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Background: Bipolar disorder (BD) is a chronic and severe mental illness. It requires a non-discontinued pharmacological treatment to prevent mood recurrences but nonadherence to medication is frequent. To this date, medication adherence in BD has been mostly evaluated in cross-sectional studies and often considered as a stable trait. We aimed to study medication adherence using a prospective person-oriented approach., Methods: 1627 BD patients were followed on a 2 years period and assessed every 6 months. Medication adherence was evaluated at each visit with the Medication Adherence Rating Scale (MARS). A latent class mixed model (LCMM) was used to identify trajectory classes of adherence over time. Regression analyses and linear mixed model were used to search for predictors and covariables of the trajectories., Results: Three distinct and robust trajectories of medication adherence have been identified: one that starts poorly and keeps deteriorating (4.8%), one that starts poorly but improves (9%) and one that starts well and keeps improving (86.2%). A good tolerance to psychotropic medications, low depressive symptoms, the absence of comorbid eating disorders and anticonvulsant medication were associated to a better prognosis of adherence. Along the follow-up, the lower were the depressive symptoms, the better was the medication adherence (p < .001) LIMITATIONS: The use of a single measure of medication adherence although it is a validated instrument and a possible positive selection bias that might limit the generalization of our findings., Conclusions: This study demonstrates that medication adherence in BD patients is a heterogeneous and potentially variable phenomenon., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Many risk factors for suicidal behavior have been identified. Much less has been done to associate risk factors with recurrence of suicidal behavior., Methods: We compared prevalence of 30 potential risk factors among 8496 depressive patient-subjects from the BRIDGE consortium with no (NSA, n = 6267), one (1SA, n = 1123), or repeated (≥2) suicide attempts (RSA, n = 1106)., Results: Prevalence of most factors ranked: RSA ≥ 1SA > NSA, with a notable opposite trend for the diagnosis of type II bipolar disorder (BD). Factors independently and significantly more present among RSA than 1SA subjects were: borderline personality, substance abuse, mood-switching with antidepressant treatment, female sex, and unsatisfactory response to antidepressant treatment. There also were notably strong associations of RSA with type I or probable BD and associated factors, including family history of BD, young onset, mixed and psychotic features., Limitations: Potential effects of treatment on risk of suicidal acts could not be evaluated adequately, as well as associations between levels of suicidal behavior and eventual death by suicide., Conclusions: In a large cohort of depressive patients, there were significant associations not only with suicidal behavior generally, but also with the intensity of suicide attempts., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Diagnostic criteria for a major depressive episode capture heterogeneous presentations across unipolar (UD) and bipolar (BD) and first-onset (FDE) depression. We evaluated the contribution of each depressive and (hypo)manic symptom to worse functioning in UD/BD/FDE subgroups., Methods: A post-hoc analysis of the BRIDGE-II-Mix study. Acutely depressed patients were stratified into UD, BD and FDE. Each (hypo)manic or depressive symptom was included in a diagnosis-specific logistic regression model with functioning as dependent variable. Better/worse functioning was set with median diagnosis-specific GAF scores cutoffs. All p values were two-tailed. Statistical significance was set at p < 0.05., Results: A total of 2768/2811 depressed individuals were enrolled. In BD (N = 716), "recurrent thoughts of death" (OR 2.48, p < 0.0001) and "feelings of worthlessness" (OR 2.28, p < 0.0001) among depressive symptoms, "aggressiveness" (OR 1.67, p = 0.022) as the unique (hypo)manic symptom, significantly contributed to worse functioning. In UD (N = 1357), "depressed mood" (OR 5.6, p = 0.031) and "diminished interest or pleasure" (OR 4.77, p < 0.0001) among depressive, "grandiosity" (OR 3.5, p = 0.014) among (hypo)manic symptoms, most significantly contributed to worse functioning. In FDE (N = 677) "recurrent thoughts of death" (OR 1.99, p < 0.0001) and "insomnia/hypersomnia" (OR 1.88, p = 0.039) among depressive, "grandiosity" (OR 5.98, p = 0.038) as (hypo)manic symptoms significantly contributed to worse functioning., Limitations: The post-hoc and cross-sectional design do not allow for prognostic or causal inferences., Conclusions: Key depressive and (hypo)manic symptoms distinctively associate with worse functional outcome in acute depression, with differential diagnostic-specific magnitude of effect. Core depressive symptoms are associated with worse functioning in unipolar depression, but not in bipolar or first-episode depression., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: current classifications of mood disorders focus on polarity rather than recurrence, separating bipolar disorder from major depressive disorder (MDD). The aim of the present study is to explore the possible relationships between number and frequency of depressive episodes and clinical variables associated to bipolarity, in a large sample of MDD patients., Methods: the clinical characteristics of 7055 patients with MDD were analyzed and compared according to the number and frequency of depressive episodes. Two stepwise backward logistic regression model were used to identify the predictive value of clinical features based on the presence of high number (≥3 episodes) and high frequency (≥3 episodes/year) of depressive episodes., Results: high-recurrence and high-frequency MDD patients showed greater family history for bipolar disorder, higher prevalence of psychotic features, more suicide attempts, higher rates of treatment resistance and mood switches with antidepressants (ADs) and higher rates of bipolarity diagnosis according to Angst criteria, compared to low-recurrence and low-frequency patients. Logistic regressions showed that a brief current depressive episode, a previous history of treatment resistance and AD-induced mood switches, a diagnosis of bipolarity and comorbid borderline personality disorder were the variables associated with both high-recurrence and high-frequency depression., Limitations: the study participating centers were not randomly selected and several variables were retrospectively assessed., Conclusions: even in the absence of hypomanic/manic episodes, high-recurrence and high-frequency MDD seem to be in continuity with the bipolar spectrum disorders in terms of clinical features and, perhaps, treatment response., (Copyright © 2019. Published by Elsevier B.V.)

Objective: This study primarily focused on the relationship between comorbid attention deficit-hyperactivity disorder (ADHD), mixed features and bipolarity in major depressive patients., Methods: The sample comprised 2777 patients with Major Depressive Episode (MDE) enrolled in a multicentre, multinational study originally designed to assess different definitions of mixed depression. Socio-demographic, familial and clinical characteristics were compared in patients with (ADHD + ) and without (ADHD-) comorbid ADHD., Results: Sixty-one patients (2.2%) met criteria for ADHD. ADHD was associated with a higher number of (hypo)manic symptoms during depression. Mixed depression was more represented in ADHD + patients than in ADHD- using both DSM-5 and experimental criteria. Differences were maintained after removing overlapping symptoms between (hypo)mania and ADHD. ADHD in MDE was also associated with a variety of clinical and course features such as onset before the age of 20, first-degree family history of (hypo)mania, past history of antidepressant-induced (hypo)manic switches, higher number of depressive and affective episodes, atypical depressive features, higher rates of bipolarity specifier, psychiatric comorbidities with eating, anxiety and borderline personality disorders., Limitations: The study was primarily designed to address mixed features in ADHD, with slightly reduced sensitivity to the diagnosis of ADHD. Other possible diagnostic biases due to heterogeneity of participating clinicians., Conclusions: In a sample of major depressive patients, the comorbid diagnosis of current ADHD is associated with bipolar diathesis, mixed features, multiple psychiatric comorbidity and a more unstable course. Further prospective studies are necessary to confirm the possible mediating role of temperamental mood instability and emotional dysregulation in such a complex clinical presentation., (Copyright © 2018. Published by Elsevier B.V.)

Background: Current classifications separate Bipolar (BD) from Major Depressive Disorder (MDD) based on polarity rather than recurrence. We aimed to determine bipolar/mixed feature frequency in a large MDD multinational sample with (High-Rec) and without (Low-Rec) >3 recurrences, comparing the two subsamples., Methods: We measured frequency of bipolarity/hypomanic features during current depressive episodes (MDEs) in 2347 MDD patients from the BRIDGE-II-mix database, comparing High-Rec with Low-Rec. We used Bonferroni-corrected Student's t-test for continuous, and chi-squared test, for categorical variables. Logistic regression estimated the size of the association between clinical characteristics and High-Rec MDD., Results: Compared to Low-Rec (n = 1084, 46.2%), High-Rec patients (n = 1263, 53.8%) were older, with earlier depressive onset, had more family history of BD, more atypical features, suicide attempts, hospitalisations, and treatment resistance and (hypo)manic switches when treated with antidepressants, higher comorbidity with borderline personality disorder, and more hypomanic symptoms during current MDE, resulting in higher rates of mixed depression according to both DSM-5 and research-based diagnostic (RBDC) criteria. Logistic regression showed age at first symptoms < 30 years, current MDE duration ≤ 1 month, hypomania/mania among first-degree relatives, past suicide attempts, treatment-resistance, antidepressant-induced swings, and atypical, mixed, or psychotic features during MDE to associate with High-Rec., Limitations: Number of MDEs for defining recurrence was arbitrary; cross-sectionality did not allow assessment of conversion from MDD to BD., Conclusions: High-Rec MDD differed from Low-Rec group for several clinical/epidemiological variables, including bipolar/mixed features. Bipolarity specifier and RBDC were more sensitive than DSM-5 criteria in detecting bipolar and mixed features in MDD., (Copyright © 2017. Published by Elsevier B.V.)

Background: The issue of antidepressant-induced mood switches to hypomania, mania, or mixed states within the course of mayor depressive disorder (MDD) has been a controversial topic. The present post-hoc analysis of the BRIDGE-II-MIX study focuses on the clinical features of patients with history of antidepressant-induced hypomania/mania (AIHM) in a large international sample of patients with major depressive episode (MDE)., Methods: 2811 subjects with major depression were enrolled in this multicentre cross-sectional study. Current mixed symptoms, socio-demographic and other clinical variables were collected and compared among MDD-AIHM, MDD and BD patients., Results: 475 patients out of 2811 had history of AIHM (16.90%). In the MDD-AIHM group, familiarity for BD and rates of atypical features and comorbid anxiety, eating and borderline personality disorders were similar to BD and significantly more frequent compared to MDD group. MDD-AIHM patients had more frequently more than 3 episodes and reported higher rates of treatment resistance, mood lability and irritability following treatment with antidepressants. Frequencies of depression with mixed features and (hypo)manic symptoms were similar in patients of MDD-AIHM and BD groups and significantly higher in both groups than in MDD., Limitations: there were widely varying rates of hospitalized patients across countries and the participating centres were not randomly selected., Conclusions: Our results strongly support the DSM-5 inclusion of MDD patients with AIHM within the rubric of bipolar disorder. Differences with other MDD and BD were also observed suggesting the possibility that MDD-AIHM may represent a specific sub-population, particularly sensitive to exogenous input from antidepressants., (Copyright © 2017. Published by Elsevier B.V.)

Background: It is increasingly recognised that reliable and valid assessments of lithium response are needed in order to target more efficiently the use of this medication in bipolar disorders (BD) and to identify genotypes, endophenotypes and biomarkers of response., Methods: In a large, multi-centre, clinically representative sample of 300 cases of BD, we assess external clinical validators of lithium response phenotypes as defined using three different recommended approaches to scoring the Alda lithium response scale. The scale comprises an A scale (rating lithium response) and a B scale (assessing confounders)., Results: Analysis of the two continuous scoring methods (A scale score minus the B scale score, or A scale score in those with a low B scale score) demonstrated that 21-23% of the explained variance in lithium response was accounted for by a positive family history of BD I and the early introduction of lithium. Categorical definitions of response suggest poor response is also associated with a positive history of alcohol and/or substance use comorbidities. High B scale scores were significantly associated with longer duration of illness prior to receiving lithium and the presence of psychotic symptoms., Limitations: The original sample was not recruited specifically to study lithium response. The Alda scale is designed to assess response retrospectively., Conclusions: This cross-validation study identifies different clinical phenotypes of lithium response when defined by continuous or categorical measures. Future clinical, genetic and biomarker studies should report both the findings and the method employed to assess lithium response according to the Alda scale., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Poor quality of sleep is frequent in euthymic bipolar patients and conveys worse clinical outcomes. We investigated the features of euthymic bipolar patients associated with poor sleep quality, with a focus on the effect of childhood trauma., Method: 493 euthymic patients with DSM-IV-defined bipolar disorders were recruited in FondaMental Advanced Centers of Expertize for Bipolar Disorders (FACE-BD) between 2009 and 2014. Clinical variables were recorded. Subjective sleep quality and history of childhood trauma were respectively measured by the Pittsburgh Sleep Quality Index (PSQI) and the Childhood Trauma Questionnaire (CTQ)., Results: Poor sleepers were older, less professionally active, had significantly higher anxiety levels, took more anxiolytic drugs and did endorse more suicide attempts and suicidal ideas than good sleepers after adjusting for anxiety levels and age. Emotional abuse was associated with poor sleep quality after adjustment for BMI, age, professional activity, and bipolar disorders (BD) type (OR=1.83; 95% CI [1.30; 3.10]; p=0.02). However, this association was lost after adjustment for anxiety levels, anxiolytic treatment and suicide ideation/attempts., Limitations: The main limitation was the type of sleep assessment, which only measured the subjective part of sleep complaints., Conclusion: A history of emotional abuse might underlie sleep problems in many bipolar patients but anxiety seems to act as a confounding factor in this relationship. New studies are needed to elucidate the role of childhood maltreatment on poor sleep among bipolar patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Literature is scarce about the characteristics of mood disorder patients with a family history (FH) of affective illness. The aim of the current study was to compare the prominent features of depressive patients with a FH of mania (FHM), those of depressive patients with a FH of depression (FHD), and those of depressive patients with no FH of affective illness (FHO)., Methods: As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 45 (9.1%) were classified as FHM, 210 (42.6%) as FHD, and 238 (48.3%) as FHO., Results: The main characteristics of FHM patients were a cyclothymic temperament, the presence of mixed features and diurnal variations of mood during depression, early sexual behaviour, a high number of mood episodes and hypomanic switches, high rates of suicide attempts and rapid cycling; diagnosis of bipolar disorder was more frequent in this group as well as comorbid obsessive compulsive disorder, posttraumatic stress disorder, bulimia, attention deficit/hyperactivity disorder and impulse control disorders. The FHD patients had more depressive temperament, generalized anxiety disorder, and anorexia nervosa. Compared to FHO, FHM and FHD showed an earlier age at onset, more comorbid anxiety disorders, as well as more psychotic features., Limitations: The following are the limitations of this study: retrospective design, recall bias, and preferential enrolment of bipolar patients with a depressive predominant polarity., Conclusions: In light of genetic studies conducted in affective disorder patients, our findings may support the hypothesis of genetic risks factors common to affective disorders and dimensions of temperament, that may extend to comorbid conditions specifically associated with bipolar or unipolar illness., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Adherence to medication is a major issue in bipolar disorder. Non-planning impulsivity, defined as a lack of future orientation, has been demonstrated to be the main impulsivity domain altered during euthymia in bipolar disorder patients. It was associated with comorbidities., Methods: To investigate relationship between adherence to medication and non-planning impulsivity, we included 260 euthymic bipolar patients. Adherence to medication was evaluated by Medication Adherence Rating Scale and non-planning impulsivity by Barrat Impulsiveness Scale. Univariate analyses and linear regression were used. We conducted also a path analysis to examine whether non-planning impulsivity had direct or indirect effect on adherence, mediated by comorbidities., Results: Adherence to medication was correlated with non-planning impulsivity, even after controlling for potential confounding factors in linear regression analysis (Beta standardized coefficient = 0.156; p = 0.015). Path analysis demonstrated only a direct effect of non-planning impulsivity on adherence to medication, and none indirect effect via substance use disorders and anxiety disorders., Limitations: Our study is limited by its cross-sectional design and adherence to medication was assessed only by self-questionnaire., Conclusions: Higher non-planning impulsivity is associated with low medication adherence, without an indirect effect via comorbidities., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: The aim of our study was to investigate, in bipolar patients, the association between tobacco status (use and dependence) and history of suicide attempt, and to assess the possible role of inflammation as a missing link in the association between smoking status and history of suicide attempt., Methods: A total of 453 adult bipolar out-patients recruited in the French FondaMental Advanced Centres of Expertise for Bipolar Disorder were divided into two subgroups: 274 patients without past history of suicide attempt (non-SA), and 179 patients with a past history of suicide attempt (SA). Tobacco use and dependence, psychiatric and somatic comorbidities, history of childhood abuse, family history of suicide were assessed. Fasting blood tests yielded samples collected for the measurement of high sensitivity (hs-)CRP., Results: The risk of suicide attempt increased with smoking dependence. Notably, bipolar patients with a history of suicide attempt were three times more likely to have severe tobacco dependence, independently of confounding factors. However, we failed to find arguments promoting the hypothesis of inflammatory markers (through hs-CRP measure) in the link between tobacco dependence and suicidal behavior., Conclusions: We found a significant association between severe tobacco dependence and history of suicide attempt, but not with level of CRP, independently of confusing factors. Longitudinal studies taken into account all these potential confusing factors are needed to confirm our results., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Literature suggests bipolars may differ in several features according to predominant polarity, but the role of temperaments remains controversial., Methods: The EPIDEP study was designed to identify bipolar patients among a large sample of major depressives. Only bipolars were included in the current study. Patients were subtyped as predominantly depressive (PD) and predominantly manic and hypomanic (PM) according to a broad (more episodes of a given polarity) and a narrow (2/3 of episodes of one polarity over the other) definition, and compared on their characteristics., Results: Among 278 bipolars, 182 (79.8%) could be subtyped as PD and 46 (20.2%) as PM (broad definition); the respective proportions were of 111 (81.6%) and 25 (18.4%) using narrow definition. Expanding the definition added little in detecting differences between groups. Compared to PDs, PMs showed more psychosis, rapid cycling, stressors at onset, family history of affective illness, and manic first episode polarity; they also received more antipsychotics and lithium. The PDs showed more chronic depression, comorbid anxiety, and received more antidepressants, anticonvulsants and benzodiazepines. The following independent variables were associated with manic/hypomanic predominant polarity: cyclothymic temperament, first hospitalization≤25 years, hyperthymic temperament, and alcohol use (only for broad definition)., Limitation: Cross-sectional design, recall bias., Conclusions: Study findings are in accord with literature except for suicidality and mixicity which were related to predominant mania, and explained by higher levels of cyclothymic and hyperthymic temperaments. Temperaments may play a key role in the subtyping of bipolar patients according to predominant polarity, which warrants confirmation in prospective studies., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Thought and language disturbances are crucial clinical features in Bipolar Disorders (BD), and constitute a fundamental basis for social cognition. In BD, clinical manifestations such as disorganization and formal thought disorders may play a role in communication disturbances. However, only few studies have explored language disturbances in BD at a neurophysiological level. Two main Event-Related brain Potentials (ERPs) have been used in language comprehension research: the N400 component, elicited by incongruous word with the preceding semantic context, and the Late Positive Component (LPC), associated with non-specifically semantic and more general cognitive processes. Previous studies provided contradictory results regarding N400 in mood disorders, showing either preserved N400 in depression or dysthymia, or altered N400 in BD during semantic priming paradigm. The aim of our study was to explore N400 and LPC among patients with BD in natural speech conditions., Methods: ERPs from 19 bipolar type I patients with manic or hypomanic symptomatology and 19 healthy controls were recorded. Participants were asked to listen to congruous and incongruous complete sentences and to judge the match between the final word and the sentence context. Behavioral results and ERPs data were analyzed., Results: At the behavioral level, patients with BD show worst performances than healthy participants. At the electrophysiological level, our results show preserved N400 component in BD. LPC elicited under natural speech conditions shows preserved amplitude but delayed latency in difference waves., Limitations: Small size of samples, absence of schizophrenic group and medication status., Conclusions: In contrast with the only previous N400 study in BD that uses written semantic priming, our results show a preserved N400 component in ecological and natural speech conditions among patients with BD. Possible implications in terms of clinical specificity are discussed., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Emotional dysregulation, characterized by high levels of both arousal and intensity of emotional responses, is a core feature of bipolar disorders (BDs). In non-clinical populations, the 40-item Affect Intensity Measure (AIM) can be used to assess the different dimensions of emotional reactivity., Methods: We analyzed the factor structure of the AIM in a sample of 310 euthymic patients with BD using Principal Component Analysis and examined associations between AIM sub-scale scores and demographic and illness characteristics., Results: The French translation of the AIM demonstrated good reliability. A four-factor solution similar to that reported in non-clinical samples (Positive Affectivity, Unpeacefulness [lack of Serenity], Negative Reactivity, Negative Intensity), explained 47% of the total variance. Age and gender were associated with Unpeacefulness and Negative reactivity respectively. 'Unpeacefulness' was also positively associated with psychotic symptoms at onset (p=0.0006), but negatively associated with co-morbid substance misuse (p=0.008). Negative Intensity was positively associated with social phobia (p=0.0005)., Limitations: We cannot definitively exclude a lack of statistical power to classify all AIM items. Euthymia was carefully defined, but a degree of 'contamination' of the self-reported levels of emotion reactivity may occur because of subsyndromal BD symptoms. It was not feasible to control for the possible impact of on-going treatments., Conclusions: The AIM scale appears to be a useful measure of emotional reactivity and intensity in a clinical sample of patients with BD, suggesting it can be used in addition to other markers of BD characteristics and sub-types., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to describe the phenomenology of mania and depression in bipolar patients experiencing a manic episode with mixed features as defined in the new Diagnostic and Statistical Manual of Mental Disorders (DSM-5)., Methods: In this multicenter, international on-line survey (the IMPACT study), 700 participants completed a 54-item questionnaire on demographics, diagnosis, symptomatology, communication of the disease, impact on life, and treatment received. Patients with a manic episode with or without DSM-5 criteria for mixed features were compared using descriptive and inferential statistics., Results: Patients with more than 3 depressive symptoms were more likely to have had a delay in diagnosis, more likely to have experienced shorter symptom-free periods, and were characterized by a marked lower prevalence of typical manic manifestations. All questionnaire items exploring depressive symptomatology, including the DSM-5 criteria defining a manic episode as "with mixed features", were significantly overrepresented in the group of patients with depressive symptoms. Anxiety associated with irritability/agitation was also more frequent among patients with mixed features., Limitations: Retrospective cross-sectional design, sensitive to recall bias. Two of the 6 DSM-5 required criteria for the specifier "with mixed features" were not explored: suicidality and psychomotor retardation., Conclusions: Bipolar disorder patients with at least 3 depressive symptoms during a manic episode self-reported typical symptomatology. Anxiety with irritability/agitation differentiated patients with depressive symptoms during mania from those with "pure" manic episodes. The results support the use of DSM-5 mixed features specifier and its value in research and clinical practice., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: In the past 20 years, much evidence has accumulated against the overly restrictive diagnostic concepts of hypomania in DSM-IV and DSM-IV-TR. We tested DSM-IV-TR and a broader modified version (DSM-IV-TRm) for their ability to detect bipolarity in patients who had been treated for bipolar disorders (BD) in psychiatric settings, and who now consulted general practitioners (GPs) for new major depressive episodes (MDE)., Methods: Bipolact II was an observational, single-visit survey involving 390 adult patients attending primary care for MDE (DSM-IV-TR criteria) in 201 GP offices in France. The participating GPs (53.3 ± 6.5 years old, 80.1% male) were trained by the Bipolact Educational Program, and were familiar with the medical care of depressive patients., Results: Of the 390 patients with MDE, 129 (33.1%) were previously known as bipolar patients (ICD-10 criteria). Most of the latter bipolar patients (89.7%) had previously been treated with antidepressants. Only 9.3% of them met DMS-IV-TR criteria for BD. Conversely, 79.1% of the 129 bipolar patients met DMS-IV-TRm criteria for BD and showed strong associations with impulse control disorders and manic/hypomanic switches during antidepressant treatment., Limitations: Limited training of participating GPs, recall bias of patients, and the study not being representative for untreated bipolar patients., Conclusions: Very few ICD-10 bipolar patients consulting French GPs for MDE met DSM-IV-TR criteria for bipolar diagnosis, which suggests that DSM-IV-TR criteria are insufficient and too restrictive for the diagnosis of BD. DSM-IV-TRm was more sensitive, but 20% of bipolar patients were undetected., (© 2013 Elsevier B.V. All rights reserved.)

Background: Previous studies have shown that major depressive patients may differ in several features according to gender, but the existence of a specific male depressive syndrome remains controversial., Methods: As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 125 (27.7%) were of male gender, whereas 317 (72.3%) were female, after exclusion of bipolar I patients., Results: Compared to women, men were more often married, had more associated mixed features, with more bipolar disorder NOS, more hyperthymic temperaments, and less depressive temperaments. Women had an earlier age at onset of depression, more depressive episodes and suicide attempts. A higher family loading was shown in men for bipolar disorder, alcohol use disorder, impulse control disorders and suicide, whereas their family loading for major depressive disorder was lower. Men displayed more comorbidities with alcohol use, impulse control, and cardiovascular disorders, with lower comorbidities with eating, anxiety and endocrine/metabolic disorders. The following independent variables were associated with male gender: hyperthymic temperament (+), alcohol use disorder (+), impulse control disorders (+), and depressive temperament (-)., Limitations: The retrospective design and the lack of specific tools to assess the male depressive syndrome., Conclusion: Study findings may lend support to the male depression syndrome concept and draw attention to the role of hyperthymic temperament, soft bipolarity as well as comorbidities as determinants of this syndrome. The latter could help recognize an entity which is probably underdiagnosed, but conveys a high risk of suicide and cardiovascular morbidity., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Previous studies have demonstrated that bipolar patients may differ in several features according to gender, but a number of the differences found remain controversial., Methods: The demographic, illness course, clinical, comorbidity and temperament characteristics of a total of 1090 consecutive DSM-IV bipolar I manic inpatients were compared according to gender., Results: Bipolar illness in women was characterised by the predominance of depression, as indicated by a depressive polarity at onset, higher rates of mixed mania, more suicidal behaviour, and a greater number of temperaments with depressive propensities. In contrast, the manic component was found to predominate in men. Men also had an earlier onset of their illness. Women displayed more comorbidities with eating, anxiety, and endocrine/metabolic disorders, whereas men were more comorbid with alcoholism and other forms of substance abuse, neurological, and cancer disorders. The following independent variables were associated with male gender: being single (+), depressive temperament (-), excessive alcohol use (+), cyclothymic temperament (-), excessive other substance use (+), mood congruent psychotic features (+), and manic polarity at onset (+)., Limitations: The retrospective design and the sample being potentially not representative of the bipolar disorder population are limitations., Conclusions: Findings from this study tend to confirm most of the differences previously observed among bipolar men and women. Furthermore, these results draw attention to the risks that may be specifically linked to gender differences in bipolar I patients., (© 2013 Elsevier B.V. All rights reserved.)

Background: Poor adherence to medication is frequent in Bipolar Disorder (BD). It is associated with illness severity and increases total medical cost. Several factors are associated with poor adherence but previous studies included heterogeneous cohorts of patients with and without current mood episode, with and without SUD., Methods: We conducted a cross-sectional study, based on the Fondamental Advanced Centers of Expertise in Bipolar Disorders. 382 patients diagnosed with BD (type I, II or NOS) according to DSM-IV, with partial or complete remission and without comorbid SUD, were included. All patients had a large standardized clinical evaluation with structured interview and self reports. Side effects were evaluated with Patient Rated Inventory of Side Effects (PRISE). Adherence behavior was measured by a self reported scale, Medication Adherence Rating Scale (MARS). Univariate analyses and linear regression models were undertaken to determine factors associated with adherence., Results: Residual depressive symptoms (β=-0.155, p=0.004), and side effects (β=-0.142, p=0.008) were the main factors associated with adherence behavior in linear regression model. We found no association with residual manic symptoms, age at assessment, marital status, number of past mood episodes as well as past psychotic symptoms., Limitation: We used no other assessment than self-rating scale for adherence behavior evaluation. We had no information concerning treatment regimen and patient/family knowledge about BD., Conclusions: Adherence behavior in bipolar patients appears to be mainly influenced by the presence of residual depressive symptoms in patients without SUD. Improvement in diagnosis and pharmacotherapy of residual depressive symptoms has to be kept in mind to face low adherence to medication., (© 2013 Elsevier B.V. All rights reserved.)

Background: Religiosity has been reported to be inversely related to depression and to suicide as well, but there is a lack of studies on its impact on bipolar disorder and especially, on depressed patients belonging to the bipolar spectrum., Methods: As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 234 (55.2%) could be classified as with high religious involvement (HRI), and 190 (44.8%) as with low religious involvement (LRI), on the basis of their ratings on the Duke Religious Index (DRI)., Results: Compared to LRI, HRI patients did not differ with respect to their religious affiliation but had a later age at onset of their affective illness with more hospitalizations, suicide attempts, associated hypomanic features, switches under antidepressant treatment, prescription of tricyclics, comorbid obsessive compulsive disorder, and family history of affective disorder in first-degree relatives. The following independent variables were associated with religious involvement: age, depressive temperament, mixed polarity of first episode, and chronic depression. The clinical picture of depressive patients with HRI was evocative of chronic mixed depressive episodes described in bipolar III patients within the spectrum of bipolar disorders., Limitations: Retrospective design, recall bias, lack of sample homogeneity, no assessment of potential protective and risk factors, and not representative for all religious affiliations., Conclusions: In depressive patients belonging to the bipolar spectrum, high religious involvement associated with mixed features may increase the risk of suicidal behavior, despite the existence of religious affiliation., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Many studies have used admixture analysis to separate age-at-onset (AAO) subgroups in bipolar patients, but few have looked at the phenomenological characteristics of these subgroups, in order to find out phenotypic markers., Methods: Admixture analysis was applied to identify the model best fitting the observed AAO distribution of a sample of 1082 consecutive DSM-IV bipolar I manic inpatients who were assessed for demographic, clinical, course of illness, comorbidity, and temperamental characteristics., Results: The model best fitting the observed distribution of AAO was a mixture of three Gaussian distributions. We could identify three AAO subgroups: early, intermediate, and late age-at-onset (EAO, IAO, and LAO, respectively). Patients in the EAO subgroup were more often single young males exhibiting severe mania with psychotic features, a subcontinuous course of illness with substance use and panic comorbidity, more suicide attempts, and temperamental components sharing hypomanic features. Patients with LAO showed a less severe picture with more depressive temperamental components, alcohol use and comorbid general medical conditions. A less typical phenotype was present in IAO patients., Limitations: The following are the limitations of this study: retrospective design, and bias toward preferential enrollment of patients with manic predominant polarity., Conclusions: This study confirms that bipolar I disorder can be subdivided into three subgroups based on AAO distribution and shows that patients from these subgroups differ in phenotypes., (© 2013 Elsevier B.V. All rights reserved.)

Background: While factors associated with mixed states have been extensively studied, data are scant regarding the clinical heterogeneity of mixed states. The EMBLEM study was a prospective, observational study on patients with manic and mixed states. We describe and compare baseline characteristics and 24-month clinical course of mixed states with predominant depressive symptoms (MSDS) and mixed states with predominant manic symptoms (MSMS)., Methods: Adult inpatients/outpatients with bipolar disorder were enrolled within the standard course of care if they initiated or changed oral medication for acute mania or mixed states. A logistic regression was used to identify the baseline factors associated with each polarity. Comparisons with mixed episode without symptom predominance (OMS) were performed for informational purpose only., Results: About 573 mixed patients were analyzed (23.7% of the cohort): 59.5% (n=341) had MSMS, 11.9% (n=68) had MSDS, and 28.6% (n=164) had OMS. At baseline, hallucinations/delusions during the index episode, inpatient status, high CGI-BP overall score, and low education level were more often associated with MSMS versus MSDS. Alcohol abuse or dependence and selective serotonin reuptake inhibitor (SSRI) or benzodiazepine use at inclusion were significantly more frequent with MSDS. MSDS had a significantly lower 24-month recurrence rate than MSMS; MSMS experienced more switches to mania whereas MSDS switched more to depression., Limitations: The post hoc dimensional definitions in the study require caution in the interpretation of the results., Conclusion: These results present evidence of clinical heterogeneity within mixed states. Predominant manic or depressive symptoms within mixed episode could influence clinicians' decisions in term of hospitalization, treatment, and perception of bipolar severity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: The efficacy of agents useful for mania is largely unproven in patients with mixed episodes., Methods: The efficacy of asenapine in the treatment of mixed episodes was assessed using post hoc analyses on pooled data from two identically designed 3-week, randomized, double-blind, flexible dose, placebo- and olanzapine-controlled trials and their 9-week, double-blind olanzapine-controlled extension study. Efficacy was measured by changes on Young Mania Rating Scale (YMRS) and Montgomery-Åsberg Depression Rating Scale (MADRS) total scores, and was analysed through analysis of covariance on observed cases of the intent-to-treat dataset., Results: In the intent-to-treat population, 295 patients had a DSM-IV-TR mixed episode (placebo: 66; olanzapine: 122; asenapine: 107) in the 3-week trials. Of these, 102 patients (olanzapine: 56; asenapine: 46) entered the 9-week extension study. At week 3, decreases in YMRS and MADRS total scores, were significantly (p<0.01) greater with asenapine (YMRS: -15.0; MADRS: -8.2) versus placebo (YMRS: -11.5; MADRS: -4.5); olanzapine did not separate from placebo (YMRS: -13.3; MADRS: -6.5). At week 12, further decreases in YMRS and MADRS total scores were observed with asenapine (YMRS: -22.4; MADRS: -11.9); non-statistically different from olanzapine (YMRS: -20.2; MADRS: -7.9)., Limitations: Results are from post hoc analyses of trials that were not designed to specifically evaluate mixed episodes., Conclusions: These exploratory analyses provide supportive evidence for the efficacy of asenapine in treating the associated symptoms of mania and depression in bipolar I patients with mixed episodes., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: The nature of the relationship between bipolar disorder (BD) and borderline personality disorder (BPD) is controversial. The aim of this study was to characterize the clinical profile of patients with BD and comorbid BPD in a world-wide sample selected during a major depressive episode (MDE)., Methods: From a general sample of 5635 in and out-patients with an MDE, who were enrolled in the multicenter, multinational, transcultural BRIDGE study, we identified 2658 subjects who met bipolarity specifier criteria. Bipolar specifier patients with (BPD+) and without (BPD-) comorbid BPD were compared on diagnostic, socio-demographic, familial and clinical characteristics., Results: 386 patients (14.5%) met criteria for BPD. A diagnosis of BD according to DSM-IV criteria was significantly more frequent in the BPD- than in BPD+, while similar rates in the two groups occurred using DSM-IV-Modified criteria. A subset of the BD criteria with an atypical connotation, such as irritability, mood instability and reactivity to drugs were significantly associated withthe presence of BPD. BPD+ patients were significantly younger than BPD- bipolar patients for age, age at onset of first psychiatric symptoms and age at first diagnosis of depression. They also reported significantly more comorbid Alcohol and Substance abuse, Anxiety disorders, Eating Disorder and Attention Deficit Hyperactivity Disorder. In comparison with BPD-, BPD+ patients showed significantly more psychotic symptoms, history of suicide attempts, mixed states, mood reactivity, atypical features, seasonality of mood episodes, antidepressants induced mood lability and irritability, and resistance to antidepressant treatments., Limitations: Centers were selected for their strong mood disorder clinical programs, recall bias is possible with a cross-sectional design, and participating psychiatrists received limited training., Conclusions: We confirm in a large sample of BD patients with MDE the high prevalence of patients who meet DSM-IV criteria for BPD. Further prospective researches should clarify whether the mood reactivity and instability captured by BPD DSM-IV criteria are distinguishable from the subjective mood of an instable, dysphoric, irritable manic/hypomanic/mixed state or simply represent a phenotypic variant of BD, related to developmental factors., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Studies on mixed depression have been conducted so far on the basis of DSM-IV manic symptoms, i.e., a list of 7 symptoms which may provide limited information on the subsyndromal features associated with a full depressive episode., Methods: As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 102 (23.8%) were classified as mixed depressives (≥3 hypomanic symptoms), and 146 (34%) as pure depressives (0 hypomanic symptom), after exclusion of bipolar I patients; hypomanic symptoms were assessed with the Multiple Visual Analog Scales of Bipolarity (MVAS-BP, 26 items) of Ahearn-Carroll in a self assessment format. A narrower definition of mixed depression, resting on those MVAS-BP items referring to DSM-IV hypomanic symptoms was also tested, as a sensitivity analysis., Results: Compared to pure depressives, mixed depressive patients had more psychotic symptoms, atypical features and suicide attempts during their index episode; their illness course was characterized by early age at onset, frequent episodes, rapid cycling, and comorbidities. Mixed depressive patients were more frequently bipolar with a family history of bipolar disorder, alcohol abuse, and suicide. A dose-response relationship was found between intradepression hypomania and several clinical features, including temperament measures. The following independent variables were associated with mixed depression: hyperthymic temperament, cyclothymic temperament, irritable temperament, and alcohol abuse. Using the narrower definition of mixed depression missed risk factors such as suicidality and comorbidities., Limitations: The following are the limitations of this study: retrospective design, recall bias, lack of sample homogeneity, no cross-validation of findings by hetero-evaluation of hypomanic symptoms., Conclusions: EPIDEP data showed the feasibility and face validity of self-assessment of intradepressive hypomania. They replicated previous findings on the severity and high suicidal risk of mixed depression profile. They confirmed, for mixed depression, that mixed states occur when mood episodes are superimposed upon temperaments of opposite polarity. They finally suggested that a definition of mixed depression only based on DSM-IV-TR hypomanic symptoms may not allow to identify the most unstable subforms of the entity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Partial/non-adherence to medication by patients with bipolar disorder is associated with exacerbation of symptoms, neurocognitive decline and increased risk of suicide and has a major influence on patient outcomes. Understanding psychiatrists' views on the causes and management of non-adherence are vital to address adherence problems effectively., Methods: A 15-question survey was conducted of 2448 psychiatrists treating patients with bipolar disorder in eight European countries to ascertain their perceptions of the level and causes of non-adherence, and their preferred methods by which to assess it., Results: A majority of patients (57%) were estimated to be partially/non-adherent. Three in four psychiatrists responded that most patients who deteriorated after stopping medication were unable to attribute this to non-adherence. An irregular daily routine/living circumstance affecting adherence was considered the most important reason for patients discontinuing medication. Only 4% of psychiatrists deemed intolerable side effects had led to most patients stopping their medication; 11% responded that drug/alcohol consumption may have impacted on adherence to medication for the majority of patients., Limitations: The survey was not distributed to all psychiatrists in the countries and the impact on the results, of any difference in the demographics of the respondents with respect to the population of psychiatrists across the eight countries, is not known., Conclusions: Partial/non-adherence remains a considerable problem amongst patients with bipolar disorder. There is a need for increased knowledge concerning partial/non-adherence at the level of the clinician-patient interaction, to reduce its impact and bring about improved clinical outcomes., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Recent reports indicate that the prevalence of bipolar disorder (BD) in patients with an acute major depressive episode might be higher than previously thought. We aimed to study systematically all patients who sought therapy for major depressive episode (MDE) within the BRIDGE study in Germany, reporting on an increased number (increased from 2 in the international BRIDGE report to 5) of different diagnostic algorithms., Methods: A total of 252 patients with acute MDE (DSM-IV confirmed) were examined for the existence of BD (a) according to DSM-IV criteria, (b) according to modified DSM-IV criteria (without the exclusion criterion of 'mania not induced by substances/antidepressants'), (c) according to a Bipolarity Specifier Algorithm which expands the DSM-IV criteria, (d) according to HCL-32R (Hypomania-Checklist-32R), and (e) according to a criteria-free physician's diagnosis., Results: The five different diagnostic approaches yielded immensely variable prevalences for BD: (a) 11.6; (b) 24.8%; (c) 40.6%; (d) 58.7; e) 18.4% with only partial overlap between diagnoses according to the physician's diagnosis or HCL-32R with diagnoses according to the three DSM-based algorithms., Conclusions: The diagnosis of BD in patients with MDE depends strongly on the method and criteria employed. The considerable difference between criteria-free physician's diagnosis and the remaining algorithms indicate the usefulness of criteria lists within the everyday clinical setting., Limitations: Diagnoses based on DSM were only made with checklists. The diagnoses of (hypo-) manic episodes in the patient history were not systematically verifiable by indirect anamnesis., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objectives: As only a few studies so far systematically reported on bipolar patients subtyped according to first-episode polarity, we took the opportunity of having at disposal a large sample of bipolar I patients to specify the characteristics of patients included in these subtypes, with a special focus on temperament and triggering events., Methods: A total of 1089 consecutive DSM-IV bipolar I manic inpatients were subtyped in manic onset (MO), depressive onset (DO) and mixed onset (MXO), and assessed for demographic, illness course, clinical, psychometric, comorbidity and temperament characteristics., Results: The main characteristics of MO patients were a hyperthymic temperamental predisposition, a first episode triggered by substance abuse and an illness course with pure, severe and psychotic mania. In comparison, DO patients had more depressive temperaments, a first episode triggered by stress and alcohol, an illness course with more episodes, cyclicity, suicide attempts, anxious comorbidity and residual symptoms. Although sharing characteristics with either MO or DO, MXO patients had more mixed episodes and cyclothymic temperament., Limitations: The following are the limitations of this study: retrospective design, bias toward preferential enrolment of MO patients, and lack of information on the number and polarity of lifetime episodes., Conclusions: Findings from this study tend to confirm most of the differences previously evidenced among patients subtyped according to first-episode polarity. Differences found in temperamental predisposition and illness onset triggering events are worth noting and may help target early preventive interventions as well as orientate the search for specific genetic risk factors., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objective: The aim of this study is to identify risk factors for suicide attempts including bipolarity., Method: The paper presents the most recent data on suicide attempts and depression with or without hypomanic features from three French "Bipolact", studies including 2249 patients with recurrent or resistant depression. Hypomania and BP-II disorder were defined by a score of 10 or more on the Hypomania Checklist-20. Attempters and non-attempters were compared, and multivariate logistic regression analyses were performed on all the significant variables obtained in univariate tests., Results: Rates of suicide attempts and of a family history of suicide were higher in BP-II disorder. Suicide attempts were best explained by a family history of suicide and mood disorders, recurrence of depression, the "irritable-risk-taking" dimension of hypomania, substance abuse, and need of psychiatric treatment., Limitations: The study does not deal with DSM-IV BP-II disorder., Conclusion: Clinicians need to be familiarized with these risk factors., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Epidemiological and clinical studies indicate that major depressive disorder is the leading cause of suicidal behaviour and that bipolar II subjects carry the highest risk. Identification of risk factors is therefore essential to prevent suicide in this population., Methods: As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1month apart, 155 (33.7%) were classified as suicide attempters, and 295 (66.3%) as nonattempters, after exclusion of bipolar I patients., Results: Compared to nonattempters, attempters had a longer duration of illness, longer delays before seeking help and correct diagnosis and a higher number of previous episodes; they were more frequently rapid cyclers, with fewer free intervals between episodes. Lifetime suicide attempts were associated with more comorbid bulimia and substance abuse. Bipolar II spectrum disorders, depressive, cyclothymic and irritable temperaments were overrepresented in attempters, as well as family history of both affective disorder and suicide attempts. The following independent variables were associated with lifetime suicide attempts: higher number of previous depressive episodes, multiple hospitalizations, cyclothymic temperament, rapid cycling and earlier age at onset., Limitations: Retrospective design, recall bias, lack of sample homogeneity, and insufficient assessment of hypomanic features during index depression., Conclusions: In major depressive disorders, family history, age at onset, illness course, comorbidity and cyclothymic temperament alongside other indices of bipolarity may help predict suicidal behaviour. Longer delays to seeking help and diagnosis in attempters emphasize the importance of early recognition of bipolar spectrum disorders., (Copyright 2009 Elsevier B.V. All rights reserved.)

Background: Our aim was to analyse existing data on the efficacy and tolerability of valproate for the treatment of acute bipolar depression., Methods: Randomized controlled trials comparing valproate with placebo were identified using searches of electronic databases in October 2008. Outcomes investigated were depression, anxiety, hypomania, attrition, and adverse events. Trial quality was assessed, and data were summarized using meta-analyses., Results: Four randomized, controlled, doubleblind trials of 142 participants were included. Trial quality was good, although individual study sample sizes were small. Study duration was six weeks (2 studies) and eight weeks (2 studies). Meta-analysis showed a significant difference in favour of valproate for reduction in depressive symptoms, both on depression symptom scales (standardized mean difference (SMD) -0.35 (95% confidence interval, -0.69, -0.02)), and participants with at least 50% improvement in symptoms - relative risk (RR) 2.00 (1.13, 3.53). Effects on anxiety symptoms were small, SMD -0.32 (-0.72, 0.08) and inconclusive (p=0.12). No evidence of a difference in mania symptoms, withdrawal for any reason, lack of effectiveness or adverse events was detected. Nausea occurred more frequently with valproate compared with placebo though the difference was not significant, RR 2.01 (0.98, 4.11). Other adverse events occurring more frequently with valproate (somnolence, fatigue/muscle weakness, headache, diarrhoea and dry mouth) did not differ significantly between treatment groups., Limitations: Sample sizes were small warranting a larger study to confirm or disprove these findings., Conclusions: Valproate is effective for the reduction of depressive symptoms of acute bipolar depression, and was well tolerated., (Copyright 2009 Elsevier B.V. All rights reserved.)

Background: Although included in successive editions of the DSM since its introduction in the IIIrd, the subtyping of manic episode into 'with mood-congruent (MCP) versus mood-incongruent (MIP) psychotic features' is yet to be fully validated., Methods: One thousand and ninety consecutive manic patients were recruited at 19 medical centers in France from December 2000 to April 2002. Patients were systematically assessed for sociodemographic characteristics, illness course, phenomenology and had to fill out biphasic mood charts during the first study week., Results: Five hundred forty-four manic patients were psychotic, 364 (33.4%) being MCP, 180 (16.5%) MIP. Although both groups scored high on the Mania Rating Scale, MIP patients had significantly more often been diagnosed as schizophrenic, or anxiety disorders, with long delays to first diagnosis as bipolar disorder. MIP were also significantly different in a variety of domains: 2:1 female/male ratio; shorter free intervals between episodes; more auditory hallucinations, reference, persecutory and somatic delusions; more stressors; more anger; higher depression scores and diurnal variation of mood, as well as anxious symptoms and hyperemotionality upon improvement., Conclusions: MCP and MIP manias occurred in nearly half of this largest sample of manic patients ever reported. As postulated 150 years ago by Falret and Baillarger in France, free intervals, characterize both forms of circular insanity. Both are prevalent and severe remitting forms of mania, but the latter differs from the former by much shorter free intervals, greater instability of mood and mixed anxious-depressive features. This is compatible with the Vienna School hypothesis that dysphoric instability of the patient may induce emotional reactions in significant others, which, in turn, might lead to extremely paranoid and psychotic symptom formation of the MIP type in manic patients. From a phenomenologic perspective--arising understandably from emotional processes-these considerations would place MIP mania more in the circular affective rather than in the schizophrenic domain.

Background: Despite extensive research recently focused on mixed mania, it is uncertain as how best to define it clinically, psychometrically (which has major bearing on its prevalence), and the methodology needed for future research. This topic is also of historical interest, because Magnan (1890) [Magnan, V., 1890. La Folie Intermittente. G Masson, Paris.] suggested that "combined [mixed] states" linked Falret's "circular insanity" with Baillarger's "dual insanity" (both described in 1854). This work eventually led to the Kraepelinian synthesis of all manic, mixed, and depressive states into the unitary rubric of "manic-depressive insanity (1899/1921)., Method: EPIMAN-II Thousand" (EPIMAN-II MILLE) is a French national collaborative study, which involved training 317 psychiatrists working in different sites representative of psychiatric practice in France. We recruited 1090 patients hospitalized for acute DSM-IV mania. assessed at index admission by the following measures: the Mania Rating Scale (MRS), the Beigel-Murphy Scale (MSRS), a newly derived checklist of depressive symptoms least contaminated by mania, MADRS for severity of depression, and the SAPS for psychotic features., Results: The rate of mixed mania, as defined by at least 2 depressive symptoms, was 30%. Even with this broad definition, we found significantly higher female representation. This clinical sub-type of mania was characterized by high frequency of past diagnostic errors, particularly those of anxiety and personality disorders. Refined definition of co-exiting depression was obtained from an abbreviated version of the MADRS (6 items), with distinct "emotional-cognitive" symptoms, and "psychomotor inhibition" factors, both of which were separable from an "irritable" factor linked to lability and poor judgment. Mixed mania was psychometrically best identified by a MADRS score of 6 (80% sensitivity, 94% specificity) and validated by a mixed polarity of first episodes, a higher rate of recurrence, psychotic features, and suicide attempts., Limitation: Cross-sectional study., Conclusions: The data deriving from EPIMAN, the largest and only national study ever conducted on mania, provide definitive characterization of the clinical and psychotic structure of mixed mania, which accounts for 1 out of 3 patients who present with mania. This figure is more accurate than higher rates reported in the literature because, in describing "mixity", we eliminated depressive features that could be contaminated by mania. Despite the prominent affective features described herein, the bipolar nature of mixed mania is often missed, with the result that these patients are diagnosed as having anxiety and/or personality disorders. It is of great public health significance for psychiatrists to recognize the bipolar nature of this condition that has been known as a major phase of manic-depressive illness since at least Magnan, a disciple of Falret and Baillarger.

Background: One of the major objectives of the French National EPIDEP Study was to show the feasibility of systematic assessment of bipolar II (BP-II) disorder and beyond. In this report we focus on the utility of the affective temperament scales (ATS) in delineating this spectrum in its clinical as well as socially desirable expressions., Methods: Forty-two psychiatrists working in 15 sites in four regions of France made semi-structured diagnoses based on DSM IV criteria in a sample of 452 consecutive major depressive episode (MDE) patients (from which bipolar I had been removed). At least 1 month after entry into the study (when the acute depressive phase had abated), they assessed affective temperaments by using a French version of the precursor of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS). Principal component analyses (PCA) were conducted on hyperthymic (HYP-T), depressive (DEP-T) and cyclothymic (CYC-T) temperament subscales as assessed by clinicians, and on a self-rated cyclothymic temperament (CYC-TSR). Scores on each of the temperament subscales were compared in unipolar (UP) major depressive disorder versus BP-II patients, and in the entire sample subdivided on the basis of family history of bipolarity., Results: PCAs showed the presence of a global major factor for each clinician-rated subscale with respective eigenvalues of the correlation matrices as follows: 7.1 for HYP-T, 6.0 for DEP-T, and 4.7 for CYC-T. Likewise, on the self-rated CYC-TSR, the PCA revealed one global factor (with an eigenvalue of 6.6). Each of these factors represented a melange of both affect-laden and adaptive traits. The scores obtained on clinician and self-ratings of CYC-T were highly correlated (r=0.71). The scores of HYP-T and CYC-T were significantly higher in the BP-II group, and DEP-T in the UP group (P<0.001). Finally, CYC-T scores were significantly higher in patients with a family history of bipolarity., Conclusion: These data uphold the validity of the affective temperaments under investigation in terms of face, construct, clinical and family history validity. Despite uniformity of depressive severity at entry into the EPIDEP study, significant differences on ATS assessment were observed between UP and BP-II patients in this large national cohort. Self-rating of cyclothymia proved reliable. Adding the affective temperaments-in particular, the cyclothymic-to conventional assessment methods of depression, a more enriched portrait of mood disorders emerges. More provocatively, our data reveal socially positive traits in clinically recovering patients with mood disorders.

Background: The modern concept of affective disorders focuses increasingly on the study of subthreshold conditions on the border of manic or depressive episodes. Indeed, a spectrum of affective conditions spanning from temperament to clinical episodes has been proposed by the senior author. As bipolar disorder is a familial illness, an examination of cyclothymic temperament (CT) in controls and relatives of bipolar patients is of major relevance., Methods: We recruited a total sample of 177 healthy symptom-free volunteers. These controls were divided into three groups. The first one is comprised of 100 normal subjects with a negative familial affective history (NFH); the second of 37 individuals, with positive affective family history (PFH); and a third of 40 subjects, with at least one sib or first-degree kin with bipolar disorder type I according to the DSM-IV (BPR). The last two groups defined at risk individuals. We interviewed all subjects with CT, as described by the senior author., Results: We found a statistically significant difference in the rates of CT between the subjects in BPR versus others. CT was also more prevalent in the PFH compared with NFH. Additionally, the simple numeration of the CT traits exhibited gradation in the distribution of individuals inside the NFH, PFH and BPR. Finally, categorically defined CT and CT traits predominated in females. LIMITATION and, Conclusion: Although not all relatives of bipolar probands were studied, our results exhibit an aggregation of CT in families with affective disorder-and more specifically those with bipolar background. These results allow us to propose the importance of including CT for phenotypic characterization of bipolar disorder. Furthermore, our results support a spectrum concept of bipolar disorder, whereby CT is distributed in ascending order in the well-relatives of those with depressive and bipolar disorders. We submit that this temperament represents a behavioral endophenotype, serving as a link between molecular and behavioral genetics.

Background: According to DSM-IV and ICD-10, hypomania which occurs solely during antidepressant treatment does not belong to the category of bipolar II (BP-II)., Methods: As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 144 (29.2%) fulfilled the criteria for bipolar II with spontaneous hypomania (BP-II Sp), and 52 (10.5%) had hypomania associated solely with antidepressants (BP-H AA)., Results: BP-II Sp group had earlier age at onset, more hypomanic episodes, and higher ratings on cyclothymic and hyperthymic temperaments, and abused alcohol more often. The two groups were indistinguishable on the hypomania checklist score (12.2+/-4.0 vs. 11.4+/-4.4, respectively, P=0.25) and on rates of familial bipolarity (14.1% vs. 11.8%, respectively, P=0.68). But BP-H AA had significantly more family history of suicide, had higher ratings on depressive temperament, with greater chronicity of depression, were more likely to be admitted to the hospital for suicidal depressions, and were more likely to have psychotic features; finally, clinicians were more likely to treat them with ECT, lithium and mood stabilizing anticonvulsants., Limitation: Naturalistic study, where treatment was uncontrolled., Conclusion: BP-H AA emerges as a disorder with depressive temperamental instability, manifesting hypomania later in life (and, by definition, during pharmacotherapy only). By the standards of clinicians who have taken care of these patients for long periods of time, BP-H AA appears as no less bipolar than those with prototypical BP-II. We submit that familial bipolarity ('genotypic' bipolarity) strongly favors their inclusion within the realm of bipolar II spectrum, as a prognostically less favorable depression-prone phenotype of this disorder, and which is susceptible to destabilization under antidepressant treatment. These considerations argue for revisions of DSM-IV and ICD-10 conventions. BP-HAA may represent a genetically less penetrant expression of BP-II; phenotypically; it might provisionally be categorized as bipolar III.

Background: Although the construct of depression has been subjected to numerous factor analytic studies and phenomenological subtypes of clinical relevance have been delineated, this is not the case for mania. The few available studies have reported at least two factors, which consist of euphoric versus dysphoric-hostile subtypes. Our objective was to replicate and further enrich this literature., Methods: In the EPIMAN French National Study we systematically evaluated 104 DSM-IV hospitalized manic patients in four university centers in different regions of France. Psychiatrists completed the Beigel-Murphy Manic State Rating Scale (MSRS), as well as the HAM-D(17), affective temperament scales, and the GAF Axis V from DSM-IV. Categorization of patients into pure versus dysphoric mania was made on the basis of clinical diagnosis, independent from psychometric measures., Results: On principal component analysis of the MSRS, three factors explained the largest variance: a global manic (23.3% variance), paranoid-hostile (14.8% variance), and psychotic (9.1% variance). After varimax rotation, we obtained seven independent factors: F1 Disinhibition-instability, F2 Paranoia-hostility, F3 Deficit, F4 Grandiosity-psychosis, F5 Elation-euphoria, F6 Depression, and F7 (Hyper)sexuality. We could not demonstrate significant correlations between the individual factors and impaired functioning on GAF. However, depressive and, to some extent, cyclothymic temperaments correlated with F6 Depression. Finally, intergroup comparisons between pure versus dysphoric mania diagnosed clinically showed high levels of F3 Deficit and F5 Elation in the pure, and of F6 Depression in dysphoric, mania; F2 Paranoia-hostility did not discriminate these two clinical forms of mania., Limitations: Although the present analyses on the Beigel-Murphy represent the largest sample studied to date, they are still underpowered and do not guarantee a stable factorial structure. Our findings are cross-sectional and require prospective validation., Conclusions: Our data suggest that 'dysphoria' as used in the literature to qualify mania is insufficiently precise, and is best further specified as 'depressive' versus 'irritable.' Moreover, our data extend the rich multidimensional phenomenology of mania beyond the existing literature: we submit that disinhibition-instability (a core 'activation' component) can, on the one hand, be associated with distinct emotional presentations (euphoric, depressive, or irritable-hostile), as well as psychotic and deficit symptomatology on the other.

Background: Because manic patients lack insight, they are generally considered unreliable observers of their own psychopathology. The present analyses sought to examine to what extent patient reports could improve formal diagnostic criteria for mania--and be validated against the Carroll-Klein (CK) psychobiological model of bipolarity., Method: 104 DSM-IV acutely manic (hospitalized) patients provided self-assessment on the Ahearn--Carroll scale, the Multiple Visual Analogue Scales of Bipolarity (MVAS-BP). A principal component analysis (PCA) was performed on MVAS-BP, and the data on factorial scores were then compared to dimensional scores according to the CK model and to factors on the Beigel-Murphy Manic State Rating Scale (MSRS) completed by psychiatrists., Results: The PCA identified a general factor accounting for 33% of the total variance; after varimax rotation, seven independent factors emerged, essentially in coherence with the signs and symptoms of DSM-IV mania, except for the 'social disinhibition' factor, which does not figure out as a distinct criterion in DSM-IV. Strong correlations were obtained (r > or = 0.80) between the four major factors of MVAS-BP and the four dimensional categories of the CK model: 'Consummatory Reward' with F1 'Elation and Inflated Self-esteem' (r=0.93), 'Incentive Reward' with F2 'Activation' (r=0.84), 'Psychomotor Pressure' with F3 'Acceleration' (r=0.85), and 'Central Pain' with F4 'Anxiety-Depression' (r=0.84). The F2 'Activation' appeared to be strongly correlated (r > or = 0.70) to all categories of the CK model. Correlational analysis between the factor structure of MVAS-BP and the MSRS showed significant coefficients on the scores assessing the emotional factors of 'Elation' and 'Depression.' Among the MVAS-BP factors, only 'Activation' was correlated to the majority of clinician ratings as obtained by the MSRS., Conclusions: These findings provide overall construct validity to the DSM-IV criteria for mania. Self-assessment of this disorder appears feasible and potentially useful in practice; lack of insight, poor judgment, and distractibility obviously require assessment by a clinician. Although our data are correlational and require prospective validation, they nonetheless suggest that (1) activation should be raised to the status of the stem criterion for mania, (2) to specify mood as elated, depressive, anxious, or irritable, and (3) to give individual status to social disinhibition (indiscriminate gregariousness) as a core pathological behavior in mania. Combining clinician- and self-observation thus produces a more precise and complete phenomenology of mania. We finally submit that the foregoing reformulation provides a psychobiological basis to the manic construct as formulated in the Carroll-Klein model.

Background: There is presently considerable uncertainty on how to best assess mixed mania. The present contribution explores the feasibility of discriminating manic and dysphoric manic states on the basis of self-rating in the acute phase of the illness., Methods: In the French four-site national EPIMAN study of 104 patients devoted to the clinical evaluation and subclassification of mania, we used the Multiple Visual Analog Scales of Bipolarity (MVAS-BP, 26 items) of Ahearn-Carroll in a self-assessment format. The study was conducted on consecutive patients hospitalized for an acute DSM-IV mania. The severity of mania was measured by the Beigel-Murphy scale (MSRS) assessed by psychiatrists. When mania abated, temperaments according to Akiskal and Mallya were administered in their French version., Results: Principal component analysis revealed a general factor explaining 33% of the variance and, after rotation, seven factors defining different dimensions of the phenomenology of mania. The factorial scores, as well as the dimensional scores of the Carrol-Klein model significantly distinguished pure versus dysphoric mania made on clinical grounds. Gender seemed to influence two factors: high 'anxious-depressive' score in females (which is in line with female overrepresentation in mixed mania), vs. high score in males on the 'gregariousness' factor (which represents social disinhibition of the hyperthymic temperament known to be more prevalent in men)., Limitation: Cross-sectional correlational study in need of longitudinal validation., Conclusions: EPIMAN data deriving from a national clinical population showed the feasiblity and face validity of self-assessment in acute mania, in particular its dysphoric subtype. Temperament in women seemed to contribute to the genesis of mixed (dysphoric) mania in accordance with Akiskal's hypothesis of opposition of temperament and polarity of bipolar episodes in mixed states. Self-assessment was capable of capturing accurately the subthreshold depressive symptomatology of mixed mania, which can be missed in hetero-evaluation by hasty clinical interview.

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.

Background: This paper presents the methodology and clinical data in mid-stream from a French multi-center study (EPIDEP) in progress on a national sample of patients with DSM-IV major depressive episode (MDE). The aim of EPIDEP is to show the feasibility of validating the spectrum of soft bipolar disorders by practising clinicians. In this report, we focus on bipolar II (BP-II)., Method: EPIDEP involves training 48 French psychiatrists in 15 sites; construction of a common protocol based on the criteria of DSM-IV and Akiskal (Soft Bipolarity), as well as criteria modified from the work of Angst (Hypomania Checklist), the Ahearn-Carroll Bipolarity Scale, HAM-D and Rosenthal Atypical Depression Scale; Semi-Structured Interview for Evaluation of Affective Temperaments (based on Akiskal-Mallya), self-rated Cyclothymia Scale (Akiskal), family history (Research Diagnostic Criteria); and prospective follow-up., Results: Results are presented on 250 (of the 537) MDE patients studied thus far during the acute phase. The rate of BP-II disorder which was 22% at initial evaluation, nearly doubled (40%) by systematic evaluation. As expected from the selection of MDE by uniform criteria, inter-group comparison between BP-II vs unipolar showed no differences on the majority of socio-demographic parameters, clinical presentation and global intensity of depression. Despite such uniformity, key characteristics significantly differentiated BP-II from unipolar: younger age at onset of first depression, higher frequency of suicidal thoughts and hypersomnia during index episode, higher scores on Hypomania Checklist and cyclothymic and irritable temperaments, and higher switching rate under current treatment. Eighty-eight percent of cases assigned to cyclothymic temperament by clinicians (with a cut-off of 10/21 items on self-rated cyclothymia) were recognized as BP-II. Evaluation of this temperament by clinician and patient correlated at a highly significant level (r=0.73; p <0.0001). Cyclothymia and hypomania were also correlated significantly (r=0.51; p < 0.001)., Limitation: In a study conducted in diverse clinical settings, it was not possible to assure that clinicians making affective diagnoses were blind to the various temperamental measures. However, bias was minimized by the systematic and/or semi-structured nature of all evaluations., Conclusion: With a systematic search for hypomania, 40% of major depressive episodes were classified as BP-II, of which only half were known to the clinicians at study entry. Cyclothymic temperamental dysregulation emerged as a robust clinical marker of BP-II disorder. These data indicate that clinicians in diverse practice settings can be trained to recognize soft bipolarity, leading to changes in diagnostic practice at a national level.