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Benazzi F.
Depression with DSM-IV atypical features: a marker for bipolar II disorder.
Eur Arch Psychiatry Clin Neurosci 2000;250(1):53-5
"The aim of the study was to find the prevalence of atypical features in bipolar II depression versus unipolar depression. Five hundred and fifty seven unipolar and bipolar II depressed outpatients were interviewed with the Structured Clinical Interview for DSM-IV, the Montgomery Asberg Depression Rating Scale, and the Global Assessment of Functioning Scale. DSM-IV atypical features were significantly more common in bipolar II patients than in unipolar patients (45.4% vs 25.4%, odds ratio 2.4). As the diagnosis of bipolar II disorder is often based on diagnosis of past hypomania, which may not be very reliable. depression with atypical features may point to bipolar II disorder diagnosis." [Abstract]

Cassano GB, Dell'Osso L, Frank E, Miniati M, Fagiolini A, Shear K, Pini S, Maser J.
The bipolar spectrum: a clinical reality in search of diagnostic criteria and an assessment methodology.
J Affect Disord 1999 Aug;54(3):319-28
"Failure to recognize subthreshold expressions of mania contributes to the frequent under-diagnosis of bipolar disorder. There are several reasons for the lower rate of recognition of subthreshold manic symptoms, when compared to the analogous pure depressive ones. These include the lack of subjective suffering, enhanced productivity, ego-syntonicity, and diurnal and seasonal rhythmicity associated with many of the manic and hypomanic symptoms, and the psychiatrists' tendency to subsume persistent or even alternating symptoms among personality disorders. Furthermore, the central diagnostic importance placed on alterations in mood distracts clinicians from paying attention to other more subtle but clinically meaningful symptoms, such as changes in energy, neurovegetative symptoms and distorted cognitions. Although officially accepted in both ICD-10 and DSM-IV, we believe bipolar II disorder is underdiagnosed because of inattention to symptoms of hypomania. Moreover, by requiring the presence of both full-blown hypomanic and major depressive episodes, current nosology fails to include symptoms or signs which are mild and do not meet threshold criteria. There is already agreement in the field that such symptoms are important for depression. We now propose that attention should also be devoted to mild symptomatic manifestations of a manic diathesis, even if such manifestations may sometimes enhance quality of life. The term 'spectrum' is used to refer to the broad range of such manifestations of a disorder from core symptoms to temperamental traits. Spectrum manifestations may be present during, between, or even in the absence of, an episode of full-blown disorder. We have developed a structured clinical interview to assess the mood spectrum (SCI-MOODS) to evaluate the whole range of depressive and manic symptoms. This instrument is currently undergoing psychometric testing procedures. Similar to the SCID interview, the SCI-MOODS interview provides a separate rating for each of the major DSM-IV symptoms, but the latter also identifies and rates subthreshold and atypical manifestations. This paper presents the concept of a subthreshold bipolar disorder and discusses the potential epidemiological, diagnostic and therapeutic relevance of such a spectrum conditions. We also describe the SCI-MOODS interview used reliably to identify the occurrence of a bipolar spectrum condition. Obviously a great deal of systematic research needs to be conducted to ascertain the reliability and validity of subthreshold bipolarity as summarized in this paper and embodied in our instrument." [Abstract]

Akiskal HS.
The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV.
J Clin Psychopharmacol 1996 Apr;16(2 Suppl 1):4S-14S
"Based on the author's work and that of collaborators, as well as other contemporaneous research, this article reaffirms the existence of a broad bipolar spectrum between the extremes of psychotic manic-depressive illness and strictly defined unipolar depression. The alternation of mania and melancholia beginning in the juvenile years is one of the most classic descriptions in clinical medicine that has come to us from Greco-Roman times. French alienists in the middle of the nineteenth century and Kraepelin at the turn of that century formalized it into manic-depressive psychosis. In the pre-DSM-III era during the 1960s and 1970s, North American psychiatrists rarely diagnosed the psychotic forms of the disease; now, there is greater recognition that most excited psychoses with a biphasic course, including many with schizo-affective features, belong to the bipolar spectrum. Current data also support Kraepelin's delineation of mixed states, which frequently take on psychotic proportions. However, full syndromal intertwining of depressive and manic states into dysphoric or mixed mania--as emphasized in DSM-IV--is relatively uncommon; depressive symptoms in the midst of mania are more representative of mixed states. DSM-IV also does not formally recognize hypomanic symptomatology that intrudes into major depressive episodes and gives rise to agitated depressive and/or anxious, dysphoric, restless depressions with flight of ideas. Many of these mixed depressive states arise within the setting of an attenuated bipolar spectrum characterized by major depressive episodes and soft signs of bipolarity. DSM-IV conventions are most explicit for the bipolar II subtype with major depressive and clear-cut spontaneous hypomanic episodes; temperamental cyclothymia and hyperthymia receive insufficient recognition as potential factors that could lead to switching from depression to bipolar I disorder and, in vulnerable subjects, to predominantly depressive cycling. In the main, rapid-cycling and mixed states are distinct. Nonetheless, there exist ultrarapid-cycling forms where morose, labile moods with irritable, mixed features constitute patients' habitual self and, for that reason, are often mistaken for "borderline" personality disorder. Clearly, more formal research needs to be conducted in this temperamental interface between more classic bipolar and unipolar disorders. The clinical stakes, however, are such that a narrow concept of bipolar disorder would deprive many patients with lifelong temperamental dysregulation and depressive episodes of the benefits of mood-regulating agents." [Abstract]

Bottlender R, Sato T, Kleindienst N, Strauss A, Moller HJ.
Mixed depressive features predict maniform switch during treatment of depression in bipolar I disorder.
J Affect Disord. 2004 Feb;78(2):149-52.
"BACKGROUND: Case observations imply that depressed patients with mixed features are of high risk for maniform switch during acute treatment. METHODS: The medical records of 158 bipolar I depressives were examined with respect to mixed depressive features at admission, naturalistic medications, and maniform switch during inpatient treatment. RESULTS: Besides pharmacological variables, the number of mixed depressive symptoms (flight of ideas, racing thoughts, logorrhea, aggression, excessive social contact, increased drive, irritability, and distractibility) at admission was associated with a higher risk for, and the acceleration of, maniform switch during inpatient treatment. LIMITATIONS: This was a retrospective study in patients receiving naturalistic treatment. The cohort was hospital based and thus not representative of the full range of bipolar affective disorder. CONCLUSIONS: In line with recent studies, our results underline the factors inherent in subjects at a higher risk of switch. Investigation of the relationships between several inherent factors and their interactions with pharmacological treatments may be important in resolving the controversy surrounding antidepressant-induced mania. Further validation studies on mixed depression are warranted." [Abstract]

Akiskal HS, Benazzi F.
Family history validation of the bipolar nature of depressive mixed states.
J Affect Disord. 2003 Jan;73(1-2):113-22.
"BACKGROUND: Recent data indicate that depressive mixed states (DMX), major depressive episode (MDE) plus few concurrent hypomanic symptoms are common in clinical practice but omitted in DSM-IV. Our aims were to find the sensitivity and specificity of DMX for the diagnosis of bipolar II disorder, and validate it against familial bipolarity. METHODS: 377 consecutive private outpatients presenting with psychoactive drug-free MDE were interviewed with the Structured Clinical Interview for DSM-IV (Clinician Version). History of past hypomanic episodes and presence of hypomanic symptoms during the index MDE were systematically recorded. Of these, 226 were bipolar II and 151 unipolar. DMX3 was defined as an MDE plus three or more intra-episodic hypomanic symptoms. RESULTS: DMX3 was present in 58.4% of bipolar II, and 23.1% of unipolar patients. It was significantly associated with variables distinguishing bipolar from strictly defined unipolar disorders (younger age at onset, more MDE recurrence, more atypical features, more bipolar II family history). Unipolar DMX3 (MDE with documented hypomania solely intra-episodically) was not significantly different from bipolar II MDE on age at onset, atypical features, and bipolar II family history. CONCLUSIONS: Results support the inclusion of DMX3 (bipolar II and 'unipolar') into the bipolar spectrum. Adding the 23% of the UP-DMX3 to the roster of less-than-manic outpatient depressives will boost the rate of bipolarity in this outpatient depressive population to a respectable 70%, the highest rate yet reported for the bipolar spectrum below the threshold of mania." [Abstract]

Benazzi F.
Bipolar II depressive mixed state: finding a useful definition.
Compr Psychiatry. 2003 Jan-Feb;44(1):21-7.
"Recent studies showed that depressive mixed state (DMX) (major depressive episode [MDE] with few hypomanic symptoms) was common among depressed outpatients. The aim of the present study was to find a clinicallly useful definition of DMX. A useful definition could be one increasing the probability of making the correct diagnosis of bipolar II. Different definitions of DMX were tested by comparing the sensitivity, specificity, and predictive power for the diagnosis of bipolar II. Three hundred thirty-six consecutive bipolar II (n = 206) and unipolar (n = 130) MDE outpatients were interviewed with the DSM-IV Structured Clinical Interview-Clinician Version (SCID-CV). Different DMX definitions were tested, based on factor analysis, multivariate regression, discriminant analysis, and logistic regression analysis results. The sensitivity, specificity, correctly classified, and receiver operating characteristic (ROC) area for bipolar II diagnosis were compared. Two factors (factor 1, including irritability, psychomotor agitation, and more talkativeness, and factor 2, including racing thoughts, irritability, and distractibility) were significantly associated with bipolar II diagnosis. Of the hypomanic symptoms most common in bipolar II DMX, only irritability and racing thoughts were significantly associated with bipolar II diagnosis on discriminant analysis. DMX with three or more concurrent hypomanic symptoms (DMX3) was strongly associated with bipolar II diagnosis. Comparisons of sensitivity, specificity, correctly classified, and ROC area of the different DMX definitions (factor 1, factor 2, DMX3, irritability during MDE, racing thoughts during MDE) for the diagnosis of bipolar II, showed that factor 1 had the best combination of sensitivity and specificity, high correctly classified and ROC, but DMX3 has the highest specificity, and slightly lower correctly classified and ROC than factor 1. A DMX definition having the highest specificity (DMX3) for bipolar II diagnosis may be more useful to clinicians, leading to few false positives. Bipolar II diagnosis has important treatment and clinical implications, but misdiagnosis is common because diagnosis is often based on history of hypomania (dependent on memory and clinical skills). A cross-sectional marker like DMX3 may increase the probability of making the correct diagnosis of bipolar II, and therefore may be a useful definition of DMX." [Abstract]

Benazzi F.
Depressive mixed state: dimensional versus categorical definitions.
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Feb;27(1):129-34.
"BACKGROUND: Recently, there has been a rebirth of studies on depressive mixed state (DMX), defined as a major depressive episode (MDE) plus few concurrent hypomanic symptoms. It is still unclear how to best define DMX. The study's aim was to test a categorical versus a dimensional definition of DMX. METHODS: Consecutive 260 bipolar II disorder and 173 unipolar MDE outpatients were interviewed with the Structured Clinical Interview for DSM-IV, when presenting for MDE treatment (drug-free). Hypomanic symptoms during index MDE were systematically assessed and graded by a hypomania rating scale (Hypomania Interview Guide, HIG). Different cutoffs of the HIG to define DMX were tested versus a categorical definition of DMX (requiring more than two concurrent hypomanic symptoms, DMX3). Sensitivity and specificity for predicting bipolar II diagnosis were compared. The best definition of DMX based on the HIG was also compared to DMX3 versus typical bipolar variables (early onset, many recurrences, atypical features, bipolar family history). RESULTS: An HIG cutoff of 8 had a specificity for predicting bipolar II diagnosis similar to that of DMX3. HIG>8 was strongly associated with bipolar family history (an important external diagnostic validator), and DMX3 was significantly associated with more bipolar variables (including bipolar family history). LIMITATION: The interview was done by a single interviewer. CONCLUSIONS: Similar specificity for predicting bipolar II disorder diagnosis and a similar strong association with bipolar family history suggest that a categorical and a dimensional definition of DMX could have similar validity. However, the dimensional definition (based on the scoring of a hypomania rating scale) could lead to a better assessment of hypomanic symptoms, resulting in more correct diagnoses of DMX." [Abstract]

Benazzi F.
Which could be a clinically useful definition of depressive mixed state?
Prog Neuropsychopharmacol Biol Psychiatry. 2002 Oct;26(6):1105-11.
"Depressive mixed state (DMX) (major depressive episode [MDE] with few superimposed hypomanic symptoms) was reported to be common among depressed outpatients. Study aim was to find if the best clinically useful definition of DMX was one based on a minimum number of hypomanic symptoms, or instead one based on the combination of specific hypomanic symptoms. METHODS: Consecutive 138 bipolar II and 83 unipolar MDE outpatients were interviewed with DSM-IV Structured Clinical Interview. DMX definitions tested were: MDE with three or more hypomanic symptoms (DMX3) and MDE with hypomanic symptoms irritability, distractibility and racing thoughts. RESULTS: DMX3, and the combination of racing thoughts, irritability and distractibility, had the same significant and nonsignificant associations with study variables. DMX3, and the combination of the specific hypomanic symptoms, significantly predicted bipolar II diagnosis. For predicting bipolar II diagnosis, DMX3 had higher specificity (86.7% vs. 50.6%), while the combination of the specific hypomanic symptoms had higher sensitivity (76.8% vs. 51.4%). CONCLUSIONS: A DMX definition with higher specificity (DMX3) for predicting bipolar II diagnosis may be more clinically useful because it may reduce misdiagnosis." [Abstract]

Benazzi F, Akiskal HS.
Delineating bipolar II mixed states in the Ravenna-San Diego collaborative study: the relative prevalence and diagnostic significance of hypomanic features during major depressive episodes.
J Affect Disord 2001 Dec;67(1-3):115-22
"BACKGROUND: Depressive mixed state (DMX), defined by hypomanic features during a major depressive episode (MDE) is under-researched. Accordingly, study aims were to find DMX prevalence in unipolar major depressive disorder (MDD) and bipolar II depressive phase, to delineate the most common hypomanic signs and symptoms during DMX, and to assess their sensitivity and specificity for the diagnosis of DMX and bipolar II. METHODS: 161 unipolar and bipolar II MDE psychotropic drug- and substance-free consecutive outpatients were interviewed during an MDE with the Structured Clinical Interview for DSM-IV. DMX was defined at two threshold levels as an MDE with two or more (DMX2), and with three or more (DMX3) simultaneous intra-episode hypomanic signs and symptoms. RESULTS: DMX2 was present in 73.1% of bipolar II, and in 42.1% of unipolar MDD (P<0.000); DMX3 was present in 46.3% of bipolar II, and in 7.8% of unipolar MDD (P<0.000). The most common hypomanic manifestations during MDE were irritability, distractibility, and racing thoughts. Irritability had the best combination of sensitivity and specificity for the diagnosis of DMX2 and DMX3. Various combinations of irritability, distractibility, and racing thoughts correctly classified the highest number of DMX2 and DMX3, and had the strongest predictive power. DMX2 had high sensitivity and low specificity for bipolar II, whereas DMX3 had low sensitivity (46.3%) and high specificity (92.1%). LIMITATIONS: Single interviewer, cross-sectional assessment, and interviewing clinician not blind to patients' unipolar vs. bipolar status. CONCLUSIONS: When conservatively defined (>or = 3 intra-episode hypomanic signs and symptoms during MDE), DMX is prevalent in the natural history of bipolar II but uncommon in unipolar MDD. These findings have treatment implications, because of growing concerns that antidepressants may worsen DMX, which in turn may respond better to mood stabilizers. These data also have methodological implications for diagnostic practice: rather than solely depending on the vagaries of the patient's memory for past hypomanic episodes, the search for hypomanic features--ostensibly elation would not be one of those--during an index depressive episode could enhance the detection of bipolar II in otherwise pseudo-unipolar patients. Strict adherence to current clinical diagnostic interview instruments (e.g. the SCID) would make such detection difficult, if not impossible." [Abstract]

Cassidy F, Ahearn E, Murry E, Forest K, Carroll BJ.
Diagnostic depressive symptoms of the mixed bipolar episode.
Psychol Med 2000 Mar;30(2):403-11
"BACKGROUND: There is not yet consensus on the best diagnostic definition of mixed bipolar episodes. Many have suggested the DSM-III-R/-IV definition is too rigid. We propose alternative criteria using data from a large patient cohort. METHODS: We evaluated 237 manic in-patients using DSM-III-R criteria and the Scale for Manic States (SMS). A bimodally distributed factor of dysphoric mood has been reported from the SMS data. We used both the factor and the DSM-III-R classifications to identify candidate depressive symptoms and then developed three candidate depressive symptom sets. Using ROC analysis we determined the optimal threshold number of symptoms in each set and compared the three ROC solutions. The optimal solution was tested against the DSM-III-R classification for crossvalidation. RESULTS: The optimal ROC solution was a set, derived from both the DSM-III-R and the SMS, and the optimal threshold for diagnosis was two or more symptoms. Applying this set iteratively to the DSM-III-R classification produced the identical ROC solution. The prevalence of mixed episodes in the cohort was 13.9% by DSM-III-R, 20.2% by the dysphoria factor and 27.4% by the new ROC solution. CONCLUSIONS: A diagnostic set of six dysphoric symptoms (depressed mood, anhedonia, guilt, suicide, fatigue and anxiety), with a threshold of two symptoms, is proposed for a mixed episode. This new definition has a foundation in clinical data, in the proved diagnostic performance of the qualifying symptoms, and in ROC validation against two previous definitions that each have face validity." [Abstract]

Cassidy F, Carroll BJ.
The clinical epidemiology of pure and mixed manic episodes.
Bipolar Disord 2001 Feb;3(1):35-40
"INTRODUCTION: Few large clinical epidemiological studies have been undertaken comparing subjects meeting criteria for mixed and pure states of bipolar disorder. In part, the difficulty comparing these states emanates from confusion in their diagnostic separation. In the current report, we use a definition derived from receiver operating characteristic (ROC) curve analysis as an alternative to the DSM-IIIR/IV definition, and we compare the two subtypes of manic episodes. METHODS: Three hundred and sixty-six patients meeting DSM-IIIR criteria for bipolar disorder, manic or mixed, were categorized using newly described criteria for mixed states. The two subtypes were compared on demographic variables and clinical history variables, using multiple analysis of variance with post hoc univariate F tests. The same analyses were conducted using the DSM-IIIR-defined subtypes. RESULTS: Using the ROC criteria, 79 subjects (21.6%) were characterized as mixed, in contrast to 51 subjects (13.9%) using DSM-IIIR criteria for bipolar disorder, mixed. The ROC-defined mixed manic group comprised more Caucasians and more females. Age of first psychiatric hospitalization was earlier and duration of illness longer in the mixed group. First episodes were unlikely to be categorized as mixed (< 5%). When the DSM-IIIR definition was employed, differences were not demonstrated. CONCLUSIONS: An earlier age of first psychiatric hospitalization and increased duration of illness, as well as a lower frequency of mixed subtype of manic episode during first hospitalization, are compatible with the view that mixed manic episodes occur more frequently later in the course of bipolar disorder. Moreover, differences in race, sex, and clinical histories of subjects in mixed episodes tend to support the separation of mixed mania as a diagnostic subtype of bipolar disorder." [Abstract]

Cassidy F, Murry E, Forest K, Carroll BJ.
Signs and symptoms of mania in pure and mixed episodes.
J Affect Disord 1998 Sep;50(2-3):187-201
"BACKGROUND: Debate continues about the diagnosis of mixed mania and the restrictiveness of the DSM-III-R and DSM-IV criteria for Bipolar Disorder, mixed. Although awareness of dysphoric features during mania continues to grow, standard mania rating instruments do not adequately assess mixed states and there is a striking disparity between the dysphoric signs and symptoms emphasized in research studies and the commonly employed DSM criteria. METHODS: Three hundred sixteen inpatients meeting DSM-III-R criteria for Bipolar Disorder, manic or mixed, were evaluated by rating 20 signs and symptoms. The frequencies of these signs and symptoms were computed for both diagnostic subtypes and compared using chi2 statistics and conditional probability parameters. RESULTS: The most frequently noted signs and symptoms in mania are motor activation, accelerated thought process, pressured speech and decreased sleep. Although euphoric mood was present in a large portion of the cohort, irritability, dysphoric mood and mood lability were also prominent in the entire cohort. Dysphoric mood, mood lability, anxiety, guilt, suicidality, and irritability were the only symptoms significantly more common in the mixed group. In contrast, grandiosity, euphoric mood, and pressured speech were significantly more often observed in the pure manic group. Contrary to popular belief, paranoia did not differ significantly between the two groups. Suicidality was present in a non-trivial 7% of the entire cohort, including some subjects who did not meet the criteria for mixed mania. LIMITATIONS: The comparison of mixed and manic episodes requires the appropriate definition of mixed states. In the current report we use the DSM-III-R definition of Bipolar Disorder, mixed, which may be too rigid. CONCLUSIONS: The data underscore that mania is not a purely euphoric state. Substantial rates of dysphoria, lability, anxiety and irritability were noted in the "pure" manic patients, as well as in those who meet the full DSM criteria for Bipolar Disorder, mixed, suggesting, that perhaps a less restrictive definition of mixed states would be more appropriate." [Abstract]

Brieger P, Roettig S, Ehrt U, Wenzel A, Bloink R, Marneros A.
TEMPS-a scale in 'mixed' and 'pure' manic episodes: new data and methodological considerations on the relevance of joint anxious-depressive temperament traits.
J Affect Disord. 2003 Jan;73(1-2):99-104.
"BACKGROUND: Temperament is an important factor in affective illness. There is some indication that mixed episodes result from an admixture of inverse temperamental factors (e.g. depressive and/or anxious) to a manic syndrome. To test this hypothesis, which has been first formulated by Akiskal [Clin. Neuropharmacol. 15 (Suppl. 1A) (1992) 632-633], we compared the temperament of non-acute bipolar affective patients with and without the history of a previous mixed episode. METHODS: Patients who had been hospitalized for a bipolar disorder were re-assessed at least 6 months after their last in-patient treatment. Those who met the criteria for a partially remitted or full affective or psychotic episode at re-assessment were excluded from the study. Data concerning illness history, current psychopathology (SCID-I interview), depression (BDI), mania (Self-Report Manic Inventory) and temperament (TEMPS-A scale) were obtained. Patients with and without a history of previous mixed episodes were compared. RESULTS: Of 49 eligible former patients, 22 subjects with and 23 subjects without a former mixed episode in bipolar affective disorder fulfilled the inclusion criteria. Subjects suffering from bipolar affective disorder exhibited significantly more depressive and anxious and less hyperthymic temperament, if they had experienced a mixed episode previously. Concerning cyclothymic and irritable temperament, bipolar affective patients with a former mixed episode presented non-significantly higher scores. Patients with a former mixed episode presented with higher depression scores than patients without such a history. No group differences were found concerning current mania scores. LIMITATIONS: (1). This is a preliminary report from an ongoing study. (2). Temperament had not been assessed premorbidly. (3). Although group comparisons revealed significant differences, these did not seem great enough to fully explain the emergence of a mixed episode. CONCLUSION: Our findings support the study's hypothesis that mixed episodes occur more often in subjects with an inverse temperament (e.g. depressive and anxious), although it cannot be ruled out that subsyndromal features of the bipolar illness had an effect on temperament assessment." [Abstract]

Goldberg JF, Garno JL, Portera L, Leon AC, Kocsis JH.
Qualitative differences in manic symptoms during mixed versus pure mania.
Compr Psychiatry 2000 Jul-Aug;41(4):237-41
"Previous studies have compared demographic and clinical-outcome features of bipolar patients with mixed or pure mania. However, little is known about the potential differences in the nature and extent of manic symptoms in mania either with or without an accompanying depression. This study examined DSM-III-R manic symptoms in a cohort of 183 bipolar I inpatients hospitalized for mixed mania (diagnosed by broad or narrow criteria) or pure manic episodes. Inpatient charts were reviewed to determine the presence of individual affective symptoms. The results indicate that clinicians were more likely to diagnose a pure mania from the beginning to end of an episode than to diagnose a mixed mania from its beginning to end. Mixed-manic patients had significantly fewer manic symptoms than pure manic patients. Grandiosity, euphoria, pressured speech, and a decreased need for sleep were more prevalent during pure versus mixed mania. Grandiosity and a diminished need for sleep were especially notable during pure mania compared with mixed mania as defined by narrow criteria for mixed states. The observed differences in manic symptom profiles between mixed and pure mania may aid in the clinical assessment of dysphoric states among bipolar patients. The data also lend support to the use of broad diagnostic criteria for defining mixed mania as an entity phenomenologically distinct from pure mania." [Abstract]

Brieger P, Ehrt U, Roettig S, Marneros A.
Personality features of patients with mixed and pure manic episodes.
Acta Psychiatr Scand. 2002 Sep;106(3):179-82.
"OBJECTIVE: To test the hypothesis that patients with a mixed manic episode show different personality features than patients with a pure manic episode. METHOD: Sixteen patients with a mixed manic episode (broad criteria) and 26 patients with a pure manic episode were assessed with diagnostic interviews (SCID I/II) as well as instruments for depression, mania and personality. RESULTS: Even after controlling for age as well as depression and mania score at assessment, no differences between the two groups emerged concerning either personality features as assessed with the NEO-five-factor inventory (NEO-FFI) or personality disorders. CONCLUSION: We found no difference between patients with mixed mania and patients with pure mania concerning their personality features. Possible reasons for this are being discussed." [Abstract]

Perugi G, Micheli C, Akiskal HS, Madaro D, Socci C, Quilici C, Musetti L.
Polarity of the first episode, clinical characteristics, and course of manic depressive illness: a systematic retrospective investigation of 320 bipolar I patients.
Compr Psychiatry 2000 Jan-Feb;41(1):13-8
"In 320 patients with established bipolar I disorder, we examined the past course on the basis of polarity at onset (depressive, mixed, and manic). Despite the obvious limitations of retrospective methodology, information on course parameters in a large sample of affective disorders is most practically obtained by such methodology. We believe that our systematic interview of patients and their relatives--as well as the systematic study of their records--minimized potential biases. Depressive onsets were the most common, accounting for 50%, followed by mixed and manic onsets in about equal proportion. In general, the polarity of episodes over time reflected polarity at onset. Those with depressive onset had significantly higher levels of rapid cycling, as well as suicide attempts, but were significantly less likely to develop psychotic symptoms. Mixed onsets, too, had high rates of suicide attempts, but differed from depressive onsets in having significantly more chronicity yet negligible rates of rapid cycling at follow-up evaluation. Because cases with depressive onset had received significantly higher rates of psychopharmacologic treatment, our data are compatible with the hypothesis that antidepressants may play a role in the induction of rapid cycling. Overall, our data support the existence of distinct longitudinal patterns within bipolar I disorder, which in turn appear correlated with the polarity at onset. In particular, rapid cycling and mixed states emerge as distinct psychopathologic processes." [Abstract]

Benazzi F.
Psychomotor changes in melancholic and atypical depression: unipolar and bipolar-II subtypes.
Psychiatry Res 2002 Nov 15;112(3):211-20
"Psychomotor changes are reported to be 'nearly always present' in the melancholic subtype of major depressive episode (MDE) in DSM-IV-TR, and are believed by some researchers to be markers of melancholia. The aim of this study was to compare melancholic and atypical forms of MDE and to determine whether psychomotor changes are core features of melancholic MDE. The Structured Clinical Interview of DSM-IV was used to consecutively assess 107 unipolar and 164 bipolar-II MDE outpatients. The criteria used to define melancholic and atypical MDE followed DSM-IV-TR. Melancholic MDE was present in 17.7% of patients; atypical MDE, in 35.0%. The group of patients with melancholic MDE had the following differences from the atypical group: higher age, higher age at onset, fewer females, more unipolar cases, fewer bipolar-II cases, lower Global Assessment of Functioning scores, more MDE symptoms, and more psychotic features. Percentages of observable and marked psychomotor changes (agitation and retardation combined) did not differ significantly between the two groups, though the melancholic group tended to have more symptoms. Retardation was significantly more common in melancholic MDE, but its frequency was very low in both melancholic and atypical cases (12.5 vs. 0.0%). Logistic regression controlling for age, gender and illness duration had little effect on the findings, which suggests that psychomotor changes are not core features of melancholic MDE." [Abstract]

Keck PE Jr, McElroy SL, Havens JR, Altshuler LL, Nolen WA, Frye MA, Suppes T, Denicoff KD, Kupka R, Leverich GS, Rush AJ, Post RM.
Psychosis in bipolar disorder: phenomenology and impact on morbidity and course of illness.
Compr Psychiatry. 2003 Jul-Aug;44(4):263-9.
"Although psychosis is common in bipolar disorder, few studies have examined the prognostic significance of psychotic features. In addition, some studies suggest that the presence of mood-incongruent psychosis, in particular, is associated with poorer outcome compared with mood-congruent psychosis. We assesses the phenomenology and prevalence of mood-congruent and mood-incongruent psychotic symptoms in 352 patients with bipolar I disorder participating in the Stanley Foundation Bipolar Treatment Network. We compared the demographic and clinical features, and measures of psychosocial and vocational functioning in patients with and without a history of psychosis. The phenomenology of psychosis in this cohort of patients with bipolar disorder was similar to that reported in earlier studies and supported the lack of diagnostic specificity of any one type of psychotic symptom. There were no significant differences between patients with and without a history of psychosis on any demographic, psychosocial, vocational, or course of illness variables. Only family history of bipolar disorder was significantly more common in patients with nonpsychotic bipolar disorder compared to patients with a history of psychosis. Among bipolar patients with a history of psychosis, only the proportion of women and lifetime prevalence rates of anxiety disorders occurred significantly more in patients with mood-incongruent delusions. In this large cohort of outpatients with bipolar I disorder, neither a history of psychosis nor of mood-incongruent psychosis had prognostic significance at entry into the Network. The lack of observable prognostic impact may have been, in part, due to the relatively high morbidity and poor functional outcome of a substantial portion of the total cohort." [Abstract]

Benazzi F.
Psychotic versus nonpsychotic bipolar outpatient depression.
Eur Psychiatry 1999 Dec;14(8):458-61
"Psychotic bipolar depression was compared with nonpsychotic bipolar depression. Psychotic (n = 59) and nonpsychotic (n = 176) bipolar depressed outpatients were SCID-DSM-IV interviewed. Psychotic bipolar depression had significantly higher severity, more chronicity, fewer atypical features and axis I co-morbidity, more bipolar I, and fewer bipolar II patients. Age at onset, duration of illness, gender, and recurrences, were not significantly different." [Abstract]

Yildiz A, Sachs GS.
Age onset of psychotic versus non-psychotic bipolar illness in men and in women.
J Affect Disord. 2003 Apr;74(2):197-201.
"OBJECTIVE: To investigate the relationship between psychotic symptoms and age at onset of bipolar illness. METHOD: The charts of bipolar patients treated at the Massachusetts General Hospital Bipolar Clinic were reviewed for age of first affective episode, demographics and history of psychotic symptoms. RESULTS: Data was obtained for 328 bipolar patients (56.7% females) of whom 42% had psychotic symptoms sometime through the course of their illness. Overall, there was no significant difference in age of onset between the psychotic and non-psychotic groups. Additional analysis carried out separately by gender found significant difference for males but not for females. Age at onset for psychotic males was significantly lower than non-psychotic males. Psychosis was less common in males than females. The mean age of onset for psychotic males was significantly lower than psychotic females. CONCLUSION: This result implies that developmental physiology underlying psychosis in bipolar illness may differ for men and women. The different proportions of males and females in the study samples may account for conflicting results reported in the literature for age of onset of psychotic bipolar illness." [Abstract]

Gonzalez-Pinto A, van Os J, Perez de Heredia JL, Mosquera F, Aldama A, Lalaguna B, Gutierrez M, Mico JA.
Age-dependence of Schneiderian psychotic symptoms in bipolar patients.
Schizophr Res. 2003 Jun 1;61(2-3):157-62.
"Psychotic symptoms frequently occur in bipolar disorder, especially in younger patients. However, whether the association with younger age also extends to psychotic symptoms that have traditionally been associated with schizophrenia, such as Schneiderian first-rank symptoms (FRSs), is unclear. This study examined FRSs in bipolar I patients and their relationship to age and gender. The sample comprised 103 consecutive inpatients who met DSM IV criteria for bipolar disorder, manic or mixed. FRSs were rated with the Scale for the Assessment of Positive Symptoms (SAPS). Interaction between FRSs and gender and FRSs and age was assessed using logistic regression. A high rate of FRSs in manic and mixed patients was found with a higher frequency in men (31%) than in women (14%; P=0.038). A monotonic increase in the association between FRSs and younger age was apparent (odds ratios (OR) over five levels: 1.42; 1.00-2.01). These results confirm previous findings that FRSs are not specific to schizophrenia and suggest in addition that a dimension of nuclear psychotic experiences of developmental origin extends across categorically defined psychotic disorders." [Abstract]

Dell'Osso L, Pini S, Tundo A, Sarno N, Musetti L, Cassano GB.
Clinical characteristics of mania, mixed mania, and bipolar depression with psychotic features.
Compr Psychiatry 2000 Jul-Aug;41(4):242-7
"This study investigated a series of clinical characteristics, including the level of insight into illness and axis I comorbidity, in 125 patients with bipolar disorder with psychotic features categorized in three groups: 62 patients with mania, 28 patients with mixed mania, and 35 patients with depression. All patients were hospitalized and were assessed in the week preceding discharge. The three groups did not differ in the severity of psychopathology as assessed by the Brief Psychiatric Rating Scale (BPRS). The mania group had a lower level of insight into the social consequences of illness than the other two groups, and compared with the group with depression, they had a lower level of insight of poor attention and of poor social judgment. As to axis I comorbidity, obsessive-compulsive disorder was found to be significantly more frequent in depression than in mania. Patients with depression more frequently reported a history of suicidality than those with mania, whereas they did not significantly differ from patients with mixed mania. Our results suggest that mixed mania as assessed at the time of the patient's discharge differs from mania and from depression with respect to a limited number of features among those examined. However, the overall level of insight into illness significantly discriminated mixed mania from mania, but not from depression." [Abstract]

DelBello MP, Carlson GA, Tohen M, Bromet EJ, Schwiers M, Strakowski SM.
Rates and predictors of developing a manic or hypomanic episode 1 to 2 years following a first hospitalization for major depression with psychotic features.
J Child Adolesc Psychopharmacol. 2003 Summer;13(2):173-85.
"INTRODUCTION: Although the presence of psychosis during major depression has been identified as a predictor of later developing mania or hypomania, to our knowledge there have been no studies examining rates and predictors of developing a manic or hypomanic episode in patients who were admitted for their first psychiatric hospitalization for major depressive disorder with psychosis (MDDP). METHODS: Patients admitted for their first psychiatric hospitalization, with a Diagnostic and Statistical Manual of Mental Disorders (fourth edition) diagnosis of MDDP, were recruited from three sites (N = 157) and evaluated prospectively for up to 2 years to identify new symptoms of mania or hypomania. Family history was assessed using the Family History-Research Diagnostic Criteria Interview. Clinical and demographic factors associated with developing a manic or hypomanic episode were identified using stepwise logistic regression. RESULTS: Thirteen percent (n = 21) of patients with MDDP developed mania or hypomania within the follow-up period. Family history of affective disorders and age at onset of MDDP were not predictive of switch. MDDP patients who were treated with antidepressants were four times less likely to develop mania or hypomania than those who were not treated with antidepressants, after controlling for site differences. CONCLUSIONS: Our findings suggest that within the first 1 to 2 years following first hospitalization for MDDP, a subset of patients will develop mania or hypomania. Additionally, our data suggest that antidepressant exposure does not increase the risk of, and may be protective against, developing a manic or hypomanic episode in patients hospitalized for MDDP." [Abstract]

Akiskal HS, Hantouche EG, Bourgeois ML, Azorin JM, Sechter D, Allilaire JF, Lancrenon S, Fraud JP, Chatenet-Duchene L.
Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from a French national study (EPIMAN).
J Affect Disord 1998 Sep;50(2-3):175-86
"BACKGROUND: This research derives from the French national multisite collaborative study on the clinical epidemiology of mania (EPIMAN). Our aim is to establish the validity of dysphoric mania along a "spectrum of mixity" extending into mixed mania with subthreshold depressive manifestations; to demonstrate the feasibility of obtaining clinically meaningful data on this entity on a national level; and to characterize the contribution of temperamental attributes and gender in its origin. METHODS: EPIMAN involves training 23 French psychiatrists in four different sites, representing four regions of France; to rigorously apply a common protocol deriving from the criteria of DSM-IV and McElroy et al.; the use of such instruments as the Beigel-Murphy, Ahearn-Carroll, modified HAM-D; and measures of affective temperaments based on the Akiskal-Mallya criteria; obtaining data on comorbidity, and family history (according to Winokur's approach as incorporated into the FH-RDC); and prospective follow-up for at least 12 months. The present report concerns the clinical and temperamental features of 104 manic patients during the acute hospital phase. RESULTS: Dysphoric mania (DM defined conservatively with fullblown depressive admixtures of five or more symptoms) occurred in 6.7%; the rate of dysphoric mania defined broadly (DM, presence of > or = 2 depressive symptoms) was 37%. Depressed mood and suicidal thoughts had the best positive predictive values for mixed mania. In comparison to pure mania (0-1 depressive symptoms), DM was characterized by female over-representation; lower frequency of such typical manic symptomatology as elation, grandiosity, and excessive involvement; higher prevalence of associated psychotic features; higher rate of mixed states in first episodes; and complex temperamental dysregulation along primarily depressive, but also cyclothymic, and irritable dimensions; such irritability was particularly apparent in mixed mania at the lowest threshold of depressive admixtures of two symptoms only. LIMITATION: In a study involving hospitalized affectively unstable psychotic patients, it was difficult to assure that psychiatrists making the clinical diagnoses would be blind to the temperamental measures. However, bias was minimized by the systematic and/or semi-structured nature of all evaluations. CONCLUSIONS: Mixed mania, defined cross-sectionally by the simultaneous presence of at least two depressive symptoms, represents a prevalent and clinically distinct form of mania. Subthreshold depressive admixtures with mania actually appear to represent the more common expression of dysphoric mania. Moreover, an irritable dimension appears to be relevant to the definition of the expression of mixed mania with the lowest threshold of depressive symptoms. Neither an extreme, nor an endstage of mania, "mixity" is best conceptualized as intrusion of mania into its "opposite" temperament - especially that defined by lifelong depressive traits - and favored by female gender. These data suggest that reversal from a temperament to an episode of "opposite" polarity represents a fundamental aspect of the dysregulation that characterizes bipolar disorder. In both men and women with hyperthymic temperament, there appears "protection" against depressive symptom formation during a manic episode which, accordingly, remains relatively "pure". Because men have higher rates of this temperament, pure mania is overrepresented in men; on the other hand, the depressive temperament in manic women seems to be a clinical marker for the well-known female tendency for depression, hence the higher prevalence of mixed mania in women." [Abstract]

Benazzi F.
Should mood reactivity be included in the DSM-IV atypical features specifier?
Eur Arch Psychiatry Clin Neurosci 2002 Jun;252(3):135-40
"BACKGROUND: The definition of atypical depression is still an unsolved issue. DSM-IV atypical features specifier criteria always require mood reactivity, but why mood reactivity should be included is unclear. The study aim was to test whether mood reactivity should be included in DSM-IV atypical features specifier. METHODS: Consecutively, 164 unipolar and 241 "soft" bipolar II major depressive episode (MDE) outpatients were interviewed with the Structured Clinical Interview for DSM-IV. The DSM-IV criteria for atypical features specifier were strictly followed. Associations were tested by univariate logistic regression. RESULTS: MDE with atypical features was present in 41.4 % of patients. Bipolar II disorder was significantly more common in patients with atypical features. MDE with atypical features was significantly associated with bipolar II, female gender, lower age of onset, more axis I comorbidity, fewer psychotic features, and more depressive mixed states. In the whole sample, mood reactivity was significantly associated with all the atypical symptoms, apart from leaden paralysis, and all the other atypical symptoms were significantly associated with each other. In the bipolar II sub-sample, mood reactivity was associated with many, but not all, atypical symptoms, while in the unipolar sub-sample it was associated with no atypical symptom. Atypical symptoms were significantly more common in mood reactive than in non-mood reactive patients, apart from leaden paralysis. Bipolar II disorder and mood reactivity were strongly associated. CONCLUSIONS: Results may support the inclusion of mood reactivity in the DSM-IV atypical features specifier for bipolar II disorder, but not for unipolar depression." [Abstract]

Pini S, Dell'Osso L, Mastrocinque C, Marcacci G, Papasogli A, Vignoli S, Pallanti S, Cassano G.
Axis I comorbidity in bipolar disorder with psychotic features.
Br J Psychiatry 1999 Nov;175:467-71
"BACKGROUND: Axis I comorbidities are prevalent among patients with severe bipolar disorder but the clinical and psychopathological implications are not clear. AIMS: To investigate characteristics of four groups of patients categorised as follows: substance abuse only (group 1), substance abuse associated with other Axis I disorders (group 2), non-substance-abuse Axis I comorbidity (group 3), no psychiatric comorbidity (group 4). METHOD: Consecutive patients with bipolar disorder with psychotic features (n = 125) were assessed using the Structured Clinical Interview for DSM-III-R--patient version, and several psychopathological scales. RESULTS: By comparison with group 4, group 1 had a higher risk of having mood-incongruent delusions, group 2 had an earlier age at onset of mood disorder, a more frequent onset with a mixed state and a higher risk of suicide, and group 3 had more severe anxiety and a better awareness of illness. CONCLUSIONS: Substance abuse, non-substance-abuse Axis I comorbidity and their reciprocal association are associated with different characteristics of bipolar disorder." [Abstract]

Akiskal HS, Bourgeois ML, Angst J, Post R, Moller H, Hirschfeld R.
Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders.
J Affect Disord 2000 Sep;59 Suppl 1:S5-S30
"Until recently it was believed that no more than 1% of the general population has bipolar disorder. Emerging transatlantic data are beginning to provide converging evidence for a higher prevalence of up to at least 5%. Manic states, even those with mood-incongruent features, as well as mixed (dysphoric) mania, are now formally included in both ICD-10 and DSM-IV. Mixed states occur in an average of 40% of bipolar patients over a lifetime; current evidence supports a broader definition of mixed states consisting of full-blown mania with two or more concomitant depressive symptoms. The largest increase in prevalence rates, however, is accounted for by 'softer' clinical expressions of bipolarity situated between the extremes of full-blown bipolar disorder where the person has at least one manic episode (bipolar I) and strictly defined unipolar major depressive disorder without personal or family history for excited periods. Bipolar II is the prototype for these intermediary conditions with major depressions and history of spontaneous hypomanic episodes; current evidence indicates that most hypomanias pursue a recurrent course and that their usual duration is 1-3 days, falling below the arbitrary 4-day cutoff required in DSM-IV. Depressions with antidepressant-associated hypomania (sometimes referred to as bipolar III) also appear, on the basis of extensive international research neglected by both ICD-10 and DSM-IV, to belong to the clinical spectrum of bipolar disorders. Broadly defined, the bipolar spectrum in studies conducted during the last decade accounts for 30-55% of all major depressions. Rapid-cycling, defined as alternation of depressive and excited (at least four per year), more often arise from a bipolar II than a bipolar I baseline; such cycling does not in the main appear to be a distinct clinical subtype - but rather a transient complication in 20% in the long-term course of bipolar disorder. Major depressions superimposed on cyclothymic oscillations represent a more severe variant of bipolar II, often mistaken for borderline or other personality disorders in the dramatic cluster. Moreover, atypical depressive features with reversed vegetative signs, anxiety states, as well as alcohol and substance abuse comorbidity, is common in these and other bipolar patients. The proper recognition of the entire clinical spectrum of bipolarity behind such 'masks' has important implications for psychiatric research and practice. Conditions which require further investigation include: (1) major depressive episodes where hyperthymic traits - lifelong hypomanic features without discrete hypomanic episodes - dominate the intermorbid or premorbid phases; and (2) depressive mixed states consisting of few hypomanic symptoms (i.e., racing thoughts, sexual arousal) during full-blown major depressive episodes - included in Kraepelin's schema of mixed states, but excluded by DSM-IV. These do not exhaust all potential diagnostic entities for possible inclusion in the clinical spectrum of bipolar disorders: the present review did not consider cyclic, seasonal, irritable-dysphoric or otherwise impulse-ridden, intermittently explosive or agitated psychiatric conditions for which the bipolar connection is less established. The concept of bipolar spectrum as used herein denotes overlapping clinical expressions, without necessarily implying underlying genetic homogeneity. In the course of the illness of the same patient, one often observes the varied manifestations described above - whether they be formal diagnostic categories or those which have remained outside the official nosology. Some form of life charting of illness with colored graphic representation of episodes, stressors, and treatments received can be used to document the uniquely varied course characteristic of each patient, thereby greatly enhancing clinical evaluation." [Abstract]

Perugi G, Toni C, Travierso MC, Akiskal HS.
The role of cyclothymia in atypical depression: toward a data-based reconceptualization of the borderline-bipolar II connection.
J Affect Disord 2003 Jan;73(1-2):87-98
"OBJECTIVE: Recent data, including our own, indicate significant overlap between atypical depression and bipolar II. Furthermore, the affective fluctuations of patients with these disorders are difficult to separate, on clinical grounds, from cyclothymic temperamental and borderline personality disorders. The present analyses are part of an ongoing Pisa-San Diego investigation to examine whether interpersonal sensitivity, mood reactivity and cyclothymic mood swings constitute a common diathesis underlying the atypical depression-bipolar II-borderline personality constructs. METHOD: We examined in a semi-structured format 107 consecutive patients who met criteria for major depressive episode with DSM-IV atypical features. Patients were further evaluated on the basis of the Atypical Depression Diagnostic Scale (ADDS), the Hopkins Symptoms Check-list (HSCL-90), and the Hamilton Rating Scale for Depression (HRSD), coupled with its modified form for reverse vegetative features as well as Axis I and SCID-II evaluated Axis II comorbidity, and cyclothymic dispositions ('APA Review', American Psychiatric Press, Washington DC, 1992). RESULTS: Seventy-eight percent of atypical depressives met criteria for bipolar spectrum-principally bipolar II-disorder. Forty-five patients who met the criteria for cyclothymic temperament, compared with the 62 who did not, were indistinguishable on demographic, familial and clinical features, but were significantly higher in lifetime comorbidity for panic disorder with agoraphobia, alcohol abuse, bulimia nervosa, as well as borderline and dependent personality disorders. Cyclothymic atypical depressives also scored higher on the ADDS items of maximum reactivity of mood, interpersonal sensitivity, functional impairment, avoidance of relationships, other rejection avoidance, and on the interpersonal sensitivity, phobic anxiety, paranoid ideation and psychoticism of the HSCL-90 factors. The total number of cyclothymic traits was significantly correlated with 'maximum' reactivity of mood and interpersonal sensitivity. A significant correlation was also found between interpersonal sensitivity and 'usual' and 'maximum' reactivity of mood. LIMITATION: Correlational study. CONCLUSIONS: Mood lability and interpersonal sensitivity traits appear to be related by a cyclothymic temperamental diathesis which, in turn, appears to underlie the complex pattern of anxiety, mood and impulsive disorders which atypical depressive, bipolar II and borderline patients display clinically. We submit that conceptualizing these constructs as being related will make patients in this realm more accessible to pharmacological and psychological interventions geared to their common temperamental attributes. More generally, we submit that the construct of borderline personality disorder is better covered by more conventional diagnostic entities." [Abstract]

Benazzi F.
Depressive mixed state frequency: age/gender effects.
Psychiatry Clin Neurosci. 2002 Oct;56(5):537-43.
"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." [Abstract]

Benazzi F.
Depressive mixed states: unipolar and bipolar II.
Eur Arch Psychiatry Clin Neurosci 2000;250(5):249-53
"Depressive mixed states (DMS) (major depressive episodes with some hypomanic symptoms) are understudied, and not classified in DSM-IV. The study aim was to find prevalence of DMS among depressed outpatients, to study clinical differences between DMS and non-DMS, and relationships of DMS with unipolar and bipolar II. Ninety eight consecutive DSM-IV bipolar II and unipolar depressed outpatients were interviewed with the Structured Clinical Interview for DSM-IV. DMS was defined as an MDE with at least two concurrent hypomanic symptoms. DMS was present in 62.2% of patients [48.7% of unipolar, 71.9% of bipolar II, (p=0.022)]. DMS had significantly fewer unipolar, more bipolar II patients, lower age at onset, and more atypical features than non-DMS. Bipolar II DMS had significantly more recurrences, more atypical features, and lower age at onset (trend) than unipolar DMS. Bipolar II DMS had (trend) lower age at onset and more atypical features than bipolar II non-DMS. High DMS prevalence has important treatment implications, as antidepressants may worsen DMS, and some antidepressant-resistant depressions may be DMS responding to mood stabilizers. DMS may be distinct from non-DMS, but not from unipolar and bipolar II disorders, and this distinction may be due mainly to high bipolar II prevalence in DMS." [Abstract]

Sato T, Bottlender R, Schroter A, Moller HJ.
Frequency of manic symptoms during a depressive episode and unipolar 'depressive mixed state' as bipolar spectrum.
Acta Psychiatr Scand. 2003 Apr;107(4):268-74.
"OBJECTIVE: To report the frequency of intra-episode manic symptoms in depressive episodes, and to evaluate unipolar depressive mixed state (DMS) as bipolar spectrum. METHOD: A total of 958 (863 unipolar, 25 bipolar II, and 70 bipolar I) depressive in-patients were assessed in terms of manic symptoms at admission, and several clinical variables using standardized methods. RESULTS: The frequency of manic symptoms (flight of idea, logorrhea, aggression, excessive social contact, increased drive, irritability, racing thoughts, and distractibility) was significantly higher in bipolar depressives than in unipolar depressives. Unipolar depressives with DMS - defined as having two or more manic symptoms - had more similarities to bipolar depressives than to other unipolar depressives in clinical variables such as onset age, family history of bipolar disorder, and possibly suicidality. CONCLUSION: Depressive mixed state is frequent, particular in bipolar depressives. Unipolar depressives with DMS may be better classified into bipolar spectrum." [Abstract]

Sato T, Bottlender R, Kleindienst N, Tanabe A, Moller HJ.
The boundary between mixed and manic episodes in the ICD-10 classification.
Acta Psychiatr Scand. 2002 Aug;106(2):109-16.
"OBJECTIVE: To investigate the boundary between ICD-10 mixed and manic episodes, which has apparently remained understudied. METHOD: In-patients with ICD-10 mixed (n=36) and manic episodes (n=145) were compared in terms of demographic, clinical, therapeutical and outcome variables. RESULTS: Of in-patients with manic episode, 26 (18%) had several depressive symptoms at admission. These patients (dysphoric manic patients) were very similar to patients with ICD-10 mixed episode in terms of current symptomatic presentations and several clinical and therapeutic variables, which were significantly different from those in patients with pure mania. CONCLUSION: The ICD-10 boundary between mixed and manic episodes is unlikely to be effective although experienced clinicians made the diagnoses. The system may have a high probability of diagnosing dysphoric manic patients as having manic episode, despite their great similarities to patients with mixed episode in terms of current psychopathological presentations as well as clinically important variables." [Abstract]

Benazzi F.
The clinical picture of bipolar II outpatient depression in private practice.
Psychopathology 2001 Mar-Apr;34(2):81-4
"Uncertainties exist about whether depressive episodes differ phenomenologically in unipolar and bipolar II patients. The aim of the present study was to better define the clinical picture and course of bipolar II depression. Three hundred and ninety-nine consecutive outpatients, presenting for treatment of unipolar and bipolar II depression, were interviewed with the Structured Clinical Interview for DSM-IV, the Montgomery-Asberg Depression Rating Scale and the Global Assessment of Functioning Scale. Bipolar II depression had significantly lower age at onset, more recurrences and more patients with DSM-IV atypical features. Gender, duration of illness, psychosis, chronicity, severity, axis I comorbidity, melancholic features, individual atypical symptoms and other symptoms of depression were not significantly different. The presence of DSM-IV atypical features predicted bipolar II diagnosis with 63% probability." [Abstract]

Benazzi F.
Early-onset versus late-onset bipolar II chronic depression.
Depress Anxiety 2001;13(1):45-9
"Age at onset is an important dimension in the classification of mood disorders. Recent findings on early-onset (EO) versus late-onset (LO) unipolar chronic depressions support this subtyping. The aim of the present study was to determine clinical differences between EO and LO bipolar II chronic depression and to support this subtyping also in bipolar II. Eighty-seven consecutive bipolar II chronic depression outpatients were interviewed with the Structured Clinical Interview for DSM-IV, the Montgomery Asberg Depression Rating Scale, and the Global Assessment of Functioning scale. EO cut-offs were 21 and 23 years of age. Variables, studied with linear and logistic regression, were age, gender, age at onset, illness duration, recurrences, atypical, melancholic, and psychotic features, axis I comorbidity, and severity. Lower age at onset was significantly associated with lower age, longer illness duration, less psychosis, less severity, more atypical features, and more axis I comorbidity. Results support the subtyping of bipolar II chronic depression in EO and LO on the basis of different clinical features." [Abstract]

Benazzi F.
Major depressive episodes with hypomanic symptoms are common among depressed outpatients.
Compr Psychiatry 2001 Mar-Apr;42(2):139-43
"Depressive mixed states (major depressive episodes [MDE] with some hypomanic symptoms) are not classified in DSM-IV. The aim of the present study was to determine the prevalence of depressive mixed states in depressed outpatients, and to compare bipolar II with unipolar depressive mixed states. Seventy consecutive bipolar II and unipolar depressed outpatients were interviewed using the DSM-IV Structured Clinical Interview (SCID). At least one hypomanic symptom was present in 90% of patients, and three or more in 28.5%. Symptoms of depressive mixed states included irritable mood, distractibility, racing thoughts, and increased talking. Bipolar II subjects had more concurrent hypomanic symptoms (three or more in 48.7% v 3.2%, P = 0.000). Depressive mixed states with three or more hypomanic symptoms correctly classified 70.0% of bipolar II subjects. These findings have important treatment implications, as antidepressants may worsen the symptoms of depressive mixed states, and mood stabilizers can be useful." [Abstract]

Sato, Tetsuya, Bottlender, Ronald, Kleindienst, Nikolaus, Moller, Hans-Jurgen
Syndromes and Phenomenological Subtypes Underlying Acute Mania: A Factor Analytic Study of 576 Manic Patients
Am J Psychiatry 2002 159: 968-974
"OBJECTIVE: There are no factor analytic studies specifically including symptoms representative of depressive inhibition among manic patients, although Kraepelin described several mixed affective states with depressive inhibition. There is controversy as to whether atypical manic features such as aggression, psychosis, and depression are likely to coexist among manic patients. The authors’ goal was to examine this controversy. METHOD: They used a standardized instrument to assess the presence or absence of 37 psychiatric symptoms in 576 consecutive inpatients who were diagnosed as having DSM-IV manic episode, nonmixed or mixed. RESULTS: A principal-component analysis followed by varimax rotation extracted seven independent interpretable factors (depressive mood, irritable aggression, insomnia, depressive inhibition, pure manic symptoms, emotional lability/agitation, and psychosis) that were relatively stable across several patient groups. A subsequent cluster analysis identified four phenomenological subtypes underlying acute mania: pure, aggressive, psychotic, and depressive (mixed) mania. Several variables, including gender, suicidality, and outcome of treatments, significantly differentiated the subtypes. CONCLUSIONS: In patients with mania, depressive inhibition may be a salient syndrome independent of depressive mood, lending some support to Kraepelin’s classification of mixed manic states on the basis of the permutations of three elements—thought disorder, mood, and psychomotor activity. Depressive inhibition, together with depressive mood and emotional lability/agitation, appears to be an important phenomenological element of mixed states. Atypical manic features such as aggression, psychosis, and depression are not likely to coexist, but they are likely separately to characterize several different subtypes potentially underl