Evidence-Based Reviews

Lithium: An underutilized element

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Despite precautions, lithium should remain a first-line therapy for bipolar disorder



In clinicians and patients alike, lithium triggers reactions ranging from apprehension and fear about adverse effects and toxicity to confusion over lithium’s usefulness compared with other mood stabilizers that do not require blood monitoring. Research from the 1950s to the 1970s demonstrated that lithium is effective for prophylaxis of mood episodes in patients with bipolar disorder and could reduce the frequency of hospitalization in patients who are depressed.1 For years, lithium was commonly prescribed to treat bipolar disorder, but in recent years its use has fallen out of favor due to concerns about its risks, and the availability of newer medications. This article reviews lithium’s origins (Box1-4), pharmacology, risks, and benefits, and makes a case for why it should remain a first-line therapy for bipolar disorder.


A brief history of lithium

Lithium was initially used in the 1840s to treat gout. William Hammond became the first physician to prescribe lithium bromide for acute mania in 1871, and in 1894, Danish psychiatrist Frederik Lange first used lithium carbonate to treat “melancholic depression.”1 In the 20th century, lithium-containing products were used to treat rheumatologic conditions such as renal calculi and other uric acid diatheses.

Lithium experienced a revival in 1949 when John Cade expanded upon Archibald Garrod’s theory regarding uric acid and gout. As a physician during WWII, Cade observed manic and depressive behaviors among prisoners.2 Theorizing that this was caused by either an excess or lack of a metabolite, he injected urine from patients with mania, depression, and schizophrenia and from healthy individuals into guinea pigs.3 Animals who received urine from patients with mania died faster than those injected with urine from a patient with schizophrenia.2 Concluding that urea was the culprit, Cade substituted the relatively water insoluble uric acid for “the most soluble of urates,” which was lithium urate.2,3 Rather than succumbing to a quicker death, guinea pigs injected with lithium urate became placid, tranquilized, lost their natural timidity, and generally did not respond to stimulation.3

Cade administered lithium carbonate and lithium citrate to himself and, because he did not experience any unwanted effects, began testing the medication on patients. Cade’s landmark 1949 paper4 notes improvement in all 10 patients with mania but little change in 6 patients with schizophrenia and 3 with chronic depression.2

In the United States, interest in lithium did not begin until the 1960s, when Samuel Gershon introduced the medication to a psychiatric hospital in Michigan. Financed by the National Institute of Mental Health, this program bought bulk lithium from a chemical supply store, and a local pharmacy formed it into capsules. Analysis of 4 controlled studies from 1963 to 1971 showed an average response rate to lithium of 78% in 116 patients with mania.1

By the end of the 1960s, many psychiatrists were prescribing lithium. At that time, lithium was not FDA-approved, but it could be prescribed as an investigational new drug by obtaining a special permit. In 1970, the FDA approved lithium for acute mania, and for prophylaxis of mania in 1975. Lithium has not yet been approved for prophylaxis of depression, despite substantial evidence indicating efficacy.1

How lithium works

Lithium has effects on neurotransmitters implicated in mania, such as glutamate, dopamine, and gamma-aminobutyric acid.5 Quiroz et al6 provide a detailed description of lithium’s effects, which can be summarized as modulating neuronal signaling pathways, including B-cell lymphoma 2 (BCL2), cAMP-response element binding protein (CREB), and glycogen synthase kinase-3 (GSK-3). Through these signaling cascades, lithium can curtail progression of neuronal apoptosis caused by the biochemical stress commonly seen in bipolar disorder pathogenesis.6

A wide range of potential adverse effects

Lithium can cause adverse effects in several organ systems. Clinicians must be aware of these effects before prescribing lithium or continuing long-term use. The most commonly documented adverse effects and symptoms of toxicity are:

  • tremor
  • renal dysfunction, including renal insufficiency and polyuria or polydipsia
  • hypothyroidism
  • hyperparathyroidism (with subsequent hypercalcemia)
  • weight gain
  • gastrointestinal (GI) symptoms.

These symptoms tend to occur when lithium serum levels are outside the reference range of 0.6 to 1.2 mEq/L, typically once blood levels reach ≥1.5 mEq/L.7 However, thyroid and renal abnormalities can occur at levels below this value, and might be related to cumulative lithium exposure.7 Adverse effects usually are precipitated by inadequate water intake or inadvertently taking an extra dose. Symptoms of lithium toxicity can be mild, moderate (GI complaints, tremor, weakness, fatigue), or severe (agitation, seizures, autonomic dysregulation, confusion, coma, death).

Lithium adverse effects and toxicity are infrequent. An analysis of 17 years of data in Sweden showed the incidence of moderate to severe lithium intoxication (serum level ≥1.5 mEq/L) was .01 patients per year.8 A recently published US analysis found the prevalence rate of lithium toxicity was 2.2%.9 Results from both groups show that drug interactions were an important cause of increased lithium levels, and specifically that initiating a medication that could interact with lithium was associated with 30-fold higher risk of needing acute care for lithium toxicity.9 Possible drug interactions include nonsteroidal anti-inflammatory drugs, diuretics, and renin-angiotensin-aldosterone system inhibitors.9 Because lithium is eliminated exclusively by the kidneys, impaired or altered renal function can increase the risk of lithium retention, leading to intoxication. Other risk factors include older age, alteration of water-salt homeostasis (fever, diarrhea, vomiting), higher number of treated chronic diseases as measured by Chronic Disease Score (range: 0 to 35; higher scores denotes higher number of treated chronic diseases and increased hospitalization risk), and higher total daily lithium dosage.9

Presentation of lithium intoxication often is mild or nonspecific, and physicians should have a low threshold for checking lithium blood levels.8 Lithium intoxication can be safely managed with volume expansion, forced diuresis, and hemodialysis.

Continue to: Lithium use during pregnancy...


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