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BACKGROUND Depressive and manic episodes within bipolar disorder (BD) and major depressive disorder (MDD) involve altered mood, sleep, and activity, alongside physiological alterations wearables can capture. OBJECTIVE Firstly, we explored whether physiological wearable data could predict (aim 1) the severity of an acute affective episode at the intra-individual level and (aim 2) the polarity of an acute affective episode and euthymia among different individuals. Secondarily, we explored which physiological data were related to prior predictions, generalization across patients, and associations between affective symptoms and physiological data. METHODS We conducted a prospective exploratory observational study including patients with BD and MDD on acute affective episodes (manic, depressed, and mixed) whose physiological data were recorded using a research-grade wearable (Empatica E4) across 3 consecutive time points (acute, response, and remission of episode). Euthymic patients and healthy controls were recorded during a single session (approximately 48 h). Manic and depressive symptoms were assessed using standardized psychometric scales. Physiological wearable data included the following channels: acceleration (ACC), skin temperature, blood volume pulse, heart rate (HR), and electrodermal activity (EDA). Invalid physiological data were removed using a rule-based filter, and channels were time aligned at 1-second time units and segmented at window lengths of 32 seconds, as best-performing parameters. We developed deep learning predictive models, assessed the channels’ individual contribution using permutation feature importance analysis, and computed physiological data to psychometric scales’ items normalized mutual information (NMI). We present a novel, fully automated method for the preprocessing and analysis of physiological data from a research-grade wearable device, including a viable supervised learning pipeline for time-series analyses. RESULTS Overall, 35 sessions (1512 hours) from 12 patients (manic, depressed, mixed, and euthymic) and 7 healthy controls (mean age 39.7, SD 12.6 years; 6/19, 32% female) were analyzed. The severity of mood episodes was predicted with moderate (62%-85%) accuracies (aim 1), and their polarity with moderate (70%) accuracy (aim 2). The most relevant features for the former tasks were ACC, EDA, and HR. There was a fair agreement in feature importance across classification tasks (Kendall W=0.383). Generalization of the former models on unseen patients was of overall low accuracy, except for the intra-individual models. ACC was associated with “increased motor activity” (NMI>0.55), “insomnia” (NMI=0.6), and “motor inhibition” (NMI=0.75). EDA was associated with “aggressive behavior” (NMI=1.0) and “psychic anxiety” (NMI=0.52). CONCLUSIONS Physiological data from wearables show potential to identify mood episodes and specific symptoms of mania and depression quantitatively, both in BD and MDD. Motor activity and stress-related physiological data (EDA and HR) stand out as potential digital biomarkers for predicting mania and depression, respectively. These findings represent a promising pathway toward personalized psychiatry, in which physiological wearable data could allow the early identification and intervention of mood episodes.

Objectives Electroconvulsive therapy (ECT) is an effective and safe treatment of certain severe mental disorders, but there are some barriers to the implementation of continuation/maintenance ECT courses in some cases. Repeated difficulties in achieving intravenous access before each session may contribute to premature ECT discontinuation. The placement of a totally implantable venous-access device (TIVAD) could be an alternative to overcome these difficulties in certain subjects. Methods For the present study we retrospectively identified all patients treated with continuation/maintenance ECT in our facilities during a 13-year period to which a TIVAD was implanted, paying attention to specific factors related to clinical characteristics, treatment course, and ECT technique. Results We identified a TIVAD in 16 (3.33%) of 481 patients receiving ECT in our unit, of whom 87.5% were female. Half of the cases met the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for schizophrenia, 6 for bipolar disorder, and 2 for major depression disorder. Age of the study cases ranged from 17 to 87 years. A total of 1957 ECT sessions were registered in this group of cases during the observation period. Patients had undergone a mean of 124.06 ± 132.41 ECT sessions before the TIVAD was implanted, with the device mean time of utilization being 5.39 ± 3.46 years. In 2 cases, the device was removed after ECT discontinuation. Few incidents associated with the implantation and operation of the TIVAD were registered, comparable to the use of this device in other clinical contexts. Conclusions This case series suggest that a TIVAD placement can be an effective and safe solution for patients in continuation/maintenance ECT courses with difficult intravenous access. Future studies will need to carefully monitor the benefit and the potential complications of TIVAD placement in patients undergoing continuation/maintenance ECT programs.

Mood disorders are severe and chronic mental conditions exacting high costs from society. The lack of reliable biomarkers to aid clinicians in tailoring pharmacotherapy based on distinguishable patient-specific traits means that the current prescribing paradigm is largely one of trial and error. Previous studies showed that different biological signatures, such as patterns of heart rate variability or electro-dermal reactivity, are associated with clinically meaningful outcomes. Against this backdrop, the advances in machine learning and the spread of wearable devices capable of providing continuous and ecological monitoring of patients may unlock great opportunities in mental healthcare. We herewith present a pilot study on mania and depression where we moved beyond the simple disease state binary classification but pursued the more informative and clinically meaningful task of differentiating between levels of disease severity. While most previous similar endeavours used recording segments extracted from the same subjects for both training and testing, we explicitly carried out model development and evaluation on segments from different groups of patients, in order to have a fair assessment of the model out-of-sample generalisation. This illustrated how individuals heterogeneity and non-disease-related dimensions of variations (e.g. sex, age, physical fitness) may dominate the signal so that in low sample size regimes a model might learn and overfit subject-specific patterns rather than capturing disease-relevant traits generalisable across disorders. Lastly, we developed a viable baseline for pre-processing raw data from wristband recordings and compared three classical and two deep-learning models to identify levels of disease severity.

Highlights • Electroconvulsive therapy during COVID-19 has logistic and infective challenges. • Aerosol-generating ventilation requires full personal protective equipment. • A systematic screening with PCR tests must be applied. • Electroconvulsive therapy should be considered an essential medical procedure. • Each electroconvulsive therapy unit should adapt its own protocol., Background During the COVID-19 pandemic, electroconvulsive therapy units have had to confront challenges such as the infectious hazard due to aerosol-generating ventilation, or the lack of staff and material resources. Our objective was to elaborate a protocol to make ECT during the COVID-19 pandemic a safer procedure for patients and professionals. Methods A multidisciplinary workgroup (including mental health, anesthesia, preventive medicine, and occupational risk professionals) was formed in the Hospital Clínic de Barcelona, in March 2020. A core group conducted a review of the scientific literature and healthcare organizations’ guidelines and wrote a protocol draft. Then, a discussion with the workgroup was made until consensus was reached. The protocol has been continuously updated. Discussions were made by group e-mailing and video conferencing. Results The protocol includes the following main areas: (1) ECT unit's structural and functional considerations; (2) SARS-CoV-2 screening protocol; (3) ECT clinical practice adaptation (personal protective equipment, airway management, recovery room, and maintenance of the facilities); (4) management of COVID-19 cases; and (5) protocol assessment. Limitations The literature review was not systematic; the consensus was not based on a structured methodology. For other ECT units, local advisories may not be valid, and resource shortages (such as anesthetist availability, or the lack of respirators and PCR tests) may impede or prevent their implementation. Conclusions During the COVID-19 pandemic, ECT should continue to be advocated as an essential medical procedure. It is recommended that each ECT unit develop its own protocol. This proposal may be used as a reference.

BackgroundImproving functioning in patients with bipolar disorder (BD) is one of the main objectives in clinical practice. Of the few psychosocial interventions that have been specifically developed to enhance the psychosocial outcome in BD, functional remediation (FR) is one which has demonstrated efficacy. The aim of this study was to examine which variables could predict improved functional outcome following the FR intervention in a sample of euthymic or subsyndromal patients with BD.MethodsA total of 92 euthymic outpatients were included in this longitudinal study, with 62 completers. Partial correlations controlling for the functional outcome at baseline were calculated between demographic, clinical and neurocognitive variables, and functional outcome at endpoint was assessed by means of the Functioning Assessment Short Test scale. Next, a multiple regression analysis was run in order to identify potential predictors of functional outcome at 2-year follow-up, using the variables found to be statistically significant in the correlation analysis and other variables related to functioning as identified in the previous scientific literature.ResultsThe regression model revealed that only two independent variables significantly contributed to the model (F(6,53): 4.003; p = 0.002), namely verbal memory and inhibitory control. The model accounted for 31.2% of the variance. No other demographic or clinical variable contributed to the model.ConclusionsResults suggest that patients with better cognitive performance at baseline, especially in terms of verbal memory and executive functions, may present better functional outcomes at long term follow-up after receiving functional remediation.

The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition introduced the specifier "with mixed features" including 3 or more nonoverlapping typical manic symptoms during a major depressive episode in bipolar disorder type I or II or unipolar major depressive disorder. Excluding overlapping excitatory symptoms, which are frequently observed in mixed depression, leaves many patients with mixed depression undiagnosed. As a consequence, alternative diagnostic criteria have been proposed, claiming for the inclusion in the rubric of mixed features the following symptoms: psychomotor agitation, mood lability, and aggressiveness. A deeper diagnostic reconsideration of mixed features in depression should be provided by the new nosologic classification systems.

Parenthood age may affect the risk for the development of different psychiatric disorders in the offspring, including bipolar disorder (BD). The present systematic review and meta-analysis aimed to appraise the relationship between paternal age and risk for BD and to explore the eventual relationship between paternal age and age at onset of BD. We searched the MEDLINE, Scopus, Embase, PsycINFO online databases for original studies from inception, up to December 2021. Random-effects meta-analyses were conducted. Sixteen studies participated in the qualitative synthesis, of which k = 14 fetched quantitative data encompassing a total of 13,424,760 participants and 217,089 individuals with BD. Both fathers [adjusted for the age of other parent and socioeconomic status odd ratio - OR = 1.29(95%C.I. = 1.13-1.48)] and mothers aged ≤ 20 years [(OR = 1.23(95%C.I. = 1.14-1.33)] had consistently increased odds of BD diagnosis in their offspring compared to parents aged 25-29 years. Fathers aged ≥ 45 years [adjusted OR = 1.29 (95%C.I. = 1.15-1.46)] and mothers aged 35-39 years [OR = 1.10(95%C.I. = 1.01-1.19)] and 40 years or older [OR = 1.2(95% C.I. = 1.02-1.40)] likewise had inflated odds of BD diagnosis in their offspring compared to parents aged 25-29 years. Early and delayed parenthood are associated with an increased risk of BD in the offspring. Mechanisms underlying this association are largely unknown and may involve a complex interplay between psychosocial, genetic and biological factors, and with different impacts according to sex and age range. Evidence on the association between parental age and illness onset is still tentative but it points towards a possible specific effect of advanced paternal age on early BD-onset.

Background: Cognitive profiles of BD patients show a demonstrated heterogeneity among young and middle-aged patients, but this issue has not yet deeply explored in Older Adults with bipolar disorder (OABD). The aim of the present study was to analyze cognitive variability in a sample of OABD. Methods: A total of 138 OABD patients and 73 healthy controls were included in this study. A comprehensive neuropsychological assessment was administered. We performed a k-means cluster analysis method based on the neurocognitive performance to detect heterogeneous subgroups. Demographic, clinical, cognitive and functional variables were compared. Finally, univariate logistic regressions were conducted to detect variables associated with the severity of the cognitive impairment. Results: We identified three distinct clusters based on the severity of cognitive impairment: (1) a preserved group (n = 58; 42%) with similar cognitive performance to HC, (2) a group showing mild cognitive deficits in all cognitive domains (n = 64; 46%) and, finally, (3) a group exhibiting severe cognitive impairment (n = 16; 12%). Older age, late onset, higher number of psychiatric admissions and lower psychosocial functioning were associated with the greatest cognitive impairment. Lower age, more years of education and higher estimated IQ were associated with a preserve cognitive functioning. Limitations: The small sample size of the severely impaired group. Conclusions: Cognitive heterogeneity remains at late-life bipolar disorder. Demographic and specific illness factors are related to cognitive dysfunction. Detecting distinct cognitive subgroups may have significant clinical implications for tailoring specific intervention strategies adapted to the level of the impairment and also to prevent cognitive decline.

Lithium remains the gold standard maintenance treatment for Bipolar Disorder (BD). However, weight gain is a side effect of increasing relevance due to its metabolic implications. We conducted a systematic review and meta-analysis aimed at summarizing evidence on the use of lithium and weight change in BD. We followed the PRISMA methodology, searching Pubmed, Scopus and Web of Science. From 1003 screened references, 20 studies were included in the systematic review and 9 included in the meta-analysis. In line with the studies included in the systematic review, the meta-analysis revealed that weight gain with lithium was not significant, noting a weight increase of 0.462 Kg (p = 0158). A shorter duration of treatment was significantly associated with more weight gain. Compared to placebo, there were no significant differences in weight gain. Weight gain was significantly lower with lithium than with active comparators. This work reveals a low impact of lithium on weight change, especially compared to some of the most widely used active comparators. Our results could impact clinical decisions.

Cel pracyLeki przeciwpadaczkowe (LPP), które są powszechnie stosowane w zapobieganiu nawrotom i leczeniu ostrych faz choroby afektywnej dwubiegunowej (ChAD) oraz zaburzeń schizoafektywnych (schizoaffective disorder, SAD), często wiążą się z działaniami niepożądanymi w czasie ciąży oraz z poważnymi wadami wrodzonymi (major congenital malformations, MCM). Celem niniejszej pracy było podsumowanie dostępnych badań oceniających skutki stosowania leków przeciwpadaczkowych u ciężarnych kobiet z ChAD i /lub SAD.MetodaPrzeszukano cztery bazy danych od początku do 18 stycznia 2019 roku. Do przeglądu włączono recenzowane badania obserwacyjne dotyczące stosowania LPP u ciężarnych kobiet z ChAD lub SAD. Wykluczono badania nieprzedstawiające danych dotyczących ChAD lub SAD, nie określające stosowanych LPP lub nie oceniające wyników ciąży lub poważnych wad wrodzonychWynikiŁączna ilość znalezionych badań wyniosła 2861. Po usunięciu zdublowanych badań i zastosowaniu kryteriów włączenia/wykluczenia do przeglądu włączono 9 badań obserwacyjnych oceniających pacjentki z ChAD i SAD. Badano następujące LPP: lamotrygina (LTG), kwas walproinowy (VPA), karbamazepina (CBZ), okskarbazepina (OXC), topiramat (TPR) i gabapentyna (GBP). Kwas walproinowy i karbamazepina były lekami przeciwpadaczkowymi, których stosowanie najczęściej wiązało się z poważnymi wadami wrodzonymi. Lamotrygina wykazywała najlepszy profil bezpieczeństwa. U leczonych i nieleczonych kobiet z ChAD obserwowano wyższe wskaźniki powikłań w czasie ciąży w porównaniu ze zdrowymi ciężarnymi.WnioskiStosowanie leków przeciwpadaczkowych w ciąży może mieć niekorzystne skutki oraz prowadzić do poważnych wad wrodzonych u dzieci kobiet z ChAD lub SAD, przy czym wyższe ryzyko występuje przy stosowaniu wyższych dawek. U tego typu pacjentek można rozważyć podawanie lamotryginy, biorąc pod uwagę niski poziom działań niepożądanych. W czasie ciąży należy unikać stosowania kwasu walproinowego i karbamazepiny.

Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are neurotrophins that play critical roles in brain neuronal function. Previous studies have established the association between BDNF and NGF signaling and severe mental disorders, but changes in BDNF plasma levels and electroconvulsive therapy (ECT) response are controversial. The aim of his study was to explore the acute effects of a single session of ECT on these neurotrophins signaling. Plasma levels of BDNF and NGF and their tyrosine kinase-type receptors expression in peripheral blood mononuclear cells (PBMCs) were determined before and two hours after a single ECT session in 30 subjects with a severe mental disorder. Two hours after an ECT session we found a statistically significant decrease of BDNF plasma levels (p=0.007). We did not find significant acute effects on NGF plasma levels or receptors expression in PBMCs. We found a significant inverse correlation between the time of convulsion and BDNF plasma levels decrease (r=-0.041, p=0.024). We have identified a decrease in BDNF plasma levels after 2h of a single ECT session. These results indicate the interest for future research in the role of neurotrophins in the response and safety of ECT.

Mixed affective states, defined as the coexistence of depressive and manic symptoms, are complex presentations of manic-depressive illness that represent a challenge for clinicians at the levels of diagnosis, classification, and pharmacological treatment. The evidence shows that patients with bipolar disorder who have manic/hypomanic or depressive episodes with mixed features tend to have a more severe form of bipolar disorder along with a worse course of illness and higher rates of comorbid conditions than those with non-mixed presentations. In the updated Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5), the definition of “mixed episode” has been removed, and subthreshold nonoverlapping symptoms of the opposite pole are captured using a “with mixed features” specifier applied to manic, hypomanic, and major depressive episodes. However, the list of symptoms proposed in the DSM–5 specifier has been widely criticized, because it includes typical manic symptoms (such as elevated mood and grandiosity) that are rare among patients with mixed depression, while excluding symptoms (such as irritability, psychomotor agitation, and distractibility) that are frequently reported in these patients. With the new classification, mixed depressive episodes are three times more common in bipolar II compared with unipolar depression, which partly contributes to the increased risk of suicide observed in bipolar depression compared to unipolar depression. Therefore, a specific diagnostic category would imply an increased diagnostic sensitivity, would help to foster early identification of symptoms and ensure specific treatment, as well as play a role in suicide prevention in this population.

Background: Brain structural and functional changes in bipolar disorder (BD) are well-established findings, but it is uncertain whether these changes are already present in first episode mania (FEM).Methods: We compared 31 FEM subjects, with 31 healthy individuals matched for age, sex, and premorbid IQ. Whole-brain voxel-wise morphometry, functional magnetic resonance imaging during the n-back task, and a functional connectivity analysis were performed.Results: There were no volumetric differences between the 2 groups. During the 2-back task, FEM patients did not perform differently from controls and activated similar regions, but they showed less deactivation in the ventromedial prefrontal cortex (vmPFC), the anterior hub of the default mode network (DMN). They showed preserved functional connectivity between the vmPFC and other regions of the DMN, but increased connectivity with the superior frontal gyrus.Conclusions: The absence of volumetric changes in FEM patients suggests that these changes could be related to progression of the illness. On the other hand, the failure of deactivation of the anterior hub of the DMN is present from the onset of the illness and may represent a core pathophysiological feature of BD.

Long-Acting Injectable Antipsychotics (LAIs) are used to overcome non-compliance in psychoses, mainly schizophrenia spectrum disorders. We aimed to summarize available evidence of studies comparing the efficacy of LAIs to placebo or oral medications for Bipolar Disorder (BD) and/or Schizoaffective Disorder (SAD). We searched six databases from inception to 28-March-2018, using the strategy: long-acting antipsychotics AND (bipolar disorder OR schizoaffective disorder OR mania OR manic OR bipolar depression). We included peer-reviewed double-blind comparisons of LAIs for any clinical outcome occurrence in BD, or open mirror studies with same prospective as retrospective assessment periods. We excluded studies reporting on mixed schizophrenia/SAD populations without reporting results separately. The pooled records amounted to 642. After duplicate removal and inclusion/exclusion criteria application, we included 15 studies, 6 double-blind and 9 open, 13 assessing BD and 2 SAD. Depot neuroleptics prevented manic, but not depressive recurrences and may worsen depressive symptoms. Risperidone long-acting injectable was found to be effective in protecting from any mood/manic symptom compared to placebo, but not from depressive recurrences. Add-on or monotherapy paliperidone palmitate in SAD patients protected from psychotic, depressive, and manic symptoms. In patients with BD-I with a manic episode at study enrolment, aripiprazole monohydrate significantly delayed time to recurrence of manic episodes without inducing depressive episodes. LAIs are effective and well-tolerated maintenance treatments for BD and SAD. They showed better efficacy in preventing mania than depression. LAIs may be first-line for BD-I and SAD patients with a manic predominant polarity and with non-adherence problems.

Breast milk is considered the best source of nutrients and provides much better protection than immune modified milk. However, the postpartum period is a phase of increased risk for all women to experience psychiatric symptoms and recurrences or new episodes of bipolar disorder (BD), especially in those who have discontinued treatment. This is a systematic review of the risks and benefits of mood stabilizers and antipsychotics during breastfeeding as they relate to the health and well-being of mothers and their infants. Evidence-based treatment advice for women with BD during lactation is also provided. This systematic review has been conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. We included studies examining the exposure and the effects of antipsychotics and mood stabilizers used to treat BD on infants during breastfeeding clearly reporting the estimated amount of drug or effects on infants. The final selection included 56 studies. The available data supports the use of lithium as a possible treatment option during breastfeeding. Carbamazepine and valproic acid are also considered relatively safe. Lamotrigine can be used but at the lowest doses and considered for individual cases. Among the antipsychotics, quetiapine and olanzapine should be considered as first-line treatment options. Risperidone may be compatible with breastfeeding under medical supervision. Clozapine and amisulpiride are currently contraindicated. Long-term outcome studies evaluating the infant׳s health and psychosocial and cognitive functioning are needed.

Background During the last fifteen years, the possibility of delivering psychoeducation programs through Internet-based platforms have been explored. Studies evaluating those programs have shown good to acceptable retention rates. In this context, we developed a smartphone application (SIMPLe) collecting information about mood symptoms and offering personalized psychoeducation messages. The main aims of this study were to evaluate the feasibility, acceptability and satisfaction of the smartphone application. Methods The study was conducted from March to August 2015. Participation in the study was proposed to a consecutive sample of adult patients attending an outpatient mental health clinic. Sociodemographic data, clinical and functional assessments alongside smartphone ownership and uses were collected at baseline and at 3 months' follow-up. A 5 item Likert-scale satisfaction questionnaire was also employed. Results 51 participants were initially enrolled in the study, 36 (74%) remained actively using the application after 3 months. The whole sample interacted with the application a mean of 77 days (SD=26.2). During these days they completed 88% of the daily tests. Over 86% of the participants agreed that the experience using the application was satisfactory. Limitations The diversity of smartphones operating systems led to a moderate, although representative, sample number. Additionally, the subjective data reporting, narrow time frame of use and stability of the patients could have affected the results. Conclusions The results confirm that this particular intervention is feasible and represent a satisfactory and acceptable instrument for the self-management of bipolar disorder as an add-on to the usual treatment but future clinical trials must still probe its efficacy.

Background Despite its importance, no distinction between none, mild, moderate and severe functional impairment is available. Categorization of functional impairment could help to better assess randomized controlled trials (RCT) and to study the correlates of functional impairment according to severity. The Functional Assessment Short Test (FAST) is one of the most widely used measures of functional impairment in bipolar disorder and related conditions, but to date no severity cut-offs have been determined for their use in clinical research and practice. Method FAST and Global Functioning Assessment (GAF) ratings from 65 euthymic outpatients with bipolar disorder at the Hospital Clinic in Barcelona were analyzed. A linear regression was computed using the FAST as the independent variable and the GAF as the dependent variable. Cut-offs scores for the FAST were estimated taking into account the GAF scores as a reference. Results Linear regression analysis with GAF scores as the dependent variable yielded the following equation: GAF score = 91,41–1,031 * FAST score. The cut-off scores for the FAST scale derived from this equation were as follows: scores from 0 to 11 included patients with no impairment. Scores from 12 to 20, represented the category of mild impairment. Moderate impairment comprised scores from 21 to 40. Finally, scores above 40 represent severe functional impairment. Further, the 4 × 4 cross-tabulation resulted in a significant association of FAST and GAF severity gradation: (Chi2= 95,095; df = 9; p Limitations In the absence of a better alternative, the GAF, a broad clinical measure, was used as gold standard for establishing FAST categories according to severity. Conclusion The categorization of functional impairment in four categories based on empirical data shows that 12, 20 and 40 represent clinically meaningful cut-offs of the FAST for mild, moderate, and severe functional impairment and for functional recovery, remission, and improvement. The proposed categories are suitable to be further implemented in clinical studies and RCTs.

The concept of well-being which focuses on positive emotions has received increased research attention. However, a consensus definition of this term is lacking. The Well-Being Index scale (WHO-5) is a generic, self-report scale that contains five Likert-type items to evaluate psychological well-being. This construct may provide a relevant outcome in bipolar disorder (BD) research and care beyond the rating of mood symptoms. Thus, in the current study, the psychometric properties of the WHO-5 Spanish version were assessed in a sample of euthymic patients with BD.Patients with BD- I and BD-II and healthy controls completed the Well-Being Index (WHO-5) together with an assessment of depressive (Hamilton Depression Rating Scale-17; HAM-D) and manic symptoms (Young Mania Rating Scale; YMRS); and a measure of psychosocial functioning (Functioning Assessment Short Test; FAST). Internal consistency reliability was measured through Cronbach's alpha. Test-retest reliability was calculated comparing the WHO-5 total score at baseline and after 10 days of the first administration. To assess the structure of the scale, a principal component analysis (PCA) was carried out. Correlations between the WHO-5, HAM-D, YMRS and FAST were calculated. Finally, a t-test for independent samples was applied to compare the WHO-5 total score in the patient and control groups.A total of 104 patients with BD and 40 healthy controls were included in this study. A Chronbach's alpha of 0.83 indicated acceptable internal consistency. A paired sample t-test revealed no significant differences between WHO-5 total score at baseline and at follow-up (tn = - 0.72; df = 15; p = 0.48). The PCA provided a single factor solution that accounted for 59.74% of the variation in WHO-5. Test-retest reliability was high (r = 0.83; p0.001). Moderate negative correlations were observed between the WHO-5 total score, the FAST (r = - 0.46.; p0.001) and the HAM-D (r = - 0.68; p0.001), but not with the YMRS (r = - 0.07; p = 0.42). Finally, significant differences were found when comparing the WHO-5 total score between patient and healthy controls (t = 5.1; df = 147; p0.001).some limitations include the lack of a comparator scale to test for validity construct and the small sample size in the test-retest reliability CONCLUSIONS: The WHO-5 shows an acceptable reliability index and measures a unitary construct in a Spanish population of euthymic patients with BD.

Objective The purpose of this study was to analyze differences in clinical and socio-demographic characteristics between older and younger bipolar outpatients paying special attention to depressive symptoms in a large, naturalistic cohort. Method Five hundred and ninety-three DSM-IV-TR bipolar outpatients were enrolled. Clinical characteristics were assessed according to DSM-IV-TR (SCID-I). Subjects were categorized into two groups according to current age (older OBD: age > 65 years; younger-YBD: age 40 years, as well as suffering from more medical comorbidities when compared to younger bipolars. Conclusion The clinical presentation of bipolar disorder in late life would be defined more frequently by melancholic depressive features and a predominantly depressive polarity. These results suggest that treatment strategies for elderly bipolar patients should focus in the prevention of depressive episodes.

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) nomenclature for the co-occurrence of manic and depressive symptoms (mixed states) has been revised in the new DSM-5 version to accommodate a mixed categorical–dimensional concept. The new classification will capture subthreshold non-overlapping symptoms of the opposite pole using a “with mixed features” specifier to be applied to manic episodes in bipolar disorder I (BD I), hypomanic, and major depressive episodes experienced in BD I, BD II, bipolar disorder not otherwise specified, and major depressive disorder. The revision will have a substantial impact in several fields: epidemiology, diagnosis, treatment, research, education, and regulations. The new concept is data-driven and overcomes the problems derived from the extremely narrow definition in the DSM-IV-TR. However, it is unclear how clinicians will deal with the possibility of diagnosing major depression with mixed features and how this may impact the bipolar–unipolar dichotomy and diagnostic reliability. Clinical trials may also need to address treatment effects according to the presence or absence of mixed features. The medications that are effective in treating mixed episodes per the DSM-IV-TR definition may also be effective in treating mixed features per the DSM-5, but new studies are needed to demonstrate it.

Background: there is a lack of scientific data regarding speed of action of antimanic treatments, a relevant issue in clinical practice. Objective: to assess differences in the speed of onset of antimanic efficacy between haloperidol (as most studied first-generation antipsychotic) and second-generation antipsychotics. Experimental procedures: meta-analysis of double-blind randomized clinical trials in acute mania, comparing treatment with haloperidol and with second-generation antipsychotics. Search was conducted in MEDLINE and CENTRAL databases (last search: September 2011). Differences in mania scale score reduction at week 1 were assessed. Results: 8 randomized clinical trials fulfilled inclusion criteria and 1 of them was excluded due to low methodological quality. 2037 Manic patients had been treated with antipsychotics in the 7 trials. Haloperidol was found to be significantly more efficacious in the reduction of the mania scale score at week 1. The effect size was small, the Standardized Mean Difference (SMD) being 0.17, with a 95% Confidence Interval ranging from 0.01 to 0.32. Haloperidol was significantly more efficacious than olanzapine (SMD: 0.40 [0.21, 0.59]) and ziprasidone (0.39 [0.18, 0.61]). A non-significant trend towards superiority of haloperidol was found over aripiprazole (SMD: 0.13 [0.02, 0.19]). There were no significant differences between haloperidol and quetiapine (0.17 [0.11, 0.44]), and haloperidol and risperidone (SMD: 0.10 [0.30, 0.09]). Conclusions: haloperidol shows a faster onset of antimanic action than second-generation antipsychotics. This difference may be related to D2 affinity. Haloperidol may be considered a treatment option in severely ill manic patients who require urgent relief of symptoms.

Background Treatment of acute mania with second-generation antipsychotics has been claimed to involve a lower risk of switch to depression than haloperidol. However, clinical guidelines clearly state that this is not a proven fact. Methods Meta-analysis of double-blind randomized controlled trials in acute mania, comparing rates of switch to depression with atypical antipsychotics and with haloperidol. Search was conducted in MEDLINE and CENTRAL databases (last search: September 2011). Results 8 randomized clinical trials fulfilled inclusion criteria. 2 of them were excluded because of low methodological quality or lack of data. 5 second-generation antipsychotics (aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) were compared to haloperidol. In the mixed effects model the Risk Ratio for depressive switch was 0.71 (0.52, 0.96) favouring atypical antipsychotics. In the random effects model the difference did not reach statistical significance. In the heterogeneity analysis, exclusion of an outlying aripiprazole trial yielded a Risk Ratio of 0.58 (0.42, 0.82) with a non-significant heterogeneity test. Although no atypical antipsychotic was individually significantly superior to haloperidol, a trend could be seen favouring olanzapine (RR=0.56 [0.29, 1.08]), quetiapine (RR=0.36 [0.10, 1.33]), and ziprasidone (RR=0.51 [0.22, 1.18]). Limitations All trials were industry supported, with some variability in dosage of haloperidol. Switch to depression was not the primary outcome of the trials. Heterogeneity could be explained as a lack of class-effect for atypicals. Conclusions Treating acute mania with atypicals is associated to 42% less risk of switch to depression than with haloperidol. Nevertheless, caution should be taken when considering this a class effect, as only olanzapine, quetiapine, and ziprasidone may show a better profile.

BackgroundRelatively few studies have investigated whether relatives of patients with bipolar disorder show brain functional changes, and these have focused on activation changes. Failure of de-activation during cognitive task performance is also seen in the disorder and may have trait-like characteristics since it has been found in euthymia.MethodA total of 20 euthymic patients with bipolar disorder, 20 of their unaffected siblings and 40 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance (ANOVA) was fitted to individual whole-brain maps from each set of patient–relative–matched pair of controls. Clusters of significant difference among the groups were used as regions of interest to compare mean activations/de-activations between them.ResultsA single cluster of significant difference among the three groups was found in the whole-brain ANOVA. This was located in the medial prefrontal cortex, a region of task-related de-activation in the healthy controls. Both the patients and their siblings showed significantly reduced de-activation compared with the healthy controls in this region, but the failure was less marked in the relatives.ConclusionsFailure to de-activate the medial prefrontal cortex in both euthymic bipolar patients and their unaffected siblings adds to evidence for default mode network dysfunction in the disorder, and suggests that it may act as a trait marker.

Background The efficacy and tolerability of antidepressants (ADs) to treat or avoid episodes of depression in bipolar disorder (BPD) patients as well as reasons for using them remain unresolved. Methods We analyzed patient-characteristics and outcomes of episodes of acute major depression among 290 adult, DSM-IV BPD patients (71% type-I, 52% women) at the Hospital Clinic of Barcelona; 80% were given an AD and 20% were not; 80% of both groups also received mood-stabilizers. We evaluated factors associated with AD-treatment using bivariate analyses and multiple logistic-regression modeling. Results Factors associated with AD-use by multivariate modeling ranked: [a] more years ill, [b] depressive first-lifetime episode, [c] more depressions/year, [d] melancholic index episode, and [e] less affective illness in first-degree relatives. Within 8 weeks, depression improved by ≥ 50%, less often among BPD patients given an AD (64.4%; 38.6% without switching into hypo/mania) than not (82.1%; 78.6% without switching). Conclusions Use of ADs to treat acute BP-depression was very common and associated with a more severe clinical history. Mood-switching was prevalent with AD-treatment even with mood-stabilizers present.

Rosa AR, Reinares M, Amann B, Popovic D, Franco C, Comes M, Torrent C, Bonnin CM, Sole B, Valenti M, Salamero M, Kapczinski F, Vieta E. Six-month functional outcome of a bipolar disorder cohort in the context of a specialized-care program. Bipolar Disord 2011: 13: 679–686. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. 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.

Introduction Controversy in antidepressant (AD) use in bipolar depression relies in its potential induction of mood switches and ineffectiveness. Responders to acute AD add-on treatment maintain response with continued treatment, whilst partial/non-responders fail to reach remission despite continuation treatment. We aimed to identify response predictors to acute AD addition in bipolar depression in order to optimize treatment choice in bipolar depression and avoid unnecessary AD exposure of people unlikely to respond. Methods Two hundred and twenty-one DSM-IV-TR depressed bipolar – type I and II – patients were treated with AD on an observational study. AD response was defined as an at least 50% drop from baseline of their HDRS17 score after 8 weeks of treatment. One hundred and thirty-eight patients (138, 62.4%) fulfilled response criteria (RI) whilst 83 patients (37.6%) did not (NRI). In all cases AD therapy was on top of previously prescribed stabilizers and/or atypical antipsychotics. Results RI patients were more likely to have had previous response to ADs, whereas NRI had a higher number of previous mood switches with ADs during past depressive episodes. Psychotic symptoms were more frequent amongst RI, whilst lifetime history of atypical depression was more frequent amongst NRI. NRI had more total, depressive, and hypomanic, but not manic or mixed, episodes in the past than RI. Analyzed through a logistic regression, higher previous response to ADs and lower rate of past hypomanic episodes in RI were the variables explaining intergroups (RI vs. NRI) differences. Discussion Taking into account the proper caution in the use of Ads in bipolar disorder, there is a subgroup of bipolar patients who might benefit from adjunctive Ads. Looking at specific clinical factors during the course of the illness could help physicians in deciding whether to use an antidepressant in a bipolar depressed patient already treated with mood stabilizers.

Introduction Despite antidepressants are widely used in treating bipolar depression, there is much debate about their utility and their potential dangers, involving mood switches and suicidality. Our hypothesis was that the pattern of initial antidepressant prescription, i.e., alone (AM) or in combination with stabilizers (AC) might impact the long-term outcome of patients with bipolar disorder (BP). We aimed to test this hypothesis and to identify outcome measures that could be predicted by initial AM or AC treatment in patients with BP. Methods We included 95 patients with DSM-IV BP from a pool of 138 patients following a BP program. Patients were rated for initial AM vs. AC treatment when they were first seen in primary care and subdivided into two groups accordingly. Differences in their clinical course were sought investigating course both retrospectively and prospectively (mean follow-up 10 years). Primary outcome measures comprised suicidality and switch rate. Results There were significantly more patients who switched in the AM group than in the AC group. The number of suicide attempts was higher in the AM group. Significance was retained after performing logistic regression. Limitations Sample size was small and severe BP patients might be overrepresented in this sample. Discussion Initial AM treatment of patients subsequently diagnosed as BP may entrain a course characterized by higher proneness to switch and suicidal behaviour. Accurate initial diagnosis of bipolar depression should prompt combined treatment with antimanic drugs.

Valenti M, Pacchiarotti I, Rosa AR, Bonnin CM, Popovic D, Nivoli AMA, Murru A, Grande I, Colom F, Vieta E. Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients. Bipolar Disord 2011: 13: 145–154. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. 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

Although pharmacotherapy is the mainstay of treatment for bipolar disorder, the combination of evidence-based psychological interventions and drug treatment enhances overall effectiveness, mostly by further protecting patients from relapse/recurrence. In recent years, well-designed controlled studies have added weight to evidence favoring specific psychotherapy modalities for bipolar disorders. However, critical issues that may limit the benefits of psychotherapy in day-to-day clinical practice have emerged. In this article, we critically examine the effectiveness of psychosocial approaches to bipolar illness by reviewing the literature, which has been substantially enriched during the past 5 years. Recent studies further support the fact that psychoeducation and cognitive-behavioral therapy are effective in bipolar disorder, especially the early stages. Family interventions based on a psychoeducational model are also effective. Intensive psychotherapies may be more effective than short, managed care-based ones. Group psychoeducation seems to have long-lasting effects and to be cost-effective. Future studies should focus on neurobiological markers of response to psychotherapy and tailor interventions to specific subtypes.

Background Rapid-cycling (RC) is a course modifier of bipolar disorder which often implicates a poor prognosis. However, the relationship of RC with suicidal features as a marker of impairment has been understudied. Methods Three hundred and five patients ( n = 305) were included in a naturalistic, systematic prospective study in a single site setting. Patients with rapid-cycling (RC) were defined as having four or more manic, mixed or depressive episodes in the year prior to baseline assessment. The two groups were compared regarding clinical and sociodemographic variables, paying special attention to suicidal features. Statistical methods consisted of chi-square statistic for the comparison of categorical data, and Student's t test for dimensional variables normally distributed. Also, a General Linear Model was used to study the main effect of different sociodemographic and clinical variables on suicidality. All statistics were two-tailed, and significance was set at p less than 0.05. Results Fifty-five patients (18%) were classified as RC, whilst 250 (82%) were considered as nonrapid-cycling (NRC). No significative difference was found in the prevalence of RC amongst bipolar I and II patients. RC was associated with depressive onset of bipolar disorder. The number of suicide attempts was significantly higher amongst RC (RC mean 0.82 [SD 1.85] vs. NRC 0.44[SD 0.94] t = 2.09, p = 0.37). Nonetheless, no significative differences were found between RC and NRC regarding the percentage of suicide attempters. On the other hand patients that presented RC showed a marked increase of lifetime history of suicidal ideation (Chi 2 = 4.363, p = 0.039). Finally, there were not any differences between RC patients and NRC in family history of suicide. Discussion Bipolar patients with RC are more likely to attempt suicide. Intensive treatment of this marker should be considered.

Objective:The aim of the present study was to assess the association between previous suicide attempts and functional impairment among euthymic patients with bipolar disorder (BD).Methods:Seventy-one Diagnostic Statistical Manual IV (DSM-IV) patients with BD and 61 healthy volunteers were recruited from the Bipolar Disorder Program at the Clinic Hospital of Barcelona. Patients with (n = 36, 50.7%) and without (n = 35, 49.3%) previous suicide attempts were assessed using the Structured Clinical Interview for DSM-IV-TR (SCID-P). Previous suicide attempts were carefully investigated by means of patient and caregiver interview and by a standard structured interview from the protocol of our BD Program. The Functioning Assessment Short Test (FAST) was employed to assess functional impairment.Results:Euthymic patients with previous suicide attempts showed functional impairment, particularly in occupational (F = 30.39; p = 0.001) and cognitive functioning (F = 18.43; p = 0.001). In addition, family history of psychiatric illness (χ2: 6.49; degrees of freedom (df) = 2;132; p = 0.010), family history of affective disorders (χ2 = 5.57; p = 0.017), psychotic symptoms (χ2 = 5.88; p = 0.014) and axis II comorbidity were associated with previous suicide attempts (χ2 = 5.16; p = 0.021).Conclusion:Bipolar patients with previous suicide attempts had lower overall functioning than patients who did not attempt suicide. Previous suicide attempts were particularly associated with the occupational and cognitive domains of functioning.

The high prevalence of comorbidity between bipolar disorder (BD) and other medical conditions, including autoimmune diseases, supports the hypothesis of the nature of BD as a biological illness category. Hence, an immune dysregulation process may play an important role in the development of at least certain subtypes of BD. Increasing evidence also suggests that the N-methyl-d-aspartate receptor (NMDAR) may be relevant in the pathophysiology of BD. A possible key mechanism underlying the physiopathology of certain autoimmune diseases that may present with affective symptoms might be the production of anti-NMDAR auto-antibodies (auto-Abs). The best characterized autoimmune anti-NMDAR disease is the anti-NMDAR encephalitis. It has been found that 4% of these patients present isolated, mostly affective, psychiatric manifestations during their illness. An interesting suggestion emerged from this overview is that the same mechanisms that trigger affective symptoms in patients with increased anti-NMDAR auto-Abs levels could be involved in the physiopathology of at least a subgroup of BD. Future studies are needed to characterize the relationship between anti-NMDAR auto-Abs and BD. The authors ofthis report wouldlike to acknowledge the support of the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (CP08/00140 and PI 12/00910), CIBERSAM (Exp. CB07/ 09/0004), the Spanish Ministry of Education and the Comissionat per a Universitats i Recerca del DIUE de la Generalitat de Catalunya to the Bipolar Disorders Group (2014 SGR 398).

Atypical antipsychotics have been used to treat patients with schizophrenia for many years, but now there is increasing evidence of their utility in the treatment of mood disorders. In the past few years, several atypical agents have received regulatory approval for use in mania. The evidence shows that atypical antipsychotics are effective in the treatment of manic symptoms, either alone or in combination with traditional mood stabilizers, such as lithium and divalproex. Although emerging data indicate that atypical antipsychotics will be a promising addition to those therapies that are currently available for managing patients during the maintenance phase of bipolar illness, their potential in the long-term management of bipolar disorder remains to be fully explored. Aripiprazole is a recently released antipsychotic medication that differs from other atypical antipsychotic agents by its mode of action as a dopamine D2 partial agonist. It is administered orally and has a long half-life. Randomized studies have demonstrated the efficacy of aripiprazole compared with placebo in the treatment of acute relapse of schizophrenia and schizoaffective disorder, maintenance treatment of schizophrenia, treatment of acute mania, and prevention of manic relapse in patients who responded to the drug during a manic episode. Further studies are ongoing in bipolar and unipolar depression. Aripiprazole is generally well tolerated compared with other antipsychotic medications, although commonly reported side effects include extrapyramidal symptoms and motoric activation similar to akathisia. Further studies and postmarketing data will be helpful in providing additional information regarding the comparative safety, efficacy and tolerability of aripiprazole in the treatment of affective disorders.

Desde su introduccion, la terapia electroconvulsiva (TEC) es un tratamiento usado en los trastornos afectivos. El avance en su tecnica lo ha convertido en una opcion util y actual tanto en el tratamiento de las fases agudas como en la prevencion de las recurrencias. El objetivo de esta revision es recoger la informacion disponible hasta la actualidad acerca del uso de la TEC en la mania. Sus indicaciones, su eficacia, su prediccion y su patron de respuesta son objeto de este trabajo, asi como sus complicaciones, sus efectos adversos y sus interacciones farmacologicas.

Background The Bipolar Depression Rating Scale (BDRS) arguably better captures symptoms in bipolar depression especially depressive mixed states than traditional unipolar depression rating scales. The psychometric properties of the Spanish adapted version, BDRS-S, are reported. Methods The BDRS was translated into Spanish by two independent psychiatrists fluent in English and Spanish. After its back-translation into English, the BDRS-S was administered to 69 DSMI-IV bipolar I and II patients who were recruited from two Spanish psychiatric hospitals. The Hamilton Depression Rating Scale (HDRS), the Montgomery–Asberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS) were concurrently administered. 42 patients were reviewed via video by four psychiatrists blind to the psychopathological status of those patients. In order to assess the BDRS-S intra-rater or test–retest validity, 22 subjects were assessed by the same investigator performing two evaluations within five days. Results The BDRS-S had a good internal consistency (Cronbach׳s α =0.870). We observed strong correlations between the BDRS-S and the HDRS ( r =0.874) and MADRS ( r =0.854) and also between the mixed symptom cluster score of the BDRS-S and the YMRS ( r =0.803). Exploratory factor analysis revealed a three factor solution: psychological depressive symptoms cluster, somatic depressive symptoms cluster and mixed symptoms cluster. Limitations A relatively small sample size for a 20-item scale. Conclusions The BDRS-S provides solid psychometric performance and in particular captures depressive or mixed symptoms in Spanish bipolar patients.

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. Language: en

Although the most distinctive clinical feature of bipolar disorder is the pathologically elevated mood, it does not usually constitute the prevalent mood state of bipolar illness. The majority of patients with bipolar disorder spend much more time in depressive episodes, including subsyndromal depressive symptoms, and bipolar depression accounts for the largest part of the morbidity and mortality of the illness. The pharmacological treatment of bipolar depression mostly consists of combinations of at least two drugs, including mood stabilizers (lithium and anticonvulsants), atypical antipsychotics, and antidepressants. Antidepressants are the most frequently prescribed drugs, but recommendations from evidence-based guidelines are not conclusive and do not overtly support their use. Among antidepressants, best evidence exists for fluoxetine, but in combination with olanzapine. Although some guidelines recommend the use of selective serotonin reuptake inhibitors or bupropion in combination with antimanic agents as first-choice treatment, others do not, based on the available evidence. Among anticonvulsants, the use of lamotrigine is overall recommended as a first-line choice, but acute monotherapy studies have failed. Valproate is generally mentioned as a second-line treatment. Lithium monotherapy is also suggested by most guidelines as a first-line treatment, but its efficacy in acute use is not totally clear. Amongst atypical antipsychotics, quetiapine, in monotherapy or as adjunctive treatment, is recommended by most guidelines as a first-line choice. Olanzapine monotherapy is also suggested by some guidelines and is approved in Japan. Armodafinil, pramipexole, ketamine, and lurasidone are recent proposals. Long-term treatment in bipolar disorder is strongly recommended, but guidelines do not recommend the use of antidepressants as a maintenance treatment. Lithium, lamotrigine, valproate, olanzapine, quetiapine, and aripiprazole are the recommended first-line maintenance options.