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.

Looking for factors affecting functioning in euthymic patients with bipolar I disorder: the importance of cognitive complaints and BDNF's Val66Met polymorphism.

INTRODUCTION: Functioning in Bipolar Disorder (BD) is affected in a substantial proportion of patients. The impact of demographic, clinical, cognitive, and genetic factors on functioning has been shown individually; however, as a complex phenomenon, a global approach to identify the most relevant as well as possible interactions is needed. METHODS: 102 patients with type I BD in euthymia were invited for evaluation of demographic, clinical, and cognitive characteristics as well as genotype for Val66Met polymorphism of BDNF gene to determine those associated with poor functioning according to the FAST scale cut-off score. Clinical evaluation included assessment of residual affective symptoms and anxiety. Cognitive evaluation included the COBRA scale, verbal memory, and executive functions testing. RESULTS: Residual depressive symptoms, anxiety, cognitive complaints and being a Met carrier were more frequent in the poor functioning group and were entered in a logistic regression model. Being a Met carrier (OR=4.46, CI=1.19-16.67) and cognitive complaints (OR=1.29, CI= 1.13-1.46) were the most important predictors of poor functioning in type I BD. LIMITATIONS: Cross-sectional study, with select population limiting generalizability of findings. CONCLUSIONS: A better understanding of underlying factors affecting cognition, including the possible involvement of BDNF Val66Met polymorphism, its systematic evaluation and a continued search for targeted treatment, along with recognition and attention of residual affective and anxious symptoms might improve psychosocial outcomes such as functioning in this population.

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.

CACNA1C Risk Variant and Mood Stabilizers Effects in the Prefrontal Cortical Thickness of Mexican Patients with Bipolar Disorder.

PURPOSE: Bipolar disorder (BD) is a condition associated with structural alterations in the prefrontal cortex (PFC); some genetic variants and mood stabilizer medications like lithium or valproate are associated with these changes. CACNA1C is a gene involved in BD pathology and brain function; carriers of the A allele of rs1006737 are reported to have increased risk for BD and increased cortical thickness (CT) in the PFC compared to non-carriers. Lithium is also associated with increased CT in the PFC of BD subjects compared to the ones on valproate. The influence of these treatments and gene variants over the PFC structure of Mexican subjects has not been explored. Therefore, we evaluate the effects of mood stabilizers and risk A allele of CACNA1C rs1006737 on the prefrontal cortical thickness of Mexican BD patients treated with lithium or valproate. PATIENTS AND METHODS: A cross-sectional study of 40 BD type I euthymic adult outpatients (20 treated with lithium and 20 with valproate) who underwent a 3T T1-weighted 3D brain scan and genotyping for CACNA1C risk allele rs1006737 was conducted. We performed a cortical thickness analysis of the dorsolateral and orbitofrontal regions of the prefrontal cortex with BrainVoyager 20.6. The effects of treatment and gene variants were analyzed with a two-way multivariate analysis of covariance. RESULTS: There was no association of CACNA1C risk allele rs1006737 with CT measures of both PFCs nor significant interaction between the genetic variant and treatment. Mood stabilizers reported the main effect on the CT measures of the right PFC of our sample. Patients on treatment with lithium showed higher mean CT on the right orbitofrontal cortex. CONCLUSION: We did not find any association between the prefrontal CT and CACNA1C risk A allele rs1006737 in BD Mexican patients treated with lithium or valproate. Our results suggest that mood stabilizers had the main effect in the CT of the right PFC.

Association between 5-HTTLPR polymorphism, suicide attempt and comorbidity in Mexican adolescents with major depressive disorder.

INTRODUCTION: The World Health Organization reports that suicide is among the leading causes of death for young people. Depression is the most frequently related disorder with suicidal behaviors. There is increasing evidence that suicidal behavior has a strong genetic contribution. Several studies report an association between the genotype "SS" and the "S" allele of the 5-HTTLPR polymorphism of the serotonin transporter gene and suicidal behavior. The aim of the study was to determine the association of variants of the serotonin transporter gene with suicidal attempt and comorbidity in depressed adolescents. METHODS: The frequencies of ss genotypes and s allele were compared between a sample of 200 adolescents with a diagnosis of depression and the antecedent of a suicide attempt who were evaluated with K-SADS-PL and a group of 235 healthy controls. Genotyping of the 5-HTTLPR polymorphism was performed by PCR. RESULTS: Analysis of the frequencies of genotypes and alleles showed a statistically significant difference between the groups (Genotypes: x2=11.1, df=2, p=0.004, Alleles: x2=11.9, df=1, p=0.0009). There were no associations with comorbid disorders. CONCLUSIONS: The results support the hypothesis that the serotonin transporter gene, specifically the s allele and the ss genotype of the 5-HTTLPR polymorphism, are related to the history of depression and suicide attempt in adolescents.

Asociación entre el polimorfismo 5-HTTLPR, el intento suicida y la comorbilidad en adolescentes mexicanos con trastorno depresivo mayor / Association between 5-HTTLPR polymorphism, suicide attempt and comorbidity in Mexican adolescents with major depressive disorder

Introducción. De acuerdo a la Organización Mundial de la Salud el suicidio se encuentra en las principales causas de muerte en niños y adolescentes. La depresión es el trastorno más asociado a la conducta suicida. Existe cada vez mayor evidencia respecto a que la conducta suicida tiene una fuerte contribución genética. Varios estudios reportan una asociación entre el genotipo "SS" y el alelo "S" del polimorfismo 5-HTTLPR del gen del transportador de serotonina y la conducta suicida. El objetivo del estudio fue establecer la asociación de las variantes del gen del transportador de serotonina con el intento suicida y la comorbilidad en pacientes adolescentes deprimidos. Metodología. Se compararon las frecuencias de genotipo "SS" y del alelo "S" entre una muestra de 200 adolescentes evaluados con la entrevista semi-estructurada K-SADSPL y una muestra de 235 controles sanos. La genotipificacion del polimorfismo 5-HTTLPR se realizó mediante PCR. Resultados. El análisis de las frecuencias de genotipos y alelos mostro diferencia estadísticamente significativas entre los grupos (Genotipos: x2=11,1, gl=2, p=0,004; Alelos: x2=11,9, gl=1, p=0,0009). No existió asociación con los trastornos comorbidos. Conclusiones. Los resultados apoyan la hipótesis de que el gen del transportador de serotonina, específicamente el alelo s y el genotipo ss del polimorfismo 5-HTTLPR, se encuentran relacionados con la historia de depresión e intento suicida en adolescentes

Introduction. The World Health Organization reports that suicide is among the leading causes of death for young people. Depression is the most frequently related disorder with suicidal behaviors. There is increasing evidence that suicidal behavior has a strong genetic contribution. Several studies report an association between the genotype "SS" and the "S" allele of the 5-HTTLPR polymorphism of the serotonin transporter gene and suicidal behavior. The aim of the study was to determine the association of variants of the serotonin transporter gene with suicidal attempt and comorbidity in depressed adolescents. Methods. The frequencies of ss genotypes and s allele were compared between a sample of 200 adolescents with a diagnosis of depression and the antecedent of a suicide attempt who were evaluated with K-SADS-PL and a group of 235 healthy controls. Genotyping of the 5-HTTLPR polymorphism was performed by PCR. Results. Analysis of the frequencies of genotypes and alleles showed a statistically significant difference between the groups (Genotypes: x2=11.1, df=2, p=0.004, Alleles: x2=11.9, df=1, p=0.0009). There were no associations with comorbid disorders. Conclusions. The results support the hypothesis that the serotonin transporter gene, specifically the s allele and the ss genotype of the 5-HTTLPR polymorphism, are related to the history of depression and suicide attempt in adolescents

El papel del gen del transportador de serotonina en los trastornos de la conducta alimentaria / Role of Serotonin Transporter Gene in Eating Disorders

Introducción: Al sistema serotoninérgico se lo ha implicado en la regulación del estado de ánimo y en la conducta alimentaria, por lo que el gen del transportador de serotonina (SLC6A4) es un buen candidato para el desarrollo de los trastornos de la conducta alimentaria (TCA). La mayoría de los estudios genéticos en los TCA se han centrado principalmente en un polimorfismo, el denominado 5-HTTLPR del gen SLC6A4. Objetivo: Realizar una revisión de los estudios de asociación entre el 5-HTTLPR y los TCA, como anorexia nerviosa, bulimia nerviosa y trastornos alimentarios no especificados. Método: Se realizó una búsqueda en MEDLINE, ISI y PubMed de las palabras clave «transportador de serotonina¼ y «TCA¼. Conclusiones: Según la revisión de 37 artículos originales, la variante S del 5-HTTLPR es un factor de riesgo de anorexia nerviosa. Además, se encontró asociación entre el alelo S y el índice de masa corporal, impulsividad, ansiedad, depresión y el tiempo de evolución en TCA. Sin embargo, en bulimia nerviosa no se reporta asociación con las variantes del 5-HTTLPR.

Background: The serotoninergic system has been implicated in mood and appetite regulation, and the serotonin transporter gene (SLC6A4) is a commonly studied candidate gene for eating disorders. However, most studies have focused on a single polymorphism (5-HTTLPR) in SLC6A4. Objective: We present the studies published on the association between eating disorders (ED) and 5-HTTLPR polymorphism in anorexia nervosa (AN), bulimia nervosa (BN), and eating disorders not otherwise specified (EDNOS). Method: Search of databases: MEDLINE, ISI, and PubMed for SLC6A4 and ED. Conclusions: From a review of 37 original articles, it was suggested that carriers of S allele is a risk factor for eating disorders, especially for AN. However, BN did not show any association. Also, BMI, impulsivity, anxiety, depression, and age of onset have been associated with S allele in ED patients.

El polimorfismo 5-HTTLPR y el intento suicida en adolescentes deprimidos / 5-HTTLPR polymorphism and suicidal attempt in depressed adolescents

La Organización Mundial de la Salud reporta que el suicidio es la tercera causa de muerte más frecuente para jóvenes de 15 a 24 años de edad y la sexta causa de muerte para niños de cinco a 14 años de edad. Los trastornos del estado de ánimo, particularmente la depresión, son los responsables de la mayor parte de los suicidios consumados. Este mayor riesgo de suicidio se ha encontrado en adultos y adolescentes. Existe cada vez mayor evidencia respecto de la hipótesis de que la conducta suicida tiene una fuerte contribución genética. Varios estudios han reportado una asociación positiva entre el genotipo "SS" y el alelo "S" del polimorfismo 5-HTTLPR del gen del transportador de serotonina y la conducta suicida. Objetivo El objetivo del presente trabajo fue establecer la asociación de las variantes polimórficas del gen del transportador de serotonina en pacientes adolescentes deprimidos con y sin antecedente de intento suicida y determinar si la presencia del genotipo "SS" estaba asociada a características específicas de la depresión. Método La muestra estuvo conformada por 53 adolescentes con diagnóstico de depresión. El diagnóstico se realizó con la entrevista diagnóstica semi-estructurada K-SADS-PL. Para la extracción del ADN genómico se obtuvo una muestra de sangre de cada uno de los pacientes. Resultados El análisis genético de las frecuencias de genotipos y alelos no mostró diferencias estadísticamente significativas entre los grupos. Sin embargo, aquellos pacientes con el genotipo "SS" tenían mayor frecuencia de desesperanza. En los pacientes con este genotipo también se encontró mayor número de intentos suicidas. Conclusiones No se observaron diferencias en la frecuencia de alelos entre pacientes con y sin intento suicida; sin embargo, el genotipo "SS" se asoció a algunas características de la depresión.

Suicide is a common cause of death in adolescents, being mainly associated with depression. In addition, the "SS" genotype and the "S" allele of 5-HTTLPR polymorphism of SLC6A4 gene of serotonin transporter have been associated with suicidal behavior. The aims of the present study were to compare the frequency of the polymorphism of SLC6A4 gene in depressed adolescents with and without history of suicidal attempt and to determine if the "SS" genotype was associated with specific clinical features. Method The study examined 53 adolescents who were evaluated with the Diagnostic Interview Schedule for Affective Disorders and Schizophrenia for school-aged children-present and lifetime version (K-SADS-PL). A DNA sample was obtained and 5HTTLPR polymorphisms of SLC6A4 gene were analyzed. Results There were no differences in the frequency of genotype and allele frequencies between groups. However, patients with the "SS" genotype reported a higher frequency of hopelessness and a greater number of suicide attempts. Conclusions The frequency of "SS" genotype did not differ between patients with and without suicidal behavior, but patients with this genotype exhibited differences in clinical features of depression which need further study.

[Role of Serotonin Transporter Gene in Eating Disorders]. / El papel del gen del transportador de serotonina en los trastornos de la conducta alimentaria.

BACKGROUND: The serotoninergic system has been implicated in mood and appetite regulation, and the serotonin transporter gene (SLC6A4) is a commonly studied candidate gene for eating disorders. However, most studies have focused on a single polymorphism (5-HTTLPR) in SLC6A4. OBJECTIVE: We present the studies published on the association between eating disorders (ED) and 5-HTTLPR polymorphism in anorexia nervosa (AN), bulimia nervosa (BN), and eating disorders not otherwise specified (EDNOS). METHOD: Search of databases: MEDLINE, ISI, and PubMed for SLC6A4 and ED. CONCLUSIONS: From a review of 37 original articles, it was suggested that carriers of S allele is a risk factor for eating disorders, especially for AN. However, BN did not show any association. Also, BMI, impulsivity, anxiety, depression, and age of onset have been associated with S allele in ED patients.

Exploring epistasis in candidate genes for antisocial personality disorder.

OBJECTIVE: To identify and characterize high-order gene-to-gene interactions in antisocial personality disorder (ASPD). METHODS: Participants for case-control study were selected from the inmate male population in Bellavista prison from Medellin. The study included 310 individuals with ASPD and 200 with no ASPD. Diagnoses were made according to a best-estimate procedure based on a semistructured interview (diagnostic interview for genetic studies 3.0). We genotyped some single-nucleotide polymorphisms in candidate genes with main serotonin pathway effects. The gene-gene interaction was examined using the multifactor dimensionality reduction method version 2.0.α. We assessed model sizes of 2 and 3 loci and counted the number of replicates that contained the causal loci in the final best model that was identified using 10-fold cross validation. RESULTS: We find epistatic interaction with catechol-O-methyl transferase (COMT), tryptophan hydroxylase, and 5-HTR2A (serotonin receptor) with ASPD. This data supports an important role of polymorphism in serotonin receptors and low enzyme activity of COMT for susceptibility to ASPD. CONCLUSION: This study suggests that gene interactions between genetic variants in COMT, 5-HTR2A and tryptophan hydroxylase gene would be associated with ASPD and influence the dopamine rewards pathways and modulate serotonin levels in ASPD.