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.^1,2,3 Off-label uses for lithium include augmentation of the action of other antidepressant drugs and treatment of aggression, posttraumatic stress disorder, and pediatric conduct disorders. Lithium for the treatment of Alzheimer’s disease is under investigation.⁴ Lithium toxicity most often results from accidental or intentional overdose, increased dose, or reduction in renal clearance of lithium.

The specific pharmacologic effect responsible for the therapeutic benefit in bipolar disorder and mania is unknown.⁵ 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. Some toxic effects of lithium may be due to inhibition of 3-glycogen synthase kinase, which is present in high quantities in the brain.⁵ Other pharmacologic effects include inhibition of inositol monophosphatase and reduction of the concentration of inositol in the cytoplasm, inhibition of adenylate cyclase and reduction of intracellular cyclic adenosine monophosphate and possibly cyclic guanosine monophosphate, and 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 excreted by the kidneys, so medications that reduce glomerular function have the potential to contribute to lithium toxicity, particularly thiazide diuretics.⁶ 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.

PHARMACOKINETICS

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.⁷ Lithium is not bound to plasma proteins and has an initial volume of distribution of 0.6 L/kg, which is similar to that of body water, but over time this can increase to 0.9 L/kg as the ion distributes throughout the body. Ingestion of a single tablet of lithium carbonate 300 milligrams containing 8.12 mEq of lithium ion will acutely raise serum lithium levels by about 0.2 mEq/L (0.2 mmol/L) in a 70-kg adult.

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 twofold to threefold.⁸ Continuation of toxic effects, even after hemodialysis, can be due to the drug’s slow movement out of the CNS. Therefore, serum levels do not predict CNS levels and only roughly correlate with clinical symptoms.

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.⁷ After continued therapy of longer than a year, the lithium elimination half-life increases, up to almost 60 hours in all ages. Lithium is not metabolized and is excreted unchanged, primarily in the urine. Like other cations of similar size, lithium is reabsorbed in the proximal tubule.

Renal insufficiency is a critical factor in the development of lithium toxicity. Changes in fluid and electrolyte status can impact lithium clearance; sodium and water loss due to heat or exercise may lead to lithium retention. The elderly are particularly prone to toxicity because of their decreased volume of distribution and reduced renal clearance. Elderly patients are at risk for lithium toxicity when concomitantly treated with either loop diuretics or angiotensin-converting enzyme inhibitors.⁹

ADVERSE EFFECTS OF CHRONIC LITHIUM THERAPY

Adverse effects during therapeutic lithium use are common, occurring in up to 90% of treated patients. The most frequent adverse effects include fine postural hand tremor, fatigue, polyuria due to loss of urinary concentration ability, hypothyroidism, and hyperparathyroidism with hypercalcemia.^10,11,12 Worsening of a baseline tremor and development of ataxia or dysarthria are important signals of developing toxicity and may signal a need to decrease the dose of lithium. Long-term lithium treatment can lead to electroencephalographic changes, including diffuse slowing, an increase in theta and delta waves, and a decrease in alpha activity.

Lithium is a common cause of drug-induced nephrogenic diabetes insipidus, which is prevalent in up to 40% of patients receiving long-term lithium treatment and occurs through decreased expression of aquaporin-2 in the distal tubule of the nephron.^13,14 This leads to decreased urinary concentrating ability, which is usually compensated in patients by increased thirst. The defect in the distal nephron can also result in an inability to acidify the urine, causing an incomplete distal renal tubular acidosis without acidemia. Long-term lithium treatment can lead to a progressive nephropathy, with a mild reduction in glomerular filtration^12,15 and about a 1% absolute risk of requiring renal replacement therapy.^15,16 Maintaining serum lithium levels below 0.8 mEq/L (0.8 mmol/L) may reduce long-term renal damage.¹⁷

GI side effects, including nausea, vomiting, and diarrhea, are common at initiation of treatment, are generally transient, and can be decreased by giving the lithium dose with food or dividing the dose over the day. Development of these symptoms during the course of treatment, on the other hand, may signal toxicity or may cause volume depletion and induce toxicity.

ECG abnormalities commonly reported with lithium use include QT interval prolongation, T-wave flattening or inversion, and significant bradycardia.¹⁸

Hypothyroidism is the most prevalent endocrine dysfunction, occurring at a rate almost six times that in the general populace.^12,19 Hyperparathyroidism and hypercalcemia are frequently reported and can be associated with stimulation of hyperplasia or adenomas.²⁰

TOXIC EFFECTS

Lithium toxicity can be divided into three main categories: acute toxicity in naïve patients, acute-on-chronic toxicity in those who take lithium long term and take an acute intentional overdose, and chronic toxicity developing in patients receiving long-term lithium therapy who experience a change in lithium dosage or decreased renal clearance.^21,22,23,24 Decreases in glomerular filtration or intravascular volume depletion are a precipitating cause in nearly all cases of chronic toxicity. Other factors may also contribute to the development of lithium toxicity (Table 181-1).²⁵

Recognizing lithium toxicity may be challenging, particularly in patients with chronic toxicity.^26,27 There is only an approximate correlation between serum levels and clinical symptoms.²⁴ Common symptoms are increased tremor, muscle fasciculations, clonus, choreoathetosis, ataxia, muscle weakness, dysarthria, agitation, and lethargy (Table 181-2).^25,27,28 It may be difficult to distinguish between lithium toxicity and organic delirium.²⁹ Although most patients present with a slowing of cognitive function, cases of lithium toxicity presenting with mania or auditory, visual, and tactile hallucinations have been reported. As toxicity worsens, confusion, lethargy, stupor, seizures, and finally coma develop.