Aleksandra Rajewska-Rager

Early and delayed onset of response to antidepressants in individual trajectories of change during treatment of major depression: A secondary analysis of data from the genome-based therapeutic drugs for depression (GENDEP) study

OBJECTIVE The timing and rate of improvement after the initiation of an antidepressant has implications for establishing the mechanism of antidepressant action and for answering the clinically relevant question of how long an appropriate trial of antidepressant medication should be. We explore the individual trajectories of relative change in depression severity to establish what proportion of individuals experience early and late onset of improvement. METHOD Longitudinal latent class analysis was applied in a secondary analysis of data obtained from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. In the GENDEP trial, conducted in 9 European academic psychiatry centers from July 2004 to June 2008, 811 treatment-seeking adult subjects with DSM-IV major depression received escitalopram or nortriptyline for 12 weeks. Montgomery-Asberg Depression Rating Scale measurements were taken weekly. The secondary analysis reported in this article was conducted in 2010. RESULTS A model with 9 latent classes provided a good description of the individual trajectories of symptom change over time. These classes included 3 nonresponder classes, 3 classes with varying degrees of improvement concentrated in the first 3 weeks (early improvement), and 3 classes with varying degrees of improvement that was more prominent in the second 3 weeks than in the first 3 weeks (delayed improvement). More than half of the subjects who eventually reached remission showed a pattern of delayed improvement, and their eventual outcome could not be predicted from early time points. Early marked response occurred more frequently in subjects treated with nortriptyline than in those treated with escitalopram (12.9% vs 7.5%, χ² = 6.29, P = .01). Delayed complete remission occurred more frequently in subjects treated with escitalopram than in those treated with nortriptyline (13.6% vs 6.1%, χ² = 11.52, P = .0007). CONCLUSIONS Both early and delayed improvement are common. Although early changes are maintained, the eventual outcome of 12-week antidepressant treatment can be accurately predicted only after 8 weeks. TRIAL REGISTRATION http://www.controlled-trials.com Identifier: ISRCTN03693000.

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.

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.

Polish validation of the TEMPS-A: the profile of affective temperaments in a college student population.

BACKGROUND AND AIMS The TEMPS-A scale is a self-evaluation measure to assess five affective temperaments: depressive, cyclothymic, hyperthymic, irritable and anxious. The scale has already been validated in over 10 languages. In this paper, the first report on the validation of the Polish version of TEMPS-A is presented. METHODS The TEMPS-A questionnaire version that includes 110 questions has been adapted following the translation-back translation methodology from English to Polish, checked by the originators of the five scales (H.S.A., K.K.A.). In the next step, the Polish version of TEMPS-A was administered to 521 Polish undergraduate students. Internal consistency of temperamental scales was measured with Cronbach-alpha coefficients. Correlation among the temperaments was examined using Pearsons bivariate correlation. Differences between sexes were tested with ANOVA. RESULTS The Cronbach-alpha and the Kuder-Richardson 20 reliability coefficients for the depressive, cyclothymic, hyperthymic, irritable and anxious temperaments were between 0.69 and 0.83. The percentage of subjects whose Z-scores were above 2 SD, was the highest among depressive (4%) and anxious (3.5%) temperaments, followed by the cyclothymic (2.9%), hyperthymic (1%), and irritable (0.6%). The strongest positive correlations between the temperamental scales were found between depressive and anxious, as well as between cyclothymic and irritable ones (correlation coefficients 0.63 and 0.57, respectively). Male subjects attained significantly higher scores for hyperthymic temperament, compared to females, while females scored significantly higher than males on cyclothymic and anxious temperaments. LIMITATIONS Our healthy young subjects are not representative of the Polish population. As external validation has been achieved in other language versions, it was not repeated in the present Polish version. CONCLUSIONS The Polish version of TEMPS-A has a good internal consistency. The findings generally cohere with those from previously validated versions in other languages.

Epistatic interaction between CRHR1 and AVPR1b variants as a predictor of major depressive disorder.

Objective Genes involved in the regulation of the hypothalamus–pituitary–adrenal axis are responsible for altered susceptibility to mood disorders. The aim of this study was to analyze the possible association of CRHR1 and AVPR1b gene variants with bipolar disorder and major depressive disorder (MDD). Methods In the study, we included 486 patients with bipolar disorder and 215 patients with MDD. Consensus diagnosis was made according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria, using the Structured Clinical Interview for DSM Disorders. The control group consisted of 712 healthy participants. Genotyping of CRHR1 and AVPR1b polymorphisms was performed using TaqMan single nucleotide polymorphism genotyping assays. Linkage disequilibrium analysis was carried out on Haploview. Gene–gene interactions were analyzed using the multifactor dimensionality reduction method. Results By single marker analysis we have found an association of rs28536160 of AVPR1b and rs4076452 and rs16940655 of CRHR1 with mood disorders (P=0.036, 0.0013, and 0.003, respectively). We observed strong linkage disequilibrium between seven CRHR1 polymorphisms grouped in two haplotype blocks; however, none of them showed an association with MDD or bipolar disorder. Similarly, no association was found for three of four strongly linked AVPR1b polymorphisms. Gene–gene interaction analysis revealed a significant epistatic interaction between AVPR1b and CRHR1 genes in susceptibility to MDD (P=0.017). Conclusion Polymorphisms of CRHR1 and AVPR1b may modify susceptibility to mood disorders.

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.

Dysregulation of miR-499, miR-708 and miR-1908 during a depression episode in bipolar disorders

Affective disorders include unipolar disorder (UP) (depression episodes) and bipolar disorder (BP) (depression and mania episodes). Currently, no biological markers are known that can help to differentiate these disorders. However, recent studies have suggested that psychiatric disorders can be connected with small, non-coding RNA, like microRNA. The objective of this study was to analyse the expression level of three microRNAs (miR-499, miR-708, miR-1908) in bipolar and unipolar disorder during depression episodes and after entering the remission state. The group consisted of adult women only, 17 UP (age: 50±17) and 15 BP (age: 33±13) patients. The expression level of miRNAs was investigated by RT-qPCR with the TaqMan assay. Our study has shown a lower expression level of miR-499 (p=0.008), miR-708 (p=0.02) and miR-1908 (p=0.004) in depression episodes of the bipolar disorder patients in comparison to remission state. We have not found similar differences in unipolar disorder and between those types in acute phase of depression and during remission. Obtained results indicate that miRNAs: miR-499, miR-708 and miR-1908 are the most promising candidates for biomarkers of depression episodes of bipolar disorder.

Risk factors for suicide among children and youths with bipolar spectrum and early bipolar disorder

In recent years much attention has been given to determine risk factors for suicide among adults with bipolar disorder. Such studies concerning children and youths, which would also take into account the specificity of the developmental age, are still too few. The ability to identify risk factors for children and youths with mood disorders, as well as the possibility to monitor them, is an essential element in preventing suicidal behaviours. Previous studies have clearly indicated that in the group of patients with an early onset of the bipolar disorder the occurrence of suicidal thoughts and intentions were significantly increased. Identifying the risk of suicide is hindered further by the complexity of the phenomenon, which is a compound interaction of various factors: biological, environmental, sociological, psychological and clinical. This is especially true with young adults suffering from mental illness and presenting a number of other psychopathological symptoms. The following paper introduces and reviews the results of current studies, which analysed the risk factors for suicide among children and youths with bipolar spectrum or already diagnosed with bipolar disorder. For this purpose we conducted the overview of recent years literature available in PubMed/MEDLINE database, including the following search criteria: early onset bipolar disorder, bipolar disorder in children and young people, the spectrum of bipolar disorder, and suicidal ideation, suicidal intent, suicide.

No association between polymorphisms and haplotypes of the AVPR1b, CRHR1 and NR3C1 genes and depression with melancholic features in the course of bipolar disorder

The present study included 130 patients with melancholic depression in the course of bipolar disorder and 732 healthy controls. No association was found for alleles, genotypes, or haplotype analysis for NR3C1, AVPR1b, and CRHR1 genes and melancholic depression.