Can Psychological, Social and Demographical Factors Predict Clinical Characteristics Symptomatology of Bipolar Affective Disorder and Schizophrenia?

Schizophrenia (SCH) is a complex, psychiatric disorder affecting 1 % of population. Its clinical phenotype is heterogeneous with delusions, hallucinations, depression, disorganized behaviour and negative symptoms. Bipolar affective disorder (BD) refers to periodic changes in mood and activity from depression to mania. It affects 0.5-1.5 % of population. Two types of disorder (type I and type II) are distinguished by severity of mania episodes. In our analysis, we aimed to check if clinical and demographical characteristics of the sample are predictors of symptom dimensions occurrence in BD and SCH cases. We included total sample of 443 bipolar and 439 schizophrenia patients. Diagnosis was based on DSM-IV criteria using Structured Clinical Interview for DSM-IV. We applied regression models to analyse associations between clinical and demographical traits from OPCRIT and symptom dimensions. We used previously computed dimensions of schizophrenia and bipolar affective disorder as quantitative traits for regression models. Male gender seemed protective factor for depression dimension in schizophrenia and bipolar disorder sample. Presence of definite psychosocial stressor prior disease seemed risk factor for depressive and suicidal domain in BD and SCH. OPCRIT items describing premorbid functioning seemed related with depression, positive and disorganised dimensions in schizophrenia and psychotic in BD. We proved clinical and demographical characteristics of the sample are predictors of symptom dimensions of schizophrenia and bipolar disorder. We also saw relation between clinical dimensions and course of disorder and impairment during disorder.

Clock gene variants differentiate mood disorders.

Genetic variations in clock-related genes were hypothesized to be involved to in the susceptibility of mood disorders MD (both unipolar (UPD) and bipolar (BPD) disorders). In our work we investigated role of gene variants form four core period proteins: CLOCK, ARNTL, TIM and PER3. The total sample comprised from 744 mood disorders inpatients (UPD = 229, BPD = 515) and 635 healthy voluntary controls. The 42 SNPs from four genes of interest were genotyped. We used single polymorphisms, haplotypes, SNPs interactions and prediction analysis using classical statistical and machine learning methods. We observed association between two polymorphisms of CLOCK (rs1801260 and rs11932595) with BPDII and two polymorphisms of TIM (rs2291739, rs11171856) with UPD. We also detected ARNTL haplotype variant (rs1160996C/rs11022779G/rs1122780T) to be associated with increased risk of MD, BPD (both types). We established significant epistatic interaction between PER3 (rs2172563) and ARNTL (rs4146388 and rs7107287) in case of BPD. Additionally relation between PER3 (rs2172563) and CLOCK (rs1268271 and rs3805148) appeared in case of UPD. Classification and Regression Trees (C and RT) showed significant predictive value for 10 polymorphisms in all analyzed genes. However we failed to obtain model with sufficient predictive power. During analyses of sleep disturbances sample, we found carriers of homozygote variants (ARNTL: rs11022778 TT, rs1562438 TT, rs1982350 AA and PER3: rs836755 CC) showing more frequent falling asleep difficulties when compare to other genotypes carriers. Our study suggested a putative role of the CLOCK, TIM, ARNTL and PER3 and polymorphisms in MD susceptibility. In our analyses we showed association of specific gene variants with particular types of MD. We also confirmed necessity of performing separate analyzes for BPD and UPD patients. Comprehensive statistical approach is required even with individual symptoms analyses.

Association, haplotype, and gene-gene interactions of the HPA axis genes with suicidal behaviour in affective disorders.

Family twin and adoption studies have noted the heritability of specific biological factors that influence suicidal behaviour. Exposure to stress is one of the factors that strongly contribute to suicide attempts. The biological response to stress involves the hypothalamic-pituitary-adrenal axis (HPA). Therefore, we found it interesting to study polymorphisms of genes involved in the HPA axis (CRHR1, NR3C1, and AVPBR1). The study was performed on 597 patients, 225 of whom had a history of suicide attempts. We did not observe any significant differences in the studied polymorphisms between the group of patients with a history of suicide attempts and the control subjects. Our haplotype analysis of the AVPR1b gene revealed an association between the GCA haplotype and suicide attempts; however, this association was not significant after correcting for multiple testing. We did not observe any other association in haplotype and MDR analysis. We report here a comprehensive analysis of the HPA axis genes and a lack of association for genetic variations regarding the risk of suicide attempts in affective disorder patients. Nonetheless, the inconsistencies with the previously published results indicate the importance of the further investigation of these polymorphisms with respect to the risk of suicide attempts.

[No association of glucocorticoid receptor gene polymorphism (rs6190) with unipolar and bipolar disorder]. / Brak zwiazku polimorfizmu (rs6190) genu receptora glikokortykoidowego z choroba afektywna jedno- i dwubiegunowa.

AIM: Functional polymorphism ER22/23EK glucocorticoid receptor leads to reduction of its resistance and to increase in its sensitivity to the glucocorticoid that regulate the functioning of the axis hypothalamus - pituitary - adrenal glands. Disturbances in the regulation of this axis are observed in patients with psychiatric disorders. The aim of this study was to demonstrate the association ER22/23EK polymorphism with bipolar disorder and major depressive disorders. METHODS: In the study 144 patients with unipolar disorders and 479 patients with bipolar disorder were included. Patients were diagnosed by two psychiatrists on the basis of medical records and interview based on SCID criteria (Structured Clinical Interview for DSM Disorders). The control group comprised 595 healthy subjects. As the research material peripheral blood was used, from which DNA was obtained. Genotyping was performed using PCR - RFLP method. RESULTS: No association of ER22/23EK polymorphism with unipolar disorder or with bipolar disorder was found. GA genotype was not observed in any of the subjects. CONCLUSION: ER22/23EK functional polymorphism of the glucocorticoid receptor gene is not associated with unipolar and bipolar disorder.

Functional polymorphism of matrix metalloproteinase-9 (MMP-9) gene and response to lithium prophylaxis in bipolar patients.

OBJECTIVE: Matrix metalloproteinase 9 (MMP-9) has been implicated in a number of pathological conditions including cancer and heart diseases, and recently also in such neuropsychiatric disorders as schizophrenia and bipolar illness. Therefore, we investigated a possible association between functional polymorphisms of the MMP-9 gene and the response to lithium, the main mood-stabilizing drug in bipolar illness. METHODS: One hundred and nine bipolar patients treated with lithium for at least 5 years were analyzed. The lithium response was assessed as--excellent: no affective episodes during lithium treatment; partial: 50% or more reduction in the episode index; no response: less than 50% reduction, no change or worsening in the episode index. The -1562C/T MMP-9 gene polymorphism (rs3918242) was assessed by PCR-RFLP method. RESULTS: Genotype distributions were not in Hardy-Weinberg equilibrium. No association was found between polymorphism studied and the quality of response to prophylactic lithium administration. CONCLUSION: The functional polymorphism of the MMP-9 gene, analyzed in this study, may not be associated with the treatment response to lithium in bipolar patients.

FYN kinase gene: another glutamatergic gene associated with bipolar disorder?

Several genes of the glutamatergic system have been implicated in both schizophrenia and bipolar disorder. The Src family tyrosine kinase FYN plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate. Although no association between FYN gene polymorphisms and schizophrenia has been demonstrated, in our previous paper we found an association between FYN polymorphisms and cognitive test performance in schizophrenic patients. The aim of this study was to find a possible association of three polymorphisms of the FYN gene with bipolar disorder. We analyzed 425 bipolar patients and 518 control subjects. Genotypes of three analyzed polymorphisms, i.e. rs706895 (-93A/G in the 5'-flanking region), rs6916861 (Ex12+894T/G in the 3'-UTR) and rs3730353 (IVS10+37T/C in intron 10) were established by PCR-RFLP. A significant association was found between rs6916861 T/G and rs3730353 T/C polymorphisms of the FYN gene and bipolar disorder. These results were also significant in the subgroups of bipolar I and early-onset (<18 years) bipolar disorder patients. No association with -93 A/G polymorphism was found. Haplotype analysis revealed that rs6916861 T/G and rs3730353 T/C polymorphisms are in linkage disequilibrium (r(2) = 0.86, D' = 0.93 with 95% CI = 0.9-0.97). The results suggest that the glutamatergic FYN gene may be associated with bipolar disorder, particularly with type I illness and early age of onset.

Variation in P2RX7 candidate gene (rs2230912) is not associated with bipolar I disorder and unipolar major depression in four European samples.

Two recent studies reported evidence for association between genetic variation of the positional candidate gene P2RX7 on chromosome 12q24 and bipolar I disorder (BPI) [Barden et al. (2006); Am J Med Genet Part B 141B:374-382; McQuillin et al. (2008); Mol Psychiatry 13:1-7] and one study found association with unipolar major depression (Mdd-UP) [Lucae et al. (2006); Hum Mol Genet 15:2438-2445]. In the present work, we aimed to replicate the SNP that showed the strongest association in the above-mentioned studies, namely rs2230912 (P2RX7-E13A) resulting in a change of the amino acid glutamine to arginine at position 460 (Gln460Arg), in four European bipolar I disorder samples from Germany, Poland, Romania, and Russia totaling 1,445 patients, in a German sample of recurrent Mdd-UP patients (N = 640), and a control sample of 2,006 subjects. We found no allelic or genotypic association between rs2230912 and BPI or Mdd-UP both in the national samples and in the combined European patient sample. Additional studies are needed to clarify the potential involvement of P2RX7 and of SNP rs2230912 in the etiology of major affective disorders.

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.

[Association between polymorphisms of Val66Met in the BDNF gene and the response to escitalopram and nortriptyline treatment in the light of the neurodevelopmental hypothesis of depression]. / Ocena zwiazku pomiedzy polimorfizmem Va166Met genu BDNF a odpowiedzia na leczenie escitalopramem i nortryptylina w swietle koncepcji neurorozwojowej depresji.

AIM: Results from pharmacogenetic studies show importance of the relationship between response to treatment with antidepressants and polymorphisms within the genes involved in the neurotransmission and signal transduction. Changes in BDNF levels were reported in response to antidepressant treatment. The aim of study was to investigate a possible association of Val66Met polymorphism in the BDNF gene with response to antidepressants in patients with depression. METHOD: In the study, 90 patients (21 male and 69 females) were included, in the age range 19-68 years and suffering from a depressive disorder of at least moderate severity and meeting the research criteria of ICD-10 and DSM-IV for major depression. All patients were given the written consent for the study. The project was accepted by the local ethics committee. Patients were randomized into two groups: one was treated with the serotonergic drug - escitalopram (n=51) with therapeutic doses between 10-20 mg/day. The second group was treated with the noradrenergic drug--nortriptyline (n=39) with a dose range of 75-150 mg/day. The DNA was extracted from blood cells by the salting out method. The genotype for polymorphism of the Val66Met BDNF gene was established by the PCR-RFLP method in the Laboratory of Psychiatric Genetics of the Psychiatric Clinic. Statistical analysis was performed with the Statistica version 7.1 Results. We have not found any association between the Val66Met polymorphism of the BDNF gene with treatment response neither to escitalopram (p = 0.751 for genotypes, p = 0.798 for alleles) nor for nortryptyline (p = 0.607 for genotypes, p = 0.607 for alleles) CONCLUSIONS: The polymorphism of the BDNF gene is not likely to be associated with treatment response to escitalopram and nortriptyline in our group of patients with depression.

Venlafaxine and sertraline does not affect the expression of genes regulating stress response in female MDD patients. / Wenlafaksyna i sertralina nie wplywaja na ekspresje genów regulujacych poziom kortyzolu u kobiet chorych na depresje.

OBJECTIVES: The aim of this study was to analyze the expression of 3 genes involved in the regulation of HPA axis: GR, HSP90 and FKBP5, in patients with major depressive disorder (MDD) before antidepressant treatment and after 8 weeks of pharmacotherapy. Additionally, we analyzed the level of glucocorticoid receptor isoforms before and after treatment. METHODS: The study included 30 female patients (aged 18-60 years), with major depres- sive disorder diagnosed on the basis of the Structured Clinical Interview for DSM-IV (SCID). Antidepressant treatment included use of sertraline or venlafaxine. The assessment of patients' mental state (severity of depression) was checked by the Hamilton Depression Rating Scale (HDRS). After 8 weeks of treatment, the same clinical and molecular tests were performed. All of the patients underwent dexamethasone suppression test (DST). MRNA was isolated from the peripheral blood to evaluate the expression of the studied genes using real-time PCR with TaqMan probes. The concentration of GR isoforms (α and ß) in serum was also determined using ELISA. Statistical analysis was performed using Statistica v.12.0 software. RESULTS: The abnormal cortisol level was only seen in 20% of patients. Dysregulation on HPA axis was observed in 10% of patients. We observed significant clinical improvement after 8 weeks of pharmacotherapy in all patients. Almost the whole group of patients (except one patient) showed full remission of symptoms. We observed significant moderate correlation between cortisol level after DST before treatment and after 8 weeks of pharmacotherapy (r2 = 0.44). The results showed no significant difference in the expression of 3 analyzed genes compared before and after 8 weeks of therapy. The results of ELISA showed decreased level of α isoform after pharmacotherapy, independent of drug. CONCLUSIONS: The results showed no significant changes in the expression of genes involved in the stress axis activity during antidepressant therapy.

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

A relationship between response to lithium prophylaxis and T-50C polymorphism of glycogen synthase kinase-3beta (GSK-3beta) 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.

Suicide behavior as a quantitative trait and its genetic background.

INTRODUCTION: Studies have not given yet a clear answer what is the genetic background of suicidal predisposition. The associations between polymorphisms of the TPH1 and 5-HTTLPR genes and violent suicidal behavior was revealed with the least inconsistencies. METHOD: We selected 10 "strong candidate genes" and 35 SNPs, SLC6A4 and ACP1 for replication study. We searched associations between precisely described suicidal phenotype in 825 affective patients and polymorphisms of selected neurobiological pathways genes as well as their interactions that constitute suicidal risk. RESULTS: The results confirm the role of TPH1, TPH2, 5HT2A, CRHR1 and ACP1 variants in the risk of suicidal behavior. LIMITATIONS: In our study we analyzed limited number of candidate genes and only one of them is linked to lithium mechanism of action. We had no data on pharmacological treatment of investigated patients and its relation to the time of suicide attempt. CONCLUSION: Our results indicate that polymorphisms of various signaling pathways are involved in the pathogenesis of suicidal behavior. Non-genetic factors are also involved in the risk of suicidal attempts.

Genotype-phenotype studies in bipolar disorder showing association between the DAOA/G30 locus and persecutory delusions: a first step toward a molecular genetic classification of psychiatric phenotypes.

OBJECTIVE: The authors previously reported an association between the D-amino acid oxidase activator (DAOA)/G30 locus and both schizophrenia and bipolar affective disorder. Given the presumed role of DAOA/G30 in the neurochemistry of psychosis and its localization in a schizophrenia and bipolar affective disorder linkage region (13q34), it was hypothesized that the bipolar affective disorder finding would be mainly due to an association with psychotic features. METHOD: The marker/haplotype associations obtained in a subset of 173 bipolar affective disorder patients with psychotic features were similar to those in the overall patient group, suggesting that stratification on the basis of psychotic features in general might be too crude a procedure. The authors therefore tested whether confining caseness to specific psychotic features would improve detection of genotype-phenotype correlations. RESULTS: In a logistic regression, "persecutory delusions" were found to be the only significant explanatory variable for the DAOA/G30 risk genotype among 21 OPCRIT symptoms of psychosis. The authors therefore tested for association between DAOA/G30 and bipolar affective disorder in the 90 cases with a history of persecutory delusions. Whereas this subset showed strong association (odds ratio=1.83 for the best marker), the remaining larger sample of 165 patients with no such history did not differ from comparison subjects, suggesting that the association between DAOA/G30 and bipolar affective disorder is due to persecutory delusions. This was confirmed in an independent study of 294 bipolar affective disorder patients and 311 comparison subjects from Poland, in which an association between bipolar affective disorder and DAOA/G30 was only seen when case definition was restricted to cases with persecutory delusions. CONCLUSIONS: These data suggest that bipolar affective disorder with persecutory delusions constitutes a distinct subgroup of bipolar affective disorder that overlaps with schizophrenia.

No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia.

Brain-derived neurotrophic factor (BDNF) regulates a variety of neuromodulatory processes during development, as well as in adulthood. It has been proposed as a risk factor for schizophrenia. We have investigated a possible association between schizophrenia and the C-270T polymorphism in the brain-derived neurotrophic factor (BDNF) gene in 397 schizophrenic patients and 380 control subjects. The diagnosis of schizophrenia was made for each patient by at least two psychiatrists, using DSM-IV and ICD-10 criteria in structured clinical interviews for DSM-IV Axis I disorders (SCID). No association was found between schizophrenia and the analyzed polymorphism, for either genotype or allele distribution (for genotype: p=0.513, for alleles: p=0.812). Differences were not statistically significant when analyzed separately by sex. For males, the differences for genotype distribution and allele frequency were p=0.078 and p=0.162 respectively and for females: p=0.441 and p=0.315. Thus, our data indicate that variations in the BDNF gene are unlikely to be an important factor in susceptibility to schizophrenia.

Prophylactic effect of lithium in bipolar affective illness may be related to serotonin transporter genotype.

Serotonin transporter promoter length polymorphism (5-HTTLPR) has been implicated in the pathogenesis of mood disorders and in the therapeutic response to serotonergic drugs. In this study, the 5-HTTLPR was estimated in 67 patients with bipolar mood disorder, receiving lithium carbonate for prophylactic purposes for the period of more than 5 years (mean 15 years). The patients were divided into excellent responders (n = 18), partial responders (n = 35) and poor responders (n = 14). In lithium non-responders, the genotype s/s and the allele s was significantly more frequent than in excellent and partial responders. The obtained results are discussed in view of other studies showing an association of S genotype with worse response to serotonergic drugs. A supposition is made that prophylactic management of bipolar illness can be optimized by defining 5-HTTLPR genotype.

Association studies of 5-HT2A and 5-HT2C serotonin receptor gene polymorphisms with prophylactic lithium response in bipolar patients.

Lithium is one of the most commonly used drugs in the prophylaxis and treatment of bipolar disorder. The mechanisms of mood stabilization by lithium incorporate its effect on serotonergic neurotransmission. This paper investigates a relationship between response to lithium prophylaxis and polymorphisms in two genes: T102C of 5-HT2A receptor and G68C (Cys23Ser) of 5-HT2C serotonin receptor gene. Genotypes were estimated in 92 bipolar patients (39 males and 53 females) who have been taking lithium for at least 5 years. The patients were classified as excellent responders, partial responders and non-responders to lithium. The obtained results suggest that these polymorphisms may not be related to the degree of prophylactic lithium response.

[Eye movement disturbances and working memory deficit in bipolar affective disorder]. / Zaburzenia ruchw oczu i deficyt pamivci operacyjnej w chorobie afektywnej dwubiegunowej.

UNLABELLED: THE AIM AND METHODS: The aim of this study was to assess the intensity and frequency of eye movement abnormalities measured with infrared reflectometry, and working memory disturbances assessed with the Wisconsin Card Sorting Test (WCST). The study was performed in 87 patients with bipolar affective illness, in 119 patients with schizophrenia and in 90 healthy persons. In patients, the assessment was done during a mild symptomatic period or in remission. RESULTS: In patients with bipolar affective illness significant disturbances of eye movement and working memory compared with healthy subjects were found. Frequency and intensity of fixation abnormalities was less intense compared to schizophrenic patients, while smooth pursuit abnormalities had a similar degree. Working memory disturbances in bipolar patients were, as to the ability of formulation of logical conception, of similar degree as in schizophrenia. On the other hand, as to the effectiveness of thinking, no difference compared with healthy controls was found. CONCLUSIONS: The results obtained suggest that eye movement and working memory disturbances may constitute neurophysiological and neuropsychological endophenotypic markers of bipolar affective illness what makes possible using them in molecular genetic studies of this illness.

Suicidal behavior in the context of disrupted rhythmicity in bipolar disorder--data from an association study of suicide attempts with clock genes.

Suicidal behavior exhibits both circadian and annual rhythms. We were seeking an association between selected candidate clock genes and suicidal behavior in bipolar patients. The study included 441 bipolar patients and 422 controls and we genotyped 41 SNPs of the CLOCK, ARNTL, TIMELESS, PER3 genes. The main positive findings built up associations between selected polymorphisms and.

Association study of functional polymorphisms in interleukins and interleukin receptors genes: IL1A, IL1B, IL1RN, IL6, IL6R, IL10, IL10RA and TGFB1 in schizophrenia in Polish population.

Schizophrenia has been associated with a large range of autoimmune diseases, with a history of any autoimmune disease being associated with a 45% increase in risk for the illness. The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neurodevelopment, neuroplasticity and neurotransmission. In particular, increases or imbalance in cytokine before birth or during the early stages of life may affect neurodevelopment and produce vulnerability to the disease. A total of 27 polymorphisms of IL1N gene: rs1800587, rs17561; IL1B gene: rs1143634, rs1143643, rs16944, rs4848306, rs1143623, rs1143633, rs1143627; IL1RN gene: rs419598, rs315952, rs9005, rs4251961; IL6 gene: rs1800795, rs1800797; IL6R gene: rs4537545, rs4845617, rs2228145, IL10 gene: rs1800896, rs1800871, rs1800872, rs1800890, rs6676671; IL10RA gene: rs2229113, rs3135932; TGF1B gene: rs1800469, rs1800470; each selected on the basis of molecular evidence for functionality, were investigated in this study. Analysis was performed on a group of 621 patients with diagnosis of schizophrenia and 531 healthy controls in Polish population. An association of rs4848306 in IL1B gene, rs4251961 in IL1RN gene, rs2228145 and rs4537545 in IL6R with schizophrenia have been observed. rs6676671 in IL10 was associated with early age of onset. Strong linkage disequilibrium was observed between analyzed polymorphisms in each gene, except of IL10RA. We observed that haplotypes composed of rs4537545 and rs2228145 in IL6R gene were associated with schizophrenia. Analyses with family history of schizophrenia, other psychiatric disorders and alcohol abuse/dependence did not show any positive findings. Further studies on larger groups along with correlation with circulating protein levels are needed.