Acta psychiat. scand. (1979) 59, 229-238 Department of Child Psychiatry (Head: Prof. K. Tolstrup), and Psychochemistry Institute (Head Prof. 0.J . Rajaelsen), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Psychopharmacological treatment of psychotic children A SURVEY
0.S.J~RGENSEN Controlled investigations on the psychopharmacological treatment of psychotic children are reviewed. Children with infantile autism might benefit from psychopharmacological medication when they grow older, e.g. above the age of 7 years. Learning might be facilitated when the psychoactive medication is able to inhibit psychotic preoccupations and idiosyncratic reactions. Schizophrenic and manic-depressive psychoses are rarely seen in childhood. A subgroup of the children with infantile autism might develop schizophrenic symptoms. Schizophrenia and manic-depressive psychosis in children are treated as in adults. Special caution must be paid to the toxic effects of imipramine.
- childhood schizophrenia - early infantile autism - manic-depressive psychosis - psychopharmacology.
Key words: Child psychiatry
The construction of controlled psychopharmacological investigations in child populations raises serious problems. The aspect of psychological and somatic development has to be considered in the selection of homogeneous index and control groups. The influence of environmental factors on the developing personality must be under control during investigations in children. The control groups must be matched for demographic data such as chronological age, IQ and social stratification (van Pruug (1969)). Also ethical problems have arisen. Children cannot give informed consent prior to participation in clinical investigations, and consent from the parents has not generally been given. Psychopharmacological investigations in child psychiatric disorders can be difficult to interpret as the content of the diagnostic categories has changed in recent years, and is still under development (Rutter et ul. (1973)). This review comprises the psychopharmacological treatment of infantile autism, schizophrenia and manic-depressive psychosis. We are well aware that other psychotic disorders are recognised in childhood, e.g. disintegrative psychosis (psychosis infantilis posterior), which has its debut in 3- to 10-year-old children. The treatment of psychotic borderline states will not be described.
OOO1-690X/79/020229-10$02.50/0 @ 1979 Munksgaard, Copenhagen
230 INFANTILE AUTISM Infantile autism was first investigated by Kanner (1943), and has been considered as an early manifestation of schizophrenia. However, studies on the hereditary, symptomatology and outcome have indicated that infantile autism is a nosological concept different from the psychotic disorders in the adult personality (Kolvin (1972a)). An extensive descriptive definition, including the characteristic language disturbances, has been given by Creak (1963). A more pragmatic definition has been used in the works of Kolvin (1971): 1. Time of onset before the age of 3 years. 2. An excessive self-isolating pattern of social behaviour. 3. At least one of the following: a) Catastrophic reactions to environmental changes, particularly of a topographical variety. b) Gross stereotypies either of a global class such as head banging, pirouetting or rocking, or of the idiosyncratic type, such as finger-flicking, specific motor patterns, and self-stimu1ation The main goal in the treatment of infantile autistic children is not only to reduce the specific symptoms listed above, but also to overcome the defect in intellectual and emotional development, which to a certain degree has been found in the adult patients (Eisenberg (1955)). As no single specific treatment until now has proved itself effective, several categories of treatment (psychological, educational, behavioural and biological) are often combined to obtain the optimal care of the autistic child.
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Phenothiazines Chlorpromazine treatment in 2- to 5-year-old psychotic children was found to reduce the psychotic symptoms, but this favourable effect was accompanied by a sedating action of the drug, even in doses as low as 20 mg per day (Campbell (1972)). The sedating action, however, is an initial phenomenon and Korein et al. (1971) have found no serious sedation after a treatment period of several weeks with chlorpromazine in doses of 2 to 9 mgkg body weight. Fluphenazine belongs to the so-called “activating” phenothiazines which are less sedating, but more prone to develop extrapyramidal side effects. After treating 6- to 12-year-old autistic children with fluphenazine, 0.3 mgkg body weight, Engelhardt et al. (1973) found significant improvement in about 30 % of the patients. Half of the fluphenazine-treated children had extrapyramidal symptoms and were then given antiparkinson medication in addition. Trifluperazine has been investigated by Fish et al. (1966) in 2- to 6-year-old psychotic children, several without speech. When doses as high as 0.7 mgkg body weight were used, improvement was found in speech function, social contact and motility, compared with a placebo-treated control group. As the symptoms improved by trifiuperazine were those specific for infantile autism, this study deserves much interest and needs to be reproduced by other groups. To our knowledge thioridazine has not been studied under sufficient control, though the low frequency of extrapyramidal side effects makes thioridazine
231 suitable in children. Reports on long-term treatment indicate that thioridazine like chlorpromazine can be tolerated in doses from 50 to 800 mg/day in 4- to 11-year-old psychotic children (Engelhardt et al. (1972)). Unwanted eflects. Like adults, children may develop extrapyramidal symptoms of 1) muscular rigidity and tremor (Parkinsonism), 2) acute dystonic reactions and, 3) akathesia. The Parkinsonian symptoms are often seen at the beginning of the treatment, manifesting as mask-like facies, shuffling gait and involuntary movements. The symptoms are dose-dependent, but in children probably independent of age (Engelhardt et al. (1973)). The mechanism behind the extrapyramidal symptoms is decreased dopaminergic activity in the basal ganglia in the brain, caused by the dopamine receptor-blocking properties of the phenothiazines. As the normal muscular tonus is maintained by a balance between the cholinergic and the dopaminergic activity in the basal ganglia, the extrapyramidal symptoms can be alleviated, or prevented, by adding an anticholiiergic drug (antiparkinson drug) to the phenothiazine medication. In children anticholinergic drugs like orphenadrine, benztropin and biperiden have been safely used in several investigations. Benzhexol should be avoided as “atropine psychosis” is a well-known complication (Black & Woollacott (1974)). Many will recommend the prophylactic use of anticholinergic medication to out-patient children starting anti-psychotic treatment, as the extrapyramidal symptoms are a most frightening experience for child and parents, but later it is essential to reduce and, if possible, stop the anticholinergic medication. Thioridazine (in doses equal to chlorpromazine) gives relatively few extrapyramidal side effects in autistic children (Engelhardt et al. (1972)). This has also been found in thioridazine-treated adult schizophrenic patients and has been explained by the high antagonistic activity of thioridazine at the muscarinic receptor sites in the brain. In fact thioridazine, in contrast to other phenothiazines, has a more potent anticholinergic effect than antidopaminergic effect and is therefore, so to say, counteracting its own Parkinson-inducing properties (Zversen (1975)). Akathisia seems to be found more frequently among phenothiazine-treated children than among adults (Engelhardt et al. (1973)). Akathisia is a state of psychic and motoric restlessness, and might therefore be taken for increased psychotic agitation leading to an erroneous increase in the dose of phenothiazine. Like the extrapyramidal symptoms, akathisia should be treated with anticholinergic drugs, but it is considered rather resistant to this medication, so a reduction in the phenothiazine dose might be the only means of alleviation. Tardive dyskinesias are serious complications of quite another nature than the extrapyramidal symptoms. They are irreversible symptoms which develop during long-term therapy with antipsychotic drugs in adult schizophrenic patients (Tarsy & Baldessarini (1977)). Tardive dyskinesias consist of choreiform movements of the limbs, and rhythmic involuntary movements of the tongue, jaws and cheeks called the buccoliiguomasticatory syndrome. These dyskiesias may persist after discontinuation of the neuroleptic therapy and are resistant to the usual anticholinergic medication. Polizos et al. (1973) found that discontinuation of pheno-
232 thiazines, mainly fluphenazine, after long-term therapy in psychotic children was followed by involuntary choreiform movements of the body, head and limbs. However, the buccolinguomasticatory syndrome which is characteristic in adult patients, was not observed in the children. The possibility exists that the choreiform movements seen after discontinuing phenothiazines were the reappearance of those motoric stereotypies, which are a part of the autistic disease per se, and not dyskinetic symptoms induced by the medication. However, the risk of tardive dyskinesias may increase during long-term therapy in psychotic children, so, if possible, drug-free intervals of a few months every year must be recommended. Gynecomastia and galactore have been described in adult schizophrenic patients during phenothiazine treatment. These side effects are probably also mediated through the antidopaminergic properties whereby the phenothiazines reversably increase the release of prolactin from the pituitary gland (Meltzer & Fang (1976)). Such side effects have not been described in children. Weight gain is a troublesome complication in phenothiazine treatment (Mc Andrew et al. (1972)) and, if necessary, the children must undergo weight control at the same time receiving a restricted, but sufficient, diet. Impairment of learning processes has been feared with phenothiazine treatment, particularly the sedating types. Helper et al. (1963) studied several learning subtests in a group of chlorpromazine-treated emotionally disturbed children, mostly unpsychotic, and, compared with a group of control children without medication, no general impairment of learning was found. In clinical practice one disadvantage of chlorpromazine is the phototoxic skin reactions, which may be seen when the children under treatment are exposed to sunlight. Overdose reactions. Acute phenothiazine intoxication from accidental ingestion was found to give sedation, and, in relatively few patients, acute dystonic reactions (Greenblatt et al. (1976)). The dystonic reactions were seen mostly in intoxications with the “activating” type of phenothiazines, and gave rise to muscular spasms, protrusion of the tongue and opistotonus. Intravenous administration of biperiden gives immediate relief. Other neuroleptic drugs The thioxanthene derivative, thiothixene, given in doses of 1-6 mg/day has been reported to improve the mental state in 3- to 7-year-old autistic children, but no effect was found on the specific symptoms of infantile autism (Campbell et a1. (1970)). In contrast to this Simeon et al. (1974), in a group of 5- to 15-year-old psychotic boys, showed that thiothixene in doses of 6-30 mg/day, given together with trihexyIphenidy1, significantly reduced abnormal motoric activity and made the children more emotionally responsive. However, the patients were not only children with infantile autism, but included schizophrenic and organic psychotic children. The side effects of the thioxanthene derivative consisted of sedation and, to a minor degree, nausea and orthostatic hypotension. Among the butyrophenone derivatives, trifluperidole in a dose of 0.5 mg/day has been found more effective than chlorpromazine for controlling autistic be-
233 haviour in 2- to 5-year-old psychotic children (Campbell (1972)), but in this short-term experiment the more pronounced sedating property of chlorpromazine might initially have acted in favour of trifluperidole. No long-term effects of trifluperidole have been investigated. Haloperidol was compared with the “activating” phenothiazine derivative fluphenazine by Engelhardt et al. (1973) and was found equally active, both quantitatively and qualitatively. Haloperidol was given in doses up to 0.3 mg/kg body weight. Without anticholinergic medication, about 25 % of the haloperidoltreated children developed extrapyramidal symptoms. According to earlier works (le Vann (1969), Barker & Fraser (1968)) it has been the impression that haloperidol was especially powerful in reducing hyperactivity and aggression, but this has not been evaluated in psychotic children. As until now only few studies have been published on the long-term effects of thioxanthene and butyrophenone derivatives, these compounds can only be recommended for medication of short duration. Other biological treatments Among biological therapeutics the psychopharmacological treatment seems the most rewarding (Campbell (1973), Campbell (1975)), but insulin coma (Annell (1955)), ECT (Bender & Keeler (1952)), and hormone therapy (Campbell et al. (1972b)) have also been investigated. Earlier investigations have indicated a disturbance in the metabolism of indole derivatives in autistic children (JGrgensen et al. (1970), Coleman (1973)). Increased serotonin levels in the blood were reported by Schain & Freedman (1961), and in an attempt to decrease the serotonin level 1-dopa treatment has been tried, but without significant behavioural improvement during the periods with lowered blood serotonin (Ritvo et al. (1971), Campbell et al. (1976)). Lithium has a specific therapeutic effect in mania, and a prophylactic action on recurrent manias and depressions in manic-depressive psychosis. Follow-up studies indicate that psychotic children when grown up do not show classic manic-depressive symptoms (Dahl (1972)), but lithium might unspecificly decrease hyperexcitability in autistic children. Lithium has been compared with placebo (Gram & Rafaelsen (1972)), and chlorpromazine (Campbell et al. (1972a)), and no obvious benefit from lithium treatment was found. However, both studies were performed on rather heterogeneous groups of patients, as not only autistic children, but also other seriously disturbed children were included. In the treatment of autistic children the use of central stimulant drugs (amphetamines (Campbell (1972)) and methylphenidate) and anti-anxiety drugs, e.g. chlordiasepoxide (Campbell (1973)) is contraindicated, as these drugs might aggravate the psychotic condition. Also antidepressant drugs like imipramine have been tried in autistic children, even in high doses. This has resulted in an intensification of the psychotic symptoms (Campbell et al. (1971)). Seizures might also be a serious effect of imipramine treatment in these patients (Petti & Campbeli (1975)).
234
SCHIZOPHRENIA Schizophrenia is found only rarely in children below the age of 10 years, but in adolescents the incidence of schizophrenia is higher. We consider schizophrenia and infantile autism to be independent nosologic entities, but the possibility that singular cases of infantile autistic children later develop schizophrenia can not be excluded. As a definition of schizophrenia, the criterias of Schneider (1966) will be used. These “symptoms of first rank” include: 1. Auditory hallucinations, often of a content of self-reference to the patient. 2. Thought disturbances, experienced as the influence of external factors on the process of thinking. Also the opposite, that the thinking of the patient can be shared by others. 3. Other experiences of influence from others on the feelings, drive and volition. The pharmacological treatment of schizophrenia in children follows the guidelines of treatment used in adult patients. Phenothiazine medication effectively reduces the schizophrenic symptoms and delays the disintegration of the personality in adults. Because of the convicting clinical studies on the effects and side effects of phenothiazine treatment in adult schizophrenia, few controlled studies have been performed in prepubertal schizophrenic patients, but clinical experience supports their equal effectiveness in children (Kolvin (1972b)). The author has preferred to use perphenazine perorally in doses up to 0.5 mg/kg/day. Because of the well-known influence of phenothiazine derivatives on the excretion of prolactine, special attention must be paid to the children’s pubertal development during the treatment. But to our knowledge no reports have described disturbed pubertal development caused by phenothiazines. MANIC-DEPRESSIVE PSYCHOSIS Since Anthony & Scott (1960) described manic-depressive psychosis in a boy before puberty it has gradually been accepted among child psychiatrists that manic-depressive psychosis, like schizophrenia, is seen in child psychiatric patients, though rarely. This definition is based on the classical symptoms described by Kraepelin and Bleuler, as operationaIized by Rafaelsen (1974): 1) Change in the mood, 2) periodic course, 3) diurnal rhythm, 4) change in psycho-motoric speed, 5) unrealistic changes in self-esteem. The pharmacological treatment of manic-depressive children is conducted as in adults. For the treatment of manic states haloperidol is the drug of choice. Depressive states should preferably be treated with tricyclic antidepressive drugs e.g. imipramine in doses between 3 and 4 mg/kg/day. As imipramine given in these antidepressive doses might induce toxic reactions in susceptible children this treatment should be initiated under constant medical supervision in hospitals. The prophylactic effects of lithium on recurrent manic and depressive phases is now well documented in adults. Lithium prophylaxis must be considered when recurrent manic or depressive states have been found in a child. Recently, Amdisen (1975) has given a thorough review on the principles of lithium treatment. As in adults, children must be treated with lithium in doses which regulate the pIasma level of lithium between 0.8 and 1.0 mmoV1.
235 Imipramine Unwanted effects. Important knowledge of the side effects and overdose reactions of imipramine in children has accumulated in later years from studies on infantile autistic and hyperkinetic children. Due to anticholinergic properties, imipramine treatment might give side effects such as dry mouth, obstipation and tachycardia (Hamilton & Mahapatra (1972), Saraf et al. (1974)). These symptoms are usually harmless in children and give no reason for change in medication. Orthostatic hypotension is a more troublesome complication, but can be prevented when the imipramine treated child takes care never to rise to an upright position too quickly. Accommodation defects, tremor and nausea are serious complications, which can not be treated or prevented. But the psychotic depression, which indicated the imipramine treatment, is itself not only painful, but also, because of suicidal impulses, a danger to the life of the child. So even serious complications might be accepted in these circumstances. Besides the indirect effects on the heart due to anticholinergic properties, imipramine also has a direct effect on the myocardium, which might give electrocardiographic (ECG) manifestations when imipramine is given in high doses. Winsberg et al. (1975) have treated seven hyperkinetic children with imipramine in doses of 5 mgkg body weighvday. ECG was recorded on each child before treatment and again after 30 days of treatment. Imipramine in this dosage, which was higher than that usually recommended in antidepressive treatment, produced ECG alterations indicating d e c t e d repolarization, as T-wave magnitude was decreased and T-wave width increased. Three children, in addition, developed increased P-Q-interval indicating atrioventricular blockade. From other studies, (Martin & Zaug (1975), Rapoport et al. (1974)), it has been demonstrated that ECG alterations were not seen when imipramine was given in doses between 1 and 3 mg/kg/day. The risk for serious cardial side effects during high dose imipramine treatment has resulted in the following statement from the U.S. Department of Health, Education, and Welfare (Food and Drug Administration): “However, we plan to approve investigational protocols for imipramine hydrochloride only when the total daily dose does not exceed 90 mg for a 40-lb child, 110 mg for a 50-lb child, 135 mg for a 60-lb child, 160 mg for a 70-lb child, and 180 mg for a 80-lb child. Furthermore, because of the findings of Winsberg and associates and because of the unreliable occurrence of other warning side effects, we will recommend regular ECG monitoring when doses approach these limits” (Hayes et al. (1975)). Seizures have been reported during imipramine treatment in children with hyperactive behaviour disorders and infantile autism (Brown et al. (1973), Petti C? Campbell (1975)). These reported cases had shown no history of seizures before imipramine treatment, but in children who are hyperkinetic or autistic, there might be an increased risk of seizures even without imipramine as a provocating factor. No conclusions can be drawn about a possible risk of seizures in depressive children under imipramine treatment.
236 ACKNOWLEDGEMENT Practical experience in the topic of psychopharmacological treatment of psychotic children has been gained during the author’s appointment as a consultant in child psychiatry a t Sofieskolen, School for Psychotic Children, Bagsvzrd, Denmark. I am very indebted to the leader of the school, Else Hansen, and the staff. REFERENCES Amdisen, A . (1975): Monitoring of lithium treatment through determination of lithium concentration. Dan. med. Bull. 22, 277-291. Annell, A . 4 . (1955): Insulin shock treatment in children with psychotic disturbances. Acta Psychother. (Basel) 3, 193-205. Anthony, J., & P. Scott (1960): Manic-depressive psychosis in childhood. Child Psychol. Psychiat. I, 53-72. Barker, P., & I . A . Fraser (1968): A controlled trial of haloperidol in children. Brit. J. Psychiat. 114, 855-857. Bender, L., & W . R. Keeler (1952): The body image of schizophrenic children following electroshock therapy. Amer. J. Orthopsychiat. 22, 335-355. Black, D., & S. Woollacott (1974): Acute toxic psychosis in two children treated with benzhexol hydrochloride (Artane). Brit. J. Psychiat. 125, 483-484. Brown, D., B. G . Winsberg, I . Bialer & M . Press (1973): Imipramine therapy and seizures: Three children treated for hyperactive behaviour disorders. Amer. J. Psychiat. 130, 210-212. Campbell, M . (1972): Acute responses of schizophrenic children to a sedative and a “stimulating” neuroleptic: A pharmacologic yardstick. Curr. ther. Res. 14, 759-766. Campbell, M. (1973): Biological interventions in psychoses of childhood. J. Autism childh. Schiz. 3, 341-373. Campbell, M . (1975): Pharmacotherapy in early infantile autism. Biol. Psychiat. 10, 399-423. Campbell, M., B. Fish, T . Shapiro & A . Floyd, Jr. (1970): Thiothixene in young disturbed children. Arch. gen. Psychiat. 23, 70-72. Campbell, M., B. Fish, T . Shapiro & A . Floyd, Jr. (1971): Imipramine in preschool autistic and schizophrenic children. J. Autism. childh. Schiz. 1, 267-282. Campbell, M., B. Fish, J . Korein, T . Shapiro, P. Collins & C . Koh (1972a): Lithium and chlorpromazine: A controlled study of hyperactive severely disturbed young children. J. Autism childh. Schiz. 2, 234-263. Campbell, M., B. Fish, R. David, T . Shapiro, P. Collins & C . Koh (1972b): Response to triiodothyronine and dextroamphetamine: A study of preschool schizophrenic children. J. Autism childh. Schiz. 2, 343-358. Campbell, M., A . M . Small, P. J . Collins, E. Friedman, R. David & N . Genieser (1976): Levodopa and levoamphetamine: A crossover study in young schizophrenic children. Curr. ther. Res. 19, 70-86. Coleman, M . (1973): Serotonin and central nervous system syndromes of childhood: A review. J. Autism childh. Schiz. 3, 27-35. Creak,E.M. (1963): Childhood psychosis. A review of 100 cases. Brit. J. Psychiat. 109, 84-89. Dahl, V. (1972): A follow-up study of a childpsychiatric clientele, with special regard to manic-depressive psychosis. In Annell, A . 4 . (ed.): Depressive states in childhood and adolescence. Almquist & Wiksell, Stockholm, pp. 534-541. Eisenberg, L. (1955): The autistic child in adolescence. Amer. J. Psychiat. 112, 607-612. Engelhardt, D . M., P. Polizos & R . A . Margolis (1972): The drug treatment of childhood psychosis. I n Smith, W.L. (ed.): Drugs, development and cerebral function. Charles C Thomas, Springfield, Ill., pp. 224-234. Engelhardt, D . M., P. Polizos, J . Waizer & S. P. Hoflman (1973): A double-blind comparison of fluphenazine and haloperidol in outpatient Schizophrenic children. J.
237 Autism childh. Schiz. 3, 128-137. Fish, B., T. Shapiro & M. Campbell (1966): Long-term prognosis and the response of schizophrenic children to drug therapy: A controlled study of trifluoperazine. Amer. J. Psychiat. 123, 32-39. Gram, L. F., & 0.J . Rafaelsen (1972): Lithium treatment of psychotic children and adolescents. Acta psychiat. scand. 48, 253-260. Greenblatt, D. J., M . D. Allen, J . Koch-Weser & R. I. Shader (1976): Accidental poisoning with psychotropic drugs in children. Amer. J. Dis. Child. 130, 507-511. Hamilton, M., & S. B. Mahapatra (1972): Antidepressive drugs. In Meyler, L., & A. Herxheimer (eds.): Side effects of drugs. Vol. 7. Excerpta medica, Amsterdam, pp. 17-37. Hayes, T . A., M. L. Panitch & E. Barker (1975): Imipramine dosage in children: A comment on “imipramine and electrocardiographic abnormalities in hyperactive children”. Amer. J. Psychiat. 132, 546-547. Helper, M. M., R . C. Wilcott & S. L. Garfield (1963): Effects of chlorpromazine on learning and related processes in emotionally disturbed children. J. cons. Psychol. 27, 1-9. Zversen, L. L. (1975): Dopamine receptors in the brain. Science 188, 1084-1089. Jergensen, 0. Sylvester, E. T. Mellerup & 0. J . Rafaelsen (1970): Amino acid excretion in urine of children with various psychiatric diseases. A thin layer chromatographic study. Dan. med. Bull. 17, 166-170. Kanner, L. (1943): Autistic disturbances of affective contact. Nervous Child 2, 217-250. Kolvin, Z. (1971): Studies in the childhood psychoses. I. Diagnostic criteria and classification. Brit. J. Psychiat. 118, 381-384. Kolvin, Z. (1972a): Infantile autism or infantile psychoses. Brit. med. I. 3, 753-755. Kolvin, 1. (1972b): Late onset psychosis. Brit. med. J. 3, 816-817. Korein, I., B. Fish, T. Shapiro, E. W . Gerner & L. Levidow (1971): EEG and behavioral effects of drug therapy in children. Chlorpromazine and diphenhydramine. Arch. gen. Psychiat. 24, 522-563. Martin, G. Z., & P. J . Zaug (1975): Electrocardiographic monitoring of enuretic children receiving therapeutic doses of imipramine. Amer. J. Psychiat. 132, 540-542. McAndrew, J . B., Q. Case & D. A . Treflert (1972): Effects of prolonged phenothiazine intake on psychotic and other hospitalized children. J. Autism childh. Schiz. 2, 75-91. Meltzer, H. Y.,& V . S. Fang (1976): The effects of neuroleptics on serum prolactin in schizophrenic patients. Arch. gen. Psychiat. 33, 279-286. Petti, T. A., & M. Campbell (1975): Imipramine and seizures. Amer. J. Psychiat. 132, 538-540. Polizos, P., D. Engelhardt, S. P. Hogman & J . Waizer (1973): Neurological consequcnccs of psychotropic drug withdrawal in schizophrenic children. J. Autism childh. Schiz. 3. 247-253. van P k a g , H. M. (1969): Psychotropic drugs in child psychiatry. Int. Pharmacopsychiat. 3, 137-154. RafaeZsen, 0.J. (1974): Manic-depressive psychosis or manic-melancholic mode. Dan. med. Bull. 21, 81-87. Rapoport, J . E., P. 0. Quinn, G. Brodbard, D. Riddle & E. Brooks (1974): Imipramine and methylphenidate treatments of hyperactive boys. A double-blind comparison. Arch. gen. Psychiat. 30, 789-793. Ritvo, E. R., A . Yuwiler, E. Geller, A . Kales. S.Rashkis, A . Schicor, S.Plotkin, R. Axelrod & C. Howard (1971): Effects of L-dopa in autism. J. Autism childh. Schiz. I , 190-205. Rutter, M., S. Lebovici, L. Eisenberg, A . V . Sneznevskij, R. Sadoun, E. Brooke & T.-Y. Lin (1969): An evaluation of the proposal for a multi-axial classification of child psychiatric disorders. Psychol. Med. 3, 244-250. Saraf, K. R., D. F. Klein, R. Gittelman-Klein & S. Groff (1974): Imipramine side effects in children. Psychopharmacol. 37, 265-274.
238 Schain, R . J., & D. X . Freedman (1961): Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J. Pediat. 58, 315-320. Schneider, K . (1966): Klinische Psychopathologie. 7th ed. Thieme, Stuttgart. Simeon, J., B. Saletu, M . Saletu, T . M . Itil & J . DaSilva (1974): Thiothixene in childhood psychoses. Advanc. Biochem. Psychopharm. 9, 519-538. Tarsy, D.,& R . J . Baldessarini (1977): The pathophysiologic basis of tardive dyskinesia. Biol. Psychiat. 12, 431-450. Ze Vann, L. 1. (1969): Haloperidol in the treatment of behavioral disorders in children and adolescents. Canad. psychiat. Ass. J. 14, 217-220. Winsberg, B. G., S. Goldstein, L. E. Yepes & J . M . Perel (1975): Imipramine and electrocardiographic abnormalities in hyperactive children. h e r . J. Psychiat. 132, 542-545.
Received July 19, 1978
Ole Sylvester Jlrgensen Department of Child Psychiatry Frederiksborg County Hospital DK-3400 Hillergid Denmark
Psychopharmacological treatment of psychotic children A SURVEY
0.S.J~RGENSEN Controlled investigations on the psychopharmacological treatment of psychotic children are reviewed. Children with infantile autism might benefit from psychopharmacological medication when they grow older, e.g. above the age of 7 years. Learning might be facilitated when the psychoactive medication is able to inhibit psychotic preoccupations and idiosyncratic reactions. Schizophrenic and manic-depressive psychoses are rarely seen in childhood. A subgroup of the children with infantile autism might develop schizophrenic symptoms. Schizophrenia and manic-depressive psychosis in children are treated as in adults. Special caution must be paid to the toxic effects of imipramine.
- childhood schizophrenia - early infantile autism - manic-depressive psychosis - psychopharmacology.
Key words: Child psychiatry
The construction of controlled psychopharmacological investigations in child populations raises serious problems. The aspect of psychological and somatic development has to be considered in the selection of homogeneous index and control groups. The influence of environmental factors on the developing personality must be under control during investigations in children. The control groups must be matched for demographic data such as chronological age, IQ and social stratification (van Pruug (1969)). Also ethical problems have arisen. Children cannot give informed consent prior to participation in clinical investigations, and consent from the parents has not generally been given. Psychopharmacological investigations in child psychiatric disorders can be difficult to interpret as the content of the diagnostic categories has changed in recent years, and is still under development (Rutter et ul. (1973)). This review comprises the psychopharmacological treatment of infantile autism, schizophrenia and manic-depressive psychosis. We are well aware that other psychotic disorders are recognised in childhood, e.g. disintegrative psychosis (psychosis infantilis posterior), which has its debut in 3- to 10-year-old children. The treatment of psychotic borderline states will not be described.
OOO1-690X/79/020229-10$02.50/0 @ 1979 Munksgaard, Copenhagen
230 INFANTILE AUTISM Infantile autism was first investigated by Kanner (1943), and has been considered as an early manifestation of schizophrenia. However, studies on the hereditary, symptomatology and outcome have indicated that infantile autism is a nosological concept different from the psychotic disorders in the adult personality (Kolvin (1972a)). An extensive descriptive definition, including the characteristic language disturbances, has been given by Creak (1963). A more pragmatic definition has been used in the works of Kolvin (1971): 1. Time of onset before the age of 3 years. 2. An excessive self-isolating pattern of social behaviour. 3. At least one of the following: a) Catastrophic reactions to environmental changes, particularly of a topographical variety. b) Gross stereotypies either of a global class such as head banging, pirouetting or rocking, or of the idiosyncratic type, such as finger-flicking, specific motor patterns, and self-stimu1ation The main goal in the treatment of infantile autistic children is not only to reduce the specific symptoms listed above, but also to overcome the defect in intellectual and emotional development, which to a certain degree has been found in the adult patients (Eisenberg (1955)). As no single specific treatment until now has proved itself effective, several categories of treatment (psychological, educational, behavioural and biological) are often combined to obtain the optimal care of the autistic child.
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Phenothiazines Chlorpromazine treatment in 2- to 5-year-old psychotic children was found to reduce the psychotic symptoms, but this favourable effect was accompanied by a sedating action of the drug, even in doses as low as 20 mg per day (Campbell (1972)). The sedating action, however, is an initial phenomenon and Korein et al. (1971) have found no serious sedation after a treatment period of several weeks with chlorpromazine in doses of 2 to 9 mgkg body weight. Fluphenazine belongs to the so-called “activating” phenothiazines which are less sedating, but more prone to develop extrapyramidal side effects. After treating 6- to 12-year-old autistic children with fluphenazine, 0.3 mgkg body weight, Engelhardt et al. (1973) found significant improvement in about 30 % of the patients. Half of the fluphenazine-treated children had extrapyramidal symptoms and were then given antiparkinson medication in addition. Trifluperazine has been investigated by Fish et al. (1966) in 2- to 6-year-old psychotic children, several without speech. When doses as high as 0.7 mgkg body weight were used, improvement was found in speech function, social contact and motility, compared with a placebo-treated control group. As the symptoms improved by trifiuperazine were those specific for infantile autism, this study deserves much interest and needs to be reproduced by other groups. To our knowledge thioridazine has not been studied under sufficient control, though the low frequency of extrapyramidal side effects makes thioridazine
231 suitable in children. Reports on long-term treatment indicate that thioridazine like chlorpromazine can be tolerated in doses from 50 to 800 mg/day in 4- to 11-year-old psychotic children (Engelhardt et al. (1972)). Unwanted eflects. Like adults, children may develop extrapyramidal symptoms of 1) muscular rigidity and tremor (Parkinsonism), 2) acute dystonic reactions and, 3) akathesia. The Parkinsonian symptoms are often seen at the beginning of the treatment, manifesting as mask-like facies, shuffling gait and involuntary movements. The symptoms are dose-dependent, but in children probably independent of age (Engelhardt et al. (1973)). The mechanism behind the extrapyramidal symptoms is decreased dopaminergic activity in the basal ganglia in the brain, caused by the dopamine receptor-blocking properties of the phenothiazines. As the normal muscular tonus is maintained by a balance between the cholinergic and the dopaminergic activity in the basal ganglia, the extrapyramidal symptoms can be alleviated, or prevented, by adding an anticholiiergic drug (antiparkinson drug) to the phenothiazine medication. In children anticholinergic drugs like orphenadrine, benztropin and biperiden have been safely used in several investigations. Benzhexol should be avoided as “atropine psychosis” is a well-known complication (Black & Woollacott (1974)). Many will recommend the prophylactic use of anticholinergic medication to out-patient children starting anti-psychotic treatment, as the extrapyramidal symptoms are a most frightening experience for child and parents, but later it is essential to reduce and, if possible, stop the anticholinergic medication. Thioridazine (in doses equal to chlorpromazine) gives relatively few extrapyramidal side effects in autistic children (Engelhardt et al. (1972)). This has also been found in thioridazine-treated adult schizophrenic patients and has been explained by the high antagonistic activity of thioridazine at the muscarinic receptor sites in the brain. In fact thioridazine, in contrast to other phenothiazines, has a more potent anticholinergic effect than antidopaminergic effect and is therefore, so to say, counteracting its own Parkinson-inducing properties (Zversen (1975)). Akathisia seems to be found more frequently among phenothiazine-treated children than among adults (Engelhardt et al. (1973)). Akathisia is a state of psychic and motoric restlessness, and might therefore be taken for increased psychotic agitation leading to an erroneous increase in the dose of phenothiazine. Like the extrapyramidal symptoms, akathisia should be treated with anticholinergic drugs, but it is considered rather resistant to this medication, so a reduction in the phenothiazine dose might be the only means of alleviation. Tardive dyskinesias are serious complications of quite another nature than the extrapyramidal symptoms. They are irreversible symptoms which develop during long-term therapy with antipsychotic drugs in adult schizophrenic patients (Tarsy & Baldessarini (1977)). Tardive dyskinesias consist of choreiform movements of the limbs, and rhythmic involuntary movements of the tongue, jaws and cheeks called the buccoliiguomasticatory syndrome. These dyskiesias may persist after discontinuation of the neuroleptic therapy and are resistant to the usual anticholinergic medication. Polizos et al. (1973) found that discontinuation of pheno-
232 thiazines, mainly fluphenazine, after long-term therapy in psychotic children was followed by involuntary choreiform movements of the body, head and limbs. However, the buccolinguomasticatory syndrome which is characteristic in adult patients, was not observed in the children. The possibility exists that the choreiform movements seen after discontinuing phenothiazines were the reappearance of those motoric stereotypies, which are a part of the autistic disease per se, and not dyskinetic symptoms induced by the medication. However, the risk of tardive dyskinesias may increase during long-term therapy in psychotic children, so, if possible, drug-free intervals of a few months every year must be recommended. Gynecomastia and galactore have been described in adult schizophrenic patients during phenothiazine treatment. These side effects are probably also mediated through the antidopaminergic properties whereby the phenothiazines reversably increase the release of prolactin from the pituitary gland (Meltzer & Fang (1976)). Such side effects have not been described in children. Weight gain is a troublesome complication in phenothiazine treatment (Mc Andrew et al. (1972)) and, if necessary, the children must undergo weight control at the same time receiving a restricted, but sufficient, diet. Impairment of learning processes has been feared with phenothiazine treatment, particularly the sedating types. Helper et al. (1963) studied several learning subtests in a group of chlorpromazine-treated emotionally disturbed children, mostly unpsychotic, and, compared with a group of control children without medication, no general impairment of learning was found. In clinical practice one disadvantage of chlorpromazine is the phototoxic skin reactions, which may be seen when the children under treatment are exposed to sunlight. Overdose reactions. Acute phenothiazine intoxication from accidental ingestion was found to give sedation, and, in relatively few patients, acute dystonic reactions (Greenblatt et al. (1976)). The dystonic reactions were seen mostly in intoxications with the “activating” type of phenothiazines, and gave rise to muscular spasms, protrusion of the tongue and opistotonus. Intravenous administration of biperiden gives immediate relief. Other neuroleptic drugs The thioxanthene derivative, thiothixene, given in doses of 1-6 mg/day has been reported to improve the mental state in 3- to 7-year-old autistic children, but no effect was found on the specific symptoms of infantile autism (Campbell et a1. (1970)). In contrast to this Simeon et al. (1974), in a group of 5- to 15-year-old psychotic boys, showed that thiothixene in doses of 6-30 mg/day, given together with trihexyIphenidy1, significantly reduced abnormal motoric activity and made the children more emotionally responsive. However, the patients were not only children with infantile autism, but included schizophrenic and organic psychotic children. The side effects of the thioxanthene derivative consisted of sedation and, to a minor degree, nausea and orthostatic hypotension. Among the butyrophenone derivatives, trifluperidole in a dose of 0.5 mg/day has been found more effective than chlorpromazine for controlling autistic be-
233 haviour in 2- to 5-year-old psychotic children (Campbell (1972)), but in this short-term experiment the more pronounced sedating property of chlorpromazine might initially have acted in favour of trifluperidole. No long-term effects of trifluperidole have been investigated. Haloperidol was compared with the “activating” phenothiazine derivative fluphenazine by Engelhardt et al. (1973) and was found equally active, both quantitatively and qualitatively. Haloperidol was given in doses up to 0.3 mg/kg body weight. Without anticholinergic medication, about 25 % of the haloperidoltreated children developed extrapyramidal symptoms. According to earlier works (le Vann (1969), Barker & Fraser (1968)) it has been the impression that haloperidol was especially powerful in reducing hyperactivity and aggression, but this has not been evaluated in psychotic children. As until now only few studies have been published on the long-term effects of thioxanthene and butyrophenone derivatives, these compounds can only be recommended for medication of short duration. Other biological treatments Among biological therapeutics the psychopharmacological treatment seems the most rewarding (Campbell (1973), Campbell (1975)), but insulin coma (Annell (1955)), ECT (Bender & Keeler (1952)), and hormone therapy (Campbell et al. (1972b)) have also been investigated. Earlier investigations have indicated a disturbance in the metabolism of indole derivatives in autistic children (JGrgensen et al. (1970), Coleman (1973)). Increased serotonin levels in the blood were reported by Schain & Freedman (1961), and in an attempt to decrease the serotonin level 1-dopa treatment has been tried, but without significant behavioural improvement during the periods with lowered blood serotonin (Ritvo et al. (1971), Campbell et al. (1976)). Lithium has a specific therapeutic effect in mania, and a prophylactic action on recurrent manias and depressions in manic-depressive psychosis. Follow-up studies indicate that psychotic children when grown up do not show classic manic-depressive symptoms (Dahl (1972)), but lithium might unspecificly decrease hyperexcitability in autistic children. Lithium has been compared with placebo (Gram & Rafaelsen (1972)), and chlorpromazine (Campbell et al. (1972a)), and no obvious benefit from lithium treatment was found. However, both studies were performed on rather heterogeneous groups of patients, as not only autistic children, but also other seriously disturbed children were included. In the treatment of autistic children the use of central stimulant drugs (amphetamines (Campbell (1972)) and methylphenidate) and anti-anxiety drugs, e.g. chlordiasepoxide (Campbell (1973)) is contraindicated, as these drugs might aggravate the psychotic condition. Also antidepressant drugs like imipramine have been tried in autistic children, even in high doses. This has resulted in an intensification of the psychotic symptoms (Campbell et al. (1971)). Seizures might also be a serious effect of imipramine treatment in these patients (Petti & Campbeli (1975)).
234
SCHIZOPHRENIA Schizophrenia is found only rarely in children below the age of 10 years, but in adolescents the incidence of schizophrenia is higher. We consider schizophrenia and infantile autism to be independent nosologic entities, but the possibility that singular cases of infantile autistic children later develop schizophrenia can not be excluded. As a definition of schizophrenia, the criterias of Schneider (1966) will be used. These “symptoms of first rank” include: 1. Auditory hallucinations, often of a content of self-reference to the patient. 2. Thought disturbances, experienced as the influence of external factors on the process of thinking. Also the opposite, that the thinking of the patient can be shared by others. 3. Other experiences of influence from others on the feelings, drive and volition. The pharmacological treatment of schizophrenia in children follows the guidelines of treatment used in adult patients. Phenothiazine medication effectively reduces the schizophrenic symptoms and delays the disintegration of the personality in adults. Because of the convicting clinical studies on the effects and side effects of phenothiazine treatment in adult schizophrenia, few controlled studies have been performed in prepubertal schizophrenic patients, but clinical experience supports their equal effectiveness in children (Kolvin (1972b)). The author has preferred to use perphenazine perorally in doses up to 0.5 mg/kg/day. Because of the well-known influence of phenothiazine derivatives on the excretion of prolactine, special attention must be paid to the children’s pubertal development during the treatment. But to our knowledge no reports have described disturbed pubertal development caused by phenothiazines. MANIC-DEPRESSIVE PSYCHOSIS Since Anthony & Scott (1960) described manic-depressive psychosis in a boy before puberty it has gradually been accepted among child psychiatrists that manic-depressive psychosis, like schizophrenia, is seen in child psychiatric patients, though rarely. This definition is based on the classical symptoms described by Kraepelin and Bleuler, as operationaIized by Rafaelsen (1974): 1) Change in the mood, 2) periodic course, 3) diurnal rhythm, 4) change in psycho-motoric speed, 5) unrealistic changes in self-esteem. The pharmacological treatment of manic-depressive children is conducted as in adults. For the treatment of manic states haloperidol is the drug of choice. Depressive states should preferably be treated with tricyclic antidepressive drugs e.g. imipramine in doses between 3 and 4 mg/kg/day. As imipramine given in these antidepressive doses might induce toxic reactions in susceptible children this treatment should be initiated under constant medical supervision in hospitals. The prophylactic effects of lithium on recurrent manic and depressive phases is now well documented in adults. Lithium prophylaxis must be considered when recurrent manic or depressive states have been found in a child. Recently, Amdisen (1975) has given a thorough review on the principles of lithium treatment. As in adults, children must be treated with lithium in doses which regulate the pIasma level of lithium between 0.8 and 1.0 mmoV1.
235 Imipramine Unwanted effects. Important knowledge of the side effects and overdose reactions of imipramine in children has accumulated in later years from studies on infantile autistic and hyperkinetic children. Due to anticholinergic properties, imipramine treatment might give side effects such as dry mouth, obstipation and tachycardia (Hamilton & Mahapatra (1972), Saraf et al. (1974)). These symptoms are usually harmless in children and give no reason for change in medication. Orthostatic hypotension is a more troublesome complication, but can be prevented when the imipramine treated child takes care never to rise to an upright position too quickly. Accommodation defects, tremor and nausea are serious complications, which can not be treated or prevented. But the psychotic depression, which indicated the imipramine treatment, is itself not only painful, but also, because of suicidal impulses, a danger to the life of the child. So even serious complications might be accepted in these circumstances. Besides the indirect effects on the heart due to anticholinergic properties, imipramine also has a direct effect on the myocardium, which might give electrocardiographic (ECG) manifestations when imipramine is given in high doses. Winsberg et al. (1975) have treated seven hyperkinetic children with imipramine in doses of 5 mgkg body weighvday. ECG was recorded on each child before treatment and again after 30 days of treatment. Imipramine in this dosage, which was higher than that usually recommended in antidepressive treatment, produced ECG alterations indicating d e c t e d repolarization, as T-wave magnitude was decreased and T-wave width increased. Three children, in addition, developed increased P-Q-interval indicating atrioventricular blockade. From other studies, (Martin & Zaug (1975), Rapoport et al. (1974)), it has been demonstrated that ECG alterations were not seen when imipramine was given in doses between 1 and 3 mg/kg/day. The risk for serious cardial side effects during high dose imipramine treatment has resulted in the following statement from the U.S. Department of Health, Education, and Welfare (Food and Drug Administration): “However, we plan to approve investigational protocols for imipramine hydrochloride only when the total daily dose does not exceed 90 mg for a 40-lb child, 110 mg for a 50-lb child, 135 mg for a 60-lb child, 160 mg for a 70-lb child, and 180 mg for a 80-lb child. Furthermore, because of the findings of Winsberg and associates and because of the unreliable occurrence of other warning side effects, we will recommend regular ECG monitoring when doses approach these limits” (Hayes et al. (1975)). Seizures have been reported during imipramine treatment in children with hyperactive behaviour disorders and infantile autism (Brown et al. (1973), Petti C? Campbell (1975)). These reported cases had shown no history of seizures before imipramine treatment, but in children who are hyperkinetic or autistic, there might be an increased risk of seizures even without imipramine as a provocating factor. No conclusions can be drawn about a possible risk of seizures in depressive children under imipramine treatment.
236 ACKNOWLEDGEMENT Practical experience in the topic of psychopharmacological treatment of psychotic children has been gained during the author’s appointment as a consultant in child psychiatry a t Sofieskolen, School for Psychotic Children, Bagsvzrd, Denmark. I am very indebted to the leader of the school, Else Hansen, and the staff. REFERENCES Amdisen, A . (1975): Monitoring of lithium treatment through determination of lithium concentration. Dan. med. Bull. 22, 277-291. Annell, A . 4 . (1955): Insulin shock treatment in children with psychotic disturbances. Acta Psychother. (Basel) 3, 193-205. Anthony, J., & P. Scott (1960): Manic-depressive psychosis in childhood. Child Psychol. Psychiat. I, 53-72. Barker, P., & I . A . Fraser (1968): A controlled trial of haloperidol in children. Brit. J. Psychiat. 114, 855-857. Bender, L., & W . R. Keeler (1952): The body image of schizophrenic children following electroshock therapy. Amer. J. Orthopsychiat. 22, 335-355. Black, D., & S. Woollacott (1974): Acute toxic psychosis in two children treated with benzhexol hydrochloride (Artane). Brit. J. Psychiat. 125, 483-484. Brown, D., B. G . Winsberg, I . Bialer & M . Press (1973): Imipramine therapy and seizures: Three children treated for hyperactive behaviour disorders. Amer. J. Psychiat. 130, 210-212. Campbell, M . (1972): Acute responses of schizophrenic children to a sedative and a “stimulating” neuroleptic: A pharmacologic yardstick. Curr. ther. Res. 14, 759-766. Campbell, M. (1973): Biological interventions in psychoses of childhood. J. Autism childh. Schiz. 3, 341-373. Campbell, M . (1975): Pharmacotherapy in early infantile autism. Biol. Psychiat. 10, 399-423. Campbell, M., B. Fish, T . Shapiro & A . Floyd, Jr. (1970): Thiothixene in young disturbed children. Arch. gen. Psychiat. 23, 70-72. Campbell, M., B. Fish, T . Shapiro & A . Floyd, Jr. (1971): Imipramine in preschool autistic and schizophrenic children. J. Autism. childh. Schiz. 1, 267-282. Campbell, M., B. Fish, J . Korein, T . Shapiro, P. Collins & C . Koh (1972a): Lithium and chlorpromazine: A controlled study of hyperactive severely disturbed young children. J. Autism childh. Schiz. 2, 234-263. Campbell, M., B. Fish, R. David, T . Shapiro, P. Collins & C . Koh (1972b): Response to triiodothyronine and dextroamphetamine: A study of preschool schizophrenic children. J. Autism childh. Schiz. 2, 343-358. Campbell, M., A . M . Small, P. J . Collins, E. Friedman, R. David & N . Genieser (1976): Levodopa and levoamphetamine: A crossover study in young schizophrenic children. Curr. ther. Res. 19, 70-86. Coleman, M . (1973): Serotonin and central nervous system syndromes of childhood: A review. J. Autism childh. Schiz. 3, 27-35. Creak,E.M. (1963): Childhood psychosis. A review of 100 cases. Brit. J. Psychiat. 109, 84-89. Dahl, V. (1972): A follow-up study of a childpsychiatric clientele, with special regard to manic-depressive psychosis. In Annell, A . 4 . (ed.): Depressive states in childhood and adolescence. Almquist & Wiksell, Stockholm, pp. 534-541. Eisenberg, L. (1955): The autistic child in adolescence. Amer. J. Psychiat. 112, 607-612. Engelhardt, D . M., P. Polizos & R . A . Margolis (1972): The drug treatment of childhood psychosis. I n Smith, W.L. (ed.): Drugs, development and cerebral function. Charles C Thomas, Springfield, Ill., pp. 224-234. Engelhardt, D . M., P. Polizos, J . Waizer & S. P. Hoflman (1973): A double-blind comparison of fluphenazine and haloperidol in outpatient Schizophrenic children. J.
237 Autism childh. Schiz. 3, 128-137. Fish, B., T. Shapiro & M. Campbell (1966): Long-term prognosis and the response of schizophrenic children to drug therapy: A controlled study of trifluoperazine. Amer. J. Psychiat. 123, 32-39. Gram, L. F., & 0.J . Rafaelsen (1972): Lithium treatment of psychotic children and adolescents. Acta psychiat. scand. 48, 253-260. Greenblatt, D. J., M . D. Allen, J . Koch-Weser & R. I. Shader (1976): Accidental poisoning with psychotropic drugs in children. Amer. J. Dis. Child. 130, 507-511. Hamilton, M., & S. B. Mahapatra (1972): Antidepressive drugs. In Meyler, L., & A. Herxheimer (eds.): Side effects of drugs. Vol. 7. Excerpta medica, Amsterdam, pp. 17-37. Hayes, T . A., M. L. Panitch & E. Barker (1975): Imipramine dosage in children: A comment on “imipramine and electrocardiographic abnormalities in hyperactive children”. Amer. J. Psychiat. 132, 546-547. Helper, M. M., R . C. Wilcott & S. L. Garfield (1963): Effects of chlorpromazine on learning and related processes in emotionally disturbed children. J. cons. Psychol. 27, 1-9. Zversen, L. L. (1975): Dopamine receptors in the brain. Science 188, 1084-1089. Jergensen, 0. Sylvester, E. T. Mellerup & 0. J . Rafaelsen (1970): Amino acid excretion in urine of children with various psychiatric diseases. A thin layer chromatographic study. Dan. med. Bull. 17, 166-170. Kanner, L. (1943): Autistic disturbances of affective contact. Nervous Child 2, 217-250. Kolvin, Z. (1971): Studies in the childhood psychoses. I. Diagnostic criteria and classification. Brit. J. Psychiat. 118, 381-384. Kolvin, Z. (1972a): Infantile autism or infantile psychoses. Brit. med. I. 3, 753-755. Kolvin, 1. (1972b): Late onset psychosis. Brit. med. J. 3, 816-817. Korein, I., B. Fish, T. Shapiro, E. W . Gerner & L. Levidow (1971): EEG and behavioral effects of drug therapy in children. Chlorpromazine and diphenhydramine. Arch. gen. Psychiat. 24, 522-563. Martin, G. Z., & P. J . Zaug (1975): Electrocardiographic monitoring of enuretic children receiving therapeutic doses of imipramine. Amer. J. Psychiat. 132, 540-542. McAndrew, J . B., Q. Case & D. A . Treflert (1972): Effects of prolonged phenothiazine intake on psychotic and other hospitalized children. J. Autism childh. Schiz. 2, 75-91. Meltzer, H. Y.,& V . S. Fang (1976): The effects of neuroleptics on serum prolactin in schizophrenic patients. Arch. gen. Psychiat. 33, 279-286. Petti, T. A., & M. Campbell (1975): Imipramine and seizures. Amer. J. Psychiat. 132, 538-540. Polizos, P., D. Engelhardt, S. P. Hogman & J . Waizer (1973): Neurological consequcnccs of psychotropic drug withdrawal in schizophrenic children. J. Autism childh. Schiz. 3. 247-253. van P k a g , H. M. (1969): Psychotropic drugs in child psychiatry. Int. Pharmacopsychiat. 3, 137-154. RafaeZsen, 0.J. (1974): Manic-depressive psychosis or manic-melancholic mode. Dan. med. Bull. 21, 81-87. Rapoport, J . E., P. 0. Quinn, G. Brodbard, D. Riddle & E. Brooks (1974): Imipramine and methylphenidate treatments of hyperactive boys. A double-blind comparison. Arch. gen. Psychiat. 30, 789-793. Ritvo, E. R., A . Yuwiler, E. Geller, A . Kales. S.Rashkis, A . Schicor, S.Plotkin, R. Axelrod & C. Howard (1971): Effects of L-dopa in autism. J. Autism childh. Schiz. I , 190-205. Rutter, M., S. Lebovici, L. Eisenberg, A . V . Sneznevskij, R. Sadoun, E. Brooke & T.-Y. Lin (1969): An evaluation of the proposal for a multi-axial classification of child psychiatric disorders. Psychol. Med. 3, 244-250. Saraf, K. R., D. F. Klein, R. Gittelman-Klein & S. Groff (1974): Imipramine side effects in children. Psychopharmacol. 37, 265-274.
238 Schain, R . J., & D. X . Freedman (1961): Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J. Pediat. 58, 315-320. Schneider, K . (1966): Klinische Psychopathologie. 7th ed. Thieme, Stuttgart. Simeon, J., B. Saletu, M . Saletu, T . M . Itil & J . DaSilva (1974): Thiothixene in childhood psychoses. Advanc. Biochem. Psychopharm. 9, 519-538. Tarsy, D.,& R . J . Baldessarini (1977): The pathophysiologic basis of tardive dyskinesia. Biol. Psychiat. 12, 431-450. Ze Vann, L. 1. (1969): Haloperidol in the treatment of behavioral disorders in children and adolescents. Canad. psychiat. Ass. J. 14, 217-220. Winsberg, B. G., S. Goldstein, L. E. Yepes & J . M . Perel (1975): Imipramine and electrocardiographic abnormalities in hyperactive children. h e r . J. Psychiat. 132, 542-545.
Received July 19, 1978
Ole Sylvester Jlrgensen Department of Child Psychiatry Frederiksborg County Hospital DK-3400 Hillergid Denmark
