Amphetamines in the management of children's hyperkinesis (hyperactivity)

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From V. SINGH , G. M. LING, 1979

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Amphetamines in the management of children's hyperkinesis

V. SINGH Children's Hospital, Vancouver, B.C., Canada
G. M. LING Director, UN Division of Narcotic Drugs, Vienna

Introduction

Hyperkinesis or hyperactivity has been commonly used to refer to a state of altered behaviour in children (Safer and Allen, 1976; Kolata, 1978). The most prominent feature of hyperactivity is the inability to maintain attention. Although hyperactivity as a clinical entity is widely recognized, the prevalence of this disorder varies from 1.0 per cent in some countries to 40.0 per cent in others. In addition, the topic of hyperactivity appears to be very controversial because of conflicting descriptions of its definition, diagnosis and treatment.
The major features of hyperactivity are:

1. Inattentiveness-which refers to a short attention span and inability to concentrate on a problem for any length of time either at play or in school;
   
2. Over activity-constant repetition of an activity which is under no voluntary control, and which surpasses normal engagement in the same tasks;
   
3. Learning impediment-usually associated with poor school work, clumsiness and lack of communication in the classroom;
   
4. Uncontrolled impulsivity-the child is described as being tense, chronically unhappy and acts on the spur of the moment without thinking.
   

This list clearly indicates that the term hyperactivity simply describes the characteristic behavioural pattern of an individual's condition at one point in time. This results in a heterogeneous group of children being classified hyperactive on the basis of a variety of tasks that they perform or the behavioural profiles that they exhibit at school, play or home. Often, the relevant subgroups can be identified, one of which is really pronounced. This type of classification poses the very real problem of defining the term hyperactivity precisely as well as evaluating the disordered behaviour by means of appropriate diagnostic measures.
Other basic problems also are inherent in the terminology of hyperactivity. For example, in diagnoses, the terms "hyperactivity" and "minimal brain damage" (MBD) are commonly used to refer to the same syndrome. However the two terms are not identical in their meaning. The hyperactive children do not always have a learning or perceptual disability which is commonly associated with the MBD syndrome. On the other hand, MBD children are not always hyperactive or excessively restless. Furthermore, there is no evidence of anatomical brain damage in hyperkinetic children, although a minimal dysfunction might occur during the development of the brain resulting in developmental hyperactivity. This term is preferred by some investigators to describe an excessively overactive child.

Basis of hyperkinesis

In the historical context, there has been a prevailing debate about hyperactivity being a "reality" or a "myth". The answer to this question resides entirely in the definition of clinical diagnostic practice. Family physicians have observed the occurrence of a set of symbols identifying altered behaviour in children, and consequently described this behavioural pattern as the "hyperactive syndrome". In recent years, however, it has become apparent that the syndrome of hyperactivity is a medico-social problem which may involve neurological components as well as social and environmental factors. Knowledge of brain function derived over the last decade suggests that behavioural profiles can be interpreted at the level of specialized biochemistry of nerve cells, with respect to discrete brain areas.
Many theories have been developed to unravel a possible neurochemical abnormality underlying hyperactivity or hyperkinesis. One of these suggests that this syndrome derives from impaired inhibitory mechanisms in the central nervous system. Since a large number of inhibitory neural pathways in the brain utilize norepinephrine, dopamine and serotonin as neurotransmitters, a "monoaminergic theory" has been developed to explain hyperactivity (see Silbergeld, 1977). This theory implies an under functioning of catecholaminergic neurons in CNS. Alternative proposals have also been suggested which include age-related immaturity in the functional development of the brain, infectious diseases, brain injury, lead poisoning and the associated effects of adverse psychosocial experiences.
For example, prolonged institutionalization during early childhood may generate difficulties in a child to form meaningful relationships which may lead to certain temperamental and cognitive abnormalities, including hyperactivity, inability to concentrate and difficulties in abstraction. Similarly, children from disorganized families may become preoccupied with the tasks of searching for reliable and satisfying contact with people, avoiding pain and compensating for deficiencies in their growth; under stress, they characteristically respond with a motor discharge of tension, and show low frustration tolerance, impulsivity and unreliable self-control. These psychosocial experiences may interact with physiological predisposition to aggravate the manifestations of the hyperkinetic syndrome.

Stimulant medication and hyperkinesis

During the past two decades, stimulant drugs have been the most frequent treatment approach for the clinical management of the child with hyperactivity. Recent studies suggest that approximately 2 per cent of all elementary school children who suffer from the hyperactive syndrome receive psycho-stimulant medication. In this context, dextroamphetamine sulfate (Dexedrine) and methylphenidate hydrochloride (Ritalin) are frequently used.
The antianxiety and antipsychotic compounds are recommended as alternative therapies in patients who fail to respond to methylphenidate or d-amphetamine. The antidepressant, imipramine and the anticonvulsant, diphenylhydantoin also are beneficial, while sedative drugs such as barbiturates are contraindicated because they tend to exacerbate hyperactivity. In a number of controlled studies it has been shown that on the average more than 50 per cent of hyperkinetic children who had been given amphetamines showed improvement while only 26 per cent did not change or were exacerbated by the drug. Similar improvement rates are seen in children to whom methylphenidate or magnesium pemoline was administered, (Steinberg, 1971).

METHYLPHENIDATE

Methylphenidate, a central stimulant, has been shown to decrease consistently hyperkinesis, aggressive behaviour and impulsivity. Methylphenidate has also been reported to increase attention span and learning performance and is effective in the management of trans-situationally hyperactive children. It is generally believed that methylphenidate stimulates the cerebral cortex, thereby enhancing the function of consciousness. It also exerts a stabilizing influence on structures such as the limbic system which play a role in determining the subject's emotional reactivity. Animal studies have shown that methylphenidate produces amphetamine-like stereotyped behaviour which is mediated by striatal dopaminergic mechanism, and it has been proposed that this CNS stimulant produces its pharmacological effects by enhancing central dopaminergic effects (Garfinkel et al., 1975). In patients who develop tolerance to the effects of methylphenidate, or in those whose parents and teachers report no improvement and for whom neuropsychological tests are unchanged, an alternative medication such as d-amphetamine or imipramine is reported to produce beneficial results.

DEXTROAMPHETAMINE

In a study Arnold et al. (1976) demonstrated that levoamphetamine and dextroamphetamine were equi-potent in treating MBD children particularly with reference to decreasing hyperactivity and aggressiveness. These authors further reported that levoamphetamine showed a decreased tendency to produce the blunt effect and the "amphetamine look" than dextroamphetamine. Levoamphetamine produces less euphoria than dextroamphetamine and reports indicate that the former compound may be a logical choice where there is concern about danger of addiction and possible abuse of the child's stimulant supply. It has been suggested earlier that the action and effects of the hyperkinetic syndrome may be produced via dopaminergic mediation. This view gains additional support from studies in which two optical insomers (dextro and levo) of amphetamines were found equipotent in inhibiting dopamine uptake; however, dextroamphetamine was ten times as potent as levoamphetamine in inhibiting the uptake of neropinephrine in brains of rats pretreated with reserpine (Coyle and Snyder, 1969).

MAGNESIUM PEMOLINE

Magnesium pemoline is another CNS stimulant which has shown promise in treatment of hyperactive children with behavioural disorders. This compound was found to be clinically and statistically superior to placebo on the various measures, which included efficacy in improving learning performance, increasing attention span and decreasing impulsivity (Page et al., 1974). In contrast to amphetamine and methylphenidate, pemoline has fewer autonomic effects and longer duration of action and therefore can be given in a single dose. Pemoline has also been shown to potentiate central catecholamine effects and has been postulated to increase attention span and memory acquisition (Plotnikoff, 1971). While the exact mode of pharmacodynamic action in man is unknown, pemoline has been reported to increase the synthesis of dopamine in rat brain (Tagliamonte et al., 1971).
This CNS stimulant elicits no effect on the synthesis rates of brain norepinephine and serotonin.

TRICYCLIC ANTIDEPRESSANTS

Imipramine and amitriptyline have been used in the treatment of hyperkinesis and have been reported to possess an effectiveness similar to that seen with amphetamines and methylphenidate. A marked improvement in learning skills, as well as progress in alertness and attention span has been noticed in such children after treatment with imipramine. This tricyclic antidepressant is sometimes used as alternative medication in the treatment of the hyperactive child, but it also tends to increase systolic and diastolic blood pressure and pulse rate. (Greenberg and Yellin, 1975).

Diet in the management of hyperkinesis

There is some evidence suggesting that hyperactive behaviour is associated with food allergies. Benzamin Feingold (1976) reported that 30 to 50 per cent of children diagnosed as hyperkinetic experienced a dramatic response to a diet free of artificial food colours and artificial food flavours. However, these observations of Feingold were not substantiated by the subsequent studies of Harley and Associates (1977), suggesting that additional research should be conducted in this area.

Stimulant drug side effects

A review of clinical data indicates that the most prominent side effects associated with the long-term use of CNS stimulants are insomnia or sleep disturbances, and decreased appetite. The next most frequent appear to be weight loss, suppressed growth rate, irritability and abdominal pain. Other side effects of lesser frequency are headaches, drowsiness, dizziness, euphoria, nightmares, tremor, dry mouth, dazed appearance, nervous tics and anxiety. Many investigators found these side effects to be temporary and easily modified by adjusting dosages downwards (Bradley, 1950; Werry and Sprague, 1974). Short-term effects, noticeable during the first or second week of treatment may include: headaches, moodiness, stomach aches, temporary insomnia, reduced appetite and some phases of depressive irritability. Long-term effects which are reported to be rare may result from the drug therapy itself. These include development of psychological dependence, altered sleep pattern and a certain degree of suppression of growth rate.

Problems of long-term drug treatment

Once stimulant therapy appears to be beneficial to a hyperactive child, the long-term or continued treatment becomes an important and interesting issue from the point of view of the school as well as the parents. The maintenance of effective treatment, the detection of unexpected changes in behaviour and adequate medical follow-up are some factors to be taken into consideration. Depending upon the course dosage and outcome of treatment, drug dependence may develop. Therefore it is important for parents and school teachers and physicians to observe the behavioural profiles of stimulant-treated children continuously over a period of several years, in order to observe the degree to which dependence may have occurred. Stimulants offer little or no benefit to hyperkinetic children over 12-13 years of age, and if such therapy is continued past this age, there is an increased risk for dependence to develop.

Present status of stimulant therapy

Subjective observations indicate that teachers perceive hyperkinetic children as having improved "achievement" while treated with stimulant drugs (Schain and Reynard, 1975; Arnold et al., 1976). There is a short-term positive effect as regards classroom manageability in terms of increased attentiveness and concentration. However, while this is positive evidence in favour of hyperactivity treatment with stimulant drugs, the rationale behind this therapeutic approach has recently been brought under question (see Kolata, 1978), mainly because of the following inherent problems of definition, the diagnostic confusion about this syndrome and the stimulant treatment for it. For example,

1. By definition, hyperkinesis refers to a syndrome of altered behaviour in children. It is also believed that hyperkinesis is simply an emotional problem which overlaps with childhood depression (Miller, 1978).
   
2. Hyperkinetic children represent a very heterogeneous group of subjects in terms of their behavioural profiles.
   
3. The diagnostic measures, which are commonly employed, relate only to visual motor activity. Similarly the evaluation of successful stimulant treatment reflects changes only in visual-motor function. Since the hyperkinetic syndrome involves dysfunction of multiple parameters, possibly at the neurological level in brain, all of these should be taken into consideration during the course of diagnosis.
   
4. Stimulant treatment is not consistently successful in that there is a group of hyperactive children benefiting from it while another group derives no benefit.
   
5. There are several side-effects which occur especially after long-term therapy with stimulant drugs, e.g. increase in heart rate and blood pressure (Rapoport et al., 1974); alteration of sleep patterns and growth rate (Safer and Allen, 1973; Weiss et al., 1975).
   
6. Prolonged use of stimulant drugs has some adverse effects on academic skills (Weiss et al., 1975). More recently, objective analyses of hyperkinetic children have revealed no improvement of their academic performance (Barkley and Cunningham, 1978).
   
7. Until recently, there was no control study of a population of normal or non-hyperactive children treated solely with amphetamine. By including such a control study Rapoport et al., (1978) found no major improvement and the amphetamine response in normal and hyper kinetic children was similar, suggesting the lack of specificity of this therapy.
   

1. The "monoaminergic theory" of hyperkinesis implies the involvement of brain catecholamines. However, there is no actual data on the levels of catecholamines estimated in hyperactive children's serum, urine or tissue biopsies. Research is needed in this area.
   
2. Recently it has been shown that the continuous administration of amphetamine to laboratory animals (rats) for as long as 110 days induces a selective and severe neurotoxic effect on dopamine nerve-terminals in the caudate nucleus, the area of the brain which is intimately associated with motor functions (Ellison et al., 1978).
   

Prospects for research and concluding remarks

Although there are general problems in interpreting animal experiments to a clinical human setting, some recent studies with animal models offer good hope for the understanding of paradoxical responses to amphetamines (Silbergeld and Goldberg, 1974; Alpern and Greer, 1977). Likewise the work of Ellison et al. (1978) with rats has yielded new information regarding the effects of amphetamine administration which might occur with stimulant therapy. Furthermore, it can be anticipated that research experiments with laboratory animals may elucidate some of the conflicting issues surrounding the hyperkinetic syndrome. In this respect the following proposals merit attention:

1. Amphetamine actions on catecholamine systems should be thoroughly screened for regional specificity in the brain. This should lead to localization of neuroanatomical substrates for hypermotility elicited in animals by this drug.
   
2. Amphetamine-induced euphoric activity should be explored in relation to other neurotransmitter substances in CNS, e.g. amino acids (glutamate, GABA, aspartate, glycine and taurine) and neuropeptides (endorphins and substance P). It may be hypothesized that if amphetamine exerts its effects through central catecholaminergic pathways then other neural systems that are interacting with them might modulate or mediate the actions of this drug. Some recent work lends support to this suggestion. Pert and Sivit (1977) have found that endorphins, like catecholaminergic agonists, potentiate spontaneous motor activity in rats. Endorphins are opiate peptides and are distributed throughout the CNS and PNS, possibly with a neuromodulator function. Another set of data are derived by the use of a neurochemical kainic acid, a structural analogue of amino acids glutamate and a very potent CNS excitant. Fibiger and his colleagues (1978) have shown that intrastrial injections of kainic acid enhance amphetamine-induced stereotyped behaviour in rats. Such an effect would be very interesting since kainic acid is also known to cause degeneration of cholinergic and GABA neurons (McGeer et al., 1976), and to induce an "active gliosis" (Singh et al., 1978).
   
3. There may be a congenital basis for childhood hyperkinesis (see Kolata, 1978). If so, then virologic and immunologic assessment should be considered.
   
4. Frequently recommended alternatives to stimulant treatment for childhood hyperkinesis such as behaviour therapy, should be encouraged. Since hyperkinesis usually refers to the syndrome of disordered behaviour in children, the modification of behaviour towards normal is socially desirable. Under behaviour therapy, this goal is achieved either by changing a specific pattern of abnormal behaviour or by developing a missing pattern of behaviour. The common tools of this type of therapy are - desensitization to fear, increasing the capacity of self-control or motivation, and group reinforcement for improved social adjustments. In general, behavioural therapy helps in the improvement of school-directed problems, but harmonious and integrated commitment between family, school and child is mandatory. Although some uncertainty exists about the usefulness of behaviour therapy (Eisenberg, 1978), there is ample evidence which suggests that the management of the hyperkinetic syndrome by means of behaviour therapy can be an effective and viable alternative to stimulant therapy (Ayllon et al., 1975; O'Leary and Pelham, 1978).
   

Childhood hyperkinesis denotes a heterogeneous group of behaviour disorders. The etiology is unclear. The criteria used to diagnose this syndrome are limited and mainly describe the child's inability to manipulate visual-motor function. This diagnostic approach does not have a strong clinical foundation and presents difficulties in distinguishing closely the characteristics of hyperactive children from childhood depression usually connected with emotional problems. While hyperkinesis does not seem to be a disease, school personnel evidently perceive child's behaviour as abnormal in relation to classroom situations and academic skills.
Stimulant medication is the most commonly prescribed form of treatment for the hyperactive child. The benefits are inconsistent: no sound evidence exists for the reported paradoxical effect of these drugs, and it has not been consistently demonstrated that children treated solely with stimulants subsequently do better in school.
Also, there is no evidence of brain lesions in hyperkinetic children. The proposal of a monoaminergic theory to explain a neurochemical basis of hyperkinesis would imply the possibility of functional neurological pathology. In this regard, it is of interest that the actions and effects of stimulant drugs used in this connection are related to catecholaminegic mechanisms in the central nervous system. Future experiments with animal models might provide a way to the nature and causes of childhood hyperactivity.

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Created 8/30/2001 19:17:23
Modified 8/30/2001 19:17:23