Delineating bipolar II mixed states in the Ravenna–San Diego collaborative study: the relative prevalence and diagnostic significance of hypomanic features during major depressive episodes

Abstract

Background: Depressive mixed state (DMX), defined by hypomanic features during a major depressive episode (MDE) is under-researched. Accordingly, study aims were to find DMX prevalence in unipolar major depressive disorder (MDD) and bipolar II depressive phase, to delineate the most common hypomanic signs and symptoms during DMX, and to assess their sensitivity and specificity for the diagnosis of DMX and bipolar II. Methods: 161 unipolar and bipolar II MDE psychotropic drug- and substance-free consecutive outpatients were interviewed during an MDE with the Structured Clinical Interview for DSM-IV. DMX was defined at two threshold levels as an MDE with two or more (DMX2), and with three or more (DMX3) simultaneous intra-episode hypomanic signs and symptoms. Results: DMX2 was present in 73.1% of bipolar II, and in 42.1% of unipolar MDD (P<0.000); DMX3 was present in 46.3% of bipolar II, and in 7.8% of unipolar MDD (P<0.000). The most common hypomanic manifestations during MDE were irritability, distractibility, and racing thoughts. Irritability had the best combination of sensitivity and specificity for the diagnosis of DMX2 and DMX3. Various combinations of irritability, distractibility, and racing thoughts correctly classified the highest number of DMX2 and DMX3, and had the strongest predictive power. DMX2 had high sensitivity and low specificity for bipolar II, whereas DMX3 had low sensitivity (46.3%) and high specificity (92.1%). Limitations: Single interviewer, cross-sectional assessment, and interviewing clinician not blind to patients’ unipolar vs. bipolar status. Conclusions: When conservatively defined (≥3 intra-episode hypomanic signs and symptoms during MDE), DMX is prevalent in the natural history of bipolar II but uncommon in unipolar MDD. These findings have treatment implications, because of growing concerns that antidepressants may worsen DMX, which in turn may respond better to mood stabilizers. These data also have methodological implications for diagnostic practice: rather than solely depending on the vagaries of the patient’s memory for past hypomanic episodes, the search for hypomanic features — ostensibly elation would not be one of those — during an index depressive episode could enhance the detection of bipolar II in otherwise pseudo-unipolar patients. Strict adherence to current clinical diagnostic interview instruments (e.g. the SCID) would make such detection difficult, if not impossible.

Introduction

DSM-IV mixed episode requires concurrent full criteria for mania and major depressive episode (MDE; American Psychiatric Association, 1994). Depressive mixed state (DMX), MDE with simultaneous intra-episode hypomanic signs and symptoms (Akiskal and Mallya, 1987, McElroy et al., 1992, Akiskal, 1996, Akiskal, 1999), is under-recognized and under-studied. It has been described in the course of bipolar I (Perugi et al., 1997), cyclothymic bipolar II patients (Akiskal, 1992), in major depressive disorder (MDD) patients overexposed to antidepressants (Akiskal and Mallya, 1987), and in the context of agitated depression (Himmelhoch et al., 1976, Koukopoulos et al., 1992). As mixed bipolar depressive state is not classified in DSM-IV, most clinicians rarely diagnose it. Common features of DMX, reported in different bipolar populations, are irritability, mood lability, agitation, crowded and/or racing thoughts, dramatic expressions of suffering, and intense sexual arousal (Akiskal and Mallya, 1987, Akiskal, 1992, Akiskal, 1996, Akiskal, 1999, Koukopoulos and Koukopoulos, 1999).

In Kraepelin’s view, it is enough to have one of the three components of affective states (psychomotor activity, mood and thinking) in a polarity opposite to the other two to qualify for a mixed state diagnosis. In line with this conceptualization, recently proposed criteria for mixed mania broader than those of DSM-IV (McElroy et al., 1992, Akiskal et al., 1998) include full mania with ≥2 depressive symptoms, usually associated with bipolar I arising from a dysthymic baseline or temperament (Akiskal, 1992, Akiskal, 1996, Akiskal, 1999, Akiskal et al., 1998). Thus, mixed states could arise from the combination of an affective episode with a temperament of opposite polarity (Akiskal et al., 1998). DMX might be analogously defined in a ‘mirror-image’ fashion as consisting of full MDE plus few intra-episode hypomanic signs or symptoms in bipolar II disorder (and possibly arising from a hyperthymic or cyclothymic temperament (Akiskal, 1992, Akiskal, 1999)). These labile and unstable mixed states are often associated with substance disorders (which can make the differential diagnosis difficult), as well as intense suicidal preoccupation (Akiskal and Mallya, 1987). DMX may thus constitute depression not responding to antidepressants, and of depression made worse by antidepressants (Akiskal, 1999, Koukopoulos and Koukopoulos, 1999). Bipolar II has been reported in 30–50% of depressed psychiatric outpatients (Akiskal and Mallya, 1987, Cassano et al., 1992, Benazzi, 1997a, Benazzi, 2001), and bipolar II depression has been considered to be of mixed nature by some (Akiskal et al., 1995). Therefore, the proper characterization of DMX has important treatment implications, as antidepressants may worsen DMX and mood stabilizers may improve DMX (Akiskal and Mallya, 1987, Akiskal, 1999, Koukopoulos and Koukopoulos, 1999).

In view of the foregoing considerations about the clinical significance of DMX, in the present communication we examine its prevalence in unipolar and bipolar II outpatient MDE, to delineate the most common hypomanic signs and symptoms present intra-episodically, and to compute the sensitivity and the specificity of the latter for the DMX diagnosis. The present analyses on 161 patients represents an extension of a previous report based on 98 patients (Benazzi, 2000); the latter paper was preliminary in nature because its relatively small sample size did not permit to test the full range of dimensional DMX permutations examined in this report. Moreover, we delineate herein the hypomanic symptom-cluster which best characterises DMX in BP-II.