Franco Benazzi, MD, PhD

 diagnosis of bipolar disorder (BP) II requires the presence of major depressive and hypomanic episodes. 

 further characterizes hypomania as requiring (a) periods of elevated or irritable mood (mood changes), which must always be present and must last at least 4 days, different from the usual mood; (b) 3 of the following 8 symptoms if mood is elevated, 4 if mood is irritable: inflated self-esteem, decreased need for sleep, more talkativeness, racing thoughts, distractibility, increased goaldirected activity, psychomotor agitation, and excessive involvement in risky activities; (c) change in functioning; (d) observable mood and functioning change; (e) no marked impairment of functioning, no psychotic symptoms; and (f) symptoms must not be caused by substances, drugs (including antidepressants), or medical disorders.

This article will focus on 3 issues of current concern: diagnostic criteria for hypomania, diagnosis of mixed depression, and management of mixed depression.

A recent series of studies has found that BP II is much more common than the 0.5% community prevalence reported by 

: the current estimate of community prevalence is about 5%.

 However, clinical studies in different settings have found a much higher prevalence of BP II among depressed outpatients, reporting an equal number with major depressive disorder (MDD) in a ratio of 1:1.

 the much higher prevalence of BP II found in these studies is related to the following methodologic advances:    

Use of semistructured interviews by trained clinicians.

A minimum duration of hypomania of 2 or more days.

Bypassing the stem question of DSM-IV to assess the history of hypomania.

Focusing the probing for history of hypomania on overactivity.

The use of fully structured interviews by lay interviewers, which used yes/no questions and did not provide for clinical evaluation, often led to underdiagnosis of BP II or misdiagnosis of BP II as MDD. The use of semistructured interviews by trained clinicians provides a clearer diagnostic perspective and consequently, a smaller margin of error.

Using the criteria of a minimum duration of hypomania of 2 or more days rather than the 

 4-day cutoff may increase accurate diagnosis. Unlike the 4-day cutoff, the 2-day cutoff is based on data that show no difference on bipolar measures such as family history, age at onset, and number of recurrences. When 

 criteria are strictly followed, BP II is often (at least 30% of the time) misdiagnosed as MDD.

 stem question requires remembering periods of elevated or irritable mood, the response to this question by patients with BP II is frequently no, since these periods may be seen as normal mood fluctuations. If the wording of the question includes much more than usual, this may be perceived as a sign of a severe mental disorder, and is often denied. Bypassing the stem question of 

 to assess the history of hypomania can provide a more accurate diagnosis.

Overactivity (increased goal-directed activities) is an observable behavior, easier to remember than the mood state required by 

. During the initial interview, relatives and friends can report on mood changes that are more easily recalled after remembering a period of overactivity. Overactivity has been found to be the core feature of hypomania, and it can have at least the same priority as mood changes for the diagnosis of BP II.

Factor analysis studies and clinical studies have supported the upgrading of overactivity. Factor analysis studies have shown that activation is the core feature of hypomania. Many 

 symptoms of hypomania (7 of 9) could be considered to be the result of an activation/excitement state of the brain: increased goal-directed activity, psychomotor agitation, decreased need for sleep, more talkativeness, racing thoughts, distractibility, and excessive involvement in risky activities.

 described 3 basic domains of mania/hypomania and depression: excitement or inhibition of mood, thinking, and behavior. He did not set any priority among them, but stated that increased busyness, ie, overactivity, was the most striking feature of hypomania. His predecessors, Falret (1854) and Hecker (1898) noted the diagnostic utility of behavioral activation for the diagnosis of disorders similar to BP II, ie, cyclothymia and circular insanity.

 Actually, in Kraepelin's view, there could be a manic state even without an elevated mood, as in the mixed state depressive or anxious mania. According to 

, elevated mood is the prototypical symptom of hypomania. This may mislead clinicians into believing that the basic feature of hypomania is elevated mood and that the other symptoms are secondary and less important.

The major depressive episodes of BP II, and not uncommonly those of MDD, may have concurrent hypomanic symptoms but cannot include elevated mood and the related inflated self-esteem. These mixed depressions thus become missed depressions. Mixed depression misdiagnosis impacts negatively on the treatment of depression. Clinical studies have shown that BP II diagnosed by setting overactivity, and not mood changes, as the priority symptom of hypomania is similar on diagnostic measures to 

 BP II, which requires mood changes for the diagnosis of hypomania. Diagnosing hypomania by requiring overactivity does not lead to overdiagnosis of BP II, and most 

 has the disadvantage of having the stem question for hypomania based on mood changes, if the response is negative, assessment must move to nonbipolar disorders. Another important disadvantage of the SCID is that it does not assess hypomania/hypomanic symptoms in a major depressive episode, leading to missing mixed depressions, especially in outpatients.

Two recent studies have reported on mixed hypomania, which is a combination of hypomania and depressive symptoms or a major depressive episode. 

 This diagnosis also will be missed by the SCID. Patients with BP II may not seek treatment for hypomania, because it is frequently seen as a period of improved functioning. Impairment in hypomania, when it occurs, is mild, and is seen more often by relatives and friends than by patients with hypomanic BP II.

Basic data support distinction between BP I and BP II

The basic data supporting a distinction between BP I and BP II

. In comparison to BP I, there are many fewer studies of BP II and there is little evidence to support the treatment guidelines. Compared with BP I, patients with BP II are more prone to episodes of depression, higher Axis I comorbidity (especially panic disorder), a higher suicide risk, and a high incidence of substance abuse.

Patients with BP II plus concurrent cyclothymic temperament (high instability of mood, thinking, and behavior) are more common in tertiary care settings (around 50% of these patients), have more Axis I comorbidity, and are at higher risk for suicide and substance abuse. Because of the negative impact that this concurrent temperament has on the course of BP II, this subgroup is referred to as dark; without the concurrent condition the subgroup is called sunny, because there are often periods of improved functioning.

 boundary between hypomania and mania is based on marked impairment of functioning in mania, but its definition is unclear and may lead to misdiagnosis. However, it helps that hypomanic episodes often have improved functioning, especially in nontertiary-care settings.

 It is unknown whether mood-stabilizing agents should be given long-term to patients with BP II. The risk of switching to hypomania with antidepressants is lower in BP II than in BP I,

 but because BP II is highly recurrent (especially depression), understanding how to prevent future episodes of depression is imperative. Depression associated with BP II is often mixed and atypical; and its treatment needs to be the focus of future studies.

Many episodes of depression (major depressive episodes) in BP II are mixed. Mixed depression (depressive mixed state) has been defined as the combination of depression and hypomanic symptoms (usually not reaching the minimum number required by 

 Hypomanic symptoms start during the depression (ie, these are not the tail of a recent hypomanic episode), and are not induced by antidepressants (ie, have a spontaneous onset), although antidepressants can induce and worsen these symptoms.

Very few studies have included samples of untreated BP II that would allow the study of spontaneous-onset intradepression hypomanic symptoms. Several definitions of mixed depression have been suggested and tested. Some require 2 or 3 hypomanic symptoms, others require 3 specific symptoms such as psychomotor agitation. The most validated definition to date requires a cutoff of 3 hypomanic symptoms. Its validation is based on stronger associations with bipolar validators, such as family history, age at onset, and BP II. This mixed depression has a positive predictive value of more than 70% for BP II.

The diagnostic validity of agitated depression has been tested in outpatients.

 Most agitated depressions are mixed (they have many intradepression hypomanic symptoms), and most are related to BP II. Inpatients with agitated depressions often have many severe manic symptoms, including psychosis (uncommon in outpatients with agitated depression). In a BP II and MDD sample, agitated depression was different on bipolar validators from nonagitated depression only when it was mixed (it was often mixed). This finding suggests that it is not psychomotor agitation alone that makes agitated depression different from nonagitated depression, which brings into question the diagnostic validity of agitated depression.

The frequency of mixed depression in BP II has ranged between 20% and 70%. Its frequency is related to the setting (eg, tertiary care vs nontertiary care, inpatients vs outpatients), the interview methods, the BP I and BP II ratio versus MDD, the study of treated samples (as mood-stabilizing treatment suppresses manic/hypomanic symptoms), and the definition used. It is more common in BP I and BP II than in MDD, but it is not uncommon in MDD (around 30% in outpatients). Mixed depression in MDD has been found to be closer to that of BP I and BP II, on bipolar family history and age at onset, than to that of nonmixed MDD.

The most common symptoms of mixed depression, which are more severe in BP I than BP II, are irritability, racing thoughts and distractibility (mental activation), psychomotor agitation (which is mild in outpatients), and talkativeness (behavioral activation). Factor analysis of these symptoms has found 2 factors: a mental activation and a behavioral activation factor. These factors closely match the factors found in the hypomania occurring outside the depression, supporting the hypomanic nature of these symptoms. In outpatients, symptoms such as irritability and racing (crowded) thoughts are often not spontaneously reported, and should be systematically assessed and psychomotor agitation is mild. Atypical depression is common in BP

 and studies have found that atypical depression is more likely than typical depression to be mixed. In this case, it is the mental activation of mixed depression that is present in atypical depression, making the combination of the 2 states possible.

The bipolar nature of mixed depression is supported by several lines of evidence:    

Close association with BP I and BP II, and with bipolar family history.

Dose-response relationship between number of intradepression hypomanic symptoms and bipolar family history loading, ie, the higher the number of symptoms, the higher the bipolar family history loading.

Factor structure of the intradepression hypomanic symptoms similar to the factor structure of the hypomania occurring outside the depression.

Mixed depression in MDD showing a closer similarity to BP I and BP II on bipolar validators than to nonmixed MDD.

MDD shifting to bipolar disorder in the long run (around 40% to 50% of cases) is more likely to have mixed depression.

With antidepressant treatment, mixed depression, compared with nonmixed depression, is more likely to switch to mania/hypomania.

The distribution of the intradepression hypomanic symptoms between BP II and MDD is not bimodal.

Two lines of evidence question the categoric definition of mixed depression,

 as reported above: (1) the distribution of the intradepression hypomanic symptoms between BP II and MDD is not bimodal, as it should have been in a categoric disorder

; and (2) the doseresponse relationship between number of intradepression hypomanic symptoms and bipolar family history loading, ie, the higher the number of symptoms, the higher the bipolar family history loading. A discontinuity, ie, no dose-response relationship, should have been found if mixed depression were a categoric disorder.

 The nonbimodal distribution of the cross-sectional intradepression hypomanic symptoms is complemented by a similar lack of bimodality in the lifetime manic/hypomanic symptoms in patients with BP I and MDD.

From a clinical practice point of view, there are several important considerations regarding mixed depression. Depressed patients should be systematically assessed for concurrent hypomanic symptoms, which, if present, should lead to a careful probing for a history of hypomania, supplemented by information from key informants. Antidepressants should be used with care in the treatment of mixed depression, since antidepressants alone (ie, without protection by mood-stabilizing agents) could worsen the concurrent hypomanic symptoms, sometimes leading to suicidal behavior.

 Irritability, psychomotor agitation, and bipolarity are possible precursors to suicidality that may be related to the effects of antidepressants.

Studies of mixed depression have shown that cross-sectionally assessed psychomotor agitation and racing/ crowded thoughts are independent predictors of suicidal ideas,

 and that mixed depression is often present before suicide attempts.

 It would thus appear that it is not antidepressants that induce suicidality, but their incorrect use.

 In mixed depression it seems logical to first control the hypomanic symptoms with mood-stabilizing drugs and then to add an antidepressant.

 Sometimes, when a patient with mixed depression has concurrent full hypomania (ie, irritability and at least 4 symptoms), quickly treating the hypomania also resolves the depression.

Controlled studies are needed, but, because of the FDA warning, cannot be undertaken. The FDA does not allow studies on antidepressants in subjects with depression who have symptoms/features (such as psychomotor agitation, irritability, hypomanic symptoms, impulsivity, bipolar depression, and bipolar family history) that may be precursors to suicidality. Therefore, retrospective studies and naturalistic studies are the only source of information about the treatment of mixed depression.

Diagnostic criteria for hypomania, mixed depression, and the treatment of mixed depression, are the current hot topics in connection with BP II. All 3 of these may have an important impact on the treatment of BP II disorder.

Franco Benazzi, MD, PhD, is director of the Hecker Psychiatry Research Center at Forli, Italy, a University of California at San Diego (USA) Collaborating Center. The focus of his research is bipolar II disorder, atypical depression, and mixed depression. He has published numerous articles on these subjects in international peer-reviewed journals. He reports that he has no conflicts of interest concerning the subject matter of this article.

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Articles

Three issues of current concern in bipolar II disorder include: diagnostic criteria for hypomania, diagnosis of mixed depression, and management of mixed depression.

Bipolar II Disorder: Current Issues in Diagnosis and Management

, 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 

 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). 

The presence of hypomanic symptoms in MDD supports the continuity between MDD and BD-II (Benazzi, 2003d). The distribution of the number of hypomanic symptoms between BD-II and MDD was near normal, not supporting the two depressive syndromes as distinct disorders (i.e., categories). Following Kendell and Jablensky's (2003) approach to diagnostic validity, points of rarity between the two syndromes would support a categorical definition. By applying this method to a sample of patients with mixed depression, a near normal curve of hypomanic symptoms was found, supporting our dimensional definition of mixed depression. 

The bipolar nature of mixed depression, studied in mixed BD-II and MDD samples, was strongly supported by a high family history of BD. Family history was assessed by interview of probands (and often of a family member) by the Family History Screen. This structured interview has the important advantage of assessing both BD-I and BD-II in first-degree relatives. There was a high frequency of BD-II in the probands of patients with mixed depression and a similarly high frequency to that of probands of patients with BD-II. Currently, family history is probably the most important diagnostic validator (Akiskal and Benazzi, 2003; Ghaemi et al., 2002). 

The diagnostic validity of mixed depression was supported by its association with classic bipolar disorder and diagnostic validators (Akiskal, 2003; Akiskal et al., 1995; Angst et al., 2003; Ghaemi et al., 2002; McMahon et al., 1994). The diagnostic validity and bipolar nature of mixed depression was also supported by finding a dose-response relationship between the number of hypomanic symptoms present during the depression and positive family history of bipolar loading. 

The bipolar nature of a subtype of mixed depression, i.e., psychomotor agitated depression, was supported by its links with bipolar validators. Mixed depression was found to be very common in BD-II samples (around 60%) and in MDD samples (around 30%), supporting its diagnostic utility (Benazzi and Akiskal, 2003c). The most common hypomanic symptoms during mixed depression were irritable mood, racing thoughts, psychomotor agitation, talkativeness and distractibility. An important finding was the positive association between racing thoughts and suicide ideation. Our studies on the increased mental activity of mixed depression were not limited to racing thoughts (increased speed of thoughts). We also included "crowded thoughts" (mind full of non-stop thoughts). This link between racing or crowded thoughts and suicide ideation could explain why treatment of mixed depression with antidepressants sometimes led to suicidal behavior, probably by increased mental and behavioral agitation (Benazzi, 2003e; Koukopoulos and Koukopoulos, 1999). 

Temperamental mood lability was found to be more common in mixed depression than in non-mixed depression, suggesting that frequent baseline mood swings may facilitate the onset of mixed depression by pushing hypomanic symptoms into depression. Akiskal et al. (1995) already showed that mood lability predicted the shift of MDD to BD-II. Mixed depression, as compared to non-mixed depression, was more likely to occur in females and at a younger age (Benazzi, 2002b). Mixed depression was found to be no more common in BD-II with hypomania-depression cycles versus BD-II without these cycles.

The impact of treatment on our mixed depression study suggests that the current underdiagnosis of BD-II could be overcome by systematic probing for a history of hypomania and improving clinicians' interviewing skills. The interview should focus on assessing any history of overactivity rather than on mood change (behavior is easier to remember and is observable and verifiable by others). Negative outcomes of antidepressant treatment (without mood stabilizers) of BD-II misdiagnosed as MDD could thus be avoided. Some of these unwanted effects include switching to hypomania, increased cycling, induction of hypomanic symptoms during depression and increased severity of mixed depression (Altshuler et al., 1995; Ghaemi et al., 2003; Koukopoulos and Koukopoulos, 1999). By diagnosing mixed depression, the possible negative outcomes of antidepressants used alone, such as increased agitation, racing thoughts, and irritability, anger and aggressivity, could potentially be avoided.

Dr. Benazzi is senior staff psychiatrist in the department of psychiatry, National Health Service in Forli, Italy, and director of the E. Hecker Outpatient Psychiatry Center in Ravenna, a collaborating center with the University of California at San Diego. 

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According to a large international study, BD-II mixed depression can easily be misdiagnosed as major depressive disorder. Proper assessment and treatment of mixed depression in BD-II could have a positive impact on outcomes in bipolar disorder.

Franco Benazzi, MD, PhD

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