Validation of the “rule of three”, the “red sign” and temperament as behavioral markers of bipolar spectrum disorders in a large sample

•Akiskal׳s proposal of the “rule of three” has not been empirically tested.•We tested this hypothesis in a large internet sample (>70,000 subjects).•Univariate analysis showed that 29 markers were overexpressed in bipolar groups.•In multivariate analysis, 11 markers differentiated unipolar from bipolar groups.•These markers may help precise clinical evaluation of major depressive episodes.