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.

Can psychopathy be prevented? Clinical, neuroimaging, and genetic data: an exploratory study.

The aim of the study was to explore the relationship among brain functional activations elicited by an emotional paradigm, clinical scores (PTSD, anxiety, and depression), psychopathic traits, and genetic characteristics (5-HTTLPR) in a group of severely maltreated children compared to a healthy control group before and after the implementation of a Trauma Focused-Cognitive Behavioral Therapy. The final sample consisted of an experimental group of 14 maltreated children (mean age = 8.77 years old, S.D. = 1.83) recruited from a non-governmental shelter in Mexico City for children who had experienced child abuse and a control group of 10 children from the general population (mean age = 9.57 years old, S.D. = 1.91). Both groups were matched according to age and gender and were assessed before and after the implementation of the aforementioned therapy by means of clinical scales and an emotional paradigm that elicited brain activations which were recorded through functional magnetic resonance imaging. Genotyping of the 5-HTTLPR polymorphism was made at first assessment. A region of interest analysis showed amygdala hyperactivation during exposure to fear and anger stimuli in the maltreated children before treatment. Following therapy, a decrease in brain activity as well as a decrease in clinical symptoms were also observed. 5-HTTLPR polymorphism did not show any effect on the severity of clinical symptoms in maltreated children. Trauma-Focused Behavioral Therapy may help reorganize the brain's processing of emotional stimuli. These observations reveal the importance of an early intervention when the mechanisms of neuroplasticity may be still recruited.

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.

Association study of Catechol-O-Methyltransferase (COMT) rs4680 Val158Met gene polymorphism and suicide attempt in Mexican adolescents with major depressive disorder.

AIM: We analyzed the association between SLC6A4, DRD2, COMT and MAOA genes and suicide attempt (SA) in Mexican adolescent patients with major depressive disorder (MDD). METHODS: The sample included 197 adolescents (127 females and 70 males) with principal diagnosis of MDD. Among them, 63 patients had SA at least once and 134 had not SA. The mean age of patients with and without SA was 15 ± 1.4 and 14 ± 1.5 years, respectively. We analyzed the genotype and allele distribution between patients with and without SA of SLC6A4 (5HTTLPR/rs25531), DRD2 (rs6275), COMT (rs4680), and MAOA (uVNTR). RESULTS: We did not find genotype or allele association between SA and SLC6A4 (χ2=0.67, p = 0.71; χ2=0.07, p = 0.77, respectively), DRD2 (χ2=0.05, p = 0.97; χ2=0.003, p = 0.95), and MAOA (females: χ2=0.86, p = 0.64; χ2=0, p = 1/males: χ2=0.008, p = 0.92) genes. However, there were differences in genotype frequencies of COMT/rs4680 between patients with SA and without SA (χ2=11.17, p = 0.003). Also, we observed a high frequency of Met158 allele showing an increased risk of having presented at least one SA (χ2=10.6, p = 0.001; OR = 1.43; 95% CI, 1.17-1.74). CONCLUSIONS: Our findings showed an association between low activity genotype and allele of Val158Met polymorphism of COMT gene and SA in Mexican adolescents with MDD.

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.