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 outcom...

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What Is a “Mood Stabilizer”? An Evidence-Based Response

Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders

The mechanism of lithium-induced diabetes insipidus was investigated in 96 patients and in a rat model. Polydipsia was reported by 40% and polyuria (more than 3 liter/day) by 12% of patients receiving lithium. Maximum concentrating ability after dehydration and vasopressin was markedly impaired in 10 polyuric patients and was reduced in 7 of 10 nonpolyuric patients studied before and during lithium therapy. Severe polyuria (more than 6 liter/day) was unresponsive to trials of vasopressin and chlorpropamide, but improved on chlorothiazide. Rats receiving lithium (3-4 meq/kg/day) developed massive polyuria that was resistant to vasopressin, in comparison to rats with comparable polyuria induced by drinking glucose. Analysis of renal tissue in rats with lithium polyuria showed progressive increase in the concentration of lithium from cortex to papilla with a 2.9-fold corticopapillary gradient for lithium. The normal corticopapillary gradient for sodium was not reduced by lithium treatment. The polyuria was not interrupted by brief intravenous doses of vasopressin (5-10 mU/kg) or dibutyryl cyclic AMP (10-15 mg/kg) capable of reversing water diuresis in normal and hypothalamic diabetes insipidus rats (Brattleboro strain). The present studies suggest that nephrogenic diabetes insipidus is a common finding after lithium treatment and results in part from interference with the mediation of vasopressin at a step distal to the formation of 3′,5′ cyclic AMP.

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On the mechanism of lithium-induced diabetes insipidus in man and the rat.

THE PURPOSE of this paper is to present the clinical results of an intensive longitudinal double-blind study in 30 manic-depressive and depressed patients; preliminary aspects of this work have been presented elsewhere.1,2In addition, we have reported on some biochemical changes occurring at various stages in the course of the lithiumcarbonate treatment of these patients2; this aspect of our work is the subject of other recent communications3,4and will not be reviewed here. The therapeutic use of lithium-carbonate in affective disorders has recently been the focus of considerable interest, particularly in light of clinical evidence that it may have beneficial effects not only in mania but also in some cases of depression.5An additional and perhaps unique feature of this drug is its reported long-term mood-stabilizing properties when used prophylactically.6If the initial clinical studies can be further substantiated, then the theoretical implications for a

Lithium-Carbonate Treatment in Depression and Mania A Longitudinal Double-Blind Study

Data are presented from psychiatric clinics in Glostrup, Prague and Zurich for 244 patients who suffered from recurrent affective disorders and were treated prophylactically with lithium. The disease course was followed by recording the numbers of psychotic episodes and hospital admissions and the durations of cycles and episodes.

Lithium effects were evaluated by two methods: (A) intra-individual comparisons of the disease course during lithium treatment and during control periods of similar length before lithium, and (B) multiple regression analyses of cycle and episode durations with lithium treatment as one of the variables.

Lithium treatment led to a pronounced and statistically significant reduction in the number of both episodes and hospital admissions. This was demonstrated at all three clinics and for each of the affective disorders, manic-depressive psychosis, recurrent depressive psychosis, and schizo-affective psychosis. The response to lithium treatment was independent of age at the start of lithium treatment, age at first episode, sex, and number of previous episodes.

The regression analyses confirmed previous observations on the course of recurrent affective psychoses. Duration of cycles decreased with increasing age at first episode and increasing number of previous episodes. There was a slight decrease of episode duration with increasing number of episodes.

Lithium treatment led to a statistically significant prolongation of the cycles, considerable in manic-depressive and recurrent depressive psychosis, and moderate in schizo-affective psychosis. In manic-depressive patients, there was a statistically significant shortening of episodes during lithium treatment.

The results afford strong evidence that lithium is an active prophylactic agent in recurrent affective disorders.

Lithium Prophylaxis in Recurrent Affective Disorders

In a longitudinal outpatient study, the authors found that lithium produced a mild decrease in depth of depression scores among patients who had been on the drug for more than seven months, as compared with patients who had been receiving lithium less than seven months. They assess the factors contributing to reported positive clinical results of maintenance lithium treatment in recurrent affective disorder.

Stanley H. Platman

Papers

The Use of Lithium in Affective Disorders: II. Prophylaxis of Depression in Chronic Recurrent Affective Disorder