Description:

Lithium is a monovalent cation similar to sodium and potassium. For clinical use, it is administered orally as the carbonate and the more water-soluble citrate salts. Lithium is the drug of choice in treating recurrent bipolar affective disorder (i.e., manic-depressive illness) and has also been used for unipolar disorder (depression). Nonpsychiatric uses of lithium include the syndrome of inappropriate secretion of ADH (SIADH), neutropenia, thyrotoxic crisis, and migraine and cluster headaches, although these are not FDA-approved uses. The use of lithium in clinical medicine dates back to 1841 when it was proposed to be an effective therapy for gout, but it was later found ineffective for this purpose. In the late 1940s, lithium chloride was used as a salt substitute. After several cases of lithium toxicity were associated with indiscriminate use, it was withdrawn from the market until 1949 when it was serendipitiously discovered that lithium was beneficial in the management of mania. Lithium carbonate was approved by the FDA in 1970. Its pharmacokinetics were not well understood until years later. Mechanism of Action: Lithium competes at cellular sites with sodium, potassium, calcium, and magnesium ions. Lithium competes with these ions at intracellular binding sites, at protein surfaces, at carrier binding sites, and at transport sites. At the cell membrane, lithium readily passes through sodium channels, and high concentrations can block potassium channels. Although the mechanism of the antimanic and antidepressant action in the CNS is not known, evidence suggests that the drug interferes with the synthesis, storage, release, and reuptake of monoamine neurotransmitters. Lithium enhances the uptake of tryptophan, increases the synthesis of serotonin, and may also enhance the release of serotonin in the CNS. Lithium does not possess sedative, depressant, or euphoriant effects. Onset of the acute antimanic effect is usually seen in 5�7 days, and the full therapeutic effect is established in 10�21 days. Lithium administration increases renal sodium and potassium clearance. These effects are attenuated by a compensatory increase in aldosterone after 2�3 days. Lithium does not affect sodium reabsorption in either the ascending limb of the loop of Henle or in the distal tubule. A decrease in renal concentrating ability occurs in 30�50% of patients while receiving lithium; it often produces a mild nephrogenic diabetes insipidus manifested as polyuria. Lithium-induced diabetes insipidus is thought to be due to inhibition of vasopressin-induced adenylate cyclase activity in the medullary collecting tubule of the nephron. Since lithium is more toxic and a less reliable agent than demeclocycline, lithium should be considered a last choice for the treatment of SIADH. Lithium enhances granulocyte production via stimulation of monocyte colony stimulating factor production. Lithium produces an increase in the total neutrophil pool and each of its components in the bone marrow and circulation. Leukocytosis peaks within 7�10 days of initiating therapy and the WBC count will return to baseline 7�10 days after discontinuing lithium.[737] The actions of lithium on the heart generally give rise to adverse (i.e., not therapeutic) effects. The most common EKG changes include flattening or inversion of the T-waves. This manifestation is thought to be due to lithium-induced inhibition of potassium cellular reuptake leading to intracellular hypokalemia. Because lithium displaces potassium, an extracellular hyperkalemia is seen and, since the intracellular:extracellular potassium balance is shifted, cardiac arrest is possible at lower than usual degrees of hyperkalemia. Pharmacokinetics: Lithium salts are administered orally. Lithium is rapidly absorbed from the GI tract, and the rate of absorption is not significantly slowed by the presence of food. Lithium carbonate in tablets or capsules is 95�100% absorbed. Bioavailability from slow-release lithium carbonate tablets is 60�90%. Lithium citrate oral solutions are essentially 100% absorbed. Lithium carbonate is most commonly used because it has a longer shelf-life and contains more lithium on a weight basis than do other salts. Peak serum concentrations after administration of lithium carbonate rapid-release formulations are reached in 0.5�3 hours, and absorption is complete within 6 hours. When extended-release tablets are used, peak lithium concentrations are observed 4�12 hours after the dose. Oral solutions of lithium citrate are extremely rapidly absorbed; peak serum levels are achieved in 15�60 minutes. Lithium has negligible protein binding and is distributed throughout the body, with slightly greater concentrations in thyroid, bone, and brain tissue. It is excreted unchanged in urine. A 300 mg dose of lithium carbonate tablets produces peak serum concentrations of 0.4�0.5 mEq/L. A similar dose in capsules gives peak serum concentrations of 0.4�0.9 mEq/L. Serum lithium concentrations tend to fluctuate for 6�10 hours after dosing, so the 12-hour post-dose serum concentration is used for monitoring purposes. Data published in 1989 confirmed that serum concentrations of 0.8�1.0 mEq/L are more effective in preventing relapse in patients with bipolar disorder than are lower concentrations of 0.4�0.6 mEq/L.[17] Steady-state serum lithium concentrations of 1�1.5 mEq/L are required to control acute mania. Toxicity is likely in most patients when levels exceed 1.5 mEq/L, although symptoms of lithium toxicity can appear in some patients with serum concentrations of 1 mEq/L or less. The narrow therapeutic ratio and interpatient variations make individual monitoring and dosage adjustment essential. Approximately 90�95% of a dose of lithium is eliminated by the kidneys. The amount eliminated through sweat, saliva, and feces is negligible under normal circumstances. Lithium is freely filtered by renal glomeruli, but it also undergoes significant renal tubular reabsorption. Thus, any decrease in GFR will reduce lithium elimination. It was once thought that tubular reabsorption occurred only in the proximal tubule but interaction studies with HCTZ and furosemide revealed substantial lithium reabsorption also occurs in the ascending limb of the loop of Henle.[1202] In patients with normal renal function, biphasic elimination is observed. The initial half-life is 0.8�1.2 hours, and the terminal half-life is approximately 20�27 hours, although reported half-life values have ranged from 5�79 hours. In young adults, the half-life is 18�24 hours, and in the elderly, it is 30�36 hours. Many factors can affect lithium clearance including hyponatremia or hypernatremia, dehydration, and diuretic use.

Indications...Dosage For the treatment of bipolar disorder: NOTE: Use lower doses in patients with impaired lithium clearance (e.g., elderly, diuretic therapy, low-salt diet, renal impairment, or dehydration). �for treatment during acute mania (target serum lithium concentration: 0.8�1.5 mEq/L): Oral dosage (regular-release tablets): Adults and adolescents: Usual dose range is 1200�1800 mg/day PO, given in 2�4 divided doses. A lower initial dosage for the first few days may minimize intolerance; adjust every 3�4 days to achieve target concentration. Usual prescribing limit 2400 mg/day PO. Elderly: See adult dosage, may require lower doses. Children�: Initially 15�20 mg/kg/day PO given in 3�4 divided doses; adjust as needed weekly to achieve target concentration. Maintenance doses range 15�60 mg/kg/day PO given in 3�4 divided doses. Do not exceed 2400 mg/day. Oral dosage (Eskalith CR� extended-release tablets): Adults and adolescents: Usual dosage is 900 mg PO twice daily (usual range 1200�1800 mg/day). A lower initial dosage for the first few days may minimize intolerance; adjust every 3�4 days to achieve target concentration. Usual prescribing limit 2400 mg/day PO. Elderly: See adult dosage, may require lower doses. Oral dosage (Lithobid� extended-release tablets): Adults and adolescents: Usual dosage is 600�900 mg PO twice daily. A lower initial dosage for first few days may minimize intolerance; adjust every 3�4 days to achieve target concentration. Usual prescribing limit 2400 mg/day PO. Elderly: See adult dosage, may require lower doses. Oral dosage (lithium citrate oral syrup - NOTE that 5 ml of lithium citrate syrup contains 8 mEq of lithium, equivalent to 300 mg of lithium carbonate): Adults and adolescents: Usual dosage 20�30 ml/day (32�48 mEq/day or 1200�1800 mg/day) PO, administered in 2�3 divided doses. A lower initial dosage for the first few days may minimize intolerance; adjust every 3�4 days to achieve target concentration. Usual prescribing limit 2400 mg/day PO. Elderly: See adult dosage, may require lower doses. Children�: Initially, 0.4�0.5 mEq/kg/day (equivalent to 15�20 mg/kg/day) PO given in 2�3 divided doses; adjust weekly as needed to achieve target concentration. Maintenance doses range 15�60 mg/kg/day PO given in 3�4 divided doses. Do not exceed 2400 mg/day. �for maintenance therapy (target serum lithium concentration: 0.6�1.2 mEq/L): Oral dosage (regular-release tablets): Adults: Usual dose 900�1200 mg/day PO given in 2�4 divided doses. A lower initial dosage during the first few days may minimize intolerance; adjust every 3�4 days to achieve target concentration. Usual prescribing limit 2400 mg/day PO. Elderly: See adult dosage, may require lower initial doses. Children�: Usual dose 15�20 mg/kg/day PO given in 3�4 divided doses. A lower initial dosage during the first few days may minimize intolerance. Adjust every 3�4 days as needed to achieve target concentration. Do not exceed 2400 mg/day. Oral dosage (Eskalith� extended-release tablets): Adults: Usual dosage is 450 mg PO twice daily (range 900�1200 mg/day). A lower initial dosage during the first few days may minimize intolerance; adjust every 3�4 days to achieve target concentration. Usual prescribing limit 2400 mg/day PO. Elderly: See adult dosage, may require lower initial doses. Oral dosage (Lithobid� extended-release tablets): Adults: Usual dosage is 600 mg PO twice daily (range 900�1200 mg/day). A lower initial dosage during the first few days may minimize intolerance; adjust every 3�4 days to achieve target concentration. Usual prescribing limit 2400 mg/day PO. Elderly: See adult dosage, may require lower initial doses. Oral dosage (lithium citrate oral syrup - NOTE that 5 ml of lithium citrate syrup contains 8 mEq of lithium, equivalent to 300 mg of lithium carbonate): Adults: Usual dosage 15�20 ml/day (24�32 mEq/day or 900�1200 mg/day) PO, given in 2�3 divided doses. A lower initial dosage during the first few days may minimize intolerance; adjust every 3�4 days to achieve target concentration. Usual prescribing limit 2400 mg/day PO. Elderly: See adult dosage, may require lower initial doses. Children�: 0.4�0.5 mEq/kg/day (equivalent to 15�20 mg/kg/day) PO given in 2�3 divided doses. A lower initial dosage during the first few days may minimize intolerance; adjust weekly as needed to achieve target concentration. Maintenance doses range 15�60 mg/kg/day PO given in 3�4 divided doses. Do not exceed 2400 mg/day. For the treatment of affective disorder or major depression�: Oral dosage (lithium carbonate): Adults: 600 mg PO three times per day. Use lower initial doses for elderly or during situations of impaired lithium excretion. Oral dosage (lithium citrate syrup): Adults: 10 mL (600 mg or 16 mEq) PO given three times per day. (NOTE: 5 ml of lithium citrate syrup contains 8 mEq of lithium, equivalent to 300 mg of lithium carbonate). Use lower initial doses for elderly or during situations of impaired lithium excretion. For the treatment of neutropenia� secondary to specific conditions: �for the treatment of chronic neutropenia� or zidovudine-induced neutropenia� in patients with AIDS: Oral dosage: Adults: Doses have ranged 300�900 mg/day PO. Children: Safe and effective use not established. �for the treatment of chemotherapy-induced neutropenia�: Oral dosage: Adults: Doses have ranged 300�1000 mg/day PO.[737] Children: Safe and effective use not established. For the treatment of inappropriate secretion of ADH (SIADH�): Oral dosage: Adults: NOTE: Demeclocycline is preferred over lithium for this use. Therefore, no dosage for lithium is included in this reference for this condition. For the treatment of agitation� or aggressive behavior associated with cyclic mood disorders, mental retardation, other organic mental syndromes, or aggression without comorbid psychiatric disorders: Oral dosage: Adults: 10�17 mg/kg/day PO given in 2�3 divided doses has been suggested. The dose should be titrated upward to achieve plasma trough concentrations of 0.5�2 mEq/L.[1170] After response achieved, adjust to normal serum concentrations. Usual prescribing limit: 2400 mg/day PO. Elderly: See adult dosage, use lower initial doses for elderly or during situations of impaired lithium excretion (e.g., diuretic therapy, low-salt diet, renal dysfunction, or dehydration). Maximum Dosage Limits: �Adults: Usual prescribing limit: 2400 mg/day PO. �Elderly: Usual prescribing limit: 2400 mg/day PO. �Adolescents: Usual prescribing limit: 2400 mg/day PO. �Children: Do not exceed 60 mg/kg/day PO or 2400 mg/day PO, whichever is less. �Infants: Not indicated. Therapeutic Drug Monitoring: �Serum concentrations should be utilized in all patients receiving lithium salts. Data confirm that serum concentrations of 0.8�1.0 mEq/L are more effective in preventing relapse in bipolar disorder than lower concentrations of 0.4�0.6 mEq/L.[17] Higher concentrations (i.e., 0.8�1.5 mEq/L) may be required for treatment of acute affective episodes. For maintenance, lithium serum concentrations of 0.6�0.8 mEq/L are recommended by the NIMH for most patients.[1674] Breakthrough episodes can be treated by increasing dose to achieve a serum concentration of 1�1.2 mEq/L. �NOTE: Plasma concentrations above 1.5 mEq/L are regularly associated with signs of toxicity. Patients more sensitive to lithium may exhibit toxic signs at serum levels of 1�1.5 mEq/L. For example, the elderly may exhibit toxicity at serum levels ordinarily tolerated by other patients. �Lithium concentrations should be obtained 12 hours after the previous dose. Approximately 300 mg of lithium carbonate will raise the plasma lithium concentration by 0.2�0.4 mEq/L in adults. �After the appropriate dose is achieved for indication, serum lithium concentrations should be obtained every 1�2 months. �Use lower initial doses for elderly or during situations of impaired lithium excretion (e.g., diuretic therapy, low-salt diet, renal dysfunction, or dehydration). Patients with hepatic impairment: Specific recommendations for dosage adjustment in patients with hepatic impairment are not available, use caution. Dosage adjustment will be needed if renal dysfunction is also present. Many factors can affect renal lithium clearance including hyponatremia or hypernatremia, dehydration, and diuretic use, some conditions may be present in the patient with hepatic impairment. Patients with renal impairment: Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available. Renal excretion of lithium is impaired in renal impairment and may lead to drug toxicity, close monitoring of serum levels and dosage adjustments is warranted. �non-FDA-approved indication

Administration Oral Administration �All dosage forms: Lithium is administered orally with food. �Extended-release products: Administer intact; do not chew, crush, or cut in half. �Oral solution: To improve the taste, may be diluted with fruit juice or other flavored beverage before administering. Do not mix with an antipsychotic (especially chlorpromazine concentrate) or antidepressant liquid since an insoluble citrate salt may be formed.

Contraindications Lithium is classified as pregnancy category D. It crosses the placental barrier freely and has been associated with fetal toxicity. Data from lithium birth registers suggest an increased incidence of neonatal goiter and an increase in cardiac anomalies, especially Ebstein's anomaly. In some cases, however, lithium therapy may be warranted during pregnancy, but patients should be warned about possible damage to the fetus. If possible, lithium should be withheld during the first trimester. Women of childbearing age who require lithium therapy should be counseled about becoming pregnant. Lithium is secreted into breast milk and is contraindicated in women who are breast-feeding. Symptoms of lithium toxicity, including ECG changes, have been observed in some breast-fed infants, whose mothers were taking lithium. Lithium therapy can cause hyponatremia by reducing resorption of sodium by the renal tubules. Lithium should be used with caution in hyponatremia. An adequate fluid intake and maintenance of salt balance are essential during lithium therapy. Lithium clearance depends on GFR. Lithium should be used with caution in patients with renal impairment or renal disease; dosage reductions are recommended. Reevaluation of treatment may be necessary depending on renal function. In addition urinary retention may delay lithium excretion and cause toxicity. Chronic lithium therapy may lead to a reduction in renal concentrating ability, with polyuria and polydipsia. Dehydration can lead to lithium toxicity. Lithium should be used with caution in patients requiring sodium restriction in their diet. Any factor leading to dehydration can affect lithium balance, such as protracted sweating or diarrhea, which may require supplemental fluid and salt intake or, alternatively, reduction or suspension of lithium therapy. Other factors that raise body temperature may lead to dehyration, such as fever, exercise, sauna or hot baths. A concurrent infection with elevated body temperature may also require reduced lithium dosage or temporary stoppage of therapy. Lithium can affect thyroid function. Lithium should be used cautiously in patients with thyroid disease, especially hypothyroidism, or in the elderly because these patients may be more susceptible to this adverse effect. Lithium should be used cautiously in patients with cardiac disease. Changes in the electrocardiogram can occur at therapeutic dosages (T wave depression or inversion), although these changes are almost always reversible (see Adverse Reactions). Rarely, sinus bradycardia, sinoatrial block, and AV block have been reported with use of therapeutic lithium dosages; patients with sick sinus syndrome may be at increased risk for these adverse events. More serious adverse cardiac effects such as intraventricular conduction defect, hypotension and cardiac arrhythmias are rare and are usually associated with severe, acute intoxication.[916] Patients with psoriasis should receive lithium with caution. Lithium therapy is known to exacerbate psoriasis. Because lithium can cause seizures and/or tremors, it should be used cautiously in patients with a preexisting seizure disorder or parkinsonism. These conditions may mask the neurotoxicity of lithium. Lithium can produce mental status changes. Patients need to be informed about the possibility of reduced mental alertness affecting their ability to drive or use machinery safely, especially when lithium therapy is instigated. Lithium should be used cautiously in patients with organic brain syndrome or CNS impairment. Lithium has produced an encephalopathic syndrome (similar to NMS) in some patients receiving concomitant neuroleptic therapy (see Drug Interactions). Brain damage produced by this syndrome may be irreversible. Bipolar disorder has an inherent risk of suicidal ideation. Patients with a history of alcohol or substance abuse, a history of attempted suicide, or those who are socially isolated may be at greatest risk. High risk patients may require lithium treatment within a hospital environment or monitoring by family or friends. Lithium should be used with caution in patients with a history of leukemia. There have been rare reports of lithium-induced hematologic neoplasms, including acute leukemia; however, a causal relationship has not been established.

Interactions Lithium may potentiate the effects of nondepolarizing neuromuscular blockers. Limited data indicate that lithium toxicity followed the addition of lisinopril to drug regimens containing lithium. It has been suggested that ACE inhibitors increase the risk of developing lithium toxicity, possibly as a result of sodium depletion which leads to increased renal tubular reabsorption of lithium. Although data are limited, all ACE inhibitors should be used cautiously, if at all, in patients already receiving lithium. Clinicians should be alert to the possibility of loss of lithium effectiveness if ACE inhibitor therapy is discontinued in a patient stabilized on lithium. Alkalinizing agents, particularly those that affect urinary pH, can increase the renal clearance of lithium. Urinary alkalinizers affect the handling of electrolytes in the nephron and these agents should be used cautiously in patients stabilized on lithium. Examples of alkalinizing agents include: potassium acetate, potassium bicarbonate, potassium citrate, sodium bicarbonate, sodium citrate, sodium lactate, and tromethamine. In addition, hypernatremia also increases lithium clearance. Due to these dual effects, the administration of sodium chloride or sodium bicarbonate may dramatically affect lithium clearance. Caffeine appears to reduce serum lithium concentrations. In 11 coffee-drinking patients stabilized on lithium, serum lithium concentrations increased during 2 weeks when coffee was withheld and fell when coffee was resumed. Lithium ADRs have also been noted to increase simultaneously with a reduction in caffeine intake. Patients taking lithium should be counseled regarding their intake of caffeine. Clinicians should note, however, that coffee, not pure caffeine, was the variable in this study. Carbamazepine and lithium are sometimes used together therapeutically. In some patients, however, adverse CNS reactions occur, despite therapeutic serum concentrations of both agents. Clinicians should also note that lithium may be useful to reverse carbamazepine-induced leukopenia, however, this beneficial effect needs to be weighed against the possibility of additive effects on thyroid function. Patients receiving these two drugs together should be monitored closely for signs of neurotoxicity (e.g., ataxia, lethargy, hyperreflexia, tremor) despite the absence of toxic serum concentrations of either agent. Carbamazepine appears to potentiate the CNS effects of lithium; in some patients, this combination is beneficial while in others, it may lead to lithium toxicity. Several calcium-channel blockers have been reported to precipitate lithium neurotoxicity. This has been reported for both diltiazem and verapamil. The interaction between verapamil and lithium is variable and unpredictable. Both decreased lithium concentrations and lithium toxicity have been reported after the addition of verapamil. The possibility of a loss of lithium's therapeutic effect due to lower serum lithium concentrations may be offset somewhat by the fact that calcium-channel blocking agents share some neuropharmacological actions with lithium; limited data suggest that oral verapamil is effective in controlling an acute manic episode either as a single agent or in combination with lithium. Because verapamil has been associated with both decreased lithium concentrations and with lithium toxicity, verapamil should be avoided in patients receiving lithium. Regarding diltiazem, although neurotoxicity was reported after the addition of diltiazem, other drugs were administered concomitantly. Until more data are available, diltiazem and verapamil should be used cautiously in patients receiving lithium. Although cyclic antidepressants and lithium can be used together therapeutically, in some cases, neurotoxicity may be increased. It has been suggested that toxicity from this combination is more likely in the elderly, although data are limited. While tricyclic antidepressants and heterocyclic antidepressants are not precluded in patients receiving lithium, they nevertheless should be used cautiously in these patients. Only limited data are available regarding the effects of combining SSRI-type antidepressants with lithium. Several cases of neurotoxicity have been reported when fluoxetine was used with lithium. A single case report documents the development of severe somnolence within 24 hours after lithium was added to fluvoxamine. A positive dechallenge was noted and symptoms did not recur when either drug was used alone. Until more data are available, SSRIs should be used cautiously in patients receiving lithium. In general, diuretics should be used cautiously in patients receiving lithium, although not all diuretics affect lithium clearance to the same degree. Lithium is reabsorbed from the proximal tubule and possibly from the loop of Henle but does not appear to be reabsorbed distally. Thus, diuretics that act within the distal tubule (e.g., thiazide diuretics, spironolactone, triamterene) can actually enhance lithium reabsorption from the proximal tubule since natriuresis stimulates a reflex increase in the proximal tubule reabsorption of both lithium and sodium. Diuretics that act at the proximal tubule (e.g., osmotic diuretics, carbonic anhydrase inhibitors) are more likely to enhance lithium clearance than other diuretics since they can interfere with the primary site of lithium tubular reabsorption. There is also evidence that lithium is reabsorbed at the loop of Henle. Lithium concentrations rose during the administration of hydrochlorothiazide but not during the administration of furosemide. This phenomenon was due to furosemide blockade of lithium reabsorption at the loop of Henle.[1202] Thus, lithium serum concentrations are likely to decrease during administration of osmotic diuretics and carbonic anhydrase inhibitors, increase during administration of thiazides and other distal tubule diuretics, and may not change during administration of loop diuretics. It is possible that loop diuretic-induced reflex increase in lithium reabsorption at the proximal tubule is offset by blockade of lithium reabsorption at the loop of Henle. In some cases, thiazide diuretics may be used to counteract lithium-induced polyuria. Several case reports indicate the administration of methyldopa to patients receiving lithium is followed by symptoms of lithium toxicity. In some cases, these symptoms occurred without a corresponding increase in lithium serum concentrations. Until more data are available, methyldopa should be used cautiously in patients receiving lithium. Metronidazole, in two case reports, has been shown to increase serum creatinine and serum lithium concentrations when administered to patients stabilized on lithium. Until more data are available, lithium concentrations should be monitored very closely if metronidazole is added. NSAIDs reduce lithium excretion and lead to elevated lithium serum concentrations. It is thought that prostaglandins are involved in the renal clearance of lithium and that NSAIDs interfere with this process, although aspirin, ASA and sulindac do not appear to significantly affect lithium clearance. Serum lithium concentrations should be monitored closely and the patient observed for signs of lithium intoxication for 4�7 days after a NSAID is either added to or discontinued during lithium therapy. Patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn. Lithium plasma concentrations were increased approximately 17% in subjects receiving lithium 450 mg twice daily and celecoxib 200 mg twice daily compared to subjects receiving lithium alone. Various reactions have resulted when lithium is administered with phenothiazines or with haloperidol. Neurotoxicity, consisting of delirium, seizures, encephalopathy, hyperpyrexia, or extrapyramidal symptoms, have occurred when lithium was administered with either thioridazine or haloperidol. Lithium and chlorpromazine each appear to affect the kinetics of the other agent. Concurrent use of lithium and molindone also can produce neurotoxic symptoms. Lithium can precipitate goiter and/or hypothyroidism. Concomitant use of lithium and potassium iodide, KI can increase the likelihood of this adverse reaction. Propranolol is sometimes used to offset lithium-induced tremor. Limited data suggest that using propranolol, even in low doses, with lithium can lead to bradycardia and syncope. In addition, lithium renal clearance has been shown to be lower when propranolol was coadministered. It is not clear if these effects are unique for propranolol or hold true for all beta-blockers. Until more data are known, clinicians should use beta-blockers with caution in patients receiving lithium. Because lithium induces a leukocytosis, it has been used to offset neutropenia, including drug-induced neutropenia. Lithium has been used successfully to reverse zidovudine, ZDV-related neutropenia in 5 patients with AIDS. Little else is known regarding the effects of using lithium and zidovudine together. The German Commission E and other groups warn that any substances that act on the CNS, including psychopharmacologic agents, may interact with the phytomedicinals kava kava, Piper methysticum; St. John's wort, Hypericum perforatum; or valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. Reduced serum lithium concentrations have been observed in previously stabilized patients who initiated daily calcitonin salmon SC injections for osteoporosis. The mechanism is not clear, but serum lithium concentrations were reduced to 30% of the baseline value in all patients studied, and fell below normal therapeutic ranges. Increased urinary lithium clearance is a proposed mechanism for the interaction.

dverse Reactions NOTE: Lithium can be a toxic drug. Many adverse reactions are dose- and concentration-related. The increase in serum concentrations that can precipitate mild to moderate adverse reactions to those producing moderate to severe reactions is small, ranging from below 1.5 mEq/L to 2.0 mEq/L and above. Serum concentrations should be monitored in all patients receiving lithium therapy. Some adverse reactions to lithium occur regularly and at therapeutic serum concentrations. These include: fine hand tremor, xerostomia, dysgeusia, weight gain, polydipsia, polyuria, mild nausea/vomiting, impotence, libido decrease, nephrotic syndrome, and diarrhea. Gastrointestinal effects often resolve with continued therapy and can be alleviated by taking divided doses with meals. If diarrhea or polyuria lead to dehydration, lithium toxicity is possible. Polydipsia and polyuria are more likely to occur during the first few weeks of treatment, and soon disappear. Polyuria may recur unexpectedly as diabetes insipidus.[917] In these cases a nephrogenic diabetes insipidus-like syndrome can develop, with constant thirst and a large output of very dilute urine. Adverse reactions that suggest lithium toxicity include: anorexia; visual impairment or disturbance; drowsiness; muscular weakness; fasciculations, or myoclonia; ataxia; dysarthria or slurred speech; stupor or coma; tremor; confusion; seizures; and arrhythmias. Serum lithium concentrations should not be allowed to rise above 2.0 mEq/L during the acute treatment phase. Serum concentrations above 3.0mEq/L can produce adverse effects involving multiple organ systems. Benign, reversible leukocytosis is routinely noted during lithium therapy. This effect appears to be secondary to an increased number of circulating neutrophils. There have been rare reports of lithium-induced secondary malignancy, including acute leukemia; however, a causal relationship has not been established. Unless the white blood cell count rises to 100,000 cells/cu mm, there is no need to discontinue lithium therapy. At therapeutic dosages, ECG abnormalities may occur in up to 30% of patients receiving lithium and are usually limited to reversible ST-T wave changes (T wave depression and rarely, T wave inversion). T wave depression may be accompanied by the development of U waves. These changes are thought to be due to intracellular myocardial potassium depletion by displacement with lithium. Development of conduction and rhythm abnormalities are rare at therapeutic dosages and may be secondary to underlying cardiac disease. Sinus bradycardia, sinoatrial block, and rarely, first-degree AV block have been reported with use of lithium at therapeutic dosages. Cardiovascular effects from lithium intoxication may include T wave inversion and/or flattening, intraventricular conduction defect, ventricular arrhythmias, hypotension, and rarely, cardiovascular collapse. In almost all reported cases, dysrhythmias, hypotension, and circulatory collapse occurred in the setting of severe, acute intoxication in patients with a clinical course complicated by a prolonged comatose state. Approximately 4% of patients develop goiter while taking lithium. Hypothyroidism has been reported, and preexisting hypothyroidism is a relative contraindication to lithium therapy. There may be an early and transient decrease in serum-bound iodine and free thyroxine, which returns to normal in a few weeks. A few patients may go on to develop a diffuse enlargement of the thyroid. Careful monitoring of thyroid function is necessary. Signs of hypothyroidism may be detected; they include: dry rough skin, alopecia, hoarseness, mania, mental depression, sensitivity to cold, swelling of the feet and lower legs, swelling of the neck. Teratogenesis is a serious concern with lithium. Its use during the first trimester has been associated with an increased incidence of congenital defects of the cardiovascular system, including the rare Ebstein's anomaly. Neural tube defects were reported in two infants out of 105 live births in 138 pregnancies. Since it is an inorganic ion, lithium can freely cross the placenta, however, because lithium is highly effective for some conditions, in some cases, its use may be necessary. If at all possible, its use during the first trimester should be avoided. Its use near term may produce reversible symptoms of lithium toxicity in the neonate. Pseudotumor cerebri has also been reported in patients receiving lithium.

Lithium Eskalith�, Lithobid�, Lithium by Roxane | Eskalith CR� | Lithonate� | Lithotabs�

737. Lee M, Hopkins LE. Attenuation of chemotherapy-induced neutropenia with lithium carbonate. Am J Hosp Pharm 1980;37:1066�71.

17. Gelenberg AJ, Kane JM, Kekller MB et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med 1989;321:1489�93.

1202. Jefferson JW, Kalin NH. Serum lithium levels and long-term diuretic use. JAMA 1979;241:1134�6.

737. Lee M, Hopkins LE. Attenuation of chemotherapy-induced neutropenia with lithium carbonate. Am J Hosp Pharm 1980;37:1066�71.

1170. Pabis DJ, Stanislav SW. Pharmacotherapy of aggressive behavior. Ann Pharmacother 1996;30:278�87.

17. Gelenberg AJ, Kane JM, Kekller MB et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med 1989;321:1489�93.

1674. Consensus Development Panel. NIMH/NIH consensus development conference statement, mood disorders: Pharmacologic prevention of recurrences. Am J Psychiatry 1985;142:469�76.

916. Demers RG, Heninger GR. Electrocardiographic T-wave changes during lithium carbonate treatment. JAMA 1971;218:381�6.

917. Balderssarini RJ, Lipinski JF. Lithium salts: 1970�1975. Ann Intern Med 1975;83:527�33.