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In order to explore valproate's spectrum of efficacy in rapid-cycling bipolar disorder, 55 patients underwent a prospective, open, 7.8-month trial designed to assess the drug's acute and prophylactic properties. Twenty patients received monotherapy, and 35 received combination therapy. Moderate to marked acute antidepressant responses were seen in 47% of the patients, prophylactic antidepressant responses in 76%, acute antimanic responses in 91%, prophylactic antimanic responses in 94%, acute responses in mixed states in 85%, and prophylactic responses in mixed states in 93%. Consistent with other anticonvulsant literature, these data suggest that valproate has marked antimanic and mixed state efficacy, but minimal to moderate antidepressant properties.

Although lithium remains the treatment of choice for manic depression, it is now well recognized that 20%-40% of patients either do not tolerate the drug or their disease does not respond to it. This subgroup of patients accounts for a substantial majority of the morbidity that accompanies this illness. For this reason, alternatives to lithium therapy will have a significant clinical impact. In a great majority of cases, the rapid-cycling variant of this disorder accounts for the resistance to lithium treatment. Recently, a growing body of literature has suggested that several medications routinely used in the management of seizure disorders, particularly carbamazepine and valproate, have therapeutic mood-altering properties. These drugs have been evaluated in numerous drug trials using open, double-blinded, longitudinal, and (in the case of carbamazepine) randomized designs. The authors comment on the phenomenology of manic depression and review the literature on use of anticonvulsants in the management of lithium-resistant manic depression.

Although the recurrent nature of manic depressive illness has been recognized since the time of Kraepelin, it has only recently been noted that this feature of the illness has prognostic significance. A subgroup of patients who experience more than four major mood swings per year has been identified as rapid cyclers and are now believed to account for a significant proportion of treatment resistance. In some instances, such rapid cycling is believed to be not only exacerbated by but possibly caused by the use of conventional unimodal antidepressants such as tricyclics. For this reason, the routine use of such antidepressants should be considered ill-advised until patients have been shown to be resistant to lithium's acute antidepressant properties. Although lithium remains the initial treatment of choice for manic depression, a substantial majority of manic depressive patients prove to be lithium-resistant and a growing body of data suggests this refractory group is accompanied by a disproportionate amount of frequent mood swings. When the lithium-resistant bipolar patient is encountered, the addition of one of two anticonvulsants, either valproate or carbamazepine, often provides significant therapeutic effects. Both valproate and carbamazepine appear to be similarly effective, but valproate may be better tolerated and easier to use.