Bipolar disorder may be associated with the highest rates of substance abuse of any psychiatric illness. Studies suggest that substance abuse in persons with bipolar disorder have lifetime prevalence rates as high as 60% with reports of cocaine abuse as high as 30%. Comorbid substance abuse in persons with bipolar disorder is associated with increased hospitalization, poorer psychiatric recovery and treatment response than in patients with bipolar disorder alone. Thus, therapeutic agents that may enhance prognosis by improving psychiatric outcomes, reducing stimulant cravings, and increasing treatment retention are of considerable interest. In a previous study conducted in this lab, we found that conventional neuroleptic agents were associated with an increase in depressive symptoms and a significant increase in stimulant cravings. These results mirror preclinical animal data that show conventional neuroleptics (i.e.haloperidol) with high dopamine receptor binding affinities actually increase cocaine self-administration in rats and monkeys. These results are clinically relevant as persons with bipolar disorder who abuse cocaine and other drugs often receive higher doses of conventional neuroleptics than those without cocaine or other drug abuse. In contrast to conventional neuroleptic therapy, atypical antipsychotics (i.e. quetiapine, risperidone), decrease self-administration of cocaine. The receptor binding profile of the atypical antipsychotics broadly vary although all agents in this drug class are known as serotonin-dopamine antagonists. Quetiapine has 'moderate' dopamine binding, while risperidone has 'high' dopamine receptor binding properties similar to conventional neuroleptic agents. Thus, our hypothesis is that quetiapine may be a more efficacious agent than risperidone in treating bipolar mood symptoms while attenuating drug cravings and use.