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

337 The treatment of bipolar mixed statesare also antagonists at 5-HT-2 receptors and norepinephrine alpha 2 -receptors,actions that may endow them with antidepressant properties.Antipsychotics, depression in mania, and switch into depressionThe response to treatment of depressive symptoms in mania has two aspects. First,there is the response of depressive symptoms that occur during the presentingmanic phase. Second, there are the depressive symptoms that emerge as the manicphase resolves; these may be regarded as postmanic depression or – especially ifthey appear suddenly – as resulting from a switch from mania to depression.In placebo-controlled studies of olanzapine in mania, 27% of patients had highdepression scores at the start (Hamilton-D > 20). Depressive symptoms improvedalong with the mania ratings within 1 week (Baker et al., 2000). This improvementin moderately severe depressive symptoms in a large proportion of bipolar patientsis compatible with model 4 (characterological response).Olanzapine and haloperidol brought about similar degrees of improvement, notonly in ratings of mania, but also of depressive symptoms in patients with highdepression scores (Hamilton-D > 20) at the start (Tohen et al., 2003). Howeverthe remission rates in patients with mixed mania (n ¼ 25, with full DSM-IVsyndromes) tended to be less than in pure mania (n ¼ 428), whether to olanzapine(39% versus 53%) or haloperidol (17% versus 48%) (Tohen et al., 2003). This is inkeeping with model 1 (mixture of elements) applying to the small proportion ofpatients with more severe depressive symptoms accompanying mania.In the placebo-controlled studies, worsening of depression was not more commonon olanzapine (3/33) than with placebo (7/35) (Baker et al., 2000). On theother hand, the risk of switching from mania to depression within 6 weeks wasfound to be less with olanzapine (6/128 or 4.7%) than with haloperidol (16/131 or12.2%) (Tohen et al., 2003; Baker et al., 2004). This suggests that certain atypicalantipsychotics may have an advantage over classical antipsychotics in preventingthe development of mixed states and depression.Combining olanzapine with lithium or valproate in manic patients (nearly alloutpatients) who had already been on the mood stabilizer for at least 2 weeks led togreater improvement than mood stabilizer with placebo in the subset (48%)of mixed mania (Tohen et al., 2002a). Depression scores also improved morewith olanzapine combination, and the proportion of patients gaining 50%improvement in depression scores was greater for olanzapine (43.1%) than formood stabilizer with placebo (9.5%).‘‘Manic defense,’’ transitions, and treatment of maniaThus there is little evidence that treatment of mania or mixed states with antimanicdrugs worsens depressive symptoms as model 5 (manic defense) predicts. Another