Activation syndrome (AS), as described by the U.S. Food and Drug Administration (FDA), comprises 10 bipolar associated symptoms which starts after antidepressant therapy. The aim of this study is to investigate whether there is a relationship between lifetime hypomanic symptoms and the development of AS in patients diagnosed with major depressive disorder (MDD). METHOD: The study was conducted at Hacettepe University Faculty of Medicine Department of Psychiatry. A total of 60 consecutive outpatients diagnosed with MDD were assessed at three time points; before the initiation of antidepressant therapy (baseline), at 2nd week and at 4th week. At the initial interview the patients completed the Hypomania Checklist-32 (HCL-32) in order to assess the lifetime history of hypomanic symptoms. Barnes Akathisia Rating Scale (BARS), Hamilton Rating Scale for Depression (HAM-D), Hamilton Anxiety Rating Scale (HAM-A) and Young Mania Rating Scale (YMRS) were utilized to detect the symptoms of AS at each assessment. RESULTS: AS was detected in 25 (41.7%) patients. The most prevalent symptoms of AS were insomnia (31.7%), anxiety (25%) and irritability (15%). A significant difference was found in the HCL-32 scores of patients with and without AS. A moderate correlation between the number of AS symptoms and HSL-32 test scores were also determined. CONCLUSION: AS development was more common among the depressed patients with lifetime history of hypomanic symptoms. Given the frequency of misdiagnosis of BPD as MDD, it would be helpful to assess the hypomanic symptoms systematically with scales similar to HSL-32 in depressive patients before prescribing antidepressant medication.