Lithium

Mogens Schou

3 I n t e r a c t i o n s o f lithium (SEDA-2, 24; SEDA-3, 23; SEDA-4, 24; SEDA-5, 24; SEDA-6, 29) Although dealt with in previous reviews the question o f lithium interactions has been the subject o f so much interest that a Special Review may be in order, covering both newer and some older material. An excellent recent review on lithium interactions with other drugs provided 221 references (1R}. The present review aims at general lines rather than at completeness o f detail; it deals with observations in humans and only occasionally refers to animal work; it puts little weight on single case reports; and it considers interaction with pathophysiological situations in addition to interactions with drugs and electric convulsive treatment. Lithium interactions o f clinical significance involve primarily the kidneys and the central nervous system. The latter has attracted more interest than the former, presumably because psychiatrists often prescribe lithium and neuroleptics together, but it is the interaction with renal elimination which merits the main interest, because occasionally it has led to severe lithium poisoning and in some cases to death.

Lithium clearance: the excretion fraction o f lithium (lithium clearance divided by creatinine clearance} remains about 0.20. However, under certain circumstances this fraction may rise, namely when fractional proximal reabsorption o f sodium and water, and hence o f lithium, is increased. This is seen in situations with threatening or manifest negative sodium and/or water balance. Under these circumstances fractional proximal reabsorption increases with a consequent fall o f the lithium clearance. I f the lithium dosage is not lowered proportionally, the serum lithium level rises and may reach a level that in itself affects renal function. A vicious circle may develop which leads to lithium poisoning. Lithium poisoning has occasionally been due to acute intake o f an overdose, but in many cases the poisoning can be traced to situations and conditions associated with negative sodium and/or fluid balance. This has been seen as a result o f administration o f a diet low in salt, start o f a slimming regimen, heavy sweating, intercurrent disease with fever, etc., and such situations should be o f major concern during lithium treatment.

Diuretics This same mechanism is at work Interactions involving the kidneys Lithium is eliminated almost exclusive!y through the kidneys. Experimental work with animals {2R) has shown that lithium is filtered freely through the glomerular membrane and reabsorbed in the proximal tubules together with, and to the same extent as, sodium and water: about 80% o f the filtered load. The remaining 20% pass into the distal parts o f the nephron, but little or no lithium is reabsorbed here, so that the lithium clearance is approximately 20% o f the glomerular filtration rate. Lithium accordingly does not share with sodium the finely regulated reabsorption which takes place in Henle's loop and the distal tubules, and lithium clearance is therefore under most circumstances a constant fraction o f the creatinine

when lithium poisoning occurs as the result o f concomitant administration o f lithium and diuretic drugs: a negative sodium balance leads to increased proximal reabsorption and consequent lowering o f the lithium clea rance (3 C - 7C). The fact may be relevant that diuretic drugs are often prescribed by physicians (general practitioners, internists} other than those who have prescribed the lithium treatment, and the former may not be aware o f the risk involved in such combined medication. Thiazide diuretics have frequently been proposed for the treatment o f lithium-induced polyuria, and there is hardly any doubt that they are effective; but the treatment requires careful monitoring because o f the risk o f adverse in teraction.

Lithium

Antibiotics Three reports on single cases deal with hypernatremia during combined administration o f lithium and ticarcillin (8 C) and with lithium accumulation during combined treatment with tetracycline (9 C) or spectinomycin (10c). The possibility cannot be excluded that the infection played a role through interference with fluid and electrolyte balance, but since some antibiotics exert a nephrotoxic action, their use during lithium treatment may require extra watchfulness. Nonsteroidal anti-inflammatory agents Interaction between lithium and nonsteroidal anti-inflammatory drugs has been reported sufficiently often to appear fully established. Drugs involved have been phenylbutazone, indomethacin, ketoprofen, oxyphenbutazone, diclofenac, and possibly ibuprofen (11C-15c). The interaction is clearly at the renal level: the renal lithium clearance falls and the serum lithium concentration rise~. An action via inhibition o f prostaglandin synthesis seems possible, and the underlying mechanism may involve reduced renal blood flow leading to lowered glomerular filtration and lowered lithium clearance. Reduced tubular reabsorption secondary to sodium loss is evidenced through animal studies (14, 16). Anesthesia Patients in long-term lithium treatment may be subjected to anesthesia as part o f electric convulsive treatment or because o f surgery. There is no clinical evidence o f interaction between lithium and the anesthetic agents themselves, but a number o f reports show that lithium may prolong the action o f both depolarizing and non-depolarizing muscle relaxants, in some cases with prolongation o f apnea (17C-24C). Anesthesiologists and surgeons should be aware o f the risk o f lithium accumulation when fluid and electrolyte balance is or becomes deranged, and it may as a general rule be wise to discontinue lithium a f e w days before major surgery (21 c, 22R). The duration o f the lithium pause must be determined individually; some patients tend to suffer manic or depressive relapse within a week after discontinuation o f lithium. Even when lithium is discontinued preoperatively, lithium-treated patients may be at extra risk during anesthesia and surgery. Many patients suffer from lithiuminduced polyuria, and since the lithium-

27

induced impairment o f renal concentrating ability reverts only slowly to normal after discontinuation o f lithium (23c), the patients may be at risk o f developing dehydration rapidly if fluid intake is restricted or extra fluid lost (139c). Parenteral fluid administration may be required preoperatively or for unconscious patients. Lithium induces loss o f both sodium, potassium and water. Usually more fluid is lost than electrolytes, and administration o f an aqueous glucose solution or o f hypotonic sodium chloride may be advantageous. In polyuric patients undergoing surgery the fluid and electrolyte balance should be monitored with particular care. One patient with moderate lithiuminduced polyuria developed episodes o f more pronounced diabetes insipidus when subjected to neuroleptanesthesia with droperidol (24c), but the authors point out that this must be a rare interaction, since many lithium-treated patients have been operated under neuroleptanesthesia with no complications.

Interactions involving the central nervous system The lithium ion enters all parts o f the central nervous system; its therapeutic and prophylactic actions in manic-depressive illness are exerted, one must assume, through regulation o f brain processes; and s y m p t o m s from the central nervous system are prominent in lithium poisoning. It is therefore not surprising that interaction with other centrally acting drugs may lead to effects involving the brain. It is indeed surprisingto what extent patients in lithium treatment can be given other psychotropic drugs without the occurrence o f interaction. In some hospitals it seems the rule rather than the exception to administer neuroleptics or antidepressants together with lithium, and only occasionally does this lead to adverse interactions. Neurolepties Few interaction reports have led to so much comment as one published in 1974 (25 c) about four patients who on combined treatment with lithium and haloperidol developed severe symptoms involving the neuromuscular system, with impairment o f consciousness, hyperthermia, and permanent neurological sequelae. Commentators have later pointed out that drug doses were unusually high, that clinical management o f the patients was poor, and that far from being representative, these four cases must

28

be considered very special ( 2 6 R - 2 8 R ). There have been further reports about interaction o f lithium and neuroleptics, in particular haloperidol, with the appearance o f neuromuscular symptoms ( 2 0 C - 4 5 C) but examination o f large groups o f patients given lithium and haloperidol concurrently show that adverse interaction is rare as long as dosages are not excessive and that the combination is clinically valuable, for example for the treatment o f acute mania and schizoaffective illness (46c-50C). A legal expert assesses the situation in the following way: 'The use o f haloperldol-lithium combination without a realization o f the state o f controversy would be indefensible. Knowledgeable use o f such a treatment mode, in consideration o f a particular patient, would be defensible and entirely justified when the requirements o f professional judgement and proper administration are met" (51R). A recent report about lithium-haloperidol incompatibility with subsequent discussion illustrates the complexity o f the interaction problem and the difficulty o f drawing definitive conclusions about individual cases (52 c - 5 5 c ) . Interest in lithium-haloperidol interactions was revived recently by the publication o f a report entitled 'Lithium/haloperidol combinations and brain damage' {56c). Seven patients treated with lithium and haloperidol and seven patients given lithium and chlorpromazine were subjected to a shortened version o f the Wechsler Adult Intelligence Scale; the former group showed significantly lower verbal-performance discrepancy than the latter. It was this difference, described in the text as 'indicative o f organic cerebral conditions" which formed the basis o f the alarming term 'brain damage' in the title. One feels that editorial alertness might have averted this. The report has been criticized for leaving out important information, for example about drug doses (5 7c - 5 9 c ) . Animal data (60) and data from human volunteers (61] and patients {62 C} reveal that plasma chlorpromazine levels may be lower during concomitant lithium administration than when chlorpromazine is given alone. The clinical significance o f this is not known. Animal experiments have given no support for the notion that concomitant administration o f haloperidol may interfere with the absorption, distribution, or excretion o f lithium (63).

M. Schou Findings concerning the effect o f combination treatment on the EEG are conflicting, with one report (64 C) describing significant augmentation o f focal abnormalities o f the left brain area and epileptic potentials, while in another report (65 C) combination o f lithium and haloperidol produced no more EEG abnormalities than either drug given alone or than no drug at all. This may be a question o f dosages used, but precise 'titrations' are not easy in clinical work. Antidepressants Depressive relapses during lithium treatment are usually treated with ECT or with concurrent administration o f antidepressants. The latter combination may in some patients aggravate tremor and motor incoordination (personal observation) or produce extrapyramidal symptoms (66 C, 67 C) and has occasionally induced seizures (68 C) but in general the two drugs show no adverse interaction, and they may in fact potentiate each other therapeutically (69 c, 70c). The antidepressants are usually discontinued some months after disappearance o f the depression. However, in some cases lithium and antidepressants are given jointly for years, and there is evidence that this long-term combination is disadvantageous. Some patients may develop frequent relapses and become so-called 'rapid cyclers" {71 c 73C). It is not clear whether this is an interaction phenomenon with mutual lowering o f prophylactic efficacy, or whether precipitation o f manias and, perhaps secondarily, depressions would have been seen also if the antidepressants had been given alone. Mania precipitation by antidepressants is a well known phenomenon in bipolar patients. In one study (74 c ) patients who switched into mania during combined treatment with lithium and antidepressants had lower serum lithium levels than patients who did not experience such a switch; this indicates that in the latter but not in the former group the lithium dosage was large enough to protect against precipitation o f manias by the antidepressant drugs, i.e. antagonism rather than synergism. Electric convulsive treatment ECT does not seem to affect renal lithium clearance or serum lithium levels (75C), and lithium treatment has not been shown to alter the seizure threshold. A number o f reports show that the administration o f E C T to patients in lithium treatment may occasionally lead

Lithium to confusion, disorientation, restlessness, aggravated memory impairment, and EEG seizure activity or overt seizures (76 R, 77 C 82C). There is also the risk mentioned above, that the effect o f the muscle relaxant agent may be prolonged. It seems therefore good general practice to discontinue lithium a f e w days before start o f ECT and not to give it again until 1 - 2 clays after the last treatment. However, there may be patients who tend to relapse so rapidly after discontinuation o f lithium that lithium must be continued during ECT or the lithium pause kept very short.

Miscellaneous interactions Carbamazepine In

an epileptic patient lithium-induced polyuria disappeared when carbamazepine was substituted f o r phenytoin ~83c). This could be due to carbamazepine's antidiuretic property [84C). In another study (85 C) the combination o f lithium and carbamazepine produced ataxia, dizziness, and feelings o f unreality, which disappeared when carbamazepine was stopped.

Diazepam In a single case profound hypothermia occurred on at least three occasions o f combined treatment with lithium and diazepam but not with either drug given alone, possibly an idiosyncratic reaction

(86cj.

Centrally acting drugs Animal studies have indicated interaction between lithium and such centrally acting drugs as morphine, codeine, dextropropoxyphene, amphetamine and methylphenidate, but clinically significant interactions have not been reported. In one patient administration o f the anorectic agent mazindol appeared to precipitate moderate lithium poisoning {87c), but it is unclear what role was played by lowered food (and sodiumJ intake and excessive sweating produced by the anorexiant.

Antihypertensive drugs Problems

involved in antihypertensive treatment o f patients given lithium have been pointed out by Schwarcz (88c), who suggests that a betablocker should be tried first; if this is inadequate, diuretic drugs could be used, possibly in combination with beta-blockers, but monitoring should be careful.

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Pharmaceutical incompatibility A

lithium citrate syrup did not mix well with various solutions o f neuroleptic drugs (89). GENERAL Patients on long-term lithium treatment have been found to experience more side effects in the first m o n t h than in the fourth and sixth months (90c); this confirms older reports of frequent initial side effects (91c). Elderly patients had a significantly greater incidence of moderate to severe side effects than younger patients (92c); neurotoxic effects were particularly frequent. This may be due to more frequent concurrent therapy with other drugs as well as to lower lithium clearance and higher CNS sensitivity.

EFFECTS ON ORGANS AND SYSTEMS

Cardiovascular system (SED 9, 44; SEDA-5, 22; SEDA-6, 28) A case of severe sinus node dysfunction during lithium poisoning (107 C) and a case of bradyarrhythmia during combined treatment with lithium and haloperidol (108 C) point to lithium effects on the heart under special circumstances, but four reviews (109R--112 R) agree that adverse cardiac reactions to lithium are infrequent and that heart disease is no contraindication to psychiatrically necessary and well monitored lithium treatment. This is illustrated by a successful coronary bypass operation in a patient on lithium (113 c ) and by uneventful convalescence after myocardial infarction during lithium treatment (114c). Practical suggestions about patient management include cardiac review prior to lithium, a pretreatment ECG in patients over 40 years, consultation of a specialist in case of concern and pulse monitoring at control visits, as well as, obviously, cardiovascular monitoring during lithium poisoning and caution with lithium-diuretic combinations (1 IoR).

Neuromuscular system (SED 9, 4 4 - 4 5 ; SEDA-4, 23; SEDA-5, 22; SEDA-6, 27) Toxic reactions involving the central nervous system, with confusion as the main symptom, are occasionally seen in patients

M. Schou

30 with a serum lithium concentration at the usual therapeutic and prophylactic level, and it has been suggested that lithium neurotoxicity is more common in patients suffering from schizophrenia or schizoaffective psychosis than in those with purely affective illness (94 c, 95c). This has, however, not been a consistent finding. Many schizophrenic and schizoaffective patients do not show toxic confusion during lithium treatment, while occasionally manic-depressive patients do. In a recent analysis of the literature (96 c ) West reaches the conclusion that schizophrenic and schizoaffective patients are not in general at increased risk of lithium neurotoxicity, but that they may be so when they are acutely ill due to a recent exacerbation of the disease. Other authors agree that lithium neurotoxicity is n o t related to diagnostic category (97c). Single cases have been reported of chorea (98c), parkinsonism (99c), and aggravation o f petit mal epilepsy during lithium treatment (100c). On rare occasions lithium treatment leads to the appearance of extrapyramidal symptoms, possibly in particularly susceptible patients. In two patients the lithium-induced parkinsonism was made worse by the antiparkinsonian drug orphenadrine ( 101 c). Mind Psychological problems during lithium treatment may be effects rather than side effects, for example the missing of hypomanic feelings of being 'high', creative, and attractive, or the patients may resent having their mind controlled by a drug (102c). Three psychological test studies published within the last year have used different experimental designs. In one study (103 c ) seven lithium-treated patients were compared with six matched manic-depressive patients not given lithium. No significant differences were found in either 'unrelated' or 'categorized' free recall, but generalization of results is limited by the smallness of the numbers. In a second study (104 c ) 21 lithium-treated manic-depressive patients were compared with 21 matched outpatients with relatively minor psychiatric difficulties and not given drugs. Intellectual efficiency was examined with a battery of tests after one year, two years and three years. The manic-depressive patients presented lower

scores than the control group, but the design prevented distinction between the effects of manic-depressive illness and the effects of lithium. Intellectual impairment did not worsen with time on lithium. In a third study (105 C) 18 manic-depressive patients were given psychometric tests before and 16 days after a switch from lithium to placebo. Memory tests showed better performance during placebo than during lithium, the most significant improvement after discontinuation of lithium being in visual retention. This is interesting, since some lithium-treated patients complain of having difficulty reading a book, because they cannot remember from one page to the next. The outcome of this study indicates that memory impairment produced by lithium is reversible. When one considers the effect of lithium on mood, it may be particularly difficult to differentiate a side effect from a desired effect. A mood rating scale was applied to 124 bipolar manic-depressive patients on chronic lithium treatment at a time when they were neither manic nor depressive, and the scores were compared with mood ratings of 36 non-patient control subjects (106c). Mean mood ratings were the same in the two groups, but mood variability was lower in the lithium-treated patients, i.e. mood was on the average more stable. This finding may be seen in relation to occasional patient complaints of feeling emotionally 'curbed' during lithium treatment. It is not clear whether there is any connection with the prophylactic action of lithium against manic and depressive relapses. Endocrine and metabolic Lithium treatment has occasionally been suspected of producing diabetes mellitus (SEDA-6, 29) but the association seems to be with affective disorder rather than with lithium (93c). Thyroid A few more cases of lithiuminduced hyperthyroidism have been reported (143 c, 144c), but hypothyroidism remains the most frequent adverse reaction. Among 73 lithium-treated manic-depressive patients, goiter was found in 37%, exophthalmus in 23%, positive thyroid autoantibodies in 24%, and abnormal TRH tests in 49% (145c). Such data should be seen in relation to the observation that some degree of hypo-

Lithium thyroidism could be found in 20 of 250 patients consecutively referred to a psychiatric hospital for depression and anergia and not having been given lithium (146c). Disappearance of lithium-induced goiter within 15 days after discontinuation of lithium has been reported (147 c). It has been suggested (148 c ) that lithium may produce lowering of thyroid function preferentially in patients with a low 'thyroid reserve' as revealed by elevated thyroid antibodies, a known history of thyroiditis, thyroid disease in the family, or prior treatment of the thyroid with radioiodine or surgery. It has also been proposed (149 c ) that a high iodine intake predisposes to lithium-induced hypothyroidism.

Parathyroid Five cases o f h y p e r p a r a t h y r o i d ism with hypercalcemia and elevated plasma levels of parathyroid hormone occurred during lithium treatment ( 150 C - 154 C). The appearance of these five reports within two years does not exclude coincidence but argues against it. In two cases (150 C, 151 C) a parathyroid adenoma could be demonstrated. One group (154 c ) plotted plasma parathyroid hormone (PTH) against serum calcium and found evidence that the parathyroid glands still retained their responsiveness but that it t o o k a higher serum calcium concentration to inhibit PTH secretion, a phenomenon known as a reset of the 'setpoint' or 'calciostat'. In this patient discontinuation of lithium led to prompt normalization of serum calcium. In a study of 10 unselected patients examined at intervals during three months of lithium treatment parathyroid hormone increased more than 40% within the first week and remained elevated throughout the treatment period; calcium excretion in the urine fell by more than 30% within the first week and remained low (155c). These patients showed no change in serum calcium. Although lithium treatment clearly affects the parathyroid glands and the metabolism of calcium, it is not known why some patients develop hypercalcemia (and parathyroid adenoma?) during lithium treatment while others do not.

Hematological A previous review (SEDA-5, 22) referred to five cases of leukemia developing during lithium treatment but quoted also the

31 conclusion of Longo (I 15 R) that 'the weight of evidence argues against lithium as a cause of leukemia'. One further case has been published (116c). A search of the Iowa registers on 710 manic-depressive patients and 571 patients with leukemia did n o t show a single case with both diseases ( 117 C ). There have been case reports of pure red blood cell aplasia (118 C ), leukopenia (119 c ) and megaloblastic anemia possibly due to folic acid deficiency (120c), all occurring during, but not necessarily caused by, lithium treatment. Use of a case control approach has been suggested for elucidating the possible connection between lithium treatment and development of leukemia (121). The occurrence of leukocytosis during lithium treatment has been confirmed in further studies (122 c , 123c).

Gastrointestinal A 17-year-old boy developed gastric ulcer after three months o f lithium treatment for a manic-depressive illness; after discontinuation of lithium the gastric complaints ceased immediately (156 c).

Urinary system (SED 9, 46; SEDA-4, 22; SEDA-5, 23; SEDA-6, 28) The Australian psychiatrist-pathologist group (124 c , 125 C) have now extended their study on kidney morphology to 47 lithium-treated patients. They distinguish between (a) chronic in terstitial nephropathy, which is found in patients about to start lithium treatment as well as in lithium-treated patients, and which is non-specific; (b) dilated distal convoluted tubules, dilated collecting ducts, and microcysts, possibly resulting from obstruction of tubules by casts; and (c) a tubular lesion with swelling and vacuolization of the cytoplasm, which is specific for lithium and which develops acutely (seen as little as 1 - 6 days after the start of lithium treatment). The appearance of such histological changes does not necessarily indicate discontinuation o f lithium treatment. Kidney biopsies of nine lithium-treated patients (126 C) and 13 lithium-treated patients (127 c ) confirm previous reports of changed morphology in some susceptible patients. Lithium effects on kidney function have been the subject of further reports (128 C -

M. Schou

32 133 C) and a number of reviews (134 R 138R). Their outcome is largely in agreement with conclusions of previous reviews in this series. Lithium treatment, even when given for many years, is unlikely to produce serious glomerular dysfunction. Lowering o f renal concentrating ability is fairly common but occurs with varying frequency in different clinic.s. Polyuric patients are at risk of dehydration and lithium poisoning if they do not drink amply. Patients with lithiuminduced polyuria may require parenteral fluid administration if they are unconscious, if they vomit massively, or if they are deprived of oral fluid intake preoperatively (139c). Hydrochlorothiazide treatment may reduce lithium-induced polyuria (140c), but the usual caution about lithium/diuretic combinations should be kept in mind. A mild distal acidification defect seems to develop more rapidly than the concentrating defect (141 c ) but is hardly of clinical significance. Proposals for laboratory monitoring of renal function in lithium-treated patients have included determinations of glomerular filtration rate and concentrating ability at yearly or half-yearly intervals, possibly on occasion kidney biopsy. However, such elaborate procedures are hardly mandatory for routine purposes; minimum requirements for adequate laboratory monitoring may include serum lithium and serum creatinine every 2 - 4 months and serum TSH every six months (142R).

Skin, hair, and nails Suppurative hidradenitis (157 c ) , acneiform eruptions (158 C), inflammatory verrucous hyperplasia of the skin (159c), and acute skin rash appearing within few hours of lithium administration (160 c ) have been seen in individual patients. Usually the skin complaints disappeared after lithium was stopped; in some cases they reappeared when lithium was started again. Diffuse hair loss from the scalp stopped spontaneously within two months in spite of continued lithium treatment (161c). A patient given

lithium declared, 'Not only do I feel better, but my toe nails are growing better as well!' (162c).

Second generation effects (SED 9, 47; SEDA-5, 24; SEDA-6, 29) Genetics Chromosome

studies on blood samples from 23 patients receiving lithium and 19 healthy control subjects did not reveal any differences ( 163 c ).

Pregnancy Tricuspid valve regurgitation in a child born to a mother given lithium during pregnancy (164 C) adds to previous retrospective reports indicating possible teratogenic effects of lithium: malformations in 25 of 217 'lithium babies', 18 of the 25 cases showing cardiovascular malformations (165c). Sperm Treatment for three weeks of physically healthy males with desipramine or lithium led to no significant change in sperm count or motility but with b o t h drugs to a significant reduction in sperm viability (166c). A series of other centrally acting agents were potent inhibitors of sperm motility. The authors write: 'The changes in sperm parameters we found should not be expected to alter the fertilization potential of the subjects, although none of our patients fathered a child during the study'.

Poisoning Lithium intoxication may be caused or precipitated by intercurrent disease (or other situations with negative salt or fluid balance), by intake of overdose with suicidal intent, or through a laboratory mistake ( 167 c - 170 c). Poisoning has also been seen during lithium treatment of thyrotoxicosis (171 c). Permanent neurological sequelae after lithium poisoning may include dysarthria and ataxia (171 C, 172c), but one patient emerged symptom-free from poisoning with a serum lithium concentration as high as 9.6 mmol/1 (169c). A b o y of six survived symptom-free from poisoning with serum lithium levels higher than 5 mmol[1 (173c).

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med. Ass., 241, 1134. 5. Jefferson, J.W. (1980): Diuretics are dangerous with lithium. Brit. med. J., 281, 1217. 6. Jefferson, J.W. and Greist, J.H. (1981): Some hazards of lithium use. Amer. J. Psychiat., 138, 93. 7. Solomon, K. (1978): Combined use of lithium and diuretics. Sth. reed. J., 71, 1098. 8. Finch, R.A. (1981): Hypernatremia during lithium and ticarcillin therapy. Sth. med. J., 74, 376. 9. McGennis, A.J. (1978): Lithium carbonate and tetracycline interaction. Brit. med. J., 2, 1183. 10. Conroy, R.W. (1978): Possible adverse drugdrug interaction report: Lithium intoxication in a spectinomycin-treated patient, lnt. Drug Ther. Newsletter, 13, 15. 11. Fr61ich, J.C., Leftwich, R., Ragheb, M. et al. (1979): Indomethacin increases plasma lithium. Brit. reed. J., 2, 1115. 12. Ragheb, M., Ban, T.A., Buchanan, D. and Fr6lich, J.C. (1980): Interaction of indomethacin and ibuprofen with lithium in manic patients under a steady-state lithium level. J. clin. Psy-

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33 Lithium treatment and kidney function: A follow-up study of 237 patients in long-term treatment. Acta psychiat, scand., 63, 333. 24. Serup, J. and Brun, C. (1981): Lithiumdroperidol interaction and risk of diabetes insipidus after neuroleptanaesthesia. Acta anaestesiol, scand., 25, 70. 25. Cohen, W.J. and Cohen, N.H. (1974): Lithium carbonate, haloperidol, and irreversible brain damage. J. Amer. reed. Ass., 230, 1283. 26. Ayd, F.J. (1980): Lithium-haloperidol for mania: Is it safe or hazardous? In: Haloperidol Update: 1958-1980, pp. 8 3 - 9 2 . Editor: F.J. Ayd. Ayd Med. Commun., Baltimore. 27. Jefferson, J.W. and Greist, J.H. (1980): Haloperidol and lithium: Their combined use and the issue of their compatibility. In: Haloperidol Update: 1958-1980, pp. 7 3 - 8 2 . Editor: F.J. Ayd. Ayd Med. Commun., Baltimore. 28. Tupin, J.P. and Schuller, A.B. (1978): Lithium and haloperidol incompatibility reviewed. Psychiat. J. Univ. Ottawa, 3, 245. 29. Alevizos, B. (1979): Toxic reactions to lithium and neuroleptics. Brit. J. Psychiat., 135, 482. 30. Bond, W.S., Carvalho, M. and Foulks, E.F. (1982): Persistent dysarthria with apraxia associated with a combination of lithium carbonate and haloperidol. J. clin. Psychiat., 43, 256. 31. Boudouresques, G., Poncet, M., Ali Cherff, A., Tafani, B. and Boudouresques, J. (1980): Enc6phalopathie aigu~, au cours d'un traitement associant phenothiazine et lithium: Une nouvelle observation avec lith6mie basse. Nouv. Presse mdd., 9, 2580. 32. Coffey, C.E. and Ross, D.R. (1980): Treatment of lithium/neuroleptic neutoroxicity during lithium maintenance. Amer. J. Psychiat., 137, 736. 33. Destee, A., Lehembre, P., Petit, H. and Warot, P. (1978): Enc~phalopathie toxique par l'association lithium-haloperidol. Lille Mdd., 23, 88. 34. Fetzer, J., Kader, G. and Danahy, S. (1981): Lithium encephalopathy: A clinical, psychiatric, and EEG evaluation. Amer. J. Psychiat., 138, 1622. 35. Kamlana, S.H., Kerry, R.J. and Khan, I.A. (1980): Lithium: Some drug interactions. Practitioner, 224, 1291. 36. Loudon, J.B. and Waring, H. (1976): Toxic reactions to lithium and haloperidol. Lancet, II, 1088. 37. Marhold, J., Zimanov~, J., Lachman, M., Kr~il, J. and Vojtechovsk~', M. (1974): To the incompatibility of haloperidol with lithium salts. Activ. nerv. sup. {Praha), 16, 199. 38. Prakash, R., Kelwala, S. and Ban, T.A. (1982): Neurotoxicity in patients with schizophrenia during lithium therapy. Comprehens. Psychiat., 23, 271. 39. Piihringer, W., Kocher, R. and Gastpar, M. (1979): Zur Frage der Inkompatibilit~t einer Lithium-Neuroleptika-Kombinationstherapie.

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