Results based on a large national database analysis confirm clinicians’ sense that depressed patients who do not respond to medication may have bipolar disorder and often present atypically. Yang Yong, Psychiatry Department, Suzhou Guangji Hospital Clinical experience and limited naturalistic observational studies suggest that refractory depression may be (due to) undetected bipolar disorder. Applying a nationwide insurance database of 1 million Taiwanese, researchers identified 2 annual continuous cohorts of depressed patients (2000 and 2003), based on the number of different antidepressant treatment trials the patients received and the level of treatment resistance associated with a subsequent diagnosis of becoming bipolar disorder (a diagnosis made by a psychiatrist on at least two occasions) over the next 5 to 8 years to determine treatment resistance characteristics. The odds of converting to a bipolar disorder diagnosis in the most difficult-to-treat group (having changed 2 antidepressant regimens) were roughly 25%. Conversion rates were significantly higher in the most difficult-to-treat group (ratio: 1.88 for the 2000 cohort; 4.94 for the 2003 cohort) and in the moderate treatment-resistant group (1 antidepressant regimen change, ratios 1.63 and 2.91, respectively) compared with conversion rates in the easiest-to-treat group (no previous antidepressants). Psychiatric co-morbidity, age, and gender did not have a significant effect on these outcomes. Based on hospitalization rates (data), there was little (found) biphasic type I affective disorder. Comment: By applying a large national database, these authors have controlled for the original investigator bias of previous naturalistic observational studies designed to show this same effect, and have made a persuasive case that perhaps a quarter of patients with refractory depression may have bipolar disorder. Many of these patients may not have the easily diagnosed bipolar I disorder, but rather bipolar II disorder and atypical affective disorder, the latter two being more difficult to diagnose. Clinicians treating patients with refractory depression should vigorously search for subtle diagnostic markers of bipolar disorder.