According to DSM-IV-TR, a mixed episode can occur only in bipolar I disorder (BD-I). A mixed episode requires a concurrent full-criteria major depressive episode (MDE) and a manic episode. Mixed mania has also been defined in the research as a manic episode plus three or more depressive symptoms (McElroy et al., 1992).
Until recently, mixed depression (i.e., MDE plus manic-hypomanic symptoms during the episode) was understudied. Most of the research comes from Perugi et al. (2001, 1997) in BD-I and Akiskal and Benazzi in bipolar II disorder (BD-II) and major depressive disorder (MDD) (Akiskal and Benazzi, 2003; Benazzi, 2000; Benazzi and Akiskal, 2001). Many of the main findings were replicated by Sato et al. (2003), Maj et al. (2003) and Judd et al. (2003).
This review will focus on BD-II and MDD outpatient mixed depression. The study setting is a large outpatient solo private practice in Italy that is more representative of mood disorders (apart from BD-I) usually seen in clinical practice in Italy. The most severe and socially disadvantaged (less representative) cases are usually seen through the national health service or university centers.
Community and clinical outpatient depression studies found that the BD-II to MDD ratio is near 1 (Angst et al., 2003; Benazzi, 2003a, 1997). Two long-term follow-up studies of MDD have also shown that around 50% of patients with MDD develop BD-I or BD-II (Angst et al., 2003; Goldberg et al., 2001). The high frequency of BD-II found in clinical outpatient depression samples is mainly related to interview methods. These include focusing more on overactivity than on mood change; use of semi-structured interviews; interviews by clinicians; and interviews of family members or close friends (Benazzi, 2003b; Benazzi and Akiskal, 2003b). The diagnosis of BD-II has higher inter-rater reliability and more correct diagnoses of BD-II and other mood disorders by these methods (Benazzi and Akiskal, 2003a; Brugha et al., 2001; Dunner and Tay, 1993; Simpson et al., 2002).
By strictly following the Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version (SCID-CV), hypomanic symptoms cannot be assessed during an MDE (Dunner and Tay, 1993). Instead, our studies in Italy always require the assessment of hypomanic symptoms using the Hypomania Interview Guide. In mixed depression, hypomanic symptoms of high mood and increased self-esteem were absent. The core hypomanic symptoms of mixed depression were irritability, racing thoughts, psychomotor agitation and talkativeness (Akiskal and Benazzi, 2003). Systematic probing, and not spontaneous reporting, showed the presence of hypomanic symptoms during depression (which are less severe than manic symptoms and therefore less easily observable) (Benazzi and Akiskal, 2003a).
In our studies, hypomanic symptoms of mixed depression had to last at least one week and be present at the time of the interview. Patients were off psychoactive drugs for at least two weeks in order to avoid including antidepressant-induced mixed states (Akiskal and Pinto, 1999). Cross-sectional interviews were performed when individuals presented voluntarily for treatment of depression. Probing for BD-II followed soon after the diagnosis of depression was given, in order to avoid a possible bias related to the knowledge of bipolar signs (Ghaemi et al., 2002). The Table shows a picture of our current sample.
Mixed depression was more common in BD-II than in MDD. However, an interesting finding was that mixed depression was not uncommon in MDD. The best definition (i.e., the most clinically useful definition as a cross-sectional marker of BD-II) of mixed depression was found to be one based on a minimum of three hypomanic symptoms during major depression (Benazzi, 2001), compared to definitions based on combinations of specific hypomanic symptoms. This definition of mixed depression was similar to that used in mixed mania. Mixed depression had the best combination of sensitivity and specificity for BD-II diagnosis, as compared to several markers of BD-II, such as atypical depression, young age at onset, many MDE recurrences or family history (Benazzi, 2003c, 2002a, 2000; Ghaemi et al., 2002). An important finding was that a family history of BD in patients with MDD mixed depression was similar to that of patients with BD-II and that it was significantly higher than for MDD non-mixed depression. This finding was replicated by Sato et al. (2003).