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Background : Bipolar disorder (BD) involves significant mood and energy shifts reflected in speech patterns. Detecting these patterns is crucial for diagnosis and monitoring, currently assessed subjectively. Advances in natural language processing offer opportunities to objectively analyze them. Aims : To (i) correlate speech features with manic-depressive symptom severity in BD, (ii) develop predictive models for diagnostic and treatment outcomes, and (iii) determine the most relevant speech features and tasks for these analyses. Methods : This naturalistic, observational study involved longitudinal audio recordings of BD patients at euthymia, during acute manic/depressive phases, and after-response. Patients participated in clinical evaluations, cognitive tasks, standard text readings, and storytelling. After automatic diarization and transcription, speech features, including acoustics, content, formal aspects, and emotionality, will be extracted. Statistical analyses will (i) correlate speech features with clinical scales, (ii) use lasso logistic regression to develop predictive models, and (iii) identify relevant speech features. Results : Audio recordings from 76 patients (24 manic, 21 depressed, 31 euthymic) were collected. The mean age was 46.0 ± 14.4 years, with 63.2% female. The mean YMRS score for manic patients was 22.9 ± 7.1, reducing to 5.3 ± 5.3 post-response. Depressed patients had a mean HDRS-17 score of 17.1 ± 4.4, decreasing to 3.3 ± 2.8 post-response. Euthymic patients had mean YMRS and HDRS-17 scores of 0.97 ± 1.4 and 3.9 ± 2.9, respectively. Following data pre-processing, including noise reduction and feature extraction, comprehensive statistical analyses will be conducted to explore correlations and develop predictive models. Conclusions : Automated speech analysis in BD could provide objective markers for psychopathological alterations, improving diagnosis, monitoring, and response prediction. This technology could identify subtle alterations, signaling early signs of relapse. Establishing standardized protocols is crucial for creating a global speech cohort, fostering collaboration, and advancing BD understanding.

Background: The COVID-19 pandemic has brought significant mental health challenges, particularly for vulnerable populations, including non-binary gender individuals. The COMET international study aimed to investigate specific risk factors for clinical depression or distress during the pandemic, also in these special populations., Methods: Chi-square tests were used for initial screening to select only those variables which would show an initial significance. Risk Ratios (RR) were calculated, and a Multiple Backward Stepwise Linear Regression Analysis (MBSLRA) was followed with those variables given significant results at screening and with the presence of distress or depression or the lack of both of them., Results: The most important risk factors for depression were female (RR = 1.59-5.49) and non-binary gender (RR = 1.56-7.41), unemployment (RR = 1.41-6.57), not working during lockdowns (RR = 1.43-5.79), bad general health (RR = 2.74-9.98), chronic somatic disorder (RR = 1.22-5.57), history of mental disorders (depression RR = 2.31-9.47; suicide attempt RR = 2.33-9.75; psychosis RR = 2.14-10.08; Bipolar disorder RR = 2.75-12.86), smoking status (RR = 1.15-5.31) and substance use (RR = 1.77-8.01). The risk factors for distress or depression that survived MBSLRA were younger age, being widowed, living alone, bad general health, being a carer, chronic somatic disorder, not working during lockdowns, being single, self-reported history of depression, bipolar disorder, self-harm, suicide attempts and of other mental disorders, smoking, alcohol, and substance use., Conclusions: Targeted preventive interventions are crucial to safeguard the mental health of vulnerable groups, emphasizing the importance of diverse samples in future research., Limitations: Online data collection may have resulted in the underrepresentation of certain population groups., Competing Interests: Declaration of competing interest None pertaining to the current paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The prevalence of medical illnesses is high among patients with psychiatric disorders. The current study aimed to investigate multi-comorbidity in patients with psychiatric disorders in comparison to the general population. Secondary aims were to investigate factors associated with metabolic syndrome and treatment appropriateness of mental disorders., Methods: The sample included 54,826 subjects (64.73% females; 34.15% males; 1.11% nonbinary gender) from 40 countries (COMET-G study). The analysis was based on the registration of previous history that could serve as a fair approximation for the lifetime prevalence of various medical conditions., Results: About 24.5% reported a history of somatic and 26.14% of mental disorders. Mental disorders were by far the most prevalent group of medical conditions. Comorbidity of any somatic with any mental disorder was reported by 8.21%. One-third to almost two-thirds of somatic patients were also suffering from a mental disorder depending on the severity and multicomorbidity. Bipolar and psychotic patients and to a lesser extent depressives, manifested an earlier (15-20 years) manifestation of somatic multicomorbidity, severe disability, and probably earlier death. The overwhelming majority of patients with mental disorders were not receiving treatment or were being treated in a way that was not recommended. Antipsychotics and antidepressants were not related to the development of metabolic syndrome., Conclusions: The finding that one-third to almost two-thirds of somatic patients also suffered from a mental disorder strongly suggests that psychiatry is the field with the most trans-specialty and interdisciplinary value and application points to the importance of teaching psychiatry and mental health in medical schools and also to the need for more technocratically oriented training of psychiatric residents.

Introduction: The current study aimed to investigate the rates of anxiety, clinical depression, and suicidality and their changes in health professionals during the COVID-19 outbreak., Materials and Methods: The data came from the larger COMET-G study. The study sample includes 12,792 health professionals from 40 countries (62.40% women aged 39.76 ± 11.70; 36.81% men aged 35.91 ± 11.00 and 0.78% non-binary gender aged 35.15 ± 13.03). Distress and clinical depression were identified with the use of a previously developed cut-off and algorithm, respectively., Statistical Analysis: Descriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses, and Factorial Analysis of Variance (ANOVA) tested relations among variables., Results: Clinical depression was detected in 13.16% with male doctors and 'non-binary genders' having the lowest rates (7.89 and 5.88% respectively) and 'non-binary gender' nurses and administrative staff had the highest (37.50%); distress was present in 15.19%. A significant percentage reported a deterioration in mental state, family dynamics, and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (24.64% vs. 9.62%; p < 0.0001). Suicidal tendencies were at least doubled in terms of RASS scores. Approximately one-third of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop clinical depression was associated with a history of Bipolar disorder (RR = 4.23)., Conclusions: The current study reported findings in health care professionals similar in magnitude and quality to those reported earlier in the general population although rates of clinical depression, suicidal tendencies, and adherence to conspiracy theories were much lower. However, the general model of factors interplay seems to be the same and this could be of practical utility since many of these factors are modifiable., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

The purpose of this study is to use a dynamic network approach as an innovative way to identify distinct patterns of interacting symptoms in patients with Major Depressive Disorder (MDD) and patients with Bipolar Type I Disorder (BD). More precisely, the hypothesis will be testing that the phenotype of patients is driven by disease specific connectivity and interdependencies among various domains of functioning even in the presence of underlying common mechanisms. In a prospective observational cohort study, hundred-forty-three patients were recruited at the Psychiatric Clinic "Villa dei Gerani" (Catania, Italy), 87 patients with MDD and 56 with BD with a depressive episode. Two nested sub-groups were treated for a twelve-week period, which allowed us to explore differences in the pattern of symptom distribution (central vs. peripheral) and their connectedness (strong vs weak) before (T0) and after (T1) treatment. All patients underwent a complete neuropsychological evaluation at baseline (T0) and at T1. A network structure was computed for MDD and BD patients at T0 and T1 from a covariance matrix of 17 items belonging to three domains-neurocognitive, psychosocial, and mood-related (affective) to identify what symptoms were driving the networks. Clinically relevant differences were observed between MDD and BD, at T0 and after 12 weeks of pharmacological treatment. At time T0, MDD patients displayed an affective domain strongly connected with the nodes of psychosocial functioning, while direct connectivity of the affective domain with the neurocognitive cluster was absent. The network of patients with BD, in contrast, revealed a cluster of highly interconnected psychosocial nodes but was guided by neurocognitive functions. The nodes related to the affective domain in MDD are less connected and placed in the periphery of the networks, whereas in BD they are more connected with psychosocial and neurocognitive nodes. Noteworthy is that, from T0 to T1 the "Betweenness" centrality measure was lower in both disorders which means that fewer "shortest paths" between nodes pass through the affective domain. Moreover, fewer edges were connected directly with the nodes in this domain. In MDD patients, pharmacological treatment primarily affected executive functions which seem to improve with treatment. In contrast, in patients with BD, treatment resulted in improvement of overall connectivity and centrality of the affective domain, which seems then to affect and direct the overall network. Though different network structures were observed for MDD and BD patients, data suggest that treatment should include tailored cognitive therapy, because improvement in this central domain appeared to be fundamental for better outcomes in other domains. In sum, the advantage of network analysis is that it helps to predict the trajectory of future phenotype related disease manifestations. In turn, this allows new insights in how to balance therapeutic interventions, involving different fields of function and combining pharmacological and non-pharmacological treatment modalities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Platania et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: During the COVID-19 pandemic various degrees of lockdown were applied by countries around the world. It is considered that such measures have an adverse effect on mental health but the relationship of measure intensity with the mental health effect has not been thoroughly studied. Here we report data from the larger COMET-G study pertaining to this question., Material and Methods: During the COVID-19 pandemic, data were gathered with an online questionnaire from 55,589 participants from 40 countries (64.85% females aged 35.80 ± 13.61; 34.05% males aged 34.90±13.29 and 1.10% other aged 31.64±13.15). Anxiety was measured with the STAI, depression with the CES-D and suicidality with the RASS. Distress and probable depression were identified with the use of a previously developed cut-off and algorithm respectively., Statistical Analysis: It included the calculation of Relative Risk (RR), Factorial ANOVA and Multiple backwards stepwise linear regression analysis RESULTS: Approximately two-thirds were currently living under significant restrictions due to lockdown. For both males and females the risk to develop clinical depression correlated significantly with each and every level of increasing lockdown degree (RR 1.72 and 1.90 respectively). The combined lockdown and psychiatric history increased RR to 6.88 The overall relationship of lockdown with severity of depression, though significant was small., Conclusions: The current study is the first which reports an almost linear relationship between lockdown degree and effect in mental health. Our findings, support previous suggestions concerning the need for a proactive targeted intervention to protect mental health more specifically in vulnerable groups., (Copyright © 2022. Published by Elsevier B.V.)

The use of randomized clinical trials, in particular placebo-controlled trials, for drug approval, is the subject of long-standing debate in the scientific community and beyond. This study offers consensus recommendations from clinical and academic experts to guide the selection of clinical trial design in psychiatry. Forty-one highly cited clinical psychiatrists and/or researchers participated in a Delphi survey. Consensus statements were developed based on the findings of a published, peer-reviewed systematic review. Participants evaluated statements in two survey rounds, following the Delphi method. The expert panel achieved consensus on 7 of 21 recommendations regarding the use of randomized clinical trials. The endorsed recommendations were: (i) Results from placebo-controlled trials are the most reliable and (ii) are necessary despite the growing placebo-effect; (iii) it is ethical to enroll patients in placebo-arms when established treatment is available, if there is no evidence of increased health risk; (iv) There is a need to approve new drugs with the same efficacy as existing treatments, but with different side-effect profiles; (v) Non-inferiority trials incur an increased risk of approving ineffective medications; (vi) The risk of approving an ineffective drug justifies trial designs that incur higher costs, and (vii) superiority trials incur the risk of rejecting potentially efficacious treatments. The endorsed recommendations inform the choice of trial-design appropriate for approval of psychopharmacological drugs. The recommendations strongly support the use of randomized clinical trials in general, and the use of placebo-controlled trials in particular., Competing Interests: Declaration of Competing Interest Guy M. Goodwin is a NIHR Emeritus Senior Investigator, holds shares in P1vital and P1Vital products and has served as consultant, advisor or CME speaker in the last 3 years for Beckley Psytech, Clerkenwell Health, Compass pathways, Evapharma, Janssen, Lundbeck, Medscape, Novartis, P1Vital, Sage, Servier. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Michael Berk is supported by a NHMRC Senior Principal Research Fellowship (1156072). MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Abbot, Astra Zeneca, Janssen and Janssen, Lundbeck and Merck and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Janssen and Janssen, Lundbeck Merck, Pfizer and Servier – all unrelated to this work. Andreas Meyer-Lindenberg has received consultant fees from: Boehringer Ingelheim, Elsevier, Brainsway, Lundbeck Int. Neuroscience Foundation, Lundbeck A/S, The Wolfson Foundation, Bloomfield Holding Ltd, Shanghai Research Center for Brain Science, Thieme Verlag, Sage Therapeutics, v Behring Röntgen Stiftung, Fondation FondaMental, Janssen-Cilag GmbH, MedinCell, Brain Mind Institute, Agence Nationale de la Recherche, CISSN (Catania Internat. Summer School of Neuroscience), Daimler und Benz Stiftung, American Association for the Advancement of Science, Servier International. Additionally, he has received speaker fees from: Italian Society of Biological Psychiatry, Merz-Stiftung, Forum Werkstatt Karlsruhe, Lundbeck SAS France, BAG Psychiatrie Oberbayern, Klinik für Psychiatrie und Psychotherapie Ingolstadt, med Update GmbH, Society of Biological Psychiatry, Siemens Healthineers, Biotest AG -All unrelated to this work. Terence A. Ketter has been a consultant to Otsuka Pharmaceuticals, Sunovion Pharmaceuticals, Abbvie, and Alkermes. Joseph Goldberg has been a consultant to BioXCel, Otsuka, Sage Pharmaceuticals, Sunovion, and WebMD, and served on the speaker boards for Allergan, Intracellular Therapies, and Sunovion. Rif S. El-Mallakh is on the speaker bureau of Alkermes, Eisai, Indivior, Intra-Cellular Therapeutics, Janssen, Lundbeck, Noven, Otsuka, Sunonvion, and Teva. Lakshmi N Yatham has been on speaker/advisory boards for, or has received research grants from Abbvie, Alkermes, Allergan, CANMAT, CIHR, DSP, Merck, and Sanofi Rasmus W. Licht has within the preceding three years served an advisory board of Janssen Cilag and Sagw, and received speaker honorarium from Astra-Zeneca, Jannsen-Cilag, Servier and Lundbeck Allan H. Young has been employed by King's College London; Honorary Consultant SLaM (NHS UK). Young has participated in paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS Allan H. Young's independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.Consultant to Johnson & Johnson and Livanova. Received honoraria for attending advisory boards and presenting talks at meetings organized by LivaNova. Prof. Alessandro Serretti is or has been consultant/speaker for: Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Bo- heringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier. Ayşegül Yildiz has nothing to declare. Jean Michel Azorin has received honoraria or research or educational conference grants from Lundbeck and Otsuka. Othman Sentissi has received advisory board honoraria or research or educational conference from Otsuka, Lilly, Lundbeck, Sandoz, Janssen and Sunovion on an institutional account for research and teaching. Prof. Gordon Parker has received lecture fees and board member honoraria from Otsuka, Servier and Lundbeck. Dr. David Bond has received consulting fees and/or research grants from Alkermes, Myriad Genetics, the National Institutes of Health, the University of Minnesota Department of Psychiatry and Behavioral Sciences, and the University of Minnesota Foundation. Prof. Giulio Perugi has received grant/research support from Eli Lilly & Co.; is on the speaker/advisory board of Sanofi-Aventis, Bristol-Myers Squibb, AstraZeneca, Eli Lilly & Co., Jannsen-Cilag, and Lundbeck; and has acted as consultant of AstraZeneca, Eli Lilly & Co., and Lundbeck. Prof. Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB- Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. Dina Popovic has served as a speaker and/or medical writer and/or consultant and/or has participated in advisory boards for Bristol-Myers Squibb, Dexel, Merck Sharp & Dohme, Janssen-Cilag, Lundbeck, Ferrer, and Forum Pharmaceuticals. None of the remaining authors have conflicts of interest to declare., (Copyright © 2022 Elsevier B.V. and ECNP. All rights reserved.)

Introduction: There are few published empirical data on the effects of COVID-19 on mental health, and until now, there is no large international study., Material and Methods: During the COVID-19 pandemic, an online questionnaire gathered data from 55,589 participants from 40 countries (64.85% females aged 35.80 ± 13.61; 34.05% males aged 34.90±13.29 and 1.10% other aged 31.64±13.15). Distress and probable depression were identified with the use of a previously developed cut-off and algorithm respectively., Statistical Analysis: Descriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses and Factorial Analysis of Variance (ANOVA) tested relations among variables., Results: Probable depression was detected in 17.80% and distress in 16.71%. A significant percentage reported a deterioration in mental state, family dynamics and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (31.82% vs. 13.07%). At least half of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop depression was associated with history of Bipolar disorder and self-harm/attempts (RR = 5.88). Suicidality was not increased in persons without a history of any mental disorder. Based on these results a model was developed., Conclusions: The final model revealed multiple vulnerabilities and an interplay leading from simple anxiety to probable depression and suicidality through distress. This could be of practical utility since many of these factors are modifiable. Future research and interventions should specifically focus on them., Competing Interests: Conflict of Interest None pertaining to the current paper., (Copyright © 2021 Elsevier B.V. and ECNP. All rights reserved.)

Objectives: The "Bipolar Disorders: Improving Diagnosis, Guidance, and Education" (BRIDGE-II-Mix) study aimed to estimate the frequency of mixed states in patients with a major depressive episode (MDE) according to different definitions and to compare their clinical validity, looking into specific features such as rapid cycling (RC)., Methods: Psychiatric symptoms, socio-demographic, and clinical variables were collected from a sample of 2811 MDE patients, of which 726 (25.8%) were diagnosed with bipolar disorder (BD). The characteristics of bipolar patients with RC (BD-RC) and without (BD-NRC) RC were compared., Results: Of 726 BD patients, 159 (21.9%) met DSM-5 criteria for RC. BD-RC group presented a higher number of lifetime depressive episodes (p < 0.001) with shorter duration of depressive episodes, and more psychiatric comorbidities, as well as higher rates of atypical features (p = 0.016) and concomitant (hypo)manic symptoms (irritable mood (p = 0.001); risky behavior (p = 0.005); impulsivity (p = 0.006); and psychomotor agitation (p = 0.029)). Patients with RC had a worse functioning (p = 0.033), more obesity (p = 0.003), and were significantly more likely to be treated with three or more drugs (p = 0.007)., Conclusions: Important clinical differences between bipolar patients with and without a RC include more depressive morbidity, higher incidence of anxiety disorders, addiction, bulimia, and borderline personality disorder, as well as atypical features during depression and symptoms such as irritability, risky behavior, impulsivity, and agitation. RC patients had poorer functioning than patients without RC, more obesity, and had to be treated with more drugs., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A cross-diagnostic, post-hoc analysis of the BRIDGE-II-MIX study was performed to investigate how unipolar and bipolar patients suffering from an acute major depressive episode (MDE) cluster according to severity and duration. Duration of index episode, Clinical Global Impression-Bipolar Version-Depression (CGI-BP-D) and Global Assessment of Functioning (GAF) were used as clustering variables. MANOVA and post-hoc ANOVAs examined between-group differences in clustering variables. A stepwise backward regression model explored the relationship with the 56 clinical-demographic variables available. Agglomerative hierarchical clustering with two clusters was shown as the best fit and separated the study population (n = 2314) into 65.73% (Cluster 1 (C1)) and 34.26% (Cluster 2 (C2)). MANOVA showed a significant main effect for cluster group (p < 0.001) but ANOVA revealed that significant between-group differences were restricted to CGI-BP-D (p < 0.001) and GAF (p < 0.001), showing greater severity in C2. Psychotic features and a minimum of three DSM-5 criteria for mixed features (DSM-5-3C) had the strongest association with C2, that with greater disease burden, while non-mixed depression in bipolar disorder (BD) type II had negative association. Mixed affect defined as DSM-5-3C associates with greater acute severity and overall impairment, independently of the diagnosis of bipolar or unipolar depression. In this study a pure, non-mixed depression in BD type II significantly associates with lesser burden of clinical and functional severity. The lack of association for less restrictive, researched-based definitions of mixed features underlines DSM-5-3C specificity. If confirmed in further prospective studies, these findings would warrant major revisions of treatment algorithms for both unipolar and bipolar depression.

Major Depressive Episode (MDE) is a transdiagnostic nosographic construct straddling Major Depressive (MDD) and Bipolar Disorder (BD). Prognostic and treatment implications warrant a differentiation between these two disorders. Network analysis is a novel approach that outlines symptoms interactions in psychopathological networks. We investigated the interplay among depressive and mixed symptoms in acutely depressed MDD/BD patients, using a data-driven approach. We analyzed 7 DSM-IV-TR criteria for MDE and 14 researched-based criteria for mixed features (RBDC) in 2758 acutely depressed MDD/BD patients from the BRIDGE-II-Mix study. The global network was described in terms of symptom thresholds and symptom centrality. Symptom endorsement rates were compared across diagnostic subgroups. Subsequently, MDD/BD differences in symptom-network structure were examined using permutation-based network comparison test. Mixed symptoms were the most central and highly interconnected nodes in the network, particularly agitation followed by irritability. Despite mixed symptoms, appetite gain and hypersomnia were significantly more endorsed in BD patients, associations between symptoms were highly correlated across MDD/BD (Spearman's r = 0.96, p<0.001). Network comparison tests showed no significant differences among MDD/BD in network strength, structure, or specific edges, with strong edges correlations (0.66-0.78). Upstream differences in MDD/BD may produce similar symptoms networks downstream during acute depression. Yet, mixed symptoms, appetite gain and hypersomnia are associated to BD rather than MDD. Symptoms during mixed-MDE might aggregate according to 2 different clusters, suggesting a possible stratification within mixed states. Future symptom-based studies should implement clinical, longitudinal, and biological factors, in order to establish tailored therapeutic strategies for acute depression., (Copyright © 2020. Published by Elsevier B.V.)

Twin studies are among the most promising strategies for studying heritable disorders, including bipolar disorder (BD). The aim of the present study was to identify distinguishing genes between monozygotic (MZ) twins with different BD phenotype and compare them to their non-affected siblings. Whole-exome sequencing (WES) can identify rare and structural variants that could detect the polygenetic burden of complex disorders. WES was performed on a family composed of two MZ twins with BD, their unaffected brother and unaffected parents. The twins have a discordant response to lithium and distinct course of illness. Following WES, six genes of particular interest emerged: Neurofibromin type 1 (NF1), Biorientation of chromosomes in cell division 1 (BOD1), Golgi-associated gamma adaptin ear-containing ARF binding protein 3 (GGA3), Disrupted in schizophrenia 1 (DISC1), Neuromedin U receptor 2 (NMUR2), and Huntingtin interacting protein 1-related (HIP1R). Interestingly, many of these influence glutamatergic pathways and thus the findings may have therapeutical implications. These results may provide important insights to unveil genetic underpinnings of BD and the response to lithium., Competing Interests: Competing interest Prof. Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. Prof. Serretti is or has been consultant/speaker for: Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier. Dr. Popovic has served as a speaker and/or medical writer or has participated in advisory boards for Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen-Cilag, Ferrer, and Forum Pharmaceuticals., (Copyright © 2020. Published by Elsevier B.V.)

Recent success of established treatment has driven concerns about the ethics of using placebo-controlled trials in psychiatry. Active-controlled (superiority or non-inferiority) trials do not include a placebo-arm and thus avoid the associated ethical concerns but show disadvantages in other respects. The aim of this paper is to review the available literature and critically discuss the evidence regarding the use of placebo-controlled- versus active-controlled trials. A MEDLINE/PubMed and Google Scholar search was performed. Studies included focused on the deliberation on placebo-controlled- versus active-controlled trials. Twenty-six studies were included. The most cited benefits of placebo-controlled trials were greater scientific reliability of the results and no average impact on patients' health. Disadvantages were mainly related to withholding effective treatment and limited generalizability. The most frequent argument in favor of active-controlled trials is the lower chance of receiving ineffective medication during the trial. Downsides include larger sample sizes, higher costs and lower scientific reliability of results. Most authors agree that all trial designs are relevant to psychiatric research depending on study goals. Whatsoever, data does not support forgoing placebo-controlled trials. Expert consensus is warranted to permit drawing conclusions on the debate on the relevance of placebo-controlled trials., Competing Interests: Conflict of Interest All authors declare that they have no conflict of interests., (Copyright © 2019. Published by Elsevier B.V.)

Background: Cognitive dysfunction represents a distinct biological and clinical dimension in major depression disorders (MDD) and cognitive performance strongly affects psychosocial functioning in patients diagnosed with MDD., Objective: To assess which neurocognitive variables at baseline predict the functional outcome of MDD patients in a 1-year follow-up study as assessed by Functioning Assessment Short Test (FAST) and whether the improvement observed on affective and cognitive symptoms in our 12 week-prospective observational study after treatment with selective serotonin reuptake inhibitors (SSRIs) and selective noradrenalin reuptake inhibitors (SNRIs) can affect the following long-term psychosocial functional outcome at 1 year in the same MDD patients., Methods: We recruited a total of 31 patients (8 males; 23 females) with MDD who had previously completed a pharmacological treatment with SSRIs (n = 22) or SNRIs (n = 9) for 12 weeks, and then continued the same pharmacological treatment for 1 year. After an average 1-year follow-up, they were interviewed with the FAST to assess functional outcome. Multivariate analyses were applied to identify clinical and neurocognitive predictors of functional outcome., Results: Total Montreal Cognitive Assessment (MoCA), Digit Span forward (Span F) and backward (Span B), and 15 Rey words immediate recall (Rey I) scores significantly correlated with FAST. However, after performing regression models only Rey immediate recall score was useful to predict long-term functional outcome (Pearson correlation coefficient R= -0.68, p < 0.001) in four specific subdomains of FAST. When considering changes in affective and cognitive symptoms at the end of the 12 weeks of pharmacological treatment with SSRI or SNRIs (T1-T0) by multiple regression analysis, we found that Span F -test predicted scores in the FAST leisure domain, whereas, changes in Span F, Frontal Assessment Battery (FAB) and Rey I predicted psychosocial functioning in the specific "cognitive" subdomains of FAST., Conclusion: Our data suggest that long-term psychosocial functioning can be influenced by neurocognitive performance at baseline, with verbal memory playing a key role in overall functioning. Furthermore, improvement in verbal memory can predict functional outcome at one year in MDD patients with a recent history of partial response to antidepressants., Competing Interests: Professor Eduard Vieta reports grants from AB-Biotics, Dainippon Sumitomo Pharma, Brain and Behaviour Foundation, Spanish Ministry of Science and Innovation (CIBERSAM), EU Horizon 2020, and Stanley Medical Research Institute, grants and personal fees from Abbott, Ferrer, Janssen, Lundbeck, SAGE, Sanofi-Aventis, and personal fees from Allergan, Angelini, Gedeon Richter, Otsuka, Sunovion, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2020 Castellano et al.)

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.)

Introduction: Bipolar disorder (BD) is a highly heritable and disabling mental illness, commonly associated with substance abuse, being alcohol abuse the most frequent. Comorbid BD and substance abuse disorders are often associated with high levels of health service utilization and destabilization of the course of illness resulting in poor treatment outcomes. Although recent genome-wide association studies have detected a number of risk genes for BD, the data is still sparse and inconclusive for those genes that may contribute to the increased risk of comorbid alcohol abuse (AA) in BD. The primary aim of the present study was to investigate the effects of 46 single-nucleotide polymorphisms (SNPs) within eight genes on different phenotypes of BD patients, such as comorbid alcohol abuse. We further assessed clinical variables associated with AA., Methods: One-hundred fifty-eight BD I and II patients were enrolled in a naturalistic cohort study. Genomic DNA of 92 patients was extracted from whole blood using standard procedures and 46 tag SNPs in eight genes of interest (ANK, CACNA1C, CACNB2, FKBP5, GRM7, ITIH3, SYNE1 and TCF4) were genotyped., Results: Seventy-one patients out of 158 (45%) satisfied diagnostic criteria for comorbid AA. Among 46 SNPs analyzed, the only SNP associated with comorbid AA was rs1034936 polymorphism in the CANCA1C gene. This polymorphism was also associated with lifetime cocaine abuse, manic switch and current atypical antipsychotics., Conclusions: Our findings suggest a role of rs1034936 CACNA1C gene variant in BD-AA group. Despite their preliminary nature, the present results may provide new insight on mechanisms underlying AA in BD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The concept of predominant polarity (PP) is defined as presenting more symptoms of one polarity. Previous studies have defined PP as one polarity (either a depression or mania episode) occurring during at least two-thirds of the lifetime., Methods: We conducted an observational study with the COPE-BD (Clinical Outcome and Psycho-Education for Bipolar Disorder, Clinical Outcome Measures Section) dataset to identify the diagnostic and treatment differences between bipolar disorder (BD) patients with and without PP., Results: The final sample included 210 BD-I (59.0%) and 146 BD-II (41.0%) patients. Of these, 28.9% patients presented predominant polarity (PP): 62 (17.4%) of those patients were depressed polarity predominant (DPP), 41 (11.5%) were manic polarity predominant (MPP), and 253 (71.1%) met criteria for bipolar disorders but did not present with PP. In comparison to this group of BD patients with undetermined polarity, the group of BD patients with PP presented more rapid cycling. Furthermore, in the undetermined polarity group, the onset of illness occurred earlier, and the duration of the illness was longer, with more hypomanic/manic and depressive episodes than patients who met the PP criteria., Limitations: This study has a naturalistic and retrospective design and does not allow a specific follow-up of polarity over time., Conclusions: These different clinical characteristics underline the importance of considering PP in patients with BD, and justify the need for differential treatment approach which could have an impact on patients' prognosis. Yet, more independent and prospective research is needed to confirm these findings, especially with the new classification of DSM-5 concerning mixed states., (Copyright © 2019. Published by Elsevier B.V.)

Objective: This post hoc analysis of the BRIDGE-II-MIX study is aimed at evaluating affective lability (AL) as a possible clinical feature of mixed depression and assessing the relationship with atypical depressive features, particularly mood reactivity (MR)., Methods: In the BRIDGE-II-MIX multicenter, cross-sectional study, 2,811 individuals suffering from a major depressive episode (MDE; DSM-IV-TR criteria), in the context of bipolar I or II disorder (BD-I, BD-II, respectively) or major depressive disorder, were enrolled between June 2009 and July 2010. Patients with (MDE-AL, n = 694) and without (MDE-noAL, n = 1,883) AL and with (MDE-MR, n = 1,035) or without (MDE-noMR, n = 1,542) MR were compared through χ² test or Student t test. Stepwise backward logistic regression models, respectively testing AL and MR as the dependent variable, were performed to differentiate the 2 clinical constructs., Results: AL was positively associated with BD-I (P < .001) and BD-II (P < .001), with DSM-5 mixed (DSM-5-MXS) (P < .001) and atypical (DSM-5-AD) features (P < .001) and negatively associated with MDD (P < .001). In the logistic regression models, MR was the variable most significantly associated with AL and vice versa (P < .001 for both). AL was positively associated with severity of mania and DSM-5-MXS and negatively correlated with severity of depression, while MR was better predicted by atypical symptoms such as hyperphagia, hypersomnia, and leaden paralysis and correlated with both comorbid anxiety disorders and DSM-5-MXS., Conclusions: Mixed and atypical depression may lie on the same continuum. MR and AL could represent the underlying matrix, bridging the gap between mixed and atypical depression., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

Relatives of people diagnosed with psychotic and affective disorders have a higher risk of developing psychiatric disorders compared to the general population. This study examined the risk of hospitalization for psychiatric disorders among siblings and parents of patients affected with major psychiatric disorders. In this large population-based case-control study, 17,895 siblings and parents of 7671 hospitalized subjects with a diagnosis of narrowly defined schizophrenia (SZ), broadly defined SZ, schizoaffective disorder (SAD), bipolar disorder (BD) or unipolar depression (UD) were identified from the Israeli Psychiatric Hospitalization Registry and compared to 71,580 age and gender-matched controls from the Israeli Population Registry. Results indicated that siblings of people diagnosed with broadly defined SZ had a significantly higher risk of hospitalization for broadly (OR=11.06, 95% CI=7.93-15.41) and narrowly defined SZ (OR=10.59, 95% CI=6.8-16.33), SAD (OR=9.69, 95% CI=4.76-19.73), BD (OR=7.46, 95% CI=21.8-25.52), UD (OR=2.84, 95% CI=1.01-8.00), and other psychiatric disorders (OR=1.85, 95% CI=1.16-2.93), compared to controls. Siblings of patients with BD had a significantly higher risk of hospitalization for broadly defined SZ (OR=2.92, 95% CI=1.11-7.71) and for other psychiatric disorders (OR=6.67, 95% CI=2.17-20.50), compared to controls. Parents of probands with SZ were at significantly increased risk for all disorders examined, except for UD and ¨other psychiatric disorders¨, which was not significant in parents of probands with BD. This large, population-based study provides evidence for common genetic risk across different psychiatric disorders., (Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.)

Background: Schizophrenia (SZ) and bipolar disorder (BD) are traditionally distinguished on the basis of progressive deterioration and long-term outcome, but a more dimensional approach is warranted. There are limited data on the occurrence of manic symptoms in patients with schizophrenia. The aim of the current study was to search for patterns in the clinical symptomatology, which may suggest the presence of one or several mood disorders under the label of schizophrenia., Subjects and Methods: Hundred-seventy-five patients diagnosed with schizophrenia according to DSM-5 were included in the study. The psychometric assessment included the Positive and Negative Syndrome Scale, Young Mania Rating Scale, The Montgomery-Åsberg Depression Rating Scale and the Calgary Depression Scale. The statistical analysis included MANOVA, Pearson Correlation coefficient and principal components analysis., Results: Significant subthreshold manic symptoms were present in 25.14% of patients. Mood symptoms correlated with positive symptoms. The PCA revealed a complex structure with 15 factors (one positive, negative, somatic, anxiety, neurocognitive, disorganization and manic, five depressive and three psychomotor/excitement/hostility/violence)., Conclusion: Psychotic mood disorders are often phenotypically indistinguishable from schizophrenia, so it is likely that psychotic affective patients have been misdiagnosed with schizophrenia. The current study suggests that there seem to be patients with mania misdiagnosed as 'schizophrenics' because of the presence of psychotic features, a condition better described as 'schizophreniform bipolar disorder'.

Multiple novel biological mechanisms putatively involved in the etiology of bipolar disorders are being explored. These include oxidative stress, altered glutamatergic neurotransmission, mitochondrial dysfunction, inflammation, cell signaling, apoptosis and impaired neurogenesis. Important clinical translational potential exists for such mechanisms to help underpin development of novel therapeutics - much needed given limitations of current therapies. These new mechanisms also help improve our understanding of how current therapeutics might exert their effects. Lithium, for example, appears to have antioxidant, immunomodulatory, signaling, anti-apoptotic and neuroprotective properties. Similar properties have been attributed to other mood stabilizers such as valproate, lamotrigine, and quetiapine. Perhaps of greatest translational value has been the recognition of such mechanisms leading to the emergence of novel therapeutics for bipolar disorders. These include the antioxidant N-acetylcysteine, the anti-inflammatory celecoxib, and ketamine - with effects on the glutamatergic system and microglial inhibition. We review these novel mechanisms and emerging therapeutics, and comment on next steps in this space., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The Bipolar Disorders: Improving Diagnosis, Guidance, and Education (BRIDGE-II-Mix) study aimed to estimate the frequency of mixed states in patients with a major depressive episode (MDE) according to different definitions and to compare their clinical validity, looking into specific features such as suicidality., Methods: A total of 2,811 subjects were enrolled in this multicenter cross-sectional study. Psychiatric symptoms, and sociodemographic and clinical variables were collected. The analysis compared the characteristics of patients with MDE with (MDE-SA group) and without (MDE-NSA) a history of suicide attempts., Results: The history of suicide attempts was registered in 628 patients (22.34%). In the MDE-SA group, women (72.5%, p = 0.028), (hypo)mania in first-degree relatives (20.5%, p < 0.0001), psychotic features (15.1%, p < 0.0001), and atypical features (9.2%, p = 0.009) were more prevalent. MDE-SA patients' previous responses to treatment with antidepressants included more (hypo)manic switches [odds ratio (OR) = 1.97, 95% confidence interval (CI): 1.58-2.44, p < 0.0001], treatment resistance (OR = 2.07, 95% CI: 1.72-2.49, p < 0.0001), mood lability (OR = 1.98, 95% CI: 1.65-2.39, p < 0.0001), and irritability (OR = 1.80, 95% CI: 1.48-2.17, p < 0.0001). Multivariate analysis evidenced that risky behavior, psychomotor agitation and impulsivity, and borderline personality and substance use disorders were the variables most frequently associated with previous suicide attempts. In the MDE-SA group, 75 patients (11.9%) fulfilled Diagnostic and Statistical Manual (DSM)-5 criteria for MDE with mixed features, and 250 patients (39.8%) fulfilled research-based diagnostic criteria for a mixed depressive episode., Conclusions: Important differences between MDE-SA and MDE-NSA patients have emerged. Early identification of symptoms such as risky behavior, psychomotor agitation, and impulsivity in patients with MDE, and treatment of mixed depressive states could represent a major step in suicide prevention., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mood stabilizers such as lithium and anticonvulsants are still standard-of-care for the acute and long-term treatment of bipolar disorder (BD). This systematic review aimed to assess the prevalence of their adverse effects (AEs) and to provide recommendations on their clinical management. We performed a systematic research for studies reporting the prevalence of AEs with lithium, valproate, lamotrigine, and carbamazepine/oxcarbazepine. Management recommendations were then developed. Mood stabilizers have different tolerability profiles and are eventually associated to cognitive, dermatological, endocrine, gastrointestinal, immunological, metabolic, nephrogenic, neurologic, sexual, and teratogenic AEs. Most of those can be transient or dose-related and can be managed by optimizing drug doses to the lowest effective dose. Some rare AEs can be serious and potentially lethal, and require abrupt discontinuation of medication. Integrated medical attention is warranted for complex somatic AEs. Functional remediation and psychoeducation may help to promote awareness on BD and better medication management.

Objectives: The aim of this study was to investigate the clinical factors associated with the development of rapid cycling, as well as to elucidate the role of antidepressants., Methods: The present study (NCT01503489) is a prospective, naturalistic cohort study conducted in a sample of 289 patients diagnosed with bipolar disorder followed and treated for up to 14 years. The patients were divided into two groups on the basis of the development of a rapid cycling course (n = 48) or no development of such a course (n = 241), and compared regarding sociodemographic, clinical, and outcome variables., Results: Among the 289 patients, 48 (16.6%) developed a rapid cycling course during the follow-up. Several differences were found between the two groups, but after performing Cox regression analysis, only atypical depressive symptoms (p = 0.001), age at onset (p = 0.015), and number of suicide attempts (p = 0.030) persisted as significantly associated with the development of a rapid cycling course., Conclusions: The development of rapid cycling during the course of bipolar disorder is associated with a tendency to chronicity, with a poorer outcome, and with atypical depressive symptomatology. Our study also suggests that the development of rapid cycling is associated with a higher use of antidepressants., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Loxapine is an antipsychotic used in psychiatry for over 40 years with a well-established profile. Loxapine is a dibenzoxazepine tricyclic antipsychotic agent, available for oral, intramuscular and inhalatory administration. In the light of the recent approval by the regulatory agencies of inhaled loxapine for use in the acute treatment of mild-to-moderate agitation in adults affected with schizophrenia or bipolar disorder, this article aims to critically review the available literature on loxapine, irrespective of its formulation. This review examines the efficacy and tolerability of the various formulations of loxapine in the treatment of agitation and aggression in patients affected with schizophrenia, bipolar disorder and other psychiatric conditions. A comprehensive and systematic literature search of PubMed/MEDLINE was conducted, and relevant pharmacodynamic and pharmacokinetic data was included. The findings from the literature were critically reviewed and synthesized. The available data suggests that the antipsychotic efficacy of loxapine is similar to the efficacy of other typical or atypical antipsychotics, with an adverse effects profile comparable to that of the typical antipsychotics at high doses for chronic treatment. As an acute treatment in agitation associated with schizophrenia or bipolar disorder, inhaled loxapine was developed as an innovative and rapid option which appears to be efficacious and tolerable.

Background: The present study aims to evaluate cognitive tolerability profile of SSRIs in long-term treatment. The secondary aim is to explore differences of side effects profile between patients with major depression (MD) and anxiety disorders (AD)., Methods: Sixty-seven consecutive patients, successfully treated with SSRIs in monotherapy for at least six months for MD or AD, were assessed for side effects, with a special focus on cognition., Results: Over 20% of MD and AD patients in long term treatment with SSRIs reported cognitive symptoms including fatigue, inattentiveness, lack of concentration, memory impairment and apathy. Recall memory impairment, attention deficit and somnolence were most frequently rated as moderate or severe. There were no significant differences in SSRI cognitive side effects profile between MD and AD patients., Limitations: Subjective measure of cognitive functioning, limited sample size, lack of a control group., Conclusions: A large proportion of depressed and anxious patients treated successfully with SSRIs for over six months reported cognitive, affective, motivational symptoms. These symptoms are likely to represent SSRI side effects rather than residual depressive symptomatology., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Several psychological interventions-including group psychoeducation, family-focused psychoeducation, and interpersonal social-rhythm therapy-have demonstrated prophylactic efficacy as an adjunct to medication in bipolar disorders (BDs). The field of psychological interventions for BD has experienced impressive progress over the last 15 years. Certain unexplored areas, however, require further research in order to establish the full potential of psychological interventions for BD. Such research should focus, among other things, on cognitive impairment associated with BD, BD in the elderly, comorbid anxiety disorders and other comorbidities, the treatment of BD in pregnant women, and the improvement of patients' overall physical health.

Background: Discrepancies between bipolar patients' reports and neuropsychological testing have been described and replicated. Unfortunately, no valid, specific, user-friendly, brief instrument is available to measure cognitive deficits as reported by these patients. The main aim of this study was to validate a novel instrument named the "cognitive complaints in bipolar disorder rating assessment" (COBRA). Second, we investigated the relationship between the COBRA, objective cognitive measures and illness course variables., Method: The total sample (N=215) included 91 bipolar disorder patients and 124 healthy controls. The psychometric properties of the COBRA (e.g. internal consistency, concurrent validity, discriminative validity, factorial analyses, ROC curve and feasibility) were analyzed. A complete neuropsychological battery was used as objective cognitive assessment., Results: The COBRA had one-factor structure with very high internal consistency (Cronbach's alpha=0.913). A high convergent validity was indicated by a strong correlation with the Frankfurt Complaint Questionnaire (ro=0.888, p<0.001). Bipolar patients experienced greater cognitive complaints compared to control group suggesting a discriminative validity of the instrument. Significant correlations were found between the COBRA and some objective cognitive measures. Furthermore, higher COBRA scores were associated with bipolar II subtype, residual depressive symptoms, hypomanic episodes and total episodes., Limitations: The cross-sectional design of the study, the influence of medication and severity of patients included., Conclusions: The COBRA showed to be a useful instrument to assess overall cognitive complaints in bipolar disorder with very satisfactory psychometric properties. Cognitive complaints were partially correlated with memory and executive function measures and with issues that may increase the subjective perception of cognitive deficits, such as subthreshold depressive symptoms and number of episodes., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Although several adjunctive psychological interventions are effective in the maintenance of bipolar disorders (BD), no attempt has been made to classify them according to their ability to prevent manic versus depressive episodes. Our study aims to rank the adjunctive psychotherapies for the prophylaxis of BD by means of their polarity index (PI)., Methods: Randomized controlled trials comparing the efficacy of a psychological intervention with a comparator in BD maintenance treatment in patients aged over 18 were systematically reviewed. Exclusion criteria were a small sample size, a study sample not exclusively composed of bipolar patients and the absence of a control group. PI is a novel metric indicating the relative antimanic versus antidepressive preventive efficacy of treatments. PI was retrieved by calculating the ratio of the number needed to treat (NNT) for prevention of depression and the NNT for prevention of mania. PI >1.0 indicates a relatively higher antimanic prophylactic efficacy and PI <1.0 a greater antidepressive efficacy., Results: A total of 9 studies were included. PI was 0.33, 0.63 and 0.89 for cognitive-behavioral therapy, 0.42 for family-focused therapy, 0.73 and 0.78 for psychoeducation, 1 for enhanced relapse prevention, 1.78 for caregiver group psychoeducation and 3.36 for brief technique-driven interventions. With regard to the PI for 1 cognitive-behavioral study, enhanced relapse prevention and brief technique-driven interventions may not be reliable since those trials were negative., Conclusions: The PI provides a measure of how much depression-preventive or (hypo) mania-preventive an intervention is and may guide the choice of adjunctive psychotherapy in the context of individualized long-term treatment of BD., (Copyright © 2013 S. Karger AG, Basel.)

Objective: To evaluate the longitudinal course and outcome of cognitive deficits and their clinical correlates in bipolar disorder., Method: One hundred thirteen participants (68 patients and 45 healthy controls) were assessed by the means of a neuropsychological battery targeting attention, psychomotor speed, verbal memory, and executive functions at baseline: 68 euthymic outpatients with a DSM-IV diagnosis of bipolar disorder (53 bipolar I and 15 bipolar II) were enrolled at the Bipolar Disorder Unit of the Hospital Clinic of Barcelona. Forty-five patients completed the follow-up. The assessments started in February 1999 and finished in July 2010. The primary outcome of the study was the change in the neuropsychological performance in the patient group., Results: Repeated-measures analyses showed significant effects of time in 2 cognitive domains: attention and executive functions. Attention slightly improved (P = .043) but executive function worsened (P = .001). Regression analyses showed that the duration of illness and baseline subdepressive symptoms were associated with poor performance in executive function. Subdepressive symptoms at endpoint were associated with poor functioning. The best predictor of low functioning was verbal memory dysfunction at baseline., Conclusions: The cognitive impairment remained stable across the follow-up period in many measures assessed except for a worsening of executive measures, which have been found to be associated with the duration of illness and subdepressive symptoms., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Over one half of bipolar patients have been reported to be more prone to either depressive or manic relapses. This study aimed to define profiles of drugs used for maintenance treatment of bipolar disorder (BD) by the means of Polarity Index. Polarity Index is a new metric indicating the relative antimanic versus antidepressive preventive efficacy of drugs. Polarity Index was retrieved by calculating Number Needed to Treat (NNT) for prevention of depression and NNT for prevention of mania ratio, as emerging from the results of randomized placebo-controlled trials. Included trials were randomized and double blind, with a minimal duration of 24 weeks, assessing effectiveness of a mood stabilizer or antipsychotic drug alone or in combination with a mood stabilizing agent versus a placebo comparator in BD maintenance treatment. Polarity Index value above 1.0 indicates a relative greater antimanic prophylactic efficacy, number below 1.0 a relative greater antidepressive efficacy. The polarity index for the drugs used in maintenance therapy for bipolar disorder was 12.09 for risperidone, 4.38 for aripiprazole, 3.91 for ziprasidone, 2.98 for olanzapine, 1.39 for lithium, 1.14 for quetiapine, and 0.40 for lamotrigine. Polarity index of valproate and oxcarbazepine may not be reliable due to the failure of their maintenance trials. The polarity index provides a measure of how much antidepressant versus antimanic a drug is in bipolar disorder prophylaxis, and may guide the choice of maintenance therapy in bipolar patients., (Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.)

Objective: Treatment of bipolar depression with antidepressants is strongly debated on the basis of the methodologically poor and insufficient data supporting their use and the widely held belief that antidepressants can induce new episodes of abnormal mood elevation or accelerate the rate of cycling. The present study aimed at identifying clinical risk factors for switch into hypomania, mania, or mixed states, within 8 weeks after introduction of an antidepressant or after increasing its dosage, in a prospective, longitudinal design., Method: 221 consecutive DSM-IV-TR depressed bipolar I and II disorder patients were treated with antidepressants, which were added to previously prescribed mood stabilizers and/or atypical antipsychotics. No patient was on antidepressant monotherapy. The patients were enrolled from October 2005 through January 2010. The primary outcome was the assessment of switch to mania or hypomania within 8 weeks after the introduction or dose increase of an antidepressant. Both groups were compared with analysis of variance and χ² procedures., Results: Treatment-emergent affective switch was detected in 54 patients (24.4%) (switch group) while 167 patients (75.6%) (nonswitch group) did not experience a treatment-related switch. The main clinical differences significantly associated with the occurrence of an antidepressant-related switch, after performing logistic regression analysis, were higher rate of previous switches (P < .001) in the switch versus the nonswitch group, lower rate of responses to antidepressants (P < .001) in the switch versus the nonswitch group, and earlier age at onset (P = .026) in the switch versus the nonswitch group., Discussion: Bipolar patients with an earlier age at onset and an illness course characterized by lower rate of response to antidepressants and higher rate of switches into mania or hypomania were found to be the ones with higher switch risk. Nevertheless, a greater number of previous antidepressant exposures was not associated with the occurrence of an antidepressant-associated switch., Trial Registration: clinicaltrials.gov Identifier: NCT01503489., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Objectives: A marked disparity between functional recovery and symptomatic improvement has been demonstrated in bipolar disorder. However, most of the previous studies have been conducted in the United States, and there is little prospective research from Europe on this topic. The main objective of the present six-month follow-up study was to assess functioning in a sample of Spanish bipolar disorder patients following an acute episode or subsyndromal state. Additionally, we also evaluated the sensitivity to change of the Functioning Assessment Short Test (FAST)., Methods: A total of 97 bipolar disorder patients with syndromal (n = 59) or subsyndromal (n = 38) symptoms were evaluated using the 17-item Hamilton Depression Rating Scale and Young Mania Rating Scale. The FAST was the primary measure to assess multiple areas of psychosocial functioning. Functioning was evaluated at four different time periods: baseline, 21 days, three months, and six months., Results: A significant improvement in global functioning was found in the whole sample over the six-month period, as indicated by a reduction of FAST total score (mean ± standard deviation) from 39.97 ± 15.10 to 30.65 ± 16.93 (F = 36.104, p = 0.0001). This was also evident in all areas of functioning studied. However, only 26.4% of remitted patients (n = 42) achieved functional recovery, while 79.6% of the total sample (N = 97) experienced clinical remission of acute symptoms., Conclusions: Although many patients presented syndromal recovery, only a minority of them achieved favorable functioning in multiple areas, even after specialized mental health care. Furthermore, the FAST scale was sensitive to detect minimal changes in functioning in both short (21 days) and long (6 months) periods, which may be relevant to the use of this scale in clinical trials., (© 2011 John Wiley and Sons A/S.)

Background: Some clinical differences between gender regarding the course and outcome of bipolar disorders have already been described and some others remain still controversial., Aims: To explore gender differences regarding clinical and socio-demographic characteristics amongst bipolar patients with particular attention to predominant polarity and depressive symptoms., Method: Data were collected from DSM-IV type I and II bipolar patients (n=604), resulting from the systematic follow-up of the Bipolar Disorders Program, Hospital Clinic of Barcelona, over an average follow-up of 10 years. Socio-demographic and clinical variables were collected in order to detect gender-related differences., Results: Bipolar women are more likely than men to show a predominance of depressive polarity as well as a depressive onset whilst men would be more likely to suffer from comorbid substance use disorders. Women significantly have a higher lifetime prevalence of psychotic depression and a higher prevalence of axis II comorbid disorders. Bipolar women are also more likely to have a family history of suicide and a lifetime history of attempted suicide. Suicide attempts are more often violent amongst bipolar men. In a backward logistic regression model, two variables were responsible for most gender-related clinical differences: type of predominant polarity - more likely to be depressive amongst women - (B=-0.794, p=0.027, Exp(B)=0.452; CI= 0.223-0.915), alcohol abuse (B=-1.095, p=0.000, Exp(B)=2990; CI= 1.817-4.919) and cocaine abuse (B=0.784, p=0.033, Exp(B)=2.189; CI= 1.066-4.496) - more prevalent amongst men., Conclusion: The main characteristic featuring bipolar women is depression, both at illness onset and as a predominant polarity all along the illness course. This may have important diagnostic and therapeutic implications., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Although there are studies describing the prevalence of patients with drug addiction and dual diagnosis, there is a paucity of data regarding the progression from psychiatric disorders to drug addiction or vice versa. A total of 1,090 patients dependent on heroin were interviewed to examine the presence of dual diagnosis and the progression from psychiatric disorders to drug dependence or vice versa. A total of 574 patients met the criteria for a dual diagnosis. A total of 362 patients progressed from substance abuse disorders to psychiatric disorders (SUD-PR) and 144 patients progressed from psychiatric disorders to drug addiction (PSY-PR). SUD-PR patients are more frequently affected by mood disorders. PSY-PR patients were more frequently diagnosed as psychotic or affected by anxiety disorders. The authors' findings suggest that the self-medication theory of dual diagnosis was relevant only for those with existing diagnoses of schizophrenia or anxiety disorders. When treating patients with a dual diagnosis, clinicians should ensure that the same attention is given to the treatment of drug dependence as it is to the treatment of comorbid psychiatric conditions., (© Taylor & Francis Group, LLC)

Background: The temperament evaluation of the Memphis, Pisa, Paris and San Diego questionnaire (TEMPS), in its rater-wise and its self-evaluation forms, has been designed to evaluate temperamental characteristics in clinical and non-clinical populations. The validation process is currently in progress in various countries. In order to improve this validation process we have extended the area of correlations of its self-evaluation form (TEMPS-A[P]) to MMPI, and to a special RS that allows assessment of the emotional-affective state following a stressful situation., Methods: In 693 candidates applying to become cadets in the Italian Air Force we have assessed the correlation between the TEMPS-A[P] and the MMPI validity and clinical scales, and administered an emotional-affective state questionnaire (EAS-RS) after they had gone through the stressful challenge of taking an academy entrance examination., Results: As regards MMPI validity scales, TEMPS-A[P] depressive candidates tend to report their symptoms sincerely. Hyperthymic candidates tend to give false answers so that others will see them in a good light. Cyclothymic and irritable candidates tend to exaggerate symptoms. As regards the MMPI clinical scales, a low level of linkage between affective temperaments and abnormal personality traits was found. As regards EAS-RS: hyperthymic temperament on one hand, and cyclothymic and depressive temperaments on the other, are characterized by counter-polar emotional states following the test; these are desirable in the first case and undesirable in the other two., Conclusions: The convergent and discriminant validity of TEMPS-A[P] was confirmed. From a personalistic point of view, temperaments seem to belong to the realm of normality rather than to that of pathology, in line with their putative adaptive role., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to elucidate the factors associated with the occurrence of mixed episodes, characterized by the presence of concomitant symptoms of both affective poles, during the course of illness in bipolar I disorder patients treated with an antidepressant, as well as the role of antidepressants in the course and outcome of the disorder., Method: We enrolled a sample of 144 patients followed for up to 20 years in the referral Barcelona Bipolar Disorder Program and compared subjects who had experienced at least one mixed episode during the follow-up (n=60) with subjects who had never experienced a mixed episode (n=84) regarding clinical variables., Results: Nearly 40% of bipolar I disorder patients treated with antidepressants experienced at least one mixed episode during the course of their illness; no gender differences were found between two groups. Several differences regarding clinical variables were found between the two groups, but after performing logistic regression analysis, only suicide attempts (p<0.001), the use of serotonin norepinephrine reuptake inhibitors (p=0.041), switch rates (p=0.010), and years spent ill (p=0.022) were significantly associated with the occurrence of at least one mixed episode during follow-up., Conclusions: The occurrence of mixed episodes is associated with a tendency to chronicity, with a poorer outcome, a higher number of depressive episodes, and greater use of antidepressants, especially serotonin norepinephrine reuptake inhibitors., (© 2011 John Wiley and Sons A/S.)

Rationale: Due to the episodic and chronic nature of bipolar disorder (BD), maintenance therapy represents a critical part of treatment; however, there is a paucity of studies comparing effectiveness of available long-term treatments., Objective: The aim of this study is to determine and compare the efficacy of pharmacological treatments for maintenance treatment of BD by means of the number needed to treat (NNT)., Methods: The efficacy of drugs used for maintenance treatment of BD, as emerging from the results of randomized controlled trials, was assessed using the size effect measure of NNT. PubMed searches were conducted on English-language articles published until May 2010 using the search terms "bipolar disorder," "mania," "mixed episode," or "bipolar depression," cross-referenced with trial characteristic search phrases and generic names of medications. The search was supplemented by manually reviewing reference lists from identified publications., Results: In 15 studies, aripiprazole, olanzapine, quetiapine, risperidone long-acting injection, lithium, lamotrigine, and divalproex proved effectiveness in terms of NNTs (≥ 10% advantage over placebo) for prevention of relapse into any mood episode. Quetiapine, lithium, risperidone long-acting injection, aripiprazole, and olanzapine are effective in manic recurrence prevention. Lamotrigine, quetiapine, and lithium present significant NNTs for prevention of depressive relapses., Conclusions: All of the pharmacological agents assessed were effective in the prevention of any kind of mood episode; however, different efficacy profiles were found for prevention of manic and/or depressive relapses. The comparison of NNT values of the available agents may represent a useful tool in clinical settings, in order to facilitate implementation of long-term pharmacological interventions in patients with BD.

Unlabelled: Colom F, Reinares M, Pacchiarotti I, Popovic D, Mazzarini L, Martínez-Arán A, Torrent C, Rosa A, Palomino-Otiniano R, Franco C, Bonnin CM, Vieta E. Has number of previous episodes any effect on response to group psychoeducation in bipolar patients? A 5-year follow-up post hoc analysis., Objective: One of the main utilities of staging in bipolar disorder is enhancing the formulation of pharmacological and non-pharmacological treatment strategies. Hence, it is essential to ascertain whether the number of previous episodes influences treatment response. Hereby, we present a 5-year post hoc study on the efficacy of group psychoeducation for bipolar disorders according to the number of previous episodes., Methods: For this subanalysis, we have compared the 5-year outcome of 120 euthymic psychoeducated versus non-psychoeducated bipolar patients according to the number of previous episodes at study entry., Results: Patients with more than seven episodes at study entry did not show any significant improvement with psychoeducation according to time to recurrence. Patients with more than 14 episodes did not benefit from psychoeducation in terms of a reduction of time spent ill. Patients with 7 or 8 episodes showed a benefit in terms of fewer days spent in hypomania, depression, mixed episodes or any episodes but not mania, while patients with 9-14 episodes showed a benefit in terms of fewer days spent in hypomania and depression but not in mixed states or mania. Only patients who presented up to 6 episodes showed reduction in time spent in any episode polarity., Conclusion: The number of previous episodes clearly worsens response to psychoeducation, perhaps in a more subtle way than that observed with other psychological therapies. Psychoeducation should be delivered as soon as possible in the illness course, supporting the idea of early intervention.

It is commonly assumed that people who are addicted to certain substances would abuse any substance. This position has never been supported by validly collected and analyzed research data. In this study, the authors examine the use of street methadone by heroin addicts seeking their first agonist opioid treatment in a clinical setting. Fifty-four heroin addicts who resorted to street methadone use were compared by socio-demographic, current clinical, and disease-related variables to 251 peers who do not use street methadone. Heroin addicts who resort to street methadone use are more likely to be females and to have a higher degree of education, are less likely to engage in polyabuse (use of more than three substances), are less severely ill, have been addicted for a shorter period of time, and have been seeking treatment sooner in the course of their disease. Also, they suffer from a wider range of psychopathological distress symptoms. In Italy, resorting to street methadone does not seem to be a surrogate form of heroin addiction, but rather represents means of harm reduction, with treatment seeking occurring shortly after its initiation. This should be accounted for when deciding on take-home policies and issues of potential methadone diversion.

Background: Much of the literature has described personality disorder constructs for heroin addicts. Building on previous work we examine the relevance of affective temperament measures in these patients., Methods: 59 consecutive stabilized methadone treated heroin addicts, 34 with and 25 without psychiatric comorbidity, were compared, regarding affective temperaments, according to the Akiskal and Mallya formulation, with 58 healthy volunteers sharing similar social and regional demographics., Results: No differences were observed between heroin addicts and controls on either depressive or hyperthymic scales. Significant discrepancies were noted in cyclothymic and irritability scales, on which heroin addicts scored higher, regardless of the presence or absence of a dual diagnosis. In a multivariate discriminant analysis, mainly cyclothymic, and (to a lesser extent) irritable traits show a distinction between heroin addicts and controls, but not between heroin addicts with and without dual diagnoses., Limitation: Cross-sectional study., Conclusion: Our data suggest a new hypothesis. Cyclothymic, and to a lesser extent irritable traits (the "dark side"), could represent the temperamental profile of heroin addicts, largely irrespective of comorbidity, and tend to cohere with previous conceptualizations hypothesizing "sensation-seeking" (and "novelty-seeking") as the main personality characteristics of addiction.