Lithium in Child and Adolescent Bonaventure
Lena,
Psychiatry
MD
lithium is now established in adult psychiatric care, its place in child and adolescent psychiatric treatment is still not clear. This is surprising, particularly
HYPERACTIVITY
Although
because the first report on the use of lithium in the younger age group appeared in 1959, almost 20 years ago. This was the publication by Van Krevelen and Van Voorst,1 in which the authors described the successful treatment of a 14-year-old boy who suffered from "periodic psychosis with longer manic and shorter depressive phases." This patient appeared to have been suffering from manic depressive illness. The two reports which followed this were by Frommer2 in England (1968) and Annell3 in Sweden (1969). Frommer described a group of 19 young people, aged 5 to 14 years, whom she treated with lithium and who displayed depressive features with extreme forms of "temper outbursts alternating with brief states of reasonableness," or who showed "continuous unconstructive mechanical activity." Frommer viewed these symptoms as a manifestation of manic depressive illness, although none of her sample suffered from typical mania. In 1969 Annell reported on 12 young people, aged 10 to 18, with serious psychiatric disturbance of a "periodic nature"; eleven of these responded favorably to lithium treatment. Only two of the 12, at most, showed symptoms that could be described as mania. Both these studies were uncontrolled, and both investigators were of the opinion that the symp¬ toms they were treating were manifestations of a manic depressive illness occurring in a masked form in the younger age group. Some other investigators have claimed the successful use of lithium in treating cases that they have described as manic depressive illness occurring in adolescents. Feinstein and Wolpert1 (1973) have used the term "juvenile manic depressive illness." Horowitz' (1977) reported on the successful use of lithium in the treatment of eight adolescents aged 15 to 18, whose conditions he diagnosed as manic depressive. Dugas et al" (1975) from France used lithium in treating 42 young people in the age range 14 to 21 years and reported that the best results were obtained in the nine patients whose conditions were diag¬ nosed as manic depressive, seven of whom responded very well. The successful use of lithium in individual patients suffering from manic depressive illness has been described by Adams et al7 (1970) and Biermann and Pflug8 (1974). From the Department of Child and Family Psychiatry, District General Hospital, Eastbourne, England. Dr Lena is now with the Department of Child Psychiatry, Royal Ottawa Hospital, Ottawa, Ontario.
Although the above group of investigators have treated young people whose conditions they diagnosed either as manic depressive or as manifesting a masked form of this disorder, generally manic depressive illness is considered very rare in children and adolescents." Some investigators have stayed clear of this diagnostic controversy and have treated symptoms or symptom complexes. Whitehead and Clarke1" (1970) treated seven hyperactive children, two of whom were psychotic and four of whom showed neurotic behavior traits. It was an uncontrolled crossover trial with lithium and placebo or thioridazine. Lithium was not found to have any appreciable effects on hyperactivity. No mention is made of the maintenance of therapeutic serum levels. Greenhill et al11 (1973) gave lithium within a doubleblind crossover design—lithium alternating with dextroamphetamine or placebo—to a group of nine children, aged 9 to 14, who were severely hyperactive and whose conditions previously had been unresponsive to drugs and psychother¬ apy. Two improved transiently, and these differed from those who did not improve in that they showed affective symptoms. Gram and Rafaelson12 (1972) treated 18 young people in the age range 8 to 22. Lithium was administered in a double-blind crossover trial. These children were psychotic with mixed diagnoses. Information on the chil¬ dren's behavior was collected through questionnaires from teachers and parents, and it was found that most of the children showed some improvement while receiving lithium, particularly at school. Campbell et al13 (1972) gave lithium and chlorpromazine in a controlled crossover trial to ten hyperactive, severely disturbed children, aged 3 to 6. Major improvement was noticed only in a 6-year-old boy with self-mutilating behavior. AGGRESSIVE BEHAVIOR
Some investigators have treated aggressive behavior. Dostal and Zvolsky11 (1970) treated 14 severely mentally retarded aggressive adolescents previously resistant to phenothiazines with lithium. The adolescents were aged 11 to 17. These investigators found that lithium had a notable anti-aggressive effect. Lena and O'Brien1, (1975) success¬ fully treated a 9-year-old boy whose main symptom was hyperaggressive behavior and who previously had not responded to other forms of treatment, including drug therapy in an inpatient psychiatric setting. Sheard1" (1975) administered lithium to 12 young people in a correctional institution, and he has also described the notable anti-
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aggressive effect of lithium. Lena et al17 (1978) reported their preliminary findings in a double-blind investigation using lithium in treating 11 young people, aged 9 to 15, none of whom were psychotic or suffered from manic depressive illness. On completion of their trial, they found that six patients improved while receiving lithium, 4 markedly so. Of the four who had improved markedly, all had hyperaggressive behavior as a prominent symptom. Lena et al took their investigation a stage further by selecting seven children and adolescents (three boys and four girls, aged 11 to 15) who had hyperaggressive behavior as their common symptom, or who had a clear history of recurrent mood disturbance. Six improved markedly, with hyperaggressive behavior responding particularly well to lithium therapy. No psychotic children were included, nor were there any who suffered from manic depressive illness. Lena et al did not find any family history of manic depressive illness in their group of adolescents whose conditions responded to lithium treatment. MONITORING LITHIUM TREATMENT Is lithium safe to use in young people? Renal clearance of lithium is high in children and hence they are less likely to suffer from serious side effects. The majority of reports published to date have not reported any serious side effects or toxic effects of lithium in the younger age group. However, particular attention should be paid to the suppressant effect of lithium on the thyroid gland and possible changes in calcium metabolism in the young person receiving lithium. Thus, it is imperative to screen young people for renal and thyroid function and to monitor them throughout lithium therapy, preferably at monthly intervals. Considering some of the recent evidence about possible harmful effects of lithium on calcium metabolism in children, the use of lithium in children under age 12 should be considered only under special circumstances. Children and adolescents receiving lithium therapy should be screened to eliminate any defects in their calcium metabolism prior to the start of lithium therapy, and preferably this should be monitored during the course of lithium therapy as well. However, in view of the present
state of
knowledge regarding its clinical efficacy, and in view of the possible biochemical and endocrinological sequelae of lithium therapy, even in older children lithium therapy would be indicated only in severe degrees of psychiatric disturbance not amenable to other forms of therapy. Lithium therapy entails frequent venipunctures, and this could be upsetting to some children. If salivary lithium estimates were found to be equally reliable, this could be a great asset to lithium therapy in the younger age group. A preliminary study carried out by Lena and Bastable18 (1978) indicates that salivary lithium estimates could be reliable, and the matter is being further investi¬ gated. Our findings show that lithium levels in saliva are higher than those found in serum and, in most instances, average about 2Vi times the serum level. CONCLUSION
The current available knowledge regarding the use of lithium in the younger age group is not yet sufficient to establish definite indications for lithium therapy. More controlled investigations over longer periods are required before this would be available. There seems to be, however, a group of severely disturbed young people who possibly could benefit from lithium therapy. These are children and adolescents showing impulsive aggressive behavior, with or without an affective component, and those showing clear-cut recurrent mood disturbances not responding to other forms of therapy. The information regarding this matter could be further clarified if investigators avoided the diagnostic confusion surrounding manic depressive illness in children and adolescents and more clearly described the particular symptoms and symptom com¬ plexes of the individuals being treated with lithium. Final¬ ly, the biochemical, endocrinological, and metabolic effects of lithium should at all times be borne in mind when lithium therapy is considered in this age group, and because of these effects, lithium should only be prescribed for a short term (up to six months). Detailed clinical guidelines and reference to some side effects such as proteinuria have recently been described by the author.1"
References 1. Van Krevelen D, Van Voorst JA: Lithium in der Behandlung einer unklarer Genese bei einem Jugendlichen. Acta Paedopsychiatr
Psychose
26:148-152,
1959.
EA, in Coppen A, Walk A (eds): Recent Developments in Disorders. London, British Journal of Psychiatry, 1968, pp 117\x=req-\
2. Frommer
Affective
136. 3. Annell AL: Lithium in the treatment of children and adolescents. Acta
Psychiatr Scand Suppl 207:19-30, 1969. 4. Feinstein S, Wolpert E: Juvenile manic-depressive illness. J Am
Acad Child Psychiatry 12:123-136, 1973. 5. Horowitz HA: Lithium and the treatment of adolescent manic-depressive illness. Dis Nerv Syst 38:480-483, 1977. 6. Dugas M, Gueriot C, Frowirth CH: Has lithium a value in child psychiatry? Rev Neuropsychiatr Infant 23:365-372, 1975. 7. Adams GL, Kivowitz J, Ziskind E: Manic-depressive psychosis, mental retardation, and chromosomal rearrangement. Arch Gen Psychiatry 23:305309, 1970. 8. Biermann I, Pflug B: A case of childhood cyclothymia associated with familial loading. Acta Paedopsychiatr 40:196-203, 1974. 9. Anthony J, Scott P: Manic-depressive psychosis in childhood. J Child
Psychol Psychiatry 1:53-72, thioridazine
on
1960.
P, Clarke L: Effect of lithium carbonate, placebo and hyperactive children. Am J Psychiatry 127:824-825, 1970.
10. Whitehead
LL, Rieder RO, Wender PH, et al: Lithium carbonate in the hyperactive children. Arch Gen Psychiatry 28:636-640, 1973. 12. Gram L, Rafaelson 0: Lithium treatment of psychotic children and adolescents: A controlled clinical trial. Acta Psychiatr Scand 48:253-260, 11. Greenhill
treatment of
1972. 13. Campbell M, Fish B, Korein J, et al: Lithium and chlorpromazine\p=m-\a controlled crossover study of hyperactive severely disturbed young children. J Autism Child Schizo 2:234-263, 1972. 14. Dostal T, Zvolsky P: Anti-aggressive effect of lithium salts in severe mentally retarded adolescents. Int Pharmacopsychiatry 5:203-207, 1970. 15. Lena B, O'Brien EMD: Success with lithium in a disturbed child. Lancet 2:1307, 1975. 16. Sheard M: Lithium in the treatment of aggression. J Nerv Ment Dis 160:108-118, 1975. 17. Lena B, Surtees SJ, Maggs R: The efficacy of lithium in the treatment of emotional disturbance in children and adolescents, in Johnson FN, Johnson S (eds): Lithium in Medical Practice. Lancaster, England, MTP Press Ltd, 1978, pp 79-83. 18. Lena B, Bastable MD: The reliability of salivary lithium estimations in children. IRCS J Med Sci 6:208, 1978. 19. Lena B: Lithium in children and adolescents, in Johnson N (ed): Handbook of Lithium Therapy. Lancaster, England, MTP Press Ltd, to be
published.
Downloaded From: http://archpsyc.jamanetwork.com/ by a BROWN UNIVERSITY User on 04/26/2016
Lena,
Psychiatry
MD
lithium is now established in adult psychiatric care, its place in child and adolescent psychiatric treatment is still not clear. This is surprising, particularly
HYPERACTIVITY
Although
because the first report on the use of lithium in the younger age group appeared in 1959, almost 20 years ago. This was the publication by Van Krevelen and Van Voorst,1 in which the authors described the successful treatment of a 14-year-old boy who suffered from "periodic psychosis with longer manic and shorter depressive phases." This patient appeared to have been suffering from manic depressive illness. The two reports which followed this were by Frommer2 in England (1968) and Annell3 in Sweden (1969). Frommer described a group of 19 young people, aged 5 to 14 years, whom she treated with lithium and who displayed depressive features with extreme forms of "temper outbursts alternating with brief states of reasonableness," or who showed "continuous unconstructive mechanical activity." Frommer viewed these symptoms as a manifestation of manic depressive illness, although none of her sample suffered from typical mania. In 1969 Annell reported on 12 young people, aged 10 to 18, with serious psychiatric disturbance of a "periodic nature"; eleven of these responded favorably to lithium treatment. Only two of the 12, at most, showed symptoms that could be described as mania. Both these studies were uncontrolled, and both investigators were of the opinion that the symp¬ toms they were treating were manifestations of a manic depressive illness occurring in a masked form in the younger age group. Some other investigators have claimed the successful use of lithium in treating cases that they have described as manic depressive illness occurring in adolescents. Feinstein and Wolpert1 (1973) have used the term "juvenile manic depressive illness." Horowitz' (1977) reported on the successful use of lithium in the treatment of eight adolescents aged 15 to 18, whose conditions he diagnosed as manic depressive. Dugas et al" (1975) from France used lithium in treating 42 young people in the age range 14 to 21 years and reported that the best results were obtained in the nine patients whose conditions were diag¬ nosed as manic depressive, seven of whom responded very well. The successful use of lithium in individual patients suffering from manic depressive illness has been described by Adams et al7 (1970) and Biermann and Pflug8 (1974). From the Department of Child and Family Psychiatry, District General Hospital, Eastbourne, England. Dr Lena is now with the Department of Child Psychiatry, Royal Ottawa Hospital, Ottawa, Ontario.
Although the above group of investigators have treated young people whose conditions they diagnosed either as manic depressive or as manifesting a masked form of this disorder, generally manic depressive illness is considered very rare in children and adolescents." Some investigators have stayed clear of this diagnostic controversy and have treated symptoms or symptom complexes. Whitehead and Clarke1" (1970) treated seven hyperactive children, two of whom were psychotic and four of whom showed neurotic behavior traits. It was an uncontrolled crossover trial with lithium and placebo or thioridazine. Lithium was not found to have any appreciable effects on hyperactivity. No mention is made of the maintenance of therapeutic serum levels. Greenhill et al11 (1973) gave lithium within a doubleblind crossover design—lithium alternating with dextroamphetamine or placebo—to a group of nine children, aged 9 to 14, who were severely hyperactive and whose conditions previously had been unresponsive to drugs and psychother¬ apy. Two improved transiently, and these differed from those who did not improve in that they showed affective symptoms. Gram and Rafaelson12 (1972) treated 18 young people in the age range 8 to 22. Lithium was administered in a double-blind crossover trial. These children were psychotic with mixed diagnoses. Information on the chil¬ dren's behavior was collected through questionnaires from teachers and parents, and it was found that most of the children showed some improvement while receiving lithium, particularly at school. Campbell et al13 (1972) gave lithium and chlorpromazine in a controlled crossover trial to ten hyperactive, severely disturbed children, aged 3 to 6. Major improvement was noticed only in a 6-year-old boy with self-mutilating behavior. AGGRESSIVE BEHAVIOR
Some investigators have treated aggressive behavior. Dostal and Zvolsky11 (1970) treated 14 severely mentally retarded aggressive adolescents previously resistant to phenothiazines with lithium. The adolescents were aged 11 to 17. These investigators found that lithium had a notable anti-aggressive effect. Lena and O'Brien1, (1975) success¬ fully treated a 9-year-old boy whose main symptom was hyperaggressive behavior and who previously had not responded to other forms of treatment, including drug therapy in an inpatient psychiatric setting. Sheard1" (1975) administered lithium to 12 young people in a correctional institution, and he has also described the notable anti-
Downloaded From: http://archpsyc.jamanetwork.com/ by a BROWN UNIVERSITY User on 04/26/2016
aggressive effect of lithium. Lena et al17 (1978) reported their preliminary findings in a double-blind investigation using lithium in treating 11 young people, aged 9 to 15, none of whom were psychotic or suffered from manic depressive illness. On completion of their trial, they found that six patients improved while receiving lithium, 4 markedly so. Of the four who had improved markedly, all had hyperaggressive behavior as a prominent symptom. Lena et al took their investigation a stage further by selecting seven children and adolescents (three boys and four girls, aged 11 to 15) who had hyperaggressive behavior as their common symptom, or who had a clear history of recurrent mood disturbance. Six improved markedly, with hyperaggressive behavior responding particularly well to lithium therapy. No psychotic children were included, nor were there any who suffered from manic depressive illness. Lena et al did not find any family history of manic depressive illness in their group of adolescents whose conditions responded to lithium treatment. MONITORING LITHIUM TREATMENT Is lithium safe to use in young people? Renal clearance of lithium is high in children and hence they are less likely to suffer from serious side effects. The majority of reports published to date have not reported any serious side effects or toxic effects of lithium in the younger age group. However, particular attention should be paid to the suppressant effect of lithium on the thyroid gland and possible changes in calcium metabolism in the young person receiving lithium. Thus, it is imperative to screen young people for renal and thyroid function and to monitor them throughout lithium therapy, preferably at monthly intervals. Considering some of the recent evidence about possible harmful effects of lithium on calcium metabolism in children, the use of lithium in children under age 12 should be considered only under special circumstances. Children and adolescents receiving lithium therapy should be screened to eliminate any defects in their calcium metabolism prior to the start of lithium therapy, and preferably this should be monitored during the course of lithium therapy as well. However, in view of the present
state of
knowledge regarding its clinical efficacy, and in view of the possible biochemical and endocrinological sequelae of lithium therapy, even in older children lithium therapy would be indicated only in severe degrees of psychiatric disturbance not amenable to other forms of therapy. Lithium therapy entails frequent venipunctures, and this could be upsetting to some children. If salivary lithium estimates were found to be equally reliable, this could be a great asset to lithium therapy in the younger age group. A preliminary study carried out by Lena and Bastable18 (1978) indicates that salivary lithium estimates could be reliable, and the matter is being further investi¬ gated. Our findings show that lithium levels in saliva are higher than those found in serum and, in most instances, average about 2Vi times the serum level. CONCLUSION
The current available knowledge regarding the use of lithium in the younger age group is not yet sufficient to establish definite indications for lithium therapy. More controlled investigations over longer periods are required before this would be available. There seems to be, however, a group of severely disturbed young people who possibly could benefit from lithium therapy. These are children and adolescents showing impulsive aggressive behavior, with or without an affective component, and those showing clear-cut recurrent mood disturbances not responding to other forms of therapy. The information regarding this matter could be further clarified if investigators avoided the diagnostic confusion surrounding manic depressive illness in children and adolescents and more clearly described the particular symptoms and symptom com¬ plexes of the individuals being treated with lithium. Final¬ ly, the biochemical, endocrinological, and metabolic effects of lithium should at all times be borne in mind when lithium therapy is considered in this age group, and because of these effects, lithium should only be prescribed for a short term (up to six months). Detailed clinical guidelines and reference to some side effects such as proteinuria have recently been described by the author.1"
References 1. Van Krevelen D, Van Voorst JA: Lithium in der Behandlung einer unklarer Genese bei einem Jugendlichen. Acta Paedopsychiatr
Psychose
26:148-152,
1959.
EA, in Coppen A, Walk A (eds): Recent Developments in Disorders. London, British Journal of Psychiatry, 1968, pp 117\x=req-\
2. Frommer
Affective
136. 3. Annell AL: Lithium in the treatment of children and adolescents. Acta
Psychiatr Scand Suppl 207:19-30, 1969. 4. Feinstein S, Wolpert E: Juvenile manic-depressive illness. J Am
Acad Child Psychiatry 12:123-136, 1973. 5. Horowitz HA: Lithium and the treatment of adolescent manic-depressive illness. Dis Nerv Syst 38:480-483, 1977. 6. Dugas M, Gueriot C, Frowirth CH: Has lithium a value in child psychiatry? Rev Neuropsychiatr Infant 23:365-372, 1975. 7. Adams GL, Kivowitz J, Ziskind E: Manic-depressive psychosis, mental retardation, and chromosomal rearrangement. Arch Gen Psychiatry 23:305309, 1970. 8. Biermann I, Pflug B: A case of childhood cyclothymia associated with familial loading. Acta Paedopsychiatr 40:196-203, 1974. 9. Anthony J, Scott P: Manic-depressive psychosis in childhood. J Child
Psychol Psychiatry 1:53-72, thioridazine
on
1960.
P, Clarke L: Effect of lithium carbonate, placebo and hyperactive children. Am J Psychiatry 127:824-825, 1970.
10. Whitehead
LL, Rieder RO, Wender PH, et al: Lithium carbonate in the hyperactive children. Arch Gen Psychiatry 28:636-640, 1973. 12. Gram L, Rafaelson 0: Lithium treatment of psychotic children and adolescents: A controlled clinical trial. Acta Psychiatr Scand 48:253-260, 11. Greenhill
treatment of
1972. 13. Campbell M, Fish B, Korein J, et al: Lithium and chlorpromazine\p=m-\a controlled crossover study of hyperactive severely disturbed young children. J Autism Child Schizo 2:234-263, 1972. 14. Dostal T, Zvolsky P: Anti-aggressive effect of lithium salts in severe mentally retarded adolescents. Int Pharmacopsychiatry 5:203-207, 1970. 15. Lena B, O'Brien EMD: Success with lithium in a disturbed child. Lancet 2:1307, 1975. 16. Sheard M: Lithium in the treatment of aggression. J Nerv Ment Dis 160:108-118, 1975. 17. Lena B, Surtees SJ, Maggs R: The efficacy of lithium in the treatment of emotional disturbance in children and adolescents, in Johnson FN, Johnson S (eds): Lithium in Medical Practice. Lancaster, England, MTP Press Ltd, 1978, pp 79-83. 18. Lena B, Bastable MD: The reliability of salivary lithium estimations in children. IRCS J Med Sci 6:208, 1978. 19. Lena B: Lithium in children and adolescents, in Johnson N (ed): Handbook of Lithium Therapy. Lancaster, England, MTP Press Ltd, to be
published.
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