Aleksandra Szczepankiewicz

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 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.

Association of 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene with bipolar disorder and schizophrenia

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism 677C>T has been shown to be a risk factor for psychiatric disorders. We investigated the genotype and allelic frequencies of MTHFR 677C>T polymorphism in the group of patients with bipolar disorder type I (BDI) (n=200) and schizophrenia (n=200), and in the control group (n=300). Odds ratio (OR) for patients with BD and schizophrenia with 677T allele was 1.988 ((95% CI=1.370-2.883); P=0.0003 (P=0.0006 after Bonferroni correction)) and 1.796 ((95% CI=1.237-2.609); P=0.0020 (P=0.0040 after Bonferroni correction)), respectively. The stratification of patients based on gender revealed significant association of 677T allele with male patients with BDI and schizophrenia (OR=2.393; 95% CI=1.429-4.006; P=0.0008 and OR=2.036; 95% CI=1.207-3.433; P=0.0073, respectively). This finding indicates possible association of BD and schizophrenia with the 1p36.3 MTHFR locus.

FKBP5 polymorphism is associated with major depression but not with bipolar disorder

BACKGROUND Altered activity of hypothalamus-pituitary-adrenal glands (HPA) axis in response to stress underlies the pathogenesis of mood disorders such as depression and bipolar disorder. Chaperone proteins regulate sensitivity of glucocorticoid receptor (GR) to steroids. We hypothesized that genetic variants within the FKBP5 - gene encoding co-chaperone protein essential in GR signaling - may influence the susceptibility to major depressive disorder and bipolar disorder. METHODS In the study participated 528 bipolar patients, 218 patients with major depressive disorder and 742 subjects from control group. Genotypes for eight FKBP5 polymorphisms (rs1360780, rs755658, rs9470080, rs4713916, rs7748266, rs9296158, rs9394309, rs3800373) were established by TagMan SNP Genotyping Assays (Applied Biosystems). Linkage disequilibrium analysis for FKBP5 gene was done in Haploview. Gene-gene interactions between FKBP5 and NR3C1 polymorphisms (reported previously) were analyzed using the multidimensionality-reduction method (MDR). RESULTS We have observed an association between five FKBP5 polymorphisms (rs1360780, rs9470080, rs4713916, rs9296158 and rs9394309) and major depressive disorder (p=0.011; p=0.007, p=0.038; p=0.030; p=0.018, respectively), but not bipolar disorder. In linkage disequilibrium analysis we found that seven FKBP5 polymorphisms build haplotype block (rs3800373, rs755658, rs9296158, rs7748266, rs1360780, rs9394309, rs9470080, respectively). We observed that two haplotype combinations (ACATTGT and CCACTAT) were significantly more frequent in the MDD patients than in controls (p=0.014 and p=0.043). We have not observed such an association for BD patients. We have found that interaction between rs9470080 of FKBP5 and rs6198 of NR3C1 influences MDD risk. LIMITATIONS The main limitations of this study include low power and limited sample size of MDD patients. CONCLUSIONS Single markers and haplotypes of FKBP5 gene and the interaction with glucocorticoid receptor gene (NR3C1) may influence MDD predisposition.

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.

Variation in GNB3 predicts response and adverse reactions to antidepressants

There is substantial inter-individual variation in response and adverse reactions to antidepressants, and genetic variation may, in part, explain these differences. GNB3 encodes the β3 subunit of the G protein complex, which is involved in the downstream signalling cascade following monoamine receptor activation. A functional polymorphism in this gene (C825T) has been associated with response to antidepressants. Several lines of evidence suggest that GNB3 moderates improvement in the neurovegetative symptoms of depression (such as sleep and appetite) and related adverse reactions independently of change in core mood symptoms. We here report analysis of data from GENDEP, a part-randomized pharmacogenomic trial, on the outcome of 811 subjects with major depression undergoing treatment with either escitalopram or nortriptyline in which the C825T SNP and three further SNPs in GNB3 were genotyped. The TT genotype was significantly associated with a superior response to nortriptyline and these effects were specific to improvements in neurovegetative symptoms. In addition, the same genotype predicted fewer incidents of treatment-emergent insomnia and greater weight gain on the same drug. Our results are consistent with previous associations with GNB3 and emphasize the importance of signalling genes in antidepressant response.

Suicidal ideation during treatment of depression with escitalopram and nortriptyline in Genome-Based Therapeutic Drugs for Depression (GENDEP): a clinical trial

BackgroundSuicidal thoughts and behaviours during antidepressant treatment, especially during the first weeks of treatment, have prompted warnings by regulatory bodies. The aim of the present study is to investigate the course and predictors of emergence and worsening of suicidal ideation during tricyclic antidepressant and serotonin reuptake inhibitor treatment.MethodsIn a multicentre part-randomised open-label study, 811 adult patients with moderate to severe unipolar depression were allocated to flexible dosage of escitalopram or nortriptyline for 12 weeks. The suicidality items of three standard measures were integrated in a suicidal ideation score. Increases in this score were classified as treatment emergent suicidal ideation (TESI) or treatment worsening suicidal ideation (TWOSI) according to the absence or presence of suicidal ideation at baseline.ResultsSuicidal ideation decreased during antidepressant treatment. Rates of TESI and TWOSI peaked in the fifth week. Severity of depression predicted TESI and TWOSI. In men, nortriptyline was associated with a 9.8-fold and 2.4-fold increase in TESI and TWOSI compared to escitalopram, respectively. Retirement and history of suicide attempts predicted TWOSI.ConclusionIncreases in suicidal ideation were associated with depression severity and decreased during antidepressant treatment. In men, treatment with escitalopram is associated with lower risk of suicidal ideation compared to nortriptyline. Clinicians should remain alert to suicidal ideation beyond the initial weeks of antidepressant treatment.Trial registrationEudraCT (No.2004-001723-38) and ISRCTN (No. 03693000).