Objective: The term "mood stabilizer" is widely used in the context of treating bipolar disorder, but the U.S. Food and Drug Administration (FDA) does not officially recognize the term, and no consensus definition is accepted among investigators. The authors propose a "two-by-two" definition by which an agent is considered a mood stabilizer if it has efficacy in treating acute manic and depressive symptoms and in prophylaxis of manic and depressive symptoms in bipolar disorder. They review the literature on the efficacy of agents in any of these four roles to determine which if any agents meet this definition of mood stabilizer.
Method: The authors conducted a comprehensive review of English-language literature describing peer-reviewed, U.S. Agency for Healthcare Research and Quality class A controlled trials in order to identify agents with efficacy in any of the four roles included in their definition of a mood stabilizer. The trials were classified as positive or negative on the basis of primary outcome variables. An "FDA-like" criterion of at least two positive placebo-controlled trials was required to consider an agent efficacious. The authors also conducted a sensitivity analysis by raising and relaxing the criteria for including trials in the review.
Results: The authors identified 551 candidate articles, yielding 111 class A trials, including 81 monotherapy trials with 95 independent analyses published through June 2002. Lithium, valproate, and olanzapine had unequivocal evidence for efficacy in acute manic episodes, lithium in acute depressive episodes and in prophylaxis of mania and depression, and lamotrigine in prophylaxis (relapse polarity unspecified). Thus, only lithium fulfilled the a priori definition of a mood stabilizer. Relaxing the quality criterion did not change this finding, while raising the threshold resulted in no agents fulfilling the definition.
Conclusions: When all four treatment roles are considered, the evidence supported a role for lithium as first-line agent for treatment of bipolar disorder. The analysis also highlights unmet needs and promising agents and provides a yardstick for evaluating new treatment strategies.