Bipolar family history of the hypomanic symptoms and dimensions of mixed depression

BACKGROUND: There are no data on the bipolar family history (BPFH) of the hypomanic symptoms and dimensions of mixed depression (defined as a depression plus concurrent hypomanic symptoms). These data may be important for the genetics of mixed depression. The study aim was to investigate the BPFH of the hypomanic symptoms of mixed depression. METHODS: Consecutive 243 bipolar II disorder (BP II) and 189 major depressive disorder (MDD) outpatients, presenting for treatment of a major depressive episode (MDE), were interviewed using the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide, and the Family History Screen. Mixed depression was defined as an MDE plus 3 or more intra-MDE hypomanic symptoms (following a definition validated by Akiskal and Benazzi [J Affect Disord 2003;73:113-22]). RESULTS: Major depressive episode with BPFH vs MDE without BPFH had significantly more BP II, lower age of onset, more MDE recurrences, more atypical depressions, more mixed depressions, and more intra-MDE hypomanic symptoms (irritability, racing/crowded thoughts, psychomotor agitation, more talkativeness, distractibility). Factor analysis of intra-MDE hypomanic symptoms found 2 factors (dimensions): one factor including psychomotor agitation and more talkativeness, and one factor including racing/crowded thoughts, irritability, and distractibility. Logistic regression showed that mixed depression was more strongly associated with BPFH than hypomanic symptoms and dimensions. There was a dose-response relationship between number of intra-MDE hypomanic symptoms and BPFH loading (marked increase at n = 3) in the entire BP II and MDD sample. CONCLUSIONS: Findings showed that hypomanic symptoms were more common in the MDE with BPFH of BP II and of MDD, suggesting that a bipolar vulnerability may be required for mixed depression. Mixed depression was more strongly associated with BPFH than hypomanic symptoms and dimensions, suggesting that it could be the focus of future FH studies.     

Challenging the unipolar–bipolar division: Does mixed depression bridge the gap?

BACKGROUND: Mixed states, i.e., opposite polarity symptoms in the same mood episode, question the categorical splitting of mood disorders in bipolar disorders and unipolar depressive disorders, and may support a continuum between these disorders. Study aim was to find if there were a continuum between hypomania (defining BP-II) and depression (defining MDD), by testing mixed depression as a 'bridge' linking these two disorders. A correlation between intradepressive hypomanic symptoms and depressive symptoms could support such a continuum, but other explanations of a correlation are possible. METHODS: Consecutive 389 BP-II and 261 MDD major depressive episode (MDE) outpatients were interviewed, cross-sectionally, with the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide (to assess intradepressive hypomanic symptoms) and the Family History Screen, by a mood disorders specialist psychiatrist in a private practice. Patients presented voluntarily for treatment of depression when interviewed drug-free and had many subsequent follow-ups after treatment start. Mixed depression (depressive mixed state) was defined as the combination of MDE (depression) and three or more DSM-IV intradepressive hypomanic symptoms (elevated mood and increased self-esteem were always absent by definition), a definition validated by Akiskal and Benazzi. RESULTS: BP-II, versus MDD, had significantly lower age at onset, more recurrences, atypical and mixed depressions, bipolar family history, MDE symptoms and intradepressive hypomanic symptoms. Mixed depression was present in 64.5% of BP-II and in 32.1% of MDD (p=0.000). There was a significant correlation between number of MDE symptoms and number of intradepressive hypomanic symptoms. A dose-response relationship between frequency of mixed depression and number of MDE symptoms was also found. CONCLUSIONS: Differences on classic diagnostic validators could support a division between BP-II and MDD. Presence of intradepressive hypomanic symptoms by itself, and correlation between intradepressive hypomanic symptoms and depressive symptoms could instead support a continuum. Other explanations of such a correlation are possible. Depending on the method used, a BP-II-MDD continuum could be supported or not.     

Bipolar II disorder and major depressive disorder: continuity or discontinuity?

AIM: To find if bipolar II disorder (BPII) and major depressive disorder (MDD) were distinct categories or overlapping syndromes. METHODS: 308 BPII and 236 MDD outpatients, presenting for major depressive episode (MDE) treatment, were interviewed with the Structured Clinical Interview for DSM-IV. History of mania and hypomania, and hypomanic symptoms present during MDE, were systematically investigated. Presence of zones of rarity between BPII and MDD depressive syndromes was assessed. Atypical and hypomanic symptoms were chosen because atypical features and depressive mixed state (ie, MDE plus more than 2 concurrent hypomanic symptoms, according to Akiskal and Benazzi 2003) were often reported to distinguish BPII from MDD depressive syndromes (more common in BPII). If BPII were a distinct category, distributions of these symptoms should show zones of rarity between BPII and MDD depressive syndromes. Histograms and Kernel density estimate were used to study distributions of these symptoms. RESULTS: BPII had significantly more atypical features and depressive mixed state than MDD. Histograms and Kernel density estimate curves of distributions of atypical and hypomanic symptoms in the entire sample did not show zones of rarity. CONCLUSIONS: Finding no zones of rarity supports a continuity between BPII and MDD (meaning partly overlapping disorders without clear boundaries).     

Impact of temperamental mood lability on depressive mixed state

BACKGROUND: Cyclothymic temperament (which includes mood lability) is common in bipolar II disorder (BP-II). Depressive mixed state (DMX), a major depressive episode (MDE) mixed with intra-episode hypomanic symptoms (3 or more, according to a recently validated definition), was found to be common in BP-II and not uncommon in major depressive disorder (MDD). The study aim was to find the impact of temperamental mood lability (TML) on DMX. METHODS: Consecutive 148 BP-II and 117 MDD outpatients presenting for MDE treatment were interviewed by the Structured Clinical Interview for DSM-IV as modified by Benazzi and Akiskal to reduce the false negative BP-II. Intra-MDE hypomanic symptoms were systematically assessed. Kraepelin, Angst, and Akiskal's definitions of temperamental mood lability (i.e., frequent up and down fluctuations of mood between major mood episodes since young age) were followed. RESULTS: DMX was present in 61.5%, TML in 52.8%. In the DMX sample, TML was present in 57.6%, and in the non-DMX sample TML was present in 45.0% (OR = 1.6, 95% CI = 1.0-2.7). In the DMX sample, independent predictors of DMX with TML were BP-II and young age at onset. Intra-MDE hypomanic symptoms, and MDE, melancholic and atypical symptoms were not significantly different between DMX patients with TML and DMX patients without TML, apart from more temperamental interpersonal sensitivity in DMX patients with TML (OR = 2.0, 95% CI = 1.0-3.8). DISCUSSION: DMX patients with TML had a younger onset age, suggesting that TML may facilitate the onset of DMX or that it may be a precursor of DMX. The association of BP-II with DMX, TML, and interpersonal sensitivity can make the course of BP-II more unstable and its treatment more complex.     

Melancholic outpatient depression in Bipolar-II vs. unipolar

BACKGROUND: DSM-IV melancholic major depressive episode (MDE) in bipolar II disorder (BP-II) is understudied. Study aim was to compare melancholic MDE in BP-II vs. unipolar major depressive disorder (MDD) on diagnostic validators and clinical features. METHODS: Consecutive 39 BP-II and 34 unipolar MDD outpatients in a private practice were interviewed (off psychopharmacotherapy) with the Structured Clinical Interview for DSM-IV, as modified by Benazzi and Akiskal [J. Affect. Disord. 73 (2003) 1], when presenting for treatment of MDE. DSM-IV criteria of melancholic features specifier were followed. Variables studied were index age, gender, age at onset of the first MDE, number of MDE recurrences, severity (measured by GAF, index MDE psychotic features, index MDE symptoms lasting more than 2 years, Axis I comorbidity), index MDE and melancholic symptoms, bipolar family history. Diagnostic validators were onset, family history, course of illness, and clinical picture. RESULTS: BP-II melancholic MDE, vs. MDD melancholic MDE, had significantly lower age at onset and more bipolar family history. Psychomotor agitation was significantly more common in BP-II melancholic MDE, but was present only in 43.5%. Psychomotor retardation was more common in MDD melancholic MDE at a trend level, but was present only in 20.5%. CONCLUSIONS: Psychomotor agitation was more common in BP-II melancholic MDE vs. unipolar MDD, while previous studies on bipolar I (BP-I) had usually found more retardation. The difference could be related to BP-I and BP-II being at least partly distinct disorders. The relatively low frequency of psychomotor change does not seem to support the view that this is the core feature of melancholia. Differences on diagnostic validators (most importantly family history) further support the distinction of melancholic MDE between BP-II and MDD, and support DSM-IV classification.     

Unipolar depression with racing thoughts: A bipolar spectrum disorder?

Major depressive disorder (MDD) with racing/crowded thoughts is understudied. Kraepelin classified 'depression with flight of ideas' in the mixed states of his manic-depressive insanity. The aim of the study was to test whether MDD with racing/crowded thoughts was close to bipolar disorders. Consecutive 379 bipolar-II disorder (BP-II) and 271 MDD depressed outpatients were interviewed using the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide, and the Family History Screen, by a senior psychiatrist in a private practice. Intra-depression hypomanic symptoms were systematically assessed. Mixed depression was defined as a major depressive episode (MDE) plus three or more intra-MDE hypomanic symptoms. MDD with racing/crowded thoughts was compared to MDD without racing/crowded thoughts on classic bipolar validators (young onset age, many recurrences, atypical and mixed depression, bipolar family history). Frequency of MDD with racing/crowded thoughts was 56.4%. MDD with racing/crowded thoughts, versus MDD without racing/crowded thoughts, had significantly lower age at onset, more MDE severity, more psychotic, melancholic, atypical, and mixed depressions, and more bipolar family history. Of the intra-MDE hypomanic symptoms, irritability, psychomotor agitation and distractibility were significantly more common in MDD with racing/crowded thoughts. Compared to BP-II on bipolar validators, validators were less common in MDD with racing/crowded thoughts. MDD with racing/crowded thoughts seemed to be a severe variant of MDD. MDD with racing/crowded thoughts versus MDD without racing/crowded thoughts, and versus BP-II, had significant differences on bipolar validators, suggesting that it may lie along a continuum linking MDD without racing/crowded thoughts and BP-II.     

Unipolar depression with bipolar family history: links with the bipolar spectrum

The aim of the present paper was to find if unipolar major depressive disorder (MDD) with bipolar family history could be included in the bipolar spectrum, by comparing it to unipolar MDD without bipolar family history, and to bipolar II disorder, on typical bipolar variables. A sample of 280 consecutive bipolar II outpatients, and a sample of 135 consecutive unipolar MDD outpatients, presenting for major depressive episode (MDE) treatment, were interviewed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (4th edn). Hypomanic symptoms during the MDE were systematically assessed. Clinical variables used to validate the inclusion of unipolar MDD with bipolar family history in the bipolar spectrum were young age of onset, many MDE recurrences, atypical features, and depressive mixed state (DMX; an MDE plus >2 concurrent hypomanic symptoms), following many previous studies reporting that these variables were typical features of bipolar disorders. Means were compared by t-test and frequencies by chi2 test (stata 7). Two-tailed P < 0.05 was chosen. Unipolar MDD with bipolar family history was present in 20% of MDD patients. Comparisons among unipolar MDD with bipolar family history (UP+BPFH), unipolar MDD without bipolar family history (UP-BPFH), and bipolar II (BPII), found that UP+BPFH versus UP-BPFH had a significantly lower age, lower age of onset, fewer recurrences, and more DMX; that UP+BPFH versus BPII had no significant differences (apart from recurrences); and that UP-BPFH versus BPII had significantly different age, age of onset, recurrences, atypical features, and DMX. Findings suggest that UP+BPFH shows many bipolar signs, and that it could therefore be included in the bipolar spectrum. Unipolar MDD with bipolar family history had a clinically significant 20.0% frequency in the unipolar MDD sample, supporting the clinical usefulness of this depression subtype. The subtyping of MDD based on bipolar family history could have treatment implications.     

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.     

Is depressive mixed state a transition between depression and hypomania?

Abstract.Background: Depressive mixed states (DMX), described systematically by Kraepelin, have recently been found common among depressed outpatients, with possible important impact on treatment. Study aim was to find if DMX in bipolar II disorder was often a transition period between depression and hypomania, as suggested by Kraepelin.Methods: 194 consecutive bipolar II major depressive episode (MDE) outpatients were interviewed with the Structured Clinical Interview for DSM-IV. Hypomanic symptoms during the index MDE were systematically assessed. DMX was defined as a MDE plus > 2 hypomanic symptoms appearing during the MDE (not before it), following Akiskal and Benazzi (2003). History of depression-hypomania cycles and vice versa (without symptom-free intervals) was assessed. If DMX were a transition period, cycles should have been more common in bipolar II with DMX than in bipolar II without DMX. To test if there were differences between DMX with history of cycles and DMX without history of cycles, the two subgroups were compared on many clinical, family history, and temperamental variables. To test if there were differences between bipolar II with DMX and bipolar II without DMX, comparisons between the two subgroups were done on variables often reported to be typically found in bipolar disorders and to be diagnostic validators (young onset, many recurrences, atypical features of depression, bipolar family history, temperamental mood lability, gender).Results: DMX was present in 70.1%, and history of cycles in 79.8%. In bipolar II without index DMX (n = 58) history of cycles was present in 86.2%; in bipolar with index DMX (n = 136) history of cycles was present in 77.2% (p = 0.175). DMX with cycles was not significantly different from DMX without cycles on all study variables (apart from agitation). Bipolar II with index DMX, versus bipolar II MDE without index DMX, had significantly more depressions with atypical features, temperamental mood lability, and more females, while age of onset, recurrences, and bipolar family history were not significantly different.Limitations: Single interviewer, cross-sectional assessment.Conclusions: Findings do not support Kraepelins view of DMX as a transition period between depression and hypomania, and a distinction between DMX with and without cycles. Findings only partly support DMX as a distinct subtype of bipolar II, which seems to require temperamental mood lability for its onset during a bipolar II MDE.     

Agitated depression: a valid depression subtype?

PURPOSE: The diagnostic validity of agitated depression (AD, a major depressive episode (MDE) with psychomotor agitation) is unclear. It is not classified in DSM-IV and ICD-10 classification of mental and behavioural disorder (ICD-10). Some data support its subtyping. This study aims to test the subtyping of AD. METHODS: Consecutive 245 bipolar-II (BP-II) and 189 major depressive disorder (MDD) non-tertiary-care MDE outpatients were interviewed (off psychoactive drugs) with Structured Clinical Interview for DSM-IV Axis I Disorders--Clinician Version (SCID-CV), Hypomania Interview Guide (HIGH-C), and Family History Screen. Intra-MDE hypomanic symptoms were systematically assessed. AD was defined as an MDE with psychomotor agitation. Mixed AD was defined as an MDE with four or more hypomanic symptoms (including agitation). FINDINGS: AD was present in 34.7% of patients. AD was mixed in 70.1% of AD patients. AD, vs. non-AD, had significantly (at alpha = 0.05) lower age at onset, more BP-II, females, atypical depressions, bipolar-I (BP-I) and BP-II family history, and was more mixed; racing/crowded thoughts, irritability, more talkativeness, and risky behaviour were significantly more common. Mixed AD, vs. non-AD, had significantly (at alpha = 0.01) lower age at onset, more intra-MDE hypomanic symptoms, BP-II, females, atypical depressions, BP-II family history, and specific hypomanic symptoms (distractibility, racing thoughts, irritable mood, more talkativeness, risky activities). Mixed AD, vs. non-mixed AD, had significantly more intra-MDE hypomanic symptoms (by definition), more recurrences, and more specific hypomanic symptoms (by definition). Non-mixed AD, vs. non-AD, had significantly more intra-MDE hypomanic symptoms and more talkativeness. CONCLUSIONS: AD was common in non-tertiary-care depression outpatients, supporting its diagnostic utility. AD and many bipolar diagnostic validators were associated, supporting its link with the bipolar spectrum. Mixed AD, but not non-mixed AD, had differences vs. non-AD similar to those of AD, suggesting that psychomotor agitation by itself may not be enough to identify AD as a subtype. Findings seem to support the subtyping of mixed AD. This subtyping may have important treatment impact, as antidepressants alone might increase agitation.     

A tetrachoric factor analysis validation of mixed depression

BACKGROUND: Mixed depression, i.e. a Major Depressive Episode plus co-occurring manic/hypomanic symptoms, has recently become the focus of research. However, its diagnostic validity and bipolar nature are still not firmly supported. A bipolar nature could have significant treatment impacts. STUDY AIM: The aim was to psychometrically validate the concept of, and the bipolar nature, of mixed depression, by using (for the first time) tetrachoric factor analysis of its hypomanic symptoms. METHODS: Consecutive 441 Bipolar II Disorder (BP-II), and 289 Major Depressive Disorder (MDD) outpatients were cross-sectionally assessed for Major Depressive Episode (MDE) and concurrent hypomanic symptoms (as binary variables) when presenting for treatment of depression, by a mood disorder specialist psychiatrist (FB), using the Structured Clinical Interview for DSM-IV (as modified by [Akiskal HS, Benazzi F. Optimizing the detection of bipolar II disorder in outpatient private practice: toward a systematization of clinical diagnostic wisdom. J Clin Psychiatry 2005; 66: 914-921.]) in a private practice. Consecutive 275 remitted BP-II were also assessed for past hypomania. Mixed depression was defined as co-occurrence of MDE and 3 or more, usually subthreshold, hypomanic symptoms. RESULTS: In multivariable logistic regression, BP-II independent predictor variables were young onset age, MDE recurrences, mixed depression, and bipolar family history. Factor analysis of past hypomania symptoms found three factors: an "irritable mental overactivity" factor, an "elevated mood" factor, and a "motor overactivity" factor. Factor analysis of intradepression hypomanic symptoms in BP-II, and in MDD, found two similar mental and motor overactivity factors. Multivariate regression of the intradepression hypomanic factors versus bipolar validators, such as bipolar family history and young onset age, found significant associations. DISCUSSION: Findings could support the diagnostic validity, and the bipolar nature, of mixed depression, on the basis of the close similarities found between the factor structure of inter-depression hypomania and intra-depression hypomanic symptoms. Impacts on treatment of a bipolar nature of mixed depression may be significant (e.g. more use of mood stabilising agents, less/no use of antidepressants).     

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.     

Inter‐episode mood lability in mood disorders: residual symptom or natural course of illness?

Residual depressive symptoms are common in mood disorders. Inter-episode mood lability (IML; i.e. frequent ups and downs of mood) is understudied as a possible residual symptom. The study aim was to find the frequency of IML, and to find if it was more likely to be a residual symptom or if it was instead part of the natural course of mood disorders. Consecutive 89 bipolar-II (BP-II) and 89 major depressive disorder (MDD) outpatients who were not on psychoactive drugs, were interviewed by the Structured Clinical Interview for the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders as modified by Benazzi and Akiskal. Kraepelin's basic definition of IML (i.e. frequent up and down fluctuations of mood between episodes) was followed. IML was present in 48.3% of the patients, significantly more common in BP-II than in MDD (62.9% vs. 33.7%, P= 0.000). The sample of BP-II and MDD plus IML, versus the sample BP-II and MDD without IML, had significantly more BP-II, lower age at onset, longer illness duration, more depressive recurrences, more depressions with atypical features, more depressive mixed states, and more family history of mood disorders. Logistic regression of IML versus recurrences, controlled for duration of illness, found odds ratio = 1.8, z= 1.6, P= 0.103. Forward stepwise multiple logistic regression of IML versus the variables found significant in the univariate analysis, showed that only BP-II (P = 0.002) and duration of illness (P = 0.015) were significant predictors of IML. IML was common in mood disorder outpatients. Its association with BP-II (an unstable disorder by definition) and duration of illness (but not with recurrences when controlled for illness duration), suggest that IML may be more likely to be part of the natural course of illness than the result of kindling induced by recurrences. Its association with depressive mixed state (a depression reported to be more difficult to treat) and the possibility that it may induce/facilitate recurrences (to be shown by prospective studies), support the need to better study IML for its possible important impact on treatment.     

Depressive mixed state: Testing different definitions

The aim of this study was to test different definitions of depressive mixed state (DMX) (major depressive episode (MDE) with some concurrent hypomanic symptoms), to find which one could better define DMX. Unipolar and bipolar II MDE outpatients (n = 168) were interviewed with the DSM-IV Structured Clinical Interview. Depressive mixed state was defined as a MDE with two or more (DMX2), and as a MDE with three or more (DMX3) concurrent hypomanic symptoms. DMX2 was present in 71.8% bipolar II patients, and in 41.5% unipolar (P < 0.01). DMX3 was present in 46.6% of bipolar II, and in 7.6% unipolar patients (P < 0.01). DMX2 and DMX3 had almost the same significant and non-significant associations with study variables (diagnosis, gender, age, age at onset, illness duration, MDE recurrences, axis I comorbidity, MDE severity, depression chronicity, hypomanic, MDE, psychotic, melancholic, and atypical symptoms and features). DMX3 was more strongly associated with bipolar II than DMX2 (odds ratio 10.4 vs 3.5). Findings suggest that DMX3 may be a better definition of DMX due to its stronger association with bipolar II disorder. Findings have important clinical and treatment implications because antidepressants may worsen DMX, and the presence of DMX may induce clinicians to assess systematically and carefully the history of past hypomania.     

The continuum/spectrum concept of mood disorders: is mixed depression the basic link?

Background Mixed states, i.e., opposite polarity symptoms in the same mood episode, question the bipolar/unipolar splitting of mood disorders, and support a spectrum view. Study aim was assessing the distribution of intradepressive hypomanic symptoms between bipolar-II (BP-II) and major depressive disorder (MDD) depressions, and testing a dose–response relationship between number of intradepressive hypomanic symptoms and bipolar family history. No bi-modality, and a dose–response relationship, would not support a categorical distinction. Methods Consecutive 389 BP-II and 261 MDD depressed outpatients were interviewed by the structured clinical interview for DSM-IV, hypomania interview guide, and family history screen, by a mood specialist psychiatrist, in a private practice. Intradepressive hypomanic symptoms were systematically assessed. Mixed depression was defined as the combination of depression and three or more intradepressive hypomanic symptoms, a validated definition. Results BP-II, versus MDD, had significantly more intradepressive hypomanic symptoms. The distribution of intradepressive hypomanic symptoms between BP-II and MDD was not bi-modal but normal-like, and a dose–response relationship was found between the number of intradepressive hypomanic symptoms and bipolar family history. Conclusions Study findings question the categorical division of BP-II and MDD, and may support the spectrum view of mood disorders.     

Defining mixed depression

BACKGROUND: Mixed depression, i.e. a major depressive episode plus co-occurring manic/hypomanic symptoms, has recently become the focus of research. However, it is still unclear if its definition should be based on specific manic symptoms or on a number/score of manic symptoms. Different definitions may have different diagnostic utility, such as treatment impacts. STUDY AIM: Study aim was to test which definition of mixed depression was more supported, by using, as diagnostic validator, early age at onset on the basis of previous studies supporting its bipolar nature. METHODS: Consecutive 336 Bipolar II Disorder (BP-II), and 224 Major Depressive Disorder (MDD) outpatients were cross-sectionally assessed for major depressive episode (MDE) and concurrent DSM-IV hypomanic symptoms when presenting for treatment of depression, by a mood disorder specialist psychiatrist using the Structured Clinical Interview for DSM-IV as modified by Akiskal and Benazzi (J Clin Psychiatry, 2005) and the Hypomania Interview Guide (HIG), in a private practice. Mixed depression was defined as co-occurrence of MDE and hypomanic symptoms. Early age at onset (EO) below 21 years was used as diagnostic validator. RESULTS: Multivariable logistic regression of EO versus all within-MDE hypomanic symptoms, controlled for BP-II, showed that no specific symptom was independently associated with EO. By ROC analysis versus EO, the best combination of sensitivity and specificity, and the highest figure of correctly classified, were shown by a cutoff number >=3 symptoms, and by a cutoff HIG score >=8. Both cutoffs had similar strength of association with EO. Mixed depression defined by >=3 within-MDE hypomanic symptoms (A), or by a HIG score >=8 (B), were more frequent in EO group versus LO group (A: 70.5% versus 49.8%; B: 60.7% versus 40.9%; p<0.001), and in BP-II versus MDD (A: 72.3% versus 39.7%; p<0.001; positive predictive value for BP-II=73.1%; B: 63.9% versus 29.0%; p<0.001; positive predictive value for BP-II=76.7%). DISCUSSION: Findings could support the diagnostic validity of a definition of mixed depression based on a cutoff number/score of within-depression hypomanic symptoms versus one based on specific symptoms, complementing and supporting previous studies using bipolar family history as validator. Diagnosing mixed depression has treatment impacts, such as careful use of antidepressants added to mood stabilising agents or no use of antidepressants, as recently shown by large naturalistic and controlled studies.     

Depressive mixed state frequency: age/gender effects

Depressive mixed state (DMX), a major depressive episode (MDE) combined with few manic/hypomanic symptoms, is understudied. Age and gender are important variables in mood disorders. The aim of the present study was to determine whether age and gender had any effect on the frequency of DMX. Consecutive unipolar (n = 144) and bipolar II (n = 218) drug-free MDE out-patients were interviewed with the Structured Clinical Interview for DSM-IV when presenting for MDE treatment. The presence of hypomanic symptoms during the index MDE was assessed systematically. Depressive mixed state was defined as a MDE with three or more concurrent hypomanic symptoms (DMX3), following previous reports. Associations were tested by logistic regression. The results showed that the DMX3 frequency was 43.9% and that it affected more females than males. Frequency decreased with age. The lower frequency with age was related to the lower frequency of bipolar II disorder with age. Bipolar disorder family history of DMX3 patients did not change with age. In conclusion, the frequency of DMX3 was high and related to age. The high frequency of DMX3 supports the clinical usefulness of the definition, as well as observations that antidepressants may worsen its hypomanic symptoms, whereas antipsychotics and mood stabilisers may treat them. A bipolar vulnerability seems to be required for the appearance of DMX3 also in later life.     

Frequency of bipolar spectrum in 111 private practice depression outpatients

Background Mood disorders included into the bipolar spectrum are increasing, and overactivity (increased goal-directed activity) has reached the status of mood change for the diagnosis of hypomania in the recent studies by Angst (2003) and Akiskal (2001). Study aim was to find frequency of bipolar spectrum in remitted depressed outpatients by including sub-syndromal hypomania. Methods 111 depression-remitted outpatients were interviewed for history of hypomania and hypomanic symptoms with the Structured Clinical Interview for DSM-IV-Clinician Version (a partly semistructured interview), as modified by Benazzi and Akiskal (2003). Bipolar I patients were not included. All past hypomanic symptoms (especially overactivity) were systematically assessed.Wording of the questions could be changed to increase/check understanding.Subsyndromal hypomania was defined as an episode of overactivity (increased goal-directed activity) plus at least 2 hypomanic symptoms. Results Frequency of bipolar II (BPII) was 68/111 (61.2%, 95% confidence interval 52% to 69.8 %), frequency of major depressive disorder (MDD) was 43/111. The most common hypomanic symptom was overactivity. In the MDD sample, sub-syndromal hypomania was present in 39.5% (15.3% of the entire sample), and had 4 median symptoms. Bipolar spectrum frequency was 76.5% (95% confidence interval 67.9% to 83.5 %). Overactivity had higher sensitivity than elevated mood for predicting BPII diagnosis. Limitations Single interviewer. Conclusions By systematic probing more focused on past overactivity than mood change, and by inclusion of sub-syndromal hypomania, bipolar spectrum frequency was higher than the near 1 to 1 ratio versus MDD reported up to now (Angst et al. 2003). Given the wide confidence interval, the value in the depression population should be around 70%. Better probing skills by clinicians, and use of semi-structured interviews could much reduce the current high underdiagnosis of BPII and related disorders in usual clinical practice.     

Validating Kraepelin's two types of depressive mixed states: "depression with flight of ideas" and "excited depression".

Despite a venerable classic tradition going back to at least Kraepelin, depressive mixed states (DMX) are not represented in official diagnostic manuals in psychiatry. We have operationalised this condition as a major depressive episode (MDE) with three or more intra-episode hypomanic signs and symptoms (DMX3). Of 320 consecutive bipolar II outpatients, presenting for MDE treatment and interviewed using the Structured Clinical Interview for DSM-IV, modified to permit the systematic evaluation of hypomanic features during the index MDE, 200 met our criteria for DMX3 (62.5%). When compared with the remaining non-DMX bipolar II, they had significantly earlier age at onset, higher percentage of females, atypical features and bipolar family history. Multivariate logistic regression ofintra-MDE hypomanic signs and symptoms found evidence supporting an "excited depression" subtype (defined by the core feature of psychomotor agitation, and further characterised by talkativeness, irritable mood and distractability) and a "depression with flight of ideas" subtype (defined by the core feature of racing/crowded thoughts, and further characterised by risky pleasurable impulses including, among others, those with intense sexual arousal). We thereby documented the existence of two distinct DMX subtypes which testify to the clinical acumen of Kraepelin (and his pupil Weygandt) who in 1899 described these two subforms of depressive mixed states in more severely ill hospitalised patients.     

Mixed states in bipolar II disorder: should full hypomania always be required?

The aim of the study was to test whether the definition of depressive mixed states (DMX) in bipolar II disorder should require satisfaction of full criteria for hypomania or if only a few hypomanic symptoms should be required. Consecutive outpatients with bipolar II major depressive episode (MDE) (n=260) were assessed with the Structured Clinical Interview for DSM-IV. Presence of hypomanic symptoms during MDE was systematically assessed, and symptoms were graded by rating scale. The following three definitions of DMX were compared: (1) MDE plus full criteria for hypomania, (2) MDE plus three or more hypomanic symptoms (DMX3), and (3) MDE plus one or two hypomanic symptoms (DMX1-2). DMX definitions were compared on variables typically associated with bipolar disorders (young age of onset, many recurrences, atypical features of depression, and bipolar family history). The distributions of hypomanic symptom scores, age, and age of onset were studied by Kernel density estimation curves and by histograms. Bimodality would support distinct disorders, whereas lack of bimodality would support continuity among the different DMX definitions. The frequency of DMX+full hypomania was 12.3%, that of DMX3 was 46.9%, and that of of DMX1-2 was 38.8%. Comparisons among the groups on bipolar validators found that most differences were not significant. Kernel density estimation curves and histograms did not show bimodality, and had near normal distribution shapes. The findings do not support a categorical definition of bipolar II DMX like that of DSM-IV for bipolar I mixed state but are consistent with a dimensional definition of bipolar II DMX. The high frequency of DMX in bipolar II MDE supports the need for controlled studies to test the effects of antidepressants on depressive mixed state (as clinical observations suggest possible negative effects).