Association of BDNF risk variant and dorsolateral cortical thickness with long-term treatment response to valproate in type I bipolar disorder: An exploratory study.

Valproate is among the most prescribed drugs for bipolar disorder; however, 87% of patients do not report full long-term treatment response (LTTR) to this medication. One of valproate's suggested mechanisms of action involves the brain-derived neurotrophic factor (BDNF), expressed in the brain areas regulating emotions, such as the prefrontal cortex. Nonetheless, data about the role of BDNF in LTTR and its implications in the structure of the dorsolateral prefrontal cortex (dlPFC) is scarce. We explore the association of BDNF variants and dorsolateral cortical thickness (CT) with LTTR to valproate in bipolar disorder type I (BDI). Twenty-eight BDI patients were genotyped for BDNF polymorphisms rs1519480, rs6265, and rs7124442, and T1-weighted 3D brain scans were acquired. LTTR to valproate was evaluated with Alda's scale. A logistic regression analysis was conducted to evaluate LTTR according to BDNF genotypes and CT. We evaluated CT differences by genotypes with analysis of covariance. LTTR was associated with BDNF rs1519480 and right dlPFC thickness. Insufficient responders with the CC genotype had thicker right dlPFC than TC and TT genotypes. Full responders reported thicker right dlPFC in TC and TT genotypes. In conclusion, different patterns of CT related to BDNF genotypes were identified, suggesting a potential biomarker of LTTR to valproate in our population.

Differences in body mass index according to fat mass- and obesity-associated (FTO) genotype in Mexican patients with bipolar disorder.

OBJECTIVES: The prevalence of obesity has dramatically increased in many countries and it is particularly high in patients with bipolar disorder (BD). A region in the first intron of the fat mass- and obesity-associated (FTO) gene, encompassing markers rs9939973, rs8050136, and rs9939609, has been consistently associated with obesity and body mass index (BMI) in different populations. We sought to determine whether FTO is associated with BMI and/or obesity in patients with BD. METHODS: The sample included 129 Mexican Mestizo patients with bipolar I or bipolar II disorder. After obtaining informed consent, participants were evaluated with the Structured Clinical Interview for DSM-IV Axis I Disorders and weight, height, and body measurements were recorded. DNA was extracted from a 5-mL blood sample and real-time polymerase chain reaction was performed. The results were analyzed with Haploview v4.2 and SPSS v21. RESULTS: Differences in mean BMI were explained by rs8050136 and rs9939609 genotypes, especially by comparing non-carriers and carriers of two copies of the risk allele (Tukey's p ≤ 0.019), with a mean difference in BMI as high as 7.81 kg/m(2) . Differences in BMI were also explained by the interaction of the genotype (rs8050136 and/or rs9939609), the use of second-generation antipsychotics, and the use of mood stabilizers (p ≤ 0.41). Obesity was also associated with these two markers when patients with and without obesity were compared. CONCLUSIONS: In patients with BD, differences in BMI may be affected by the presence of FTO risk alleles, especially in homozygous individuals for these variants. Besides evaluating the possible metabolic effects of certain antipsychotics or mood stabilizers, it is important to evaluate the role of other factors such as FTO risk alleles.

Genetic analysis of the ZNF804A gene in Mexican patients with schizophrenia, schizoaffective disorder and bipolar disorder.

BACKGROUND: Evidence suggests that schizophrenia (SCZ), schizoaffective disorder (SAD) and bipolar disorder (BPD) share genetic risk variants. ZNF804A gene has been associated with these disorders in different populations. GWAS and candidate gene studies have reported association between the rs1344706 A allele with SCZ, SAD and BPD in European and Asian populations. In Mexican patients, no studies have specifically analyzed ZNF804A gene variants with these disorders. The aim of the study was to analyze the rs1344706 and identify common and rare variants in a targeted region of the ZNF804A gene in Mexican patients with SCZ, BPD and SAD compared with a control group. METHODS: We genotyped the rs1344706 in 228 Mexican patients diagnosed with SCZ, SAD and BPD, and 295 controls. Also, an additional sample of 167 patients with these disorders and 170 controls was analyzed to identify rare and common variants using the Sanger-sequence analysis of a targeted region of ZNF804A gene. RESULTS: Association analysis of rs1344706 observed a higher frequency of A allele in the patients compared with the control group; however, did not show statistical differences after Bonferronís correction (χ2 = 5.3, p = 0.0208). In the sequence analysis, we did not identify rare variants; however, we identified three common variants: rs3046266, rs1366842 and rs12477430. A comparison of the three identified variants between patients and controls did not show statistical differences (p > 0.0125). Finally, haplotype analysis did not show statistical differences between SCZ, SAD and BPD and controls. CONCLUSIONS: Our findings did not support the evidence suggesting that ZNF804A gene participates in the etiology of SCZ, SAD and BPD. Future studies are needed in a larger sample size to identify the effect of this gene in psychiatric disorders.

Ten-year course of treated bipolar I disorder: The role of polarity at onset.

INTRODUCTION: Early-stage predictors of illness course are needed in bipolar disorder (BD). Differences among patients with a first depressive versus maniac/hypomanic episode have been stated, although in most studies, memory bias and time from onset to start of specialized treatment might interfere. The aim was to compare the first 10 years of illness course according to polarity at onset. METHODS: 49 type I BD patients admitted for treatment for a first-time affective episode and a following 10-year attendance to the institution were included. A retrospective year by year comparison according to polarity at onset (depressive (DPO) or maniac (MPO)) was performed. Cramer's V and Cohen d were computed to determine effect size. RESULTS: 59.2% (n = 29) started with MPO. Both groups were similar in demographic and social outcome characteristics, clinical features, and treatment variables. Patients with DPO reported more depressive episodes than MPO patients (U = 149.0 p < .001, Cohen's d = 0.87); both groups had a similar number of manic episodes. Only during the first year of follow-up, suicide attempts (SA) were more frequent in patients with DPO while the presence of a psychotic episode and psychiatric hospitalizations were more frequent in the MPO group. CONCLUSION: According to these findings, it can be concluded that illness onset is only indicative of depressive predominant polarity but is not related to other poor prognostic variables after the first year of illness onset, in treated BD. SA in the first year of an affective disorder could represent a marker of BD.

Prefrontal cortical thickness and clinical characteristics of long-term treatment response to valproate in bipolar disorder.

Valproate compositions are frequently used to treat bipolar disorder (BD); however, 87% of patients do not report full response in the long-term. There is scarce information about the clinical features and brain structural characteristics of long-term treatment response (LTTR) to this medication. In this study, we aim to evaluate the clinical characteristics and prefrontal cortical thickness (CT) of LTTR to valproate in BD. We evaluated 30 BD outpatients on valproate treatment, and 20 controls with a 3T T1-weighted 3D brain scan and Alda's scale for LTTR. An analysis of covariance was used to evaluate CT measures and a logistic regression was conducted to predict the full response (FR) using clinical features and CT measures. Patients with an insufficient response (IR) reported thinner right frontal eye fields, anterior and dorsolateral prefrontal cortexes compared with controls. FR patients presented thicker right dorsolateral prefrontal cortex than IR and no differences with controls. Patients with mixed features presented increased odds of achieving FR, while CT measures reported non-significant results. This is the first study to report mixed features as a clinical predictor of valproate LTTR. Our findings also suggest better preservation of the right prefrontal cortex of subjects with FR to valproate.

Neuropsychiatric Genetics of Psychosis in the Mexican Population: A Genome-Wide Association Study Protocol for Schizophrenia, Schizoaffective, and Bipolar Disorder Patients and Controls.

No large-scale genome-wide association studies (GWASs) of psychosis have been conducted in Mexico or Latin America to date. Schizophrenia and bipolar disorder in particular have been found to be highly heritable and genetically influenced. However, understanding of the biological basis of psychosis in Latin American populations is limited as previous genomic studies have almost exclusively relied on participants of Northern European ancestry. With the goal of expanding knowledge on the genomic basis of psychotic disorders within the Mexican population, the National Institute of Psychiatry Ramón de la Fuente Muñiz (INPRFM), the Harvard T.H. Chan School of Public Health, and the Broad Institute's Stanley Center for Psychiatric Research launched the Neuropsychiatric Genetics Research of Psychosis in Mexican Populations (NeuroMex) project to collect and analyze case-control psychosis samples from 5 states across Mexico. This article describes the planned sample collection and GWAS protocol for the NeuroMex study. The 4-year study will span from April 2018 to 2022 and aims to recruit 9,208 participants: 4,604 cases and 4,604 controls. Study sites across Mexico were selected to ensure collected samples capture the genomic diversity within the Mexican population. Blood samples and phenotypic data will be collected during the participant interview process and will contribute to the development of a local biobank in Mexico. DNA extraction will be done locally and genetic analysis will take place at the Broad Institute in Cambridge, MA. We will collect extensive phenotypic information using several clinical scales. All study materials including phenotypic instruments utilized are openly available in Spanish and English. The described study represents a long-term collaboration of a number of institutions from across Mexico and the Boston area, including clinical psychiatrists, clinical researchers, computational biologists, and managers at the 3 collaborating institutions. The development of relevant data management, quality assurance, and analysis plans are the primary considerations in this protocol article. Extensive management and analysis processes were developed for both the phenotypic and genetic data collected. Capacity building, partnerships, and training between and among the collaborating institutions are intrinsic components to this study and its long-term success.

Work motivation in patients with bipolar disorder: Associated factors.

BACKGROUND: Occupational functioning is severely impaired in patients with bipolar disorder (BD). Work motivation (WM), defined as the psychological processes that determine the direction, intensity, and persistence of action within the work, is an essential component of work-related functioning. AIM: To assess whether WM is affected in patients with BD and which clinical and sociodemographic factors are related to low WM. METHODS: In all, 95 euthymic BD patients were invited to answer the Motivation for Work Questionnaire and the Rating Scale on Subjective Cognitive Deficits in Bipolar Disorder (COBRA). RESULTS: A total of 49.5% ( n = 47) of the patients were classified in the Low Motivated (LM) group. Unemployment and the report of more subjective cognitive complaints were predictors of poor WM in this sample ((OR) = 3.01 and 7.10, respectively). CONCLUSIONS: Perceived cognitive deficits related to the disorder and current unemployment negatively impact WM in patients with BD. In addition to symptomatic recovery, the need of the inclusion of personal and occupational areas in the comprehensive treatment of patients with BD is necessary.

Psychometric properties and cross-cultural comparison of the cognitive complaints in bipolar disorder rating assessment (COBRA) in Mexican patients with bipolar disorder.

Bipolar Disorder (BD) is a serious and frequent mental health condition that is sometimes fatal. Several longitudinal studies have found an important correlation between cognition and functionality in BD. Despite the known importance of cognitive symptoms in BD, evaluation of cognitive deficits is not routinely done in clinical settings, as assessment is time-consuming and requires neuropsychological testing. The aim was to evaluate the psychometric properties of the subjective cognitive deficits in bipolar disorder (COBRA) rating scale in a Mexican sample of patients with BD and perform a cross-cultural comparison with the results obtained in other cultures. Ninety-two Healthy Subjects and 80 euthymic patients with BD were asked to complete the COBRA rating scale. The psychometric properties found in Mexican population show a good internal consistency and good discriminant validity with control subjects. Adequate congruence coefficients were obtained between the COBRA analyses in Mexican population and Spanish population and acceptable when compared to Japanese population. The COBRA scale is a brief and valid measure of cognitive complaints in BD for use in Mexican population.

Consideraciones clínicas y endocrinológicas en mujeres con trastorno bipolar / Clinical and endocrine considerations in bipolar women

El trastorno bipolar es una de las enfermedades mentales más discapacitantes. Existen diferencias en cuanto al tipo de episodios más frecuentes, la polaridad predominante y la frecuencia de comorbilidad según el sexo. En la mujer es importante considerar la etapa de vida reproductiva en que se encuentra, pues se sabe que puede influir en el curso de la enfermedad. Se ha informado una elevada comorbilidad del trastorno bipolar con trastorno disfórico premenstrual y una exacerbación de los síntomas en el período premenstrual en el 44% al 65%, que puede conducir a un peor curso de la enfermedad. El embarazo no parece incrementar la presencia de episodios de la enfermedad; sin embargo, el tratamiento se complica de forma importante, mientras que la suspensión de la medicación puede llevar a recaídas, el mantenerlo puede llevar a resultados obstétricos negativos, malformaciones congénitas e incluso alteraciones del neurodesarrollo. De tal manera que la evaluación de riesgo-beneficio en estas pacientes tiene que ser muy cautelosa. En el posparto, claramente se relaciona con un incremento en el riesgo de presentar algún episodio afectivo. Al llegar a la transición a la menopausia parecieran incrementarse los episodios de tipo depresivo. La relación entre el ciclo reproductivo y la presencia de episodios de enfermedad, así como los estudios en otras entidades psiquiátricas, han llevado a considerar que una relación entre las hormonas gonadales y los neurotransmisores podrían subyacer a esta entidad. En el presente artículo describimos algunas de las observaciones relacionadas con estrógenos, progesterona y sus metabolitos, testosterona y deshidroepiandrosterona

Bipolar disorder is one of the most disabling psychiatric illnesses. Some characteristics of the disorder vary with sex, such as predominant polarity, frequency and type of comorbidity, and type of episodes presented. In the case of bipolar women, it is important to consider reproductive events, due to their influence in the course of the disorder. High comorbidity of bipolar disorder and premenstrual dysphoric disorder with an exacerbation of symptoms in the premenstrual period has been reported in 44% to 65% which may lead to a worse disease course. In general, women with premenstrual symptom exacerbation show more affective - particularly depressive - episodes, more frequent relapses, and more severe symptomatology. Pregnancy does not appear to increase presence of bipolar episodes, but significantly complicates treatment. On the one hand, stopping the treatment, particularly abruptly, increases the risk of relapse; while on the other, the use of mood stabilizers represents a risk for the newborn. Poor neonatal outcomes, congenital malformations and neurodevelopment alterations in children of mothers exposed to mood stabilizers during pregnancy have been reported. So, a meticulous benefit-risk assessment should be carried out in pregnant bipolar women. In the postpartum period, a clearer relation with increased risk of affective episode has been observed; while the perimenopause increases depressive episodes. The inter-relation between reproductive cycle and bipolar episodes suggests that gonadal hormones are involved in their physio-pathology. Here we discuss some of the observations related to testosterone, dehydroepiandrosterone, estrogens, and progesterone

Comparación del funcionamiento cognitivo en pacientes con trastorno bipplar tipo II en eutimia vesus trastorno bippolar tipo I en eutimia y controles / Comparison of Cognitive Functioning in Bipolar Disorder Type II Patientes in Euthymia vs. Bippolar Disorder Type I in Euthymia and Controls

Introducción. El trastorno bipolar (TBP) se encuentra clasificado dentro de los trastornos del estado del ánimo, se trata de una enfermedad común, recurrente y severa que causa un impacto considerable en el bienestar del paciente y una significativa carga económica para el individuo y la sociedad. Según el DSM IV el TBP se puede clasificar en Tipo I y II, el TBP I se caracteriza por la presencia de un episodio de manía o mixto que se alterna con episodios de depresión. El TBP II se presenta con episodios de depresión y al menos un episodio de hipomanía. Se ha estimado que 30 a 50% de los pacientes con TBP en remisión fracasan en alcanzar el nivel premórbido de funcionamiento psicosocial y esta discapacidad puede estar asociada a alteraciones cognitivas. Varios estudios han reportado que estas alteraciones se presentan fundamentalmente durante los episodios, las principales están relacionadas con la memoria verbal y funciones ejecutivas, y estas deficiencias persisten aún cuando el paciente se encuentra en eutimia. Existen pocos estudios que comparen las diferencias en el funcionamiento cognitivo entre pacientes con TBP I y II, el conocer estas diferencias y su repercusión en la calidad de vida de los pacientes, nos permitirá desarrollar nuevas estrategias de tratamiento que se enfoquen en rehabilitar estas funciones acorde al perfil neuropsicológico de cada grupo. Objetivo. Comparar el funcionamiento cognitivo en pacientes con TBP I y II en eutimia y sujetos controles y determinar si existe relación con la calidad de vida percibida por los pacientes. Material y métodos. Estudio comparativo, transversal, homodémico Muestra: Pacientes del sexo masculino y femenino, edad 18-60 años con diagnóstico TBP II en eutimia los últimos 4 meses, con un puntaje <7 en la Escala de Depresión de Hamilton y <6 en la Escala de manía de Young. (n=18) Se excluyó: Pacientes con dependencia a alcohol y otras sustancias o antecedente de terapia electroconvulsiva ...

Bipolar Disorder (BPD) is classed among mood disorders. It is a common, recurrent and severe disease which causes considerable impact on the patient's wellbeing and an economic burden for the individual an society. According to the DSM IV, BPD can be classified into Type I and II. BPD Type I is characterized by the presence of a manic or mixed episode which alternates with depression episodes. BPD II is accompanied with depression episodes and at least one hypomanic episode. It has been estimated that 30 to 50 % of patients with remitting BPD fail to achieve the premorbid level of psychosocial functioning and this impairmet may be associated to congnitive alterations. Several studies have reported that these alterations mostly occur during the occurrence of the episodes. The main alterations are related to verbal memory and executive functions, and these deficiencies still persist when the patient is experiencing euthymia. Few studies have compared the differences in cognitive functioning between BPD I and BPD II patients. Knowing these differences and their impact on the patients' quality of life will enable us to develop new treatment strategies focused on adapting such strategies to the neuropsychological profile of each group of patient. Purpose: to compare the cognitive functioning between BPD I and BPD II patients with euthymia and control subjects, and to determine whether it is related with the patients' quality of life as perceived by them. Materials and methods: comparative, longitudinal, homodemic study. Sample: Male and female patients aged 18-60 years-old who had been diagnosed with BPD II in euthymia during the last 4 months, with a < 7 score in the Hamilton Rating Scale for Depression and a < 6 score inthe Young Mania Rating Scale (n=18). Exclusion criteria: Patients with alcohol and other substances abuse, or with a history of electroconvulsive therapy during the previous year. Patients with a history of CVA or CET were also excluded ...