Toward a validation of a new definition of agitated depression as a bipolar mixed state (mixed depression).

PURPOSE: As psychotic agitated depression is now a well-described form of mixed state during the course of bipolar I disorder, we sought to investigate the diagnostic validity of a new definition for agitated (mixed) depression in bipolar II (BP-II) and major depressive disorder (MDD). MATERIALS AND METHODS: Three hundred and thirty six consecutive outpatients presenting with major depressive episodes (MDE) but without history of mania were evaluated with the Structured Clinical Interview for DSM-IV when presenting for the treatment of MDE. On the basis of history of hypomania they were assigned to BP-II (n = 206) vs. MDD (n = 130). All patients were also examined for hypomania during the current MDE. Mixed depression was operationally defined by the coexistence of a MDE and at least two of the following excitatory signs and symptoms as described by Koukopoulos and Koukopoulos (Koukopoulos A, Koukopoulos A. Agitated depression as a mixed state and the problem of melancholia. In: Akiskal HS, editor. Bipolarity: beyond classic mania. Psychiatr Clin North Am 1999;22:547-64): inner psychic tension (irritability), psychomotor agitation, and racing/crowded thoughts. The validity of mixed depression was investigated by documenting its association with BP-II disorder and with external variables distinguishing it from unipolar MDD (i.e., younger age at onset, greater recurrence, and family history of bipolar disorders). We analyzed the data with multivariate regression (STATA 7). RESULTS: MDE plus psychic tension (irritability) and agitation accounted for 15.4%, and MDE plus agitation and crowded thoughts for 15.1%. The highest rate of mixed depression (38.6%) was achieved with a definition combining MDE with psychic tension (irritability) and crowded thoughts: 23.0% of these belonged to MDD and 76.9% to BP-II. Moreover, any of these permutations of signs and symptoms defining mixed depression was significantly and strongly associated with external validators for bipolarity. The mixed irritable-agitated syndrome depression with racing-crowded thoughts was further characterized by distractibility (74-82%) and increased talkativeness (25-42%); of expansive behaviors from the criteria B list for hypomania, only risk taking occurred with some frequency (15-17%). CONCLUSIONS: These findings support the inclusion of outpatient-agitated depressions within the bipolar spectrum. Agitated depression is validated herein as a dysphorically excited form of melancholia, which should tip clinicians to think of such a patient belonging to or arising from a bipolar substrate. Our data support the Kraepelinian position on this matter, but regrettably this is contrary to current ICD-10 and DSM-IV conventions. Cross-sectional symptomatologic hints to bipolarity in this mixed/agitated depressive syndrome are virtually absent in that such patients do not appear to display the typical euphoric/expansive characteristics of hypomania-even though history of such behavior may be elicited by skillful interviewing for BP-II. We submit that the application of this diagnostic entity in outpatient practice would be of considerable clinical value, given the frequency with which these patients are encountered in such practice and the extent to which their misdiagnosis as unipolar MDD could lead to antidepressant monotherapy, thereby aggravating it in the absence of more appropriate treatment with mood stabilizers and/or atypical antipsychotics.     

Does psychomotor agitation in major depressive episodes indicate bipolarity?

BACKGROUND: Kraepelin's partial interpretation of agitated depression as a mixed state of "manic-depressive insanity" (including the current concept of bipolar disorder) has recently been the focus of much research. This paper tested whether, how, and to what extent both psychomotor symptoms, agitation and retardation in depression are related to bipolarity and anxiety. METHOD: The prospective Zurich Study assessed psychiatric and somatic syndromes in a community sample of young adults (N = 591) (aged 20 at first interview) by six interviews over 20 years (1979-1999). Psychomotor symptoms of agitation and retardation were assessed by professional interviewers from age 22 to 40 (five interviews) on the basis of the observed and reported behaviour within the interview section on depression. Psychiatric diagnoses were strictly operationalised and, in the case of bipolar-II disorder, were broader than proposed by DSM-IV-TR and ICD-10. As indicators of bipolarity, the association with bipolar disorder, a family history of mania/hypomania/cyclothymia, together with hypomanic and cyclothymic temperament as assessed by the general behavior inventory (GBI) [15], and mood lability (an element of cyclothymic temperament) were used. RESULTS: Agitated and retarded depressive states were equally associated with the indicators of bipolarity and with anxiety. Longitudinally, agitation and retardation were significantly associated with each other (OR = 1.8, 95% CI = 1.0-3.2), and this combined group of major depressives showed stronger associations with bipolarity, with both hypomanic/cyclothymic and depressive temperamental traits, and with anxiety. Among agitated, non-retarded depressives, unipolar mood disorder was even twice as common as bipolar mood disorder. CONCLUSION: Combined agitated and retarded major depressive states are more often bipolar than unipolar, but, in general, agitated depression (with or without retardation) is not more frequently bipolar than retarded depression (with or without agitation), and pure agitated depression is even much less frequently bipolar than unipolar. The findings do not support the hypothesis that agitated depressive syndromes are mixed states. LIMITATIONS: The results are limited to a population up to the age of 40; bipolar-I disorders could not be analysed (small N).     

The role of atypical antipsychotics in bipolar depression and anxiety disorders

Abstract:  Bipolar disorder is a complex condition that includes symptoms of mania, depression, and often anxiety. Diagnosing and treating bipolar depression is challenging, with the disorder often being diagnosed as unipolar depression. In addition, comorbid anxiety can be a significant detractor to successful outcomes, increasing symptom severity, frequency of episodes and suicide rates, and decreasing response to antidepressant therapy. Anxiety often precedes and hastens the onset of bipolar disorder, and a shared genetic etiology has been suggested. Studies have demonstrated the efficacy of atypical antipsychotics for the acute and maintenance treatment of mania. Evidence from studies in patients with treatment-resistant major depressive disorder and bipolar depression indicate that these agents may also have antidepressant effects. In open trials in patients with bipolar mania, risperidone therapy has led to significant reductions in depression scores compared with baseline. Reductions in depression scores in patients with bipolar mania have been significantly greater with olanzapine compared with placebo. In patients with bipolar depression, the combination of olanzapine and fluoxetine resulted in significant improvement in depression compared with olanzapine alone or placebo. Although little data are available on the effects of these agents on comorbid anxiety in patients with bipolar disorder, some atypical antipsychotics have demonstrated efficacy in patients with anxiety disorders, including obsessive-compulsive disorder, post-traumatic stress disorder, and generalized anxiety disorder. Thus, atypical antipsychotics represent an important therapeutic option for the treatment of bipolar disorder, providing improvements in manic, depressive, and anxiety symptoms.     

Diagnosing bipolar disorder: signs and symptoms

Bipolar disorder occurs in up to 2% of the community, but the prevalence is much higher among first-degree relatives of individuals with bipolar disorder. Following Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria assists clinicians in making an accurate diagnosis of bipolar I or bipolar II disorder and in distinguishing bipolar disorders from other illnesses such as major depressive disorder, medical conditions, and substance use. Additionally, always asking depressed patients about mania and using mnemonics to check for symptoms of mania and major depression can help physicians accurately diagnose and treat bipolar disorder.     

Suicidal Behavior in Mood Disorders: Response to Pharmacological Treatment

Suicidal behavior is strongly associated with depression, especially if accompanied by behavioral activation, dysphoria, or agitation. It may respond to some treatments, but the design of scientifically sound, ethical trials to test for therapeutic effects on suicidal behavior is highly challenging. In bipolar disorder, and possibly also unipolar major depression, an underprescribed medical intervention with substantial evidence of preventive effects on suicidal behavior is long-term treatment with lithium. It is unclear whether this effect is specifically antisuicidal or reflects beneficial effects of lithium on depression, mood instability, and perhaps aggression and impulsivity. Antisuicidal effects of anticonvulsant mood stabilizers (carbamazepine, lamotrigine, valproate) appear to be less than with lithium. Further evaluation is needed for potential antisuicidal effects of atypical antipsychotics with growing evidence of efficacy in depression, particularly acute bipolar depression, while generally lacking risk of inducing agitation, mania, or mood instability. Short-term and long-term value and safety of antidepressants are relatively secure for unipolar depression but uncertain and poorly tested for bipolar depression; their effects on suicidal risk in unipolar depression may be age-dependent. Sedative anxiolytics are virtually unstudied as regards suicidal risks. Adequate management of suicidal risks in mood disorder patients requires comprehensive, clinically skillful monitoring and timely interventions.     

Mood patterns and classification in bipolar disorder

PURPOSE OF REVIEW: The aim of this review is to highlight recent studies that have questioned the current split of mood disorders into the categories of bipolar and depressive disorders. RECENT FINDINGS: A continuity between bipolar disorders (mainly bipolar II disorder) and major depressive disorder was supported by several lines of evidence: depressive mixed states (mixed depression) and dysphoric (mixed) hypomania (opposite polarity symptoms in the same episode do not support the splitting between mania/hypomania and depression); family history, major depressive disorder is the most common mood disorder in relatives of bipolar probands; lack of points of rarity between the depressive syndromes of bipolar II disorder and major depressive disorder; bipolar features in major depressive disorder; major depressive disorder shifting to bipolar disorders; history of manic/hypomanic symptoms in major depressive disorder and correlation between lifetime manic/hypomanic symptoms and depressive symptoms in major depressive disorder; factors of hypomania inside major depressive disorder; recurrent course of major depressive disorder; depression more common than mania and hypomania in bipolar disorders; trait mood lability in major depressive disorder. SUMMARY: This review of the recent findings on the relationship between bipolar disorders (especially bipolar II disorder) and depressive disorders seems to support a continuity among mood disorders, and runs against the current classification of mood disorders dividing them into independent categories. Further research is needed in the area, in part because of its possible treatment impact.     

Depressive and manic symptoms are not opposite poles in bipolar disorder

Johnson SL, Morriss R, Scott J, Paykel E, Kinderman P, Kolamunnage‐Dona R, Bentall RP. Depressive and manic symptoms are not opposite poles in bipolar disorder. Objective: This study of 236 individuals with bipolar disorders employed longitudinal analyses to determine whether the symptoms of mania and depression can be understood as one dimension (with depression and mania as opposites) or two relatively independent dimensions. Method: Weekly severity ratings of manic and depression were assessed using the Longitudinal Interval Follow‐up Evaluation‐II for 72 weeks. The within‐subjects correlation of manic and depressive severity was examined using random effects regression. Results: Contrary to the one‐dimension model, mania and depression symptoms were not negatively related. Indeed, the correlations of mania with depressive symptoms were quite small. Conclusion: The data suggest that depressive and manic symptoms are not opposite poles. Rather depressive and manic symptoms appear to fluctuate relatively independently within bipolar disorder.     

Devenir des troubles bipolaires et place du trouble dysphorique prémenstruel dans le DSM-5

In the field of bipolar disorders, the fifth edition of the DSM has clarified the definition of manic mood, which includes irritability and expansiveness. This elevated mood is associated with increased goal-directed activity or energy. A full manic episode that emerges during an antidepressant treatment (e.g., medication, electroconvulsive therapy) is now sufficient evidence for a manic episode diagnosis and therefore for a bipolar disorder I diagnosis. If so a mood-stabilizer treatment is required. The DSM-5 authors call for more caution in case of hypomanic episodes induced by antidepressant treatment, especially if only one or two symptoms are present. On the other hand, if there are psychotic features, the episode is, by definition, manic. Several studies have judged the bereavement exclusion criteria irrelevant to fulfil the diagnosis of major depressive episode, that is why this exclusion criteria has disappeared from DSM-5. This might help for a better management of major depressive episode in case of mourning. The lack of consensual definition of mixed state led to the suppression of the mixed episode in this new edition of the DSM. It is however possible to specify the mixed features in manic, hypomanic and depressive episodes. This decision is in coherence with Emil Kraepelin's inheritance. In fact, Kraepelin himself described several mixed states, essentially as transition states between the two main clinical pictures (mania and depression) of the manic-depressive illness. In this perspective, clinical pictures such as agitated depression, dysphoric manic or hypomanic episodes can be reconsidered and one can hope that studies will be conducted to deepen the knowledge of those episodes from a clinical, physiopathological and therapeutic point of view. Finally the premenstrual dysphoric disorder has moved from the appendix B (for the research) of the DSM-IV to the “diagnostic criteria and codes” (section II) of the DSM-5. This disorder is quite frequently associated with bipolar disorder II whose prognosis it worsens while complicating its therapeutic management. In the paper, the premenstrual dysphoric disorder is described on an historical, clinical, physiopathological and therapeutic level, within the limits of current knowledge about this uncommon psychiatric syndrome. Its DSM-5 diagnostic criteria are also summarized and commented upon. This official entry of the premenstrual dysphoric disorder in the DSM-5 shows the willingness of the American Psychiatric Association to incorporate uncommon psychiatric syndromes in its diagnostic classification.     

The role of mood stabilisers in the treatment of the depressive facet of bipolar disorders

It was previously shown that available mood stabilisers are used to treat bipolar depression. As part of the natural course of illness, patients with bipolar disorder often suffer from episodes of depression more frequently and for longer durations than mania. A major challenge in the treatment of bipolar depression is the tendency for antidepressant medications, particularly tricyclic antidepressants, to precipitate episodes of mania, or to increase cycle frequency or symptom intensity. Thus, exploring the utility of mood stabilisers as monotherapy for bipolar depression is important. The aim of this review it to collate data involving the effects of some mood stabilisers like lithium, carbamazepine, valproate and lamotrigine in depressive aspects of bipolar disorder, but as well using an animal model of depression, to understand their mechanism of action.     

Prevalence and effects of mood disorders on work performance in a nationally representative sample of U.S. workers

OBJECTIVE: Research on the workplace costs of mood disorders has focused largely on major depressive episodes. Bipolar disorder has been overlooked both because of the failure to distinguish between major depressive disorder and bipolar disorder and by the failure to evaluate the workplace costs of mania/hypomania. METHOD: The National Comorbidity Survey Replication assessed major depressive disorder and bipolar disorder with the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) and work impairment with the WHO Health and Work Performance Questionnaire. A regression analysis of major depressive disorder and bipolar disorder predicting Health and Work Performance Questionnaire scores among 3,378 workers was used to estimate the workplace costs of mood disorders. RESULTS: A total of 1.1% of the workers met CIDI criteria for 12-month bipolar disorder (I or II), and 6.4% meet criteria for 12-month major depressive disorder. Bipolar disorder was associated with 65.5 and major depressive disorder with 27.2 lost workdays per ill worker per year. Subgroup analysis showed that the higher work loss associated with bipolar disorder than with major depressive disorder was due to more severe and persistent depressive episodes in those with bipolar disorder than in those with major depressive disorder rather than to stronger effects of mania/hypomania than depression. CONCLUSIONS: Employer interest in workplace costs of mood disorders should be broadened beyond major depressive disorder to include bipolar disorder. Effectiveness trials are needed to study the return on employer investment of coordinated programs for workplace screening and treatment of bipolar disorder and major depressive disorder.     

Diagnostic reliability of bipolar II disorder

BACKGROUND: Although the diagnostic reliability of major depression and mania has been well established, that of hypomania and bipolar II (BPII) disorder has not. This remains an important issue for clinicians, especially for those undertaking genetic studies of BP disorder since bipolar I (BPI) and BPII disorders often cluster in the same families. We have assessed our diagnostic reliability of BP disorders, recurrent unipolar disorder, and their constituent episodes (major depression, mania, and hypomania) using interview and best-estimate diagnostic procedures used in a genetic study of families with BPI disorder. METHODS: Reliability was assessed for (1) co-rated Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews of 37 subjects including 15 with BP disorders; (2) test-retest Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews of 26 subjects including 13 with BP disorders; and (3) best-estimate diagnoses made by 2 noninterviewing psychiatrists on 524 subjects in a genetic linkage study of BPI disorder. Diagnoses were based on Research Diagnostic Criteria for a Selected Group of Functional Disorders, except that recurrent major depression as well as hypomania was required for a diagnosis of BPII disorder. RESULTS: On co-rated interviews, we observed complete agreement between interviewers for diagnosing major depressive, manic, and hypomanic episodes. For test-retest interviews, the Cohen kappa coefficients were 0.83 for manic, 0.72 for hypomanic, and 1.0 for major depressive episodes. At the best-estimate level, the Cohen kappa coefficients were 0.99 for BPI, 0.99 for BPII, and 0.98 for recurrent unipolar disorder. CONCLUSION: Good interrater reliability for BPII can be achieved when the interviews and best-estimate diagnoses are done by experienced psychiatrists.     

The bipolar spectrum and the antidepressant view of the world

Whereas much progress has been made in the diagnosis and treatment of schizophrenia and depression in recent years, bipolar disorder continues to be frequently misunderstood, leading to its inconsistent diagnosis and treatment. In this article, we seek to identify the causes of this problem and suggest possible solutions, based on a critical review of studies concerning the nosology of bipolar disorder and the effects of antidepressant agents. Bipolar disorder appears to be underdiagnosed as well as frequently misdiagnosed as unipolar major depressive disorder. Underdiagnosis can stem from patients' impaired insight into mania and failure to involve family members in the diagnostic process and also from clinicians' inadequate understanding of manic symptoms. Underdiagnosis may also reflect disagreement about the breadth of the bipolar spectrum. We therefore propose a heuristic definition of "bipolar spectrum disorder," a diagnosis that gives greater weight to family history and antidepressant-induced manic symptoms. This diagnosis would include all forms of bipolar illness that are not type I or II . The evidence also suggests that antidepressants are probably overused and mood stabilizers underused. We consequently recommend aggressive use of mood stabilizers and less emphasis on antidepressants. In summary, the state of diagnosis and treatment in bipolar disorder is suboptimal. More diagnostic attention to the criteria for mania is necessary. In addition, the current pattern of antidepressant use in bipolar disorder does not appear to be evidence-based.     

The relationship of major depressive disorder to bipolar disorder: Continuous or discontinuous?

Recent studies have questioned current diagnostic systems that split mood disorders into the independent categories of bipolar disorders and depressive disorders. The current classification of mood disorders runs against Kraepelin’s unitary view of manic-depressive insanity (illness). The main findings of recent studies supporting a continuity between bipolar disorders (mainly bipolar II disorder) and major depressive disorder are presented. The features supporting a continuity between bipolar II disorder and major depressive disorder currently are 1) depressive mixed states (mixed depression) and dysphoric (mixed) hypomania (opposite polarity symptoms in the same episode do not support a splitting of mood disorders); 2) family history (major depressive disorder is the most common mood disorder in relatives of bipolar probands); 3) lack of points of rarity between the depressive syndromes of bipolar II disorder and major depressive disorder; 4) major depressive disorder with bipolar features such as depressive mixed states, young onset age, atypical features, bipolar family history, irritability, racing thoughts, and psychomotor agitation; 5) a high proportion of major depressive disorders shifting to bipolar disorders during long-term follow-up; 6) a high proportion of major depressive disorders with history of manic and hypomanic symptoms; 7) factors of hypomania present in major depressive disorder episodes; 8) recurrent course of major depressive disorder; and 9) depressive symptoms much more common than manic and hypomanic symptoms in the course of bipolar disorders.     

Gender differences in subtypes of late-onset depression and mania

BACKGROUND: It is currently not known whether elderly men and women present with different subtypes of depression and mania/bipolar disorder. The aim of this study was to compare the prevalence of subtypes of a single depressive episode and mania/bipolar disorder according to the ICD-10 for elderly men and women in a nationwide sample of all out- and inpatients in psychiatric settings. METHODS: All patients older than 65 years who received a diagnosis of a single depressive episode and mania/bipolar disorder in the period from 1994 to 2002 at the end of their first outpatient treatment or at their first discharge from psychiatric hospitalization in Denmark were identified in a nationwide register. RESULTS: A total of 9837 patients aged more than 65 years received a diagnosis of a single depressive episode (69.9% were women) and 443 a diagnosis of mania/bipolar disorder (61.6% were women) at the end of their first contact with psychiatric health care. Slightly more women than men received a diagnosis of mild (70.8%) or moderate depression (67.4%) compared to severe depression (65.9%). Men more often presented with a single depressive episode with comorbid substance abuse or comorbid somatic illness. No gender differences were found in the prevalence of depression with or without melancholic or psychotic symptoms. Men more often presented with mania/bipolar disorder with comorbid substance abuse. CONCLUSIONS: The distributions of the subtypes of a single depressive episode or mania/bipolar disorder are remarkably similar for male and female patients aged over 65 years with first contact with the psychiatric health-care system.     

Strategies to reduce misdiagnosis of bipolar depression

Research over the past decade indicates that the prevalence of bipolar disorder is similar to that of major depression. The author discusses complexities in the diagnosis of bipolar disorder, especially in distinguishing bipolar from unipolar depression. Bipolar depression is associated with more mood lability, more motor retardation, and greater time spent sleeping. Early age of onset, a high frequency of depressive episodes, a greater percentage of time ill, and a relatively acute onset or offset of symptoms are suggestive of bipolar disorder rather than major depression. Because DSM-IV criteria require a manic or hypomanic episode for a diagnosis of bipolar disorder, many patients are initially diagnosed and treated as having major depression. Treatment of bipolar disorder with antidepressants alone is not efficacious and may exacerbate hypomania, mania, or cycling. It is important that clinicians be alert to any hint of bipolarity developing in the course of antidepressant therapy, especially among patients with first-episode major depression.     

The relationship of major depressive disorder to bipolar disorder: Continuous or discontinuous?

Recent studies have questioned current diagnostic systems that split mood disorders into the independent categories of bipolar disorders and depressive disorders. The current classification of mood disorders runs against Kraepelin’s unitary view of manic-depressive insanity (illness). The main findings of recent studies supporting a continuity between bipolar disorders (mainly bipolar II disorder) and major depressive disorder are presented. The features supporting a continuity between bipolar II disorder and major depressive disorder currently are 1) depressive mixed states (mixed depression) and dysphoric (mixed) hypomania (opposite polarity symptoms in the same episode do not support a splitting of mood disorders); 2) family history (major depressive disorder is the most common mood disorder in relatives of bipolar probands); 3) lack of points of rarity between the depressive syndromes of bipolar II disorder and major depressive disorder; 4) major depressive disorder with bipolar features such as depressive mixed states, young onset age, atypical features, bipolar family history, irritability, racing thoughts, and psychomotor agitation; 5) a high proportion of major depressive disorders shifting to bipolar disorders during long-term follow-up; 6) a high proportion of major depressive disorders with history of manic and hypomanic symptoms; 7) factors of hypomania present in major depressive disorder episodes; 8) recurrent course of major depressive disorder; and 9) depressive symptoms much more common than manic and hypomanic symptoms in the course of bipolar disorders.     

A continuity between bipolar II depression and major depressive disorder?

BACKGROUND: A recent series of studies has questioned the current categorical split of mood disorders into bipolar and depressive disorders. Mixed states, especially mixed depression (i.e., depression plus co-occurring, noneuphoric, hypomanic symptoms) might support a continuity between bipolar II (BP-II) depression and major depressive disorder (MDD). The aim of the study was to assess the distribution of intradepressive hypomanic symptoms rating between BP-II and MDD depressions. A bi-modal distribution would support a categorical distinction, and no bi-modality would support continuity. METHODS: Consecutive 389 BP-II and 261 MDD major depressive episode (MDE) outpatients were interviewed (off psychoactive drugs) with the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide (HIG, to assess intradepressive hypomanic symptoms), and the Family History Screen, by a mood specialist psychiatrist in a private practice. Mixed depression was defined as MDE plus 3 or more intradepressive, noneuphoric hypomanic symptoms, a definition validated by Akiskal and Benazzi. The distribution of intradepressive hypomanic symptoms rating was studied by Kernel density estimate and by histogram. RESULTS: BP-II depression, versus MDD depression, had significantly lower age at onset, was significantly more likely to be atypical and mixed, had more depression recurrences, and a higher bipolar family history loading. BP-II depression, versus MDD depression, had significantly more irritability, racing/crowded thoughts, distractibility, psychomotor agitation, talkativeness, increased goal-directed activity, and excessive risky activities. HIG scores were significantly higher in BP-II. The distribution of intradepressive hypomanic symptoms rating showed no bi-modality in the entire depression sample. CONCLUSIONS: Interpretation of study findings relies on the method used to define a categorical disorder. By using classic diagnostic validators (such as family history and age at onset), BP-II and MDD depressions would seem to be distinct disorders. Instead, by using the 'bi-modality' approach, a continuity would seem to be supported. Which of these methods for classification is the best has yet to be shown.     

Family history validation of a definition of mixed depression

PURPOSE: The study aim was to test different definitions of mixed depression, defined as a depression with concurrent hypomanic symptoms. METHODS: Consecutive 245 non-tertiary care outpatients with bipolar II disorder (BP-II) and 189 non-tertiary care outpatients with major depressive disorder (MDD) were interviewed (off psychoactive drugs) using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I Disorders-Clinician Version, Hypomania Interview Guide (HIG), and Family History Screen when presenting for major depressive episode (MDE) treatment. Intra-MDE hypomanic symptoms were systematically assessed. Mixed depression was defined as an MDE with concurrent hypomanic symptoms. Receiver operating characteristic (ROC) analysis and multivariate analysis were used to test different definitions of mixed depression (dimensional and categorical ones). Factor analysis was also used. Bipolar family history was the validator. FINDINGS: Bipolar II disorder, vs MDD, had significantly more intra-MDE hypomanic symptoms (racing/crowded thoughts, irritable mood, psychomotor agitation, more talkativeness, and increased goal-directed and risky activities). Major depressive episode plus 3 or more hypomanic symptoms was present in 68.7% of BP-II and 42.3% of MDD. A "motor activation" factor, including psychomotor agitation and talkativeness, and a "mental activation" factor including racing/crowded thoughts were found. Different definitions (dimensional and categorical ones) of mixed depression were tested vs bipolar family history as validator (ie, MDE plus more than 1, 2, 3, and 4 concurrent hypomanic symptoms, MDE plus psychomotor agitation, MDE plus racing thoughts). Major depressive episode plus more than 1 hypomanic symptom had the highest sensitivity but the lowest specificity. Instead, MDE plus more than 4 hypomanic symptoms had the lowest sensitivity and the highest specificity. The better-balanced combination of sensitivity and specificity was shown by MDE plus more than 2 hypomanic symptoms. The same definition also showed the highest ROC area value. Multivariate regression of bipolar family history vs different mixed depression definitions found that the only strong and significant predictor was MDE plus more than 2 hypomanic symptoms. A dose-response relationship was found between the number of hypomanic symptoms during MDE and the bipolar family history loading. CONCLUSIONS: Mixed depression (MDE plus 3 or more hypomanic symptoms) was common in BP-II and MDD. A dimensional definition based on 3 or more hypomanic symptoms during depression was the most supported by using bipolar family history as validator. The study of mixed depression may be important for its possible impact on treatment (antidepressants could increase hypomanic symptoms, and mood stabilizers and antipsychotics could control hypomanic symptoms during antidepressant treatment).     

Stabilization of mood from below versus above baseline in bipolar disorder: a new nomenclature

Management of bipolar disorder has traditionally emphasized the acute treatment of mania. Although acute treatment of mania is a critical aspect of care, this emphasis has tended to overshadow other important phases of bipolar disorder, such as depression, hypomania, and subsyndromal symptoms. We offer a reconceptualization of bipolar disorder that highlights unmet needs and the importance of differential spectra of efficacy. In this reconceptualization, bipolar disorder can be viewed as an aberration of mood, behavior, and cognition from baseline (euthymia). "Below baseline" is characterized by depression and subsyndromal depression. "Above baseline" is characterized by mania, mixed states, hypomania, and subsyndromal mood elevation. In contrast to the treatment options for mania, the options for depression are limited. This new nomenclature emphasizes the need to develop mood stabilizers that possess the ability to stabilize mood "from below baseline," either alone or in combination with other agents. In this article, the treatment options for bipolar disorder, with a focus on depression and rapid cycling, are discussed according to this new conceptualization of management from below and above baseline.     

Symptoms of depression as possible markers of bipolar II disorder

Underdiagnosis and misdiagnosis of bipolar-II disorder (BP-II) as a major depressive disorder (MDD) are frequently reported. The study aim was to find which symptoms of depression could be possible cross-sectional markers of BP-II, in order to reduce underdiagnosing BP-II. METHODS: Consecutive 379 BP-II and 271 MDD major depressive episode (MDE) outpatients were interviewed with the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide, and the Family History Screen, by a senior psychiatrist in a private practice. Inside-MDE hypomanic symptoms (elevated mood and increased self-esteem always absent by definition) were systematically assessed. Mixed depression was defined as an MDE plus 3 or more inside-MDE hypomanic symptoms, a definition validated by Akiskal and Benazzi. RESULTS: The MDE symptoms significantly more common in BP-II versus MDD were weight gain, increased eating, hypersomnia, psychomotor agitation, worthlessness, and diminished ability to concentrate. The inside-MDE hypomanic symptoms significantly more common in BP-II were distractibility, racing/crowded thoughts, irritability, psychomotor agitation, more talkativeness, increased risky and goal-directed activities. Multiple logistic regression showed that hypersomnia, racing/crowded thoughts, irritability, and psychomotor agitation were independent predictors of BP-II. Irritability had the most balanced combination of sensitivity and specificity predicting BP-II. Psychomotor agitation had the highest specificity but the lowest sensitivity. Racing/crowded thoughts had the highest sensitivity but the lowest specificity. These symptoms had a similar positive predictive value (PPV) for BP-II, which was around 70% (PPV is more clinically useful than sensitivity and specificity), which in turn was similar to the PPV of mixed depression and atypical depression (two diagnostic clinical markers of BP-II). All possible combinations of these symptoms had a PPV similar to that of the individual symptoms. The validity as BP-II markers of these symptoms was supported by a significant association with bipolar family history. CONCLUSIONS: Hypersomnia, racing/crowded thoughts, irritability, and psychomotor agitation may be useful, cross-sectional markers of BP-II. Finding these symptoms in depression should lead the clinician to careful probing for history of hypomania, which should reduce the BP-II misdiagnosed as MDD. Results may also have treatment impacts, as antidepressants used alone (i.e., no concurrent mood stabilising agent) in BP-II depression misdiagnosed as MDD may increase cycling.