B ~ PSYCI~.ATRY 1991;30:| 167-! 170
li67
CASE REPORT
Restless Legs Syndrome Induced by Li um Takeshi Terao, Michi Terao, Reiji Yoshimura, and K a z O o Abe
Introduction The restless legs syndrome (RLS) has been observed in association with heredity, pregnancy, poliomyelitis, infectious diseases, avitaminosis, different types of anemia, diabetes, and intake of certain drugs (promethazine and prochlorperazine) (Ekbom 1960). Although a variety of chugs such as L-dopa, bromocriptine, carbamazepine, aM clonazepam are used to treat RLS (Waiters and Hening 1987), Paik et al (1989) reported three cases of RLS induced by mianserin. Therefore, some psychotropics induce ~ , whereas others can alleviate it. The efficacy of lithium in manic-depressive illness is well established. Furthermore, lithium potentiation of antidepressants is available for not only depression (de Montigny et al 1983; Heninger et al 1983; Terao et al 1990) but also obsessive-compulsive disorder (Rasmussen 1984). In this article, we present what we believe to be the first case of lithium-induced ~ S , and discuss the neuropharmacological implications of RLS.
Case Report Mr I, an 18-year-old male, met the DSM-III-R criteria for obsessive-compulsive disorder. At the age of 15 years, he manifested mysophobia with compulsive washing of his hands. In November 1989 and May 1990, he was admitted to our hospital. Throughout his two hospitalizations, he showed no symptoms of RLS. On June 19, 1990, he was readmitted for the third time. Physical examination revealed no abnormalities. Serum iron~ foiic acid, vitamin Bl2, and thyroid function were within normal limits. To permit measurement of serum-free 3-methoxy-4-hydroxyphenytglycol (MHPG), he was instructed to refrain from several kinds of foods that might affect the catecholamine metabolism following previous methods (Markianos and Beckman 1976; Takahashi et al 1977; Halbreich et al 1990), and kept at complete rest for 1 hr before blood was drawn at 8:00 AM. Electroencepha!ography and computed tomography of the brain showed no abnormalities. Because clomipramine had appeared to make him aggressive during his first i~ospitalization, he was put on lithium (800 rag/day, 0.6-0.7
From the Departments of Psychiatry (IF, RY, KA) and Ergonomics (MT), University of Occupational and Environmental Health, School of Medicine. Kitakyushu, 807, Japan. Address reprint requests to Takeshi Terao, M.D., Department of Psychiatry, University of Occupational and Environmental Health, School of Medicine, Kitakyushu 807, Japan. Received January 23, 1991; revised April 16, 1991.
© 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
1168
BIOL PSYCHIATRY 1991;30:1167-1170
T. Terao et al
mEq/L) alone. On June 25, he was additionally put on levomepromazine 5 mg at night because of insonmia. Although levomepromazine was increased (15 mg on the 26th and 25 mg on the 27th, respectively), his insomnia was further exacerbated. He complained of an unpleasant creeping sensation in his lower legs at night. The sensation disappeared the next morning. Therefore, we considered the possibility that RLS was induced by levomepromazine and discontinued it on June 28. The following day, serum-free MHPG was 2.5 ng/ml. Thereafter, the sensation was alleviated, although slight paresthesia and insomnia pe~isted. On July 2, se~m-free M H ~ was 2.5 ng/ml. Because compulsive symptoms remained, we increased lithium to 1000 mg/day on July 4. On July 6 and 13, serum-free MHPG was 3.4 and 4.5 ng/ml, respectively. On the night of the 13th, he complained of a severe creeping sensation in his lower legs and an urge to move or rub them. He also found it difficult to fall asleep. Because 5-HTP is reported to alleviate RLS (Walters and Hening 1987), we tried its precursor, L-tryptophan, to treat RLS. We told him to take L-tryptophan when he -ould not endure the sensation. Because it alleviated the seasation partially, he took it occasionally As we suspected that lithium (0.8-0.9 mEq/L) induced RLS, the dosage was reduced to 400 m~day (0.3-0.4 mEq/L) on July 18. The following day, RLS was alleviated and serum-free MHPG was decreased to 3.5 ng/ml on the 20th. Thereafter, he was put on lithium 400 rag/day without RLS and discharged in October. In order to investigate the relationship between the severity of RLS and serum free MHPG approximately, we rated RLS as follows: 0, no symptoms; 1, sfight paresthesia and prolonged sleep latency; and 2, severe paresthesia and severe insomnia. As a result, RLS ratings were 0 (May 18), I (June 29, July 2, 6, 20), and 2 (July 13), respectively. On the other hand, serum-free MHPG (ng/ml) was 2.1 (May 18), 2.5 (June 29, July 2), 3.4 (July 6), 3.5 (July 20), and 4.5 (July 13). There was a significant correlation between RLS ratings and serum-free MHPG (r = 0.86, p < 0.05).
Discussion The symptoms of our case satisfied Brodeur's inclusion criteria for RLS (paresthesia leading to an urge to move the legs at bedtime and prolonged sleep latency) (Brodeur et al 1988). All other medical conditions possibly associated with RLS were absent. During his third hospitalization, levomepromazine appeared to exacerbate ~RLS in a dose-dependent manner. Because dopaminergic antagonists, such as pimozide (Akpinar 1982) and promethazine (Ekbom 1960), are known to worsen RLS, levomepromazine might also worsen RLS via dopaminergic antagonism. Six days after levomepromazide withdrawal, lithium was increased from 800 to 1000 m~day. Because the half-life of levomepromazine is about 15-30 hr (Dahl 1976), the relapse of RLS was considered to be due to the increase of lithium (200 rag), in accordance with the increase of serumfree MHPG. After the reduction of lithium (600 rag), RLS improved and serum-free MHPG decreased concurrently. There was a positive correlation between RLS ratings and serum-free MHPG (r = 0.86, p < 0.05). Serum MHPG is regarded to be largely derived from the central nervous system in humans (Takahashi et al 1977). Grundstein et al (1986) also demonstrated a significant relationship between serum MHPG and hypothalamic noradrenergic neural activity in the rat. Lithium action has been widely studied in relation to the noradrenergic functions in the central nervous system. These studies showed that the catecholamine content in the brain was unchanged (Corrodi et al i969; Ho et al 1970) or increased (Casado et al 1989)
RLS Inducedby Lithium
BR~L PSVOV,A~V
|991130"A167-i |7~
1169
by lithium treatment. The synthesis of dopamine was decreased (Friedmaa and 1973), but the activity of tyrosine hydroxylase was increased (Segal et al 1975) by fi~um. However, our data (Terao et al 1991) supported the enhancing effect of lithium on t ~ noradrenergic functions. Therefore, it seems possible that lithium exacerbated RLS, at ,,east in part, via the noradrenergic system. Further studies, including other noradrenergic metabolites, semtonergic metabolites, second messengers, and polygraphic sleep sradies are ~ to investigate lithium-induced RLS. The authors thank Special Reference Laboratory, Tokyo, Japan, for measuring senun free MHPG.
References Akpinar S (1982): Treatment of restless legs syndrome with ievodopa plus benserazide. Arch Neurol 39:739. B._rode~rC, Mon~laisi_r _], Godbout R, Marinier R (1988): Treatment of restless legs syndrome and periodic movements during sleep with t.-dopa: A double-blind, controlled study. Neurology 38:1845-1848. Casado M, Arag6n MC, Gim6nez C (1989): Determination of nmnoamines in rat brain r e g i ~ after chronic administration of lithium. Neurochem Res 14:905-908. Cormdi H, Fuxe K, Schou M (1969): Tl:¢ effect of prolonged lithium administration on cerebral monoamine neurons in the rat. Life Sci 8:643-651. Dahl SG (1976): Pharmacokinetics of methotrimeprazine after single and multiple doses. Clin Pharmacol Ther 19:435-442. de Montigny C, Cournoyer G, Morissete R, LangloJs R, CaiI16G (1983): Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression: Correlations with the neurobiotogic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system. Arch Gen Psychiatry 40:1327-1334. Ekbom KA (1960): Restless legs syndrome. Neurology 10:868-873. Friedman E, Gershon S (1973): Effect of lithium on brain dopamine. Nature 243:520-521. Grundstein HS, Gleeson RM, Smythe GA (1986): Relationship between hypothalamic nomd~nergic neuronal activity and serum 3-methoxy-4-hydroxyphenylethylene glycol in the rat. L(fe Sci 39:207-213. Halbreich U, Castaneda R, Galanter M, Mandola R, Sharpless N (1990): Plasma MHPG and age in detoxified alcoholics Biol Psychiatry 27:026-630. Heninger GR, Chamey DS, Sternberg DE (1983): Lithium carbonate augmentation of antidepressant treatment. Arch Gen Psychiatry 40:1335-1342. Ho AKS, Loh HH, Craves F, Hitzemann P,J, Gershon S (1970): The effect of proIoaged lithium treatment on the synthesis rate and turnover of monoamines in brain regions of rats. Eur J Pharmacol 10:72-78. Markianos E, Beckmann H (1976): Diurnal changes in dopamine-13-hydroxylase, homovanillic acid and 3-methoxy-4-hydroxyphenylglycol in serum of man. J Neural Transm 39:79-93. Paik IH, Lee C, Choi BM, Chae YL, Kim CE (1989): Miansedn-induced restless legs syndrome. Br J Psychiatry 155:415-417. Rasmussen S (1984): Lithinm and tryptophan augmentation in clomipramine-resistant obsessive compulsive disorder. Am J Psychiatry 141 :1283-1285. Segal DS, Callaghan M, Mandell AJ (1975): Alterations in behaviour and catecholamine biosynthesis induced by lithium. Nature 254:58-59. Ta.k~_hashi S~ Godse DD~ Warsh JJ, Stancer HC (1977): A gas chromatographic-mass spectrometric
1170
BIOL PSYCHIATRY 1991;30:1!67 1170
T. Terao et al
(GC-MS) assa3, for 3-methoxy-4-hydroxyphenethyleneglycol and vanilraandelic acid in human serum. Ciin C?,im Acta 81:182-192. Terao T, Yoshimura R, Abe K (1990): Lithium cafoonate potentiation of tetracyclic antidepressants. Biol Psychiatry 28:1075-1077. Terao T, Yanagihara N, Abe K, lzumi F (1991): Lithium ~ n t and catecholamine synthesis ~.nd secretion. Jpn J Pharmacol 55 (suppl I):204P. Waiters AS, Hening W (1987): Clinical presentation and ncurophatmacology of restless legs syndrome. Clin Neuropha~col 10:225-237.
li67
CASE REPORT
Restless Legs Syndrome Induced by Li um Takeshi Terao, Michi Terao, Reiji Yoshimura, and K a z O o Abe
Introduction The restless legs syndrome (RLS) has been observed in association with heredity, pregnancy, poliomyelitis, infectious diseases, avitaminosis, different types of anemia, diabetes, and intake of certain drugs (promethazine and prochlorperazine) (Ekbom 1960). Although a variety of chugs such as L-dopa, bromocriptine, carbamazepine, aM clonazepam are used to treat RLS (Waiters and Hening 1987), Paik et al (1989) reported three cases of RLS induced by mianserin. Therefore, some psychotropics induce ~ , whereas others can alleviate it. The efficacy of lithium in manic-depressive illness is well established. Furthermore, lithium potentiation of antidepressants is available for not only depression (de Montigny et al 1983; Heninger et al 1983; Terao et al 1990) but also obsessive-compulsive disorder (Rasmussen 1984). In this article, we present what we believe to be the first case of lithium-induced ~ S , and discuss the neuropharmacological implications of RLS.
Case Report Mr I, an 18-year-old male, met the DSM-III-R criteria for obsessive-compulsive disorder. At the age of 15 years, he manifested mysophobia with compulsive washing of his hands. In November 1989 and May 1990, he was admitted to our hospital. Throughout his two hospitalizations, he showed no symptoms of RLS. On June 19, 1990, he was readmitted for the third time. Physical examination revealed no abnormalities. Serum iron~ foiic acid, vitamin Bl2, and thyroid function were within normal limits. To permit measurement of serum-free 3-methoxy-4-hydroxyphenytglycol (MHPG), he was instructed to refrain from several kinds of foods that might affect the catecholamine metabolism following previous methods (Markianos and Beckman 1976; Takahashi et al 1977; Halbreich et al 1990), and kept at complete rest for 1 hr before blood was drawn at 8:00 AM. Electroencepha!ography and computed tomography of the brain showed no abnormalities. Because clomipramine had appeared to make him aggressive during his first i~ospitalization, he was put on lithium (800 rag/day, 0.6-0.7
From the Departments of Psychiatry (IF, RY, KA) and Ergonomics (MT), University of Occupational and Environmental Health, School of Medicine. Kitakyushu, 807, Japan. Address reprint requests to Takeshi Terao, M.D., Department of Psychiatry, University of Occupational and Environmental Health, School of Medicine, Kitakyushu 807, Japan. Received January 23, 1991; revised April 16, 1991.
© 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
1168
BIOL PSYCHIATRY 1991;30:1167-1170
T. Terao et al
mEq/L) alone. On June 25, he was additionally put on levomepromazine 5 mg at night because of insonmia. Although levomepromazine was increased (15 mg on the 26th and 25 mg on the 27th, respectively), his insomnia was further exacerbated. He complained of an unpleasant creeping sensation in his lower legs at night. The sensation disappeared the next morning. Therefore, we considered the possibility that RLS was induced by levomepromazine and discontinued it on June 28. The following day, serum-free MHPG was 2.5 ng/ml. Thereafter, the sensation was alleviated, although slight paresthesia and insomnia pe~isted. On July 2, se~m-free M H ~ was 2.5 ng/ml. Because compulsive symptoms remained, we increased lithium to 1000 mg/day on July 4. On July 6 and 13, serum-free MHPG was 3.4 and 4.5 ng/ml, respectively. On the night of the 13th, he complained of a severe creeping sensation in his lower legs and an urge to move or rub them. He also found it difficult to fall asleep. Because 5-HTP is reported to alleviate RLS (Walters and Hening 1987), we tried its precursor, L-tryptophan, to treat RLS. We told him to take L-tryptophan when he -ould not endure the sensation. Because it alleviated the seasation partially, he took it occasionally As we suspected that lithium (0.8-0.9 mEq/L) induced RLS, the dosage was reduced to 400 m~day (0.3-0.4 mEq/L) on July 18. The following day, RLS was alleviated and serum-free MHPG was decreased to 3.5 ng/ml on the 20th. Thereafter, he was put on lithium 400 rag/day without RLS and discharged in October. In order to investigate the relationship between the severity of RLS and serum free MHPG approximately, we rated RLS as follows: 0, no symptoms; 1, sfight paresthesia and prolonged sleep latency; and 2, severe paresthesia and severe insomnia. As a result, RLS ratings were 0 (May 18), I (June 29, July 2, 6, 20), and 2 (July 13), respectively. On the other hand, serum-free MHPG (ng/ml) was 2.1 (May 18), 2.5 (June 29, July 2), 3.4 (July 6), 3.5 (July 20), and 4.5 (July 13). There was a significant correlation between RLS ratings and serum-free MHPG (r = 0.86, p < 0.05).
Discussion The symptoms of our case satisfied Brodeur's inclusion criteria for RLS (paresthesia leading to an urge to move the legs at bedtime and prolonged sleep latency) (Brodeur et al 1988). All other medical conditions possibly associated with RLS were absent. During his third hospitalization, levomepromazine appeared to exacerbate ~RLS in a dose-dependent manner. Because dopaminergic antagonists, such as pimozide (Akpinar 1982) and promethazine (Ekbom 1960), are known to worsen RLS, levomepromazine might also worsen RLS via dopaminergic antagonism. Six days after levomepromazide withdrawal, lithium was increased from 800 to 1000 m~day. Because the half-life of levomepromazine is about 15-30 hr (Dahl 1976), the relapse of RLS was considered to be due to the increase of lithium (200 rag), in accordance with the increase of serumfree MHPG. After the reduction of lithium (600 rag), RLS improved and serum-free MHPG decreased concurrently. There was a positive correlation between RLS ratings and serum-free MHPG (r = 0.86, p < 0.05). Serum MHPG is regarded to be largely derived from the central nervous system in humans (Takahashi et al 1977). Grundstein et al (1986) also demonstrated a significant relationship between serum MHPG and hypothalamic noradrenergic neural activity in the rat. Lithium action has been widely studied in relation to the noradrenergic functions in the central nervous system. These studies showed that the catecholamine content in the brain was unchanged (Corrodi et al i969; Ho et al 1970) or increased (Casado et al 1989)
RLS Inducedby Lithium
BR~L PSVOV,A~V
|991130"A167-i |7~
1169
by lithium treatment. The synthesis of dopamine was decreased (Friedmaa and 1973), but the activity of tyrosine hydroxylase was increased (Segal et al 1975) by fi~um. However, our data (Terao et al 1991) supported the enhancing effect of lithium on t ~ noradrenergic functions. Therefore, it seems possible that lithium exacerbated RLS, at ,,east in part, via the noradrenergic system. Further studies, including other noradrenergic metabolites, semtonergic metabolites, second messengers, and polygraphic sleep sradies are ~ to investigate lithium-induced RLS. The authors thank Special Reference Laboratory, Tokyo, Japan, for measuring senun free MHPG.
References Akpinar S (1982): Treatment of restless legs syndrome with ievodopa plus benserazide. Arch Neurol 39:739. B._rode~rC, Mon~laisi_r _], Godbout R, Marinier R (1988): Treatment of restless legs syndrome and periodic movements during sleep with t.-dopa: A double-blind, controlled study. Neurology 38:1845-1848. Casado M, Arag6n MC, Gim6nez C (1989): Determination of nmnoamines in rat brain r e g i ~ after chronic administration of lithium. Neurochem Res 14:905-908. Cormdi H, Fuxe K, Schou M (1969): Tl:¢ effect of prolonged lithium administration on cerebral monoamine neurons in the rat. Life Sci 8:643-651. Dahl SG (1976): Pharmacokinetics of methotrimeprazine after single and multiple doses. Clin Pharmacol Ther 19:435-442. de Montigny C, Cournoyer G, Morissete R, LangloJs R, CaiI16G (1983): Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression: Correlations with the neurobiotogic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system. Arch Gen Psychiatry 40:1327-1334. Ekbom KA (1960): Restless legs syndrome. Neurology 10:868-873. Friedman E, Gershon S (1973): Effect of lithium on brain dopamine. Nature 243:520-521. Grundstein HS, Gleeson RM, Smythe GA (1986): Relationship between hypothalamic nomd~nergic neuronal activity and serum 3-methoxy-4-hydroxyphenylethylene glycol in the rat. L(fe Sci 39:207-213. Halbreich U, Castaneda R, Galanter M, Mandola R, Sharpless N (1990): Plasma MHPG and age in detoxified alcoholics Biol Psychiatry 27:026-630. Heninger GR, Chamey DS, Sternberg DE (1983): Lithium carbonate augmentation of antidepressant treatment. Arch Gen Psychiatry 40:1335-1342. Ho AKS, Loh HH, Craves F, Hitzemann P,J, Gershon S (1970): The effect of proIoaged lithium treatment on the synthesis rate and turnover of monoamines in brain regions of rats. Eur J Pharmacol 10:72-78. Markianos E, Beckmann H (1976): Diurnal changes in dopamine-13-hydroxylase, homovanillic acid and 3-methoxy-4-hydroxyphenylglycol in serum of man. J Neural Transm 39:79-93. Paik IH, Lee C, Choi BM, Chae YL, Kim CE (1989): Miansedn-induced restless legs syndrome. Br J Psychiatry 155:415-417. Rasmussen S (1984): Lithinm and tryptophan augmentation in clomipramine-resistant obsessive compulsive disorder. Am J Psychiatry 141 :1283-1285. Segal DS, Callaghan M, Mandell AJ (1975): Alterations in behaviour and catecholamine biosynthesis induced by lithium. Nature 254:58-59. Ta.k~_hashi S~ Godse DD~ Warsh JJ, Stancer HC (1977): A gas chromatographic-mass spectrometric
1170
BIOL PSYCHIATRY 1991;30:1!67 1170
T. Terao et al
(GC-MS) assa3, for 3-methoxy-4-hydroxyphenethyleneglycol and vanilraandelic acid in human serum. Ciin C?,im Acta 81:182-192. Terao T, Yoshimura R, Abe K (1990): Lithium cafoonate potentiation of tetracyclic antidepressants. Biol Psychiatry 28:1075-1077. Terao T, Yanagihara N, Abe K, lzumi F (1991): Lithium ~ n t and catecholamine synthesis ~.nd secretion. Jpn J Pharmacol 55 (suppl I):204P. Waiters AS, Hening W (1987): Clinical presentation and ncurophatmacology of restless legs syndrome. Clin Neuropha~col 10:225-237.
