Once Down for the Count, Lithium Lives to Fight Again

The importance of the topic was underscored by the overflow crowd attending a workshop on the last day of APA’s 2002 annual meeting in May. The psychiatrists simply wanted to know about the latest information on a very old “friend”—lithium.

Eric Smith, M.D., a PGY-2 psychiatry resident at Boston University Medical Center chaired the workshop, titled “Lithium Revisited.” He was joined by bipolar experts Frederick Goodwin, M.D., research professor of psychiatry and behavioral sciences at the George Washington University School of Medicine, and James W. Jefferson, M.D., distinguished senior scientist at the Madison Institute of Medicine and director of the Lithium Information Center, who served as discussants.

Both Goodwin and Jefferson praised Smith for an excellent overview of a drug that Goodwin characterized as “born well before the chair of this workshop!”

Indeed, Smith reviewed 50 years of experience in using lithium in bipolar states, noting that by far, it is the one drug in all of psychopharmacology with a “fully documented history of efficacy.” There are, Smith noted, over a dozen placebo-controlled clinical trials documenting the drug’s effects in reducing the frequency of manic episodes as well as stabilizing cycling between mania and depression, on average producing a fourfold reduction of episodes of mania or depression.

Not only is the drug a well-established mood stabilizer, Smith said, but “recent research has documented that lithium has some neuroprotective effects, and it is by far the most effective treatment for reducing—by as much as 50 percent—the overwhelming mortality associated with bipolar disorder.” Lithium is the only drug that has been documented to decrease significantly both suicidal gestures and decrease the number of completed suicides among patients with bipolar disorder.

“But,” Smith hedged, “it has a huge side-effect profile and correspondingly huge problems with patient compliance. Simply put, patients feel so much better taking it, but they stop taking it to avoid the side effects.”

Chronic lithium therapy is commonly associated with nausea, diarrhea, dizziness, and blurry vision. In more severe cases, it is often referred to as “lithium intoxication,” which can be associated with headache, excessive sweating, electrolyte disturbances, ataxia, tremor, seizure, and in severe toxicity, coma leading to death.

“Clinicians are always warned to check serum lithium levels,” Smith noted, “but you have to remember that the serum level must be correlated with the clinical response. In some people, toxicity can and does occur at what would on average be considered a therapeutic level.”

The accepted therapeutic level, he noted, is being rethought, based on recent research. “A therapeutic level now seems to be in the range of 0.6 to 1.0 milliequivalents per liter rather than what older references said, which was to keep your patients between 0.8 and 1.2.” Keeping the serum levels lower achieves equal efficacy, Smith said, but can drastically reduce side effects. In addition, using long-acting lithium, given daily at bedtime, also has been shown recently to reduce side effects.

Goodwin and Jefferson agreed that lithium is by far the most effective mood stabilizer. They disagreed somewhat on its side-effect profile, especially in the long-term effects of lithium therapy. Goodwin actively champions combination therapy, using lower doses of lithium along with another mood stabilizer—he often adds low doses of divalproex—and has done studies that indicate that patients on combination therapy do just as well symptomatically, while experiencing fewer side effects.

Smith noted that a good number of current bipolar experts do believe in lithium and use it frequently, in spite of recent research suggesting that it has fallen out of favor.

“As long as you get a good history, talk openly and candidly about the side effects of lithium with your patients, and monitor those side effects over time,” Smith concluded, “lithium is still the drug of choice in bipolar disorder. It is the most effective medication we have and, when appropriately managed, is quite safe.”

The Web site for the Lithium Information Center is www.miminc.org/aboutlithinfoctr.html. ▪