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Objective: Remitted bipolar disorder (BD) patients frequently present with chronic mood instability and emotional hyper-reactivity, associated with poor psychosocial functioning and low-grade inflammation. We investigated emotional hyper-reactivity as a dimension for characterization of remitted BD patients, and clinical and biological factors for identifying those with and without emotional hyper-reactivity., Method: A total of 635 adult remitted BD patients, evaluated in the French Network of Bipolar Expert Centers from 2010-2015, were assessed for emotional reactivity using the Multidimensional Assessment of Thymic States. Machine learning algorithms were used on clinical and biological variables to enhance characterization of patients., Results: After adjustment, patients with emotional hyper-reactivity (n = 306) had significantly higher levels of systolic and diastolic blood pressure (P < 1.0 × 10 -8 ), high-sensitivity C-reactive protein (P < 1.0 × 10 -8 ), fasting glucose (P < 2.23 × 10 -6 ), glycated hemoglobin (P = 0.0008) and suicide attempts (P = 1.4 × 10 -8 ). Using models of combined clinical and biological factors for distinguishing BD patients with and without emotional hyper-reactivity, the strongest predictors were: systolic and diastolic blood pressure, fasting glucose, C-reactive protein and number of suicide attempts. This predictive model identified patients with emotional hyper-reactivity with 84.9% accuracy., Conclusion: The assessment of emotional hyper-reactivity in remitted BD patients is clinically relevant, particularly for identifying those at higher risk of cardiometabolic dysfunction, chronic inflammation, and suicide., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To evaluate aggressiveness during a major depressive episode (MDE) and its relationship with bipolar disorder (BD) in a post hoc analysis of the BRIDGE-II-MIX study., Method: A total of 2811 individuals were enrolled in this multicenter cross-sectional study. MDE patients with (MDE-A, n = 399) and without aggressiveness (MDE-N, n = 2412) were compared through chi-square test or Student's t-test. A stepwise backward logistic regression model was performed., Results: MDE-A group was more frequently associated with BD (P < 0.001), while aggressiveness was negatively correlated with unipolar depression (P < 0.001). At the logistic regression, aggressiveness was associated with the age at first depressive episode (P < 0.001); the severity of mania (P = 0.03); the diagnosis of BD (P = 0.001); comorbid borderline personality disorder (BPD) (P < 0.001) but not substance abuse (P = 0.63); no current psychiatric treatment (P < 0.001); psychotic symptoms (P = 0.007); the marked social/occupational impairment (P = 0.002). The variable most significantly associated with aggressiveness was the presence of DSM-5 mixed features (P < 0.001, OR = 3.815). After the exclusion of BPD, the variable of lifetime suicide attempts became significant (P = 0.013, OR = 1.405)., Conclusion: Aggressiveness seems to be significantly associated with bipolar spectrum disorders, independently from BPD and substance abuse. Aggressiveness should be considered as a diagnostic criterion for the mixed features specifier and a target of tailored treatment strategy., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To explore the prevalence and clinical profile of males and females who develop antidepressant treatment-emergent mania (ATEM)., Method: From an original sample of 754 patients with BD, we identified ATEM+ cases (n = 75) and ATEM- controls (n = 135) that met stringent criteria. We specifically examined the combinations of clinical factors that best classified males and females as ATEM+ cases., Results: Seventy-five individuals were classified as ATEM+; 87% of ATEM events occurred during antidepressant monotherapy. Regression analyses demonstrated that the presence of an alcohol and/or substance use disorder [Odds Ratio (OR) 6.37], a history of one or more suicide attempts (OR 4.19) and higher number of depressive episodes per year of illness (OR 1.71) correctly classified 73% of males. In contrast, 84% of females were correctly classified on the basis of a positive history of thyroid disorder (OR 3.23), a positive family history of BD I (OR 2.68) and depressive onset polarity (OR 2.01)., Conclusion: Using stringent definitions of ATEM status to reduce the probability of inclusion of false-positive cases and false-negative controls, we identified for the first time that the risk profiles for the development of an ATEM differ significantly according to gender., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: The aim of our study was to investigate, in bipolar patients, whether affect lability was associated with suicidal ideation incidence during 2-year follow-up, and which subtype of affect lability was associated with suicidal ideation., Method: A total of 319 euthymic or mildly depressed bipolar outpatients recruited in the French FondaMental Advanced Centres of Expertise for Bipolar Disorder were divided into two subgroups according to the occurrence of suicidal ideation during a 2-year follow-up. Affect lability was assessed by the French version of the Affect Lability Scale., Results: Bipolar patients with high affect lability were more likely to report suicidal ideation during follow-up, even after adjustment for age, study level, rapid cycling, current depression level, anxiety disorder, and lifetime history SA (OR = 2.47; 95% CI [1.15-5.30], P = 0.01). The risk of suicidal ideation increased with the level of affect lability. More specifically, the propensity to switch from neutral to elation affect, from anxious to depressive affect (or inversely), and from neutral to anger affect predicted suicidal ideation., Conclusion: Reducing affective lability could become a new therapeutic target of suicidal prevention in bipolar disorder., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To identify risk factors for suicide attempts (SA) in individuals commencing treatment for a manic or mixed episode., Method: A total of 3390 manic or mixed cases with bipolar disorder (BD) type I recruited from 14 European countries were included in a prospective, 2-year observational study. Poisson regression models were used to identify individual and treatment factors associated with new SA events. Two multivariate models were built, stratified for the presence or absence of prior SA., Results: A total of 302 SA were recorded prospectively; the peak incidence was 0-12 weeks after commencing treatment. In cases with a prior history of SA, risk of SA repetition was associated with younger age of first manic episode (P = 0.03), rapid cycling (P < 0.001), history of alcohol and/or substance use disorder (P < 0.001), number of psychotropic drugs prescribed (P < 0.001) and initiation of an anticonvulsant at study entry (P < 0.001). In cases with no previous SA, the first SA event was associated with rapid cycling (P = 0.02), lifetime history of alcohol use disorder (P = 0.02) and initiation of an anticonvulsant at study entry (P = 0.002)., Conclusion: The introduction of anticonvulsants for a recent-onset manic or mixed episode may be associated with an increased risk of SA. Further BD studies must determine whether this link is causal., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: It is suggested that age at onset (AAO) of bipolar I disorder (BP-I) is decreasing. We tested for a birth-cohort effect on AAO using admixture analysis., Method: A clinical sample of 3896 BP-I cases was analysed using two approaches: (i) in a subsample with untruncated AAO × birth year distribution (n = 1865), we compared the best-fitting model for the observed AAO in patients born ≤1960 and >1960, (ii) to control for potential confounders, two separate subsamples born ≤1960 and >1960 were matched for age at interview (n = 250), and a further admixture analysis was undertaken., Results: The two approaches indicated that the proportion of cases in the early AAO category was significantly greater in cases born >1960; manic onsets were also more frequent in the early onset BP-I cases born >1960., Conclusion: The decrease in AAO of BP-I in recent birth-cohorts appears to be associated with an increase in the proportion of cases in the early onset subgroup; not with a decrease in the mean AAO in each putative subgroup. This could indicate temporal changes in exposure to risk factors for mania., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: The study focused on the relationship between mixed depression and borderline personality disorder (BPD)., Method: The sample comprised 2811 patients with a major depressive episode (MDE). Clinical characteristics were compared in patients with (BPD+) and without (BPD-) comorbid BPD and in BPD+ with (MXS+) and without (MXS-) mixed features according to DSM-5 criteria., Results: A total of 187 patients (6.7%) met the criteria for BPD. A DSM-IV-TR diagnosis of bipolar disorder (BD) was significantly more frequent in patients with BPD+ than in patients with BPD. Patients with BPD+ were significantly younger and reported lower age at onset than BPD-. Patients with BPD+ also showed more hypomania/mania in first-degree relatives in comparison with patients with BPD-, as well as more psychiatric comorbidity, mixed features, atypical features, suicide attempts, prior mood episodes and antidepressant-induced hypo/manic switches. Mixed features according to DSM-5 criteria were observed in 52 (27.8%) BPD+. In comparison with MXS-, MXS+ were significantly younger at age of onset and at prior mood episode and had experienced more mood episodes and hypo/manic switches with antidepressant treatments., Conclusion: Major depressive episode patients with comorbid BPD reported a high prevalence of mixed features and BD. The presence of DSM-5 mixed features in MDE patients with BPD may be associated with complex course and reduced treatment response., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Psychosocial trauma during childhood is associated with schizophrenia vulnerability. The pattern of grey matter decrease is similar to brain alterations seen in schizophrenia. Our objective was to explore the links between childhood trauma, brain morphology and schizophrenia symptoms., Method: Twenty-one patients with schizophrenia stabilized with atypical antipsychotic monotherapy and 30 healthy control subjects completed the study. Anatomical MRI images were analysed using optimized voxel-based morphometry (VBM). Childhood trauma was assessed with the Childhood Trauma Questionnaire, and symptoms were rated on the Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS) (disorganization, positive and negative symptoms). In the schizophrenia group, we used structural equation modelling in a path analysis., Results: Total grey matter volume was negatively associated with emotional neglect (EN) in patients with schizophrenia. Whole-brain VBM analyses of grey matter in the schizophrenia group revealed a specific inversed association between EN and the right dorsolateral prefrontal cortex (DLPFC). Path analyses identified a well-fitted model in which EN predicted grey matter density in DLPFC, which in turn predicted the disorganization score., Conclusion: Our findings suggest that EN during childhood could have an impact on psychopathology in schizophrenia, which would be mediated by developmental effects on brain regions such as the DLPFC., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Identifying bipolar patients at high-suicide risk is a major health issue. To improve their identification, we compared dimensional and neuropsychological profile of bipolar patients with or without history of suicide attempt, taking into account suicidal severity (i.e. admission to intensive ward)., Method: A total of 343 adult euthymic bipolar out-patients recruited in the French FondaMental Advanced Centres of Expertise for Bipolar Disorder were divided into three subgroups: 214 patients without history of suicide attempt, 88 patients with past history of non-severe suicide attempt and 41 patients with past history of severe suicide attempt. General intellectual functioning, speed of information processing, verbal learning and memory, verbal fluency and executive functioning were assessed., Results: Severe suicide attempters had lower affective intensity and lability than non-severe attempters. Severe suicide attempters outperformed non-severe attempters for verbal learning and non-attempters for Stroop word reading part after adjustment for study centre, age, gender, educational level, antipsychotics use, depression score, anxious and addictive comorbidities., Conclusion: Neuropsychological tasks commonly used to assess bipolar patients do not seem accurate to identify suicide attempters in euthymic patients. In the future, decision-making and emotional recognition tasks should be assessed. Moreover, clinical and neuropsychological profiles should be considered together to better define suicidal risk., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This review traces the history of negative symptom profiles in neuropsychiatry from their earliest emergence in the 19th century to the current psychiatric concepts and therapeutic approaches. Recent investigations performing exploratory and confirmatory factor analysis have suggested that negative symptoms are multidimensional, including evidence for at least two distinct negative symptom subdomains: diminished expression and amotivation. Preliminary studies have demonstrated the clinical validity of this distinction. Several potential pathophysiological validating factors based on brain imaging analysis of emotional experiences and expressions in individuals with schizophrenia are examined. Finally, the potential of different treatment strategies, including medications and various psychotherapeutic techniques, to most favorably treat each of these subdomains is discussed., (© 2014 John Wiley & Sons Ltd.)

Objective: The aim of this study was to explore any heterogeneity in the 6-month clinical response in patients with antipsychotic drug-naive schizophrenia and to determine predictors of that outcome., Method: 467 patients with antipsychotic drug-naive schizophrenia were included in France nationwide and followed up over 6 months. To identify trajectories of clinical response, a latent class growth analysis (LCGA) was performed using the Clinical Global Impression-Severity (CGI-S) scores at baseline, 1, 3, and 6 months. Regression models were used to identify predictors of trajectory membership., Results: Five trajectory groups were identified: a rapid response group (n = 45), a gradual response group (n = 204), patients remaining mildly ill (n = 133), patients remaining very ill (n = 23), and a group with unsustained clinical response (n = 62). Predictors of the 6-month clinical response were baseline CGI-S score (odds ratio: 3.1; 95% confidence interval, 2.1-4.4) and negative symptoms (OR, 1.5; 95% CI, 1.2-1.9). The sole predictor of rapid response as compared to gradual response was employment (OR, 2.5; 95% CI, 1.2-4.9)., Conclusion: Clinical response in patients with schizophrenia 6 months after a first-ever antipsychotic drug initiation is heterogeneous. Therapeutic strategies in first episode should take account of symptom severity and early clinical response, to maximize the chances of recovery., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: The study focuses on the controversial relationship between borderline personality disorder (BPD) and bipolar disorder (BD), defined according to different criteria set, in a world-wide sample of patients with a current major depressive episode (MDE)., Method: A total of 5635 patients with an MDE were enrolled in a multinational study, designed to assess varying definition of hypo/mania and familial and clinical variables associated with bipolarity. Patients with (BPD+) and without (BPD-)comorbid BPD were compared on sociodemographic, familial and clinical characteristics., Results: Five hundred and thirty-two patients (9.3%) met criteria for BPD. A diagnosis of BD was more frequent in BPD+ than in BPD- using either DSM-IVTR-modified criteria or the bipolar specifier. BPD+ were younger than BPD- depressives with regard to age and age at onset. They also showed more hypomania/mania in first-degree relatives in comparison to BPD- as well as more psychiatric comorbidity, psychotic symptoms, mixed states, atypical features, seasonality of mood episodes, suicide attempts, prior mood episodes and antidepressants-induced hypo/manic switches., Conclusion: In our sample, selected on the basis of the presence of a mood disorder, the BD-BPD connection is confirmed by the high prevalence of bipolarity in depressive patients with BPD and by the significant association with familial and clinical features classically considered as external validators of bipolarity., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In parallel to considerable progress in understanding and treatment of bipolarity and despite growing interest in old age psychiatry, late-onset bipolar illness (LOBI) has remained relatively understudied so far, probably in reason of its complexity. To update available data, a systematic review was conducted, focusing on the main issues addressed in literature in regard to this topic. In addition to data on epidemiology, clinical features and treatment, five main issues could be identified: LOBI as secondary disorder, LOBI as expression of a lower vulnerability to the disease, LOBI as subform of pseudodementia, LOBI as risk factor for developing dementia, and LOBI as bipolar type VI (bipolarity in the context of dementia like processes). Levels of available evidence were found to vary according to the addressed issue. Although the concept of bipolar type VI could be criticized for subsuming under one single heading all the four other issues, this concept may be of pragmatic value in helping clinicians to orientate both diagnosis process and treatment decisions. Among others, the question as to whether some forms of bipolar type VI could constitute a special risk factor for developing dementia deserves further investigation. More studies are also needed to better disentangle the effects of age at onset from those of age itself., (© 2011 Blackwell Publishing Ltd.)

Objective: This analysis used data from the large (n = 1208) European Schizophrenia Cohort to examine the association between subjective side-effects of antipsychotic medication and the Mental and Physical Composite Scores (MCS; PCS) of the SF-36 scale., Method: Relationships between the subjective evaluation of side-effects identified from the Subjective Side-Effects Scale and the adjusted mean score on the PCS and MCS were examined. Where appropriate, these associations of subjective side-effects were compared with those of the same side-effects measured objectively., Results: In this study, subjective side-effects of antipsychotic medication were linked either to both the PCS and the MCS or, in a few instances, to neither. Subjective evaluations of sexual side-effects were associated only with the MCS, those of sialorrhoea only with the PCS. Objective ratings of extrapyramidal side-effects were related neither to PCS nor to MCS., Conclusion: These data suggest that side-effects, whether subjective or objective, may need to be considered individually in relation to their impact on quality of life.

Objective: To evaluate the distributions of body mass index in a large sample of patients with schizophrenia, and to examine the association between body weight and antipsychotic drugs., Method: The data source was baseline data from a national survey conducted in 2005-2006 in 5756 patients., Results: The mean age of the patients was 37.1 +/- 11.8 years, and the mean BMI was 25.5 +/- 5.2 kg/m(2). In the final logistic regression model, the prevalence of obesity was significantly higher in female patients, age 40-59 vs. 18-29 years, patients in sheltered employment (vs. no income), out-patients (vs. full-time in-patients) and patients treated with concomitant antidepressant. There was a higher rate of obesity, relative to an absence of antipsychotics at entry, for patients receiving the following individual drugs: clozapine, olanzapine, risperidone and amisulpride., Conclusion: In patients treated with atypical antipsychotics, we found a significantly higher prevalence of obesity than in those not treated with any antipsychotic medication.

Objective: We tested whether factors other than episode severity contributed to psychosis in mania., Method: Psychiatrists collected systematic clinical data on 1090 hospitalized DSM-IV manic patients in France, and completed the Mania Rating Scale (MRS) and the Scale for the Assessment of Positive Symptoms (SAPS)., Results: Using DSM-IV specifiers, 21.9% were non-severe, 28.2% severe without psychosis, and 49.9% severe with psychosis. On the MRS, patients with psychosis scored significantly higher (P < 0.0001) than non-severe, but did not differ from the severe without psychosis. We found significant correlations between both the Hallucination and the Delusion subscores of the SAPS and the MRS, as well as correlations between age, single marital status, comorbid social phobia and psychotic mania., Conclusion: Apart from episode severity, social isolation - associated with younger age, single marital status and social phobia - seems to make a contribution to the origin of manic psychosis largely independent from such severity.

Objective: Depressive symptoms in schizophrenia are associated with a substantial morbidity and mortality burden. The 'International Survey of Depression in Schizophrenia' was designed to evaluate current awareness and clinical approaches in this area., Method: A 48-item questionnaire was distributed to approximately 80 000 consultant psychiatrists world-wide. Responses were analysed using descriptive statistics., Results: Respondents demonstrated considerable awareness of the prevalence and consequences of depression in schizophrenia. Although there was widespread adjunctive use of antidepressants, one-third of respondents indicated that they rarely or never prescribe these agents in combination with antipsychotic medication. There were considerable variations in opinions about the best approach to the treatment of depressive symptoms associated with schizophrenia., Conclusion: The considerable clinical burden of depressive symptomatology in schizophrenia was acknowledged by the majority of respondents to this survey. There was, however, little agreement on the best management strategy.

Mood disorders in schizophrenia are common and are associated with a poor outcome, an increased risk of relapse and a high rate of suicide. Consequently, treatment strategies need to take mood disorders into account. In depressed and actively psychotic schizophrenic and schizoaffective patients, treatment with neuroleptic plus antidepressant may be less effective than neuroleptic alone. However, patients with post-psychotic depression on maintenance neuroleptics respond well to tricyclic antidepressants. Mood disorders can be caused by neuroleptics and if so will often improve if the dose is reduced or if the drug is changed. Anticholinergics may also help. In schizoaffective disorder, lithium is usually beneficial, especially for patients with classical affective disorder. Carbamazepine may be more effective in patients with schizoaffective and schizophreniform disorders. At doses comparable with those effective in schizophrenia, clozapine may be as good or better than conventional neuroleptics in schizophrenic patients with psychotic mood disorder or schizoaffective disorder. In patients with high BPRS anxiety/depression scores, risperidone (8 mg/day) was more effective than haloperidol (10 mg/day). Risperidone at a mean dose of 8.6 mg/day was also more effective than haloperidol (mean dose 9.2 mg/day) or levomepromazine (methotrimeprazine -- mean dose 125 mg/day) on the Psychotic Anxiety Scale. Mood-related symptoms are therefore amenable to treatment. Risperidone and clozapine appear to be good candidates for the long-term treatment of mood disorders in schizophrenia, although long-term, double-blind, controlled studies are needed to confirm this.

Plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) were found to be significantly higher in manic patients than in age- and sex-matched normal controls (n = 22). In 18 manic patients plasma MHPG correlated with manic symptoms but not with anxiety, depression, motor behaviour, acute psychosis, schizophrenia and severity of illness. A positive correlation between MHPG and grandiosity items on rating scales suggests a link with cognitive contents and therefore a relationship with central factors.