Lithium Carbonate (Lithotabs, Eskalith, Lithane, Lithobid) and Lithium Citrate (Cibalith-S)
Currently, lithium carbonate is approved by the FDA only for the treatment of manic episodes of bipolar disorders and for maintenance therapy of bipolar patients with a history of mania; the drug is approved only for persons 12 years of age and older. Over the past three decades, however, lithium carbonate has been investigated in the treatment of many child and adolescent disorders, but especially in the treatment of children with severe aggression directed toward self or others, children with bipolar or similar disorders, and behaviorally disturbed children whose parents are known lithium responders. One major impetus for this research was that standard antipsychotic agents, which were frequently used to control severe behavioral disorders and sometimes mania, not only could cause cognitive dulling when used in sufficient dosage to control symptoms, but also carried significant risk of causing tardive dyskinesia when used on a long-term basis (Platt et al. 1984
Contraindications for Lithium Carbonate Administration
Administration of lithium carbonate is relatively contraindicated in individuals with significant renal or cardiovascular disease, severe debilitation, severe dehydration, or sodium depletion, because these conditions are associated with a very high risk of lithium toxicity. Patients with such disorders should be thoroughly assessed, usually in consultation with the person providing medical care, before beginning lithium therapy.
Except under urgent circumstances, adolescents who are likely to become pregnant should not be administered lithium; this is particularly true of those in early pregnancy. Lithium carbonate is associated with a significant increase in cardiac teratogenicity, especially with Ebstein’s anomaly. A significantly increased incidence of other cardiac anomalies has also been reported. Kallen and Tandberg (1983)
reported that 7% of the infants of women who used lithium in early pregnancy had serious heart defects other than Ebstein’s anomaly.
Significant thyroid disease is a relative contraindication to lithium carbonate therapy; however, with careful monitoring of thyroid function and the use of supplemental thyroid preparations when necessary, it may be used when other drugs are not effective and the potential benefits outweigh the risks.
Interactions of Lithium Carbonate with Other Drugs
There are several reports that increased neuroleptic toxicity with an encephalopathic syndrome or neuroleptic malignant syndrome may occur when lithium and neuroleptics are used concomitantly, but this has usually been seen with high doses. The simultaneous use of lithium and neuroleptic agents, however, may be indicated in some cases of mania or schizoaffective psychoses, and many patients have received both a neuroleptic and lithium with no untoward effects.
Elevations in lithium serum concentration and increased risk of neurotoxic lithium effects may occur when carbamazepine and lithium are used simultaneously, because carbamazepine decreases lithium renal clearance.
Many other drugs may increase or decrease serum lithium levels by influencing its absorption or excretion by the kidneys; for example, tetracyclines increase lithium levels.
One major difficulty associated with the administration of lithium carbonate is its low therapeutic index; lithium toxicity is closely related to serum lithium levels and may occur at doses of lithium carbonate close to those necessary to achieve therapeutic serum lithium levels. Adverse or side effects are those unwanted symptoms that occur at therapeutic serum lithium levels, whereas toxic effects occur when serum lithium levels exceed therapeutic levels. However, this is not
an absolute, as patients who are unusually sensitive to lithium may develop toxic signs at serum levels below 1.0 mEq/L (PDR, 2000
Lithium toxicity may be heralded by diarrhea, vomiting, mild ataxia, coarse tremor, muscular weakness and fasciculations (twitches), drowsiness, sedation, slurred speech, and impaired coordination. Patients and/or their caretakers must be made familiar with the symptoms of early lithium toxicity and instructed to discontinue lithium immediately and contact their physician if such signs occur. Increasingly severe and life-threatening toxic effects, including cardiac arrhythmias and severe central nervous system difficulties such as impaired consciousness, confusion, stupor, seizures, coma, and death, may occur with further elevations in serum lithium levels.
No specific treatment for lithium toxicity is available. If signs of early lithium toxicity appear, the drug should be withheld, lithium levels determined, and the medication resumed at a lower dosage only after 24 to 48 hours. Severe lithium toxicity is life-threatening and requires hospital admission, treatments to reduce the concentration of the lithium ion, and supportive measures.
Lithium’s low therapeutic index and its pharmacokinetics make it necessary to administer lithium carbonate tablets or immediate-release capsules in divided doses, usually three or four times daily, to maintain therapeutic serum levels without toxicity. Even controlled-release tablets must be administered every 12 hours. It is essential that a laboratory capable of determining serum lithium levels rapidly and accurately be readily available to the clinician. For accuracy and serial comparisons, determinations of serum lithium levels should be made when lithium concentrations are relatively stable, and at the same time each day. Typically, blood is drawn 12 hours after the last dose of lithium and immediately before the morning dose (trough level).
Saliva lithium levels have also been used to monitor lithium levels in children, which avoids the necessity of repeated venipunctures, an upsetting experience for some children and adolescents. Perry et al. (1984)
reported that saliva lithium levels in 15 children diagnosed with undersocialized aggressive conduct disorder averaged approximately 2.5 times higher than serum lithium levels, with saliva/serum ratios for individual children ranging from 1.56 to 3.99. Weller et al. (1987)
found that saliva lithium levels were approximately 1.82 times those of serum levels in 14 prepubertal children receiving lithium for treatment of bipolar disorder. Saliva/serum lithium ratios in these children ranged from 1.50 to 2.32. Vitiello et al. (1988)
reported saliva lithium levels to be 2.84 times those of serum lithium levels in nine children, six of whom were diagnosed with conduct disorder and three of whom were diagnosed with adjustment disorders. Saliva/serum lithium ratios in these children ranged from 2.08 to 3.88. Bernstein (1988)
found that in adults the ratio of saliva lithium levels to serum lithium levels varied from 1:1 to as high as 3:1. Despite the rather marked interindividual variability in the saliva/serum ratio, it appears to be relatively constant for a given individual. Therefore, to be clinically useful, a stable saliva/serum lithium level ratio must be calculated for each patient.
Although some patients who are unusually sensitive to lithium may exhibit toxic effects at serum levels below 1 mEq/L, for most patients mild-to-moderate toxic effects occur at serum levels between 1.5 and 2 mEq/L, and moderate-to-severe reactions occur at levels of 2 mEq/L and above. Younger subjects may be at greater risk than adults for developing adverse effects at lower serum lithium levels. Many adverse effects have been reported to occur in children at serum levels well below 1 mEq/L (Campbell et al. 1984a
). The most common adverse effects of lithium
carbonate in 36 children, aged 3 to 13 years and diagnosed with conduct disorder (N
= 24), infantile autism (N
= 8), or other (N
= 4) were weight gain in 44.4%, excessive sedation in 27.8%, decreased motor activity in 25%, and stomachache, vomiting, tremor, and/or irritability in 19.4% of patients (Campbell et al. 1984a
Lithium decreases sodium reuptake by the renal tubules; hence adequate sodium intake must be maintained. This is especially important if there is significant sodium loss during illness (e.g., sweating, vomiting, or diarrhea) or because of changes in diet or elimination of electrolytes. The importance of adequate ingestion of ordinary table salt and fluids should be emphasized. Caution during hot weather or vigorous exertion has been advised, because additional salt loss and concomitant dehydration secondary to pronounced diaphoresis may cause the serum lithium levels of patients on maintenance lithium to increase and move into the toxic range. This may also be true of sweating caused by elevated body temperature secondary to infection or heat without exercise (e.g., sauna), but some evidence suggests that heavy sweating caused by exercise may result in lowered rather than elevated serum lithium levels. Jefferson et al. (1982)
studied four healthy athletes who were stabilized on lithium for 1 week before running a 20-km race. At the end of the race, the subjects were dehydrated but their serum lithium levels had decreased by 20%. The authors found that the sweat-to-serum ratio for the lithium ion was approximately four times greater than that for the sodium ion. These authors concluded that strenuous exercise with extensive perspiration was more likely to decrease rather than increase serum lithium levels, and patients were more likely to require either no change or an increase, rather than a decrease, in dosage of lithium to maintain therapeutic levels. The authors do caution, however, that any conditions that significantly alter fluid and electrolyte balance, including strenuous exercise with heavy sweating, should be carefully monitored with serum lithium levels.
Untoward Effects of Lithium Carbonate
Lithium carbonate is frequently reported to have adverse effects early in the course of treatment. Most of these diminish or disappear during the first weeks of treatment.
These early adverse effects include fine tremor (unresponsive to antiparkinsonism drugs), polydipsia, and polyuria that may occur during initial treatment and persist or be variably present throughout treatment. Nausea and malaise or general discomfort may initially occur but usually subside with ongoing treatment. Weight gain, headache, and other gastrointestinal complaints such as diarrhea may also occur. Taking lithium with meals or after meals or increasing the dosage more gradually may be helpful in controlling gastrointestinal symptoms.
Later adverse effects are often related to serum level, including levels in the therapeutic range; these include continued hand tremor that may worsen, polydipsia, polyuria, weight gain and edema, thyroid and renal abnormalities, dermatologic abnormalities (including acne), fatigue, leukocytosis, and other symptoms. As serum levels increase, toxicity increases and other, more severe untoward effects, discussed earlier under toxicity, appear.
Abnormalities in renal functioning (diminution of renal concentrating ability) and morphologic structure (glomerular and interstitial fibrosis and nephron atrophy) have been reported in adults on long-term lithium maintenance. Occasional proteinuria was reported in a 14-year-old girl (Lena et al. 1978
). Vetro et al. (1985)
reported that after 1 year of lithium treatment, one child developed polyuria with
daytime enuresis and impaired renal concentration. Other parameters of renal function did not change, and polyuria ceased within a few days of lithium’s being discontinued. Five other children on long-term lithium therapy showed transient albuminuria that remitted spontaneously, and discontinuation of treatment was not necessary (Vetro et al. 1985
Lithium may also interfere with thyroid function, with decreased circulating thyroid hormones and increased thyroid-stimulating hormone (TSH). Vetro et al. (1985)
reported that two children developed goiter with normal function after 1.5 to 2 years of lithium therapy.
Neuroleptic malignant syndrome has been reported in a few patients who were administered neuroleptic drugs and lithium simultaneously.
reported specific adverse effects of lithium in 14 retarded adolescent males, that interfered with patient management despite significant therapeutic gains. Polydipsia, polyuria, and nocturnal enuresis were so severe as to alienate staff who cared for the youngsters. These symptoms remitted within 2 weeks of discontinuing lithium (Dostal, 1972