CARBOLITH
Lithium Carbonate

Use:
Treatment of manic episodes of manic-depressive illness. Initiate treatment at 600-900 mg/day in 3 divided doses; increase to 1,200-1,800 mg/day in 3 divided doses to achieve serum lithium concentrations between 0.8 and 1.2 mmol/L. Adjust dose according to clinical response and trough serum level (12 h) after steady state is reached (4-5 days). After the acute manic episode subsides, adjust dose to maintain a level of 0.6-1.0 mmol/L. The average dosage range at this stage is usually 450-1,200 mg/day. If a satisfactory antimanic response is not obtained in 14 days, consider discontinuing lithium.

Once patients are stabilized on a maintenance dose with a multiple dosing schedule and once stable therapeutic blood levels are reached, consider a once-daily dosage regimen. The total daily dose, when given as a single dose, may be about 5-30% lower than when given in divided doses over the day.

Geriatrics: Starting dose should not exceed 300 mg/day accompanied by frequent serum level monitoring (concentrations should not exceed 1 mmol/L; usual range: 600-1,200 mg/day).

Contraindications:
Significant renal or cardiovascular disease, severe debilitation or dehydration or sodium depletion, patients receiving diuretics.

Precautions:
Lithium has a narrow therapeutic/toxic ratio - serum lithium concentrations must be measured regularly. Maintain patients on lithium therapy under careful clinical and laboratory control throughout treatment - periodic review and monitoring of kidney, cardiovascular and thyroid function is advisable. Gradual discontinuation of lithium is advised unless abrupt withdrawal is necessary because of toxicity. Safety/efficacy in children < 12 years of age not established. Women of childbearing potential, pregnancy, lactation: Assess expected benefits of therapy vs. possible hazards.

Side effects: Mild adverse effects can occur even if serum lithium levels are 1 mmol/L. Initial postabsorptive symptoms including g.i. discomfort, nausea, vertigo, muscle weakness, and a dazed feeling frequently disappear after stabilization of therapy. More common and persistent side effects: fine hand tremor, fatigue, thirst, polyuria. Mild to moderate toxic reactions occur at lithium levels of 1.5 to 2 mmol/L; moderate to severe reactions at levels > 2 mmol/L. Progressive intoxication may be manifest3ed by confusion, increasing disorientation, muscle twitchings, hyper-reflexia, nystagmus, seizures, diarrhea, vomiting, and eventually coma and death.

Interactions:
ACEIs, methyldopa, metronidazole, tetracycline, thiazide diuretics (increased risk of lithium toxicity), anticonvulsants (increased risk of CNS toxicity), calcium channel blockers (increased risk of neurotoxicity), NSAIDs (increased steady-state plasma lithium levels), SSRIs (increased risk of lithium toxicity or seratonin syndrome), haloperidol (encephalopathy resembling the malignant neuroleptic syndrome), iodides (increased hypothyroid effects), phenothiazines (neurotoxicity with thioridazine, lithium-induced reductions in plasma chlorpromazine levels, phenothiazine-induced increases in red blood cell uptake of lithium, chlorpromazine-induced increases in renal lithium excretion), sodium bicarbonate (enhanced lithium excretion). Lithium may prolong the action of neuromuscular blockers. Increased lithium doses may be required to maintain its effects in patients on theophylline.

Patient tips:
Discontinue therapy and contact physician if signs of lithium toxicity occur. Caution re dizziness, decreased mental alertness (NB driving). Maintain adequate fluid intake and avoid dietary changes which might reduced or increase salt intake.

Supplied:
150 mg, 300 mg, 600 mg capsules.

Pharmacology

Antimanic Agent

Lithium is a monovalent cation which belongs to the group of alkali metals together with sodium, potassium and other elements with which it shares some of its properties.

The mechanism whereby lithium controls manic episodes and possibly influences affective disorders is not yet known.

Unlike other antimanic agents, it does not possess general sedative properties. There is evidence, however, that lithium alters sodium transport and may interfere with ion exchange mechanisms and nerve conduction. Fluid and electrolyte metabolism are believed to be altered in affective disorders and this may be related to the therapeutic action of lithium. Lithium enhances the uptake of norepinephrine and serotonin into the synaptosomes, thus reducing their action. It reduces release of norepinephrine from synaptic vesicles and inhibits production of cyclic AMP.

Lithium is inactive in most screening psychopharmacological tests but it produces marked potentiation of amphetamine hyperactivity in animals. It does not appear to protect against the action of stimulant and convulsive drugs and produces only slight potentiation of CNS depressants.

Lithium can replace sodium in extracellular fluid and during the process of depolarization it has an extremely rapid intracellular influx. However, it is not effectively removed by the sodium pump, thereby preventing the cellular reentry of potassium. As a result, it interferes with electrolyte distribution across the neuronal membrane, leading to a fall in membrane potential and changes in conduction and neuronal excitability. In humans, lithium alters the excitability of the CNS as measured by cortical evoked potentials.

Balance studies indicate that lithium may produce a transitory diuresis with increase in sodium and potassium excretion. A period of equilibrium or slight retention may follow but persistent polyuria may occur in some patients. There is evidence that therapeutic doses of lithium decrease the 24-hour exchangeable sodium. Longitudinal metabolic studies have demonstrated cumulative lithium retention in some patients without undue rise in plasma lithium values, indicating a possible intracellular retention of lithium. There is some evidence that lithium may affect the metabolism of potassium, magnesium and calcium.

ECG changes with lithium have been reported in man.

The primary toxic effects in man appear to be on the central nervous system.

Pharmacokinetics:
Lithium ions are rapidly absorbed from the gastrointestinal tract and plasma lithium peaks are reached 2 to 4 hours after lithium administration. The distribution of lithium in the body approximates that of total body water, but its passage across the blood-brain barrier is slow and at equilibration the CSF lithium level reaches only approximately half the plasma concentration.

The elimination half-life of lithium averages 20 to 24 hours. Half-life in geriatric patients and patients with impaired renal function is increased, 36 and 40 to 50 hours have been reported respectively.

Lithium is excreted primarily in urine with less than 1% being eliminated with the feces. Lithium is filtered by the glomeruli and 80% of the filtered lithium is reabsorbed in the tubules, probably by the same mechanism responsible for sodium reabsorption. The renal clearance of lithium is proportional to its plasma concentration. About 50% of a single dose of lithium is excreted in 24 hours. A low salt intake resulting in low tubular concentration of sodium will increase lithium reabsorption and might result in retention or intoxication.

Renal lithium clearance is, under ordinary circumstances, remarkably constant in the same individual but decreases with age and falls when sodium intake is lowered. The dose necessary to maintain a given concentration of serum lithium depends on the ability of the kidney to excrete lithium. However, renal lithium excretion may vary greatly between individuals and lithium dosage must, therefore, be adjusted individually. In clinical reports, it has been noted that serum lithium may rise an average of 0.2 to 0.4 mmol/L after intake of 300 mg and 0.3 to 0.6 mmol/L after intake of 600 mg of lithium carbonate. It has been suggested that manic patients retain larger amounts of lithium during the active manic phase, but recent studies have been unable to confirm a clear difference in excretion patterns. However, patients in a manic state seem to have an increased tolerance to lithium.

Indications

Acute manic episodes in patients with bipolar affective disorders. Maintenance therapy has been found useful in preventing or diminishing the frequency of subsequent relapses in bipolar manic-depressive patients (with a history of mania).

Contraindications

Patients with severe cardiovascular or renal disease and those with evidence of severe debilitation or dehydration, sodium depletion, brain damage. Conditions requiring low sodium intake.

Precautions

Lithium therapy requires reaching plasma concentrations of lithium which are relatively close to the toxic concentration. Lithium is excreted primarily by the kidney; adequate renal function and adequate salt and fluid intake are essential in order to avoid lithium accumulation and intoxication. Thus, a decision to initiate lithium therapy should be preceded by a thorough clinical examination and evaluation of each patient, including laboratory determinations, ECG, and a very careful assessment of renal function. When sodium intake is lowered, lithium excretion is reduced. Diminished intake or excessive loss of salt and fluids, as a result of vomiting, diarrhea, perspiration or use of diuretics will also increase lithium retention. Thus, lithium should not be given to patients on a salt-free diet and sodium depletion must be carefully avoided. Therefore, it is essential for the patient to maintain a normal diet including adequate salt and fluid intake during lithium therapy. Salt supplements and additional fluids may be required if excessive losses occur. If diuretics are used during lithium therapy the serum lithium concentration must be closely monitored.

Drug Interactions:
Thiazide diuretics, furosemide, spironolactone, methyldopa, indomethacin, phenylbutazone and piroxicam can increase lithium concentrations. Acetazolamide, sodium bicarbonate, sodium chloride, theophylline and mannitol can decrease lithium concentrations. Neurotoxicity may be increased by concomitant use of haloperidol, phenothiazines, carbamazepine or phenytoin.

Maintain patients on lithium therapy under careful clinical and laboratory control throughout treatment. Means of obtaining accurate determination of serum lithium concentrations should be available, since frequent serum determinations are required especially during the initial period of treatment. Lithium toxicity is closely related to serum lithium concentrations and during treatment they should usually not exceed 1.5 mmol/L, if serious adverse reactions and lithium intoxication are to be avoided. This lithium concentration refers to a blood sample drawn before the patient has had his first lithium dose of the day, therefore, 9 to 12 hours after his last dose of drug. Serum lithium concentrations should usually be monitored 3 times weekly and blood studies and urinalysis weekly during the initial period of administration and periodically as required thereafter. If lithium levels exceed 1.5 mmol/L, discontinue the drug and, if appropriate, resume administration at a lower concentration after 24 hours. Prodromal toxic signs such as fatigue, muscular weakness, incoordination, drowsiness, coarse tremors, diarrhea and vomiting provide a sensitive warning of lithium intoxication. The patient and his family should be warned to notify the physician immediately if any such adverse reactions should occur.

Patients with underlying cardiovascular disease should be observed carefully for signs of arrhythmias. Geriatric patients appear to be more susceptible to adverse effects even when lithium levels are therapeutic.

There have been reports of withdrawal symptoms from lithium and lithium rebound. Thus, gradual discontinuation is recommended unless abrupt withdrawal is necessary because of toxicity.

There is evidence of decreased tolerance to lithium once the acute manic episode breaks. Therefore, when the acute attack subsides, the dosage should be reduced rapidly in order to produce serum lithium concentrations no higher than between 0.6 and 1.0 mmol/L.

In view of the limited dosage range of lithium compared to other psychotropic agents, particular care is required for the patient to receive exactly the prescribed number of lithium tablets or capsules.

Periodic review and monitoring of kidney and cardiovascular function is advisable during therapy with lithium carbonate. Perform other laboratory tests as indicated by the patient's clinical condition. The appearance of signs of toxicity or a rise in the blood concentration of lithium after the dosage is stabilized should alert the physician to determine the reasons for lithium accumulation.

Since the formation of nontoxic goiters has been reported during lithium therapy, examine the thyroid gland before treatment and perform appropriate thyroid function tests. Nontoxic goiters reported during prolonged lithium therapy have disappeared following discontinuation of the medication. Treatment with small doses of thyroxine in patients who develop a diffuse nontoxic goiter may stop further growth or lead to shrinkage of the gland.

Pregnancy:
Lithium should not be given during pregnancy without careful weighing of risk versus benefit. Lithium should be used during pregnancy only in severe disease for which safer drugs cannot be used or are ineffective. When possible, lithium should be withdrawn for at least the first trimester unless it is determined that this would seriously endanger the mother.

Data from lithium birth registries suggest that the drug may increase the incidence of cardiac and other anomalies, especially Ebstein's anomaly.

When lithium is used during pregnancy, serum lithium concentrations should be carefully monitored and dosage adjusted if necessary since renal clearance of the drug and distribution of the drug into erythrocytes may be increased during pregnancy. Pregnant women receiving lithium may have subtherapeutic serum lithium concentrations if dosage of the drug is not increased during pregnancy. Immediately postpartum, renal clearance of lithium may decrease to pre-pregnancy levels; therefore, to decrease the risk of postpartum lithium intoxication, dosage of the drug should be reduced 1 week before parturition or when labor begins.

Lactation:
Lithium passes into milk and its use should be avoided during lactation as concentrations are 33 to 50% of those in the mother's serum.

Geriatrics:
See under Dosage.

Adverse Effects

Mild adverse effects may be encountered even when serum lithium values remain below 1 mmol/L. The most frequent adverse effects are the initial postabsorptive symptoms, believed to be associated with a rapid rise in serum lithium concentrations. They include, gastrointestinal discomfort, nausea, vertigo, muscle weakness and a dazed feeling and frequently disappear after stabilization of therapy. The more common and persistent adverse reactions are: fine tremor of the hands, and, at times, fatigue, thirst, polyuria and nephrogenic diabetes insipidus. These do not necessarily require reduction of dosage.

Mild to moderate toxic reactions may occur at lithium concentrations from 1.5 to 2 mmol/L, and moderate to severe reactions at concentrations above 2 mmol/L.

A number of patients may experience lithium accumulation during initial therapy, increasing to toxic concentrations and requiring immediate discontinuation of the drug. Some elderly patients with lower renal clearances for lithium may also experience different degrees of lithium toxicity, requiring reduction or temporary withdrawal of medication. However, in patients with normal renal clearance the toxic manifestations appear to occur in a fairly predictable sequence related to serum lithium concentrations. The usually transient gastrointestinal symptoms are the earliest side effects to occur. A mild degree of fine tremor of the hands may persist throughout therapy. Thirst and polyuria may be followed by increased drowsiness, ataxia, tinnitus and blurred vision, indicating early intoxication. As intoxication progresses the following manifestations may be encountered: confusion, increasing disorientation, muscle twitchings, hyperreflexia, nystagmus, seizures, diarrhea, vomiting, and eventually coma and death.

The following adverse effects have been reported usually related to serum lithium concentrations:

Gastrointestinal:
Anorexia, nausea, vomiting, diarrhea, thirst, dryness of the mouth, metallic taste, abdominal pain, weight gain or loss.

Neurologic:
General muscle weakness, ataxia, tremor, muscle hyperirritability, (fasciculation, twitchings, especially of facial muscles and clonic movements of the limbs), choreoathetotic movement, hyperactive deep tendon reflexes.

CNS:
Anesthesia of the skin, slurred speech, blurring of vision, blackout spells, headache, seizures, cranial nerve involvement, psychomotor retardation, somnolence, toxic confusional states, restlessness, stupor, coma, acute dystonia. EEG changes recorded consisted of diffuse slowing, widening of the frequency spectrum, potentiation and disorganization of background rhythm. Sensitivity to hyperventilation and paroxysmal bilateral synchronous delta activity have also been described.

Cardiovascular:
Arrhythmia, hypotension, ECG changes consisting of flattening or inversion of T waves, peripheral circulatory failure, cardiac collapse.

Genitourinary:
Albuminuria, oliguria, polyuria, glycosuria.

Allergic:
Allergic vasculitis.

Dermatologic:
Dryness and thinning of the hair, leg ulcers, skin rash, pruritis,

Hematologic:
Anemia, leucopenia, leucocytosis.

Metabolic:
Transient hyperglycemia, slight elevation of plasma magnesium, goiter formation.

Nontoxic, diffuse or nodular goiters have developed in some patients after initiation of therapy, apparently unrelated to other signs of lithium toxicity. A decrease of PBI and increased I(131) uptake also have been reported.

Hypercalcemia, associated with lithium induced hyper- parathyroidism, has also been reported.

Miscellaneous:
General fatigue, dehydration, peripheral edema.

Overdose

Symptoms:
Lithium toxicity is closely related to the concentration of lithium in the blood and is usually associated with serum concentrations in excess of 2 mmol/L. Early signs of toxicity which may occur at lower serum concentrations were described under Adverse Effects and usually respond to reduction of dosage. Lithium intoxication has been preceded by the appearance or aggravation of the following symptoms: sluggishness, drowsiness, lethargy, coarse hand tremor or muscle twitchings, loss of appetite, vomiting, and diarrhea. Occurrence of these symptoms requires immediate cessation of medication and careful clinical reassessment and management. Signs and symptoms of lithium intoxication have already been described under Adverse Effects.

Treatment:
Discontinue lithium therapy. Support respiratory and cardiovascular functions. Depending on mental status, use ipecac syrup or gastric lavage. Follow with activated charcoal and saline cathartic if multiple ingestion is suspected (charcoal does not adsorb lithium effectively). Restore fluid and electrolyte balance. Urinary alkalinization may have a limited effect on increasing lithium excretion. Give a benzodiazepine as needed for agitation and/or seizures. Phenytoin may be needed for seizures.

Hemodialysis is the treatment of choice when the above measures fail to improve the patients clinical condition, reduce the serum lithium level or lithium level is >3.5 mmol/L. Hemodialysis is more effective than peritoneal dialysis but peritoneal dialysis is somewhat effective and can be used if hemodialysis is not available.

Dosage

The therapeutic dose for the treatment of acute mania should be based primarily on the patient's clinical condition. It must be individualized for each patient according to blood concentrations and clinical response. For manic patients, the dosage should be adjusted to obtain serum concentrations between 0.8 and 1.2 mmol/L (in blood samples drawn before the patient has had his first lithium dose of the day).

In properly screened adult patients, the suggested initial daily dosage for acute mania is 900 to 1800 mg (15 to 20 mg/kg), divided into 3 doses. In view of the large variability of renal lithium excretion between individuals, it is suggested that lithium treatment be started at a dose between 600 and 900 mg/day, reaching a level of 1200 to 1800 mg in divided doses on the second day. Depending on the patient's clinical condition, the initial dosage should be adjusted to produce the desired serum lithium concentration. The weight of the patient should also influence the choice of the initial dose.

Elderly and debilitated patients, and those with significant renal impairment should be prescribed lithium with particular caution. Starting dose should not exceed 300 mg/day accompanied by frequent serum level monitoring. Serum concentrations of 0.4 to 0.6 mmol/L are usually effective in elderly patients.

After the acute manic episode subsides, usually within a week, the dosage should be rapidly reduced to achieve serum concentrations between 0.6 and 1.0 mmol/L (with the concentration kept below 1.5 mmol/L), since there is evidence at this time of a decreased tolerance to lithium. The average suggested dosage at this stage is 900 mg/day, divided into 3 doses, with a range usually between 450 and 1200 mg/day. If a satisfactory response is not obtained in 14 days, discontinue lithium therapy. When the manic attack is controlled, maintain lithium administration during the expected duration of the manic phase, since early withdrawal might lead to relapse. It is essential to maintain clinical supervision of the patient and monitor lithium concentrations as required during treatment (see Precautions).

Lithium may be used concomitantly with neuroleptic drugs, but additional studies are required to determine the relative advantage of single, combined or sequential treatment of manic episodes.

Children:
0.5 to 1.5 g/m(2) in divided doses for the acute phase; the maintenance dose should be adjusted to maintain lithium serum concentrations of 0.5 to 1.2 mmol/L. Dose in children should not exceed adult dose.

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