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Pharmacological and biochemical aspects of hyperkinetic disorders
Nrur,,phlrrna,‘nk,y,. Vol IX, pp 923 to 929 Perpamon Press Ltd ,979. Pnnted ,n Great Bnta~n
PHARMACOLOGICAL AND BIOCHEMICAL ASPECTS OF HYPERKINETIC DISORDERS Pharmacology
B. E. LEONARD Department, University College, Galway. Eire
In 1977, the Dutch Interdisciplinary Society of Biological Psychiatry held a symposium in Amsterdam entitled “Minima1 Brain Dysfunction: Fact or Fiction?“. While this title was undoubtedly intended to be provocative, for who would doubt that the functional integrity of the brain can become disturbed, it served to emphasize the confusion regarding the symptomology and possible aetiology of this childhood disorder. Thus, such diagnostic labels as “brain damage syndrome”, “hyperactivity syndrome”, “minimal brain damage”, “specific learning disability” and the “hyperkinetic syndrome” have all been used interchangeably. In genera1 however, all these abnormal behavioural states are characterized by hyperactivity, impulsiveness, distractibility and excitability. In addition, aggressive and anti-social behaviour, specific learning problems and emotional lability are generally considered to be part of the hyperkinetic disorders. As in all areas of psychiatric medicine, theories aimed at explaining the aetiology, or rather aetiologies, of the hyperkinetic syndrome abound and seem to cause confusion rather than a deeper understanding of the problem. Theories include brain damage (Millichap and Johnson, 1974), biochemical disorders (Wender, 1975), minor congenital physical abnormalities (Rapoport and Quinn, 1975), reduced central nervous system arousal (Satterfield and Cantwell, 1975), genetic disorders (Cantwell, 1972) or simply a biological variation made manifest by universal compulsory education (Werry, Minde, Guzman, Weiss, Dogan and Hoy 1972). Undoubtedly it is possible to visualize an interconnection between these theories but clearly more evidence based on clinical parameters rather than animal models must become available before such a unifying theory is advanced. Although both clinicians and experimentalists have shown a considerable interest in the hyperkinetic disorders in recent years, it would be incorrect to interpret this as a fashionable concentration of research on a newly discovered disease. Indeed, as early as 40 B.C. patterns of motor aphasia were described in children which would probably be diagnosed as a hyperkinetic disorder today. In more recent times, Hoffman (1845) gave a detailed account of such disorders in his thesis entitled “Der Strumpelpeter oder lustige Geschichtern und drollige Bilder”. Not only was the clinical picture of the hyperkinetic child well established by the first half of the twentieth century but the pharmacological
treatment with dextro-amphetamine was first attempted, with considerable success, by Bradley in 1934 (Bradley, 1950). The stimulant drugs, amphetamine and methylphenidate still remain the drugs of choice for the treatment of such disorders today. The purpose of this contribution is to review some of the pharmacological, neurological and biochemical studies which have been made in patients, and on animal models, of hyperkinetic disorders in the hope that such an approach may lead to a clearer understanding of the aetiology of the disease. NEUROLOGICAL AND
GENETIC
ASPECTS
It is not unreasonable to assume that damage to the brain in utero or during the early stages of post natal development may lead eventually to the physical and psychological symptoms associated with hyperkinetic disorders. Millichap, Aymat, Sturgis, Larsen and Egan (1968) have shown for example, in their study of hyperkinetic children, that 57’4 of the patients had a history of brain injury or cerebra1 damage and that all but one of these patients had neurological signs of minimal brain dysfunction. Unfortunately, other investigators have been unable to show a clear correlation between such symptoms and minor brain damage. Thus, Prechtl (1978) has shown that the interindividual variation amongst children who have been classified as suffering from minimal brain damage is considerable and the degree of the abnormality often varies in different situations. One reason for such a high variability is due to the fact that the derranged central nervous system possesses a large number of compensating processes which have adaptive functions in early post natal life. For example, lesions of the cerebral cortex may produce different behavioural effects depending upon the age of the animal as it only functions in the control of most subcortical structures relatively late in brain development (cf. Wetzel, Thompson, Horel and Meyer, 1965). In general, both clinical and experimental studies suggest that if the brain is structurally damaged early in development there is sufficient plasticity present to allow it to compensate for the damge. Such factors may be important in attempting to understand the neurological basis of hyperkinetic disorders and might also help to explain the wide variation in the symptoms of children classified as suffering from such disorders. The differences in the sever-
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B. E.
ity of the symptoms with different social situations may also be evidence of abnormal neuronal “rewiring” resulting from neurological damage in early development. Thus, Thompson (1969) has shown that when monkeys were amygdalectomized in the first 2 months of birth and then tested 3 years later in a test cage, the experimental animals were hyperactive relative to sham operated controls. These differences disappeared after the animals were left in the cage for 24 hr but at this time the experimental animals explored more than the controls and chewed more objects in the cage. Specific studies on the sequelae of mild head injury are lacking but it is clear that psychiatric disorder, in the absence of persisting motor or sensory signs. may follow such injury. Thus. Shaffer, Chadwick and Rutter, (19753, in a detailed follow-up study of patients who were known to have suffered head injury, found that approximately two-thirds of such patients were behaviourally disturbed but that only one tenth showed any signs of neurological impairment. Other investigators have come to similar conclusions (Klonoff and Paris, 1974). The evidence implicating chronic malnutrition during the early stages of brain development in the causation of hy~rkinetic disorders is somewhat equivocal but there seems little doubt that lead intoxication at such a period of development leads to cognitive and/or behavioural difficulties in the absence of persisting motor or sensory handicaps (de la Burde and Choate, 1972, 1975). Experimental studies have shown that newborn rats suckling mothers who have been fed on a diet containing 4:; lead carbonate displayed increased locomotor activity, aggressiveness and excessive stereotyped behaviour, as manifested by self grooming (Sauerhoffe and Michaelson, 1973). These authors also reported that the whole brain dopamine content of the weanling rat was significantly reduced as a consequence of the lead intoxication. From such studies, it would appear that heavy metal exposure during maturation of the brain could be responsible, at least in some cases, for the onset of hyperkinetic symptoms. Viral infections may also cause neurological damage which could later result in hyperkinetic disorders. Thus. the first widespread description of such disorders occurred early in this century following the pandemic of influenza particularly in those children suffering from menigoencephalitis (Bond. 1932). The contribution of an inherited predisposition to the development of hyperkinetic disorders is di~cult to assess. There is some evidence that the frequency of psychiatric disorders, particularly alcoholism and sociopathy, amongst the biological parents of hyperkinetic children is increased (Morrison and Steward, 1971). In an investigation in which the incidence of such disorders was assessed in groups of children who were in the care of foster parents, it was found that the incidence of hyperkinetic disorder was significantly higher amongst siblings than amongst those
LEONARD
who were unrelated (Safer. 1973). While such studies may provide a pointer to the possible involvement of genetic factors in the aetiology of the disease none of the studies fully account for the environmental, particularly social, factors which may play a crucial rofe in the early stages of development. Wender (I 978) has recently reviewed the evidence which favours a genetic brain for the hyperkinetic disorders. Another aspect of hyperkinetic disorders which seem worthy of consideration concerns the subsequent development of such patients on reaching maturity. In a detailed anterospective study by Wood_ Reimherr, Wenders and Johnson, (1971) it was found that a group of children who had been diagnosed as suffering from minima1 brain damage 8-10 years previously had a twenty times greater risk of antisocial behaviour or psychiatric illness on reaching maturity than did those who were apparently normal during childhood. These investigators found that 607; of such adults patients responded beneficially to methylphenidate treatment. Other studies also indicate that there is an increased incidence of hyperkinetic-like behaviour in adults diagnosed as suffering from personality disorders and such symptoms as impulsive behaviour. low frustration tolerance, social and interpersonal inadequacy are probably the adult equivalent of the hyperkinetic symptoms seen in childhood (O’Neal and Robbins, 1958; Quitkin and Klein. 1969). From the evidence presented above it can be concluded that although neurological damage, genetic predisposition. viral infection and lead toxicity may play a role in the causation of hyperkinetic behaviour in some cases there is, as yet, insufficient evidence to implicate minimal brain damage as the primary cause of such a behavioural abnormality. BIOCHEMICAL ASPECTS
AND BEHAVIOCRAL
OF HYPERKINETIC
DISORDERS
While there is little direct evidence from clinical studies to substantiate the view that an abnormality of brain biogenic amine metabolism underlies hyperkinetic disorders, there is considerable circumstantial evidence to support such a hypothesis. Such evidence comes from psychological studies on patients. from animal models of hyperkinesia which involve changes in brain biogenic amine metabolism and from an investigation of the mode of action of therapeutically effective drugs on central neurotransmission. Wender (1974) has suggested that the decreased attentiveness and an inability to focus on relevant detail and on ~gure-ground discrimination is evidence that hyperkinetic children are hyper-aroused. In addition, the incidence of sleep difficulties appear to be increased in such children. Such symptoms of hyperarousal may be a consequence of increased activity of the noradrenergic system in the brain. However other investigators, when studying the EEG of hyperkinetic children have come to the conclusion that such patients are under-aroused (Stevens. Sachdev and
Pharmacological
and biochemical
Milstein, 1968; Wickler, Dixon and Parker, 1970) a review supported by the findings of Satterfield and Dawson (1973) who found that these children had a higher galvanic skin resistance than normals. The hypothesis that hyperkinetic children are hypo-aroused is conceptually more attractive than that suggesting a hyper-aroused state as there is abundant clinical evidence that such stimulant drugs as amphetamine and methylphenidate, which appear to act by releasing catecholamines in the brain thereby increasing the level of arousal, are effective in the treatment of hyperkinetic disorders. Nevertheless another interpretation of the beneficial effects of stimulant drugs is possible if it is assumed that the hyperkinetic disorders reflect a hyper-aroused state. Amphetamine can produce stereotyped behaviour patterns in adults (Rylander, 1971) which becomes increasingly “constricted” with increasing doses of the drug. Sroufe and Steward (1973) therefore postulate that the stimulant drugs produce a certain degree of behavioural stereotypy in hyperkinetic children so that the behaviour becomes “constricted” thereby enabling the children to perform repetitive, routine tasks requiring sustained attention. Thus, the stimulant drugs may be pictured as converting a hyperactive state into a stereotyped state thereby resulting in the paradoxical effect of stimulants on hyperkinetic disorders. However, the question arises as to whether stimulant drugs do have a paradoxical effect in that they specifically reduce the hyperactivity of hyperkinetic children. Thus Rapoport et al. (1978) studied the behavioural, cognitive and electrophysiological effects of amphetamine on normal pubertal boys and found that the drug caused a marked decrease in motor activity and reaction time and improved performance on cognitive tests, an effect similar to that observed in hyperkinetic children. Reichard and Elder (1977) have also concluded from their studies of the effect of caffeine on reaction time that this stimulant drug does not produce a paradoxical effect but rather a more intense response than that seen in normal children. One possible explanation for this paradoxical effect of stimulant drugs on hyperkinetic disorders might arise from the nature of the parameters being measured to assess the clinical state. Thus Sprague and Sleator (1977) found that methylphenidate optimally enhances learning in hyperkinetic children at a dose of 0.3 mg/kg and that higher doses produce a decrement in learning. However, social behaviour showed a marked improvement only when doses of l.Omg/kg were administered. Different behavioural effects therefore occur at different doses of the drug and certain psychological abnormalities, for example performance of verbal tasks, appear to be uninfluenced by the drug (Gittelman-Klein and Klein, 1976). The situation regarding the long term efficacy of stimulant drugs on hyperkinetic behaviour is further complicated by the fact that the learning ability of such children is only maintained in the presence of the drug, a condition known as state-dependent learning (Swanson and
aspects
of hyperkinetic
disorders
925
Kinsbourne, 1976) whereas normal children do not show such behaviour. As there does not appear to be a general agreement about the paradoxical effect of stimulant drugs on hyperkinetic disorders, it would be of interest to know what biochemical differences are manifest between hyperkinetic and normal children with regard to the differences in the state dependent learning effect of these drugs. The most direct evidence for the involvement of brain catecholamines in the aetiology of hyperkinetic disorders comes from the studies of Shetty and Chase (1976) who reported that the lumbar cerebrospinal fluid samples of the major dopamine and serotonin metabolites (homovanillic acid and 5-hydroxyindole acetic acid) did not differ significantly from agematched normal children. However d-amphetamine treatment substantially reduced the concentration of the dopamine metabolite without affecting that of 5-hydroxyindole acetic acid. The rate of decline in the concentration of homovanillic acid was closely correlated with the degree of clinical improvement. Other investigators have also determined the concentrations of dopamine metabolites in the CSF of hyperkinetic children. Unlike Shetty and Chase (1976) however. Shaywitz, Cohen and Bowers (1977) found that in the six patients investigated, the homovanillic acid concentration was reduced by 50% before treatment with stimulant drugs. Clearly there are ethical difficulties in undertaking such invasive studies on children but the finding by Wood et al. (1976) that “Minimal brain dysfunction” also occurs in adults who had hyperkinetic disorders in childhood should enable more complete studies to be undertaken on the biochemical changes underlying this disorder. Nevertheless, if it assumed that homovanillic acid concentrations in the CSF may be used as a crude index of dopamine turnover in the brain (i.e. an index of the rate of synthesis, release and inactivation) such the study of Shaywitz et al. (1977) would suggest that dopamine turnover is reduced in hyperkinetic disorders. Presumably the further reduction in the concentration of the dopamine metabolite after amphetamine treatment is due to the reduced reuptake of dopamine (and hence reduced intraneuronal metabolism) caused by the drug. Experimental evidence also supports the hypothesis that changes in dopaminergic activity may be causative of hyperkinetic disorders. Shaywitz, Yager and Klopper (1976) found that when brain dopamine was depleted in neonatal rats by 6-hydroxydopamine treatment the total activity of the animals was significantly greater between 12 and 22 days but then declines to control levels. This suggests that a biochemical lesion involving the dopaminergic system, either pre- or post natally, may be instrumental in producing hyperkinetic behaviour in a later pre-pubertal state. This model would not explain the fact that hyperkinetic symptoms also occur in the adult however (Wood er al., 1976). Other experimental evidence implicating a disorder
926
B. E.
LEONARD
of dopamine metabolism in the hyperactivity state comes from the studies of Alpern and Greer (1977) who found that both amphetamine and the dopamine receptor agonist apomorphine attenuated central excitability (as assessed by incidence of myoclonic seizures) and hyperactivity of genetically predisposed mice but both drugs increased the excitability of adult mice of the same genetic strain. The same criticism however, can be made of this animal model as the one proposed by Shaywitz er ul. (1976). Lesions of the ventro-media1 tegmental area in rats also produce hyperactivity and several behavioural deficits which may be ascribed to a destruction of the A10 groups of dopaminergic cell bodies (LeMoal, Stinus, Simon, Tassin, Thierry. Blanc. Glowinski and Cardo, 1977). The behavioural changes are not correlated with changes in cortical serotonin or noradrenaline concentrations but do correlate with those of dopamine in some limbic regions; low doses of amphetamine reverse the behavioural deficits. This animal model seems particularly relevant to the evaluation of the relationship between adaptive and hyperkinetic behaviour and brain dopaminergic function but its relevance to an understanding of hyperkinetic disorders in children remains to be seen, It is not the purpose of this presentation to give a detailed account of the various animal models of hyperkinetic behaviour. For completeness it will suffice to say that both hyper- (Hess and Dopfner. 1961) and hypo(Jacobs, Mosko and Trulson. 1977) activity of the central serotonergic system can cause marked hyperactivity of rodents. There is some evidence from clinical studies of hyperkinetic children that the platelet serotonin concentration of hyperkinetic children is subnormal (Wender, 1969; Coleman, 1971) but there is little evidence that such an abnormality is connected with the aetiology of the disease. Indirect studies of the effects of amphetamine however. shows that not only does this drug release catecholamines in the central nervous system and prolong their action at central receptor sites by reducing their re-uptake but. at the same dose, it increases serotonin turnover (Leonard, 1972) and increases the concentration of tryptophan (Leonard and Shallice. 1971). Other investigators have shown that this drug releases serotonin from serotonin-containing neurones (Fuxe and Ungerstedt. 1970). Thus. in addition to the catecholamines. the possibility arises that an abnormality in the serotonergic system may underlie some types of hyperkinetic disorder and that such a system may be involved in the mechanism whereby amphetaminelike drugs are therapeutically effective [see Brase and Loh (1975) for a review of this area]. From this short review it can be concluded that the evidence implicating an abnormality in catecholamine and/or serotonin metabolism in the causation of hyperkinetic disorder is largely circumstantial and based upon the supposed mode of action of stimulant drugs that are clinically effective in ameliorating at least some of the symptoms of the disorder.
PHAR~MACOI~OGICAI. ASPECTS
The stimulant drugs. d-amphetamine and methylphenidate, are still the drugs of choice in the treatment of hyperkinetic children (Conners, 1972). Indeed. the efficacy of these drugs is so well established that they are used as standard medication against which drugs such as imipramine (Rapoport, Quinn, Bradbard. Riddle and Brooks. 1974) or magnesium pemoline (Conners, 1974) are compared. The view, that the use of methylphenidate is preferable to amphetamine (Weiss, Minde, Douglas, Werry and Sykes, 1971) now seems questionable (Winsberg, Press. Bialer and Kupietz, 1974). Both drugs. when administered in high therapeutic doses (l-2 mg!kg/day) cause anorexia weight loss. sleeplessness and growth suppression and there is evidence that growth suppression persists as long as high doses of the stimulant are administered (Safer and Allen, 1975). Low doses of the drugs (0.34.5 m&kg/day) appear to be clinically effective in most cases and cause fewer side effects (Sprague and Sleator. 1973). Despite the well established fact that stimulants frequently cause dependency in adults (Connell. 1958; Tolentino. 1957) there is no evidence of long term abuse or dependency problems in follow up studies on children who have been treated with such drugs (Lipman. 1974: Weiss 1975). The stimulant profile of amphetamine in animals and human adults suggests that its pharmacological activity is ascribable to an increased activity of the catecholaminergic system in the brain. There is experimental evidence to suggest that the drug releases dopamine from its newly synthesized storage pool (Scheel-Kruger, 1972; Heikkila. Orlansky, Mytilincou and Cohen, 1975) and reduces the re-uptake of this amine into the presynaptic nerve terminal (Raiteri. Bertollini. Angelini and Levi. 1975). It is less certain however whether amphetamine has the same effect on noradrenaline release as ill rim studies clearly show that the main action of the drug is to inhibit noradrenaline re-uptake rather than to cause release of this amine (Raiteri, Levi and Federico, 1974). Leonard (1972) reported that high acute doses of this drug increased the release of noradrenaline in the rat brain iri V&J. There is indirect evidence to support the view that the hyperactivity and stereotypy caused by the drug is largely attributable to its effect on the dopaminergic system (Thornburg and Moore. 1973): the greater mood elevating effect of the rl- over the I-isomer of amphetamine (Smith and Davis. 1977) would also appear to be due to the enhanced potency of the d-isomer in inhibiting dopamine uptake. While methylphenidate has a somewhat similar clinical profile to amphetamine. experimental data suggests that the former drug depletes catecholamines from their less labile storage pools (Thornburg and Moore, 1973) and that its main pharmacological action is due to an inhibition of catecholamine uptake with little effect on amine release (Hendley. Snyder. Fairely and Lapidus. 1972).
Pharmacological
and biochemical aspects of hyperkinetic disorders
Despite the abundance of evidence showing that the stimulant drugs affect brain catecholamine metabolism both in animals and man, it is well established that serotonin metabolism is also affected in equivalent doses (see above). Furthermore, high acute doses (5 mg/kg) increase the concentration of the inhibitory transmitter substance y-aminobutyric acid (Leonard and Shallice, 1971) whereas lower doses of amphetamine administered chronically to rats causes a decrease in the concentration of this amino-acid in several brain regions, (Lynch and Leonard, 1978). As there is evidence that a close inter relationship exists between y-aminobutyric acid and the biogenic amines in the basal ganglia as well as in other brain regions, it would seem premature to ascribe the therapeutic effects of drugs such as amphetamine to one specific neurotransmitter system. Tricyclic antidepressants have been shown by controlled clinical trials (Greenberg, Yellin, Spring and Metcalf, 1975; Rapoport et al., 1974) to be of some value in the treatment of hyperkinetic disorders, their responses are generally less predictable and less striking than the stimulants. It is generally accepted that the tricyclic antidepressants act by reducing the reuptake of noradrenaline and/or serotonin into the nerve ending an effect which may partly account for their antidepressant action (Glowinski, Iversen and Axelrod, 1966; Carlsson, Carrodi, Fuxe and Hokfelt, 1969). This subject has been reviewed elsewhere (Leonard, 1975, 1979). However, just because such drugs have an antidepressant action in adults there is no evidence to support the contention that they produce a beneficial effect in the hyperkinetic child by acting in the same way. The mode of action of tricyclit antidepressants in the treatment of hyperkinetic disorders therefore remains an enigma. Furthermore, the high doses necessary to produce a therapeutic response in hyperkinetic disorders (up to 14 mg/kg/day) predispose the patients to such serious side effects as seizures and cardiotoxicity (Hayes. Panitch and Barker, 1975). Neuroleptics are also commonly used in the treatment of hyperkinetic disorders but their action appears to be relatively non specific in that they depress hyperactivity in children at doses that also reduce attention and cognition (Werry and Aman, 1975). Furthermore such side effects as extrapyrimidal disorders and xerostomia often restrict the u& of such drugs. Thus, the neuroleptics cannot be considered to be specific therapeutics agents for the treatment of hyperkinetic disorders. As the primary biochemical action of such drugs appears to be the blockade of dopamine receptors in’ihe brain (Van Praag, 1977; Kebabian, Petzold and Greengard. 1972), whereas it has been postulated that the beneficial effects of stimulant drugs are partly ascribable to their ability to stimulate dopamine receptors (see above), it is understandable why the neuroleptics are of limited clinical value in the treatment of hyperkinetic disorders. Other drugs which have been found to be of limited
927
value in the treatment of hyperkinetic disorders inelude the mildly stimulant drug, magnesium pemoline and lithium salts (Greenhill, Rieder. Wender, Buchbaum and Kahn, 1973) but their usefulness as assessed by double blind clinical trial has yet to be established. After briefly reviewing the evidence upon which the various theories of hyperkinetic disorders are based one can have sympathy with the views expressed by Eugene Bleuler (1911) when commenting on psychiatric medicine in general: “Theories which comb&e correct and false facts are more dangerous to science than complete errors; and hypotheses which are only “justified in a certain sense” always create confusion because the necessary reservations cannot always be stated. Clear cut concepts can only be reformed if we ruthlessly reject everything that does not belong to them, regardless of whether we are dealing with simple problems or with entire theories”. Perhaps it is too pessimistic to say that there are no indications of the biochemical basis for the hyperkinetic disorders but more research needs to be directed towards establishing what changes in neurotransmitter metabolism actually occur in patients. While ethical considerations may limit investigations on children, the probability that adults also suffer from such disorders make such investigations a practical proposition. Experimental studies on animals have largely been restricted to the action of stimulant drugs on biogenic amine metabolism. Relatively little research seems to have been devoted to the effect of such drugs on the developing brain and on other neurotransmitter systems in which amino acids and acetylcholine for example play a role. Until such broad areas have at least been superficially explored it seems conceptually restrictive to confine the explanation of hyperkinetic disorders to a disorder of catecholamine metabolism which in some unexplained way may only occur before puberty.
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Psych&. 132: 546-547. Prechtl. H. F. R. (1978). Minimal brain dysfunction svnHeikkila, R. E.. Orlansky, H.. Mytilineou, C. and Cohen. drome and the plasticity of the nervous system. Adr. &i. G. (1975). Amphetamine: evaluation of d- and i-isomers Psiriiiat. 1: 96.- 105. as releasing agents and uptake inhibitors for “H-dopaQuitkin, F. and Klein. D. F. (1969). Two behavioural synmine and “H-norepinephrine in slices of rat neostriatum dromes in young adults related to possible minimal and cerebral cortex. J. Phurakzc. rxp. Thu. 194: 47-56. brain dysfunction. J. Psyhiar. Rta. 7: !31-142. Hendley, E. D., Snyder. S. H.. Fairely, J. J. and Lapidus. Rapoport, J. and Quinn. P. (1975). Minor physical anomJ. B. (1972).Stereoselectivity of catecholamine uptake by alies (stigmata) and early developmental deviation: A brain synaptosome: studies with ephedrine. methylmajor biologic subgroup of ‘hyperactive children‘. In?. J. phenidatc and phenyl-2-piperidge carbinol. J. Plmrmtrc. Mehi. H<%iiril. 4: 1-Q-44. e\-p. Titer. 183: 103 116. Rapoport. J.. Quinn. P., Bradbard. G.. Riddle. K. and Hess, S. M. and Doprner. W. (1961). Behavioural effects Brooks. E. (1974). Imipramine and methylphcnidate and brain amine content in rats. Archs int. ~h~~r~t~~~~d~~. treatment of hyperactive boys. A double-blind compari?-her. 134: 89-99. son. Archs yen. P.src&t. 30: 789-793. Hoffman. H. (1895). Der Strumpelpeter. o&r lustiqu GcsRapoport. J. L.. Buchsbaum. M. S., Zahn, T. P.. Wenichichtern und drollige Rildw. I&l Verlag, Leipzig. gartner. H.. Ludlow. C. and Mikkelsen. E. I 197X). S<,icm-c Jacobs. B. L.. Mosko. S. S. and Trulson. M. E. (1977). The iw:560-m investigation of the role of serotonin in mammalian beRaiteri. M.. Levi. G. and Federico. R. (19741. ri-Amphehaviour. In: Nrurohiology of Skrp cmd Memor? tarnine and the release of ‘H-norepinephrine from (Drucker, R. R. and McGough. J. L., Eds). pp. 99-l 34. synaptosomes. Eur. J. Phnrnw. 28: 23<-246 Academic Press. New York. Raiteri. M.. Bertoltini. A.. Angelini. F. and Levi, G. (1975). Kebabian, J. W.. Petzold, G. L. and Greengard, P. (1972). &Amphetamine as a releaser on uptake inhibitor of bioDopamine-sensitive adenylate cyclase in the caudate nugenie amines in synaptosomes. Eur. J. Phurmtrc. 34: cleus of rat brain. and its similarity to the ‘dopamine 189- 195. receptor’. Proc. mart. Acud. Sci. U.S.A. 69: 21452149. Reichard. C. C. and Elder. S. T. (1977). T’he effects of cafKlonoff, H. and Paris, R. (lY74). Immediate, short term feine on reaction time in hyperkinctic and normal and residue effects of acute head injuries in children: children. Am. J. Psyclrint. 134: 144-148. Neuropsychological and neurological correlates In : Rylander. G. (1971). Stereotypy in man following amphetClinical Neurops~chulogy~ Current Stutus und Application amine abuse. In: The Correlation qf Adrwse f?ficrs in (Reiton and Davidson, Eds), Habtead Press. New York. zbfa~~wifk Ohsar~~rtwn.s ir? Anirncrfs (Buken. E. Ed.). p, 28. Le Meal, M.. Stinus, L., Simon. H.. Tassin, J. P.. Thierry. Excerpta Medica Congress Series No. 120. Amsterdam. Safer, D. J. (1973). .A familial factor in imnimal brain dysA. M.. Blanc, G.. Glowinski, J. and Cardo. B. (1977). function. &.+a~>. (;ener. 3: 175-I 86. Behavioural effects of a lesion in the ventral mesence-
Pharmacological
and biochemical
Safer. D. and Allen, K. (1975). Side effects from long-term use of stimulants on children. [nf. J. Me~?f. Heulrh 4: 105--l 18. Satterfield. J. and Cantwell. D. (1975). Psychopharmacology in the prevention of antisocial and delinquent behaviour. Inr. J. Mrnr. ffr~lt/~ 4: 227-237. Satterfield. J. H. and Dawson, M. E. (1973). Electrodermol correlates of hyperactivity in children. ~s~~~o~~~~io~og~, 8: 191-197. Sauerhoffe, M. and Michaelson, I. A. (1973). Hyperactivity and brain catecholamines in lead exposed developing rats. Science 182: 195-205. Scheel-Kruger. J. (1972). Some aspects of the mechanism of action o? vari&s stimulant .amphetamine analogues. F&a
os\~chiat. neural.
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neerl. 75: 179- 192.
Shaffer, ‘D:. Chadwick. 0. and Rutter. M. (1975). Psychiatric outcome of localized head injury in children. In: Outcome
f$ sewre
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(Porter, S. and Fitzsimons. T. W., Eds). fiba Foundation Symposium No. 34. Elsevier-Excerpta Medica-North Holland. Amsterdam. Shaywitz. B. A.. Cohen. D. J. and Bowers, M. B. (1977). CSF monoamine metabolites in children with minimal brain dysfunction: evidence for alteration of brain dopamine. A preliminary report. J. Pediat. 90: 67.-71, Shaywitz, B. A., Yager, R. D. and Klopper, J. H. (1976). Selective brain dopamine depletion in developing rats: an experimental model of minimal brain dysfunction. Science 191: 305-308. Shetty. T. and Chase, T. N. (1976). Central monoamines and hyperkinesis of childhood. IYeurolo(ly 26: lO@lO2. Smith, R. C. and Davis, J. M. (1977). Comparative effects of d-amphetamine, l-amphetamine and methylphenidate on mood in man. ~.~~~~lo~~~~~eoio~~ 53: I- 12. Sprague, R. and Sleator, E. (1973). Effects of psychopharmacological agents on learning disorders. Pediar. Chins IV. Am. 20: 719-735. Sprague, R. L. and Sleator. E. K. (1977). Methylphenidate in hyperkinetic children: differences in dose effects on learning and social behaviour. Science t98: 12741276. Sroufe, L. A. and Stewart. M. A. (1973). Treating problem children with stimulant drugs. New Engl. J. Med. 282: 407.413. Stevens, J. R., Sachdev, K. and Milstein, V. (1968). Behaviour disorders of children and electroencephalogr~im. Archs Nerrrof. 18: 166177. Swanson, J. M. and Kinsbourne, M. (1976). Stimulantrelated state dependent learning in hyperactive children. Science 192: 1354.-1357. Thompson. C. I. (1969). Time in test cage and behaviour after amygdalectomy in infact rhesus monkeys. Physiof. Behuc. 4: 249-254. Thornburg. J. E. and Moore. K. E. (1973). The relative importance of dopaminergic and noradrenergic neuronal
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systems of the stimulation of locomotor activity induced by amphetamine and other drugs. Neuropharnzucologj 12: 853. Tolentino. I, (1957). Psychotic reactions and psychosis due to /3-phenylisopropylamine and sympathomimetic drugs (amphetamine group). In: Psychotropic Drugs (Garattini, S. and Ghetti. V.. Eds), p. 585. Elsevier. Amsterdam. Van Praag, H. M. (1977). The significance of dopamine for the mode of action of neuroleptics and the pathogenesis of schizophrenia. Br. J. Psychiat. 130: 463474. Weiss. G. (1975). The natural history of hyperactivity in childhood treatment with stimulant medication at different ages. A summary of research findings. Inf. J. Mint. Health 4: 213~226. Weiss, G., Minde. K., Douglas, B.. Werry, J. and Sykes. D. (1971). Comparison of the effect of chlorpromazine, dextro amphetamine, and methylphenidate on the behaviour and intellectual functiomng of hyperactive children. fun. Evird. Assor. J. 104: X-25. Wender. P. H. (1979). Platelet serotonin level in children with “minimal brain dysfunction”. Lancer 2: 1012. Wender. P. H. (1974). Some speculations concerning a possible biochemical basis of minimal brain dysfunction. Lifr Sci. 14: 160551621. Wender, P. H. (1978). Minimal brain dysfunction: an overview. In: Ps!chopharmacolog~: a Generation of‘ Progress (Lipton. M. A.. Di Mascio, A. and Killam. K. F.. Eds). pp. 1429-1435. Raven Press, New York. Wender. P. 11975). Sueculations concerninp a uossible biochemical basis of minimal brain dysfunction. inr. f. Ment. Health 4: 1l-28. Werry. J. and Aman. M. (1975). Methylphenidate and haloperidol in children. Efiects on attention, memory and activity. Archs gnu. Psychiat. 32: 790-795. Werry. J., Minde. K., Guzman, A.. Weiss. G., Dogan. K. and Hoy. E. (1972). Studies on the hyperactive child. VII: Neurological compared with neurotic and normal children. Am. J. Orthopsphiut. 42: 441451. Wetzei. A. B., Thompson. V. E., Horel, J. A. and Meyer, P. M. (i965). Some consequences of perinatal lesions of the visual cortex in the cat. Psvclron. Sci. 3: 381-382. Wikler. A. W.. Dixon, J. F. and Parker. J. B. (1970). Brain function in problem children and controls: Psychometric. neurological and electroencephalographic comparisons. Am. J. Psychiar. 127: 634-645. Winsberg, B.. Press, M., Bialer. I. and Kupietz. S. (1974). Deurro-amphetamine and methylphenidate in the treatment of hyperactive~a~gressive children. Pediatrics 53: 236-241. Wood, D. R., Reimherr, F. W., Wenders, P. H. and Johnson. G. E. (1976). Diagnosis and treatment of minimal brain dysfunction in adults. Ark gen. Psychiat. 33: 1453--1461. L.
PHARMACOLOGICAL AND BIOCHEMICAL ASPECTS OF HYPERKINETIC DISORDERS Pharmacology
B. E. LEONARD Department, University College, Galway. Eire
In 1977, the Dutch Interdisciplinary Society of Biological Psychiatry held a symposium in Amsterdam entitled “Minima1 Brain Dysfunction: Fact or Fiction?“. While this title was undoubtedly intended to be provocative, for who would doubt that the functional integrity of the brain can become disturbed, it served to emphasize the confusion regarding the symptomology and possible aetiology of this childhood disorder. Thus, such diagnostic labels as “brain damage syndrome”, “hyperactivity syndrome”, “minimal brain damage”, “specific learning disability” and the “hyperkinetic syndrome” have all been used interchangeably. In genera1 however, all these abnormal behavioural states are characterized by hyperactivity, impulsiveness, distractibility and excitability. In addition, aggressive and anti-social behaviour, specific learning problems and emotional lability are generally considered to be part of the hyperkinetic disorders. As in all areas of psychiatric medicine, theories aimed at explaining the aetiology, or rather aetiologies, of the hyperkinetic syndrome abound and seem to cause confusion rather than a deeper understanding of the problem. Theories include brain damage (Millichap and Johnson, 1974), biochemical disorders (Wender, 1975), minor congenital physical abnormalities (Rapoport and Quinn, 1975), reduced central nervous system arousal (Satterfield and Cantwell, 1975), genetic disorders (Cantwell, 1972) or simply a biological variation made manifest by universal compulsory education (Werry, Minde, Guzman, Weiss, Dogan and Hoy 1972). Undoubtedly it is possible to visualize an interconnection between these theories but clearly more evidence based on clinical parameters rather than animal models must become available before such a unifying theory is advanced. Although both clinicians and experimentalists have shown a considerable interest in the hyperkinetic disorders in recent years, it would be incorrect to interpret this as a fashionable concentration of research on a newly discovered disease. Indeed, as early as 40 B.C. patterns of motor aphasia were described in children which would probably be diagnosed as a hyperkinetic disorder today. In more recent times, Hoffman (1845) gave a detailed account of such disorders in his thesis entitled “Der Strumpelpeter oder lustige Geschichtern und drollige Bilder”. Not only was the clinical picture of the hyperkinetic child well established by the first half of the twentieth century but the pharmacological
treatment with dextro-amphetamine was first attempted, with considerable success, by Bradley in 1934 (Bradley, 1950). The stimulant drugs, amphetamine and methylphenidate still remain the drugs of choice for the treatment of such disorders today. The purpose of this contribution is to review some of the pharmacological, neurological and biochemical studies which have been made in patients, and on animal models, of hyperkinetic disorders in the hope that such an approach may lead to a clearer understanding of the aetiology of the disease. NEUROLOGICAL AND
GENETIC
ASPECTS
It is not unreasonable to assume that damage to the brain in utero or during the early stages of post natal development may lead eventually to the physical and psychological symptoms associated with hyperkinetic disorders. Millichap, Aymat, Sturgis, Larsen and Egan (1968) have shown for example, in their study of hyperkinetic children, that 57’4 of the patients had a history of brain injury or cerebra1 damage and that all but one of these patients had neurological signs of minimal brain dysfunction. Unfortunately, other investigators have been unable to show a clear correlation between such symptoms and minor brain damage. Thus, Prechtl (1978) has shown that the interindividual variation amongst children who have been classified as suffering from minimal brain damage is considerable and the degree of the abnormality often varies in different situations. One reason for such a high variability is due to the fact that the derranged central nervous system possesses a large number of compensating processes which have adaptive functions in early post natal life. For example, lesions of the cerebral cortex may produce different behavioural effects depending upon the age of the animal as it only functions in the control of most subcortical structures relatively late in brain development (cf. Wetzel, Thompson, Horel and Meyer, 1965). In general, both clinical and experimental studies suggest that if the brain is structurally damaged early in development there is sufficient plasticity present to allow it to compensate for the damge. Such factors may be important in attempting to understand the neurological basis of hyperkinetic disorders and might also help to explain the wide variation in the symptoms of children classified as suffering from such disorders. The differences in the sever-
923
924
B. E.
ity of the symptoms with different social situations may also be evidence of abnormal neuronal “rewiring” resulting from neurological damage in early development. Thus, Thompson (1969) has shown that when monkeys were amygdalectomized in the first 2 months of birth and then tested 3 years later in a test cage, the experimental animals were hyperactive relative to sham operated controls. These differences disappeared after the animals were left in the cage for 24 hr but at this time the experimental animals explored more than the controls and chewed more objects in the cage. Specific studies on the sequelae of mild head injury are lacking but it is clear that psychiatric disorder, in the absence of persisting motor or sensory signs. may follow such injury. Thus. Shaffer, Chadwick and Rutter, (19753, in a detailed follow-up study of patients who were known to have suffered head injury, found that approximately two-thirds of such patients were behaviourally disturbed but that only one tenth showed any signs of neurological impairment. Other investigators have come to similar conclusions (Klonoff and Paris, 1974). The evidence implicating chronic malnutrition during the early stages of brain development in the causation of hy~rkinetic disorders is somewhat equivocal but there seems little doubt that lead intoxication at such a period of development leads to cognitive and/or behavioural difficulties in the absence of persisting motor or sensory handicaps (de la Burde and Choate, 1972, 1975). Experimental studies have shown that newborn rats suckling mothers who have been fed on a diet containing 4:; lead carbonate displayed increased locomotor activity, aggressiveness and excessive stereotyped behaviour, as manifested by self grooming (Sauerhoffe and Michaelson, 1973). These authors also reported that the whole brain dopamine content of the weanling rat was significantly reduced as a consequence of the lead intoxication. From such studies, it would appear that heavy metal exposure during maturation of the brain could be responsible, at least in some cases, for the onset of hyperkinetic symptoms. Viral infections may also cause neurological damage which could later result in hyperkinetic disorders. Thus. the first widespread description of such disorders occurred early in this century following the pandemic of influenza particularly in those children suffering from menigoencephalitis (Bond. 1932). The contribution of an inherited predisposition to the development of hyperkinetic disorders is di~cult to assess. There is some evidence that the frequency of psychiatric disorders, particularly alcoholism and sociopathy, amongst the biological parents of hyperkinetic children is increased (Morrison and Steward, 1971). In an investigation in which the incidence of such disorders was assessed in groups of children who were in the care of foster parents, it was found that the incidence of hyperkinetic disorder was significantly higher amongst siblings than amongst those
LEONARD
who were unrelated (Safer. 1973). While such studies may provide a pointer to the possible involvement of genetic factors in the aetiology of the disease none of the studies fully account for the environmental, particularly social, factors which may play a crucial rofe in the early stages of development. Wender (I 978) has recently reviewed the evidence which favours a genetic brain for the hyperkinetic disorders. Another aspect of hyperkinetic disorders which seem worthy of consideration concerns the subsequent development of such patients on reaching maturity. In a detailed anterospective study by Wood_ Reimherr, Wenders and Johnson, (1971) it was found that a group of children who had been diagnosed as suffering from minima1 brain damage 8-10 years previously had a twenty times greater risk of antisocial behaviour or psychiatric illness on reaching maturity than did those who were apparently normal during childhood. These investigators found that 607; of such adults patients responded beneficially to methylphenidate treatment. Other studies also indicate that there is an increased incidence of hyperkinetic-like behaviour in adults diagnosed as suffering from personality disorders and such symptoms as impulsive behaviour. low frustration tolerance, social and interpersonal inadequacy are probably the adult equivalent of the hyperkinetic symptoms seen in childhood (O’Neal and Robbins, 1958; Quitkin and Klein. 1969). From the evidence presented above it can be concluded that although neurological damage, genetic predisposition. viral infection and lead toxicity may play a role in the causation of hyperkinetic behaviour in some cases there is, as yet, insufficient evidence to implicate minimal brain damage as the primary cause of such a behavioural abnormality. BIOCHEMICAL ASPECTS
AND BEHAVIOCRAL
OF HYPERKINETIC
DISORDERS
While there is little direct evidence from clinical studies to substantiate the view that an abnormality of brain biogenic amine metabolism underlies hyperkinetic disorders, there is considerable circumstantial evidence to support such a hypothesis. Such evidence comes from psychological studies on patients. from animal models of hyperkinesia which involve changes in brain biogenic amine metabolism and from an investigation of the mode of action of therapeutically effective drugs on central neurotransmission. Wender (1974) has suggested that the decreased attentiveness and an inability to focus on relevant detail and on ~gure-ground discrimination is evidence that hyperkinetic children are hyper-aroused. In addition, the incidence of sleep difficulties appear to be increased in such children. Such symptoms of hyperarousal may be a consequence of increased activity of the noradrenergic system in the brain. However other investigators, when studying the EEG of hyperkinetic children have come to the conclusion that such patients are under-aroused (Stevens. Sachdev and
Pharmacological
and biochemical
Milstein, 1968; Wickler, Dixon and Parker, 1970) a review supported by the findings of Satterfield and Dawson (1973) who found that these children had a higher galvanic skin resistance than normals. The hypothesis that hyperkinetic children are hypo-aroused is conceptually more attractive than that suggesting a hyper-aroused state as there is abundant clinical evidence that such stimulant drugs as amphetamine and methylphenidate, which appear to act by releasing catecholamines in the brain thereby increasing the level of arousal, are effective in the treatment of hyperkinetic disorders. Nevertheless another interpretation of the beneficial effects of stimulant drugs is possible if it is assumed that the hyperkinetic disorders reflect a hyper-aroused state. Amphetamine can produce stereotyped behaviour patterns in adults (Rylander, 1971) which becomes increasingly “constricted” with increasing doses of the drug. Sroufe and Steward (1973) therefore postulate that the stimulant drugs produce a certain degree of behavioural stereotypy in hyperkinetic children so that the behaviour becomes “constricted” thereby enabling the children to perform repetitive, routine tasks requiring sustained attention. Thus, the stimulant drugs may be pictured as converting a hyperactive state into a stereotyped state thereby resulting in the paradoxical effect of stimulants on hyperkinetic disorders. However, the question arises as to whether stimulant drugs do have a paradoxical effect in that they specifically reduce the hyperactivity of hyperkinetic children. Thus Rapoport et al. (1978) studied the behavioural, cognitive and electrophysiological effects of amphetamine on normal pubertal boys and found that the drug caused a marked decrease in motor activity and reaction time and improved performance on cognitive tests, an effect similar to that observed in hyperkinetic children. Reichard and Elder (1977) have also concluded from their studies of the effect of caffeine on reaction time that this stimulant drug does not produce a paradoxical effect but rather a more intense response than that seen in normal children. One possible explanation for this paradoxical effect of stimulant drugs on hyperkinetic disorders might arise from the nature of the parameters being measured to assess the clinical state. Thus Sprague and Sleator (1977) found that methylphenidate optimally enhances learning in hyperkinetic children at a dose of 0.3 mg/kg and that higher doses produce a decrement in learning. However, social behaviour showed a marked improvement only when doses of l.Omg/kg were administered. Different behavioural effects therefore occur at different doses of the drug and certain psychological abnormalities, for example performance of verbal tasks, appear to be uninfluenced by the drug (Gittelman-Klein and Klein, 1976). The situation regarding the long term efficacy of stimulant drugs on hyperkinetic behaviour is further complicated by the fact that the learning ability of such children is only maintained in the presence of the drug, a condition known as state-dependent learning (Swanson and
aspects
of hyperkinetic
disorders
925
Kinsbourne, 1976) whereas normal children do not show such behaviour. As there does not appear to be a general agreement about the paradoxical effect of stimulant drugs on hyperkinetic disorders, it would be of interest to know what biochemical differences are manifest between hyperkinetic and normal children with regard to the differences in the state dependent learning effect of these drugs. The most direct evidence for the involvement of brain catecholamines in the aetiology of hyperkinetic disorders comes from the studies of Shetty and Chase (1976) who reported that the lumbar cerebrospinal fluid samples of the major dopamine and serotonin metabolites (homovanillic acid and 5-hydroxyindole acetic acid) did not differ significantly from agematched normal children. However d-amphetamine treatment substantially reduced the concentration of the dopamine metabolite without affecting that of 5-hydroxyindole acetic acid. The rate of decline in the concentration of homovanillic acid was closely correlated with the degree of clinical improvement. Other investigators have also determined the concentrations of dopamine metabolites in the CSF of hyperkinetic children. Unlike Shetty and Chase (1976) however. Shaywitz, Cohen and Bowers (1977) found that in the six patients investigated, the homovanillic acid concentration was reduced by 50% before treatment with stimulant drugs. Clearly there are ethical difficulties in undertaking such invasive studies on children but the finding by Wood et al. (1976) that “Minimal brain dysfunction” also occurs in adults who had hyperkinetic disorders in childhood should enable more complete studies to be undertaken on the biochemical changes underlying this disorder. Nevertheless, if it assumed that homovanillic acid concentrations in the CSF may be used as a crude index of dopamine turnover in the brain (i.e. an index of the rate of synthesis, release and inactivation) such the study of Shaywitz et al. (1977) would suggest that dopamine turnover is reduced in hyperkinetic disorders. Presumably the further reduction in the concentration of the dopamine metabolite after amphetamine treatment is due to the reduced reuptake of dopamine (and hence reduced intraneuronal metabolism) caused by the drug. Experimental evidence also supports the hypothesis that changes in dopaminergic activity may be causative of hyperkinetic disorders. Shaywitz, Yager and Klopper (1976) found that when brain dopamine was depleted in neonatal rats by 6-hydroxydopamine treatment the total activity of the animals was significantly greater between 12 and 22 days but then declines to control levels. This suggests that a biochemical lesion involving the dopaminergic system, either pre- or post natally, may be instrumental in producing hyperkinetic behaviour in a later pre-pubertal state. This model would not explain the fact that hyperkinetic symptoms also occur in the adult however (Wood er al., 1976). Other experimental evidence implicating a disorder
926
B. E.
LEONARD
of dopamine metabolism in the hyperactivity state comes from the studies of Alpern and Greer (1977) who found that both amphetamine and the dopamine receptor agonist apomorphine attenuated central excitability (as assessed by incidence of myoclonic seizures) and hyperactivity of genetically predisposed mice but both drugs increased the excitability of adult mice of the same genetic strain. The same criticism however, can be made of this animal model as the one proposed by Shaywitz er ul. (1976). Lesions of the ventro-media1 tegmental area in rats also produce hyperactivity and several behavioural deficits which may be ascribed to a destruction of the A10 groups of dopaminergic cell bodies (LeMoal, Stinus, Simon, Tassin, Thierry. Blanc. Glowinski and Cardo, 1977). The behavioural changes are not correlated with changes in cortical serotonin or noradrenaline concentrations but do correlate with those of dopamine in some limbic regions; low doses of amphetamine reverse the behavioural deficits. This animal model seems particularly relevant to the evaluation of the relationship between adaptive and hyperkinetic behaviour and brain dopaminergic function but its relevance to an understanding of hyperkinetic disorders in children remains to be seen, It is not the purpose of this presentation to give a detailed account of the various animal models of hyperkinetic behaviour. For completeness it will suffice to say that both hyper- (Hess and Dopfner. 1961) and hypo(Jacobs, Mosko and Trulson. 1977) activity of the central serotonergic system can cause marked hyperactivity of rodents. There is some evidence from clinical studies of hyperkinetic children that the platelet serotonin concentration of hyperkinetic children is subnormal (Wender, 1969; Coleman, 1971) but there is little evidence that such an abnormality is connected with the aetiology of the disease. Indirect studies of the effects of amphetamine however. shows that not only does this drug release catecholamines in the central nervous system and prolong their action at central receptor sites by reducing their re-uptake but. at the same dose, it increases serotonin turnover (Leonard, 1972) and increases the concentration of tryptophan (Leonard and Shallice. 1971). Other investigators have shown that this drug releases serotonin from serotonin-containing neurones (Fuxe and Ungerstedt. 1970). Thus. in addition to the catecholamines. the possibility arises that an abnormality in the serotonergic system may underlie some types of hyperkinetic disorder and that such a system may be involved in the mechanism whereby amphetaminelike drugs are therapeutically effective [see Brase and Loh (1975) for a review of this area]. From this short review it can be concluded that the evidence implicating an abnormality in catecholamine and/or serotonin metabolism in the causation of hyperkinetic disorder is largely circumstantial and based upon the supposed mode of action of stimulant drugs that are clinically effective in ameliorating at least some of the symptoms of the disorder.
PHAR~MACOI~OGICAI. ASPECTS
The stimulant drugs. d-amphetamine and methylphenidate, are still the drugs of choice in the treatment of hyperkinetic children (Conners, 1972). Indeed. the efficacy of these drugs is so well established that they are used as standard medication against which drugs such as imipramine (Rapoport, Quinn, Bradbard. Riddle and Brooks. 1974) or magnesium pemoline (Conners, 1974) are compared. The view, that the use of methylphenidate is preferable to amphetamine (Weiss, Minde, Douglas, Werry and Sykes, 1971) now seems questionable (Winsberg, Press. Bialer and Kupietz, 1974). Both drugs. when administered in high therapeutic doses (l-2 mg!kg/day) cause anorexia weight loss. sleeplessness and growth suppression and there is evidence that growth suppression persists as long as high doses of the stimulant are administered (Safer and Allen, 1975). Low doses of the drugs (0.34.5 m&kg/day) appear to be clinically effective in most cases and cause fewer side effects (Sprague and Sleator. 1973). Despite the well established fact that stimulants frequently cause dependency in adults (Connell. 1958; Tolentino. 1957) there is no evidence of long term abuse or dependency problems in follow up studies on children who have been treated with such drugs (Lipman. 1974: Weiss 1975). The stimulant profile of amphetamine in animals and human adults suggests that its pharmacological activity is ascribable to an increased activity of the catecholaminergic system in the brain. There is experimental evidence to suggest that the drug releases dopamine from its newly synthesized storage pool (Scheel-Kruger, 1972; Heikkila. Orlansky, Mytilincou and Cohen, 1975) and reduces the re-uptake of this amine into the presynaptic nerve terminal (Raiteri. Bertollini. Angelini and Levi. 1975). It is less certain however whether amphetamine has the same effect on noradrenaline release as ill rim studies clearly show that the main action of the drug is to inhibit noradrenaline re-uptake rather than to cause release of this amine (Raiteri, Levi and Federico, 1974). Leonard (1972) reported that high acute doses of this drug increased the release of noradrenaline in the rat brain iri V&J. There is indirect evidence to support the view that the hyperactivity and stereotypy caused by the drug is largely attributable to its effect on the dopaminergic system (Thornburg and Moore. 1973): the greater mood elevating effect of the rl- over the I-isomer of amphetamine (Smith and Davis. 1977) would also appear to be due to the enhanced potency of the d-isomer in inhibiting dopamine uptake. While methylphenidate has a somewhat similar clinical profile to amphetamine. experimental data suggests that the former drug depletes catecholamines from their less labile storage pools (Thornburg and Moore, 1973) and that its main pharmacological action is due to an inhibition of catecholamine uptake with little effect on amine release (Hendley. Snyder. Fairely and Lapidus. 1972).
Pharmacological
and biochemical aspects of hyperkinetic disorders
Despite the abundance of evidence showing that the stimulant drugs affect brain catecholamine metabolism both in animals and man, it is well established that serotonin metabolism is also affected in equivalent doses (see above). Furthermore, high acute doses (5 mg/kg) increase the concentration of the inhibitory transmitter substance y-aminobutyric acid (Leonard and Shallice, 1971) whereas lower doses of amphetamine administered chronically to rats causes a decrease in the concentration of this amino-acid in several brain regions, (Lynch and Leonard, 1978). As there is evidence that a close inter relationship exists between y-aminobutyric acid and the biogenic amines in the basal ganglia as well as in other brain regions, it would seem premature to ascribe the therapeutic effects of drugs such as amphetamine to one specific neurotransmitter system. Tricyclic antidepressants have been shown by controlled clinical trials (Greenberg, Yellin, Spring and Metcalf, 1975; Rapoport et al., 1974) to be of some value in the treatment of hyperkinetic disorders, their responses are generally less predictable and less striking than the stimulants. It is generally accepted that the tricyclic antidepressants act by reducing the reuptake of noradrenaline and/or serotonin into the nerve ending an effect which may partly account for their antidepressant action (Glowinski, Iversen and Axelrod, 1966; Carlsson, Carrodi, Fuxe and Hokfelt, 1969). This subject has been reviewed elsewhere (Leonard, 1975, 1979). However, just because such drugs have an antidepressant action in adults there is no evidence to support the contention that they produce a beneficial effect in the hyperkinetic child by acting in the same way. The mode of action of tricyclit antidepressants in the treatment of hyperkinetic disorders therefore remains an enigma. Furthermore, the high doses necessary to produce a therapeutic response in hyperkinetic disorders (up to 14 mg/kg/day) predispose the patients to such serious side effects as seizures and cardiotoxicity (Hayes. Panitch and Barker, 1975). Neuroleptics are also commonly used in the treatment of hyperkinetic disorders but their action appears to be relatively non specific in that they depress hyperactivity in children at doses that also reduce attention and cognition (Werry and Aman, 1975). Furthermore such side effects as extrapyrimidal disorders and xerostomia often restrict the u& of such drugs. Thus, the neuroleptics cannot be considered to be specific therapeutics agents for the treatment of hyperkinetic disorders. As the primary biochemical action of such drugs appears to be the blockade of dopamine receptors in’ihe brain (Van Praag, 1977; Kebabian, Petzold and Greengard. 1972), whereas it has been postulated that the beneficial effects of stimulant drugs are partly ascribable to their ability to stimulate dopamine receptors (see above), it is understandable why the neuroleptics are of limited clinical value in the treatment of hyperkinetic disorders. Other drugs which have been found to be of limited
927
value in the treatment of hyperkinetic disorders inelude the mildly stimulant drug, magnesium pemoline and lithium salts (Greenhill, Rieder. Wender, Buchbaum and Kahn, 1973) but their usefulness as assessed by double blind clinical trial has yet to be established. After briefly reviewing the evidence upon which the various theories of hyperkinetic disorders are based one can have sympathy with the views expressed by Eugene Bleuler (1911) when commenting on psychiatric medicine in general: “Theories which comb&e correct and false facts are more dangerous to science than complete errors; and hypotheses which are only “justified in a certain sense” always create confusion because the necessary reservations cannot always be stated. Clear cut concepts can only be reformed if we ruthlessly reject everything that does not belong to them, regardless of whether we are dealing with simple problems or with entire theories”. Perhaps it is too pessimistic to say that there are no indications of the biochemical basis for the hyperkinetic disorders but more research needs to be directed towards establishing what changes in neurotransmitter metabolism actually occur in patients. While ethical considerations may limit investigations on children, the probability that adults also suffer from such disorders make such investigations a practical proposition. Experimental studies on animals have largely been restricted to the action of stimulant drugs on biogenic amine metabolism. Relatively little research seems to have been devoted to the effect of such drugs on the developing brain and on other neurotransmitter systems in which amino acids and acetylcholine for example play a role. Until such broad areas have at least been superficially explored it seems conceptually restrictive to confine the explanation of hyperkinetic disorders to a disorder of catecholamine metabolism which in some unexplained way may only occur before puberty.
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