OBJECTIVES: To assess the clinical outcomes of modern second-generation antidepressant medication use in bipolar disorder, with a focus on the risk of induced manic-switching for adult patients with bipolar depression. METHODS: Bipolar disorder subjects were identified with a new depressive episode in a national managed care plan between January, 1998 and December, 2002. A case-control study design was applied for which cases and controls were defined by whether having mania-related visits in the 12-months continuous enrollment after episode initiation. The date of first mania-related visit after depression was the index date of manic-switching for cases and a random date was assigned for controls. Based on the pharmacy records, 2050 patients were established having treatment of antidepressant monotherapy, mood stabilizer monotherapy, or antidepressant-mood stabilizer combination therapy within 30 days prior to the index date. A logistic regression with difference-in-difference approach was employed to predict the probabilities of having manic-switching by different types of treatment. RESULTS: Patients with antidepressant monotherapy and antidepressant-mood stabilizer combination therapy were 31% (n=87) and 29% (n=82) in the case group and 43% (n=768) and 27% (n=481) in the control group. Using logistic regression to adjust for patient demographics, clinical-related and health-related variables, the odds ratios for having manic-switching in relation to antidepressant monotherapy and antidepressant-mood stabilizer combination therapy were 2.71 (95% CI: 1.32-5.56; p<0.01) and 1.51 (95% CI: 0.81-2.81; p=0.20) respectively, compared to mood stabilizer monotherapy. CONCLUSIONS: This study further validates the national practice guidelines for bipolar disorder with a case-control study design, which does not have the study limitations of typical intent-to-treat approach. Similar results were identified, indicating a risk of induced manic-switching by antidepressant monotherapy yet not by antidepressant-mood stabilizer combination therapy with second-generation antidepressants.