Multiple indices of depression were used to evaluate the prophylactic efficacy of lithium carbonate versus placebo in a 4-year, double-blind study of unipolar, bipolar I, and bipolar II patients diagnosed according to strict criteria. Our data indicate lithium prophylaxis of depression on several indices in all three subtypes of affective illness. Additional studies are needed, comparing tricyclic antidepressants alone, monoamine oxidase inhibitors alone, or either drug combination with lithium carbonate for prophylaxis in clearly defined depressive subtypes.