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

357 Use of atypical antipsychotic agentsstabilizers. Interestingly, however, results were not consistent across mixed andmanic episodes; both adjunctive antipsychotic treatments were effective for manicpatients and neither was for mixed patients. In fact, among mixed patients, thegroup who had placebo added to lithium or divalproex had the greatest meanimprovement. Depression ratings were not reported. Discontinuation rates duringthe 3-week study were 35% on risperidone, 53% on haloperidol, and 49% onplacebo. Extrapyramidal symptom ratings worsened significantly in the haloperidolgroup, but not the risperidone group, compared to placebo. Adverse events ofextrapyramidal disorder were reported in 28% of patients receiving adjunctivehaloperidol compared to 13% of those receiving risperidone and 4% of those onplacebo.A second study enrolling 150 patients in acute manic or mixed episodes failed toconfirm the superiority of risperidone over placebo as an adjunct to divalproex,lithium, or carbamazepine (Yatham, 2000). In this study, the contribution ofrisperidone was least apparent among those patients using carbamazepine astheir primary mood stabilizer, raising the possibility that accelerated metabolismsecondary to activation of cytochrome CYP-2D6 may have been an importantcontributor to the failure of risperidone to differentiate from placebo. Detailedinformation on efficacy within diagnostic subgroups is not yet available forthis study.A South African group (Segal et al., 1998) published a double-blind, randomizedmonotherapy comparison of risperidone 6 mg/day and haloperidol 10 mg/day tolithium (mean level 0.53 mmol/l week 1, 0.62 mmol/l week 3, 0.72 mmol/l week 4)for hospitalized patients with acute mania, many with psychosis. Improvementfrom baseline YMRS was not statistically significantly different among the treatmentgroups, with 55% reduction on lithium, 43% on risperidone, and 41% onhaloperidol. Depression ratings are not reported. However, extrapyramidal symptomswere similar in the risperidone and haloperidol groups, with both worseningsubstantially compared to the lithium group. Given dose-related extrapyramidalside-effects with risperidone, it is possible that lower doses would have beenassociated with lower neurological side-effects than haloperidol 10 mg; likewisethe small sample size (15 patients per group) and absence of a placebo controlnecessitate caution in interpreting the lack of statistically significant difference inmania improvement across these groups.Two placebo-controlled trials have shown promising efficacy of risperidonemonotherapy for acute mania. In a USA-based study, Hirschfeld and collaborators(2004) evaluated risperidone 1–6 mg/day (mean modal dose 4.1 mg/day) forpatients hospitalized with acute mania. Mean YMRS improvement after 3 weeksof treatment was superior on risperidone (38% improvement, n ¼ 134) than onplacebo (17% improvement, n ¼ 125, P