It was over a quarter center ago (1970) that lithium was FDA-approved for the treatment of mania, and it has been almost that long (1974) since it was approved for the long-term maintenance treatment of bipolar disorder. It is no longer the glamour drug of psychiatry, even in the United States where its introduction lagged years behind the rest of the world. The extent of its effectiveness has been questioned (with justification)-results in recent naturalistic (real-life) studies fell far short of the placebo-controlled research trials of the 1970s and the majority of people on long-term lithium treatment require intermittent or continuous use of ancillary medications to maintain stability. It is a drug with side effects at therapeutic levels (tremor, weight gain, excessive urination, cognitive impairment and others), and severe, sometimes fatal, neurotoxicity if levels get too high. Adverse interactions with drugs and diet can be problematic-certain diuretics, nonsteroidal anti-inflammatory drugs and cardiac medications, and low-salt (sodium) diets can elevate blood lithium levels to toxicity.

Has lithium become obsolete-a horse and buggy trying to compete with today's sleek, fast cars (in the form of anticonvulsant mood stabilizers such as carbamazepine [Tegretol], divalproex [Depakote], valproic acid [Depakene], gabapentin [Neutontin] and lamotrigine [Lamictal])? In my opinion, the answer is quite clearly, 'No.'

Lithium's long history in psychiatry and medicine in general has produced a wealth of information about the drug. Our database at the Lithium Information Center contains over 26,000 lithium-related articles. Lithium is an established and familiar entity with clearly defined efficacy as monotherapy for acute mania and bipolar depression and for preventive treatment of bipolar and major depressive disorder, and as an augmenter of antidepressants for treatment-resistant major depressive episodes. Just how well the others stack up against lithium in some of these areas has not yet been determined in well designed, comparative studies. And we do know that anticonvulsant mood stabilizers have their own spectrum of side effects and drug interactions.

Clinicians have concluded that divalproex is more effective than lithium for rapid cycling and mixed states, yet this conclusion is based more on impression than on rigorously obtained research data. It is reasonably well established that patients in these categories are less responsive to lithium than slow cyclers with classic mania, and it is fortunate that patients in these categories sometimes respond to divalproex. However, the only way to determine comparative efficacy of these two drugs those conditions would be to treat patients who had not been previously exposed to either drug (a quite difficult undertaking given the widespread use of lithium and increasing use of divalproex). Since divalproex is now being used as a first-line treatment for rapid cycling and mixed states, it is not unreasonable to expect that sometimes the shoe will be on the other foot: namely, some divalproex non-responders will respond to lithium.

With regard to long-term prophylactic treatment, only carbamazepine has been compared to lithium in published controlled clinical trials (none of which are without design flaws). While carbamazepine appears to be an effective maintenance treatment for bipolar disorder, a large European study suggested that it is not as effective as lithium in reducing suicidality.

Studies with the new anticonvulsants, gabapentin and lamotrigine, are just getting under way. For now, they must be viewed as promising additions to our bipolar drug arsenal, but additions that require considerable testing before their true potential can be established.

Reports of lithium's death have been greatly exaggerated. Lithium remains the best established drug for treating all aspects of bipolar disorder, and it will continue to be used widely throughout the world for years to come. At the same time, the growing availability of alternatives to lithium, especially in the form of anticonvulsants, has been a major therapeutic advance, and ongoing comparative research will do much to firmly determine their roles in the treatment of bipolar disorder. Already, there is considerable enthusiasm among clinicians regarding the benefits of combining lithium with one or more anticonvulsants to overcome treatment resistance.

James W. Jefferson, MD, is Distinguished Senior Scientist and Co-Director of the Lithium Information Center at the Dean Foundation; Clinical Professor of Psychiatry, University of Wisconsin Medical School; and a member of the National DMDA Scientific Advisory Board. The Lithium Information Center can be reached at 1-608-827-2390.

Editor's Note: According to expect consensus guidelines published recently in the Journal of Clinical Psychiatry Supplement 12A, Volume 57, 1996 (A. Frances, et al.), lithium is considered first-line treatment for classic, euphoric manic, while vaproate (most commonly used as divalproex [Depakote]) is considered first-line treatment for mixed or dysphoric mania and for rapid-cycling mania. A patient and family version of the Expert Concensus Treatment Guidelines for Bipolar Disorder is available free of charge. To request a copy, contact National DMDA at 1-800-82-NDMDA.