Malgorzata Maciukiewicz

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.

Serum Neurotrophin Concentrations in Polish Adolescent Girls with Anorexia Nervosa

Objectives: Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) plays an important role in weight regulation and eating behaviors as well as in the activity-dependent neuroplasticity underlying learning and memory behaviors involving the hippocampus. In anorexia nervosa (AN) patients, abnormal serum BDNF concentrations, cognitive impairments and specific personality traits have been traditionally observed. This study explores the levels of four serum neurotrophins [BDNF, neurotrophin 3 (NTF3), neurotrophin 4 (NTF4) and glial cell line-derived neurotrophic factor (GDNF)] with respect to their use as potential biomarkers for AN. This study also investigates any associations that might exist between serum neurotrophin levels and neurocognitive impairment or personality traits. Methods: Serum neurotrophin concentrations were measured in 60 AN patients (AN group) and 45 healthy controls (HC group). We correlated the serum levels of the four neurotrophins BDNF, NTF3, NTF4 and GDNF and the clinical type of anorexia. We also analyzed the relationship between serum neurotrophin levels and the Beck Depression Inventory, body mass index, executive functions by the Wisconsin Card Sorting test (WCST) and personality dimensions by the Temperament and Character Inventory (TCI) test. Results: Serum NTF4 concentrations were significantly lower when comparing all AN patients (34.7 ± 72.5 pg/ml) or restriction type AN patients (29.1 ± 62.5 pg/ml) with the HC group (58.4 ± 135.8 pg/ml; p = 0.004 and p = 0.005, respectively). A significant correlation (p < 0.005) between BDNF serum levels and patient personality dimensions as measured by the TCI test was observed. Furthermore, significant correlations were observed between NTF4 and GDNF serum levels and executive function as measured by the WCST. Conclusions: These data suggest that NTF4 might serve as a biomarker for AN. Furthermore, BDNF and GDNF serum levels appear to be associated with personality traits and executive function.

Preliminary evidence for association of genome-wide significant DRD2 schizophrenia risk variant with clozapine response

AIM The recent Psychiatric Genomics Consortium genome-wide association study identified an SNP, rs2514218, located 47kb upstream of the DRD2 gene to be associated with risk for schizophrenia (p = 2.75e-11). Since all antipsychotics bind to dopamine D2 receptors, we examined rs2514218 in relation to response to antipsychotic treatment. PATIENTS & METHODS We investigated the SNP in relation to treatment response in a prospective study consisting of 208 patients (151 Caucasians, 42 African-Americans and 15 others) treated with clozapine for 6 months. RESULTS rs2514218 was associated with total score change in the brief psychiatric rating scale under an additive model (pcorr= 0.033). CONCLUSION Our finding provides evidence for rs2514218 association with antipsychotic response, but further replication is required before firm conclusions can be drawn.

Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis

Background: The catechol-O-methyltransferase (COMT) enzyme plays a crucial role in dopamine degradation, and the COMT Val158Met polymorphism (rs4680) is associated with significant differences in enzymatic activity and consequently dopamine concentrations in the prefrontal cortex. Multiple studies have analyzed the COMT Val158Met variant in relation to antipsychotic response. Here, we conducted a meta-analysis examining the relationship between COMT Val158Met and antipsychotic response. Methods: Searches using PubMed, Web of Science, and PsycInfo databases (03/01/2015) yielded 23 studies investigating COMT Val158Met variation and antipsychotic response in schizophrenia and schizo-affective disorder. Responders/nonresponders were defined using each study’s original criteria. If no binary response definition was used, authors were asked to define response according to at least 30% Positive and Negative Syndrome Scale score reduction (or equivalent in other scales). Analysis was conducted under a fixed-effects model. Results: Ten studies met inclusion criteria for the meta-analysis. Five additional antipsychotic-treated samples were analyzed for Val158Met and response and included in the meta-analysis (ntotal=1416). Met/Met individuals were significantly more likely to respond than Val-carriers (P=.039, ORMet/Met=1.37, 95% CI: 1.02–1.85). Met/Met patients also experienced significantly greater improvement in positive symptoms relative to Val-carriers (P=.030, SMD=0.24, 95% CI: 0.024–0.46). Posthoc analyses on patients treated with atypical antipsychotics (n=1207) showed that Met/Met patients were significantly more likely to respond relative to Val-carriers (P=.0098, ORMet/Met=1.54, 95% CI: 1.11–2.14), while no difference was observed for typical-antipsychotic-treated patients (n=155) (P=.65). Conclusions: Our findings suggest that the COMT Val158Met polymorphism is associated with response to antipsychotics in schizophrenia and schizo-affective disorder patients. This effect may be more pronounced for atypical antipsychotics.

Genetic variation in IL-1β, IL-2, IL-6, TSPO and BDNF and response to duloxetine or placebo treatment in major depressive disorder.

AIM This study investigated polymorphisms of five inflammatory-related genes for association with duloxetine and placebo response in patients with major depression. PATIENTS & METHODS Twenty SNPs in IL-1β, IL-2, IL-6, TSPO and BDNF were genotyped in major depressive disorder patients treated with either duloxetine (n = 215) or placebo (n = 235) for up to 8 weeks. Treatment response was measured with the Montgomery-Åsberg Depression Rating Scale. RESULTS IL-6 variants rs2066992 and rs10242595 were nominally associated with response to duloxetine (p = 0.047 and p = 0.028, respectively). Notably, the variant rs2066992 was also associated with placebo response (p = 0.026). However, none of our results remained significant after correction for multiple testing. CONCLUSION Our findings tentatively suggest that IL-6 variants play a role in duloxetine and placebo response, which warrants further investigation.

Norepinephrine Transporter Gene Variants and Remission From Depression With Venlafaxine Treatment in Older Adults

OBJECTIVE The primary objective of this study was to investigate five putatively functional variants of the norepinephrine transporter (SLC6A2, NET) and serotonin transporter (SLC6A4, SERT) genes and remission in depressed older adults treated with venlafaxine. A secondary objective was to analyze 17 other variants in serotonergic system genes (HTR1A, HTR2A, HTR1B, HTR2C, TPH1, TPH2) potentially involved in the mechanism of action of venlafaxine. METHOD The sample included 350 adults age 60 or older with DSM-IV-defined major depressive disorder and a score of at least 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS). Participants received protocolized treatment with open-label venlafaxine, up to 300 mg/day for approximately 12 weeks, as part of a three-site clinical trial. Each individual was genotyped for 22 polymorphisms in eight genes, which were tested for association with venlafaxine remission (a MADRS score ≤10) and changes in MADRS score during treatment. RESULTS After adjusting for multiple comparisons, NET variant rs2242446 (T-182C) was significantly associated with remission (odds ratio=1.66, 95% CI=1.13, 2.42). Individuals with the rs2242446 C/C genotype were more likely to remit (73.1%) than those with either the C/T (51.8%) or the T/T genotype (47.3%). Individuals with the C/C genotype also had a shorter time to remission than those with the C/T or T/T genotypes and had a greater percentage change in MADRS score from baseline to end of treatment (up to week 12). CONCLUSIONS NET rs2242446/T-182C may serve as a biomarker to predict the likelihood of remission with venlafaxine in older adults with major depression. These findings may help to optimize antidepressant outcomes in older adults.

Family-based association study of interleukin 6 (IL6) and its receptor (IL6R) functional polymorphisms in schizophrenia in the Polish population.

Schizophrenia is a heterogeneous disorder and its etiology remains incompletely elucidated. Among possible causes, immunological factors have been implicated in its pathogenesis and course. The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neurodevelopment, neuroplasticity and neurotransmission. Recent studies indicate a role of excessive interleukin-6 (IL6) signaling in the pathogenesis of schizophrenia. Findings regarding changes in the circulating levels of soluble interleukin-6 receptor (sIL6R) in schizophrenia have been equivocal. The study was performed on a group of 147 trio (patients diagnosed with schizophrenia and their healthy parents). Polymorphisms of IL6 (rs1800795, rs1800797) and IL6R (rs4537545, rs4845617, rs2228145) genes were genotyped with the use of TaqMan SNP Genotyping Assays. No association of the polymorphisms from IL6 and IL6R genes with schizophrenia was found. We also investigated haplotypes in IL6 gene (consisting of rs1800795 and rs1800797) and in IL6R gene (consisting of rs4537545, rs2228145). We also found no preference in transmission of any haplotype. Our results do not support the theory that polymorphisms of IL6 and IL6R genes are involved in the pathogenesis of schizophrenia. It seems advisable to carry out further examinations of the role of these polymorphisms in schizophrenia by means of TDT method and classical (case-control) association method.

A comprehensive analysis of mitochondrial genes variants and their association with antipsychotic-induced weight gain

Antipsychotic Induced Weight Gain (AIWG) is a common and severe side effect of many antipsychotic medications. Mitochondria play a vital role for whole-body energy homeostasis and there is increasing evidence that antipsychotics modulate mitochondrial function. This study aimed to examine the role of variants in nuclear-encoded mitochondrial genes and the mitochondrial DNA (mtDNA) in conferring risk for AIWG. We selected 168 European-Caucasian individuals from the CATIE sample based upon meeting criteria of multiple weight measures while taking selected antipsychotics (risperidone, quetiapine or olanzapine). We tested the association of 670 nuclear-encoded mitochondrial genes with weight change (%) using MAGMA software. Thirty of these genes showed nominally significant P-values (<0.05). We were able to replicate the association of three genes, CLPB, PARL, and ACAD10, with weight change (%) in an independent prospectively assessed AIWG sample. We analyzed mtDNA variants in a subset of 74 of these individuals using next-generation sequencing. No common or rare mtDNA variants were found to be significantly associated with weight change (%) in our sample. Additionally, analysis of mitochondrial haplogroups showed no association with weight change (%). In conclusion, our findings suggest nuclear-encoded mitochondrial genes play a role in AIWG. Replication in larger sample is required to validate our initial report of mtDNA variants in AIWG.

Family association study of Transforming Growth Factor-Beta 1 gene polymorphisms in schizophrenia

OBJECTIVES Schizophrenia is a serious mental illness with chronic symptoms and significant impairment in psychosocial functioning. An etiopathological role for immunologic abnormalities in schizophrenia was hypothesized. Inflammatory markers are well-known etiological factors for psychiatric disorders, including schizophrenia. Several studies have investigated the possible effects of antipsychotics on inflammation and neurogenesis. Additionally, antiinflammatory adjuvant therapy has been under investigation as a treatment option for schizophrenia. Transforming Growth Factor Beta 1 (TGFB1) signaling is critical for many biological processes, including proliferation, development, differentiation and regeneration. Multiple members of the TGFB1 superfamily play a role in the developing nervous system and are regulated by neuronal activity. We conducted family-based study to assess whether TGFB1 gene is associated with susceptibility to schizophrenia in Polish population. METHODS Two functional polymorphisms: rs1800469 (C-509T) and rs1800470 (T869C) of TGFB1 gene were analyzed within a group of 147 trios (patients diagnosed with schizophrenia and their healthy parents) using Transmission Disequilibrium Test (TDT). RESULTS No association of these polymorphisms with schizophrenia was found in Polish population. CONCLUSIONS Further studies on larger groups along with correlation with circulating protein levels are needed.