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Lithium is one of the most effective medications for the continuous treatment of bipolar disorder. It is particularly useful for the treatment of acute manic episodes and reduces rates of suicide associated with affective disorders.1,2 Among agents used to treat depression, lithium is associated with high morbidity and mortality indices (events per 1000 exposures).3


Lithium is a simple ion with a complex mechanism of action that is not fully understood. It is postulated to involve primary monoamine neurotransmission, via a direct interaction between the lithium ion and cellular enzymes, influencing the secondary signaling pathways of dopamine, serotonin, and norepinephrine.1,4 Lithium competes with other similar cations, including sodium, potassium, magnesium, and calcium, and displaces them from intracellular and extracellular sites. Interference with sodium ions at the sodium channel and the sodium-potassium pump on the cell membrane is responsible for lithium’s adverse effect on myocardial electrical activity. Lithium inhibits arginine vasopressin, an effect that is responsible for polyuria and nephrogenic diabetes insipidus seen during lithium therapy. Other pharmacologic effects include interference with the release and reuptake of norepinephrine at the nerve terminal site. Lithium may enhance serotonin release, particularly from the hippocampus, and has been implicated in serotonin syndrome when combined with other medications that alter serotonin metabolism. Lithium is handled by the kidney similar to sodium; anything that may increase sodium absorption, such as medications that reduce glomerular function, has the potential to contribute to lithium toxicity.5


After oral ingestion of therapeutic doses, lithium is rapidly and almost completely absorbed, although delayed absorption may occur with sustained-release products and after ingestion of a large number of tablets.6 Lithium is not bound to plasma proteins and has an initial volume of distribution between 0.6 and 0.9 L/kg. Ingestion of a single tablet of lithium carbonate 300 milligrams containing 8.12 mEq of lithium ion is expected to increase the lithium concentration by approximately 0.1 to 0.3 mEq/L (assuming a normal volume of distribution in a patient with a weight of 50 to 100 kg).

Lithium exhibits a prolonged redistribution phase and tissue burden. Lithium distribution into and out of the brain is slower, resulting in neurologic effects that do not correlate with serum levels. The lithium concentrations in the brain and in the serum may differ by two- to three-fold.7 Continuation of toxic effects, even after hemodialysis, can be due to the drug’s slow movement out of the CNS and redistribution. Serum concentrations can serve as a marker of exposure but are poor predictors for severity of toxicity. Thus, clinical signs and symptoms provide a more accurate indicator of CNS lithium concentrations compared to serum concentrations.

The elimination half-life after a single dose of lithium is about 18 to 24 hours in young adults and almost twice that in the elderly.6...

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