Dis. Child. 128: 319-323 (Sept.)

12. Safer, D. J., and Allen, R. P.: Factors influencing the suppressant effect of two stimulant drugs on the growth of hyperactive children , Pediatrics 51: 660 (Apr.) 1973. 13. Safer, D. J., Allen, R. P., and Barr, E : Growth rebound after termination of stimulant drugs, J. Pediatr. 86: 113 (Jan.)

1975. 14. Gross, M. D. : Growth of hyperkinetic children taking

1974. 4. Haller, J. S.: Minimal brain dysfunction syndrome, Am. J. Dis. Child. 129: 1319-1324 (Nov.) 1975. 5. Werry, J. S.: Medication for hyperkinetic children, Drugs 11: 81-89 (Feb.) 1976. 6. Wender, P. H.: Minimal brain dysfunction in children, Pediatr. Clin. North Am. 20: 187-202 (Feb.) 1973. 7. Sprague, R. L., and Sleator, E K.: Effects of psychopharmacologic agents on learning disorders, Pediatr. Clin. North Am. 20: 719-735 (Aug.) 1973. 8. Millichap, J. G. : Drugs in management of hyperkinetic and perceptually handicapped children, J. Am. Med. Assoc. 206: 1527 (Nov. 11) 1968. 9. Winsberg, B. G., Yepes, L. E , and Bialer, I.: Pharmacologic management of children with hyperactive/aggressive/ inattentive behavior disorders, Clin. Pediatr. 15: 471-477 (May) 1976. 10. Safer, D. J., and Allen, R. P.: Single daily dose methylphenidate in hyperactive children , Dis. Nerv. Syst. 34: 325-328 (Aug.-Sept.) 1973.

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methylphenidate, dextroamphetamine, or imipramine/ desipramine, Pediatrics 58: 423-431 (Sept.) 1976. Gross, M. D.: A comparison of dextroamphetamine and racemic amphetam ine in the treatment of minimal brain dysfunction or hyperkinetic syndrome, Dis. Nerv. Syst. 37: 14-16 (Jan .) 1976. Arnold , L. E., Huestis, R. D., et al.: Levoamphetamine vs. dextroamphetamine in minimal brain dysfunction, Arch. Gen. Psychiatry 33: 292-301 (Mar.) 1976. Arnold, L. E., Wender, P. H., et al.: Levoamphetamine and dextroamphetamine: comparative efficacy in the hyperkinetic syndrome, Arch. Gen. Psychiatry 27: 816-822 (Dec.) 1972. Laufer, M. W.: Long-term management and some follow-up findings on the use of drugs with minimal cerebral syndromes, J. Learn. Dis. 4: 55 (Jan .) 1971 . Conners, C. K., Taylor, E. , et al.: Magnesium pemoline and dextroamphetamine: a controlled study in children with minimal brain dysfunction, Psychopharmacologia 26: 321-336 (Oct.) 1972.

a variety of serious psychiatric disorders in adult life. Hyperactivity usually disappears at puberty, but the secondary characteristics of the disorder are not always lost. Academic underachievement, impulsive character disorders, sociopathy, schizophrenia and other recognized psychiatric disorders may then become the diagnosis. It is difficult, with the present medical evidence and in light of limited follow-up data, to give an adequate prognosis. In the words of Bernard Fox of the National Institute of Neurological Diseases and Stroke, "The symptoms of MBD may be less obvious in the young adult than in the schoolchild because of changing behavioral demands-some jobs, for example, may not penalize the diverting of attention-or, if an adult has repeated car accidents, they usually are not attributed to MBD." In summary, MBD is a common disorder of primary grade-school children that can remain into adult life. The cardinal features involve behavioral difficulties and academic deficiencies in the presence of normal intelligence. Treatment with psychostimulants is effective in approximately 75-80 percent of affected children for improvement of behavioral symptoms. The cognitive disability of the disorder rarely will be totally alleviated by drug therapy, and other nonpharmacological psychotherapeutic measures must be used hand-in-hand with these agents. When all these approaches are effectively used, there is no reason for the quality of life of these patients to be any different from that of the rest of the population. •

20. Klein-Gittelman, R. , Klein, D. F. , et al.: Comparative effects of methylphenidate and thioridazine in hyperkinetic children, Arch. Gen. Psychiatry 23: 1217-1231 (Oct.)

1976. 21 . Werry, J. S., and Aman , M. G.: Methylphenidate and haloperidol in children, Arch. Gen. Psychiatry 32: 790-795 (June) 1975. 22. Greenblatt, D., and Shader, R., in Benzodiazepines in clinical practice, Raven Press, New York, New York,

1974. 23. Erenberg, G.: Drug therapy in minimal brain dysfunction: a commentary, J. Pediatr. 81: 359-365 (Aug.) 1972. . 24. Schnackenberg, R. C.: Caffeine as a substitute for schedule II stimulants in hyperkinetic children, Am. J. Psychiatry 130:

796-798 (July) 1073. 25. Huestis, R. D., Arnold , L. E., et al.: Caffeine vs. methylphenidate and d-amphetamine in minimal brain dysfunction ; a double-blind comparison , Am. J. Psychiatry 132:

868-870 (Aug.) 1975. 26. Conners, C.: Pharmacotherapy, in Psychology disorders of childhood , Wiley, New York, New York, 1972, p. 316. 27. Greenhill, L. L. , Reider, R. 0 ., et al. : Lithium carbonate in the treatment of hyperactive children, Arch. Gen. Psychiatry 28: 636-640 (May) 1973. 28. Lewis, J. A. , and Young , R. : Deanol and methylphenidate in minimal brain dysfunction, Clin. Pharmacol. Ther. 17: 534-540 (May) 1975. 29. David, O. J. , Hoffman, S. P., et al.: Lead and hyperactivity. behavioral response to chelation : a pilot study, Am. J. Psychiatry 133: 1155-1158 (Oct.) 1976.

Journal of the American Pharmaceutical Association