Bipolar Disorders: Mixed States, Rapid-Cycling, and Atypical Forms

342 J. Cookson and S. Ghalib21/46 (46%) of lithium-resistant patients (80% had mixed mania) responded toanticonvulsant therapy, which usually involved carbamazepine.In the placebo-controlled study of Pope et al.(1991) of valproate in 23 patientswith lithium-resistant mania, the antimanic response was not associated withmeasures of dysphoria. Valproate differs in its mechanism of action from antipsychoticdrugs, reducing presynaptic dopamine release as opposed to blockingpostsynaptic receptors (Yatham et al., 2002). Freeman et al.(1992) conducted a 3-week randomized controlled trial, comparing lithium and valproate in 27 patientswith mania, of whom eight had mixed mania and 19 pure mania. The response rateon lithium (12/13) was non-significantly higher than on valproate (9/14), andnon-responders to valproate had significantly lower depression scores than theresponders.Swann et al.(1997) had quite different findings. They investigated the relationshipbetween depressive symptoms and response to treatment with lithium orvalproate among 179 patients with mania in the trial of Bowden et al. (1994).Mixed states were associated with poor response to lithium, compared with puremania. By contrast, the presence of depressive symptoms had no effect on theresponse to valproate. A limitation of this study is that a proportion of patients(75/179) admitted to the trial were already known to be non-responders tolithium. Thus, a bias against lithium was introduced at the start of the trial, andthe validity of the concept of ‘‘lithium non-responder’’ was confirmed.Nevertheless, among patients with pure mania there were fewer drop-outs forlack of effect on lithium (29%) than on valproate (40%). Performing a multipleregression analysis to identify factors that might predict response to lithium orvalproate, they found no correlation with gender, number of previous episodes,psychotic features, or history of substance abuse.Two studies have compared valproate with olanzapine in mania. One of thesehas reported the response in mixed mania, which comprised 43% of the sample(Tohen et al., 2002a, 2002b). Although the response to olanzapine was greater andmore rapid than that to valproate, each drug was effective in mixed mania to only aslightly lesser extent than in pure mania. The improvement in depression scoreswas similar in the two treatment groups.Electroconvulsive therapy is potentially a useful option in mania, especially intreatment-resistant cases (Okasha, 2002).Combining lithium and antidepressants in prophylaxis of mixed maniaPrien et al. (1988) conducted a double-blind, prophylactic study of lithium,imipramine, and the combination in three subgroups, including 34 with puremania, 46 with mixed mania with mild depression (Hamilton-D score 7–14), and 23with mixed mania with moderate to severe depression (Hamilton-D score 15).