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

359 Use of atypical antipsychotic agentsZajecka et al., 2002; Tohen et al., 2003a). Olanzapine has proven relatively free ofthe depressive symptom worsening and extrapyramidal side-effects that limit theusefulness of conventional antipsychotic agents.Two placebo-controlled studies of olanzapine monotherapy for acute maniahave been published (Tohen et al., 1999, 2000) and one for addition to treatmentwith valproate or lithium (Tohen et al., 2002b).A 3-week study compared olanzapine 5–20 mg/day (n ¼ 70) to placebo (n ¼ 66)for inpatients in acute manic or mixed episodes (Tohen et al., 1999). Olanzapinetreatedpatients had 36% mean reduction in YMRS, superior to 18% meanimprovement on placebo. Response rates, defined as 50% or greater YMRSimprovement, were 48.6% for olanzapine-treated patients and 24.2% for placebotreatedpatients. Efficacy was consistent across psychotic and non-psychoticsubgroups: interaction P ¼ 0.880. Interaction was also non-significant (P ¼ 0.998)for manic versus mixed subgroups. In this case, the advantage of olanzapine overplacebo was evident for the manic group (37% versus 16% YMRS improvement),but in the mixed group YMRS reduction on olanzapine averaged 28% versus 25%on placebo. Interaction was likely non-significant because so few mixed patientswere enrolled in this study: there were only 12 per treatment group. MeanHamilton Depression ratings improved similarly in olanzapine (23%) and placebo(21%) groups. The 39% discontinuation rate in the olanzapine group was significantlylower than the 65% discontinuation rate on placebo. Change in extrapyramidalsymptom ratings (Simpson-Angus and Barnes Akathisia scales) did notdiffer between treatment groups.A second trial (Tohen et al., 2000), this time of 4 weeks’ duration, comparedolanzapine 5–20 mg/day (n ¼ 55) to placebo (n ¼ 60) for inpatients in acute manicor mixed episodes. The 51% mean reduction in YMRS during olanzapine treatmentwas superior to the 28% mean improvement on placebo. Response rates,defined as an individual’s mania rating improvement of 50% or more, were 65%on olanzapine versus 43% on placebo (P ¼ 0.02). In this study, olanzapine’sadvantage was particularly evident in psychotic patients (mean YMRS reductionof 52% versus 13% on placebo; in non-psychotic patients, mean improvementswere 51% and 44%). The test of interaction was nearing significance (P ¼ 0.110);this finding is discrepant from other available studies, which point to olanzapineefficacy as great or greater among non-psychotic than psychotic patients; it mayreflect the particularly large improvement on placebo for non-psychotic individualsin this particular trial. In this study, the efficacy of olanzapine was consistentacross mixed and manic episodes (interaction P ¼ 0.706). Mean HamiltonDepression ratings trended to superior improvement on olanzapine (45%) comparedto placebo (28%). The 32% discontinuation rate in the olanzapine groupwas significantly lower than the 58% discontinuation rate on placebo. Change in