This chapter reviews controlled findings regarding the impact of variant bipolar presentations to predicting treatment response with atypical antipsychotic agents. In the case of atypical antipsychotic medications, some findings are available regarding their use in patients with rapid-cycling bipolar disorder, as well as mania complicated by depression or psychosis. Antipsychotic agents may have unidirectional antimanic properties, tending to accelerate switch to depression or to cause dysphoria even in those without a primary mood disorder. The chapter primarily focuses on the relative response within diagnostic subgroups, especially psychotic versus non-psychotic, mixed versus manic, and rapid versus non-rapid cycling. Clozapine was the first of the atypical antipsychotic agents, with clinical trials in schizophrenia starting over three decades ago. Cerain other antipsychotic agents include risperidone, olanzapine, and aripiprazole. A diverse array of atypical antipsychotic medications has evidence of usefulness in mania, including lithium, anticonvulsants, antipsychotics, atypical antipsychotics, benzodiazepines, and calcium channel blockers.