Antidepressant Response and Subthreshold Bipolarity in ‘‘Unipolar’’ Major Depressive Disorder

It has been known for a long time that compared to unipolar major depression, antidepressants work less frequently in the depressive episode of Diagnostic and Statistical Manual of Mental Disorders, Third Edition/Fourth Edition (DSM-III/IV) defined bipolar disorder because most of well-controlled studies failed to show a significant effect of antidepressants in bipolar I or II depression. However, most recent findings show that this high rate of antidepressant resistance is not limited only for the classical (threshold) forms of bipolar I or II depression. One study showed that 80% of patients with antidepressant (AD)-resistant ‘‘unipolar’’ depressive disorder have threshold and subthreshold bipolar disorder; and in many cases, the bipolar nature of antidepressant-resistant depression became evident only after a 1-year follow-up. In a study on 880 outpatients with major depressive episode, Rybakowski et al found that the rate of antidepressant-resistant depression, defined as lack of response to 3 or more antidepressant treatment trials, was similar in bipolar (I + II) disorder and bipolar spectrum disorder (24% and 30%, respectively), whereas the same rate in pure unipolar depression was 16%. In addition, it has been found that the rate of bipolar spectrum disorder among the 212 DSM-IVYdefined antidepressant-responsive inpatients with unipolar major depressive disorder was 3.8% but the same figure in 68 antidepressant-resistant inpatients was 47.1%, indicating that the underlying bipolar diathesis was an important contributor to antidepressant nonresponse. The retrospective chart review of 17 patients with ‘‘prebipolar’’ major depression (ie, patients who became bipolar I and II during the 7-year follow-up) and of 17 patients with pure unipolar depression showed that family history of completed suicide and bipolar disorder, early onset of major depressive episode, as well as treatment-emergent mixed depression, mood lability, psychomotor activation, suicidality, and nonresponse to antidepressant monotherapy were significantly more common in the patients with prebipolar major depression than in patients with pure unipolar depressive. The prevalence of excellent response was 41% in the prebipolar depression and 82% in the pure unipolar depression, and the rates of nonresponders were 41% and 0%, respectively.

Despite the fact that this was a small-scale retrospective study, the results point in the expected direction and are in good agreement with the findings of a very recent study on almost 4000 patients that found that the rate of antidepressant nonresponse was almost 3 times more frequent in patients with DSM-IV unipolar major depressive disorder who become bipolar during the 2- 3-year follow-up (26%-27%) than in those who remained unipolar (9%Y10%).10 Another study, including more than 1000 outpatients with current major depressive episode also reported that bipolarity features, as assessed by Mood Disorder Questionnaire and hypomania checklist 32, were significantly associated with antidepressant resistance. The retrospective chart review of 122 patients with primary diagnosis of unipolar major depressive disorder has shown that early onset of major depressive disorder was significantly associated with antidepressant resistance and later bipolar conversion. Initial antidepressant resistance was significantly more prevalent in bipolar converters than in patients with pure unipolar (40% vs 11%). The analysis of Correa et al. including almost 200 paper also shows that patients with antidepressant-resistant depression have a high rate of hidden bipolar disorder. A recent study also reported that in antidepressant-resistant adolescent unipolar major depression, the predictors of nonresponse or partial response were higher baseline depression score, higher baseline intradepressive mania score, and increasing intradepressive mania score during treatment.