As a mood stabilizer for patients with bipolar disorder, lithium was the darling of U.S. psychiatry from the 1970s to well into the 1990s. It then began an ill-deserved, gradual fall from grace and today could be considered a pharmaceutical endangered species. But why?
Did lithium lose effectiveness? Is it too toxic? Is its side effect burden too heavy? Does it interact adversely with too many medicines? Is it too cumbersome to use? Was it just a fad whose time came and went—a psychiatric pet rock? Did it fall prey to the marketing might behind patent-protected drugs? Was it replaced by more effective and safer drugs?
You are partially correct if you checked “all of the above,” because all contain a kernel of truth. At the same time, each is an exaggeration that does grave injustice to a remarkable medication. In addition, psychiatry appears to pay only lip service to convincing evidence that lithium is the only mood stabilizer that reduces the risk of suicide during long-term treatment.1
Some psychiatrists rationalize that “lithium is too difficult to use, so I never prescribe it.”2,3 My response is simply, “try it, and I think you’ll like it.” Measuring serum lithium concentrations is simple, accurate, and inexpensive. And we know quite a bit about how lithium dosage and blood level relate to response and tolerability.
Where does lithium stand?
Lithium is the first solid element in the periodic table (atomic number 3, atomic weight 6.94) (Box 1). As a treatment for bipolar disorder, lithium’s rise to prominence in the United States was far from rapid. Its antimanic properties were described by John Cade in Australia in 1949 in an open-label case series, but it was not FDA-approved for 20 years—for acute manic episodes in 1970 and for maintenance therapy “in those manic depressive patients with a history of mania” in 1974. Today, lithium shares FDA-approved manic episode billing with chlorpromazine (1973), divalproex (1995), and olanzapine (2000), but it remains the only FDA-approved drug for maintenance (although the FDA is considering a bipolar depression maintenance indication for lamotrigine).
HOW LITHIUM IS METABOLIZED
Lithium has no meaningful protein binding and no metabolites, being excreted almost entirely by the kidneys. Its elimination half-life of 18 to 24 hours may be longer in the elderly and shorter in youth because of age-dependent variations in glomerular filtration rate. For unclear reasons, renal lithium clearance appears to be more rapid in obese persons.
Lithium preparations available in the United States include standard-release (150, 300, 600 mg), slow-release (Lithobid and generic 300 mg), and controlled-release (Eskalith CR 450 mg) forms of lithium carbonate and a lithium citrate liquid. Lithium carbonate, 300 mg, and lithium citrate, 5 cc, each contain about 8 mmols of lithium. Lithium and lithium carbonate are not the same—there are 56.36 mg of lithium in 300 mg of lithium carbonate. The correct formula for lithium carbonate is Li2CO3, not LiCO3 as is commonly and erroneously written.
With the standard-release preparation, peak serum levels are reached in about 1 1/2 hours and with the slow- and controlled-release forms in about 4 to 4 1/2 hours. At times, the slower-release forms may be better tolerated, but they are also a bit more costly (although all forms of lithium are inexpensive, compared with other mood stabilizers).
If you examine lithium’s status relative to other bipolar medications, you’ll find some inconsistencies. For example:
- Clinical practice guidelines from the Department of Veterans Affairs (January 1999) recommended lithium as the first-line agent for acute and prophylactic treatment of manic and mixed states, bipolar depression, and rapid cycling.4
- The Expert Consensus Guidelines (April 2000) gave at least equal billing—if not preferred status—to divalproex for those indications.5
- The American Psychiatric Association’s (APA) revised guidelines (April 2002) gave the nod to lithium for classic elated mania and bipolar depression but to divalproex for mixed mania and rapid cycling.6 Divalproex was rated comparable to lithium for maintenance therapy, despite the lack of convincing data.
- The European perspective (January 2002) is most similar to that of the Department of Veterans Affairs, favoring lithium for acute mania, bipolar depression, and long-term treatment.7
There is no clear winner (or loser) in the battle for bipolar marketplace supremacy. The belief that one drug does everything is a fantasy for all but a small minority of patients with bipolar disorder. Polypharmacy is the rule, and rational polypharmacy the goal. To exclude lithium from the arsenal of bipolar drugs would be folly, yet lithium prescribing seems to have become a vanishing art. One of my psychopharmacologist colleagues recently expressed bewilderment at the number of “treatment-resistant” bipolar patients referred to him who had never been treated with lithium.