Anna Leszczynska-Rodziewicz

Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain-derived neurotrophic factor gene

Abstract  The measures of prefrontal cognition have been used as endophenotype in molecular‐genetic studies. Brain‐derived neurotrophic factor (BDNF) has been implicated in cognitive functions and in the pathogenesis of major psychoses. This study investigates the relationship between Val66Met polymorphisms of the BDNF gene and prefrontal cognitive function in 129 patients with schizophrenia and 111 patients with bipolar mood disorder. Cognitive tests included the Wisconsin Card Sorting Test (WCST), with such domains as number of perseverative errors, non‐perseverative errors, completed corrected categories, conceptual level responses, and set to the first category, and the N‐back test, where mean reaction time and percent of correct reactions were measured. Genotyping for Val66Met BDNF polymorphism was done by polymerase chain reaction method. In schizophrenia, no relationship between Val66Met polymorphism of the BDNF gene and the results of the WCST was observed. Patients with Val/Val genotype had a higher percentage of correct reactions in the N‐back test than those with the remaining genotypes. Bipolar patients with Val/Val genotype obtained significantly better results on three of five domains of the WCST. No relationship between BDNF polymorphism and the results of the N‐back test was found in this group. A limitation to the results could be variable psychopathological state and medication during cognitive testing and lack of Hardy–Weinberg equilibrium in schizophrenia group. Val66Met polymorphism of the BDNF gene may be associated with cognitive performance on the WCST in bipolar mood disorder but not in schizophrenia. An association of this polymorphism with performance on the N‐back test in schizophrenia and not in bipolar illness may suggest that in schizophrenia, the BDNF system may be connected with early phases of information processing.

Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder

Summary Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar disorder. A functional polymorphism Val66Met of BDNF gene was studied in patients with schizophrenia (n=336), bipolar affective disorder (n=352) and healthy controls (n=375). Consensus diagnosis by at least two psychiatrists, according to DSM-IV and ICD-10 criteria, was made for each patient using a structured clinical interview for DSM-IV Axis I disorders (SCID). No association was found between the studied polymorphism and schizophrenia or bipolar affective disorder either for genotype or allele distribution (for genotype: p=0.210 in schizophrenia, p=0.400 in bipolar disorder; for alleles: p=0.260 in schizophrenia, p=0.406 in bipolar disorder). Results were also not significant when analysed by gender. For males genotype distribution and allele frequency were (respectively): p=0.480 and p=0.312 in schizophrenia, p=0.819 and p=0.673 in bipolar affective disorder. Genotype distribution and allele frequency observed in the female group were: p=0.258 for genotypes, p=0.482 for alleles in schizophrenia; p=0.432 for genotypes, p=0.464 for alleles in bipolar affective disorder. A subgroup of schizophrenic (n=62) and bipolar affective patients (n=28) with early age at onset (18 years or younger) was analysed (p=0.328 for genotypes, p=0.253 for alleles in schizophrenia; p=0.032 for genotypes, p=0.858 for alleles in bipolar affective disorder).

Response to lithium prophylaxis: interaction between serotonin transporter and BDNF genes.

Both serotonin transporter and brain‐derived neurotrophic factor (BDNF) genes have been previously implicated in the efficacy of lithium prophylaxis. The aim of the present study was to assess a possible interaction between serotonin transporter genotype (5HTTLPR) and BDNF Val66Met polymorphism, and the prophylactic response to lithium. The study was performed on 111 patients with bipolar mood disorders (43 male, 68 female), aged 30–77 (mean 54 years) who have been treated with lithium carbonate for at least 5 years (5–27 years, mean 15 years). In the group studied, 31 patients (28%) were classified as excellent responders (ER), 54 (49%) as partial responders (PR), and 26 (23%) as non‐responders (NR) to lithium prophylaxis. Age at onset of the illness, duration of illness before treatment introduction and on lithium as well as number of affective episodes before lithium treatment did not differ between these three subgroups of patients. A significant interaction between BDNF and 5HTTLPR polymorphism and lithium response was found. S individuals (patients with s/s or s/l genotype) having Val/Val genotype were significantly more frequent in NR compared with ER or/and PR. Also, S individuals showed extreme differences in response to lithium prophylaxis depending on having either Val/Val or (Val/Met + Met/Met) genotypes of BDNF polymorphism: 9/48 (19%) of ER and 18/48 (37%) of NR in the first group, and 12/30 (40%) and 1/30 (3%) in the second group, respectively. The results obtained may show a significant epistatic interaction between 5‐HTTLPR and BDNF polymorphism, and response to lithium prophylaxis.

Association studies of the BDNF and the NTRK2 gene polymorphisms with prophylactic lithium response in bipolar patients.

The neuroplasticity hypothesis of bipolar disorder indicates that the BDNF/Trk signaling pathway is associated with the pathogenesis of this illness and treatment with mood stabilizers, such as lithium. This paper describes a relationship between response to lithium prophylaxis and polymorphisms of two functionally connected genes: BDNF and NTRK2, in bipolar illness. Analyses of four SNPs of the BDNF gene (rs2030324, rs988748, rs6265 [Val66Met]and rs2203877) and three of the NTRK2 gene (rs1187326, rs2289656, rs1187327) were performed in the 108 bipolar patients, classified as excellent responders (23%), partial responders (51%) and nonresponders (26%) to lithium. An association of C/G (rs988748) and G/A (rs6265) polymorphisms of the BDNF gene with a degree of prophylactic lithium response were found. No association with lithium response was revealed with the polymorphism of NTRK2 gene, neither with interaction of BDNF and NTRK2 genes.

Association Analysis of the GSK-3β T–50C Gene Polymorphism with Schizophrenia and Bipolar Disorder

Glycogen synthase kinase-3β (GSK-3β) has been implicated in the pathogenesis of major psychoses. In this paper, the T–50C polymorphism of the GSK-3β gene has been studied in patients with schizophrenia (n = 432), patients with bipolar disorder (n = 416) and in a healthy control group (n = 408). Consensus diagnosis by at least two psychiatrists was made for each patient, according to DSM-IV and ICD-10 criteria, using the Structured Clinical Interview for DSM-IV Axis I Disorders. Genotypes were established by the polymerase chain reaction-restriction fragment length polymorphism method. We have found a trend towards an association for the C allele in the whole group of schizophrenic patients (p = 0.088) and for the heterozygous T/C genotype of bipolar patients (0.095). Significant differences of genotype distribution and allele frequencies of the T–50C polymorphism were found in the female group of bipolar II patients (p = 0.015 for genotypes and p = 0.009 for alleles). In conclusion, this polymorphism may be associated with female gender in bipolar II disorder.

Association study of the glycogen synthase kinase-3β gene polymorphism with prophylactic lithium response in bipolar patients

A relationship between response to lithium prophylaxis and T-50C polymorphism of glycogen synthase kinase-3β (GSK-3β) gene was investigated in 89 bipolar patients (41 male and 48 female) who have been taking lithium for at least 5 years. The patients were delineated as excellent responders, partial responders and non-responders to lithium. The results obtained suggest that this polymorphism may not be related to the degree of prophylactic lithium response.

Glucocorticoid receptor polymorphism is associated with major depression and predominance of depression in the course of bipolar disorder.

BACKGROUND A strong association has been found between dysregulation of hypothalamic-pituitary-adrenal (HPA) axis and depression and bipolar disorder. Glucocorticoid receptor is one of the involved receptors and its gene has been recognized as a candidate gene for major depressive disorder and bipolar disorder. Therefore, we investigated if polymorphism of the glucocorticoid receptor gene (NR3C1), involved in the regulation of HPA axis, may alter susceptibility as well as the course of major depressive disorder and bipolar disorder. METHODS In the study we included 514 patients with bipolar disorder and 193 patients with major depressive disorder. Consensus diagnosis by at least two psychiatrists was made, according to DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria, using SCID (Structured Clinical Interview for DSM Disorders). Control group consisted of 732 healthy subjects. Genotyping for eight NR3C1 polymorphisms was done with use of TaqMan SNP (single nucleotide polymorphism) Genotyping Assays. Linkage disequilibrium analysis was done in Haploview. RESULTS We have found three polymorphisms (rs6198, rs6191 and rs33388) to be associated with major depressive disorder (MDD) and the same polymorphisms were associated with the predominance of depressive symptoms in the course of bipolar disorder. In linkage disequilibrium analysis we observed two haplotype blocks, however, none of those shows involvement in susceptibility to MDD or bipolar disorder. LIMITATIONS The main limitation of this study is relatively small sample size of MDD patients group. CONCLUSIONS Polymorphisms of NR3C1 gene analyzed in this study may modify susceptibility to major depressive disorder and seem to influence the course of bipolar disorder.

Dopamine receptor D1 gene -48A/G polymorphism is associated with bipolar illness but not with schizophrenia in a Polish population.

Dysregulation of dopaminergic neurotransmission has been implicated in the etiology of major psychoses. The dopamine D1 receptor (DRD1) plays a role in some brain functions and mechanisms of psychotropic drugs. Therefore, the DRD1 gene makes a good candidate gene for molecular genetic studies in schizophrenia and bipolar affective disorder. In the present study, the –48A/G polymorphism of the DRD1 gene was estimated in patients with schizophrenia (n = 407) or bipolar affective disorder (n = 380), and in healthy controls (n = 399). No association was found between the polymorphism studied and schizophrenia, either in the whole group of patients or in subgroups divided by gender, age at onset or predominance of positive or negative symptoms. A statistical trend was obtained for an association between this polymorphism and bipolar affective disorder (p = 0.059 for genotypes, p = 0.073 for alleles). The G/G genotype and G allele were significantly more frequent in patients with bipolar disorder, type II (p = 0.016 for genotypes, p = 0.008 for alleles), especially in the women subgroup (p = 0.054 for genotypes, p = 0.024 for alleles). An association between the G/G genotype and bipolar affective disorder with disease onset after 18 years of age was also found (p = 0.022). These data suggest that the –48A/G polymorphism of the DRD1 gene may be involved in the etiology of bipolar disorder in a Polish population.

Lack of support for a genetic association of the XBP1 promoter polymorphism with bipolar disorder in probands of European origin

Lack of support for a genetic association of the XBP1 promoter polymorphism with bipolar disorder in probands of European origin

Body weight as a predictor of antidepressant efficacy in the GENDEP project

BACKGROUND Being overweight or obese may be associated with poor response to antidepressants. The present report explores the moderation of antidepressant response by body weight to establish the specificity to antidepressant mode of action, type of depressive symptoms and gender. METHODS Height and weight were measured in 797 men and women with major depression treated with escitalopram or nortriptyline for twelve weeks as part of the Genome Based Therapeutic Drugs for Depression (GENDEP) project. Body mass index (BMI) and obesity (BMI>30) were tested as predictors of change in depressive symptoms using mixed linear models. RESULTS Higher BMI and obesity predicted poor response to nortriptyline but did not significantly influence response to escitalopram. The moderation of response by body weight was due to differential improvement in neurovegetative symptoms, including sleep and appetite. The relationship between body weight and change in neurovegetative symptoms was moderated by gender with obese men responding less to nortriptyline and obese women having poorer response to both antidepressants. LIMITATIONS As no placebo arm was included, the specificity of findings to antidepressants is relative. Lack of specific measures precluded accounting for differences in body fat distribution. CONCLUSIONS Body weight should be considered in the assessment of depression as it may inform the selection of antidepressant treatment.