Affective switch is an important clinical issue when treating bipolar disorder. Though commonly seen in clinical practice, the benefits of prescribing antidepressants for bipolar depression are still controversial. To date, there have been few genetic studies and no genome-wide association study (GWAS), focusing on manic switch following bipolar depression. This study aims to investigate the effects of individual genomics and antidepressant medication on the risk of manic switch in bipolar I disorder (BPI). A total of 1004 patients with BPI who had at least one depressive episode with complete data on antidepressant treatment and outcome were included. Clinical assessment of mania and depression was performed by trained psychiatric nurses and psychiatrists using the Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry (SCAN), and the diagnosis of BPI was made according to DSM-IV criteria. Manic switch was defined as a manic episode occurring within eight weeks of remission from an acute depressive episode. The age at first depressive episode of the study patients was 30.7 years (SD 12.5) and 56% of all patients were female. GWAS was carried out in a discovery group of 746 patients, followed by replication in an independent group of 255 patients. The top SNP rs10262219 on chromosome 7 showed the strongest allelic association with manic switch ( = 2.21 × 10) in GWAS, which was however not significantly replicated. Antidepressant treatment significantly (odds ratio 1.7; 95% CI 1.3-2.2; < 0.001) increased the risk of manic switch. In logistic regression analysis, the CC genotype of rs10262219 (odds ratio 3.0; 95% CI 1.7-5.2) and antidepressant treatment (odds ratio 2.3; 95% CI 1.4-3.7) significantly increased the risk of manic switch with a joint effect (odds ratio 5.9; 95% CI 3.7-9.4). In conclusion, antidepressant medication and rs10262219 variants jointly increased the risk of manic switch after bipolar depression.