Pharmacological treatment of bipolar depression: qualitative systematic review of double-blind randomized clinical trials.

Randomized clinical trial (RCT) is the best study design for treatment-related issues, yet these studies may present a number of biases and limitations. The objective of this study is to carry out a qualitative analysis of RCT methodology in the treatment of bipolar depression (BD). A systematic review covering the last 20 years was performed on PubMed selecting double-blind RCTs for BD. The identification items of the articles, their design, methodology, outcome and grant-related issues were all analyzed. Thirty articles were included, all of which had been published in journals with an impact factor >3. While almost half studies (46.7%) used less than 50 patients as a sample, 70% did not describe or did not perform sample size calculation. The Last Observation Carried Forward (LOCF) method was used in 2/3 of the articles and 53.4% of the studies had high sample losses (>20%). Almost half the items were sponsored by the pharmaceutical industry and 33.3% were sponsored by institutions or research foundations. Articles on the pharmacological treatment of BD have several limitations which hinder the extrapolation of the data to clinical practice. Methodological errors and biases are common and statistical simplifications compromise the consistency of the findings.

Variations in seasonal solar insolation are associated with a history of suicide attempts in bipolar I disorder.

BACKGROUND: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. METHODS: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun's electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). RESULTS: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. CONCLUSION: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.

Association of pro-inflammatory cytokines with clinical features in euthymic patients with Bipolar-I-Disorder.

BACKGROUND: A chronic low-grade inflammatory state appears to be a relevant mechanism in the pathophysiology of bipolar disorder. Pro-inflammatory cytokines may influence disease course and individual symptomatology; and biological markers correlating with illness features may be of utility in clinical decision making during euthymia. METHODS: 51 euthymic outpatients with Bipolar-I-Disorder (BD-I) and 93 healthy controls (HC) were investigated. Comparisons between groups, and correlations with clinical features were performed. Serum concentrations of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and soluble interleukin-6 receptor (sIL-6R) were evaluated by ELISA under highly standardized conditions. Clinical features included duration of illness, number of previous suicide attempts and mood episodes (manic, hypomanic, depressive), scores of the Young Mania Rating Scale (YMRS), the Inventory of Depressive Symptoms (IDS-30), the Pittsburg Sleep Quality Index (PSQI), and the Global Assessment of Functioning (GAF). RESULTS: No significant difference in serum concentrations of IL-1ß, TNF-α, and sIL-6R between BD-I euthymic patients and HC could be identified. Among euthymic BD-I patients, a positive correlation of rs = 0.47 (p = 0.004) between levels of IL-1ß and IDS-30 score was identified. LIMITATIONS: The design was cross-sectional, most patients were receiving medication, only 3 cytokines were assessed, only euthymic BD-I patients were evaluated. CONCLUSIONS: The findings suggest that elevated pro-inflammatory cytokine concentrations are likely state rather than trait markers of BD-I. It also seems unlikely that cytokine concentrations are clinically informative interepisode. An inflammatory component might possibly be involved in the pathophysiology of subsyndromic depression in BD-I, and conceivably of bipolar depression per se.

Val66Met polymorphism association with serum BDNF and inflammatory biomarkers in major depression.

OBJECTIVES: Current evidence supports participation of neurotrophic and inflammatory factors in the pathogenesis of major depressive disorder (MDD). Some studies reported an association between the Val66Met polymorphism (rs6265) of brain-derived neurotrophic factor (BDNF) gene with MDD and peripheral BDNF levels. However, no previous studies have examined the association of this polymorphism with inflammation. The present study assessed the association of the Val66Met polymorphism with serum levels of BDNF and inflammatory markers among depressed outpatients. METHODS: All participants (n = 73) met DSM-IV criteria for a unipolar depressive episode. The serum levels of BDNF and inflammatory biomarkers (IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ) were compared between individuals presenting with at least one Met allele (Met-carriers) and those homozygous for the Val allele. RESULTS: In our sample (84.9% female, mean age 52.4 ± 10.3 years), 24.7% (n = 18) were Met-carriers. After Bonferroni correction, the Met allele was significantly associated with higher BDNF and lower TNF-α. These associations persisted after adjusting for potential confounders. CONCLUSIONS: The pattern of low BDNF and high inflammation in MDD may be influenced by the Val66Met polymorphism. The association of a polymorphism in the BDNF gene with inflammatory markers in addition to BDNF levels suggests an interaction between these systems.

Depression Dimensions: Integrating Clinical Signs and Symptoms from the Perspectives of Clinicians and Patients.

BACKGROUND: Several studies have recognized that depression is a multidimensional construct, although the scales that are currently available have been shown to be limited in terms of the ability to investigate the multidimensionality of depression. The objective of this study is to integrate information from instruments that measure depression from different perspectives-a self-report symptomatic scale, a clinician-rated scale, and a clinician-rated scale of depressive signs-in order to investigate the multiple dimensions underlying the depressive construct. METHODS: A sample of 399 patients from a mood disorders outpatient unit was investigated with the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale (HDRS), and the Core Assessment of Psychomotor Change (CORE). Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) were used to investigate underlying dimensions of depression, including item level analysis with factor loadings and item thresholds. RESULTS: A solution of six depression dimensions has shown good-fit to the data, with no cross-loading items, and good interpretability. Item-level analysis revealed that the multidimensional depressive construct might be organized into a continuum of severity in the following ascending order: sexual, cognitive, insomnia, appetite, non-interactiveness/motor retardation, and agitation. CONCLUSION: An integration of both signs and symptoms, as well as the perspectives of clinicians and patients, might be a good clinical and research alternative for the investigation of multidimensional issues within the depressive syndrome. As predicted by theoretical models of depression, the melancholic aspects of depression (non-interactiveness/motor retardation and agitation) lie at the severe end of the depressive continuum.

Association between core-assigned melancholia and the melancholia subscale of the HAM-D.

BACKGROUND: Clinical observation and research data suggest that major depression (MD) is a heterogeneous disorder, possibly representing a group of different clinical entities. The identification of more homogeneous subtypes of depression could enhance research and enable development of more specific treatments. A melancholic subtype of MD, defined by the presence of observable psychomotor disturbance (PMD), is proposed to be more homogeneous and associated with biological determinants. The aim of this study was to investigate the homogeneity of this melancholic subtype in terms of symptoms by searching for an association between melancholia and a unidimensional subscale of the Hamilton Depression Rating Scale (HAM-D) proposed to have biological validity (HAM-D6). METHODS: A cross-sectional assessment of 385 outpatients presenting with a unipolar major depressive episode was carried out to evaluate depressive symptoms using the HAM-D and melancholic or nonmelancholic subtype, according to the CORE measure of PMD. RESULTS: Melancholic patients exhibited more severe depressive symptoms, mainly associated with the HAM-D6. The items of this melancholia subscale represent 42.3% of the total HAM-D and were responsible for 59.4% of between-group differences. Correlation analysis showed similar results. LIMITATIONS: Most patients received previous treatment, and some were not at the nadir of the episode when assessed. This could have lowered the CORE measure sensibility. CONCLUSION: Melancholic depression, as assigned by the CORE measure, represents a more severe and homogeneous subtype of MD. This observation may allow identification of proper biomarkers and development of more specific treatments.

Translation and cross-cultural adaptation of the Temperament & Personality Questionnaire into Brazilian Portuguese.

INTRODUCTION: The Temperament & Personality Questionnaire (T&P) is a self-report instrument designed to evaluate personality styles overrepresented in patients with depression. This report briefly describes the translation and adaptation of the T&P into Brazilian Portuguese. METHODS: The procedures, which included 10 steps, followed guidelines for the adaptation of self-report instruments defined by the International Society For Pharmacoeconomics and Outcomes Research (ISPOR) Task Force for Translation and Cultural Adaptation. RESULTS: The author of the original T&P questionnaire authorized and participated in the translation conducted by the authors and independent native speakers. Evaluation of the translated questionnaire indicated that only minor adjustments were required in the Portuguese version. CONCLUSIONS: The Brazilian version of T&P, translated and adapted following a rigid standardized process, is available for use free of charge and may be especially useful in pursuing links between personality styles and depressive conditions.

Biological differences between melancholic and nonmelancholic depression subtyped by the CORE measure.

BACKGROUND: The purpose of this study was to compare melancholic patients rated by the CORE measure of observable psychomotor disturbance with nonmelancholic and control subjects across a set of biomarkers. METHODS: Depressed patients were classified as melancholic or nonmelancholic by using the CORE measure. Both groups of patients, as well as control subjects, were compared for a set of clinical and laboratory measures. Serum levels of brain-derived neurotrophic factor, of two markers of oxidative stress (protein carbonyl content [PCC] and thiobarbituric acid reactive substances [TBARS]), and of several immunity markers (interleukin [IL]-2, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor-alpha, and interferon-gamma) were analyzed. RESULTS: Thirty-three depressed patients and 54 healthy controls were studied. Depressive patients showed higher IL-4, IL-6, and PCC values than healthy controls. Thirteen (39%) of the depressed patients were assigned as melancholic by the CORE measure. They generated lower interferon-gamma (compared with nonmelancholic depressed patients) and TBARS (compared with both the nonmelancholic subset and controls) and returned higher IL-6 levels than controls. Both depressive groups generated higher PCC scores than controls, with no difference between melancholic and nonmelancholic subsets. CONCLUSION: A sign-based measure to rate melancholia was able to replicate and extend biological findings discriminating melancholic depression. Signs of psychomotor disturbance may be a useful diagnostic measure of melancholia.

Translation and cross-cultural adaptation of the Temperament & Personality Questionnaire into Brazilian portuguese / Tradução e adaptação cultural para o português brasileiro do Temperament and Personality Questionnaire

Introduction: The Temperament & Personality Questionnaire (T&P) is a self-report instrument designed to evaluate personality styles overrepresented in patients with depression. This report briefly describes the translation and adaptation of the T&P into Brazilian Portuguese. Methods: The procedures, which included 10 steps, followed guidelines for the adaptation of self-report instruments defined by the International Society For Pharmacoeconomics and Outcomes Research (ISPOR) Task Force for Translation and Cultural Adaptation. Results: The author of the original T&P questionnaire authorized and participated in the translation conducted by the authors and independent native speakers. Evaluation of the translated questionnaire indicated that only minor adjustments were required in the Portuguese version. Conclusions: The Brazilian version of T&P, translated and adapted following a rigid standardized process, is available for use free of charge and may be especially useful in pursuing links between personality styles and depressive conditions (AU)

Introdução: O Temperament & Personality Questionnaire (T&P) é um instrumento de autorrelato criado para avaliar quais estilos de personalidade têm maior representação em pacientes com depressão. Este trabalho descreve brevemente o processo de tradução e adaptação do T&P para o português brasileiro. Métodos: A tradução e a adaptação cultural se desenvolveram em 10 passos e seguiram as diretrizes para adaptação de instrumentos de autorrelato definidas por força-tarefa do ISPOR (International Society For Pharmacoeconomics and Outcomes Research). Resultados: O autor do questionário T&P original autorizou e participou da tradução feita pelos autores e por falantes nativos independentes. A avaliação do questionário traduzido mostrou que apenas pequenos ajustes foram necessários na versão em português. Conclusões: A versão brasileira do questionário T&P, traduzido e adaptado seguindo um rígido processo padronizado, está disponível gratuitamente e pode ser de grande utilidade na pesquisa sobre as relações entre estilos de personalidade e quadros depressivos (AU)