To the Editor: The article on agitated depression in bipolar depression by Mario Maj, M.D., Ph.D., et al. (1) is a considerable contribution to our understanding of the nature and clinical implications of depressive mixed states in bipolar I disorder. The authors reported that manic symptoms during a depressive episode are considerably overlapping with agitated depression in bipolar I depressives. The data also implied that bipolar I depressives with and without depressive mixed states may require differential acute therapeutic strategies and may present differential long-term outcomes.

However, there are two limitations in the data presentations. First, the results on anxiety symptoms were not reported. Agitation during a depressive episode has sometimes been related to extremely severe anxiety, while many studies have reported that subjects with bipolar I depression less frequently show anxiety symptoms than unipolar depressives (2). It is important to know how three symptom clusters—agitation, mania, and anxiety symptoms—are related in bipolar I depressives. The relationship among the three symptom clusters may have led to a definitive answer to the longstanding question of whether agitation during a bipolar I depressive episode is related more to severe anxiety or to admixed manic symptoms, as the classic authors recognized it. Second, the lack of data on patients with unipolar and bipolar II depression may lead to readers’ failure to take a general view of manic symptoms during a depressive episode since two separate research groups already started to observe manic symptoms during a depressive episode in both unipolar and bipolar depressives. Benazzi (3) reported that manic symptoms during a depressive episode were more frequent in outpatients with bipolar II disorder than unipolar depressive disorder. However, more than 10% of unipolar depressives had considerable manic symptoms. Our Munich study (4, 5), which included subjects with bipolar I depression as well, provided similar results. The Munich study also factor-analyzed a broad range of depressive and manic symptoms, including anxiety symptoms. In the analysis, the agitated manic factor, which is composed of psychomotor/thought excitement and irritability, was extracted separately from the anxiety factor in 95 subjects with bipolar disorder and 863 subjects with unipolar depression combined, a finding suggesting that agitation and manic symptoms compose one salient syndrome independent of anxiety in depressive disorders. Consistent with the results of Dr. Maj et al., euphoria and grandiosity did not load on our agitated manic factor.

As the authors acknowledged, more appropriate treatment strategies might be developed in the future when one takes depressive mixed states into account. The therapeutic implications of depressive mixed states would be more important in patients who have not ever experienced a hypomanic or manic episode. Patients with depressive mixed states are likely to be diagnosed as suffering from unipolar depression, according to DSM-IV. However, there is some evidence suggesting that these patients have a bipolar nature in terms of age at first onset of mood disorder and family history of bipolar disorder (5, 6). Evidence of depressive mixed states, emerging in unipolar as well as bipolar I depressives, seems to necessitate a reconsideration of the DSM-IV boundary between unipolar and bipolar disorders.