A systematic review of interventions in the early course of bipolar disorder I or II: a report of the International Society for Bipolar Disorders Taskforce on early intervention.

BACKGROUND: Given the likelihood of progressive illness in bipolar disorder (BD), it is important to understand the benefits and risks of interventions administered early in illness course. We conducted a systematic review of the effectiveness of interventions in the early course of BD I or II. METHODS: We completed a systematic search on MEDLINE, PsycINFO, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL and Google Scholar from 1/1/1979 till 14/9/2022. We included controlled trials examining intervention effects on symptomatic, course, functional and tolerability outcomes of patients in the 'early course' of BD I or II. We classified patients to be in early course if they (a) were seeking help for the first time for a manic episode, (b) had a lifetime history of up to 3 manic episodes, or (c) had up to 6 lifetime mood episodes. Evidence quality was assessed using the GRADE approach. RESULTS: From 4135 unique publications we included 25 reports representing 2212 participants in 16 randomized studies, and 17,714 participants from nine non-randomized studies. Available evidence suggested that in early illness course, lithium use was associated with lower recurrence risk compared with other mood stabilizers. Mood stabilizers were also associated with better global functioning, compared with the use of antipsychotics in the medium term. While summative findings regarding psychological therapies were limited by heterogeneity, family-focused and cognitive-behavioral interventions were associated with reduced recurrence risk or improved symptomatic outcomes. There was some evidence that the same pharmacological interventions were more efficacious in preventing recurrences when utilized in earlier rather than later illness course. CONCLUSIONS AND RECOMMENDATIONS: While there are promising initial findings, there is a need for more adequately powered trials to examine the efficacy and tolerability of interventions in youth and adults in early illness course. Specifically, there is a compelling need to compare the relative benefits of lithium with other pharmacological agents in preventing recurrences. In addition to symptomatic outcomes, there should be a greater focus on functional impact and tolerability. Effective pharmacological and psychological interventions should be offered to those in early course of BD, balancing potential risks using shared decision-making approaches.

Multi-state outcome analysis of treatments (MOAT): application of a new approach to evaluate outcomes in longitudinal studies of bipolar disorder.

Survival analyzes are usually based on a single point in time predefined event. Dissatisfied with this approach to evaluating maintenance treatment outcomes, we developed the Multi-state Outcome Analysis of Treatments (MOAT) methodology using a combined database from two FDA registration studies of lamotrigine, lithium and placebo. MOAT partitions total survival time into clinically distinct periods operationally defined by cutpoints on rating scales. For bipolar disorder (BD), the clinical states are remission, subsyndromal and syndromal mania, mixed states or depression. MOAT results can be crossed with information about tolerability and functioning to yield an outcome system integrating efficacy and tolerability. As found in the original analysis, both drugs were associated with longer time in study compared with the placebo. MOAT supplements this by finding that both drugs increased the time remitted compared with placebo. However, a substantial amount of time in all three treatments was spent in subsyndromal depression. Time with manic symptoms was reduced with lithium, but not lamotrigine. Patients on placebo neither benefitted nor had adverse effects from the assignment but experienced more syndromal levels of symptoms and were terminated from the study sooner than either drug treated group. Lithium was associated with both benefit in time manic and worse tolerability compared with placebo. In summary, lamotrigine was associated with limited therapeutic benefit but not harm; lithium with both benefit and harm; and placebo with neither. MOAT describes not only quantity but also quality of time spent in longitudinal studies, providing a more clinically informative picture than Kaplan-Meier survival analysis.

Comparison of psychotic bipolar disorder, schizoaffective disorder, and schizophrenia: an international, multisite study.

OBJECTIVE: Nosological distinctions among schizoaffective disorder (SA), bipolar I disorder with psychotic features (BDp), and schizophrenia (SZ) remain unresolved. METHOD: We compared 2269 subjects with psychotic features in DSM-IV-TR diagnoses (1435 BDp, 463 SZ, 371 SA) from 8 collaborating international sites, by 12 sociodemographic and clinical measures, all between diagnostic pairs. RESULTS: In bivariate comparisons, SA was consistently intermediate between BDp and SZ for 11/12 features (except onset stressors), and SZ vs. BDp differed in all 12 factors. SA differed from both BDp and SZ in 9/12 factors: SA and BDp were similar in education and suicidal ideation or acts; SA and SZ were similar in education, onset stressors, and substance abuse. Meta-analytic comparisons of diagnostic pairs for 10 categorical factors indicated similar differences of SA from both SZ and BDp. Multivariate modeling indicated significantly independent differences between BDp and SZ (8 factors), SA vs. SZ (5), and BDp vs. SA (3). Measurement variance was similar for all diagnoses. CONCLUSION: SA was consistently intermediate between BDp and SZ. The three diagnostic groups ranked: BDp > SA > SZ related to lesser morbidity or disability. The findings are not consistent with a dyadic Kraepelinian categorization, although the considerable overlap among the three DSM-IV diagnostic groups indicates uncertain boundaries if they represent distinct disorders.

Obesity, but not metabolic syndrome, negatively affects outcome in bipolar disorder.

OBJECTIVE: Examine the effects of obesity and metabolic syndrome on outcome in bipolar disorder. METHOD: The Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6-month trial comparing lithium- and quetiapine-based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models. RESULTS: At baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome. CONCLUSION: Obesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium- or quetiapine-based treatment.

Staging systems in bipolar disorder: an International Society for Bipolar Disorders Task Force Report.

OBJECTIVE: We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for bipolar disorders are outlined. METHOD: We reviewed the literature pertaining to bipolar disorders, focusing on the first episode onwards. We systematically searched data on staging models for bipolar disorders and allied studies that could inform the concept of staging. RESULTS: We report on several dimensions that are relevant to staging concepts in bipolar disorder. We consider whether staging offers a refinement to current diagnoses by reviewing clinical studies of treatment and functioning and the potential utility of neurocognitive, neuroimaging and peripheral biomarkers. CONCLUSION: Most studies to date indicate that globally defined late-stage patients have a worse overall prognosis and poorer response to standard treatment, consistent with patterns for end-stage medical disorders. We believe it is possible at this juncture to speak broadly of 'early'- and 'late'-stage bipolar disorder. Next steps require further collaborative efforts to consider the details of preillness onset and intermediary stages, and how many additional stages are optimal.

Antecedents of manic versus other first psychotic episodes in 263 bipolar I disorder patients.

OBJECTIVE: As initial episode type can predict later morbidity in bipolar disorder, we tested the hypothesis that clinical antecedents might predict initial episode types. METHOD: We studied 263 first-episode, adult, DSM-IV-TR type I bipolar disorder (BD-I) subjects within the McLean-Harvard-International First-Episode Project. Based on blinded assessments of antecedents from SCID examinations and clinical records, we compared first lifetime manic vs. other (mixed, depressive, or non-affective) major psychotic episodes. RESULTS: We identified 32 antecedents arising at early, intermediate or later times, starting 12.3±10.7 years prior to first lifetime major psychotic episodes. Based on multivariate modeling, antecedents associated significantly and independently with other (n=113) more than manic (n=150) first lifetime major psychotic episodes ranked by odds ratio: more early attentional disturbances, more late depression, more early perplexity, more detoxification, more early unstable mixed affects, more antidepressants, more early dysphoria, more intermediate depression, more early impulsivity, more late anhedonia, longer early-to-intermediate intervals, more intermediate substance abuse, more family history of major depression, and younger at earliest antecedents. Antecedents selectively preceding manic more than other first psychotic episodes included more late behavioral problems and more risk of familial BD-I. CONCLUSION: Clinical antecedents in adult, BD-I patients, beginning a decade before first major episodes and progressing through sequential stages were dissimilar in manic vs. other first psychotic episodes.

DSM-5 mixed specifier for manic episodes: evaluating the effect of depressive features on severity and treatment outcome using asenapine clinical trial data.

BACKGROUND: To describe the frequency of mixed specifier as proposed in DSM-5 in bipolar I patients with manic episodes, and to evaluate the effect of mixed specifier on symptom severity and treatment outcome. METHODS: This post-hoc analysis used proxies for DSM-5 mixed features specifier by using MADRS or PANSS items. RESULTS: Of the 960 patients analysed, 34%, 18% and 4.3% of patients, respectively, had ≥3 depressive features with mild (score ≥1 for MADRS items and ≥2 for PANSS item), moderate (score ≥2 MADRS, ≥3 PANSS) and severe (score ≥3 MADRS, ≥4 PANSS) symptoms. In patients with ≥3 depressive features and independent of treatment: MADRS remission (score ≤12) rate decreased with increasing severity (61-43%) and YMRS remission (score ≤12) was similar for mild and moderate patients (36-37%), but higher for severe (54%). In asenapine-treated patients, the MADRS remission rate was stable regardless of baseline depressive symptom severity (range 64-67%), whereas remission decreased with increasing severity with olanzapine (63-38%) and placebo (49-25%). Reduction in YMRS was significantly greater for asenapine compared with placebo at day 2 across the 3 severity cut-offs and continued to decrease throughout the treatment period. The difference between olanzapine and placebo was statistically significant in mild and moderate patients. LIMITATIONS: Results are from post-hoc analyses. CONCLUSIONS: These analyses support the validity of proposed DSM-5 criteria. They confirm that depressive features are frequent in bipolar patients with manic episodes. With increasing baseline severity of depressive features, treatment outcome was poorer with olanzapine and placebo, but remained stable with asenapine.

Efficacy of olanzapine monotherapy in acute bipolar depression: a pooled analysis of controlled studies.

BACKGROUND: The efficacy and safety of olanzapine monotherapy in bipolar depression has been evaluated in 2 placebo-controlled studies. METHODS: We pooled data from 2 previously published studies examining olanzapine monotherapy in patients with bipolar I depression. Changes from baseline to 6 weeks in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, MADRS-6 (included items: apparent sadness, reported sadness, inner tension, lassitude, inability to feel, and pessimistic thoughts) score, and individual MADRS item scores were assessed with an analysis of variance (ANOVA) model. Influence of patient baseline characteristics (age, gender, MADRS total score, age at onset of bipolar disorder, psychotic features, melancholic feature, mixed features [≥2 on ≥3 Young Mania Rating Scale items], and racial origin) on the efficacy of olanzapine monotherapy was examined with an ANOVA model for each factor and stepwise multiple regression analysis. RESULTS: Included were a total of 690 olanzapine-group and 524 placebo-group patients. MADRS total, MADRS-6, and all individual MADRS item scores (except concentration difficulties and suicidal thoughts) showed significantly (P≤0.05) greater decreases from baseline to 6 weeks in olanzapine-treated patients than those on placebo. The only baseline characteristic associated with response to olanzapine was melancholic feature. LIMITATIONS: The study was limited by omission of patients with bipolar II disorder, post hoc analysis of data from only two clinical trials, and exclusion of suicidal patients. CONCLUSIONS: Olanzapine monotherapy improved core symptoms of depression in patients with bipolar I depression. Additionally, we identified melancholic feature as a baseline factor associated with improved treatment response to olanzapine.

Comparison of objective and subjective assessments of sleep time in subjects with bipolar disorder.

INTRODUCTION: Sleep disturbance is a core feature of bipolar disorder. To date there are a limited number of studies that compare subjective and objective measures of sleep in populations of subjects with mood disorders. This study evaluated the relationship between subjective and objective measurements of total sleep time (TST) in a bipolar type I disorder (BD I) population. METHODS: Thirty-nine subjects diagnosed with BD I participated in the study. Mood symptoms were assessed via YMRS and IDS-30-C. Subjects wore an actigraph device and maintained a sleep diary for seven consecutive days. Differences between TST as estimated via sleep diaries and actigraphy were calculated. RESULTS: Objective and subjective measures of TST were significantly correlated (r=0.5151, p=0.0008). Secondary analysis revealed that the severity of depressive symptoms did correlate to this discrepancy (t=2.65, p=0.01). LIMITATIONS: The impact that medications have on the accuracy of TST reported was not investigated. Also, sleep diaries may have acted to prompt subjects to pay closer attention to their sleep habits and therefore more accurately report TST than in the average clinical setting. CONCLUSION: The results of the current study demonstrate a significant correlation between the estimation of TST as measured objectively via actigraphy and subjectively via sleep diaries in BD patients. Mood symptomotology might impact the accuracy of TST reported. Further study is warranted.

Episode cycles with increasing recurrences in first-episode bipolar-I disorder patients.

BACKGROUND: Preliminary review of a century of studies of the course of manic-depressive syndromes produced 40 reports, of which approximately one-third report evidence of shortening wellness intervals or cycle-lengths with more recurrences, and two-thirds did not. METHODS: We evaluated inter-episode intervals (cycle-length) in 128 clinically-treated, DSM-IV bipolar-I disorder patients followed prospectively and systematically over 5.7 years, with 6.5 episodes/person. RESULTS: As expected, cycle-length varied inversely with total cycle-count/person; however, multivariate linear regression found only longer initial hospitalization and fewer total cycles to be associated with cycle-length, whereas cycle-number (1, 2, 3, etc.), sex, intake-age, and first-episode polarity were not. Regression of within-subject cycle-length versus cycle-number yielded individual slope-functions with pseudo-random distribution (28% fell within ±1 month/cycle of the null [zero-slope]). Mean duration of early and late euthymic intervals (cycles 2 vs. 5) in patients with matched recurrence-counts was nearly identical. CONCLUSIONS: The course of bipolar-I disorder from onset was largely random or chaotic over nearly 6 years from onset. Only a minority of patients showed either cycle-acceleration or slowing, without changes in wellness intervals. The findings may be influenced by treatment-effects, but seem to indicate that most current bipolar-I disorder patients are unlikely to show progressive shortening of recurrence-cycles.

Predominant recurrence polarity among 928 adult international bipolar I disorder patients.

OBJECTIVE: To test the hypothesis that patients with bipolar disorder (BPD) differ demographically and clinically within subgroups based on the predominant-polarity of major recurrences. METHOD: We tested factors for association with predominantly (≥2 : 1) depressive vs. mania-like episodes with 928 DSM-IV type-I BPD subjects from five international sites. RESULTS: Factors preliminarily associated with predominant-depression included: electroconvulsive treatment, longer latency-to-BPD diagnosis, first episode depressive or mixed, more suicide attempts, more Axis-II comorbidity, ever having mixed-states, ever married, and female sex. Predominant-mania was associated with: initial manic or psychotic episodes, more drug abuse, more education, and more family psychiatric history. Of the 47.3% of subjects without polarity-predominance, risks for all factors considered were intermediate. Expanding the definition of polarity-predominance to ≥51% added little, but shifting mixed-states to 'predominant-depression' increased risk of suicidal acts from 2.4- to 4.5-fold excess over predominant-mania-hypomania, and suicidal risk was associated continuously with increasing proportions of depressive or mixed episodes. CONCLUSION: Subtyping by predominant-polarity yielded predictive associations, including the polarity of first episodes and risk of suicide attempts. Such subtyping may contribute to improve planning of clinical care and to biological studies of BPD.

Stigma and functioning in patients with bipolar disorder.

OBJECTIVE: The aim of this study was to investigate the impact of self-rated stigma and functioning in patients with bipolar disorder in Latin-America. METHODS: Two-hundred and forty-one participants with bipolar disorder were recruited from three Latin American countries (Argentina, Brazil, and Colombia). Functional impairment was assessed with the Functioning Assessment Short Test (FAST) and experiences with and impact of perceived stigma was evaluated using the Inventory of Stigmatizing Experiences (ISE). RESULTS: Higher scores of self-perceived stigma were correlated with lower scores of functioning. After multiple regression analysis, being on disability benefit, current mood symptoms and functioning were associated with self-perceived stigma. CONCLUSIONS: This is the first study to demonstrate an association between stigma and poor functioning in bipolar disorder. Possible implications of such findings for practitioners are discussed. LIMITATIONS: The main limitation of this study is that the Inventory of Stigmatizing Experiences has not yet been validated in a population of bipolar patients in our countries. The sample size and heterogeneous clinical subjects from different countries and cultures limit the generalization of the present findings.

Functioning and symptomatic outcomes in patients with bipolar I disorder in syndromal remission: a 1-year, prospective, observational cohort study.

BACKGROUND: Recent studies demonstrate that many Bipolar Disorder (BD) patients experience mild symptoms and/or suffer significant functional impairment during periods of syndromal remission, suggesting greater relapse risk and need for more intensive therapeutic strategies. However, most studies have cross-sectional designs and other methodological limitations. This study aimed to prospectively evaluate whether the presence of subsyndromal symptoms and level of functionality have long-term consequences in BD patients in syndromal remission. METHODS: A 1-year, prospective, observational cohort study of BD patients in syndromal remission assessed participants at study entry and 3, 6 and 12months after baseline on a range of clinical, social and functional outcomes. RESULTS: A total of 473 BD patients were screened at 51 study sites across Spain. Finally, 398 patients with bipolar I disorder in syndromal remission were included. After the 12-month, follow-up period, 87.6% of patients remained in syndromal remission, 79.9% of patients were free of subsyndromal symptoms, but only 53.5% had normal levels of functionality. Patients without subsyndromal symptoms and with normal levels of functionality at baseline had longer time to relapse, lower relapse risk, fewer changes on medication and hospitalizations, better employment, less medical/psychiatric leaves and better functional household membership. LIMITATIONS: Limitations of this study are related with its naturalistic design. CONCLUSIONS: In a prospectively assessed BD cohort with all patients in syndromal remission at baseline, syndromal remission was not always accompanied by normal functioning and/or the presence subsyndromal symptoms. Interventions, including medication and psychosocial approaches, should go beyond syndromal remission and target subsyndromal symptoms and functional recovery.

Predicting the course and outcome of bipolar disorder: a review.

Despite of advances in pharmacological and non-pharmacological treatments, bipolar disorder often entails multiple relapses and impaired psychological functioning. The extent to which modern treatments have influenced the natural course of a mental disorder is uncertain. Prediction of the course and outcome of bipolar disorders continues to be challenging, despite the multiple research efforts worldwide. Due to a lack of laboratory diagnostic tests and biomarkers, psychiatric interview and examination provide the basis for outcome prediction. While considered to have more favorable prognosis than schizophrenia, it is not uncommon for bipolar disorder to include persisting alterations of psychosocial functioning. Although long-term symptomatic remission does not guarantee functional recovery, it may have a favorable impact on long-term overall prognosis. The high degree of treatment resistance in patients with bipolar disorder highlights the need to develop better identification of outcome predictors, prognosis and treatment intervention, designed to reverse or prevent this illness burden. This review summarizes the main factors involved in predicting the course and outcome of bipolar disorder.

In search of optimal lithium levels and olanzapine doses in the long-term treatment of bipolar I disorder. A post-hoc analysis of the maintenance study by Tohen et al. 2005.

PURPOSE: The aim of this study was to investigate whether lower lithium levels (LoLi) or olanzapine doses (LoOL) are risk factors for future mood episodes in patients with bipolar I disorder. METHODS: A post-hoc analysis of the olanzapine-lithium-maintenance study [31] was performed using proportional hazards Cox regression models and marginal structural models (MSMs), adjusting for non-random assignments of dose during treatment. RESULTS: The LoLi group (<0.6 mmol/L) had a significantly increased risk of manic/mixed (hazard ratio [HR]=1.96, p=0.042), but not depressive (HR=2.11, p=0.272) episodes, compared to the combined medium (0.6-0.79 mmol/L) and high lithium level (≥0.8 mmol/L) groups. There was no significant difference in risk between the two higher lithium level groups (0.6-0.79 mmol/L; ≥0.8 mmol/L) for new manic/mixed (HR=0.96, p=0.893) or depressive (HR=0.95, p=0.922) episodes. The LoOL group (<10mg/day) showed a significantly increased risk of depressive (HR=2.24, p=0.025) episodes compared to the higher olanzapine (HiOL) dose group (HiOL: 10-20 mg/day), while there was no statistically significant difference in risk for manic/mixed episodes between the two groups (HR=0.94, p=0.895). CONCLUSION: Lithium levels≥0.6 mmol/L and olanzapine doses≥10mg/day may be necessary for optimal protection against manic/mixed or depressive episodes, respectively in patients with bipolar I disorder.

Onset-age of bipolar disorders at six international sites.

BACKGROUND: Onset-age is a stable characteristic of bipolar disorder (BPD) patients of clinical and probable psychobiological importance, but large pooled clinical samples from multiple sites employing modern diagnostic criteria to quantify onset-age remain rare. METHODS: We pooled diagnostic, demographic, and clinical data from 1566 BPD patients from six international sites (5 European, 1 US) to compare onset-ages in subgroups. RESULTS: Median+/-IQR onset in 1090 BP-I patients was 5.8 years younger than 476 BP-II cases (24.3+/-18.3 vs. 30.1+/-13.8 years; p<0.0001). Onset-age ranked: [a] BP-I men (23.0+/-12.8); [b] BP-I women (26.0+/-14.2); [c] BP-II men (29.7+/-19.1); and [d] BP-II women (30.1+/-17.5 years. Juvenile-onset (

Translation of randomised controlled trial findings into clinical practice: comparison of olanzapine and valproate in the EMBLEM study.

OBJECTIVES: The aim of this study was to compare the outcomes of olanzapine- and valproate-treated patients in an observational study of acute mania with the results of a randomised controlled trial (RCT) assessing the same treatments. METHODS: EMBLEM (European Mania in Bipolar Evaluation of Medication) was a 2-year, prospective, observational study of health outcomes associated with the treatment of mania. Severity of mania and depression were assessed at baseline and 6 weeks using the YMRS and the 5-item version of the HAMD, respectively. RESULTS: 621 patients were analysed (n=107 valproate, n=514 olanzapine). Both groups improved from baseline to 6 weeks in mean YMRS and HAMD-5 total scores, with greater mean improvements in the olanzapine compared with the valproate group. Olanzapine was associated with more weight gain and less gastrointestinal difficulties than valproate. DISCUSSION: The EMBLEM results support those of the RCT, which suggest that olanzapine monotherapy seems to be more effective than valproate monotherapy in the treatment of acute mania.

Predominant previous polarity as an outcome predictor in a controlled treatment trial for depression in bipolar I disorder patients.

INTRODUCTION: We hypothesized that predominant episode-polarity would predict response to treatment of depressive episodes in bipolar I disorder (BPD) patients with treatment in a placebo-controlled trial, in the sense that patients with manic predominant polarity (PM) would respond better than patients with depressive predominant polarity (PD). METHOD: This post-hoc analysis of a published trial examined outcomes of 788 depressed (MADRS score >or=20) adult BPD patients with baseline and follow-up assessments, according to their predominant polarity based on previous recurrences of mania-hypomania vs. depression in >or=2:1 excess. Patients (total=833) were randomized to an 8-week trial of treatment with placebo (n=377), olanzapine (5-20 mg/day; n=370), or olanzapine/fluoxetine combination (OFC; 6/25, 6/50, or 12/50 mg/day; n=86). Treatment response was based on improvement in Clinical Global Impression of depression severity (CGI-D). We analyzed for associations of this outcome with predominant lifetime illness-polarity, based on retrospective SCID-based assessment of individual clinical history. RESULTS: Predominant polarity could be demonstrated in 367/788 patients (46.6%), showing a 2.7-fold excess of predominant depressive over manic past-illnesses (34.1%/12.4%), with similar distribution by sex and among treatment-arms. Moreover, based on least-square change in CGI-D severity (based on a mixed model of repeated measures [MMRM]), predominant polarity has different impact in the treatment outcome for each gender. Men with predominantly manic polarity had statistically significant better improvement than men with predominantly depressive polarity. Such difference was not observed in the female population. Other outcome measures yielded similar conclusions. CONCLUSIONS: Predominant previous depressive>manic episodes selectively yielded poorer responses of BPD to treatment for acute BP depression, particularly in men.

Patterns of drug treatment for manic episode in the clinical practice. Outcomes of the Spanish sample in the EMBLEM Study.

INTRODUCTION: Although treatment for mania has been studied extensively in randomized clinical trials, there are few data that address how these patients are truly managed in clinical, functional, and economic terms in the psychiatric practice in Spain. OBJECTIVE: To determine prescribing patterns in Spain on the basis of the Spanish sample of bipolar patients in manic or mixed phase included as part of the pan-European EMBLEM Study. METHOD: The EMBLEM Study recruited 3,681 patients, 312 of whom (8.47%) were included in Spain. Patients had to be adults with a diagnosis of bipolar disorder who were initiating treatment for a manic phase. They underwent evaluation using the Spanish versions of scales that measure severity of mania (the Young Mania Rating Scale, CGI-BP and the Hamilton Scale) and functional level (LCM, SLICE of LIFE). Information was collected regarding drug and treatment adherence variables. RESULTS: Prior to being admitted into the study, 42% of the patients were receiving polytherapy, 35% were on monotherapy, and 23% were not taking any medication whatsoever. Forty percent of the patients presented partial or total non-compliance with the treatment prescribed. During the first stage of the study, in the case of single-drug treatment, acute management for mania consisted of mean daily doses of 25 mg of olanzapine, 6.6 mg of risperidone, 9.5 mg of haloperidol, 165 mg of lamotrigine, 938.5 mg of valproate, and 909 mg of lithium, whereas when combined therapy was used, the following doses were used: olanzapine, 22.1 mg; risperidone, 7.3 mg; haloperidol, 12.3 mg; lamotrigine, 1,75.1 mg; valproate, 1,038.4 mg, and lithium, 1012.6 mg. Of those patients who were on monotherapy at the beginning of the study 51% were treated with a single drug, whereas 48% were receiving polytherapy. Among the participants who were receiving combined treatment when they began the study, almost all of them, 94%, were prescribed combined treatment. In the case of the hospitalized patients who made up 88% of the sample, the vast majority, 92%, had improved by the time the study was completed. Mean time to release from hospital was 24 days. DISCUSSION: In Spain, treatment for mania is essentially based on combined treatments, hospitalization, and antimania drugs that are prescribed at somewhat higher doses than those recommended in the corresponding prescribing information documents, which indicates that the clinical reality of this entity is far more complex than clinical trials conducted in experimental conditions suggest.

Functional impairment in patients with mania: baseline results of the EMBLEM study.

OBJECTIVES: The European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) is a large-scale prospective observational multicentre study to evaluate the longitudinal course of bipolar disorder and its associations with pharmacological treatment following an acute manic or mixed episode. We present an overview of the study design and patient characteristics at baseline while focusing on factors influencing work performance in the year prior to enrollment. METHODS: A total of 530 investigators across 14 European countries enrolled 3,681 patients with acute mania between December 2002 and June 2004. Longitudinal observations are ongoing until July 2006. Socio-demographic variables, psychiatric history, clinical status and information on pharmacological treatment for bipolar disorder were recorded. Items from the SLICE of LIFE were applied, including a measure of work impairment during the previous year. The distribution of the baseline characteristics was analysed with descriptive statistics. Eighteen variables were investigated as hypothesized risk factors for work impairment applying logistic regression models. RESULTS: In the previous year, 28 and 68% of patients were classified as having 'low' and 'high' work impairment, respectively. Clinical Global Impression - Bipolar Disorder (CGI-BP) overall, CGI-BP depression at baseline, rapid cycling during the previous 12 months, age between 35 and 64 years, substance abuse other than alcohol and cannabis and living without a partner or as dependent household member were significantly associated with work impairment during the previous year. CONCLUSIONS: EMBLEM is to our knowledge the largest prospective observational study assessing patients during and after an acute episode of mania. Work impairment is significant in the year prior to an acute episode of mania.