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Lithium is an effective and approved drug for the treatment of bipolar disorder and acute episodes of mania.1 Unapproved uses for lithium include augmentation of the action of other antidepressant drugs and treatment of aggression, post-traumatic stress disorder, and pediatric conduct disorders. Lithium toxicity most often results from accidental or intentional overdose or from an alteration in lithium clearance secondary to impaired renal function.

It has been estimated that up to 75% to 90% of patients who are treated with lithium over the long term develop toxicity at some time during their therapy.2 During 2008, the American Association of Poison Control Centers received reports of 6492 potential toxic exposures to lithium with four reported deaths.3

Lithium has several known pharmacologic effects, but which ones are responsible for the therapeutic benefit in treating bipolar disorder and mania is unknown.4 As would be expected, lithium competes with other similar cations, including sodium, potassium, magnesium, and calcium, displacing them from both intracellular and extracellular sites. Interference with sodium ions at the sodium channel and the sodium-potassium pump located on the cell membrane is responsible for the adverse effect that lithium has on myocardial electrical activity. Lithium inhibits arginine vasopressin, an effect that is responsible for a common adverse effect seen during lithium therapy. Some of the toxic effects of lithium may be due to inhibition of 3-glycogen synthase kinase, which is present in high quantities in the brain.4

Lithium inhibits inositol monophosphatase and reduces the concentration of inositol in the cytoplasm.5 Intracellular inositol depletion is one of the proposed mechanisms for the therapeutic effect of lithium in bipolar disorders. Lithium inhibits adenylate cyclase, decreasing intracellular cyclic adenosine monophosphate and possibly cyclic guanosine monophosphate. Lithium is also thought to interfere with the release and reuptake of the neurotransmitter 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.

Risk of lithium toxicity increases when it is combined with other medications. Most often toxicity involves a drug–drug interaction with lithium (Table 175-1). Although patients are routinely cautioned about pharmacologic interactions, they may not understand that nonprescription herbal diuretics may also potentiate toxicity.6 An important potential interaction relevant to the emergency physician is that neuromuscular blocking agents such as succinylcholine, vecuronium, and pancuronium may result in a prolonged neuromuscular blockade when given to patients receiving long-term lithium therapy.7

Table 175-1 Drugs That Interact with Lithium

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