Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression?

Background: There is widespread clinical belief that unrecognized bipolar disorder (BD) is a frequent contributor to apparent treatment resistant depression (TRD). This review attempts to assess the degree to which prevailing empirical data supports that view. Methods: All English-language articles published between January 1998 and January 2008 that focused on adults with major depressive disorder (MDD) and BD bearing on the question "Is unrecognized BD a frequent contributor to apparent TRD in patients initially diagnosed with MDD?" were reviewed. Results: 196 articles were reviewed; the preponderance of the data suggested: 1) TRD populations demonstrate high rates of hidden bipolar disorder, 2) there is not sufficient evidence to unequivocally support or reject the hypothesis that patients who relapse despite continued antidepressant treatment are likely to have bipolar spectrum disorder, 3) patients initially diagnosed with MDD do not demonstrate high rates of switching to mania or hypomania when treated with antidepressants and 4) in patients diagnosed with BD, antidepressants are not robustly effective and are poorly tolerated. Limitations: The main limitation of this review is that none of the individual studies were designed to test our primary hypothesis. Conclusions: This review provides at least moderate support to the hypothesis that BD is a contributor to apparent TRD. Thus, clinicians treating MDD are urged to search for "soft" signs of bipolarity and to be prepared to alter diagnosis and treatment strategies accordingly.