Publications by authors named "Brigitta Bondy"

87 Publications

Classical Risk Factors and Inflammatory Biomarkers: One of the Missing Biological Links between Cardiovascular Disease and Major Depressive Disorder.

Int J Mol Sci 2018 06 12;19(6). Epub 2018 Jun 12.

Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University of Munich, Nußbaumstraße 7, D-80336 Munich, Germany.

Background: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied whether MDD without CVD or other somatic diseases influences classical and inflammatory biomarkers of cardiovascular risk. In addition, we investigated the influence of proinflammatory cytokines on antidepressant treatment outcome.

Methods: In a case-control design, 310 adults (MDD patients without CVD, CVD patients, and cardiologically and psychiatrically healthy matched controls) were investigated. MDD patients were recruited after admission in a psychiatric university hospital. Primary outcome criteria were clinical depression ratings (HAM-D scale), vital signs, classical cardiovascular risk factors and inflammatory biomarkers which were compared between MDD patients and healthy controls.

Results: We detected an enhanced cardiovascular risk in MDD. Untreated prehypertension and signs directing to a metabolic syndrome were detected in MDD. Significantly higher inflammatory biomarkers such as the high sensitivity C-reaktive protein (hsCRP) and proinflammatory acute phase cytokines interleukine-1β (IL-1β) and interleukine-6 (IL-6) underlined the higher cardiovascular risk in physically healthy MDD patients. Surprisingly, high inflammation markers before treatment were associated with better clinical outcome and faster remission. The rate of MDD in CVD patients was high.

Conclusions: Patients suffering from MDD are at specific risk for CVD. Precise detection of cardiovascular risks in MDD beyond classical risk factors is warranted to allow effective prophylaxis and treatment of both conditions. Future studies of prophylactic interventions may help to provide a basis for prophylactic treatment of both MDD and CVD. In addition, the high risk for MDD in CVD patients was confirmed and underlines the requirement for clinical attention.
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http://dx.doi.org/10.3390/ijms19061740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032328PMC
June 2018

Associations of NEUROD2 polymorphisms and change of cognitive dysfunctions in schizophrenia and schizoaffective disorder after eight weeks of antipsychotic treatment.

Cogn Neuropsychiatry 2017 Jul 4;22(4):280-297. Epub 2017 May 4.

a Department of Psychiatry and Psychotherapy , Ludwig-Maximilians-University Munich , Munich , Germany.

Introduction: NEUROD2 is a neurospecific helix-loop-helix transcription factor which has an impact on the regulation of glutamatergic and GABAergic genes. We investigated an association of NEUROD2 with neurocognitive dysfunctions in schizophrenia and schizoaffective disorder patients before and during treatment with different second-generation antipsychotics.

Methods: Patients were genotyped for four different polymorphisms of the NEUROD2 gene ((rs9889354(A/G), rs1877032(C/T), rs12453682(C/T) and rs11078918(C/G)). Cognitive function was assessed at baseline and week 8. Results of individual neuropsychological tests were assigned to six cognitive domains (reaction time and quality; executive function; working, verbal and visual memory) and a general cognitive index.

Results: 167 patients were included in the study. The NEUROD2 exonic polymorphism rs11078918 showed significant associations with verbal memory and executive functions, whereas the NEUROD2 polymorphism rs12453682 was significantly associated with working and verbal memory, executive functions and with a cognitive index. Significant associations were found at baseline and after eight weeks. Moreover, significant associations between the change in neuropsychological test results during antipsychotic treatment and the NEUROD2 polymorphisms rs11078918 and rs12453682 were observed.

Conclusions: Our findings suggest that the NEUROD2 gene could play a role in the pathophysiology of neurocognitive dysfunctions as well as in the change of cognitive symptoms under antipsychotic treatment in schizophrenia and schizoaffective disorder.
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http://dx.doi.org/10.1080/13546805.2017.1322502DOI Listing
July 2017

Oxytocin and vasopressin levels are decreased in the plasma of male schizophrenia patients.

Acta Neuropsychiatr 2014 Dec 7;26(6):347-55. Epub 2014 Oct 7.

1Department of Psychiatry and Psychotherapy,Ludwig Maximilian University,Munich,Germany.

Objective: Impaired social functioning and autistic symptoms are characteristics of schizophrenia. The social hormones oxytocin (OT) and arginine-vasopressin (AVP) both modulate social interaction and therefore may be involved in the pathogenesis of schizophrenia. We investigated whether men with schizophrenia show altered OT and AVP levels compared with healthy controls (HC) and whether autism symptoms are associated with OT levels.

Methods: Forty-one men with non-acute schizophrenia and 45 matched HC were enrolled. Schizophrenia was assessed with the Positive and Negative Syndrome Scale (PANSS). Blood samples were collected on 2 days, and plasma OT and AVP levels were measured by ELISA immunoassay.

Results: The schizophrenia patients had significantly lower plasma OT levels than the HC; a similar trend was found for AVP. Plasma OT levels were associated with severe life events, fewer important attached persons, and a higher score on the PANSS negative scale; the most dominant PANSS items were 'preoccupation', 'emotional withdrawal', and 'passive/apathetic social withdrawal'.

Conclusion: These findings support an association between the social hormones OT and AVP and schizophrenia. We suggest that OT metabolism may be altered in schizophrenia, but other possible causes for decreased plasma OT levels in schizophrenia patients include decreased OT synthesis, mRNA expression, and translation. Especially the 'autistic' symptoms of schizophrenia seem to be closely linked to an altered metabolism of OT, the 'attachment' hormone.
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http://dx.doi.org/10.1017/neu.2014.20DOI Listing
December 2014

Effects of escitalopram/quetiapine combination therapy versus escitalopram monotherapy on hypothalamic-pituitary-adrenal-axis activity in relation to antidepressant effectiveness.

J Psychiatr Res 2014 May 31;52:15-20. Epub 2014 Jan 31.

Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, 80336 Munich, Germany.

The hypothalamic-pituitary-adrenocortical (HPA) system is believed to play an important role in the pathophysiology of major depressive disorder. In this context, the atypical antipsychotic quetiapine (QUE) has been shown to inhibit HPA system activity in healthy subjects. In this study we investigated whether the putative inhibitory effects of QUE on HPA system activity may contribute to its antidepressant efficacy. We analyzed the effects of QUE as an augmentation to the selective serotonin reuptake inhibitor (SSRI) escitalopram (ESC) on HPA system activity in comparison to a monotherapy with ESC in relation to the antidepressant effectiveness. HPA axis activity (cortisol and ACTH) was measured by means of the dexamethasone/corticotropin-releasing hormone (DEX/CRH) test which was performed before (week 0) and during (week 1, week 5) antidepressant psychopharmacotherapy. The combination therapy, but not the ESC monotherapy showed significantly inhibiting effects on HPA system activity leading to stepwise down-regulation. ACTH concentrations were reduced in the ESC/QUE group during five weeks of treatment. The inhibitory effect of QUE maybe involved in its antidepressant effects as an augmentation strategy.
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http://dx.doi.org/10.1016/j.jpsychires.2014.01.013DOI Listing
May 2014

Serum levels of brain-derived neurotrophic factor are unchanged after transcranial direct current stimulation in treatment-resistant depression.

J Affect Disord 2013 Sep 7;150(2):659-63. Epub 2013 May 7.

Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany.

Background: Brain-derived neurotrophic factor (BDNF) plays an important role in differentiation and repair of neurons in the adult brain. BDNF serum levels have been found to be lower in depressed patients than in healthy subjects. In a couple of studies, effective antidepressant treatment including electroconvulsive therapy led to an increase in BDNF serum levels. As transcranial direct current stimulation (tDCS) is currently discussed as novel therapeutic intervention in major depression, we investigated BDNF serum levels during tDCS in therapy-resistant depression.

Methods: Twenty-two patients with a major depressive episode participated in a double-blind placebo-controlled trial and received randomized cross over treatment with 2 weeks active and 2 weeks sham tDCS (1 or 2 mA for 20 min, anode over the left dorsolateral prefrontal cortex, cathode right supraorbital cortex).

Results: Clinical assessment only showed a modest and non-significant improvement in HAMD, BDI and CGI in both groups. BDNF serum levels were measured at baseline, after 2 and after 4 weeks. There was neither a significant change of BDNF levels following active tDCS, nor were severity of depressive symptoms and BDNF levels correlated.

Limitations: The small sample size, its heterogeneity, the short observation period and a cross-over design without an interval between both conditions.

Conclusions: tDCS did not change BDNF serum levels unlike other established antidepressant interventions in this treatment resistant sample. However, larger studies are needed.
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http://dx.doi.org/10.1016/j.jad.2013.03.015DOI Listing
September 2013

Tryptophan metabolism and immunogenetics in major depression: a role for interferon-γ gene.

Brain Behav Immun 2013 Jul 15;31:128-33. Epub 2013 Apr 15.

Department of Psychiatry, Ludwig-Maximilian University Munich, Nussbaumstr. 7, D-80336 Munich, Germany.

The tryptophan metabolism and immune activation play a role in pathophysiology of major depressive disorders. The pro-inflammatory cytokine interferon-γ transcriptionally induces the indoleamine 2,3-dioxygenase enzyme that degrades the tryptophan and thus induces serotonin depletion. The polymorphism of certain cytokine genes was reported to be associated with major depression. We investigated the association between interferon-γ (IFNγ) gene CA repeat polymorphism, the profile of serotonin and tryptophan pathway metabolites and clinical parameters in 125 depressed patients and 93 healthy controls. Compared to controls, serum tryptophan and 5-hydroxyindoleacetic acid (5HIAA) concentrations in the patients were significantly lower and serum kynurenine concentrations were significantly higher at baseline (p<0.0001). The presence of IFNγ CA repeat allele 2 homozygous has significant association with higher kynurenine concentrations in controls (F=4.47, p=0.038) as well as in patients (F=3.79, p=0.045). The existence of interferon-γ CA repeat allele 2 (homo- or heterozygous) showed significant association with increase of tryptophan breakdown over time during the study period (F=6.0, p=0.019). The results indicated the association between IFNγ CA repeat allele 2, tryptophan metabolism and the effect of medication.
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http://dx.doi.org/10.1016/j.bbi.2013.04.003DOI Listing
July 2013

Brain-derived neurotrophic factor Val66Met polymorphism and early life adversity affect hippocampal volume.

Am J Med Genet B Neuropsychiatr Genet 2013 Mar 22;162B(2):183-90. Epub 2013 Jan 22.

Department of Psychiatry and Institute of Neuroscience, University of Dublin, Trinity College Dublin, Dublin, Ireland.

The interaction between adverse life events during childhood and genetic factors is associated with a higher risk to develop major depressive disorder (MDD). One of the polymorphisms found to be associated with MDD is the Val66MET polymorphism of brain-derived neurotrophic factor (BDNF). The aim of our two-center study was to determine how the BDNF Val66Met polymorphism and childhood adversity affect the volumetric measures of the hippocampus in healthy individuals and people with MDD. In this two-center study, 62 adult patients with MDD and 71 healthy matched controls underwent high-resolution magnetic resonance imaging. We used manual tracing of the bilateral hippocampal structure with help of the software BRAINS2, assessed childhood adversity using the Childhood Trauma Questionnaire and genotyped Val66Met BDNF SNP (rs6265). MDD patients had smaller hippocampal volumes, both in the left and right hemispheres (F = 5.4, P = 0.022). We also found a significant interaction between BDNF allele and history of childhood adversity (F = 6.1, P = 0.015): Met allele carriers in our samples showed significantly smaller hippocampal volumes when they did have a history of childhood adversity, both in patients and controls. Our results highlight how relevant stress-gene interactions are for hippocampal volume reductions. Subjects exposed to early life adversity developed smaller hippocampal volumes when they carry the Met-allele of the BDNF polymorphism.
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http://dx.doi.org/10.1002/ajmg.b.32130DOI Listing
March 2013

Brain-derived neurotrophic factor Val66Met polymorphism and early life adversity affect hippocampal volume.

Am J Med Genet B Neuropsychiatr Genet 2013 Mar 22;162B(2):183-90. Epub 2013 Jan 22.

Department of Psychiatry and Institute of Neuroscience, University of Dublin, Trinity College Dublin, Dublin, Ireland.

The interaction between adverse life events during childhood and genetic factors is associated with a higher risk to develop major depressive disorder (MDD). One of the polymorphisms found to be associated with MDD is the Val66MET polymorphism of brain-derived neurotrophic factor (BDNF). The aim of our two-center study was to determine how the BDNF Val66Met polymorphism and childhood adversity affect the volumetric measures of the hippocampus in healthy individuals and people with MDD. In this two-center study, 62 adult patients with MDD and 71 healthy matched controls underwent high-resolution magnetic resonance imaging. We used manual tracing of the bilateral hippocampal structure with help of the software BRAINS2, assessed childhood adversity using the Childhood Trauma Questionnaire and genotyped Val66Met BDNF SNP (rs6265). MDD patients had smaller hippocampal volumes, both in the left and right hemispheres (F = 5.4, P = 0.022). We also found a significant interaction between BDNF allele and history of childhood adversity (F = 6.1, P = 0.015): Met allele carriers in our samples showed significantly smaller hippocampal volumes when they did have a history of childhood adversity, both in patients and controls. Our results highlight how relevant stress-gene interactions are for hippocampal volume reductions. Subjects exposed to early life adversity developed smaller hippocampal volumes when they carry the Met-allele of the BDNF polymorphism.
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http://dx.doi.org/10.1002/ajmg.b.32130DOI Listing
March 2013

No influence of brain-derived neurotrophic factor (BDNF) polymorphisms on treatment response in a naturalistic sample of patients with major depression.

Eur Arch Psychiatry Clin Neurosci 2013 Aug 11;263(5):405-12. Epub 2012 Sep 11.

Department of Psychiatry and Psychotherapy, Psychiatric Clinic, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, 80336, Munich, Germany.

The role of the brain-derived neurotrophic factor (BDNF) in the pathophysiology of major depressive disorder (MDD) remains to be elucidated. Recent post hoc analyses indicated a potential association of three polymorphisms in the BDNF gene with worse treatment outcome in patients with the subtype of melancholic depression. We aimed at replicating these findings in a German naturalistic multicenter follow-up. Three polymorphisms in the BDNF gene (rs7103411, rs6265 (Val66Met) and rs7124442) were genotyped in 324 patients with MDD and 470 healthy controls. We applied univariate tests and logistic regression models stratifying for depression subtype and gender. The three polymorphisms were not associated with MDD as diagnosis. Further, no associations were found in univariate tests. With logistic regression, we only found a tendency towards an association of the rs6265 (Val66Met) polymorphism with overall response to treatment (response rates: GG (val/val) < GA (val/met) < AA (met/met); p = 0.0129) and some gender differences for the rs6265 (Val66Met) and rs7103411 polymorphisms. Treatment outcome stratified for subtypes of depression did not differ significantly between the investigated polymorphisms or using haplotype analyses. However, results showed a tendency towards significance. At this stage, we cannot support an influence of these three polymorphisms. Further studies in larger patient samples to increase sample sizes of subgroups are warranted.
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http://dx.doi.org/10.1007/s00406-012-0364-1DOI Listing
August 2013

DNA methylation analysis of the angiotensin converting enzyme (ACE) gene in major depression.

PLoS One 2012 13;7(7):e40479. Epub 2012 Jul 13.

Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.

Background: The angiotensin converting enzyme (ACE) has been repeatedly discussed as susceptibility factor for major depression (MD) and the bi-directional relation between MD and cardiovascular disorders (CVD). In this context, functional polymorphisms of the ACE gene have been linked to depression, to antidepressant treatment response, to ACE serum concentrations, as well as to hypertension, myocardial infarction and CVD risk markers. The mostly investigated ACE Ins/Del polymorphism accounts for ~40%-50% of the ACE serum concentration variance, the remaining half is probably determined by other genetic, environmental or epigenetic factors, but these are poorly understood.

Materials And Methods: The main aim of the present study was the analysis of the DNA methylation pattern in the regulatory region of the ACE gene in peripheral leukocytes of 81 MD patients and 81 healthy controls.

Results: We detected intensive DNA methylation within a recently described, functional important region of the ACE gene promoter including hypermethylation in depressed patients (p = 0.008) and a significant inverse correlation between the ACE serum concentration and ACE promoter methylation frequency in the total sample (p = 0.02). Furthermore, a significant inverse correlation between the concentrations of the inflammatory CVD risk markers ICAM-1, E-selectin and P-selectin and the degree of ACE promoter methylation in MD patients could be demonstrated (p = 0.01 - 0.04).

Conclusion: The results of the present study suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD and probably a common pathogenic factor for the bi-directional relationship between MD and cardiovascular disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040479PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396656PMC
March 2013

Possible association between OPRM1 genetic variance at the 118 locus and alcohol dependence in a large treatment sample: relationship to alcohol dependence symptoms.

Alcohol Clin Exp Res 2012 Jul 6;36(7):1230-6. Epub 2012 Feb 6.

Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University, Munich, Germany.

Background: Several lines of evidence from previous research indicate that opioid receptors play an important role in ethanol reinforcement and alcohol dependence (AD) risk. Conflicting results were reported on the role of the mu-opioid receptor (OPRM1) polymorphism A118G (Asn40Asp, rs1799971) in the development of alcoholism.

Methods: We investigated a total number of 1,845 alcohol-dependent subjects recruited from inpatient facilities in Germany and 1,863 controls for the mu-opioid receptor (OPRM1) polymorphism using chi-square statistics.

Results: An association between the OPRM variant and AD was detected (p = 0.022), in recessive (AA vs. GA/GG) and co-dominant (AA vs. GA) models of inheritance. An association between the OPRM variant and the DSM-IV criterion "efforts to cut down or could not" (p = 0.047) was found, but this did not remain significant after the correction for multiple testing.

Conclusions: The results indicate that this functional OPRM variant is associated with risk of AD and these findings apply to more severe AD, although the association is only nominally significant.
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http://dx.doi.org/10.1111/j.1530-0277.2011.01714.xDOI Listing
July 2012

Genetics in psychiatry: are the promises met?

Authors:
Brigitta Bondy

World J Biol Psychiatry 2011 Mar;12(2):81-8

Psychiatric Clinic of University Munich, Section Psychiatric Genetics and Neurochemistry, Munich, Germany.

Objectives: Psychiatric disorders are among the most heritable common disorders, and for more than 20 years researchers have tried to unravel genetic susceptibility genes. This review briefly outlines the pros and cons of genetic approaches, important advances and possible future directions for readers not familiar with genetic studies.

Methods: In this article the results of 20 years molecular genetics in psychiatry are shortly and critically summarized on the basis of important reviews and meta-analyses of the last decade, without describing and enumerating the different findings (see special reviews).

Results: Conventional linkage and candidate association studies revealed numerous, but also inconsistent and sometimes contradictory results. The reasons are assumed to include the complexity of the disorder with interaction of several genes of small effects, lack of a valid phenotype, and invalid statistical and methodological issues. Recent systematic genome-wide association studies (GWAS) have reported association of some common variants for schizophrenia and bipolar disorder. However, the risk conferred by these variants is small and genome-wide significance is rare. Also structural variations might be important, and interesting data are arising from copy-number-variations (CNVs).

Conclusions: Although the new data from GWAS are promising, they still do not meet our initial expectations, identifying a "susceptibility gene". However, they opened new aspects concerning aetiology of psychoses, and the incorporation of new approaches, as epigenetics, or gene-environment interaction, is needed in future study designs.
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http://dx.doi.org/10.3109/15622975.2010.546428DOI Listing
March 2011

Major depressive disorder is associated with cardiovascular risk factors and low Omega-3 Index.

J Clin Psychiatry 2011 Sep 14;72(9):1242-7. Epub 2010 Dec 14.

Department of Psychiatry and Psychotherapy, Ludwig Maximilian University of Munich, Nussbaumstrasse 7, D-80336 Munich, Germany.

Objective: Cardiovascular disease (CVD) and major depressive disorder (MDD) are frequent worldwide and have a high comorbidity rate. Omega-3 fatty acids have been suggested as disease modulators for both CVD and MDD. Therefore, we studied whether polyunsaturated fatty acids and the Omega-3 Index may represent markers for assessment of the cardiovascular risk in somatically healthy patients suffering from MDD.

Method: We conducted a case-control study from July 2004 to December 2007 in 166 adults (86 inpatients with MDD but without CVD from the Department of Psychiatry and Psychotherapy and 80 age- and sex-matched healthy controls from an outpatient clinic of the Division of Preventive Cardiology, Ludwig Maximilian University of Munich, Germany). Information gathered at baseline included MDD diagnosis according to DSM-IV criteria, depression ratings, conventional cardiovascular risk factors, and fatty acid and interleukin-6 determinations. Fatty acid composition was analyzed according to the HS-Omega-3 Index methodology. During the study, patients received no supplementation with omega-3 fatty acids. The main inclusion criteria were the diagnosis of MDD according to DSM-IV and a 17-item Hamilton Depression Rating Scale (HDRS-17) score of at least 17. Treatment response and remission were defined using the HDRS-17.

Results: Several conventional risk factors such as high triglyceride (mean, 152 mg/dL vs 100 mg/dL; P < .001) and fasting glucose (mean, 96 mg/dL vs 87 mg/dL; P = .005) values as well as greater waist circumference (mean, 97 cm vs 87 cm; P = .019) and higher body mass index (calculated as kg/m(2); mean, 26 vs 24; P = .011) were more prevalent in MDD patients in comparison with controls. The Omega-3 Index (mean, 3.9% vs 5.1%; P < .001) and individual omega-3 fatty acids were significantly lower in MDD patients. An Omega-3 Index < 4% was associated with high concentrations of the proinflammatory cytokine interleukin-6 (χ(2) = 7.8, P = .02).

Conclusions: Conventional cardiovascular risk factors, the Omega-3 Index, and interleukin-6 levels indicated an elevated cardiovascular risk profile in MDD patients currently free of CVD. Our results support the employment of strategies to reduce the cardiovascular risk in still cardiovascularly healthy MDD patients by targeting conventional risk factors and the Omega-3 Index.
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http://dx.doi.org/10.4088/JCP.09m05895bluDOI Listing
September 2011

Lack of association between SNPs in the NEUROD2 gene and alcohol dependence in a German patient sample.

Psychiatry Res 2011 May 28;187(1-2):220-3. Epub 2010 Sep 28.

Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany.

Results of a human post mortem study performed by our own group have suggested that the transcription factor NEUROD2, which plays a role in neuronal development, as well as in the development of anxiety and risk behavior in mice, might be a susceptibility factor for addictive disorders. Therefore the aim of the present study was to analyze a possible relation between genetic variants in the NEUROD2 gene and alcohol dependence in a sample of the Munich Gene Bank of Alcoholism (MGBA). We performed single SNP (single nucleotide polymorphism) and haplotype studies in 430 alcohol-dependent patients and 365 healthy controls with four SNPs covering the gene region of NEUROD2. Neither single SNP nor haplotype analysis could detect significant associations with alcohol dependence. Additionally we could not detect any relation of the analyzed genetic variants to Cloninger's Type 1/2 or Babor's Type A/B classification, to the age of onset or to the amount of alcohol intake. Our results do not provide evidence for an involvement of NEUROD2 polymorphisms in the pathophysiology of alcohol dependence. Further association studies are needed to confirm our findings.
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http://dx.doi.org/10.1016/j.psychres.2010.08.031DOI Listing
May 2011

Lack of association between SNPs in the NEUROD2 gene and alcohol dependence in a German patient sample.

Psychiatry Res 2011 May 28;187(1-2):220-3. Epub 2010 Sep 28.

Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany.

Results of a human post mortem study performed by our own group have suggested that the transcription factor NEUROD2, which plays a role in neuronal development, as well as in the development of anxiety and risk behavior in mice, might be a susceptibility factor for addictive disorders. Therefore the aim of the present study was to analyze a possible relation between genetic variants in the NEUROD2 gene and alcohol dependence in a sample of the Munich Gene Bank of Alcoholism (MGBA). We performed single SNP (single nucleotide polymorphism) and haplotype studies in 430 alcohol-dependent patients and 365 healthy controls with four SNPs covering the gene region of NEUROD2. Neither single SNP nor haplotype analysis could detect significant associations with alcohol dependence. Additionally we could not detect any relation of the analyzed genetic variants to Cloninger's Type 1/2 or Babor's Type A/B classification, to the age of onset or to the amount of alcohol intake. Our results do not provide evidence for an involvement of NEUROD2 polymorphisms in the pathophysiology of alcohol dependence. Further association studies are needed to confirm our findings.
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http://dx.doi.org/10.1016/j.psychres.2010.08.031DOI Listing
May 2011

Association of a common mineralocorticoid receptor gene polymorphism with salivary cortisol in healthy adults.

Psychoneuroendocrinology 2011 Feb 15;36(2):298-301. Epub 2010 Sep 15.

Department of Psychiatry and Psychotherapy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

A common polymorphism of the mineralocorticoid receptors (MR) gene has been associated with cortisol levels after dexamethasone. However, if and how this MR gene variant affects basal cortisol secretion throughout the day is unknown. The aim of our study was to examine the association between the MR gene polymorphism -2G/C (rs2070951) and salivary cortisol measured at four time points during the day in the Stress, Atherosclerosis, and ECG Study (STRATEGY). We recruited healthy adults from the general population (n=133, distributed equally across four age groups, 30-70 years). Salivary cortisol was assessed at 0800, 1200, 1600 and 2200 h. We found a significant effect of genotype indicating that homozygous G allele carriers had higher overall salivary cortisol levels (F=4.5, p=0.01). Furthermore, we found a significant time × group interaction indicating that the group effect was predominantly driven by higher 0800 h salivary cortisol levels in G/G homozygotes (F=2.9, p=0.02). Participants homozygous for the G allele also had greater area under the curve (AUC) cortisol secretion compared to C allele carriers (F=6.4, p=0.01). Our findings suggest that being homozygous for the G allele of the MR gene polymorphism -2G/G is associated with higher cortisol levels in healthy adults, especially in the morning during peak cortisol secretion. This polymorphism may contribute to the interindividual variability in stress responsiveness and might be involved in stress-related disorders.
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http://dx.doi.org/10.1016/j.psyneuen.2010.08.003DOI Listing
February 2011

Serotonin transporter gene-linked polymorphic region (5-HTTLPR) and diurnal cortisol: A sex by genotype interaction.

Biol Psychol 2010 Oct 15;85(2):344-6. Epub 2010 Jul 15.

Faculty of Psychology and Neuroscience, Maastricht University, The Netherlands.

In interaction with stressful life events, the serotonin transporter gene-linked polymorphic region (5-HTTLPR) is associated with depression. In response to stress, the hypothalamic-pituitary-adrenal (HPA) axis is activated. HPA activity is often increased in depression. Thus, one potential mechanism by which 5-HTTLPR might increase risk for depression is by its impact on HPA activity. We examined the effects of 5-HTTLPR on diurnal saliva cortisol secretion (0800 h, 1200 h, 1600 h, 2200 h) in 130 healthy adults (66 men, 64 women) equally distributed across four age groups (30-70 years) using the tri-allelic classification [high-expressing (LA/LA), intermediate-expressing (LG/LA, LA/S), low-expressing (S/S, S/LG)]. We found a significant sex by 5-HTTLPR interaction on cortisol secretion. In men, higher cortisol levels were associated with lower transcriptional activity of 5-HTTLPR, whereas no such trend was observed in women. Our results suggest that men and women differ in serotonergic mediation of HPA-axis activity. This might contribute to sex-specific risk for depression.
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http://dx.doi.org/10.1016/j.biopsycho.2010.07.007DOI Listing
October 2010

Association of ADH4 genetic variants with alcohol dependence risk and related phenotypes: results from a larger multicenter association study.

Addict Biol 2011 Apr;16(2):323-33

Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University, Halle-Wittenberg, Julius-Kühn-Str. 7, D–06112 Halle, Germany.

Genetic variants of the alcohol-metabolizing enzyme ADH4, located on chromosome 4q22-4q23, have been related to alcohol dependence (AD) risk in previous research. The aim of this association study in a large multicenter sample of alcohol-dependent individuals and controls is to confirm ADH4 single nucleotide polymorphism (SNP) and haplotype association with AD and relevant related phenotypes. One thousand, six hundred and twenty-two (1622) inpatient subjects and 1469 control subjects with DSM-IV. AD from four addiction treatment centres were included. Characteristics of AD and related phenotypes including alcohol withdrawal, Cloninger's type I and II and first ages of drinking, regular drinking and AD onset were obtained using standardized structured interviews. After subjects were genotyped for 2 ADH4 polymorphisms, single SNP case-control and haplotype analyses were conducted. Both variants--rs1800759 and rs1042364--and the A-A and C-G haplotypes were significantly related to AD across samples. Furthermore, associations with AD-related phenotypes and subtypes revealed a potential protective influence of this haplotype. This study confirms the significant relationship of ADH4 variants with AD and related phenotypes. While the rs1800759 and rs1042364 A-A haplotype had a potential protective influence on the risk for several AD-related phenotypes, this effect is rather small compared to functional variants of other alcohol or acetaldehyde-metabolizing enzymes like ALDH2*2 or ADH1B*2.
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http://dx.doi.org/10.1111/j.1369-1600.2010.00236.xDOI Listing
April 2011

Homer-1 polymorphisms are associated with psychopathology and response to treatment in schizophrenic patients.

J Psychiatr Res 2011 Feb 3;45(2):234-41. Epub 2010 Jul 3.

Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University of Munich, Nußbaumstrasse 7, 80336 Munich, Germany.

The HOMER 1 protein plays a crucial role in mediating glutamatergic neurotransmission. It has previously shown to be a candidate gene for etiology and pathophysiology of different psychiatric diseases such as schizophrenia. To identify genes involved in response to antipsychotics, subgroups of animals were treated with haloperidol (1 mg/kg, n = 11) or saline (n = 12) for one week. By analyzing microarray data, we replicated the observed increase of Homer 1 gene expression. Furthermore, we genotyped 267 schizophrenic patients, who were treated monotherapeutically with different antipsychotics within randomized-controlled trials. Psychopathology was measured weekly using the PANSS for a minimum of four and a maximum of twelve weeks. Correlations between PANSS subscale scores at baseline and PANSS improvement scores after four weeks of treatment and genotypes were calculated by using a linear model for all investigated SNP's. We found an association between two HOMER 1 polymorphisms (rs2290639 and rs4704560) and different PANSS subscales at baseline. Furthermore all seven investigated polymorphisms were found to be associated with therapy response in terms of a significant correlation with different PANSS improvement subscores after four weeks of antipsychotic treatment. Most significant associations have been shown between the rs2290639 HOMER 1 polymorphism and PANSS subscales both at baseline conditions and after four weeks of antipsychotic treatment. This is the first study which shows an association between HOMER 1 polymorphisms and psychopathology data at baseline and therapy response in a clinical sample of schizophrenic patients. Thus, these data might further help in detecting differential therapy response in individuals with schizophrenia.
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http://dx.doi.org/10.1016/j.jpsychires.2010.06.004DOI Listing
February 2011

Childhood stress, serotonin transporter gene and brain structures in major depression.

Neuropsychopharmacology 2010 May 10;35(6):1383-90. Epub 2010 Feb 10.

Department of Psychiatry, Institute of Neuroscience, Trinity College, Dublin, Ireland.

The underlying neurobiology of major depression (MD) is likely to represent an interaction between genetic susceptibility and environmental factors such as stress. We investigated, in a multimodal high-resolution magnetic resonance imaging (MRI) genetic study, whether reduced hippocampal volumes and other brain alterations are associated with the tri-allelic polymorphism of the serotonin transporter and childhood stress in patients with MD and healthy subjects. Patients with MD and healthy participants were investigated using high-resolution MRI and genotyping for serotonin transporter polymorphism in the promoter region of the serotonin transporter gene (SLC6A4, 5-HTTLPR). Region of interest analysis of the hippocampus, whole-brain voxel-based morphometry (VBM), and assessment of childhood stress were carried out. Patients carrying the risk S-allele developed smaller hippocampal volumes when they had a history of emotional neglect compared with patients who only had one risk factor (environmental or genetic). In patients, childhood stress also predicted further hippocampal white matter alterations independently from the genotype. Moreover, the left prefrontal cortex was smaller in patients, whereby childhood stress resulted in larger prefrontal volumes in those subjects carrying the non-risk L-allele, suggesting preventive effects. The findings indicate that subjects with both environmental and genetic risk factors are susceptible to stress-related hippocampal changes. Structural brain changes due to stress represent part of the mechanism by which the illness risk and outcome might be genetically mediated.
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http://dx.doi.org/10.1038/npp.2010.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055341PMC
May 2010

Alternative splicing and extensive RNA editing of human TPH2 transcripts.

PLoS One 2010 Jan 29;5(1):e8956. Epub 2010 Jan 29.

Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.

Brain serotonin (5-HT) neurotransmission plays a key role in the regulation of mood and has been implicated in a variety of neuropsychiatric conditions. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT. Recently, we discovered a second TPH isoform (TPH2) in vertebrates, including man, which is predominantly expressed in brain, while the previously known TPH isoform (TPH1) is primarly a non-neuronal enzyme. Overwhelming evidence now points to TPH2 as a candidate gene for 5-HT-related psychiatric disorders. To assess the role of TPH2 gene variability in the etiology of psychiatric diseases we performed cDNA sequence analysis of TPH2 transcripts from human post mortem amygdala samples obtained from individuals with psychiatric disorders (drug abuse, schizophrenia, suicide) and controls. Here we show that TPH2 exists in two alternatively spliced variants in the coding region, denoted TPH2a and TPH2b. Moreover, we found evidence that the pre-mRNAs of both splice variants are dynamically RNA-edited in a mutually exclusive manner. Kinetic studies with cell lines expressing recombinant TPH2 variants revealed a higher activity of the novel TPH2B protein compared with the previously known TPH2A, whereas RNA editing was shown to inhibit the enzymatic activity of both TPH2 splice variants. Therefore, our results strongly suggest a complex fine-tuning of central nervous system 5-HT biosynthesis by TPH2 alternative splicing and RNA editing. Finally, we present molecular and large-scale linkage data evidencing that deregulated alternative splicing and RNA editing is involved in the etiology of psychiatric diseases, such as suicidal behaviour.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008956PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813293PMC
January 2010

A genetic variant of HTR2C may play a role in the manifestation of Tourette syndrome.

Psychiatr Genet 2010 Feb;20(1):35-8

Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Germany. 7 May 2008 Revised 11 August 2009

Gilles de la Tourette syndrome (GTS) (MIM 137580) is a complex neuropsychiatric disorder probably originating from a disturbed interplay of several neurotransmitter systems in the prefrontal-limbic-basal ganglia loop. Polygenetic multifactorial inheritance has been postulated; nevertheless, no confirmed susceptible genes have been identified yet. As neuroimaging studies allude to dopaminergic and serotonergic dysfunction in GTS and serotonin as an important factor for dopamine release, genotyping of common polymorphisms in the serotonergic receptor (HTR1A: C-1019G; HTR2A: T102C, His452Tyr, A-1438G; HTR2C: C-759T, G-697C) and transporter genes (SLC6A4) was carried out in 87 patients with GTS, compared with 311 matched controls. We found a nominally significant association between both polymorphisms in the HTR2C and the GTS, which was more pronounced in male patients. Analysis of the further serotonergic polymorphisms did not reveal any significant result. A modified function of these promoter polymorphisms may contribute to the complex interplay of serotonin and dopamine and then to the manifestation of GTS.
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http://dx.doi.org/10.1097/YPG.0b013e32833511ceDOI Listing
February 2010

A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression.

Arch Gen Psychiatry 2009 Sep;66(9):966-975

Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).

Context: The efficacy of antidepressant drug treatment in depression is unsatisfactory; 1 in 3 patients does not fully recover even after several treatment trials. Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome.

Objective: To identify genetic and clinical determinants of antidepressant drug treatment outcome in depression.

Design: Genomewide pharmacogenetic association study with 2 independent replication samples.

Setting: We performed a genomewide association study in patients from the Munich Antidepressant Response Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single-nucleotide polymorphisms highly related to outcome in both genomewide association studies was genotyped in a sample of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.

Participants: A total of 339 inpatients with a depressive episode (MARS sample), a further 361 inpatients with depression (German replication sample), and 832 outpatients with major depression (STAR*D sample).

Main Outcome Measures: We generated a multilocus genetic variable that described the individual number of alleles of the selected single nucleotide polymorphisms associated with beneficial treatment outcome in the MARS sample ("response" alleles) to evaluate additive genetic effects on antidepressant drug treatment outcome.

Results: Multilocus analysis revealed a significant contribution of a binary variable that categorized patients as carriers of a high vs low number of response alleles in the prediction of antidepressant drug treatment outcome in both samples (MARS and STAR*D). In addition, we observed that patients with a comorbid anxiety disorder combined with a low number of response alleles showed the least favorable outcome.

Conclusion: These results demonstrate the importance of multiple genetic factors combined with clinical features in the prediction of antidepressant drug treatment outcome, which underscores the multifactorial nature of this trait.
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http://dx.doi.org/10.1001/archgenpsychiatry.2009.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465570PMC
September 2009

No association of alcohol dependence with SLC6A5 and SLC6A9 glycine transporter polymorphisms.

Addict Biol 2009 Sep 24;14(4):506-8. Epub 2009 Jul 24.

Psychiatrische Klinik, Nussbaumstrasse 7, 80336 Munich, Germany.

To determine whether glycine transporter polymorphisms are associated with alcoholism, three genetic variants of SLC6A5 and two polymorphisms of SLC6A9 were genotyped in 463 German non-alcoholic controls and 644 German alcohol-dependent subjects. Association was investigated employing chi-square statistics and haplotype analysis. There was a significant association between the SLC6A5 polymorphism (rs1443547) and alcohol dependence as alcoholic individuals had a lower rate of AG-allele (chi(2) = 6.048, P = 0.049, d.f. = 2), which did not remain significant after correction for multiple testing. There was no association between SLC6A9 glycine transporter polymorphisms and alcohol dependence, and also none in haplotype analysis.
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http://dx.doi.org/10.1111/j.1369-1600.2009.00170.xDOI Listing
September 2009

SNAP-25 genotype influences NAA/Cho in left hippocampus.

J Neural Transm (Vienna) 2008 Nov 23;115(11):1513-8. Epub 2008 Aug 23.

Department of Psychiatry and Psychotherapy, Georg-August-University Goettingen, von-Siebold-Str. 5, 37075, Göttingen, Germany.

The SNAP-25 gene is an integral part of the vesicle docking and fusion machinery that controls neurotransmitter release. Several post mortem studies revealed a reduction of SNAP-25 protein in the hippocampus of patients with schizophrenia and bipolar disorder (BD). Thirty-eight patients with schizophrenia, BD or obsessive-compulsive disorder and 17 healthy controls participated in the study. Proton magnetic resonance spectroscopy in left hippocampus was performed in each individual. Three single nucleotide polymorphisms (SNP) of the SNAP-25 gene were genotyped. Individuals with the homozygous CC genotype of the DdeI SNP presented a significantly higher ratio of N-acetyl-aspartate (NAA)/choline-containing compounds (Cho) in the left hippocampus compared to the group of individuals with the homozygous TT genotype. The SNAP-25 genotype may modulate synaptic plasticity and neurogenesis in the left hippocampus, and altered NAA/Cho ratio may be an indicator for this genetic modulation of neuronal function in the hippocampus.
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http://dx.doi.org/10.1007/s00702-008-0103-yDOI Listing
November 2008

Effects of mirtazapine on dehydroepiandrosterone-sulfate and cortisol plasma concentrations in depressed patients.

J Psychiatr Res 2009 Feb 15;43(5):538-45. Epub 2008 Aug 15.

Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University, Nussbaumstrasse 7, 80336 Munich, Germany.

Background: Among the neuroactive steroids, dehydroepiandrosterone sulfate (DHEA-S) is at least in part produced in the adrenal gland and is therefore under the control of the hypothalamic-pituitary-adrenocortical (HPA)-system. In the present study, the impact of mirtazapine on DHEA-S and cortisol (COR) levels was investigated in relation to clinical response in depressed patients.

Methods: A total of 23 inpatients suffering from a major depressive episode (DSM-IV criteria) underwent 5-week treatment with mirtazapine (45 mg/day). Plasma samples were taken weekly at 0800 h and quantified for COR and DHEA-S levels.

Results: Mirtazapine significantly reduced both COR and DHEA-S concentrations, but had no impact on the COR/DHEA-S ratio. The percentage decrease of DHEA-S, but not that of COR was significantly and positively correlated with the percentage reduction in the sum score of the Hamilton Depression Rating Scale at week 5, suggesting a relationship between DHEA-S reduction and clinical efficacy of mirtazapine. There was a significant positive correlation between the decline in COR and DHEA-S levels.

Conclusions: Apparently, the decrease in COR and DHEA-S concentrations conjointly reflects an attenuating impact of mirtazapine on HPA axis activity, thereby decreasing the adrenal secretion of COR and DHEA-S.
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http://dx.doi.org/10.1016/j.jpsychires.2008.07.003DOI Listing
February 2009

Low level of harm avoidance is associated with serotonin transporter functional haplotype in alcohol-dependent individuals.

Psychiatr Genet 2008 Apr;18(2):59-63

Department of addiction research/Clinic of Psychiatry/LMU Munich/Nussbaumstrasse 7/80336 Munich/Germany.

Background: The serotonin transporter gene (SLC6A4) encodes a trans-membrane protein (5-HTT) that plays an important role in regulating serotonergic neurotransmission, which is known to be involved in many psychiatric disorders. A polymorphism in the transcriptional control region containing long (L) and short (S) variants (5-HTTLPR) as well as alleles of the variable number tandem repeats (VNTR) region were demonstrated. Higher serotonin levels among carriers of the S allele might exhibit increased liability of serotonin-mediated, psychopathology-like anxiety and depression and may impair social skills reflected by harm avoidance.

Objective: To analyze the data of alcohol-dependent, unrelated German individuals for a significant association between serotonin transporter gene and history of depression as well as TCI scales.

Methods: We characterized 368 alcohol-dependent participants by TCI and SSAGA/history of depression. HHT and VNTR genes were amplified by polymerase chain reaction.

Main Results: No significant association was found between history of depression and 5-HTTLPR (F=0.42, P=0.65, d.f.=2) as well as between history of depression and VNTR (F=0.24, P=0.91, d.f.=2). As harm avoidance is often associated with history of depression, the TCI was used. Regarding the TCI temperament and character scale scores, no significant association was found between harm avoidance and this genetic variant 5-HTTLPR (F=0.55, P=0.57, d.f.=2), and between harm avoidance and VNTR (F=0.39, P=0.81, d.f.=2). Haplotype analysis showed significant relationship between low level of harm avoidance and haplotype S/12 (chi=7.01, P=0.00). Haplotype analysis of history of depression (chi=2.04, P=0.742) showed no significant result.

Conclusion: Our results indicate an association between S/12 haplotype of SLC6A4 and low level of harm avoidance.
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http://dx.doi.org/10.1097/YPG.0b013e3282f60333DOI Listing
April 2008

Associations of SNAP-25 polymorphisms with cognitive dysfunctions in Caucasian patients with schizophrenia during a brief trail of treatment with atypical antipsychotics.

Eur Arch Psychiatry Clin Neurosci 2008 Sep 17;258(6):335-44. Epub 2008 Mar 17.

Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University of Munich, Nussbaumstrasse 7, 80336, Munich, Germany.

The synaptosomal-associated protein of 25 kDa (SNAP-25) is part of the soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment receptor (SNARE), which mediates synaptic neurotransmission. In earlier studies a possible involvement of this protein in schizophrenia has been shown. As neurocognitive impairment is a core feature in the pathology of schizophrenia and considered to be a putative endophenotype according to genetic studies we investigated the influences of different SNAP-25 polymorphisms on neuropsychological test results before and during treatment with atypical antipsychotics. A total of 104 schizophrenic patients treated with atypical antipsychotics were genotyped for three different polymorphisms of the SNAP-25 gene (MnlI, TaiI and DdeI in the 3'-UTR). Cognitive function was assessed at baseline, week 4 or 6 and week 8 or 12. Results of individual neuropsychological tests were assigned to six cognitive domains (reaction time and quality; executive function; working, verbal and visual memory) and a general cognitive index. The MnlI and TaiI polymorphisms showed no associations to deficits on neuropsychological test results. In contrast, we observed a significant relation between the DdeI polymorphism of the SNAP-25 gene and cognitive dysfunctions. Homozygote T/T allele carriers of the DdeI polymorphism showed significant better neuropsychological test results in cognitive domains verbal memory and executive functions than those with the combined T/C and C/C genotypes (P < 0.01) at all three time points, but no differences in response to treatment with atypical antipsychotics. Additionally, TT carriers exhibited significantly better results in a general cognitive index (P < 0.05). As we observed an association between the DdeI polymorphism of the SNAP-25 gene and cognitive dysfunctions of schizophrenic patients our finding suggests that the SNAP-25 gene could play a role in the pathophysiology of neurocognitive dysfunctions in schizophrenia but is not predictive for treatment response with atypical antipsychotics.
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http://dx.doi.org/10.1007/s00406-007-0800-9DOI Listing
September 2008