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.29
The DSM-IV 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.30-32 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,33,34 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.35
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 DSM-IV for the diagnosis of hypomania).17,21,22,36-43 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.44 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 BP4,9,45 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.46
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.39-43
- 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.42
- Factor structure of the intradepression hypomanic symptoms similar to the factor structure of the hypomania occurring outside the depression.8,16,25,47
- Mixed depression in MDD showing a closer similarity to BP I and BP II on bipolar validators than to nonmixed MDD.39-42
- MDD shifting to bipolar disorder in the long run (around 40% to 50% of cases) is more likely to have mixed depression.48-50
- With antidepressant treatment, mixed depression, compared with nonmixed depression, is more likely to switch to mania/hypomania.51-5
- The distribution of the intradepression hypomanic symptoms between BP II and MDD is not bimodal.54,55
Two lines of evidence question the categoric definition of mixed depression,55 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 disorder54; 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.42,55 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.56
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.36 Irritability, psychomotor agitation, and bipolarity are possible precursors to suicidality that may be related to the effects of antidepressants.57
Studies of mixed depression have shown that cross-sectionally assessed psychomotor agitation and racing/ crowded thoughts are independent predictors of suicidal ideas,58,59 and that mixed depression is often present before suicide attempts.60 It would thus appear that it is not antidepressants that induce suicidality, but their incorrect use.58-60 In mixed depression it seems logical to first control the hypomanic symptoms with mood-stabilizing drugs and then to add an antidepressant.35 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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