Maria Skibinska

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.

Single ketamine infusion in bipolar depression resistant to antidepressants: are neurotrophins involved?

We investigated serum brain‐derived neurotrophin factor (BDNF), nerve growth factor (NGF), neurotrophin‐3 (NTF3), neurotrophin‐4 (NTF4) and the glial‐derived neurotrophic factor (GDNF), in relation to ketamine efficacy, in bipolar depressed patients resistant to treatment with antidepressants.

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.

Association of Tumor Necrosis Factor –308G/A Promoter Polymorphism with Schizophrenia and Bipolar Affective Disorder in a Polish Population

Background/Aims: Schizophrenia (SCH) and bipolar affective disorder (BPAD) are complex disorders with significant participation of genetic risk factors. Several lines of evidence point to the role of shared neurobiological mechanisms and common genetic background in SCH and BPAD. Immune disturbances have been suggested as contributing factor in the pathogenesis of both SCH and BPAD. The gene coding cytokine tumor necrosis factor (TNF) has been the object of a number of association studies in SCH, with ambiguous results. Only 3 such studies were performed in BPAD. The aim of our study was to perform a case-control association analysis of the TNF –308G/A polymorphism in a Polish sample of patients with SCH, BPAD and healthy controls. Methods: We genotyped the TNF –308G/A polymorphism (rs1800629) by PCR-RFLP in 348 patients with SCH, 361 patients with BPAD and in 351 controls. Results: We observed an association of the –308G allele with both SCH (p = 0.008) and BPAD (p = 0.039), and also with a positive family history in patients with SCH (p = 0.048) and BPAD (p = 0.027). For TNF genotypes, the association was only seen in SCH (p = 0.018). Conclusions: Our results may point to an association of the TNF –308G allele and –308G/G genotype with both SCH and BPAD, and to a relationship of the –308G allele with the risk of SCH and BPAD in patients with a positive family history. TNF could be potentially a susceptibility gene, shared between SCH and BPAD. Complex TNF gene studies – based on multiple single-nucleotide polymorphisms and involving haplotype analysis – are necessary for the clarification of currently contradictory findings.

Suicide attempts and psychological risk factors in patients with bipolar and unipolar affective disorder

Suicide is an important clinical problem in psychiatric patients. The highest risk of suicide attempts is noted in affective disorders. The aim of the study was looking for suicide risk factors among personality dimensions and value system in patients with diagnosis of unipolar and bipolar affective disorder (n=189 patients, n=101 controls). To establish the diagnosis, we used SCID (Structured clinical interview for diagnostic and statistical manual of mental disorders, fourth edition) questionnaire, TCI (Temperament and Character Inventory) questionnaire and Value Survey--to assess the personality. The main limitations of the study are number of participants, lack of data about stressful life events and treatment with lithium. Novelty seeking and harm avoidance dimensions constituted suicide attempt risk factors in the group of patients with affective disorders. Protective role of cooperativeness was discovered. Patients with and without suicide attempt in lifetime history varied in self-esteem position in Value Survey.