- Email: [email protected]
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J.W. Jefferson
3 A review of the comparative efficacy and tolerability of drug treatments for bipolar disorder included tolerability comparisons of lithium versus carbamazepine, lithium versus valproate semisodium, and lithium versus other medications (1R). When 60 patients (22 men, 38 women) who had taken lithium for 1 year or more (mean 6.9 years; mean serum concentration 0.74 mmol/1) were interviewed about adverse effects, 60% complained of polyuria-polydipsia syndrome (serum creatinine concentrations were normal) and 27% had hypothyroidism requiting treatment (2c). Weight gain was more common in women (47% vs. 18%) as were hypothyroidism (37% vs. 9%) and skin problems (16% vs. 9%), while tremor was more common in men (54% vs. 26%). Weight gain of over 5 kg in the first year of treatment was the only independent variable predictive of hypothyroidism. How knowledgeable 1 2 3 patients in a lithium clinic (mean treatment duration 12.1 years) were about lithium has been assessed with 63 questions based on the Lithium Knowledge Test. About two-thirds of the questions were answered correctly, and knowledge about lithium was not related to diagnosis, education, or sex. There was a negative association between increasing age and knowledge, and this was independent of the duration of lithium treatment (3c). Even in a specialized lithium clinic, it seems that patient education could be improved upon, with the hope of a positive outcome on the effectiveness and safety of treatment.
ORGANS AND SYSTEMS C a r d i o v a s c u l a r Investigators who used a Bayesian confidence propagation network to 9 2003 Elsevier Science B.V. All rights reserved.
Side Effects of Drugs, Annual 26 J.K. Aronson, ed.
Lithium mine the World Health Organization International Drug Monitory Database for information on antipsychotic drugs and heart muscle disorders found 17 case reports involving lithium (4R). There was a significant association with lithium and cardiomyopathy, but not with myocarditis. However, a causal relation could not be established. Two reviews of drug-related congenital malformation briefly mentioned lithium and cardiovascular teratogenesis, but no new information was provided (5 r, 6r). Likewise, two reviews of the cardiac effects of psychotropic drugs briefly mentioned lithium and dysrhythmias, with a focus on sinus node dysfunction (7 r, 8r). Case reports of adverse cardiovascular effects of lithium have included the following: 9 a 52-year-old man who took an overdose of lithium (serum concentration 4.58 mmol/1) and developed asymptomatic sinus bradycardia with sinus node dysfunction and multiple atrial extra beats, which resolved after hemodialysis (9A), 9 a 59-year-old woman with syncope and sick sinus syndrome, which remitted when lithium was withdrawn, recurred when lithium was restarted, and then persisted despite lithium withdrawal; after a pacemaker was implanted she was treated successfully with lithium for 7 years (10A); 9 a 66-year-old woman with pre-existing first-degree AV block who, about 2 weeks after beginning lithium therapy, developed sinus bradycardia, a junctional rhythm, a prolonged QT interval, and syncopal episodes (serum lithium concentration 1.4 mmol/1 in a 40-hour sample); she was treated successfully with a pacemaker and a lower dose of lithium (11A); 9 a 36-year-old man who became hypomanic "after lithium was withdrawn because of symptomatic first-degree atrioventricular block (although how first-degree block could have caused symptoms is unclear) (12A); 9 a 59-year-old man who was noted to have tachycardia, a shortened QT interval, and non-specific ST-T changes while hospitalized with lithium-associated hypercalcemia (13 A); 9 a 13-year-old boy in whom lithium induced a "pseudo-myocardial infarct pattern" on the electrocardiogram (this may have been an overinterpretation of non-specific T-wave changes) (14A); 19
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20 44-year-old woman with atropine-resistant but isoprenaline-sensitive bradycardia (36 bpm), thought to be due to sinus node dysfunction related to lithium, fentanyl, and propofol (t5A).
9 a
Respiratory A 60-year-old woman with bipolar disorder since the age of 29 developed idiopathic pulmonary fibrosis (cryptogenic fibrosing alveolitis) after having taken lithium for 9 years (16A). Whether lithium played a causal role is at best highly speculative. Nervous system (see also Drug overdose) A case-control study of delirium in 22 psychiattic in-patients showed that lithium was one of the risk factors (adjusted odds ratio of 2.23) (17c). Four of 17 patients who had paroxetine added to lithium as an adjunctive antidepressant developed symptoms suggestive of emerging serotonin syndrome (e.g. nausea, vomiting, diarrhea, sweating, anxiety, oversleeping) (see also Drug interactions) (18c). Although the English abstract of a Polish review concluded that there is no evidence of significant cognitive deficits caused by lithium (19r), others would take issue with this conclusion (20M). Case reports of adverse nervous system effects of lithium have included the following: 9 permanent cerebellar sequelae in a 36-year-old man after intoxication at therapeutic lithium concentrations (21A); 9 a prolonged seizure after ECT in a 45-year-old man taking lithium, amfebutamone, and venlafaxine (see also Drug interactions) (22A); 9 worse stuttering in a 48-year-old man while taking lithium with improvement when he was switched to valproate (23"); 9 severe essential tremor, which was at first mistaken for tardive dyskinesia in an 80-year-old woman taking lithium; it resolved almost completely when lithium was withdrawn (24A). Neuromuscular Lithium has been implicated in impaired athletic prowess in two cases (25A). 21-year-old man had muscular incoordination while fast bowling (cricket), which improved when he switched to valproate. 9 A 71-year-old woman was unable to serve properly at tennis until she stopped taking lithium.
9 A
Endocrine
Thyroid The prevalence of thy-
roperoxidase antibodies was higher in 226 bipolar patients (28%) than in population control
J. W. Jefferson
and psychiatric control groups (3-18%). While there was no association with lithium exposure, the presence of antibodies increased the risk of lithium-induced hypothyroidism (26c). When 22 men and 38 women who had taken lithium for at least a year (mean 6.9 years) for bipolar disorder were evaluated for adverse effects, hypothyroidism requiring thyroid supplementation was found in 16 (14 women and two men); nine had a goiter (2c). The area from which some of the patients came was known to have a high background incidence of thyroid dysfunction. In 1989, 150 patients at different stages of lithium therapy had thyroid function assessed and subsequently, 118 were reassessed at least once and 54 completed a 10-year follow-up (27c). The annual rates of new thyroid dysfunction were subclinical hypothyroidism 1.7%, goiter 2.1%, and autoimmunity 1.4%. While these figures were little different from those found in the general population, the authors acknowledged that lithium was a potential cause of thyroid dysfunction. Serum TSH concentrations were raised (to 10 mU/1 or more) in 13 of 61 children aged 5-17 years taking lithium and valproate for up to 20 weeks (28c). Of 42 bipolar patients who had taken lithium for 4-156 months, three had subclinical hypothyroidism, three had subclinical hyperthyroidism, and one was overtly hyperthyroid (29c). Goiter by ultrasonography was present in 38% and n~i'ld thyroid dysfunction was suggested in 48% because of an apparent increased conversion of free T4 to free T 3. There was no correlation between the duration of lithium therapy and thyroid abnormalities. A retrospective record review of 300 patients with Graves' disease and 100 with silent thyroiditis who had undergone thyroid scans showed that the likelihood of lithium exposure was 4.7 times higher in the latter, suggesting a link between lithium and thyrotoxicosis caused by silent thyroiditis (30c). Case reports of adverse thyroid effects of lithium have included the following: 9 56-year-old man taking lithium whose TSH concentration was abnormally high (50 mU/1) (31A); 9 a 44-year-old woman who had taken lithium for l0 years and who developed swelling of the fight lobe of the thyroid and hypothyroidism (15A);
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9 a 63-year-old woman taking long-term lithium who developed subclinical hypothyroidism and primary hyperparathyroidism (32A); 9 a 30-year-old man taking long-term ciclosporin and prednisolone following a bone-marrow transplant and long-term lithium for bipolar disorder who developed subacute thyroiditis, but without a clear relation to lithium (33A); 9 a 27-year-old man who developed thyrotoxicosis while taking lithium (34A).
Parathyroid Links between lithium and parathyroid dysfunction abound. Total serum calcium and intact parathyroid hormone concentrations were measured in 15 patients taking long-term lithium and 10 lithium-naive patients; both were significantly higher in the lithium group (35c). While the number of lithium patients with abnormally high concentrations was not stated, mean intact parathyroid hormone concentrations were almost twice the upper limit of the reference range (102 vs. 55 pg/ml). Parathyroid tumors from nine patients with lithium-associated hyperparathyroidism (six multiglandular, three uniglandular) have been compared with 13 non-lithium-associated sporadic parathyroid tumors with regard to gross genomic alterations (36c). Gross chromosomal alterations were absent in most of the lithium group and were more common in the sporadic group. A lithium chloride solution caused changes in gravicurvature, statocyte ultrastructure, and calcium balance in pea root, believed to be due to effects of lithium on the phosphoinositide second messenger system (37E). The implications with regard to human parathyroid function are obscure. Case reports of adverse parathyroid effects of lithium have included the following: 9 three cases of hyperparathyroidism among 26 cases of chronic lithium poisoning (see also Drug overdose) (38n); 9 a 78-year-old man who had taken lithium for 30 years who presented with dehydration, azotemia, hypernatremia, hypercalcemia, and increased parathyroid hormone concentrations (39A); 9 a 63-year-old woman taking long-term lithium therapy who had primary hyperparathyroidism (32A); 9 a woman who had taken lithium for 15 years who became hypercalcemic and stopped taking lithium, but 2 years later had two parathyroid adenomas removed surgically (40A);
21 9 a 42-year-old man who had taken lithium for 17 years and who had raised serum calcium and parathyroid hormone concentrations, which norrealized after removal of a parathyroid adenoma (41A); 9 a 59-year-old man with hypercalcemia and increased parathyroid hormone concentrations 3 months after starting lithium, which normalized after lithium was withdrawn (13A); 9 three cases of lithium-related hyperparathyroidism from Denmark (42A) and one from Spain (43A).
Diabetes insipidus Two of 10 patients taking long-term lithium therapy were thought to have hypothalamic diabetes insipidus, because of a positive response to desmopressin (44c). Metabolic It has been reported that diabetes mellitus is three times more common in bipolar patients than in the general population (45r). However, the authors of this review also pointed out that data are conflicting with regard to the effects of lithium on blood glucose concentrations. An increased lithium dosage requirement in a hyperglycemic 40-year-old woman was attributed to the osmotic diuretic effect of glycosuria, increasing lithium excretion (46A). In two cases of lithium intoxication, type 2 diabetes mellitus was felt to be a contributing factor (47A). Electrolyte balance Potassium A 25-yearold man had a single episode of generalized flaccid hypokalemic paralysis while taking lithium. He responded to intravenous potassium, lithium was stopped, and 1 year later there were no further episodes (48A). While the authors believed that lithium had been the cause, without confirmation by rechallenge this remains far from conclusive.
Sodium Hypernatremia can occur secondary to dehydration in patients taking lithium and is not uncommon in association with lithium poisoning. Lithium-induced diabetes insipidus is often a contributing factor (see also Urinary tract and Drug overdose). Hematologic The effects of lithium on hemopoiesis have been studied in 100 patients who had developed chronic granulocytopenia after cancer chemotherapy or radiotherapy (49c). The mean leukocyte count rose by 46%, but there were no changes in platelet or erythrocyte counts. However, there was a significant
22 increase in platelet count in those whose baseline values were below 150 x 109/1. Lithium was well tolerated (mean serum concentration 0.59 mmol/1). Granulocyte counts and granulocyte colonystimulating factor (G-CSF) concentrations were measured in 18 patients before and after 1 and 4 weeks of lithium treatment, and compared with values in 20 patients taking long-term lithium (50c). At week 4, the granulocyte count was significantly higher than at baseline or at week 1, or in the long-term group. There was only a non-significant increase in G-CSF concentration at weeks 1 and 4. The granulocyte count in those taking long-term lithium did not differ significantly from the baseline values in the other group. Mouth and teeth The issue has been raised of whether oral lithium therapy was responsible for failure of titanium dental implants in a 62-year-old man (51A). Pancreas All cases of drug-induced pancreatitis (n = 47) reported to the Danish Committee on Adverse Drug Reactions between 1968 and 1999 have been analysed; one involved lithium (plus a neuroleptic drug) (52c). Whether lithium was causally involved is not known. U r i n a r y t r a c t In a retrospective study, 114 patients who had taken lithium for 4-30 years were compared with 94 unmedicated age- and sex-matched controls with regard to changes in creatinine concentrations (53c). Of the patients taking lithium 21% had blood creatinine concentrations that had increased gradually and were now over the top of the reference range. This finding was associated with episodes of lithium intoxication and with diseases and other medications that could also affect glomerular function. Sex, psychiatric diagnosis, duration of treatment, cumulative dose, and serum lithium concentrations did not predict an abnormal creatinine concentration. Renal function has been assessed in 10 patients taking long-term lithium (over 3 years, mean 80 months), 10 taking short-term lithium (3 years or less, mean 16 months), and 10 lithium-naive patients (44r Serum BUN and creatinine concentrations were within the reference ranges and did not differ among the
Chapter 3
J. W. Jefferson
groups, but 24-hour creatinine clearance was significantly lower in those taking long-term lithium (73 vs. 125 and 150 ml/min). There were no significant differences among the groups in urine osmolality after 8-hour water deprivation and desmopressin, but partial nephrogenic diabetes insipidus was diagnosed in four long-term and two short-term patients and hypothalamic diabetes insipidus in two long-term patients. The authors concluded that long-term lithium therapy is a risk factor for renal impairment. There have been several case reports of lithium-related nephrogenic diabetes insipidus, sometimes associated with dehydration and lithium intoxication (39 A, 54A--57A). For example, a 77-year-old woman who had taken lithium for 10 years developed delirium, hypernatremia, prerenal azotemia, and a serum lithium concentration of 1.4 mmol/1; her condition was attributed to dehydration related to partial nephrogenic diabetes insipidus (54A). An 83-year-old man developed nephrotic syndrome while taking lithium (58A). Two studies in rats have potential implications for humans. In rats with mild to severe lithium-induced nephropathy, urine N-acetyl-bD-glucosamihidase (NAG) was an early indicator of renal insufficiency (59E). Both 6Li and 7Li caused reduced urine concentrating ability and increased urine volume and renal tubular lesions, but 6Li was more nephrotoxic (60E). The authors suggested that eliminating 6Li from pharmaceutical products might reduce nephrotoxicity (altl~bugh 6Li accounts for only about 7% of the lithium in such products). Skin Six months after beginning lithium, a man in his late twenties developed severe truncal ache, which worsened over 5 years, at which time lithium was withdrawn (61A). Nevertheless, the lesions were still present 4 years later, leading to the conclusion that lithium had caused irreversible acne. Of course, the association could have been coincidental. Skin and h a i r A 55-year-old man (erroneously reported by me in SEDA-25 to be a woman), who had taken lithium and haloperidol for 11 years, developed hyperkeratotic follicular papules on his scalp, extremities, and trunk, which on biopsy were suggestive of follicular mycoses fungoides (625). He also had a
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1-year history of scalp, axillary, and pubic hair loss. Following replacement of lithium with valproate, his hair regrew and the papules cleared almost completely in 3 months. Hair When a split hair sample from a healthy volunteer was sent to six commercial laboratories in the USA for trace mineral analysis, marked variations in results were found (including lithium concentrations), leading to the conclusion that such analyses were unreliable (63~). Sexual function A 17-year-old man had taken risperidone for 2 years without adverse effects, but 12 weeks after lithium was added he reported prolonged erections (lasting 1-3 hours) 2-5 times daily; risperidone was tapered and withdrawn and the problem resolved (64 A). Reproductive system In an in vitro study, LY294002, a phosphatidylinositol-3-kinase inhibitor, overcame impaired human sperm motility induced by lithium chloride (65E). At blood concentrations within the human target range, oral lithium caused degenerative changes in testicular morphology in spotted munia (Lonchura punctulata), a seasonally breeding sub-tropical finch (66E). How this might relate to effects in men is open to question. Immunologic Lithium has complex effects on immune function, as suggested by a study of 10 healthy volunteers who had increases in interleukin-4 and interleukin-lO concentrations, and falls in interleukin-2 and interferon concentrations (67c). The clinical implications of these findings are unclear. Death Evidence continues to accrue that long-term lithium therapy reduces suicidal behavior. A retrospective study divided high-risk patients into excellent, moderate, and poor responders to lithium and showed that no further suicide attempts occurred in 93%, 83%, and 49% respectively (68c). The substantial reduction in suicidal tendency in the poor responder group suggested an antisuicidal effect of lithium beyond its mood stabilizing properties, although the psychosocial benefits of lithium clinic treatment could have been contributing factors. For deaths related to lithium toxicity, see Drug overdose.
23
LONG-TERM EFFECTS Withdrawal Of 30 patients with major depressive disorder who had responded to lithium augmentation for antidepressant-resistant depression, 15 were switched to placebo over 1-7 days (69c). Two became manic, and it was suggested that lithium withdrawal may have uncovered latent bipolar disorder (70r). When 21 elderly patients with a major depressive episode who had responded to lithium augmentation had lithium withdrawn gradually (over 2-12 weeks), nine relapsed but none became manic (7 lC). Whether gradual withdrawal protected against withdrawal mania or whether there were no latent bipolar patients in the study is unknown.
SECOND-GENERATION EFFECTS Pregnancy and lactation The treatment of bipolar disorder during pregnancy and lactation has been reviewed, with reference to lithiumrelated maternal, fetal, and neonatal toxicity, morphological and behavioral teratogenicity, carcinogenicity and mutagenicity, and miscellaneous effects (72R). Elsewhere the effects of lithium, valproic acid, and carbamazepine during pregnancy (73R), and drug-induced congenital defects (with only a brief mention of lithium) (6 r) have been reviewed. A more specific review dealing with the use of drugs during pregnancy in women with renal disease mentioned the need for lithium dosage reduction in such cases (74r). A 37-year-old woman with severe bipolar disorder, who continued to take lithium throughout pregnancy, had a normal delivery but was not allowed to breast-feed (75A). In a review of the use of psychotropic drugs during breast-feeding it was briefly mentioned that lithium was not advisable but was justified under certain circumstances (76r). Lithium was also briefly discussed in a review of xenobiotics and breast-feeding (77r).
RISK FACTORS Age In a cross-sectional study of 12 octogenarians (average age 84 years) who had
24 taken lithium for an average of 54 months (mean serum concentration 0.42 mmol/l), none became toxic and none had to stop treatment because of adverse effects. Transient renal function abnormalities were noted, one patient developed nephrogenic diabetes insipidus, and one became hypothyroid (78c). For lithium therapy in very old people the authors advised close monitoring in a specialized setting.
DRUG ADMINISTRATION D r u g formulations Brain lithium concentrations (measured by magnetic resonance spectroscopy) after the use of a modified-release formulation (Lithobid SR) or an immediaterelease formulation have been compared in a crossover design (79c). There were higher brain concentrations with the modified-release formulation, but whether this has clinical implications requires further study. Formulations of lithium carbonate tablets with various binding substances have been discussed (80c). Drug additives Gelatin is derived from natural pork and beef products and is present in some lithium formulations. Since certain religions forbid the consumption of gelatin, knowing that it is present in Eskalith capsules and Eskalith CR and absent in Eskalith tablets (not available in the USA) and Lithobid SR might influence prescribing practices under certain circumstances (81r). The same would apply to other lithium products.
Drug dosage regimens In an open-label pilot study of rapid administration of slow-release lithium (20 mg/kg/day in two divided doses) for acute mania, five of 15 patients completed 10 days of treatment, seven improved sooner and were discharged, and two withdrew because of adverse effects (bradycardia in one and tremor, fatigue, and diarrhea in the other; one patient appears not to have been accounted for); two other patients also had asymptomatic bradycardia (82c). A review of loading strategies in acute mania included a section on lithium (83r). A small study of brain lithium concentrations measured by magnetic resonance spectroscopy showed higher brain:serum lithium
Chapter 3
J. W. Jefferson
concentration ratios in subjects taking a single dally dose (n = 5) than in those taking a twicedaily regimen (n = 3) (84c). Even to speculate about the possible clinical implications of this finding would be premature. D r u g a d m i n i s t r a t i o n route To determine the safety of using lithium chloride dilution to measure cardiac output, the pharmacokinetic and toxic effects of intravenous lithium chloride have been studied in six conscious healthy Standardbred horses (85E). The mean peak serum concentration was 0.56 mmol/1. There were no toxic effects nor significant changes in laboratories studies, electrocardiograms, or gastrointestinal motility. Three horses had increased urine output. A similar study was performed in patients undergoing cardiac surgery and healthy volunteers; the highest dose of LiC1 was 0.6 mmol given intravenously five times at 2-minute intervals (86c). Unfortunately, no mention was made of tolerability or adverse effects.
Drug overdose There are three forms of lithium overdose: 9 acute (abrupt overdose in a drug-naive person); 9 chronic (gradual accumulation, reaching toxic concentrations); 9 acute-on-chronic (abrupt overdose by a person already taking lithium), Overdose secondary to drug interactions is discussed in that section. The 2000 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System listed six lithium-related deaths (four cases of intentional suicide and two of therapeutic error) and two other deaths in which lithium was not listed as the primary cause (87R). A total of 4663 lithium-related exposures were reported, in which death was the outcome in 13 and a major life-threatening event or cause of significant disability in 267. A retrospective study of 97 cases of lithium poisoning treated at a regional center in Australia over 13 years found severe neurotoxicity in 28 (26 were cases of chronic poisoning and two were acute-on-chronic) (38c). Risk factors were nephrogenic diabetes insipidus, older age,
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abnormal thyroid function, and impaired renal function. In a retrospective study of 114 patients admitted to a toxicological ICU with suspected lithium intoxication, 81 had definite intoxication; 78% were deliberate overdoses and 22% were accidental (due, for example, to renal insufficiency, dehydration, drug interactions, poor compliance, drunkenness). Most were treated conservatively with gastric lavage and forced diuresis; hemodialysis was used only in 3-6%. Two of those who took a deliberate overdose and one of those who took an accidental overdose died (88c). Cases of lithium toxicity in a municipal hospital over a 10-year period involved eight women (mean age 66 years); neurological symptoms were the most common presentations (89c). Two were acute overdoses and the rest were chronic intoxications. There was one death (group not specified). A 64-year-old woman had a two-week history of daily bilateral holocranial headache as the presenting complaint of lithium toxicity (serum concentration 2.5 mmol/1); dosage reduction resolved the headache and the extrapyramidal and cerebellar findings (90A). Another toxic patient presented with nonconvulsive status epilepticus and a serum lithium concentration of 1.9 mmol/1 (91A). Non-reversible lithium neurotoxicity continues to be reported (92 A, 93A), including a case of lithium overdose (serum lithium concentration 3.9 mmol/1) with persistent severe ataxia for 9 months that improved markedly when inadvertently treated with high-dose buspirone (120-160 mg/day) (94A). Hemodialysis (56 A, 95 A, 96A), sometimes with additional continuous venovenous hemofiltration dialysis (97 A, 98A), continues to be described as a successful intervention for lithium poisoning. Peritoneal dialysis is a far less efficient way to clear lithium from the body. One patient treated in this way had permanent neurological abnormalities and another died; a third toxic patient who also had diabetic ketoacidosis died after treatment with hydration and insulin (99A). On the other hand, a 51-yearold woman who took fifty 450 mg slow-release lithium carbonate tablets had a serum lithium concentration of 10.6 mmol/1 13 hours later, but no evidence of neurotoxicity or nephrotoxicity. She was treated conservatively with intravenous
25 fluids and recovered fully (100 A). Acute lithium overdose is often tolerated better than chronic intoxication. An 85-year-old woman became gradually toxic (serum lithium 2.9 mmol/1) in a nursing home (101A). Despite only conservative management, there was slow but complete resolution of severe neurological symptoms, including coma, fixed pupils, and Cheyne-Stokes respiration.
DRUG INTERACTIONS In a review of the pharmacokinetics of mood stabilizers and new anticonvulsants, lithium drug interactions were only briefly mentioned (102r).
Anesthetics
Sinus bradycardia (36 bpm) developed in a 44-year-old woman taking lithium, fentanyl, and propofol (15 A) (see also Cardiovascular).
Antibiotics
A 40-year-old woman developed nausea, malaise, impaired concentration, trembling, unsteadiness, diarrhea, and muscle spasm in association with a serum lithium concentration of 2.1 mmol/1 while taking trimethoprim 300 mg/day (103A). The interaction was attributed to the amiloride-like diuretic effect of the latter, causing lithium retention.
Anticonvulsants
In a review of pharmacokinetic interactions between antiepileptic drugs and psychotropic drugs, there were no clinically significant interactions of lithium with gabapentin, lamotrigine, valproate, or topiramate, although serum lithium concentrations were reduced slightly by topiramate (104r). Lithium intoxication in a 33-year-old man was attributed to carbamazepine-induced renal insufficiency (105A).
Antidepressants Of 17 patients who took paroxetine as an adjunct to lithium therapy, retrospectively evaluated, four developed symptoms suggestive of an evolving serotonin syndrome that remitted when either drug was withdrawn (see also Nervous system) (l 8c). A 45-year-old man taking lithium, amfebutamone, and venlafaxine developed a prolonged
Chapter 3
26 seizure after ECT, thought to have been caused by a lowering of the seizure threshold due to amfebutamone (although a role of the other two drugs could not be excluded) (22A).
Antipsychotic drugs
A 59-year-old man taking lithium, haloperidol, and carbamazepine had impaired memory, impaired attention, and an encephalopathy-like pattern on EEG that normalized when haloperidol was withdrawn (106A). Olanzapine 5 mg/day was added, and 3 weeks later he became disoriented. Surprisingly, the olanzapine was continued and he remained disoriented. A 13-year-old boy with rhabdomyolysis ascribed to olanzapine was also taking lithium, so that a drug interaction could not be excluded (14A).
Diuretics
A 26-year-old woman had been stable on lithium (serum concentration 1.1 mmol/1), but after taking herbal diuretics for 2-3 weeks
J. W. Jefferson
developed manifestations of lithium toxicity (serum concentration 4.5 mmol/1) (107A).
NSAIDs
A man of unspecified age developed cognitive impairment and a serum lithium concentration of 2.4 mmol/1 after taking ibuprofen for shoulder pain (108A). In a review of celecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor, increased serum lithium concentration was mentioned as a possibility, but no specifics were provided (109r). A 44-year-old woman taking nimesulide, a COX-2 inhibitor, and ciprofloxacin developed lithium intoxication (serum concentration 3.23 mmol/1) complicated by renal insufficiency; the interaction was attributed to nimesulide (110A).
Xanthines There have been case reports of caffeine withdrawal leading to increased serum lithium concentrations, assumed to be due to reduced renal lithium clearance (111 r).
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9. Newland KD, Mycyk MB. Hemodialysis reversal of lithium overdose cardiotoxicity. Am J Emerg Med 2002; 20: 67-8. 10. TeraoT. Lithium therapy with pacemaker. Pharmacopsychiatry 2002; 35: 35. 11. Delva NJ, Hawken ER. Preventing lithium intoxication. Guide for physicians. Can Fam Phys 2001; 47: 159,5-600. 12. Montes JM, Ferrando L. Gabapentin-induced anorgasmia as a cause of noncompliance in a bipolar patient. Bipolar Disord 2001; 3: 52. 13. Rifai MA, Moles JK, Harrington DP. Lithiuminduced hypercalcemia and parathyroid dysfunction. Psychosomatics 2001; 42: 359-61. 14. Rosebraugh CJ, Flockhart DA, Yasuda SU, Woosley RL. Olanzapine-induced rhabdomyolysis. Ann Pharmacother 2001; 35: 1020-3. 15. Uchiyama Y, Nakao S, Asai T, Shingu K. A case of atropine-resistant bradycardia in a patient on long-term lithium medication [Japanese]. Jpn J Anesthesiol 2001; 50 1229-31. 16. Bhandari S, Samellas D. Bipolar affective disorder and idiopathic pulmonary fibrosis. J Clin Psychiatry 2001; 62: 574-5. 17. Patten SB, Williams JVA, Petcu R, Oldfield R. Delirium in psychiatric inpatients: a case-control study. Can J Psychiatry 2001; 46: 162-6. 18. Fagiolini A, Buysse DJ, Frank E, Houck PR, Luther JF, Kupfer DJ. Tolerability of combined treatment with lithium and paroxetine in patients
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with bipolar disorder and depression. J Clin Psychopharmacol 2001; 21: 474-8. 19. Suwalska A, Lojko D, Rybakowski J. Wplyw lekow normotymicznych na czynnosci poznawcze. Psychiatr Pol 2001; 35: 245-56. 20. Arts BMG, Honig A, Riedel WJ, Ponds RWHM. Cognitive effects of lithium; a metaanalysis and proposal for screening. Tijdschr Psychiatr 1998; 40: 466-8. 21. Van der Steenstraten IM, Achilles RA. Irreversibele neurologische schade na een lithiumintoxicatie bij therapeutische concentraties. Tijdschr Psychiatr 2001; 43: 271-5. 22. Conway CR, Nelson LA. The combined use of bupropion, lithium, and venlafaxine during ECT: a case of prolonged seizure activity. J ECT 2001; 17: 216-18. 23. Netski AL, Piasecki M. Lithium-induced exacerbation of stutter. Ann Pharmacother 2001; 35: 961. 24. Davis JM. Lithium intoxication and pontine haemorrhage. Acta Psychiatr Scand 2001; 103: 401. 25. Grounds D. Connection between lithium and muscular incoordination. Aust NZ J Psychiatry 2002; 36: 142-3. 26. Kupka RW, Nolen WA, Post RM, McElroy SL, Altshuler LL, Denicoff KD, Frye MA, Keck PE, Leverich GS, Rush A J, Suppes T, Pollio C, Drexhage HA. High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure. Biol Psychiatry 2002; 51:305-11. 27. Bocchetta A, Mossa P, Velluzzi F, Mariotti S, Del Zompo M, Loviselli A. Ten-year follow-up of thyroid function in lithium patients. J Clin Psychopharmacol 2001; 21: 594-8. 28. Gracious BL. Elevated TSH in bipolar youth prescribed both lithium and divalproex sodium. Int Drug Ther Newslett 2001; 36: 94-5. 29. ~ayk6ylti A, ~apoglu I, 0ntivar N, Erdem F, ~etinkaya R. Thyroid abnormalities in lithiumtreated patients with bipolar affective disorder. J Int Med Res 2002; 30: 80--4. 30. Miller KK, Daniels GH. Association between lithium use and thyrotoxicosis caused by silent thyroiditis. Clin Endocrinol (Oxf) 2001; 55: 501-8. 31. Bermudes RA. Psychiatric illness or thyroid disease? Don't be misled by false lab tests. Curr Psychiatry 2002; 1: 51-2, 57-61. 32. Mira SA, Gimeno EJ, Diaz-Guerra GM, Carranza YFH. Alteraciones tiroideas y paratiroideas asociadas al tratamiento cr6nico con litio. A prop6sito de un caso. Rev Esp Enferm Metab Oseas 2001; 10: 153-6. 33. Obuobie K, A1-Sabah A, Lazarus JH. Subacute thyroiditis in an immunosuppressed patient. J Endocrinol Invest 2002; 25: 169-71. 34. Scanelli G. Tireotossicosi da litio. Descrizione di un caso e revisione della letteratura. Recenti Prog Med 2002; 93: 100-3. 35. Turan MT, Esel E, Tutus A, Sofuoglu S, G6niik AS. Lithium-induced alterations in parathormone function in patients with bipolar disorder. Bull Clin Psychopharmacol 2001; 11: 96-100. 36. Dwight T, Kyt61~i S, Teh BT, Theodosopoulos G, Richardson AL, Philips J, Twigg S, Delbridge L.
27 Marsh D J, Nelson AE, Larsson C, Robinson BG. Genetic analysis of lithium-associated parathyroid tumors. Eur J Endocrinol 2002; 146: 619-27. 37. Belyavskaya NA. Lithium-induced changes in gravieurvature, statocyte ultrastructure and calcium balance of pea roots. Adv Space Res 2001; 27:9616. 38. Oakley PW, Whyte IM, Carter GL. Lithium toxicity: an iatrogenic problem in susceptible individuals. Aust NZ J Psychiatry 2001; 35: 833~-0. 39. Krastins MG, Phelps KR. Nephrogenic diabetes insipidus and hyperparathyroidism in a patient receiving chronic lithium therapy. J Am Geriatr Soc 2002; 50: S140. 40. Dieserud F, Brun AC, L~ihne PE, Normann E. Litiumbehandling og hyperparatyreoidisme. Tidsskr Nor Laegeforen 2001; 121: 2602-3. 41. Pieri-Balandraud N, Hugueny P, Henry JF, Tournebise H, Dupont C. Hyperparathyroidie induite par le lithium. Un nouveau cas. Rev Med Interne 2001; 22: 4 6 ~ 4 . 42. Valeur N, Andersen RS. Lithium-induced dysfunction of the parathyroid hormone. Ugeskr Laeg 2002; 164: 639-40. 43. Catal~ JC, Rubio AB, Fern~indez CC, Ballester YAH. Hiperparatiroidismo asociada al tratamiento con litio. Rev Esp Enferm Metab Oseas 2001; 10: 157-8. 44. Turan T, Esel E, Tokg6z B, Asian S, Sofuoglu S, Utas C, Kelestimur E Effects of short- and long-term lithium treatment on kidney functioning in patients with bipolar mood disorder. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 651-5. 45. Cassidy E Diabetes mellitus in manicdepressive patients. Essent Psychopharmacol 2001; 4: 49-57. 46. Cyr M, Guia MAC, Laizure SC. Increased lithium dose requirement in a hyperglycemic patient. Ann Pharmacother 2002; 36: 427-9. 47. Uzu T, Ichida K, Ko M, Tsukurimichi S, Yamato M, Takahara K, Ohashi M, Yamauchi A, Nomura M. Two cases of lithium intoxication complicated by type 2 diabetes mellitus [Japanese]. J Jpn Diabetes Soc 2001; 44: 767-70. 48. Chdmali KR, Suarez JI, Katirji B. Acute hypokalemic paralysis associated with long-term lithium therapy. Muscle Nerve 2001; 24: 297-8. 49. Hager ED, Dziambor H, H6hmann D, Winkler P, Strama H. Effects of lithium on thrombopoiesis in patients with low platelet cell counts following chemotherapy or radiotherapy. Biol Trace Elem Res 2001; 83: 139-48. 50. Esel E, Ozdemir MA, Turan MT, Basttirk M, Kili~ H, K6se K, G6ntil AS, Sofuoglu S. Effects of lithium treatment on granulocytes and granulocyte colony-stimulating factor in patients with bipolar affective disorder. Bull Clin Psychopharmacol 2001; 11: 28-32. 51. Corica M, Borcese R, Savoldi E. Can the lithium therapy cause titanium implant failure? J Dent Res 2001; 80: 1246. 52. Andersen V, Sonne J, Andersen M. Spontaneous reports on drug-induced pancreatitis in Den-
28 mark from 1968 to 1999. Eur J Clin Pharmacol 2001; 57: 517-21. 53. Lepkifker E, Sverdlik A, Iancu I, Ziv R. Renal failure in long-term lithium treatment. Bipolar Disord 2001; 3 Suppl 1: 45. 54. Mukhopadhyay D, Gokulkrishnan L, Mohanaruban K. Lithium-induced nephrogenic diabetes insipidus in older people. Age Ageing 2001; 30: 347-50. 55. Eustatia-Rutten CFA, Tamsma JT, Meinders AE. Lithium-induced nephrogenic diabetes insipidus. Neth J Med 2001; 58: 137-42. 56. Lal3nig E, Berent R, Wallner M, Jagsch C, Auer J, Eber B. Manisch-depressive Patientin mit Polyurie unter Lithiumtherapie. Intensivmedizin 2001; 38: 26-30. 57. Waise A, Fisken RA. Unsuspected nephrogenic diabetes insipidus. Br Med J 2001; 323: 96-7. 58. Herrero-Mendoza MD, Caramelo C, Bellver#,lvarez TM, Lopez-Cubero L. Sindrome nefrotico y tratamiento con litio. Med Clin (Barc) 2001; 116: 758-9. 59. Ida S, Yokota M, Ueoka M, Kiyoi K, Takiguchi Y. Mild to severe lithium-induced nephropathy models and urine N-acetyl-b-D-glucosaminidase in rats. Methods Find Exp Clin Pharmacol 2001; 23: 445-8. 60. Stoll PM, Stokes PE, Okamoto M. Lithium isotopes: differential effects on renal function and histology. Bipolar Disord 2001; 3: 174-80. 61. Oztas P, Aksakal AB, Oztas MO. Severe acne with lithium. Ann Pharrnacother 2001; 35: 961-2. 62. Francis GJ, Silverman AR, Saleh O, Lee GJ. Follicular mycosis fungoides associated with lithium. J Am Acad Dermatol 2001; 44: 308-9. 63. Seidel S, Kreutzer R, Smith D, McNeel S, Gilliss D. Assessment of commercial laboratories performing hair mineral analysis. J Am Med Assoc 2001; 285: 67-72. 64. Owley T, Leventhal B, Cook EH. Risperidoneinduced prolonged erections following the addition of lithium. J Child Adolesc Psychopharmacol 2001; 11: 441-2. 65. Luconi M, Marra F, Gandini L, Filimberti E, Lenzi A, Forti G, Baldi E. Phosphatidylinositol 3kinase inhibition enhances human sperm motility. Hum Reprod 2001; 16: 1931-7. 66. Banerji TK, Maitra SK, Dey M, Hawkins HK. Gametogenic responses of the testis in spotted munia (Lonchura punctulata; ayes) to oral administration of lithium chloride. Endocr Res 2001; 27: 345-56. 67. Rapaport MH, Manji HK. The effects of lithium on ex vivo cytokine production. Biol Psychiatry 2001; 50: 217-24. 68. Ahrens B, Miiller-Oerlinghausen B. Does lithium exert an independent antisuicidal effect? Pharmacopsychiatry 2001; 34: 132-6. 69. Bauer M, Bschor T, Kunz D, Bergh6fer A, Str6hle A, Mtiller-Oerlinghausen B. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psychiatry 2000; 157: 1429-35.
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70. Faedda GL, Tondo L, Baldessarini ILl. Lithium discontinuation: uncovering latent bipolar disorder? Am J Psychiatry 2001; 158: 1337-8. 71. Fahy S, Lawlor BA. Discontinuation of lithium augmentation in an elderly cohort. Int J Geriatr Psychiatry 2001; 16: 10(O-9. 72. Davis LL, Shannon S, Drake RG, Petty E The treatment of bipolar disorder during pregnancy. In: Yonkers KA, Little BB, editors. Management of Psychiatric Disorders in Pregnancy. London: Arnold, 2001: 122-33. 73. Iqbal MM, Sohhan T, Mahmud SZ. The effects of lithium, valproic acid, and carbamazepine during pregnancy and lactation. Clin Toxicol 2001; 39: 381-92. 74. Keller F, Griesshammer M, H~iussler U, Paulus W, Schwarz A. Pregnancy and renal failure. The case for application of dosage guidelines. Drugs 2001; 61: 1901-20. 75. Retamal PC, Cantillano VA. Tratamiento de la enfermedad bipolar durante el embarazo y puerperio. Cast clinico. Rev Med Chi12001; 129: 556-60. 76. Butt VK, Suri R, Altshuler L, Stowe Z, Hendrick VC, Muntean E. The use of psychotropic medications during breast-feeding. Am J Psychiatry 2001; 158: 1001-9. 77. Howard CR, Lawrence RA. Xenobiotics and breastfeeding. Pediatr Clin North Am 2001; 48: 485-504. 78. Fahy S, Lawlor BA. Lithium use in octogenarians. Int J Geriatr Psychiatry 2001; 16: 1000-3. 79. Henry ME, Moore CM, Demopolas C, Cote J, Renshaw PF. A comparison of brain lithium levels attained with immediate and sustained release lithium. Biol Psychiatry 2001; 49 Suppl 8:119S. 80. Gazikolovic E, Obrenovic D, Nicovic Z. Formulation of lithium carbonate tablets with various binding substances [Serbo-Croatian]. Vojnosanit Pregl 2001; 58: 641-4. 81. Sattar SP, Pinals DA. When taking medications is a sin. Psychiatr Serv 2002; 53: 213-14. 82. Keck PE~, Strakowski SM, Hawkins JM, Dunayevich E, Tugrul KC, Bennett JA, McElroy SL. A pilot study of rapid lithium administration in the treatment of acute mania. Bipolar Disord 2001; 3: 68-72. 83. Carroll BT, Thalassinos A, Fawver JD. Loading strategies in acute mania. CNS Spectrums 2001; 6: 919-22, 30. 84. Stares JC, Boada F, Spencer S, Mallinger AG, Dippold CS, Wells KF, Frank E, Keshavan MS, Gershon S, Kupfer DJ. Brain lithium concentrations in bipolar disorder patients: preliminary 7Li magnetic resonance studies at 3T. Biol Psychiatry 2001; 49: 437-43. 85. Hatfield CL, McDonell WN, Lemke KA, Black WD. Pharmacokinetics and toxic effects of lithium chloride after intravenous administration in conscious horses. Am J Vet Res 2001; 62: 1387-92. 86. Jonas MM, Linton RAF, O'Brien TK, Band DM, Linton NWF, Kelly F, Burden TJ, Chevalier SFA, Thompson RPH, Birch NJ, Powell JJ. The pharmacokinetics of intravenous lithium chloride in patients and normal volunteers. J Trace Microprobe Techn 2001; 19: 313-20.
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87. Litovitz TL, Klein-Schwartz W, White S, Cobaugh DJ, Youniss J, Omslaer JC, Drab A, Benson BE. 2000 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2001; 19: 337-95. 88. Montagnon F, Said S, Lepine JP. Lithium: poisonings and suicide prevention. Eur Psychiatry 2002; 17: 92-5. 89. Meltzer E, Steinlauf S. The clinical manifestations of lithium intoxication. Isr Med Assoc J 2002; 4: 265-7. 90. Bigal ME, Bordini CA, Speciali JG. Daily headache as a manifestation of lithium intoxication. Neurology 2001; 57: 1733-4. 91. Kuruvilla PK, Alexander J. Lithium toxicity presenting as non-convulsive status epilepticus (NCSE). Aust NZ J Psychiatry 2001; 35: 852. 92. Garc/a-Resa E, Blasco-Fontecilla H, ValbuenaBriones A. Sindrome de neurotoxicidad irreversible por litio. Med Clin (Barc) 2001; 116: 357. 93. Roy M, Fond L, Ratrema M, Convers Ph, Lutz MF, Cath6bras P. Intoxication au lithium: complications neurologiques sev6res. Presse Med 2001; 30: 900-1. 94. Megna J, O'Dell M. Ataxia from lithium toxicity successfully treated with high-dose buspirone: a single-case experimental design. Arch Phys Med Rehabil 2001; 82:1145-8. 95. Peces R, Pobes A. Effectiveness of haemodialysis with high-flux membranes in the extracorporeal therapy of life-threatening acute lithium intoxication. Nephrol Dial Transplant 2001; 16: 1301-3. 96. Danel V, Rhodes AS, Saviuc P, Hanna J. Intoxication grave par le lithium: h propos de deux cas. JEUR 2001; 14: 134-6. 97. Meyer RJ, Flynn JT, Brophy PD, Smoyer WE, Kershaw DB, Custer JR, Bunchman TE. Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children. Am J Kidney Dis 2001; 37: 1044-7. 98. Beckmann U, Oakley PW, Dawson AH, Byth PL. Efficacy of continuous venovenous hemodialy-
29 sis in the treatment of severe lithium toxicity. Clin Toxicol 2001; 39: 393-7. 99. Suraya Y, Yoong KY. Lithium neurotoxicity. Med J Malaysia 2001; 56: 378-81. 100. Nagappan R, Parkin WG, Holdsworth SR. Acute lithium intoxication. Anaesth Intensive Care 2002; 30: 90-2. 101. Dolamore MJ. Case report: lithium toxicity in a nursing home patient. Ann Long-Term Care 2001; 9: 56--61. 102. Wang PW, Ketter TA. Pharmacokinetics of mood stabilizers and new anticonvulsants. Psychopharmacol Bull 2002; 36: 44-66. 103. De Vries PL. Lithiumintoxicatie bij gelijktijdig gebruik van trimethoprim. Ned Tijdschr Geneeskd 2001; 145: 539-40. 104. Spina E, Perucca E. Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs. Epilepsia 2002; 43 Suppl 2: 37-44. 105. Mayan H, Golubev N, Dinour D, Farfel Z. Lithium intoxication due to carbamazepineinduced renal failure. Ann Pharmacother 2001; 35: 560-2. 106. Swartz CM. Olanzapine-lithium encephalopathy. Psychosomatics 2001; 42: 370. 107. Pyevich D, Bogenschutz ME Herbal diuretics and lithium toxicity. Am J Psychiatry 2001; 158: 1329. 108. Joseph DiGiacomo. Interview with F Flach. Risk management issues associated with psychopharmacological treatment. Essent Psychopharmacol 2001; 4: 137-50. 109. Davies NM, Gudde TW, De Leeuw AWC. Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis. Expert Opin Pharmacother 2001; 2:139-52. 110. Bocchia M, Bertola G, Morganti D, Toscano M, Colombo E. Intossicazione da litio e uso di nimesulide. Recenti Prog Med 2001; 92: 462. 111. Donovan JL, DeVane CL. A primer on caffeine pharmacology and its drug interactions in clinical psychopharrnacology. Psychopharmacology Bull 2001; 35: 30---48.
3 A review of the comparative efficacy and tolerability of drug treatments for bipolar disorder included tolerability comparisons of lithium versus carbamazepine, lithium versus valproate semisodium, and lithium versus other medications (1R). When 60 patients (22 men, 38 women) who had taken lithium for 1 year or more (mean 6.9 years; mean serum concentration 0.74 mmol/1) were interviewed about adverse effects, 60% complained of polyuria-polydipsia syndrome (serum creatinine concentrations were normal) and 27% had hypothyroidism requiting treatment (2c). Weight gain was more common in women (47% vs. 18%) as were hypothyroidism (37% vs. 9%) and skin problems (16% vs. 9%), while tremor was more common in men (54% vs. 26%). Weight gain of over 5 kg in the first year of treatment was the only independent variable predictive of hypothyroidism. How knowledgeable 1 2 3 patients in a lithium clinic (mean treatment duration 12.1 years) were about lithium has been assessed with 63 questions based on the Lithium Knowledge Test. About two-thirds of the questions were answered correctly, and knowledge about lithium was not related to diagnosis, education, or sex. There was a negative association between increasing age and knowledge, and this was independent of the duration of lithium treatment (3c). Even in a specialized lithium clinic, it seems that patient education could be improved upon, with the hope of a positive outcome on the effectiveness and safety of treatment.
ORGANS AND SYSTEMS C a r d i o v a s c u l a r Investigators who used a Bayesian confidence propagation network to 9 2003 Elsevier Science B.V. All rights reserved.
Side Effects of Drugs, Annual 26 J.K. Aronson, ed.
Lithium mine the World Health Organization International Drug Monitory Database for information on antipsychotic drugs and heart muscle disorders found 17 case reports involving lithium (4R). There was a significant association with lithium and cardiomyopathy, but not with myocarditis. However, a causal relation could not be established. Two reviews of drug-related congenital malformation briefly mentioned lithium and cardiovascular teratogenesis, but no new information was provided (5 r, 6r). Likewise, two reviews of the cardiac effects of psychotropic drugs briefly mentioned lithium and dysrhythmias, with a focus on sinus node dysfunction (7 r, 8r). Case reports of adverse cardiovascular effects of lithium have included the following: 9 a 52-year-old man who took an overdose of lithium (serum concentration 4.58 mmol/1) and developed asymptomatic sinus bradycardia with sinus node dysfunction and multiple atrial extra beats, which resolved after hemodialysis (9A), 9 a 59-year-old woman with syncope and sick sinus syndrome, which remitted when lithium was withdrawn, recurred when lithium was restarted, and then persisted despite lithium withdrawal; after a pacemaker was implanted she was treated successfully with lithium for 7 years (10A); 9 a 66-year-old woman with pre-existing first-degree AV block who, about 2 weeks after beginning lithium therapy, developed sinus bradycardia, a junctional rhythm, a prolonged QT interval, and syncopal episodes (serum lithium concentration 1.4 mmol/1 in a 40-hour sample); she was treated successfully with a pacemaker and a lower dose of lithium (11A); 9 a 36-year-old man who became hypomanic "after lithium was withdrawn because of symptomatic first-degree atrioventricular block (although how first-degree block could have caused symptoms is unclear) (12A); 9 a 59-year-old man who was noted to have tachycardia, a shortened QT interval, and non-specific ST-T changes while hospitalized with lithium-associated hypercalcemia (13 A); 9 a 13-year-old boy in whom lithium induced a "pseudo-myocardial infarct pattern" on the electrocardiogram (this may have been an overinterpretation of non-specific T-wave changes) (14A); 19
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20 44-year-old woman with atropine-resistant but isoprenaline-sensitive bradycardia (36 bpm), thought to be due to sinus node dysfunction related to lithium, fentanyl, and propofol (t5A).
9 a
Respiratory A 60-year-old woman with bipolar disorder since the age of 29 developed idiopathic pulmonary fibrosis (cryptogenic fibrosing alveolitis) after having taken lithium for 9 years (16A). Whether lithium played a causal role is at best highly speculative. Nervous system (see also Drug overdose) A case-control study of delirium in 22 psychiattic in-patients showed that lithium was one of the risk factors (adjusted odds ratio of 2.23) (17c). Four of 17 patients who had paroxetine added to lithium as an adjunctive antidepressant developed symptoms suggestive of emerging serotonin syndrome (e.g. nausea, vomiting, diarrhea, sweating, anxiety, oversleeping) (see also Drug interactions) (18c). Although the English abstract of a Polish review concluded that there is no evidence of significant cognitive deficits caused by lithium (19r), others would take issue with this conclusion (20M). Case reports of adverse nervous system effects of lithium have included the following: 9 permanent cerebellar sequelae in a 36-year-old man after intoxication at therapeutic lithium concentrations (21A); 9 a prolonged seizure after ECT in a 45-year-old man taking lithium, amfebutamone, and venlafaxine (see also Drug interactions) (22A); 9 worse stuttering in a 48-year-old man while taking lithium with improvement when he was switched to valproate (23"); 9 severe essential tremor, which was at first mistaken for tardive dyskinesia in an 80-year-old woman taking lithium; it resolved almost completely when lithium was withdrawn (24A). Neuromuscular Lithium has been implicated in impaired athletic prowess in two cases (25A). 21-year-old man had muscular incoordination while fast bowling (cricket), which improved when he switched to valproate. 9 A 71-year-old woman was unable to serve properly at tennis until she stopped taking lithium.
9 A
Endocrine
Thyroid The prevalence of thy-
roperoxidase antibodies was higher in 226 bipolar patients (28%) than in population control
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and psychiatric control groups (3-18%). While there was no association with lithium exposure, the presence of antibodies increased the risk of lithium-induced hypothyroidism (26c). When 22 men and 38 women who had taken lithium for at least a year (mean 6.9 years) for bipolar disorder were evaluated for adverse effects, hypothyroidism requiring thyroid supplementation was found in 16 (14 women and two men); nine had a goiter (2c). The area from which some of the patients came was known to have a high background incidence of thyroid dysfunction. In 1989, 150 patients at different stages of lithium therapy had thyroid function assessed and subsequently, 118 were reassessed at least once and 54 completed a 10-year follow-up (27c). The annual rates of new thyroid dysfunction were subclinical hypothyroidism 1.7%, goiter 2.1%, and autoimmunity 1.4%. While these figures were little different from those found in the general population, the authors acknowledged that lithium was a potential cause of thyroid dysfunction. Serum TSH concentrations were raised (to 10 mU/1 or more) in 13 of 61 children aged 5-17 years taking lithium and valproate for up to 20 weeks (28c). Of 42 bipolar patients who had taken lithium for 4-156 months, three had subclinical hypothyroidism, three had subclinical hyperthyroidism, and one was overtly hyperthyroid (29c). Goiter by ultrasonography was present in 38% and n~i'ld thyroid dysfunction was suggested in 48% because of an apparent increased conversion of free T4 to free T 3. There was no correlation between the duration of lithium therapy and thyroid abnormalities. A retrospective record review of 300 patients with Graves' disease and 100 with silent thyroiditis who had undergone thyroid scans showed that the likelihood of lithium exposure was 4.7 times higher in the latter, suggesting a link between lithium and thyrotoxicosis caused by silent thyroiditis (30c). Case reports of adverse thyroid effects of lithium have included the following: 9 56-year-old man taking lithium whose TSH concentration was abnormally high (50 mU/1) (31A); 9 a 44-year-old woman who had taken lithium for l0 years and who developed swelling of the fight lobe of the thyroid and hypothyroidism (15A);
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9 a 63-year-old woman taking long-term lithium who developed subclinical hypothyroidism and primary hyperparathyroidism (32A); 9 a 30-year-old man taking long-term ciclosporin and prednisolone following a bone-marrow transplant and long-term lithium for bipolar disorder who developed subacute thyroiditis, but without a clear relation to lithium (33A); 9 a 27-year-old man who developed thyrotoxicosis while taking lithium (34A).
Parathyroid Links between lithium and parathyroid dysfunction abound. Total serum calcium and intact parathyroid hormone concentrations were measured in 15 patients taking long-term lithium and 10 lithium-naive patients; both were significantly higher in the lithium group (35c). While the number of lithium patients with abnormally high concentrations was not stated, mean intact parathyroid hormone concentrations were almost twice the upper limit of the reference range (102 vs. 55 pg/ml). Parathyroid tumors from nine patients with lithium-associated hyperparathyroidism (six multiglandular, three uniglandular) have been compared with 13 non-lithium-associated sporadic parathyroid tumors with regard to gross genomic alterations (36c). Gross chromosomal alterations were absent in most of the lithium group and were more common in the sporadic group. A lithium chloride solution caused changes in gravicurvature, statocyte ultrastructure, and calcium balance in pea root, believed to be due to effects of lithium on the phosphoinositide second messenger system (37E). The implications with regard to human parathyroid function are obscure. Case reports of adverse parathyroid effects of lithium have included the following: 9 three cases of hyperparathyroidism among 26 cases of chronic lithium poisoning (see also Drug overdose) (38n); 9 a 78-year-old man who had taken lithium for 30 years who presented with dehydration, azotemia, hypernatremia, hypercalcemia, and increased parathyroid hormone concentrations (39A); 9 a 63-year-old woman taking long-term lithium therapy who had primary hyperparathyroidism (32A); 9 a woman who had taken lithium for 15 years who became hypercalcemic and stopped taking lithium, but 2 years later had two parathyroid adenomas removed surgically (40A);
21 9 a 42-year-old man who had taken lithium for 17 years and who had raised serum calcium and parathyroid hormone concentrations, which norrealized after removal of a parathyroid adenoma (41A); 9 a 59-year-old man with hypercalcemia and increased parathyroid hormone concentrations 3 months after starting lithium, which normalized after lithium was withdrawn (13A); 9 three cases of lithium-related hyperparathyroidism from Denmark (42A) and one from Spain (43A).
Diabetes insipidus Two of 10 patients taking long-term lithium therapy were thought to have hypothalamic diabetes insipidus, because of a positive response to desmopressin (44c). Metabolic It has been reported that diabetes mellitus is three times more common in bipolar patients than in the general population (45r). However, the authors of this review also pointed out that data are conflicting with regard to the effects of lithium on blood glucose concentrations. An increased lithium dosage requirement in a hyperglycemic 40-year-old woman was attributed to the osmotic diuretic effect of glycosuria, increasing lithium excretion (46A). In two cases of lithium intoxication, type 2 diabetes mellitus was felt to be a contributing factor (47A). Electrolyte balance Potassium A 25-yearold man had a single episode of generalized flaccid hypokalemic paralysis while taking lithium. He responded to intravenous potassium, lithium was stopped, and 1 year later there were no further episodes (48A). While the authors believed that lithium had been the cause, without confirmation by rechallenge this remains far from conclusive.
Sodium Hypernatremia can occur secondary to dehydration in patients taking lithium and is not uncommon in association with lithium poisoning. Lithium-induced diabetes insipidus is often a contributing factor (see also Urinary tract and Drug overdose). Hematologic The effects of lithium on hemopoiesis have been studied in 100 patients who had developed chronic granulocytopenia after cancer chemotherapy or radiotherapy (49c). The mean leukocyte count rose by 46%, but there were no changes in platelet or erythrocyte counts. However, there was a significant
22 increase in platelet count in those whose baseline values were below 150 x 109/1. Lithium was well tolerated (mean serum concentration 0.59 mmol/1). Granulocyte counts and granulocyte colonystimulating factor (G-CSF) concentrations were measured in 18 patients before and after 1 and 4 weeks of lithium treatment, and compared with values in 20 patients taking long-term lithium (50c). At week 4, the granulocyte count was significantly higher than at baseline or at week 1, or in the long-term group. There was only a non-significant increase in G-CSF concentration at weeks 1 and 4. The granulocyte count in those taking long-term lithium did not differ significantly from the baseline values in the other group. Mouth and teeth The issue has been raised of whether oral lithium therapy was responsible for failure of titanium dental implants in a 62-year-old man (51A). Pancreas All cases of drug-induced pancreatitis (n = 47) reported to the Danish Committee on Adverse Drug Reactions between 1968 and 1999 have been analysed; one involved lithium (plus a neuroleptic drug) (52c). Whether lithium was causally involved is not known. U r i n a r y t r a c t In a retrospective study, 114 patients who had taken lithium for 4-30 years were compared with 94 unmedicated age- and sex-matched controls with regard to changes in creatinine concentrations (53c). Of the patients taking lithium 21% had blood creatinine concentrations that had increased gradually and were now over the top of the reference range. This finding was associated with episodes of lithium intoxication and with diseases and other medications that could also affect glomerular function. Sex, psychiatric diagnosis, duration of treatment, cumulative dose, and serum lithium concentrations did not predict an abnormal creatinine concentration. Renal function has been assessed in 10 patients taking long-term lithium (over 3 years, mean 80 months), 10 taking short-term lithium (3 years or less, mean 16 months), and 10 lithium-naive patients (44r Serum BUN and creatinine concentrations were within the reference ranges and did not differ among the
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groups, but 24-hour creatinine clearance was significantly lower in those taking long-term lithium (73 vs. 125 and 150 ml/min). There were no significant differences among the groups in urine osmolality after 8-hour water deprivation and desmopressin, but partial nephrogenic diabetes insipidus was diagnosed in four long-term and two short-term patients and hypothalamic diabetes insipidus in two long-term patients. The authors concluded that long-term lithium therapy is a risk factor for renal impairment. There have been several case reports of lithium-related nephrogenic diabetes insipidus, sometimes associated with dehydration and lithium intoxication (39 A, 54A--57A). For example, a 77-year-old woman who had taken lithium for 10 years developed delirium, hypernatremia, prerenal azotemia, and a serum lithium concentration of 1.4 mmol/1; her condition was attributed to dehydration related to partial nephrogenic diabetes insipidus (54A). An 83-year-old man developed nephrotic syndrome while taking lithium (58A). Two studies in rats have potential implications for humans. In rats with mild to severe lithium-induced nephropathy, urine N-acetyl-bD-glucosamihidase (NAG) was an early indicator of renal insufficiency (59E). Both 6Li and 7Li caused reduced urine concentrating ability and increased urine volume and renal tubular lesions, but 6Li was more nephrotoxic (60E). The authors suggested that eliminating 6Li from pharmaceutical products might reduce nephrotoxicity (altl~bugh 6Li accounts for only about 7% of the lithium in such products). Skin Six months after beginning lithium, a man in his late twenties developed severe truncal ache, which worsened over 5 years, at which time lithium was withdrawn (61A). Nevertheless, the lesions were still present 4 years later, leading to the conclusion that lithium had caused irreversible acne. Of course, the association could have been coincidental. Skin and h a i r A 55-year-old man (erroneously reported by me in SEDA-25 to be a woman), who had taken lithium and haloperidol for 11 years, developed hyperkeratotic follicular papules on his scalp, extremities, and trunk, which on biopsy were suggestive of follicular mycoses fungoides (625). He also had a
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1-year history of scalp, axillary, and pubic hair loss. Following replacement of lithium with valproate, his hair regrew and the papules cleared almost completely in 3 months. Hair When a split hair sample from a healthy volunteer was sent to six commercial laboratories in the USA for trace mineral analysis, marked variations in results were found (including lithium concentrations), leading to the conclusion that such analyses were unreliable (63~). Sexual function A 17-year-old man had taken risperidone for 2 years without adverse effects, but 12 weeks after lithium was added he reported prolonged erections (lasting 1-3 hours) 2-5 times daily; risperidone was tapered and withdrawn and the problem resolved (64 A). Reproductive system In an in vitro study, LY294002, a phosphatidylinositol-3-kinase inhibitor, overcame impaired human sperm motility induced by lithium chloride (65E). At blood concentrations within the human target range, oral lithium caused degenerative changes in testicular morphology in spotted munia (Lonchura punctulata), a seasonally breeding sub-tropical finch (66E). How this might relate to effects in men is open to question. Immunologic Lithium has complex effects on immune function, as suggested by a study of 10 healthy volunteers who had increases in interleukin-4 and interleukin-lO concentrations, and falls in interleukin-2 and interferon concentrations (67c). The clinical implications of these findings are unclear. Death Evidence continues to accrue that long-term lithium therapy reduces suicidal behavior. A retrospective study divided high-risk patients into excellent, moderate, and poor responders to lithium and showed that no further suicide attempts occurred in 93%, 83%, and 49% respectively (68c). The substantial reduction in suicidal tendency in the poor responder group suggested an antisuicidal effect of lithium beyond its mood stabilizing properties, although the psychosocial benefits of lithium clinic treatment could have been contributing factors. For deaths related to lithium toxicity, see Drug overdose.
23
LONG-TERM EFFECTS Withdrawal Of 30 patients with major depressive disorder who had responded to lithium augmentation for antidepressant-resistant depression, 15 were switched to placebo over 1-7 days (69c). Two became manic, and it was suggested that lithium withdrawal may have uncovered latent bipolar disorder (70r). When 21 elderly patients with a major depressive episode who had responded to lithium augmentation had lithium withdrawn gradually (over 2-12 weeks), nine relapsed but none became manic (7 lC). Whether gradual withdrawal protected against withdrawal mania or whether there were no latent bipolar patients in the study is unknown.
SECOND-GENERATION EFFECTS Pregnancy and lactation The treatment of bipolar disorder during pregnancy and lactation has been reviewed, with reference to lithiumrelated maternal, fetal, and neonatal toxicity, morphological and behavioral teratogenicity, carcinogenicity and mutagenicity, and miscellaneous effects (72R). Elsewhere the effects of lithium, valproic acid, and carbamazepine during pregnancy (73R), and drug-induced congenital defects (with only a brief mention of lithium) (6 r) have been reviewed. A more specific review dealing with the use of drugs during pregnancy in women with renal disease mentioned the need for lithium dosage reduction in such cases (74r). A 37-year-old woman with severe bipolar disorder, who continued to take lithium throughout pregnancy, had a normal delivery but was not allowed to breast-feed (75A). In a review of the use of psychotropic drugs during breast-feeding it was briefly mentioned that lithium was not advisable but was justified under certain circumstances (76r). Lithium was also briefly discussed in a review of xenobiotics and breast-feeding (77r).
RISK FACTORS Age In a cross-sectional study of 12 octogenarians (average age 84 years) who had
24 taken lithium for an average of 54 months (mean serum concentration 0.42 mmol/l), none became toxic and none had to stop treatment because of adverse effects. Transient renal function abnormalities were noted, one patient developed nephrogenic diabetes insipidus, and one became hypothyroid (78c). For lithium therapy in very old people the authors advised close monitoring in a specialized setting.
DRUG ADMINISTRATION D r u g formulations Brain lithium concentrations (measured by magnetic resonance spectroscopy) after the use of a modified-release formulation (Lithobid SR) or an immediaterelease formulation have been compared in a crossover design (79c). There were higher brain concentrations with the modified-release formulation, but whether this has clinical implications requires further study. Formulations of lithium carbonate tablets with various binding substances have been discussed (80c). Drug additives Gelatin is derived from natural pork and beef products and is present in some lithium formulations. Since certain religions forbid the consumption of gelatin, knowing that it is present in Eskalith capsules and Eskalith CR and absent in Eskalith tablets (not available in the USA) and Lithobid SR might influence prescribing practices under certain circumstances (81r). The same would apply to other lithium products.
Drug dosage regimens In an open-label pilot study of rapid administration of slow-release lithium (20 mg/kg/day in two divided doses) for acute mania, five of 15 patients completed 10 days of treatment, seven improved sooner and were discharged, and two withdrew because of adverse effects (bradycardia in one and tremor, fatigue, and diarrhea in the other; one patient appears not to have been accounted for); two other patients also had asymptomatic bradycardia (82c). A review of loading strategies in acute mania included a section on lithium (83r). A small study of brain lithium concentrations measured by magnetic resonance spectroscopy showed higher brain:serum lithium
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concentration ratios in subjects taking a single dally dose (n = 5) than in those taking a twicedaily regimen (n = 3) (84c). Even to speculate about the possible clinical implications of this finding would be premature. D r u g a d m i n i s t r a t i o n route To determine the safety of using lithium chloride dilution to measure cardiac output, the pharmacokinetic and toxic effects of intravenous lithium chloride have been studied in six conscious healthy Standardbred horses (85E). The mean peak serum concentration was 0.56 mmol/1. There were no toxic effects nor significant changes in laboratories studies, electrocardiograms, or gastrointestinal motility. Three horses had increased urine output. A similar study was performed in patients undergoing cardiac surgery and healthy volunteers; the highest dose of LiC1 was 0.6 mmol given intravenously five times at 2-minute intervals (86c). Unfortunately, no mention was made of tolerability or adverse effects.
Drug overdose There are three forms of lithium overdose: 9 acute (abrupt overdose in a drug-naive person); 9 chronic (gradual accumulation, reaching toxic concentrations); 9 acute-on-chronic (abrupt overdose by a person already taking lithium), Overdose secondary to drug interactions is discussed in that section. The 2000 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System listed six lithium-related deaths (four cases of intentional suicide and two of therapeutic error) and two other deaths in which lithium was not listed as the primary cause (87R). A total of 4663 lithium-related exposures were reported, in which death was the outcome in 13 and a major life-threatening event or cause of significant disability in 267. A retrospective study of 97 cases of lithium poisoning treated at a regional center in Australia over 13 years found severe neurotoxicity in 28 (26 were cases of chronic poisoning and two were acute-on-chronic) (38c). Risk factors were nephrogenic diabetes insipidus, older age,
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abnormal thyroid function, and impaired renal function. In a retrospective study of 114 patients admitted to a toxicological ICU with suspected lithium intoxication, 81 had definite intoxication; 78% were deliberate overdoses and 22% were accidental (due, for example, to renal insufficiency, dehydration, drug interactions, poor compliance, drunkenness). Most were treated conservatively with gastric lavage and forced diuresis; hemodialysis was used only in 3-6%. Two of those who took a deliberate overdose and one of those who took an accidental overdose died (88c). Cases of lithium toxicity in a municipal hospital over a 10-year period involved eight women (mean age 66 years); neurological symptoms were the most common presentations (89c). Two were acute overdoses and the rest were chronic intoxications. There was one death (group not specified). A 64-year-old woman had a two-week history of daily bilateral holocranial headache as the presenting complaint of lithium toxicity (serum concentration 2.5 mmol/1); dosage reduction resolved the headache and the extrapyramidal and cerebellar findings (90A). Another toxic patient presented with nonconvulsive status epilepticus and a serum lithium concentration of 1.9 mmol/1 (91A). Non-reversible lithium neurotoxicity continues to be reported (92 A, 93A), including a case of lithium overdose (serum lithium concentration 3.9 mmol/1) with persistent severe ataxia for 9 months that improved markedly when inadvertently treated with high-dose buspirone (120-160 mg/day) (94A). Hemodialysis (56 A, 95 A, 96A), sometimes with additional continuous venovenous hemofiltration dialysis (97 A, 98A), continues to be described as a successful intervention for lithium poisoning. Peritoneal dialysis is a far less efficient way to clear lithium from the body. One patient treated in this way had permanent neurological abnormalities and another died; a third toxic patient who also had diabetic ketoacidosis died after treatment with hydration and insulin (99A). On the other hand, a 51-yearold woman who took fifty 450 mg slow-release lithium carbonate tablets had a serum lithium concentration of 10.6 mmol/1 13 hours later, but no evidence of neurotoxicity or nephrotoxicity. She was treated conservatively with intravenous
25 fluids and recovered fully (100 A). Acute lithium overdose is often tolerated better than chronic intoxication. An 85-year-old woman became gradually toxic (serum lithium 2.9 mmol/1) in a nursing home (101A). Despite only conservative management, there was slow but complete resolution of severe neurological symptoms, including coma, fixed pupils, and Cheyne-Stokes respiration.
DRUG INTERACTIONS In a review of the pharmacokinetics of mood stabilizers and new anticonvulsants, lithium drug interactions were only briefly mentioned (102r).
Anesthetics
Sinus bradycardia (36 bpm) developed in a 44-year-old woman taking lithium, fentanyl, and propofol (15 A) (see also Cardiovascular).
Antibiotics
A 40-year-old woman developed nausea, malaise, impaired concentration, trembling, unsteadiness, diarrhea, and muscle spasm in association with a serum lithium concentration of 2.1 mmol/1 while taking trimethoprim 300 mg/day (103A). The interaction was attributed to the amiloride-like diuretic effect of the latter, causing lithium retention.
Anticonvulsants
In a review of pharmacokinetic interactions between antiepileptic drugs and psychotropic drugs, there were no clinically significant interactions of lithium with gabapentin, lamotrigine, valproate, or topiramate, although serum lithium concentrations were reduced slightly by topiramate (104r). Lithium intoxication in a 33-year-old man was attributed to carbamazepine-induced renal insufficiency (105A).
Antidepressants Of 17 patients who took paroxetine as an adjunct to lithium therapy, retrospectively evaluated, four developed symptoms suggestive of an evolving serotonin syndrome that remitted when either drug was withdrawn (see also Nervous system) (l 8c). A 45-year-old man taking lithium, amfebutamone, and venlafaxine developed a prolonged
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26 seizure after ECT, thought to have been caused by a lowering of the seizure threshold due to amfebutamone (although a role of the other two drugs could not be excluded) (22A).
Antipsychotic drugs
A 59-year-old man taking lithium, haloperidol, and carbamazepine had impaired memory, impaired attention, and an encephalopathy-like pattern on EEG that normalized when haloperidol was withdrawn (106A). Olanzapine 5 mg/day was added, and 3 weeks later he became disoriented. Surprisingly, the olanzapine was continued and he remained disoriented. A 13-year-old boy with rhabdomyolysis ascribed to olanzapine was also taking lithium, so that a drug interaction could not be excluded (14A).
Diuretics
A 26-year-old woman had been stable on lithium (serum concentration 1.1 mmol/1), but after taking herbal diuretics for 2-3 weeks
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developed manifestations of lithium toxicity (serum concentration 4.5 mmol/1) (107A).
NSAIDs
A man of unspecified age developed cognitive impairment and a serum lithium concentration of 2.4 mmol/1 after taking ibuprofen for shoulder pain (108A). In a review of celecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor, increased serum lithium concentration was mentioned as a possibility, but no specifics were provided (109r). A 44-year-old woman taking nimesulide, a COX-2 inhibitor, and ciprofloxacin developed lithium intoxication (serum concentration 3.23 mmol/1) complicated by renal insufficiency; the interaction was attributed to nimesulide (110A).
Xanthines There have been case reports of caffeine withdrawal leading to increased serum lithium concentrations, assumed to be due to reduced renal lithium clearance (111 r).
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28 mark from 1968 to 1999. Eur J Clin Pharmacol 2001; 57: 517-21. 53. Lepkifker E, Sverdlik A, Iancu I, Ziv R. Renal failure in long-term lithium treatment. Bipolar Disord 2001; 3 Suppl 1: 45. 54. Mukhopadhyay D, Gokulkrishnan L, Mohanaruban K. Lithium-induced nephrogenic diabetes insipidus in older people. Age Ageing 2001; 30: 347-50. 55. Eustatia-Rutten CFA, Tamsma JT, Meinders AE. Lithium-induced nephrogenic diabetes insipidus. Neth J Med 2001; 58: 137-42. 56. Lal3nig E, Berent R, Wallner M, Jagsch C, Auer J, Eber B. Manisch-depressive Patientin mit Polyurie unter Lithiumtherapie. Intensivmedizin 2001; 38: 26-30. 57. Waise A, Fisken RA. Unsuspected nephrogenic diabetes insipidus. Br Med J 2001; 323: 96-7. 58. Herrero-Mendoza MD, Caramelo C, Bellver#,lvarez TM, Lopez-Cubero L. Sindrome nefrotico y tratamiento con litio. Med Clin (Barc) 2001; 116: 758-9. 59. Ida S, Yokota M, Ueoka M, Kiyoi K, Takiguchi Y. Mild to severe lithium-induced nephropathy models and urine N-acetyl-b-D-glucosaminidase in rats. Methods Find Exp Clin Pharmacol 2001; 23: 445-8. 60. Stoll PM, Stokes PE, Okamoto M. Lithium isotopes: differential effects on renal function and histology. Bipolar Disord 2001; 3: 174-80. 61. Oztas P, Aksakal AB, Oztas MO. Severe acne with lithium. Ann Pharrnacother 2001; 35: 961-2. 62. Francis GJ, Silverman AR, Saleh O, Lee GJ. Follicular mycosis fungoides associated with lithium. J Am Acad Dermatol 2001; 44: 308-9. 63. Seidel S, Kreutzer R, Smith D, McNeel S, Gilliss D. Assessment of commercial laboratories performing hair mineral analysis. J Am Med Assoc 2001; 285: 67-72. 64. Owley T, Leventhal B, Cook EH. Risperidoneinduced prolonged erections following the addition of lithium. J Child Adolesc Psychopharmacol 2001; 11: 441-2. 65. Luconi M, Marra F, Gandini L, Filimberti E, Lenzi A, Forti G, Baldi E. Phosphatidylinositol 3kinase inhibition enhances human sperm motility. Hum Reprod 2001; 16: 1931-7. 66. Banerji TK, Maitra SK, Dey M, Hawkins HK. Gametogenic responses of the testis in spotted munia (Lonchura punctulata; ayes) to oral administration of lithium chloride. Endocr Res 2001; 27: 345-56. 67. Rapaport MH, Manji HK. The effects of lithium on ex vivo cytokine production. Biol Psychiatry 2001; 50: 217-24. 68. Ahrens B, Miiller-Oerlinghausen B. Does lithium exert an independent antisuicidal effect? Pharmacopsychiatry 2001; 34: 132-6. 69. Bauer M, Bschor T, Kunz D, Bergh6fer A, Str6hle A, Mtiller-Oerlinghausen B. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psychiatry 2000; 157: 1429-35.
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70. Faedda GL, Tondo L, Baldessarini ILl. Lithium discontinuation: uncovering latent bipolar disorder? Am J Psychiatry 2001; 158: 1337-8. 71. Fahy S, Lawlor BA. Discontinuation of lithium augmentation in an elderly cohort. Int J Geriatr Psychiatry 2001; 16: 10(O-9. 72. Davis LL, Shannon S, Drake RG, Petty E The treatment of bipolar disorder during pregnancy. In: Yonkers KA, Little BB, editors. Management of Psychiatric Disorders in Pregnancy. London: Arnold, 2001: 122-33. 73. Iqbal MM, Sohhan T, Mahmud SZ. The effects of lithium, valproic acid, and carbamazepine during pregnancy and lactation. Clin Toxicol 2001; 39: 381-92. 74. Keller F, Griesshammer M, H~iussler U, Paulus W, Schwarz A. Pregnancy and renal failure. The case for application of dosage guidelines. Drugs 2001; 61: 1901-20. 75. Retamal PC, Cantillano VA. Tratamiento de la enfermedad bipolar durante el embarazo y puerperio. Cast clinico. Rev Med Chi12001; 129: 556-60. 76. Butt VK, Suri R, Altshuler L, Stowe Z, Hendrick VC, Muntean E. The use of psychotropic medications during breast-feeding. Am J Psychiatry 2001; 158: 1001-9. 77. Howard CR, Lawrence RA. Xenobiotics and breastfeeding. Pediatr Clin North Am 2001; 48: 485-504. 78. Fahy S, Lawlor BA. Lithium use in octogenarians. Int J Geriatr Psychiatry 2001; 16: 1000-3. 79. Henry ME, Moore CM, Demopolas C, Cote J, Renshaw PF. A comparison of brain lithium levels attained with immediate and sustained release lithium. Biol Psychiatry 2001; 49 Suppl 8:119S. 80. Gazikolovic E, Obrenovic D, Nicovic Z. Formulation of lithium carbonate tablets with various binding substances [Serbo-Croatian]. Vojnosanit Pregl 2001; 58: 641-4. 81. Sattar SP, Pinals DA. When taking medications is a sin. Psychiatr Serv 2002; 53: 213-14. 82. Keck PE~, Strakowski SM, Hawkins JM, Dunayevich E, Tugrul KC, Bennett JA, McElroy SL. A pilot study of rapid lithium administration in the treatment of acute mania. Bipolar Disord 2001; 3: 68-72. 83. Carroll BT, Thalassinos A, Fawver JD. Loading strategies in acute mania. CNS Spectrums 2001; 6: 919-22, 30. 84. Stares JC, Boada F, Spencer S, Mallinger AG, Dippold CS, Wells KF, Frank E, Keshavan MS, Gershon S, Kupfer DJ. Brain lithium concentrations in bipolar disorder patients: preliminary 7Li magnetic resonance studies at 3T. Biol Psychiatry 2001; 49: 437-43. 85. Hatfield CL, McDonell WN, Lemke KA, Black WD. Pharmacokinetics and toxic effects of lithium chloride after intravenous administration in conscious horses. Am J Vet Res 2001; 62: 1387-92. 86. Jonas MM, Linton RAF, O'Brien TK, Band DM, Linton NWF, Kelly F, Burden TJ, Chevalier SFA, Thompson RPH, Birch NJ, Powell JJ. The pharmacokinetics of intravenous lithium chloride in patients and normal volunteers. J Trace Microprobe Techn 2001; 19: 313-20.
Lithium
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